Professor Christian Heiss FESC, FRCP

Professor of Cardiovascular Medicine, Head of Department of Clinical and Experimental Medicine, NHS Consultant Interventional Angiology
Internist, Interventional Angiologist and Cardiologist



Sven Baasen, Patricia Wischmann, Johanna Schremmer, Roberto Sansone, Maximilian Spieker, Georg Wolff, Florian Bönner, Christine Quast, Christian Heiss, Malte Kelm, Lucas Busch (2024)Endovascular treatment of flow-limiting iliofemoral stenosis improves left ventricular diastolic function in patients with HFpEF by reducing aortic pulsatile load, In: Circulation: Heart Failure Lippincott, Williams & Wilkins

Background: Recent research indicates that there is a high prevalence of HFpEF in patients with PAD. We hypothesized that endovascular treatment (EVT) of flow-limiting peripheral stenosis improves left ventricular diastolic function (LVDF).Methods: Thirty patients with symptomatic PAD and HFpEF according to HFA-PEFF score who were scheduled for EVT or angiography were investigated at baseline, the day after EVT (n=25) or angiography (control, n=5), and at 4 months follow-up. Peripheral hemodynamics were determined by the total peripheral resistance (TPR), common femoral artery flow and ABI. Aortic function was measured by the arterial compliance, AIx, and PWV. Aortic pulsatile load was estimated as the characteristic impedance of the proximal aorta (Zc) and the magnitude of wave reflection (RC). Left ventricular mass index (LVMI), LV mean wall thickness, and systolic and diastolic function were assessed using echocardiography. Patient-centered outcomes were treadmill walking distance (TMWD) and NYHA class.Results: After EVT, peripheral hemodynamics changed significantly with a decrease in TPR and increases in CFA flow and ABI. Aortic function improved after EVT, with significantly reduced AIx and PWV and increased compliance immediately and at follow-up, resulting in a reduction in aortic pulsatile load (Zc, RC). Concurrently, LVDF improved after EVT compared to control, acutely and at follow-up, with increased septal and lateral e´ velocities and a decreased E/e´ and LAVI. The LVMI and LV mean wall thickness decreased at follow-up. The NYHA class and TMWD improved post-EVT at follow-up. AIx, PWV and arterial compliance were identified as independent contributors to E/e´.Conclusion: EVT of flow-limiting iliofemoral stenosis reduces aortic pulsatile load and concurrently lowers TPR. This beneficial effect is associated with acute and sustained improvement of LVDF.

Mária Rašiová, Oliver Schlager, Christian Heiss, Marianne Brodmann, Dan-Mircea Olinic, Vinko Boc, Giacomo Buso, Jill Belch, Lucia Mazzolai, Juraj Madaric (2024)Adverse reactions after intravascular iodinated contrast media administration and their management, In: VASA : European Journal of Vascular Medicine53(3)pp. 193-203 Hogrefe

Endovascular interventions and diagnostic examinations using iodinated contrast media (ICM) are standard of care in current vascular medicine. Although ICM use is generally considered safe, it may be associated with adverse reactions, vary from minor disturbances to rare, but severe life-threatening complications. This position paper of European Society of Vascular Medicine integrates current knowledge and summarizes the key information related to the use of intravascular ICM, serving as recommendation on prevention and management of acute, late, and very late adverse reactions. It should help the health professionals in all fields of vascular medicine to make decisions in daily practice for safe use of contrast media.

Fabian Nienhaus, Moritz Walz, Maik Rothe, Annika Jahn, Susanne Pfeiler, Lucas Busch, Manuel Stern, Christian Heiss, Lilian Vornholz, Sandra Cames, Mareike Cramer, Vera Schrauwen-Hinderling, Norbert Gerdes, Sebastian Temme, Michael Roden, Ulrich Flögel, Malte Kelm, Florian Bönner (2023)Quantitative assessment of angioplasty-induced vascular inflammation with ¹⁹F cardiovascular magnetic resonance imaging, In: Journal of Cardiovascular Magnetic Resonance25(1)54 BioMed Central

Background Macrophages play a pivotal role in vascular inflammation and predict cardiovascular complications. Fluorine-19 magnetic resonance imaging (¹⁹F MRI) with intravenously applied perfluorocarbon allows a background-free direct quantification of macrophage abundance in experimental vascular disease models in mice. Recently, perfluorooctyl bromide-nanoemulsion (PFOB-NE) was applied to effectively image macrophage infiltration in a pig model of myocardial infarction using clinical MRI scanners. In the present proof-of-concept approach, we aimed to non-invasively image monocyte/macrophage infiltration in response to carotid artery angioplasty in pigs using ¹⁹F MRI to assess early inflammatory response to mechanical injury. Methods In eight minipigs, two different types of vascular injury were conducted: a mild injury employing balloon oversize angioplasty only (BA, n = 4) and a severe injury provoked by BA in combination with endothelial denudation (BA + ECDN, n = 4). PFOB-NE was administered intravenously three days after injury followed by ¹H and ¹⁹F MRI to assess vascular inflammatory burden at day six. Vascular response to mechanical injury was validated using X-ray angiography, intravascular ultrasound and immunohistology in at least 10 segments per carotid artery. Results Angioplasty was successfully induced in all eight pigs. Response to injury was characterized by positive remodeling with predominantly adventitial wall thickening and concomitant infiltration of monocytes/macrophages. No severe adverse reactions were observed following PFOB-NE administration. In vivo 19F signals were only detected in the four pigs following BA + ECDN with a robust signal-to-noise ratio (SNR) of 14.7 ± 4.8. Ex vivo analysis revealed a linear correlation of ¹⁹F SNR to local monocyte/macrophage cell density. Minimum detection limit of infiltrated monocytes/macrophages was estimated at approximately 410 cells/mm2. Conclusions In this proof-of-concept study, ¹⁹F MRI enabled quantification of monocyte/macrophage infiltration after vascular injury with sufficient sensitivity. This may provide the opportunity to non-invasively monitor vascular inflammation with MRI in patients after angioplasty or even in atherosclerotic plaques.

Christoph Kalka, Lisa Lippik, Folker Wenzel, Hanno Hoppe, Hak-Hong Keo, Christian Heiss, Nicolas Diehm (2023)Role of Lp(a) in patients with erectile dysfunction undergoing angioplasty for symptomatic pelvic artery disease, In: VASA: European Journal of Vascular Medicine52(4)pp. 230-238 Hogrefe

Background: Atherosclerotic disease of erection-related arteries is a major reason for erectile dysfunction (ED). Lp(a) has been implied in the pathophysiology of atherosclerosis in the coronary and lower limb arteries. Here, we investigated if Lp(a) plays a specific role in ED due with symptomatic pelvic artery atherosclerosis. Patients and methods: Out of 276 consecutive patients treated for ED with angioplasties on proximal (69%) and distal (31%, distal to Alcock channel) erection-related arteries, 236 patients (age: 62±10 years) of which Lp(a) values were available were retrospectively analyzed. Results: The baseline International Index of Erectile Function-15 (IIEF-15) score was 29±15 and significantly increased to 43±20 (increase: 14±21) after treatment at average follow up of 286±201 days. In 25%, Lp(a) values were elevated to more than 30 mg/dL. Hypercholesterolemia, coronary, lower extremity peripheral, and polyvascular disease were more common in patients with Lp(a) ≥60 mg/dl. Anatomic arterial lesion distribution (proximal/distal), improvement in IIEF-15 and clinically driven re-intervention rate (overall 7%) did not differ between patients with

Christian Heiss, Dan-Mircea Olinic, Jill J F Belch, Marianne Brodmann, Lucia Mazzolai, Agata Stanek, Juraj Madaric, Andrew Krentz, Oliver Schlager, Michael Lichtenberg, Ulrich Frank (2022)Management of chronic peripheral artery disease patients with indication for endovascular revascularization A position paper by the European Society of Vascular Medicine, In: VASA51(3)pp. 121-137 Hogrefe

With an increasing global burden of patients with chronic peripheral artery disease (PAD) the safe and effective provision of lower limb revascularisation is a growing medical need. Endovascular procedures for the treatment of PAD have become a crucial cornerstone of modern vascular medicine, and the first line revascularisation approach if technically feasible and taking patient choice into consideration. With the increasing age of patients with PAD and the increasing number of comorbidities open vascular surgery is also often not feasible. We outline a framework of key messages, endorsed by the board of the European Society of Vascular Medicine for pre-, peri- and post procedural management of patients requiring endovascular arterial procedures of the lower limbs. These key messages emphasize the important and increasing role of interventional vascular physicians.

Michael Gröne, Miriam Schillings, Dragos Duse, Nicolas Kramser, Christine Quast, Christian Heiss, Roberto Sansone, Christian Jung, Malte Kelm, Ralf Erkens (2023)Cocoa flavanol supplementation preserves early and late radial artery function after transradial catheterization, In: Food and Function14(10)pp. 4824-4835 Royal Society of Chemistry

Background: The transradial approach for coronary angiography is associated with fewer complications and preferred over the femoral approach. Injury to the radial artery (RA) endothelium elicits intimal hyperplasia, possibly resulting in total occlusion and limb functional decline. Flavanols are known to improve endothelial function. Effects on arterial remodeling after mechanical injury are unknown. Objective: To investigate the effects of cocoa flavanols on (a) intimal hyperplasia and (b) endothelial functional recovery after mechanical vascular wall injury through transradial coronary angiography (TCA). Methods: Primary endpoint in this double-blind, randomized, controlled trial was RA intima-media thickness (IMT) after 6 months follow-up (FU). Secondary endpoints were RA flow-mediated vasodilation (FMD) and fractional diameter change (Fdc). Further luminal diameter and circulating endothelial microparticles (EMP) were assessed. Thirty-six male patients undergoing elective TCA were included. Flavanol or matched placebo supplementation started 7 days prior TCA (cocoa flavanol 1000 mg day−1) for 14 days. Four measurements spanned three periods over 6-moths-FU. Results: TCA induced sustained intimal hyperplasia in the placebo-, but not in the flavanol-group (IMT 0.44 ± 0.01 vs. 0.37 ± 0.01 mm, p = 0.01). FMD decreased after TCA in both groups, but recovered to baseline after 6 months in the flavanol group only. Fdc acutely decreased, EMPs increased in the placebo-, not in the flavanol -group. Luminal diameter remained unchanged in both groups. Conclusion: Peri-interventional cocoa flavanol supplementation prevents long-term intima media thickening and endothelial dysfunction 6 months after TCA opening the perspective for dietary interventions to mitigate endothelial cell damage and intimal hyperplasia after mechanical injury.

Jiaying Hu, Robin Mesnage, Kieran Tuohy, Christian Heiss, Ana Rodriguez-Mateos (2024)(Poly)phenol-related gut metabotypes and human health: an update, In: Food & function

Dietary (poly)phenols have received great interest due to their potential role in the prevention and management of non-communicable diseases. In recent years, a high inter-individual variability in the biological response to (poly)phenols has been demonstrated, which could be related to the high variability in (poly)phenol gut microbial metabolism existing within individuals. An interplay between (poly)phenols and the gut microbiota exists, with (poly)phenols being metabolised by the gut microbiota and their metabolites modulating gut microbiota diversity and composition. A number of (poly)phenol metabolising phenotypes or metabotypes have been proposed, however, potential metabotypes for most (poly)phenols have not been investigated, and the relationship between metabotypes and human health remains ambiguous. This review presents updated knowledge on the reciprocal interaction between (poly)phenols and the gut microbiome, associated gut metabotypes, and subsequent impact on human health.

MARIAM BAPIR, PAOLA CAMPAGNOLO, Ana Rodriguez-Mateos, Simon S. SKENE, CHRISTIAN HEISS (2022)Assessing variability in vascular response to cocoa with personal devices: a series of double-blind randomized cross-over n-of-1 trials, In: Frontiers Nutrition9886597

Controlled clinical intervention studies have demonstrated that cocoa flavanols (CF) can decrease blood pressure and arterial stiffness in healthy humans, although a large variability in the effect size across trials has been reported. Here, we evaluated intra- and inter-individual variability of responses to CF in everyday life using a series of n-of-1 trials in healthy free-living individuals with normal blood pressure carrying personal devices. Eleven healthy young humans participated in a repeated cross-over randomized controlled double-blind n-of-1 trial. On eight consecutive days, each volunteer consumed on alternating days 6 CF capsules (862 mg CF) on four days and 6 matched placebo capsules (P, 0 mg CF/day) on another 4 days in one of two randomized sequences (CF-P-CF-P-CF-P-CF-P or P-CF-P-CF-P-CF-P-CF). On each day the capsules were taken at the same time in the morning with breakfast after baseline measurements. Each subject was provided with an upper arm blood pressure monitor and a finger clip that measures pulse wave velocity (PWV). Measurements of blood pressure, heart rate and PWV were taken at least hourly over 12 hours during the day by the participants. On the first 2 days measurements were performed under supervision to provide training. The overall mixed model analysis showed that CF significantly decreased 12 h systolic blood pressure and PWV by -1.4±0.3 mmHg and - -0.11±0.03 m/s, respectively. Peak effects were observed within the first 3 hours (1.5 h SBP: -4.9±2.2 mmHg, PWV: -0.32±0.17 m/s)and again after 8 h post ingestion. Large inter-individual variation in responses was found (intra-cluster correlation coefficients [ICC]: 0.41, 0.41). When analysing single individuals’ datasets, there was also considerable between-day variation in individual responses that varied greatly between subjects (ICC: 0-0.30, 0-0.22, 0-0.45). Effect sizes inversely correlated with baseline blood pressure values both between-- and within-subjects. The data confirm that cocoa can decrease blood pressure and arterial stiffness in everyday life when elevated within the normal range. The large inter- and intra-individual variation in responses call for more personalized nutritional intervention strategies.

Ulrich Frank, Sigrid Nikol, Jill Belch, Vinko Boc, Marianne Brodmann, Patrick H Carpentier, Ali Chraim, Caitriona Canning, Evangelos Dimakakos, Anders Gottsäter, Christian Heiss, Lucia Mazzolai, Juraj Madaric, Dan Mircea Olinic, Zsolt Pécsvárady, Pavel Poredoš, Isabelle Quéré, Karel Roztocil, Agata Stanek, Dragan Vasic, Adriana Visonà, Jean-Claude Wautrecht, Miroslav Bulvas, Mary-Paula Colgan, Walter Dorigo, Graeme Houston, Thomas Kahan, Holger Lawall, Isak Lindstedt, Guillaume Mahe, Romeo Martini, Giles Pernod, Stanislaw Przywara, Marc Righini, Oliver Schlager, Piotr Terlecki (2019)ESVM Guideline on peripheral arterial disease, In: VASA : European Journal of Vascular Medicine48(Supplement 102)pp. 1-12 Hogrefe

The objective of the present guideline is to provide evidence-based, comprehensive and optimal care recommendations for patients with atherosclerotic peripheral artery disease (PAD) of the lower limbs. The guideline is meant to aid medical personnel and patients in making decisions regarding the optimal diagnostic and therapeutic measures for patients with PAD, and to aid with action and decision routes, which may be modified in justified cases. Guidelines established by scientific medical societies are not legally binding for physicians and may thus neither cause liability nor release physicians from liability. What legally constitutes a medical standard in the treatment of a given individual can only be determined individually. The present guideline thus does not relieve physicians from their obligation to individually manage their patients by appraising their patients’ overall situation. The present guideline aims to compile the most significant evidence and information on the treatment of peripheral arterial disorders from various specialties to offer the reader reliable assistance in everyday practical clinical life.

H L Busch, M Stern, K Tzetou, R Sansone, C Heiss, M Kelm (2019)Blood pressure lowering by peripheral arterial angioplasty, In: European heart journal40(Supplement_1)ehz745.1083 Oxford University Press

Objective We hypothesized that the endovascular treatment of flow limiting peripheral stenosis may decrease arterial blood pressure (BP). Methods We prospectively enrolled 381 consecutive patients with PAD scheduled for PTA. Clinical baseline characteristics and BP responses to PTA or angiography were analyzed. In a subgroup of 30 patients, we analyzed intra-procedural central aortic BP before and after PTA of iliac (n=15) and femoropoliteal arteries (n=10) and diagnostic angiography (n=5). Results Systolic BP (SBP) decreased after PTA of iliac (−19 mmHg, 95% CI: −15, −23 mmHg), femoropopliteal (−12 mmHg, 95% CI: −9, −15 mmHg), and BTK arteries (−7 mmHg, 95% CI: −1, −14 mmHg) but not after diagnostic angiography (−2 mmHg, 95% CI: 2, −6 mmHg) as compared to baseline. Diastolic BP (DBP) decreased after iliac (−5 mmHg, 95% CI: −2, −9 mmHg) and femoropopliteal (−4 mmHg, 95% CI: −1, −6 mmHg) angioplasty, but not after BTK PTA (1 mmHg, 95% CI: 6, −8 mmHg) or angiography (5 mmHg, 95% CI: −10, 12 mmHg). Mean central BP (CBP) acutely decreased after iliac (−20 mmHg [95% CI: −12, −32 mmHg] / −7 mmHg [95% CI: −6, −9 mmHg]) and femoropopliteal artery PTA (−9 mmHg [95% CI: −8, −12 mmHg] / −4 mmHg [95% CI: −3, −6 mmHg]) but not after diagnostic angiography. Iliac PTA achieved the most pronounced peripheral and central SBP lowering effect (p

S Baasen, M Stern, Y Heinen, L Goerdes, R Sansone, C Heiss, M Kelm, L Busch (2021)Angioplasty of flow limiting stenosis improves left ventricular diastolic dysfunction in patients with peripheral artery disease, In: European heart journal42(Supplement_1) Oxford University Press

Background Peripheral artery disease (PAD) is associated with hypertension and left ventricular diastolic dysfunction (LVDD). Objective We hypothesized that endovascular treatment of flow limiting peripheral stenosis may improve LVDD. Methods In this prospective single center trial, 23 patients with PAD Rutherford stage 2–4 were included. Augmentation index (AIx), central systolic blood pressure (cSBP) and ankle brachial index (ABI) were measured at baseline one day before, one day after and at follow up 4 months after angioplasty. LVDD was assessed by echocardiography at baseline and at follow up. Results Mean E/E' ratio was significantly lower at follow up (11.9±4.4 to 10.2±4.4; p

T Herbrand, H V Coester, H De Vries, C Heiss, T Heise, M Kelm, R Sansone (2019)More precise assessment of flow-mediated dilation by measuring individually determined maximum dilatory peak time in healthy middle-aged subjects and patients with diabetes mellitus type 2, In: European heart journal40(Supplement_1)ehz748.0762 Oxford University Press

The assessment of flow-mediated dilation (FMD) is widely used in clinical research to quantify endothelial function. FMD is calculated by subtracting the artery's baseline diameter from the peak diameter during hyperemia. However, there is no consensus on how to determine peak diameter. Many authors report FMD results based on values assessed at predefined time points. This may limit the accuracy and reproducibility of FMD. We hypothesised that FMD values using maximum dilatory peak time (MDP) would differ from those using predefined time points. Using individually determined MDP may lead to a lower number of subjects needed to show significance for a given difference in FMD. FMD was measured in middle-aged subjects with and without diabetes mellitus type 2 (T2DM) by ultrasound (12-MHz transducer). In a subset of subjects, FMD was measured again 30 days later. All measurements were performed by certified research physicians and evaluated using appropriate software. FMD values were compared at 60 s and 90 s after start of hyperaemia and at MDP during hyperaemia. FMD was measured in 100 healthy subjects and 72 subjects with T2DM (mean ± SD age 57±6 years, healthy: body mass index 26.2±3 kg/m2, blood pressure 127±10 /80±7 mmHg, DMT2: body mass index 29±3 kg/m2, blood pressure 135±11 / 86±5 mmHg, HbA1c 7.1±0.7%). FMD in healthy subjects was lower at predefined time points compared to MDP (least square mean difference (95% CI)) 60 s vs. MDP −1.14% (−1.72 to −0.56; p

Martin B. Whyte, Prash Vas, Philip A. Kelly, Christian Heiss, Michael D. Feher (2020)Nitric oxide and phosphodiesterase-5 inhibitors: possible treatments for COVID-19 in diabetes, In: BRITISH JOURNAL OF DIABETES20(2)pp. 81-83 Assoc British Clinical Diabetologists

Individuals with type 2 diabetes, hypertension and obesity havepoor outcomes from coronavirus-19 (COVID-19). The presence ofmicrovascular disease (retinopathy, microalbuminuria or neuropa-thy) is an independent risk factor for early death in COVID-19.Microvascular dysfunction is a systemic condition which includespulmonary manifestations. Impaired gas transfer, due to micro-angiopathy in type 2 diabetes, suggests that individuals will bevulnerable to the pro-inflammatory state and microthrombi char-acteristic of ‘endothelitis’ in COVID-19. Drugs that improve bloodflow in the intrapulmonary peri-alveolar microcirculation – namely,nitric oxide or phosphodiesterase-5 inhibitors – are thereforepromising candidates for clinical trials in COVID-19.

R Foerster, M Stern, Y Heinen, S Baasen, R Sansone, C Heiss, M Kelm, H L Busch (2021)Impact of peripheral angioplasty on wound oxygenation measured with near-infrared spectroscopy in patients with critical limb ischemia, In: European heart journal42(Supplement_1)ehab724.2028 Oxford University Press

Background Near-infrared Spectroscopy (NIRS) has been proposed as a promising noninvasive tool for the assessment of hemoglobin oxygen saturation (StO2) in complex wounds in patients with critical limb ischemia (CLI). Objective Up today, NIRS measurements are undertaken at single points near the wound, but not in the wound. Methods In this prospective, single center study, 34 patients with PAD Rutherford stage 4–6 were included. We analyzed StO2 maps in and around the wound at baseline one day before and one day after angioplasty using a NIRS camera; macrovascular function was assessed by Doppler ultrasound with spectral analysis including ankle-brachial index (ABI). Results Baseline StO2 of the wound area was 63% (± 3.66 [SE]) and 34% in the wound (± 4.8 [SE]). After successful angioplasty, wound area StO2 significantly increased to 71% (± 3.09 [SE]; p

Jean-Claude Wautrecht, Dan-Mircea Olinic, Mariella Catalano, Colin Baines, Jill Belch, Ales Blinc, Ivo Buschmann, Denisa Celovska, Mary-Paula Colgan, Evangelos Dimakakos, Christian Heiss, Endre Kolossvary, Matija Kozak, Bram Kroon, Lucia Mazzolai, George Marakomichelakis, Zsolt Pecsvarady, Maria A. Pias Canedo, Isabelle Quere, Karel Roztocil, Gerit H. Schernthaner, Aleksander Sieron, Jonas Spaak, Muriel Sprynger, Agata Stanek, Daniel Staub, Dragan Vasic, Adriana Visona, andrea Willfort-Ehringer (2022)UeMS training requirements for angiology/Vascular Medicine: european Standards of Postgraduate Medical Specialist training (2022 Updated Version), In: International angiology41(3)pp. 258-274 Edizioni Minerva Medica

Abstract Background The transradial approach is commonly preferred over the femoral approach for coronary angiography to reduce vascular complications like bleeding, aneurysm formation and all-cause mortality ensuring early ambulation after coronary procedures. However, there is growing evidence that damage to the radial artery endothelium elicits intimal hyperplasia, vascular remodeling and might ultimately lead to total vessel occlusion. Objective Our study aimed to investigate the effects of dietary flavanol intervention on (a) early endothelial functional recovery and (b) late structural changes i.e. intimal hyperplasia after mechanical vascular wall injury in the human forearm model during coronary angiography. Methods Radial artery flow-mediated vasodilation (RA-FMD), local stiffness (fractional diameter change, Fdc), intima-media thickness (IMT), luminal and external arterial diameter at the site of intervention and the contralateral control artery were measured in 38 male patients (19 flavanol intervention, 19 placebo control) undergoing transradial coronary angiography (TCA) at baseline, after 7 days of 450mg flavanol supplementation BID, directly after TCA and 6 months after TCA. Circulating levels of endothelial microparticle (EMP) subpopulations CD31+/41-, CD62e+and CD144+were analyzed simultaneously as a surrogate for endothelial functional integrity and activation. Results One week of flavanol supplementation, not placebo, significantly increased RA-FMD (8.88±2.03% vs. 11.17±2.89%, p

Lucia Mazzolai, Adriano Alatri, Alessandra Bura Riviere, Marco De Carlo, Christian Heiss, Christine Espinola-Klein, Oliver Schlager, Henrik Sillesen, Daniel Staub, Jose F. Rodriguez-Palomares, Aline Verstraeten, Victor Aboyans, (2021)Progress in aorta and peripheral cardiovascular disease research, In: Cardiovascular research117(9)pp. 2045-2053 Oxford Univ Press

Although coronavirus disease 2019 seems to be the leading topic in research number of outstanding studies have been published in the field of aorta and peripheral vascular diseases likely affecting our clinical practice in the near future. This review article highlights key research on vascular diseases published in 2020. Some studies have shed light in the pathophysiology of aortic aneurysm and dissection suggesting a potential role for kinase inhibitors as new therapeutic options. A first proteogenomic study on fibromuscular dysplasia (FMD) revealed a promising novel disease gene and provided proof-of-concept for a protein/lipid-based FMD blood test. The role of NADPH oxidases in vascular physiology, and particularly endothelial cell differentiation, is highlighted with potential for cell therapy development. Imaging of vulnerable plaque has been an intense field of research. Features of plaque vulnerability on magnetic resonance imaging as an under-recognized cause of stroke are discussed. Major clinical trials on lower extremity peripheral artery disease have shown added benefit of dual antithrombotic (aspirin plus rivaroxaban) treatment.

Theresa Herbrand, Hans-Veit Coester, Roberto Sansone, Annelie Fischer, Christian Heiss, Tim Heise, Malte Kelm, Hans J. DeVries (2021)Improving the Assessment of Flow-Mediated Dilation Through Detection of Peak Time in Healthy Subjects and Subjects With Type 2 Diabetes, In: Angiology72(5)0003319720984884pp. 434-441 Sage

The assessment of flow-mediated dilation (FMD) is widely used to quantify endothelial function. Historically, FMD was determined at 60 seconds post-cuff deflation. We investigated whether FMD would be more accurate if determined at maximum dilatory peak (MDP) than at 60 seconds in healthy subjects and subjects with type 2 diabetes mellitus (T2DM). We studied 95 healthy and 72 subjects with T2DM and assessed FMD at MDP, 60 and 90 seconds. Twenty-four healthy and 12 subjects with T2DM underwent a repeat FMD after 28 days. In healthy subjects, FMD at MDP was higher than at 60 and 90 seconds, with mean difference MDP versus 60 seconds 1.14% (95% CI: 0.6-1.7); P < .0001 and MDP versus 90 seconds 1.9% (95% CI: 1.3-2.5) with similar results in T2DM, that is, 1.0% (95% CI: 0.1-1.9) and 2.3% (95% CI: 1.3-3.2), respectively. Intraindividual variability was lowest with MDP compared with 60 and 90 seconds, that is, 15.0 versus 23.2% and 40.0%, respectively, resulting in a more than 2-fold reduction in necessary sample size. In healthy subjects and subjects with T2DM, assessment of FMD using MDP results in a more accurate and precise assessment leading to a substantial reduction in sample size.

Jill J.F. Belch, Marianne Brodmann, Iris Baumgartner, Christoph J. Binder, Manuela Casula, Christian Heiss, Thomas Kahan, Paolo Parini, Pavel Poredos, Alberico L. Catapano, Lale Tokgözoğlu (2021)Lipid-lowering and anti-thrombotic therapy in patients with peripheral arterial disease: European Atherosclerosis Society/European Society of Vascular Medicine Joint Statement, In: Atherosclerosis33855pp. 55-63 Elsevier B.V

Patients with peripheral arterial disease (PAD) are at very high risk of cardiovascular events, but risk factor management is usually suboptimal. This Joint Task Force from the European Atherosclerosis Society and the European Society of Vascular Medicine has updated evidence on the management on dyslipidaemia and thrombotic factors in patients with PAD. Guidelines recommend a low-density lipoprotein cholesterol (LDLC) goal of more than 50% reduction from baseline and

Jill J. F. Belch, Marianne Brodmann, Iris Baumgartner, Christoph J. Binder, Manuela Casula, Christian Heiss, Thomas Kahan, Paolo Parini, Pavel Poredos, Alberico L. Catapano, Lale Tokgozoglu (2021)Lipid-lowering and anti-thrombotic therapy in patients with peripheral arterial disease: European Atherosclerosis Society/European Society of Vascular Medicine Joint Statement, In: VASA50(6)pp. 401-411 HOGREFE AG-HOGREFE AG SUISSE

Patients with peripheral arterial disease (PAD) are at very high risk of cardiovascular events, but risk factor management is usually suboptimal. This Joint Task Force from the European Atherosclerosis Society and the European Society of Vascular Medicine has updated evidence on the management on dyslipidaemia and thrombotic factors in patients with PAD. Guidelines recommend a low-density lipoprotein cholesterol (LDLC) goal of more than 50% reduction from baseline and

Lucas Busch, Manuel Stern, Lisa Dannenberg, Philipp Mourikis, Michael Gröne, Göksen Özaslan, Yvonne Heinen, Christian Heiss, Roberto Sansone, Amin Polzin, Malte Kelm (2021)Impact of high on-treatment platelet reactivity after angioplasty in patients with peripheral arterial disease, In: Platelets (Edinburgh)32(3)391pp. 391-397 Taylor & Francis

Objective: High on-treatment platelet reactivity (HTPR) to dual antiplatelet therapy (DAPT) predicts adverse events in coronary artery disease patients. In peripheral artery disease (PAD) patients, data concerning the clinical impact of HTPR are limited. Therefore, we evaluated the incidence of (i) HTPR to DAPT and (ii) its impact on 6 months outcome after angioplasty. Methods and results: In this prospective single center analysis, we investigated 102 consecutive patients with PAD from 2016 to 2017. All patients underwent peripheral endovascular treatment due to intermittent claudication (Fontaine IIb). Clopidogrel effects were measured using vasodilator-stimulated protein phosphorylation (VASP) assay, aspirin effects by light-transmission aggregometry (LTA). Major adverse limb events (MALE), major adverse cardiac and cerebrovascular events (MACCE) and BARC bleeding (bleeding academic research consortium classification) within 6 months were assessed. HTPR to clopidogrel (n = 37, 36%), to aspirin (n = 11, 11%) and to both (n = 11, 11%) were frequent. Compared to sufficient platelet inhibition by aspirin and clopidogrel (n = 43, 42%), patients with dual HTPR showed a higher risk of MALE at 6 months (27% vs. 7%; hazard ratio [HR]: 4.45; 95% confidence interval [CI]: 1.1 to 67.8; p = .03). This was independent of diabetes, creatinine, body mass index, and age as well as of procedural details in a multivariate logistic regression analysis. MACCE (n = 2) and BARC bleeding rates (n = 2) were low. Conclusion: In this small exploratory study, HTPR was frequent in PAD patients. Furthermore, the results are suggestive that MALE might be associated with dual HTPR. This leads to the hypothesis that optimized antithrombotic regimens post percutaneous transluminal angioplasty should be tested in clinical trials.

THERESA Herbrand, HANS VEIT Coester, J. HANS Devries, CHRISTIAN Heiss, TIM Heise, MALTE Kelm, ROBERTO Sansone (2019)2216-PUB: More Precise Assessment of Flow-Mediated Dilation (FMD) by Measuring at Maximum Dilatory Peak Time (MDP) in Subjects With and Without Type 2 Diabetes (T2D), In: Diabetes (New York, N.Y.)68(Supplement_1)

FMD is widely used to quantify endothelial function. FMD is calculated from the artery’s baseline diameter and peak diameter during reactive hyperemia. To this day, many published FMD results are based on values assessed at predefined time points, e.g., 60 s after start of hyperemia, rather than at the time of MDP. This may limit the accuracy and reproducibility of FMD. We hypothesized that FMD values at MDP would be higher and more reproducible than at predefined times, resulting in a lower number of subjects needed to show significance for a given difference in FMD. FMD was measured in subjects with and without T2D by ultrasound (12 MHz transducer; GE Logiq P7, GE Healthcare, Germany). In a subset of subjects, FMD was measured again after 30 days. All measurements were performed by certified physicians and evaluated by three certified FMD analysts using Brachial Analyzer 5 (MIA LLC, U.S.). FMD values at 60 s and 90 s after start of hyperemia were compared to FMD at MDP using ANOVA. In this study, 100 healthy middle-aged subjects and 52 subjects with T2D (mean ± SD age 56 ± 5.4 years, T2D HbA1c 7.2 ± 0.7%) underwent FMD. FMD was measured again in 25 healthy subjects after 30 days. Overall, FMD was lower at predefined time points compared to MDP (least square mean difference (95% CI)) 60 s vs. MDP 1.12% ( 1.56; -0.68); p

Mariam Bapir, Gavrielle R. Untracht, Julie E. A. Hunt, John H. McVey, Jenny Harris, Simon S. Skene, Paola Campagnolo, Nikolaos Dikaios, Ana Rodriguez-Mateos, David D Sampson, Danuta M. Sampson, Christian Heiss (2022)Age-Dependent Decline in Common Femoral Artery Flow-Mediated Dilation and Wall Shear Stress in Healthy Subjects, In: Life12(12)2023 MDPI

Femoral artery (FA) endothelial function is a promising biomarker of lower extremity vascular health for peripheral artery disease (PAD) prevention and treatment; however, the impact of age on FA endothelial function has not been reported in healthy adults. Therefore, we evaluated the reproducibility and acceptability of flow-mediated dilation (FMD) in the FA and brachial artery (BA) (n = 20) and performed cross-sectional FA- and BA-FMD measurements in healthy non-smokers aged 22–76 years (n = 50). FMD protocols demonstrated similar good reproducibility. Leg occlusion was deemed more uncomfortable than arm occlusion; thigh occlusion was less tolerated than forearm and calf occlusion. FA-FMD with calf occlusion was lower than BA-FMD (6.0 ± 1.1% vs 6.4 ± 1.3%, p = 0.030). Multivariate linear regression analysis indicated that age (−0.4%/decade) was a significant independent predictor of FA-FMD (R2 = 0.35, p = 0.002). The age-dependent decline in FMD did not significantly differ between FA and BA (pinteraction agexlocation = 0.388). In older participants, 40% of baseline FA wall shear stress (WSS) values were

Alexander Rodway, Michelle Stafford, Sophie Wilding, Nikolaos Ntagiantas, Vasileios Patsiogiannis, Charlotte Allan, James Clark, Felipe Pazos Casal, Ajay Pankhania, Thomas Loosemore, Christian Heiss, Benjamin Field (2021)Day case angioplasty in a secondary care setting-initial experience, In: VASApp. 1-7 Hogrefe AG

Background: Peripheral artery disease presents an increasing healthcare burden worldwide. Day-case angioplasty in a secondary care setting can be a safe and effective means of meeting the growing demand for lower limb revascularisation. We evaluated the safety and efficacy of a day-case-based angioplasty service in a UK district general hospital. Patients and methods: Consecutive patients undergoing endovascular revascularisation between August 2018–February 2020 were analysed retrospectively. All patients were discussed at a multi-disciplinary (diabetic foot) team meeting following a day case algorithm. Patient and procedural characteristics, technical success, peri-procedural complications, and 30-day outcome of day-case angioplasties were compared with those requiring overnight stay or were hospitalized. Results: Fifty-seven percent of 138 patients were diabetic, mean age 75 ± 12 years, 95% had critical limb ischaemia (Fontaine III 12%, IV 83%), and baseline ankle brachial pressure index [ABPI] 0.40 ± 0.30. Sixty-three patients (45%) were treated as planned day cases, 21 (15%) required overnight admission for social indications. Fifteen (11%) were planned admissions with the need for sequential debridement procedures, and 39 (28%) were already hospitalised at the time of referral to the vascular service. The overall technical success was 92% and not successful procedures mainly occurred in patients > 80 years. The ABPI increased at the initial follow-up to 0.84 ± 0.18. Fifty-three percent required treatment of > 1 level, 80% included recanalisations of chronic total occlusions, and average total lesion length was 133 ± 90 mm. Closure devices were employed in all cases. There were no major peri-procedural complications. A single minor access-site related bleeding episode (0.8%) occurred, requiring 24 h observation in hospital. While significantly more wounds had closed in out-patients, the mortality, major amputation and target lesion revascularization did not differ between groups. Conclusions: Safe and effective day-case-based angioplasty can be provided in a secondary care setting for patients with critical limb ischaemia needing complex multi-level procedures.

MARIAM BAPIR, Gabrielle Untracht, Debbie Cooke, John H. McVey, Simon S. SKENE, Paola Campagnolo, Martin B. Whyte, Nikolaos Dikaios, Ana Rodriguez-Mateos, David D Sampson, Danuta M. Sampson, Christian Heiss (2022)Cocoa flavanol consumption improves lower extremity endothelial function in healthy individuals and people with type 2 diabetes, In: Food & Function13(20)pp. 10439-10448 Royal Society of Chemistry

Background: Diabetes and age are major risk factors for the development of lower extremity peripheral artery disease (PAD). Cocoa flavanol (CF) consumption is associated with lower risk for PAD and improves brachial artery (BA) endothelial function. Objectives: to assess if femoral artery (FA) endothelial function and dermal microcirculation are impaired in individuals with type 2 diabetes mellitus (T2DM) and evaluate the acute effect of CF consumption on FA endothelial function. Methods: In a randomised, controlled, double-blind, cross-over study, 22 individuals (n = 11 healthy, n = 11 T2DM) without cardiovascular disease were recruited. Participants received either 1350 mg CF or placebo capsules on 2 separate days in random order. Endothelial function was measured as flow-mediated dilation (FMD) using ultrasound of the common FA and the BA before and 2 hours after interventions. The cutaneous microvasculature was assessed using optical coherence tomography angiography. Results: Baseline FA-FMD and BA-FMD were significantly lower in T2DM (FA: 3.2 ± 1.1% [SD], BA: 4.8 ± 0.8%) compared to healthy (FA: 5.5 ± 0.7%, BA: 6.0 ± 0.8%); each p < 0.001. Whereas in healthy individuals FA-FMD did not significantly differ from BA-FMD (p = 0.144), FA-FMD was significantly lower than BA-FMD in T2DM (p = 0.003) indicating pronounced and additional endothelial dysfunction of lower limb arteries (FA-FMD/BA-FMD: 94 ± 14% [healthy] vs. 68 ± 22% [T2DM], p = 0.007). The baseline FA blood flow rate (0.42 ± 0.23 vs. 0.73 ± 0.35 l min−1, p = 0.037) and microvascular dilation in response to occlusion in hands and feet were significantly lower in T2DM subjects than in healthy ones. CF increased both FA- and BA-FMD at 2 hours, compared to placebo, in both healthy and T2DM subgroups (FA-FMD effect: 2.9 ± 1.4%, BA-FMD effect 3.0 ± 3.5%, each pintervention< 0.001). In parallel, baseline FA blood flow and microvascular diameter significantly increased in feet (3.5 ± 3.5 μm, pintervention< 0.001) but not hands. Systolic blood pressure and pulse wave velocity significantly decreased after CF in both subgroups (−7.2 ± 9.6 mmHg, pintervention = 0.004; −1.3 ± 1.3 m s−1, pintervention = 0.002). Conclusions: Individuals with T2DM exhibit decreased endothelial function that is more pronounced in the femoral than in the brachial artery. CFs increase endothelial function not only in the BA but also the FA both in healthy individuals and in those with T2DM who are at increased risk of developing lower extremity PAD and foot ulcers.

GAVRIELLE REBECCA UNTRACHT, NIKOLAOS DIKAIOS, Abdullah Khan Durrani, Mariam Bapir, Marinko V. Sarunic, David D Sampson, Christian Heiss, DANUTA SAMPSON (2022)Pilot study of optical coherence tomography angiography-derived microvascular metrics in hands and feet of healthy and diabetic people

Optical coherence tomography angiography (OCTA) is a non-invasive, high-resolution imaging modality with growing application in dermatology and microvascular assessment. Accepted reference values for OCTA-derived microvascular parameters in skin do not yet exist but need to be established to drive OCTA into the clinic. In this pilot study, we assess a range of OCTA microvascular metrics at rest and after post-occlusive reactive hyperaemia (PORH) in the hands and feet of 52 healthy individuals and 11 individuals with well-controlled type 2 diabetes mellitus (T2DM). We calculate each metric, measure test-retest repeatability, and evaluate correlation with demographic risk factors. Our study delivers extremity-specific, age-dependent reference values and coefficients of repeatability of nine microvascular metrics at baseline and at the maximum of PORH. Significant differences are not seen for age-dependent microvascular metrics in hand, but they are present for several metrics in the foot. Significant differences are observed between hand and foot, both at baseline and maximum PORH for most of the microvascular metrics, with generally higher values in the hand. Despite a large variability over a range of individuals, as is expected based on heterogeneous ageing phenotypes of the population, the test-retest repeatability is 3.5% to 18% of the mean value for all metrics, which highlights the opportunities for OCTA-based studies in larger cohorts, for longitudinal monitoring, and for assessing the efficacy of interventions. Additionally, branchpoint density in the hand and foot and changes in vessel diameter in response to PORH stood out as good discriminators between healthy and T2DM groups, which indicates their potential value as biomarkers. This study, building on our previous work, represents a further step towards standardized OCTA in clinical practice and research.

Karla Fabiola Corral-Jara, Saivageethi Nuthikattu, John Rutledge, Amparo Villablanca, Reedmond Fong, Christian Heiss, Javier I. Ottaviani, Dragan Milenkovic (2022)Structurally related (−)-epicatechin metabolites and gut microbiota derived metabolites exert genomic modifications via VEGF signaling pathways in brain microvascular endothelial cells under lipotoxic conditions: Integrated multi-omic study, In: Journal of Proteomics263104603 Elsevier

Dysfunction of blood-brain barrier formed by endothelial cells of cerebral blood vessels, plays a key role in development of neurodegenerative disorders. Epicatechin exerts vasculo-protective effects through genomic modifications, however molecular mechanisms of action, particularly on brain endothelial cells, are largely unknow. This study aimed to use a multi-omic approach (transcriptomics of mRNA, miRNAs and lncRNAs, and proteomics), to provide novel in-depth insights into molecular mechanisms of how metabolites affect brain endothelial cells under lipid-stressed (as a model of BBB dysfunction) at physiological concentrations. We showed that metabolites can simultaneously modulate expression of protein-coding, non-coding genes and proteins. Integrative analysis revealed interactions between different types of RNAs and form functional groups of genes involved in regulation of processing like VEGF-related functions, cell signaling, cell adhesion and permeability. Molecular modeling of genomics data predicted that metabolites decrease endothelial cell permeability, increased by lipotoxic stress. Correlation analysis between genomic modifications observed and genomic signature of patients with vascular dementia and Alzheimer's diseases showed opposite gene expression changes. Taken together, this study describes for the first time a multi-omic mechanism of action by which (-)-epicatechin metabolites could preserve brain vascular endothelial cell integrity and reduce the risk of neurodegenerative diseases. SIGNIFICANCE: Dysfunction of the blood-brain barrier (BBB), characterized by dysfunction of endothelial cells of cerebral blood vessels, result in an increase in permeability and neuroinflammation which constitute a key factor in the development neurodegenerative disorders. Even though it is suggested that polyphenols can prevent or delay the development of these disorders, their impact on brain endothelial cells and underlying mechanisms of actions are unknow. This study aimed to use a multi-omic approach including analysis of expression of mRNA, microRNA, long non-coding RNAs, and proteins to provide novel global in-depth insights into molecular mechanisms of how (-)-epicatechin metabolites affect brain microvascular endothelial cells under lipid-stressed (as a model of BBB dysfunction) at physiological relevant conditions. The results provide basis of knowledge on the capacity of polyphenols to prevent brain endothelial dysfunction and consequently neurodegenerative disorders.

Christian Heiss, Alex Pitcher, Jill J F Belch, Marco De Carlo, Holger Reinecke, Iris Baumgartner, Lucia Mazzolai, Victor Aboyans (2020)The year in cardiology: Aorta and peripheral circulation, In: European Heart Journal41(4)pp. 501-508b Oxford University Press

Similar to previous years, 1–3 the current article reviews groundbreaking science published 2019 in the area of aortic and peripheral arterial diseases (PAD) as well as venous thromboembolic disease (VTE) that will affect our daily clinical practice. With the growing recognition of PAD, it will be necessary to consolidate imprecisions in terminology. Many are used to the acronym PAD for atherosclerotic disease of the lower extremity arteries. Others have used the same acronym to qualify atherosclerotic disease of the lower extremity arteries and carotid arteries. In the current article and in line with the European Society of Cardiology (ESC) guidelines, 4 we have stringently used the specific terms lower extremity arterial disease (LEAD) and reserved PAD as the umbrella term encompassing all arterial diseases other than aorta and coronaries

Bernardo Meza-Torres, Fabrizio Carinci, Christian Heiss, Mark Joy, Simon de Lusignan (2021)Health service organisation impact on lower extremity amputations in people with type 2 diabetes with foot ulcers: systematic review and meta-analysis, In: Acta Diabetologicapp. 1-13

Despite the evidence available on the epidemiology of diabetic foot ulcers and associated complications, it is not clear how specific organizational aspects of health care systems can positively affect their clinical trajectory. We aim to evaluate the impact of organizational aspects of care on lower extremity amputation rates among people with type 2 diabetes affected by foot ulcers. We conducted a systematic review of the scientific literature published between 1999 and 2019, using the following key terms as search criteria: people with type 2 diabetes, diagnosed with diabetic foot ulcer, treated with specific processes and care pathways, and LEA as primary outcome. Overall results were reported as pooled odds ratios and 95% confidence intervals obtained using fixed and random effects models. A total of 57 studies were found eligible, highlighting the following arrangements: dedicated teams, care pathways and protocols, multidisciplinary teams, and combined interventions. Among them, seven studies qualified for a meta-analysis. According to the random effects model, interventions including any of the four arrangements were associated with a 29% reduced risk of any type of lower extremity amputation (OR = 0.71; 95% CI 0.52-0.96). The effect was larger when focusing on major LEAs alone, leading to a 48% risk reduction (OR = 0.52; 95% CI 0.30-0.91). Specific organizational arrangements including multidisciplinary teams and care pathways can prevent half of the amputations in people with diabetes and foot ulcers. Further studies using standardized criteria are needed to investigate the cost-effectiveness to facilitate wider implementation of improved organizational arrangements. Similarly, research should identify specific roadblocks to translating evidence into action. These may be structures and processes at the health system level, e.g. availability of professionals with the right skillset, reimbursement mechanisms, and clear organizational intervention implementation guidelines.

Dragan Milenkovic, Tatjana Ruskovska, Ana Rodriguez-Mateos, CHRISTIAN HEISS (2021)Polyphenols could prevent sars-cov-2 infection by modulating the expression of mirnas in the host cells, In: Aging and disease12(5) Aging and Disease

Coronaviruses (CoVs) are single-stranded RNA viruses which following virus attachment and entry into the host cell, particularly type 2 pneumocytes but also endothelial cells, release RNA into cytosol where it serves as a matrix for the host translation machinery to produce viral proteins. The viral RNA in cytoplasm can interact with host cell microRNAs which can degrade viral RNA and/or prevent viral replication. As such host cellular miRNAs represent key cellular mediators of antiviral defense. Polyphenols, plant food bioactives, exert antiviral properties, which is partially due to their capacity to modulate the expression of miRNAs. The objective of this work was to assess if polyphenols can play a role in prevention of SARS-CoV-2 associated complications by modulating the expression of host miRNAs. To test this hypothesis, we performed literature search to identify miRNAs that could bind SARS-CoV-2 RNA as well as miRNAs which expression can be modulated by polyphenols in lung, type 2 pneumocytes or endothelial cells. We identified over 600 miRNAs that have capacity to bind viral RNA and 125 miRNAs which expression can be modulated by polyphenols in the cells of interest. We identified that there are 17 miRNAs with both the capacity to bind viral RNA and which expression can be modulated by polyphenols. Some of these miRNAs have been identified as having antiviral properties or can target genes involved in regulation of processes of viral replication, apoptosis or viral infection. Taken together this analysis suggests that polyphenols could modulate expression of miRNAs in alveolar and endothelial cells and exert antiviral capacity.

Marcus Thieme, Hans Krankenberg, Tom Schilling, Stefan Betge, Grigorios Korosoglou, Christos Rammos, Markus Vosseler, Christine Espinola-Klein, Britta Heilmeier, Oliver J. Müller, Ralf Langhoff, Nasser Malyar, Erwin Blessing, Lutz Caspary, Birgit Linnemann, Christian Heiss, Wulf Ito, (2023)Endovascular interventions in outpatient care: Statement paper of the German Society of Angiology (DGA)-Society for Vascular Medicine e.V., In: Hogrefe Vasa52(3)pp. 141-146 Hogrefe

Endovascular arterial revascularisations for the treatment of symptomatic peripheral arterial disease are constantly increasing in importance and number due to the changing age structure and high numbers of comorbidities in the German population. Patients with peripheral artery disease are often at increased risk for peri- and post-procedural complications including severe cardiovascular events. Due to limited financial and human resources and considerable risks of hospitalization, endovascular interventions that were previously reserved for hospitalized patients are now progressively considered to be performed as day case procedures. More than one third of these procedures are performed in Germany by internists with a specialization in angiology. In the current position paper the German Society of Angiology endorsed by the European Society of Vascular Medicine, summarizes the requirements and risk factors to be considered for the planning, safe performance and post procedural care of endovascular revascularizations in outpatients. The performance of endovascular procedures for peripheral artery disease both in hospitalised and outpatients should be accompanied by a mandatory quality assurance process that should not only capture procedural data, but also require documentation of complications and longterm outcome.

Simon De Lusignan, F. D. Richard Hobbs, Harshana Liyanage, Julian Sherlock, Filipa Ferreira, Manasa Tripathy, Christian Heiss, Michael D. Feher, Mark P. Joy (2022)Long term follow up of direct oral anticoagulants and warfarin therapy on stroke, with all-cause mortality as a competing risk, in people with atrial fibrillation: Sentinel network database study, In: PloS one17(9)e0265998 Public Library of Science

Background We investigated differences in risk of stroke, with all-cause mortality as a competing risk, in people newly diagnosed with atrial fibrillation (AF) who were commenced on either direct oral anticoagulants (DOACs) or warfarin treatment. Methods and results We conducted a retrospective cohort study of the Oxford Royal College of General Practitioners (RCGP) Research and Surveillance Centre (RSC) database (a network of 500 English general practices). We compared long term exposure to DOAC (n = 5,168) and warfarin (n = 7,451) in new cases of AF not previously treated with oral anticoagulants. Analyses included: survival analysis, estimating cause specific hazard ratios (CSHR), Fine-Gray analysis for factors affecting cumulative incidence of events occurring over time and a cumulative risk regression with time varying effects.We found no difference in CSHR between stroke 1.08 (0.72–1.63, p = 0.69) and all-cause mortality 0.93 (0.81–1.08, p = 0.37), or between the anticoagulant groups. Fine-Gray analysis produced similar results 1.07 (0.71–1.6 p = 0.75) for stroke and 0.93 (0.8–1.07, p = 0.3) mortality. The cumulative risk of mortality with DOAC was significantly elevated in early follow-up (67 days), with cumulative risk decreasing until 1,537 days and all-cause mortality risk significantly decreased coefficient estimate:: -0.23 (-0.38–0.01, p = 0.001); which persisted over seven years of follow-up. Conclusions In this large, contemporary, real world primary care study with longer follow-up, we found no overall difference in the hazard of stroke between warfarin and DOAC treatment for AF. However, there was a significant time-varying effect between anti-coagulant regimen on all-cause mortality, with DOACs showing better survival. This is a key methodological observation for future follow-up studies, and reassuring for patients and health care professionals for longer duration of therapy

Alexander Rodway, Lydia Hanna, Jenny Harris, Rachael Jarrett, Charlotte Allen, Felipe Pazos Casal, Benjamin Field, Martin Brunel Whyte, Nikolaos Ntagiantas, Ivan Walton, Ajay Pankhania, Simon Skene, Gary D. Maytham, Christian Heiss (2024)Prognostic and predictive value of ultrasound-based estimated ankle brachial pressure index at early follow-up after endovascular revascularization of chronic limb-threatening ischaemia: a prospective, single-centre, service evaluation, In: EClinicalMedicine68ARTICLES| VOLUME 68, 102410, FEBRUARY 2024 Elsevier

Background Ankle brachial pressure index can be estimated (eABPI) using cuffless ankle Doppler ultrasound. We evaluated the prognostic value of eABPI measured during pre- and post-procedural ultrasound exams to predict the clinical outcome after endovascular revascularisations. Methods In this prospective, single-centre, service evaluation, consecutive patients with symptomatic peripheral artery disease undergoing lower limb endovascular revascularisations between July, 26 2018 and January, 13 2022 at Surrey and Sussex Healthcare NHS Trust (Redhill, UK) were analysed. eABPI was determined using the higher acceleration index measured with angle-corrected duplex ultrasound in ankle arteries before and ≤1 month post-procedure. Clinical outcomes (mortality, major amputations, amputation-free survival [AFS], clinically driven target lesion revascularization [cdTLR], major adverse limb events [MALE; cdTLR and major amputation], wound healing) were assessed over 1 year. Findings Of 246 patients treated, for 219 patients (median 75 [IQR 66–83] years) pre- and post-procedural eABPI (0.50 [0.33–0.59] and 0.90 [0.69–1.0], p < 0.0001) were available, respectively. In n = 199 patients with chronic limb-threatening ischaemia (CLTI) Kaplan–Meier survival analyses showed that higher post-procedural, but not pre-procedural, eABPI was associated with favourable AFS, MALE, cdTLR, and wound healing. This was confirmed in Cox regression analysis and remained significant with adjustment for pre-procedural eABPI, age, sex, co-morbidities, treated levels, wound score, and foot infection. Whereas all clinical outcomes, except for survival, were significantly better at ≥0.7 vs

Alexander Rodway, Darren Cheal, Charlotte Allan, Felipe Pazos-Casal, Lydia Hanna, Benjamin Field, Ajay Pankhania, Philip James Aston, Simon Skene, Gary D. Maytham, Christian Heiss (2022)Ankle Doppler for Cuffless Ankle Brachial Index Estimation and Peripheral Artery Disease Diagnosis Independent of Diabetes, In: Journal of clinical medicine12(1)97

Ankle brachial pressure index (ABPI) is the first-line test to diagnose peripheral artery disease (PAD). Its adoption in clinical practice is poor and its validity, particularly in diabetes, is limited. We hypothesised that ABPI can be accurately and precisely estimated based on cuffless Doppler waveforms. Retrospective analysis of standard ABPI and handheld Doppler waveform characteristics (n = 200). Prospective analysis of angle-corrected Doppler acceleration index (AccI, n = 148) and standard ABPI with testing of performance to diagnose PAD as assessed with imaging reference standards in consecutive patients. The highest AccI from handheld Doppler at ankle arteries was significantly logarithmically associated with the highest standard ABPI (E[y] = 0.32 ln [1.71 ∗ x + 1], p < 0.001, R2 = 0.68, n = 100 limbs). Estimated ABPI (eABPI) based on AccI closely resembled ABPI (r = 0.81, p < 0.001, average deviation −0.01 ± 0.13 [SD], n = 100 limbs). AccI from angle-corrected Doppler in patients without overt media sclerosis (ABPI ≤ 1.1) improved ABPI prediction (E[y] = 0.297 ∗ ln[0.039 ∗ x + 1], R2 = 0.92, p = 0.006, average deviation 0.00 ± 0.08, n = 100). In a population (n = 148 limbs) including diabetes (56%), chronic limb-threatening ischaemia (51%) and media sclerosis (32%), receiver operating characteristics analysis of (angle-corrected) eABPI performed significantly better than standard ABPI to diagnose PAD defined by ultrasound (ROC AUC = 0.99 ± 0.01, p < 0.001; sensitivity: 97%, specificity: 96%) at the ≤0.9 cut-off. This was confirmed with CT angiography (ROC AUC = 0.98, p < 0.001, sensitivity: 97%, specificity: 100%) and was independent of the presence of diabetes (p = 0.608). ABPI can be estimated based on ankle Doppler AccI without compression, and eABPI performs better than standard ABPI to diagnose PAD independent of diabetes. eABPI has the potential to be included as a standard component of lower extremity ultrasound.

Martin B. Whyte, Prashanth Vas, Christian Heiss, Michael D. Feher (2020)The contribution of diabetic micro-angiopathy to adverse outcomes in COVID-19, In: Diabetes Research and Clinical Practice164108217 Elsevier

Increasing evidence points to endothelial cell dysfunction as a key pathophysiological factor in severe coronavirus disease-19 (COVID-19), manifested by platelet aggregation, microthrombi and altered vasomotor tone. This may be driven by direct endothelial cell entry by the virus, or indirectly by activated inflammatory cascade. Major risk groups identified for adverse outcomes in COVID-19 are diabetes, and those from the Black, Asian and ethnic minority (BAME) populations. Hyperglycaemia (expressed as glycated haemoglobin or mean hospital glucose) correlates with worse outcomes in COVID-19. It is not known whether hyperglycaemia is causative or is a surrogate marker - persistent hyperglycaemia is well known as an aetiological agent in microangiopathy. In this article, we propose that pre-existing endothelial dysfunction of microangiopathy, more commonly evident in diabetes and BAME groups, makes an individual vulnerable to the subsequent ‘endothelitis’ of COVID-19 infection.

Christian Heiss (2023)Peripheral arterial disease and the cardiometabolic syndrome: assessment and management, In: Cardiovascular Endocrinology & Metabolismpp. 469-489 Elsevier Inc

The burden of peripheral arterial disease (PAD) is steadily increasing worldwide and smoking, diabetes, hypertension, and hypercholesterolemia are major risk factors. While it was estimated that in 2010 202 million people lived with PAD, this number increased to 237 million in 2015. In parallel, the number of people with diabetes is increasing, which was at 422 million in 2014 and is estimated increase to 578 million by 2030 according to the World Health Organization. It is likely that the increase in PAD is driven in part by the global diabetes pandemic and also by aging populations. The prevalence of PAD is twice as high in diabetic versus nondiabetic populations and up to 74% of patients with lower limb amputations have been diagnosed with diabetes. Overall, patients with concomitant diabetes and PAD exhibit worse outcomes regarding perioperative complications, amputation rate, and mortality rate when compared to nondiabetic patients. However, PAD is often underdiagnosed and undertreated. The best management of patients with PAD entails early and intensive treatment of both (cardiometabolic) risk factors and limb-specific symptoms, including revascularization, wound care, and improvement of patency after revascularization. It includes optimal pharmacological therapy as well as nonpharmacological measures such as smoking cessation, healthy diet, weight loss, and regular physical exercise.

CHRISTIAN HEISS, Ana Rodriguez-Mateos, MARIAM BAPIR, Simon S. SKENE, H Sies, MALTE KELM (2022)Flow-mediated dilation reference values for evaluation of endothelial function and cardiovascular health, In: Cardiovascular research OUP

Aims: Endothelial function is essential for cardiovascular health, and flow-mediated dilation (FMD) is an established technique to measure it. This paper is to assess FMD values in apparently healthy individuals and provide reference values to facilitate wider clinical use.Methods and Results: In 1,579 apparently healthy individuals (aged 18-76), fasted FMD values (data from 44 studies, 6 institutions, 22 operators) were normally distributed and inversely univariately correlated with age, body-mass-index, glucose, cholesterol, blood pressure, and brachial artery diameter. Significant multivariate predictors of FMD were age (-0.4%/decade), BMI (0.04%/kg/m2), smoking (-0.7%), and brachial artery diameter (-0.44%/mm) that together explained 19% of the variability independent of operator, institution or ultrasound machine. Individuals in the high FMD tertile (>6.8%) were younger, had smaller brachial artery diameter, lower blood pressure and cholesterol. In individuals with low- and intermediate fatal cardiovascular risk (SCORE), 26% and 53% of individuals, respectively, had FMD values in the low tertile (<5.4%). After adding data from 385 patients with stable coronary artery disease (CAD), ROC analysis (c=0.841, p<0.001) showed that FMD of >6.5% excluded CAD (95% sensitivity; 60% specificity) and FMD <3.1% excluded 95% healthy individuals (95% specificity, 31% sensitivity). A meta-analysis and meta-regression of 82 clinical trials (11 countries, n=3,509) using similar FMD methodology showed that despite considerable heterogeneity (I2=0.97) FMD in healthy individuals was on average 6.4% (95%CI: 6.2%, 6.7%) with no significant differences between countries but a significant age-dependent decline (-0.3%/decade, R2=0.13).Conclusions: We provide an age-adapted frame of FMD reference intervals in apparently healthy individuals for use as a biomarker of CV health. As the degree of vascular endothelial function integrates environmental and genetic factors with classical CV risk factors, FMD may more comprehensively classify individuals with and without standard modifiable cardiovascular risk factors and serve as a target for cardiovascular prevention.

Bernd Krabbe, Christine Espinola-Klein, Nasser Malyar, Marianne Brodmann, Lucia Mazzolai, Jill J F Belch, Oliver J Müller, Christian Heiss (2023)Health effects of e-cigarettes and their use for smoking cessation from a vascular perspective: A consensus statement of the German Society of Vascular Medicine endorsed by the European Society of Vascular Medicine, In: VASA52(2)pp. 81-85 Hogrefe

Tobacco consumption is one of the most important risk factors for cardiovascular disease. Despite all efforts to curb any form of smoking, the number of e-cigarette users is still rising more than tabacco smoking decreases. E-cigarettes are often advertised as less harmful than regular cigarettes and helpful for smoking cessation. But e-cigarettes are not risk-free and their use causes vascular damage. There is concern about long-term health risks of e-cigarettes or when non-smokers use them as first nicotine contact. Furthermore, their use for smoking cessation is discussed controversially. To optimize treatment and medical counselling of current smokers and e-cigarette users, we present an evidence-based overview of the most important issues of e-cigarette use from a vascular medicine point of view. The key messages are presented as a position statement of the German Society of Vascular Medicine and endorsed by the European Society of Vascular Medicine.

Peijun Gong, Christian Heiss, Danuta Sampson, Qiang Wang, Zhihong Yuan, David Sampson (2020)Detection of localized pulsatile motion in cutaneous microcirculation by speckle decorrelation optical coherence tomography angiography, In: Journal of Biomedical Optics25(9)095004 Society of Photo-optical Instrumentation Engineers

Significance: Pulsatility is a vital characteristic of the cardiovascular system. Characterization of the pulsatility pattern locally in the peripheral microvasculature is currently not readily available and would provide an additional source of information which may prove important in understanding the pathophysiology of arterial stiffening, vascular ageing, and their linkage with cardiovascular disease development. Aim: We aim to confirm the suitability of speckle decorrelation optical coherence tomography angiography (OCTA) under various non-contact/contact scanning protocols for the visualization of pulsatility patterns in vessel-free tissue and in the microvasculature of peripheral human skin. Results: Results from 5 healthy subjects show distinct pulsatile patterns both in vessel-free tissue with either non-contact or contact imaging and in individual microvessels with contact imaging; respectively, likely caused by the pulsatile pressure and pulsatile blood flow. The pulse rates show good agreement with those from pulse oximetry, confirming that the pulsatile signatures reflect pulsatile hemodynamics. Conclusions: This study demonstrates the potential of speckle decorrelation OCTA for measuring localized peripheral cutaneous pulsatility and defines scanning protocols necessary to undertake such measurements. Non-contact imaging should be used for the study of pulsatility in vessel-free tissue and contact imaging with strong mechanical coupling in individual microvessels. Further studies of microcirculation based upon this method and protocols are warranted.

Dragan Milenkovic, Ana Rodriguez-Mateos, Margarete Lucosz, Geoffrey Istas, Ken Declerck, Roberto Sansone, René Deenen, Karl Köhrer, Karla Fabiola Corral-Jara, Joachim Altschmied, Judith Haendeler, Malte Kelme, Wim Vanden Berghe, Christian Heiss (2022)Flavanol Consumption in Healthy Men Preserves Integrity of Immunological-Endothelial Barrier Cell Functions: Nutri(epi)genomic Analysis, In: Molecular Nutrition & Food Research2100991 Wiley

Scope While cocoa flavanol (CF) consumption improves cardiovascular risk biomarkers, molecular mechanisms underlying their protective effects are not understood. Objective To investigate nutri(epi)genomic effects of CF and identify regulatory networks potential mediating vascular health benefits. Methods and Results Twenty healthy middle-aged men consume CF (bi-daily 450 mg) or control drinks for 1 month. Microarray analysis identifies 2235 differentially expressed genes (DEG) involved in processes regulating immune response, cell adhesion, or cytoskeleton organization. Distinct patterns of DEG correlate with CF-related changes in endothelial function, arterial stiffness, and blood pressure. DEG profile negatively correlates with expression profiles of cardiovascular disease patients. CF modulated DNA methylation profile of genes implicates in cell adhesion, actin cytoskeleton organization, or cell signaling. In silico docking analyses indicate that CF metabolites have the potential of binding to cell signaling proteins and transcription factors. Incubation of plasma obtained after CF consumption decrease monocyte to endothelial adhesion and dose-dependently increase nitric oxide-dependent chemotaxis of circulating angiogenic cells further validating the biological functions of CF metabolites. Conclusion In healthy humans, CF consumption may mediate vascular protective effects by modulating gene expression and DNA methylation towards a cardiovascular protective effect, in agreement with clinical results, by preserving integrity of immunological-endothelial barrier functions.

BERNARDO MEZA TORRES, S Cunningham, CHRISTIAN HEISS, Mark Joy, Michael D. Feher, GP Leese, SIMON DE LUSIGNAN, F Carinci (2022)Adherence to General Diabetes and Foot Care Processes, with Prompt Referral, Are Associated with Amputation-Free Survival in People with Type 2 Diabetes and Foot Ulcers: A Scottish National Registry Analysis, In: Journal of diabetes research20227414258

Aims. To compare different packages of care across care providers in Scotland on foot-related outcomes. Methods. A retrospective cohort study with primary and secondary care electronic health records from the Scottish Diabetes Registry, including 6,845 people with type 2 diabetes and a first foot ulcer occurring between 2013 and 2017. We assessed the association between exposure to care processes and major lower extremity amputation and death. Proportional hazards were used for time-to-event univariate and multivariate analyses, adjusting for case-mix characteristics and care processes. Results were expressed in terms of hazard ratios with 95% confidence intervals. Results. 2,243 (32.7%) subjects had a major amputation or death. Exposure to all nine care processes at all ages ( HR = 0.63 ; 95% CI: 0.58-0.69; p < .001 ) and higher foot care attendance in people aged >70 years ( HR = 0.88 ; 0.78-0.99; p = .03 ) were associated with longer major amputation-free survival. Waiting time ≥ 12 weeks between ulceration and clinic attendance was associated with worse outcomes ( HR = 1.59 ; 1.37-1.84; p < .001 ). In people > 70 years, minor amputations were associated with improved major amputation-free survival ( HR = 0.69 ; 0.52-0.92; p = .01 ). Conclusions. Strict adherence to a standardised package of general diabetes care before foot ulceration, timely foot care after ulceration, and specific treatment pathways were associated with longer major amputation-free survival among a large cohort of people with type 2 diabetes in Scotland, with a larger impact on older age groups.

CHRISTIAN HEISS, Ana Rodriguez-Mateos (2021)Experimental Evidence that (-)-Epicatechin and Anthocyanins Modulate Glucagon-Like Peptide-1 Metabolism: Relevant for Humans?, In: Journal of Nutrition Oxford University Press

Flavanols, in particular (-)-epicatechin (EC) and anthocyanins (AC) are among the most abundant plant food bioactives present in the diet. Both epidemiological and clinical dietary intervention trials support their cardiometabolic health benefits.(1-3) Intervention trials have shown consistent and promising effects upon their consumption on biomarkers of human cardiometabolic health including improvements in endothelial function, blood pressure, blood lipids and glucose metabolism in healthy, at risk and diseased people. However, the mechanisms of action are still not entirely understood. In a paper published in this issue of The Journal of Nutrition, Cremonini et al. (4) demonstrate in mice and GLUTag cells, a model of enteroendocrine L cells, how EC, different ACs and AC metabolites increase glucagon-like peptide-1 (GLP-1) by modulation of its metabolism.

Luc Bergougnan, Grit Andersen, Leona Plum-Mörschel, Maria Francesca Evaristi, Bruno Poirier, Agnes Tardat, Marcel Ermer, Theresa Herbrand, Jorge Arrubla, Hans Veit Coester, Roberto Sansone, Christian Heiss, Olivier Vitse, Fabrice Hurbin, Rania Boiron, Xavier Benain, David Radzik, Philip Janiak, Anthony J Muslin, Lionel Hovsepian, Stephane Kirkesseli, Paul Deutsch, Ashfaq A Parkar (2020)Endothelial-protective effects of a G-protein-biased sphingosine-1 phosphate receptor-1 agonist, SAR247799, in type-2 diabetes rats and a randomized placebo-controlled patient trial, In: British journal of clinical pharmacologypp. 1-18

AIMSSAR247799 is a G-protein-biased sphingosine-1 phosphate receptor-1 (S1P1 ) agonist designed to activate endothelial S1P1 and provide endothelial-protective properties, while limiting S1P1 desensitization and consequent lymphocyte-count reduction associated with higher doses. The aim was to show whether S1P1 activation can promote endothelial effects in patients and, if so, select SAR247799 doses for further clinical investigation. METHODSType-2 diabetes patients, enriched for endothelial dysfunction (flow-mediated dilation, FMD

Christoph Kalka, Denise Surberg, Iris Baumgartner, Nicolas Diehm, CHRISTIAN HEISS (2021)Low carotid intima media thickness excludes lower limb peripheral artery disease, In: VASA - European Journal of Vascular Medicine Hogrefe
Lucas Busch, Manuel Stern, René M'Pembele, Lisa Dannenberg, Philipp Mourikis, Michael Gröne, Göksen Özaslan, Yvonne Heinen, Christian Heiss, Roberto Sansone, Ragnar Huhn, Malte Kelm, Amin Polzin (2021)Impact of high on-treatment platelet reactivity after angioplasty in patients with critical limb ischemia, In: Vascular Pharmacology106925 Elsevier

Objectives Dual antiplatelet therapy (DAPT) with aspirin and clopidogrel is standard of care in patients with peripheral artery disease (PAD) after percutaneous transluminal angioplasty (PTA). However, high on treatment platelet reactivity (HTPR) to DAPT is frequent and associated with major adverse limb events (MALE) in PAD patients. Nevertheless, association of MALE and HTPR in patients with critical limb ischemia (CLI) is not known. Moreover, comorbidities might confound response to antiplatelet medication further. Hence, in this trial we analyzed pharmacodynamic responses to DAPT and clinical events in CLI patients post PTA. Methods In this prospective single center pilot analysis, we included 71 CLI patients. Patients received DAPT after PTA. Antiplatelet effect were measured by light transmission aggregometry (LTA) and vasodilator-stimulated protein phosphorylation assay (VASP). MALE, major adverse cardiac and cerebrovascular events (MACCE) and BARC bleeding within 12 months follow-up were assessed. Results Mean age of patients was 73.37 ± 7.36 years and 47 (66.2%) were male. Overall HTPR appeared in 46 patients (64.8%). MALE and MACCE showed no differences between patients with and patients without HTPR. However, bleeding was higher in patients with sufficient pharmacodynamic response to DAPT (Bleeding - HTPR: 13.4% vs. no HTPR: 36.0%; log-rank HR: 0.32; 95% CI 0.1079 to 0.9396 p = 0.0217). This finding remained robust in multivariate analysis. Conclusion HTPR to DAPT is frequent in CLI patients. However, bleeding was higher in patients with sufficient response to DAPT. Ischemic events did not differ. Hence, CLI patients might benefit from an alternative antithrombotic approach.

Evangelos Dimakakos, Georgia Gomatou, Mariella Catalano, Dan-Mircea Olinic, Alex C Spyropoulos, Anna Falanga, Anthony Maraveyas, Aaron Liew, Sam Schulman, Jill Belch, Grigorios Gerotziafas, Peter Marschang, Benilde Cosmi, Jonas Spaak, Konstantinos Syrigos, Christian Heiss (2022)Thromboembolic Disease in Patients With Cancer and COVID-19: Risk Factors, Prevention and Practical Thromboprophylaxis Recommendations–State-of-the-Art, In: Anticancer research42(7)3261pp. 3261-3274

Cancer and COVID-19 are both well-established risk factors predisposing to thrombosis. Both disease entities are correlated with increased incidence of venous thrombotic events through multifaceted pathogenic mechanisms involving the interaction of cancer cells or SARS-CoV2 on the one hand and the coagulation system and endothelial cells on the other hand. Thromboprophylaxis is recommended for hospitalized patients with active cancer and high-risk outpatients with cancer receiving anticancer treatment. Universal thromboprophylaxis with a high prophylactic dose of low molecular weight heparins (LMWH) or therapeutic dose in select patients, is currentlyindicated for hospitalized patients with COVID-19. Also, prophylactic anticoagulation is recommended for outpatients with COVID-19 at high risk for thrombosis or disease worsening. However, whether there is an additive risk of thrombosis when a patient with cancer is infected with SARS-CoV2 remains unclear In the current review, we summarize and critically discuss the literature regarding the epidemiology of thrombotic events in patients with cancer and concomitant COVID-19, the thrombotic risk assessment, and the recommendations on thromboprophylaxis for this subgroup of patients. Current data do not support an additive thrombotic risk for patients with cancer and COVID-19. Of note, patients with cancer have less access to intensive care unit care, a setting associated with high thrombotic risk. Based on current evidence, patients with cancer and COVID-19 should be assessed with well-established risk assessment models for medically ill patients and receive thromboprophylaxis, preferentially with LMWH, according to existing recommendations. Prospective trials on well-characterized populations do not exist.

Lucas Busch, Yvonne Heinen, Manuel Stern, Georg Wolff, Goksen Ozaslan, Konstantina Tzetou, Roberto Sansone, Christian Heiss, Malte Kelm (2021)Angioplasty of flow-limiting stenosis reduces aortic and brachial blood pressure in patients with peripheral artery disease, In: Journal of the American Heart Association10(14)019724pp. e019724-e019724 Wiley

BACKGROUND: Arterial hypertension affects cardiovascular outcome in patients with peripheral artery disease (PAD). We hypothesized that angioplasty of peripheral arterial stenoses decreases aortic (aBP) and brachial blood pressure (bBP). METHODS AND RESULTS: In an index cohort (n=30), we simultaneously measured aBP, bBP, augmentation index (AIx), and aortic pulse wave velocity (PWV) before and after angioplasty of the iliac and femoropopliteal arteries; diagnostic angiography served as a control. In an all-comer registry cohort (n=381), we prospectively measured bBP in patients scheduled for angioplasty of the iliac, femoral, and crural arteries or diagnostic angiography. Systolic aBP decreased after iliac (Delta-25 mmHg; 95% CI, -30 to -20; P

J. Schremmer, L. Busch, S. Baasen, Y. Heinen, R. Sansone, C. Heiss, Christian Heiss, M. Kelm, M. Stern (2023)Chronic PCSK9 inhibitor therapy leads to sustained improvements in endothelial function, arterial stiffness, and microvascular function, In: Microvascular Research148104513 Elsevier

Background Proprotein convertase subtilisin/kexin type 9 inhibitors (PCSK9i) effectively decrease low-density lipoprotein cholesterol (LDL-C) and reduce cardiovascular events in patients at very high cardiovascular risk. Recent short-term studies suggest a partially LDL-C independent beneficial effect of PCSK9 inhibitor (PCSK9i) therapy on endothelial function and arterial stiffness, whereas it is unknown if this effect persists and what the effect is on microcirculation. Objective To investigate the effects of PCSK9i therapy on vascular parameters beyond its lipid lowering effect. Methods In this prospective trial, 32 patients at very high cardiovascular risk and indication for PCSK9i therapy were included. Measurements were performed at baseline and after 6 months of PCSK9i treatment. Endothelial function was assessed as flow-mediated dilation (FMD). Arterial stiffness was measured as pulse wave velocity (PWV) and aortic augmentation index (AIx). Peripheral tissue oxygenation (StO2) as a marker of microvascular function was assessed at the distal extremities using near-infrared spectroscopy camera. Results Six months of PCSK9i therapy decreased LDL-C levels from 141 ± 54 to 60 ± 30 mg/dl (−56 ± 21 %, p 

Carina Henning, Anna Branopolskia, Paula Follert, Oksana Lewandowska, Aysel Ayhan, Marcel Benkhoff, Ulrich Flögel, MALTE KELM, CHRISTIAN HEISS, Eckhard Lammert (2020)Endothelial β1 Integrin-Mediated Adaptation to Myocardial Ischemia, In: Thrombosis and Haemostasis

Background: Short episodes of myocardial ischemia can protect from myocardial infarction. However, the role of endothelial β1 integrin in these cardioprotective ischemic events is largely unknown. Objective: In this study we investigated whether endothelial β1 integrin is required for cardiac adaptation to ischemia and protection from myocardial infarction. Methods: Here we introduced transient and permanent left anterior descending artery (LAD) occlusions in mice. We inhibited β1 integrin by intravenous injection of function-blocking antibodies and tamoxifen-induced endothelial cell (EC)-specific deletion of Itgb1. Furthermore, human ITGB1 was silenced in primary human coronary artery ECs using siRNA. We analyzed the numbers of proliferating ECs and arteries by immunohistochemistry, determined infarct size by magnetic resonance imaging (MRI) and TTC staining, and analyzed cardiac function by MRI and echocardiography. Results: Transient LAD occlusions were found to increase EC proliferation and arteriole formation in the entire myocardium. These effects required β1 integrin on ECs, except for arteriole formation in the ischemic part of the myocardium. Furthermore, this integrin subunit was also relevant for basal and mechanically-induced proliferation of human coronary artery ECs. Notably, β1 integrin was needed for cardioprotection induced by transient LAD occlusions, and the absence of endothelial β1 integrin resulted in impaired growth of blood vessels into the infarcted myocardium and reduced cardiac function after permanent LAD occlusion. CONCLUSIONS: We showed that endothelial β1 integrin is required for adaptation of the heart to cardiac ischemia and protection from myocardial infarction.

Alexander D. Rodway, Jenny Harris, Lydia Hanna, Charlotte Allan, Felipe Pazos Casal, Ciara Ciara Giltinan, Ali Dehghan-Nayeri, Andre Santos, Martin B. Whyte, Nikolaos Ntagiantas, Ivan Walton, Richard Brown, Simon Skene, Ajay Pankhania, Benjamin C. T. Field, Gary D. Maytham, Christian Heiss (2023)Understanding the Impact of COVID-19 on Angioplasty Service and Outcome of Patients Treated for Chronic Limb-Threatening Ischaemia: A Single-Centre Retrospective Cohort Study, In: Biomedicines11(7)2034 MDPI

We evaluated the impact of COVID-19 restriction on the angioplasty service and outcome of chronic limb threatening ischaemia (CLTI) patients undergoing lower limb angioplasty in a UK secondary care setting. Consecutive patients were analysed retrospectively. Pre-COVID-19 (08/2018-02/2020), 106 CLTI-patients (91% Fontaine 4; 60% diabetes mellitus) and during COVID-19 (03/2020-07/2021) 94 patients were treated (86% Fontaine 4; 66% diabetes mellitus). While the average monthly number of patients treated did not change, the proportion of day cases significantly increased (53% to 80%) and hospitalised patients decreased. Patients treated in £14/5 days after referral significantly increased to 64/63%. Kaplan-Meier survival analysis (30-day/1-year) showed that neither wound healing nor mortality were significantly changed during COVID-19. In day cases, 1-year but not 30-day major amputations significantly increased, and clinically driven target lesion revascularisation decreased during COVID-19. 1-year mortality was significantly worse in hospitalised as compared to day cases (14% vs 43%) at similar wound healing rates (83% vs 84%). The most frequent known-causes-of-death were infectious disease (64%) and cardiovascular (21%) was less frequent. Despite COVID-19 restriction a safe and effective angioplasty service was maintained while shortening waiting times. Very high mortality rates in hospitalised patients may indicate that CLTI patients need to be referred and treated more aggressively earlier.

Yong Li, Yifan Xu, Melanie Le Sayec, Haonan Wu, Paola Dazzan, Chiara Nosarti, Christian Heiss, Rachel Gibson, Ana Rodriguez-Mateos (2023)(Poly)phenol intake, plant-rich dietary patterns and cardiometabolic health: a cross-sectional study, In: Food & Function Royal Society of Chemistry

Diet is an important modifiable risk factor for cardiometabolic diseases. Plant foods contain a complex mixture of nutrients and bioactive compounds such as (poly)phenols. Plant-rich dietary patterns have been associated with reduced cardiometabolic risk in epidemiological studies. However, studies have not fully considered (poly)phenols as a mediating factor in the relationship. A cross-sectional analysis was conducted in 525 healthy participants, aged 41.6 ± 18.3 years. Volunteers completed the validated European Prospective Investigation into Diet and Cancer (EPIC) Norfolk Food Frequency Questionnaire (FFQ). We investigated the associations between plant-rich dietary patterns, (poly)phenol intake, and cardiometabolic health. Positive associations were found between (poly)phenols and higher adherence to dietary scores, except for the unhealthy Plant-based Diet Index (uPDI), which was negatively associated with (poly)phenol intake. Correlations were significant for healthy PDI (hPDI), with positive associations with proanthocyanidins (r = 0.39, p < 0.01) and flavonols (r = 0.37, p < 0.01). Among dietary scores, Dietary Approaches to Stop Hypertension (DASH) showed negative associations with diastolic blood pressure (DBP), total cholesterol (TC), low-density lipoproteins cholesterol (LDL-C), and non-high-density lipoproteins cholesterol (Non-HDL-C) (stdBeta -0.12 to -0.10, p < 0.05). Mediterranean-DASH Intervention for Neurodegenerative Delay (MIND) score was positively associated with flow-mediated dilation (FMD, stdBeta = 0.10, p = 0.02) and negatively associated with 10-year Atherosclerotic Cardiovascular Disease (ASCVD) risk score (stdBeta = -0.12, p = 0.01). Higher intake of flavonoids, flavan-3-ols, flavan-3-ol monomers, theaflavins, and hydroxybenzoic acids (stdBeta: -0.31 to -0.29, p = 0.02) also showed a negative association with a 10-year ASCVD risk score. Flavanones showed significant associations with cardiometabolic markers such as fasting plasma glucose (FPG) (stdBeta = -0.11, p = 0.04), TC (stdBeta = -0.13, p = 0.03), and the Homeostasis Model Assessment (HOMA) of beta cell function (%B) (stdBeta = 0.18, p = 0.04). Flavanone intake was identified as a potential partial mediator in the negative association between TC and plant-rich dietary scores DASH, Original Mediterranean diet scores (O-MED), PDI, and hPDI (proportion mediated = 0.01% to 0.07%, p < 0.05). Higher (poly)phenol intake, particularly flavanone intake, is associated with higher adherence to plant-rich dietary patterns and favourable biomarkers of cardiometabolic risk indicating (poly)phenols may be mediating factors in the beneficial effects.

Ben C. Creagh-Brown, Aikaterini Papadopoulou, Matthew Dickinson, Theophilus L. Samuels, Christian Heiss, Julie Hunt, Lui Forni (2022)Remote Ischaemic Preconditioning in Intra-Abdominal Cancer Surgery (RIPCa): A Pilot Randomised Controlled Trial, In: Journal of Clinical Medicine11(7)1770 MDPI

There is limited evidence on the effect of remote ischaemic preconditioning (RIPC) following non-cardiac surgery. The aim of this study was to investigate the effect of RIPC on morbidity following intra-abdominal cancer surgery. We conducted a double blinded pilot randomised controlled trial that included 47 patients undergoing surgery for gynaecological, pancreatic and colorectal malignancies. The patients were randomized into an intervention (RIPC) or control group. RIPC was provided by intermittent inflations of an upper limb tourniquet. The primary outcome was feasibility of the study, and the main secondary outcome was postoperative morbidity including perioperative troponin change and the urinary biomarkers tissue inhibitor of metalloproteinases-2 and insulin-like growth factor-binding protein 7 (TIMP-2*IGFBP-7). The recruitment target was reached, and the protocol procedures were followed. The intervention group developed fewer surgical complications at 30 days (4.5% vs. 33%), 90 days (9.5% vs. 35%) and 6 months (11% vs. 41%) (adjusted p 0.033, 0.044 and 0.044, respectively). RIPC was a significant independent variable for lower overall postoperative morbidity survey (POMS) score, OR 0.79 (95% CI 0.63 to 0.99) and fewer complications at 6 months including pulmonary OR 0.2 (95% CI 0.03 to 0.92), surgical OR 0.12 (95% CI 0.007 to 0.89) and overall complications, OR 0.18 (95% CI 0.03 to 0.74). There was no difference in perioperative troponin change or TIMP2*IGFBP-7. Our pilot study suggests that RIPC may improve outcomes following intra-abdominal cancer surgery and that a larger trial would be feasible.

Francesca Leo, Thomas Krenz, Georg Wolff, Mathias Weidenbach, Christian Heiss, Malte Kelm, Brant Isakson, Miriam Margherita Cortese-Krott (2020)Assessment of tissue perfusion and vascular function in mice by scanning laser Doppler perfusion imaging, In: Biochemical Pharmacology Elsevier

Post-occlusive reactive hyperemia (PORH) is a key feature of physiological vasomotion to appropriately match the supply/demand ratio of tissues. This adaptive mechanism is severely disturbed in endothelial dysfunction with a reduced flow-mediated dilation (FMD). Reduced PORH and FMD are powerful prognostic risk factors in cardiovascular disease. While these parameters are frequently determined in human beings, comparable methods applicable to mouse models are sparse. We aimed to evaluate the applicability and accuracy of scanning laser Doppler perfusion imaging (LDPI) to measure PORH in the mouse hindlimb. Changes in mean perfusion in response to vasoactive drugs and PORH (assessed by scanning LDPI) were compared with changes in diameter and blood flow in the femoral artery, as assessed by high-resolution ultrasound. We found that the measured LDPI signal significantly correlated with changes of inflow into the femoral artery. Vasodilation induced by administration of nitroglycerine and acetylcholine increased vessel diameter, blood flow and mean perfusion, while vasoconstriction following administration of epinephrine decreased all three parameters. PORH was induced by temporal occlusion of the femoral artery with an external cuff. During occlusion, mean perfusion decreased to a condition of zero-perfusion and release of the cuff induced an immediate increase in blood flow that was followed by femoral artery dilation driving PORH/ perfusion. Surgical removal of the femoral artery decreased mean perfusion to a zero-perfusion level and fully abolished PORH. Importantly, the measurement of the PORH response by scanning LDPI is highly reproducible as determined by repeated measurements and intra/interobserver variation analysis. Last, we found that the PORH response was dependent on nitric oxide synthase and cyclooxygenase and declined with age. Thus, we here provide novel and robust non-invasive methods to serially measure tissue perfusion at baseline and during physiological and pharmacological modulation of vasomotor tone in the hindlimb of mice. The application of these LDPI scanning and ultrasound-based methods may be useful for testing the effects of drugs affecting vasomotor function or future elucidation of mechanisms leading to vasomotor dysfunction in mice in vivo.

Stefan Betge, Christiane Engelbertz, Christine Espinola-Klein, Wulf Ito, Christian Heiss, Britta Heilmeier, Ralf Langhoff, Nasser Malyar (2023)Analysis of endovascular therapy for peripheral arterial disease in all German hospitals, In: VASA - European Journal of Vascular Medicine Hogrefe

Background: The quality of vascular care has significantly improved in part by the expansion of endovascular techniques for the treatment of symptomatic peripheral artery disease (PAD) in recent years. In Germany these are primarily provided by the three disciplines of vascular surgery, angiology, and interventional radiology (IR). However, the relative contribute of angiologists to the total number of cases performed is unknown. Patients and methods: In the present study, we analysed the respective contribution of vascular surgery, angiology, and IR to the delivery of endovascular revascularisations in symptomatic PAD in Germany based on the legally mandatory quality reports representative for the reporting year 2018. Results: Vascular surgery is the most common speciality reporting procedures in German hospitals (n=579; 25.1%), followed by IR (n=264; 11.5%), angiology (n=189; 8.2%) and cardiology (n=17; 0.7%). The combination of vascular surgery and IR was reported in 202 (8.8%), vascular surgery and angiology in 167 (7.2%) and angiology and IR in 65 (2.8%) hospitals, and 63 (2.7%) hospitals reported the combination of all three disciplines. Not every department performed catheter interventions. The analysis of procedures per centre revealed that angiology centres provided the highest numbers for both basic procedures and more complex techniques such as atherectomy, rotational thrombectomy, lithoplasty, selective thrombolysis or the use of re-entry devices. In total, angiology centres provided 24.4% of the total procedures or 23.9% of the so-called basic procedures as a surrogate for patient numbers. Conclusions: While each of the disciplines contribute significantly to the endovascular procedures, angiology centres perform more procedures per centre and more complex procedures than the other disciplines highlighting the important quantitative and qualitative contribution of angiology specialists to the care of vascular patients. The inpatient catheter interventional care of patients with PAD is still too rarely carried out in a multi-disciplinary manner in Germany.

Christian Heiss, Stefano Barco, Christian-Alexander Behrendt, Marianne Brodmann, Eva Freisinger, Sasan Partovi, Christos Rammos, Oliver J. Mueller (2023)The year in vascular medicine: Highlights in Vasa - European Journal of Vascular Medicine 2022, In: VASA52(1)pp. 3-5 HOGREFE AG-HOGREFE AG SUISSE
Irundika H. K. Dias, Ivana Milic, Christian Heiss, Opeyemi S. Ademowo, Maria Cristina Polidori, Andrew Devitt, Helen R. Griffiths (2020)Inflammation, Lipid (Per)oxidation, and Redox Regulation, In: Antioxidants & redox signaling33(3)pp. 166-190 Mary Ann Liebert, Inc

Recent Advances: Inflammation is central to age-related decline in health and exhibits a complex relationship with mitochondrial redox state and metabolic function. Improvements in mass spectrometric methods have led to the identification of families of oxidized phospholipids (OxPLs), cholesterols, and fatty acids that increase during inflammation and which modulate nuclear factor erythroid 2-related factor 2 (Nrf2), peroxisome proliferator-activated receptor gamma (PPAR gamma), activator protein 1 (AP1), and NF-kappa B redox-sensitive transcription factor activity. Critical Issues: The kinetic and spatial resolution of the modified lipidome has profound and sometimes opposing effects on inflammation, promoting initiation at high concentration and resolution at low concentration of OxPLs. Future Directions: There is an emerging opportunity to prevent or delay age-related inflammation and vascular comorbidity through a resolving (oxy)lipidome that is dependent on improving mitochondrial quality control and restoring redox homeostasis.

Joel Constans, Alessandra Bura-Riviere, Adriana Visona, Marianne Brodmann, Pierre Abraham, Dan-Mircea Olinic, Juraj Madaric, Sabine Steiner, Isabelle Quere, Lucia Mazzolai, Jill Belch, Christian Heiss, Zsolt Pecsvarady, Karel Roztocil, Mary-Paula Colgan, Dragan Vasic, Anders Gottsater, Evangelos Dimakakos, Ali Chraim, Pavel Poredos, Patrick H. Carpentier, Jean-Claude Wautrecht, Agata Stanek, Vinco Boc (2019)Urgent need to clarify the definition of chronic critical limb ischemia - a position paper from the European Society for Vascular Medicine, In: VASA48(3)223pp. 223-227 HOGREFE AG-HOGREFE AG SUISSE

Chronic critical lower limb ischemia (CLI) has been defined as ischemia that endangers the leg. An attempt was made to give a precise definition of CLI, based on clinical and hemodynamic data (Second European Consensus). CLI may be easily defined from a clinical point of view as rest pain of the distal foot or gangrene or ulceration. It is probably useful to add leg ulcers of other origin which do not heal because of severe ischemia, and to consider the impact of frailty on adverse outcome. From a hemodynamic viewpoint there is no consensus and most of the existing classifications are not based upon evidence. We should thus propose a definition and then validate it in a prospective cohort in order to define the patients at major risk of amputation, and also to define the categories of patients whose prognosis is improved by revascularisation. From today's available data, it seems clear that the patients with a systolic toe pressure (STP) below 30 mmHg must be revascularised whenever possible. However other patients with clinically suspected CLI and STP above 30 mmHg must be evaluated and treated in specialised vascular units and revascularisation has to be discussed on a case by case basis, taking into account other data such as the WiFi classification for ulcers. In conclusion, many useful but at times contradictory definitions of CLI have been suggested. Only a few have taken into account evidence, and none have been validated prospectively. This paper aims to address this and to give notice that a CLI registry within Europe will be set up to prospectively validate, or not, the previous and suggested definitions of CLI.

Christian Heiss, Alex Pitcher, Jill J.F. Belch, Marco De Carlo, Holger Reinecke, Iris Baumgartner, Lucia Mazzolai, Victor Aboyans (2020)The year in cardiology: aorta and peripheral circulation
The year in cardiology 2019, In: Cardiologia Croatica15(7-8)214pp. 214-227 Hrvatsko kardiološko društvo
Abdullah Ismat, Markus Rupp, Gero Knapp, Christian Heiss, Gabor Szalay, Christoph Biehl (2020)Treatment of proximal fifth metatarsal fractures with an ulna hook plate, In: Foot (Edinburgh, Scotland)42101653pp. 101653-101653

Fractures of the base of the fifth metatarsal bone present one of the commonest fractures of the metatarsal bones. Conventionally intramedullary screws and tension band wiring have been used as internal fixation methods. Lately hook plates have also served as an alternative fixation method. We hereby report on our experience with the hook plate used in treating fractures of the proximal fifth metatarsal. 21 patients treated with the hook plate for proximal fifth metatarsal fractures were assessed clinically and radiologically. Average time to union in primarily treated fractures (n=18) was 7.7 weeks (range 4.5-16 weeks). Average time to return of activities of daily living (ADLs) was 10.3 weeks (range 4.5-37 weeks). The average AOFAS midfoot score was 30.4 preoperatively and 95.2 postoperatively (p

Sameh Attia, Jonas Diefenbach, Daniel Schmermund, Sebastian Boettger, Joern Pons-Kuehnemann, Christine Scheibelhut, Christian Heiss, Hans-Peter Howaldt (2020)Donor-Site Morbidity after Fibula Transplantation in Head and Neck Tumor Patients: A Split-Leg Retrospective Study with Focus on Leg Stability and Quality of Life, In: Cancers12(8)2217pp. 1-23 Mdpi

The free fibula flap has been one of the most important microvascular grafts for orofacial reconstruction for more than 30 years. The complication rates at the donor-site reported in literature are considered to be low, but the published data vary greatly in some cases. In particular, restrictions in the stability and balance of the involved leg and their effects on the quality of life have been described very inconsistently to date. Therefore, this study mainly focuses on the stability and balance of the affected leg in a split-leg design. Between December 2014 and January 2018, out of 119 subjects who underwent mainly jaw ablative tumor surgery and reconstruction using a fibula flap, 68 subjects were examined for donor site morbidity. Besides reporting general types of complications, two specific test procedures were used. The Star Excursion Balance Test (SEBT) as a practical test for ankle function and the Foot and Ankle Disability Index (FADI) as a questionnaire in order to assess quality of life, depending on the lower leg function. SEBT revealed an average of 55.3 cm with the operated leg as the supporting leg, which corresponds to 95.5% of 57.9 cm achieved with the healthy leg as the supporting leg. An average FADI score of 89.4% was recorded. SEBT and FADI seem to be suitable methods of examination for subjects post fibular transplantation and pointed out minimal limitations of the involved legs in comparison to the unaffected legs. These limitations were clinically not relevant and they had minor influence on the subjects' quality of life and their daily activities.

Christoph Biehl, Markus Rupp, Volker Alt, Christian Heiss, Thaqif El Khasswana, Gabor Szalay (2020)Peri-Prosthetic Joint Infection after Finger Joint Arthroplasty, In: Surgical infections21(5)pp. 445-450 Mary Ann Liebert, Inc

Background: Endoprosthetic treatment of finger joints is an established procedure. However, data on peri-prosthetic finger joint infections (PJI) are rare. The goal of this retrospective study was to assess infection rates and treatment outcomes after PJI of the finger joints. Methods: Between 1984 and 2014, 1,195 finger joints (978 metacarpal and 217 proximal interphalangeal [PIP] joints) in 518 patients were treated. A retrospective record analysis was conducted. Besides demographic data, infection rates, types of revision surgery, and treatment outcomes were evaluated. Treatment strategies changed during the treatment period. Routinely assessed patient-reported outcome measures, namely the QuickDASH score, visual analogue scale (VAS), an everyday function score (activities of daily living; ADL), and an adapted Clayton score, were compared. Results: In 36 finger joints of 30 patients, a post-operative peri-prosthetic infection could be identified (3%). Infections occurred on average 3.8 years after arthroplasty. For meta-carpal phalangeal (MCP) joints, the best clinical outcomes could be observed after a two-stage revision procedure (QuickDASH score 86). Arthrodesis performed in a one-stage procedure achieved favorable outcomes in PIP joints (QuickDASH score 89). Re-infection mandating revision surgery occurred in seven joints in five patients (7/36; 19.4%). In 25 patients with 29 finger joints, there was no re-infection and no need for revision. Conclusion: Peri-prosthetic infection of finger joint prostheses occurs in approximately 3% of all cases, which is a higher rate than in the more common hip and knee procedures. For MCP joint revision surgery, a two-stage procedure seems to be the best treatment choice. For PIP joint revision, a single-stage revision with arthrodesis in a functional position achieves a good outcome.

Gero Knapp, Florian Moller, Christian Heiss, Matthias Mulke, Gabor Szalay (2021)Surgical treatment of the ulnar styloid process using an angle-stable hook plate in fractures and symptomatic nonunions, In: Operative Orthopädie und Traumatologie33(5)pp. 430-435 Urban & Vogel

Objective Anatomical reduction of dislocated fractures using an angle-stable hook plate. Surgical revision of symptomatic nonunions with the aim of bone regeneration. Indications Dislocated fractures of the ulnar styloid process with involvement of the ulnar fovea. Combined fractures with instability of the distal radioulnar joint and symptomatic nonunions. Contraindications Undisplaced fractures of the ulnar styloid process and asymptomatic nonunions. Surgical technique Dorsoradial access to the distal ulna between the 6th extensor tendon compartment and the tendon of the flexor carpi ulnaris muscle. Exposition of the fracture/nonunion. In case of nonunions, excision and freshening of the fracture ends. Reduction is carried out using the hooks of the plate, if necessary additional attachment of autologous cancellous bone in case of nonunions. Fixation of the plate over the gliding hole and subsequent filling of the angular stable screw holes. Postoperative management Depending on the accompanying injury, immobilization in a forearm plaster splint for 1-2 weeks. Active movement exercises of the fingers from postoperative day 1, if necessary lymph drainage. After bone development, load build-up under ergotherapy guidance. Results Bony healing was achieved in 100% of our cases. The surgical treatment of symptomatic nonunions as well as dislocated fractures of the ulnar styloid process using an angle-stable hook plate has proven to be successful.

Qusai Alkhasawnah, Sera Elmas, Keywan Sohrabi, Sameh Attia, Sascha Heinemann, Thaqif El Khassawna, Christian Heiss (2021)Confirmation of Calcium Phosphate Cement Biodegradation after Jawbone Augmentation around Dental Implants Using Three-Dimensional Visualization and Segmentation Software, In: Materials14(22)7084 Mdpi

The use of autologous bone graft for oral rehabilitation of bone atrophy is considered the gold standard. However, the available grafts do not allow a fast loading of dental implants, as they require a long healing time before full functionality. Innovative bioactive materials provide an easy-to-use solution to this problem. The current study shows the feasibility of calcium phosphate cement paste (Paste-CPC) in the sinus. Long implants were placed simultaneously with the cement paste, and provisional prosthetics were also mounted in the same sessions. Final prosthetics and the full loading took place within the same week. Furthermore, the study shows for the first time the possibility to monitor not only healing progression using Cone Beam Computer tomography (CBCT) but also material retention, over two years, on a case study example. The segmented images showed a 30% reduction of the cement size and an increased mineralized tissue in the sinus. Mechanical testing was performed qualitatively using reverse torque after insertion and cement solidification to indicate clinical feasibility. Both functional and esthetic satisfaction remain unchanged after one year. This flowable paste encourages the augmentation procedure with less invasive measure through socket of removed implants. However, this limitation can be addressed in future studies.

Ian M. Black, Christian Heiss, Mukesh Jain, Artur Muszynski, Russell W. Carlson, Dean W. Gabriel, Parastoo Azadi (2021)Structure of Lipopolysaccharide from Liberibacter crescens Is Low Molecular Weight and Offers Insight into Candidatus Liberibacter Biology, In: International journal of molecular sciences22(20)11240 Mdpi

Huanglongbing (HLB) disease, also known as citrus greening disease, was first reported in the US in 2005. Since then, the disease has decimated the citrus industry in Florida, resulting in billions of dollars in crop losses and the destruction of thousands of acres of citrus groves. The causative agent of citrus greening disease is the phloem limited pathogen Candidatus Liberibacter asiaticus. As it has not been cultured, very little is known about the structural biology of the organism. Liberibacter are part of the Rhizobiaceae family, which includes nitrogen-fixing symbionts of legumes as well as the Agrobacterium plant pathogens. To better understand the Liberibacter genus, a closely related culturable bacterium (Liberibacter crescens or Lcr) has attracted attention as a model organism for structural and functional genomics of Liberibacters. Given that the structure of lipopolysaccharides (LPS) from Gram-negative bacteria plays a crucial role in mediating host-pathogen interactions, we sought to characterize the LPS from Lcr. We found that the major lipid A component of the LPS consisted of a pentaacylated molecule with a beta-6-GlcN disaccharide backbone lacking phosphate. The polysaccharide portion of the LPS was unusual compared to previously described members of the Rhizobiaceae family in that it contained ribofuranosyl residues. The LPS structure presented here allows us to extrapolate known LPS structure/function relationships to members of the Liberibacter genus which cannot yet be cultured. It also offers insights into the biology of the organism and how they manage to effectively attack citrus trees.

C. Biehl, C. Schaefer, C. Heiss, A. Brobeil, T. Dreyer, S. Gattenloehner, G. Szalay (2020)Neurofibroma in Children hand - Case Report and Literature Review, In: Handchirurgie, Mikrochirurgie, plastische Chirurgie52(1)pp. 29-32 Thieme Medical Publishers

Neurofibromas rarely occur before the age of 7 in children. They are a rarity on the hand, especially if they are accompanied by sensory disturbances and impairment of the gripping function. We report on a 9-year-old girl with symptomatic neurofibroma of the third and fourth ray of the right palm.

Kirsten L Johansen, Pranav S Garimella, Caitlin W Hicks, Philip A Kalra, Dearbhla M Kelly, Sven Martens, Kunihiro Matsushita, Pantelis Sarafidis, Manish M Sood, Charles A Herzog, Michael Cheung, Michel Jadoul, Wolfgang C Winkelmayer, Holger Reinecke, Christian Heiss (2021)Central and peripheral arterial diseases in chronic kidney disease: conclusions from a Kidney Disease: Improving Global Outcomes (KDIGO) Controversies Conference, In: Kidney international100(1)35pp. 35-48

Chronic kidney disease (CKD) affects about 10% of all populations worldwide, with about 2 million people requiring dialysis. Although patients with CKD are at high risk of cardiovascular disease and events, they are often underrepresented or excluded in clinical trials, leading to important knowledge gaps about how to treat these patients. KDIGO (Kidney Disease: Improving Global Outcomes) convened the fourth clinical Controversies Conference on the heart, kidney and vasculature in Dublin, Ireland, in February 2020, entitled Central and Peripheral Arterial Diseases in Chronic Kidney Disease. A global panel of multidisciplinary experts from the fields of nephrology, cardiology, neurology, surgery, radiology, vascular biology, epidemiology, and health economics attended. The objective was to identify key issues related to the optimal detection, management, and treatment of cerebrovascular diseases, central aortic disease, renovascular disease, and peripheral artery disease in the setting of CKD. This report outlines the common pathophysiology of these vascular processes in the setting of CKD, describes best practices for their diagnosis and management, summarizes areas of uncertainty, addresses ongoing controversial issues, and proposes a research agenda to address key gaps in knowledge that, when addressed, could improve patient care and outcomes.

Asif Shajahan, Nitin T. Supekar, Digantkumar Chapla, Christian Heiss, Kelley W. Moremen, Parastoo Azadi (2020)Simplifying Glycan Profiling through a High-Throughput Micropermethylation Strategy, In: SLAS technology25(4)2472630320912929pp. 367-379 Elsevier

Glycoproteins play key roles in various molecular and cellular functions and are among the most difficult to analyze biomolecules on account of their microheterogeneity, non-template-driven synthesis, and low abundances. The stability, serum half-life, immunogenicity, and biological activity of therapeutic glycoproteins, including antibodies, vaccines, and biomarkers, are regulated by their glycosylation profile. Thus, there is increasing demand for the qualitative and quantitative characterization and validation of glycosylation on glycoproteins. One of the most important derivatization processes for the structural characterization of released glycans by mass spectrometry (MS) is permethylation. We have recently developed a permethylation strategy in microscale that allows facile permethylation of glycans and permits the processing of large sample sets in nanogram amounts through high-throughput sample handling. Here, we are reporting the wide potential of micropermethylation-based high-throughput structural analysis of glycans from various sources, including human plasma, mammalian cells, and purified glycoproteins, through an automated tandem electrospray ionization-mass spectrometry (ESI-MSn) platform. The glycans released from the plasma, cells, and glycoproteins are permethylated in microscale in a 96-well plate or microcentrifuge tube and isolated by a C18 tip-based cleanup through a shorter and simple process. We have developed a workflow to accomplish an in-depth automated structural characterization MS program for permethylated N/O-glycans through an automated high-throughput multistage tandem MS acquisition. We have demonstrated the utility of this workflow using the examples of sialic acid linkages and bisecting GlcNAc (N-acetylglucosamine) on the glycans. This approach can automate the high-throughput screening of glycosylation on large sample sets of glycoproteins, including clinical glycan biomarkers and glycoprotein therapeutics.

Joseph Deering, Alexandre Presas, Bryan E.J. Lee, David Valentin, Bosco Yu, Christian Heiss, Kathryn Grandfield, Wolfram A. Bosbach (2020)Response of Saos-2 osteoblast-like cells to kilohertz-resonance excitation in porous metallic scaffolds, In: Journal of the mechanical behavior of biomedical materials106103726pp. 103726-103726 Elsevier Ltd

Post-operative therapy for joint replacement is often performed to optimize bone volume and bone-implant contact. Methods, such as pulsed therapeutic ultrasound, have been shown to be a valuable addition to regular physiotherapy to increase bone regeneration. To evaluate the efficacy of kilohertz-frequency (kHz) resonant stimuli to additively manufactured implant analogues, Saos-2 cells were seeded onto porous stainless steel scaffolds and flat substrates. Resonant frequency modes were mapped in the low kHz range, and cells were subjected to daily stimulus for 10 min at a frequency of 1.278 kHz. kHz-frequency excitation was found to increase normalized alkaline phosphatase production by almost twofold on metallic substrates relative to non-vibrated control scaffolds, while peak velocity influenced alkaline phosphatase production on porous scaffolds but not flat substrates. Total cell proliferation was downregulated by excitation, and all excited samples displayed larger variability. This work indicates that vibration within the range of 0.16–0.48 mm/s may reduce cell proliferation, but favour osteogenic gene expression. This study highlights the potential of using kHz-resonance therapy to mitigate early-onset pore occlusion to achieve uniform osseointegration through porous metallic scaffolds. [Display omitted]

Fabian Hemm, Monika Fijak, Jan Belikan, Marian Kampschulte, Thaqif El Khassawna, Adrian Pilatz, Christian Heiss, Katrin Susanne Lips (2021)Bone Status in a Mouse Model of Experimental Autoimmune-Orchitis, In: International journal of molecular sciences22(15)7858 Mdpi

Investigations in male patients with fertility disorders revealed a greater risk of osteoporosis. The rodent model of experimental autoimmune-orchitis (EAO) was established to analyze the underlying mechanisms of male infertility and causes of reduced testosterone concentration. Hence, we investigated the impact of testicular dysfunction in EAO on bone status. Male mice were immunized with testicular homogenate in adjuvant to induce EAO (n = 5). Age-matched mice were treated with adjuvant alone (adjuvant, n = 6) or remained untreated (control, n = 7). Fifty days after the first immunization specimens were harvested. Real-time reverse transcription-PCR indicated decreased bone metabolism by alkaline phosphatase and Cathepsin K as well as remodeling of cell-contacts by Connexin-43. Micro computed tomography demonstrated a loss of bone mass and mineralization. These findings were supported by histomorphometric results. Additionally, biomechanical properties of femora in a three-point bending test were significantly altered. In summary, the present study illustrates the induction of osteoporosis in the investigated mouse model. However, results suggest that the major effects on bone status were mainly caused by the complete Freund's adjuvant rather than the autoimmune-orchitis itself. Therefore, the benefit of the EAO model to transfer laboratory findings regarding bone metabolism in context with orchitis into a clinical application is limited.

Alexandre Presas, David Valentin, Joseph Deering, Marian Kampschulte, Bosco Yu, Kathryn Grandfield, Elisa Mele, Christoph Biehl, Gabriele A. Krombach, Christian Heiss, Wolfram A. Bosbach (2021)Resonance vibration interventions in the femur: Experimental-numerical modelling approaches, In: Journal of the mechanical behavior of biomedical materials124104850pp. 104850-104850 Elsevier Ltd

External vibration excitation might be key to many novel non-surgical interventions for pathologies in the musculoskeletal system and in other parts of the human organism. Lack of understanding about vibration patterns, their controllability, and reproducibility are three limitations of ongoing research. This study establishes a bovine vibration model and animal model replacements for future research. We used biological samples (n=5) and one polyurethane sample of the bovine femur. Mechanical resonance was measured experimentally and analysed numerically by finite element method. The experiments obtained 5 distinct mode shapes for the biological sample set, with standard deviation < 7.5%. Finite element analysis of the biological samples can replicate experimental mode shape deflection. The use of polyurethane changes resonance character but results are also good approximations of the biological samples. A model of the bovine femur with consistent resonance behaviour is presented with alternatives (polyurethane and finite element analysis) that can serve in reducing the number of necessary biological samples. Future work will be to adapt results to human anatomy. Of clinical interest will be to influence bone pathologies such as post-surgical non-union, or bone functionality as part of haematopoiesis and endocrine secretion.

Christoph Biehl, Lotta Biehl, Ingo Helmut Tarner, Ulf Mueller-Ladner, Christian Heiss, Martin Heinrich (2022)Microangiopathy in Inflammatory Diseases-Strategies in Surgery of the Lower Extremity, In: Life (Basel, Switzerland)12(2)200 Mdpi

Background: Patients with an inflammatory disease frequently develop chronic angiopathy of the capillaries. Due to this pathology, there is an increased rate of complications in lower extremity surgical procedures. It is not uncommon for microangiopathic wound healing disorders to cause deep infections and fistulas, which lead to prolonged courses and hospitalizations. In addition, adhesions and ossifications of the contractile elements occur regularly. This sometimes results in serious limitations of the mobility of the patients. The study aims to present the results of a combination of vacuum and physical therapy. Patient and methods: A retrospective study of six patients with systemic sclerosis undergoing joint-related procedures of the lower extremity between 2015 and 2020 was performed. In addition to characterization of the patients and therapy, special attention was paid to cutaneous wound healing, affection of the fascia and displacement layers, and sclerosis of the muscle and tendon insertion. Results: The characterized structures (skin, tendon, fascia) show pathological changes at the microangiopathic level, which are associated with delayed healing and less physical capacity. Early suture removal regularly results in secondary scar dehiscence. With a stage-adapted vacuum therapy with sanitation of the deep structures and later on a dermal vacuum system, healing with simultaneous mobilization of the patients could be achieved in our patient cohort. Conclusion: In the case of necessary interventions on the lower extremity, such as trauma surgery, additional decongestive measures in the sense of regular and sustained lymphatic therapy and adapted physiotherapy are indispensable.

Asif Shajahan, Lauren E. Pepi, Daniel S. Rouhani, Christian Heiss, Parastoo Azadi (2021)Glycosylation of SARS-CoV-2: structural and functional insights, In: Analytical and bioanalytical chemistry413(29)pp. 7179-7193 Springer Nature

The COVID-19 pandemic is caused by the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2). Similar to other coronaviruses, its particles are composed of four structural proteins: spike (S), envelope (E), membrane (M), and nucleocapsid (N) proteins. S, E, and M proteins are glycosylated, and the N protein is phosphorylated. The S protein is involved in the interaction with the host receptor human angiotensin-converting enzyme 2 (hACE2), which is also heavily glycosylated. Recent studies have revealed several other potential host receptors or factors that can increase or modulate the SARS-CoV-2 infection. Interestingly, most of these molecules bear carbohydrate residues. While glycans acquired by the viruses through the hijacking of the host machinery help the viruses in their infectivity, they also play roles in immune evasion or modulation. Glycans play complex roles in viral pathobiology, both on their own and in association with carrier biomolecules, such as proteins or glycosaminoglycans (GAGs). Understanding these roles in detail can help in developing suitable strategies for prevention and therapy of COVID-19. In this review, we sought to emphasize the interplay of SARS-CoV-2 glycosylated proteins and their host receptors in viral attachment, entry, replication, and infection. Moreover, the implications for future therapeutic interventions targeting these glycosylated biomolecules are also discussed in detail.

Christian Heiss, Parastoo Azadi (2020)Carbohydrate Structure Analysis: Methods and Applications, In: SLAS technology25(4)305pp. 305-306 Sage
Ursula Sommer, Stephan Laurich, Lucie de Azevedo, Katharina Viehoff, Sabine Wenisch, Ulrich Thormann, Volker Alt, Christian Heiss, Reinhard Schnettler (2020)In Vitro and In Vivo Biocompatibility Studies of a Cast and Coated Titanium Alloy, In: Molecules (Basel, Switzerland)25(15)3399 Mdpi

The biocompatibility of a cast porous and with a calcium titanate reaction layer functionalized titanium alloy (Ti-6Al-7Nb) was tested by means of cell culture, and a small (rat) and large animal (sheep) model. The uncoated titanium material served as a control. In-vitro tests included the validation of osteoblast-like cells attached to the surface of the material with scanning electron microscopy and immunofluorescence of cytoskeletal actin as well as their osteogenic development, the ability to mineralize, and their vitality. Following the in-vitro tests a small animal (rat) and big animal (sheep) model were accomplished by inserting a cylindrical titanium implant into a drill hole defect in the femoral condyle. After 7, 14, and 30 days (rat) and 6 months (sheep) the condyles were studied regarding histological and histomorphometrical characteristics. Uncoated and coated material showed a good biocompatibility both in cell culture and animal models. While the defect area in the rat is well consolidated after 30 days, the sheep show only little bone inside the implant after 6 months, possibly due to stress shielding. None of the executed methods indicated a statistically significant difference between coated and uncoated material.

Nitin T. Supekar, Asif Shajahan, Anne S. Gleinich, Daniel S. Rouhani, Christian Heiss, Digantkumar Gopaldas Chapla, Kelley W. Moremen, Parastoo Azadi (2021)Variable posttranslational modifications of severe acute respiratory syndrome coronavirus 2 nucleocapsid protein, In: Glycobiology (Oxford)31(9)pp. 1080-1092 Oxford Univ Press

Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), which causes coronavirus disease 2019 (COVID-19), started in 2019 in China and quickly spread into a global pandemic. Nucleocapsid protein (N protein) is highly conserved and is the most abundant protein in coronaviruses and is thus a potential target for both vaccine and point-of-care diagnostics. N Protein has been suggested in the literature as having posttranslational modifications (PTMs), and accurately defining these PTMs is critical for its potential use in medicine. Reports of phosphorylation of N protein have failed to provide detailed site-specific information. We have performed comprehensive glycomics, glycoproteomics and proteomics experiments on two different N protein preparations. Both were expressed in HEK293 cells; one was in-house expressed and purified without a signal peptide (SP) sequence, and the other was commercially produced with a SP channeling it through the secretory pathway. Our results show completely different PTMs on the two N protein preparations. The commercial product contained extensive N- and O-linked glycosylation as well as O-phosphorylation on site Thr393. Conversely, the native N Protein model had O-phosphorylation at Ser176 and no glycosylation, highlighting the importance of knowing the provenance of any commercial protein to be used for scientific or clinical studies. Recent studies have indicated that N protein can serve as an important diagnostic marker for COVID-19 and as a major immunogen by priming protective immune responses. Thus, detailed structural characterization of N protein may provide useful insights for understanding the roles of PTMs on viral pathogenesis, vaccine design and development of point-of-care diagnostics.

Thaqif El Khassawna, Gero Knapp, Nadja Scheibler, Deeksha Malhan, Nike Walter, Christoph Biehl, Volker Alt, Christian Heiss, Markus Rupp (2021)Mortality, Risk Factors and Risk Assessment after Periprosthetic Femoral Fractures-A Retrospective Cohort Study, In: Journal of clinical medicine10(19)4324 Mdpi

Periprosthetic femoral fracture (PFF) is a devastating complication. Here, the authors aimed to determine the influence of the timing of surgery as a risk factor for mortality and poor postoperative outcome in patients suffering from PFF. A retrospective descriptive analysis of patients treated for PFF between January 2010 and March 2018 was performed. In addition to patient and treatment characteristics, we assessed mortality rates and postoperative functional outcome by using the Harris Hip and WOMAC score. One-year mortality after PFF was 10.7%. Delayed surgery after 48 h did not negatively influence mortality after PFF. The postoperative hospital stay did not influence the mortality rate, nor did it correlate with medical scores of comorbidities, general health or functionalities. Cementation of stem correlated negatively with the WOMAC score. Deceased patients had a higher Charlson Comorbidity Index (CCI) score, while American society of Anaesthesiologists (ASA) scores did not show a significant difference. There were no differences between ORIF and revision arthroplasty. In conclusion, delayed surgery after 48 h does not negatively influence mortality after PFF. The CCI seems to be a suitable tool to assess patients' risk for increased mortality after PFF, while the usually used ASA score is not able to achieve a relevant risk assessment.

T Rassaf, R Westenfeld, J Balzer, T Lauer, M Merx, J Floege, S Steiner, C Heiss, M Kelm, C Meyer (2010)Modulation of peripheral chemoreflex by neurohumoral adaptations after kidney transplantation, In: European Journal of Medical Research15(Sup 2)pp. pp83-87 biomedcentral

Background Peripheral chemoreceptors residing predominantly in the carotid body monitor changes in arterial blood oxygen and are mechanistically linked to the cardiorespiratory control by the autonomic nervous system. Enhanced sympathetic activation is common in end-stage renal disease and kidney transplantation has been shown to improve cardiorespiratory reflex measures of autonomic function. Objective The aim of the present study was to test whether improvement in renal function following kidney transplantation is related to an improvement in chemosensory function. Methods and Results We compared hyperoxic chemoreflex sensitivity (CHRS) in patients after renal transplantation (RTX) to that in patients on maintenance hemodialysis (HD), and that of age- and gender-matched healthy controls. In addition, we investigated the impact of common confounding factors including pharmacological neurohumoral modulation and diabetes mellitus. The difference in the R-R intervals divided by the difference in the oxygen pressures before and after deactivation of the chemoreceptors by 5-min inhalation of 7 L oxygen was calculated as the hyperoxic CHRS. Autonomic activity was characterized by 24-h time-domain heart rate variability (HRV) parameters. CHRS was improved in RTX patients as compared to HD patients being related to HRV. CHRS was related to the concomitant presence of diabetes and medication with cyclosporine. Conclusion Our findings indicate that chemosensory activity following kidney transplantation is related to cardiac autonomic control, but functional testing might only be useful to characterize the time course and extent of sympathetic activation in selected patients due to existing co-morbidities and immunosuppressive medication in this population.

CHRISTIAN HEISS, Geoffrey Istas, Rodrigo P. Feliciano, Timon Weber, Brian Wang , Claudia Favari, Pedro Mena, Daniele Del Rio, Ana Rodriguez-Mateos (2022)Daily consumption of cranberry improves endothelial function in healthy adults: a double blind randomized controlled trial, In: Food & function Royal Society of Chemistry
Mariam Bapir, Simon S Skene, Paola Campagnolo, Christian Heiss (2022)Poster No. 094 Age-dependent decline in common femoral artery flow-mediated dilation and wall shear stress in healthy subjects, In: Cardiovascular research118(Supplement_2)

Abstract Background Femoral artery (FA) endothelial function is a promising biomarker for peripheral artery disease (PAD) prevention. We assessed FA flow-mediated dilation (FMD) in healthy adults of various ages. Material and methods Repeated common FA and brachial artery (BA) FMD measurements were performed with ultrasound induced by5 minutes distal cuff occlusion (thigh, calf, forearm) to assess intra- and interindividual variability and acceptability (n = 10). We then performeda cross-sectional study with FA- and BA-FMD measurements in healthy participants aged 18–80 (n = 53). Results and conclusions All FMD protocols had good reproducibility with average deviation of −0.1% (SD 0.6%, 0.9%, 0.6%) but thigh occlusion was less well tolerated. BA- and FA-FMD with thigh occlusion did not significantly differ while FA-FMD with calf occlusion was significantly lower (−1.0 ± 0.9%). Both FA-FMD and BA-FMD inversely correlated with age and baseline diameter and positively with wall shear stress (WSS). FA-FMD and BA-FMD correlated significantly (r = 0.57, P < 0.001). The baseline diameter was significantly greater in the FA as compared to the BA while the WSS was significantly lower. At the onset of reactive hyperaemia, the mean flow velocity, WSS and flow reserve were lower in the FA as compared to the BA. A large proportion of FA WSS values in older participants were below 5 dyne/ cm2 which is regarded as pro-atherogenic. FA endothelial function declines with age in parallel with the BA. FAs exhibits stronger age-dependent enlargement as compared to the BA leading to a critical decrease in WSS that may explain part of the age-dependent predisposition for PAD.

U Nixdorff, S Achenbach, F Bengel, P Faggiano, S Fernández, Christian Heiss, T Mengden, FG Mureddu, E Nagel, V Puntmann, V Zamorano (2015)Imaging in Cardiovascular Prevention, In: Stephan Gielen, Guy De Backer, Massimo Piepoli, David Wood (eds.), The ESC Textbook of Preventive Cardiology Oxford University Press
Dominik Schuler, Roberto Sansone, Christian Heiss, Malte Kelm (2013)Is there a Role for Antioxidants in the Treatment of Stable Angina?, In: Current Pharmaceutical Design19(9)pp. 1601-1615 Bentham Science

Medical treatment plays an important role in the therapy of coronary artery disease and stable angina. Whereas nitrates are used to improve symptoms, beta-blockers, statins, and ACE-inhibitors/angiotensin receptor blockers are given also to target prognosis in part by slowing the progression of disease. Major cardiovascular risk factors including tobacco smoking, physical inactivity, obesity, arterial hypertension, hyperlipidemia, and diabetes mellitus were associated with overproduction of reactive oxygen species (ROS). In animal models, increased ROS production was associated with the initial steps of atherosclerosis including vascular cell dysfunction, intimal hypertrophy, the formation and destabilization of plaque. As a consequence, ROS were believed to be major contributors to the development of cardiovascular diseases and antioxidant treatments were proposed as promising therapeutic strategies. Nevertheless, intervention studies with antioxidant vitamins have failed to positively affect cardiovascular outcome in prospective trials. Specific inhibitors of prooxidant enzymes are being developed but their efficacy to improve cardiovascular endpoints has not been tested so far. Newer evidence suggests that phytonutrients including flavanols may posses vascular protective effects that are independent of their antioxidant properties observed in vitro. Taken together, there is currently not enough evidence that treatment with antioxidants per se will play a role in cardiovascular medicine.

Roberta R. Holt, Christian Heiss, Malte Kelm, Carl L. Keen (2012)The Potential of Flavanol and Procyanidin Intake to Influence Age-Related Vascular Disease, In: Journal of Nutrition in Gerontology and Geriatrics31(3)pp. 290-323 Taylor & Francis

Advancing age is an independent major risk factor for cardiovascular disease (CVD). Age-associated impairments in the control of inflammation, excessive oxidative stress, and reduced cellular repair can all contribute to the development and progression of CVD. Current recommendations for both the primary and secondary prevention of CVD promote lifestyle modifications that include the adoption of healthy dietary patterns, such as the consumption of diets rich in plant foods, as these have been associated with a lower lifetime risk for the development of CVD. The potential for a diet rich in plant foods to be cardiovascular protective is also supported by prospective studies that suggest the intake of foods providing high amounts of certain phytochemicals, in particular flavanols and procyanidins, reduce the risk for CVD. These observations are further supported by a number of dietary intervention trials that show improvements in vascular function and reduced platelet reactivity following the consumption of high flavanol foods. In the current article we review a selection of these studies, and comment on some of the potential mechanisms that have been postulated to underlie the health effects of flavanol and procyanidin-rich foods.

T. Rassaf, C. Rammos, U. B. Hendgen-Cotta, Christian Heiss, W. Kleophas, F. Dellanna, J. Floege, G. R. Hetzel, M. Kelm (2015)Vasculoprotective Effects of Dietary Cocoa Flavanols in Patients on Hemodialysis: A Double-Blind, Randomized, Placebo-Controlled Trial, In: Clinical Journal of the American Society of Nephrology11(1)pp. 108-118 American Society of Nephrology

Background and objectives: Hemodialysis (HD) per se entails vascular dysfunction in patients with ESRD. Endothelial dysfunction is a key step in atherosclerosis and is characterized by impaired flow–mediated dilation (FMD). Interventional studies have shown that cocoa flavanol (CF)–rich supplements improve vascular function. Aim of this study was to investigate the effect of flavanol–rich bioactive food ingredients on acute and chronic HD–induced vascular dysfunction in ESRD. Design, setting, participants, & measurements: We conducted a randomized, double–blind, placebo–controlled trial from 2012 to 2013. Fifty-seven participants were enrolled, ingested CF-rich beverages (900 mg CF per study day), and were compared with those ingesting CF-free placebo. This included (1) a baseline cross–over acute study to determine safety and efficacy of CF and (2) a subsequent chronic parallel group study with a 30-day follow-up period to study effects of CF on HD–mediated vascular dysfunction entailing (3) an acute substudy during HD in flavanol-naive patients and (4) an acute on chronic study during HD. Primary and secondary outcome measures included changes in FMD and hemodynamics. Results: CF ingestion was well tolerated. Acute ingestion improved FMD by 53% (3.2±0.6% to 4.8±0.9% versus placebo, 3.2±0.7% to 3.3±0.8%; P

Claudia Favari, Pedro Mena, Claudio Curti, Geoffrey Istas, Christian Heiss, Daniele Del Rio, Ana Rodriguez-Mateos (2020)Kinetic profile and urinary excretion of phenyl-γ-valerolactones upon consumption of cranberry: a dose–response relationship, In: Food & Function11(5)pp. 3975-3985 Royal Society of Chemistry

Cranberries are a rich source of poly(phenols), mainly monomeric and oligomeric flavan-3-ols. However, information on the appearance of their main circulating microbial metabolites, namely phenyl-γ-valerolactones and phenylvaleric acid, is lacking despite its relevance to understanding the health effects attributed to cranberries. The aim of this study was to evaluate the absorption, metabolism and urinary excretion of cranberry flavan-3-ols through the targeted analysis of phenyl-γ-valerolactones and their related phenylvaleric acids, considering also their potential as biomarkers of flavan-3-ol intake and inter-individual variability in their appearance in plasma and urine. A six-arm acute crossover, randomized, double-blinded, controlled intervention trial was performed in ten healthy males who consumed a cranberry juice drink (375, 716, 1131, 1396, 1741 mg of total flavan-3-ols) or an isocaloric control drink with one-week washout. Plasma and urine were analyzed by UHPLC-ESI-QqQ-MS/MS and 22 compounds were identified. Glucuronide and sulfate conjugates of 5-(3′,4′-dihydroxyphenyl)-γ-valerolactone were the main circulating and excreted metabolites after cranberry juice intake, with glucuronidation appearing to be the most favorable conjugation route. These compounds reached maximum plasma concentration at about 4–6 h. Plasma and urinary concentrations of the sum of the metabolites increased in relation to the amounts of cranberry flavan-3-ols provided by the drink, showing a clear and linear dose-dependent relationship and underscoring their potential as biomarkers of flavan-3-ol intake. A high inter-individual variability in circulating and urinary metabolite levels was observed and, interestingly, some subjects seemed to display a greater efficiency in metabolizing flavan-3-ols and producing phenyl-γ-valerolactones.

Michael Gröne, Dragos Duse, Nicolas Kramser, Niklas Ophoff, Hendrik Schweers, Fabian Voß, Christine Quast, Roberto Sansone, Christian Heiss, Christian Jung, Malte Kelm, Ralf Erkens (2023)Cocoa flavanols improve peakVO2 and exercise capacity in a randomized double blinded clinical trial in healthy elderly people, In: Food & function14(16)pp. 7562-7573 Royal Society of Chemistry

Background: Loss of functional capacity is one of the hallmarks in cardiovascular aging. Cocoa flavanols (CF) exert favorable effects on endothelial function, blood pressure, and inflammation. These cardiovascular health markers worsen with increasing age and limit functional exercise capacity. Aim: To investigate the effect of CF on cardiorespiratory-fitness in healthy elderly people. Methods: In a randomized, double-masked, placebo-controlled, parallel-group dietary intervention trial, 68 healthy elderly people (55–79 years, 28 female) received either 500 mg of CF or a nutrient-matched control capsule twice a day for 30 days. Primary endpoint was defined as peak oxygen consumption (VO2) in a cardiopulmonary exercise test (CPET). Secondary endpoints were oxygen pulse (VO2 per heart rate (HR)), resting blood pressure (BP), and resting vascular function. Results: After 30 days of CF intake peakVO2 increased by 190 ml min−1 (95% CI 1–371 ml min−1) and peakVO2 per kg by 2.5 ml (min kg)−1 (95% CI 0.30–4.2 ml (min kg)−1). O2-pulse increased by 1.7 ml (95% CI 0.29–3.2 ml) and max exercise capacity by 9.6 W (95% CI 2.1–17.7 W). CF decreased resting systolic and diastolic BP by 5.4 mmHg (95% CI −10.7 to −0.1 mmHg) and 2.9 mmHg (95% CI −5.5 to −0.4 mmHg), respectively. Flow-mediated vasodilation (FMD) increased by an absolute 1.3% (95% CI 0.76–1.79%) in the CF group. Indexes of pulmonary function were not affected. No changes for primary and secondary endpoints were detected in control. Conclusion: CF substantially improve markers of cardiorespiratory fitness in healthy elderly humans highlighting their potential to preserve cardiovascular health with increasing age.

Javier I. Ottaviani, Christian Heiss, Jeremy P.E. Spencer, Malte Kelm, Hagen Schroeter (2018)Recommending flavanols and procyanidins for cardiovascular health: Revisited, In: Molecular Aspects of Medicine61pp. 63-75 Elsevier

The last 8 years have seen significant developments in our understanding of dietary flavanols and procyanidins in the context of human health and nutrition. During the same time, recognition of the importance of nutrition in primary disease prevention and health maintenance has increased. In addition, the concept of dietary bioactives (food constituents that although not essential to human life and procreation, may nevertheless play an important role in disease risk reduction, primary disease prevention, and healthy aging) has been created and developed. Applying assessment criteria specific to health maintenance and primary disease prevention, we aimed at broadly evaluating and discussing currently available data on flavanols and procyanidins, with an eye towards potentially advancing the future development of dietary guidelines and public health recommendations. Novel insights and advancements as well as current gaps and shortcomings in our understanding are identified and discussed. While centered on flavanols and procyanidins, the outcomes of this review may also have broader relevance for the further development of the concept of bioactives, and any future framework for the assessment of their role in human health and nutrition.

Eva S. Kehmeier, Wolfgang Lepper, Martina Kropp, Christian Heiss, Ulrike Hendgen-Cotta, Jan Balzer, Mirja Neizel, Christian Meyer, Marc W. Merx, P Verde, Christian Ohmann, Gerd Heusch, Malte Kelm, Tienush Rassaf (2012)TNF-α, myocardial perfusion and function in patients with ST-segment elevation myocardial infarction and primary percutaneous coronary intervention, In: Clinical Research in Cardiology101(10)pp. 815-827 Springer Nature

Aims To characterize the time course of tumor necrosis factor-α (TNF-α) serum levels along with myocardial perfusion and contractile function in patients with ST-segment elevation myocardial infarction (STEMI) and successful primary percutaneous coronary intervention (PCI). Methods Serum levels of TNF-α, interleukin 6 (IL-6), and C-reactive protein (CRP) were measured in 42 patients with STEMI before, one and 6 days after successful PCI. Myocardial perfusion was assessed by contrast-enhanced echocardiography (ceEcho), contractile function by unenhanced two-dimensional (2DE) and real-time three-dimensional echocardiography. In a subset of 18 patients, infarct size was quantified by late gadolinium enhancement cardiovascular magnetic resonance imaging (LGE-CMR) on day six. Results TNF-α serum levels were in the upper normal range within the first 12 h from symptom onset and increased continuously until day six, while IL-6 and CRP increased subsequently with a peak on day one after STEMI. Serum TNF-α on day one after PCI correlated with perfusion defects, wall motion abnormalities, and infarct size (ceEcho: r = 0.52, p = 0.005; 2DE: r = 0.56, p = 0.002; LGE-CMR: r = 0.83–0.86; p < 0.0001). Using multiple regression linear analysis, infarct size on day six was predicted by serum TNF-α 1 day after PCI (p = 0.006, adjusted R 2 0.638). Conclusion Our data reflect the clinical significance of early TNF-α elevation in patients with STEMI and primary PCI (Controlled Clinical Trials number, NCT00529607).

Christian Heiss, Christian Meyer, Matthias Totzeck, Ulrike B. Hendgen-Cotta, Yvonne Heinen, Peter Luedike, Stefanie Keymel, Nassim Ayoub, Jon O. Lundberg, Eddie Weitzberg, Malte Kelm, Tienush Rassaf (2012)Dietary inorganic nitrate mobilizes circulating angiogenic cells, In: FREE RADICAL BIOLOGY AND MEDICINE52(9)pp. 1767-1772 ELSEVIER SCIENCE INC

Nitric oxide (NO) was implicated in the regulation of mobilization and function of circulating angiogenic cells (CACs). The supposedly inert anion nitrate, abundant in vegetables, can be stepwise reduced in vivo to form nitrite, and consecutively NO, representing an alternative to endogenous NO formation by NO synthases. This study investigated whether inorganic dietary nitrate influences mobilization of CACs. In a randomized double-blind fashion, healthy volunteers ingested 150 ml water with 0.15 mmol/kg (12.7 mg/kg) of sodium nitrate, an amount corresponding to 100–300 g of a nitrate-rich vegetable, or water alone as control. Mobilization of CACs was determined by the number of CD34+/KDR+ and CD133+/KDR+ cells using flow cytometry and the mobilization markers stem cell factor (SCF) and stromal cell-derived factor-1a (SDF-1α) were determined in plasma via ELISA. Nitrite and nitrate were measured using high-performance liquid chromatography and reductive gas-phase chemiluminescence, respectively. NOS-dependent vasodilation was measured as flow-mediated vasodilation. Further mechanistic studies were performed in mice after intravenous application of nitrite together with an NO scavenger to identify the role of nitrite and NO in CAC mobilization. Nitrate ingestion led to a rise in plasma nitrite together with an acute increase in CD34+/KDR+ and CD133+/KDR+-CACs along with increased NOS-dependent vasodilation. This was paralleled by an increase in SCF and SDF-1α and the maximal increase in plasma nitrite correlated with CD133+/KDR+-CACs (r = 0.73, P = 0.016). In mice, nitrate given per gavage and direct intravenous injection of nitrite led to CAC mobilization, which was abolished by the NO scavenger cPTIO, suggesting that nitrite mediated its effect via formation of NO. Dietary inorganic nitrate acutely mobilizes CACs via serial reduction to nitrite and NO. The nitrate–nitrite–NO pathway could offer a novel nutritional approach for regulation of vascular regenerative processes.

E. Wood, S. Hein, C. Heiss, C. Williams, Ana Rodriguez-Mateos (2019)Blueberries and cardiovascular disease prevention, In: Food and Function10(12)pp. 7621-7633 Royal Society of Chemistry

Blueberries are a rich source of (poly)phenols, particularly anthocyanins. Epidemiological studies indicate that anthocyanin-rich foods including blueberries are associated with a reduction in the risk of cardiovascular disease. These observational findings are supported by a number of randomized-controlled trials showing improvements in biomarkers of cardiovascular disease risk. The beneficial effects of blueberry (poly)phenols are particularly clear when measuring flow-mediated dilation over various timeframes and study populations. However, other outcomes are less clear, such as effects on blood pressure, arterial stiffness and blood lipid profile. This may be due to the heterogeneity existing in study designs, such as duration of the intervention, and the health status of participants. Longer-term RCTs using gold standard methods in relevant populations which can be translated to the general public are needed to clarify and strengthen the evidence available. While circulating phenolic blueberry metabolites have been linked with improvements in vascular function, the biological activities and mechanisms of action of individual metabolites and their interaction in vivo are still unknown. Evaluating the bioactivities of metabolites alone and together, and analysing their structure-activity relationship in well-designed and physiologically relevant experimental and human studies are needed to understand the mechanisms of how these metabolites affect vascular function.

Jill Belch, Anita Carlizza, Patrick H. Carpentier, Joel Constans, Faisel Khan, Jean-Claude Wautrecht, Adriana Visona, Christian Heiss, Marianne Brodeman, Zsolt Pécsvárady, Karel Roztocil, Mary-Paula Colgan, Dragan Vasic, Anders Gottsäter, Beatrice Amann-Vesti, Ali Chraim, Pavel Poredoš, Dan-Mircea Olinic, Juraj Madaric, Sigrid Nikol, Ariane L. Herrick, Muriel Sprynger, Peter Klein-Weigel, Franz Hafner, Daniel Staub, Zan Zeman (2017)ESVM guidelines – the diagnosis and management of Raynaud’s phenomenon, In: Vasa46(6)pp. 413-423 Hogrefe

Regarding the clinical diagnosis of Raynaud’s phenomenon and its associated conditions, investigations and treatment are substantial, and yet no international consensus has been published regarding the medical management of patients presenting with this condition. Most knowledge on this topic derives from epidemiological surveys and observational studies; few randomized studies are available, almost all relating to drug treatment, and thus these guidelines were developed as an expert consensus document to aid in the diagnosis and management of Raynaud’s phenomenon. This consensus document starts with a clarification about the definition and terminology of Raynaud’s phenomenon and covers the differential and aetiological diagnoses as well as the symptomatic treatment.

Patricia I. Oteiza, Christian Heiss (2018)Introduction to special issue on Polyphenols and Health, In: Archives of Biochemistry and Biophysics652pp. 1-2 Elsevier

The understanding of the beneficial effects of plant bioactives on human health is of critical interest considering the already observed and proven benefits for some of them, i.e. fiber and control of glycemia, stanols mitigating hypercholesterolemia. In the field of polyphenols, and as discussed in the introductory review [1], research has grown exponentially in the last 25 years, at a faster rate than for other bioactives. Although there is a significant lack of information on major aspects of the relevance of dietary polyphenols on human health, the field has advanced significantly. Thus, there is considerably more information on the absorption, distribution, metabolism, and excretion (ADME) of polyphenols in healthy humans [2]. In particular, it is important to consider that humans can have major differences in metabolizing capacity given individual differences in intestinal microbiota and in the genes involved in ADME [2,3]. Characterization of polyphenol metabolism in different species (e.g. humans [2,3] and rats [4] is relevant for the evaluation of how the extensive experimental research originated in rodents can be extrapolated to the actions of individual polyphenols in humans.

Rodrigo P. Feliciano, Albert Boeres, Luca Massacessi, Geoffrey Istas, M. Rita Ventura, Cláudia Nunes dos Santos, Christian Heiss, Ana Rodriguez-Mateos (2016)Identification and quantification of novel cranberry-derived plasma and urinary (poly)phenols, In: Archives of Biochemistry and Biophysics599pp. 31-41 Elsevier

Cranberries are a rich source of (poly)phenols, in particular proanthocyanidins, anthocyanins, flavonols, and phenolic acids. However, little is known about their bioavailability in humans. We investigated the absorption, metabolism, and excretion of cranberry (poly)phenols in plasma and urine of healthy young men after consumption of a cranberry juice (787 mg (poly)phenols). A total of 60 cranberry-derived phenolic metabolites were identified using UPLC-Q-TOF-MS analysis with authentic standards. These included sulfates of pyrogallol, valerolactone, benzoic acids, phenylacetic acids, glucuronides of flavonols, as well as sulfates and glucuronides of cinnamic acids. The most abundant plasma metabolites were small phenolic compounds, in particular hippuric acid, catechol-O-sulfate, 2,3-dihydroxybenzoic acid, phenylacetic acid, isoferulic acid, 4-methylcatechol-O-sulfate, α-hydroxyhippuric acid, ferulic acid 4-O-sulfate, benzoic acid, 4-hydroxyphenyl acetic acid, dihydrocaffeic acid 3-O-sulfate, and vanillic acid-4-O-sulfate. Some benzoic acids, cinnamic acids, and flavonol metabolites appeared in plasma early, at 1–2 h post-consumption. Others such as phenylacetic acids, benzaldehydes, pyrogallols, catechols, hippuric and dihydrocinnamic acid derivatives appear in plasma later (Tmax 4–22 h). The 24 h urinary recovery with respect to the amount of (poly)phenols consumed was 6.2%. Our extensive description of the bioavailability of cranberry (poly)phenols lays important groundwork necessary to start understanding the fate of these compounds in humans.

P. Horn, M. M. Cortese-Krott, N. Amabile, C. Hundsdorfer, K.-D. Kroncke, M. Kelm, C. Heiss (2012)Circulating Microparticles Carry a Functional Endothelial Nitric Oxide Synthase That Is Decreased in Patients With Endothelial Dysfunction, In: Journal of the American Heart Association2(1)pp. e003764-e003764 Wiley

Background-—Microparticles (MPs) are circulating membrane particles of less than a micrometer in diameter shed from endothelial and blood cells. Recent literature suggests that MPs are not just functionally inert cell debris but may possess biological functions and mediate the communication between vascular cells. As a significant proportion of MPs originate from platelets and endothelial cells, we hypothesized that MPs may harbor functional enzymes including an endothelial NO synthase (eNOS). Methods and Results-—Using immunoprecipitation and Western blot analysis, we found that human circulating MPs carry an eNOS. Ca2+ and L-arginine-dependent NOS activity of crude enzyme extract from MPs was determined by measuring the conversion of [3H]-L-arginine to [3H]-citrulline and NOS-dependent nitrite production. NOS-dependent NO production in intact MPs was assessed by the NO-specific fluorescent probe MNIP-Cu. In patients with cardiovascular disease, endothelial dysfunction was associated with an increase in the total number of circulating MPs as well as a significant decrease in the expression and activity of eNOS in MPs. No difference in reactive oxygen species was noted in MPs isolated from either group. Conclusions-—Our data further support the concept that circulating MPs may not only retain phenotypic markers but also preserve the functionality of enzymes of the cells they originate from, including eNOS.

Christian Heiss, Ana Rodriguez-Mateos, Malte Kelm (2015)Central Role of eNOS in the Maintenance of Endothelial Homeostasis, In: Antioxidants & Redox Signaling22(14)pp. 1230-1242 Mary Ann Liebert

Significance: Disruption of endothelial function is considered a key event in the development and progression of atherosclerosis. Endothelial nitric oxide synthase (eNOS) is a central regulator of cellular function that is important to maintain endothelial homeostasis. Recent Advances: Endothelial homeostasis encompasses acute responses such as adaption of flow to tissue's demand and more sustained responses to injury such as re-endothelialization and sprouting of endothelial cells (ECs) and attraction of circulating angiogenic cells (CAC), both of which support repair of damaged endothelium. The balance and the intensity of endothelial damage and repair might be reflected by changes in circulating endothelial microparticles (EMP) and CAC. Flow-mediated vasodilation (FMD) is a generally accepted clinical read-out of NO-dependent vasodilation, whereas EMP are upcoming prognostically validated markers of endothelial injury and CAC are reflective of the regenerative capacity with both expressing a functional eNOS. These markers can be integrated in a clinical endothelial phenotype, reflecting the net result between damage from risk factors and endogenous repair capacity with NO representing a central signaling molecule. Critical Issues: Improvements of reproducibility and observer independence of FMD measurements and definitions of relevant EMP and CAC subpopulations warrant further research. Future Directions: Endothelial homeostasis may be a clinical therapeutic target for cardiovascular health maintenance.

Patrick Horn, Nicolas Amabile, Franca S. Angeli, Roberto Sansone, Berthold Stegemann, Malte Kelm, Matthew L. Springer, Yerem Yeghiazarians, Hagen Schroeter, Christian Heiss (2014)Dietary flavanol intervention lowers the levels of endothelial microparticles in coronary artery disease patients, In: BRITISH JOURNAL OF NUTRITION111(07)pp. 1245-1252 CAMBRIDGE UNIV PRESS

Current evidence suggests that regenerative v. degenerative endothelial responses can be integrated in a clinical endothelial phenotype, reflecting the net result between damage from risk factors and endogenous repair capacity. We have previously shown that a cocoa flavanol (CF) intervention can improve endothelial function and increase the regenerative capacity of the endothelium by mobilising circulating angiogenic cells in patients with coronary artery disease (CAD). The aim of the present study was to investigate whether CF can lower the levels of circulating endothelial microparticles (EMP), markers of endothelial integrity, along with improvements in endothelial function. The levels of EMP in the frozen plasma samples of CAD patients were measured along with endothelial function (flow-mediated vasodilation, FMD); n 16, FMD data published previously), and these data were compared with those of young (n 12) and age-matched (n 12) healthy control subjects. The CAD patients exhibited significantly increased levels of EMP along with impaired FMD when compared with the healthy control subjects. The levels of CD144+ and CD31+/41− EMP were inversely correlated with FMD (r − 0·67, P= 0·01 and r − 0·59, P= 0·01, respectively). In these CAD patients, the levels of EMP were measured after they had consumed a drink containing 375 mg of CF (high-CF intervention, HiFI) or 9 mg of CF (macro- and micronutrient-matched low-CF control, LoFl) twice daily over a 30-d period in a randomised, double-blind, cross-over study. After 1 month of HiFI, the levels of CD31+/41− and CD144+ EMP decreased ( − 25 and − 23 %, respectively), but not after LoFl. Our data show that flavanols lower the levels of EMP along with higher endothelial function, lending evidence to the novel concept that flavanols may improve endothelial integrity.

Carina Henning, Anna Branopolski, Dominik Schuler, Dimitrios Dimitroulis, Patrik Huelsemann, Christopher Nicolaus, Roberto Sansone, Jelle Ludolf Postma, Daniel Eberhard, Ferdinand Le Noble, Malte Kelm, Eckhard Lammert, Christian Heiss (2019)Requirement of ?1 integrin for endothelium-dependent vasodilation and collateral formation in hindlimb ischemia, In: Scientific Reports Nature Research

An acute increase in blood flow triggers flow-mediated dilation (FMD), which is mainly mediated by endothelial nitric oxide synthase (eNOS). A long-term increase in blood flow chronically enlarges the arterial lumen, a process called arteriogenesis. In several common human diseases, these processes are disrupted for as yet unknown reasons. Here, we asked whether β1 integrin, a mechanosensory protein in endothelial cells, is required for FMD and arteriogenesis in the ischemic hindlimb. Permanent ligation of the femoral artery in C57BL/6J mice enlarged pre-existing collateral arteries and increased numbers of arterioles in the thigh. In the lower leg, the numbers of capillaries increased. Notably, injection of β1 integrin-blocking antibody or tamoxifen-induced endothelial cell-specific deletion of the gene for β1 integrin (Itgb1) inhibited both arteriogenesis and angiogenesis. Using high frequency ultrasound, we demonstrated that β1 integrin-blocking antibody or endothelial cell-specific depletion of β1 integrin attenuated FMD of the femoral artery, and blocking of β1 integrin function did not further decrease FMD in eNOS-deficient mice. Our data suggest that endothelial β1 integrin is required for both acute and chronic widening of the arterial lumen in response to hindlimb ischemia, potentially via functional interaction with eNOS.

Andrea Schanz, Dunja M. Baston-Büst, Christian Heiss, Ines M. Beyer, Jan S. Krüssel, Alexandra P. Hess (2014)Interferon stimulated gene 15 expression at the human embryo−maternal interface, In: Archives of Gynecology and Obstetrics290(4)pp. 783-789 Springer Berlin Heidelberg

Purpose In early pregnancy the dialogue between maternal endometrium and embryo is a key process in establishing a receptive decidua and placental network. Decidual ISG15 induction is thought to promote pregnancy maintenance and development. ISG15 is involved in RNA splicing, cytoskeletal organization, stress response and further intracellular processes. Methods ISG15 expression was examined immunohistologically in paraffin-embedded human placental and decidual tissue samples of all pregnancy trimesters on adjacent sections (first trimester n = 5, second n = 5, third n = 3). Samples were processed using a protocol applying a rabbit polyclonal ISG15 antibody. A mouse monoclonal cytokeratin seven antibody was utilized to identify the different placental departments and decidual glands. Staining results and anatomical features were evaluated blindly with strict rating criteria. Results ISG15 expression was identified in first and second trimester tissue samples. ISG15 localized especially to the extravillous cytotrophoblasts in the maternal wall and in maternal blood vessel. Expression was detected in cytotrophoblast progenitor cells in the placental villi and the cell column with a maximum in the first trimester. The syncytial layer stained positive in first and second trimester samples. Third trimester samples showed no expression of ISG15 at all. Conclusions ISG15 abundance in the human placenta is an interesting finding, with implications for placental development, fetal growth and potential defense mechanism against infections. The maximal expression of ISG15 in the first and second trimester of pregnancy suggests that ISG function is needed when placental and embryo development is enormous and embryo susceptibility to external influences is high.

Ana Rodriguez-Mateos, Michael Hezel, Hilal Aydin, Malte Kelm, Jon O. Lundberg, Eddie Weitzberg, Jeremy P.E. Spencer, Christian Heiss (2015)Interactions between cocoa flavanols and inorganic nitrate: Additive effects on endothelial function at achievable dietary amounts, In: FREE RADICAL BIOLOGY AND MEDICINE80pp. 121-128 ELSEVIER SCIENCE INC

Dietary intervention studies have shown that flavanols and inorganic nitrate can improve vascular function, suggesting that these two bioactives may be responsible for beneficial health effects of diets rich in fruits and vegetables. We aimed to study interactions between cocoa flavanols (CF) and nitrate, focusing on absorption, bioavailability, excretion, and efficacy to increase endothelial function. In a double-blind randomized, dose–response crossover study, flow-mediated dilation (FMD) was measured in 15 healthy subjects before and at 1, 2, 3, and 4 h after consumption of CF (1.4–10.9 mg/kg bw) or nitrate (0.1–10 mg/kg bw). To study flavanol–nitrate interactions, an additional intervention trial was performed with nitrate and CF taken in sequence at low and high amounts. FMD was measured before (0 h) and at 1 h after ingestion of nitrate (3 or 8.5 mg/kg bw) or water. Then subjects received a CF drink (2.7 or 10.9 mg/kg bw) or a micro- and macronutrient-matched CF-free drink. FMD was measured at 1, 2, and 4 h thereafter. Blood and urine samples were collected and assessed for CF and nitric oxide (NO) metabolites with HPLC and gas-phase reductive chemiluminescence. Finally, intragastric formation of NO after CF and nitrate consumption was investigated. Both CF and nitrate induced similar intake-dependent increases in FMD. Maximal values were achieved at 1 h postingestion and gradually decreased to reach baseline values at 4 h. These effects were additive at low intake levels, whereas CF did not further increase FMD after high nitrate intake. Nitrate did not affect flavanol absorption, bioavailability, or excretion, but CF enhanced nitrate-related gastric NO formation and attenuated the increase in plasma nitrite after nitrate intake. Both flavanols and inorganic nitrate can improve endothelial function in healthy subjects at intake amounts that are achievable with a normal diet. Even low dietary intake of these bioactives may exert relevant effects on endothelial function when ingested together.

H. Seidel, E. Stegemann, Christian Heiss (2014)Kardiovaskuläre und hämostaseologische Sicht retinaler Gefäßverschlüsse. (Vascular diseases of the retina), In: Der Ophthalmologe111(1)pp. 23-30 Springer

Hintergrund Plötzlich auftretende Sehminderungen sind oft durch akute Gefäßverschlüsse des hinteren Augenabschnitts bedingt und verlaufen schmerzlos. Bei den Gefäßverschlüssen der hinteren Augenabschnitte unterscheidet man arterielle von venösen Okklusionen. Dabei finden sich mit etwa 60 % aller Fälle häufiger venöse als arterielle Verschlüsse. Zusätzlich gibt es jedoch auch Mischbilder. Ziel der Arbeit Der Beitrag bietet eine Zusammenfassung der aktuellen Datenlage zur interdisziplinären Diagnostik und Therapie retinaler Gefäßverschlüsse. Material und Methoden Es erfolgte eine selektive Literaturrecherche unter Berücksichtigung klinisch relevanter kardiovaskulärer und hämostaseologischer Aspekte. Ergebnisse Die ophthalmologische Lokalisation des betroffenen Gefäßsegments kann dem Internisten entscheidende Hinweise für die weiterführende Diagnostik und Therapie geben. Bei arteriellen Verschlüssen muss an ein thromboembolisches Geschehen gedacht, Emboliequellen müssen identifiziert und diese internistisch behandelt werden. Venösen Verschlüssen liegen meist lokale Prozesse auf dem Hintergrund thrombophiler Hämostasestörungen oder blutdruckassoziierte venöse Stase zugrunde. Prognostisch sind die Lokalisation, das Ausmaß, die Dauer und die Intensität der retinalen Ischämie von besonderer Bedeutung. Diskussion Diese Erkrankungen des Auges sind meist eine Folge von internistischen Grunderkrankungen und stellen daher eine interdisziplinäre Herausforderung dar.

D. Schuler, R. Sansone, T. Freudenberger, A. Rodriguez-Mateos, G. Weber, T. Y. Momma, C. Goy, J. Altschmied, J. Haendeler, J. W. Fischer, M. Kelm, C. Heiss (2014)Measurement of Endothelium-Dependent Vasodilation in Mice--Brief Report, In: ARTERIOSCLEROSIS THROMBOSIS AND VASCULAR BIOLOGY34(12)pp. 2651-2657 LIPPINCOTT WILLIAMS & WILKINS

Objective — Endothelium-dependent, flow-mediated vasodilation after an increase in shear stress at the endothelial lining of conduit arteries during reactive hyperemia after ischemia is a fundamental principle of vascular physiology adapting blood flow to demand of supplied tissue. Flow-mediated vasodilation measurements have been performed in human studies and are of diagnostic and prognostic importance, but have been impossible because of technical limitations in transgenic mice to date, although these represent the most frequently used animal model in cardiovascular research. Approach and Results — Using high-frequency ultrasound, we visualized, quantified, and characterized for the first time endothelium-dependent dilation of the femoral artery after temporal ischemia of the lower part of the hindlimb and demonstrated that the signaling was almost exclusively dependent on stimulation of endothelial nitric oxide synthase, similar to acetylcholine, completely abolished after pharmacological or genetic inhibition of endothelial nitric oxide synthase and endothelial denudation, substantially impaired in mice of increasing age and cholesterol-fed ApoE knock outs and increased by the dietary polyphenol (−)-epicatechin. Intra- and interindividual variability were similar to the human methodology. Conclusions — The physiology of flow-mediated vasodilation in mice resembles that in humans underscoring the significance of this novel technology to noninvasively, serially, and reliably quantify flow-mediated vasodilation in transgenic mice.—

Michael Gröne, Roberto Sansone, Phillip Höffken, Patrick Horn, Ana Rodriguez-Mateos, Hagen Schroeter, Malte Kelm, Christian Heiss (2019)Cocoa flavanols improve endothelial functional integrity in healthy young and elderly subjects, In: Journal of Agricultural and Food Chemistry American Chemical Society

Cocoa flavanols (CF) can improve vascular stiffness, blood pressure, and flow-mediated dilation (FMD) in healthy subjects. Endothelial microparticles (EMPs) are markers of endothelial functional integrity reflecting activation and injury. In plasma samples, we investigated whether age-dependent changes in circulating EMPs exist and whether CFs decrease EMPs in healthy humans. The concentrations of CD31+/41-, CD144+, and CD62e+-EMPs (flow-cytometry) were increased in healthy elderly (n=19) as compared to young (n=20) non-smokers. EMPs correlated with age, systolic blood pressure, and pulse wave velocity. CD31+/41- and CD62e+-EMPs inversely correlated with FMD. Following 2 weeks twice-daily CF consumption (450 mg), CD31+/41- and CD144+-EMPs decreased both in young and elderly subjects compared to CF-free control. The EMP decrease inversely correlated with FMD improvements. Cardiovascular aging is associated with increased EMPs that can be modulated by dietary flavanols along with improvements in vascular function. This indicates that flavanol consumption can improve endothelial functional integrity in healthy humans.

Anna Vogiatzoglou, Angela A. Mulligan, Robert N. Luben, Marleen A. H. Lentjes, Christian Heiss, Malte Kelm, Marc W. Merx, Jeremy P. E. Spencer, Hagen Schroeter, Gunter G. C. Kuhnle (2014)Assessment of the dietary intake of total flavan-3-ols, monomeric flavan-3-ols, proanthocyanidins and theaflavins in the European Union, In: BRITISH JOURNAL OF NUTRITION111(08)pp. 1463-1473 CAMBRIDGE UNIV PRESS

Dietary interventions with flavan-3-ols have shown beneficial effects on vascular function. The translation of these findings into the context of the health of the general public requires detailed information on habitual dietary intake. However, only limited data are currently available for European populations. Therefore, in the present study, we assessed the habitual intake of flavan-3-ol monomers, proanthocyanidins (PA) and theaflavins in the European Union (EU) and determined their main food sources using the EFSA (European Food Safety Authority) Comprehensive European Food Consumption Database. Data for adults aged 18–64 years were available from fourteen European countries, and intake was determined using the FLAVIOLA Flavanol Food Composition Database, developed for the present study and based on the latest US Department of Agriculture and Phenol-Explorer databases. The mean habitual intake of flavan-3-ol monomers, theaflavins and PA ranged from 181 mg/d (Czech Republic) to 793 mg/d (Ireland). The highest intakes of flavan-3-ol monomers and theaflavins were observed in Ireland (191/505 mg/d) and the lowest intakes in Spain (24/9 mg/d). In contrast, the daily intake of PA was highest in Spain (175 mg/d) and lowest in The Netherlands (96 mg/d). Main sources were tea (62 %), pome fruits (11 %), berries (3 %) and cocoa products (3 %). Tea was the major single contributor to monomer intake (75 %), followed by pome fruits (6 %). Pome fruits were also the main source of PA (28 %). The present study provides important data on the population-based intake of flavanols in the EU and demonstrates that dietary intake amounts for flavan-3-ol monomers, PA and theaflavins vary significantly across European countries. The average habitual intake of flavan-3-ols is considerably below the amounts used in most dietary intervention studies.

Christian Heiss (2019)Electronic cigarettes: Replacing one evil with another?, In: European Journal of Preventive Cardiology26(11)pp. 1217-1218 SAGE Publications

Cigarette smoking is still the most important avoidable cardiovascular risk factor. The World Health Organization estimates that 20.2% (34.1% male, 6.1% females) of the world’s population aged ≥15 years were current smokers in 2015. Within non-communicable diseases, tobacco use is estimated to be responsible for 10% of all deaths from cardiovascular diseases, 22% of all cancer deaths and 36% of all deaths from diseases of the respiratory system. Recent data suggest that tobacco smoking may also increase the risk of atrial fibrillation. Electronic cigarettes may be an effective way to assist with smoking cessation. A recent randomized trial demonstrated that electronic cigarettes were more effective for smoking cessation at one year than nicotine replacement therapy. However, the smoking cessation rate was only 18%, and among participants with one-year abstinence, 80% of those in the e-cigarette group were still using electronic cigarettes. This brings up the question of whether this approach merely replaces one evil with another. Clearly, knowledge on the safety of electronic cigarettes is critical in answering this question.

Ana Rodriguez-Mateos, Christian Heiss, Gina Borges, Alan Crozier (2013)Berry (Poly)phenols and Cardiovascular Health, In: Journal of Agricultural and Food Chemistry62(18)pp. 3842-3851 ACS Publications

Berries are a rich source of (poly)phenols, including anthocyanins, flavan-3-ols, procyanidins, flavonols, ellagitannins, and hydroxycinnamates. Epidemiological evidence indicates that the cardiovascular health benefits of diets rich in berries are related to their (poly)phenol content. These findings are supported by small-scale randomized controlled studies (RCTs) that have shown improvements in several surrogate markers of cardiovascular risk such as blood pressure, endothelial function, arterial stiffness, and blood lipids after acute and short-term consumption of blueberries, strawberries, cranberries, or purified anthocyanin extracts in healthy or diseased individuals. However, firm conclusions regarding the preventive value of berry (poly)phenols cannot be drawn due to the small number of existing studies and limitations that apply to the available data, such as lack of controls or failure to assess the absorption and metabolism of (poly)phenols. Although the current evidence is promising, more long-term RCTs are needed to establish the role of berry (poly)phenols to support cardiovascular health

Ana Rodriguez-Mateos, Geoffrey Istas, Lisa Boschek, Rodrigo P Feliciano, Charlotte E Mills, Céline Boby, Sergio Gomez-Alonso, Dragan Milenkovic, Christian Heiss (2019)Circulating anthocyanin metabolites mediate vascular benefits of blueberries: insights from randomized controlled trials, metabolomics, and nutrigenomics, In: The Journals of Gerontology: Series A74(7)pp. p 967-976 Oxford University Press (OUP)

Potential health benefits of blueberries may be due to vascular effects of anthocyanins which predominantly circulate in blood as phenolic acid metabolites. We investigated which role blueberry anthocyanins and circulating metabolites play in mediating improvements in vascular function and explore potential mechanisms using metabolomics and nutrigenomics. Purified anthocyanins exerted a dose-dependent improvement of endothelial function in healthy humans, as measured by flow-mediated dilation (FMD). The effects were similar to those of blueberries containing similar amounts of anthocyanins while control drinks containing fiber, minerals, or vitamins had no significant effect. Daily 1-month blueberry consumption increased FMD and lowered 24h-ambulatory-systolic-blood-pressure. Of the 63 anthocyanin plasma metabolites quantified, 14 and 17 correlated with acute and chronic FMD improvements, respectively. Injection of these metabolites improved FMD in mice. Daily blueberry consumption led to differential expression (>1.2-fold) of 608 genes and 3 microRNAs, with Mir-181c showing a 13-fold increase in peripheral blood mononuclear cells. Patterns of 13 metabolites were independent predictors of gene expression changes and pathway enrichment analysis revealed significantly modulated biological processes involved in cell adhesion, migration, immune response, and cell differentiation. Our results identify anthocyanin metabolites as major mediators of vascular bioactivities of blueberries and changes of cellular gene programs.

Volker Schulze, Christian Meyer, Christian Eickholt, Roberto Sansone, Stefanie Keymel, Christian Heiss, Tienush Rassaf, Malte Kelm, Stephan Steiner (2018)Impact of Continuous Positive Airway Pressure on Left Ventricular Systolic Loading and Coronary Flow Reserve in Healthy Young Men, In: Heart, Lung and Circulation27(3)pp. 344-349 Elsevier

Background: Increased augmentation index (AIx) is accompanied by an elevated cardiovascular risk. A reduction of AIx is known for long-term continuous positive airway pressure (CPAP) therapy. We hypothesised that acute preload and left ventricular workload effects AIx and subendocardial viability ratio (SEVR) as a marker of coronary flow reserve. Methods: Increased augmentation index and central blood pressure parameters were measured by radial artery tonometry in 17 healthy men (32/ ± 6 years) at rest and during CPAP ventilation at pressures of 5, 10 mbar and after recovery. In a subset of seven individuals, haemodynamic parameters and autonomic function were additionally examined using combined impedance cardiography and continuous noninvasive blood pressure monitoring. Results: Continuous positive airway pressure reduced heart rate corrected (AIx@75) (-2.8 ± 8.1 [rest] to −10.7 ± 11.3 [5 mbar], p < 0.01, to −12.2 ± 10.5% [10 mbar], p < 0.01) and systolic time integral as a marker of left ventricular workload (2115 ± 231 [rest] to 1978 ± 290 [5 mbar], p = 0.02 to 1940 ± 218 [10 mbar], p < 0.01 to 2013 ± 241 mmHg/s per min [recovery], p = 0.03), while central systolic pressure did not change during CPAP. Total Peripheral Resistance Index increased reaching level of significance at 10 mbar CPAP condition (1701 ± 300 [rest] to 1850 ± 301 dyn*s*m2/cm5 [10 mbar], p = 0.04). There was a reversible increase of SEVR under CPAP conditions. Conclusions: Continuous positive airway pressure ventilation acutely reduces AIx, heart rate and left ventricular workload in healthy young men. These effects seem to be mediated by left ventricular filling pressure, workload and reflection wave. Furthermore, we found an increase of subendocardial viability ratio as an indication for a rising coronary flow reserve by CPAP.

Y. Heinen, E. Stegemann, R. Sansone, K. Benedens, R. Wagstaff, J. Balzer, T. Rassaf, T. Lauer, M. Kelm, C. Heiss (2015)Local Association Between Endothelial Dysfunction and Intimal Hyperplasia: Relevance in Peripheral Artery Disease, In: Journal of the American Heart Association4(2)pp. e001472-e001472 Wiley

Background Endothelial dysfunction is a key factor in the development of atherosclerosis. Commonly, endothelial function is determined in the brachial artery, whereas patients with peripheral artery disease (PAD) present with lower limb atherosclerosis. We hypothesized that in PAD, a segmental or local association exists between endothelial dysfunction and atherosclerotic structural changes. Methods and Results We used ultrasound to study endothelial function as flow‐mediated vasodilation, intima media thickness, and local stiffness of the superficial femoral artery (SFA) and brachial artery (BA). PAD patients with symptomatic SFA or below‐the‐knee disease were compared with age‐matched patients without PAD and young healthy controls. PAD patients with SFA or below‐the‐knee disease exhibited endothelial dysfunction of the proximal SFA (flow‐mediated vasodilation: 3.9±0.6%, 3.7±0.6%) compared with healthy controls (7.4±1.0%) and patients without PAD (5.4±0.6%). Brachial artery flow‐mediated vasodilation values were not different in PAD patients with SFA or below‐the‐knee disease compared with patients without PAD, but they were significantly lower than those of healthy controls. Endothelial dysfunction correlated with increased intima media thickness or plaque thickness at the site of flow‐mediated vasodilation measurement across vascular sites. In PAD patients with SFA disease, SFA flow‐mediated vasodilation was further impaired within and distal to stenosis (prestenosis 3.9±0.6%, intrastenosis 2.3±0.7%, poststenosis 2.5±0.6%) and recovered within 24 hours after SFA balloon angioplasty to prestenotic values but not to the brachial artery or SFA values in patients without PAD or controls. Conclusion A close association exists between local endothelial function and atherosclerotic structural remodeling, suggesting that in PAD, local and segmental factors—in addition to systemic factors—influence local endothelial function. Our data point toward a pathophysiological role for lower extremity endothelial dysfunction in PAD.

A. Schanz, K. Red-Horse, A.P. Hess, D.M. Baston-Büst, C. Heiss, J.S. Krüssel (2014)Oxygen regulates human cytotrophoblast migration by controlling chemokine and receptor expression, In: Placenta35(12)pp. 1089-1094 Elsevier

Introduction Placental development involves the variation of oxygen supply due to vascular changes and cytotrophoblast invasion. Chemokines and their receptors play an important role during placental formation. Herein, the analysis of the chemokine/receptor pair CXCL12/CXCR4 and further chemokine receptors, such as CCR1, CCR7 and CXCR6 expression in human cytotrophoblasts was conducted. Methods Human cytotrophoblasts were examined directly after isolation or after incubation with different oxygen tensions and a chemical HIF-stimulator for 12 h with realtime PCR, immunoblot, immunohistochemistry. Conditioned media of placental villi, decidua, and endothelial cells was used for ELISA analysis of CXL12. Cytotrophoblast migration assays were conducted applying conditioned media of endothelial cells, a CXCL12 gradient, and different oxygen level. Endometrial and decidual tissue was stained for CXCL12 expression. Results An upregulation of CXCL12, CXCR4, CCR1, CCR7 and CXCR6 was observed after cytotrophoblast differentiation. Low oxygen supply upregulated CXCR4, CCR7 and CXCR6, but downregulated CXCL12 and CCR1. In contrast to the HIF associated upregulation of the aforementioned proteins, downregulation of CXCL12 and CCR1 seemed to be HIF independent. Cytotrophoblast migration was stimulated by low oxygen, the application of a CXCL12 gradient and endothelial cell conditioned media. CXCL12 was detected in endometrial vessels, glands and conditioned media of placental and decidual tissue, but not decidual vessels. Discussion/conclusion Taken together, oxygen supply and cytotrophoblast differentiation seem to be regulators of chemokine and receptor expression and function in human cytotrophoblasts. Therefore, this system seems to be involved in placental development, directed cytotrophoblast migration in the decidual compartment and a subsequent sufficient supply of the growing fetus.

Marc W. Merx, Patrick Horn, Gülsüm Erkilet, Verena Veulemans, Patric Kröpil, Leon Schurgers, Tobias Zeus, Christian Heiss, Malte Kelm, Ralf Westenfeld (2016)Microparticle-Induced Coagulation Relates to Coronary Artery Atherosclerosis in Severe Aortic Valve Stenosis, In: PLOS ONE11(3)e0151499 Public Library of Science

Background Circulating microparticles (MPs) derived from endothelial cells and blood cells bear procoagulant activity and promote thrombin generation. Thrombin exerts proinflammatory effects mediating the progression of atherosclerosis. Aortic valve stenosis may represent an atherosclerosis-like process involving both the aortic valve and the vascular system. The aim of this study was to investigate whether MP-induced thrombin generation is related to coronary atherosclerosis and aortic valve calcification. Methods In a cross-sectional study of 55 patients with severe aortic valve stenosis, we assessed the coronary calcification score (CAC) as indicator of total coronary atherosclerosis burden, and aortic valve calcification (AVC) by computed tomography. Thrombin-antithrombin complex (TATc) levels were measured as a marker for thrombin formation. Circulating MPs were characterized by flow cytometry according to the expression of established surface antigens and by measuring MP-induced thrombin generation. Results Patients with CAC score below the median were classified as patients with low CAC, patients with CAC Score above the median as high CAC. In patients with high CAC compared to patients with low CAC we detected higher levels of TATc, platelet-derived MPs (PMPs), endothelial-derived MPs (EMPs) and MP-induced thrombin generation. Increased level of PMPs and MP-induced thrombin generation were independent predictors for the severity of CAC. In contrast, AVC Score did not differ between patients with high and low CAC and did neither correlate with MPs levels nor with MP-induced thrombin generation. Conclusion In patients with severe aortic valve stenosis MP-induced thrombin generation was independently associated with the severity of CAC but not AVC indicating different pathomechanisms involved in coronary artery and aortic valve calcification.

Emilia Stegemann, R. Sansone, B. Stegemann, M. Kelm, C. Heiss (2015)Validation of High-Resolution Ultrasound Measurements of Intima–Media Thickness of the Radial Artery for the Assessment of Structural Remodeling, In: Angiology66(6)pp. 574-577 Sage Publications

Radial artery (RA) intima–media thickness (IMT) could be used to study short- and long-term structural vascular adaptation following transradial cardiac catheterization. We aimed at assessing the reliability and reproducibility of RA-IMT measurement. Using high-resolution ultrasound, we studied RA-IMT in 17 patients, who underwent transradial catheterization via the right RA 1 to 12 months before. Radial artery intima–media thickness was measured in both arms, with the left RA as control. Repeated measurements were performed by 2 examiners and offline analyses were performed by independent blinded interpreters. Radial artery intima–media thickness was highly reliable with an interclass correlation coefficient (ICC) of 0.911 [0.870-0.939], a high examiner (ICCexaminer 0.910 [0.883-0.931]), and interpreter agreement (ICCinterpreter 0.963 [0.954-0.971]). Intima–media thickness at the radial access site was significantly increased compared with the contralateral RA (0.30 ± 0.056 vs 0.41 ± 0.055 mm, P < .00001). Radial artery intima–media thickness can be measured reliably using high-resolution ultrasound. Initial data suggest that transradial catheterization leads to long-term structural adaption processes.

Emilia Stegemann, Lucas Busch, Berthold Stegemann, Thomas Lauer, Rainer Hoffmann, Christian Heiss, Malte Kelm (2015)Evaluation of a Structured Training Program for Arterial Femoral Sheath Removal after Percutaneous Arterial Catheter Procedures by Assistant Personnel, In: The American Journal of Cardiology115(7)pp. 879-883 Elsevier
Manuel Stern, Melanie Broja, Roberto Sansone, Michael Gröne, Simon Skene, Joerg Liebmann, Christoph Suschek, Matthias Born, Malte Kelm, Christian Heiss (2018)Blue light exposure decreases systolic blood pressure, arterial stiffness, and improves endothelial function in humans, In: European Journal of Preventive Cardiology25(17)pp. 1875-1883 SAGE Publications

Aims: Previous studies have shown that ultraviolet light can lead to release of nitric oxide (NO) from the skin and decrease blood pressure. In contrast to visible light local application of UV light bears a cancerogenic risk. Here, we investigated whether whole body exposure to visible blue light can also decrease blood pressure and increase endothelial function in healthy subjects. Methods: In a randomized cross-over study, 14 healthy male subjects were exposed on 2 days to monochromatic blue light or blue light with a filter foil (control light) over 30 min. We measured blood pressure (primary endpoint), heart rate, forearm vascular resistance, forearm-blood-flow, endothelial function (flow-mediated dilation), pulse wave velocity, and plasma NO species (NOx), nitrite, and nitroso compounds (RXNO) (secondary endpoints) during and up to 2 hours after exposure. Results: Blue light exposure significantly decreased systolic blood pressure and increased heart rate as compared to control. In parallel, blue light significantly increased forearm-blood-flow, flow-mediated dilation, circulating NOx and RXNO while it decreased forearm vascular resistance and pulse wave velocity. Conclusion: Whole body irradiation with visible blue light at real world doses improves blood pressure, endothelial function, and arterial stiffness by NO released from photolabile intracutanous NO metabolites into circulating blood.

Ana Rodriguez-Mateos, Raquel Del Pino-García, Trevor W. George, Alberto Vidal-Diez, Christian Heiss, Jeremy P. E. Spencer (2014)Impact of processing on the bioavailability and vascular effects of blueberry (poly)phenols, In: MOLECULAR NUTRITION & FOOD RESEARCH58(10)pp. 1952-1961 WILEY-V C H VERLAG GMBH

Scope Blueberries are a rich source of flavonoids and phenolic acids. Currently, little information is available regarding the impact of processing on the bioavailability and the bioactivity of blueberry (poly)phenols. Methods and results In a randomized, controlled crossover trial, ten healthy volunteers consumed (a) blueberry‐containing baked products, (b) an unprocessed blueberry drink containing the same amount of freeze‐dried blueberry powder as used in the baked products, and (c) matched control baked products. Endothelial function was measured as flow‐mediated dilation (FMD) and plasma samples taken at baseline and at 1, 2, 4, and 6 h postconsumption. Although processing did not significantly change the total (poly)phenolic amount, the processed products contained significantly less anthocyanins (−42%), more chlorogenic acid (23%), no flavanol nonamers or decamers, and significantly more flavanol dimers and trimers (36% and 28%, respectively). FMD increased after 1, 2, and 6 h consumption of the baked products to a similar degree as the unprocessed blueberries, despite significant differences in the levels of individual plasma metabolites. No changes were observed after the consumption of the control product. Conclusion Careful processing can preserve important biological activities of blueberries despite changing the blueberry (poly)phenol composition and plasma metabolite profile.

Patrick Horn, Daniel Stern, Verena Veulemans, Christian Heiss, Tobias Zeus, Marc W. Merx, Malte Kelm, Ralf Westenfeld (2015)Improved endothelial function and decreased levels of endothelium-derived microparticles after transcatheter aortic valve implantation, In: EuroIntervention10(12)pp. 1456-1463 Europa Digital & Publishing

AIMS: Degenerative aortic valve stenosis (AVS) is independently associated with endothelial dysfunction and increased levels of circulating endothelium-derived microparticles (EMPs) as a marker of compromised endothelial integrity. The aim of this study was to investigate whether therapy for severe AVS by transcatheter aortic valve implantation (TAVI) improves endothelial function and decreases EMPs. METHODS AND RESULTS: Fifty-six patients with indication for TAVI due to symptomatic severe AVS were prospectively enrolled. Brachial wall shear stress (WSS), endothelial function and circulating microparticles (MPs) were measured before and three months following TAVI. Endothelial function was assessed as flow-mediated dilation (FMD) using ultrasound. MP subpopulations were discriminated by flow cytometry according to the expression of established surface antigens: CD31+/CD41-, CD144+ and CD62E+ as EMPs and CD41+ as platelet-derived MPs (PMPs). In patients with severe AVS, decreased brachial WSS was an independent predictor of low FMD. At three-month follow-up after TAVI, WSS and FMD increased along with decreased levels of EMPs as compared to pre TAVI. Decrease of CD31+/CD41-, CD144+ and CD62E+ EMP levels correlated with the increase of FMD. CONCLUSIONS: Therapy for AVS by TAVI was associated with improved endothelial function and integrity indicating beneficial effects of TAVI on systemic arterial function.

Ana Rodriguez-Mateos, Natalia Toro-Funes, Tania Cifuentes-Gomez, Miriam Cortese-Krott, Christian Heiss, Jeremy P.E. Spencer (2014)Uptake and metabolism of (−)-epicatechin in endothelial cells, In: ARCHIVES OF BIOCHEMISTRY AND BIOPHYSICS559pp. 17-23 ELSEVIER SCIENCE INC

Accumulating evidence suggest that diets rich in cocoa flavanols may have beneficial effects on cardiovascular health. The major cocoa flavanol monomer, (−)-epicatechin (EC), is readily absorbed and circulates primarily as glucuronidated, sulfated, and O-methylated metabolites in human plasma. However, cellular metabolism, for example in endothelial cells, is less well defined. In the present study we detail the uptake and cellular metabolism of EC and its major in vivo metabolites, (−)-epicatechin-3′-β-d-glucuronide (E3G), (−)-epicatechin-3′-sulfate (E3S), 3′-O-methyl-(−)-epicatechin-5-sulfate (3ME5S), and 3′-O-methyl-(−)-epicatechin-7-sulfate (3ME7S) in human endothelial (HUVEC), liver (HepG2) and intestinal epithelial cells (Caco-2 monolayer). Our results indicate that EC associates with HUVECs, leading to its intracellular metabolism to 3ME7G and 3ME7S. In contrast, none of the metabolites were taken up by the cells. The metabolic rate and pattern of metabolism in HUVECs was similar to that observed in HepG2 cells, whilst in Caco-2 cells EC was metabolized to E3G, 3ME5G, 3ME7G, 4ME5G, 4ME7G and 3ME7S. Our data support the notion that endothelial cells may contribute significantly to EC metabolism. However, major human circulating metabolites are not accounted for in these model systems underscoring that caution should be taken when drawing conclusions on in vivo flavanol metabolism from in vitro experiments.

Verena Veulemans, Shazia Afzal, Paul Ledwig, Christian Heiss, Lucas Busch, Roberto Sansone, Dagmar B. Soetemann, Oliver Maier, Laura Kleinebrecht, Malte Kelm, Tobias Zeus, Katharina Hellhammer (2018)Stent fractures after common femoral artery bail-out stenting due to suture device failure in TAVR, In: Vasa47(5)pp. 393-401 Hogrefe

Background: Vascular access site-related complications are frequent in the context of transfemoral transcatheter aortic valve replacement (TAVR). The implantation of a covered stent graft is an effective treatment option for bleeding control. However, the external iliac and common femoral arteries are exposed to flexion of the hip joint. Therefore, stent compression and stent/strut fractures may occur, facilitating stent occlusion. Patients and methods: In all 389 patients who received transfemoral TAVR from 2013–2015 at the Düsseldorf Heart Centre, we monitored the management of vascular access site-related complications. Our analyses focused on immediate technical success and bleeding control, primary patency, and the occurrence of stent/strut fractures after six to 12 months of follow-up. Results: Vascular access site-related complications occurred in 13 % (n = 51), whereof in 10 patients, the bleeding was successfully managed by prolonged compression. In 40 out of 51 patients, a covered stent graft was implanted in the common femoral artery, leading to 100 % immediate bleeding control. After a mean follow-up of 334 ± 188 days, 28 stents out of 29 patients with completed follow-up (excluding e. g. death) were without flow-limiting stenosis (primary patency 97 %) or relevant stent compression (diameter pre/post 8.6/8.1 mm, p = 0.048, late lumen loss 1.1 ± 0.2 mm, mean flow velocity 92 ± 34 cm/s). In four asymptomatic patients, stent/strut fractures were detected (14 %) without flow-limiting stenosis. Conclusions: The implantation of a covered stent graft is highly effective and safe to control vascular access site-related complications after TAVR. Stent/strut fractures in the flexible segment of the common femoral artery may occur, as consequently verified by X-ray visualization, but show no impairment on flow or clinical parameters after six to 12 months.

Ulrich Frank, Sigrid Nikol, Jill Belch, Vinko Boc, Marianne Brodmann, Patrick H. Carpentier, Ali Chraim, Caitriona Canning, Evangelos Dimakakos, Anders Gottsäter, Christian Heiss, Lucia Mazzolai, Juraj Madaric, Dan Mircea Olinic, Zsolt Pécsvárady, Pavel Poredoš, Isabelle Quéré, Karel Roztocil, Agata Stanek, Dragan Vasic, Adriana Visonà, Jean-Claude Wautrecht, Miroslav Bulvas, Mary-Paula Colgan, Walter Dorigo, Graeme Houston, Thomas Kahan, Holger Lawall, Isak Lindstedt, Guillaume Mahe, Romeo Martini, Giles Pernod, Stanislaw Przywara, Marc Righini, Oliver Schlager, Piotr Terlecki (2019)ESVM Guideline on peripheral arterial disease, In: Vasa48(Supple)pp. 1-79 Hogrefe
Javier I. Ottaviani, Tony Y. Momma, Christian Heiss, Catherine Kwik-Uribe, Hagen Schroeter, Carl L. Keen (2011)The stereochemical configuration of flavanols influences the level and metabolism of flavanols in humans and their biological activity in vivo, In: FREE RADICAL BIOLOGY AND MEDICINE50(2)pp. 237-244 ELSEVIER SCIENCE INC

Abstract Extensive epidemiological and clinical evidence associates diets high in flavanol-containing foods with cardiovascular health benefits in humans. Catechin and epicatechin, the most common flavanols in foods, are present in the diet in different enantiomeric forms. This study investigated the influence of the stereochemical configuration of flavanols on their absorption, metabolism, and biological activity. Healthy adult males were asked to consume equal amounts of the stereochemically pure flavanols (−)­epicatechin, (−)­catechin, (+)­catechin, and (+)­epicatechin (1.5 mg/kg bw) in a well-defined cocoa-based, dairy-containing drink matrix, and flavanol levels were subsequently determined in plasma and 24-h urine. The results obtained show that the stereochemical configuration of flavanols has a profound influence on their uptake and metabolism in humans. In addition, we assessed the vasodilatory activity of each flavanol stereoisomer in vivo and found (−)-epicatechin to be the single stereoisomer capable of mediating a significant arterial dilation response. Importantly, this effect was independent of the classic antioxidant properties of flavanols. Overall, these results indicate that the proposed beneficial health effects associated with the consumption of flavanol-containing foods will significantly depend on the stereochemical configuration of the flavanols ingested.

Anna Vogiatzoglou, Angela A Mulligan, Amit Bhaniani, Marleen A.H Lentjes, Alison McTaggart, Robert N. Luben, Christian Heiss, Malte Kelm, Marc W. Merx, Jeremy P.E Spencer, Hagen Schroeter, Kay-Tee Khaw, Gunter G.C. Kuhnle (2015)Associations between flavan-3-ol intake and CVD risk in the Norfolk cohort of the European Prospective Investigation into Cancer (EPIC-Norfolk), In: Free Radical Biology and Medicine84pp. 1-10 Elsevier

Dietary intervention studies suggest that flavan-3-ol intake can improve vascular function and reduce the risk of cardiovascular diseases (CVD). However, results from prospective studies failed to show a consistent beneficial effect. Associations between flavan-3-ol intake and CVD risk in the Norfolk arm of the European Prospective Investigation into Cancer and Nutrition (EPIC-Norfolk) were investigated. Data were available from 24,885 (11,252 men; 13,633 women) participants, recruited between 1993 and 1997 into the EPIC-Norfolk study. Flavan-3-ol intake was assessed using 7-day food diaries and the FLAVIOLA Flavanol Food Composition database. Missing data for plasma cholesterol and vitamin C were imputed using multiple imputation. Associations between flavan-3-ol intake and blood pressure at baseline were determined using linear regression models. Associations with CVD risk were estimated using Cox regression analyses. Median intake of total flavan-3-ols was 1034 mg/d (range: 0–8531 mg/d) for men and 970 mg/d (0–6695 mg/d) for women, median intake of flavan-3-ol monomers was 233 mg/d (0–3248 mg/d) for men and 217 (0–2712 mg/d) for women. There were no consistent associations between flavan-3-ol monomer intake and baseline systolic and diastolic blood pressure (BP). After 286,147 person-years of follow-up, there were 8463 cardiovascular events and 1987 CVD related deaths; no consistent association between flavan-3-ol intake and CVD risk (HR 0.93, 95% CI: 0.87; 1.00; Q1 vs Q5) or mortality was observed (HR 0.93, 95% CI: 0.84; 1.04). Flavan-3-ol intake in EPIC-Norfolk is not sufficient to achieve a statistically significant reduction in CVD risk.

Dirk Blondin, Christian Heiss (2013)Vascular Imaging Using MR Angiography. (MR-Angiografie zur Gefäßdiagnostik)., In: Aktuelle Kardiologie2(2)pp. 112-118

Contrast enhanced magnetic resonance angiography (MRA) with gadolinium containing contrast media has evolved to a standard non-invasive imaging modality. High quality 3D vessel reconstructions can be acquired using conventional MR scanners together with body surface coils and 3D gradient sequences. The predominant indications for MRAs lie in the diagnostics, planning of vascular interventions and surgery of patients suffering from peripheral artery disease. With high sensitivity and specificity clinically relevant stenoses can be detected and collateral vessels identified. Methodological limitations mainly lie in the imaging of small and peripheral arteries and stented segments. The most important contraindications comprise conventional cardiac pacemakers, implantable defibrillators, paramagnetic implants, and 1st trimester pregnancy. Furthermore, in patients with severe renal failure (glomerular filtration rate of less than 30 ml/min/1.73 m2) gadolinium containing contrast medium should not be used as these patients are at increased risk of development of nephrogenic systemic fibrosis for which no treatment exists. Novel contrast free MRA techniques (e.g. QISS) have been developed and are currently under clinical validation but are not yet widely available.

Kranthi Pinnamaneni, Richard E. Sievers, Rikki Sharma, Amanda M. Selchau, Gustavo Gutierrez, Eric J. Nordsieck, Robert Su, Songtao An, Qiumei Chen, Xiaoyin Wang, Ronak Derakhshandeh, Kirstin Aschbacher, Christian Heiss, Stanton A. Glantz, Suzaynn F. Schick, Matthew L. Springer (2013)Brief Exposure to Secondhand Smoke Reversibly Impairs Endothelial Vasodilatory Function, In: Nicotine & Tobacco Research16(5)pp. 584-590 Oxford Journals

Introduction: We sought to determine the effects of brief exposures to low concentrations of tobacco secondhand smoke (SHS) on arterial flow-mediated dilation (FMD, a nitric oxide-dependent measure of vascular endothelial function), in a controlled animal model never before exposed to smoke. In humans, SHS exposure for 30min impairs FMD. It is important to gain a better understanding of the acute effects of exposure to SHS at low concentrations and for brief periods of time. Methods: We measured changes in FMD in rats exposed to a range of real-world levels of SHS for durations of 30min, 10min, 1min, and 4 breaths (roughly 15 s). Results: We observed a dose-response relationship between SHS particle concentration over 30min and post-exposure impairment of FMD, which was linear through the range typically encountered in smoky restaurants and then saturated at higher concentrations. One min of exposure to SHS at moderate concentrations was sufficient to impair FMD. Conclusions: Brief SHS exposure at real-world levels reversibly impairs FMD. Even 1min of SHS exposure can cause reduction of endothelial function.

Christian Meyer, Christian Heiss, Christine Drexhage, Eva S. Kehmeier, Jan Balzer, Anja Mühlfeld, Marc W. Merx, Thomas Lauer, Harald Kühl, Jürgen Floege, Malte Kelm, Tienush Rassaf (2010)Hemodialysis-Induced Release of Hemoglobin Limits Nitric Oxide Bioavailability and Impairs Vascular Function, In: Journal of the American College of Cardiology55(5)pp. 454-459 Elsevier

Objectives This study sought to characterize the impact of hemodialysis (HD)-induced release of hemoglobin on the bioavailability of nitric oxide (NO) and endothelial function. Background Patients on chronic HD suffer from endothelial dysfunction and a massively increased risk for cardiovascular events. Although dialysis-dependent and -independent factors are discussed, the exact mechanisms are not fully understood. Methods In 14 HD patients (56 ± 15 years of age), endothelial function was determined by measuring flow-mediated dilation (FMD) of the brachial artery using high-resolution ultrasound before and after treatment. The NO consumption activity of plasma isolated from patients before and after hemodialysis was studied with an NO-sensitive electrode. Results HD impaired FMD (3.5 ± 2.6% to 1.7 ± 1.4%, p = 0.04) without affecting brachial artery diameter (4.7 ± 0.6 mm vs. 4.4 ± 0.9 mm, p = 0.27). This was accompanied by an increase in cell-free plasma hemoglobin (196 ± 43 mg/l to 285 ± 109 mg/l, p = 0.01), which led to a decrease in the bioavailability of free NO by more than 70%. Oxidation of the released plasma ferrous hemoglobin prevented the consumption of NO. The amount of decompartmentalized hemoglobin after HD correlated inversely with the change in FMD (r = −0.65, p = 0.041). Conclusions Our data support a role of HD-induced release of hemoglobin in the pathogenesis of endothelial dysfunction in patients with end-stage renal disease. Approaches that oxidize free plasma hemoglobin may restore NO bioavailability and may have potential beneficial effects on vascular function. (Influence of Hemodialysis on Endothel-Depending Dilatation of Peripheral Arteries; NCT00764192)

Anna Eckers, Sascha Jakob, Christian Heiss, Thomas Haarmann-Stemmann, Christine Goy, Vanessa Brinkmann, Miriam M. Cortese-Krott, Roberto Sansone, Charlotte Esser, Niloofar Ale-Agha, Joachim Altschmied, Natascia Ventura, Judith Haendeler (2016)The aryl hydrocarbon receptor promotes aging phenotypes across species, In: Scientific Reports6(1)19618 Nature Publishing Group

The ubiquitously expressed aryl hydrocarbon receptor (AhR) induces drug metabolizing enzymes as well as regulators of cell growth, differentiation and apoptosis. Certain AhR ligands promote atherosclerosis, an age-associated vascular disease. Therefore, we investigated the role of AhR in vascular functionality and aging. We report a lower pulse wave velocity in young and old AhR-deficient mice, indicative of enhanced vessel elasticity. Moreover, endothelial nitric oxide synthase (eNOS) showed increased activity in the aortas of these animals, which was reflected in increased NO production. Ex vivo, AhR activation reduced the migratory capacity of primary human endothelial cells. AhR overexpression as well as treatment with a receptor ligand, impaired eNOS activation and reduced S-NO content. All three are signs of endothelial dysfunction. Furthermore, AhR expression in blood cells of healthy human volunteers positively correlated with vessel stiffness. In the aging model Caenorhabditis elegans, AhR-deficiency resulted in increased mean life span, motility, pharynx pumping and heat shock resistance, suggesting healthier aging. Thus, AhR seems to have a negative impact on vascular and organismal aging. Finally, our data from human subjects suggest that AhR expression levels could serve as an additional, new predictor of vessel aging.

Christian Heiss, Ioakim Spyridopoulos, Judith Haendeler (2017)Interventions to slow cardiovascular aging: Dietary restriction, drugs and novel molecules, In: Experimental Gerontology109pp. 108-118 Elsevier

Cardiovascular aging is a highly dynamic process. Despite the fact that cardiovascular function and structure change with age, they can still be modulated even in aged humans. The most prominent approaches to improve age-dependent vascular changes include dietary restriction and pharmacologic agents interacting with signaling pathways implicated in this context. These include inhibition of TOR, glycolysis, and GH/IGF-1, activation of sirtuins, and AMPK, as well as modulators of inflammation, epigenetic pathways, and telomeres. Promising nutritional approaches include Mediterranean diet and novel dietary bioactives including flavanols, anthocyanins, and lignins. Many plant bioactives improve cardiovascular parameters implied in vascular healthy aging including endothelial function, arterial stiffness, blood pressure, cholesterol, and glycemic control. However, the mechanism of action of most bioactives is not established and it remains to be elucidated whether they act as dietary restriction mimetics or via other modes of action. Even more importantly, whether these interventions can slow or even reverses components of cardiovascular aging itself and can increase healthspan or longevity in humans needs to be determined.

Rodrigo P Feliciano, Sarah Pritzel, Christian Heiss, Ana Rodriguez-Mateos (2015)Flavonoid intake and cardiovascular disease risk, In: Current Opinion in Food Science2pp. 92-99 Elsevier

Emerging evidence from epidemiological and randomized controlled trials (RCTs) support protective effects of foods and dietary supplements rich in flavonoids against cardiovascular disease (CVD). Epidemiological studies provide valuable information in this field but the estimation of flavonoid intake is still prone to bias due to limitations of food-frequency-questionnaires and lack of biomarkers. Advancements in mass spectrometry led to more accurate flavonoid quantification in foods and biological fluids and development of comprehensive metabolomic databases. Current research is still struggling with the establishment and validation of new biomarkers of flavonoid intake. Efforts to create adequate standardized materials and well-matched controls used in RCTs have also improved data robustness. However, the relationship between flavonoid intake and CVD is still not fully established.

Christian Heiss (2016)Electronic cigarettes increase EPCs, In: Atherosclerosis255pp. 119-121 Elsevier
T Mengden, M Hausberg, Christian Heiss, A Mitchell, U Nixdorff, C Ott, A Schmidt-Trucksäss, S Wassertheurer (2016)Arterielle Gefäßsteifigkeit – Ursachen und Konsequenzen (Arterial stiffness – Causes and consequences), In: Der Kardiologe10(1)pp. 38-46 Springer Berlin Heidelberg

Measurement of the aortic pulse wave velocity (aPWV) is a direct measure for the arterial stiffness of the aorta and is 4–9 m/s in normotensive healthy individuals, depending on age. In comparison to classical cardiovascular parameters, the aPWV has an additive predictive value for cardiovascular events. An increase in the aPWV of 1 m/s is associated with an increase in cardiovascular risk of up to 15 %. The differentiation between calcified arteriosclerosis and non-calcified atherosclerosis is clinically important. The presence of atherosclerosis, such as coronary heart disease, cannot be directly deduced from a finding of increased vascular stiffness. The gold standard for measurement of aortic stiffness is considered to be the PWV between the carotid and femoral arteries. Until the results of further studies are available, an aPWV above 10 m/s should be considered as pathological in normotensive individuals. Many of the instruments available on the market for measurement of vascular stiffness still show an insufficient standardization with respect to the measurement method and measurement accuracy. A standardized validation against invasive or non-invasive gold standards should be available, independent of the manufacturer and an additive predictive value confirmed by epidemiological and prognostic studies. The most important therapeutic aim of the treatment of arterial vascular stiffness is a normalization of blood pressure values according to the current European Society of Hypertension (ESH) guidelines. Based on long-term influences on vascular remodeling, according to the current state of the art blockers of the renin-angiotensin-aldosterone system are assumed to be more suitable to achieve extended effects on vascular stiffness other than pure blood pressure effects. Whether antihypertensive therapy with the target parameter of vascular stiffness also has a positive influence on concrete cardiovascular endpoints, is the subject of currently running studies.

Alena Welters, Carina Klüppel, Jessica Mrugala, Laura Wörmeyer, Thomas Meissner, Ertan Mayatepek, Christian Heiss, Daniel Eberhard, Eckhard Lammert (2017)NMDAR antagonists for the treatment of diabetes mellitus-Current status and future directions, In: Diabetes, Obesity and Metabolism19(S1)pp. 95-106 Wiley

Diabetes mellitus is characterized by chronically elevated blood glucose levels accelerated by a progressive decline of insulin‐producing β‐cells in the pancreatic islets. Although medications are available to transiently adjust blood glucose to normal levels, the effects of current drugs are limited when it comes to preservation of a critical mass of functional β‐cells to sustainably maintain normoglycemia. In this review, we recapitulate recent evidence on the role of pancreatic N‐methyl‐D‐aspartate receptors (NMDARs) in β‐cell physiology, and summarize effects of morphinan‐based NMDAR antagonists that are beneficial for insulin secretion, glucose tolerance and islet cell survival. We further discuss NMDAR‐mediated molecular pathways relevant for neuronal cell survival, which may also be important for the preservation of β‐cell function and mass. Finally, we summarize the literature for evidence on the role of NMDARs in the development of diabetic long‐term complications, and highlight beneficial pharmacologic aspects of NMDAR antagonists in diabetic nephropathy, retinopathy as well as neuropathy.

Hagen Schroeter, Christian Heiss, Jeremy P.E. Spencer, Carl L. Keen, Joanne R. Lupton, Harold H. Schmitz (2010)Recommending flavanols and procyanidins for cardiovascular health: Current knowledge and future needs, In: Molecular Aspects of Medicine31(6)pp. 546-557 Elsevier

Data on the potential health benefits of dietary flavanols and procyanidins, especially in the context of cardiovascular health, are considerable and continue to accumulate. Significant progress has been made in flavanol analytics and the creation of phytonutrient-content food databases, and novel data emanated from epidemiological investigations as well as dietary intervention studies. However, a comprehensive understanding of the pharmacological properties of flavanols and procyanidins, including their precise mechanisms of action in vivo, and a conclusive, consensus-based accreditation of a causal relationship between intake and health benefits in the context of primary and secondary cardiovascular disease prevention is still outstanding. Thus, the objective of this review is to identify and discuss key questions and gaps that will need to be addressed in order to conclusively demonstrate whether or not dietary flavanols and procyanidins have a role in preventing, delaying the onset of, or treating cardiovascular diseases, and thus improving human life expectancy and quality of life.

Stefanie Keymel, Benedikt Schueller, Roberto Sansone, Rabea Wagstaff, Stephan Steiner, Malte Kelm, Christian Heiss (2016)Oxygen dependence of endothelium-dependent vasodilation: importance in chronic obstructive pulmonary disease, In: Archives of Medical Science14(2)pp. 297-306 Termedia Publishing

Introduction: Epidemiological studies have shown increased morbidity and mortality in patients with coronary artery disease (CAD) and chronic obstructive pulmonary disease (COPD). We aimed to characterize the oxygen dependence of endothelial function in patients with CAD and coexisting COPD. Go to: Material and methods: In CAD patients with and without COPD (n = 33), we non-invasively measured flow-mediated dilation (FMD) and intima-media thickness (IMT) of the brachial artery (BA), forearm blood flow (FBF), and perfusion of the cutaneous microcirculation with laser Doppler perfusion imaging (LDPI). In an experimental setup, vascular function was assessed in healthy volunteers (n = 5) breathing 12% oxygen or 100% oxygen in comparison to room air. Go to: Results: COPD was associated with impaired FMD (3.4 ±0.5 vs. 4.2 ±0.6%; p < 0.001) and increased IMT (0.49 ±0.04 vs. 0.44 ±0.04 mm; p 65 mm Hg and pO2 ≤ 65 mm Hg revealed even lower FMD in patients with lower pO2 (3.0 ±0.5 vs. 3.7 ±0.4%; p < 0.01). Multivariate analysis showed that pO2 was a predictor of FMD independent of the forced expiratory volume and pack years. Exposure to hypoxic air led to an acute decrease in FMD, whereby exposure to 100% oxygen did not change vascular function. Conclusions: Our data suggest that in CAD patients with COPD, decreased systemic oxygen levels lead to endothelial dysfunction, underlining the relevance of cardiopulmonary interaction and the potential importance of pulmonary treatment in secondary prevention of vascular disease.

C. Meyer, E. Göpel, J. Siegrist, C. Heiss, M. Kelm, T. Rassaf (2011)Lifestyle modification programs protecting cardiovascular health in Germany and Sweden, In: Bundesgesundheitsblatt - Gesundheitsforschung - Gesundheitsschutz54(2)pp. 213-220 Springer-Verlag

A large amount of evidence, including neurohumoral, inflammatory, and metabolic physiological adaptations, emphasize the importance of the individual lifestyle as a public health concern. The related burden of chronic diseases in the European Union, which could be minimized by appropriate lifestyles, requires consistent transfer of evidence-based prevention guidelines. Due to the epidemiologic importance of cardiovascular diseases and innovative health-promoting strategies in Sweden, a comparative analysis between German and Swedish practices preventing cardiovascular events in high-risk populations is presented in this paper. This qualitative analysis demonstrates that lifestyle-related risk and protective factors based on smoking, physical activity, nutrition, and psychosocial determinants are of growing importance in cardiac death prevention. Especially in Sweden, behavioral prevention is joined by condition prevention. In Germany, intersectoral rehabilitation concepts improve patient adherence to behavioral recommendations but interdisciplinary communication between different health experts needs to be improved. The health-promoting hospital composes a health professional's interface, which is based on the understanding that behavioral risk factors are not only highly interrelated, but also require sophisticated healthcare delivery to optimize health management effectiveness.

Ana Rodriguez-Mateos, Timon Weber, Simon Skene, Javier I Ottaviani, Alan Crozier, Malte Kelm, Hagan Schroeter, Christian Heiss (2018)Assessing the respective contributions of dietary flavanol monomers and procyanidins in mediating cardiovascular effects in humans: Randomized-controlled, double-masked intervention trial, In: The American Journal of Clinical Nutrition108(6)nqy229pp. 1229-1237 American Society for Nutrition

Background: Flavanols are an important class of food bioactives that can improve vascular function even in healthy subjects. Cocoa flavanols (CFs) are comprised principally of the monomer, (−)-epicatechin (~20%) with a degree of polymerisation of 1 (DP1), and oligomeric procyanidins (~80%, DP2-10). Objective: To investigate the relative contribution of procyanidins and (−)-epicatechin to CF intake-related improvements in vascular function in healthy volunteers. Design: In a randomized, controlled, double-masked, parallel-group dietary intervention trial, 45 healthy men, (18-35 years), consumed once daily for 1 month (a) a DP1-10 cocoa extract containing 130 mg of (−)-epicatechin and 560 mg of procyanidins (b) a DP2-10 cocoa extract containing 20 mg (−)-epicatechin and 540 mg procyanidins or (c) a Control that was flavanol-free with identical micro- and macronutrient composition. ( NCT02728466) Results: Consumption of DP1-10, but neither DP2-10 nor the Control, significantly increased flow-mediated vasodilation (primary endpoint), and the level of structurally-related (−)-epicatechin metabolites (SREMs) in the circulatory system, while decreasing pulse wave velocity and blood pressure. Total cholesterol significantly decreased after daily intake of both DP1-10 and DP2-10 as compared to the Control. Conclusions: CF-related improvements in vascular function predominantly relate to intake of flavanol monomers and circulating SREMs in healthy humans, but not to the more abundant procyanidins and gut microbiome-derived CF-catabolites. Reduction in total cholesterol was linked to consumption of procyanidins but not necessarily that of (-)-epicatechin.

Ana Rodriguez-Mateos, Catarina Rendeiro, Triana Bergillos-Meca, Setareh Tabatabaee, Trevor W George, Christian Heiss, Jeremy PE Spencer (2013)Intake and time dependence of blueberry flavonoid–induced improvements in vascular function: a randomized, controlled, double-blind, crossover intervention study with mechanistic insights into biological activity, In: American Journal of Clinical Nutrition98(5)pp. 1179-1191 American Society for Nutrition

Background: There are very limited data regarding the effects of blueberry flavonoid intake on vascular function in healthy humans. Objectives: We investigated the impact of blueberry flavonoid intake on endothelial function in healthy men and assessed potential mechanisms of action by the assessment of circulating metabolites and neutrophil NADPH oxidase activity. Design: Two randomized, controlled, double-blind, crossover human-intervention trials were conducted with 21 healthy men. Initially, the impact of blueberry flavonoid intake on flow-mediated dilation (FMD) and polyphenol absorption and metabolism was assessed at baseline and 1, 2, 4, and 6 h after consumption of blueberry containing 766, 1278, and 1791 mg total blueberry polyphenols or a macronutrient- and micronutrient-matched control drink (0 mg total blueberry polyphenols). Second, an intake-dependence study was conducted (from baseline to 1 h) with 319, 637, 766, 1278, and 1791 mg total blueberry polyphenols and a control. Results: We observed a biphasic time-dependent increase in FMD, with significant increases at 1–2 and 6 h after consumption of blueberry polyphenols. No significant intake-dependence was observed between 766 and 1791 mg. However, at 1 h after consumption, FMD increased dose dependently to ≤766 mg total blueberry polyphenol intake, after which FMD plateaued. Increases in FMD were closely linked to increases in circulating metabolites and by decreases in neutrophil NADPH oxidase activity at 1–2 and 6 h. Conclusions: Blueberry intake acutely improves vascular function in healthy men in a time- and intake-dependent manner. These benefits may be mechanistically linked to the actions of circulating phenolic metabolites on neutrophil NADPH oxidase activity. This trial was registered at as NCT01292954 and NCT01829542.

Stephan Langer, Niklas Paulus, Christian Heiss, Thomas A. Koeppel, Andreas Greiner, Alexandra Buhl, Thomas Lauer, Maria Kokozidou, Michael J. Jacobs, Gabriele A. Krombach (2011)Cardiovascular remodeling after AVF surgery in rats assessed by a clinical MRI scanner, In: MAGNETIC RESONANCE IMAGING29(1)pp. 57-63 ELSEVIER SCIENCE INC

Purpose To evaluate a cardiovascular magnetic resonance imaging (MRI) technique which allows the longitudinal analysis of cardiovascular remodeling in a rodent femoral arteriovenous fistula (AVF) model by means of a clinical scanner. Materials and Methods Eight rats underwent femoral AVF surgery and four rats served as controls. Vascular and cardiac morphology as well as cardiac function was assessed from Week 3 to 12 using contrast-enhanced, time-resolved magnetic resonance angiography (MRA) and cardiac MRI (cine gradient-echo sequence) at 3 T in one imaging session. Results Arteriovenous surgery resulted in progressive venous dilation and a subsequent cardiac adaptation. This procedure led to downstream vasodilation of the iliac vein and inferior vena cava of 179% and 188%, respectively (3 weeks). To accommodate the increased returning blood volume, cardiac output (CO) increased significantly (P=.014; 6 weeks). This was caused by increased end-diastolic volume (EDV), stroke volume (SV) and heart rate (HR) consistent with an increased volume load. A continuous increase in heart weight peaked at 12 weeks. This increase combined with a distinct end-diastolic left ventricular dilation implied eccentric hypertrophy. Conclusion Small rodent MRI is feasible and clearly depicts fistula maturation and cardiac alterations. This technique proved to be a valuable tool for longitudinal in vivo monitoring in this model, which strongly resembles clinical findings in hemodialysis patients.

Tienush Rassaf, Christian Heiss, Sarah Mangold, Thorsten Leyendecker, Eva S. Kehmeier, Malte Kelm, Thomas Lauer (2010)Vascular Formation of Nitrite After Exercise Is Abolished in Patients With Cardiovascular Risk Factors and Coronary Artery Disease, In: Journal of the American College of Cardiology55(14)pp. 1502-1503 Elsevier
Christian Heiss, Malte Kelme (2010)Chocolate consumption, blood pressure, and cardiovascular risk, In: European Heart Journal31(13)pp. 1554-1556 Oxford University Press

This editorial refers to ‘Chocolate consumption in relation to blood pressure and risk of cardiovascular disease in German adults’†, by B. Buijsse et al., on page 1616

Christian Heiss, C. L. Keen, M. Kelm (2010)Flavanols and cardiovascular disease prevention, In: European Heart Journal31(21)pp. 2583-2592 Oxford University Press

Diet is a major lifestyle factor in the primary and secondary prevention of numerous chronic diseases, including myocardial infarction, stroke, and diabetes. Epidemiological studies suggest that the beneficial cardiovascular health effects of diets rich in fruits and vegetables are in part mediated by their flavonoid content, with particular benefits provided by one member of this family, the flavanols. This concept is supported by findings from small-scale intervention studies with surrogate endpoints including endothelium-dependent vasodilation, blood pressure, platelet function, and glucose tolerance. Mechanistically, short-term effects on endothelium-dependent vasodilation following the consumption of flavanol-rich foods, as well as purified flavanols, have been linked to an increased nitric oxide bioactivity in healthy humans, and those with increased cardiovascular risk. The critical biological target(s) for flavanols have yet to be identified and the extent to which these acute results are important in the context of long-term human health is unknown. While flavanols represent a promising class of food components with respect to their ability to lower cardiovascular risk the flavanol-rich foods used in many trials have been poorly defined with respect to their flavanol content and flavanol-isomer profile; several studies have lacked appropriate controls, and the long-term randomized controlled intervention trials with flavanol-rich foods are missing. Thus, while the literature regarding flavanols and vascular health is encouraging, more in-depth and well-controlled clinical and experimental studies are needed to better define the potential protective vascular effects of these nutrients and their therapeutic value in cardiovascular medicine.

Isabel Albers, Erika Zernickel, Manuel Stern, Melanie Broja, Busch Hans Lucas, Christian Heiss, Vera Grotheer, Joachim Windolf, Christoph V. Suschek (2019)Blue light (λ=453 nm) nitric oxide dependently induces β-endorphin production of human skin keratinocytes in-vitro and increases systemic β-endorphin levels in humans in-vivo, In: Free Radical Biology and Medicine145pp. 78-86 Elsevier

β-Endorphin exerts a broad spectrum of physiological activity on mood, immune functions, pain management, reward effects, and behavioral stability. β-Endorphin is produced in certain neurons within the central and peripheral nervous system but also in the skin, especially in response to ultraviolet radiation. In the present study we have investigated the impact of visible blue light at λ = 453 nm (BL) on β-endorphin production of primary human skin keratinocytes (hKC) in-vitro as well as on systemic β-endorphin formation of whole-body exposed subjects in-vivo. We found that BL irradiation significantly enhanced both keratinocytic β-endorphin production of hKC cultures as well as systemic β-endorphin concentrations in light exposed healthy subjects. Interestingly, in hKC cultures elevated β-endorphin formation was paralleled by significantly increased levels of non-enzymatically generated nitric oxide (NO), whereas elevated systemic β-endorphin values of BL-exposed subjects were accompanied by enhanced systemic concentration of bioactive NO-derivates. These findings point to a pivotal role of NO in the molecular mechanism of the observed BL-induced effects, and indeed, exogenously applied NO was able to significantly enhance β-endorphin production in hKC cultures. Thus, our finding of BL-induced increases in systemic β-endorphin concentration in-vivo can be plausibly explained by an event sequence comprising 1.) BL-driven non-enzymatic formation of NO in the exposed skin tissue, 2.) systemic distribution of cutaneously produced NO in the Form of bioactive nitroso compounds, 3.) a subsequent NO-dependent induction of β-endorphin synthesis in epidermal keratinocytes, and 4.) probably also a NO-dependent modulation of β-endorphin synthesis in specialized neurons within the central and peripheral nervous system.

Christian Heiss, Juraj Madaric, Jill Belch, Marianne Brodmann, Lucia Mazzolai (2019)The compelling arguments for the need of medical vascular physicians in Europe, In: Vasapp. 1-5 Hogrefe

The burden of vascular diseases is growing worldwide, as the population ages, prompting a call to action not only in terms of awareness but also and most urgently in recognizing the need for vascular physicians, also called angiologists. Vascular medicine views the vascular system (arteries, veins, and lymphatics) as a whole, unique, and independent entity requiring specialized competencies. Vascular physicians offer a holistic and comprehensive approach to vascular patients including provision of interventional procedures, management of a heterogeneous group of multi-morbid and frail patients affected by multi-vessel diseases, and connecting different specialists in a multidisciplinary effort. Vascular medicine practise varies across European countries. While it is a firmly accepted medical speciality in many European countries it is not formally recognized by the European Union limiting adoption in the other countries. The lack of vascular physicians likely accounts for inequality of care of vascular patients as compared for example to patients with heart disease and might contribute to adverse outcomes and healthcare costs associated with vascular diseases. To move forward in the struggle to provide efficient care for multimorbid poly-vascular patients, it is essential to establish vascular medicine programs in Europe and worldwide. Important steps to achieve this goal include improving public awareness of vascular diseases, attain formal recognition by the EU of angiology/vascular medicine as a medical specialty, creating specialized treatment guidelines, and to harmonize vascular care in Europe.

Andrea Schanz, Margarete Lukosz, Alexandra P Hess, Dunja M Baston-Büst, Jan S Krüssel, Christian Heiss (2015)hCG stimulates angiogenic signals in lymphatic endothelial and circulating angiogenic cells, In: Journal of Reproductive Immunology110pp. 102-108 Elsevier

Human chorionic gonadotropin (hCG) has long been associated with the initiation and maintenance of pregnancy, where angiogenesis plays an important role. However, the function of hCG in angiogenesis and the recruitment of vascular active cells are not fully understood. In this study, the role of hCG and its receptor in circulating angiogenic and human endothelial cells, including lymphatic, uterine microvascular, and umbilical vein endothelial cells, was examined. Immunohistochemistry and immunoblot analysis were used to detect LH/hCG receptor expression and the expression of hCG-induced angiogenic molecules. HIF-1α was determined via ELISA and downstream molecules, such as CXCL12 and CXCR4, via real-time PCR. Chemotaxis was analyzed using Boyden chambers. Our results show that the LH/hCG receptor was present in all tested cells. Furthermore, hCG was able to stimulate LH/hCG-receptor-specific migration in a dose-dependent fashion and induce key angiogenic molecules, including HIF-1α, CXCL12, and CXCR4. In conclusion, our findings underscore the importance of hCG as one of the first angiogenic molecules produced by the conceptus. hCG itself alters endothelial motility, recruitment, and expression of pro-angiogenic molecules and may therefore play an important role in vascular adaption during implantation and early placental formation.

Ulrich Sydlik, Henrike Peuschel, Adnana Paunel-Görgülü, Stefanie Keymel, Ursula Krämer, Alexander Weissenberg, Matthias Kroker, Samira Seghrouchni, Christian Heiss, Joachim Windolf, Andreas Bilstein, Malte Kelm, Jean Krutmann, Klaus Unfried (2012)Recovery of neutrophil apoptosis by ectoine: a new strategy against lung inflammation, In: European Respiratory Journal41(2)pp. 433-442 European Respiratory Society

The life span of neutrophilic granulocytes has determining impact on the intensity and duration of neutrophil driven lung inflammation. Based on the compatible solute ectoine, we aimed to prevent anti-apoptotic reactions in neutrophils triggered by the inflammatory microenvironment in the lung. Neutrophils from COPD patients and control individuals were exposed to inflammatory mediators and xenobiotics in the presence or absence of ectoine. The in vivo relevance of this approach was tested in xenobiotic-induced lung inflammation in rats. The reduction of apoptosis rates of ex vivo exposed neutrophils from persons of all study groups was significantly restored in the presence of ectoine. However, natural apoptosis rates not altered by inflammatory stimuli were not changed by ectoine. Mechanistic analyses demonstrated the preventive effect of ectoine on the induction of anti-apoptotic signalling. Neutrophilic lung inflammation induced by single or multiple exposition of animals to environmental particles was reduced after the therapeutic intervention with ectoine. Analyses of neutrophils from bronchoalveolar lavage indicate that the in vivo effect is due to the restoration of neutrophil apoptosis. Ectoine, a compound of the highly compliant group of compatible solutes, demonstrates a reproducible and robust effect on the resolution of lung inflammation.

Dominik Schuler, Roberto Sansone, Christopher Nicolaus, Malte Kelm, Christian Heiss (2018)Repetitive remote occlusion (RRO) stimulates eNOS-dependent blood flow and collateral expansion in hindlimb ischemia, In: Free Radical Biology and Medicine129pp. 520-531 Elsevier

Objective: Collateral expansion is an important compensatory mechanism to alleviate tissue ischemia after arterial occlusion. We investigated the efficacy and mechanisms of temporary remote hindlimb occlusion to stimulate contralateral blood flow and collateral expansion after hindlimb ischemia in mice and evaluated translation to peripheral artery disease in humans. Methods and Results: We induced unilateral hindlimb ischemia via femoral artery excision in mice. We studied central hemodynamics, blood flow, and perfusion of the ischemic hindlimb during single and repetitive remote occlusion (RRO) of the contralateral non-ischemic hindlimb with a pressurized cuff. Similar experiments were performed in patients with unilateral peripheral artery disease (PAD). Contralateral occlusion of the non-ischemic hindlimb led to an acute increase in blood flow to the ischemic hindlimb without affecting central blood pressure and cardiac output. The increase in blood flow was sustained even after deflation of the pressure cuff. RRO over 12 days (8/day, each 5 min) led to significantly increased arterial inflow, lumen expansion of collateral arteries, and increased perfusion of the chronically ischemic hindlimb as compared to control. In NOS3-/- and after inhibition of NOS (L-NAME), and NO (ODQ), the acute and chronic effects of contralateral occlusion were abrogated and stimulation of guanylyl cyclase with cinaciguate exhibited a similar response as RRO and was not additive. Pilot studies in PAD patients demonstrated that contralateral occlusion increased arterial inflow to ischemic limbs and improved walking distance. Conclusions: Repetitive remote contralateral occlusion stimulates arterial inflow, perfusion, and functional collateral expansion in chronic hindlimb ischemia via an eNOS-dependent mechanism underscoring the potential of remote occlusion as a novel treatment option in peripheral artery disease.

Rodrigo Feliciano, Charlotte Mills, Geoffrey Istas, Christian Heiss, Ana Rodriguez-Mateos (2017)Absorption, Metabolism and Excretion of Cranberry (Poly)phenols in Humans: A Dose Response Study and Assessment of Inter-Individual Variability, In: Nutrients9(3)268 MDPI

The beneficial health effects of cranberries have been attributed to their (poly)phenol content. Recent studies have investigated the absorption, metabolism and excretion of cranberry (poly)phenols; however, little is known about whether they follow a dose response in vivo at different levels of intake. An acute double-blind randomized controlled trial in 10 healthy men with cranberry juices containing 409, 787, 1238, 1534 and 1910 mg total (poly)phenols was performed. Blood and urine were analyzed by UPLC-Q-TOF-MS. Sixty metabolites were identified in plasma and urine including cinnamic acids, dihydrocinnamic, flavonols, benzoic acids, phenylacetic acids, benzaldehydes, valerolactones, hippuric acids, catechols, and pyrogallols. Total plasma, but not excreted urinary (poly)phenol metabolites, exhibited a linear dose response (r2 = 0.74, p < 0.05), driven by caffeic acid 4-O-ß-d-glucuronide, quercetin-3-O-ß-d-glucuronide, ferulic acid 4-O-ß-d-glucuronide, 2,5-dihydroxybenzoic acid, 2,4-dihydroxybenzoic acid, ferulic acid, caffeic acid 3-O-ß-d-glucuronide, sinapic acid, ferulic acid 4-O-sulfate, 3-hydroxybenzoic acid, syringic acid, vanillic acid-4-O-sulfate, (4R)-5-(3′-hydroxyphenyl)-γ-valerolactone-4′-O-sulfate, 4-methylgallic acid-3-O-sulfate, and isoferulic acid 3-O-sulfate (all r2 ≥ 0.89, p < 0.05). Inter-individual variability of the plasma metabolite concentration was broad and dependent on the metabolite. Herein, we show that specific plasma (poly)phenol metabolites are linearly related to the amount of (poly)phenols consumed in cranberry juice. The large inter-individual variation in metabolite profile may be due to variations in the gut microbiome. View Full-Text

Emilia Stegemann, Catharina Tegtmeier, Nana Yaw Bimpong-Buta, Roberto Sansone, Mark Uhlenbruch, Andreas Richter, Berthold Stegemann, Michael Roden, Ralf Westenfeld, Malte Kelm, Christian Heiss (2015)Carbondioxide-Aided Angiography Decreases Contrast Volume and Preserves Kidney Function in Peripheral Vascular Interventions, In: Angiology67(9)pp. 875-881 SAGE Publications

Chronic kidney disease is a common comorbidity in patients with peripheral artery disease. We investigated the safety and efficacy of carbon dioxide (CO2) as supplemental contrast agent to decrease contrast volume during fluoroscopy-guided peripheral vascular procedures in routine angiological practice. We analyzed 191 consecutive interventions of the lower extremity in claudicants and critical limb ischemia (CLI) that were performed with iodinated contrast media (ICM) alone (n = 154) or with the aided or exclusive use of CO2 (n = 37). The technical success rate, total irradiation, and intervention time were not significantly different between ICM and CO2. No severe procedure-related complications occurred. The contrast volume was lower in CO2 than in ICM. Although kidney function, creatinine, and estimated glomerular filtration rate was lower in CO2 at baseline, the incidence of contrast-induced nephropathy was lower in CO2 compared to ICM. These data support CO2 as an alternative supplemental contrast agent that can be applied safely and efficiently to lower contrast volume during peripheral vascular interventions preventing kidney dysfunction even in patients with disease of the popliteal artery and below the knee and CLI.

Ana Rodriguez-Mateos, Rodrigo P Feliciano, Albert Boeres, Timon Weber, Claudia Nunes dos Santos, M. Rita Ventura, Christian Heiss (2016)Cranberry (poly)phenol metabolites correlate with improvements in vascular function: A double-blind, randomized, controlled, dose-response, crossover study, In: Molecular Nutrition & Food Research60(10)pp. 2130-2140 Wiley

Scope Cranberries are rich in potentially bioactive (poly)phenols. The aim of this paper was to investigate whether cranberry juice intake can improve vascular function in healthy men in a dose‐ and time‐dependent manner, and to understand which of the circulating (poly)phenol metabolites correlate with vascular effects. Methods and results A double‐blind randomized controlled crossover trial was conducted in ten healthy males. Flow‐mediated dilation (FMD), blood pressure, pulse wave velocity and augmentation index were investigated at baseline, 1, 2, 4, 6, and 8 h post‐consumption of cranberry juices containing 409, 787, 1238, 1534, and 1910 mg of total cranberry (poly)phenols (TP), and a control drink. Plasma (poly)phenol metabolites were analyzed by UPLC‐Q‐TOF MS using authentic standards. We observed dose‐dependent increases in FMD at 1, 2, 4, 6, and 8 h with a peak at 4 h and maximal effects with juice containing 1238 mg TP. A total of 60 metabolites were quantified in plasma after cranberry consumption. Twelve (poly)phenol metabolites significantly correlated with the increases in FMD, including ferulic and caffeic acid sulfates, quercetin‐3‐O‐ß‐D‐glucuronide and a γ‐valerolactone sulfate. Conclusion (Poly)phenols in cranberry juice can improve vascular function in healthy males and this is linked to the presence of specific newly identified plasma metabolites.

Geoffrey Istas, Ken Declerck, Maria Pudenz, Katarzyna Szarc vel Szic, Veronica Lendinez-Tortajada, Montserrat Leon-Latre, Karen Heyninck, Guy Haegeman, Jose A. Casasnovas, Maria Tellez-Plaza, Clarissa Gerhauser, Christian Heiss, Ana Rodriguez-Mateos, Wim Vanden Berghe (2017)Identification of differentially methylated BRCA1 and CRISP2 DNA regions as blood surrogate markers for cardiovascular disease, In: Scientific Reports75120 Nature Publishing Group

Genome-wide Illumina InfiniumMethylation 450 K DNA methylation analysis was performed on blood samples from clinical atherosclerosis patients (n = 8) and healthy donors (n = 8) in the LVAD study (NCT02174133, NCT01799005). Multiple differentially methylated regions (DMR) could be identified in atherosclerosis patients, related to epigenetic control of cell adhesion, chemotaxis, cytoskeletal reorganisations, cell proliferation, cell death, estrogen receptor pathways and phagocytic immune responses. Furthermore, a subset of 34 DMRs related to impaired oxidative stress, DNA repair, and inflammatory pathways could be replicated in an independent cohort study of donor-matched healthy and atherosclerotic human aorta tissue (n = 15) and human carotid plaque samples (n = 19). Upon integrated network analysis, BRCA1 and CRISP2 DMRs were identified as most central disease-associated DNA methylation biomarkers. Differentially methylated BRCA1 and CRISP2 regions were verified by MassARRAY Epityper and pyrosequencing assays and could be further replicated in blood, aorta tissue and carotid plaque material of atherosclerosis patients. Moreover, methylation changes at BRCA1 and CRISP2 specific CpG sites were consistently associated with subclinical atherosclerosis measures (coronary calcium score and carotid intima media thickness) in an independent sample cohort of middle-aged men with subclinical cardiovascular disease in the Aragon Workers’ Health Study (n = 24). Altogether, BRCA1 and CRISP2 DMRs hold promise as novel blood surrogate markers for early risk stratification and CVD prevention.

STEFANIE KEYMEL, JULIA SICHWARDT, JAN BALZER, EMILIA STEGEMANN, TIENUSH RASSAF, PETRA KLEINBONGARD, MALTE KELM, Christian Heiss, Thomas LAUER (2010)Characterization of the Non-Invasive Assessment of the Cutaneous Microcirculation by Laser Doppler Perfusion Scanner, In: Microcirculation17pp. pp358-366 Wiley

Objective:  Microcirculatory dysfunction contributes to morbidity and mortality in vascular diseases. Here, we aimed at establishing a sensitive and valid method to measure microvascular reactivity during post‐occlusive reactive hyperemia (PORH) using scanning laser Doppler perfusion imaging (LDPI) of the forearm. Methods:  In a first series, LDPI was methodologically evaluated on the volar forearm of healthy volunteers (n = 10) before and after one to five minutes of upper arm occlusion. In a second series, readings were performed in 20 healthy subjects and 20 patients with coronary artery disease (CAD). Results:  Three minutes of forearm occlusion were sufficient to induce maximal vasodilation during PORH as indicated by maximal increase in perfusion unit (PU) amplitude that did not further increase after five‐minute occlusion. Five‐minute occlusion led to a significant prolongation of PORH with greater area under curve (AUC) suggesting longer lasting vasodilation of microvessels. The five‐minute occlusion was associated with lower variability as compared with three minutes (intraindividual variability: 9–17% vs. 12–21%; interindividual variability: 13–24% vs. 14–26%). CAD patients exhibited significantly reduced amplitude (105 ± 49 vs. 164 ± 35 PU; p 

M. M. Cortese-Krott, Z Rodriguez-Mateos, R. Sansone, G. G. C. Kuhnle, S. Thasian-Sivarajah, T. Krenz, P. Horn, C. Krisp, D. Wolters, C. Heiss, K.-D. Kroncke, N. Hogg, M. Feelisch, M. Kelm (2012)Human red blood cells at work: identification and visualization of erythrocytic eNOS activity in health and disease, In: BLOOD120(20)pp. 4229-4237 AMERICAN SOCIETY OF HEMATOLOGY

A nitric oxide synthase (NOS)-like activity has been demonstrated in human red blood cells (RBCs), but doubts about its functional significance, isoform identity and disease relevance remain. Using flow cytometry in combination with the NO-imaging probe DAF-FM we find that all blood cells form NO intracellularly, with a rank order of monocytes > neutrophils > lymphocytes > RBCs > platelets. The observation of a NO-related fluorescence within RBCs was unexpected given the abundance of the NO-scavenger oxyhemoglobin. Constitutive normoxic NO formation was abolished by NOS inhibition and intracellular NO scavenging, confirmed by laser-scanning microscopy and unequivocally validated by detection of the DAF-FM reaction product with NO using HPLC and LC-MS/MS. Employing immunoprecipitation, ESI-MS/MS-based peptide sequencing and enzymatic assay we further demonstrate that human RBCs contain an endothelial NOS (eNOS) that converts L-3H-Arginine to L-3H-Citrulline in a Ca2+/Calmodulin-dependent fashion. Moreover, in patients with coronary artery disease, red cell eNOS expression and activity are both lower than in age-matched healthy individuals and correlate with the degree of endothelial dysfunction. Thus, human RBCs constitutively produce NO under normoxic conditions via an active eNOS isoform the activity of which is compromised in patients with coronary artery disease.

Emilia Stegemann, Roberto Sansone, Christian Heiss (2016)Carbon Dioxide Angiography Is a Standard Technique to Supplement Iodinated Contrast Angiography and Can Be a Feasible Alternative, In: Angiology67(10)pp. 974-974 SAGE Publications
C. Espinola-Klein, J. B. Dahm, C. Heiß, R. Zahn, C. Tiefenbacher (2018)Kommentar zu den Leitlinien (2017) der ESC zu peripheren arteriellen Erkrankungen, In: Der Kardiologe12(4)pp. 241-249 Springer Medizin

Die 2017 veröffentlichte „European Society of Cardiology“(ESC)-Leitlinie „Periphere Arterielle Erkrankungen“ (PAE, „peripheral arterial diseases“) umfasst Empfehlungen zur Diagnostik und Therapie von atherosklerotischen Manifestationen in peripheren Gefäßen. Es werden zu allen arteriellen Versorgungsgebieten mit Ausnahme der Aorta und Koronararterien Empfehlungen formuliert. Der folgende Kommentar bezieht sich auf die Übersetzung der Pocket-Leitlinie und ist fokussiert auf die Empfehlungen zur Sekundärprävention, zur peripheren arteriellen Verschlusskrankheit (pAVK) und zur Karotisstenose. In den Empfehlungen zur Sekundärprävention wird die Atherosklerose als Erkrankung des gesamten Gefäßsystems betrachtet. Generell wird eine konsequente Einstellung der kardiovaskulären Risikofaktoren mit absoluter Rauchkarenz, dem Einsatz von Statinen sowie einer Blutdruck- und Blutzuckerkontrolle empfohlen. Patienten mit Claudicatio intermittens sollten möglichst ein supervidiertes Gehtraining betreiben. Ein Thrombozytenaggregationshemmer sollte gegeben werden, wenn eine symptomatische pAVK vorliegt oder bei weiteren Manifestationen der Atherosklerose wie beispielsweise einer koronaren Herzerkrankung (KHK). Liegt eine starke Einschränkung im Alltag vor, wird eine Revaskularisation empfohlen. Bei Vorliegen einer Indikation zur Revaskularisation sollte bei kurzen Gefäßverschlüssen (z. B.

Roberto Sansone, Maximilian Baaken, Patrick Horn, Dominik Schuler, Ralf Westenfeld, Nicolas Amabile, Malte Kelm, Christian Heiss (2018)Endothelial microparticles and vascular parameters in subjects with and without arterial hypertension and coronary artery disease, In: Data in Brief19pp. 495-500 Elsevier

Endothelial microparticles (EMPs) are markers of endothelial injury and activation. The role of EMPs in arterial hypertension is not well understood and EMPs are increased both in arterial hypertension and coronary artery disease (CAD). The data presented here show EMPs as defined by CD31+/41−, CD62e+, and CD144+ surface markers and vascular hemodynamic parameters including office and central blood pressure, heart rate, aortic augmentation index, pulse wave velocity, flow-mediated dilation, nitroglycerin-mediated dilation, brachial artery diameter, hyperemic wall shear stress, and laser Doppler perfusion of the cutaneous microcirculation of normotensives and hypertensives with and without CAD.

Rodrigo Feliciano, Geoffrey Istas, Christian Heiss, Ana Rodriguez-Mateos (2016)Plasma and Urinary Phenolic Profiles after Acute and Repetitive Intake of Wild Blueberry, In: Molecules21(9)1120 MDPI

Recent studies have shown that blueberries may have cardiovascular and cognitive health benefits. In this work, we investigated the profile of plasma and urine (poly)phenol metabolites after acute and daily consumption of wild blueberries for 30 days in 18 healthy men. The inter-individual variability in plasma and urinary polyphenol levels was also investigated. Blood samples were collected at baseline and 2 h post-consumption on day 1 and day 30. Twenty-four-hour urine was also collected on both days. A total of 61 phenolic metabolites were quantified in plasma at baseline, of which 43 increased after acute or chronic consumption of blueberries over one month. Benzoic and catechol derivatives represented more than 80% of the changes in phenolic profile after 2 h consumption on day 1, whereas hippuric and benzoic derivatives were the major compounds that increased at 0 and 2 h on day 30, respectively. The total (poly)phenol urinary excretion remained unchanged after 30 days of wild blueberry intake. The inter-individual variability ranged between 40%–48% in plasma and 47%–54% in urine. Taken together, our results illustrate that blueberry (poly)phenols are absorbed and extensively metabolized by phase II enzymes and by the gut microbiota, leading to a whole array of metabolites that may be responsible for the beneficial effects observed after blueberry consumption.

U. B. Hendgen-Cotta, P. Luedike, M. Totzeck, M. Kropp, A. Schicho, P. Stock, C. Rammos, M. Niessen, C. Heiss, J. O. Lundberg, E. Weitzberg, M. Kelm, T. Rassaf (2012)Dietary Nitrate Supplementation Improves Revascularization in Chronic Ischemia, In: CIRCULATION126(16)pp. 1983-1992 American Heart Association

BACKGROUND: Revascularization is an adaptive repair mechanism that restores blood flow to undersupplied ischemic tissue. Nitric oxide plays an important role in this process. Whether dietary nitrate, serially reduced to nitrite by commensal bacteria in the oral cavity and subsequently to nitric oxide and other nitrogen oxides, enhances ischemia-induced remodeling of the vascular network is not known. METHODS AND RESULTS: Mice were treated with either nitrate (1 g/L sodium nitrate in drinking water) or sodium chloride (control) for 14 days. At day 7, unilateral hind-limb surgery with excision of the left femoral artery was conducted. Blood flow was determined by laser Doppler. Capillary density, myoblast apoptosis, mobilization of CD34(+)/Flk-1(+), migration of bone marrow-derived CD31(+)/CD45(-), plasma S-nitrosothiols, nitrite, and skeletal tissue cGMP levels were assessed. Enhanced green fluorescence protein transgenic mice were used for bone marrow transplantation. Dietary nitrate increased plasma S-nitrosothiols and nitrite, enhanced revascularization, increased mobilization of CD34(+)/Flk-1(+) and migration of bone marrow-derived CD31(+)/CD45(-) cells to the site of ischemia, and attenuated apoptosis of potentially regenerative myoblasts in chronically ischemic tissue. The regenerative effects of nitrate treatment were abolished by eradication of the nitrate-reducing bacteria in the oral cavity through the use of an antiseptic mouthwash. CONCLUSIONS: Long-term dietary nitrate supplementation may represent a novel nutrition-based strategy to enhance ischemia-induced revascularization.

Ana Rodriguez-Mateos, Tania Cifuentes-Gomez, Isidro Gonzalez-Salvador, Javier I. Ottaviani, Hagen Schroeter, Malte Kelm, Christian Heiss, Jeremy P. E. Spencer (2015)Influence of age on the absorption, metabolism, and excretion of cocoa flavanols in healthy subjects, In: Molecular Nutrition & Food Research59(8)pp. 1504-1512 Wiley

Scope An understanding of the pharmacokinetics of structurally related (−)‐epicatechin metabolites (SREM) is a prerequisite for considering cocoa flavanols (CF) in the context of dietary recommendations. The objective of this study was to compare the absorption, metabolism, and excretion of SREM in healthy young and elderly Caucasian men. Methods and results Intraindividual variability of SREM was assessed in seven young subjects, after consuming 10.7 mg CF/kg body weight (BW) on two occasions separated by 1 week. The effect of age on flavanols ADME was assessed in 20 young (18–35 years) and 20 elderly (65–80 years) healthy male subjects receiving 5.3 and 10.7 mg total CF/kg BW or 1 g of acetaminophen as a control to compare differences in Phase II metabolism on three days separated by 1 week of wash‐out. Blood and urine samples were collected for 24‐h post consumption. The intraindividual variation, measured as CV(%) with respect to the area‐under‐the‐curve of the concentration over time (AUC(0‐6h)) of SREM, was 16%, while the interindividual variation in AUC(0‐6h), was 38%, comparable to acetaminophen (39%). The AUC(0‐6h) and the 24‐h excretion of total SREM was not significantly different between young and elderly subjects. At the high intake amount, the AUC(0‐6h) of (−)‐epicatechin‐3′‐β‐D‐glucuronide was greater in elderly subjects, whereas the AUC(0‐6h) of 3′‐O‐methyl‐(−)‐epicatechin‐5‐sulfate and 3′‐O‐methyl‐(−)‐epicatechin‐7‐sulfate as well as the 24‐h urinary excretion of γ‐valerolactone metabolites were lower in the elderly. Conclusion Cocoa flavanols are absorbed, metabolized, and excreted in healthy young and elderly subjects with relatively small differences between the two groups.

A. Schanz, D. Baston-Bust, J.S. Krussel, C. Heiss, W. Janni, A.P. Hess (2011)CXCR7 and syndecan-4 are potential receptors for CXCL12 in human cytotrophoblasts, In: Journal of Reproductive Immunology89(1)pp. 18-25 Elsevier

The placenta forms the interface between the mother and the fetus. During placental development cytotrophoblasts differentiate to form the syncytium or to invade the decidual wall to breach maternal vessels and establish the blood flow in the intervillous space. This process is still not well understood but it is proposed that chemokines and their receptors are involved in guiding cytotrophoblasts to the decidua and maternal vessels as well as attracting immunocompetent cells to the implantation site. CXCL12 is a chemokine expressed by cytotrophoblasts and is involved in cytotrophoblast invasion, differentiation and survival. One of its receptors, CXCR4, has been detected on cytotrophoblasts. Recent data show that CXCR7 and syndecan-4 might partially mediate CXCL12 function in other cell types. In this study, we examined CXCR7 and syndecan-4 expression at the maternal–fetal interface via immmunolocalization in placental tissue sections and in isolated cytotrophoblasts. We further used immunoblot analyses to confirm the data. We were able to show that cytotrophoblasts express both receptors and that upregulation occurs during the differentiation process of cytotrophoblasts towards the invasive phenotype. On a functional level CXCR7 seems not to be involved in JAR cell chemotaxis, suggesting a different function of this receptor. In conclusion, we propose that CXCL12 binds to CXCR4, but also to CXCR7 and syndecan-4. These three receptors could mediate different functions of CXCL12, such as cell migration, directed invasion, proliferation and survival. The latter molecules might also be involved in the development of placental pathologies, such as preeclampsia or choriocarcinoma growth.

S. Keymel, C. Heiss, P. Kleinbongard, M. Kelm, T. Lauer (2011)Impaired Red Blood Cell Deformability in Patients with Coronary Artery Disease and Diabetes Mellitus, In: HORMONE AND METABOLIC RESEARCH43(11)pp. 760-765 GEORG THIEME VERLAG

Patients with diabetes mellitus (DM) have an increased cardiovascular morbidity and mortality. There is increasing evidence that diabetes mellitus is associated with pathological hemorheological alterations, which might contribute to impaired coronary blood flow in coronary artery disease (CAD). We hypothesize that red blood cell (RBC) deformability is impaired in diabetic patients with CAD in comparison to nondiabetic patients with CAD. RBC deformability was measured in 21 patients with CAD and type 2 diabetes mellitus (CAD+DM) and 24 patients with CAD (CAD–DM). RBC deformability was measured by the Laser-assisted optical rotational cell analyzer by determining the elongation index (EI). RBC deformability was reduced in patients with CAD+DM in comparison to patients with CAD–DM (EI @ 1.12 Pa 0.236 ± 0.008 vs. 0.260 ± 0.005, p = 0.007). Inverse univariate correlations were found between the EI @ 1.12 Pa and plasma glucose concentration (r =-0.57; p

CHRISTIAN MEYER, GEERT MORREN, JENS MUEHLSTEFF, CHRISTIAN HEISS, THOMAS LAUER, PATRICK SCHAUERTE, TIENUSH RASSAF, HELMUT PURERFELLNER, MALTE KELM (2011)Predicting Neurally Mediated Syncope Based on Pulse Arrival Time: Algorithm Development and Preliminary Results, In: Journal of Cardiovascular Electrophysiology22(9)pp. 1042-1048 Wiley

Prediction of Neurally Mediated Syncope. Background: Neurally mediated syncope (NMS) is a common disorder that is triggered by orthostatic stress. The circulatory adjustments to orthostatic stress occur just prior to a sudden loss of consciousness. NMS prediction would protect patients from falls or accidents. Methods and Results: Based on simultaneously recorded heart rate (HR) and pulse wave during 70° head‐up tilt (HUT) table testing we investigated a syncope warning system. In 14 patients with a history of suspected NMS we tested 2 algorithms based on HR and/or pulse arrival time (PAT). When the cumulative risk exceeded the threshold, which was calculated during the first 2 minutes following the posture change to upright position, a syncope prediction alarm was triggered. All syncopes (n = 7) were detected more than 16 seconds before the onset of dizziness or unconsciousness by using a prediction alarm based on HR and PAT (syncope prediction algorithm 2). No false alarm was generated in patients with negative HUT (n = 7). Syncope prediction was improved by detecting the slope of HR changes as compared with monitoring PAT changes alone (syncope prediction algorithm 1). The duration between the prediction alarm and the occurrence of syncope was 99 ± 108 seconds. Conclusion: Predicting NMS is feasible by monitoring HR and the onset of the pulse wave at the periphery. This approach might improve NMS management. 

Stephan Langer, Maria Kokozidou, Christian Heiss, Jennifer Kranz, Tina Kessler, Niklas Paulus, Thilo Krüger, Michael J. Jacobs, Christina Lente, Thomas A. Koeppel (2010)Chronic kidney disease aggravates arteriovenous fistula damage in rats, In: KIDNEY INTERNATIONAL78(12)pp. 1312-1321 Elsevier

Neointimal hyperplasia (NIH) and impaired dilatation are important contributors to arteriovenous fistula (AVF) failure. It is unclear whether chronic kidney disease (CKD) itself causes adverse remodeling in arterialized veins. Here we determined if CKD specifically triggers adverse effects on vascular remodeling and assessed whether these changes affect the function of AVFs. For this purpose, we used rats on a normal diet or on an adenine-rich diet to induce CKD and created a fistula between the right femoral artery and vein. Fistula maturation was followed noninvasively by high-resolution ultrasound (US), and groups of rats were killed on 42 and 84 days after surgery for histological and immunohistochemical analyses of the AVFs and contralateral femoral vessels. In vivo US and ex vivo morphometric analyses confirmed a significant increase in NIH in the AVFs of both groups with CKD compared to those receiving a normal diet. Furthermore, we found using histological evaluation of the fistula veins in the rats with CKD that the media shrank and their calcification increased significantly. Afferent artery dilatation was significantly impaired in CKD and the downstream fistula vein had delayed dilation after surgery. These changes were accompanied by significantly increased peak systolic velocity at the site of the anastomosis, implying stenosis. Thus, CKD triggers adverse effects on vascular remodeling in AVFs, all of which contribute to anatomical and/or functional stenosis.

J. Klasen, D. Blondin, P. Schmitt, X. Bi, R. Sansone, H.-J. Wittsack, P. Kröpil, M. Quentin, J. Kuhlemann, F. Miese, C. Heiss, M. Kelm, G. Antoch, R.S. Lanzman (2012)Nonenhanced ECG-gated quiescent-interval single-shot MRA (QISS-MRA) of the lower extremities: Comparison with contrast-enhanced MRA, In: Clinical Radiology67(5)pp. 441-446 Elsevier Ltd

Aim To evaluate electrocardiogram (ECG)-gated quiescent-interval single-shot magnetic resonance angiography (QISS-MRA) for nonenhanced assessment of peripheral artery occlusive disease (PAOD) using contrast-enhanced MRA (CE-MRA) as the reference standard. Materials and methods Twenty-seven patients (mean age 66.6 ± 10.8 years) with PAOD were included in the study. QISS-MRA and CE-MRA of the lower extremity were performed using a 1.5 T MR scanner. In each patient, subjective image quality and the degree of stenosis were evaluated on a four-point scale for 15 predefined arterial segments. Results Twenty-five of the 27 patients were considered for analysis. Subjective image quality of QISS-MRA was significantly lower for the distal aorta, pelvic arteries, and femoral arteries as compared to CE-MRA (p < 0.01), while no significant difference was found for other vascular segments. The degree of stenosis was overestimated with QISS-MRA in 23 of 365 (6.3%) segments and underestimated in two of 365 (0.5%) segments. As compared to CE-MRA, QISS-MRA had a high sensitivity (98.6%), specificity (96%) as well as positive and negative predictive value (88.7 and 99.6%, respectively) for the detection of significant stenosis (≥50%). Conclusion ECG-gated QISS-MRA is a promising imaging technique for reliable assessment of PAOD without the use of contrast material.

Andrea Schanz, Virginia D. Winn, Susan J. Fisher, Marion Blumenstein, Christian Heiss, Alexandra P. Hess, Jan S. Kruessel, Michael Mcmaster, Robyn A. North (2011)Pre-eclampsia is associated with elevated CXCL12 levels in placental syncytiotrophoblasts and maternal blood, In: European Journal of Obstetrics and Gynecology and Reproductive Biology157(1)pp. 32-37 ELSEVIER IRELAND LTD

Objectives Placental derived vasculogenic/angiogenic substances in maternal blood are dysregulated in pre-eclampsia. We hypothesized that CXCL12, a chemokine with vasculogenic actions, is amongst such molecules. Study design CXCL12, CXCL16, CXCR4, and CXCR6 immunolocalization in placental tissue was analyzed in pre-eclampsia (n = 8) in comparison to controls (n = 8). CXCL12, measured by ELISA in blood, in women diagnosed with pre-eclampsia (n = 14) and prior to the development of pre-eclampsia (at 20 weeks’ gestation, n = 20) was compared with CXCL12 concentrations in gestation-matched, healthy control subjects (n = 34). Results In placental tissue, syncytiotrophoblast staining for CXCL12 was increased in pre-eclampsia. Maternal serum CXCL12 was increased in pre-eclampsia [2000 (SD 402) vs 1484 (SD 261) pg/ml, P = 0.01] but not in plasma obtained at 20 weeks of gestation prior to the onset of pre-eclampsia [1183 (SD 336) vs 1036 (SD 144) pg/ml, P = 0.09]. Conclusion Our data suggest that the syncytiotrophoblast contributes to a pre-eclampsia-associated increase in CXCL12 levels in maternal blood. These findings support the hypothesis that an imbalance of angiogenic factors contributes to the pathogenesis of pre-eclampsia.

Christian Heiss (2018)Chronische mesenteriale Ischämie, In: Deutsche Medizinische Wochenschrift143(20)pp. 1426-1429 Georg Thieme Verlag

Was ist neu? Definition und Ursachen: Der chronischen mesenterialen Ischämie (CMI) liegen Stenosen oder Verschlüsse des Truncus coeliacus, Arteria mesenteria superior oder inferior zugrunde. Die häufigste Ursache ist die Atherosklerose (90%), aber auch eine fibromuskuläre Dysplasie oder Vasculitis. Endsprechend sind die Risikofaktoren Rauchen, arterielle Hypertonie, Dyslipidämie und hohes Lebensalter. Frauen sind häufiger betroffen als Männer. Epidemiologie: Die symptomatische CMI ist relativ selten (5% aller ischämischen intestinalen Ereignisse). Die Prävalenz der asymptomatischen CMI ist nicht gut untersucht, scheint aber bei Erwachsenen im Bereich von 14-15% zu liegen und ist häufiger bei der peripheren arteriellen Verschlusskrankheit (27%) oder abdominellem Aortenaneurysma (40%). Am häufigsten ist der Tuncus coeliacus betroffen. Diagnosestellung: Nahrungsabhängige Beschwerden zusammen mit Unterernährung aber erhaltenem Appetit und ein abdominelles Strömungsgeräusch können wichtige klinische Hinweise auf eine CMI sein, die zur Durchführung einer Duplex Ultraschalluntersuchung und funktionellen Untersuchungen in einem spezialisierten Zentrum führen sollte. Zur Planung des weiteren Vorgehens kann eine CT Angiographie notwendig sein. Therapie: Die Therapie der Wahl einer symptomatischen CMI insbesondere bei Mehrgefäßerkrankung ist die Revaskularisation. In den meisten Fällen wird aufgrund niedriger post-interventioneller Mortalität bei meist multimorbiden Patienten und ausgezeichneter klinischer und technischer Erfolgsrate dem endovaskulären Vorgehen der Vorzug gegeben. Sekundärprophylaxe: Wie bei der KHK und pAVK sollte bei Patienten mit Atherosklerose der Mesenterialarterien Lebensstilmodifikation und optimale medikamentöse Therapie mit Statinen und Aspirin zur Risikoreduktion eingesetzt werden ohne dass jedoch Studien in diesem Patientenkollektiv existieren. Nach Revaskularisation ist Plättchenhemmung indiziert. = = = What is new? Definition and causes: Chronic mesenteric ischemia (CMI) is caused by stenosis or occlusion of the celiac trunk, superior mesenteric artery or inferior artery. The most common cause is atherosclerosis (˃90%), but also fibromuscular dysplasia or vasculitis. In conclusion, the risk factors are smoking, arterial hypertension, dyslipidemia and old age. Women are more affected than men. Epidemiology: Symptomatic CMI is relatively rare (5% of all ischemic intestinal events). The prevalence of asymptomatic CMI has not been well studied but appears to be in the range of 14-15% in adults and is more common in peripheral arterial disease (27%) or abdominal aortic aneurysm (40%). The most commonly affected is the tunic coeliacus. Diagnosis: Diet-related disorders along with malnutrition but appetite and abdominal flow noise may be important clinical indications of CMI that should lead to a duplex ultrasound examination and functional examinations in a specialized center. To plan further procedures, CT angiography may be necessary. Therapy: The treatment of choice of symptomatic CMI, especially in multivessel disease, is revascularization. In most cases, because of low post-interventional mortality in mostly multimorbid patients and excellent clinical and technical success rates, endovascular procedures are preferred. Secondary prophylaxis: As with CHD and PAOD, lifestyle modification and optimal drug therapy with statins and aspirin should be used to reduce risk in patients with atherosclerosis of the mesenteric arteries, but studies in this patient population do not exist. After revascularization, platelet inhibition is indicated.

Roberto Sansone, Javier I Ottaviani, Ana Rodriguez-Mateos, Yvonne Heinen, Dorina Noske, Jeremy P Spencer, Alan Crozier, Marc W Merx, Malte Kelm, Hagen Schroeter, Christian Heiss (2016)Methylxanthines enhance the effects of cocoa flavanols on cardiovascular function: randomized, double-masked controlled studies, In: The American Journal of Clinical Nutrition105(2)pp. 352-360 Oxford Academic

Background: Cocoa flavanol intake, especially that of (−)-epicatechin, has been linked to beneficial effects on human cardiovascular function. However, cocoa also contains the methylxanthines theobromine and caffeine, which may also affect vascular function. Objective: We sought to determine whether an interaction between cocoa flavanols and methylxanthines exists that influences cocoa flavanol–dependent vascular effects. Design: Test drinks that contained various amounts of cocoa flavanols (0–820 mg) and methylxanthines (0–220 mg), either together or individually, were consumed by healthy volunteers (n = 47) in 4 different clinical studies—3 with a randomized, double-masked crossover design and 1 with 4 parallel crossover studies. Vascular status was assessed by measuring flow-mediated vasodilation (FMD), brachial pulse wave velocity (bPWV), circulating angiogenic cells (CACs), and blood pressure before and 2 h after the ingestion of test drinks. Results: Although cocoa flavanol intake increased FMD 2 h after intake, the consumption of cocoa flavanols with methylxanthines resulted in a greater enhancement of FMD. Methylxanthine intake alone did not result in statistically significant changes in FMD. Cocoa flavanol ingestion alone decreased bPWV and diastolic blood pressure and increased CACs. Each of these changes was more pronounced when cocoa flavanols and methylxanthines were ingested together. It is important to note that the area under the curve of the plasma concentration of (−)-epicatechin metabolites over time was higher after the co-ingestion of cocoa flavanols and methylxanthines than after the intake of cocoa flavanols alone. Similar results were obtained when pure (−)-epicatechin and the methylxanthines theobromine and caffeine were consumed together. Conclusion: A substantial interaction between cocoa flavanols and methylxanthines exists at the level of absorption, in which the methylxanthines mediate an increased plasma concentration of (−)-epicatechin metabolites that coincides with enhanced vascular effects commonly ascribed to cocoa flavanol intake. This trial was registered at as NCT02149238.

T. Driesen, D. Schuler, R. Schmetter, C. Heiss, M. Kelm, J. W. Fischer, T. Freudenberger (2015)A systematic approach to assess locoregional differences in angiogenesis, In: Histochemistry and Cell Biology145(2)pp. 213-225 Springer

Skeletal muscle tissue differs with regard to the abundance of glycolytic and oxidative fiber types. In this context, capillary density has been described to be higher in muscle tissue with more oxidative metabolism as compared to that one with more glycolytic metabolism, and the highest abundance of capillaries has been found in boneward-oriented moieties of skeletal muscle tissue. Importantly, capillary formation is often analyzed as a measure for angiogenesis, a process that describes neo-vessel formation emanating from preexisting vessels, occurring, i.e., after arterial occlusion. However, a standardized way for investigation of calf muscle capillarization after surgically induced unilateral hind limb ischemia in mice, especially considering these locoregional differences, has not been provided so far. In this manuscript, a novel, methodical approach for reliable analysis of capillary density was established using anatomic–morphological reference points, and a software-assisted way of capillary density analysis is described. Thus, the systematic approach provided conscientiously considers intra-layer differences in capillary formation and therefore guarantees for a robust, standardized analysis of capillary density as a measure for angiogenesis. The significance of the methodology is further supported by the observation that capillary density in the calf muscle layers analyzed negatively correlates with distal lower limb perfusion measured in vivo.

Qiumei Chen, Monika Varga, Xiaoyin Wang, Daniel J. Haddad, Songtao An, Lejla Medzikovic, Ronak Derakhshandeh, Dmitry S. Kostyushev, Yan Zhang, Brian T. Clifford, Emmy Luu, Olivia M. Danforth, Ruslan Rafikov, Wenhui Gong, Stephen M. Black, Sergey V. Suchkov, Jeffrey R. Fineman, Christian Heiss, Kirstin Aschbacher, Yerem Yeghiazarians, Matthew L. Springer (2016)Overexpression of Nitric Oxide Synthase Restores Circulating Angiogenic Cell Function in Patients With Coronary Artery Disease: Implications for Autologous Cell Therapy for Myocardial Infarction, In: Journal of the American Heart Association5(1)e002257 Wiley, on behalf of American Heart Association

Background Circulating angiogenic cells (CACs) are peripheral blood cells whose functional capacity inversely correlates with cardiovascular risk and that have therapeutic benefits in animal models of cardiovascular disease. However, donor age and disease state influence the efficacy of autologous cell therapy. We sought to determine whether age or coronary artery disease (CAD) impairs the therapeutic potential of CACs for myocardial infarction (MI) and whether the use of ex vivo gene therapy to overexpress endothelial nitric oxide (NO) synthase (eNOS) overcomes these defects. Methods and Results We recruited 40 volunteers varying by sex, age (< or ≥45 years), and CAD and subjected their CACs to well‐established functional tests. Age and CAD were associated with reduced CAC intrinsic migration (but not specific response to vascular endothelial growth factor, adherence of CACs to endothelial tubes, eNOS mRNA and protein levels, and NO production. To determine how CAC function influences therapeutic potential, we injected the 2 most functional and the 2 least functional CAC isolates into mouse hearts post MI. The high‐function isolates substantially improved cardiac function, whereas the low‐function isolates led to cardiac function only slightly better than vehicle control. Transduction of the worst isolate with eNOS cDNA adenovirus increased NO production, migration, and cardiac function of post‐MI mice implanted with the CACs. Transduction of the best isolate with eNOS small interfering RNA adenovirus reduced all of these capabilities. Conclusions Age and CAD impair multiple functions of CACs and limit therapeutic potential for the treatment of MI. eNOS gene therapy in CACs from older donors or those with CAD has the potential to improve autologous cell therapy outcomes.

Patrick Horn, Theodor Baars, Kahlert Philipp, Christian Heiss, Ralf Westenfeld, Malte Kelm, Raimund Erbel, Gerd Heusch,, Petra Kleinbongard (2015)Release of Intracoronary Microparticles during Stent Implantation into Stable Atherosclerotic Lesions under Protection with an Aspiration Device, In: PloS ONE10(4)e0124904 Public Library of Science

Objective Stent implantation into atherosclerotic coronary vessels impacts on downstream microvascular function and induces the release of particulate debris and soluble substances, which differs qualitatively and quantitatively between native right coronary arteries (RCAs) and saphenous vein grafts on right coronary arteries (SVG-RCAs). We have now quantified the release of microparticles (MPs) during stent implantation into stable atherosclerotic lesions and compared the release between RCAs and SVG-RCAs. Methods In symptomatic, male patients with stable angina and a stenosis in their RCA or SVG-RCA, respectively (n = 14/14), plaque volume and composition were analyzed using intravascular ultrasound before stent implantation. Coronary aspirate was retrieved during stent implantation with a distal occlusion/aspiration device and divided into particulate debris and plasma. Particulate debris was weighed. Platelet-derived MPs (PMPs) were distinguished by flow cytometry as CD41+, endothelium-derived MPs (EMPs) as CD144+, CD62E+ and CD31+/CD41-, leukocyte-derived MPs as CD45+, and erythrocyte-derived MPs as CD235+. Results In patients with comparable plaque volume and composition in RCAs and SVG-RCAs, intracoronary PMPs and EMPs were increased after stent implantation into their RCAs and SVG-RCAs (CD41+: 2729.6±645.6 vs. 4208.7±679.4 and 2355.9±503.9 vs. 3285.8±733.2 nr/µL; CD144+: 451.5±87.9 vs. 861.7±147.0 and 444.6±74.8 vs. 726.5±136.4 nr/µL; CD62E+: 1404.1±247.7 vs. 1844.3±378.6 and 1084.6±211.0 vs. 1783.8±384.3 nr/µL, P

Christian Heiss, Sarah Jahn, Melanie Taylor, Wendy May Real, Franca S. Angeli, Maelene L. Wong, Nicolas Amabile, Megha Prasad, Tienush Rassaf, Javier I. Ottaviani, Shirley Mihardja, Carl L. Keen, Matthew L. Springer, Andrew Boyle, William Grossman, Stanton A. Glantz, Hagen Schroeter, Yerem Yeghiazarians (2010)Improvement of Endothelial Function With Dietary Flavanols Is Associated With Mobilization of Circulating Angiogenic Cells in Patients With Coronary Artery Disease, In: Journal of the American College of Cardiology56(3)pp. 218-224 Elsevier

Objectives In patients with coronary artery disease (CAD) medically managed according to currently accepted guidelines, we tested whether a 1-month dietary intervention with flavanol-containing cocoa leads to an improvement of endothelial dysfunction and whether this is associated with an enhanced number and function of circulating angiogenic cells (CACs). Background Dietary flavanols can improve endothelial dysfunction. The CACs, also termed endothelial progenitor cells, are critical for vascular repair and maintenance of endothelial function. Methods In a randomized, controlled, double-masked, cross-over trial, 16 CAD patients (64 ± 3 years of age) received a dietary high-flavanol intervention (HiFI [375 mg]) and a macronutrient- and micronutrient-matched low-flavanol intervention (LoFI [9 mg]) twice daily in random order over 30 days. Results Endothelium-dependent vasomotor function, as measured by flow-mediated vasodilation of the brachial artery, improved by 47% in the HiFI period compared with the LoFI period. After HiFI, the number of CD34+/KDR+-CACs, as measured by flow cytometry, increased 2.2-fold as compared with after LoFI. The CAC functions, as measured by the capacity to survive, differentiate, proliferate, and to migrate were not different between the groups. The HiFI led to a decrease in systolic blood pressure (mean change over LoFI: −4.2 ± 2.7 mm Hg), and increase in plasma nitrite level (mean change over LoFI: 74 ± 32 nM). Applying a mixed-effects linear regression model, the results demonstrated a significant increase in flow-mediated vasodilation and a decrease in systolic blood pressure with increasing levels of CD34+/KDR+-CACs. Conclusions Sustained improvements in endothelial dysfunction by regular dietary intake of flavanols are associated with mobilization of functional CACs. (Effect of Cocoa Flavanols on Vascular Function in Optimally Treated Coronary Artery Disease Patients: Interaction Between Endothelial Progenitor Cells, Reactivity of Micro- and Macrocirculation; NCT00553774).

Roberto Sansone, Maximilian Baaken, Patrick Horn, Dominik Schuler, Ralf Westenfeld, Nicolas Amabile, Malte Kelm, Christian Heiss (2018)Release of endothelial microparticles in patients with arterial hypertension, hypertensive emergencies and catheter-related injury, In: Atherosclerosis273pp. 67-74 Elsevier

Background and aims Circulating endothelial microparticles (EMPs) are increased in arterial hypertension. The role of physicomechanical factors that may induce EMP release in vivo is still unknown. We studied the relationship of EMPs and physicomechanical factors in stable arterial hypertension and hypertensive emergencies, and investigated the pattern of EMP release after mechanical endothelial injury. Methods In a pilot study, 41 subjects (50% hypertensives) were recruited. EMPs were discriminated by flow-cytometry (CD31+/41-, CD62e+, CD144+). Besides blood pressure measurements, pulse-wave-analysis was performed. Flow-mediated dilation (FMD), nitroglycerin-mediated dilation (NMD), and wall-shear-stress (WSS) were measured ultrasonographically in the brachial artery; microvascular perfusion by laser-Doppler ( NCT02795377). We studied patients with hypertensive emergencies before and 4 h after BP lowering by urapidil (n = 12) and studied the release of EMPs due to mechanical endothelial injury after coronary angiography (n = 10). Results Hypertensives exhibited increased EMPs (CD31+/41-, CD144+, CD62e+) as compared to normotensives and EMPs univariately correlated with systolic BP (SBP), augmentation index, and pulse wave velocity and inversely with FMD. CD31+/41--EMPs correlated with diameter and inversely with WSS and NMD. CD62e+ and CD144+-EMPs inversely correlated with microvascular function. During hypertensive emergency, only CD62e+ and CD144+-EMPs were further elevated and FMD was decreased compared to stable hypertensives. Blood pressure lowering decreased CD62e+ and CD144+-EMPs and increased FMD. CD31+/41—EMPs, diameter, and WSS remained unaffected. Similar to hypertensive emergency, catheter-related endothelial injury increased only CD144+ and CD62e+-EMPs. Conclusions EMP release in hypertension is complex and may involve both physicomechanical endothelial injury and activation (CD144+, CD62e+) and decreased wall shear stress (CD31+/41-). Graphical abstract In arterial hypertension, increased systolic blood pressure and decreased wall shear stress (due to greater arterial diameter) are associated with the release of endothelial microparticles (EMPs). We linked this with distinct patterns of mechanical injury, activation, and endothelial dysfunction (CD62e+ and CD144+-EMPs) and decreased endothelial protection (CD31+/41--EMPs), respectively. EMPs may be part of a vicious self-perpetuating cycle involving endothelial dysfunction.

Roberto Sansone, Beate Stanske, Stefanie Keymel, Dominik Schuler, Patrick Horn, Diyar Saeed, Udo Boeken, Ralf Westenfeld, Artur Lichtenberg, Malte Kelm, Christian Heiss (2015)Macrovascular and microvascular function after implantation of left ventricular assist devices in end-stage heart failure: Role of microparticles, In: The Journal of Heart and Lung Transplantation34(7)pp. 921-932 Elsevier
Christian Heiss, A. Schanz, N. Amabile, S. Jahn, Q. Chen, M. L. Wong, T. Rassaf, Y. Heinen, M. Cortese-Krott, W. Grossman, Y. Yeghiazarians, M. L. Springer (2010)Nitric Oxide Synthase Expression and Functional Response to Nitric Oxide Are Both Important Modulators of Circulating Angiogenic Cell Response to Angiogenic Stimuli, In: Arteriosclerosis, Thrombosis, and Vascular Biology30(11)pp. 2212-2218

Objective Circulating angiogenic cells (CACs), also termed endothelial progenitor cells, play an integral role in vascular repair and are functionally impaired in coronary artery disease (CAD). The role of nitric oxide (NO) in CAC function is poorly understood. We hypothesized that CAC migration toward angiogenic signals is modulated by both NO synthase (NOS) expression and functional response to NO. Methods and Results Similar to endothelial cells, CAC chemotaxis to VEGF was blocked by inhibition of NOS, phosphoinositide-3 kinase, or guanylyl cyclase, or by treatment with an NO scavenger. Addition of a NO donor (SNAP) and the NOS-substrate L-arginine increased random cell migration (chemokinesis) and enhanced VEGF-dependent chemotaxis. Healthy CACs expressed eNOS, but eNOS was not detected in CAD patient CACs. Both chemokinesis and chemotaxis to VEGF of patient CACs were decreased compared to healthy CACs, but were restored to healthy values by SNAP. In parallel, CAD patients exhibited lower flow-mediated vasodilation and plasma NO source nitrite than young healthy subjects, indicating endothelial dysfunction with reduced NO bioavailability. Conclusions NOS activity is required for CAC chemotaxis. In CAD patients, impairment of NOS expression and NO bioavailability, rather than response to NO, may contribute to CAC dysfunction and limit their regenerative capacity.

Christian Heiss, Roberto Sansone, Hakima Karimi, Moritz Krabbe, Dominik Schuler, Ana Rodriguez-Mateos, Thomas Kraemer, Miriam Margherita Cortese-Krott, Gunter G. C. Kuhnle, Jeremy P. E. Spencer, Hagen Schroeter, Marc W. Merx, Malte Kelm (2015)Impact of cocoa flavanol intake on age-dependent vascular stiffness in healthy men: a randomized, controlled, double-masked trial, In: AGE3756 Springer

Increased vascular stiffness, endothelial dysfunction, and isolated systolic hypertension are hallmarks of vascular aging. Regular cocoa flavanol (CF) intake can improve vascular function in healthy young and elderly at-risk individuals. However, the mechanisms underlying CF bioactivity remain largely unknown. We investigated the effects of CF intake on cardiovascular function in healthy young and elderly individuals without history, signs, or symptoms of cardiovascular disease by applying particular focus on functional endpoints relevant to cardiovascular aging. In a randomized, controlled, double-masked, parallel-group dietary intervention trial, 22 young (

Roberto Sansone, Ana Rodriguez-Mateos, Jan Heuel, David Falk, Dominik Schuler, Rabea Wagstaff, Gunter G. C. Kuhnle, Jeremy P. E. Spencer, Hagen Schroeter, Marc W. Merx, Malte Kelm, Christian Heiss (2015)Cocoa flavanol intake improves endothelial function and Framingham Risk Score in healthy men and women: a randomised, controlled, double-masked trial: the Flaviola Health Study, In: British Journal of Nutrition114(08)pp. 1246-1255 Cambridge University Press

Cocoa flavanol (CF) intake improves endothelial function in patients with cardiovascular risk factors and disease. We investigated the effects of CF on surrogate markers of cardiovascular health in low risk, healthy, middle-aged individuals without history, signs or symptoms of CVD. In a 1-month, open-label, one-armed pilot study, bi-daily ingestion of 450 mg of CF led to a time-dependent increase in endothelial function (measured as flow-mediated vasodilation (FMD)) that plateaued after 2 weeks. Subsequently, in a randomised, controlled, double-masked, parallel-group dietary intervention trial ( NCT01799005), 100 healthy, middle-aged (35–60 years) men and women consumed either the CF-containing drink (450 mg) or a nutrient-matched CF-free control bi-daily for 1 month. The primary end point was FMD. Secondary end points included plasma lipids and blood pressure, thus enabling the calculation of Framingham Risk Scores and pulse wave velocity. At 1 month, CF increased FMD over control by 1·2 % (95 % CI 1·0, 1·4 %). CF decreased systolic and diastolic blood pressure by 4·4 mmHg (95 % CI 7·9, 0·9 mmHg) and 3·9 mmHg (95 % CI 6·7, 0·9 mmHg), pulse wave velocity by 0·4 m/s (95 % CI 0·8, 0·04 m/s), total cholesterol by 0·20 mmol/l (95 % CI 0·39, 0·01 mmol/l) and LDL-cholesterol by 0·17 mmol/l (95 % CI 0·32, 0·02 mmol/l), whereas HDL-cholesterol increased by 0·10 mmol/l (95 % CI 0·04, 0·17 mmol/l). By applying the Framingham Risk Score, CF predicted a significant lowering of 10-year risk for CHD, myocardial infarction, CVD, death from CHD and CVD. In healthy individuals, regular CF intake improved accredited cardiovascular surrogates of cardiovascular risk, demonstrating that dietary flavanols have the potential to maintain cardiovascular health even in low-risk subjects.

Geoffrey Istas, Rodrigo P. Feliciano, Timon Weber, Rocio Garcia-Villalba, Francisco Tomas-Barberan, Christian Heiss, Ana Rodriguez-Mateos (2018)Plasma urolithin metabolites correlate with improvements in endothelial function after red raspberry consumption: A double-blind randomized controlled trial, In: Archives of Biochemistry and Biophysics651pp. 43-51 Elsevier

Raspberries are a rich source of ellagitannins and anthocyanins. The aim of this work was to investigate whether raspberry consumption can improve vascular function and to understand which phenolic metabolites may be responsible for the effects. A 3 arm double-blind randomized controlled crossover human intervention trial was conducted in 10 healthy males. Flow-mediated dilation (FMD) was measured at baseline, 2 h, and 24 h post-consumption of 200 g and 400 g of red raspberries containing 201 or 403 mg of total (poly)phenols, or a matched control drink. Raspberry (poly)phenol metabolites were analyzed in plasma and urine by UPLC-QTOF mass spectrometry using authentic standards. Significant improvements in FMD were observed at 2 h (1.6% (95%CI 1.2, 1.9) and 1.2% (95% CI 0.8, 1.5)) and 24 h (1.0% (95% CI 0.6, 1.2) and 0.7% (95%CI 0.2, 0.9)) post-consumption of the 200 and 400 g raspberry drinks as compared to control, respectively. Plasma ellagic acid, urolithin A-3-glucuronide and urolithin A-sulfate correlated with the improvements in FMD at 2 and 24 h post consumption, respectively. Consumption of dietary achievable amounts of red raspberries acutely improves endothelial function up to 24 h and ellagitannins may be responsible for the observed effect.

Rolando S. Matos, Davide Maselli, Christian Heiss, Paola Campagnolo, John Henderson Mcvey (2022)3D printed bioreactor enabling the pulsatile culture of native and angioplastied large arteries, In: Frontiers in Cardiovascular Medicine9864580 Frontiers Media

Routine interventions such as balloon angioplasty, result in vascular activation and remodeling, often requiring re-intervention. 2D in vitro models and small animal experiments have enabled the discovery of important mechanisms involved in this process, however the clinical translation is often underwhelming. There is a critical need for an ex vivo model representative of the human vascular physiology and encompassing the complexity of the vascular wall and the physical forces regulating its function. Vascular bioreactors for ex vivo culture of large vessels are viable alternatives, but their custom-made design and insufficient characterization often hinders the reproducibility of the experiments. The objective of the study was to design and validate a novel 3D printed cost-efficient and versatile perfusion system, capable of sustaining the viability and functionality of large porcine arteries for 7 days and enabling early post-injury evaluations. MultiJet Fusion 3D printing was used to engineer the EasyFlow insert, converting a conventional 50 ml centrifuge tube into a mini bioreactor. Porcine carotid arteries either left untreated or injured with an angioplasty balloon, were cultured under pulsatile flow for up to 7 days. Pressure, heart rate, medium viscosity and shear conditions were adjusted to resemble arterial in vivo hemodynamics. Tissue viability, cell activation and matrix remodeling were analyzed by immunohistochemistry, and vascular function was monitored by duplex ultrasound. Culture conditions in the EasyFlow bioreactor preserved endothelial coverage and smooth muscle organization and extracellular matrix structure in the vessel wall, as compared to static culture. Injured arteries presented hallmarks of early remodeling, such as intimal denudation, smooth muscle cell disarray and media/adventitia activation in flow culture. Duplex ultrasound confirmed continuous pulsatile blood flow conditions, dose-dependent vasodilator response to nitroglycerin in untreated vessels and impaired dilator response in angioplastied vessels. The scope of this work is to validate a low-cost, robust and reproducible system to explore the culture of native and injured large arteries under pulsatile flow. While the study of vascular pathology is beyond the scope of the present paper, our system enables future investigations and provides a platform to test novel therapies and devices ex vivo, in a patient relevant system.

Rolando Matos, Davide Maselli, John Mcvey, Christian Heiss, Paola Campagnolo 3D printed bioreactor enabling the physiological culture and the study of pathological processes in large vessels, In: bioRxiv Cold Spring Harbor Laboratory Press

Routine cardiovascular interventions such as balloon angioplasty, result in vascular activation and remodeling, often requiring re-interventions. 2D in vitro culture models and small animal experiments have enabled the discovery of important molecular and cellular pathways involved in this process, however the clinical translation of these results is often underwhelming. There is a critical need for an ex vivo model representative of the human vascular physiology and encompassing the complexity of the vascular wall and the physical forces regulating its function. Vascular bioreactors for ex vivo culture of large vessels are viable alternatives, but their custom-made design and insufficient characterization often hinders the reproducibility of the experiments. The objective of the study was to design and validate a novel 3D printed cost-efficient and versatile perfusion system, capable of sustaining the viability and functionality of large porcine arteries for 7 days and enabling monitoring of post-injury remodeling. MultiJet Fusion 3D printing technology was used to engineer the EasyFlow insert, converting a conventional 50 ml centrifuge tube into a mini bioreactor. Porcine carotid arteries either left untreated or injured with a conventional angioplasty balloon, were cultured under pulsatile flow for up to 7 days. Pressure, heart rate, medium viscosity and shear conditions were adjusted to represent the typical arterial physiology. Tissue viability, cell activation and matrix remodeling were analyzed by immunohistochemistry, and vascular function was monitored by duplex ultrasound. Physiological blood flow conditions in the EasyFlow bioreactor preserved endothelial coverage and smooth muscle organization and extracellular matrix structure in the vessel wall, as compared to static culture. Injured arteries presented hallmarks of early remodeling, such as intimal denudation, smooth muscle cell disarray and media/adventitia activation. Duplex ultrasound confirmed physiological hemodynamic conditions, dose-dependent vasodilator response to nitroglycerin in untreated vessels and impaired dilator response in angioplastied vessels. We here validate a low-cost, robust and reproducible system to study large blood vessels physiopathology, laying the basis for future investigations into the pathological remodeling of blood vessels and creating a platform to test novel therapies and devices ex vivo in a patient relevant system. Competing Interest Statement The authors have declared no competing interest.

Mark Joy, John Williams, Subo Emanuel, Debasish Kar, Xuejuan Fan, Gayathri Delanerolle, Benjamin CT Field, Christian Heiss, Kevin G Pollock, Belinda Sandler, Jasleen Arora, James P Sheppard, Michael D. Feher, F. D. Richard Hobbs, Simon De Lusignan (2022)Trends in direct oral anticoagulant (DOAC) prescribing in English primary care (2014- 2019), In: Heart

Background: In England, most prescribing of direct-acting oral anticoagulants for atrial fibrillation (AF) is in primary care. However, there remain gaps in our understanding of dosage and disparities in use. We aimed to describe trends in direct oral anticoagulant (DOAC) prescribing, including dose reduction in people with renal impairment and other criteria, and adherence. Methods: Using English primary care sentinel network data from 2014 to 2019, we assessed appropriate DOAC dose adjustment with creatinine clearance (CrCl). Our primary care sentinel cohort was a subset of 722 general practices, with 6.46 million currently registered patients at the time of this study. Results: Of 6 464 129 people in the cohort, 2.3% were aged ≥18 years with a diagnosis of AF, and 30.8% of these were prescribed vitamin K antagonist and 69.1% DOACs. Appropriate DOAC prescribing following CrCl measures improved between 2014 and 2019; dabigatran from 21.3% (95% CI 15.1% to 28.8%) to 48.7% (95% CI 45.0% to 52.4%); rivaroxaban from 22.1% (95% CI 16.7% to 28.4%) to 49.9% (95% CI 48.5% to 53.3%); edoxaban from 10.0% (95% CI 0.3% to 44.5%) in 2016 to 57.6% (95% CI 54.5% to 60.7%) in 2019; apixaban from 30.8% (95% CI 9.1% to 61.4%) in 2015 to 60.5% (95% CI 57.8% to 63.2%) in 2019. Adherence was highest for factor Xa inhibitors, increasing from 50.1% (95% CI 47.7% to 52.4%) in 2014 to 57.8% (95% CI 57.4% to 58.2%) in 2019. Asian and black/mixed ethnicity was associated with non-adherence (OR 1.81, 95% CI 1.56 to 2.09) as was male gender (OR 1.19, 95% CI 1.15 to 1.22), higher socioeconomic status (OR 1.60, 95% CI 1.52 to 1.68), being an ex-smoker (OR 1.12, 95% CI 1.06 to 1.19) and hypertension (OR 1.07, 95% CI 1.03 to 1.17). Conclusions: The volume and quality of DOAC prescribing has increased yearly. Future interventions to augment quality of anticoagulant management should target disparities in adherence.

Pedro Mena, Claudia Favari, Animesh Acharjee, Saisakul Chernbumroong, Letizia Bresciani, Claudio Curti, Furio Brighenti, CHRISTIAN HEISS, Ana Rodriguez-Mateos, Daniele Del Rio (2021)Metabotypes of flavan-3-ol colonic metabolites after cranberry intake: elucidation and statistical approaches, In: European Journal of Nutrition Springer

Purpose: Extensive inter-individual variability exists in the production of flavan-3-ol metabolites. Preliminary metabolic phenotypes (metabotypes) have been defined, but there is no consensus on the existence of metabotypes associated with the catabolism of catechins and proanthocyanidins. This study aims at elucidating the presence of different metabotypes in the urinary excretion of main flavan-3-ol colonic metabolites after consumption of cranberry products and at assessing the impact of the statistical technique used for metabotyping. Methods: Data on urinary concentrations of phenyl-γ-valerolactones and 3-(hydroxyphenyl)propanoic acid derivatives from two human interventions has been used. Different multivariate statistics, principal component analysis (PCA), cluster analysis, and partial least square-discriminant analysis (PLS-DA), have been considered. Results: Data pre-treatment plays a major role on resulting PCA models. Cluster analysis based on k-means and a final consensus algorithm lead to quantitative-based models, while the expectation-maximization algorithm and clustering according to principal component scores yield metabotypes characterized by quali-quantitative differences in the excretion of colonic metabolites. PLS-DA, together with univariate analyses, has served to validate the urinary metabotypes in the production of flavan-3-ol metabolites and to confirm the robustness of the methodological approach. Conclusions: This work proposes a methodological workflow for metabotype definition and highlights the importance of data pre-treatment and clustering methods on the final outcomes for a given dataset. It represents an additional step toward the understanding of the inter-individual variability in flavan-3-ol metabolism.

Rolando Szilveszter Matos, Akram Jassim Jawad Jawad, Davide Maselli, John H. McVey, Christian Heiss, Paola Campagnolo (2023)Ex Vivo Perfusion Culture of Large Blood Vessels in a 3D Printed Bioreactor, In: JoVE MyJove Corporation

Vascular disease forms the basis of most cardiovascular diseases (CVDs), which remain the primary cause of mortality and morbidity worldwide. Efficacious surgical and pharmacological interventions to prevent and treat vascular disease are urgently needed. In part, the shortage of translational models limits the understanding of the cellular and molecular processes involved in vascular disease. Ex vivo perfusion culture bioreactors provide an ideal platform for the study of large animal vessels (including humans) in a controlled dynamic environment, combining the ease of in vitro culture and the complexity of the live tissue. Most bioreactors are, however, custom manufactured and therefore difficult to adopt, limiting the reproducibility of the results. This paper presents a 3D printed system that can be easily produced and applied in any biological lab, and provides a detailed protocol for its setup, enabling users operation. This innovative and reproducible ex vivo perfusion culture system enables the culture of blood vessels for up to 7 days in physiological conditions. We expect that adopting a standardized perfusion bioreactor will support a better understanding of physiological and pathological processes in large animal blood vessels and accelerate the discovery of new therapeutics.

Aikaterini Papadopoulou, Matthew Dickinson, Theophilus L. Samuels, Christian Heiss, Lui Forni, B Creagh-Brown (2023)Efficacy of remote ischaemic preconditioning on outcomes following non-cardiac non-vascular surgery: a systematic review and meta-analysis, In: Perioperative medicine (London)12(1)

Remote ischaemic preconditioning (RIPC) has been investigated as a simple intervention to potentially mitigate the ischaemic effect of the surgical insult and reduce postoperative morbidity. This review systematically evaluates the effect of RIPC on morbidity, including duration of hospital stay and parameters reflective of cardiac, renal, respiratory, and hepatic dysfunction following non-cardiac non-vascular (NCNV) surgery. The electronic databases PubMed, Embase, and the Cochrane Central Register of Controlled Trials (CENTRAL) were searched from their inception date to November 2021. Studies investigating the effect of local preconditioning or postconditioning were excluded. Methodological quality and risk of bias were determined according to the Revised Cochrane risk-of-bias tool for randomised trials (RoB 2). Calculation of the odds ratios and a random effects model was used for dichotomous outcomes and mean differences or standardised mean differences as appropriate were used for continuous outcomes. The primary outcomes of interest were cardiac and renal morbidity, and the secondary outcomes included other organ function parameters and hospital length of stay. A systematic review of the published literature identified 36 randomised controlled trials. There was no significant difference in postoperative troponin or acute kidney injury. RIPC was associated with lower postoperative serum creatinine (9 studies, 914 patients, mean difference (MD) - 3.81 µmol/L, 95% confidence interval (CI) - 6.79 to - 0.83, p = 0.01, I = 5%) and lower renal stress biomarker (neutrophil gelatinase-associated lipocalin (NGAL), 5 studies, 379 patients, standardized mean difference (SMD) - 0.66, 95% CI - 1.27 to - 0.06, p = 0.03, I = 86%). RIPC was also associated with improved oxygenation (higher P O /F O , 5 studies, 420 patients, MD 51.51 mmHg, 95% CI 27.32 to 75.69, p < 0.01, I = 89%), lower biomarker of oxidative stress (malondialdehyde (MDA), 3 studies, 100 patients, MD - 1.24 µmol/L, 95% CI - 2.4 to - 0.07, p = 0.04, I = 91%)) and shorter length of hospital stay (15 studies, 2110 patients, MD - 0.99 days, 95% CI - 1.75 to - 0.23, p = 0.01, I = 88%). This meta-analysis did not show an improvement in the primary outcomes of interest with the use of RIPC. RIPC was associated with a small improvement in certain surrogate parameters of organ function and small reduction in hospital length of stay. Our results should be interpreted with caution due to the limited number of studies addressing individual outcomes and the considerable heterogeneity identified. PROSPERO CRD42019129503.

M. Stern, J. Schremmer, S. Scharm, S. Baasen, Y. Heinen, R. Sansone, A. Polzin, C Jung, CHRISTIAN HEISS, M. Kelm, L. Busch (2022)Microvascular tissue perfusion after postcatheterization pseudoaneurysm treatment, In: Clinical hemorheology and microcirculation8 IOS Press

OBJECTIVE:This study aims to investigate the application value of three-dimensional arterial spin labeling (ASL) perfusion imaging in detecting cerebral hemodynamics of neonates with hypoxic-ischemic encephalopathy (HIE). METHODS:Sixty normal full-term neonates and 60 HIE neonates were enrolled in this study and were respectively divided into three groups: the 1–3 days group, the 4–7 days group, and the 8–15 days group. The brains of these neonates were scanned with the 3D ASL sequence, and cerebral blood flow (CBF) images were obtained. The CBF values of the bilateral symmetrical brain regions and brain stem were measured on CBF images, and the values were averaged. The cerebral blood flow of HIE neonates in the 1–3 days group, the 4–7 days group, and the 8–15 days group was compared with normal neonates at matched ages, and the characteristics of cerebral hemodynamics in HIE neonates at different ages were summarized. RESULTS:The CBF values of the basal ganglia, thalamus, and brainstem in the 1–3 days HIE group were higher than normal neonates at matched ages, and the CBF value of the frontal lobe was lower than the normal group, and the differences were statistically significant (P 

GAVRIELLE REBECCA UNTRACHT, ROLANDO SZILVESZTER MATOS, NIKOLAOS DIKAIOS, MARIAM BAPIR, ABDULLAH KHAN DURRANI, Teemapron Butsabong, PAOLA CAMPAGNOLO, DAVID SAMPSON, CHRISTIAN HEISS, DANUTA SAMPSON (2021)OCTAVA: An open-source toolbox for quantitative analysis of optical coherence tomography angiography images, In: Plos One16(12)pp. 1-22 Public Library of Science

Optical coherence tomography angiography (OCTA) performs non-invasive visualization and characterization of microvasculature in research and clinical applications mainly in ophthalmology and dermatology. A wide variety of instruments, imaging protocols, processing methods and metrics have been used to describe the microvasculature, such that comparing different study outcomes is currently not feasible. With the goal of contributing to standardization of OCTA data analysis, we report a user-friendly, open-source toolbox, OCTAVA (OCTA Vascular Analyzer), to automate the pre-processing, segmentation, and quantitative analysis of en face OCTA maximum intensity projection images in a standardized workflow. We present each analysis step, including optimization of filtering and choice of segmentation algorithm, and definition of metrics. We perform quantitative analysis of OCTA images from different commercial and non-commercial instruments and samples and show OCTAVA can accurately and reproducibly determine metrics for characterization of microvasculature. Wide adoption could enable studies and aggregation of data on a scale sufficient to develop reliable microvascular biomarkers for early detection, and to guide treatment, of microvascular disease.

Christian Heiss, M Kelm, T Lauer (2012)Bestimmung der Intima-Media Dicke, In: Knut Kröger, Ernst Gröchenig, Frans Santosa (eds.), Nicht invasive Diagnostik angiologischer Krankheitsbilder ABW Wissenschaftsverlagsgesellschaft
T Lauer, M Kelm, Christian Heiss (2012)Fluß-mediierte Dilatation, In: Knut Kröger, Ernst Gröchenig, Frans Santosa (eds.), Nicht-invasive Diagnostik angiologischer Krankheitsbilder ABW Wissenschaftsverlagsgesellschaft
R Sansone, Christian Heiss (2014)Kaffee und Tee – schlecht oder gut für den Blutdruck?, In: Druckpunkte
Christian Heiss (2015)"Yes, FMD should be measured in the lower extremity of PAD patients!", In: Journal of the American Heart Association Wiley Open Access
L Busch, M Kelm, Christian Heiss (2014)Biomarker der Plaqueruptur, In: Kompendium Herz Kreislauf.30pp. 6-12 Thieme
Stefanie Keymel, Yvonne Heinen, Jan Balzer, Tienush Rassaf, Malte Kelm, Thomas Lauer, Christian Heiss (2011)Characterization of macro-and microvascular function and structure in patients with type 2 diabetes mellitus, In: American Journal of Cardiovascular Research1(1)pp. pp68-75 e-Century Publishing Corporation

Objective: Diabetes mellitus (DM) leads to accelerated progression of arteriosclerosis with an increased risk of coronary events in comparison to non-diabetic patients with coronary artery disease (CAD). The precise and early detection of DM-induced vascular alterations is crucial to identify patients with high risk for cardiovascular complications. Thus, we aimed at simultaneously characterizing functional, physicomechanical, and structural vascular alterations in diabetic patients using a non-invasive approach. Research Design and Methods: In CAD patients with and without type 2 diabetes mellitus (n=50), we non-invasively measured flow-mediated dilation (FMD) of the brachial artery as a marker for endothelial function, fractional diameter changes (FDC) as a marker for physicomechanical properties, intima-media thickness (IMT) as a marker for structural properties, and forearm blood flow (FBF) as a marker for microvascular function. Results: DM was associated with reduced FMD (2.5±0.2 vs 4.8±0.4%; p≤0.001) indicating impaired macrovascular endothelial function. In parallel, reduced FDC (0.024±0.002 vs 0.034±0.004; p≤0.05) and increased IMT (0.38±0.01 vs 0.31±0.01mm; p≤0.001) indicated increased stiffness and enhanced structural alterations. Furthermore, reduced forearm blood flow during reactive hyperemia (10.7±1.0 vs. 15.3±1.4mL/min*100mL; p≤0.05) was found indicating microvascular dysfunction. Plasma glucose and HbA1c correlated with FMD (glucose: r=-0.32; HbA1c: r=-0.45), IMT (glucose: r=0.54; HbA1c: r=0.48) and FBF (glucose: r=-0.30) suggesting diabetes-specific effects on vascular properties. Conclusion: In patients with CAD, DM leads to functional and structural vascular alterations of the peripheral vasculature which are determined by the control of the disease underlining the relevance of a strict control of the DM to prevent accelerated atherosclerosis.

Christine Espinola-Klein, Johannes B. Dahm, Christian Heiss, Christiane Tiefenbacher, Ralf Zahn (2017)Pocket-Leitlinie: Diagnose und Therapie der peripheren arteriellen Erkrankung (Version 2017) European Society of Cardiology

Diese Pocket-Leitlinie ist eine von der Deutschen Gesellschaft für Kardiologie – Herz- und Kreislaufforschung e.V. (DGK) übernommene Stellungnahme der European Society of Cardiology (ESC) und der European Society for Vascular Surgery (ESVS), die den gegenwärtigen Erkenntnisstand wiedergibt und Ärzten die Entscheidungsfindung zum Wohle ihrer Patienten erleichtern soll. Die Leitlinie ersetzt nicht die ärztliche Evaluation des individuellen Patienten und die Anpassung der Diagnostik und Therapie an dessen spezifische Situation. Die Pocket-Leitlinie enthält gekennzeichnete Kommentare der Autoren der Pocket- Leitlinie, die deren Einschätzung darstellen und von der Deutschen Gesellschaft für Kardiologie getragen werden. Die Erstellung dieser Leitlinie ist durch eine systematische Aufarbeitung und Zusammenstellung der besten verfügbaren wissenschaftlichen Evidenz gekennzeichnet. Das vorgeschlagene Vorgehen ergibt sich aus der wissenschaftlichen Evidenz, wobei randomisierte, kontrollierte Studien bevorzugt werden. Der Zusammenhang zwischen der jeweiligen Empfehlung und dem zugehörigen Evidenzgrad ist gekennzeichnet.

Roberto Sansone, Emilia Stegemann, Göksen Özaslan, Dominik Schuler, Margarete Lukosz, Ana Rodriguez-Mateos, Thomas Lauer, Ralf Westenfeld, Malte Kelm, Christian Heiss (2014)Early and late response-to-injury in patients undergoing transradial coronary angiography: arterial remodeling in smokers, In: American Journal of Cardiovascular Disease4(2)pp. pp47-57 e-Century Publishing

Objectives: To investigate the effect of smoking on vascular response to transradial coronary angiography (TCA). Background: Cigarette smoking is the most important modifiable cardiovascular risk factor associated with endothelial dysfunction. Methods: Radial artery flow-mediated vasodilation (RA-FMD), local stiffness (fractional diameter change), intima-media thickness (IMT), luminal and external arterial diameter were measured in 40 current smokers (CS) and former smokers (FS) at 6-14 months at the site of previous TCA and contralateral control artery. Vascular regenerative capacity was studied as chemotactic cell migration in vitro and ex vivo (n=10) and the time course of endothelial functional recovery following RA-FMD up to 72 h after TCA (n=10). Results: At 10 ± 3 months after TCA, subjects exhibited significant local stiffening and increased IMT as compared to the control arm. These late structural changes were significantly more pronounced in CS as compared to FS. IMT thickening correlated with packyears, number of daily cigarettes, and inversely with RA-FMD. Nitric oxide synthase (NOS)-dependent chemotaxis of CS’ circulating angiogenic cells was impaired. Ex vivo incubation of endothelial cells with CS’ plasma inhibited NOS-dependent endothelial wound closure and chemotaxis. In vivo, TCA acutely decreased RA-FMD. At 24 h, RA-FMD had recovered in FS but remained impaired at 24 h and only recovered at 48 h in CS. Conclusion: In active smokers, transradial coronary angiography is associated with delayed early recovery from transient endothelial dysfunction, decreased NOS-dependent vascular regeneration, and late arterial remodeling pointing towards potential harmful effects of transradial coronary angiography on vascular function in distinct subsets of patients.

J Balzer, T Lauer, M Preik, Christian Heiss, BE Strauer, M Kelm (2005)Contributions of microvascular disease to abnormal endothelium-dependent arterial dilation in conduit arteries of hypertensive patients, In: Otmar Schober,, Jürgen Schrader (eds.), Cardiovisionen 2004 Verlag Ferdinand Schöningh