Prof. Dr. Christian Heiss has a joined appointment by The University of Surrey and Surry and Sussex NHS Healthcare Trust as a Professor of Cardiovascular Medicine. He is an internationally recognized expert in diagnostic, interventional, and experimental cardiovascular medicine. His research interests include basic mechanisms of vascular homeostasis and human interventions for improvement of cardiovascular health and healthy aging. His clinical work focuses on the prevention and endovascular treatment of complex multi-level atherosclerosis in particular in patients with peripheral artery disease.
Professor Heiss has previously headed the Vascular Medicine program at the Department of Cardiology, Pulmonology, and Vascular Medicine of the University of Düsseldorf, in Germany. He received training in basic cardiovascular research, clinical cardiology, and vascular medicine. After completing Medical School and dissertation at Heinrich-Heine University Düsseldorf, he did a post-doctoral research fellowship in Biochemistry and Molecular Biology in Düsseldorf and an American Heart Association research fellowship in Molecular Cardiology at the University of California San Francisco. He was also an affiliated faculty member at the Nutrition Department of the University of California Davis. He then returned to the University of Düsseldorf as a clinical consultant and headed a translational research group. He received the prestigious Eden’s Award for Excellence in Cardiovascular Research of the University of Düsseldorf for his work on endothelial dysfunction and adaptation in the pathophysiology of atherosclerosis.
He has published more than one hundred manuscripts in international peer reviewed journals https://www.ncbi.nlm.nih.gov/sites/myncbi/1JmzFebqF6S/bibliography/9013163/public/?sort=date&direction= descending and serves on the board of the European Society of Vascular Medicine, UEMS Division of Vascular Medicine, and the advisory board of the German Vascular Medicine Society. He has obtained research funding from the German Research Council, the European Union, as well as industry and charity and has coordinated multi-center collaborative projects such the FLAVIOLA project funded by the European Union investigating the effects of dietary flavanols on human cardiovascular health.
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.
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 (Clinicaltrials.gov: 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).
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.
EMP release in hypertension is complex and may involve both physicomechanical endothelial injury and activation (CD144+, CD62e+) and decreased wall shear stress (CD31+/41-).
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.
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 (Ã90%), 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.
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
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).
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.
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.
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)
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?0.001), ratio (4.7?±?1.8 vs. 7.1?±?1.8; p?0.001), and AUC (1656?±?1070 vs. 2723?±?864?PU?×?minutes; p?=?0.001).
Conclusion:? Scanning LDPI is a feasible and reproducible method for non?invasive assessment of the cutaneous microcirculatory response during PORH.
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.
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.
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.
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.
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.
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+.
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
Stenting in stable atherosclerotic lesions is associated with a substantial release not only of PMPs, but also of EMPs in RCAs and SVG-RCAs. Their release does not differ between RCAs and SVG-RCAs.
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.?
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.
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.
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.
To characterize the time course of tumor necrosis factor-± (TNF-±) 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).
Serum levels of TNF-±, 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.
TNF-± 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-± 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
Our data reflect the clinical significance of early TNF-± elevation in patients with STEMI and primary PCI (Controlled Clinical Trials number, NCT00529607).
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?32?²?D?glucuronide was greater in elderly subjects, whereas the AUC(0?6h) of 32?O?methyl?(?)?epicatechin?5?sulfate and 32?O?methyl?(?)?epicatechin?7?sulfate as well as the 24?h urinary excretion of ³?valerolactone metabolites were lower in the elderly.
Cocoa flavanols are absorbed, metabolized, and excreted in healthy young and elderly subjects with relatively small differences between the two groups.
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.
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
ECG-gated QISS-MRA is a promising imaging technique for reliable assessment of PAOD without the use of contrast material.
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.
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).
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].
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.
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 d766 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 clinicaltrials.gov as NCT01292954 and NCT01829542.
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.
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 ( 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.
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
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.
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.
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.
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.
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.
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.
COPD was associated with impaired FMD (3.4 ±0.5 vs. 4.2 ±0.6%; p 65 mm Hg and pO2 d 65 mm Hg revealed even lower FMD in patients with lower pO2 (3.0 ±0.5 vs. 3.7 ±0.4%; p 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.
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.
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.
Continuous positive airway pressure reduced heart rate corrected (AIx@75) (-2.8 ± 8.1 [rest] to ?10.7 ± 11.3 [5 mbar], p 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.
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 ³?valerolactone sulfate.
(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.
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.
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.
We sought to determine whether an interaction between cocoa flavanols and methylxanthines exists that influences cocoa flavanol?dependent vascular effects.
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.
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.
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 clinicaltrials.gov as NCT02149238.
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
Conclusions: Dietary CF ingestion mitigates acute HD?induced and chronic endothelial dysfunction in patients with ESRD and thus, improves vascular function in this high-risk population. Larger clinical trials are warranted to test whether this translates into an improved cardiovascular prognosis in patients with ESRD.
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.
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.
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.
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.
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.
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.
Diese Erkrankungen des Auges sind meist eine Folge von internistischen Grunderkrankungen und stellen daher eine interdisziplinäre Herausforderung dar.
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.
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).
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.
Brief SHS exposure at real-world levels reversibly impairs FMD. Even 1min of SHS exposure can cause reduction of endothelial function.
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.
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.
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.
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.
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.
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.?
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.
Careful processing can preserve important biological activities of blueberries despite changing the blueberry (poly)phenol composition and plasma metabolite profile.
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.
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.
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.
Therapy for AVS by TAVI was associated with improved endothelial function and integrity indicating beneficial effects of TAVI on systemic arterial function.
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).
To investigate the relative contribution of procyanidins and (?)-epicatechin to CF intake-related improvements in vascular function in healthy volunteers.
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. (ClinicalTrials.gov NCT02728466)
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.
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.
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.
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.
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.
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.
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.
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.
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.
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.
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.
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 , 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 . 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 
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.
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 ²1 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 ²1
integrin-blocking antibody or tamoxifen-induced endothelial cell-specific deletion of the gene for ²1
integrin (Itgb1) inhibited both arteriogenesis and angiogenesis. Using high frequency ultrasound, we
demonstrated that ²1 integrin-blocking antibody or endothelial cell-specific depletion of ²1 integrin
attenuated FMD of the femoral artery, and blocking of ²1 integrin function did not further decrease FMD in
eNOS-deficient mice. Our data suggest that endothelial ²1 integrin is required for both acute and chronic
widening of the arterial lumen in response to hindlimb ischemia, potentially via functional interaction with
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
(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.
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.