Zhang Y, Wu J, Jeevaratnam K, King JH, Guzadhur L, Ren X, Grace AA, Lei M, Huang CL, Fraser JA (2013) Conduction slowing contributes to spontaneous ventricular arrhythmias in intrinsically active murine RyR2-P2328S hearts., J Cardiovasc Electrophysiol 24 (2) pp. 210-218
INTRODUCTION: The familial condition catecholaminergic polymorphic ventricular tachycardia (CPVT) is characterized by episodic bidirectional ventricular tachycardia (BVT), polymorphic ventricular tachycardia (PVT), and ventricular fibrillation following adrenergic challenge. It is associated with mutations involving the cardiac ryanodine receptor (RyR2). METHODS AND RESULTS: We explored for a slowing of myocardial conduction that could potentially result in a substrate for the spontaneous arrhythmogenesis that was observed following introduction of isoproterenol and caffeine in intrinsically beating murine RyR2-P2328S hearts. Such pharmacological challenge increased the number of arrhythmic episodes in electrocardiographic recordings from intact anesthetized mice, with the greatest effects in the homozygote RyR2(S/S). Arrhythmias took the form of bigeminy, BVT, monomorphic ventricular tachycardia, and PVT, as found in human CPVT. Ventricular epicardial conduction velocities (CVs) measured using multielectrode array recordings and maximum action potential upstroke rates, (dV/dt)(max), measured using intracellular microelectrodes were indistinguishable in untreated wild-type (WT) and RyR2(S/S). Pharmacological challenge of RyR2(S/S), but not WT hearts, then reduced CV and (dV/dt)(max) and also revealed a strongly arrhythmic phenotype. There was no evidence of gross structural or fibrotic changes in either RyR2(+/S) or RyR2(S/S) hearts on light microscopy. CONCLUSIONS: We associate altered ventricular myocardial CV potentially resulting in arrhythmogenic substrate with arrhythmic properties associated with genetic RyR2 alterations for the first time.
Lee NYS, Khoo WKS, Adnan MA, Mahalingam TP, Fernandez AR, Jeevaratnam K (2016) The pharmacological potential of Phyllanthus niruri, JOURNAL OF PHARMACY AND PHARMACOLOGY 68 (8) pp. 953-969 WILEY-BLACKWELL
Jeevaratnam K, Zhang Y, Guzadhur L, Duehmke RM, Lei M, Grace AA, Huang CL (2010) Differences in sino-atrial and atrio-ventricular function with age and sex attributable to the Scn5a+/- mutation in a murine cardiac model., Acta Physiol (Oxf) 200 (1) pp. 23-33
AIM: To investigate the interacting effects of age and sex on electrocardiographic (ECG) features of Scn5a(+/-) mice modelling Brugada syndrome. METHODS: Recordings were performed on anaesthetized wild-type (WT) and Scn5a(+/-) mice and differences attributable to these risk factors statistically stratified. RESULTS: Scn5a(+/-) exerted sex-dependent effects upon sino-atrial function that only became apparent with age. RR intervals were greater in old male than in old female Scn5a(+/-). Atrio-ventricular (AV) conduction was slower in young female mice, whether WT and Scn5a(+/-), than the corresponding young male WT and Scn5a(+/-). However, PR intervals lengthened with age in male but not in female Scn5a(+/-) giving the greatest PR intervals in old male Scn5a(+/-) compared with either old male WT or young male Scn5a(+/-) mice. In contrast, PR intervals were similar in old female Scn5a(+/-) and in old female WT. QTc was prolonged in Scn5a(+/-) compared with WT, and female Scn5a(+/-) compared with female WT. Age-dependent alterations in durations of ventricular repolarization relative to WT affected male but not female Scn5a(+/-). Thus, T-wave durations were greater in old male Scn5a(+/-) compared with old male WT, but indistinguishable between old female Scn5a(+/-) and old female WT. Finally, analysis for combined interactions of genotype, age and sex demonstrated no effects on P wave and QRS durations and QTc intervals. CONCLUSION: We demonstrate for the first time that age, sex and genotype exert both independent and interacting ECG effects. The latter suggest alterations in cardiac pacemaker function, atrio-ventricular conduction and ventricular repolarization greatest in ageing male Scn5a(+/-).
Zhang Y, Guzadhur L, Jeevaratnam K, Salvage SC, Matthews GD, Lammers WJ, Lei M, Huang CL, Fraser JA (2014) Arrhythmic substrate, slowed propagation and increased dispersion in conduction direction in the right ventricular outflow tract of murine Scn5a+/- hearts., Acta Physiol (Oxf) 211 (4) pp. 559-573
AIM: To test a hypothesis attributing arrhythmia in Brugada Syndrome to right ventricular (RV) outflow tract (RVOT) conduction abnormalities arising from Nav 1.5 insufficiency and fibrotic change. METHODS: Arrhythmic properties of Langendorff-perfused Scn5a+/- and wild-type mouse hearts were correlated with ventricular effective refractory periods (VERPs), multi-electrode array (MEA) measurements of action potential (AP) conduction velocities and dispersions in conduction direction (CD), Nav 1.5 expression levels, and fibrotic change, as measured at the RVOT and RV. Two-way anova was used to test for both independent and interacting effects of anatomical region and genotype on these parameters. RESULTS: Scn5a+/- hearts showed greater arrhythmic frequencies during programmed electrical stimulation at the RVOT but not the RV. The Scn5a+/- genotype caused an independent increase of VERP regardless of whether the recording site was the RVOT or RV. Effective AP conduction velocities (CV s), derived from fitting regression planes to arrays of observed local activation times were reduced in Scn5a+/- hearts and at the RVOT independently. AP conduction velocity magnitudes derived by averaging MEA results from local vector analyses, CV*, were reduced by the Scn5a+/- genotype alone. In contrast, dispersions in conduction direction, were greater in the RVOT than the RV, when the atrioventricular node was used as the pacing site. The observed reductions in Nav 1.5 expression were attributable to Scn5a+/-, whereas increased levels of fibrosis were associated with the RVOT. CONCLUSIONS: The Scn5a+/- RVOT recapitulates clinical findings of increased arrhythmogenicity through reduced CV reflecting reduced CV* attributable to reduced Nav 1.5 expression and increased CD attributable to fibrosis.
Jeevaratnam K, Nadarajah VD, Judson JP, Nalliah S, Abdullah MF (2010) Periodic assessment of plasma sFlt-1 and PlGF concentrations and its association with placental morphometry in gestational hypertension (GH) - a prospective follow-up study., BMC Pregnancy Childbirth 10
BACKGROUND: Hypertensive disorders in pregnancy contributes to about 12% of maternal deaths in Malaysia and similarly worldwide. Early detection and adequate management are preventable strategies. Biochemical markers of abnormal angiogenesis would be more specific in early detection than routine blood pressure and proteinuria measurements. The aim of this study was to estimate maternal plasma PlGF and sFlt-1 levels in pregnant women with gestational hypertension at three intervals of pregnancy and correlate these biomarker levels with placental morphometry. METHODS: Venous blood samples (antepartum, intrapartum and post partum periods) were drawn to estimate for sFlt-1 and PlGF levels while placental tissue samples were examined for placental morphometry. RESULTS: PlGF levels were lower in gestational hypertension (GH) compared to normotensive during antepartum and intrapartum period, whereas sFlt-1 levels were elevated in GH at antepartum, intrapartum and postpartum intervals during pregnancy. An inverse relationship between these two biomarkers was observed through correlation analysis. PlGF levels were inversely correlated with total villous surface area of the placental periphery (TCsa-C) and villous capillarization (VC-C) of the placental periphery. CONCLUSION: We established periodic values of for sFlt-1 and PlGF levels for the first time in an ethnically diverse Malaysian setting. We suggest the development of GH in women is related to defective capillarization. In demonstrating periodic changes, this study suggest the possibility of developing GH and other long term health complications as a result of prolonged exposure to sFlt-1. The correlation between PlGF levels and morphometric findings also support possible capillarization defect.
Jeevaratnam K, Poh Tee S, Zhang Y, Rewbury R, Guzadhur L, Duehmke R, Grace AA, Lei M, Huang CL (2011) Delayed conduction and its implications in murine Scn5a(+/-) hearts: independent and interacting effects of genotype, age, and sex., Pflugers Arch 461 (1) pp. 29-44
We explored for relationships between SCN5A haploinsufficiency, implicated in clinical arrhythmogenicity, and right ventricular (RV) conduction disorders in Langendorff-perfused, male and female, and young (3 months) and old (>12 month old) Scn5a ( +/-) and wild type (WT) hearts. The investigated conditions of genotype, age, and sex affected latencies but not repolarization time courses of RV monophasic action potentials. This prompted examination of the patterns of RV epicardial activation, its dispersion, and their interrelationships as possible arrhythmic mechanisms using a 64-channel, multi-electrode array. Mean ventricular activation times (T*(MEAN)), spatial dispersions (D* (S)) between recording channels/cardiac cycle, and maximum activation times (T* (MAX)) representing the slowest possible conduction in any given heart were all higher in old male Scn5a ( +/-) compared with young male and old female Scn5a ( +/-) and old male WT. Temporal dispersions (D*(T)) of recording channels were similarly higher in old male Scn5a (+/-) compared with old male WT. All groupings of D*(T), D*(S), and T*(MAX) nevertheless linearly correlated with T*(MEAN), with indistinguishable slopes. The variates explored thus influence D*(T), D*(S), and T*(MAX) through actions on T*(MEAN). These findings in turn correlated with increased levels of fibrosis in young male, young female, and old male Scn5a ( +/-) compared with the corresponding WTs. We thus demonstrate for the first time independent and interacting effects of genotype, age, and sex on epicardial conduction and its dispersions at least partially attributable to fibrotic change, resulting in the greatest effects in old male Scn5a ( +/-) in an absence of alterations in repolarization time courses. This directly implicates altered depolarization in the clinical arrhythmogenicity associated with Scn5a ( +/-).
Guzadhur L, Pearcey SM, Duehmke RM, Jeevaratnam K, Hohmann AF, Zhang Y, Grace AA, Lei M, Huang CL (2010) Atrial arrhythmogenicity in aged Scn5a+/DeltaKPQ mice modeling long QT type 3 syndrome and its relationship to Na+ channel expression and cardiac conduction., Pflugers Arch 460 (3) pp. 593-601
Recent studies have reported that human mutations in Nav1.5 predispose to early age onset atrial arrhythmia. The present experiments accordingly assess atrial arrhythmogenicity in aging Scn5a+/KPQ mice modeling long QT3 syndrome in relationship to cardiac Na(+) channel, Nav1.5, expression. Atrial electrophysiological properties in isolated Langendorff-perfused hearts from 3- and 12-month-old wild type (WT), and Scn5a+/KPQ mice were assessed using programmed electrical stimulation and their Nav1.5 expression assessed by Western blot. Cardiac conduction properties were assessed electrocardiographically in intact anesthetized animals. Monophasic action potential recordings demonstrated increased atrial arrhythmogenicity specifically in aged Scn5a+/DeltaKPQ hearts. These showed greater action potential duration/refractory period ratios but lower atrial Nav1.5 expression levels than aged WT mice. Atrial Nav1.5 levels were higher in young Scn5a+/DeltaKPQ than young WT. These levels increased with age in WT but not Scn5a+/DeltaKPQ. Both young and aged Scn5a+/DeltaKPQ mice showed lower heart rates and longer PR intervals than their WT counterparts. Young Scn5a+/DeltaKPQ mice showed longer QT and QTc intervals than young WT. Aged Scn5a+/DeltaKPQ showed longer QRS durations than aged WT. PR intervals were prolonged and QT intervals were shortened in young relative to aged WT. In contrast, ECG parameters were similar between young and aged Scn5a+/DeltaKPQ. Aged murine Scn5a+/DeltaKPQ hearts thus exhibit an increased atrial arrhythmogenicity. The differing Nav1.5 expression and electrocardiographic indicators of slowed cardiac conduction between Scn5a+/DeltaKPQ and WT, which show further variations associated with aging, may contribute toward atrial arrhythmia in aged Scn5a+/DeltaKPQ hearts.
Zhang Y, Fraser JA, Jeevaratnam K, Hao X, Hothi SS, Grace AA, Lei M, Huang CL (2011) Acute atrial arrhythmogenicity and altered Ca(2+) homeostasis in murine RyR2-P2328S hearts., Cardiovasc Res 89 (4) pp. 794-804
AIMS: The experiments explored for atrial arrhythmogenesis and its possible physiological background in recently developed hetero-(RyR2(+/S)) and homozygotic (RyR2(S/S)) RyR2-P2328S murine models for catecholaminergic polymorphic ventricular tachycardia (VT) for the first time. They complement previous clinical and experimental reports describing increased ventricular arrhythmic tendencies associated with physical activity, stress, or catecholamine infusion, potentially leading to VT and ventricular fibrillation. METHODS AND RESULTS: Atrial arrhythmogenic properties were compared at the whole animal, Langendorff-perfused heart, and single, isolated atrial myocyte levels using electrophysiological and confocal fluorescence microscopy methods. This demonstrated that: (i) electrocardiographic parameters in intact anaesthetized wild-type (WT), RyR2(+/S) and RyR2(S/S) mice were statistically indistinguishable both before and after addition of isoproterenol apart from increases in heart rates. (ii) Bipolar electrogram and monophasic action potential recordings showed significantly higher incidences of arrhythmogenesis in isolated perfused RyR2(S/S), but not RyR2(+/S), relative to WT hearts during either regular pacing or programmed electrical stimulation. The addition of isoproterenol increased such incidences in all three groups. (iii) However, there were no accompanying differences in cardiac anatomy or action potential durations at 90% repolarization and refractory periods. (iv) In contrast, episodes of diastolic Ca(2+) release were observed under confocal microscopy in isolated fluo-3-loaded RyR2(S/S), but not RyR2(+/S) or WT, atrial myocytes. The introduction of isoproterenol resulted in significant diastolic Ca(2+) release in all three groups. CONCLUSIONS: These findings establish acute atrial arrhythmogenic properties in RyR2-P2328S hearts and correlate these with altered Ca(2+) homeostasis in an absence of repolarization abnormalities for the first time.
Guzadhur L, Jiang W, Pearcey SM, Jeevaratnam K, Duehmke RM, Grace AA, Lei M, Huang CL (2012) The age-dependence of atrial arrhythmogenicity in Scn5a+/- murine hearts reflects alterations in action potential propagation and recovery., Clin Exp Pharmacol Physiol 39 (6) pp. 518-527
1. In the present study, we investigated the effect of age on atrial electrophysiological properties in Scn5a(+/-) hearts used to model corresponding increases in atrial arrhythmic tendency in human Brugada syndrome. 2. Atrial action potential initiation, propagation and recovery were compared in young (3 month old) and aged (12 month old), wild-type (WT) and Scn5a(+/-) hearts. Multielectrode array recordings assessed the spatial propagation of intrinsic electrical activity in superfused atrial preparations, whereas bipolar electrogram recordings measured basic cycle lengths (BCL) in Langendorff preparations. The duration of electrogram activity (EGD) during regular and extrasystolic stimulation with programmed electrical stimulation provided EGD ratios and atrial effective refractory periods (AERP). Monophasic recordings measured action potential durations (APD). 3. Systematic statistical explorations for independent and interacting effects of age and the Scn5a(+/-) condition demonstrated that both young and aged Scn5a(+/-) mice exhibited slowed propagation of atrial excitation relative to corresponding WT mice, with the greatest effects in aged Scn5a(+/-) mice, which additionally exhibited increased intrinsic BCL. 4. Young Scn5a(+/-) mice exhibited greater EGD and EGD ratios, as well as APD/AERP ratios, suggesting increased arrhythmic tendency compared with WT mice. 5. Aged Scn5a(+/-) mice exhibited normal EGD, EGD ratios and APD compared to aged WT and young Scn5a(+/-), and increased AERP and smaller APD/AERP ratios compared with young Scn5a(+/-). 6. These electrophysiological findings indicate increased atrial arrhythmogenicity with maximal effects on both conduction and repolarization characteristics in young compared with aged Scn5a(+/-) mice.
Pau A, Jeevaratnam K, Chen YS, Fall AA, Khoo C, Nadarajah VD (2013) The Multiple Mini-Interview (MMI) for student selection in health professions training - a systematic review., Med Teach 35 (12) pp. 1027-1041
BACKGROUND: The Multiple Mini-Interview (MMI) has been used increasingly for selection of students to health professions programmes. OBJECTIVES: This paper reports on the evidence base for the feasibility, acceptability, reliability and validity of the MMI. DATA SOURCES: CINAHL and MEDLINE STUDY ELIGIBILITY CRITERIA: All studies testing the MMI on applicants to health professions training. STUDY APPRAISAL AND SYNTHESIS METHODS: Each paper was appraised by two reviewers. Narrative summary findings on feasibility, acceptability, reliability and validity are presented. RESULTS: Of the 64 citations identified, 30 were selected for review. The modal MMI consisted of 10 stations, each lasting eight minutes and assessed by one interviewer. The MMI was feasible, i.e. did not require more examiners, did not cost more, and interviews were completed over a short period of time. It was acceptable, i.e. fair, transparent, free from gender, cultural and socio-economic bias, and did not favour applicants with previous coaching. Its reliability was reported to be moderate to high, with Cronbach's alpha = 0.69-0.98 and G = 0.55-0.72. MMI scores did not correlate to traditional admission tools scores, were not associated with pre-entry academic qualifications, were the best predictor for OSCE performance and statistically predictive of subsequent performance at medical council examinations. CONCLUSIONS: The MMI is reliable, acceptable and feasible. The evidence base for its validity against future medical council exams is growing with reports from longitudinal investigations. However, further research is needed for its acceptability in different cultural context and validity against future clinical behaviours.
Ning F, Luo L, Ahmad S, Valli H, Jeevaratnam K, Wang T, Guzadhur L, Yang D, Fraser JA, Huang CL-H, Ma A, Salvage SC (2015) The RyR2-P2328S mutation downregulates Na(v)1.5 producing arrhythmic substrate in murine ventricles, PFLUGERS ARCHIV-EUROPEAN JOURNAL OF PHYSIOLOGY 468 (4) pp. 655-665 SPRINGER
Jeevaratnam K, Rewbury R, Zhang Y, Guzadhur L, Grace AA, Lei M, Huang CL (2012) Frequency distribution analysis of activation times and regional fibrosis in murine Scn5a+/- hearts: the effects of ageing and sex., Mech Ageing Dev 133 (9-10) pp. 591-599
Both Brugada Syndrome (BrS) and progressive cardiac conduction defect (PCCD) are associated respectively with diffuse and discrete alterations in conduction pathways affected by ageing and sex. This study assessed for contributions of such processes to the mechanism of conduction changes in Scn5a(+/-) and WT hearts stratified by age (3 and 12 months) and sex. In vivo electrocardiographic chest-lead assessment demonstrated greater incidences of bundle branch block in all Scn5a(+/-) mice compared to WT. Frequency analysis of right ventricular (RV) epicardial activation obtained from a 64-channel multi-electrode array demonstrated greater prominence of late conducting components in Scn5a(+/-) compared to WT male, and in male compared to female Scn5a(+/-) following stratification by genotype and sex. Similar differences were observed between old male Scn5a(+/-) and young male Scn5a(+/-), old female Scn5a(+/-), and old male WT, following stratification by genotype, age and sex. These findings directly correlated with histomorphometric assessment of regional fibrosis in both septa and free walls preferentially involving the RV. We demonstrate complex alterations in conduction distributions suggesting a conversion of normal to slow-conducting tissue, modulated by ageing and sex, coupled with fibrosis in Scn5a(+/-) hearts. These features suggest an overlap between pathophysiological processes related to BrS and PCCD in Scn5a(+/-) hearts.
Duehmke RM, Pearcey S, Stefaniak JD, Guzadhur L, Jeevaratnam K, Costopoulos C, Pedersen TH, Grace AA, Huang CL (2012) Altered re-excitation thresholds and conduction of extrasystolic action potentials contribute to arrhythmogenicity in murine models of long QT syndrome., Acta Physiol (Oxf) 206 (3) pp. 164-177
AIM: QT interval prolongation reflecting delayed action potential (AP) repolarization is associated with polymorphic ventricular tachycardia and early after depolarizations potentially initiating extrasystolic APs if of sufficient amplitude. The current experiments explored contributions of altered re-excitation thresholds for, and conduction of, such extrasystolic APs to arrhythmogenesis in Langendorff-perfused, normokalaemic, control wild-type hearts and two experimental groups modelling long QT (LQT). The two LQT groups consisted of genetically modified, Scn5a(+/KPQ) and hypokalaemic wild-type murine hearts. METHODS: Hearts were paced from their right ventricles and monophasic AP electrode recordings obtained from their left ventricular epicardia, with recording and pacing electrodes separated by 1 cm. An adaptive programmed electrical stimulation protocol applied pacing (S1) stimulus trains followed by premature (S2) extrastimuli whose amplitudes were progressively increased with progressive decrements in S1S2 interval to maintain stimulus capture. Such protocols culminated in either arrhythmic or refractory endpoints. RESULTS: Arrhythmic outcomes were associated with (1) lower conduction velocities in their initiating extrasystolic APs than refractory outcomes and (2) higher conduction velocities in the LQT groups than in controls. Furthermore, (3) the endpoints were reached at longer S1S2 coupling intervals and with smaller stimulus amplitudes in the LQT groups compared with controls. This was despite (4) similar relationships between conduction velocity and S1S2 coupling interval and between re-excitation thresholds and S1S2 coupling interval in all three experimental groups. CONCLUSIONS: Arrhythmias induced by extrasystolic APs in the LQT groups thus occur under conditions of higher conduction velocity and greater sensitivity to extrastimuli than in controls.
King JH, Wickramarachchi C, Kua K, Du Y, Jeevaratnam K, Matthews HR, Grace AA, Huang CL, Fraser JA (2013) Loss of Nav1.5 expression and function in murine atria containing the RyR2-P2328S gain-of-function mutation., Cardiovasc Res 99 (4) pp. 751-759
AIMS: Recent studies reported slowed conduction velocity (CV) in murine hearts homozygous for the gain-of-function RyR2-P2328S mutation (RyR2(S/S)) and associated this with an increased incidence of atrial and ventricular arrhythmias. The present experiments determined mechanisms contributing to the reduced atrial CV. METHODS AND RESULTS: The determinants of CV were investigated in murine RyR2(S/S) hearts and compared with those in wild-type (WT) and slow-conducting Scn5a(+/-) hearts. Picrosirius red staining demonstrated increased fibrosis only in Scn5a(+/-) hearts. Immunoblot assays showed similar expressions of Cx43 and Cx40 levels in the three genotypes. In contrast, Nav1.5 expression was reduced in both RyR2(S/S) and Scn5a(+/-) atria. These findings correlated with intracellular microelectrode and loose-patch-clamp studies. Microelectrode measurements showed reduced maximum rates of depolarization in Scn5a(+/-) and RyR2(S/S) atria compared with WT, despite similar diastolic membrane potentials. Loose-patch-clamp measurements demonstrated reduced peak Na(+) currents (INa) in the Scn5a(+/-) and RyR2(S/S) atria relative to WT, with similar normalized current-voltage relationships. In WT atria, reduction in INa could be produced by treatment with high extracellular Ca(2+), caffeine, or cyclopiazonic acid, each expected to produce an acute increase in [Ca(2+)]i. CONCLUSION: RyR2(S/S) atria show reduced levels of Nav1.5 expression and Na(+) channel function. Reduced Na(+) channel function was also observed in WT atria, following acute increases in [Ca(2+)]i. Taken together, the results suggest that raised [Ca(2+)]i produces both acute and chronic inhibition of Na(+) channel function. These findings may help explain the relationship between altered Ca(2+) homeostasis, CV, and the maintenance of common arrhythmias such as atrial fibrillation.
Jeevaratnam K, Guzadhur L, Goh YM, Grace AA, Huang CL-H (2015) Sodium channel haploinsufficiency and structural change in ventricular arrhythmogenesis, ACTA PHYSIOLOGICA 216 (2) pp. 186-202 WILEY-BLACKWELL
Recent papers have attributed arrhythmic substrate in murine RyR2-P2328S hearts to reduced action potential (AP) conduction velocities (CV), reflecting acute functional inhibition and/or reduced expression of sodium channels. We explored for acute effects of direct Epac (exchange protein directly activated by cAMP)-mediated ryanodine receptor-2 (RyR2) activation on arrhythmic substrate and CV. Monophasic action potential recordings demonstrated that initial steady (8-Hz) extrinsic pacing elicited ventricular tachycardia (VT) in 0 of 18 Langendorff-perfused wild-type mouse ventricles before pharmacological intervention. The Epac activator 8-CPT (8-(4-chlorophenylthio)-2'-O-methyladenosine-3',5'-cyclic monophosphate) (VT in 1 of 7 hearts), and the RyR2 blocker dantrolene, either alone (0 of 11) or with 8-CPT (0 of 9) did not then increase VT incidence (p>0.05). Both progressively increased pacing rates and programmed extrasystolic (S2) stimuli similarly produced no VT in untreated hearts (n = 20 and n = 9 respectively). 8-CPT challenge then increased VT incidences (5 of 7 and 4 of 8 hearts respectively; p0.05). 8-CPT but not dantrolene, whether alone or combined with 8-CPT, correspondingly increased AP latencies (1.14±0.04 (n=7), 1.04±0.03 (n=10), 1.09±0.05 (n=8) relative to respective control values). In contrast, AP durations, conditions for 2:1 conduction block and ventricular effective refractory periods remained unchanged throughout. We thus demonstrate for the first time that acute RyR2 activation reversibly induces VT in specific association with reduced CV.
Long QT Syndrome 3 (LQTS3) arises from gain-of-function Nav1.5 mutations, prolonging action
potential repolarisation and electrocardiographic (ECG) QT interval, associated with increased agedependent
risk for major arrhythmic events, and paradoxical responses to ²-adrenergic agents.
We investigated for independent and interacting efects of age and Scn5a+/KPQ genotype in
anaesthetised mice modelling LQTS3 on ECG phenotypes before and following ²-agonist challenge, and
upon fbrotic change. Prolonged ventricular recovery was independently associated with Scn5a+/KPQ
and age. Ventricular activation was prolonged in old Scn5a+/KPQ mice (p=0.03). We associated
Scn5a+/KPQ with increased atrial and ventricular fbrosis (both: p
increased fbrosis with age (p
repolarisation alternans (p=0.02). Dobutamine increased ventricular rate (p
atrioventricular conduction (PR segment-p=0.02; PR interval-p=0.02) and incidences of repolarisation
in ventricular repolarisation following corresponding increases in ventricular rate. The present fndings
implicate interactions between age and Scn5a+/KPQ in prolonging ventricular activation, correlating
them with fbrotic change for the frst time, adding activation abnormalities to established recovery
abnormalities in LQTS3. These fndings, together with dynamic electrophysiological responses to
²-adrenergic challenge, have therapeutic implications for ageing LQTS patients.
The development of novel drugs specifically directed at the ion channels underlying particular features of cardiac action potential
(AP) initiation, recovery, and refractoriness would contribute to an optimized approach to antiarrhythmic therapy that minimizes
potential cardiac and extracardiac toxicity. Of these, Kþ channels contribute numerous and diverse currents with specific actions
on different phases in the time course of AP repolarization. These features and their site-specific distribution make particular Kþ
channel types attractive therapeutic targets for the development of pharmacological agents attempting antiarrhythmic therapy in
conditions such as atrial fibrillation. However, progress in the development of such temporally and spatially selective antiarrhythmic
drugs against particular ion channels has been relatively limited, particularly in view of our incomplete understanding of
the complex physiological roles and interactions of the various ionic currents. This review summarizes the physiological properties
of the main cardiac potassium channels and the way in which they modulate cardiac electrical activity and then critiques a
number of available potential antiarrhythmic drugs directed at them.