We report for the first time abnormalities in cardiac ventricular electrophysiology in a genetically modified murine model lacking the Scn3b gene (Scn3b(-/-)). Scn3b(-/-) mice were created by homologous recombination in embryonic stem (ES) cells. RT-PCR analysis confirmed that Scn3b mRNA was expressed in the ventricles of wild-type (WT) hearts but was absent in the Scn3b(-/-) hearts. These hearts also showed increased expression levels of Scn1b mRNA in both ventricles and Scn5a mRNA in the right ventricles compared to findings in WT hearts. Scn1b and Scn5a mRNA was expressed at higher levels in the left than in the right ventricles of both Scn3b(-/-) and WT hearts. Bipolar electrogram and monophasic action potential recordings from the ventricles of Langendorff-perfused Scn3b(-/-) hearts demonstrated significantly shorter ventricular effective refractory periods (VERPs), larger ratios of electrogram duration obtained at the shortest and longest S(1)-S(2) intervals, and ventricular tachycardias (VTs) induced by programmed electrical stimulation. Such arrhythmogenesis took the form of either monomorphic or polymorphic VT. Despite shorter action potential durations (APDs) in both the endocardium and epicardium, Scn3b(-/-) hearts showed DeltaAPD(90) values that remained similar to those shown in WT hearts. The whole-cell patch-clamp technique applied to ventricular myocytes isolated from Scn3b(-/-) hearts demonstrated reduced peak Na(+) current densities and inactivation curves that were shifted in the negative direction, relative to those shown in WT myocytes. Together, these findings associate the lack of the Scn3b gene with arrhythmic tendencies in intact perfused hearts and electrophysiological features similar to those in Scn5a(+/-) hearts.

This study investigated membrane transport mechanisms influencing relative changes in cell volume (V) and resting membrane potential (E(m)) following osmotic challenge in amphibian skeletal muscle fibres. It demonstrated a stabilization of E(m) despite cell shrinkage, which was attributable to elevation of intracellular [Cl(-)] above electrochemical equilibrium through Na(+)-Cl(-) and Na(+)-K(+)-2Cl(-) cotransporter action following exposures to extracellular hypertonicity. Fibre volumes (V) determined by confocal microscope x z - scanning of cutaneous pectoris muscle fibres varied linearly with [1/extracellular osmolarity], showing insignificant volume corrections, in fibres studied in Cl(-)-free, normal and Na(+)-free Ringer solutions and in the presence of bumetanide, chlorothiazide and ouabain. The observed volume changes following increases in extracellular tonicity were compared with microelectrode measurements of steady-state resting potentials (E(m)). Fibres in isotonic Cl(-)-free, normal and Na(+)-free Ringer solutions showed similar E(m) values consistent with previously reported permeability ratios P(Na)/P(K)(0.03-0.05) and P(Cl)/P(K) ( approximately 2.0) and intracellular [Na(+)], [K(+)] and [Cl(-)]. Increased extracellular osmolarities produced hyperpolarizing shifts in E(m) in fibres studied in Cl(-)-free Ringer solution consistent with the Goldman-Hodgkin-Katz (GHK) equation. In contrast, fibres exposed to hypertonic Ringer solutions of normal ionic composition showed no such E(m) shifts, suggesting a Cl(-)-dependent stabilization of membrane potential. This stabilization of E(m) was abolished by withdrawing extracellular Na(+) or by the combined presence of the Na(+)-Cl(-) cotransporter (NCC) inhibitor chlorothiazide (10 microM) and the Na(+)-K(+)-2Cl(-) cotransporter (NKCC) inhibitor bumetanide (10 microM), or the Na(+)-K(+)-ATPase inhibitor ouabain (1 or 10 microM) during alterations in extracellular osmolarity. Application of such agents after such increases in tonicity only produced a hyperpolarization after a time delay, as expected for passive Cl(-) equilibration. These findings suggest a model that implicates the NCC and/or NKCC in fluxes that maintain [Cl(-)](i) above its electrochemical equilibrium. Such splinting of [Cl(-)](i) in combination with the high P(Cl)/P(K) of skeletal muscle stabilizes E(m) despite volume changes produced by extracellular hypertonicity, but at the expense of a cellular capacity for regulatory volume increases (RVIs). In situations where P(Cl)/P(K) is low, the same co-transporters would instead permit RVIs but at the expense of a capacity to stabilize E(m).

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.

Mutations involving cardiac ion channels result in abnormal action potential formation or propagation, leading to cardiac arrhythmias. Despite the large impact on society of sudden cardiac death resulting from such arrhythmias, understanding of the underlying cellular mechanism is poor and clinical risk stratification and treatment consequently limited. Basic research using molecular techniques, as well as animal models, has proved extremely useful in improving our knowledge of inherited arrhythmogenic syndromes. This offers the practitioner tools to accurately diagnose rare disorders and provides novel markers for risk assessment and a basis for new strategies of treatment.

Incidence of cardiac arrhythmias increases significantly with age. In order to effectively stratify arrhythmic risk in the aging population it is crucial to elucidate the relevant underlying molecular mechanisms. The changes underlying age-related electrophysiological disruption appear to be closely associated with mitochondrial dysfunction. Thus, the present review examines the mechanisms by which age-related mitochondrial dysfunction promotes arrhythmic triggers and substrate. Namely, via alterations in plasmalemmal ionic currents (both sodium and potassium), gap junctions, cellular Ca2+ homeostasis, and cardiac fibrosis. Stratification of patients' mitochondrial function status permits application of appropriate anti-arrhythmic therapies. Here, we discuss novel potential anti-arrhythmic pharmacological interventions that specifically target upstream mitochondrial function and hence ameliorates the need for therapies targeting downstream changes which have constituted traditional antiarrhythmic therapy.

In the wake of the controversy surrounding the SYMPLICITY HTN-3 trial and data from subsequent trials, this review aims to perform an updated and more comprehensive review of the impact of renal sympathetic denervation on cardiac arrhythmias.

The Scn5a gene encodes the major pore-forming Nav 1.5 (α) subunit, of the voltage-gated Na+ channel in cardiomyocytes. The key role of Nav 1.5 in action potential initiation and propagation in both atria and ventricles predisposes organisms lacking Scn5a or carrying Scn5a mutations to cardiac arrhythmogenesis. Loss-of-function Nav 1.5 genetic abnormalities account for many cases of the human arrhythmic disorder Brugada syndrome (BrS) and related conduction disorders. A murine model with a heterozygous Scn5a deletion recapitulates many electrophysiological phenotypes of BrS. This study examines the relationships between its Scn5a+/- genotype, resulting transcriptional changes, and the consequent phenotypic presentations of BrS. Of 62 selected protein-coding genes related to cardiomyocyte electrophysiological or homeostatic function, concentrations of mRNA transcribed from 15 differed significantly from wild type (WT). Despite halving apparent ventricular Scn5a transcription heterozygous deletion did not significantly downregulate its atrial expression, raising possibilities of atria-specific feedback mechanisms. Most of the remaining 14 genes whose expression differed significantly between WT and Scn5a+/- animals involved Ca2+ homeostasis specifically in atrial tissue, with no overlap with any ventricular changes. All statistically significant changes in expression were upregulations in the atria and downregulations in the ventricles. This investigation demonstrates the value of future experiments exploring for and clarifying links between transcriptional control of Scn5a and of genes whose protein products coordinate Ca2+ regulation and examining their possible roles in BrS.

Mitochondrial dysfunction underlying metabolic disorders such as obesity and diabetes mellitus is strongly associated with cardiac arrhythmias. Murine Pgc-1α-/- hearts replicate disrupted mitochondrial function and model the associated pro-arrhythmic electrophysiological abnormalities. Quantitative PCR, western blotting and histological analysis were used to investigate the molecular basis of the electrophysiological changes associated with mitochondrial dysfunction. qPCR analysis implicated downregulation of genes related to Na+-K+ ATPase activity (Atp1b1), surface Ca2+ entry (Cacna1c), action potential repolarisation (Kcnn1), autonomic function (Adra1d, Adcy4, Pde4d, Prkar2a), and morphological properties (Myh6, Tbx3) in murine Pgc-1α-/- ventricles. Western blotting revealed reduced NaV1.5 but normal Cx43 expression. Histological analysis revealed increased tissue fibrosis in the Pgc-1α-/- ventricles. These present findings identify altered transcription amongst a strategically selected set of genes established as encoding proteins involved in cardiac electrophysiological activation and therefore potentially involved in alterations in ventricular activation and Ca2+ homeostasis in arrhythmic substrate associated with Pgc-1α deficiency. They complement and complete previous studies examining such expression characteristics in the atria and ventricles of Pgc-1 deficient murine hearts.

Voltage-gated sodium channels comprise an ion-selective α-subunit and one or more associated β-subunits. The β3-subunit (encoded by the SCN3B gene) is an important physiological regulator of the heart-specific sodium channel, Nav1.5. We have previously shown that when expressed alone in HEK293F cells, the full-length β3-subunit forms trimers in the plasma membrane. We extend this result with biochemical assays and use the proximity ligation assay (PLA) to identify oligomeric β3-subunits, not just at the plasma membrane, but throughout the secretory pathway. We then investigate the corresponding clustering properties of the α-subunit and the effects upon these of the β3-subunits. The oligomeric status of the Nav1.5 α-subunit in vivo, with or without the β3-subunit, has not been previously investigated. Using super-resolution fluorescence imaging, we show that under conditions typically used in electrophysiological studies, the Nav1.5 α-subunit assembles on the plasma membrane of HEK293F cells into spatially localized clusters rather than individual and randomly dispersed molecules. Quantitative analysis indicates that the β3-subunit is not required for this clustering but β3 does significantly change the distribution of cluster sizes and nearest-neighbor distances between Nav1.5 α-subunits. However, when assayed by PLA, the β3-subunit increases the number of PLA-positive signals generated by anti-(Nav1.5 α-subunit) antibodies, mainly at the plasma membrane. Since PLA can be sensitive to the orientation of proteins within a cluster, we suggest that the β3-subunit introduces a significant change in the relative alignment of individual Nav1.5 α-subunits, but the clustering itself depends on other factors. We also show that these structural and higher-order changes induced by the β3-subunit do not alter the degree of electrophysiological gating cooperativity between Nav1.5 α-subunits. Our data provide new insights into the role of the β3-subunit and the supramolecular organization of sodium channels, in an important model cell system that is widely used to study Nav channel behavior.

Deficiencies in the transcriptional co-activator, peroxisome proliferative activated receptor, gamma, coactivator-1β are implicated in deficient mitochondrial function. The latter accompanies clinical conditions including aging, physical inactivity, obesity, and diabetes. Recent electrophysiological studies reported that Pgc-1β-/- mice recapitulate clinical age-dependent atrial pro-arrhythmic phenotypes. They implicated impaired chronotropic responses to adrenergic challenge, compromised action potential (AP) generation and conduction despite normal AP recovery timecourses and background resting potentials, altered intracellular Ca2+ homeostasis, and fibrotic change in the observed arrhythmogenicity.

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 exchange protein directly activated by cAMP (Epac)-mediated ryanodine receptor-2 (RyR2) activation on arrhythmic substrate and CV. Monophasic action potential (MAP) 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>.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; P<.05). However, dantrolene, whether alone (0 of 10 and 1 of 13) or combined with 8-CPT (0 of 10 and 0 of 13) did not increase VT incidence relative to those observed in untreated hearts (P>.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.

Acute RyR2 activation by exchange protein directly activated by cAMP (Epac) reversibly perturbs myocyte Ca2+ homeostasis, slows myocardial action potential conduction, and exerts pro-arrhythmic effects. Loose patch-clamp studies, preserving in vivo extracellular and intracellular conditions, investigated Na+ current in intact cardiomyocytes in murine atrial and ventricular preparations following Epac activation. Depolarising steps to varying test voltages activated typical voltage-dependent Na+ currents. Plots of peak current against depolarisation from resting potential gave pretreatment maximum atrial and ventricular currents of -20.23 ± 1.48 (17) and -29.8 ± 2.4 (10) pA/μm2 (mean ± SEM [n]). Challenge by 8-CPT (1 μmol/L) reduced these currents to -11.21 ± 0.91 (12) (P < .004) and -19.3 ± 1.6 (11) pA/μm2 (P < .04) respectively. Currents following further addition of the RyR2 inhibitor dantrolene (10 μmol/L) (-19.91 ± 2.84 (13) and -26.6 ± 1.7 (17)), and dantrolene whether alone (-19.53 ± 1.97 (8) and -27.6 ± 1.9 (14)) or combined with 8-CPT (-19.93 ± 2.59 (12) and -29.9 ± 2.5(11)), were indistinguishable from pretreatment values (all P >> .05). Assessment of the inactivation that followed by applying subsequent steps to a fixed voltage 100 mV positive to resting potential gave concordant results. Half-maximal inactivation voltages and steepness factors, and time constants for Na+ current recovery from inactivation in double-pulse experiments, were similar through all the pharmacological conditions. Intracellular sharp microelectrode membrane potential recordings in intact Langendorff-perfused preparations demonstrated concordant variations in maximum rates of atrial and ventricular action potential upstroke, (dV/dt)max . We thus demonstrate an acute, reversible, Na+ channel inhibition offering a possible mechanism for previously reported pro-arrhythmic slowing of AP propagation following modifications of Ca2+ homeostasis, complementing earlier findings from chronic alterations in Ca2+ homeostasis in genetically-modified RyR2-P2328S hearts.

What is the central question of this study? Can we experimentally replicate atrial pro-arrhythmic phenotypes associated with important chronic clinical conditions, including physical inactivity, obesity, diabetes mellitus and metabolic syndrome, compromising mitochondrial function, and clarify their electrophysiological basis? What is the main finding and its importance? Electrocardiographic and intracellular cardiomyocyte recording at progressively incremented pacing rates demonstrated age-dependent atrial arrhythmic phenotypes in Langendorff-perfused murine Pgc1β-/- hearts for the first time. We attributed these to compromised action potential conduction and excitation wavefronts, whilst excluding alterations in recovery properties or temporal electrophysiological instabilities, clarifying these pro-arrhythmic changes in chronic metabolic disease. Atrial arrhythmias, most commonly manifesting as atrial fibrillation, represent a major clinical problem. The incidence of atrial fibrillation increases with both age and conditions associated with energetic dysfunction. Atrial arrhythmic phenotypes were compared in young (12-16 week) and aged (>52 week) wild-type (WT) and peroxisome proliferative activated receptor, gamma, coactivator 1 beta (Ppargc1b)-deficient (Pgc1β-/- ) Langendorff-perfused hearts, previously used to model mitochondrial energetic disorder. Electrophysiological explorations were performed using simultaneous whole-heart ECG and intracellular atrial action potential (AP) recordings. Two stimulation protocols were used: an S1S2 protocol, which imposed extrasystolic stimuli at successively decremented intervals following regular pulse trains; and a regular pacing protocol at successively incremented frequencies. Aged Pgc1β-/- hearts showed greater atrial arrhythmogenicity, presenting as atrial tachycardia and ectopic activity. Maximal rates of AP depolarization (dV/dtmax ) were reduced in Pgc1β-/- hearts. Action potential latencies were increased by the Pgc1β-/- genotype, with an added interactive effect of age. In contrast, AP durations to 90% recovery (APD90 ) were shorter in Pgc1β-/- hearts despite similar atrial effective recovery periods amongst the different groups. These findings accompanied paradoxical decreases in the incidence and duration of alternans in the aged and Pgc1β-/- hearts. Limiting slopes of restitution curves of APD90 against diastolic interval were correspondingly reduced interactively by Pgc1β-/- genotype and age. In contrast, reduced AP wavelengths were associated with Pgc1β-/- genotype, both independently and interacting with age, through the basic cycle lengths explored, with the aged Pgc1β-/- hearts showing the shortest wavelengths. These findings thus implicate AP wavelength in possible mechanisms for the atrial arrhythmic changes reported here.

Induced pluripotent stem cells (iPSCs) were generated from peripheral blood mononuclear cells (PBMCs) isolated from the peripheral blood of a 4 month-old boy with catecholaminergic polymorphic ventricular tachycardia carrying the double heterozygous mutations RyR2-A1855D and SCN10A-Q1362H. PBMCs were reprogrammed using non-integrative Sendai viral vectors containing reprogramming factors OCT4, SOX2, KLF4 and C-MYC. The iPSCs were shown to express pluripotent markers, have trilineage differentiation potential, carry RyR2-A1855D and SCN10A-Q1362H mutations and have a normal karyotype. They will be useful for studying the pathogenesis of CPVT patients with ≥2 variants.

Catecholaminergic polymorphic ventricular tachycardia (CPVT) predisposes to ventricular arrhythmia due to altered Ca(2+) homeostasis and can arise from ryanodine receptor (RyR2) mutations including RyR2-P2328S. Previous reports established that homozygotic murine RyR2-P2328S (RyR2 (S/S)) hearts show an atrial arrhythmic phenotype associated with reduced action potential (AP) conduction velocity and sodium channel (Nav1.5) expression. We now relate ventricular arrhythmogenicity and slowed AP conduction in RyR2 (S/S) hearts to connexin-43 (Cx43) and Nav1.5 expression and Na(+) current (I Na). Stimulation protocols applying extrasystolic S2 stimulation following 8 Hz S1 pacing at progressively decremented S1S2 intervals confirmed an arrhythmic tendency despite unchanged ventricular effective refractory periods (VERPs) in Langendorff-perfused RyR2 (S/S) hearts. Dynamic pacing imposing S1 stimuli then demonstrated that progressive reductions of basic cycle lengths (BCLs) produced greater reductions in conduction velocity at equivalent BCLs and diastolic intervals in RyR2 (S/S) than WT, but comparable changes in AP durations (APD90) and their alternans. Western blot analyses demonstrated that Cx43 protein expression in whole ventricles was similar, but Nav1.5 expression in both whole tissue and membrane fractions were significantly reduced in RyR2 (S/S) compared to wild-type (WT). Loose patch-clamp studies similarly demonstrated reduced I Na in RyR2 (S/S) ventricles. We thus attribute arrhythmogenesis in RyR2 (S/S) ventricles resulting from arrhythmic substrate produced by reduced conduction velocity to downregulated Nav1.5 reducing I Na, despite normal determinants of repolarization and passive conduction. The measured changes were quantitatively compatible with earlier predictions of linear relationships between conduction velocity and the peak I Na of the AP but nonlinear relationships between peak I Na and maximum Na(+) permeability.

Ventricular arrhythmogenesis in long QT 3 syndrome (LQT3) involves both triggered activity and re-entrant excitation arising from delayed ventricular repolarization. Effects of specific L-type Ca2+ channel antagonism were explored in a gain-of-function murine LQT3 model produced by a DeltaKPQ 1505-1507 deletion in the SCN5A gene. Monophasic action potentials (MAPs) were recorded from epicardial and endocardial surfaces of intact, Langendorff-perfused Scn5a+/Delta hearts. In untreated Scn5a+/Delta hearts, epicardial action potential duration at 90% repolarization (APD90) was 60.0 +/- 0.9 ms compared with 46.9 +/- 1.6 ms in untreated wild-type (WT) hearts (P < 0.05; n = 5). The corresponding endocardial APD(90) values were 52.0 +/- 0.7 ms and 53.7 +/- 1.6 ms in Scn5a+/Delta and WT hearts, respectively (P > 0.05; n = 5). Epicardial early afterdepolarizations (EADs), often accompanied by spontaneous ventricular tachycardia (VT), occurred in 100% of MAPs from Scn5a+/Delta but not in any WT hearts (n = 10). However, EAD occurrence was reduced to 62 +/- 7.1%, 44 +/- 9.7%, 10 +/- 10% and 0% of MAPs following perfusion with 10 nm, 100 nm, 300 nm and 1 mum nifedipine, respectively (P < 0.05; n = 5), giving an effective IC50 concentration of 79.3 nm. Programmed electrical stimulation (PES) induced VT in all five Scn5a+/Delta hearts (n = 5) but not in any WT hearts (n = 5). However, repeat PES induced VT in 3, 2, 2 and 0 out of 5 Scn5a+/Delta hearts following perfusion with 10 nm, 100 nm, 300 nm and 1 mum nifedipine, respectively. Patch clamp studies in isolated ventricular myocytes from Scn5a+/Delta and WT hearts confirmed that nifedipine (300 nm) completely suppressed the inward Ca2+ current but had no effect on inward Na+ currents. No significant effects were seen on epicardial APD90, endocardial APD90 or ventricular effective refractory period in Scn5a+/Delta and WT hearts following perfusion with nifedipine at 1 nm, 10 nm, 100 nm, 300 nm and 1 microm nifedipine concentrations. We conclude that L-type Ca2+ channel antagonism thus exerts specific anti-arrhythmic effects in Scn5a+/Delta hearts through suppression of EADs.

Reductions in cardiac action potential wavelength, and the consequent wavebreak, have been implicated in arrhythmogenesis. Tachyarrhythmias are more common in the Brugada syndrome, particularly following pharmacological challenge, previously modelled using Scn5a(+/-) murine hearts. Propagation latencies and action potential durations (APDs) from monophasic action potential recordings were used to assess wavelength changes with heart rate in Langendorff-perfused wild-type (WT) and Scn5a(+/-) hearts. Recordings were obtained from right (RV) and left (LV) ventricular, epicardial and endocardial surfaces during incremental pacing, before and following flecainide or quinidine challenge. Conduction velocities (θ'), action potential wavelengths (λ' = APD × θ'), and their corresponding alternans depended non-linearly upon diastolic interval (DI). Maximum θ' was lower in Scn5a(+/-) RV epicardium than endocardium. Flecainide further reduced θ', accentuating this RV conduction block. Quinidine reduced maximum θ' in WT and caused earlier conduction failure in the RV of both Scn5a(+/-) and WT. Use of recovery wavelengths (λ'0 = DI × θ') rather than DI, provided novel λ restitution plots of λ' against λ'0, which sum to a basic cycle distance permitting feedback analysis. λ' restitution gradient better correlated with alternans magnitude than either APD or θ restitution gradient. The large differences in θ' and APD restitution contrasted with minor differences in maximum λ' between epi- and endocardia of untreated hearts, and quinidine-treated WT hearts. Strikingly, all regions and conditions converged to a common instability point, implying a conserved relationship. Flecainide or quinidine decreased the pacing rates at which this occurred, through reducing basic cycle distance, in the Scn5a(+/-) RV epicardium, directly predictive of its arrhythmic phenotype.

Increasing evidence implicates chronic energetic dysfunction in human cardiac arrhythmias. Mitochondrial impairment through Pgc-1β knockout is known to produce a murine arrhythmic phenotype. However, the cumulative effect of this with advancing age and its electrocardiographic basis have not been previously studied. Young (12-16 weeks) and aged (>52 weeks), wild type (WT) (n = 5 and 8) and Pgc-1β-/- (n = 9 and 6), mice were anaesthetised and used for electrocardiographic (ECG) recordings. Time intervals separating successive ECG deflections were analysed for differences between groups before and after β1-adrenergic (intraperitoneal dobutamine 3 mg/kg) challenge. Heart rates before dobutamine challenge were indistinguishable between groups. The Pgc-1β-/- genotype however displayed compromised nodal function in response to adrenergic challenge. This manifested as an impaired heart rate response suggesting a functional defect at the level of the sino-atrial node, and a negative dromotropic response suggesting an atrioventricular conduction defect. Incidences of the latter were most pronounced in the aged Pgc-1β-/- mice. Moreover, Pgc-1β-/- mice displayed electrocardiographic features consistent with the existence of a pro-arrhythmic substrate. Firstly, ventricular activation was prolonged in these mice consistent with slowed action potential conduction and is reported here for the first time. Additionally, Pgc-1β-/- mice had shorter repolarisation intervals. These were likely attributable to altered K+ conductance properties, ultimately resulting in a shortened QTc interval, which is also known to be associated with increased arrhythmic risk. ECG analysis thus yielded electrophysiological findings bearing on potential arrhythmogenicity in intact Pgc-1β-/- systems in widespread cardiac regions.

Recent studies reported that energetically deficient murine Pgc-1β-/- hearts replicate age-dependent atrial arrhythmic phenotypes associated with their corresponding clinical conditions, implicating action potential (AP) conduction slowing consequent upon reduced AP upstroke rates.

Ageing and several age-related chronic conditions including obesity, insulin resistance and hypertension are associated with mitochondrial dysfunction and represent independent risk factors for atrial fibrillation (AF).