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Sodium channel haploinsufficiency and structural change in ventricular arrhythmogenesis

Jeevaratnam K, Guzadhur L, Goh YM, Grace AA, Huang CL

Acta Physiol (Oxf), 2016 Feb;216(2):186-202.
PMID: 26284956 DOI: 10.1111/apha.12577

Normal cardiac excitation involves orderly conduction of electrical activation and recovery dependent upon surface membrane, voltage-gated, sodium (Na(+) ) channel α-subunits (Nav 1.5). We summarize experimental studies of physiological and clinical consequences of loss-of-function Na(+) channel mutations. Of these conditions, Brugada syndrome (BrS) and progressive cardiac conduction defect (PCCD) are associated with sudden, often fatal, ventricular tachycardia (VT) or fibrillation. Mouse Scn5a(+/-) hearts replicate important clinical phenotypes modelling these human conditions. The arrhythmic phenotype is associated not only with the primary biophysical change but also with additional, anatomical abnormalities, in turn dependent upon age and sex, each themselves exerting arrhythmic effects. Available evidence suggests a unified binary scheme for the development of arrhythmia in both BrS and PCCD. Previous biophysical studies suggested that Nav 1.5 deficiency produces a background electrophysiological defect compromising conduction, thereby producing an arrhythmic substrate unmasked by flecainide or ajmaline challenge. More recent reports further suggest a progressive decline in conduction velocity and increase in its dispersion particularly in ageing male Nav 1.5 haploinsufficient compared to WT hearts. This appears to involve a selective appearance of slow conduction at the expense of rapidly conducting pathways with changes in their frequency distributions. These changes were related to increased cardiac fibrosis. It is thus the combination of the structural and biophysical changes both accentuating arrhythmic substrate that may produce arrhythmic tendency. This binary scheme explains the combined requirement for separate, biophysical and structural changes, particularly occurring in ageing Nav 1.5 haploinsufficient males in producing clinical arrhythmia.

Matched MeSH terms: Arrhythmias, Cardiac/genetics*
Fulltext Sodium channel biophysics, late sodium current and genetic arrhythmic syndromes

Chadda KR, Jeevaratnam K, Lei M, Huang CL

Pflugers Arch., 2017 06;469(5-6):629-641.
PMID: 28265756 DOI: 10.1007/s00424-017-1959-1

Arrhythmias arise from breakdown of orderly action potential (AP) activation, propagation and recovery driven by interactive opening and closing of successive voltage-gated ion channels, in which one or more Na+ current components play critical parts. Early peak, Na+ currents (I Na) reflecting channel activation drive the AP upstroke central to cellular activation and its propagation. Sustained late Na+ currents (I Na-L) include contributions from a component with a delayed inactivation timecourse influencing AP duration (APD) and refractoriness, potentially causing pro-arrhythmic phenotypes. The magnitude of I Na-L can be analysed through overlaps or otherwise in the overall voltage dependences of the steady-state properties and kinetics of activation and inactivation of the Na+ conductance. This was useful in analysing repetitive firing associated with paramyotonia congenita in skeletal muscle. Similarly, genetic cardiac Na+ channel abnormalities increasing I Na-L are implicated in triggering phenomena of automaticity, early and delayed afterdepolarisations and arrhythmic substrate. This review illustrates a wide range of situations that may accentuate I Na-L. These include (1) overlaps between steady-state activation and inactivation increasing window current, (2) kinetic deficiencies in Na+ channel inactivation leading to bursting phenomena associated with repetitive channel openings and (3) non-equilibrium gating processes causing channel re-opening due to more rapid recoveries from inactivation. All these biophysical possibilities were identified in a selection of abnormal human SCN5A genotypes. The latter presented as a broad range of clinical arrhythmic phenotypes, for which effective therapeutic intervention would require specific identification and targeting of the diverse electrophysiological abnormalities underlying their increased I Na-L.

Matched MeSH terms: Arrhythmias, Cardiac/genetics
Fulltext Age-dependent atrial arrhythmic phenotype secondary to mitochondrial dysfunction in Pgc-1β deficient murine hearts

Valli H, Ahmad S, Chadda KR, Al-Hadithi ABAK, Grace AA, Jeevaratnam K, et al.

Mech Ageing Dev, 2017 Oct;167:30-45.
PMID: 28919427 DOI: 10.1016/j.mad.2017.09.002

INTRODUCTION: 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).
MATERIALS AND METHODS: Atrial arrhythmogenesis was investigated in Langendorff-perfused young (3-4 month) and aged (>12 month), wild type (WT) and peroxisome proliferator activated receptor-γ coactivator-1β deficient (Pgc-1β-/-) murine hearts modeling age-dependent chronic mitochondrial dysfunction during regular pacing and programmed electrical stimulation (PES).
RESULTS AND DISCUSSION: The Pgc-1β-/- genotype was associated with a pro-arrhythmic phenotype progressing with age. Young and aged Pgc-1β-/- hearts showed compromised maximum action potential (AP) depolarization rates, (dV/dt)max, prolonged AP latencies reflecting slowed action potential (AP) conduction, similar effective refractory periods and baseline action potential durations (APD90) but shortened APD90 in APs in response to extrasystolic stimuli at short stimulation intervals. Electrical properties of APs triggering arrhythmia were similar in WT and Pgc-1β-/- hearts. Pgc-1β-/- hearts showed accelerated age-dependent fibrotic change relative to WT, with young Pgc-1β-/- hearts displaying similar fibrotic change as aged WT, and aged Pgc-1β-/- hearts the greatest fibrotic change. Mitochondrial deficits thus result in an arrhythmic substrate, through slowed AP conduction and altered repolarisation characteristics, arising from alterations in electrophysiological properties and accelerated structural change.

Matched MeSH terms: Arrhythmias, Cardiac/genetics*
Fulltext Cardiomyocyte ionic currents in intact young and aged murine Pgc-1β-/- atrial preparations

Valli H, Ahmad S, Jiang AY, Smyth R, Jeevaratnam K, Matthews HR, et al.

Mech Ageing Dev, 2018 01;169:1-9.
PMID: 29197478 DOI: 10.1016/j.mad.2017.11.016

INTRODUCTION: 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.
MATERIALS AND METHODS: We tested a hypothesis implicating Na+ current alterations as a mechanism underlying these electrophysiological phenotypes. We applied loose patch-clamp techniques to intact young and aged, WT and Pgc-1β-/-, atrial cardiomyocyte preparations preserving their in vivo extracellular and intracellular conditions.
RESULTS AND DISCUSSION: Depolarising steps activated typical voltage-dependent activating and inactivating inward (Na+) currents whose amplitude increased or decreased with the amplitudes of the activating, or preceding inactivating, steps. Maximum values of peak Na+ current were independently influenced by genotype but not age or interacting effects of genotype and age on two-way ANOVA. Neither genotype, nor age, whether independently or interactively, influenced voltages at half-maximal current, or steepness factors, for current activation and inactivation, or time constants for recovery from inactivation following repolarisation. In contrast, delayed outward (K+) currents showed similar activation and rectification properties through all experimental groups. These findings directly demonstrate and implicate reduced Na+ in contrast to unchanged K+ current, as a mechanism for slowed conduction causing atrial arrhythmogenicity in Pgc-1β-/- hearts.

Matched MeSH terms: Arrhythmias, Cardiac/genetics
Fulltext Pro-arrhythmic atrial phenotypes in incrementally paced murine Pgc1β-/- hearts: effects of age

Valli H, Ahmad S, Fraser JA, Jeevaratnam K, Huang CL

Exp Physiol, 2017 12 01;102(12):1619-1634.
PMID: 28960529 DOI: 10.1113/EP086589

NEW FINDINGS: 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.

Matched MeSH terms: Arrhythmias, Cardiac/genetics
Fulltext Reduced cardiomyocyte Na+ current in the age-dependent murine Pgc-1β-/- model of ventricular arrhythmia

Ahmad S, Valli H, Smyth R, Jiang AY, Jeevaratnam K, Matthews HR, et al.

J Cell Physiol, 2019 Apr;234(4):3921-3932.
PMID: 30146680 DOI: 10.1002/jcp.27183

Peroxisome proliferator-activated receptor-γ coactivator-1 deficient (Pgc-1β-/- ) murine hearts model the increased, age-dependent, ventricular arrhythmic risks attributed to clinical conditions associated with mitochondrial energetic dysfunction. These were accompanied by compromised action potential (AP) upstroke rates and impaired conduction velocities potentially producing arrhythmic substrate. We tested a hypothesis implicating compromised Na+ current in these electrophysiological phenotypes by applying loose patch-clamp techniques in intact young and aged, wild-type (WT) and Pgc-1β-/- , ventricular cardiomyocyte preparations for the first time. This allowed conservation of their in vivo extracellular and intracellular conditions. Depolarising steps elicited typical voltage-dependent activating and inactivating inward Na+ currents with peak amplitudes increasing or decreasing with their respective activating or preceding inactivating voltage steps. Two-way analysis of variance associated Pgc-1β-/- genotype with independent reductions in maximum peak ventricular Na+ currents from -36.63 ± 2.14 (n = 20) and -35.43 ± 1.96 (n = 18; young and aged WT, respectively), to -29.06 ± 1.65 (n = 23) and -27.93 ± 1.63 (n = 20; young and aged Pgc-1β-/- , respectively) pA/μm2 (p

Matched MeSH terms: Arrhythmias, Cardiac/genetics
Fulltext Ventricular pro-arrhythmic phenotype, arrhythmic substrate, ageing and mitochondrial dysfunction in peroxisome proliferator activated receptor-γ coactivator-1β deficient (Pgc-1β-/-) murine hearts

Ahmad S, Valli H, Chadda KR, Cranley J, Jeevaratnam K, Huang CL

Mech Ageing Dev, 2018 Jul;173:92-103.
PMID: 29763629 DOI: 10.1016/j.mad.2018.05.004

INTRODUCTION: Ageing and age-related bioenergetic conditions including obesity, diabetes mellitus and heart failure constitute clinical ventricular arrhythmic risk factors.
MATERIALS AND METHODS: Pro-arrhythmic properties in electrocardiographic and intracellular recordings were compared in young and aged, peroxisome proliferator-activated receptor-γ coactivator-1β knockout (Pgc-1β-/-) and wild type (WT), Langendorff-perfused murine hearts, during regular and programmed stimulation (PES), comparing results by two-way ANOVA.
RESULTS AND DISCUSSION: Young and aged Pgc-1β-/- showed higher frequencies and durations of arrhythmic episodes through wider PES coupling-interval ranges than WT. Both young and old, regularly-paced, Pgc-1β-/- hearts showed slowed maximum action potential (AP) upstrokes, (dV/dt)max (∼157 vs. 120-130 V s-1), prolonged AP latencies (by ∼20%) and shortened refractory periods (∼58 vs. 51 ms) but similar AP durations (∼50 ms at 90% recovery) compared to WT. However, Pgc-1β-/- genotype and age each influenced extrasystolic AP latencies during PES. Young and aged WT ventricles displayed distinct, but Pgc-1β-/- ventricles displayed similar dependences of AP latency upon (dV/dt)max resembling aged WT. They also independently increased myocardial fibrosis. AP wavelengths combining activation and recovery terms paralleled contrasting arrhythmic incidences in Pgc-1β-/- and WT hearts. Mitochondrial dysfunction thus causes pro-arrhythmic Pgc-1β-/- phenotypes by altering AP conduction through reducing (dV/dt)max and causing age-dependent fibrotic change.

Matched MeSH terms: Arrhythmias, Cardiac/genetics