Familial Hypertrophic Cardiomyopathy-Linked Mutant Troponin T Causes Stress-Induced Ventricular Tachycardia and Ca ²⁺ -Dependent Action Potential Remodeling

Abstract

Abstract-The cardiac troponin T (TnT) I79N mutation has been linked to familial hypertrophic cardiomyopathy and high incidence of sudden death, despite causing little or no cardiac hypertrophy in patients. Transgenic mice expressing mutant human TnT (I79N-Tg) have increased cardiac contractility, but no ventricular hypertrophy or fibrosis. Enhanced cardiac function has been associated with myofilament Ca 2ϩ sensitization, suggesting altered cellular Ca 2ϩ handling. In the present study, we compare cellular Ca 2ϩ transients and electrophysiological parameters of 64 I79N-Tg and 106 control mice in isolated myocytes, isolated perfused hearts, and whole animals. Ventricular action potentials (APs) measured in isolated I79N-Tg hearts and myocytes were significantly shortened only at 70% repolarization. No significant differences were found either in L-type Ca 2ϩ or transient outward K ϩ currents, but inward rectifier K ϩ current (IK1) was significantly decreased. More critically, Ca 2ϩ transients of field-stimulated ventricular I79N-Tg myocytes were reduced and had slow decay kinetics, consistent with increased Ca 2ϩ sensitivity of I79N mutant fibers. AP differences were abolished when myocytes were dialyzed with Ca 2ϩ buffers or after the Na ϩ -Ca 2ϩ exchanger was blocked by Li ϩ . At higher pacing rates or in presence of isoproterenol, diastolic Ca 2ϩ became significantly elevated in I79N-Tg compared with control myocytes. Ventricular ectopy could be induced by isoproterenol-challenge in isolated I79N-Tg hearts and anesthetized I79N-Tg mice. Freely moving I79N-Tg mice had a higher incidence of nonsustained ventricular tachycardia (VT) during mental stress (warm air jets). We conclude that the TnT-I79N mutation causes stress-induced VT even in absence of hypertrophy and/or fibrosis, arising possibly from the combination of AP remodeling related to altered Ca is an autosomal-dominant disease resulting from mutations in genes encoding cardiac contractile proteins and is an important cause of sudden cardiac death. 1 Genotype/phenotype correlation studies suggest that the prognostic significance of most mutations is related to the degree of cardiac hypertrophy and fibrosis. 2,3 An exception to this are patients with cardiac troponin T (TnT) mutations such as TnT-I79N, 4 who often die suddenly at a young age, 5 even though cardiac hypertrophy and fibrosis are either mild or nonexistent. 6 Although it is generally assumed that these sudden deaths are caused be ventricular arrhythmias, such evidence has been difficult to obtain, 7 and no data exist for the TnT-I79N mutation.In vitro studies of skinned fibers reconstituted with mutant TnT protein show that FHC-linked troponin T mutations almost universally increase myofilament Ca 2ϩ sensitivity. 8 Because Ca 2ϩ binding to the troponin complex represents the largest component of dynamic Ca 2ϩ buffering during the cardiac cycle, 9 our modeling studies predict that the increased myofilament Ca 2ϩ sensitivity would significantly alter intracellular Ca 2ϩ transients. 10 Thus, T...

Allele and species dependent contractile defects by restrictive and hypertrophic cardiomyopathy-linked troponin I mutants

“…This altered Ca 2+ transient decay could be directly related to the increased myofilament Ca 2+ sensitivity of HCM and RCM mutant sarcomeres (figure 2). By directly increasing myofilament Ca 2+ sensitivity with the acute expression of mutant cTnI alleles, we speculate that the myofilament's cytosolic Ca 2+ buffering capacity, in turn, is increased causing cytosolic Ca 2+ removal to slow, similar to reports from HCM mutant cardiac troponin T alleles [40]. Heightened myofilament Ca 2+ buffering could have severe down-stream consequences by augmenting Ca 2+ cycling and becoming a potential substrate for arrhythmias [40], all of which have been associated with HCM in human patients [4;23].…”

Hypertrophy, Fibrosis, and Sudden Cardiac Death in Response to Pathological Stimuli in Mice With Mutations in Cardiac Troponin T

“…This is the second report showing a high incidence of sudden cardiac death in mouse models of FHC without overt heart failure. 10 The proposed mechanism is the development of ventricular tachycardias, 21 which we also observed on adrenergic stimulation. In contrast to the study by Knollmann et al, 10 we observed death in mice only on stimulation of both adrenergic pathways.…”

Somatic events modify hypertrophic cardiomyopathy pathology and link hypertrophy to arrhythmia

“…The variable risk for sudden death associated with cardiac troponin T gene mutations is illustrative of this complexity; both human HCM patients (11,17) and mouse models (34,35) with one of these mutations exhibit little myocardial fibrosis but increased arrhythmogenicity.…”