Familial hypertrophic cardiomyopathy-linked mutant troponin T causes stress-induced ventricular tachycardia and Ca2+-dependent action potential remodeling.
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 Ca2+ sensitization, suggesting altered cellular Ca2+ handling. In the present study, we compare cellular Ca2+ 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 Ca2+ or transient outward K+ currents, but inward rectifier K+ current (IK1) was significantly decreased. More critically, Ca2+ transients of field-stimulated ventricular I79N-Tg myocytes were reduced and had slow decay kinetics, consistent with increased Ca2+ sensitivity of I79N mutant fibers. AP differences were abolished when myocytes were dialyzed with Ca2+ buffers or after the Na+-Ca2+ exchanger was blocked by Li+. At higher pacing rates or in presence of isoproterenol, diastolic Ca2+ 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 Ca2+ transients and suppression of IK1.
Knollmann
Björn C
BC
Department of Pharmacology, Georgetown University Medical Center, 3900 Reservoir Rd, N.W., Washington, DC 20007, USA. knollmb@georgetown.edu
Kirchhof
Paulus
P
Sirenko
Syevda G
SG
Degen
Hubertus
H
Greene
Anne E
AE
Schober
Tilmann
T
Mackow
Jessica C
JC
Fabritz
Larissa
L
Potter
James D
JD
Morad
Martin
M
D000200:Action Potentials / Q000187:drug effects / Q000502:physiology*; D000758:Anesthesia; D000818:Animals; D001794:Blood Pressure / Q000187:drug effects; D002118:Calcium / Q000378:metabolism*; D024741:Cardiomyopathy, Hypertrophic, Familial / Q000235:genetics / Q000503:physiopathology*; D002316:Cardiotonic Agents / Q000494:pharmacology; D004562:Electrocardiography; D005838:Genotype; D006352:Heart Ventricles / Q000187:drug effects / Q000503:physiopathology; D006801:Humans; D066298:In Vitro Techniques; D007545:Isoproterenol / Q000494:pharmacology; D051379:Mice; D008822:Mice, Transgenic; D009154:Mutation; D032383:Myocytes, Cardiac / Q000378:metabolism / Q000502:physiology; D013315:Stress, Psychological / Q000503:physiopathology; D017180:Tachycardia, Ventricular / Q000503:physiopathology*; D020107:Troponin T / Q000235:genetics*
D002316:Cardiotonic Agents; D020107:Troponin T; D007545:Isoproterenol; D002118:Calcium