Myofilament Ca2+ sensitization causes susceptibility to cardiac arrhythmia in mice.
In human cardiomyopathy, anatomical abnormalities such as hypertrophy and fibrosis contribute to the risk of ventricular arrhythmias and sudden death. Here we have shown that increased myofilament Ca2+ sensitivity, also a common feature in both inherited and acquired human cardiomyopathies, created arrhythmia susceptibility in mice, even in the absence of anatomical abnormalities. In mice expressing troponin T mutants that cause hypertrophic cardiomyopathy in humans, the risk of developing ventricular tachycardia was directly proportional to the degree of Ca2+ sensitization caused by the troponin T mutation. Arrhythmia susceptibility was reproduced with the Ca2+-sensitizing agent EMD 57033 and prevented by myofilament Ca2+ desensitization with blebbistatin. Ca2+ sensitization markedly changed the shape of ventricular action potentials, resulting in shorter effective refractory periods, greater beat-to-beat variability of action potential durations, and increased dispersion of ventricular conduction velocities at fast heart rates. Together these effects created an arrhythmogenic substrate. Thus, myofilament Ca2+ sensitization represents a heretofore unrecognized arrhythmia mechanism. The protective effect of blebbistatin provides what we believe to be the first direct evidence that reduction of Ca2+ sensitivity in myofilaments is antiarrhythmic and might be beneficial to individuals with hypertrophic cardiomyopathy.
Baudenbacher
Franz
F
Department of Biomedical Engineering and Physics, Institute for Integrative Biosystems Research and Education, Vanderbilt University, Nashville, Tennessee, USA.
Schober
Tilmann
T
Pinto
Jose Renato
JR
Sidorov
Veniamin Y
VY
Hilliard
Fredrick
F
Solaro
R John
RJ
Potter
James D
JD
Knollmann
Björn C
BC
D008841:Actin Cytoskeleton / Q000378:metabolism* / Q000473:pathology; D000200:Action Potentials / Q000187:drug effects; D000818:Animals; D002118:Calcium / Q000378:metabolism*; D002312:Cardiomyopathy, Hypertrophic / Q000139:chemically induced / Q000235:genetics / Q000378:metabolism* / Q000473:pathology / Q000503:physiopathology; D002316:Cardiotonic Agents / Q000009:adverse effects* / Q000494:pharmacology; D002415:Cats; D016757:Death, Sudden, Cardiac; D004195:Disease Models, Animal; D004198:Disease Susceptibility; D005260:Female; D005355:Fibrosis / Q000139:chemically induced / Q000235:genetics / Q000378:metabolism / Q000473:pathology / Q000503:physiopathology; D006576:Heterocyclic Compounds, 4 or More Rings / Q000494:pharmacology; D006801:Humans; D008297:Male; D051379:Mice; D008817:Mice, Mutant Strains; D011804:Quinolines / Q000009:adverse effects* / Q000494:pharmacology; D012307:Risk Factors; D017180:Tachycardia, Ventricular / Q000139:chemically induced / Q000235:genetics / Q000378:metabolism* / Q000473:pathology / Q000503:physiopathology; D013829:Thiadiazines / Q000009:adverse effects* / Q000494:pharmacology; D020107:Troponin T / Q000235:genetics / Q000378:metabolism
D002316:Cardiotonic Agents; D006576:Heterocyclic Compounds, 4 or More Rings; D011804:Quinolines; D013829:Thiadiazines; D020107:Troponin T; C070609:EMD 53998; C472645:blebbistatin; D002118:Calcium