title: Myofilament Ca2+ sensitization causes susceptibility to cardiac arrhythmia in mice.
abstract: 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.
authors.affiliation: Department of Biomedical Engineering and Physics, Institute for Integrative Biosystems Research and Education, Vanderbilt University, Nashville, Tennessee, USA.
authors.forename: Franz
authors.initials: F
authors.lastname: Baudenbacher
authors.forename: Tilmann
authors.initials: T
authors.lastname: Schober
authors.forename: Jose Renato
authors.initials: JR
authors.lastname: Pinto
authors.forename: Veniamin Y
authors.initials: VY
authors.lastname: Sidorov
authors.forename: Fredrick
authors.initials: F
authors.lastname: Hilliard
authors.forename: R John
authors.initials: RJ
authors.lastname: Solaro
authors.forename: James D
authors.initials: JD
authors.lastname: Potter
authors.forename: Björn C
authors.initials: BC
authors.lastname: Knollmann
mesh_terms: 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
chemical_list: D002316:Cardiotonic Agents; D006576:Heterocyclic Compounds, 4 or More Rings; D011804:Quinolines; D013829:Thiadiazines; D020107:Troponin T; C070609:EMD 53998; C472645:blebbistatin; D002118:Calcium