Familial Hypertrophic Cardiomyopathy (FHC) is an autosomal-dominant disease resulting from mutations in genes encoding sarcomeric proteins. Cardiac arrhythmias and sudden death are a major cause for the high mortality of patients with sarcomeric mutations. While there is a rough relationship between prognosis and the degree of cardiac hypertrophy and fibrosis, this genotype/phenotype correlation is weak. In particular, the mechanism(s) that cause ventricular arrhythmias in young patients with either limited or absent myocardial hypertrophy or fibrosis are poorly understood. In vitro studies have shown that most FHC-linked mutations in sarcomeric proteins (e.g., troponin T, troponin I, tropomyosin) increase myofilament Ca2+ sensitivity. Our work during the last funded period strongly suggests that increased Ca2+ sensitivity in and of itself may be pro-arrhythmic: Transgenic mice expressing Ca2+- sensitizing mutations of troponin T (TnT-I79N, TnT-F110I) have an increased incidence of ventricular arrhythmias that occur in the absence of myocardial hypertrophy or fibrosis. In contrast, transgenic mice expressing the relatively benign FHC-linked TnT-R278C mutation, which does NOT increase Ca2+ sensitivity, do NOT develop ventricular arrhythmias. Further supporting this hypothesis we showed that acutely increasing myofilament Ca2+ sensitivity with EMD57033 in wild-type animals also increased the risk for ventricular tachycardia (VT). Moreover, myofilament de-sensitization and contractile uncoupling prevented the pro- arrhythmic effects of the TnT-mutants and EMD. Based on these data we found that EMD exerted its effect by duplicating the altered myocyte Ca2+ handling, action potential remodeling, afterdepolarizations and ventricular arrhythmias seen in transgenic mouse hearts expressing Ca2+-sensitizing TnT mutants. Thus, we hypothesize that increased myofilament Ca2+ sensitivity contributes to the risk for ventricular arrhythmias.
Each AIM will examine specific mechanisms that could contribute to this chain of events. In addition to studying mice expressing FHC-linked mutations, we will also use Ca2+ sensitization by EMD to model effects of sarcomeric mutations in rabbits to test the hypothesis in a model with more human-like cardiac electrophysiology.
AIM 1 : To determine the effect of myofilament Ca2+ sensitization on cardiac Ca2+ handling AIM 2: To determine the effect of myofilament Ca2+ sensitization on the ventricular action potential and its heart rate dependence AIM 3: To determine the effect of myofilament Ca2+ sensitization on cell-cell coupling and on arrhythmia susceptibility in the intact heart The results of the proposed experiments will significantly advance our understanding of arrhythmia mechanisms responsible for the high rate of sudden cardiac death in sarcomeric cardiomyopathies.

Public Health Relevance

Research Lay Summary Familial hypertrophic cardiomyopathy is the most common inherited heart disease associated with heart enlargement and a high mortality rate from abnormal heart rhythms (=arrhythmias). The proposed research focuses on discovering the underlying mechanism(s) responsible for the arrhythmias. Result from our studies may provide new therapeutic strategies for this presently incurable disease.

National Institute of Health (NIH)
National Heart, Lung, and Blood Institute (NHLBI)
Research Project (R01)
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Electrical Signaling, Ion Transport, and Arrhythmias Study Section (ESTA)
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Lathrop, David A
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Vanderbilt University Medical Center
Internal Medicine/Medicine
Schools of Medicine
United States
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Johnson, Christopher N; Potet, Franck; Thompson, Matthew K et al. (2018) A Mechanism of Calmodulin Modulation of the Human Cardiac Sodium Channel. Structure 26:683-694.e3
Wang, Lili; Kim, Kyungsoo; Parikh, Shan et al. (2018) Hypertrophic cardiomyopathy-linked mutation in troponin T causes myofibrillar disarray and pro-arrhythmic action potential changes in human iPSC cardiomyocytes. J Mol Cell Cardiol 114:320-327
Raucci Jr, Frank J; Shoemaker, M Benjamin; Knollmann, Bjorn C (2017) Clinical phenotype of HCN4-related sick sinus syndrome. Heart Rhythm 14:725-726
Wang, Lili; Kryshtal, Dmytro O; Kim, Kyungsoo et al. (2017) Myofilament Calcium-Buffering Dependent Action Potential Triangulation in Human-Induced Pluripotent Stem Cell Model of Hypertrophic Cardiomyopathy. J Am Coll Cardiol 70:2600-2602
Parikh, Shan S; Blackwell, Daniel J; Gomez-Hurtado, Nieves et al. (2017) Thyroid and Glucocorticoid Hormones Promote Functional T-Tubule Development in Human-Induced Pluripotent Stem Cell-Derived Cardiomyocytes. Circ Res 121:1323-1330
Gomez-Hurtado, Nieves; Blackwell, Daniel Jesse; Knollmann, Bjorn Christian (2017) Modelling human calmodulinopathies with induced pluripotent stem cells: progress and challenges. Cardiovasc Res 113:437-439
Knollmann, Björn C (2017) Cardiac regulatory mechanisms: new concepts and challenges. J Physiol 595:3683-3684
Gomez-Hurtado, Nieves; Boczek, Nicole J; Kryshtal, Dmytro O et al. (2016) Novel CPVT-Associated Calmodulin Mutation in CALM3 (CALM3-A103V) Activates Arrhythmogenic Ca Waves and Sparks. Circ Arrhythm Electrophysiol 9:
Stroud, Dina Myers; Yang, Tao; Bersell, Kevin et al. (2016) Contrasting Nav1.8 Activity in Scn10a-/- Ventricular Myocytes and the Intact Heart. J Am Heart Assoc 5:
Kryshtal, Dmytro O; Dawling, Sheila; Seger, Donna et al. (2016) In Vitro Studies Indicate Intravenous Lipid Emulsion Acts as Lipid Sink in Verapamil Poisoning. J Med Toxicol 12:165-71

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