Mutations in several myofibrillar proteins have been implicated as causes of heritable hypertrophic cardiomyopathies (HCM), and among these, mutations in cardiac myosin binding protein-C (encoded by MYBPC3) are among the most common and have been associated with increased risk for sudden cardiac arrest (SCA) at an early age. However, the cause of SCA is not understood, nor is the observation that some patients expressing mutant cMyBP-C exhibit the hypertrophy and functional sequelae that are characteristic of HCM while others do not. To address these issues, this subproject explores the mechanisms of Ca2+ -triggered arrhythmias in animal models of HCM and also identifies factors such as hypertrophy and co-expression of ion channelopathies that contribute to the profound heterogeneity in the clinical manifestations of disease. The specific hypotheses are: (1) the severity of contractile dysfunction, hypertrophy and SCA stratifies with the degree of cMyBP-C dysfunction, being greatest for C-terminal truncations in which the mutant protein is not incorporated into the myofilaments, (2) the risk of SCA in patients with /WY6PC3rHCM is influenced by the concomitant expression of pro-arrhythmic ion channel polymorphisms, and (3) HCM mutations in MYBPC3, alone or in combination with mutations/polymorphisms in ion channels, cause increased risk of SCA beyond that due to hypertrophy alone. We will test these hypotheses in a series of experiments in which the functional consequences of HCM mutations are studied in living animals and in post-mortem tissue from human HCM hearts. In vivo functional assays will include pressure-volume loops and electrocardiography under resting conditions and during exercise stress testing;in vitro functional assays will include assessment of arrhythmic activity in Langendorff-perfused hearts and both Ca2+ handling and action potentials in isolated cells. The time course and reversibility of effects on contractile and electrophysiological function due to variable expression of HCM mutant cMyBP-C will be studied in transgenic animals in which expression of mutant cMyBP-C is controlled by a tetracycline-inducible system. Results from these studies will provide new insights into the mechanisms underlying disease phenotypes in HCM due to mutations in MYBPC3.

Agency
National Institute of Health (NIH)
Institute
National Heart, Lung, and Blood Institute (NHLBI)
Type
Research Program Projects (P01)
Project #
5P01HL094291-05
Application #
8509774
Study Section
Heart, Lung, and Blood Initial Review Group (HLBP)
Project Start
Project End
Budget Start
2013-07-01
Budget End
2014-06-30
Support Year
5
Fiscal Year
2013
Total Cost
$620,528
Indirect Cost
$160,286
Name
University of Wisconsin Madison
Department
Type
DUNS #
161202122
City
Madison
State
WI
Country
United States
Zip Code
53715
Escobar, Ariel L; Valdivia, Héctor H (2014) Cardiac alternans and ventricular fibrillation: a bad case of ryanodine receptors reneging on their duty. Circ Res 114:1369-71
Kalscheur, Matthew M; Vaidyanathan, Ravi; Orland, Kate M et al. (2014) KCNJ2 mutation causes an adrenergic-dependent rectification abnormality with calcium sensitivity and ventricular arrhythmia. Heart Rhythm 11:885-94
Zhao, Yan-Ting; Valdivia, Héctor H (2014) Ca2+ nanosparks: shining light on the dyadic cleft but missing the intensity of its signal. Circ Res 114:396-8
Loaiza, Randall; Benkusky, Nancy A; Powers, Patricia P et al. (2013) Heterogeneity of ryanodine receptor dysfunction in a mouse model of catecholaminergic polymorphic ventricular tachycardia. Circ Res 112:298-308
Wooten, Eric C; Hebl, Virginia B; Wolf, Matthew J et al. (2013) Formin homology 2 domain containing 3 variants associated with hypertrophic cardiomyopathy. Circ Cardiovasc Genet 6:10-8
Reynolds, Julia O; Chiang, David Y; Wang, Wei et al. (2013) Junctophilin-2 is necessary for T-tubule maturation during mouse heart development. Cardiovasc Res 100:44-53
Landstrom, A P; Ackerman, M J (2012) Beyond the cardiac myofilament: hypertrophic cardiomyopathy- associated mutations in genes that encode calcium-handling proteins. Curr Mol Med 12:507-18
Giudicessi, John R; Ackerman, Michael J (2012) Potassium-channel mutations and cardiac arrhythmias--diagnosis and therapy. Nat Rev Cardiol 9:319-32
Ullrich, Nina D; Valdivia, Hector H; Niggli, Ernst (2012) PKA phosphorylation of cardiac ryanodine receptor modulates SR luminal Ca2+ sensitivity. J Mol Cell Cardiol 53:33-42
Bos, J Martijn; Subramaniam, Malayannan; Hawse, John R et al. (2012) TGF?-inducible early gene-1 (TIEG1) mutations in hypertrophic cardiomyopathy. J Cell Biochem 113:1896-903

Showing the most recent 10 out of 22 publications