Hypertrophic Cardiomyopathy (HCM) is a relatively common disorder, affecting 1/500 individuals. The clinical spectrum is vast, ranging from normal cardiac function and lifespan to aggressive cardiomyopathic remodeling and early sudden cardiac death. Since the first genetic linkage study in 1990, mutations in all of the known sarcomeric proteins have been implicated as causal for the disease and the familial form of the disorder (FHC) is thought to comprise over 50% of all cases. It has long been noted that the subset of the disease caused by mutations in the thin filament proteins is particularly complex, whereby many patients do not develop the """"""""classic"""""""" left ventricular hypertrophy, but instead undergo aggressive ventricular remodeling and experience a significant frequency of sudden cardiac death. More recently, patients carrying a mutation (Asp230Asn) in the central """"""""gatekeeper'protein of the regulatory thin filament, tropomyosin (TM) have been shown to develop a complex bimodal clinical syndrome, resulting in acute cardiac failure in infants and a late development of systolic dysfunction in adults. This unique clinical presentation highlights important questions regarding the pathogenesis of FHC that remain unanswered, in particular, what is the primary biophysical defect in thin filament regulation at the level of the complex and what regulates the changing patterns of ventricular remodeling over time? In the last funding period of this grant we developed a series of multifaceted methodological approaches including a novel computational model of the thin filament, a modification of the in vitro motility assay and unique mouse models that enabled us to develop an integrated in silico - in vitro - in vivo system for studying the effects of thin filament mutations from the atomic to whole-heart levels. We applied this approach to a subset of cardiac troponin mutations and found that the effects of single mutations can be """"""""propagated"""""""" through the mutant proteins to globally affect thin filament regulation and cause progressive cardiovascular remodeling. We now turn our attention to both TM and cTnT and focus on two unique disease mechanisms that are likely to be involved in the earliest development of cardiomyopathic remodeling via two Specific Aims: 1) To determine the mechanism(s) underlying the differential ventricular remodeling caused by known mutations in the TNT1-TM head-to-tail overlap domain and to modulate the DCM phenotype via cTnT isoform-switching in vivo;2) To define the functional role of the highly conserved TNT1 C- terminal """"""""unstructured"""""""" domain and determine the pathogenic mechanism underlying the severe, progressive cardiomyopathies caused by mutations in this region. This new focus on early disease mechanisms is particularly important given the high potential for identifying points of therapeutic intervention to change the natural history of this complex cardiomyopathy in patients before they develop end-stage disease.

Public Health Relevance

Familial Hypertrophic Cardiomyopathy is an often devastating and common cardiac genetic disease and the continuing difficulty in linking genotype to phenotype limits our therapeutic options. We have developed a robust integrated computational - cellular - whole heart approach that will improve our understanding of how independent mutations cause this complex disorder and lead to better therapeutic options, especially in young people.

Agency
National Institute of Health (NIH)
Institute
National Heart, Lung, and Blood Institute (NHLBI)
Type
Research Project (R01)
Project #
5R01HL075619-11
Application #
8773592
Study Section
Cardiac Contractility, Hypertrophy, and Failure Study Section (CCHF)
Program Officer
Adhikari, Bishow B
Project Start
2003-12-01
Project End
2017-05-31
Budget Start
2014-06-01
Budget End
2015-05-31
Support Year
11
Fiscal Year
2014
Total Cost
Indirect Cost
Name
University of Arizona
Department
Internal Medicine/Medicine
Type
Schools of Medicine
DUNS #
City
Tucson
State
AZ
Country
United States
Zip Code
85721
Lynn, Melissa L; Lehman, Sarah J; Tardiff, Jil C (2018) Biophysical Derangements in Genetic Cardiomyopathies. Heart Fail Clin 14:147-159
Lynn, M L; Tal Grinspan, L; Holeman, T A et al. (2017) The structural basis of alpha-tropomyosin linked (Asp230Asn) familial dilated cardiomyopathy. J Mol Cell Cardiol 108:127-137
Coppini, Raffaele; Mazzoni, Luca; Ferrantini, Cecilia et al. (2017) Ranolazine Prevents Phenotype Development in a Mouse Model of Hypertrophic Cardiomyopathy. Circ Heart Fail 10:
McConnell, Mark; Tal Grinspan, Lauren; Williams, Michael R et al. (2017) Clinically Divergent Mutation Effects on the Structure and Function of the Human Cardiac Tropomyosin Overlap. Biochemistry 56:3403-3413
Tardiff, Jil C (2017) Assessing the Phenotypic Burden of Preclinical Sarcomeric Hypertrophic Cardiomyopathy-New Assessments to Guide Diagnosis and Management. JAMA Cardiol 2:428-429
Behunin, Samantha M; Lopez-Pier, Marissa A; Mayfield, Rachel M et al. (2016) Liver Kinase B1 complex acts as a novel modifier of myofilament function and localizes to the Z-disk in cardiac myocytes. Arch Biochem Biophys 601:32-41
Crocini, C; Ferrantini, C; Scardigli, M et al. (2016) Novel insights on the relationship between T-tubular defects and contractile dysfunction in a mouse model of hypertrophic cardiomyopathy. J Mol Cell Cardiol 91:42-51
Tardiff, Jil C (2016) The Role of Calcium/Calmodulin-Dependent Protein Kinase II Activation in Hypertrophic Cardiomyopathy. Circulation 134:1749-1751
Duncker, Dirk J; Bakkers, Jeroen; Brundel, Bianca J et al. (2015) Animal and in silico models for the study of sarcomeric cardiomyopathies. Cardiovasc Res 105:439-48
Gollapudi, Sampath K; Tardiff, Jil C; Chandra, Murali (2015) The functional effect of dilated cardiomyopathy mutation (R144W) in mouse cardiac troponin T is differently affected by ?- and ?-myosin heavy chain isoforms. Am J Physiol Heart Circ Physiol 308:H884-93

Showing the most recent 10 out of 34 publications