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.
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.
|Moore, Rachel K; Abdullah, Salwa; Tardiff, Jil C (2014) Allosteric effects of cardiac troponin TNT1 mutations on actomyosin binding: a novel pathogenic mechanism for hypertrophic cardiomyopathy. Arch Biochem Biophys 552-553:21-8|
|Moore, Rachel K; Grinspan, Lauren Tal; Jimenez, Jesus et al. (2013) HCM-linked ?160E cardiac troponin T mutation causes unique progressive structural and molecular ventricular remodeling in transgenic mice. J Mol Cell Cardiol 58:188-98|
|Tardiff, Jil C (2011) Thin filament mutations: developing an integrative approach to a complex disorder. Circ Res 108:765-82|
|Jimenez, Jesus; Tardiff, Jil C (2011) Abnormal heart rate regulation in murine hearts with familial hypertrophic cardiomyopathy-related cardiac troponin T mutations. Am J Physiol Heart Circ Physiol 300:H627-35|
|Rice, Ron; Guinto, Pia; Dowell-Martino, Candice et al. (2010) Cardiac myosin heavy chain isoform exchange alters the phenotype of cTnT-related cardiomyopathies in mouse hearts. J Mol Cell Cardiol 48:979-88|
|Guinto, Pia J; Haim, Todd E; Dowell-Martino, Candice C et al. (2009) Temporal and mutation-specific alterations in Ca2+ homeostasis differentially determine the progression of cTnT-related cardiomyopathies in murine models. Am J Physiol Heart Circ Physiol 297:H614-26|
|Hoyer, Kirsten; Krenz, Maike; Robbins, Jeffrey et al. (2007) Shifts in the myosin heavy chain isozymes in the mouse heart result in increased energy efficiency. J Mol Cell Cardiol 42:214-21|
|Haim, Todd E; Dowell, Candice; Diamanti, Theodhor et al. (2007) Independent FHC-related cardiac troponin T mutations exhibit specific alterations in myocellular contractility and calcium kinetics. J Mol Cell Cardiol 42:1098-110|
|Ingwall, Joanne S (2006) On the hypothesis that the failing heart is energy starved: lessons learned from the metabolism of ATP and creatine. Curr Hypertens Rep 8:457-64|
|Chandra, Murali; Tschirgi, Matthew L; Tardiff, Jil C (2005) Increase in tension-dependent ATP consumption induced by cardiac troponin T mutation. Am J Physiol Heart Circ Physiol 289:H2112-9|
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