Melissa Lynn Abstract
Melissa Lynn
Ph.D. Candidate
Physiological Sciences-GIDP
Basic Cardiovascular Sciences Scientific Sessions
New Orleans, LA
July 13-14, 2015
Abstract
An oft-noted component of sarcomeric DCM is the observation that patients within families carrying the same primary mutation exhibit significant phenotypic variability. This lack of a distinct link between genotype and phenotype has complicated clinical management. In a recent study of two unrelated multigenerational families with the tropomyosin (Tm) mutation Asp230Asn (D230N), a striking “bimodal” distribution of severity was observed. In these families, many children (<1 year) with the mutation presented with a severe form of DCM that led to sudden, often fatal CHF while adults developed a mild to moderate DCM in mid-life. Of note, children who survived the initial presentation often recovered significant systolic function into young adulthood. A potential hypothesis to explain this improvement despite the continued presence of the mutant Tm, is that the phenotype is modified by other thin filament isoforms. Thus, we propose that the age-dependent remodeling seen in children with D230N Tm is a result of temporal isoform switches involving a closely linked Tm binding partner cardiac Troponin T (cTnT). Our initial biophysical studies (Regulated-IVM) revealed a decreased Ca2+ sensitivity in filaments containing D230N Tm that is more severe in the presence of fetal TnT (cTnT1), suggesting a modulatory role for cTnT1. Cardiac performance, assessed via 2D echo, in our novel D230N Tm x cTnT1 double transgenic (DTg) mouse model found a significantly reduced % FS for DTg (17%) mice as compared to D230N Tm (21%) littermates. This reduction in %FS was seen at 4 months but not 2 suggesting a progressive cardiomyopathy. Current efforts aim to model the early phase of this “bimodal” phenotype and assess the potential for disease reversibility using a cardiac specific inducible cTnT1 transgenic mouse model. Furthermore, we propose that modulation by cTnT1 could represent a more general mechanism for the progressive remodeling seen in human heart failure. Preliminary in vitro studies with human tissue found that RNA levels of cTnT1 are significantly higher in failing hearts as compared to non-failing. Together these data suggest an isoform dependent mechanism for the “bimodal” phenotype in patients carrying D230N Tm that could translate to other sarcomeric cardiomyopathies.
Abstract (for Lay Audience)
Cardiomyopathies are the leading cause of death in children with heart disease, dilated cardiomyopathy (DCM) being the most common form. Recent studies estimate that at least 30 percent of cases are inherited mutations in cardiac proteins. This primary disease of the heart muscle often has a bimodal distribution of severity whereby young children (<1 year) present with a severe, often fatal form of the disease. Strikingly, if they survive the initial presentation they often recover significant pump function, going on to lead relatively normal lives, yet remain at risk of worsening later in life. This disconnect between the effects of the primary mutation and the clinical manifestation complicates management and is a major problem impeding discovery of effective therapeutics. The driving question for this study is how do patients within families, carrying the same primary mutation throughout life, have distinct age-dependent clinical presentations. Specifically we are addressing how a single amino acid mutation (Asp230Asn) in tropomyosin (a structural protein of cardiac muscle) identified as a cause of DCM in two large multi-generational families can give rise to this bimodal distribution. To this end we are asking what is the effect on the primary DCM of a fetal protein cTnT1 (a regulatory protein of cardiac muscle) and how much is required to modify severity. We will address these questions using two unique mouse models that allow us to test for and track the effect of cTnT1 expression in hearts carrying the primary DCM causing mutation. If our hypothesis that the fetal protein cTnT1 plays a role in modulating the severity of the primary DCM phenotype is proven it could lay the groundwork for eventual therapeutic approaches. It is therefore very important that we determine the amount of cTnT1 required to modulate disease severity. Given this information therapeutics could be developed that alter the expression of the cardiac fetal gene program thus preventing the early, severe onset affecting young children in families with a history of cardiomyopathy. Long term, if expression of fetal genes like cTnT1 is proven to be a more general mechanism in cardiomyopathies it could represent a sea-change view that could lead to better clinical prognostics and therapeutics for this highly complex disorder.