D230N-Tm Induced Dilated Cardiomyopathy and the Role of Fetal cTnT Isoform Switching in Modulating Disease Severity

Abstract

In 1980, the World Health Organization task force first sought to define and classify cardiomyopathies. They defined cardiomyopathies as "heart muscle diseases of unknown cause" with three main classifications including: hypertrophic cardiomyopathy (HCM), dilated cardiomyopathy (DCM), and restrictive cardiomyopathy [1]. Over the next three decades it became patently obvious that this simple definition was not sufficient to describe the complex heterogeneity of diseases present in the patient population. More robust definitions were necessary for mechanistic links to be established and meaningful therapeutics to be developed. Since then the accepted definition of a cardiomyopathy has evolved and the classifications have greatly expanded. The most recent definition from the American Heart Association Council on Clinical Cardiology states: Cardiomyopathies are a heterogeneous group of diseases of the myocardium associated with mechanical and/or electrical dysfunction that usually (but not invariably) exhibit inappropriate ventricular hypertrophy or dilatation and are due to a variety of causes that frequently are genetic. Cardiomyopathies either are confined to the heart or are part of generalized systemic disorders, often leading to cardiovascular death or progressive heart failure–related disability [2]. This latest definition (2006) reflects the growing recognition of molecular genetics as a key factor in the development of cardiomyopathies and highlights the ever-growing complexity of disease classification. Today the genetic basis of HCM and DCM is widely recognized yet our understanding of the precise mechanisms underlying the disease remains unclear. To add to this disconnect, by the time patients become symptomatic, pathology has progressed past the initial phase, where meaningful treatment could occur, to advanced end-stage pathology. By this time often the only treatment options available become "blunt sword" therapeutics that are non-specific and used primarily for symptom management. In fact, over the last 3 decades there has been a marked decline in the innovation of cardiovascular pharmaceuticals owed partially to the vast complexity of disease presentation and progression [3]. In this dissertation, I will focus on a genetic sarcomeric DCM caused by a mutation in alpha-tropomyosin (Tm). Using novel accurate mouse models as a tool we will define the mechanism by which it leads to disease, investigate how disease severity due to the mutation is modified in an age-dependent manner, and examine what this mechanism could mean in the larger picture of cardiomyopathic disease progression. I hope to convince you that by using accurate models of this DCM at multiple levels of biological complexity to tease out the precise mechanisms of disease we can establish meaningful genotype-phenotype relationships that could lead to the development of specific novel therapeutics.