Reviews of Translational Medicine and Genomics in Cardiovascular Disease: New Disease Taxonomy and Therapeutic Implications

Abstract

The enduring subdivision of cardiomyopathies into hypertrophic (HCM), dilated (DCM), and restrictive (RCM) categories reflects the emphasis of traditional classifications on morphology. Rapid advances in the genetic interrogation of these disorders have redefined their taxonomy and revealed potential conflicts between the old and new classifications. Hypertrophic cardiomyopathy has been redefined as a disease of perturbed sarcomere function. Dilated cardiomyopathy is a disease that results from more varied perturbations, including, but not limited to, defects of the cytoskeleton. Positional cloning and candidate gene approaches have been successful in identifying >40 disease loci, many of which have led to disease genes in HCM, DCM, RCM, and arrhythmogenic right ventricular cardiomyopathy. These findings provide mechanistic insights, permit genetic screening, and to a limited extent, facilitate prognostication. Although single gene analyses rapidly focus down to the underlying mechanistic pathways, they do not take account of all relevant variation in the human genome. Correspondingly, advances in genomics, through microarrays, have facilitated characterization of these broader downstream elements. As well as refining the taxonomic reclassification of cardiomyopathies, these genomic approaches, coupled with functional studies, have identified novel potential therapeutic targets, such as cardiac energetics, calcium handling, and apoptosis. We review the successes and pitfalls of genetic and genomic approaches to cardiomyopathy and their impact on current and future clinical care.

Dilated and Hypertrophic Cardiomyopathy Mutations in Troponin and α-Tropomyosin Have Opposing Effects on the Calcium Affinity of Cardiac Thin Filaments

“…HCM, a disease characterized by thickening of the left ventricle and septum in the absence of other cardiac or systemic disease, is caused by mutations to at least 9 genes encoding cardiac contractile proteins. 1 The most commonly reported mutations occur in the thick filament proteins ␤-myosin heavy chain and cardiac myosin-binding protein-C. 2 However, HCM mutations have also been identified in the genes encoding the thin filament regulatory proteins ␣-tropomyosin, 3,4 cardiac troponin (cTn)T, 3,4 and cTnI, 5 and to date, at least 62 HCM mutations in these genes have been identified (DNA Mutation Database: Familial Hypertrophic Cardiomyopathy; http://www.angis.org. au/Databases/Heart).…”

Alteration of gene expression during progression of hypertension-induced cardiac dysfunction in rats

“…Hypertension is one of the major risk factors for left ventricular (LV) dysfunction and heart failure (5,22). Several studies correlate the physiology of cardiac dysfunction with mRNA expression profiling, using different models and examining different stages of the disease (1,10,14,27). These studies employed microarrays, which provide information on the expression of a large number of genes although the information is not quantitative (29).…”

Avaliação diagnóstica da cardiomiopatia hipertrófica em fase clínica e pré-clínica

“…Molecular genetic diagnosis is a valuable tool for assessing familial forms of the disease, particularly those associated with sudden death or late clinical expression 2,6,7 . It enables the early release of normal family members and follow-up of those who carry mutations but have no evidence of the disease.…”

“…This is a familial disease with predominantly autosomal dominant pattern of inheritance 6 . More than 400 mutations in genes encoding sarcomeric proteins have already been identified 6,7 (Table 1). Mutations in the -myosin heavy chain (MYH7) and myosin-binding protein C (MYBPC3) genes seem to account for 60% to 80% of the cases 6 .…”