MD Conference Express AHA 2011 - (Page 6)

n F E A T U R E Harnessing Genetics to Improve Cardiovascular Care Written by Maria Vinall The Paul Dudley White International Lecture was presented by Hugh C. Watkins, MD, PhD, Oxford, United Kingdom. Prof. Watkins described how the impact of genetics will grow and become a valuable tool for predicting efficacy, as well as aid in the development of treatments for individuals who are at risk of developing cardiovascular disease. Both Mendelian mutations (that cause inherited diseases that run in families) and common susceptibility variants that have been identified through a genome wide association study (GWAS) improve our understanding of biology and have the potential to identify new drug targets. Mendelian mutations are rare but have a very large effect and are strongly predictive, while common variants have a small effect and are not very good for predicting individual risk of a given disease. An understanding of Mendelian or inherited disease variants can lead to understanding causality and certain proof. As an example, genetic research showed that hypertrophic cardiomyopathy (HCM) was caused by mutations in sarcomeric protein genes—in particular, mutations in the thick and thin filament proteins that are associated with contraction. In vitro functional assays show that HCM mutations increase the Ca2+ sensitivity of contractility, whereas dilated cardiomyopathy mutations decrease it. Because troponin is the major Ca2+ buffer in the cardiomyocyte sarcoplasm, it has been suggested that Ca2+ affinity changes that are caused by cardiomyopathy mutant proteins may directly affect the transient Ca2+ and hence calcium handling and hypertrophy signaling [Robinson P et al. Circ Res 2007]. Further, the mutations that cause HCM increase activation of the heart muscle, increase the energy that is used to generate contraction, and deplete adenosine triphosphate (ATP). In a study that investigated cardiac energetics in subjects with mutations in three different familial HCM disease genes, some of whom were nonpenetrant carriers without hypertrophy, the cardiac phosphocreatine (PCr)-to-ATP ratio was reduced in the HCM subjects by ~30% relative to controls in all three disease gene groups. The PCr/ATP ratio was equally reduced in subjects with and without left ventricular hypertrophy (Figure 1). This bioenergetic deficit in genotype-confirmed HCM, even in those without hypertrophy, supports a proposed link between altered cardiac energetics and development of the disease phenotype [Crilley J et al. J Am Coll Cardiol 2003]. Prof. Watkins pointed out new unpublished data that show that the preexisting energetic deficit in HCM is acutely exacerbated by exercise. Figure 1. PCr/ATP Ratio. 3.0 2.5 2.0 * * Peer-Reviewed Highlights from the PCr/ATP 1.5 1.0 0.5 scientificsessions.org my.americanheart.org 0 Controls All Patients No LVH ß-MHC cTnT MyBPC PCr=Phosphocreatine; ATP=Adenosine triphosphate; LVH=Left ventricular hypertrophy; ß-MHC=Beta-myosin heavy chain; cTNT=Cardiac troponin T; MyBPC=Myosin binding protein C. *p<0.001 Reprinted from Journal of the American College of Cardiology, 41 /10, Crilley J et al, Hypertrophic cardiomyopathy due to sarcomeric gene mutations is characterized by impaired energy metabolism irrespective of the degree of hypertrophy, Pages 1776-1782, Copyright 2003, with permission from the American College of Cardiology. 6 January 2012 www.mdconferencexpress.com  http://www.mdconferencexpress.com http://my.americanheart.org/professional/Sessions/ScientificSessions/Scientific-Sessions_UCM_316900_SubHomePage.jsp http://www.scientificsessions.org http://my.americanheart.org http://www.mdconferencexpress.com

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MD Conference Express AHA 2011

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