Discovering the genetic basis of human heart disease presents a remarkable opportunity to predict and prevent disease. By identifying at-risk individuals prior to clinical diagnosis and fostering development of novel therapies to delay or prevent clinical expression, genetic discoveries can transform medicine. Hypertrophic cardiomyopathy (HCM) provides a paradigm for fulfilling this opportunity. HCM is the most common monogenic cardiovascular disorder and is caused by dominant mutations in sarcomere genes. Clinical characteristics include left ventricular hypertrophy (LVH), myocardial fibrosis, diastolic dysfunction, and an increased risk for arrhythmias, sudden death and heart failure. Unexplained LVH, the defining clinical feature of HCM, is a relatively late manifestation of disease and typically emerges around the time of puberty. In contrast, gene-based diagnosis identifies not only individuals who carry pathogenic mutations (G+) and have overt disease (LVH+), but also at-risk G+ individuals who have not yet developed a clinical diagnosis of HCM (LVH-). Our investigations of G+/LVH- preclinical HCM subjects have identified novel early phenotypes in this important subset, thus providing insight into the initial consequences of sarcomere mutations and disease pathogenesis. Impaired LV relaxation and increased myocardial collagen synthesis both precede the onset of LVH. Furthermore, preclinical mutation carriers are a unique at-risk population to target therapies to prevent disease progression. Promising work in animal models has shown that early pharmacologic therapy can counteract the effect of pathogenic sarcomere mutation and diminish the emergence of HCM. Molecular network analysis in mouse models of HCM identified a central role for transforming growth factor-beta (TGF) activation in myocardial fibrogenesis. Administration of neutralizing antibody or angiotensin II receptor blockade to inhibit TGF- activation in prehypertrophic HCM mice was associated with less development of hypertrophy and fibrosis compared with placebo. Collectively these data suggest considerable benefit from defining genetic susceptibility and intervening early in HCM. Through our 2-stage CTRIP studies, we will foster clinical translation of these key scientific discoveries, culminating in a Phase II multicenter, doubleblind, placebo-controlled randomized clinical trial to assess the safety and efficacy of the potent ARB, candesartan, in attenuating disease progression, using early phenotypes as surrogate endpoints to monitor treatment response. With these efforts, we will begin to reshape the clinical paradigm for treating adult-onset genetic disorders, based on early diagnosis, mechanistic insight, and disease modification.

Public Health Relevance

Fundamental research discoveries have provided critical insight into how subtle changes in our DNA lead to the dramatic changes in cardiac structure and function that characterize HCM. This knowledge can enable new therapeutic strategies to interrupt pathogenesis. Clinical translation of these breakthroughs will lead to a future when genetic destiny can be changed. Early treatment can be targeted to at-risk, genetically susceptible individuals to offset the consequences of pathogenic mutations and prevent disease progression

Agency
National Institute of Health (NIH)
Institute
National Heart, Lung, and Blood Institute (NHLBI)
Type
Specialized Center (P50)
Project #
5P50HL112349-03
Application #
8657104
Study Section
Special Emphasis Panel (ZHL1-CSR-H (F1))
Program Officer
Burns, Kristin
Project Start
2012-05-15
Project End
2018-07-31
Budget Start
2015-08-01
Budget End
2016-07-31
Support Year
3
Fiscal Year
2015
Total Cost
$2,237,613
Indirect Cost
$635,835
Name
Brigham and Women's Hospital
Department
Type
DUNS #
030811269
City
Boston
State
MA
Country
United States
Zip Code
02115
Axelsson Raja, Anna; Farhad, Hoshang; Valente, Anne Marie et al. (2018) Prevalence and Progression of Late Gadolinium Enhancement in Children and Adolescents With Hypertrophic Cardiomyopathy. Circulation 138:782-792
Ho, Carolyn Y; Day, Sharlene M; Colan, Steven D et al. (2017) The Burden of Early Phenotypes and the Influence of Wall Thickness in Hypertrophic Cardiomyopathy Mutation Carriers: Findings From the HCMNet Study. JAMA Cardiol 2:419-428
Cirino, Allison L; Lakdawala, Neal K; McDonough, Barbara et al. (2017) A Comparison of Whole Genome Sequencing to Multigene Panel Testing in Hypertrophic Cardiomyopathy Patients. Circ Cardiovasc Genet 10:
Ho, Carolyn Y; McMurray, John J V; Cirino, Allison L et al. (2017) The Design of the Valsartan for Attenuating Disease Evolution in Early Sarcomeric Hypertrophic Cardiomyopathy (VANISH) Trial. Am Heart J 187:145-155
Hiremath, Pranoti; Lawler, Patrick R; Ho, Jennifer E et al. (2016) Ultrasonic Assessment of Myocardial Microstructure in Hypertrophic Cardiomyopathy Sarcomere Mutation Carriers With and Without Left Ventricular Hypertrophy. Circ Heart Fail 9:
Ho, Carolyn Y; Charron, Philippe; Richard, Pascale et al. (2015) Genetic advances in sarcomeric cardiomyopathies: state of the art. Cardiovasc Res 105:397-408
Poggesi, Corrado; Ho, Carolyn Y (2014) Muscle dysfunction in hypertrophic cardiomyopathy: what is needed to move to translation? J Muscle Res Cell Motil 35:37-45
Cirino, Allison L; Ho, Carolyn Y (2013) Genetic testing for inherited heart disease. Circulation 128:e4-8
Dunn, Kyla E; Caleshu, Colleen; Cirino, Allison L et al. (2013) A clinical approach to inherited hypertrophy: the use of family history in diagnosis, risk assessment, and management. Circ Cardiovasc Genet 6:118-31
Valente, Anne Marie; Lakdawala, Neal K; Powell, Andrew J et al. (2013) Comparison of echocardiographic and cardiac magnetic resonance imaging in hypertrophic cardiomyopathy sarcomere mutation carriers without left ventricular hypertrophy. Circ Cardiovasc Genet 6:230-7

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