Hypertrophic cardiomyopathy (HCM), an autosomal dominant disorder characterized by histopathologic findings myocyte disarray and fibrosis, has clinical manifestations of unexplained left ventricular hypertrophy (LVH), diastolic dysfunction, and an increased risk for sudden death. It is a common genetic cardiovascular disorder, affecting approximately 1 in 1000 individuals in the general population. The identification of sarcomere gene mutations as the molecular basis of HCM differentiates this disorder from other types of inherited or secondary causes of LVH. Despite increasingly sophisticated understanding of the causal genetic defects, the precise phenotypic manifestations remain relatively poorly understood. Collaborative basic science and human clinical studies to define the full spectrum of the HCM phenotype are required before molecular discoveries can be effectively translated into the practical management of disease. Genetic-based diagnosis allows for early identification of individuals at risk for developing HCM, prior to the expression of typical clinical manifestations (e.g. LVH). Greater understanding of the preclinical phase of this condition may ultimately inspire rational treatment strategies that will move from contemporary symptom palliation to altering the natural history of disease. Precise identification of early clinical markers of genetic disease will also provide benchmarks for monitoring treatment efficacy. This 2-part longitudinal study proposes to examine and manipulate the early stages of HCM. First, a genotype-positive preclinical population will be examined to detect early alterations in contractile function and myocardial architecture incorporating serial echocardiography with Doppler tissue and strain analysis, gadolinium-enhanced cardiac magnetic resonance imaging, and assessment of serum biomarkers of hemodynamic stress. Second, a pilot interventional trial will be performed to assess the tolerability and efficacy of diltiazem treatment of this preclinical population in improving parameters of diastolic function and to serve as the basis for future larger-scale trials of efficacy.

National Institute of Health (NIH)
National Heart, Lung, and Blood Institute (NHLBI)
Mentored Patient-Oriented Research Career Development Award (K23)
Project #
Application #
Study Section
Special Emphasis Panel (ZHL1-CSR-Q (O1))
Program Officer
Scott, Jane
Project Start
Project End
Budget Start
Budget End
Support Year
Fiscal Year
Total Cost
Indirect Cost
Brigham and Women's Hospital
United States
Zip Code
Ho, Carolyn Y; Cirino, Allison L; Lakdawala, Neal K et al. (2016) Evolution of hypertrophic cardiomyopathy in sarcomere mutation carriers. Heart 102:1805-1812
Ho, Carolyn Y (2016) Integrating Genetics and Medicine: Disease-Modifying Treatment Strategies for Hypertrophic Cardiomyopathy. Prog Pediatr Cardiol 40:21-23
Ho, Carolyn Y; Lakdawala, Neal K; Cirino, Allison L et al. (2015) Diltiazem treatment for pre-clinical hypertrophic cardiomyopathy sarcomere mutation carriers: a pilot randomized trial to modify disease expression. JACC Heart Fail 3:180-8
Cirino, Allison L; Ho, Carolyn Y (2013) Genetic testing for inherited heart disease. Circulation 128:e4-8
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
Ho, Carolyn Y (2012) Hypertrophic cardiomyopathy in 2012. Circulation 125:1432-8
Ho, Carolyn Y (2012) Genetic considerations in hypertrophic cardiomyopathy. Prog Cardiovasc Dis 54:456-60
Lakdawala, Neal K; Thune, Jens Jakob; Maron, Barry J et al. (2011) Electrocardiographic features of sarcomere mutation carriers with and without clinically overt hypertrophic cardiomyopathy. Am J Cardiol 108:1606-13
Ho, Carolyn Y (2011) New Paradigms in Hypertrophic Cardiomyopathy: Insights from Genetics. Prog Pediatr Cardiol 31:93-98
Ho, Carolyn Y (2010) Genetics and clinical destiny: improving care in hypertrophic cardiomyopathy. Circulation 122:2430-40; discussion 2440

Showing the most recent 10 out of 14 publications