Hypertrophic cardiomyopathy (HCM) is the most common monogenic heart disease (prevalence 1 in 500) and the most frequent cause of sudden cardiac death (SCD) in the young. It is characterized by unexplained left ventricular hypertrophy (LVH), diffuse and patchy fibrosis, and myofibrillar disarray. While the majority of patients remain asymptomatic, prognosis is poor in a subset who present with SCD or progress to heart failure (HF). Current methods to predict risk of these adverse events and to target therapy are limited. Current medical therapy does not protect against SCD, nor does it prevent development of HF. Therefore, the identification of novel risk markers would help develop therapeutic targets aimed at altering the phenotypic expression to impact the natural history, especially SCD and HF. Cardiovascular magnetic resonance (CMR) is emerging as a powerful tool for diagnosis and risk stratification in HCM including assessment of LV mass and pattern of hypertrophy. Late gadolinium enhancement by CMR is a marker of focal myocardial fibrosis which is thought to underlie the arrhythmogenic substrate as well as promote development of HF. We hypothesize that HCM patients with a higher primary outcome event rate can be identified by novel CMR findings. The majority of cases of HCM are autosomal dominant and about 60% are caused by mutations in genes encoding cardiac sarcomeric proteins. However, the relationship between genetic mutation, disease phenotype, and clinical outcomes remains poorly understood. We hypothesize that HCM patients with sarcomeric HCM mutations will have a higher primary outcome event rate and more marked myocardial pathology on CMR than those without. Furthermore, there may be a link between sarcomeric mutations and fibrosis, as mutation carriers with overt HCM as well as those without hypertrophy has elevated markers of collagen turnover. We therefore hypothesize that serum biomarkers of collagen metabolism in HCM will predict outcomes. Thus, the Specific Aim is to develop a predictive model of cardiovascular outcomes in HCM by: 1) using exploratory data mining methods to identify demographic, clinical, and novel CMR, genetic and biomarker variables associated with the outcomes and 2) develop a score from the predictive model that can be used to assess risk given a patient's combination of risk factors, thus establishing the evidence base to enable clinical trial design to reduce morbidity and mortality in HCM in a cost-effective manner. We propose a natural history study of 2750 patients with clinically diagnosed HCM studied at baseline with novel CMR, genotyping, and serum biomarkers of collagen turnover and myocardial injury, enrolled over a 2-year period and followed for 3-5 years (mean of 4 years). The study will be powered to identify risk markers with a hazard ratio of 1.5 or greater for the primary endpoint, which will be cardiac death (including SCD and HF death), aborted SCD (appropriate discharge of an implantable cardioverter-defibrillator), and need for heart transplantation. Secondary endpoints include all- cause mortality, ventricular tachyarrhythmias, hospitalization for heart failure, atrial fibrillation, and stroke.

Public Health Relevance

Hypertrophic cardiomyopathy is the most common monogenic heart disease and the most frequent cause of sudden cardiac death in the young and a common cause of heart failure in older patients. Defining novel cardiac magnetic resonance, genetic, and biomarkers to identify those at risk of adverse events is the goal of this project.

National Institute of Health (NIH)
National Heart, Lung, and Blood Institute (NHLBI)
Research Project--Cooperative Agreements (U01)
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Clinical and Integrative Cardiovascular Sciences Study Section (CICS)
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Desvigne-Nickens, Patrice
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University of Virginia
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Raman, Betty; Wen, David; Chan, Kenneth et al. (2018) Discrepancy Between Pathological Progression and Clinical Stability in a Young Patient With Hypertrophic Cardiomyopathy. Circ Cardiovasc Imaging 11:e008154
Kramer, Christopher M; Neubauer, Stefan (2018) Further Refining Risk in Hypertrophic Cardiomyopathy With Late Gadolinium Enhancement by CMR. J Am Coll Cardiol 72:871-873
Sengupta, Partho P; Kramer, Christopher M; Narula, Jagat et al. (2017) The Potential of Clinical Phenotyping of Heart Failure With Imaging Biomarkers for Guiding Therapies: A Focused Update. JACC Cardiovasc Imaging 10:1056-1071
Patel, Amit R; Kramer, Christopher M (2017) Role of Cardiac Magnetic Resonance in the Diagnosis and Prognosis of Nonischemic Cardiomyopathy. JACC Cardiovasc Imaging 10:1180-1193
Balfour Jr, Pelbreton C; Gonzalez, Jorge A; Kramer, Christopher M (2017) Non-invasive assessment of low- and intermediate-risk patients with chest pain. Trends Cardiovasc Med 27:182-189
Salerno, Michael; Kramer, Christopher M (2016) Myocardial Extracellular Volume: Unifying Form and Function in Heart Failure With Preserved Ejection Fraction. J Am Coll Cardiol 67:1826-1828
Kramer, Christopher M; Appelbaum, Evan; Desai, Milind Y et al. (2015) Hypertrophic Cardiomyopathy Registry: The rationale and design of an international, observational study of hypertrophic cardiomyopathy. Am Heart J 170:223-30
Kramer, Christopher M (2015) Novel magnetic resonance imaging end points for physiologic studies in peripheral arterial disease: elegance versus practicality. Circ Cardiovasc Imaging 8:
Kramer, Christopher M (2015) Role of Cardiac MR Imaging in Cardiomyopathies. J Nucl Med 56 Suppl 4:39S-45S
Gonzalez, Jorge A; Kramer, Christopher M (2015) Role of Imaging Techniques for Diagnosis, Prognosis and Management of Heart Failure Patients: Cardiac Magnetic Resonance. Curr Heart Fail Rep 12:276-83

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