Sharlene M. Day, MD
Anjali Tiku Owens, MD
The heritable cardiomyopathies, a group of diseases that includes hypertrophic cardiomyopathy (HCM) and dilated cardiomyopathy (DCM), are a leading cause of morbidity and mortality and a dilemma for cardiologists, who have few therapies to address their underlying genetic or molecular pathologies despite more than two decades of advances in imaging and genomics.
This is beginning to change, however, in part through the investigative efforts at Penn Medicine's Center for Inherited Cardiac Disease, a program fast becoming a leading source of research into novel treatments for heritable heart disease. Among the genetic cardiologists and researchers affiliated with the Center is Medical Director Anjali Tiku Owens, MD, Scientific Director Kiran Musunuru, MD, PhD, and Sharlene M. Day, MD, Director of Translational Research in the Division of Cardiovascular Medicine and Cardiovascular Institute.
The Center for Inherited Cardiac Disease offers a comprehensive range of services and access to specialists for patients with inherited heart conditions and their family members. Specialists at the Center do both consultative and lifelong longitudinal care for patients who either have disease or are at risk of developing disease.
The Thickening Heart: About the Inherited Cardiomyopathies
The predominant types of inherited heart disease (and the focus of this article) are hypertrophic cardiomyopathy (HCM) and familial dilated cardiomyopathy (DCM). Other forms of heritable cardiomyopathy, including inherited arrhythmogenic cardiomyopathy and familial amyloid cardiomyopathy, are the focus of treatment and research programs led by Francis Marchlinski, MD, and Brian Drachman, MD, respectively.
Dr. Marchlinski is Director of Penn Electrophysiology and Dr. Drachman leads the cardiology unit of Penn Medicine's comprehensive Amyloidosis Program and its research efforts in familial amyloid cardiomyopathy.
The most common of the heritable cardiomyopathies (estimated to affect 1 in 500 persons), hypertrophic cardiomyopathy is a chronic condition that causes hypercontractility and consequent heart muscle thickening. HCM places people at risk for heart failure, atrial fibrillation and (in a small subset of patients), sudden death. There are two main types of HCM, distinguished by their relative capacity to impede blood flow in the heart.
In obstructive HCM (oHCM, the more common of the two) septal thickening reduces blood flow from the left ventricle to the aorta. Nonobstructive HCM results in myocardial thickening and stiffening that affects the heart's pumping and relaxing capacity, but does not mechanically block blood flow. Mutations in more than 40 genes have been associated with HCM, with those encoding sarcomeric (muscle) proteins being the most commonly mutated in familial HCM.
At this time, the principal treatments for HCM are repurposed drugs for arrhythmias and heart failure (i.e., beta blockers, calcium channel blockers, disopyramide, diuretics), septal reduction therapy, ablations for atrial arrhythmias, implantable cardioverter defibrillators for those at increased risk for sudden cardiac death and heart transplantation in advanced disease.
In a recent podcast, Dr. Owens explained that the difference between HCM and familial dilated cardiomyopathy is found in the underlying structure and function of the heart.
"Hypertrophic cardiomyopathy causes asymmetric hypertrophy, usually of the left ventricle resulting in hyper-contractility and often very abnormal diastolic function," she explained. "By contrast, familial dilated cardiomyopathy results in a weakened heart muscle with dilation of the left ventricle and a reduction in systolic function or contractile function."
The hallmarks of DCM include LV dilation, reduced systolic function, depressed myocardial contractility and arrhythmias. Persons with DCM are at increased risk for heart failure, arrhythmias and sudden cardiac death. Genetically, the most heterogenous of the heritable cardiomyopathies, DCM has been associated with mutations in > 50 genes. The most commonly mutated gene in familial DCM is titin (TTN) which has an integral role in cardiac and skeletal muscle sarcomere function.
Mutations in the protein Lamin A/C encoded by the gene LMNA are less common but are associated with high penetrance and worse prognosis. Familial DCM is treated with drugs developed for systolic heart failure, implanted devices for those with dyssynchrony or arrhythmias, and ventricular assist device (VAD) or heart transplantation for persons with advanced disease.
Moderating the Cause: Penn Research in Heritable Heart Disease
Hypertrophic Cardiomyopathy (HCM)
Dr. Owens is the principal investigator at Penn Medicine for two Phase III randomized, double-blind, placebo-controlled, multi-center studies of mavacamten, a novel, pill-based, allosteric modulator of cardiac myosin: ^EXPLORER-HCM (NCT03470545) and ^VALOR-HCM (NCT04349072). An ^extension trial for the EXPLORER and MAVERICK studies (NCT03723655) is also under way at Penn.
In a recent interview, Dr. Day elaborated on the mechanisms of mavacamten.
"Mavacamten is the first drug developed specifically to treat patients with hypertrophic cardiomyopathy," Dr. Day explained. "The drug binds to myosin, the molecular motor of the heart muscle cells to inhibit the turnover of ATP or energy utilization and dampen down contraction."
Too forceful contraction of the heart in hypertrophic cardiomyopathy leads to left ventricular outflow tract obstruction and significant symptoms, and eventually in many patients contributes to the need for medications, surgery and other treatments.
In clinical and preclinical studies, mavacamten has been shown to reduce biomarkers of cardiac wall stress, lessen excessive cardiac contractility and increase diastolic compliance.
Now complete, EXPLORER-HCM is a randomized, double-blind, placebo-controlled, multicenter Phase 3 study of patients with symptomatic, obstructive HCM (NYHA Class II-III). In an August report in Lancet on EXPLORER-HCM co-authored by Dr. Owens, treatment with mavacamten was found to improve exercise capacity, reduce left ventricular outflow tract obstruction, and improve NYHA functional class and health status in patients with obstructive hypertrophic cardiomyopathy. The trial was performed in a study population generally representative of patients with obstructive HCM in the general population, and its results highlight the benefits of disease-specific treatment for the disease.
Dr. Owens was a co-author on a sub-study analysis of EXPLORER that investigated the effect of mavacamten versus placebo on cardiac structure and function as documented by cardiac magnetic resonance (CMR) imaging. In this sub-study, the primary endpoint was the change in LV mass index (LVMI) from baseline to week 30. Exploratory endpoints included change in cellular hypertrophy, left atrial volume index (LAVI), LV function, and myocardial fibrosis, among others.
At the sub-study conclusion, mavacamten was associated with significant reduction in LVMI and LAVI, predictors of poor prognosis in oHCM. There were no changes in fibrosis or MCF observed over 30 weeks, and contractile function remained normal. Reductions in hypertrophy and LA volumes were observed concurrent with reductions in levels of plasma biomarkers of myocardial stress and injury. This assessment was the first to show the favorable impact of a pharmacologic agent on cardiac remodeling in HCM.
An application for FDA approval of mavacamten in symptomatic obstructive HCM is anticipated in early 2021.
VALOR-HCM is a randomized, double-blind, placebo-controlled, multicenter Phase 3 study of patients with symptomatic, obstructive HCM (NYHA Class III-IV) who meet guideline criteria for septal reduction therapy and have been referred for an invasive septal reduction therapy (SRT). VALOR-HCM is intended to provide direct clinical evidence of mavacamten's ability to mitigate the need for SRT. This trial is currently enrolling at Penn Medicine.
Familial Dilated Cardiomyopathy (DCM)
The Penn Center for Inherited Cardiac Disease is also participating in a phase 3, multinational, randomized, placebo-controlled trial of the investigational agent ^ARRY-371797 in patients with symptomatic dilated cardiomyopathy due to a Lamin A/C gene mutation. ARRY 371797 is an orally active, small molecule, p38 mitogen-activated protein kinase inhibitor. LMNA A/C mutations are a cause of DCM, and LMNA-dilated cardiomyopathy has been linked to a constellation of effects, including arrhythmias, LV failure and sudden death.
This study, which is currently enrolling at Penn Heart and Vascular, is looking at the drug's efficacy, safety, and effect on functional capacity.
A second clinical investigation ongoing at Penn is evaluating the effectiveness of a family communication intervention in improving the uptake and impact of family member clinical screening in DCM. The ^DCM Precision Medicine Study will recruit a cohort from a multi-center US consortium to receive explicit recommendations and assistance on the clinical screening of relatives, and a tailored intervention to help DCM probands* communicate DCM risk to their family members. The hoped for outcome of these efforts is improvement in the uptake and impact of necessary clinical and genetic testing among potentially affected family members.
Dr. Owens is the PI for both of these studies, which are currently accruing at Penn Heart and Vascular.
*According to the NIH, a proband is typically "the first affected individual in a family who brings a genetic disorder to the attention of the medical community." About 40 percent of DCM probands have pathogenic or likely pathogenic variants in genes previously implicated in DCM.
To refer a patient or learn more about clinical trial options at the Center for Inherited Cardiac Disease, please call 215-615-0044.
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