Understanding Hypertrophic Cardiomyopathy
By Amanda Chase, PhD
October 29, 2019
Hypertrophic cardiomyopathy (HCM) is a cardiovascular disease characterized by the heart muscle (myocardium) becoming abnormally thick. The thickened heart muscle makes it harder for the heart to pump blood. There are usually no symptoms, but for some, this results in shortness of breath, chest pain, or arrhythmias. HCM is usually diagnosed in late adolescence or young adulthood, and is the leading cause of sudden cardiac death in those under age 35. Current treatment is only symptomatic relief, including heart muscle reduction surgery, defibrillator placement, or heart transplant. A new therapeutic approach to treat the disease is urgently needed, but rational drug discovery has been hampered by a lack of understanding of the molecular basis of the disease.
HCM patients display hypercontractility, although the mechanism generating hypercontractility is not understood. It is known that HCM is most often caused by gene mutations, specifically in genes encoding β-cardiac myosin, a motor protein that drives heart muscle contractions. How mutations in the cardiac motor protein leads to altered power output of the protein, thus affecting heart muscle contractility, is not known. Recently, a team of researchers from Stanford University Cardiovascular Institute, led by Kathleen Ruppel, MD, James Spudich, PhD, and first author Arjun Adhikari, PhD, sought to address this question. They generated myosin proteins with four HCM-causing mutations, all known to be clinically pathogenic, and investigated how those HCM-causing mutations alter myosin activity. Their results were recently published in Nature Communications. The researchers were able to show that the specific mutations tested led to an increase in the percentage of myosin motors available to interact with actin; myosin binding to actin results in the power stroke of the myosin motor that drives muscle contraction. Thus, the HCM-causing mutations led to increased cardiac muscle contractility, as seen in HCM patients. Together, the authors were able show that HCM mutations in β-cardiac myosin lead to hypercontractility. These results shed light on a fundamental concept of HCM development, and pushes forward the understanding of the molecular basis of HCM.
Other authors from the Stanford Cardiovascular Institute include Darshan Trivedi, Saswata Sarkar, Dan Song, Kristina Kookier, and Daniel Bernstein. Funding was provided by NIH GM33289, HL117138, T32HL094274, and F32HL140772; Lucile Packard CHRI fellowship; Stanford CVI postdoctoral award; and American Heart Association 16POST30890005 and 17post33411070.