Researchers in a University of Cincinnati College of Medicine laboratory are taking two approaches to advance the understanding of heart disease.
Brittany Duncan, a doctoral student in molecular, cellular and biochemical pharmacology, is testing an investigational drug’s impact on diabetic cardiomyopathy in animal models. Diabetic cardiomyopathy is a disorder of the heart muscle in people with diabetes. It can lead to inability of the heart to circulate blood through the body effectively with accumulation of fluid in the lungs or legs.
Duncan’s colleague, Sholeh Bazrafshan, MD, a UC visiting scholar, is examining the impact exercise-related stress can have on individuals who carry a genetic variant of a heart protein linked to hypertrophic cardiomyopathy, commonly known as an enlarged heart.
Both presented their research abstracts at the virtual meeting of the American Heart Association scientific sessions in November and are part of a team of researchers working under Sakthivel Sadayappan, PhD, professor of internal medicine and scientific director of the UC Heart, Lung and Vascular Institute.
Diabetic cardiomyopathy is defined as the presence of abnormal cardiac structure and performance in the absence of other cardiac risk factors such as coronary artery disease, hypertension or significant disease in the valves of the heart.
Duncan is testing the effectiveness of the drug mavacamten in correcting diabetic-mediated diastolic dysfunction. Mavacamten, produced by MyoKardia, is currently in a Phase 3 clinical trial for treatment of obstructive hypertrophic cardiomyopathy. It targets excess contractility and improved relaxation in the heart.
“In this diabetic animal model we see that the functioning of the left ventricle is near normal and is capable of supplying the perfusion needs of the body,” says Duncan. “However, simultaneously we also see improved relaxation and excess contractility initially. My research focuses on prevention and rescue studies. What I hope to do is to use the drug mavacameten, a cardiac specific myosin inhibitor, to offer a protective element to the heart in the presence of diabetes.”
Sadayappan, also a co-author on the abstract, says Duncan’s research project is designed to advance our knowledge of how Type 2 diabetic patients develop heart failure.
“Specifically, she studies a sub-type of heart failure called ‘heart failure with preserved ejection fraction (HFpEF),’ which is defined as heart failure symptoms with normal systolic but depressed diastolic function,” explains Sadayappan. “Importantly, about 45% of HFpEF patients have Type 2 diabetes and its presence in these patients markedly increases the chance of hospitalization and risk of death.”
Duncan, a native of Jackson, Mississippi, holds a bachelor of science degree in chemistry from Jackson State University, and a master’s degree in medical sciences from Hampton University, in Hampton, Virginia.
Other collaborators on her American Heart Association abstract include Mohammed Arif, PhD; Rohit Singh, PhD; and Evangelia Kranias, PhD.
Scholar Bazrafshan, a physician trained in Iran, is completing research training at UC. She holds a master’s degree in aerospace medicine from Wright State University in Dayton, Ohio. In Sadayappan’s lab, Bazrafshan is looking at the importance of the stress echo in discovering hidden cardiac traits which play a role in an enlarged heart.
The Sadayappan lab has focused on delineating the role of a genetic variant of myosin binding protein-C (MyBP-C) plays in the regulation, structure and function of cardiac muscles. That genetic variant is predominant in people of South Asian descent and may predispose these individuals to hypertrophic cardiomyopathy.
Hypertrophic cardiomyopathy is a disease in which the heart muscles become abnormally thick or “enlarged.” The disease is estimated to affect one in 500 people.
Bazrafshan along with other researchers invited 26 individuals who were of South Asian descent to perform a stress echocardiography. The group includes carriers and non-carriers for the MYBPC3 gene mutation (25bp deletion).
“The results were striking,” says Bazrafshan. “Though the subjects were asymptomatic and seem to be normal at baseline without any stress, MYBPC3 gene carriers show cardiac dysfunction upon exercise which is an early sign of disease development. Our work supports the importance of genetic screening especially in primary care settings and as part of a precision medicine approach.”
Sadayappan, also a co-author of the abstract presented to the AHA, says the study shows testing would provide valuable information for clinicians who could consider treatment options that might prevent the development of heart disease. “This study had a limited number of subjects and in the future we hope to recruit additional individuals and complete our finding with defined evidence that his MYBPC3 gene mutation is pathogenic.”
Other collaborators on Bazrafshan’s AHA abstract include Singh along with Robert Sibilia; Saavia Girgla, MD; Shiv Kumar Viswanathan, PhD; Megan Puckelwartz, PhD; Elizabeth McNally, MD, PhD; Kiranpal Sangha, PharmD; Mashhood Kakroo, MD; Roman Jandarov, PhD; David Harris, MD; Jack Rubinstein, MD, and Richard Becker, MD.