UPMC Children’s Heart Institute Researcher Mousumi Moulik, MD, Receives NIH R01 to Study Circadian Regulation of Cardiac Stress in HFpEF
October 9, 2026
A new National Institutes of Health R01 grant will investigate how disruption of the body's internal molecular clock may contribute to Heart Failure with Preserved Ejection Fraction (HFpEF), a condition that accounts for more than half of all heart failure cases and has limited treatment options.
The study, "Clock Regulation of Stress Pathways in HFpEF," is co-led by Mousumi Moulik, MD, associate professor of pediatrics, Division of Pediatric Cardiology, and director of the Pediatric Cardiovascular Genetics Program at the UPMC Children's Heart Institute, and Vijay K. Yechoor, MD, professor of medicine, director of the Diabetes and Beta Cell Biology Center at the University of Pittsburgh School of Medicine, and chief of endocrinology at the VA Pittsburgh Healthcare System.
Dr. Moulik and colleagues will examine how the heart's intrinsic circadian clock helps protect against chronic metabolic stress and whether circadian disruption increases susceptibility to cardiometabolic HFpEF, a form of heart failure commonly associated with obesity, insulin resistance, type 2 diabetes, and hypertension.
"Most therapies that work for HFrEF have not shown the same benefit in HFpEF, suggesting the two conditions arise through different biological mechanisms," Dr. Moulik says. "We want to determine whether circadian disruption is a modifiable risk factor that contributes to HFpEF development and whether there are opportunities for intervention after disease onset."
Circadian Disruption and Cardiac Resilience
The body's circadian clocks coordinate cellular activities with daily cycles of light exposure, feeding, activity, and rest. While the brain contains the central circadian clock, individual organs, including the heart, maintain their own molecular clocks that regulate metabolism, energy use, and responses to stress.
Modern lifestyle factors such as shift work, irregular sleep schedules, and social jet lag can disrupt synchronization between the central and peripheral clocks. Chronic circadian disruption has been associated with obesity, diabetes, hypertension, and cardiovascular disease.
"Our hypothesis is that the molecular clock regulates critical stress-adaptation pathways that help the heart remain resilient under chronic metabolic stress," Dr. Moulik says.
A Dual-Hit Model for HFpEF
The project builds on preliminary studies showing that a high-fat diet combined with chronic circadian disruption produced obesity, insulin resistance, hypertension, and cardiac changes consistent with HFpEF. Neither stressor alone resulted in HFpEF.
"Many individuals have obesity, diabetes, or hypertension but never develop HFpEF," Dr. Moulik says. "We believe circadian disruption may represent an additional environmental factor that reduces the heart's ability to adapt to these existing stressors."
Unlike many experimental models that rapidly induce disease, this study uses a chronic exposure model in which HFpEF develops gradually over months, more closely reflecting the human condition.
Identifying New Therapeutic Targets
The research will focus on three interconnected mechanisms: mitochondrial stress responses, metabolic flexibility, and communication among cardiac cell types that regulate inflammation and fibrosis. The study will combine animal studies with human induced pluripotent stem cell-derived cardiomyocytes and molecular analyses of human cardiac tissue.
The goal is to identify circadian clock-regulated pathways that preserve cardiac resilience and could serve as new therapeutic targets.
"Once HFpEF develops, we want to know whether there is still an opportunity to strengthen the molecular clock or the pathways it controls," Dr. Moulik says. "Equally important, we hope to determine whether circadian disruption itself can be identified and mitigated as a preventable risk factor before heart failure begins."
While focused on adult cardiometabolic HFpEF, the findings may also provide insights into other forms of human heart failure due to predominant diastolic dysfunction, including those seen in a subset of patients with complex congenital heart disease and single ventricle physiology.
References and Further Reading
