In the U.S. alone, over 6.7 million people have heart failure, a number that is projected to increase to more than 8.5 million by 2030. Heart failure is a progressive condition in which the heart struggles to pump enough blood and oxygen to support the organs in the body.
In a new paper, “Integrated Systems Biology Identifies Disruptions in Mitochondrial Function and Metabolism as Key Contributors to HFpEF,” published in JACC, John Elrod, professor and director of the Aging + Cardiovascular Discovery Center, and his team in the Lewis Katz School of Medicine at Temple University are investigating a type of heart failure called HFpEF. In collaboration with a team at Cedar-Sinai, led by David Lefer, director of translational research in cardiac surgery, these researchers are seeking new insights on the mechanics and progression of the disease, in hopes of identifying new targets for developing clinical treatments.
Heart failure cases are broadly categorized into two types: heart failure with reduced ejection fraction (HFrEF) and heart failure with preserved ejection fraction (HFpEF). While some clinical drug trials have been effective in treating HFrEF, few have been able to address HFpEF. Due to lack of understanding the disease process and therapies to address it, the National Heart, Lung and Blood Institute of the National Institutes of Health has urged researchers to prioritize the study of HFpEF, labeling it as the current greatest unmet need in cardiovascular medicine.
“HFpEF was really unrecognized until about a decade ago,” explained Elrod. “Clinically, it wasn’t well-characterized and we knew nothing about the mechanisms driving this disease. So that's what we set out to do in this paper.”
Elrod’s team employed a systems-biology approach to learn more about the disease, with a goal of gaining a deeper and more complex understanding of HFpEF. Researchers understand HFpEF to be a metabolically driven disease, and Elrod’s team wanted to learn more about how metabolic processes are affected in heart cells.
“We took a deep dive on the changes in gene expression and the changes in metabolism that showed up very early in the disease,” Elrod explained. “Something unique to this paper is what we found in mitochondrial remodeling, or the changes in how the mitochondria in the cells looks and how they’re connected to other organelles.”
Through their investigation, Elrod’s team discovered that the addition of obesity, alongside preexisting hypertension and vascular dysfunction, was a driving factor in the development of HFpEF. Elrod’s team also utilized RNA sequencing to investigate all changes in heart cell gene expression and observed the cell’s mitochondria via electron microscopy imaging, which provided super high-resolution images for researchers to observe the changes in mitochondrial shape and structure over the course of the disease.
After gathering their multifaceted data, Elrod’s team conducted an integrated pathway analysis, in which they overlayed changes in gene expression with changes in metabolic processes to illuminate a deeper understanding of the progression of the disease and its impact on cell function.
While more research is required to develop potential therapies for HFpEF patients, Elrod plans to continue his investigation into the metabolic pathways involved with HFpEF to discover if drugs or genetic changes can alter the course of the disease in this model system.
“This is a discovery-based study. That always excites me most because we don’t have a preconceived notion about what we will see,” shared Elrod. “We are going in to look at everything and find a signature, a target or pathway to go after. We are discovering the unknown and then testing new hypotheses.”
—Isabella López