More than 3 million Americans have a form of heart failure called heart failure with preserved ejection fraction (HFpEF) that is associated with a high rate of hospitalization and death. About 25% of patients die within the first year after diagnosis.
Heart failure is on the rise, spurred by an aging population and high rates of obesity, diabetes, sleep apnea, and cardiovascular diseases. Yet genetic and metabolic factors that could improve early diagnosis of HFpEF are not well defined.
Now a multi-institutional group led by Vanderbilt Health and the Mass General Brigham Heart and Vascular Institute in Boston has identified a “signature” of metabolic molecules associated with exercise-induced physiologic deficits that, when released into the bloodstream, signal heightened heart failure risk.
These findings, reported online April 7 in the journal Circulation, provide a “road map” linking aspects of human metabolism and physiology to HFpEF.
The work uses state-of-the-art physiologic measures derived during exercise in patients with HFpEF alongside circulating metabolites, human genetics, and large population-based studies to define an individual’s risk of developing heart failure.
“Heart failure with preserved ejection fraction is difficult to diagnose and hard to treat,” Ravi Shah, MD, co-director of the Vanderbilt Diabetes Center, stated. “This work joins a large body of literature telling us that HFpEF is not just a disease of the heart. It relies on how our entire body’s metabolic system works together.”
Genetic methods developed at Vanderbilt were used to identify genes in specific tissues that were linked to the physiology of patients with HFpEF and to clinical metabolic disorders including kidney disease, obesity, and diabetes, said Eric Gamazon, PhD, co-director of the Vanderbilt Diabetes Center’s Functional Multi-Omics of Diabetes Core.
Shah, who holds the Gottlieb C. Friesinger II Endowed Chair in Cardiovascular Medicine, and Gamazon, associate professor of Medicine in the Division of Genetic Medicine and Clinical Pharmacology, were co-senior authors of the study with Gregory Lewis, MD, heart failure section head at Mass General.
Classically, HFpEF has been thought of as a disease of the heart itself, when the heart’s left ventricle is stiff and does not relax sufficiently to fill completely with blood between contractions.
While the muscular left ventricle can still squeeze most of the blood it receives into the circulation between beats (thus the term, “preserved ejection fraction”), it cannot pull in enough blood during relaxation to meet the body’s need for oxygen.
Patients who have this kind of heart failure often feel fatigued and have difficulty breathing, especially when they exercise. This is known as “exercise intolerance.”
More recently, research at Vanderbilt Health and elsewhere has helped broaden the definition of HFpEF as a syndrome that links muscle, lungs, fat, and other organs and tissues.
In this study, which involved 11 institutions across the country, researchers used invasive hemodynamic cardiopulmonary exercise testing to measure metabolic function during exercise in 820 patients with HFpEF.
Thin tubes were inserted into an artery in the forearm and a vein in the neck to draw blood samples, while patients rode stationary bicycles and breathed into spirometers for lung function testing.
The study quantified seven exercise-induced physiologic deficits that frequently co-existed in various combinations, and which contributed to exercise intolerance. Patients with five or more exercise deficits had a nearly four-fold increase in the risk of cardiovascular complications and death.
The researchers then measured the association between heart failure and the metabolite “signature,” a unique profile of small molecules, in 6,345 participants in the Multi-Ethnic Study of Atherosclerosis, a longitudinal national study.
They mapped key “physiologic deficit-implicated” metabolites to genes in different tissues through a technology developed by the team and large-scale genome-wide association studies to identify metabolic mechanisms shared by HFpEF and its “co-morbidities,” including obesity, kidney disease, and diabetes.
These findings support a shift from a cardio-centric perspective, toward a multi-organ framework for evaluating exercise intolerance and prognosis for heart failure.
The study represents “the largest to-date resource of phenotypic and metabolic profiles of HFpEF-defining exercise deficits, providing feasible metabolic biomarkers of HFpEF susceptibility,” the researchers concluded.
Lindsey Stolze, PhD, a statistical genetic analyst in the Department of Biostatistics at Vanderbilt Health, is co-first author of the paper with Isabela Landsteiner, MD, of Mass General, and Tess Peterson, MPH, PhD, of the University of Minnesota.
Other co-authors who are currently full-time at Vanderbilt Health are Andrew Perry, MD, Phillip Lin, PhD, Quanhu Sheng, PhD, Shilin Zhao, PhD, and Kaushik Amancherla, MD, MSCI.
This work was supported by a four-year, $2.6-million grant (R01HL151841) awarded in 2020 by the National Heart, Lung, and Blood Institute of the National Institutes of Health. Lewis and Shah were the grant’s co-principal investigators.
