Approximately 3 million people in the United States are living with a condition called heart failure with preserved ejection fraction, or HFpEF. The number of people with this form of heart failure, which is more common in women than men, is growing alongside a rise in risk factors like aging, hypertension, diabetes, and obesity. Additionally, more than 80% of HFpEF patients also face pulmonary hypertension, or increased blood pressure in the vasculature of the lungs. For patients with this combined condition, called PH-HFpEF, the prognosis can be daunting. Those with HFpEF face debilitating symptoms, frequent hospitalizations, and an annual mortality rate of 15%. Meanwhile, several promising clinical trials have recently failed.
“HFpEF is incredibly common,” says Farhan Raza , a cardiologist and researcher at the University of Wisconsin–Madison’s Cardiovascular Research Center who treats patients with HFpEF. “Many patients feel profoundly breathless and have dramatically poor quality of life from this disease. Even simple daily activities, such as walking to the mailbox, can leave them breathless and exhausted.”
However, not all people at high risk will develop HFpEF, and clinicians can struggle to detect the disease in early stages when it's most treatable. Meanwhile, researchers are just beginning to understand the mechanisms that cause and exacerbate HFpEF, knowledge which could lead to new treatments.
“A big challenge is that we don't know why some people develop HFpEF who have the same medical problems of obesity, hypertension and diabetes, and why some people don’t,” says Raza. What’s more, “detection of the disease is a challenge. Then, when people have this problem, sometimes we recognize it too late and they’ve already developed damage to other parts of their body, like kidney failure or liver failure, and they've lost a lot of muscle mass and become very frail.”
In a new study publishing in the American Heart Association's journal Circulation: Heart Failure on August 24th, a group of clinicians and scientists from the University of Wisconsin–Madison and the Morgridge Institute for Research, led by Raza, have made progress both in detecting the severity of HFpEF and in understanding the mechanisms behind it. They report an improved clinical method for characterizing PH-HFpEF patients’ prognosis and have found potential mechanistic and molecular changes contributing to the condition, which could be targets for future therapies.
HFpEF occurs when the walls of the heart’s left ventricle, which pumps blood through arteries and into the body, stiffen and thicken. As a result, the heart can’t generate enough blood flow for day-to-day activities and people experience severe fatigue. Moreover, the increased pressures in the heart get transmitted back to the lungs, leading to lung damage and pulmonary hypertension that in turn causes severe breathlessness. As the disease advances, it can precipitate dysfunction of the heart’s right ventricle (RV), which pumps blood into the lungs to get oxygenated.
Commonly applied clinical tests can’t fully capture the state of the disease or the mechanisms causing it to worsen, which makes finding potential treatments more difficult. In fact, a series of clinical trials working under the hypothesis that reducing pulmonary hypertension with drugs like sildenafil might improve symptoms of HFpEF failed and sent doctors back to the drawing board.
“It's almost like water flowing through a river, and instead of having normal flow, somebody throws a bunch of boulders in it that causes turbulence and high pressure,” says Raza. “Then, if you send more flow through that river, like with traditional pulmonary hypertension medicines such as sildenafil, it’s going to cause higher turbulence and flooding upstream in the lungs.”
More recently, another promising therapy for PH-HFpEF, oral levosimendan, also failed in a clinical trial. Raza says this points to a need to understand each patient’s unique cardiopulmonary physiology and find a path beyond a one-size-fits-all approach, which can obscure benefits from the most promising therapies.
To learn more about HFpEF, the research team of the new study evaluated a set of 48 PH-HFpEF patients who had received comprehensive cardiac assessments, including invasive testing and cardiac MRIs. Of those, 29 had normal RV function, while 19 were experiencing dysfunction. From that group of 48 patients, subsets received further advanced tests, including detailed study of the pulmonary arteries with invasive catheterization, cardiac MRIs that measure how blood flows over time, and biopsies of heart tissue for molecular and genetic analysis.
They found that PH-HFpEF patients with RV dysfunction experienced higher rates of mortality and hospitalization and that RV function is a better prognostic indicator than other methods used by clinicians to classify the severity of HFpEF. They were also able to show that issues arising in the left heart might lead to stress on the RV and contribute to its dysfunction.
In addition to the tests that measured blood flow in and around the heart, the analysis of biopsied tissue revealed several pathways that appear to be involved in HFpEF. The most robust link was related to a diminishment of the function of mitochondria, the metabolic powerhouse of our cells. There also appeared to be an increase in RNA metabolism and transport. This supports previous research that RNA metabolism and mitochondrial dysfunction are important to the development of heart disease.
“Based on our findings, one of the strongest biological themes is energy metabolism,” says Wei Guo , a muscle biologist at UW–Madison and co-author on the study. “Many of the genes we identified are linked to mitochondrial function and cellular energy production, suggesting that disrupted energy metabolism may play an important role in HFpEF.”
The analysis used a relatively new technology, called long-read RNA sequencing , which allows researchers to detect particular variants of genes that might be expressed in longer or shorter versions. They found a handful of genes are differently expressed between patients with and without RV dysfunction. While these results are preliminary, it’s possible that some of these gene expression variants might be tied to HFpEF. One example is GATD3, which could be a target for future study and potential treatment development.
“GATD3 has a variant expressed much more highly in right ventricle dysfunction. Since GATD3 is involved in mitochondria function, it may be playing a role in HFpEF”, says Ron Stewart , a bioinformatics investigator at the Morgridge Institute whose research group led the long-read RNA sequencing aspect of the study.
Going forward, the team plans to build on these findings in larger studies that develop a clearer picture of the molecular and cell-level variation between the heart tissue of patients with normal RV function versus those with dysfunction. This could lead to a clinical scenario where HFpEF patients are able to have their heart tissue analyzed for specific mechanisms causing RV failure and then receive a precision treatment designed to work for them.
Raza hopes that continuing this work will help “develop a very good pipeline of running a highly sophisticated analysis that can say, ‘this specific patient belongs in a subgroup where we know this one mechanism has kind of gone bonkers.’ Then, we can treat them with an already approved drug that addresses that exact mechanism. While these are early results, I think our study does a pretty good job of introducing this strong pipeline, which will translate into human precision clinical trials within a few years.”
“We are deeply grateful to every patient who has chosen to take part in this research,” Raza adds. “Their generosity, and the trust they place in us, is creating knowledge that will benefit countless patients and families in the years to come.”
As an independent research organization, the Morgridge Institute for Research explores uncharted scientific territory to discover tomorrow’s cures. In affiliation with the University of Wisconsin–Madison, we support researchers who take a fearless approach to advancing human health in emerging fields such as regenerative biology, metabolism, virology and biomedical imaging. Through public programming, we work to inspire scientific curiosity in everyday life. Learn more at: morgridge.org
Circulation Heart Failure
10.1161/CIRCHEARTFAILURE.126.014620
Observational study
People
Multimodal Framework of Left Heart–Pulmonary Vascular Remodeling Underlying Right Ventricular Failure in PH-HFpEF
24-Aug-2026