Doctors and scientists race to understand a growing form of heart failure

Heart failure with preserved ejection fraction (HFpEF) is becoming increasingly common, particularly as obesity, diabetes, high blood pressure and aging continue to rise. Around 3 million people in the United States are estimated to live with the condition, which affects women more often than men.

More than 80% of people with HFpEF also develop pulmonary hypertension, creating a particularly dangerous combination known as PH-HFpEF. The condition can cause severe shortness of breath, fatigue, repeated hospitalizations and a high risk of death. Yet doctors still have limited tools for detecting the disease early and predicting how quickly it will progress.

A new study by researchers at the University of Wisconsin–Madison and the Morgridge Institute for Research offers new clues about both the progression of PH-HFpEF and the biological mechanisms behind it. The findings were published in Circulation: Heart Failure.

Right heart function may be key to prognosis

HFpEF develops when the walls of the heart's left ventricle become thicker and stiffer, reducing the heart's ability to fill properly and deliver enough blood to the body. The resulting pressure can be transmitted to the lungs, causing pulmonary hypertension and eventually placing excessive strain on the right ventricle, which pumps blood to the lungs.

The researchers studied 48 patients with PH-HFpEF who underwent detailed cardiac evaluations, including invasive testing and cardiac MRI. Twenty-nine patients had normal right ventricular function, while 19 had signs of right ventricular dysfunction.

Patients with impaired right ventricular function had higher rates of hospitalization and mortality. The researchers found that right ventricular performance was a more useful indicator of prognosis than some of the conventional methods used to assess HFpEF severity.

Advanced imaging also showed that abnormalities originating in the left side of the heart may increase stress on the right ventricle and contribute to its eventual failure.

Energy production and mitochondria may play a role

The team also analyzed heart tissue from a subset of patients using molecular and genetic techniques. One of the strongest signals involved impaired mitochondrial function. Because mitochondria are responsible for producing much of the energy needed by cells, disruptions in their activity may contribute to the progression of HFpEF.

The researchers also identified changes in RNA metabolism and transport, supporting previous evidence that altered cellular energy metabolism and mitochondrial dysfunction may be involved in heart disease.

Using long-read RNA sequencing, the scientists identified several genes whose activity differed between patients with normal and impaired right ventricular function. One gene of particular interest was GATD3, which is associated with mitochondrial function and was expressed at substantially higher levels in patients with right ventricular dysfunction.

The findings are preliminary, and further studies are needed to determine whether these molecular changes directly contribute to HFpEF or could be targeted therapeutically.

Toward more personalized treatment

The researchers believe that a better understanding of the molecular differences between patients could eventually lead to more individualized treatment strategies.

Rather than treating all HFpEF patients in the same way, doctors could potentially identify the specific biological mechanism driving disease in each patient and select a therapy designed to target it.

The team plans to conduct larger studies to further investigate the molecular and cellular changes associated with right ventricular failure. The researchers hope this approach could eventually support precision clinical trials and more effective treatments for patients with PH-HFpEF.

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