A new study reveals that disrupted energy metabolism and mitochondrial dysfunction play a key role in heart failure with preserved ejection fraction (HFpEF), particularly in patients with right ventricular dysfunction. The research identifies specific genes like GATD3 that could help clinicians diagnose HFpEF severity earlier and develop personalized treatments for the three million Americans affected by this condition.
- More than 80% of patients with HFpEF also experience pulmonary hypertension, leading to high hospitalization rates and 15% mortality risk
- Right ventricular dysfunction is a stronger indicator of disease severity than other clinical methods
- The study proposes using heart tissue analysis and genetic testing to enable earlier diagnosis and personalized treatment with approved drugs targeting specific mechanisms
A study published in Circulation: Heart Failure revealed new understanding in the underlying mechanisms of heart failure with preserved ejection fraction (HFpEF) and diagnosing it and detecting severity. Scientists from the University of Wisconsin-Madison and the Morgridge Institute for Research authored the paper, “Multimodal Framework of Left Heart-Pulmonary Vascular Remodeling Underlying Right Ventricular Failure in PH-HFpEF.”
According to researchers, approximately three million Americans have HFpEF, of which more than 80% also experience pulmonary hypertension (PH-HFpEF). These patients can have adverse symptoms, multiple hospitalizations and a 15% chance of mortality.
Additionally, the risk of HFpEF, which is greater in women than men, has increased due to factors like aging, obesity and diabetes. However, not everyone at high risk develops this form of heart failure, and researchers have struggled to identify why this is and diagnose it in early stages.
“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,” said Farhan Raza, MD, a cardiologist and researcher at the UW-Madison’s Cardiovascular Research Center, in a news release.
In a retrospective study, the research team evaluated data from 48 patients with PH-HFpEF who had undergone clinical cardiac assessments, including MRIs and other invasive testing. Results showed 29 patients had normal right ventricle (RV) function and 19 patients had RV dysfunction. The patients received additional testing, such as catheterization to measure blood flow over time in the pulmonary arteries and heart tissue biopsies to analyze genetics and molecular makeup.
The researchers found that the subset of patients with RV dysfunction had higher rates of hospitalization and mortality than those with normal RV, suggesting that RV function was a better indicator of disease severity than other clinical methods. In addition, they detected issues in the left heart that could increase stress and contribute to RV dysfunction.
Data analysis also linked HFpEF to reduced function in the mitochondria and increased RNA metabolism.
“Based on our findings, one of the strongest biological themes is energy metabolism. 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,” said study co-author Wei Guo, PhD, a muscle biologist at UW-Madison.
Using long-read RNA sequencing, the scientists discovered specific genes, including GATD3, that were expressed differently in patients who had and didn’t have RV dysfunction.
“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,” said Ron Stewart, PhD, a bioinformatics investigator at the Morgridge Institute.
Dr. Raza said the new understanding could help clinicians diagnose HFpEF severity in patients earlier and more accurately by testing heart tissue for specific mechanisms. It could also lead to advanced, personalized treatments that improve outcomes.
“[This work can] 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,” Dr. Raza said. “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.”
