Research Spotlight: Exercise Testing Unmasks HFpEF as a Multi-Organ Disease

Isabela Landsteiner, MD, and Gregory Lewis, MD, of Mass General Brigham Heart and Vascular Institute, are the lead and senior authors of a paper published in Circulation, “Multi-organ physiologic deficits during exercise identify clinical and molecular predisposition to heart failure with preserved ejection fraction.” Lewis and Ravi Shah, MD, of Vanderbilt University Medical Center, are co-corresponding authors.

Q: What challenges or unmet needs make this study important?

More than 1% of adults in the United States have heart failure with preserved ejection fraction (HFpEF). This means their hearts pump normally, but are stiff and don’t relax well, leading to major limitations in physical activity and stamina. Current diagnostic and risk stratification tools do not capture the biological complexity of HFpEF or explain why people with this condition have very different clinical courses.

A novel approach to mapping the reserve capacity of multiple organ systems at the same time during exercise provides a unique opportunity to identify biomarker patterns associated with a reduced ability to exercise. We can then use these patterns to understand the origins of HFpEF and learn how combinations of physiological abnormalities influence patient outcomes.

Q: What central question(s) were you investigating?

We investigated exercise-derived physiological deficits across multiple organ systems to better understand HFpEF. Specifically, we asked three questions:

• How are cardiac, pulmonary, vascular and peripheral limitations during exercise distributed and how do they co-exist within individuals with HFpEF?
• Are the number and type of these deficits associated with worse clinical outcomes?
• And lastly, can a broad array of circulating metabolites serve as “signatures” of physiological deficits and be used to predict who will develop heart failure in the general population?

Q: What methods or approach did you use?

To answer these questions, we used invasive cardiopulmonary exercise testing (iCPET): a detailed method that measures heart, lung and metabolic responses during exercise, for which Massachusetts General Hospital is a national referral center. In over 800 patients with HFpEF, we quantified seven key physiological deficits spanning cardiac function, pulmonary vascular function, breathing reserve, excess exercise metabolic cost of obesity and peripheral oxygen use by skeletal muscle.

We measured hundreds of small molecules in the blood—sampled at the time of iCPET—to identify patterns associated with each deficit, using combinations of metabolites to create distinct metabolic signatures. We then applied these signatures to resting blood samples from a large community-based cohort of over 6,000 individuals without heart failure with 20 years of subsequent follow up, permitting us to determine whether these signatures accurately predicted which people would eventually develop heart failure.

Finally, we integrated genetic data from large population studies to further trace the origins of these metabolic patterns.

Q: What did you find?

We found that exercise intolerance in HFpEF is driven by an array of various combinations of physiological deficits spanning cardiac and extra-cardiac systems, rather than a single abnormality in heart function. The number of these deficits strongly predicted the degree of exercise intolerance as well as hospitalization-free survival. Study participants with five or more deficits unmasked by exercise had a nearly fourfold higher risk of cardiovascular events or death.

Each deficit was associated with a distinct metabolic profile, reflecting pathways such as inflammation, mitochondrial dysfunction and impaired energy use. Importantly, these metabolic signatures predicted the development of heart failure in otherwise healthy individuals when followed for over two decades, even after accounting for established clinical risk factors. When combined, these signatures further improved the ability to predict who would develop heart failure.

Q: What are the real-world implications, particularly for patients?

These findings support a shift in how we think about HFpEF—from a focus on isolated cardiac limitations affecting functional capacity to a broader view of impaired multi‑organ system reserve capacity that drives functional limitations and strongly predicts disease course.

For patients, this means that symptoms like shortness of breath may arise from several interacting systems, not just the heart. By identifying specific combinations of deficits and their “rank order” in individual patients, clinicians may be able to better tailor treatments—for example, targeting peripheral muscle dysfunction, pulmonary vascular abnormalities or metabolic inefficiency (depending on the individual profile of deficits unmasked by exercise).

In addition, the ability to detect the metabolic signatures of these patterns in a drop of blood raises the possibility of more accessible, non-invasive tools for risk assessment and stratification.

Q: What part of this work feels most meaningful to you personally?

What feels most meaningful is the opportunity to connect physiology with biology in a way that reflects how patients actually experience disease. During clinical encounters, patients often describe limitations that are not fully explained by standard tests. This work reinforces the idea that exercise can serve as a window into hidden abnormalities and that these abnormalities have measurable biological correlates and implications for future outcomes.

Bridging detailed physiological assessment with advances in metabolomics and genetics allowed us to further understand HFpEF as a systemic condition. For our research team, this represents an important step toward more individualized patient-centered care.

Authorship: In addition to Lewis and Landsteiner, Mass General Brigham authors include Takenori Ikoma, Laura P. Cohen, Ilya Giverts, Joseph Campain and Rajeev Malhotra. Additional authors are listed in the paper.

Paper cited: Landsteiner, I., et al. “Multi-organ physiologic deficits during exercise identify clinical and molecular predisposition to heart failure with preserved ejection fraction.” Circulation. DOI: 10.1161/CIRCULATIONAHA.125.077579

Funding: This study was funded by National Heart, Lung, and Blood Institute (NHLBI) (R01 HL151841).

Disclosures: Dr. Lewis is supported by NHLBI (R01 HL151841) and (HL159514) for this work; NHLBI (U01 5U01HL160278-05) and an Americal Heart Association Strategically Focused Research Network Award for related work; and the Jeffrey and Mary Ellen Jay Chair in Heart Failure and the Heart Failure Research Innovation Fund. He has been a consultant for and received research support from American Regent, AskBio, Bayer, Edwards and Pharmacosmos and has received research support from institutional relationships with Amgen, Applied Therapeutics, AstraZeneca, Cytokinetics Pfizer, Alexion and Rivus.

Dr. Landsteiner is supported by an American Heart Association Strategically Focused Research Network Award and the MGH Heart Failure Research Innovation Fund and has no disclosures.

Co-author and other disclosures can be found in the paper.