Challenging the Hemodynamic Hypothesis in HFpEF: Is Exercise Capacity Limited by Elevated Pulmonary Capillary Wedge Pressure?

Patients who have heart failure with preserved ejection fraction (HFpEF, also called “diastolic heart failure”) have clinical signs and symptoms of heart failure and an ejection fraction greater than 50%. Exercise intolerance is a defining characteristic of HFpEF and a major cause of morbidity. In the outpatient setting, many patients with HFpEF are euvolemic with normal cardiac filling pressures, but when they exercise, their cardiac filling pressures dramatically increase. Conventional wisdom has held that this elevated cardiac filling pressure during exercise results in exercise intolerance in HFpEF, likely by causing shortness of breath. Yet the key hypothesis that reducing peak cardiac filling pressures can improve exercise tolerance in HFpEF has not been thoroughly tested.

In work we presented at #AHA21, we lowered the peak cardiac filling pressure in patients with HFpEF acutely with nitroglycerin and measured their exercise capacity. Gold standard measures for exercise capacity (peak oxygen uptake, VO2) and hemodynamics (pulmonary capillary wedge pressure, PCWP) were made during invasive cardiopulmonary exercise tests. We found that cardiac filling pressures were markedly elevated during exercise, even if they were normal at rest, and nitroglycerin significantly lowered the peak wedge pressure. To our surprise, peak VO2 was completely unchanged with nitroglycerin (less than 1% difference). This study challenges a major therapeutic paradigm in HFpEF by demonstrating that lowering cardiac filling pressures during exercise is insufficient to improve exercise capacity. Our findings also suggest that the exertional PCWP response during exercise is a secondary phenomenon rather than a primary cause of exercise intolerance in HFpEF. One of us (JM) was honored to receive the Samuel A. Levine Early Career Clinical Investigator Award for presentation of this work.

There’s more to come! This study includes preliminary findings from Dr. Ben Levine’s NIH-funded program project grant, “Mechanisms of Exercise Intolerance in Heart Failure with Preserved Ejection Fraction.” The investigative team for that grant combines the expertise of national leaders in cardiovascular, pulmonary, vascular, and autonomic physiology at the Institute for Exercise and Environmental Medicine, UT Southwestern, and UT Arlington. Our objective is to broadly investigate why patients with HFpEF experience exercise intolerance and learn how their exercise capacity and quality of life can be improved.