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Men and Women with HFpEF Differ in Physiologic Responses to Exercise

Key findings

  • This cross-sectional study involved 295 patients (174 women) carefully defined according to prespecified physiologic criteria
  • Women with heart failure with preserved ejection fraction (HFpEF) had a significantly lower burden of cardiometabolic comorbidities than men and similar percent predicted peak oxygen consumption
  • Women with HFpEF exhibited significantly worse peripheral oxygen extraction during cardiopulmonary exercise testing, worse right and left ventricular systolic reserve and worse diastolic reserve compared with men
  • These differences in exercise response suggest that the pathophysiologic mechanisms of HFpEF may be distinct among women and men

Heart failure with preserved ejection fraction (HFpEF) is substantially more prevalent in women than men, and differences in cardiovascular structure, adaptations to physiologic stress and comorbidity burden have all been proposed as explanations. However, exercise intolerance is a central feature of HFpEF, and little is known about sex differences in cardiac and extracardiac reserve with exercise.

Emily Lau, MD, research fellow, and Jennifer E. Ho, MD, cardiologist in the Heart Failure and Transplant Program and the Cardiovascular Research Center at Massachusetts General Hospital, and colleagues recently investigated differences in physiologic responses to cardiopulmonary exercise testing in men and women with rigorously defined HFpEF. In JAMA Cardiology, they report that women demonstrated greater deficits in oxygen delivery and utilization, suggesting that the mechanisms of HFpEF may be distinct in women and men.

Study Design

The research team analyzed data on 295 patients with left ventricular ejection fraction (LVEF) ≥50% and chronic New York Heart Association class II to IV symptoms who had physiologic evidence of HFpEF according to prespecified criteria. 174 (59%) were women. The patients underwent cardiopulmonary exercise testing with invasive hemodynamic monitoring at Mass General between December 2006 and June 2017.

Cardiometabolic Comorbidities

In adjusted multivariable analyses, women had significantly lower odds of diabetes, hypertension and previous myocardial infarction than men did, although similar odds of obesity.

Gas Exchange and Hemodynamics

Despite maximal effort during exercise in both groups and similar percent predicted peak oxygen consumption, women demonstrated significantly worse results than men with regard to:

  • Gas exchange parameters: peak oxygen consumption, peak workload, maximum voluntary ventilation, ventilation/carbon dioxide production slope and peripheral oxygen extraction
  • Hemodynamic parameters: pulmonary artery pressure, pulmonary capillary wedge pressure, cardiac output, RV and LV systolic reserve (change in EF) and diastolic reserve

The disparity in peripheral oxygen extraction persisted even after adjustment for hemoglobin level, which has been proposed to be a major driver of sex differences in oxygen transport and utilization.

Multivariable Analyses

Sex differences in peripheral oxygen extraction, LV and RV systolic reserve and diastolic reserve persisted after adjustment for age, body mass index, hypertension, diabetes, smoking status and previous myocardial infarction, and after further adjustment for history of atrial fibrillation.

Applying the Findings to Future Research

These differences in exercise response suggest that the pathophysiologic drivers of HFpEF may be distinct in women and men and may explain sex differences in its prevalence and natural history. A better understanding of sex differences might ultimately contribute to the development of targeted therapies.

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The various definitions of heart failure with preserved ejection fraction (HFpEF) miss up to 85% of patients with abnormal rest or exercise filling pressures, cardiologists at Massachusetts General Hospital have found. Better hemodynamic phenotyping is needed to target patients at highest risk.