Mechanisms of Exercise Intolerance in Heart Failure With Preserved Ejection Fraction

Abstract

Background Exercise capacity as measured by peak oxygen uptake (Vo2) is similarly impaired in patients with heart failure with preserved ejection fraction (HFpEF) and heart failure with reduced ejection fraction (HFrEF). However, characterization of how each component of Vo2 changes in response to incremental exercise in HFpEF versus HFrEF has not been previously defined. We hypothesized that abnormally low peripheral o2 extraction (arterio-mixed venous o2 content difference, [C(a-v)o2]) during exercise significantly contributes to impaired exercise capacity in HFpEF. Methods and Results We performed maximum incremental cardiopulmonary exercise testing with invasive hemodynamic monitoring on 104 patients with symptomatic NYHA II to IV heart failure (HFpEF, n=48, peak Vo2=13.9±0.5 mL kg−1 min−1, mean±SEM, and HFrEF, n=56, peak Vo2=12.1±0.5 mL kg−1 min−1) and 24 control subjects (peak Vo2 27.0±1.7 mL kg−1 min−1). Peak exercise C(a-v)o2 was lower in HFpEF compared with HFrEF (11.5±0.27 versus 13.5±0.34 mL/dL, respectively, P<0.0001), despite no differences in age, hemoglobin level, peak respiratory exchange ratio, Cao2, or cardiac filling pressures. Peak C(a-v)o2 and peak heart rate emerged as the leading predictors of peak Vo2 in HFpEF. Impaired peripheral o2 extraction was the predominant limiting factor to exercise capacity in 40% of patients with HFpEF and was closely related to elevated systemic blood pressure during exercise (r=0.49, P=0.0005). Conclusions In the first study to directly measure C(a-v)o2 throughout exercise in HFpEF, HFrEF, and normals, we found that peak C(a-v)o2 was a major determinant of exercise capacity in HFpEF. The important functional limitation imposed by impaired o2 extraction may reflect intrinsic abnormalities in skeletal muscle or peripheral microvascular function, and represents a potential target for therapeutic intervention.

The Future of Heart Failure Diagnosis, Therapy, and Management

“…Evidence of chronotropic incompetence can be documented, 59 and abnormal oxygen extraction by the peripheral skeletal musculature, as well, 60 both of which would limit oxygen delivery to the periphery and result in symptoms of exertional intolerance. An interesting group of patients was highlighted who have almost completely normal invasive hemodynamic measures at rest (including normal brain natriuretic peptide levels) but who develop very abnormal hemodynamics only during exercise.…”

A novel cardiac output response to stress test developed to improve diagnosis and monitoring of heart failure in primary care

“…The same study suggests that 50% of patients with heart failure reduced ejection fraction demonstrate reduced cardiac index at rest compared with healthy controls 26. However, it appears that both heart failure patients with reduced as well as preserved ejection fraction demonstrate diminished cardiac output (cardiac index) in response to exercise‐induced stress 27, 28, 29…”

Exercise Intolerance in Heart Failure with Preserved Ejection Fraction

“…In support, Dhakal et al showed that peripheral oxygen extraction was lower in HFpEF compared to controls and HFrEF patients and was the major determinant of reduced exercise capacity. 16 The discrepancies in the above studies can be explained by Little and Borlaug, 9 who observed that although peripheral abnormalities were largely associated with exercise limitations, a cardiac limitation was present and could be the first and foremost underlying cause. It is also likely that common comorbidities associated with HFpEF such as pulmonary disease, obesity, and diabetes may contribute to exercise intolerance independent of the heart.…”