Impaired Exercise Tolerance in Heart Failure With Preserved Ejection Fraction: Quantification of Multiorgan System Reserve Capacity

Abstract

Exercise intolerance is a principal feature of heart failure with preserved ejection fraction (HFpEF), whether or not there is evidence of congestion at rest. The degree of functional limitation observed in HFpEF is comparable to patients with advanced heart failure and reduced ejection fraction. Exercise intolerance in HFpEF is characterized by impairments in the physiological reserve capacity of multiple organ systems, but the relative cardiac and extracardiac deficits vary among individuals. Detailed measurements made during exercise are necessary to identify and rank-order the multiorgan system limitations in reserve capacity that culminate in exertional intolerance in a given person. We use a case-based approach to comprehensively review mechanisms of exercise intolerance and optimal approaches to evaluate exercise capacity in HFpEF. We also summarize recent and ongoing trials of novel devices, drugs, and behavioral interventions that aim to improve specific exercise measures such as peak oxygen uptake, 6-min walk distance, heart rate, and hemodynamic profiles in HFpEF. Evaluation during the clinically relevant physiological perturbation of exercise holds promise to improve the precision with which HFpEF is defined and therapeutically targeted.

Keywords: exercise; heart failure with preserved ejection fraction; hemodynamics.

Copyright © 2020 American College of Cardiology Foundation. All rights reserved.

Figures

Figure 1.. The role of exercise intolerance in HFpEF.

Exercise intolerance is a cardinal manifestation of HFpEF. Whether ambulatory patients with exercise intolerance progress to the phenotype of rest congestion with frequent need for hospitalization requires further investigation, but exercise intolerance in itself is a highly morbid condition in HFpEF.

Figure 2.. Clinical vignette summary.

A. Clinical data summary. Abbreviations: ECG, electrocardiogram; LV, left ventricular; RV, right ventricular; LA, left atrium; TR, tricuspid regurgitation; FEV1, forced expiratory volume in 1 second; FVC, forced vital capacity; TLC, total lung capacity; DLCO, diffusing capacity for carbon monoxide; RA, right atrium; PA, pulmonary artery; PCW, pulmonary capillary wedge; CO, cardiac output; CI, cardiac index; PVR, pulmonary vascular resistance B. Relationship of pulmonary capillary wedge pressure and mean pulmonary artery pressure to cardiac output with exercise. C. Key physiologic measures obtained by invasive cardiopulmonary exercise test.

Figure 3.. Pathophysiologic contributors to exercise intolerance in HFpEF.

The various physiologic contributors to exertional intolerance are summarized and organized based on their impact on cardiac versus extra-cardiac reserve capacity impairments. Abbreviations: LA, left atrial; Sys, systemic; PV, pulmonary vascular; O2, oxygen

Figure 4.. Role of diagnostic testing modalities to understand exercise intolerance in HFpEF.

Exercise tests that may be utilized in the evaluation of HFpEF are shown and key variables derived from each test are listed. Abbreviations: ECG, electrocardiogram; PA, pulmonary artery; WMA, wall motion abnormality; RAP, right atrial pressure; VD/VT, physiologic dead space; PaCO2, partial pressure of CO2 in arterial blood

Figure 5.. Methods to integrate physiologic contributors to exercise intolerance from the Clinical Vignette.

A. Guide to interpretation of invasive CPET with case vignette annotations. Relevant values for the patient in the representative Clinical Vignette are provided in blue. Abbreviations: RER, respiratory exchange ratio; VE, minute ventilation; MVV, maximum ventilatory ventilation; SaO2, arterial oxygen saturation; O2, oxygen; HTN, hypertension; RA, right atrial; RVEF, right ventricular ejection fraction; TPG, transpulmonary gradient; B. Personalized O2 pathways assessment. I. The percent predicted value achieved by the patient in the clinical vignette for each of the 6 components of the O2 pathway are displayed II. The y-axis represents the VO2 deficit recovered. This can be calculated as the expected improvement in a patient’s normalized peak VO2 that would result from correcting the deficit, while the other O2 pathway parameters remain fixed(17).

Figure 5.. Methods to integrate physiologic contributors to exercise intolerance from the Clinical Vignette.

A. Guide to interpretation of invasive CPET with case vignette annotations. Relevant values for the patient in the representative Clinical Vignette are provided in blue. Abbreviations: RER, respiratory exchange ratio; VE, minute ventilation; MVV, maximum ventilatory ventilation; SaO2, arterial oxygen saturation; O2, oxygen; HTN, hypertension; RA, right atrial; RVEF, right ventricular ejection fraction; TPG, transpulmonary gradient; B. Personalized O2 pathways assessment. I. The percent predicted value achieved by the patient in the clinical vignette for each of the 6 components of the O2 pathway are displayed II. The y-axis represents the VO2 deficit recovered. This can be calculated as the expected improvement in a patient’s normalized peak VO2 that would result from correcting the deficit, while the other O2 pathway parameters remain fixed(17).

Central Illustration.. Peak VO2 required for activities of daily living relative to average peak VO2 observed in HFpEF.

he mean peak VO2 observed in HFpEF patients was calculated as the average among 13 studies reporting upright exercise testing with an N ≥20 (2,5,9,21,51,62)(online ref. 1–7). Estimated METs required for each activity was provided by Haskell et al (online ref. 8). Numbers provided are the percentage of the average peak VO2 observed in HFpEF patients (14.9 ml/kg/min) required to complete each task. Anaerobic (lactate) threshold is represented as the characteristic proportion of peak VO2 at which it occurs.