Impact of atrial fibrillation on exercise capacity in heart failure with preserved ejection fraction: a RELAX trial ancillary study

Abstract

Background: Atrial fibrillation (AF) is common among patients with heart failure and preserved ejection fraction (HFpEF), but its clinical profile and impact on exercise capacity remain unclear. RELAX (Phosphodiesterase-5 Inhibition to Improve Clinical Status and Exercise Capacity in HFpEF) was a multicenter randomized trial testing the impact of sildenafil on peak VO2 in stable outpatients with chronic HFpEF. We sought to compare clinical features and exercise capacity among patients with HFpEF who were in sinus rhythm (SR) or AF.

Methods and results: RELAX enrolled 216 patients with HFpEF, of whom 79 (37%) were in AF, 124 (57%) in SR, and 13 in other rhythms. Participants underwent baseline cardiopulmonary exercise testing, echocardiogram, biomarker assessment, and rhythm status assessment before randomization. Patients with AF were older than those in SR but had similar symptom severity, comorbidities, and renal function. β-blocker use and chronotropic indices were also similar. Despite comparable left ventricular size and mass, AF was associated with worse systolic (lower EF, stroke volume, and cardiac index) and diastolic (shorter deceleration time and larger left atria) function compared with SR. Pulmonary artery systolic pressure was higher in AF. Patients with AF had higher N-terminal pro-B-type natriuretic peptide, aldosterone, endothelin-1, troponin I, and C-telopeptide for type I collagen levels, suggesting more severe neurohumoral activation, myocyte necrosis, and fibrosis. Peak VO2 was lower in AF, even after adjustment for age, sex, and chronotropic response, and VE/VCO2 was higher.

Conclusions: AF identifies an HFpEF cohort with more advanced disease and significantly reduced exercise capacity. These data suggest that evaluation of the impact of different rate or rhythm control strategies on exercise tolerance in patients with HFpEF and AF is warranted.

Clinical trial registration: URL: http://www.clinicaltrials.gov. Unique identifier: NCT00763867.

Keywords: atrial fibrillation; exercise; heart failure.

Figure 1. Biomarkers of neurohumoral activity in HFpEF patients in atrial fibrillation and sinus rhythm

(a) Plasma NT-proBNP, (b) aldosterone, (c) endothelin-1, (d) troponin I, (e) uric acid, (f) c-reactive protein. White bars (atrial fibrillation), black bars (sinus rhythm). Median (75^th percentile) shown.

Figure 2. Chronotropic response to exercise in HFpEF patients in atrial fibrillation and sinus rhythm

(a) Heart rates at rest and at peak exercise, (b) prevalence of chronotropic incompetence during exercise (calculated using standard [Astrand] or Brawner formulae; p-values AF vs. SR), (c) relationship between chronotropic index (Brawner formula) and peak VO₂, (d) relationship between chronotropic index and peak workload. Results for unadjusted linear regression shown for patients in atrial fibrillation (red line) and sinus rhythm (black line). p-values (c) and (d) refer to interaction terms between rhythm status and chronotropic index.