Rate-Adaptive Atrial Pacing for Heart Failure With Preserved Ejection Fraction

Abstract

ImportanceReduced heart rate during exercise is common and associated with impaired aerobic capacity in heart failure with preserved ejection fraction (HFpEF), but it remains unknown if restoring exertional heart rate through atrial pacing would be beneficial.ObjectiveTo determine if implanting and programming a pacemaker for rate-adaptive atrial pacing would improve exercise performance in patients with HFpEF and chronotropic incompetence.Design, Setting, and ParticipantsSingle-center, double-blind, randomized, crossover trial testing the effects of rate-adaptive atrial pacing in patients with symptomatic HFpEF and chronotropic incompetence at a tertiary referral center (Mayo Clinic) in Rochester, Minnesota. Patients were recruited between 2014 and 2022 with 16-week follow-up (last date of follow-up, May 9, 2022). Cardiac output during exercise was measured by the acetylene rebreathe technique.InterventionsA total of 32 patients were recruited; of these, 29 underwent pacemaker implantation and were randomized to atrial rate responsive pacing or no pacing first for 4 weeks, followed by a 4-week washout period and then crossover for an additional 4 weeks.Main Outcomes and MeasuresThe primary end point was oxygen consumption (V̇o2) at anaerobic threshold (V̇o2,AT); secondary end points were peak V̇o2, ventilatory efficiency (V̇e/V̇co2 slope), patient-reported health status by the Kansas City Cardiomyopathy Questionnaire Overall Summary Score (KCCQ-OSS), and N-terminal pro-brain natriuretic peptide (NT-proBNP) levels.ResultsOf the 29 patients randomized, the mean age was 66 years (SD, 9.7) and 13 (45%) were women. In the absence of pacing, peak V̇o2 and V̇o2 at anaerobic threshold (V̇o2,AT) were both correlated with peak exercise heart rate (r = 0.46-0.51, P < .02 for both). Pacing increased heart rate during low-level and peak exercise (16/min [95% CI, 10 to 23], P < .001; 14/min [95% CI, 7 to 21], P < .001), but there was no significant change in V̇o2,AT (pacing off, 10.4 [SD, 2.9] mL/kg/min; pacing on, 10.7 [SD, 2.6] mL/kg/min; absolute difference, 0.3 [95% CI, −0.5 to 1.0] mL/kg/min; P = .46), peak V̇o2, minute ventilation (V̇e)/carbon dioxide production (V̇co2) slope, KCCQ-OSS, or NT-proBNP level. Despite the increase in heart rate, atrial pacing had no significant effect on cardiac output with exercise, owing to a decrease in stroke volume (−24 mL [95% CI, −43 to −5 mL]; P = .02). Adverse events judged to be related to the pacemaker device were observed in 6 of 29 participants (21%).Conclusions and RelevanceIn patients with HFpEF and chronotropic incompetence, implantation of a pacemaker to enhance exercise heart rate did not result in an improvement in exercise capacity and was associated with increased adverse events.Trial RegistrationClinicalTrials.gov Identifier: NCT02145351

Rate-Adaptive Pacing for Heart Failure With Preserved Ejection Fraction

“…Borlaug et al found that although pacing predictably increased exercise heart rate, there was no improvement in exercise capacity or any other outcome. A likely cause was that the increase in exercise heart rate was counterbalanced by a reduction in exercise stroke volume, such that exercise cardiac output was unchanged.…”

“…In this issue of JAMA , Borlaug and colleagues report the results of a important clinical trial, which are likely to alter paradigms and clinical guidelines for heart failure with preserved ejection fraction (HFpEF) . The prevalence of this syndrome has progressively increased, and HFpEF has become the most common form of heart failure, particularly in older persons, women, and Black individuals .…”

“…Cardiac output is the product of heart rate and left ventricular stroke volume. The current trial by Borlaug et al is predicated on the observation that patients with HFpEF often have significantly reduced heart rate responses to exercise (chronotropic incompetence), and this is correlated with their reduced peak V̇ o 2 . They tested the hypothesis that rate-adaptive atrial pacing would increase heart rate during exercise, thereby increasing exercise cardiac output and improving peak V̇ o 2 …”

“…The well-designed, well-conducted, randomized clinical trial by Borlaug et al is a monumental achievement. HFpEF trials are notoriously challenging, particularly those using invasive procedures and implanted devices, both of which were used in the present trial.…”

“…This finding is credible, since in healthy persons and patients with cardiovascular disease, including HFpEF, heart rate and stroke volume are inversely tightly related at rest, and pacing-induced heart rate increases result in inexorable, progressive declines in end-diastolic volume and stroke volume, resulting in unchanged cardiac output . In the present trial, it was hoped that the adaptations invoked during exercise (such as autonomic withdrawal, β-adrenergic drive, and increased venous return) would overcome the dynamic, inverse relationship between heart rate and stroke volume, but such was not the case . A pacing study during exercise in healthy persons found similar results .…”