Chronotropic Incompetence Is a Contributor to Cardiovascular Functional Impairment in Patients with Heart Failure with Preserved Ejection Fraction and CKD

Background: Chronotropic incompetence (CI) is a hallmark of heart failure with preserved ejection fraction (HFpEF), the predominant HF phenotype in chronic kidney disease (CKD). CI has been linked with impaired cardiovascular functional capacity (CVC) in the general population, however CI in CKD remains largely unstudied. Herein, we investigated the role of CI with moderate-to-severe decrements in kidney function and its link with VO2Peak (gold-standard index of CVC) in HFpEF patients from the RELAX trial. Methods: We conducted a cross-sectional analysis of baseline data from 213 participants in the RELAX trial: a double-blind, randomized trial comparing sildenafil vs placebo in patients with HFpEF (NYHA class II–III). All participants underwent cardiopulmonary exercise testing (CPET). We stratified the cohort into tertiles by peak heart rate (HRPeak): >119bpm, 97-118bpm and <96bpm. Group differences were assessed by ANOVA , Kruskal-Wallis, or chi-square tests. Inferential analysis was conducted using Pearson’s correlation analysis and multiple linear regression. Results: Groups were well-matched by gender and BMI (all P’s>0.05). Patients with lower HRPeak (<96bpm) were older and had more comorbidities, including hypertension, dyslipidemia, pacemaker use, and higher beta-blocker use (all P’s<0.05). CKD was most prevalent in this group (62.3%), with lower eGFR than higher HRPeak tertiles (>119 bpm: 64.0 [50.3, 82.0] mL/min/1.73m2 vs 97-118 bpm: 57.4 [43.2, 76.2] mL/min/1.73m2 and 60–96 bpm: 48.3 [37.6; 62.0] mL/min/1.73m2, P<0.001). Significantly, VO2Peak was impaired in the lowest HRPeak tertile (10.5±2.3 mL/min/kg, P<0.001) versus the highest tertile (13.7±3.1 mL/min/kg). Maximal workload and endurance time were also significantly reduced in the lower tertiles (all P<0.001). HRPeak showed positive correlations with eGFR (r=0.27) and VO2Peak (r=0.41; both P<0.001), and remained independently associated with VO2Peak after adjusting for age, sex, eGFR, beta-blocker use, diabetes, and ejection fraction. Conclusion: CI commonly affects HFpEF patients with CKD and is associated with impaired in VO2Peak. Funding: Private Foundation Support