The Relationship Between Chronotropic Incompetence and Exercise Response in Patients with Chronic Heart Failure with Reduced Ejection Fraction



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Purpose: The purpose of this study was to (1) characterize the relationship between chronotropic incompetence (CI) and exercise capacity in patients with heart failure (HF) with reduced ejection fraction (HFrEF), and to (2) determine if patients with HFrEF and CI have an attenuated adaptation to exercise training compared to HFrEF patients without CI. Methods: This study was a secondary analysis of de-identified, participant-level data from the multicenter, randomized, controlled HF-ACTION clinical trial. Participants with chronic HFrEF (left ventricular ejection fraction ≤35%) on guideline-directed medical therapy (GDMT) that included a beta-adrenergic blocking agent with New York Heart Association (NYHA) class II to IV heart failure symptoms were included. Baseline analyses included all HF-ACTION participants meeting the eligibility criteria for this secondary analysis. Analyses of 3-month exercise training adaptation included participants randomized to the exercise training arm of the HF-ACTION trial. CI was classified as a failure to achieve at least 80% of heart rate reserve (HRR) on the baseline cardiopulmonary exercise test (CPET), and participants were grouped according to presence or absence of CI at baseline. Pearson correlation and linear regression were used to determine the strength and direction of association of HRR and exercise capacity at baseline. Between CI group differences in baseline characteristics were determined using independent t-tests. Difference in exercise training adaptation after 3-months of exercise training between CI groups was determined using an independent t-test. Pearson correlation and linear regression were used to determine the strength and direction of association of baseline HRR and change in exercise capacity. Potential confounders were added to the linear regression model to determine any substantial effect. The potential confounding effect of adherence to the exercise training intervention on change in VO2peak was examined using correlations and independent t-tests to compare the mean change in VO2peak between adherence quartiles. Results: 982 of 1,116 participants (88.0%) had CI at baseline. Lower HRpeak (118 ± 18 bpm versus 155 ± 13 bpm, p<0.001), VO2peak (14.9 ± 4.5 mL/kg/min versus 18.9 ± 5.3 mL/kg/min, p<0.001), and HRR (51 ± 16 percent versus 92 ± 10 percent, p<0.001) were observed in participants with CI compared to those without CI. Conversely, participants with baseline CI had a higher O2 pulse (11.8 ± 4.0 mL/beat versus 10.9 ± 3.8 mL/beat, p=0.015). HRR was positively correlated with VO2peak at baseline (r=0.442; p<0.001). Exercise training-induced increases in VO2peak were 0.83 ± 2.35 mL/kg/min and 1.32 ± 2.48 mL/kg/min for the CI and no CI groups, respectively (p=0.174). There was a statistically larger increase in O2 pulse (p=0.012) in the no CI group compared to the group with CI (1.13 ± 1.30 mL/beat versus 0.50 ± 1.66 mL/beat, respectively). HRpeak increased in participants with CI (1.4 ± 13.6 bpm; p=0.045) and decreased in participants without CI (-7.4 ± 15.4 bpm; p=0.001). Conclusion: CI burden was high in the HFrEF subset. Overall, CI was associated with lower VO2peak and poorer CPET outcomes at baseline. Exercise training appears to be an effective therapeutic strategy to improve exercise capacity in HFrEF patients.