Chronotropic incompetence as a critical predictor for cardiovascular outcomes in heart failure with preserved ejection function

Abstract Background Chronotropic incompetence (CI), linked with exercise intolerance, is a prevalent feature of heart failure with preserved ejection fraction (HFpEF). Our study aimed to explore the impact of CI on cardiovascular outcomes in HFpEF patients. Methods From November 2019 to December 2022, we enrolled 359 subjects who underwent invasive cardiopulmonary exercise testing (iCPET) due to heart failure symptoms. After excluding individuals without HFpEF (those with resting pulmonary capillary wedge pressure [PCWP] < 15mmHg or exercise PCWP < 25mmHg), we identified 113 patients for long-term follow-up. Our assessment of cardiovascular outcomes encompassed hospitalization for heart failure (HHF) and cardiovascular death. We employed Cox regression analysis to evaluate the associations between exercise hemodynamic parameters and outcomes. Results Among the cohort, 85 (75.2%) subjects with CI were older (71 vs. 66 years) and more frequently women (61 vs. 28%) compared to those without CI. At peak exercise, patients with CI exhibited significantly reduced left atrial booster strain, impaired right ventricle-arterial coupling, decreased systemic vascular resistance, cardiac output (CO), stroke volume, VO2, respiratory exchange ratio, and minute ventilation/carbon dioxide production (VE/VCO2) slope. A significant increase in PCWP (36 ± 10 vs. 26 ± 11mmHg, p=0.012) was noted in patients with CI. Over a median follow-up of 22.6 months, 20 (17.7%) subjects experienced cardiovascular events. Multivariate Cox proportional analyses revealed that CI (Hazard ratio [HR] 1.725, 95% confidence intervals [CI] 1.212-2.413) and an elevated PCWP/CO slope (HR 1.829, 95% CI 1.331-2.382) were predictive of outcomes. Conclusions Patients with CI demonstrated heightened filling pressure, a steeper VE-VCO2 slope, and reduced VO2 compared to those without CI. These factors likely contribute to adverse cardiovascular outcomes in HFpEF patients with CI.