Chronotropic response in heart failure: clinical, structural, and metabolic predictors and long-term mortality

Aims The aim of the project was to better define chronotropic incompetence (CI) and evaluate its clinical determinants and relation to clinical outcomes in heart failure (HF). Methods Data from the MyoVasc study (NCT04064450) were analysed. Subjects underwent deep clinical phenotyping, including cardiopulmonary exercise testing (CPET). Individuals with a respiratory exchange ratio < 1.0 were excluded. Continuous predicted heart rate reserve (pHRR) operationalized CI. A reference range for CI was derived from a healthy subsample not taking β-blockers. Determinants of CI were assessed with a bidirectional stepwise approach and clinical outcomes by Cox regressions. Results The analysis sample included 880 subjects [median age 63 years (interquartile range 55; 72); 30.0% women]. Symptomatic HF was present in 42.8% (377) of subjects and 64.7% (n = 569) were considered chronotropic incompetent based on the traditional 80% threshold. According to the new reference range, CI was defined as a pHRR < 56.4%. Peak oxygen uptake (VO2), β-blockers, age, sex, smoking, CPET protocol, HF severity, C-peptide, and a fatty liver were among the CI determinants. No phenotype-specific pattern of CI determinants was observed. In Cox regression analysis, CI independently predicted all-cause death [hazard ratio (HR) per standard deviation (SD) decrease in pHRR (HRSD) 1.77 (1.42; 2.21); P < .0001], cardiac death [HRSD 1.74 (1.08; 2.80); P = .023], and worsening of HF (HRSD 1.39 [1.01; 1.91], P = .046). Conclusion Chronotropic incompetence was a strong predictor of clinical outcomes. Its associations with hyperinsulinemia and abnormal liver function underlined the connection between metabolism and CI. This highlights the relevance of impaired response to exercise in the clinical course of HF with implication for risk stratification.