Background: Heart rate recovery (HRR) is cardiac measure of autonomic dysfunction (AD). A Decreased HRR has been reported to be associated with all-cause mortality in heart failure (HF) patients. However, the predictive value of HRR for HF-specific clinical outcome is not yet understood.
Methods: Data of the MyoVasc study (N=3,289), a prospective cohort study on chronic HF (NCT04064450), were analyzed. Participants underwent a 5 hour highly standardized examination at a dedicated study center including cardiopulmonary exercise testing (CPET). CPET was performed on a bicycle ergometer according to an adjusted WHO protocol. HF was classified according to the Universal Definition of HF. Medication affecting HRR60 and clinical determinants of HRR60 were identified in regression analyses and subsequently considered as covariates in outcome analyses. To analyze HF-specific outcome, worsening of HF defined as a composite of cardiac death, HF hospitalization and ambulatory worsening requiring medical therapy, was analyzed as primary study endpoint. Information on clinical outcome was derived from structured follow-up with subsequent validation via source data and independent adjudication of clinical endpoints.
Results: The analysis sample comprised N=1,288 individuals with available information on HRR60 (mean age: 65.0±10.4 years, female sex: 28.2%) ranging from HF stage B to D. In univariate analysis, worse HRR60 was associated with higher levels of NT-proBNP (P for trend <0.0001). In multivariable regression analysis, the following clinical determinants associated with HRR60 were identified: age (β-estimate -0.17 (95% confidence interval (CI) -0.22; -0.12), P<0.0001), female sex (β-estimate: -0.17 (95%CI -0.28; -0.06), P=0.003), diabetes mellitus (β-estimate: -0.16 (95%CI -0.28; -0.03), P<0.012), smoking (β-estimate: -0.30 (95%CI -0.41; -0.18) P<0.0001), obesity (β-estimate: -0.23 (95%CI -0.33, -0.12), P<0.0001), history of stroke (β-estimate: -0.21 (95%CI -0.38; -0.04), P=0.014), peripheral artery disease (β-estimate -0.34 (95%CI -0.54; -0.14), P=0.00081), and chronic kidney disease (β-estimate: -0.28 (95% CI: -0.42; -0.14), P<0.0001). In Cox regression analyses HRR60 was identified as an independent predictor of clinical outcome as reflected by all-cause death (HRlog(HRR60)[per -1SD]: 1.53 (95%CI 1.27; 1.86), P<0.0001) and worsening of HF (HRlog(HRR60)[per -1SD] 1.20 (95%CI 1.05; 1.47), P=0.012) independent of age, sex, clinical determinants and medication. Further analysis revealed that HRR60 was a robust predictor of outcome after adjustment for age, sex and NT-proBNP. Sensitivity analysis demonstrated that HRR60 was predictive for worsening of HF for both individuals with preserved ejection fraction (HFpEF) (HRlog(HRR60)[per -1SD] 1.66 (95%CI 1.29; 2.15), P=0.0001) (HF stage C/D, LVEF≥50%) and reduced ejection fraction (HFrEF) (HRlog(HRR60)[per -1SD]1.22 (95%CI 1.05; 1.42); P=0.01) (HF stage C/D, LVEF<50%) as well as for all-cause mortality (HFrEF: HRlog(HRR60)[per -1SD]1.51 (95%CI 1.18; 1.93), P=0.001; HFpEF: HRlog(HRR60)[per -1SD] 2.04 (95%CI 1.51; 2.77), P<0.0001).
Conclusion: In the present study, HRR60 was identified as a strong predictor of clinical outcome in individuals with HF, irrespective of the HF phenotype and independent of a large set of confounders including NT-proBNP. This underlines the relevance of HRR as a proxy for AD for the clinical course of HF with potential implications for risk stratification and intervention.