Aging and Heart Rate in Heart Failure: Clinical Implications for Long-term Mortality Josep Lupón, MD, PhD; Mar Domingo, MD, PhD; Marta de Antonio, MD, PhD; Elisabet Zamora, MD, PhD; Javier Santesmases, MD; Crisanto Díez-Quevedo, MD, PhD; Salvador Altimir, MD; Maribel Troya, MD; Paloma Gastelurrutia, PhD; and Antoni Bayes-Genis, MD, PhD Abstract Objective: To assess the relationship between resting heart rate and long-term all-cause mortality in ambulatory patients with heart failure (HF) relative to age, considering that although heart rate has been strongly associated with mortality in HF, the influence of age on target heart rate is incompletely characterized. Patients and Methods: Consecutive patients in sinus rhythm referred to an ambulatory HF clinic of a university hospital between August 1, 2001, and March 31, 2012, were included. Unadjusted and adjusted Cox regression analyses were performed to assess heart rate as a prognostic marker, both as a continuous variable and after categorization into quintiles. Smooth spline estimates and hazard ratios (HRs) were plotted for 2 age strata (<75 years vs 75 years) for each individual heart rate. Results: A total of 1033 patients were included (766 men [74.2%]; mean age, 65.112.6 years). During a mean follow-up of 4.63.3 years (median, 3.8 years [25th-75th percentile, 1.9-6.9]), 476 patients (46.1%) died. Mortality was associated with a statistically greater heart rate in the total cohort (HR, 1.18; 95% CI, 1.11-1.26; P<.001). From a clinical viewpoint, this means an 18% increased risk for every 10-beats/min elevation in heart rate. The same characteristics were present in the relationship between heart rate assessed after 6 months and long-term mortality (HR, 1.30; 95% CI, 1.20-1.42; P<.001). Overall, the prognostic importance of heart rate in ambulatory patients with HF was largely influenced by patient age. Remarkably, in the elderly population (75 years), heart rate below 68 beats/min conferred an increased risk of death, whereas in younger patients, mortality exhibited a declining slope at even the lowest heart rates. Conclusion: Our research, if applicable to the prospective management of patients with ambula- tory HF, suggests that patients aged 75 years or older have the best outcomes with target heart rates of 68 beats/min; however, younger patients may benefit from lower heart rates, even below 55 beats/min. ª 2015 Mayo Foundation for Medical Education and Research n Mayo Clin Proc. 2015;90(6):765-772 E levated resting heart rate is associated with the occurrence of cardiovascular complications and poor outcomes in different diseases, including heart failure (HF). 1 The current target of HF treatment is to reduce heart rate, 2,3 and the benefits of b-adrenergice blocking drugs are thought to be due to such a reduction. 4 Data derived from clinical trials on b-blockers 5,6 suggest that the most determinant b-blocker effect is derived from the reduction in the heart rate rather than the drug dose. Alter- native treatments with the goal of reducing heart rate, as with the b-adrenergiceindependent angina pectoris treatment ivabradine, also improve the prognosis of patients with HF 7 and reaffirm this concept. 8 However, the influence of age on target heart rate is unknown because most of the studies that have assessed the influ- ence of heart rate on HF prognosis have not included large numbers of elderly patients. 7,9 The same benefits of heart rate reduction are assumed to occur across all age strata, but this aspect has not been well studied. Our aim was to assess the relationship be- tween resting heart rate in ambulatory patients with HF in sinus rhythm (SR) and long-term From the Heart Failure Unit, Hospital Universitari Ger- mans Trias i Pujol, Badalona, Barcelona, Spain (J.L., M.D., M.A., E.Z., J.S., C.D.-Q., S.A., M.T., A.B.-G.); Department of Medicine (J.L., E.Z., A.B.-G.) and Department of Psychi- atry (C.D.-Q.), Universitat Autònoma de Barcelona, Barcelona, Spain; and Ger- mans Trias i Pujol Health Sciences Research Institute, Badalona, Barcelona, Spain (P.G.). ORIGINAL ARTICLE Mayo Clin Proc. n June 2015;90(6):765-772 n http://dx.doi.org/10.1016/j.mayocp.2015.02.019 www.mayoclinicproceedings.org n ª 2015 Mayo Foundation for Medical Education and Research 765