Ivabradine for Heart Rate Reduction During Exercise in Healthy Adults

Overview

During exercise, working muscles require more oxygen. The heart meets this demand in two ways: by beating faster (heart rate) and by pumping more blood with each beat (stroke volume). Heart rate increases steadily with exercise intensity until exhaustion, but the amount of blood pumped with each beat tends to plateau at moderate intensities. Why the amount of blood pumped with each beat becomes limited before heart rate, however, is not well understood. Studying these mechanisms is difficult because most drugs that lower heart rate also affect how strongly the heart pumps, making it hard to separate the two effects. One medication that can help with this is ivabradine, which is used to treat people with heart disease who have high resting heart rates. It slows the heart rate without changing how strongly the heart pumps. This study will investigate whether ivabradine lowers heart rate during exercise in healthy younger and older adults, and whether a higher dose lowers heart rate more. The results will help us better understand how heart rate influences the heart's ability to supply oxygen to the body during exercise, and what limits the ability to exercise as people age. Participants will: * Attend three visits at SportsCardiologyBC in Vancouver * Complete a cycling exercise test at each visit to measure heart rate and how hard they can exercise * Take ivabradine (a heart-rate-lowering medication) before the exercise test at Visits 2 and 3 (a lower dose at Visit 2 and a higher dose at Visit 3) * Be monitored for side effects including slow heart rate, visual symptoms, and headache.

Heart rate and stroke volume are generally considered as two independent factors which influence cardiac output, yet they are interlinked by cellular (e.g., calcium handling) and hemodynamic (e.g., diastolic pressure decay) mechanisms. Delineating how heart rate and stroke volume influence cardiac output and exercise capacity, even within healthy individuals, has historically been experimentally difficult as pharmacologic perturbations, such as beta-adrenergic antagonists, influence both heart rate and heart muscle performance. Ivabradine selectively reduces heart rate in a dose-dependent manner, without impacting myocardial contractility, cardiac afterload, or venous return. However, it has largely been studied in clinical outcome trials in adults with heart failure, or safety studies in younger healthy adults. As such, there is a knowledge gap on how ivabradine influences heart rate and exercise capacity in healthy younger and older adults. Study Purpose To characterize the effects of two single doses of ivabradine (7.5 mg and 12.5 mg) on heart rate during incremental exercise in younger and older healthy adults. Exploratory Aim To assess the safety and tolerability of two single doses of ivabradine (7.5 mg and 12.5 mg) in younger and older healthy adults. Hypothesis Ivabradine will produce dose-dependent reductions in peak exercise heart rate and heart rate/work-rate relationships (anticipated to be approximately 10-15%, on average). Research Design Unblinded, non-randomized, repeated measures design. Study Visits Visit 1 (1.5 hours): Screening, consent, assessments of anthropometrics, seated heart rate and blood pressure, a resting 12-lead electrocardiogram, and a cardiopulmonary exercise test with 12-lead electrocardiogram. Pre-menopausal females will also be required to complete a urine pregnancy test and confirm a negative result prior to participation. Visits 2 and 3 (4 hours each): A single oral dose of ivabradine will be administered at each visit: 7.5 mg at Visit 2 and 12.5 mg at Visit 3. Doses are administered in this fixed order so that all participants are observed at the lower dose before proceeding to the higher dose. Following drug administration, participants will be seated and observed for 90 minutes with continuous heart rate monitoring and blood pressure recorded at 15-minute intervals. Participants will then complete an incremental exercise test on a cycle ergometer with 12-lead ECG monitoring, following the same work-rate protocol used in Visit 1. Following exercise, participants will be seated and observed for 120 minutes with continuous heart rate monitoring and blood pressure recorded at 15-minute intervals. Statistical Analysis Data will be analyzed using SPSS Statistics (v.30, IBM Inc). Normality will be assessed by the Shapiro-Wilk test. Omnibus testing will be conducted using analysis of variance (ANOVA), the Friedman test, or the Kruskal-Wallis test with significant effects tested post hoc. If all compared groups or conditions approximate a normal distribution, data will be presented as mean ± standard deviation with paired comparisons made using t-tests. Otherwise, data will be presented as median (inter-quartile range) with paired comparisons made using the Mann-Whitney U or Wilcoxon Signed Rank tests. Associations will be explored with Pearson correlations and linear regression. Sample Size Justification Based on existing literature describing the effect of ivabradine on heart rate during exercise in healthy adults, a sample size of 20 provides 95% power to detect a 5 beats per minute difference between 7.5 mg and 12.5 mg trials, assuming a standard deviation of 5 beats per minute and a two-tailed alpha of 0.05 adjusted for three post-hoc paired t-tests.