Chronotropic incompetence, beta-blockers, and functional capacity in advanced congestive heart failure: Time to pace?

Background: Chronotropic incompetence (CI) is often seen in subjects with chronic congestive heart failure (CHF). The prevalence of CI, its mechanisms and association with beta-blocker use as well as exercise capacity have not been clearly defined. Methods and results: Cardiopulmonary exercise tolerance testing data for 278 consecutive patients with systolic CHF was analyzed. CI, defined as the inability to reach 80% of maximally predicted heart rate was present in 128 of 278 subjects (46%). The prevalence of CI was highest in those with most impaired exercise capacity (72, 48, and 24% for subjects with a VO₂ of < 14.0, 14.0-20.0, and > 20.0 ml/kg/min respectively; p = 0.001). While subjects with CI had lower peak exercise heart rate (114 vs. 152 bpm), and lower peak VO₂ (15.4 vs. 19.9 ml/kg/min), they were equally likely to be on chronic beta-blocker therapy (74% vs. 71%; p = 0.51). Heart rate and norepinephrine (NE) levels were measured during exercise in a separate cohort of 24 subjects with CHF. There was no difference in beta-blocker dose between subjects with and without CI, however, exercise induced NE release and Chronotropic Responsiveness Index, a measure of post-synaptic beta-receptor sensitivity to NE, were lower in subjects with CI (1687 ± 911 vs. 2593 ± 1451 pg/ml p = 0.08; CRI 12.7 ± 5.7 vs. 22.1 ± 4.7, p = 0.002). Conclusions: CI occurs in > 70% of subjects with advanced systolic CHF irrespective of beta-blocker use and is associated with a trend toward impaired NE release, post-synaptic beta-receptor desensitization and reduced exercise capacity.