Ivabradine therapy to unmask heart rate-independent effects of β-blockers on pulse wave reflections

Background Prior studies suggest that beta-blockers lead to increased pulse wave reflections, thereby negating the blood pressure lowering effects on cardiovascular mortality. Parts of these effects may be induced by the heart rate reduction under beta-blockade. The aim of this study was to unmask heart rate-independent effects of beta-blockade on pulse wave reflections by switching therapy from beta-blockers to ivabradine, an I-f channel inhibitor without impact on systemic hemodynamics. Methods 14 male patients (age 61 +/- 3 years, LVEF 62 +/- 1 %) with arterial hypertension and coronary artery disease (CAD) under chronic beta-blocker therapy at moderate dosage and additional renin-angiotensin system-blocking therapy were included. We determined radial augmentation index (rAI) by radial applanation tonometry in patients under beta-blockade both at rest and during early recovery after exercise. beta-Blockers were then replaced by ivabradine. Six weeks later, patients were re-tested at rest and after exercise under ivabradine therapy. Results Mean heart rate (68 +/- 3 vs. 63 +/- 3 bpm; p = ns) and resting mean arterial pressure (98 +/- 2 vs. 98 +/- 2 mmHg; p = ns) were not different between beta-blocker or ivabradine therapy, respectively. The rAI remained unchanged after switching therapy from beta-blocker to ivabradine (86 +/- 2 vs. 84 +/- 4 %; p = ns). Post exercise, the rAI revealed an identical decrease in both groups (-7.2 +/- 2.4 vs. -5.4 +/- 2.5 %, p = ns). The increase in heart rate between resting conditions and early recovery post exercise was inversely correlated with the decrease of rAI under beta-blockade (r = -0.70; p < 0.01) and showed a trend towards correlation under ivabradine (r = -0.52; p = 0.07). Conclusion In men at the age of 60 years and CAD, beta-blockade does not exert heart rate-independent, pleiotropic effects on peripheral pulse wave reflections, both at rest or after exercise. Our results fit well within recent studies, demonstrating the fundamental influence of heart rate on rAI.