ß-Blockers and ivabradine differentially affect cardiopulmonary function and left ventricular filling index.

OBJECTIVE: Patients with left ventricular (LV) diastolic dysfunction are characterized by exertional dyspnoea. Heart rate (HR) reduction by ß-blockers can improve exercise tolerance by prolonging LV filling, but their negative inotropic and lusitropic properties can be detrimental in this disease. We tested the effects of administering ivabradine, a HR-lowering drug without impact on cardiac kinetics that may favorably affect diastolic function. METHODS: Twenty-four patients with coronary artery disease (CAD) and normal LV ejection fraction on chronic ß-blocker therapy were included. NT-proBNP serum levels were determined prior to and after cardiopulmonary exercise. ß-Blockers were then replaced by ivabradine and patients were re-tested after 6 weeks. Patients were initially classified as having a low (E/e' ≤ 8; n = 11) or high (E/e' > 8; n = 13) LV filling index. RESULTS: E/e' significantly decreased during ivabradine therapy in patients with high E/e' (10.7 ± 2.9 vs. 8.9 ± 1.7; p < 0.01), whereas no difference occurred in patients with low E/e' (6.4 ± 0.7 vs. 6.5 ± 1.1; p = ns). With ivabradine, patients with high E/e' had an increased oxygen uptake at the anaerobic threshold (from 10.8 ± 1.4 to 11.8 ± 1.9 ml/min/kg; p < 0.05) and a steeper slope of the initial oxygen pulse curve (from 293 ± 109 to 359 ± 117 µl/beat/kg/W; p < 0.05). Moreover, patients with high E/e' had lower NT-proBNP serum levels at rest (169 ± 207 vs. 126 ± 146 pg/ml; p < 0.05) and after exercise (190 ± 256 vs. 136 ± 162 pg/ml; p < 0.05) during ivabradine therapy. CONCLUSIONS: In patients with CAD and elevated E/e', switching therapy from ß-blockers to ivabradine may cause a reduction in LV filling pressures and an improved stroke volume response to exercise.

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

BACKGROUND: Prior studies suggest that ß-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 ß-blockade. The aim of this study was to unmask heart rate-independent effects of ß-blockade on pulse wave reflections by switching therapy from ß-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 ß-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 ß-blockade both at rest and during early recovery after exercise. ß-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 ß-blocker or ivabradine therapy, respectively. The rAI remained unchanged after switching therapy from ß-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 ß-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, ß-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.