Effects of heart rate reduction with ivabradine on vascular stiffness and endothelial function in chronic stable coronary artery disease

Introduction: Epidemiological and clinical studies have shown a relevant association between heart rate and cardiovascular mortality. Experimental studies identified vascular effects of heart rate reduction with the If channel inhibitor ivabradine. Therefore, the effects of heart rate reduction on endothelial function and indices of arterial stiffness were examined in patients with stable coronary artery disease in a prospective, placebo-controlled clinical crossover study. Methods and results: Twenty-three patients (18 men and 5 women) with a resting heart rate (HR) of at least 70 beats per minute (bpm) and stable coronary artery disease were enrolled in this study. In a cross-over design, all patients were treated with ivabradine (Iva, 7.5mg b. i. d.) and placebo for 6 months each. Iva reduced heart rate by 11.4 bpm (Iva 58.8 +/- 8.2 bpm vs. placebo 70.2 +/- 8.3 bpm, P <0.0001). Augmentation index (AIx75), carotid-femoral pulse wave velocity (cfPWV) and central aortic blood pressure were measured using applanation tonometry (SphygmoCor). HRR by Iva increased AIx75 by 12.4% (Iva 24.3 +/- 10.5% vs. placebo 21.3 +/- 10.1%, P < 0.05) and reduced cfPWV by 14.1% (Iva 6.3 +/- 1.7 m/s vs. placebo 7.3 +/- 1.4 m/s, P < 0.01). Iva increased mean central blood pressure by 7.8% (Iva 107.5 +/- 15.4mmHg vs. placebo 99.1 +/- 12.2 mmHg, P < 0.001). Endothelial function was determined measuring the flow-mediated vasodilation (FMD) of the brachial artery. HRR by Iva increased FMD by 18.5% (Iva 7.3 +/- 2.2% vs. placebo 6.0 +/- 2.0%, P<0.001). Aortic distensibility was characterized by MRI. HRR by Iva increased aortic distensibility by 33.3% (Iva 0.003 +/- 0.001/mmHg vs. placebo 0.002 +/- 0.010/mmHg, P<0.01) and circumferential cyclic strain by 37.1% (Iva 0.062 +/- 0.027 vs. placebo 0.039 +/- 0.018, P<0.0001). Conclusion: Heart rate reduction with Iva increased endothelium-dependent vasodilation and reduced arterial stiffness in patients with stable CAD. These findings corroborate and expand the results collected in experimental studies and indicate the importance of heart rate as a determinant of vascular function.