Study to Investigate the Effect of Heart Rate Reduction With Ivabradine on Vascular Elastic Properties and Endothelial Function in Patients With Stable Coronary Heart Disease

A Randomised, Placebo Controlled, Double Blind, Cross-over, Single Center Clinical Study to Investigate the Effect of Heart Rate Reduction With Ivabradine on Vascular Elastic Properties and Endothelial Function in Patients With Stable Coronary Heart Disease

This study investigates whether chronic heart rate reduction with ivabradine (Procoralan®, Servier, France) affects aortic compliance and endothelial function in patients with chronic stable coronary artery disease.

Experimental and clinical data suggest that sustained elevation of heart rate contributes to the pathogenesis of vascular disease (1, 2). In animal studies accelerated heart rate is associated with signalling events leading to vascular oxidative stress, endothelial dysfunction and acceleration of atherogenesis (3). The underlying mechanisms are only partially understood and appear to correlate with mechanic properties such as reduction of vascular compliance. Heart rate reduction by I(f)-channel inhibition with ivabradine (Procoralan®, Servier, France) attenuates oxidative stress, improves endothelial function and reduces the formation of atherosclerotic plaques in mice models of lipid-induced atherosclerosis (1, 4).

Aortic stiffness is a consequence of arterial aging and vascular risk factors and determinates cardiovascular mortality (5). Heart rate depending repetitive pulsations appear to induce fatigue and fracture of elastin lamellae of central arteries. As a result the vessel stiffens and pulse wave reflections return earlier to the heart. In consequence aortic pressure rises and pulsations of flow extend further into smaller vessels of organs (notably the brain and kidney). Stiffening leads to increased left ventricular (LV) load with hypertrophy, decreased capacity for myocardial perfusion, and increased hemodynamic stresses on small arterial vessels.

Several experimental investigations revealed an interaction between heart rate and vascular compliance demonstrating a positive association between increased heart rate and arterial stiffness (6). Recent experimental data suggest that heart rate reduction by ivabradine (Procoralan®, Servier, France) significantly improves aortic distensibility in cholesterol fed ApoE -/- mice measured by MRI technique (7). While a benefit of pharmacological heart rate reduction on vascular outcomes was observed in animal studies, prospective clinical data are limited and evidence determining whether chronic modulation of heart rate can improve vascular function and compliance in patients with chronic stable coronary artery disease is needed.

Inclusion Criteria:

• Age > 18 years old
• Resting heart rate ≥ 70 bpm
• Sinus rhythm
• Chronic stable coronary artery disease (CAD)
• Coronary artery disease proven by coronary angiography
• Written informed consent to participate in the study

Exclusion Criteria:

• Acute coronary syndrome
• CAD treated best by surgical coronary bypass
• Stroke/TIA
• Resting heart rate < 70 bpm
• Indwelling pacemaker or AICD
• Severe valvular heart disease
• Any other rhythm than sinus
• Sick-Sinus-Syndrome, SA nodal block, >2nd degree atrio-ventricular block
• Untreated arterial hypertension
• Arterial hypotension (<90/50mmHg)
• Severe hepatic failure
• Heart failure (NYHA class III - IV)
• Patient already treated with study drug
• Symptomatic PAD
• Known diabetes mellitus
• Pre-menopausal women
• Hypersensitivity against ivabradine or adjuvants
• Coexisting drug treatment with Cytochrom P450 3A4-inhibitors