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.
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, 7.5 mg 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 ± 15.4 mmHg 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).
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.
aFirst Department of Medicine, University Medical Centre Mannheim (UMM), Faculty of Medicine Mannheim, University of Heidelberg and DZHK (German Center for Cardiovascular Research) Partner Site Heidelberg/Mannheim, Theodor-Kutzer-Ufer, Mannheim
bClinic for Diagnostic and Interventional Radiology, Saarland University Hospital, University of the Saarland
cInstitute for Medical Biometry, Epidemiology and Informatics (IMBEI), Saarland University, Campus Homburg
dDepartment of Internal Medicine III, Saarland University Hospital, University of the Saarland, Kirrbergerstraße, Homburg/Saar
eClinic and Polyclinic for Cardiology, University of Leipzig, Liebigstraße, Leipzig
fDepartment of Internal Medicine II, Klinikum Saarbrücken, Winterberg, Saarbrücken, Germany
Correspondence to Anna Lena Hohneck, University Medical Centre, Theodor-Kutzer-Ufer, Mannheim, Germany. E-mail: firstname.lastname@example.org
Abbreviations: ACE, angiotensin converting enzyme; AIx75, augmentation index; ARB, angiotensin receptor blocker; AV, atrioventricular; b.i.d., bis in die (twice daily); BP, blood pressure; bpm, beats per minute; CAD, coronary artery disease; CD, diastolic circumference; cfPWV, carotid–femoral pulse wave velocity; CS, systolic circumference; CVD, coronary vessel disease; FMD, flow-mediated dilation; NMD, nitromediated dilation; GTN, glyceroletrinitrate; HR, heart rate; HRR, heart rate reduction; ICD, implantable cardioverter-defibrillator; Iva, ivabradine; NO, nitric oxide; PP, pulse pressure; PWA, pulse wave analysis; PWV, pulse wave velocity; RAAS, renin–angiotensin–aldosterone system; RCT, randomized controlled trial; SEM, standard error of the mean
Received 15 May, 2018
Accepted 3 October, 2018