January 1, 2010Open Access
Heart Rate Reduction by Ivabradine Reduces Diastolic Dysfunction and Cardiac Fibrosis
Structured PICO
Does heart rate reduction with ivabradine prevent cardiac dysfunction and fibrosis associated with dyslipidemia in New Zealand White rabbits?
P
Population
New Zealand White rabbits
I
Intervention
Ivabradine (17 mg/kg/day) added to a 0.5% cholesterol-enriched diet for 12 weeks
C
Comparator
0.5% cholesterol-enriched diet only (CD) or standard diet
O
Outcome
Heart rate, left ventricular (LV) systolic function, diastolic function and LV regional myocardial performance index (MPI) measured by echocardiographysurrogate
In a hypercholesterolemic rabbit model, heart rate reduction with ivabradine attenuated diastolic dysfunction and cardiac fibrosis, providing preclinical rationale for testing pure heart rate reduction in diastolic heart failure.
Abstract
OBJECTIVES: To determine if heart rate (HR) reduction with ivabradine (IVA), a selective inhibitor of the pacemaker I(f) current, prevents cardiac dysfunction associated with dyslipidemia. METHODS: New Zealand White rabbits received either a standard diet, a 0.5% cholesterol-enriched diet only (CD), or a 0.5% CD with IVA (17 mg/kg/day) for 12 weeks. HR, left ventricular (LV) systolic function, diastolic function and LV regional myocardial performance index (MPI) were studied using echocardiography. Histological analysis included cardiac interstitial fibrosis and collagen type I fibers. Plasma levels of angiotensin II and aldosterone were quantified by immunoassays. RESULTS: IVA reduced HR by approximately 11%. IVA improved MPI and attenuated LV diastolic dysfunction (DD) (92% mild and 8% moderate DD with IVA vs. 54% mild and 46% moderate DD in CD group). IVA also reduced atrial fibrosis (p = 0.027), ventricular fibrosis (p = 0.0002) and ventricular collagen type I (p = 0.0042). IVA decreased plasma angiotensin II levels (p = 0.042), and both angiotensin II and aldosterone levels were correlated with HR (p = 0.038 and 0.008). CONCLUSION: Selective HR reduction with IVA reduces DD and cardiac fibrosis in hypercholesterolemic rabbits. These beneficial effects of IVA support testing pure HR reduction in patients with diastolic heart failure.