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      Heart Rate Reduction by Ivabradine Reduces Diastolic Dysfunction and Cardiac Fibrosis

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          Abstract

          Objectives: To determine if heart rate (HR) reduction with ivabradine (IVA), a selective inhibitor of the pacemaker I<sub> f</sub> 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.

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          Most cited references20

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          Influence of heart rate on mortality among persons with hypertension: the Framingham Study.

          Previous studies have shown positive associations between heart rate and both all-cause and cardiovascular mortality. These relationships, however, have not been investigated in persons with hypertension. Using 36-year follow-up data from the Framingham Study, we evaluated from 4530 subjects, aged 35 to 74, whose blood pressures were > or = 140 mm Hg systolic or > or = 90 mm Hg diastolic and who were not treated with antihypertensive medication. We used pooled logistic regression to calculate biennial mortality rates. Odds ratios and 95% confidence intervals for each increment in heart rate of 40 beats/min, adjusted for age and systolic blood pressure level, were: for all-cause mortality, 2.18 (1.68, 2.83) for men and 2.14 (1.59, 2.88) for women; and for cardiovascular mortality, 1.68 (1.19, 2.37) for men and 1.70 (1.08, 2.67) for women. Exclusion of outcomes in the first 2 or 4 years after measurement of heart rate did not materially change the results, which suggests that rapid heart is not merely an indicator of preexisting illness. Therefore heart rate may be an independent risk factor for cardiovascular death in persons with hypertension.
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            Heart rate reduction by ivabradine reduces oxidative stress, improves endothelial function, and prevents atherosclerosis in apolipoprotein E-deficient mice.

            Elevated heart rate is associated with increased cardiovascular morbidity. We hypothesized that selective heart rate reduction may influence endothelial function and atherogenesis and tested the effects of the I(f) current inhibitor ivabradine in apolipoprotein E-deficient mice. Male apolipoprotein E-deficient mice fed a high-cholesterol diet were treated with ivabradine (10 mg . kg(-1) . d(-1)) or vehicle for 6 weeks (n=10 per group). Ivabradine reduced heart rate by 13.4% (472+/-9 versus 545+/-11 bpm; P 40% and in the ascending aorta by >70% (P<0.05). Heart rate reduction by ivabradine had no effect on the number of endothelial progenitor cells and did not alter aortic endothelial nitric oxide synthase, phosphorylated Akt, vascular cell adhesion molecule-1, or intercellular adhesion molecule-1 expression but decreased monocyte chemotactic protein-1 mRNA and exerted potent antioxidative effects. Ivabradine reduced vascular NADPH oxidase activity to 48+/-6% and decreased markers of superoxide production and lipid peroxidation in the aortic wall (P<0.05). The in vivo effects of ivabradine were absent at a dose that did not lower heart rate, in aortic rings treated ex vivo, and in cultured vascular cells. In contrast to ivabradine, treatment with hydralazine (25 mg . kg(-1) . d(-1) for 6 weeks) reduced blood pressure (-15%) but increased heart rate (37%) and did not improve endothelial function, atherosclerosis, or oxidative stress. Selective heart rate reduction with ivabradine decreases markers of vascular oxidative stress, improves endothelial function, and reduces atherosclerotic plaque formation in apolipoprotein E-deficient mice.
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              A practical approach to the echocardiographic evaluation of diastolic function.

              A number of recent community-based epidemiologic studies suggest that 40% to 50% of the cases of heart failure have preserved left ventricular systolic function. Although diastolic heart failure is often not well clinically recognized, it is associated with marked increases in morbidity and all-cause mortality. Doppler echocardiography has emerged as the principal clinical tool for the assessment of left ventricular diastolic function. Doppler mitral inflow velocity-derived variables remain the cornerstone of the evaluation of diastolic function. Pulmonary venous Doppler flow indices and mitral inflow measurements with Valsalva's maneuver are important adjuncts for differentiating normal and pseudonormal mitral inflow patterns. Unfortunately, these Doppler flow variables are significantly influenced by loading conditions and, therefore, the results from these standard techniques can be inconclusive. Recently, color M-mode and Doppler tissue imaging have emerged as new modalities that are less affected by preload and, thus, provide a strong complementary role in the assessment of diastolic function. This review will discuss the diastolic properties of the left ventricle, Doppler echocardiographic evaluation, and grading of diastolic dysfunction.
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                Author and article information

                Journal
                CRD
                Cardiology
                10.1159/issn.0008-6312
                Cardiology
                S. Karger AG
                0008-6312
                1421-9751
                2010
                January 2011
                08 January 2011
                : 117
                : 3
                : 234-242
                Affiliations
                aResearch Center, Montreal Heart Institute, Université de Montréal, Montreal, Que., Canada; bInstitut de Recherches Internationales Servier, Courbevoie, France
                Author notes
                *Jean-Claude Tardif, MD, Montreal Heart Institute, 5000 Belanger Street, Montreal, QC H1T 1C8 (Canada), Tel. +1 514 376 3330, ext. 3612, Fax +1 514 593 2500, E-Mail jean-claude.tardif@icm-mhi.org
                Article
                322905 Cardiology 2010;117:234–242
                10.1159/000322905
                21212673
                a8929203-9a78-4744-ac97-04b4f01994ca
                © 2011 S. Karger AG, Basel

                Open Access License: This is an Open Access article licensed under the terms of the Creative Commons Attribution-NonCommercial 3.0 Unported license (CC BY-NC) ( http://www.karger.com/OA-license), applicable to the online version of the article only. Distribution permitted for non-commercial purposes only. Drug Dosage: The authors and the publisher have exerted every effort to ensure that drug selection and dosage set forth in this text are in accord with current recommendations and practice at the time of publication. However, in view of ongoing research, changes in government regulations, and the constant flow of information relating to drug therapy and drug reactions, the reader is urged to check the package insert for each drug for any changes in indications and dosage and for added warnings and precautions. This is particularly important when the recommended agent is a new and/or infrequently employed drug. Disclaimer: The statements, opinions and data contained in this publication are solely those of the individual authors and contributors and not of the publishers and the editor(s). The appearance of advertisements or/and product references in the publication is not a warranty, endorsement, or approval of the products or services advertised or of their effectiveness, quality or safety. The publisher and the editor(s) disclaim responsibility for any injury to persons or property resulting from any ideas, methods, instructions or products referred to in the content or advertisements.

                History
                : 19 October 2010
                Page count
                Figures: 4, Tables: 2, Pages: 9
                Categories
                Original Research

                General medicine,Neurology,Cardiovascular Medicine,Internal medicine,Nephrology
                Echocardiography,Heart rate,Collagen,Hypercholesterolemia,Diastolic dysfunction

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