Heart Rate Reduction by Ivabradine Reduces Diastolic Dysfunction and Cardiac Fibrosis

Busseuil, David; Shi, Yanfen; Mecteau, Mélanie; Brand, Geneviève; Gillis, Marc‐Antoine; Thorin, Éric; Asselin, Caroline; Roméo, Philippe; Leung, Tack Ki; Latour, Jean-Gilles; Rosiers, Christine Des; Bouly, Muriel; Rhéaume, Éric; Tardif, Jean‐Claude

doi:10.1159/000322905

Cited by 64 publications

(45 citation statements)

References 59 publications

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“…33 Recently, it was reported that HR reduction by ivabradine was able to reduce diastolic dysfunction and cardiac fibrosis in an experimental model of hypercholesterolemia. 34 It has been shown that ivabradine increases diastolic time 35 and enhanced ventricular relaxation during peak exercise 36 to a greater extent than ␤-blockers, which is in agreement with our findings. In contrast to ␤-blockers, ivabradine did not decrease the maximal rise in LV pressure with time (dP/dt max ) or alter postsystolic wall thickening.…”

Section: Discussionsupporting

confidence: 93%

Role of Heart Rate Reduction in the Prevention of Experimental Heart Failure

Becher

Lindner²,

Miteva³

et al. 2012

Hypertension

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Abstract-To investigate whether heart rate reduction via I f -channel blockade and ␤-receptor blockade prevents left ventricular (LV) dysfunction, we studied ivabradine and metoprolol in angiotensin II-induced heart failure. Cardiac dysfunction in C57BL/6J mice was induced by implantation of osmotic pumps for continuous subcutaneous dosing of angiotensin II (1.8 mg/kg per day SC) over a period of 3 weeks. Ivabradine (10 mg/kg per day) and metoprolol (90 mg/kg per day), which resulted in similar heart rate reduction, or placebo treatments were simultaneously started with infusion of angiotensin II. After 3 weeks, LV function was estimated by conductance catheter technique, cardiac remodeling assessed by estimation of cardiac hypertrophy, fibrosis, and inflammatory stress response by immunohistochemistry or PCR, respectively. Compared with controls, angiotensin II infusion resulted in hypertension in impaired systolic (LV contractility, stroke volume, end systolic elastance, afterload, index of arterial-ventricular coupling, and cardiac output; PϽ0.05) and diastolic (LV relaxation, LV end diastolic pressure, , and stiffness constant ␤; PϽ0.05) LV function. This was associated with a significant increase in cardiac hypertrophy and fibrosis. Increased cardiac stress was also indicated by an increase in cardiac inflammation and apoptosis. Both ivabradine and metoprolol led to a similar reduction in heart rate. Metoprolol also reduced systolic blood pressure. Ivabradine led to a significant improvement in systolic and diastolic LV function (PϽ0.05). This was associated with less cardiac hypertrophy, fibrosis, inflammation, and cardiac apoptosis (PϽ0.05). Metoprolol treatment did not prevent the reduction in cardiac function and adverse remodeling, despite a reduction of the inflammatory stress response. Behind heart rate reduction, additional beneficial cardiac effects contribute to heart failure prevention with I f -channel inhibition. (Hypertension. 2012;59:949-957.) • Online Data Supplement Key Words: angiotensin II Ⅲ cardiac dysfunction Ⅲ diastolic dysfunction Ⅲ ivabradine Ⅲ metoprolol Ⅲ heart rate A rterial hypertension is the most common chronic disease. It is the leading risk factor for death attributed to stroke, myocardial infarction, or end-stage renal failure. 1,2The current available classes of antihypertensive drugs reduce these risks. However, their role in the prevention of chronic heart failure (CHF) is still under investigation. It has been shown in the Antihypertensive and Lipid-Lowering Treatment to Prevent Heart Attack Trial that the diuretic chlorthalidone but not the calcium channel blocker amlodipine or the angiotensin-converting enzyme inhibitor lisinopril effectively reduced the risk of heart failure.3 Several metaanalyses have shown that lowering blood pressure by 5 mmHg reduces the risk of CHF development by Ϸ20%.4-6 These studies have included those analyzing angiotensin-converting enzyme inhibitors, angiotensin II (Ang II) type 1 receptor blockers, calcium channel blockers, and ␤-blockers....

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Section: Discussionsupporting

confidence: 93%

Role of Heart Rate Reduction in the Prevention of Experimental Heart Failure

Becher

Lindner²,

Miteva³

et al. 2012

Hypertension

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“…Circulating angiotensin II levels were significantly lowered by ivabradine and correlated with HR. Aldosterone levels also correlated with HR during treatment and were lower with ivabradine [16]. Results in experimental studies are consistent with the effects of ivabradine on cardiac remodeling [11].…”

Section: Discussionsupporting

confidence: 76%

“…Busseuil et al [16] demonstrated that selective HR reduction with ivabradine prevented the detrimental effects of hypercholesterolemia on LV myocardial performance. Ivabradine attenuated LV diastolic dysfunction, reduced left atrial and LV structural remodeling (interstitial fibrosis), and reduced LV collagen type I in hypercholesterolemic rabbits.…”

Section: Discussionmentioning

confidence: 99%

Effects of ivabradine therapy on heart failure biomarkers

et al. 2015

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Background: Heart rate (HR) reduction is associated with improved outcomes in patients with heart failure (HF) and biomarkers can be a valuable diagnostic tool in HF management. The primary aim of our study was to evaluate the short-term (6 months) effect of ivabradine on N-terminal pro B-type natriuretic peptide (NT-proBNP), CA-125, and cystatin-C values in systolic HF outpatients, and secondary aim was to determine the relationship between baseline HR and the and , and cystatin-C were taken at baseline and at the end of a 6-month follow-up in both groups. Results: There was a significant decrease in NYHA class in the ivabradine group (2.67 ± ± 0.47 vs. 1.85 ± 0.61, p < 0.001). When ivabradine and control groups were compared, a significant difference was also found in NHYA class 6 months later (p = 0.013). A significant decrease was found in HR in the ivabradine and control groups (84.10 ± 8.76 vs. 68.36 ± ± 8.32 bpm, p = 0.001; 84.51 ± 10 vs. 80.40 ± 8.3 p < 0.001),353.02 ± 1,453.77 vs. 717.81 ± 834.76 pg/mL, p < 0.001) in the ivabradine group. When ivabradine and control groups were compared after 6 months, a significant decrease was found in all HF parameters (respectively;. Creatinine level was significantly decreased and glomerular filtration rate (GFR) was significantly increased in the ivabradine group (1.02 ± 0.26 vs. 0.86 ± 0.17, creatinine: p = 0.001; 79.26 Cardiology Journal 2015, Vol. 22, No. 5, 501-509 DOI: 10.5603/CJ.a2015.0012 Copyright © 2015 Via Medica ISSN 1897 , and cystatin-C may prove to be useful in biomarker panels evaluating ivabradine therapy response in HF patients. (Cardiol J 2015; 22, 5: 501-509) bpm, p = 0.001). When both groups were compared, a significant difference was also found in HR after 6 months (p = 0.001). A significant decrease was found in cystatin-C (2.10 ± 0.73 vs. 1.50 ± 0.44 mg/L, p < 0.001),

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“…This use is supported in recent literature due to its heart rate lowering effect. [14][15][16] Ivabradine has a beneficial effect in DCM especially in those who have heart rates not controlled with beta blockers. In few patients due to the heart rate lowering effect of beta blockers, syncope occurred and in those cases Digoxin was used as an alternative.…”

Section: Discussionmentioning

confidence: 99%

Assessment of drug utilization pattern and rationality of drug use in treatment of dilated cardiomyopathy in a tertiary care teaching hospital of rural Bengal

Banerjee

Mandal

Mukhopadhyay

et al. 2016

Int J Basic Clin Pharmacol

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Background: Dilated cardiomyopathy (DCM) is an important underlying cause of congestive heart failure and/or arrhythmias. The introduction of therapy combining diuretics, digoxin and angiotensin converting enzyme inhibitors (ACEI) has significantly decreased mortality and morbidity. The aim of the study was undertaken to identify the pattern of drugs most commonly prescribed for DCM and to assess the rationality behind such use.Methods: This was a prospective study undertaken between 1st July and 31st August 2015. Prescriptions were reviewed and analyzed using the World Health Organization (WHO) indicators for drug utilization studies. Rationality and cost of therapy per prescription was also evaluated.Results: We encountered 78 patients of DCM in the OPD of Cardiology (prevalence of 4.94%). The average number of drugs per prescription was 6.64. Generic prescriptions were made in 90% encounters. As part of therapy, diuretics and ACE inhibitors or angiotensin receptor blockers, were prescribed in all cases. Our results show a distinctive drug use pattern where beta blockers were used more commonly than digoxin. Other commonly prescribed agents were antiplatelet drugs and statins. Antibiotics were prescribed in 8.7% cases and no injectable drug was prescribed. Average drug cost per encounter was 10.63 INR.Conclusions: To conclude, we found a typical and rational pattern of drug use. Diuretics, ACEI and beta blockers were found to be most commonly used agents. This study provides a clear picture of drug use in this special clinical condition in rural Bengal and paves the way for larger and long term studies.

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Heart Rate Reduction by Ivabradine Reduces Diastolic Dysfunction and Cardiac Fibrosis

Cited by 64 publications

References 59 publications

Role of Heart Rate Reduction in the Prevention of Experimental Heart Failure

Role of Heart Rate Reduction in the Prevention of Experimental Heart Failure

Effects of ivabradine therapy on heart failure biomarkers

Assessment of drug utilization pattern and rationality of drug use in treatment of dilated cardiomyopathy in a tertiary care teaching hospital of rural Bengal

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