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This Article Full Text Full Text (PDF) All Versions of this Article: 296/2/H435    most recent 00591.2008v1 Alert me when this article is cited Alert me if a correction is posted Citation Map Services Email this article to a friend Similar articles in this journal Similar articles in PubMed Alert me to new issues of the journal Download to citation manager Citing Articles Citing Articles via HighWire Citing Articles via Web of Science (1) Citing Articles via Google Scholar Google Scholar Articles by Milliez, P. Articles by Delcayre, C. Search for Related Content PubMed PubMed Citation Articles by Milliez, P. Articles by Delcayre, C.

Beneficial effects of delayed ivabradine treatment on cardiac anatomical and electrical remodeling in rat severe chronic heart failure

¹Institut National de la Santé et de la Recherche Médicale U942, Lariboisière Hospital, Paris; ²Cardiology Department, University of Caen, Cote de Nacre Hospital, Caen; and ³Denis Diderot University, Paris, France

Submitted 6 June 2008 ; accepted in final form 2 December 2008

We tested the hypothesis that heart rate (HR) reduction, induced by the selective hyperpolarization-activated current inhibitor ivabradine (Iva), might improve left ventricular (LV) function, structure, and electrical remodeling in severe post-myocardial infarction (MI) chronic heart failure (HF). MI was produced in adult male Wistar rats. After 2 mo, echocardiography was performed before the randomization into MI and MI + Iva (10 mg·kg^–1·day^–1) groups. After 3 mo of treatment, echocardiography and 24-h telemetry were recorded. Cardiac collagen, mRNA, and protein expressions of angiotensin-converting enzyme (ACE) and ANG II type 1 (AT₁) receptor were quantified. As a result, at 2 mo post-MI, all rats displayed severe congestive HF signs (ejection fraction < 30%). At 5 mo post-MI, body and heart weights were similar in the MI and MI + Iva groups. LV ejection fraction and LV end-diastolic pressure were worsened in the MI group, whereas both were improved with Iva. Iva reduced HR by 10.4% (P < 0.03 vs. MI) and ventricular premature complexes by 89% (P < 0.03) and improved HR variability (standard deviation of the RR interval) by 22% (P < 0.05). There were no effects of Iva on PR, QRS, and QT durations. Interstitial fibrosis in the MI-remote LV was markedly reduced by Iva (4.0 ± 0.1 vs. 1.8 ± 0.1%, P < 0.005). Increases in ventricular gene and protein expressions of ACE and AT₁ receptor in MI were completely blunted by Iva. In conclusion, these data indicated that HR reduction by Iva prevents the worsening of LV dysfunction and remodeling that may be related to a downregulation of cardiac renin-angiotensin-aldosterone system transcripts. Such beneficial effects of Iva on cardiac remodeling open new clinical perspectives for the treatment of severe HF.

heart rate; cardiac fibrosis; renin-angiotensin-aldosterone system

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