title: Beneficial effects of delayed ivabradine treatment on cardiac anatomical and electrical remodeling in rat severe chronic heart failure.
abstract: 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 x kg(-1) x 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 (AT(1)) 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 AT(1) 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.
authors.affiliation: INSERM U942, Cardiovascular Research Center INSERM Lariboisière, Paris, France. paulmilliez@hotmail.com
authors.forename: Paul
authors.initials: P
authors.lastname: Milliez
authors.forename: Smail
authors.initials: S
authors.lastname: Messaoudi
authors.forename: Johnny
authors.initials: J
authors.lastname: Nehme
authors.forename: Camille
authors.initials: C
authors.lastname: Rodriguez
authors.forename: Jane-Lise
authors.initials: JL
authors.lastname: Samuel
authors.forename: Claude
authors.initials: C
authors.lastname: Delcayre
mesh_terms: D000818:Animals; D000889:Anti-Arrhythmia Agents / Q000008:administration & dosage*; D001552:Benzazepines / Q000008:administration & dosage*; D003094:Collagen / Q000378:metabolism; D004195:Disease Models, Animal; D004334:Drug Administration Schedule; D015150:Echocardiography, Doppler; D015716:Electrocardiography, Ambulatory; D005355:Fibrosis; D006333:Heart Failure / Q000188:drug therapy* / Q000209:etiology / Q000473:pathology / Q000503:physiopathology; D006339:Heart Rate / Q000187:drug effects*; D000077550:Ivabradine; D008297:Male; D009203:Myocardial Infarction / Q000150:complications / Q000188:drug therapy / Q000503:physiopathology; D009206:Myocardium / Q000378:metabolism / Q000473:pathology*; D007703:Peptidyl-Dipeptidase A / Q000378:metabolism; D012333:RNA, Messenger / Q000378:metabolism; D051381:Rats; D017208:Rats, Wistar; D044140:Receptor, Angiotensin, Type 1 / Q000378:metabolism; D012084:Renin-Angiotensin System / Q000187:drug effects / Q000235:genetics; D012720:Severity of Illness Index; D013318:Stroke Volume / Q000187:drug effects; D013686:Telemetry; D018487:Ventricular Dysfunction, Left / Q000188:drug therapy* / Q000209:etiology / Q000473:pathology / Q000503:physiopathology; D016277:Ventricular Function, Left / Q000187:drug effects*; D017725:Ventricular Pressure / Q000187:drug effects; D020257:Ventricular Remodeling / Q000187:drug effects*
chemical_list: D000889:Anti-Arrhythmia Agents; D001552:Benzazepines; D012333:RNA, Messenger; D044140:Receptor, Angiotensin, Type 1; D000077550:Ivabradine; D003094:Collagen; D007703:Peptidyl-Dipeptidase A