Long-term heart rate reduction induced by the selective I(f) current inhibitor ivabradine improves left ventricular function and intrinsic myocardial structure in congestive heart failure.
BACKGROUND
Heart rate reduction (HRR) improves left ventricular (LV) filling, increases myocardial O2 supply, and reduces myocardial O2 consumption, which are all beneficial in congestive heart failure (CHF). However, the long-term effects of HRR on cardiac function and remodeling are unknown.


RESULTS
We assessed, in rats with CHF, the effects of long-term HRR induced by the selective I(f) current inhibitor ivabradine (as food admix for 90 days starting 7 days after coronary artery ligation). To assess intrinsic modifications of LV tissue induced by long-term HRR, all parameters were reassessed 3 days after interruption of treatment. Ivabradine decreased heart rate over the 90-day treatment period (-18% versus untreated at 10 mg x kg(-1) x d(-1)), without modifying blood pressure, LV end-diastolic pressure, or dP/dt(max/min). Ivabradine significantly reduced LV end-systolic but not end-diastolic diameter, which resulted in preserved cardiac output due to increased stroke volume. In the Langendorff preparation, ivabradine shifted LV systolic but not end-diastolic pressure-volume relations to the left. Ivabradine decreased LV collagen density and increased LV capillary density without modifying LV weight. Three days after interruption of treatment, the effects of ivabradine on LV geometry, shortening, and stroke volume persisted despite normalization of heart rate.


CONCLUSIONS
In rats with CHF, long-term HRR induced by the selective I(f) inhibitor ivabradine improves LV function and increases stroke volume, preserving cardiac output despite the HRR. The improvement of cardiac function is related not only to the HRR per se but also to modifications in the extracellular matrix and/or function of myocytes as a consequence of long-term HRR.
Mulder
Paul
P
INSERM U644, UFR de Médecine et de Pharmacie, Rouen, France.
Barbier
Stephane
S
Chagraoui
Abdeslam
A
Richard
Vincent
V
Henry
Jean Paul
JP
Lallemand
Françoise
F
Renet
Sylvanie
S
Lerebours
Guy
G
Mahlberg-Gaudin
Florence
F
Thuillez
Christian
C
D000818:Animals; D001552:Benzazepines / Q000494:pharmacology* / Q000627:therapeutic use; D002196:Capillaries / Q000187:drug effects; D002302:Cardiac Output / Q000187:drug effects; D003094:Collagen / Q000032:analysis; D004353:Drug Evaluation, Preclinical; D006333:Heart Failure / Q000188:drug therapy* / Q000209:etiology / Q000473:pathology / Q000503:physiopathology; D006339:Heart Rate / Q000187:drug effects*; D006352:Heart Ventricles / Q000187:drug effects / Q000473:pathology; D017136:Ion Transport / Q000187:drug effects; D000077550:Ivabradine; D008297:Male; D009203:Myocardial Infarction / Q000150:complications; D009206:Myocardium / Q000737:chemistry; D051381:Rats; D017208:Rats, Wistar; D012849:Sinoatrial Node / Q000187:drug effects; D013318:Stroke Volume / Q000187:drug effects; D016277:Ventricular Function, Left / Q000187:drug effects*; D020257:Ventricular Remodeling / Q000187:drug effects
D001552:Benzazepines; D000077550:Ivabradine; D003094:Collagen