Postmyocardial infarction remodeling and coronary reserve: effects of ivabradine and beta blockade therapy.
We compared the effects of heart rate reduction (HRR) by the hyperpolarization-activated pacemaker current (I(f)) channel inhibitor ivabradine (MI+Iva) and the beta(1)-blocker atenolol (MI+Aten) on ventricular remodeling and perfusion after myocardial infarction (MI) in middle-aged (12 mo) Sprague-Dawley rats. Mean HRR was virtually identical in the two treated groups (19%). Four weeks after coronary artery ligation, maximal myocardial perfusion fell in the MI group but was preserved in infarcted rats treated with either Iva or Aten. However, coronary reserve in the remodeled hearts was preserved only with Iva, since Aten treatment elevated baseline perfusion in response to a higher wall stress. The higher maximal perfusion noted in the two treated groups was not due to arteriogenesis or angiogenesis. Plasma levels of angiotensin (ANG) II and myocardial ANG type 1 (AT(1)) receptor and transforming growth factor (TGF)-beta1 were reduced during the first week of treatment by both Iva and Aten. Moreover, treatment also reduced arteriolar perivascular collagen density. Despite these similar effects of Iva and Aten on vascularity and ANG II, Iva, but not Aten, attenuated the decline in ejection fraction and lowered left ventricular (LV) end-diastolic volume (LVEDV)-to-LV mass ratio, determined by echocardiography. In conclusion, 1) Iva has advantages over Aten in postinfarction therapy that are not due to differential effects of the drugs on heart rate, and 2) age limits growth factor upregulation, angiogenesis, and arteriogenesis in the postinfarcted heart.
Department of Anatomy and Cell Biology, Department of Internal Medicine, and Cardiovascular Center, University of Iowa, Iowa City, IA 52242, USA.
Lance P
LP
Christensen
Ron-Ling
RL
Zhang
Wei
W
Zheng
Joseph J
JJ
Campanelli
Eduard I
EI
Dedkov
Robert M
RM
Weiss
Robert J
RJ
Tomanek
D000319:Adrenergic beta-Antagonists / Q000627:therapeutic use*; D000804:Angiotensin II / Q000096:biosynthesis / Q000502:physiology; D000818:Animals; D001262:Atenolol / Q000627:therapeutic use*; D001552:Benzazepines / Q000627:therapeutic use*; D001920:Bradykinin / Q000378:metabolism; D002316:Cardiotonic Agents / Q000627:therapeutic use*; D003094:Collagen / Q000378:metabolism; D003326:Coronary Circulation / Q000187:drug effects; D004562:Electrocardiography; D006339:Heart Rate / Q000187:drug effects; D007150:Immunohistochemistry; D036341:Intercellular Signaling Peptides and Proteins / Q000378:metabolism; D000077550:Ivabradine; D008297:Male; D009203:Myocardial Infarction / Q000188:drug therapy* / Q000473:pathology; D018919:Neovascularization, Physiologic / Q000187:drug effects / Q000502:physiology; D009929:Organ Size; D010477:Perfusion; D051381:Rats; D017207:Rats, Sprague-Dawley; D044140:Receptor, Angiotensin, Type 1 / Q000096:biosynthesis / Q000502:physiology; D020257:Ventricular Remodeling / Q000502:physiology*
D000319:Adrenergic beta-Antagonists; D001552:Benzazepines; D002316:Cardiotonic Agents; D036341:Intercellular Signaling Peptides and Proteins; D044140:Receptor, Angiotensin, Type 1; D000804:Angiotensin II; D000077550:Ivabradine; D001262:Atenolol; D003094:Collagen; D001920:Bradykinin