Angiotensin receptor blockade and angiotensin-converting-enzyme inhibition limit adverse remodeling of infarct zone collagens and global diastolic dysfunction during healing after reperfused ST-elevation myocardial infarction.
To determine whether therapy with the angiotensin II type 1 receptor blocker (ARB) candesartan and the comparator angiotensin-converting-enzyme inhibitor (ACEI) enalapril during healing after reperfused ST-elevation myocardial infarction (RSTEMI) limit adverse remodeling of infarct zone (IZ) collagens and left ventricular (LV) diastolic dysfunction, we randomized 24 dogs surviving anterior RSTEMI (90-min coronary occlusion) to placebo, candesartan, and enalapril therapy between day 2 and 42. Six other dogs were sham. We measured regional IZ and non-infarct zone (NIZ) collagens (hydroxyproline; types I/III; cross-linking), transforming growth factor-beta (TGF-beta) and topography at 6 weeks, and hemodynamics, LV diastolic and systolic function, and remodeling over 6 weeks. Compared to sham, placebo-RSTEMI differentially altered regional collagens, with more pronounced increase in TGF-beta, hydroxyproline, and type I, insoluble, and cross-linked collagens in the IZ than NIZ, and increased IZ soluble and type III collagens at 6 weeks, and induced persistent LV filling pressure elevation, diastolic and systolic dysfunction, and LV remodeling over 6 weeks. Compared to placebo-RSTEMI, candesartan and enalapril limited adverse regional collagen remodeling, with normalization of type III, soluble and insoluble collagens and decrease in pyridinoline cross-linking in the IZ at 6 weeks, and attenuation of LV filling pressure, diastolic dysfunction, and remodeling over 6 weeks. The results suggest that candesartan and enalapril during healing after RSTEMI prevent rather than worsen adverse remodeling of IZ collagens and LV diastolic dysfunction, supporting the clinical use of ARBs and ACEIs during subacute RSTEMI.
Jugdutt
Bodh I
BI
2C2 Walter Mackenzie Health Sciences Centre, Division of Cardiology, Department of Medicine, University of Alberta and Hospitals, Edmonton, Alberta, Canada. bjugdutt@ualberta.ca
Idikio
Halliday
H
Uwiera
Richard R E
RR
D047228:Angiotensin II Type 1 Receptor Blockers / Q000627:therapeutic use; D057911:Angiotensin Receptor Antagonists; D000806:Angiotensin-Converting Enzyme Inhibitors / Q000627:therapeutic use*; D000818:Animals; D001562:Benzimidazoles / Q000627:therapeutic use; D001713:Biphenyl Compounds; D003094:Collagen / Q000187:drug effects / Q000378:metabolism*; D004285:Dogs; D004656:Enalapril / Q000627:therapeutic use; D006909:Hydroxyproline / Q000378:metabolism; D009203:Myocardial Infarction / Q000188:drug therapy* / Q000473:pathology; D015425:Myocardial Reperfusion; D007703:Peptidyl-Dipeptidase A / Q000737:chemistry* / Q000378:metabolism; D013777:Tetrazoles / Q000627:therapeutic use; D053773:Transforming Growth Factor beta1 / Q000378:metabolism; D018487:Ventricular Dysfunction, Left / Q000188:drug therapy* / Q000209:etiology / Q000473:pathology; D020257:Ventricular Remodeling / Q000187:drug effects*; D014945:Wound Healing
D047228:Angiotensin II Type 1 Receptor Blockers; D057911:Angiotensin Receptor Antagonists; D000806:Angiotensin-Converting Enzyme Inhibitors; D001562:Benzimidazoles; D001713:Biphenyl Compounds; D013777:Tetrazoles; D053773:Transforming Growth Factor beta1; D004656:Enalapril; D003094:Collagen; D007703:Peptidyl-Dipeptidase A; D006909:Hydroxyproline; C081643:candesartan