Aging-related early changes in markers of ventricular and matrix remodeling after reperfused ST-segment elevation myocardial infarction in the canine model: effect of early therapy with an angiotensin II type 1 receptor blocker.
BACKGROUND
Elderly patients with reperfused ST-segment-elevation myocardial infarction are at increased risk for left ventricular remodeling. Extracellular matrix damage has been implicated in early remodeling. We hypothesized that aging results in enhanced early reperfusion injury and left ventricular remodeling after reperfused ST-segment-elevation myocardial infarction and that early therapy initiated at the time of reperfusion with an angiotensin II type 1 receptor blocker such as candesartan attenuates age-related increases in reperfusion injury and remodeling.


RESULTS
We randomized 3 groups of dogs (age, 1 to 2, 2.1 to 5, and 5.1 to 10 years) with reperfused ST-segment-elevation myocardial infarction (90 minutes of ischemia, 2 hours of reperfusion) to therapy with placebo or candesartan (1 mg/kg CV-11974) over 30 minutes from the onset of reperfusion. Reperfusion in placebo groups was associated with aging-related changes in the ischemic zones in markers of damage (increased ischemic injury, infarct size [as percent risk], cardiomyocyte apoptosis, blood flow impairment, no reflow), structural remodeling (increased left ventricular dilation and dysfunction), extracellular matrix remodeling (increased expression of secretory leucocyte protease inhibitor, secreted protein acidic and rich in cysteine, osteopontin, a disintegrin and metalloproteinase-10 and -17, and matrix metalloproteinase-9 and -2), and inflammation (increased inducible nitric oxide synthase, proinflammatory cytokines interleukin-6 and tumor necrosis factor-alpha, and transforming growth factor-beta(1); decreased antiinflammatory cytokine interleukin-10). Compared with placebo, candesartan attenuated these age-dependent changes.


CONCLUSIONS
Aging results in age-dependent early increases in markers of damage and adverse structural and matrix remodeling after ST-segment-elevation myocardial infarction reperfused after 90 minutes of ischemia, and early therapy initiated at the time of reperfusion with the angiotensin II type 1 receptor blocker candesartan attenuates these changes. This strategy needs clinical confirmation.
Jugdutt
Bodh I
BI
Division of Cardiology, Walter MacKenzie Health Sciences Centre, University of Alberta, Edmonton, Alberta, Canada. bjugdutt@ualberta.ca
Jelani
Anwar
A
Palaniyappan
Ariv
A
Idikio
Halliday
H
Uweira
Richard E
RE
Menon
Vijay
V
Jugdutt
Catherine E
CE
D000375:Aging / Q000502:physiology*; D047228:Angiotensin II Type 1 Receptor Blockers / Q000627:therapeutic use*; D000806:Angiotensin-Converting Enzyme Inhibitors / Q000627:therapeutic use; D000818:Animals; D017209:Apoptosis; D001562:Benzimidazoles / Q000627:therapeutic use; D001713:Biphenyl Compounds; D001794:Blood Pressure; D004195:Disease Models, Animal; D004285:Dogs; D004452:Echocardiography; D015151:Immunoblotting; D020778:Matrix Metalloproteinase 2; D020780:Matrix Metalloproteinase 9; D009203:Myocardial Infarction / Q000188:drug therapy / Q000401:mortality / Q000473:pathology / Q000503:physiopathology*; D015425:Myocardial Reperfusion; D010919:Placebos; D016133:Polymerase Chain Reaction; D012313:RNA / Q000235:genetics / Q000302:isolation & purification; D015427:Reperfusion Injury / Q000188:drug therapy; D013599:Systole / Q000502:physiology; D013777:Tetrazoles / Q000627:therapeutic use
D047228:Angiotensin II Type 1 Receptor Blockers; D000806:Angiotensin-Converting Enzyme Inhibitors; D001562:Benzimidazoles; D001713:Biphenyl Compounds; D010919:Placebos; D013777:Tetrazoles; D012313:RNA; D020778:Matrix Metalloproteinase 2; D020780:Matrix Metalloproteinase 9; C081643:candesartan