Losartan and acute myocardial infarction in insulin-resistant Zucker fatty rats: reduced ventricular arrhythmias and improved survival.
Insulin resistance (IR) and diabetes increase the risk of acute myocardial infarction (MI). Angiotensin receptor blockers (ARBs) have been shown to reduce the risk of cardiovascular events in patients with hypertension and diabetes, and to be beneficial after a large MI. Whether pretreatment with ARBs is beneficial in acute MI is unknown. We evaluated whether pre-, peri-, and post-MI treatment with the ARB losartan improved the outcome in the IR Zucker fatty rat (ZFR). ZFR (n=264) received either losartan (3 mg/kg daily) or vehicle for 7 d prior to MI. Early (24 h) protocol (n=31): ventricular arrhythmias were evaluated post-MI using continuous ambulatory ECG monitoring. Late (38 d) protocol (n=233): losartan was increased to 10 mg/kg daily 10 d post-MI and to 30 mg/kg daily 20 d post-MI. Blood glucose, cardiac hemodynamics and remodeling, GLUT-4, fetal gene expression, and survival were evaluated. In large-MI rats, losartan improved early survival (43% vs. 27% in controls, p=0.01) and late survival (23% vs.15% in controls, p=0.02). Improved early survival was associated with a reduction in ventricular arrhythmias. Losartan reduced pulmonary congestion, cardiac hypertrophy, and fetal gene expression in the absence of statistically significant changes in ventricular dilatation and hemodynamics. Blood glucose and cardiac GLUT-4 expression did not change with losartan. In IR ZFR, losartan improves post-MI survival, likely as a result of an early reduction in ventricular arrhythmias. There was also an associated reduction in pulmonary congestion, hypertrophy, and fetal gene expression.
Pourdjabbar
Ali
A
Division of Cardiology, St. Michael's Hospital, University Health Network, Toronto, ON, Canada.
Parker
Thomas G
TG
Desjardins
Jean-François
JF
Nguyen
Quang Trinh
QT
Tsoporis
James N
JN
Lapointe
Nathalie
N
Rouleau
Jean-Lucien
JL
D047228:Angiotensin II Type 1 Receptor Blockers / Q000494:pharmacology*; D000818:Animals; D001145:Arrhythmias, Cardiac / Q000517:prevention & control; D001794:Blood Pressure / Q000187:drug effects; D005786:Gene Expression Regulation / Q000187:drug effects; D051275:Glucose Transporter Type 4 / Q000235:genetics / Q000378:metabolism; D006352:Heart Ventricles / Q000187:drug effects; D017379:Hypertrophy, Left Ventricular / Q000188:drug therapy; D019808:Losartan / Q000494:pharmacology*; D008297:Male; D009203:Myocardial Infarction / Q000188:drug therapy*; D012333:RNA, Messenger / Q000378:metabolism; D051381:Rats; D011924:Rats, Zucker; D016019:Survival Analysis; D016276:Ventricular Function; D020257:Ventricular Remodeling / Q000187:drug effects
D047228:Angiotensin II Type 1 Receptor Blockers; D051275:Glucose Transporter Type 4; D012333:RNA, Messenger; D019808:Losartan