Angiotensin II Type 1 Receptor Blocker Attenuates Exacerbated Left Ventricular Remodeling and Failure in Diabetes-Associated Myocardial Infarction

Diabetes mellitus adversely affects the outcomes in patients with myocardial infarction (MI), due in part to the exacerbation of left ventricular (LV) remodeling. Although angiotensin II type 1 receptor blocker (ARB) has been demonstrated to be effective in the treatment of heart failure, information about the potential benefits of ARB on advanced LV failure associated with diabetes is lacking. To induce diabetes, male mice were injected intraperitoneally with streptozotocin (200 mg/kg). At 2 weeks, anterior MI was created by ligating the left coronary artery. These animals received treatment with olmesartan (0.1 mg/kg/day; n = 50) or vehicle (n = 51) for 4 weeks. Diabetes worsened the survival and exaggerated echocardiographic LV dilatation and dysfunction in MI. Treatment of diabetic MI mice with olmesartan significantly improved the survival rate (42% versus 27%, P < 0.05) without affecting blood glucose, arterial blood pressure, or infarct size. It also attenuated LV dysfunction in diabetic MI. Likewise, olmesartan attenuated myocyte hypertrophy, interstitial fibrosis, and the number of apoptotic cells in the noninfarcted LV from diabetic MI. Post-MI LV remodeling and failure in diabetes were ameliorated by ARB, providing further evidence that angiotensin II plays a pivotal role in the exacerbated heart failure after diabetic MI.

[1]  M. Pfeffer,et al.  Ventricular Remodeling After Myocardial Infarction: Experimental Observations and Clinical Implications , 1990, Circulation.

[2]  Teven,et al.  MORTALITY FROM CORONARY HEART DISEASE IN SUBJECTS WITH TYPE 2 DIABETES AND IN NONDIABETIC SUBJECTS WITH AND WITHOUT PRIOR MYOCARDIAL INFARCTION , 2000 .

[3]  E. Sonnenblick,et al.  Myocyte Death in Streptozotocin-Induced Diabetes in Rats Is Angiotensin II- Dependent , 2000, Laboratory Investigation.

[4]  R. Califf,et al.  Outcome of patients with diabetes mellitus and acute myocardial infarction treated with thrombolytic agents. The Thrombolysis and Angioplasty in Myocardial Infarction (TAMI) Study Group. , 1993, Journal of the American College of Cardiology.

[5]  I. Tikkanen,et al.  Cardiomyocyte apoptosis and ventricular remodeling after myocardial infarction in rats. , 2001, American journal of physiology. Heart and circulatory physiology.

[6]  A. Takeshita,et al.  Pioglitazone, a Peroxisome Proliferator-Activated Receptor-&ggr; Agonist, Attenuates Left Ventricular Remodeling and Failure After Experimental Myocardial Infarction , 2002, Circulation.

[7]  A. Jaffe,et al.  The effect of diabetes mellitus on prognosis and serial left ventricular function after acute myocardial infarction: contribution of both coronary disease and diastolic left ventricular dysfunction to the adverse prognosis. The MILIS Study Group. , 1989, Journal of the American College of Cardiology.

[8]  A. Takeshita,et al.  Streptozotocin-induced hyperglycemia exacerbates left ventricular remodeling and failure after experimental myocardial infarction. , 2003, Journal of the American College of Cardiology.

[9]  A. Jaffe,et al.  The effect of diabetes mellitus on prognosis and serial left ventricular function after acute myocardial infarction: contribution of both coronary disease and diastolic left ventricular dysfunction to the adverse prognosis. The MILIS Study Group. , 1989, Journal of the American College of Cardiology.

[10]  M. Pfeffer,et al.  Valsartan in acute myocardial infarction trial (VALIANT): rationale and design. , 2000, American heart journal.

[11]  Karl Swedberg,et al.  Valsartan, captopril, or both in myocardial infarction complicated by heart failure, left ventricular dysfunction, or both. , 2003, The New England journal of medicine.

[12]  K. Sunagawa,et al.  Selective disruption of MMP-2 gene exacerbates myocardial inflammation and dysfunction in mice with cytokine-induced cardiomyopathy. , 2005, American journal of physiology. Heart and circulatory physiology.

[13]  A. Jaffe,et al.  Letters to the editor Reply , 1989 .

[14]  A. Takeshita,et al.  Targeted deletion of MMP-2 attenuates early LV rupture and late remodeling after experimental myocardial infarction. , 2003, American journal of physiology. Heart and circulatory physiology.

[15]  Shokei Kim,et al.  Contribution of cardiac renin-angiotensin system to ventricular remodelling in myocardial-infarcted rats. , 1993, Journal of molecular and cellular cardiology.

[16]  A. Takeshita,et al.  Important role of local angiotensin II activity mediated via type 1 receptor in the pathogenesis of cardiovascular inflammatory changes induced by chronic blockade of nitric oxide synthesis in rats. , 2000, Circulation.

[17]  K. Dickstein,et al.  Effects of losartan and captopril on mortality and morbidity in high-risk patients after acute myocardial infarction: the OPTIMAAL randomised trial , 2002, The Lancet.

[18]  F. Eberli,et al.  Progressive left ventricular remodeling and apoptosis late after myocardial infarction in mouse heart. , 2000, American journal of physiology. Heart and circulatory physiology.

[19]  Bruce H. R. Wolffenbuttel,et al.  Effects of ramipril on cardiovascular and microvascular outcomes in people with diabetes mellitus: results of the HOPE study and MICRO-HOPE substudy , 2000, The Lancet.

[20]  H. Drexler,et al.  Comparative effects of chronic angiotensin-converting enzyme inhibition and angiotensin II type 1 receptor blockade on cardiac remodeling after myocardial infarction in the rat. , 1994, Circulation.

[21]  S. Yusuf,et al.  Effects of ramipril on cardiovascular and microvascular outcomes in people with diabetes mellitus: results of the HOPE study and MICRO-HOPE substudy. Heart Outcomes Prevention Evaluation Study Investigators. , 2000 .

[22]  R. Califf,et al.  Angiographic findings and outcome in diabetic patients treated with thrombolytic therapy for acute myocardial infarction: the GUSTO-I experience. , 1996, Journal of the American College of Cardiology.

[23]  D. Kass,et al.  beta-blockade prevents sustained metalloproteinase activation and diastolic stiffening induced by angiotensin II combined with evolving cardiac dysfunction. , 2000, Circulation research.

[24]  R. Weiss,et al.  Antioxidants attenuate myocyte apoptosis in the remote non-infarcted myocardium following large myocardial infarction. , 2000, Cardiovascular research.

[25]  A. Maseri,et al.  Myocardial Cell Death in Human Diabetes , 2000, Circulation research.

[26]  O. Carretero,et al.  Effects of angiotensin-converting enzyme inhibitors and angiotensin II type 1 receptor antagonists in rats with heart failure. Role of kinins and angiotensin II type 2 receptors. , 1997, The Journal of clinical investigation.

[27]  K. Weber,et al.  Extracellular matrix remodeling in heart failure: a role for de novo angiotensin II generation. , 1997, Circulation.

[28]  P. Buttrick,et al.  Experimental diabetes is associated with functional activation of protein kinase C epsilon and phosphorylation of troponin I in the heart, which are prevented by angiotensin II receptor blockade. , 1997, Circulation research.

[29]  Shokei Kim,et al.  Effects of candesartan and cilazapril on rats with myocardial infarction assessed by echocardiography. , 1999, Hypertension.

[30]  C. Kramer,et al.  Combined Angiotensin II Receptor Antagonism and Angiotensin-Converting Enzyme Inhibition Further Attenuates Postinfarction Left Ventricular Remodeling , 2001, Circulation.

[31]  E. J. Brown,et al.  Effect of captopril on mortality and morbidity in patients with left ventricular dysfunction after myocardial infarction. Results of the survival and ventricular enlargement trial. The SAVE Investigators. , 1992, The New England journal of medicine.

[32]  M. Cooper,et al.  Pathogenesis, prevention, and treatment of diabetic nephropathy , 1998, The Lancet.