impact of diabetes on left ventricular remodeling

Conditions: Diabetes

Summary: the investigators hypothesize that in patients with diabetes and acute myocardial infarction (mi), ang ii type-1 receptor blockade (at1rb) attenuates left ventricle (lv) remodeling to a greater extent than angiotensin converting enzyme (ace) inhibitor therapy and that the addition of xanthine oxidase (xo) inhibitor, allopurinol, results in further improvement in lv remodeling and function in the follow-up phase after mi.

following myocardial infarction (mi), the incidence of heart failure and mortality rates are approximately two-fold higher in patients with diabetes compared to those without diabetes. this increased risk for heart failure and mortality appears to be refractory to currently available treatments such as angiotensin converting enzyme (ace) inhibitors, despite the effectiveness of such treatments in reducing overall morbidity and mortality following mi. hyperglycemia stimulates cardiomyocyte angiotensin ii (ang ii) formation, which has been implicated in increased myocyte cell death in diabetes. furthermore, in humans, chymase is the predominant pathway of ang ii formation and this pathway of ang ii production is not blocked by ace inhibition. therefore, in diabetes where ang ii levels may already be elevated due to hyperglycemia the increase in ang ii formation associated with left ventricular (lv) remodeling continued ang ii formation from chymase could be particularly detrimental. in addition to enhanced ang ii production, hyperglycemia and diabetes also amplify the production of reactive oxygen species (ros). ros are associated with increased in lv remodeling and myocyte apoptosis. furthermore, xanthine oxidase (xo), an important source of ros in myocytes, is increased in a rat model of myocardial infarction and in diabetes. thus, increased xo-mediated ros production following mi may be especially damaging in diabetic patients where ros production is already elevated. interestingly, acute treatment with allopurinol, an inhibitor of xo, improves cardiac function in heart failure and improves endothelial dysfunction in patients with type-2 diabetes. to test our hypothesis the investigators will investigate the following aims in diabetic patients after acute mi: aim 1: show that the progression of lv remodeling and dysfunction in diabetic patients will be attenuated to greater extent by at1rb than by ace inhibitor. aim 2: show that the addition of xo inhibition results in further attenuation of lv remodeling than with at1rb or ace inhibitor alone. aim 3: show that baseline and follow-up lv remodeling and dysfunction and inflammatory markers differ in diabetic and non-diabetic patients post-mi.

Eligibility criteria:
inclusion criteria: 1. 21 years old or older 2. mi documented by increase in troponin \> 0.78 ng/ml or ckmb ≥ 3% of total ck patients who have type-2 diabetes defined by any one of the following: 3. confirmed (i.e., two or more readings) fasting blood glucose \>126mg/dl; or 4. random glucose ≥200mg/dl; or 5. 2 hour glucose ≥200mg/dl following 75g of glucose; or 6. current treatment with diet or oral agents directed at the control of hyperglycemia either alone or in combination with insulin; or 7. current treatment with insulin with no prior history of diabetic ketoacidosis. exclusion criteria: 1. type-1 diabetes. 2. class iii or iv heart failure. 3. cardiomyopathy (including hypertrophic and amyloidosis). 4. congenital or pericardial diseases. 5. intolerance to either ace inhibitor, at1-rb or allopurinol. 6. renal failure with creatinine \> 2.5 mg/dl. 7. renal artery stenosis. 8. severe comorbidity such as liver disease or malignancy. 9. pregnancy (negative pregnancy test and effective contraceptive methods are required prior to enrollment of females of childbearing potential (not post-menopausal or surgically sterilized). 10. chronic steroid use. 11. unable to understand or cooperate with protocol requirements. 12. severe claustrophobia. 13. presence of a pacemaker or non-removable hearing aid. 14. presence of metal clips in the body.

Keywords: diabetes acute mi ang ii type-1 receptor blockade (at1rb) lv remodeling ace inhibitor therapy xo inhibitor, allopurinol systolic dysfunction diastolic dysfunction lv dimensions cardiac mri