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.
Study Type
INTERVENTIONAL
Allocation
RANDOMIZED
Purpose
TREATMENT
Masking
NONE
Enrollment
72
The starting dose of Ramipril will be 2.5 mg once daily and rapidly titrated upward to 5 mg once daily after 5 days if systolic blood pressure is greater than 100 mmHg. After one month the patient will return to clinic for blood pressure check and will be titrated up to 10 mg once daily.
The starting dose of Candesartan cilexetil will be 4 mg or 8 mg once daily and doubled every 2 weeks, if systolic blood pressure is greater than 100 mmHg, to a maximum dose of 32 mg once daily. After one month the patient will return to clinic for blood pressure check and will be titrated up to 32 mg once daily.
The starting dose of Allopurinol is 300 mg daily.
University of Alabama at Birmingham
Birmingham, Alabama, United States
Left Ventricular End Diastolic Volume Indexed to Body Surface Area (LVEDV/BSA)
LVEDV/BSA: As an indicator of heart size, the blood volume of the heart is related to the body size. The relation of heart blood volume to body size is more accurate in determining pathology because larger people require a larger heart blood volume. The values that are too high or too low indicate a diseased myocardium. This is a measure of LV Diastolic Function. Since some visits did not occur at the scheduled 6 month intervals, the results have been divided into 3-month visit intervals.
Time frame: 5 visits per Participant over 2 years (about every 6 months)
Left Ventricular End-Diastolic Radius to Wall Thickness (LVED Radius/Wall Thickness)
LVED Radius/Wall thickness As an indicator of heart muscle mass and heart volume chamber diameter, the end-diastolic radius indexed to end diastolic wall thickness determines whether there is an adequate amount of heart muscle to pump the heart blood volume obtained from a two-dimensional analysis. The values that are too high or too low indicate a diseased myocardium. This is a measure of LV Geometry. Since some visits did not occur at the scheduled 6 month intervals, the results have been divided into 3-month visit intervals for reporting purposes.
Time frame: 5 visits per Participant over 2 years (about every 6 months)
Left Ventricular End-diastolic Mass Indexed to Left Ventricular End-diastolic Volume (LVED Mass/LVEDV)
LVED Mass/LVEDV: As an indicator of heart muscle mass and heart blood volume, the mass indexed to end diastolic volume determines whether there is an adequate amount of heart muscle to pump the heart blood volume obtained from a three-dimensional analysis. The values that are too high or too low indicate a diseased myocardium. This is a measure of LV Geometry. Since some visits did not occur at the scheduled 6 month intervals, the results have been divided into 3-month visit intervals for reporting purposes.
Time frame: 5 visits per Participant over 2 years (about every 6 months)
Left Ventricular Ejection Fraction (LVEF)
LVEF is a calculation of heart pump function determined from the volume after complete filling minus the volume after complete contraction divided by the volume after complete filling. A value of 55% or greater is normal. This is a measure of LV Systolic Function. Since some visits did not occur at the scheduled 6 month intervals, the results have been divided into 3-month visit intervals for reporting purposes
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Time frame: 5 visits per Participant over 2 years (about every 6 months)
Left Ventricular End Systolic Volume Indexed to Body Surface Area (LVESV/BSA)
LVESV/BSA: The end systolic volume is the blood volume of the heart at the end of contraction and is an index of the pump function of the heart. This relation to body size is more accurate in determining pathology because larger people require a larger heart blood volume. The values that are too high or too low indicate a diseased myocardium. This is a measure of LV Systolic Function. Since some visits did not occur at the scheduled 6 month intervals, the results have been divided into 3-month visit intervals.
Time frame: 5 visits per Participant over 2 years (about every 6 months)
LV End Systolic Maximum Shortening (LVES Max Shortening)
By identifying three points in three different planes in the heart muscle, the maximum shortening is the average of the difference between the distance between these three points at the end of filling of the heart and the end of contraction divided by the length at the end of filling times 100. The maximum shortening is a three dimensional analysis. The higher values indicate a healthy heart. This is a measure of LV Systolic Function. Since some visits did not occur at the scheduled 6 month intervals, the results have been divided into 3-month visit intervals for reporting purposes.
Time frame: 5 visits per Participant over 2 years (about every 6 months)
Peak Early Filling Rate Normalized to EDV
The Peak Early Filling Rate Normalized to EDV is calculated from the slope of the volume during the early filling of the heart with respect to time. The higher values indicate a very healthy heart muscle and lower values are indicative of a very stiff muscle. This is a measure of LV Diastolic Function. Since some visits did not occur at the scheduled 6 month intervals, the results have been divided into 3-month visit intervals for reporting purposes.
Time frame: 5 visits per Participant over 2 years (about every 6 months)