Effect of Mineralocorticoid Receptor Blockade in T2D
Effect of Mineralocorticoid Receptor Blockade in T2D
Reduced coronary flow reserve (CFR), an indicator of coronary microvascular dysfunction, is seen in type 2 diabetes mellitus (T2DM) and predicts cardiac mortality. Since aldosterone plays a key role in vascular injury, the aim of this study was to determine whether mineralocorticoid receptor (MR) blockade improves CFR in individuals with T2DM. Sixty-four men and women with well-controlled diabetes on chronic ACE inhibition (enalapril 20 mg/day) were randomized to add-on therapy of spironolactone 25 mg, hydrochlorothiazide (HCTZ) 12.5 mg, or placebo for 6 months. CFR was assessed by cardiac positron emission tomography at baseline and at the end of treatment. There were significant and similar decreases in systolic blood pressure with spironolactone and HCTZ but not with placebo. CFR improved with treatment in the spironolactone group as compared with the HCTZ group and with the combined HCTZ and placebo groups. The increase in CFR with spironolactone remained significant after controlling for baseline CFR, change in BMI, race, and statin use. Treatment with spironolactone improved coronary microvascular function, raising the possibility that MR blockade could have beneficial effects in preventing cardiovascular disease in patients with T2DM.
Individuals with type 2 diabetes mellitus (T2DM) have an increased risk of cardiovascular disease (CVD). Diabetes accelerates coronary artery atherosclerosis and impairs coronary microvascular function. In the absence of significant epicardial coronary artery disease, patients with T2DM and impaired myocardial blood flow (MBF) (coronary flow reserve [CFR] below median) have a 3.2-fold increased rate of cardiac death in comparison with those with CFR above median. Thus, CFR is a good intermediate marker of CVD.
Aldosterone plays a critical role in the pathophysiology of CVD. In heart failure patients, mineralocorticoid receptor (MR) blockade improves cardiac morbidity and mortality. MR blockade reduces coronary microvascular damage in a rodent model of angiotensin II–dependent cardiovascular injury, suggesting that excess MR activation promotes injury to the coronary microvasculature. Further, preclinical studies demonstrate that excess MR activation contributes to vascular injury in obesity and diabetes.
We hypothesized that in humans with T2DM without clinical ischemic heart disease, addition of MR blockade to chronic ACE inhibitor (ACEI) therapy would improve coronary microvascular function, as assessed by quantitative positron emission tomography (PET) measures of CFR.
Abstract and Introduction
Abstract
Reduced coronary flow reserve (CFR), an indicator of coronary microvascular dysfunction, is seen in type 2 diabetes mellitus (T2DM) and predicts cardiac mortality. Since aldosterone plays a key role in vascular injury, the aim of this study was to determine whether mineralocorticoid receptor (MR) blockade improves CFR in individuals with T2DM. Sixty-four men and women with well-controlled diabetes on chronic ACE inhibition (enalapril 20 mg/day) were randomized to add-on therapy of spironolactone 25 mg, hydrochlorothiazide (HCTZ) 12.5 mg, or placebo for 6 months. CFR was assessed by cardiac positron emission tomography at baseline and at the end of treatment. There were significant and similar decreases in systolic blood pressure with spironolactone and HCTZ but not with placebo. CFR improved with treatment in the spironolactone group as compared with the HCTZ group and with the combined HCTZ and placebo groups. The increase in CFR with spironolactone remained significant after controlling for baseline CFR, change in BMI, race, and statin use. Treatment with spironolactone improved coronary microvascular function, raising the possibility that MR blockade could have beneficial effects in preventing cardiovascular disease in patients with T2DM.
Introduction
Individuals with type 2 diabetes mellitus (T2DM) have an increased risk of cardiovascular disease (CVD). Diabetes accelerates coronary artery atherosclerosis and impairs coronary microvascular function. In the absence of significant epicardial coronary artery disease, patients with T2DM and impaired myocardial blood flow (MBF) (coronary flow reserve [CFR] below median) have a 3.2-fold increased rate of cardiac death in comparison with those with CFR above median. Thus, CFR is a good intermediate marker of CVD.
Aldosterone plays a critical role in the pathophysiology of CVD. In heart failure patients, mineralocorticoid receptor (MR) blockade improves cardiac morbidity and mortality. MR blockade reduces coronary microvascular damage in a rodent model of angiotensin II–dependent cardiovascular injury, suggesting that excess MR activation promotes injury to the coronary microvasculature. Further, preclinical studies demonstrate that excess MR activation contributes to vascular injury in obesity and diabetes.
We hypothesized that in humans with T2DM without clinical ischemic heart disease, addition of MR blockade to chronic ACE inhibitor (ACEI) therapy would improve coronary microvascular function, as assessed by quantitative positron emission tomography (PET) measures of CFR.
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