Alvaro D. Facta

Coronary Circulatory Dysfunction in Insulin Resistance, Impaired Glucose Tolerance, and Type 2 Diabetes Mellitus

Background—Abnormal coronary endothelial reactivity has been demonstrated in diabetes and is associated with an increased rate of cardiovascular events. Our objectives were to investigate the presence of functional coronary circulatory abnormalities over the full spectrum of insulin resistance and to determine whether these would differ in severity with more advanced states of insulin resistance. Methods and Results—Myocardial blood flow (MBF) was measured with positron emission tomography and 13N-ammonia to characterize coronary circulatory function in states of insulin resistance without carbohydrate intolerance (IR), impaired glucose tolerance (IGT), and normotensive and hypertensive type 2 diabetes mellitus (DM) compared with insulin-sensitive (IS) individuals. Indices of coronary function were total vasodilator capacity (mostly vascular smooth muscle–mediated) during pharmacological vasodilation and the nitric oxide–mediated, endothelium-dependent vasomotion in response to cold pressor testing. Total vasodilator capacity was similar in normoglycemic individuals (IS, IR, and IGT), whereas it was significantly decreased in normotensive (−17%) and hypertensive (−34%) DM patients. Compared with IS, endothelium-dependent coronary vasomotion was significantly diminished in IR (−56%), as well as in IGT and normotensive and hypertensive diabetic patients (−85%, −91%, and −120%, respectively). Conclusions—Progressively worsening functional coronary circulatory abnormalities of nitric oxide–mediated, endothelium-dependent vasomotion occur with increasing severity of insulin-resistance and carbohydrate intolerance. Attenuated total vasodilator capacity accompanies the more clinically evident metabolic abnormalities in diabetes.

Chronic inflammation and impaired coronary vasoreactivity in patients with coronary risk factors.

Background—The goal of this study was to examine a possible association between systemic microinflammation, as reflected by C-reactive protein (CRP) serum levels, and coronary vasomotion in patients with coronary risk factors but with angiographically normal coronary arteries. Methods and Results—Coronary vasomotor function was studied in response to cold pressor testing (CPT) in 71 patients with normal angiograms. In all patients, CPT-induced changes in epicardial luminal area (LA; mm2) were assessed with quantitative angiography. Within 20 days, myocardial blood flow (MBF) responses to CPT were measured (mL · g−1 · min−1) noninvasively with 13N-ammonia and PET imaging. The CPT-induced mean changes in LA and in MBF in patients with elevated CRP (≥0.5 mg/dL) were significantly impaired compared with patients presenting with CRP levels within normal range (<0.5 mg/dL) (&Dgr;LA, −1.09±0.86 versus 0.45±0.63 mm2; &Dgr;MBF, 0.06±0.18 versus 0.44±0.31 mL · g−1 · min−1; P<0.0001, respectively). Coronary LA changes and MBF responses to CPT were inversely correlated with CRP serum levels (r=−0.84 and r=−0.63; P<0.0001). Lastly, regression analysis revealed a significant correlation between the changes in LA and MBF during CPT for patients with elevated CRP levels and those for patients with normal CRP levels (r=0.56 and r=0.66; P<0.001). Conclusions—These findings suggest a direct association between systemic microinflammation and altered coronary vasomotor function of both the epicardial conductance and the arteriolar resistance vessels.

Improvement in coronary vascular dysfunction produced with euglycaemic control in patients with type 2 diabetes

Objective: To determine the effect of plasma glucose lowering on coronary circulatory function in type 2 diabetes mellitus. Methods: Twenty patients with type 2 diabetes and 18 weight-matched controls were studied. At baseline, myocardial blood flow (MBF) was measured with [13N]ammonia and positron emission tomography at rest, during cold pressor testing (CPT), and during adenosine hyperaemia. In diabetic patients, MBF and blood chemistry were analysed again after 3 months of glucose-lowering treatment with glyburide and metformin. Results: Although hyperaemic MBF did not differ significantly between the patients and controls (1.81 (0.38) v 1.97 (0.43) ml/min/g; mean (SD)), the CPT-induced MBF increase (ΔMBF) was significantly less in diabetic patients than in controls (0.07 (0.07) v 0.25 (0.12) ml/min/g; p<0.001). Treatment with glyburide and metformin significantly decreased plasma glucose concentrations from 207 (76) to 134 (52) mg/dl (p<0.001). This decrease in plasma glucose was paralleled by a significant increase in ΔMBF in response to CPT (0.20 (0.16) from 0.07 (0.07) ml/min/g; p<0.001), which tended to be lower than in controls at baseline (0.20 (0.16) v 0.25 (0.12) ml/min/g; p  =  NS). The decrease in plasma glucose concentrations correlated significantly with the improvement in ΔMBF in response to CPT (r = 0.67, p<0.01). Conclusions: Type 2 diabetes mellitus is associated with abnormal MBF response to CPT, which can be significantly improved by euglycaemic control with glyburide and metformin. The close association between the decrease in plasma glucose concentration and the improvement in coronary vasomotor function in response to CPT suggests a direct adverse effect of raised plasma glucose concentration on diabetes-related coronary vascular disease.

Improvement in coronary endothelial function is independently associated with a slowed progression of coronary artery calcification in type 2 diabetes mellitus

AIMS To examine a relationship between alterations of structure and function of the arterial wall in response to glucose-lowering therapy in type 2 diabetes mellitus (DM) after a 1-year follow-up (FU). METHODS AND RESULTS In DM (n = 22) and in healthy controls (n = 17), coronary artery calcification (CAC) was assessed with electron beam tomography and carotid intima-media thickness (IMT) with ultrasound, whereas coronary function was determined with positron emission tomography-measured myocardial blood flow (MBF) at rest, during cold pressor testing (CPT), and during adenosine stimulation at baseline and after FU. The decrease in plasma glucose in DM after a mean FU of 14 +/- 1.9 months correlated with a lower progression of CAC and carotid IMT (r = 0.48, P < or = 0.036 and r = 0.46, P < or = 0.055) and with an improvement in endothelium-related DeltaMBF to CPT and to adenosine (r = 0.46, P < or = 0.038 and r = 0.36, P < or = 0.056). After adjusting for metabolic parameters by multivariate analysis, the increases in DeltaMBF to CPT after glucose-lowering treatment remained a statistically significant independent predictor of the progression of CAC (P < or = 0.001 by one-way analysis of variance). CONCLUSION In DM, glucose-lowering treatment may beneficially affect structure and function of the vascular wall, whereas the observed improvement in endothelium-related coronary artery function may also mediate direct preventive effects on the progression of CAC.