Role of endogenous ET-1 in the regulation of myocardial blood flow in lean and obese humans.

Endothelin is an important determinant of peripheral vascular tone, and increased endogenous endothelin activity contributes to peripheral vascular dysfunction in human obesity. The contributions of endothelin to the regulation of coronary vascular tone in health in humans have not been well studied. We hypothesized that the contribution of endothelin to the regulation of myocardial perfusion would be augmented in human obesity. Using [NH(3)]ammonia positron emission tomography (PET), we measured myocardial perfusion under resting and adenosine-stimulated conditions on two separate days, with and without concurrent exposure to BQ123, an antagonist of type A endothelin receptors (1 micromol/min IV beginning 90 min before measurement). We studied 10 lean and 9 obese subjects without hypertension, hyperlipidemia, or diabetes mellitus. We observed a BQ123-induced increase in resting myocardial perfusion of approximately 40%, not different between lean and obese subjects (BQ123-induced increase in flow: lean 0.12 +/- 0.20, obese 0.32 +/- 0.51 ml/g/min, P = 0.02 BQ123 effect, P = 0.27 comparing response across groups). Although basal flow rates varied by region of the myocardium, the BQ123 effect was seen in all regions. BMI and cholesterol were significantly related to BQ123-induced increases in basal tone in multivariable analysis. There was no baseline difference in the adenosine-stimulated increase in blood flow between lean and obese subjects, and BQ123 failed to augment these responses in either group. These observations suggest that endothelin is an important contributor to the regulation of myocardial perfusion under resting conditions in healthy lean and obese humans, with increased contributions in proportion to increasing obesity.

Usefulness of positron emission tomography in predicting long-term outcome in patients with diabetes mellitus and ischemic left ventricular dysfunction.

We assessed the value of positron emission tomography to predict long-term outcome in patients with diabetes and ischemic left ventricular (LV) dysfunction. Circumferential profiles of nitrogen-13 ammonia (NH3) and fluorine-18 fluorodeoxyglucose uptakes were obtained in 61 patients who had diabetes and ischemic LV dysfunction. Patient profiles were compared with those from a normal database. NH3 and fluorine-18 fluorodeoxyglucose defect sizes and extent of perfusion-metabolism mismatch (percentage of myocardium with fluorine-18 fluorodeoxyglucose uptake minus NH3 uptake >2 SD above the normal difference) were determined. Patients were followed every 6 months. Over a mean follow-up of 4.3 years, cardiac death occurred in 52% of patients who underwent revascularization and 61% of those who underwent medical therapy (p = 0.69). No clinical or imaging variables predicted cardiac death in patients who underwent revascularization. In those who received medical therapy, mismatch in > or =3% of the left ventricle (risk ratio 4.0, p = 0.01) was the only multivariate predictor of cardiac death. Revascularization improved survival of patients who had mismatch of > or =3% at 4 years (p = 0.003) and at 8 years (p = 0.012) of follow-up. Patients who had mismatch > or =3% and ejection fraction <30% had the greatest improvement in survival with revascularization compared with medical therapy (p <0.0001). Revascularization also improved 4-year survival of patients who had NH3 perfusion defects of > or =25% of the left ventricle (p = 0.02). In conclusion, mismatch identifies medically treated patients who have diabetes and LV dysfunction, who are at high risk for cardiac death. Intermediate- and long-term survival of patients who have diabetes and mismatch may be improved with revascularization, and those who have significant mismatch and severe LV dysfunction have the greatest benefit.