Effects of endothelin a receptor blockade on endothelial function in patients with chronic heart failure.

BACKGROUND: Chronic heart failure (CHF) is associated with impaired endothelium-dependent vasodilation and increased basal vascular tone due, in part, to elevated endothelin-1 plasma levels. In the present study, we investigated whether a reduction of vascular tone using an endothelin A receptor blocker attenuates the impairment of endothelium-dependent, flow-mediated vasodilation (FMD). METHODS AND RESULTS: Twenty-one patients with CHF randomly received either the endothelin A receptor blocker LU 135252 (30 mg/d, n=7; 300 mg/d, n=7) or a placebo (n=7). Using high-resolution ultrasound, FMD and endothelium-independent, nitroglycerin-induced dilation of the brachial artery were assessed at baseline in the 21 patients with CHF and in 11 controls and after 3 weeks treatment in the 21 patients with CHF. FMD at baseline was impaired in all 21 patients with CHF (3.2+/-2%) when compared with the 11 controls (9.7+/-4.9%; P=0.0005). In comparison with baseline, FMD significantly improved after 3 weeks of treatment with LU 135252 in all 14 patients receiving it (from 3.0+/-2.0% to 4.9+/-2.9%; P=0.04), but FMD remained unchanged with placebo. Subgroup analysis, according to different dosages, revealed a significant increase of FMD compared with baseline (from 2.4+/-1.5% to 5.5+/-2.4%; P=0.03) in the patients treated with the low-dose (30 mg/d), whereas a high dose of 300 mg/d failed to increase FMD significantly. Improvement in the high-dose group, however, may have been masked by reduced vasodilator capacity due to a significant increase in vessel size (from 4.8+/-0.4 to 5.1+/-0.7 mm; P=0.03). CONCLUSIONS: These results suggest that endothelin A receptor blockade improves FMD in CHF patients.

Effects of vitamin E on chronic and acute endothelial dysfunction in smokers.

OBJECTIVES: The aims of this study were to determine whether chronic or acute impairment of flow mediated vasodilation (FMD) in the brachial artery of smokers can be restored or preserved by the antioxidant vitamin E. BACKGROUND: Transient impairment of endothelial function after heavy cigarette smoking and chronic endothelial dysfunction in smokers result at least in part from increased oxidative stress. METHODS: We studied 22 healthy male smokers (mean +/- SD, 23 +/- 9 cigarettes per day) randomly assigned to receive either 600 IU vitamin E per day (n = 11, age 28 +/- 6 years) or placebo (n = 11, age 27 +/- 6 years) for four weeks and 11 age-matched healthy male nonsmokers. Flow mediated vasodilation and endothelium-independent, nitroglycerin-induced dilation were assessed in the brachial artery using high resolution ultrasound (7.5 MHz) at baseline and after therapy. Subjects stopped smoking 2 h before the ultrasound examinations. At the end of the treatment period, a third scan was obtained 20 min after smoking a cigarette (0.6 mg nicotine, 7 mg tar) to estimate transient impairment of FMD. RESULTS: Flow mediated vasodilation at baseline was abnormal in the vitamin E (5.3 +/- 3.8, p < 0.01) and in the placebo group (6.4 +/- 3.5, p < 0.05) compared with nonsmoking controls (11.6 +/- 4.7). Using a two-way repeated measures analysis of variance (ANOVA) to examine the effects of vitamin E on FMD, we found no effect for the grouping factor (p = 0.5834) in the ANOVA over time but a highly significant difference with respect to time (p = 0.0065). The interaction of the time factor and the grouping factor also proved to be significant (p = 0.0318). Flow mediated vasodilation values remained similar after treatment for four weeks in both groups but declined faster after smoking a cigarette in subjects taking placebo compared with those receiving vitamin E (p values from successive differences for the time/group factor: 0.0001/0.0017). The transient attenuation of FMD (calculated as the percent change in FMD) was related to the improvement of the antioxidant status, estimated as percent changes in thiobarbituric acid-reactive substances (r = -0.67, p = 0.0024). Nitroglycerin-induced dilation did not differ between study groups at baseline or after therapy. CONCLUSIONS: These results demonstrate that oral supplementation of vitamin E can attenuate transient impairment of endothelial function after heavy smoking due to an improvement of the oxidative status but cannot restore chronic endothelial dysfunction within four weeks in healthy male smokers.

Effects of successful parathyroidectomy on altered arterial reactivity in patients with hypercalcaemia: results of a 3-year follow-up study.

OBJECTIVE: Serum calcium was found to be an independent, prospective risk factor for myocardial infarction. We have previously shown that altered arterial reactivity in the course of primary hyperparathyroidism, a disease characterized by hypercalcaemia, may predominantly involve the arterial media and not the endothelium as observed in patients with various stages of atherosclerosis. The present study was performed to test whether successful parathyroidectomy can improve vascular reactivity in patients with primary hyperparathyroidism. SUBJECTS AND DESIGN: Endothelium-dependent, flow-mediated and endothelium-independent, nitroglycerin-induced dilatation were assessed by brachial artery ultrasound (7 MHz) in 18 patients with primary hyperparathyroidism (mean +/- SD; age, 55.1 +/- 12.6) prior to and 3 years after successful parathyroidectomy. RESULTS: Parathyroidectomy resulted in significant decreases of PTH (242 +/- 186 vs. 34 +/- 24 ng/l, P = 0. 0001) and serum calcium levels (2.8 +/- 0.3 vs. 2.4 +/- 0.1 mm/l, P = 0.00001) and in an increase of serum phosphate levels (0.78 +/- 0. 23 vs. 1.17 +/- 0.18 mm/l, P = 0.00001). However, normalization of hormone and electrolyte levels did not lead to an improvement of flow-mediated dilatation (12.1 +/- 3.1 vs. 11.0 +/- 5.4&, P = 0.49) or nitroglycerin-induced dilatation (12.5 +/- 3.1 vs. 13.2 +/- 6.8%, P = 0.68) within the follow-up period. No changes were observed with respect to the risk factor profile, vessel size and blood flow. CONCLUSION: These data suggest that restoration of normocalcaemia by parathyroidectomy cannot improve vascular reactivity in patients with primary hyperparathyroidism but may prevent further progression of vascular disease within this period of time.

Endothelial dysfunction in patients with polycythaemia vera.

Patients with polycythaemia vera (PV) are at increased risk of developing arterial and venous thromboembolic complications. We investigated whether endothelium-dependent, flow-mediated vasodilatation (FMD) is impaired in PV patients without clinical evidence of artery disease as observed in patients with conventional cardiovascular risk factors. FMD and endothelium-independent, nitroglycerine-induced vasodilatation (NMD) were assessed using high-resolution ultrasound in the brachial artery of 20 patients with PV and 20 sex- and age-matched control subjects (CTL). FMD was markedly impaired in PV patients compared with CTL (7.6 +/- 2.9% versus 11.6 +/- 5.7%, P = 0.009) whereas NMD was similar in both study groups. The impairment of FMD was independently related to the presence of PV (r = -0.434, P = 0.009) and vessel size (r = -0.107, P = 0.038) but was not related to haematocrit values and platelet counts. The results demonstrate that PV is associated with endothelial dysfunction in the pre-clinical phase of arterial disease. However, the precise mechanisms by which PV leads to this altered vascular reactivity remain unclear.