Treatment of endothelial dysfunction

From: http://content.onlinejacc.org/cgi/content/full/34/3/631#T4

Role of the endothelium...

Assessment of endothelial...

Endothelial dysfunction

Treatment of endothelial...

Perspective

Conclusion

References





In the 1990s, studies have demonstrated that endothelial dysfunction in both animal models and humans can be attenuated by a variety of interventions (Table 4).









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Table 4 Treatment Associated With Improvement of Endothelial Dysfunction in Humans









Cholesterol lowering. Ohara et al. (73) demonstrated that cholesterol feeding increased the production of superoxide from the endothelium of rabbit aorta, and that dietary lowering of cholesterol not only improved endothelium-dependent vasodilation, but also normalized endothelial superoxide production (74). The finding that cholesterol lowering was associated with an improvement in endothelium-dependent vascular relaxation is in keeping with prior animal studies (75).

We studied the effect of LDL lowering and the combination of LDL lowering and antioxidant therapy on coronary epicardial endothelial function (76). Whereas LDL lowering resulted in an improvement in endothelial function, the combination of lovastatin and probucol resulted in near normalization in endothelial function. The acetylcholine response at follow-up, or the improvement in endothelial response over the study period, was closely related to the resistance of LDL oxidation (63). Whereas we treated patients for one year, Tamai et al. (77) recently demonstrated that forearm blood flow can be modulated within hours after LDL pheresis, demonstrating the dynamic nature of this process. Studies with other modalities to lower cholesterol have shown improved function as well, suggesting that it is the cholesterol-lowering effect and not the pleiotrophic effect of the statins that are important (31,78).



Antioxidants. Animal studies by Keaney et al. (79,80) have demonstrated beneficial effects of probucol and antioxidant vitamin therapy beyond protection of LDL. Recently, studies have demonstrated that vitamin C acutely improves endothelium-dependent responses in the forearm circulation in patients with a variety of risk factors (81–84). Long-term studies on vascular function in humans with vitamin C have not been reported.



Although alpha-tocopherol has been shown to protect LDL against oxidation in humans (85), longer-term studies using antioxidant vitamins have not shown any effect on endothelium-dependent vasodilation (86,87). Recently, two weeks of vitamin E treatment was shown to decrease P-selectin in patients with hypercholesterolemia, suggesting attenuation of endothelial activation (19).



Angiotensin-converting enzyme (ACE) inhibition. Angiotensin II has been shown to increase superoxide production via membrane-bound NADH/NADPH (88). Although it is unclear whether angiotensin II blockers result in improved endothelial function, these data are available for ACE inhibitors (8,89). The ACE inhibitors could potentially improve endothelium-dependent vasodilator responses through decreased levels of angiotensin II, increased levels of bradykinin and NO.



In humans, acute administration of ACE inhibitors augmented endothelium-dependent vasodilation in both the coronary and peripheral circulation (90,91). Mancini et al. (92) recently reported that the tissue-specific ACE inhibitor quinapril attenuated coronary endothelial dysfunction in patients with coronary artery disease.



To assess the potential differences in tissue specificity among ACE inhibitors (93) and the importance of the bradykinin effect, we recently compared quinapril, enalapril, losartan and amlodipine in a cross-over design in 80 patients with coronary artery disease. Over an 8-week treatment period, improvement in brachial artery FMD was only seen in the quinapril group, suggesting potential differences among vasoactive medications (94). Two recent studies using enalapril or lisinopril reported negative results as well (95,96). The effect of lowering blood pressure by other means on endothelial function is less clear, but it appears that ACE inhibitors have unique vascular protective properties.



Hormone replacement therapy. Hormone replacement with estrogen has been shown to improve endothelium-dependent vasorelaxation acutely in a number of animal models, including primate coronary arteries (97). It is likely that benefit is both NO dependent and independent (98).



Sack et al. (99) demonstrated that estrogen attenuates the susceptibility of LDL to oxidation in women. Studies in postmenopausal women demonstrated that acetylcholine-induced coronary vasoconstriction (100,101), but not metabolic vasodilation (102), can be attenuated in as little as 10 min by either intracoronary or intravenous administration of estrogen. Guetta et al. have demonstrated that the acute beneficial effects of estrogen on blood flow are NO related because this can be attenuated with L-NMMA (103). Improved endothelial vascular responses have been demonstrated in the peripheral circulation after nine weeks of estradiol therapy (104), and these effects were not attenuated by the coadministration of progesterone (105). Medroxyprogesterone, which is commonly used in combination with estrogen, probably has a detrimental effect on endothelial responses (106). Long-term studies evaluating the effect of hormone replacement on coronary endothelium-dependent vasodilation are underway.



Other interventions. Augmentation of NO production by L-arginine supplementation has been shown to improve vascular relaxation acutely in certain conditions (107). A recent study demonstrated improved brachial artery FMD in hypercholesterolemic subjects after four weeks of oral L-arginine supplementation (108). It is interesting to note that Quyyumi (109) more recently demonstrated augmentation of Ach-induced changes in forearm blood flow acutely with both L- and D-arginine, suggesting other mechanisms of action of arginine.



A variety of other interventions that have been shown to modulate vasomotor responses in humans are shown in Table 4. Most of these were administered acutely, and further studies are required to assess their long-term use.


Table 4 Treatment Associated With Improvement of Endothelial Dysfunction in Humans




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Acute



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Chronic



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LDL lowering with pheresis LDL lowering with statins, resins

ACE inhibition ACE inhibition

Antioxidants (Vitamin C and E + C) Antioxidants (probucol with lovastatin)

Estrogen Estrogen

L-arginine, D-arginine Estrogen + progesterone

Tetrahydrobiopterin, methyltetrahydrofolate L-arginine

Deferoxamine Exercise

Glutathione

Calcium channel blockers



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ACE = angiotensin-converting enzyme; LDL = low-density lipoprotein.