is endothelial dysfunction reversible?

Is Endothelial Dysfunction Reversible? Roland E. Schmieder, MD, and Hans P. Schobel, MD

To date, the published database concerning the impact of therapy on endothelial function in essential hypertension and hypercholesterolemia is small and incomplete. Chronic antihypertensive therapy had not yet been proven to restore endothelial function in patients with essential hypertension. In contrast, chronic lipid-lowering therapy is effective

in restoring endothelial function of the coronary and peripheral circulation in patients with hypercholesterolemia. A beneficial effect was already documented after 3 months of therapy with fluvastatin but full restoration may last more than 1 year.

(AmJ Cardio11995; 76:117A-121A)

T he endothelium is both a target for and a mediator of cardiovascular disease. Changes in endothelial function occur early in the

course of atherosclerosis. Studies have shown that the endothelium is functionally abnormal in the early stages of atherosclerosis, before plaques ex- ist, and certainly before clinical detection of atherogenic lesions. 1,2 The endothelium plays a pivotal role in synthesizing biologically active substances that modulate the vascular tone of the underlying smooth muscle cells (SMC). 3-6 One important endothelium-derived relaxing mediator is nitric oxide, which is formed from L-arginine by the activation of a constitutive form of the enzyme nitric oxide synthase. 7 The fact that nitric oxide is released both into the lumen (to inactivate plate- lets) and away from the lumen (to relax vascular smooth muscles) suggests that it protects against thrombosis and vasoconstriction. In addition, nitric oxide is capable of inhibiting the migration and proliferation of vascular SMC in a further protec- tive property. 5,6

E N D O T H E L I A L F U N C T I O N IN EARLY ATHEROSCLEROSIS

Several investigators have now reported that regulation of vascular tone is abnormal in coronary arteries even before early signs of atherosclerotic lesions in the vascular wall can be detected by angiography, s,9 When the endothelium is removed experimentally or is dysfunctional (as in atherosclerosis), normal vasodilation is replaced by paradoxical vasoconstriction. When acetylcholine, which normally induces vasodilation, is infused into coronary arteries of patients with atherosclerosis, loss of dilation and paradoxical vasoconstriction have been observed. 8-1° Recent experimental and clini-

From the Department of Medicine IV, University Erlangen-NOrnberg, WOrnberg, Germany.

Address for reprints: Roland E. Schmieder, MD, Medizinische Klinik IV/Nephrologie, Universit~t Erlangen-N0rnberg, Breslauer Str. 201, D-90471 NOrnberg, Germany.

cal studies have suggested that the abnormalities of endothelium-dependent relaxation in atherosclerosis may extend to the microvasculature of the coronary circulation, even though these vessels are free of overt atherosclerosis. 1° In patients without obstructive coronary atherosclerosis, but with various cardiovascular risk factors, the response of small coronary vessels to acetylcholine has been shown to be markedly blunted. 9,n

The current review will focus on the evidence that changes in endothelial function occur early in the course of vascular disease in patients with cardiovascular risk factors, such as arterial hypertension and hypercholesterolemia. One intriguing question is, of course, whether this early alteration of the endothelium (representing an early stage of atherosclerosis before histologic defects are evi- dent) can be stopped or even reversed.

E N D O T H E L I A L D Y S F U N C T I O N I N ESSENTIAL H Y P E R T E N S I O N

Arterial hypertension is a major risk factor for the development of atherosclerosis. Whether endothelial function is impaired in essential hypertension is controversial. Flow-dependent vasodilation of the brachial artery, which is in part dependent on an intact endothelial function, has not been found to be impaired in patients with essential hypertension. 12 Similarly, in a recent study, we found a nearly identical arterial compliance of the radial artery after intra-arterial infusion of acetylcholine, thereby suggesting an intact endothelial function and interaction of the endothelium with the underlying SMC. 13 At the level of resistance vessels, clinical studies have demonstrated that patients with essential hypertension have impaired endothelium-dependent vasodilation. 14-]6 The abnormal endothelial function contributes substantially to an increased peripheral vascular resistance, which is the major hemodynamic hallmark in arterial hypertension. In contrast, in vitro resis, tance arteries from patients with essential hyperten-

A SYMPOSIUM: MANAGEMENT OF HYPERLIPIDEMIA 117A

sion respond normally to acetylcholine. 17 The latter finding was supported by a recent in vivo study, which found a preserved endothelium-dependent vasodilation of forearm resistance vessels in hypertensive patients.IS

How can these different findings be reconciled? One possibility is that the occurrence of endothelial dysfunction does not affect all hypertensive patients to the same-degree. Indeed, a bimodal distribution of the abnormality in the endogenous nitric oxide vasodilator system was found in human essential hypertension. 19 Alternatively, factors that appear to be important for the development of endothelial dysfunction, such as duration and sever- ity of hypertension, may differ between the reported trials. Obviously, more studies are required to answer the question whether endothelial function is impaired in essential hypertension.

A defect in the endothelium-derived nitric oxide system could be explained either by a reduction in .basal nitric oxide synthesis 2°,21 or by a disturbed coupling of muscarine receptors with nitric oxide synthase. 2°,22 Administration of an inhibitor of the endothelial synthesis of nitric oxide (L-NG-mono - methyl 1-arginine [L-NMMA]) produced a significantly greater decrease in blood flow in control subjects than in hypertensive patients, pointing to an impaired basal nitric oxide synthesis. ]6 Further- more, our own results suggest an impaired endothelial functional synthesis reserve in essential hypertension because the endothelium-dependent interaction with vascular SMC of conduit arteries was attenuated in hypertensive patients but not in normotensive control subjects after blockade of the angiotensin converting enzyme (ACE) and of volt- age-dependent calcium channels. 13 In normal humans, the availability of substrate for production of nitric oxide is a rate-limiting step for endothelium- dependent vascular relaxation. In contrast, increased availability of nitric oxide precursor (infusion of L-arginine) did not modify endothelium- mediated vasodilation in hypertensive patients. 2° Thus, basal nitric oxide synthesis and nitric oxide synthase appeared to be impaired to some extent in essential hypertension.

IS ENDOTHELIAL FUNCTION REVERSIBLE IN ARTERIAL HYPERTENSION?

Single doses of the ACE inhibitors enalapri123 and captopri124 augmented endothelium-dependent vasodilation in normotensive and hypertensive subjects, respectively. It was hypothesized that this effect was produced by an enhanced bradyki-

nin activity through inhibition of the degradation of bradykinin by converting enzyme inhibition. Bradykinin is a known stimulus for nitric oxide release, thereby promoting endothelium-dependent vasodilation. 2s,26 Subsequent experiments have suggested that the sulfhydryl group of ACE inhibitors (captopril, zofenoprilat) may potentiate the effect on the endogenous nitric oxide system. 27 New data in humans, however, contradict these experimental investigations. The abnormal endothelium-dependent vasodilation of forearm resistance vessels found at baseline in hypertensive patients was not improved by antihypertensive therapy with ACE inhibitors given for 7-8 weeks, regardless of whether a sulfhydryl group was pre- sent. 2s In accordance with these findings, the vascular responses to acetylcholine (endothelium-dependent vasodilation) were not modified after discontinuation of antihypertensive therapy with various drugs. 29 Further, a preliminary trial with ACE inhibitors found that they did not improve endotheiium-dependent vasodilation as a drug class (captopril, enalapril). 3°

Most recently, the potential effects of antihypertensive therapy on nitric oxide synthesis was examined in more detail. 31 After therapy with both the ACE inhibitor enalapril and the calcium entry blocker amlodipine, the abnormal response to the nitric oxide inhibitor L-NMMA was restored to normal with normalization of blood pressure by antihypertensive drugs with different modes of action. Whether this restoration of the impaired nitric oxide synthase in hypertensive patients is a consequence of the change in blood pressure or a result of the antihypertensive compound per se needs to be examined in subsequent studies. The latter study indicates that the basal formation of nitric oxide, which was found to be impaired in essential hypertension, can be normalized in essential hypertension.

ENDOTHELIAL DYSFUNCTION IN HYPERCHOLESTEROLEMIA

Several studies have consistently confirmed that the endothelium-dependent vasodilation in response to acetylcholine (or metacholin) is impaired in hypercholesterolemic patients. 32-36 The impaired production or release of endothelium- derived relaxing factors was found in the coronary circulation and peripheral arteries of hypercholesterolemic patients long before structural vascular changes, clinical symptoms of coronary or peripheral artery disease, or histologic changes occur.

The reduction in basal blood flow and increase

118A THE AMERICAN JOURNAL OF CARDIOLOGY VOLUME 76 JULY 13, 1995

in vascular resistance produced by the inhibition of nitric oxide synthase (with L-NMMA) were not significantly different between patients with hypercholesterolemia and normal controls. 34 The fact that L-NMMA caused similar reductions of forearm blood flow in control and hypercholesterolemic patients indicates that basal nitric oxide synthesis is comparable in the 2 groups and, there- fore, cannot b~e held responsible for the endothelial dysfunction in hypercholesterolemia. In contrast, the inhibition of nitric oxide synthase by L-NMMA blunted the vasodilation to acetylcholine markedly in normal individuals but only marginally in hypercholesterolemic patients. 34 Thus, despite a normal basal nitric oxide synthase activity, hypercholesterolemic patients had a defect in the release of nitric oxide that may explain the impaired endothelium- dependent vasodilation. Further, subsequent studies found that the nitric oxide synthesis in response to bradykinin is normal, but is impaired in response to acetylcholine, s6 These findings point to a selec- tive impairment in the acetylcholine receptor- activated signal transduction pathway in hypercholesterolemic patients, with preservation of normal biologic activity of nitric oxide via alternative path- ways. 22

Endothelial dysfunction appears not to be caused by low density lipoproteins per se, but predomi- nantly by oxidized low density lipoproteins. These low density lipoproteins have received increasing attention because of their potential cytotoxic and atherogenic properties. In vitro studies have shown that endothelium-dependent vasodilatory impairment is found only in the presence of oxidized, but not native, low density lipoprotein, s7 Thus, the strong association between elevated low density lipoprotein cholesterol and endothelium dysfunction found particularly in the early preclinical stages of coronary atherosclerosis 38 seem to be related to the multiple atherogenic action of oxidized low density lipoprotein. 39,4°

Lipid-lowering therapy and endothelial function: Treatment of atherosclerosis in humans by aggressive cholesterol-lowering strategies there- fore may normalize impaired endothelium-dependent vasodilation. This concept was first supported by experimental studies. In an experimental trial, a potent inhibitor of 3-hydroxy-3-methylglutaryl co- enzyme A (HMG-CoA) reductase was given to cholesterol-fed rabbits, and at the end of the second week they underwent an experimental myocardial ischemia. 41 In the treated rabbits, lipid- lowering treatment was associated with less marked ischemic damage to the rabbit myocardium than in

control rabbits without treatment. Interestingly, arteries isolated from animals whose cholesterol was not reduced developed defects in endothelium- dependent relaxation in both large arteries and coronary resistance vessels. 41

In humans, clinical trials confirmed the beneficial effect of cholesterol-lowering therapy on endothelium-dependent relaxation in hypercholesterolemic patients. 42 In 25 patients with increased total serum cholesterol, vasodilatory response to acetylcholine in the coronary circulation--assessed by computer-assessed quantitative angiography--was found to be improved after 6 months of cholesterol- reducing therapy (diet and cholestyramine): the paradoxical vasoconstrictive action of acetylcholine was reduced from 21.7% to 13.3%. In addition, the improvement of acetylcholine-induced vasodilatory response was related to the cholesterol concentration achieved after therapy. 42 These data have now been confirmed by a study examining the impact of cholesterol lowering and antioxidant therapy on endothelium-dependent coronary vasomotion. In particular, the combination of lovastatin and probucol appeared to improve substantially endothelium-dependent coronary vasodilation. 43 Thus, these studies provide evidence that impaired endothelium-dependent relaxation associated with hypercholesterolemia is reversible with cholesterol- lowering therapy.

HOW QUICKLY IS ENDOTHELIAL FUNCTION RESTORED IN HYPERCHOLESTEROLEMIA?

Most studies examining the function of the nitric oxide system have used invasive tests involving the infusion of nitric oxide inhibitors, such as L-NMMA, or acetylcholine, which stimulates the release of nitric oxide. These tests can be used to determine whether basal nitric oxide formation (baseline response to L-NMMA) or the receptor- mediated release of nitric oxide (infusion of acetylcholine) is impaired. Alternatively, flow-dependent vasodilation of large arteries is dependent on nitric oxide synthesis, thereby allowing the applica- tion of this noninvasive strategy in clinical trials. The increase in forearm blood flow following reactive hyperemia in human forearm vessels (flow- dependent vasodilation) depends on intact endothelium and underlying SMC. 44 In particular, release of nitric oxide appears to play a significant role during the late phase of reactive hyperemia in the peripheral and coronary circulation, 4s,46 but the contribution of the nitric oxide system to the vasodilation following reactive hyperemia has been

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Before therapy 3 Months 6 Months after therapy after therapy

FIGURE 1. Forearm blood flow (FBF) at baseline and peak response to reactive hyperemia with fluvastatin at weeks O, 12, and 24. [ ] = baseline; • = peak response.

found to be modest. 47 In patients with hypercholesterolemia, flow-dependent vasodilation of forearm vascular resistance vessels was documented to be impaired, which is in accordance with invasive studies.33,36

In a clinical longitudinal study, we examined vasodilation after reactive hyperemia in human forearm vessels 3 times to assess the time course of restoration of the impaired endothelial function in patients with hypercholesterolemia (unpublished data). The noninvasive approach appeared to be the only feasible method of conducting repeated measurements in humans. A total of 24 patients with elevated serum cholesterol > 250 mg/dL were included in the study protocol and were treated with the HMG-CoA reductase inhibitor fluvastatin. In 5 of these, the dose of fluvastatin was titrated from 40 to 80 mg/day to achieve a reduction of serum low density lipoprotein cholesterol of at least 30%. Endothelial function was assessed by measuring forearm blood flow by plethysmography before starting therapy, and then after 12 and 24 weeks of treatment. Recordings were evaluated by 2 investigators who had no knowledge of either the patients' clinical data or of the week when the test had been performed.

In these patients, total serum cholesterol fell from 291 --- 33 to 202 ___ 28 mg/dL at week 12 and to 211 --- 18 mg/dL at week 24 (p <0.001). Low density lipoprotein cholesterol decreased from 213 __+ 32 to 125 _+ 27 mg/dL at week 12 and to 124 ___ 8 mg/dL at week 24 (p < 0.001). High density lipoprotein cholesterol increased significantly only after 24 weeks of treatment (from 45 --. 11 to 51 _-_4- 50 mg/dL; p <0.05). Forearm blood flow at baselinembefore reactive hyperemia--was not significantly different at the 3 examinations. The peak response in forearm blood .flow following reactive hyperemia increased at week 12 and week 24 (Figure 1). The percent increase of forearm blood flow following reactive hyperemia was augmented at week 12 (171 -4- 144%; p < 0.05 vs week 0) and

week 24 (218 --+ 228%; p < 0.05 vs week 0) com- pared with the week 0 response (defined to be 100%; Figure 1).

In this noninvasive clinical study involving hypercholesterolemic patients, 40 mg/day fluvastatin lowered low density lipoprotein cholesterol levels by >30% in 19 patients. In parallel, endothelial function--as assessed, in part, by flow-mediated vasodilation--improved progressively after lipid- lowering treatment with fluvastatin. Of note was

• the fact that the vasodilator capacity of the forearm resistance vessels improved after 12 weeks and was even more pronounced after 24 weeks, although no concomitant reduction in total cholesterol or low density lipoprotein cholesterol took place. Our hypothesis is that the rapid changes observed after 12 weeks of treatment with fluvastatin were related more to functional changes such as the restoration of endothelial function, and the effects after 24 weeks were related more to changes in structural abnormalities in the forearm vasculature. This hypothesis, however, has to be proven by invasive measurement of endothelium-dependent vasodilation (intra-arterial infusion of acetylcholine) and endothelium-independent vasodilation (intra-arterial infusion of sodium nitroprusside). Of note was the fact that after 12 days of lipid-lowering therapy with an HMG-CoA reductase inhibitor, no effect was found on endothelium-dependent vasodilation of epicardial arteries: 8 but this was documented after 5.5 months. 48 The restoration of endothelium function was still not complete after 1 year : 3

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is endothelial dysfunction reversible?

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