(Circulation. 1997;95:1126-1131.)
© 1997 American Heart Association, Inc.
Articles |
Simvastatin, an HMG–Coenzyme A Reductase Inhibitor, Improves Endothelial Function Within 1 Month
the Department of Cardiology and Medicine, Royal Perth (Australia) Hospital and the Department of Human Movement, University of Western Australia, Perth (D.G.).
Correspondence to Gerard O'Driscoll, Department of Cardiology, Royal Perth Hospital, Wellington St, Perth, Western Australia 6000.
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Abstract |
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Background Cholesterol-lowering therapy can improve cardiovascular morbidity and mortality in patients with atherosclerosis. Although the mechanisms responsible are unclear, these benefits precede macroscopic changes in the vasculature. Emerging evidence that improvement in endothelial function may occur requires substantiation; in particular, it is unclear how early any such improvement would be detectable after initiation of therapy.
Methods and Results This randomized, double-blind, placebo-controlled crossover study evaluated the effect of simvastatin (20 mg daily for 4 weeks) on endothelium-dependent and endothelium-independent vasodilation and on the response to the inhibitor of nitric oxide synthesis, NG-monomethyl-L-arginine (L-NMMA), in the forearm vasculature of subjects with moderate elevation of total serum cholesterol (6.0 to 10.0 mmol/L) by use of strain-gauge plethysmography. Studies were repeated after 3 more months of open therapy. When the results are expressed as percentage changes in flow in the infused arm relative to the noninfused arm, the vasodilator response to acetylcholine was significantly increased after 4 weeks of treatment with simvastatin (P<.0005), and this improvement was further enhanced after 3 months (P<.005). Concurrently, simvastatin augmented the vasoconstrictor response to L-NMMA, an effect that was maintained at 3 months (P<.0005). The response to the endothelium-independent vasodilator sodium nitroprusside was unaltered.
Conclusions These observations indicate that within 1 month of treatment with simvastatin, both the stimulated and basal nitric oxide dilator functions of the endothelium are augmented, and the benefits of this HMG–coenzyme A reductase inhibitor persist with continued therapy.
Key Words: blood flow • cholesterol • endothelium • hypercholesterolemia
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Introduction |
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Hypercholesterolemia is a risk factor for cardiovascular disease, particularly ischemic heart disease, and several recent studies have indicated that cholesterol reduction is associated with decreased cardiovascular morbidity and mortality in patients with established disease1 2 and in subjects with mild hypercholesterolemia.3 In other studies, clinical improvement has been documented in response to lipid-lowering therapy despite relatively minor angiographic changes, suggesting that benefits are not causally related only to regression of obstructive disease.4 5 It has been proposed that enhanced endothelial function might contribute to the improvement in clinical status.6 7 8
Hypercholesterolemia is associated with impaired endothelial function,9 10 11 12 and animal13 14 and human7 15 16 studies indicate that endothelial function improves with lowering of serum cholesterol. In human large coronary arteries, NO-dependent, ACh-stimulated vasoconstriction was attenuated after 6 months.6 15 Although a recent report indicated that lipid lowering increased forearm vasodilation in response to serotonin after 3 months of treatment,16 a previous study found that despite significant reduction of serum cholesterol after 12 days of therapy, no difference in coronary vascular function was evident between patients treated with lovastatin and those given placebo.7 Thus, it remains unclear how early improvement in endothelial function might occur in response to lipid-lowering therapy.
In this study, we documented an effect on both basal NO-mediated dilatation and ACh-stimulated dilatation, largely NO dependent, in the forearm vasculature after 4 weeks of therapy with the HMG-CoA reductase inhibitor simvastatin.
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Methods |
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Subjects
Subjects were eligible for entry if they had a total serum cholesterol of 6.0 to 10.0 mmol/L and were not receiving cholesterol-lowering therapy. All undertook a screening program consisting of a medical history and examination and full hematologic and biochemical profiles, including measurement of serum electrolytes, liver function, uric acid, creatine phosphokinase, and serum lipids. The following were excluded: cigarette smokers; premenopausal women; those with renal or hepatic impairment, hypertension, or diabetes mellitus; and patients taking vitamin supplements or vasoactive drugs such as nitrates, calcium channel antagonists, ß-blockers, or ACE inhibitors. The study protocol was approved by Royal Perth Hospital Ethics Committee, and subjects gave written informed consent.
Ten subjects (8 men, 2 women; age, 50±2 years [mean±SE]) with total serum cholesterol concentrations ranging from 6.2 to 7.5 mmol/L were enrolled. Medical histories and examinations were unremarkable except for 2 men, 1 of whom had undergone coronary artery bypass surgery and another who had surgically treated peripheral vascular disease several years earlier. Both were asymptomatic. Apart from 1 patient who was on aspirin 150 mg daily, no subject was taking medication before or for the duration of the experimental period.
Study Design
The effect of 4 weeks of simvastatin therapy was studied by use of a randomized, double-blind, placebo-controlled crossover protocol that was followed by 3 months of open therapy. Subjects were randomized in equal numbers to receive simvastatin 20 mg daily (Zocor, Merck Sharp & Dohme) or a similarly packaged placebo. After 4 weeks, each subject returned for a study of forearm vascular function. Then, after crossover, they were restudied 4 weeks later. Of the 10 subjects, 2 withdrew at this time, and the remainder continued on simvastatin 20 mg daily for 3 more months and returned for a final study. Subjects refrained from drinking alcohol or caffeine-containing beverages 12 hours before the procedure. At each visit, the biochemical and hematologic parameters were repeated. There were no adverse side effects.
Vascular Function Protocol
Investigations were conducted in a quiet, climate-controlled laboratory (24°C; relative humidity, 55%) with subjects lying supine and both forearms resting above heart level. A 20-gauge arterial cannula (Arrow) was introduced into the brachial artery of the nondominant arm under local anesthesia with <2 mL of 1% lidocaine (Astra Pharmaceuticals) to transduce pressure and infuse drugs or physiological saline. FBF (mL/100 mL forearm tissue per minute) was measured simultaneously in both arms by gallium/indium strain-gauge (SG24, Medasonics) plethysmography. Each wrist was connected to a flow-regulated source of compressed air, and the arm cuffs were connected to a rapid-inflation device (E20, D.E. Hokanson). Output from the strain gauges passed through an amplifier (SPG 16, Medasonics) and was sampled by an on-line microcomputer at 75 Hz before being displayed on a monitor in real time. A software program coordinated the acquisition, storage, and display of data, as well as inflation and deflation of the arm cuffs, ensuring that blood flow measures were synchronized with cuff inflation during recording periods. Intra-arterial pressure was measured continuously (Transpac, Abbot Laboratories) throughout the study. Drug infusions were administered with a constant-rate infusion pump (IVAC 770, IVAC Corp).
Baseline measurements started at least 20 minutes after cannulation of the brachial artery, when FBF had stabilized. Blood flow measurements were taken by inflating the wrist cuffs to 220 mm Hg to exclude the hands from the circulation and rapidly inflating the upper arm cuffs to 45 mm Hg for 10 of every 15 seconds throughout the baseline and drug infusion periods. Output from the strain gauges was stored, and the average of the last five flow measurements from each period was used for analysis. Between infusions, the cuffs were deflated, allowing at least 15 minutes for FBF to recover before further baseline measures.
All solutions were prepared aseptically from sterile stock solutions or ampoules immediately before infusion into the brachial artery. ACh (Miochol, Johnson & Johnson) was infused at 10, 20, and 40 µg/min, each for 3 minutes, to produce a cumulative dose-response curve. This was followed by SNP (David Bull Laboratories) infusion at 2, 4, and 8 µg/min, each for 3 minutes, and then L-NMMA (Clinalfa) at 2, 4, and 8 µmol/min, each for 5 minutes.
Statistical Analysis
Absolute measurements of FBF are subject to error due to the lack of precise standards for calibration purposes, so it is appropriate to describe induced changes relative to baseline measurements. Furthermore, although the low doses of drugs infused in the study produced negligible systemic effects and showed no effect on blood pressure or heart rate, it was necessary to exclude an alteration in overall hemodynamics as a cause of the flow changes seen in the infused forearm. Thus, FBF was measured simultaneously in both arms (although only one arm was infused), and the noninfused arm served as a control. As in previous articles,17 18 19 20 FBF in the infused arm is described as a ratio to that in the noninfused arm. Changes in these ratios during ACh, SNP, and L-NMMA infusions are expressed as percentage changes from the baseline immediately preceding each drug administration.
Results are expressed as mean±SE. Two-way ANOVA with repeated measures was used to compare simvastatin and placebo treatments at the three doses. When a significant difference was revealed by this analysis, comparisons at each drug infusion level were made by use of two-tailed t tests. A value of P<.05 was considered significant.
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Results |
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Table 1
presents the serum lipid levels, heart rate, and blood pressure data at the time of the placebo study and after 4 weeks and 3 additional months of simvastatin therapy. After 4 weeks of therapy, total serum cholesterol was 19% lower than after placebo (P<.02), LDL cholesterol was 28% lower (P<.05), triglycerides were 21% lower (P=NS), and HDL cholesterol was not significantly different. The 3-month levels were similarly depressed relative to the placebo measures. Other biochemical and hematologic variables were unaltered.
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The baseline FBF values preceding infusion of ACh, SNP, and L-NMMA were not different in either arm, indicating an adequate washout period between drug infusions. The responses to intra-arterial drug infusions in terms of measured absolute FBF (Table 2) were not different between simvastatin and placebo treatment periods. However, such direct comparisons are not the most appropriate. The percentage changes in flow, from the preceding baseline and relative to the noninfused arm, induced by the drug infusions are presented in Table 3 and graphically shown in Fig 1. The vasodilation induced by ACh increased significantly between placebo and 4 weeks (P<.0005, ANOVA) and between placebo and 3 months of simvastatin therapy (P<.0001). The ACh response was also significantly enhanced at 3 months relative to 4 weeks (P<.01). The decrease in FBF induced by L-NMMA was significantly greater after 4 weeks (P<.01) and 3 months (P<.0005) of therapy relative to placebo. The L-NMMA response at 3 months was slightly but not significantly greater than at 4 weeks. The results of paired t tests between placebo and treatment groups at each drug dose are listed in Table 3. Forearm vascular responses in each individual subject improved in individuals while on treatment relative to responses obtained from subjects on placebo (Fig 2). Fig 2 also shows that there was no relation between the percentage increase in blood flow ratio in response to ACh and the decrease in serum cholesterol in individuals at either 4 weeks or 3 months. Similarly, the change in response to L-NMMA was not related to the decrease in cholesterol. Responses to the endothelium-independent vasodilator SNP were not significantly altered by simvastatin therapy.
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P<.005). The response to L-NMMA was significantly different after 4 weeks (
indicates placebo; 
, 1 month of simvastatin; and 
, 3 months of simvastatin.
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Discussion |
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This study examined the effects of cholesterol-lowering therapy with the HMG-CoA reductase inhibitor simvastatin on the endothelial function of patients with moderately elevated serum cholesterol. After 4 weeks of treatment with simvastatin (20 mg daily), the vasodilator response to ACh was significantly increased, as was L-NMMA–induced vasoconstriction, indicating that both stimulated and basal vasodilator function of the endothelium were enhanced. By contrast, the response to the endothelium-independent vasodilator SNP was unchanged. Improvement in endothelial function increased with continued administration of simvastatin despite the absence of further reduction in serum cholesterol, and there was no relation between the decrease in cholesterol and the improvement in endothelial function. FBF responses to infused agents were analyzed by reference to the basal flow in the infused and noninfused arms, as in previous studies.17 18 19 20 This corrects first for inaccuracy in strain-gauge calibration in the absence of independent absolute flow measurements and second for any other changes occurring in hemodynamics. Examination of measured values of absolute FBF did not reveal the differences between simvastatin and placebo periods that did exist.
It is now known that abnormal function of the endothelium is detectable before the establishment of obvious intimal lesions in patients with risk factors for atherosclerosis.21 22 23 A number of studies performed in animals12 24 and in the coronary9 10 25 and peripheral11 26 vascular beds of humans indicate that hypercholesterolemia impairs endothelial function and that the degree of impairment is correlated with serum cholesterol concentration.15 In addition, cholesterol-lowering interventions can reverse endothelial dysfunction in both the coronary and peripheral vasculature.6 7 8 15 16 27 However, these studies were not randomized,6 15 27 were performed in patients with established atherosclerosis,7 8 or documented improvement after longer periods of treatment (6 months in the coronary circulation6 7 15 and 3 months16 or at least 8 weeks27 in the peripheral circulation). We have demonstrated, after 4 weeks of therapy, improvement in endothelial function in the forearm vascular bed, one seldom prone to atherosclerosis, in previously untreated subjects with hypercholesterolemia using a randomized, double-blind, placebo-controlled crossover design.
The present study is the first to report that vascular changes occur rapidly and to indicate that L-NMMA–mediated vasoconstriction is enhanced after cholesterol-lowering therapy, indicative of an augmented basal effect of NO. The disparity between this finding and that of Stroes et al,16 who reported unchanged L-NMMA responses after 3 months of combined simvastatin and cholestyramine administration, may be attributable to differences in patient characteristics, study design, or analysis. Stroes et al16 recruited predominantly premenopausal women suffering from familial hypercholesterolemia who had higher cholesterol levels and had been treated previously with lipid-lowering therapy. The study was not placebo controlled and did not construct a dose-response curve to L-NMMA, although the single dose used was the same as our highest infusion level. That study, however, found a convincing difference in dose-response curves to the endothelium-dependent serotonin according to treatment status, the dose being the calculated plasma concentration of serotonin in the FBF and the response being expressed as the percentage decrease in vascular resistance induced.
Decreased availability of the NO substrate L-arginine or impaired activity of the NO synthase enzyme is not primarily responsible for the impaired endothelial function in hypercholesterolemia,28 and although the effect of NO is impaired, its production is increased.29 Excess endothelial-derived superoxide generation occurs in hypercholesterolemia, and these radicals can inactivate NO,30 augment oxidation of LDL,31 and lead to increased endothelial cell membrane damage through generation of peroxynitrite and hydroxyl radicals. Oxidized LDL inhibits the production of NO from L-arginine,32 a finding that may explain the observation in both humans33 and animals34 that impaired endothelium-dependent relaxation in hypercholesterolemia can be reversed by the provision of excess substrate (L-arginine).33 35 36 This benefit of L-arginine is lost after lipid-lowering therapy.16 Further evidence that the oxidation state is important is provided by the observation that despite a similar reduction in serum cholesterol with lipid-lowering therapy alone or in combination with an antioxidant, endothelium-dependent coronary vasomotion was improved significantly more with the latter regimen.8 Subsequently, the coronary vascular response to ACh was found to vary inversely with the in vitro oxidizability of LDL.37 However, Garcia et al38 have shown that superoxide dismutase coinfusion had no effect on ACh responses in hypercholesterolemic subjects, failing to support the theory of extracellular destruction of NO by superoxide anions.
The relative potency of the HMG-CoA reductase inhibitors cannot be assessed from the literature concerning endothelial function, but simvastatin is more potent, perhaps as much as twice as potent, than pravastatin, fluvastatin, and lovastatin in lowering cholesterol. It was interesting that the improvement in endothelial function with simvastatin therapy did not correlate with the decrease in serum cholesterol. This may be due to the relatively small numbers, the relative consistency of the decrease in cholesterol, and the imprecision in measurements. In addition to these factors, a biological lag phase might explain why the improvement between 4 weeks and 3 months was not associated with a further decrease in serum cholesterol. However, there is the possibility that the improvement in endothelial function might not be due solely to a reduction in circulating cholesterol concentration. Administration of fish oils improved endothelial function without altering serum cholesterol.27 Perhaps the effects of HMG-CoA reductase inhibitors, other than lipid lowering per se, such as inhibition of cholesterol synthesis or lowering oxidized LDL could improve endothelial function, whereas other effects such as reduced monocyte chemotaxis or smooth muscle cell migration and proliferation39 40 and reduced platelet thrombus formation recently demonstrated in vitro41 could contribute to cardiovascular benefit. It is also possible that simvastatin may be acting as an antioxidant, which is consistent with the observation that human monocyte-derived macrophages treated with simvastatin showed a dose-dependent decrease in superoxide formation.42 Whatever the precise mechanisms responsible for the damaging effect of hypercholesterolemia on the endothelium and for the beneficial effect of HMG-CoA reductase inhibition, the benefit is rapidly induced and continues without a further decrease in cholesterol levels.
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Selected Abbreviations and Acronyms |
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Acknowledgments |
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This study was supported by Healthway, W.A. We are grateful to Merck, Sharpe and Dohme for the supply of simvastatin.
Received July 15, 1996; revision received October 2, 1996; accepted October 13, 1996.
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G. I. Boger, T. K. Rudolph, R. Maas, E. Schwedhelm, E. Dumbadze, A. Bierend, R. A. Benndorf, and R. H. Boger Asymmetric Dimethylarginine Determines the Improvement of Endothelium-Dependent Vasodilation by Simvastatin: Effect of Combination With Oral L-Arginine J. Am. Coll. Cardiol., June 12, 2007; 49(23): 2274 - 2282. [Abstract] [Full Text] [PDF]
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P. Di Napoli, A. A. Taccardi, A. Grilli, M. A. De Lutiis, A. Barsotti, M. Felaco, and R. De Caterina Chronic treatment with rosuvastatin modulates nitric oxide synthase expression and reduces ischemia-reperfusion injury in rat hearts Cardiovasc Res, June 1, 2005; 66(3): 462 - 471. [Abstract] [Full Text] [PDF]
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M. Trovati and F. Cavalot Optimization of Hypolipidemic and Antiplatelet Treatment in the Diabetic Patient with Renal Disease J. Am. Soc. Nephrol., January 1, 2004; 15(90010): S12 - 20. [Abstract] [Full Text]
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L. K. Newby, A. Kristinsson, M. V. Bhapkar, P. E. Aylward, A. P. Dimas, W. W. Klein, D. K. McGuire, D. J. Moliterno, F. W. A. Verheugt, W. D. Weaver, et al. Early Statin Initiation and Outcomes in Patients With Acute Coronary Syndromes JAMA, June 19, 2002; 287(23): 3087 - 3095. [Abstract] [Full Text] [PDF]
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 J. R Chiong and A. B Miller Review: Renin-angiotensin system antagonism and lipid-lowering therapy in cardiovascular risk management Journal of Renin-Angiotensin-Aldosterone System, June 1, 2002; 3(2): 96 - 102. [Abstract] [PDF]
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H. Krum and J. J. McMurray Statins and chronic heart failure: do we need a large-scale outcome trial? J. Am. Coll. Cardiol., May 15, 2002; 39(10): 1567 - 1573. [Abstract] [Full Text] [PDF]
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K. E. Ferrier, M. H. Muhlmann, J.-P. Baguet, J. D. Cameron, G. L. Jennings, A. M. Dart, and B. A. Kingwell Intensive cholesterol reduction lowers blood pressure and large artery stiffness in isolated systolic hypertension J. Am. Coll. Cardiol., March 20, 2002; 39(6): 1020 - 1025. [Abstract] [Full Text] [PDF]
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S. Wassmann, U. Laufs, K. Muller, C. Konkol, K. Ahlbory, A. T. Baumer, W. Linz, M. Bohm, and G. Nickenig Cellular Antioxidant Effects of Atorvastatin In Vitro and In Vivo Arterioscler Thromb Vasc Biol, February 1, 2002; 22(2): 300 - 305. [Abstract] [Full Text] [PDF]
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