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European Journal of Heart Failure 2005 7(7):1126-1132; doi:10.1016/j.ejheart.2005.03.007
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© 2005 European Society of Cardiology

Effects of combined administration of low dose atorvastatin and vitamin E on inflammatory markers and endothelial function in patients with heart failure

Dimitris Tousoulis*, Charalambos Antoniades, Carmen Vassiliadou, Marina Toutouza, Christos Pitsavos, Costas Tentolouris, Athanasios Trikas and Christodoulos Stefanadis

Cardiology Unit, Hippokration Hospital, Athens University Medical School, A Cardiology Department 69 S. Karagiorga, 16675 Athens, Greece

* Corresponding author. Tel.: +30 210 7782446; fax: +30 210 7485039. E-mail address: tousouli{at}med.uoa.gr


   Abstract
Top
 Abstract
1. Introduction
 2. Methods
 3. Results
 4. Discussion
 References
 
Background: Heart failure has been associated with impaired endothelial function, increased inflammatory process and elevated oxidative stress status. Both statins and vitamin E separately improve endothelial function in patients with hypercholesterolemia and/or advanced atherosclerosis.

Aim: To evaluate the effect of atorvastatin alone or in combination with vitamin E on endothelial function and serum levels of interleukin-6 (IL-6), tumor necrosis factor alpha (TNF-{alpha}) and vascular cells adhesion molecule (sVCAM-1) in patients with ischemic heart failure.

Methods: Thirty-eight male patients with ischemic cardiomyopathy were randomly divided into three groups and received either atorvastatin 10 mg/day (n=14), a combination of atorvastatin 10 mg/day plus vitamin E 400 IU/day (n=12), or no statin or antioxidant treatment (n=12), controls) for 4 weeks. Forearm blood flow (FBF) was measured using venous occlusion strain-gauge plethysmography. Forearm vasodilatory response to reactive hyperemia (RH%) or to nitrate (NTG%) was defined as the percent change of FBF from rest to the maximum flow during reactive hyperemia or after nitrate administration, respectively.

Results: RH% was significantly improved in both the atorvastatin-treated (p<0.01) and atorvastatin plus vitamin E groups (p<0.05), but the increase was significantly higher in the atorvastatin-treated group (p<0.05). Serum levels of IL-6, TNF-{alpha} and sVCAM-1 were decreased in the atorvastatin-treated group (p<0.05 for all), but remained unaffected in the other two groups (p=NS for all).

Conclusions: Low dose atorvastatin treatment improves endothelial function and reduces the expression of proinflammatory cytokines and adhesion molecules in patients with ischemic heart failure, an effect partly depressed by vitamin E.

Key Words: Heart failure • Inflammation • Cytokines • Statins • Lipids • Vitamins

Received September 29, 2004; Accepted March 3, 2005


   1. Introduction
Top
 Abstract
 1. Introduction
2. Methods
 3. Results
 4. Discussion
 References
 
Evidence suggests that endothelial function is impaired in patients with heart failure [1,2]. Furthermore, heart failure is characterized by increased levels of proinflammatory cytokines such as interleukin-6 (IL-6) and tumor necrosis factor (TNF-{alpha}), as a result of increased production by the failing myocardium and peripheral tissues [3]. These proinflammatory cytokines stimulate the expression of adhesion molecules in endothelial cells such as soluble vascular cell adhesion molecule (sVCAM-1) [4,5], and depress NO production [6].

Statins have a number of additional properties beyond their lipid-lowering effect, they have anti-inflammatory properties [7] and they also increase nitric oxide bioavailability, in patients with coronary artery disease [8,9]. Similarly, antioxidant treatment with vitamin E also improves endothelial function in patients with coronary artery disease or in patients with risk factors for atherosclerosis [10]. However, the combined effect of atorvastatin and vitamin E is controversial, since although this combination improves endothelial function in hypercholesterolemic subjects [11], it has been associated with a negative effect on long-term survival of patients with coronary artery disease [12], while its role in patients with ischemic heart failure is still unknown.

In the present study we evaluated the effect of low dose atorvastatin treatment alone or in combination with vitamin E, on endothelial function and the expression of proinflammatory cytokines and adhesion molecules, in patients with ischemic heart failure.


   2. Methods
Top
 Abstract
 1. Introduction
 2. Methods
3. Results
 4. Discussion
 References
 
2.1. Study population
Thirty-eight patients with ischemic heart failure were included in this study. All patients had angiographically documented ischemic cardiomyopathy, with left ventricular ejection fraction ≤ 35% assessed by ultrasound. All patients had been in a stable clinical state for at least 3 months before study entry. Exclusion criteria were left ventricular hypertrophy, acute and chronic inflammatory disease involving organs other than the heart and other cardiac disease, smoking, fasting cholesterol levels > 210 mg/dl or use of lipid-lowering agents during the past 6 months, and use of antioxidant vitamins or other dietary supplements. Hypertension was defined as a systolic blood pressure ≥ 140 mm Hg, a diastolic blood pressure ≥ 90 mm Hg, or current use of antihypertensive medication. Diabetes mellitus was defined as fasting glucose ≥ 110 mg/dl, non-fasting glucose ≥ 160 mg/dl or a history of treatment of diabetes. All patients were receiving treatment with diuretics and ACE-inhibitors (Table 1). This treatment remained unchanged in all the study groups throughout the study period, any patients with symptoms who required changes in their treatment were excluded from the study. Patients receiving any vitamins or nutritional supplements during the previous 6 months were excluded from the study.


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  		Table 1 Baseline characteristics

 
2.2. Study protocol
Medical history was obtained by standardized and validated interviewer-administered questionnaires. The patients were randomly divided into three treatment groups, by the dynamic random allocation method. Fourteen patients received atorvastatin 10 mg/day, 12 received atorvastatin 10 mg/day plus vitamin E 400 IU/day and 12 received no statin treatment (Controls), for 4 weeks.

Forearm blood flow, determined using strain-gauge plethysmography, was used to assess forearm vasodilatory response to reactive hyperemia and to nitrate administration. Venous blood samples were collected at the beginning of the study and after 4 weeks of treatment. Patients were asked to discontinue any vasoactive agents (e.g. alcohol, coffee or vasoactive drugs except diuretics and ACEi) for 24 h before each measurement. Subjects were asked to take the last dose of test medication 12 h before the beginning of the second visit. The investigation conforms with the principles outlined in the Declaration of Helsinki, was approved by the Institutional Ethics Committee and each patient gave written informed consent.

2.3. Forearm blood flow measurements
All measurements were performed between 10:00 and 13:00. Before measurements were started, subjects were rested in a supine position, in a dark quiet room under constant temperature 22–25 °C, for 30 min. Forearm blood flow (FBF) was measured using strain-gauge plethysmography, as previously described [13–15]. Briefly, the strain-gauge was secured to the upper part of the left forearm, connected to the plethysmography device and supported above the level of the right atrium. A venous occlusion cuff, placed on the upper arm, was inflated to 40 mm Hg for 7 s in each 15-s cycle to occlude venous outflow from the arm, using a rapid cuff inflator (EC-400, D.E. Hokanson, Inc). The FBF output signal was transmitted to a personal computer (Hokanson NIVP3 software). FBF was finally calculated as the % change of arm volume/100 ml tissue/min.

2.4. Determination of reactive hyperemia
After 30 min rest in the supine position, basal FBF was determined as the mean of 10 consecutive measurements of FBF at rest. Then the effect of reactive hyperemia and sublingual nitroglycerin on FBF was measured. To induce reactive hyperemia, a second cuff placed at the distal part of the forearm was inflated in 300 mm Hg for 5 min.

After the release of the ischemia cuff, FBF was measured for 4 min and time-course curves were plotted [14,15]. The release of the ischemic occlusion cuff was followed by a 15-min recovery period before the administration of sublingual nitroglycerin. Nitroglycerin, 0.4 mg, was then administered sublingually, after FBF had returned to baseline. Forearm vasodilatory response to reactive hyperemia (RH%) was expressed as the percentage change of FBF from baseline to the maximum flow during reactive hyperemia, following the release of the ischemia cuff [13,15]. Forearm vasodilatory response to nitrate (NTG%) was expressed as the percentage change of FBF from baseline to the maximum flow after sublingual administration of nitroglycerin. A pre-study sample-size calculation indicated that a sample of eight patients was sufficient to detect a 20% improvement in reactive hyperemia, and a sample of 12 patients was sufficient to detect a 15% improvement in reactive hyperemia with a power of 90% and {alpha}=0.05.

2.5. Biochemical measurements
Blood samples were obtained after a 12-h fasting period and centrifuged at 3000xg at 4 °C for 10 min to obtain serum. Samples were frozen at –70 °C until assayed. The serum lipid level was measured by standard and validated methods. Serum vitamin E concentration was determined by high performance liquid chromatography. Circulating levels of IL-6, TNF-{alpha} and sVCAM-1 were determined by ELISA (ELISA kits by R&D Systems Inc. USA) and standard methodology. The lower detection limits of the ELISA kits were 0.094 pg/ml for IL-6, and 0.12 pg/ml for TNF-{alpha} and 0.60 ng/ml for sVCAM-1.

2.6. Statistical analysis
Data were tested for normal distribution by Kolmokorov–Smirnov test. All normally distributed variables are expressed as mean±S.D. Multigroup comparisons of variables were carried out by one-way analysis of variance (ANOVA) followed by Bonferroni's correction. Two-way ANOVA for repeated measurements on two factors was used to analyze the effect of treatment on time-course curves of FBF during reactive hyperemia. Changes in RH%, NTG% and all the biochemical parameters within each group were assessed by paired t-test, while the differences of the changes in each parameter between groups were assessed by ANOVA for repeated measurements. Correlations between variables were evaluated by determining Pearson's coefficient. A p-value < 0.05 was considered statistically significant. All statistical analyses were performed by SPSS 11.5 statistical package.


   3. Results
Top
 Abstract
 1. Introduction
 2. Methods
 3. Results
4. Discussion
 References
 
No significant differences were observed in demographic characteristics at baseline (Table 1). After 4 weeks of treatment, cholesterol and triglyceride levels were significantly decreased in both the atorvastatin (p<0.01 for both) and atorvastatin+vitamin E-treated groups (p<0.01 for both), but remained unchanged in the control group (p=NS, Table 2). Vitamin E levels were significantly increased only in the vitamin E-treated group (p<0.01, Table 2). New York Heart Association class and ejection fraction remained unchanged after treatment (Tables 1 and 2).


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  		Table 2 Effects of atorvastatin and vitamin E on forearm vasodilatory response to reactive hyperemia, inflammatory process and endothelium-derived components

 
3.1. Effects of atorvastatin and vitamin E on endothelial function
Forearm blood flow at rest, maximum flow after nitrate administration and NTG% remained unchanged in all study groups (Table 2; Fig. 1). However, RH% was significantly increased in both atorvastatin-treated (p<0.01) and atorvastatin+vitamin E-treated group (p<0.05), but remained unchanged in the control group (p=NS). The increase of RH% (delta-RH%) in the atorvastatin-treated group (45.7 [95% CI: 18.3 to 73.3]%) was significantly higher than that in atorvastatin+vitamin E-treated group (9.16 [95% CI: 2.16 to 16.2]%, p<0.05) (Fig. 1). Maximum hyperemic flow was only increased in the atorvastatin-treated group (Table 2). The time-course curves during reactive hyperemia showed a significant increase in hyperemic flow after treatment, in the atorvastatin-treated group (p<0.05) after 4 weeks of treatment, but remained unchanged in the other groups (p=NS) (Fig. 2).


Figure 1
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  		Fig. 1 Atorvastatin significantly improved forearm vasodilatory response to reactive hyperemia (RH%) in patients with heart failure, while this effect was slightly decreased by co-administration of vitamin E. Forearm vasodilatory response to nitrate (NTG%) remained unaffected in all study groups. Black bars: before treatment; white bars: after treatment; values expressed as means±S.E.M. *p<0.05; **p<0.01; NSp=not significant vs. before treatment.

 


Figure 2
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  		Fig. 2 Line graphs show forearm blood flow (FBF) at rest and during reactive hyperemia, at baseline ({blacksquare}) and after treatment ({circ}). Treatment with atorvastatin alone (c) significantly augmented reactive hyperemia (p<0.05), while no effect was observed in the atorvastatin+vitamin E (b) or control groups (a). *p<0.05; values expressed as means±S.E.M.

 
3.2. Effects of atorvastatin and vitamin E on inflammatory markers
Serum levels of TNF-{alpha} were significantly decreased in the atorvastatin-treated group (p<0.05), but remained unchanged in the control and atorvastatin+vitamin E-treated groups (p=NS for both; Table 2 and Fig. 3). Furthermore, the change in TNF-{alpha} levels (delta-TNF-{alpha}) in the atorvastatin-treated group (–1.11 [95% CI: –2.1 to –0.08] pg/ml) was significantly higher than the change in the atorvastatin+vitamin E group (by +0.15 [95% CI: –0.57 to +0.87] pg/ml, p<0.05). Similarly, serum levels of sVCAM-1 were significantly decreased only in the atorvastatin group (p<0.05), levels remained unchanged in the control and atorvastatin+vitamin E groups (p=NS for both; Table 2 and Fig. 4). Furthermore, the change in sVCAM-1 levels (delta-sVCAM-1) observed in the atorvastatin group (–203 [95% CI: –355.7 to –9.9] ng/ml) was significantly greater than the change in the atorvastatin+vitamin E group (–23.0 [95% CI: –140.4 to 93.0] ng/ml, p<0.05) or the control group (by –6.2 [95% CI: –98.2 to 85.5] ng/ml, p<0.05).


Figure 3
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  		Fig. 3 Atorvastatin significantly decreased serum levels of interleukin-6 (IL-6) and tumor necrosis factor alpha (TNF-{alpha}) in patients with heart failure, but levels were unchanged in the atorvastatin+vitamin E and control groups. Black bars: before treatment; white bars: after treatment; values expressed as means±S.E.M.; *p<0.05; NSp=not significant vs. before treatment.

 


Figure 4
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  		Fig. 4 Atorvastatin significantly decreased serum levels of sVCAM-1 in patients with heart failure, but levels were unchanged in the atorvastatin+vitamin E and control groups. Black bars: before treatment; white bars: after treatment; values expressed as means±S.E.M. *p<0.05; NSp=not significant vs. before treatment.

 
IL-6 levels were significantly decreased only in the atorvastatin-treated group (p<0.05) and remained unchanged in the other groups (p=NS for both; Table 2 and Fig. 3). The change in IL-6 levels (delta-IL-6) in the atorvastatin-treated group (–2.4 [95% CI: –4.46 to –0.39] ng/ml) was not significantly different compared to the change in the control (–1.16 [95% CI: –2.57 to +1.15] ng/ml, p=NS) and atorvastatin+vitamin E groups (–2.2 [95% CI: –4.75 to +0.33] ng/ml, p=NS for both).

At baseline, RH% was correlated with IL-6 (r=–0.602, p=0.001), TNF-{alpha} (r=–0.358, p=0.029) and sVCAM-1 (r=–0.488, p=0.002), while the improvement of RH% (delta-RH%) in the atorvastatin-treated group was significantly correlated with delta-IL-6 (r=–0.580, p=0.036), delta-TNF-{alpha} (r=–0.596, p=0.032) and delta-sVCAM-1 (r=–0.650, p=0.016).


   4. Discussion
Top
 Abstract
 1. Introduction
 2. Methods
 3. Results
 4. Discussion
References
 
The results of this study show that low dose atorvastatin treatment improves forearm vasodilatory response to reactive hyperemia and decreases serum levels of IL-6, TNF-{alpha} and sVCAM-1 in patients with heart failure. These beneficial effects of atorvastatin were partly prevented by vitamin E.

4.1. Inflammation and heart failure: the role of atorvastatin
In patients with heart failure, the failing myocardium is a major source of proinflammatory cytokines [16–18], which significantly contribute to the pathophysiology of heart failure [3]. Furthermore, TNF-{alpha} is increased in end-stage heart failure irrespective of the cause of heart failure, and directly affects endothelial function [18–21]. Cytokines depress myocardial contractility due to uncoupling of beta-adrenergic signaling and alterations in intracellular calcium homeostasis [22,23]. Cytokines also induce structural changes in the failing myocardium and may promote cardiomyocyte apoptosis as well as activate metalloproteinases and impair the expression of their inhibitors, contributing to cardiac remodeling [24,25].

Statins reduce the inflammatory process, independent of reductions in LDL [26], and they also down-regulate the expression of several adhesion molecules directly or indirectly by reducing plasma levels of cytokines [27]. However, the role of lipid-lowering treatment in heart failure is controversial, since both LDL and HDL bind to endotoxin, neutralizing its effect [28], and it has been reported that heart failure patients with increased LDL levels may have better prognosis than those with lower LDL [29]. However, it is unknown whether atorvastatin treatment modifies the outcome of these patients by reducing the expression of proinflammatory cytokines or by affecting the expression of adhesion molecules, especially in patients with cholesterol levels within the normal range.

In the present study we evaluated the effects of atorvastatin treatment on the inflammatory process in patients with ischemic heart failure and normal cholesterol levels. We demonstrated that atorvastatin treatment (10 mg/day for 4 weeks) significantly improves endothelial function and decreases serum levels of IL-6 and TNF-{alpha} as well as the soluble form of VCAM-1 in patients with heart failure and normal cholesterol levels.

4.2. Endothelial dysfunction in heart failure: the role of atorvastatin
Heart failure is associated with endothelial dysfunction, which may be the result of a variety of mechanisms, such as the increased levels of cytokines (i.e. tumor necrosis alpha (TNF-{alpha})) impairing the expression of NO-synthase [30], impaired endothelial–receptor–signal transduction pathways and increased angiotensin-converting enzyme activity enhancing the breakdown of bradykinin [31]. Increased endothelium dependent vasoconstrictor agents observed in heart failure (i.e. cycloxygenase-dependent factor) [31] as well as reactive oxygen species such as oxidized LDL (ox-LDL) [32] also counteract the vasodilating effects of nitric oxide [31]. We have previously shown that although the underlying atherosclerosis significantly contributes to the development of endothelial dysfunction and increased inflammatory process in patients with ischemic heart failure, the failing heart itself seems to be the most important component of these alterations in these patients [6].

Statins seem to improve endothelial function, by increasing eNOS expression, while they decrease the uptake and generation of oxidized LDL [33,34], attenuate vascular superoxide anion generation [34], and increase levels of natural antioxidants [34]. Therefore, they increase NO bioavailability, through both its increased production and decreased oxidative inactivation [34].

In the present study, we demonstrated that atorvastatin treatment (10 mg/day for 4 weeks) significantly increases both RH% and the time-course of forearm hyperemic response, suggesting an improvement of endothelial function in patients with ischemic heart failure and normal cholesterol levels. Furthermore, the significant correlations between statin-induced changes in inflammatory status and respective improvement of endothelial function indicate that a pathophysiologic link may exist between endothelial function and inflammatory process in heart failure.

4.3. Vitamin E, endothelial function and inflammatory process
Free radicals are important contributors to the deterioration of the decompensating myocardium [35], while several factors associated with heart failure such as increased cytokine stimulation [36] are known stimuli for peroxidative damage [37–40]. Vitamin E, a lipid-soluble antioxidant, improves endothelial function and depresses the inflammatory process in patients with risk factors for atherosclerosis [41,42], while its role in heart failure is unclear.

Combined administration of vitamin E and simvastatin is superior to simvastatin alone in improving endothelial function in patients with hypercholesterolemia [11], as a result of the additive antioxidant effect of vitamin E on the pleiotropic effects of simvastatin. However, recent studies have shown that combined administration of antioxidant vitamins and simvastatin or pravastatin failed to improve endothelial function in older patients with hypercholesterolemia [43]. This controversy could be the result of aging-related structural changes in the vasculature, which may contribute to impaired response of endothelial cells to statin treatment. Furthermore, these differences in endothelial function between younger and older hypercholesterolemic patients may be partly explained by the reduced synthesis and release of NO and its increased degradation by oxygen-derived free radicals [43]. Recently, the role of combined administration of statins and vitamin E has been questioned, since addition of vitamin E to simvastatin treatment had rather negative effects on the prognosis of patients with coronary artery disease [12]. This interaction appears to result from substantial and specific blunting by this vitamin of the expected increase in the level of the protective HDL2 subfraction [44]—an effect that has been found with the potent non-vitamin antioxidant probucol [45]. Furthermore, recent data suggests that high-dose vitamin E (≥ 400 IU/day) may increase all-cause mortality [46], possibly as a result of its prooxidant effect at this dosage [47]. A limitation of the present study was the open-label design, and the lack of an atorvastatin with placebo-treated group. Therefore, the possibility that a placebo effect could modify the results of the study cannot be excluded.

This is the first study examining the effect of 4-week treatment with vitamin E (400 IU/day) on atorvastatin-induced improvement of endothelial function and inflammatory process, in patients with ischemic heart failure and normal cholesterol levels. We found that the beneficial effects observed by atorvastatin treatment on forearm vasodilatory response to reactive hyperemia as well as on proinflammatory cytokines and adhesion molecule expression were reduced by co-administration of vitamin E.

4.4. Conclusions
In the present study we have shown that 4-week treatment with low dose atorvastatin improves forearm vasodilatory response to reactive hyperemia and depresses the inflammatory process by reducing the expression of proinflammatory cytokines IL-6 and TNF-{alpha} and sVCAM-1, in normocholesterolemic patients with ischemic heart failure. However when vitamin E 400 IU/day was added in the treatment, these beneficial effects of atorvastatin were decreased. Further large-scale randomised trials are needed to elucidate the exact role of statins alone or in combination with antioxidant vitamins, in patients with heart failure.


   References
Top
 Abstract
 1. Introduction
 2. Methods
 3. Results
 4. Discussion
 References
 

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