Statin Therapy Is Associated With Improved Cardiovascular Outcomes and Levels of Inflammatory Markers in Patients With Heart Failure

Journal of Cardiac Failure Vol. 11 No. 8 2005

Statin Therapy Is Associated With Improved Cardiovascular Outcomes and Levels of Inflammatory Markers in Patients With Heart Failure SRIKANTH SOLA, MD,1 MUHAMMAD Q.S. MIR, MD,1 SANJAY RAJAGOPALAN, MD,2 TAREK HELMY, MD,1 NEERAJ TANDON, MD,3 AND BOBBY V. KHAN, MD, PhD1 Atlanta, Georgia; New York, New York; Shreveport, Louisiana

ABSTRACT Background: We wished to determine whether the addition of statins affect cardiovascular events and markers of inflammation in patients with heart failure. Methods and Results: A total of 446 patients with heart failure and ejection fraction #35% were followed in a prospective, nonrandomized fashion and were classified according to treatment with a statin. We determined all-cause mortality, cardiovascular morbidity, and serum markers of inflammation over a 24month period. Statin therapy in patients with heart failure was associated with decreased all-cause mortality at 2 years compared with those not on statin therapy (15% versus 33%, P ! .005) as well as hospitalizations for heart failure (22% versus 38%, P 5 .001) and nonfatal myocardial infarction (11% versus 15%, P ! .001). In addition, statin therapy was associated with a decrease in serum levels of C-reactive protein (1.12 6 0.13 versus 1.47 6 0.11 mg/dL, P 5 .001), interleukin-6 (13.3 6 0.8 versus 17.3 6 1.4 ng/dL, P 5 .001), and tumor necrosis factor-alpha receptor II (24.3 6 1.0 versus 34.5 6 3.0 ng/dL, P 5 .001). Conclusion: The use of statin therapy in this nonrandomized trial was associated with a significant reduction in all-cause mortality and cardiac morbidity. In addition, the improvement in levels of several serum inflammatory markers with statin therapy suggests in part possible mechanisms by which these agents may exert their benefits. Key Words: Statins, heart failure, inflammation.

several years away.7 To date, only limited data are available on the impact of statins in reducing adverse cardiovascular events in patients with heart failure.8 Statins have many effects beyond lipid lowering that make them of potential benefit in patients with heart failure of both ischemic and nonischemic etiologies. Statins facilitate nitric oxide (NO) synthesis and improve endothelial function, both of which are typically impaired in patients with heart failure.9,10 In addition, they inhibit the synthesis of inflammatory cytokine and chemokines, improve autonomic function, and reverse myocardial remodeling.11,12 Finally, statins may retard the progression of myocardial dysfunction in heart failure, particularly those with an ischemic etiology, by promoting plaque stabilization and reducing the progress of coronary artery disease. Given the large amount of data supporting the potential role for statins in heart failure, we hypothesized that statin therapy would reduce cardiac morbidity and mortality in patients with heart failure, regardless of etiology. We undertook the present study to evaluate the effects of statin therapy in patients with heart failure, and to elucidate potential mechanisms of these effects.

Hydroxymethylglutaryl CoA reductase inhibitors (statins) have been shown to lower morbidity and mortality in coronary artery disease and other atherosclerosis related diseases.1–4 In addition, subanalyses of data from several of these studies have found that statin therapy reduces the risk of developing heart failure in patients with coronary artery disease.5,6 The major clinical trials however, have generally excluded patients with heart failure, and the results of randomized trials of statin therapy in heart failure are still

From the 1Emory University School of Medicine, Division of Cardiology, Atlanta, Georgia; 2Mount Sinai School of Medicine, Division of Cardiology, New York, New York; and 3Louisiana State University Health Sciences Center, Division of Cardiology, Shreveport, Louisiana. Manuscript received September 29, 2004; revised manuscript received May 23, 2005; revised manuscript accepted May 25, 2005. Reprint requests: Bobby V. Khan, MD, PhD, Division of Cardiology, Department of Medicine, Emory University School of Medicine, 69 Jesse Hill Drive SE, #C247, Atlanta, GA 30303. Supported by an unrestricted educational grant from Pfizer Pharmaceuticals and funds from the Emory Medical Care Foundation. 1071-9164/$ - see front matter Ó 2005 Elsevier Inc. All rights reserved. doi:10.1016/j.cardfail.2005.05.011

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608 Journal of Cardiac Failure Vol. 11 No. 8 October 2005 Methods Patients Men and women age 18 years or older were eligible for enrollment if they had: (1) New York Heart Association class II to III heart failure; (2) left ventricular ejection fraction of #35%, as documented by echocardiography or ventriculography within 1 year before enrollment; and (3) stable doses of heart failure medications for 3 months before enrollment. Patients were excluded from the study if they had been prescribed a statin during the 1 year before enrollment, or had had a previous adverse event related to statin use. Patients were recruited from outpatient cardiology and internal medicine clinics at 3 university medical centers. All patients had previously undergone coronary angiography within 1 year of enrollment. Written informed consent was obtained from all patients. Study Design Patients were prescribed statins at the discretion of their treating physician; medications were not assigned in a randomized manner. Patients were considered to be on statin therapy if treatment began !3 months after enrollment and continued throughout the study period. Patients were characterized as having coronary artery disease if they had $70% stenosis in at least 1 major epicardial coronary artery on previous cardiac catheterization. Patients were classified as having nonischemic cardiomyopathy if they had no prior history of a myocardial infarction and no significant coronary artery disease on cardiac catheterization. Study visits took place at 0, 12, and 24 months. Ejection fraction was determined by transthoracic echocardiography obtained at during each study visit. The study protocol complies with the Declaration of Helsinki and was approved by the institutional review boards at the participating institutions. Laboratory Measurements Laboratory samples were collected at each study visit and stored at 280  C after centrifugation. An aliquot was drawn, and erythrocyte superoxide dismutase (E-SOD) activity was determined using hemolysates and commercially available kits (Randox Lab Ltd, Dublin, Ireland; Cat. No. SDI 25). Briefly, superoxide radicals produced by xanthine and xanthine oxidase reacts with 2-(4-iodophenyl)-3-(4-nitrophenol)-5-phenyltetrazolium chloride to form a red formazan dye.13 The E-SOD activity is then measured by the degree of inhibition of this reaction. E-SOD activity was expressed as U/g Hb.14 For analysis of serum interleukin-6 (IL-6), studies were performed on each sample in triplicate. A total of 60 mL of serum were used for analysis, and enzyme-linked immunosorbent assay was performed. The levels of total serum IL-6 were determined on a plate reader at an optical density of 420 nm. High-sensitivity C-reactive protein (hsCRP) was measured with an immunoprecipitation assay. Serum tumor necrosis factor-alpha receptor II (TNF-a RII) was measured as an indirect marker of monocyte/macrophage stimulation.15 The interassay variability was !10%, and the intra-assay variability was !5% for all four markers. Blood glucose was measured using a glucose dehydrogenase method after precipitation of proteins by trichloroacetic acid. Low-density lipoprotein (LDL) and high-density lipoprotein fractions were separated from fresh serum by combined ultracentrifugation and precipitation. Lipoprotein fraction cholesterol and triglycerides were measured enzymatically.

Study Endpoints The primary endpoint of the study was a combination of allcause mortality and hospitalization for heart failure. Secondary endpoints included levels of inflammatory markers, serum lipid levels, and hospitalization for acute coronary syndromes or nonfatal myocardial infarction. Outcomes were tracked through scheduled study visits, periodic review of hospital and clinic medical records, and personal or telephone interview with household contacts. Study endpoints were adjudicated by investigators blinded to treatment status. Acute coronary syndrome was defined as resting chest pain compatible with myocardial ischemia of $20 minutes’ duration within 12 hours of hospital presentation.16 A diagnosis of myocardial infarction was based on the recommendations of the American College of Cardiology and the European Society of Cardiology.16 Statistical Analysis All values are presented as the mean 6 standard deviation for continuous variables and as the percentage of total patients for categorical variables. The independent sample t test and chi-square test were used for comparison of continuous and categorical variables, respectively. A P value of !.05 was considered statistically significant, and all P values were 2-sided. Survival curves were calculated by the Kaplan-Meier method. Univariate and multivariate Cox regression analyses were used to calculate the estimated hazard ratio (HR) with 95% confidence interval (CI). Calculations were performed with SPSS software (version 10.0, Statistical Package for the Social Sciences, Chicago, IL).

Results Study Population

A total of 446 patients (277 men and 169 women) were enrolled in the study and followed for an average of 24 6 5 months. The etiologies of heart failure included ischemic (44%) and nonischemic (56%, including idiopathic, valvular, alcoholic, or peripartum) cardiomyopathy. Fiftyseven percent of the study population was treated with a statin, including 54% of ischemic and 59% of nonischemic patients. The characteristics of the study cohorts are shown in Table 1. There was no significant difference in baseline LDL cholesterol, high-density lipoprotein cholesterol, or triglyceride levels between the two cohorts. The prevalence of therapy with individual statins and other lipid-lowering medications is shown in Table 2. Relationship Between Statin Therapy and All-Cause Mortality and Cardiac Morbidity

There were 101 deaths during the 2-year follow-up period. As shown in Fig. 1, survival at 1 year was 92.1% in patients treated with statins versus 86.8% in those not treated with statins (HR 0.86, 95% CI 0.80–0.92, P 5 .02). The two-year survival rates were also significantly different; 85% in patients treated with statins versus 67% in those not treated with statins (HR 0.71, 95% CI 0.57– 0.84, P ! .001). Within the statin therapy group, three variables were found to be associated with worsened survival by Cox regression analysis: heart failure from an

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Table 1. Patient Demographics and Baseline Characteristics

Age (years) Men (%) Body mass index (kg/m2) Systolic BP (mmHg) Diastolic BP (mmHg) Ejection fraction (%) NYHA II (%) NYHA III (%) Baseline history Ischemic etiology (%) Hypertension (%) Smoking (%) Diabetes (%) Laboratory values LDL cholesterol (mmol/L) HDL cholesterol (mmol/L) Triglycerides (mmol/L) Fasting glucose (mg/dL) Hemoglobin A1C (%) Baseline medications ACE inhibitor or ARB (%) b-blocker (%) Aldosterone blocker (%) Diuretics (%)

Statin Treatment (n 5 255)

No Statin Treatment (n 5 191)

55.4 6 6.4 157 (62) 24.3 6 3.8 119 6 11 72 6 10 33 6 5 76 (30) 179 (70)

53.8 6 5.7 120 (63) 23.5 6 4.3 116 6 11 75 6 9 34 6 4 63 (33) 128 (67)

107 105 87 61 2.8 1.1 2.8 93 5.0

(42) (41) (34) (24)

6 6 6 6 6

230 184 28 163

0.1 0.2 0.5 15 0.7

(90) (72) (11) (64)

88 69 57 52 2.7 1.0 2.9 91 4.9

(46) (36) (30) (27)

6 6 6 6 6

164 126 19 125

0.3 0.1 0.4 19 0.6

(86) (66) (10) (65)

P 5 nonsignificant for difference in baseline characteristics between the study cohorts. BP, blood pressure; NYHA, New York Heart Association; LDL, lowdensity lipoprotein; HDL, high-density lipoprotein; ACE, angiotensinconverting enzyme; ARB, angiotensin receptor blocker.

ischemic etiology; left ventricular ejection fraction !25%; and diabetes mellitus (Table 3). Statin therapy was also associated with a lower risk of cardiac morbidity. During the 2-year follow-up, patients with heart failure who were treated with statins were less Table 2. Prevalence of Lipid-Lowering Therapy and Effect on Cholesterol Levels Statin Treatment (n 5 255) Statins Atorvastatin (%) Pravastatin (%) Simvastatin (%) Fluvastatin (%) Other Gemfibrozil (%) Fenofibrate (%) Nicotinic acid (%) Change from baseline in LDL cholesterol (mmol/L) Change from baseline in HDL cholesterol (mmol/L) Change from baseline in triglycerides (mmol/L)

150 46 41 15

(59) (18) (16) (6)

No Statin Treatment (n 5 191)

P Value

Fig. 1. Kaplan-Meier curves demonstrate 2-year survival (%) in heart failure patients receiving statin therapy (n 5 255) or not receiving statin therapy (n 5 191).

likely to be hospitalized for an exacerbation of their heart failure (Fig. 2) than were patients not treated with statins (HR 0.77, 95% CI 0.62–0.91, P ! .001). Similarly, 11% and 18% of patients treated with statins experienced a nonfatal myocardial infarction or were hospitalized for acute coronary syndromes, compared with 15% and 23% of those not treated with statins, as shown in Table 4 (HR 0.68, 95% CI 0.49–0.86 for non-fatal myocardial infarction, P ! .001; HR 0.67, 95% CI 0.44–0.90 for acute coronary syndromes, P ! .001). Within the cohort of patients treated with statins, there was no significant difference in hospitalizations for either heart failure in patients with ischemic versus non-ischemic etiologies of heart failure (data not shown). Relationship Between Statin Therapy and Inflammatory Markers

Compared with an increase in serum levels of IL-6 from 16.7 6 1.3 to 17.1 6 1.3 ng/dL in patients not treated with statins (P 5 .001), IL-6 levels decreased from 17.1 6 1.4 to 13.3 6 0.8 ng/dL in those patients treated with statins. As

16 (6) 10 (4) 15 (6) 20.8 6 0.09

d d d d d d d d 10.08 6 0.01

!.001

10.06 6 0.01

10.01 6 0.01

NS

Table 3. Cox Regression Analysis of Clinical Factors Associated With Survival in Patients Treated With Statins Subgroup

20.18 6 0.04

20.04 6 0.01

!.03

LDL, low-density lipoprotein; HDL, high-density lipoprotein; NS, not significant.

Age !55 years Female EF O25 EF !25 Ischemic etiology Diabetes mellitus EF, ejection fraction.

Relative Risk

95% CI

P Value

0.79 0.67 0.51 0.33 0.33 0.24

0.53–1.18 0.31–1.10 0.26–0.85 0.12–0.73 0.10–0.68 0.08–0.43

.34 .24 .098 .033 .028 .019

610 Journal of Cardiac Failure Vol. 11 No. 8 October 2005 Given an absolute mortality difference of 18% between cohorts at the end our study, approximately 5.6 patients with heart failure would have to be treated for 2 years with a statin to prevent 1 death. These data confirm the results of a previous retrospective study in which therapy with statins was associated with lower mortality and need for heart transplantation in patients with heart failure referred to a heart failure clinic at a tertiary medical center.8 In addition, these data reinforce findings from a nonrandomized comparison within the Losartan Heart Failure Survival Study (ELITE II), which showed a mortality benefit in patients with heart failure who were treated with statins.17 The Pleiotropic Effects of Statins

Fig. 2. Percentage of patients with at least 1 hospitalization for exacerbation of heart failure in patients receiving statin therapy (n 5 255) or not receiving statin therapy (n 5 191). HF 5 heart failure.

shown in Table 5, similar reductions were seen in serum levels of hsCRP and TNF-a RII in patients treated with statins compared with the non-statin group. Finally, E-SOD activity increased in patients treated with statins compared to those who were not (701 6 65 versus 572 6 79 U/g Hb; P 5 .001). Discussion This study shows a substantial benefit with statin therapy in patients with heart failure, regardless of etiology. Total mortality, non-fatal myocardial infarction, and the need for hospitalization from heart failure or acute coronary syndromes were all reduced in the cohort of patients treated with statins. In addition, statin therapy was associated with reductions in levels of CRP, TNF-a RII, and IL-6 as well as an increase in E-SOD activity, suggesting an association between changes in proinflammatory and pro-oxidative markers and cardiovascular outcomes. Table 4. Comparison of Clinical Outcomes in Heart Failure Patients Treated With Statins and Patients Not Treated With Statins Statin Treatment No Statin Treatment P (n 5 255) (n 5 191) Value Total mortality (%) Non-fatal MI (%) Hospitalization for HF (%) Acute coronary syndrome (%)

38 (15) 19 (11) 57 (22)

63 (33) 28 (15) 72 (37)

!.0001 .002 !.0001

47 (18)

43 (23)

.0009

HF, heart failure; MI, myocardial infarction.

Inflammatory mediators play an important role in the development and progression of heart failure. These mediators, or cytokines, are generally pharmacologically active proteins that are secreted by a variety of cell types in response to a variety of stimuli. Among the cytokines, TNF-a plays an important role in the progression of heart failure. TNF-a has been implicated in the development of left ventricular dysfunction, pathologic left ventricular remodeling, endothelial dysfunction, increased cardiac myocyte apoptosis, and the development of anorexia and cachexia, among other effects.18,19 The reproducibility of plasma concentrations of soluble TNF receptors, however, are much higher than that of TNF-a itself and may explain why soluble TNF receptors such as TNF-a RII predict both short-term20 and long-term21 prognosis better than TNF-a in heart failure patients. Other cytokines, such as IL-6, are involved in myocyte hypertrophy, myocardial dysfunction, and muscle wasting. Higher levels of IL-6, as well as the inflammatory marker CRP, are associated with a poorer prognosis in heart failure patients.22–24 Statins have important anti-inflammatory effects and downregulate C-reactive protein and inflammatory cytokines, which are activated in heart failure of any etiology.11 Our data found a reduction in serum levels of hsCRP as well as TNF-a IIR and IL-6 in patients treated with statins. In addition, statin treatment was associated with an increase in E-SOD activity, suggesting that statins also have antioxidant activity in this patient population. E-SOD catalyzes the reaction of superoxide anions (O2 2 ) to hydrogen peroxide (H2O2), making it a central element in the maintenance of the vascular redox balance. As such, superoxide dismutase is indirectly involved in regulating levels of NO bioavailability. Other investigators have found that statin therapy lowers systemic levels of protein-bound nitrotyrosine (NO2Tyr), a marker for oxidant stress mediated via pathways involving NO derived oxidants.25,26 In addition to their anti-inflammatory and antioxidant effects, there are a number of other potential mechanisms that we hypothesize may account for the beneficial effects of statin therapy observed in this study. These include the inhibition of atherosclerosis as well as the direct effects of lipid lowering and plaque stabilization, attenuation of pathological

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Table 5. Effects of Statin Therapy on Inflammatory Markers Baseline Statin Treatment (n 5 255) hsCRP (mg/dL) IL-6 (ng/dL) TNF-a RII (ng/dL) Erythrocyte superoxide dismutase (U/g Hb)

1.5 17.1 33.4 578

6 6 6 6

0.2 1.4 4.2 49

Follow Up

No Statin Treatment (n 5 191) 1.4 16.7 33.3 588

6 6 6 6

0.2 1.3 3.2 66

P value NS NS NS NS

Statin Treatment

No Statin Treatment

1.1 13.3 24.3 701

1.5 17.3 34.5 572

6 6 6 6

0.1 0.8 1.0 65

6 6 6 6

0.1 1.4 3.0 79

P value .001 .001 .001 !.005

hsCRP, high-sensitivity C-reactive protein; IL-6, interleukin-6; TNF-a RII, tumor necrosis factor receptor II; NS, not significant.

myocardial remodeling, improvement of endothelial dysfunction, and inhibition of neurohormonal activation. Coronary artery disease is an important cause of heart failure, accounting for more than 60% of all new diagnoses in some patient populations.27 Statins have been clearly shown to reduce the incidence of atherosclerosis-related events in patients with established coronary artery disease, even in patients with baseline LDL cholesterol levels of !2.6 mmol/L.4 Statins promote plaque stabilization within atherosclerotic lesions through depletion of the lipid core, strengthening of the fibrous cap, and inhibition of macrophage migration and proliferation. By inhibiting the progression of coronary atherosclerosis, statins may decrease the incidence of acute coronary syndromes, including myocardial infarction, and attenuate the progression of left ventricular dysfunction in patients with ischemic cardiomyopathy. However, the benefits of statins in lowering mortality go far beyond the benefits seen in reducing the incidence of myocardial infarction, suggesting that statins have other effects that may be associated with a reduction in mortality from heart failure. Statins also have direct effects on pathologic ventricular remodeling and angiotensin II activity, providing therapeutic benefit to patients with both ischemic and nonischemic etiologies of their heart failure. Statin therapy has been associated with reverse remodeling and increased survival in rodent models of heart failure.12,28 Physiologically, this corresponds to a reduction collagen expression in rats treated with cerivastatin and a decrease in matrix metalloproteinase activity in mice treated with fluvastatin when used in models of heart failure after myocardial infarction.29 Endothelial dysfunction is ubiquitous in patients with heart failure, and a poorer level of endothelial function is associated with a higher mortality from heart failure. Statin therapy may have beneficial effects in heart failure through improved endothelial function, most likely mediated through an increase in NO bioavailability. Statins enhance endothelial NO synthase activity and activate the Akt pathway, both of which result in an increase in NO bioavailability.29,30 In addition, statins are associated with an increase in E-SOD activity as described above, leading to an attenuation of NO degradation within the vasculature. Finally, statins may normalize sympathetic excitation in heart failure, leading to an improvement in neurohormonal status. Plasma norepinephrine levels serve as an index of

sympathetic nervous system activation, and higher levels are associated with greater heart failure severity and a higher mortality from heart failure.30 Several animal studies suggest that statin therapy reduces plasma norepinephrine levels in animal models of heart failure, indicating a decrease in sympathetic activation.31,32 Together, these data suggest multiple mechanisms by which statins may be of benefit in patients with heart failure from systolic dysfunction, resulting in a reduction in total mortality, non-fatal myocardial infarction, and hospitalizations for heart failure and acute coronary syndromes. These benefits occurred in stable heart failure patients who were well treated with angiotensin-converting enzyme inhibitors and b-blockers, suggesting that statins exert their benefits independently of these latter agents. The results of this study support the hypothesis that statins are beneficial in patients with heart failure from systolic dysfunction, but further confirmation is needed from randomized placebocontrolled trials such as the ongoing Gruppo Italiano per lo Studio della Sopravivenza nell’ Infarcto miocardico (GISSI-HF).33 Limitations of the Study

Our study has several limitations that must be noted. Allocation of statin therapy was not randomized, as the decision to prescribe statins was at the discretion of the patient’s treating physician. As such, the study was not blinded or placebo-controlled. In addition, information on dosing and duration of treatment with statin therapy was not evaluated, nor did we analyze the relationship between statin therapy, levels of inflammatory markers, and adverse cardiovascular events. Although our data show an association between statin therapy and lower mortality and cardiac morbidity, given the study’s design, we cannot make a causal relationship between statin therapy and the observed outcomes. Finally, a dropout rate of approximately 22% from patient deaths will introduce some degree of bias to the observed changes in serum inflammatory marker levels. Conclusions Currently, only 23% to 55% of patients with heart failure receive statin therapy, compared with approximately 80%

612 Journal of Cardiac Failure Vol. 11 No. 8 October 2005 to 85% of those with coronary artery disease.34,35 Our data suggest that statin therapy is associated with improved outcomes in patients with heart failure from systolic dysfunction. Furthermore, statin therapy is associated with a reduction in several markers of inflammation in this patient population, highlighting a potential mechanism by which statins exert their benefits. Together, these data suggest that statin therapy may be a useful adjunct in the management of patients with heart failure, regardless of etiology. Confirmation in a large, randomized placebo controlled trial is warranted. References 1. Randomized trial of cholesterol lowering in 4444 patients with coronary heart disease: the Scandinavian Simvastatin Survival Study (4S). Lancet 1994;344:1383–9. 2. Sacks FM, Pfeffer MA, Moye LA, Rouleau JL, Rutherford JD, Cole TG, et al. The effect of pravastatin on coronary events after myocardial infarction in patients with average cholesterol levels. N Engl J Med 1996;335:1001–9. 3. The Long-term Intervention with Pravastatin in Ischemic Disease (LIPID) Study Group, Prevention of cardiovascular events and death with pravastatin in patients with coronary heart disease and a broad range of initial cholesterol levels. N Engl J Med 1998;339:1349–57. 4. The Heart Protection Study Collaborative Group. The MRC/BHF Heart Protection Study of cholesterol lowering with simvastatin in 20,536 high-risk individuals: a randomized placebo controlled trial. Lancet 2002;360:7–22. 5. Kjekshus JK, Pedersen TR, Olsson AG, Faergeman O, Pyorala K. The effects of simvastatin on the incidence of heart failure in patients with coronary heart disease. J Card Fail 1997;3:249–54. 6. Aronow WS, Ahn C. Frequency of congestive heart failure in older persons with prior myocardial infarction and serum low-density lipoprotein cholesterol $125 mg/dL treated with statins versus no lipid lowering drug. Am J Cardiol 2002;90:147–9. 7. Krum H, McMurray JJ. Statins and chronic heart failure: do we need a large-scale outcome trial? J Am Coll Cardiol 2002;39:1567–73. 8. Horwich TB, MacLellan WR, Fonarow GC. Statin therapy is associated with improved survival in ischemic and non-ischemic heart failure. J Am Coll Cardiol 2004;43:642–8. 9. Drexler H, Horning BD. Endothelial dysfunction in human disease. J Mol Cell Cardiol 1999;31:51–60. 10. Koh KK. Effects of statins on vascular wall: vasomotor function, inflammation, and plaque stability. Cardiovasc Res 2000;47:648–57. 11. Lefer DJ. Statins as potent anti-inflammatory drugs. Circulation 2002; 106:2041–2. 12. Hayashidani S, Tsutsui H, Shiomi T, Suematsu N, Kinugawa N, Ide T, et al. Fluvastatin, a 3-hyroxy-3-methylglutaryl coenzyme A reductase inhibitor, attenuates left ventricular remodeling and failure after experimental myocardial infarction. Circulation 2002;105:868–73. 13. Erel O, Kocyigit A, Bulut V, Gurel MS. Reactive nitrogen and oxygen intermediates in patients with cutaneous leishmaniasis. Memorias do Instituto Oswaldo Cruz 1999;94:179–83. 14. McCord JM, Fridowich I. Superoxide dismutase: an enzymatic function for erythrocuprein. J Biol Chem 1969;249:6049–55. 15. Porsch-Oezcueruemez M, Kunz D, Kloer H, Luley C. Evaluation of serum levels of solubilized adhesion molecules and cytokine receptors in coronary heart disease. J Am Coll Cardiol 1999;34:1995–2001. 16. Braunwald E, Antman EM, Beasley JW, Califf RM, Cheitlin MD, Hochman JS, et al. ACC/AHA guidelines for the management of patients with unstable angina and non-ST-segment elevation myocardial infarction: executive summary and recommendations: a report of

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