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J Am Coll Cardiol, 2006; 47:332-337, doi:10.1016/j.jacc.2005.06.088
(Published online 20 December 2005). © 2006 by the American College of Cardiology Foundation |
* Division of Cardiology, Emory University School of Medicine, Atlanta, Georgia
Division of Cardiology, Louisiana State University Health Sciences Center, Shreveport, Louisiana.
Manuscript received March 24, 2005; revised manuscript received June 6, 2005, accepted June 14, 2005.
* Reprint requests and correspondence to: Dr. Bobby V. Khan, Division of Cardiology, Department of Medicine, Emory University School of Medicine, 69 Jesse Hill Drive SE, C233, Atlanta, Georgia 30303. (Email: bkhan{at}emory.edu).
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Abstract |
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 Top Abstract MethodsResultsAtorvastatin therapy and...DiscussionReferences |
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BACKGROUND: Despite advances in therapy, morbidity and mortality from heart failure (HF) remain high. We wished to determine whether treatment with atorvastatin affects left ventricular (LV) systolic function and markers of inflammation in patients with nonischemic HF.
METHODS: A total of 108 patients with nonischemic HF and a left ventricular ejection fraction (LVEF) 
35% were randomized to either atorvastatin 20 mg/day or placebo in a double-blinded fashion for a 12-month period. The LVEF and LV end-diastolic diameter (LVEDD) and left ventricular end-systolic diameter (LVESD) were determined by echocardiography. Serum markers of inflammation and oxidation were also measured.
RESULTS: The LVEF increased from 0.33 ± 0.05 to 0.37 ± 0.04 (p = 0.01) in the atorvastatin group over the 12-month follow-up period, whereas those patients in the placebo group experienced a decline in ejection fraction during the same time period. In addition, LVEDD was reduced from 57.1 ± 5.9 mm to 53.4 ± 5.1 mm (p = 0.007) and LVESD was reduced from 42.4 ± 3.8 mm to 39.1 ± 3.8 mm (p = 0.02) in the cohort of patients treated with atorvastatin; these dimensions increased in the placebo group. There was an increase in erythrocyte superoxide dismutase (E-SOD) activity, and there were significant reductions in serum levels of high sensitivity C-reactive protein, interleukin-6 (IL-6), and tumor necrosis factor-alpha receptor II (TNF-
RII) in the atorvastatin group.
CONCLUSIONS: The use of atorvastatin in patients with nonischemic HF improves LVEF and attenuates adverse LV remodeling. The effects on soluble levels of several inflammatory markers with atorvastatin suggest, in part, mechanisms by which statins might exert their beneficial effects in nonischemic HF.
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Hydroxymethylglutaryl CoA reductase inhibitors (statins) have been shown to reduce morbidity and mortality in coronary artery disease (CAD) and other atherosclerosis-related diseases (5–8); however, only limited data are available on the effect of statins in reducing adverse cardiovascular events in patients with HF (9,10). Statins have many effects beyond lipid-lowering that make them of potential benefit in patients with HF 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 HF (11,12). In addition, they inhibit the synthesis of inflammatory cytokines and chemokines, improve autonomic function, and reverse myocardial remodeling (13,14). Moreover, statins might retard the progression of myocardial dysfunction in HF by promoting plaque stabilization and reducing the progress of CAD.
We hypothesized that statin therapy would improve LV function and markers of inflammation in patients with nonischemic etiologies of HF. We undertook the present pilot study to evaluate the effects of therapy with atorvastatin on echocardiographic indexes of LV function and serum markers of inflammation in patients with nonischemic etiologies of HF and systolic dysfunction.
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Methods |
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TopAbstractMethodsResultsAtorvastatin therapy and...DiscussionReferences |
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35%, as documented by echocardiography or ventriculography during the one year before enrollment; and 3) stable doses of HF medications for three months before enrollment. Patients were excluded if they: 1) had been receiving a statin during the six months before enrollment; 2) had had a prior adverse event related to statin use; or 3) had diabetes mellitus. Patients were classified as having nonischemic cardiomyopathy if they had no prior clinical history of a myocardial infarction and no coronary artery stenoses >50% on cardiac catheterization performed during the one year before enrollment. Written informed consent was obtained from all patients.
Study design.
Patients (n = 108) were randomized in a double-blinded fashion to either atorvastatin (20 mg/day) or matching placebo for a 12-month period. Study visits took place at 0, 6, and 12 months. Transthoracic echocardiography was performed at each study visit, and LVEF, LV mass/body surface area, and LV systolic and diastolic diameters were determined. Blood was drawn at each study visit to measure several markers of inflammation. The primary end point of the study was change in LVEF, as determined by transthoracic echocardiography. Secondary end points included changes in several markers of inflammation and/or oxidation, including high sensitivity C reactive protein (hsCRP), IL-6, tumor necrosis factor- receptor II (TNF- RII), and erythrocyte superoxide dismutase (E-SOD). The study protocol complies with the Declaration of Helsinki and was approved by the institutional review board.
Echocardiographic assessment. Two-dimensional transthoracic echocardiograms were performed at 0, 6, and 12 months. Left ventricular systolic function and cardiac dimensions indexed to body surface area were determined. The heart was imaged in parasternal short axis view to obtain LV wall thickness and parasternal long axis view to measure ejection fraction, which was determined with Simpson’s rule. Left ventricular end-diastolic diameter (LVEDD) and left ventricular end-systolic diameter (LVESD) diameters were measured from M-mode tracings. The LV mass index was calculated by the Penn-cube method, as previously described (15). The images were reviewed by two independent echocardiographers who were blinded to the subject’s clinical status during the study period, and any discrepancies in interpretations were resolved.
Laboratory measurements.
Laboratory samples were collected at each study visit and stored at –80°C after centrifugation. An aliquot was drawn, and E-SOD activity was determined with hemolysates and commercially available kits (Cat. No. SDI 25, Randox Lab. Ltd., Crumlin, County Antrim, Ireland). 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 (16). The E-SOD activity is then measured by the degree of inhibition of this reaction. The E-SOD activity was expressed as U/g Hb. For analysis of serum IL-6, studies were performed on each sample in triplicate. Sixty microliters of serum were used for analysis, and enzyme-linked immunosorbent assay (ELISA) was performed. The levels of total serum IL-6 were determined on a plate reader at an optical density of 420 nm. High sensitivity CRP was measured with an immunoprecipitation assay. Serum TNF- RII was measured as an indirect marker of monocyte/macrophage stimulation (17). The interassay variability was <10% and the intra-assay variability was <5% for all four markers. We found no interference by atorvastatin or its metabolites in these assays.
Blood glucose was measured with a glucose dehydrogenase method after precipitation of proteins by trichloroacetic acid. Low-density lipoprotein (LDL) and high-density lipoprotein (HDL) fractions were separated from fresh serum by combined ultracentrifugation and precipitation. Lipoprotein fraction cholesterol and triglycerides were measured enzymatically.
Statistical analysis. All values presented are the mean ± standard deviation for continuous variables and as the percentage of total patients for categorical variables. The independent sample t test and chi-square were used for comparison of continuous and categorical variables, respectively. Two-way analysis of variance (ANOVA) was used to compare laboratory and serial echocardiographic data between the groups. Data were analyzed by intention to treat, with a secondary analysis performed with paired samples (patients with complete baseline and follow-up data available). A p value of <0.05 was considered statistically significant, and all p values were two-sided. Calculations were performed with Statistical Package for the Social Sciences (SPSS) software (version 10.0, Chicago, Illinois).
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TopAbstractMethodsResultsAtorvastatin therapy and...DiscussionReferences |
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RII, and hsCRP and increases E-SOD activity.
In patients treated with atorvastatin, serum soluble levels of IL-6 decreased from 17.1 ± 1.4 ng/dl to 13.3 ± 0.8 ng/dl over the 12-month study period, with no significant change in the placebo group (Table 4). Similar reductions in serum levels of TNF- RII and hsCRP were noted in the atorvastatin group, with no significant change in the placebo group. Activity of E-SOD, an anti-oxidative marker, was lower in the atorvastatin group at baseline when compared with placebo (550 ± 58 U/g Hb for atorvastatin vs. 580 ± 60 U/g Hb for placebo; p = 0.009) but increased significantly in the atorvastatin group at the end of the follow-up period (649 ± 43 U/g Hb for atorvastatin vs. 577 ± 38 U/g Hb for placebo; p < 0.0001).
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Atorvastatin therapy and clinical events |
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TopAbstractMethodsResultsAtorvastatin therapy and...DiscussionReferences |
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Discussion |
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TopAbstractMethodsResultsAtorvastatin therapy and...DiscussionReferences |
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RII, and IL-6 as well as an increase in E-SOD activity, suggesting an association between changes in pro-inflammatory and pro-oxidative markers and LV systolic function. The patients in our study were largely either NYHA functional class II or III in symptoms. Baseline medical therapy was good, with 88% of the study population receiving either an angiotensin-converting enzyme inhibitor or angiotensin receptor blocker and 69% receiving a beta-blocker at the time of enrollment. Mean baseline LDL and HDL cholesterol values were 3.2 ± 0.5 mmol/l and 1.1 ± 0.2 mmol/l, respectively, suggesting that the benefits of atorvastatin therapy in patients with nonischemic HF occur at cholesterol values that are below the current National Cholesterol Education Program III guidelines for the initiation of lipid-lowering therapy.
Currently, few data are available on the effects of statins in patients with nonischemic etiologies of HF. The major statin trials have generally excluded patients with HF, although subanalyses of data from several of these studies have found that statin therapy reduces the risk of developing ischemic HF in patients with prior CAD (18,19). Several non-randomized comparisons, such as the Prospective Randomized Amlodipine Survival Evaluation (PRAISE) and the Antiarrhythmics Versus Implantable Defibrillators (AVID) trials, demonstrated a mortality benefit in patients with ischemic and/or nonischemic HF who were treated with statins (20–24).
The data from our study also confirm the results of a randomized trial by Node et al. (25), in which 53 subjects with nonischemic dilated cardiomyopathy were randomized to simvastatin 10 mg/day versus matching placebo for 14 weeks. The authors found that patients treated with simvastatin had a lower NYHA functional class compared with patients receiving placebo (2.04 ± 0.06 vs. 2.32 ± 0.05, p < 0.01), which corresponded to an improved LVEF in the simvastatin group (34 ± 3% to 41 ± 4%, p < 0.05) but not in the placebo group. In addition, plasma concentrations of TNF-, IL-6, and B-type natriuretic peptide were significantly lower in the simvastatin group compared with the placebo group. Taken together, the results of these two randomized trials suggest that statins might have a role in improving symptoms and blunting the pro-inflammatory state in patients with nonischemic HF.
Inflammation in HF.
Inflammatory mediators play an important role in the development and progression of HF. 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- plays an important role in the progression of HF. Tumor necrosis factor-alpha has been implicated in the development of LV dysfunction, pathologic LV remodeling, endothelial dysfunction, increased cardiac myocyte apoptosis, and the development of anorexia and cachexia, among other effects (26,27) The reproducibility of plasma concentrations of soluble TNF receptors, however, are much higher than that of TNF- itself and might explain why soluble TNF receptors such as TNF- RII predict both short-term (28) and long-term (29) prognosis better than TNF- in HF 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 HF patients (2–4).
Statins have important anti-inflammatory effects and downregulate CRP and inflammatory cytokines, which are activated in HF of any etiology (13) Our data showed a reduction in serum levels of hsCRP as well as TNF- RII and IL-6 in patients with HF 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. Erythrocyte superoxide dismutase catalyzes the reaction of superoxide anions (O2–) 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 nitric oxide 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 (30,31).
In addition to their anti-inflammatory and antioxidant effects, there are a number of other potential mechanisms that might 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 myocardial remodeling, improvement of endothelial dysfunction, and inhibition of neurohormonal activation (13,14,32,33).
Study limitations. Our study has several limitations that must be noted. As a pilot study that focused on mechanisms of action, the number of subjects was small (n = 108) and follow-up was limited to 12 months. Thus, the study was not powered to evaluate the effect of atorvastatin on clinical outcomes in this patient population. Similarly, data on the effects of atorvastatin in patients with both nonischemic HF and diabetes are not available, because many patients with known diabetes are already on a statin, which was an exclusion criterion in our study. Nevertheless, the results of this study suggest that therapy with atorvastatin might be of benefit in patients with nonischemic HF and systolic dysfunction. A large-scale randomized trial of statins in this patient population is warranted.
Conclusions. Currently, only 20% to 30% of patients with nonischemic HF receive statin therapy, compared with approximately 50% to 55% of those with an ischemic etiology of HF and 80% to 85% of patients with CAD (34,35). Our findings suggest that the use of atorvastatin in patients with nonischemic HF and systolic dysfunction is associated with an improvement in LV dysfunction, an attenuation of adverse LV remodeling, and an improvement in HF symptoms (NYHA functional class). The anti-inflammatory and antioxidative effects of statins might play a role in these findings, but their relationship to changes in clinical outcomes is not known.
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Footnotes |
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125 mg/dl treated with statins versus no lipid lowering drug Am J Cardiol 2002;90:147-149.[CrossRef][ISI][Medline]This article has been cited by other articles:
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p = 0.004 for the difference in ejection fraction at 12 months between the placebo and the atorvastatin groups.