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The effects of short term statin treatment on left ventricular function and inflammatory markers in patients with chronic heart failure

The effects of short term statin treatment on left ventricular function and inflammatory markers in patients with chronic heart failure
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  The effects of short term statin treatment on left ventricular function andinflammatory markers in patients with chronic heart failure Cemil Gürgün  a, ⁎ , Müge Ild ı zl ı  a  , O ğ uz Yavuzgil  a  , Aytül Sin  b , An ı l Apayd ı n  c ,Cahide Ç ı nar   a  , Hakan Kültürsay  a  a   Ege University Faculty of Medicine, Cardiology Department, Turkey  b  Ege University Faculty of Medicine, Immunology Department, Turkey c  Ege University Faculty of Medicine, Cardiovascular Surgery Department, Turkey Received 12 January 2006; received in revised form 7 November 2006; accepted 13 November 2006Available online 22 February 2007 Abstract  Background:  Statins may provide additional benefits in patients with cardiac failure due to their pleiotropic effects besides their cholesterol-lowering actions. In this study, we aimed to evaluate the impact of 12-week fluvastatin therapy on the inflammatory cytokines and theventricular performance markers in patients with heart failure.  Methods and results:  Fourty chronic heart failure patients, twenty with idiopathic dilated cardiomyopathy (DCM group) and 20 with ischemiccardiomyopathy (ICM group), for whom statin treatment was indicated according to Adult Treatment Panel III were included to this open labeland prospective study. After a 12-week treatment with fluvastatin 80 mg/day; clinical functional capacity, echocardiographic indices of cardiac performance and inflammatory markers were evaluated. After the treatment, functional capacity (in DCM group: 2.05±0.4 versus 1.65±0.6,  p =0.005; in ICM group: 2.25±0.5 versus 1.8±0.6,  p =0.003), left ventricular ejection fraction, LVEF (from 30±5% to 33±5%,  p =0.001 inDCM and 29±4% to 31±5%,  p =0.001 in ICM group) and tissue Doppler mitral annular systolic velocity, Sm (5.8±1 cm/s to 7±1 cm/s,  p =0.001 in DCM and 5.4±0.8 cm/s to 7±1 cm/s,  p =0.001 in ICM group) improved. Tumor necrosis factor- α  and interleukin-6 levelsdecreased, but no significant changes in high sensitive C-reactive protein and brain natriuretic peptide levels were detected with the fluvastatintreatment in both groups. Conclusion:  Fluvastatin improved cardiac functions and the clinical symptoms in HF patients with either idiopathic dilated or ischemicetiology. This positive effect of fluvastatin which might be secondary to inflammatory modulation was more marked in patients with ischemicetiology. Statins in HF deserves special attention by means of further large-scale trials.© 2007 Elsevier Ireland Ltd. All rights reserved.  Keywords:  Heart failure; Statins; Inflammation Heart failure (HF) is the leading cause of cardiovascular mortality and morbidity. Regardless of its etiology, systemicinflammation plays an important role in the pathogenesis of heart failure [1]. Therefore, extensive research has beenmade about the potential benefits of various anti-inflamma-tory drugs in the treatment of heart failure. Statins cause amarked decrease in mortality and morbidity in coronaryartery disease primarily by lowering cholesterol. Some of the beneficial effects of statins could be attributable to their  positive pleiotropic and anti-inflammatory effects [2].Though the exact relation between the pleiotropic effectsof statins and the cholesterol metabolism is not known, theseagents have been shown to decrease the C-reactive protein(CRP) levels, regulate the endothelial functions and positively affect the left ventricular remodeling [3,4]. The beneficial potential of statins other than their lipid loweringeffects has not been studied widely in patients with heart  International Journal of Cardiology 123 (2008) 102 – ⁎ Corresponding author. Ege University Faculty of Medicine, CardiologyDepartment, 35100  İ zmir, Turkey. Tel.: +90 232 3904001; fax: +90 2323903287.  E-mail address:  (C. Gürgün).0167-5273/$ - see front matter © 2007 Elsevier Ireland Ltd. All rights reserved.doi:10.1016/j.ijcard.2006.11.152  failure. Furthermore, patients with left ventricular systolicdysfunction have been excluded nearly in all of the major statin trials focused on the cholesterol levels [5 – 7]. Whether to use or not to use statins in HF is still controversial. In thisopen label and prospective study, we aimed to investigate theeffects of 12-week of fluvastatin treatment in HF patients byevaluating the clinical status, inflammatory markers and theleft ventricular functions. 1. Materials and methods 1.1. Study population Fourty patients with heart failure due to idiopathic dilated(DCM) or ischemic cardiomyopathy (ICM), and with left ventricular ejection fraction of less than 40% enrolled to thestudy. DCM group consisted of twenty patients with normalcoronary arteries confirmed by coronary angiography, and inwhom no other etiologic factor was found to explain the HF.Twenty patients with a history of coronary artery disease,confirmed by coronary angiography, with no revasculariza-tion indication based on viability tests such as dobutaminestress echocardiography or thallium 201 myocardial perfu-sion scintigraphy consisted the ICM group. All patients hadhypercholesterolemia requiring treatment according to National Cholesterol Education Program Expert Panel onDetection, Evaluation, and Treatment of High BloodCholesterol in Adults (Adult Treatment Panel III) [8].Because of ethical concerns like placebo administration tohyperlipidemic HF patients, especially those of ischemicetiology which would leave them untreated, or initiation of statin treatment in normolipidemic HF patients, only HF patients with therapeutical indication according to ATP IIIGuideline were included in the study. Patients with acuteheart failure, acute coronary syndrome, severe valvulopathy,non-cardiac systemic disease, secondary hyperlipidemia,hypersensitivity or contraindications to statins and those withsevere hepatic and renal dysfunctions were excluded fromthe study. Informed consent was obtained from all patients before participation to this study. The study complies withthe declaration of Helsinki and was performed in accordancewith the institutional approved protocols. 1.2. Study protocol  At the initial evaluation of the patients, regular physicalexamination, determination of the clinical functional capac-ity [9], ECG, telecardiography and transthoracic echocardi-ography (TTE) were performed. Statins were discontinued in patients who were on statin treatment 2 weeks before.Routine biochemistry, hemogram, lipid profiles, interleukin-6 (IL-6), tumor necrosis factor- α  (TNF- α ), high sensitive C-reactive protein (hs-CRP) and brain natriuretic peptide(BNP) levels were measured in patients following a 30-minute rest at supine position after a 12-hour fasting period.Oral administration of fluvastatin 80 mg/day was initiated in both groups. After 6 weeks of statin treatment, liver transaminases (ALT, AST) and creatinine kinase (CPK)enzyme levels and regular urine analyses were obtained todetect the possible side effects of the statins. After 3 monthsof treatment, regular biochemical tests, lipid profile mea-surement, echocardiography, measurement of IL-6, TNF- α ,hs-CRP and BNP levels and clinical functional classes of the patients were reevaluated and comparison was made between the pre-treatment and post-treatment values. 1.3. Echocardiographic examination TTE was performed in all patients (Philips, Sonos 7500).Echocardiography results were evaluated by two indepen-dent physicians who were blind to the groups. Two-dimensional measurements were recorded from the para-sternal long axis, areas at end-diastole and end-systole werecalculated based on the apical four- and two-chamber viewsand thus left ventricular cavity volumes and left ventricular ejection fraction were calculated via modified Simpson'smethod [10]. Myocardial contraction and diastolic functionswere evaluated by measuring the valvular functions by color Doppler, mitral flow E and A wave velocities and E/A ratio by spectral Doppler followed by the measurement of themyocardial systolic wave (Sm), and early (Em) and late(Am) wave peak velocity gradients from mitral annulus at the apical four-chamber and parasternal long axis views byusing pulse wave tissue Doppler  [10]. Table 1Patient characteristics at baselineDCM group( n =20)ICM group( n =20)  p Age (years) 65±9 63±10 0.635Gender (female/male (%)) 8/12 (40/60) 4/16 (20/80) 0.301 NYHA functional capacity (mean) 2.05±0.4 2.25±0.4 0.750Risk factorsSmoking (%) 35 35 1Hypertension (%) 30 35 1Diabetes mellitus (%) 20 30 0.460Atrial fibrillation (%) 35 35 1HF period (years) 3.3±2 4.6±2 0.920Left ventricular ejection fraction (%) 31±5 30±5 0.507Systolic blood pressure (mm Hg) 122±16 118±15 0.420Diastolic blood pressure (mm Hg) 76±9 80±7 0.125Serum lipidsTotal cholesterol (mg/dl) 238±44 196±29 0.001Triglyceride (mg/dl) 180±76 145±89 0.181HDL-cholesterol (mg/dl) 45±8 41±8 0.103LDL-cholesterol (mg/dl) 158±37 128±25 0.004hs-CRP (mg/dl) 0.506±0.350 0.530±0.348 0.831IL-6 (pg/ml) 4.97±3.95 4.03±3.26 0.417TNF- α  (pg/ml) 3.24±2.07 4.3±3.9 0.335BNP (ng/ml) 23.12±12.52 23.76±12.52 0.887Medications usedDiuretic (%) 20 (100) 20 (100) 1ACE inhibitor (%) 17 (85) 19 (95) 0.605ARB (%) 3 (15) 2 (10) 1Digoxin (%) 10 (50) 13 (65) 0.522Beta-blocker (%) 18 (90) 20 (100) 0.487103 C. Gürgün et al. / International Journal of Cardiology 123 (2008) 102  –  107   1.4. Biochemical measurements Routine biochemical investigations (hemogram, fasting blood glucose, urea, creatinine, Na + , K  + , uric acid, ALT,AST, CPK) were performed, and lipid profiles (totalcholesterol, triglyceride, HDL cholesterol, LDL cholesterol)andhs-CRPvalues weremeasuredinbloodsamplesobtainedafter12-hourfasting.Bloodsampleswerecentrifugedandthesera were stored at   − 80 °C. After the completion of patient enrollment and follow-up, BNP (Phoenix PharmaceuticalsBNP kit, Belmont,California), IL-6(BioSource InternationalImmunoassay hIL-6 kit, Nivelles, Belgium) and TNF- α (BioSource International Immunoassay TNF- α  ultra sensi-tive kit, Nivelles, Belgium) values were measured in allserum samples by the use of enzyme linked-immuno-sorbent assay(ELISA)method.Thehs-CRPlevelsweremeasuredonthe same day without any delay by immunoturbudimetricmethod (Tina-quant r sensitive CPR, Roche Diagnostic). Theinterpretation of serum levels of cytokines was done withgreat caution due to its high variability. 1.5. Statistical analysis Intra-group analyses of the DCM and ICM groups withrespect to baseline patient characteristics were performed bythe independent 2-group  t   test. For inter-group comparisons,  X  2 or Fischer analysis was used as appropriate. WilcoxonSigned Ranks test was used for intra-group changes.Pearson's correlation analysis was used for the correlationanalyses. Quantitative variables were expressed as average±standard deviation.  p b 0.05 value was accepted as statisti-cally significant. 2. Results There were no significant differences in demographiccharacteristics between DCM and ICM groups (Table 1). As Fig. 1. Changes of the inflammatory markers and BNP levels in both groups. Figs. a, b, c and d show changes of TNF- α , IL-6, hsCRP and BNP levelsrespectively (IL-6: interleukin-6, TNF- α : tumor necrosis factor- α , hs-CRP: high sensitive c-reactive protein, BNP: brain natriuretic peptide, DCM: dilatedcardiomyopathy, ICM: ischaemic cardiomyopathy).Table 2Echocardiographic parameters of both groups after treatment Echo parametersDCM group ( n : 20) ICM group ( n : 20)Before After   p  Before After   p LVESD (cm) 4.5±0.9 4.2±0.9 0.04 4.4±0.5 4.2±0.5 0.005LVEDD (cm) 5.8±0.8 5.6±0.7 0.3 5.9±0.6 5.7±0.6 0.1LA (cm) 5.1±0.5 4.9±0.4 0.3 5.2±0.5 5±0.4 0.2LVEF (%) 30±5 33±5 0.001 29±4 31±5 0.001Sm (cm/s) 5.8±1 7±1 0.001 5.4±0.8 7±1 0.001Em (cm/s) 6.7±2 7.9±2 0.1 7.9±1 8.8±2 0.04E/Em 11.6±5.3 9.2±3.8 0.1 12.9±2.8 10.2±4.5 0.028LVESD: Left ventricular end-systolic diameter, LVEDD: left ventricular end-diastolic diameter, LA: left atrium, LVEF: left ventricular ejectionfraction, Sm: left ventricular peak systolic velocity at tissue Doppler recordings, E: transmitral peak early diastolic velocity at transthoracicechocardiography, Em: Left ventricular peak early diastolic velocity at tissueDoppler recordings.104  C. Gürgün et al. / International Journal of Cardiology 123 (2008) 102  –  107   for the parameters recorded at baseline, only total cholesteroland LDL cholesterol levels were higher in the DCM group,compared to ICM group. This expected difference in lipid profile resulted from the selection of the hyperlipidemic patients who would receive statin treatment based on theATP III Guidelines.Twelve-week administration fluvastatin 80 mg/day waswell tolerated by all patients. No side effects nor anysignificant changes in liver function tests and CPK levelswere observed. Only one patient from the DCM group washospitalized due to decompensated CHF during the treat-ment period. A significant decrease was observed in totalcholesterol and LDL-cholesterol levels in both groups after 12 weeks of treatment. In the DCM group, total cholesterollevel decreased from 238±44 mg/dl to 186±37 mg/dl(  p b 0.001), triglyceride level decreased from 180±76 mg/dlto 137±51 mg/dl (  p b 0.001) and LDL-cholesterol level from157±36 mg/dl to 111±31 mg/dl (  p b 0.001). HDL-choles-terol level increased from 44.7 mg/dl to 48±26 mg/dl(  p =0.5). In the ICM group, total cholesterol level decreasedfrom 196±29 mg/dl to 161±31 mg/dl (  p b 0.001), triglyc-eride level decreased from 145±88 mg/dl to 142±56 mg/dl(  p =0.8), LDL-cholesterol level from 127±24 mg/dl to 94±24 mg/dl (  p b 0.001) and HDL-cholesterol level from 40±7 mg/dl to 38±7 mg/dl (  p =0.5). No significant changes were detected in TNF- α , IL-6, hs-CRP and BNP levels of the patients in the DCM group withfluvastatin treatment. However, IL-6, TNF- α  and hs-CRPlevels tended to decrease following the treatment. In ICMgroup; a significant decrease in TNF- α  (  p =0.01) and a non-significant decrease in IL-6 levels were observed withfluvastatin treatment. Also the decrease in the BNP value didnot reach statistical significance. No change was observed inthe hs-CRP value after the treatment (Fig. 1a, b, c and d).The pre- and post-treatment echocardiographic patient data are presented in the Table 2. Left ventricular end-systolic diameter was significantly decreased, ejectionfraction (Fig. 2) and the tissue Doppler Sm value weresignificantly increased in both groups. In ICM group, whilethe tissue Doppler Em values were increased, E/Em ratio wasdecreased significantly after treatment.There were correlations between changes in ejectionfraction and LDL cholesterol levels ( r  = − 0.512,  p =0.021)and between tissue Doppler systolic velocity and TNF- α levels ( r  = − 0.507,  p =0.023) in ICM group. No correlationwas found between changing in inflammatory markers andechocardiographic parameters for DCM patients.A marked decrease was observed in the NYHA functionalcapacity of both groups after the treatment (in DCM group:2.05±0.4 versus 1.65±0.6,  p =0.005; in ICM group: 2.25±0.5 versus 1.8±0.6,  p =0.003). The improvement infunctional capacity was apparent in the ICM group. Thedetails of the changes in functional capacity of the patientsare presented in Fig. 3. 3. Discussion Since the emergence of the role of inflammation in the pathophysiology of HF, statins have been suggested to provide an additional benefit for HF patients due to their  pleiotropic effects. The low cholesterol levels observed inHF patients seem to be a marker of terminal disease rather  Fig. 2. Left ventricular ejection fraction changes of both groups after treatment.Fig. 3. Functional capacity (NYHA class) changes of both groups after treatment.105 C. Gürgün et al. / International Journal of Cardiology 123 (2008) 102  –  107   than causing an increased mortality [11]. Rauchhaus et al.demonstrated that total cholesterol levels below 200 mg/dlare poor prognostic factors in HF patients irrespective of theother risk factors [12]. Low cholesterol levels may be theresult rather than the reason for poor prognosis in patientswith heart failure. Due to lack of large-scale trials and the presence of certain trials demonstrating that the lowcholesterol levels were associated with increased mortalityin HF, concerns have been raised about the use of statins inthis group of patients [13].In several trials in HF patients, it was reported that short-term statin treatment improves the left ventricular systolicfunctions, decreases the levels of inflammatory cytokines and provides survival advantage [14,15]. Many other properties of statins such as directly decreasing coronary ischemia byimproving endothelial functions and providing plaque stabi-lization,mightbeeffectiveindecreasingtheprogressionofHF[16]. The cause of immune activation in heart failure isunknown; myocardium itself, endotoxemia or hypoxia maystimulate the production of inflammatory cytokines in HF patients. The main elements of immune system, considered to berelatedwiththe pathogenesisofHF; cytokines (TNF- α , IL-1 and 6), C-reactive protein, adhesion molecules, auto-antibodies, nitric oxide and endothelin-1 [17]. TNF- α  levelswere indicated to be high in HF and in certain trials, theselevels were reported to be correlated with the severity of HF[18,19]. TNF- α  was shown to trigger apoptosis, pathologicalfibrosis and the left ventricular remodeling and have negativeinotropic effects on myocardium [20]. Another important cytokineconsideredinthepathogenesisofheartfailureisIL-6.In the study performed by Node et al. in patients with HF dueto idiopathic dilated cardiomyopathy, a marked decrease wasreported in the IL-6 and TNF- α levels of the patients with 14-week low-dose statin treatment  [21]. Although a statisticalsignificance could not be obtained, the decrease of the meanTNF- α andIL-6levelsofourpatientsinthisgroupisapositiveresult with respect to the anti-inflammatory efficacy of thefluvastatin. Like other inflammatory markers we investigated,hs-CRP values did not exhibit a significant change in either  patient group. When the mean hs-CRP values of our patientswere evaluated, a rather low value relative to the HF patient  population is observed [22]. We believe that the absence of anadditional decrease in CRP values after the fluvastatintreatment may result from the low basal values. This result also indicates that our patient population is a relatively stablegroup. When the echocardiographic parametersof the patientswere evaluated, significant increases were observed in the left ventricular ejection fraction and in the myocardial systoliccontraction rate values by tissue Doppler in both groups. Themean increase in the left ventricular ejection fractions wasdeterminedtobe2.9%intheDCMgroupand1.9%intheICMgroup.Inasimilarstudy,a7%increasewasreportedintheleft ventricular ejection fraction in patients with idiopathic dilatedcardiomyopathy with statin treatment  [21]. When the patient dataofthisstudyareexamined,thepatientsaredetectedtousethe drugs such as ACE inhibitors, beta blockers and diureticsrelativelyless compared toour patient population and they areobservedtoconstitutearelativelylessstablepatientpopulationwithrespecttoBNPlevels.Inaddition,patientswithnoviablemyocardial tissue under risk and no revascularizationindication were included in our ICM patient group. Thereexists data which support that hibernated myocardial tissue benefits largely from statin treatment  [23]. These properties of our patients may explain why the increase in their systolicfunctions is not high. Despite this; fluvastatin treatment isobserved to offer additional positive effects even for arelatively stabile patient population on optimum treatment,with no chance for revascularization. The detection of acorrelation between the decrease in TNF- α  values of the patients in the ICM group and the increase in myocardialsystolic velocity gradients supports that fluvastatin may have positive effects on myocardial contractility via their anti-inflammatory properties. Another possible mechanism that explains the positive effects of statins on the left ventricular functions inHFpatientsmaybethe increaseinthe myocardial blood flow reserve. Statins were shown to increase themyocardial blood flow reserve in individuals with hypercho-lesterolemia [24]. It is known that myocardial blood flowreserve decreases proportionally with the severity of HF in patient with DCM [25]. The increase in endothelial NOS production [26] and the decrease in myocardial oxygenconsumption[27]causedbystatinsmaybethemechanismsbywhich statins increase the myocardial blood flow reserve. Inaddition, Abraham et al. reported an increase in myocardialcapillary density in animal subjects with statin treatment,without markedly lowering the cholesterol [15]. This result may indicate that statins improve myocardial microcirculation bydirectlyshowinga vasculoprotective effect. The significant increase in the left ventricular ejection fraction and tissueDoppler Sm values in our study may reflect the effect of thefluvastatin in increasing myocardial blood flow reserve. In both groups, improvement was achieved in left ventricular diastolic parameters with the fluvastatin treatment. Thesevalues reached a level of statistical significance in the ICMgroup. There are no data showing an improvement in the left ventricular diastolic functions with the use of statins in theliterature to date. The improvement obtained in the diastolicfunctions as well as in the systolic functions with statintreatment in our study may be a significant implication for further studies. Nevertheless, preliminary results of a recent trial (UNIVERSE) was concluded that high dose rosuvastatindid not beneficially alter parameters of LV remodeling andinflammatory markers [28]. No significant decrease wasachieved in BNP values in either group, however there was atendency towards a decline in these values in the ICM group.As previously indicated, the relatively low pre-treatment BNPvaluesofthepatientsinbothgroupscouldbeattributabletotherelative stability of our patient population. Additionally, theimprovement in the left ventricular dysfunction was moremarked at the tissue level than the data of ventricular functionindices. We believe that the fluctuation in BNP values,triggered by left ventricular pressure and the increase in 106  C. Gürgün et al. / International Journal of Cardiology 123 (2008) 102  –  107 
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