The influence of atorvastatin on parameters of inflammation left ventricular function ...

12 Pages·2013·0.97 MB·English

Bielecka-Dabrowaetal.LipidsinHealthandDisease2013,12:47
http://www.lipidworld.com/content/12/1/47
RESEARCH Open Access
The influence of atorvastatin on parameters of
inflammation left ventricular function,
hospitalizations and mortality in patients with
–
dilated cardiomyopathy 5-year follow-up
Agata Bielecka-Dabrowa1*, Dimitri P Mikhailidis2, Manfredi Rizzo3,4, Stephan von Haehling5,
Jacek Rysz6 and Maciej Banach1*
Abstract
Background: Weassessedtheinfluenceofatorvastatinonselectedindicatorsofaninflammatorycondition,left
ventricularfunction,hospitalizationsandmortalityinpatientswithdilatedcardiomyopathy(DCM).
Methods:Weincluded68DCMpatientswithleftventricularejectionfraction(LVEF)≤40%treatedoptimallyina
prospective,randomizedstudy.Theywereobservedfor5years.Patientsweredividedintotwogroups:patientswho
werecommencedonatorvastatin40mgdailyfortwomonthsfollowedbyanindividuallymatcheddoseof10or
20mg/day(groupA),andpatientswhoweretreatedaccordingtocurrentrecommendationswithoutstatintherapy
(groupB).
Results:After5-yearfollow-upweassessed45patientsofmeanage59±11years-22patientsingroupA(77%male)
and23patientsingroupB(82%male).Interleukin-6,tumornecrosisfactoralpha,anduricacidconcentrationswere
significantlylowerinthestatingroupthaningroupB(14.96±4.76vs.19.02±3.94pg/ml,p=0.012;19.10±6.39vs.
27.53±7.39pg/ml,p=0.001,and5.28±0.48vs.6.53±0.46mg/dl,p=0.001,respectively).Inpatientsonstatintherapya
reductionofN-terminalpro-brainnatriureticpeptideconcentration(from1425.28±1264.48to1098.01±1483.86pg/ml,
p=0.045),decreaseinleftventriculardiastolic(from7.15±0.90to6.67±0.88cm,p=0.001)andsystolicdiameters(from
5.87±0.92to5.17±0.97,p=0.001)incomparisontoinitialvalueswereobserved.Wealsoshowedthesignificantincrease
ofLVEFinpatientsafterstatintherapy(from32.0±6.4to38.8±8.8%,p=0.016).Basedonacomparisonofcurvesusing
thelog-ranktest,theprobabilityofsurvivalto5yearswassignificantlyhigherinpatientsreceivingstatins(p=0.005).
Conclusions:Atorvastatininasmalldosesignificantlyreducelevelsofinflammatorycytokinesanduricacid,improve
hemodynamicparametersandimprove5-yearsurvivalinpatientswithDCM.
Keywords:Atorvastatin,Dilatedcardiomyopathy,Heartfailure,Inflammation
Introduction or congenital heart disease which is so significant that it
According to the European Society of Cardiology (ESC), leads toanobservedpathology ofthemyocardium [1].
dilated cardiomyopathy (DCM) is recognized based on DCM occurs more frequently in men and is most
dilation and systolic dysfunction of the left ventricle, un- common between the ages of 20 and 60 years [1,2].
less a patient simultaneously suffers from coronary ar- About 1 in 3 cases of congestive heart failure (CHF) is
tery disease (CAD), hypertension, valvular heart disease due to DCM. Despite treatment, CHF is a progressive
disease with high morbidity and mortality, suggesting
that important pathogenic mechanisms remain active
andunmodifiedbycurrently available treatment [1,2].
*Correspondence:[email protected];[email protected]
1DepartmentofHypertension,ChairofNephrologyandHypertension, The cause of mortality in these patients is either end-
MedicalUniversityofLodz,Lodz,Poland organ dysfunction due to pump failure or arrhythmia-
Fulllistofauthorinformationisavailableattheendofthearticle
©2013Bielecka-Dabrowaetal.;licenseeBioMedCentralLtd.ThisisanOpenAccessarticledistributedunderthetermsofthe
CreativeCommonsAttributionLicense(http://creativecommons.org/licenses/by/2.0),whichpermitsunrestricteduse,
distribution,andreproductioninanymedium,providedtheoriginalworkisproperlycited.
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relateddeath[3,4].Withinrecentyearsmoreandmoreevi- effects may differ between the lipophilic and hydrophilic
dencehasbeenpresentedindicatingthatautoimmunologic statins[16].
processes, cellular as well as humoral ones, are involved in Therefore the aim of our study was to assess the asso-
the pathogenesis of dilated cardiomyopathy [3]. The com- ciation between 5-year atorvastatin therapy and indica-
mon presence of viral genetic material in the myocardium tors of an inflammatory condition and clinical outcomes
of patients with DCM provides the most compelling evi- inpatientswithDCM.
dence, but proof of causality is still lacking [3,4]. In ad-
dition,autoimmunereactionshavebeendescribedinmany Methods
studies, indicating them as an important etiologic factor Studypopulation
[3,4]. A pivotal role for autoimmunity in a substantial pro- Inaprospectivestudy,68patientswithDCM(accordingto
portionofpatientswithDCMissupportedbythepresence the 2008 European Society of Cardiology [ESC] classifica-
of organ-specific autoantibodies, inflammatory infiltrates tion)ofeithersex,aged18yearsorolderwithleftventricu-
and pro-inflammatory cytotoxic cytokines [3-6]. Further- lar ejection fraction (LVEF) ≤40% treated with optimal
more, familial occurrence of DCM has been described in medical therapy, were followed for 5 years [17,18]. Mean
about20–30%ofcases,withthepresenceofautoantibodies diseasedurationwas7.5±1.9years.Nopatientshadsignifi-
andabnormalcytokineprofilesinfirst-degreerelativeswith cantcoronaryarterydisease(>30%stenosis)asdetermined
asymptomatic left ventricular enlargement [3,4]. This sug- by cardiac catheterization performed within a year before
gests the involvement of a disrupted humoral and cellular the enrolment [19,20]. Arterial hypertension was not diag-
immunityearlyinthedevelopmentofthedisease[3,4]. nosedinanyofthepatients.Dateofdeathwasascertained
Despite their lipid-lowering and anti-atherosclerotic by questioning relatives or patients’ general practitioners
effects statins have also important pleiotropic properties. and estimated as close as possible to half year frames. Pa-
Theylimit signaltransmissionfrommembranereceptors tientswererandomizedtooneoftwogroups:A–patients
and slow down pathologic remodeling of the heart and who were commenced on atorvastatin 40 mg daily for 2
vessels, inhibit the action of angiotensin II, inhibit apop- months followed by an individually matched dose of 10 or
tosis,improveendothelialfunction,retardtheprogression 20mg/day;andB–patientswhoweretreatedaccordingto
of heart failure symptoms, reduce the level of N-terminal currentguidelines[21]withoutstatintherapy.
pro-brain natriuretic peptide (NT-proBNP), restore auto- The exclusion criteria were as follows: blood pressure
nomic nervous system balance and might have a protec- (BP) ≥140/90 or <90/60 mmHg; congenital heart disease;
tive influence on renal function and blood pressure [7,8]. acquired valvular disease with the exception of mitral
Previous studies have demonstrated that statins reduce incompetence secondary to left ventricular dilatation;
vascularandmyocardialoxidativestressbyinhibitingRac- persistent hyperactivity of aminotransferases with an unex-
induced nicotinamide adenine dinucleotide phosphatase plainedetiology;muscledisorderswhichmightcausedrug-
(NADPH) oxidase activity and reducing oxidized low induced myopathy; uncontrolled diabetes; liver diseases,
density lipoprotein (LDL) concentration by activated creatinine level >2 mg/dl and/or glomerular filtration rate
monocyte-derived macrophages [9]. They also reduce (GFR) <30 ml/min; alcohol or drug abuse; chronic inflam-
intracellular reactive oxygen species (ROS) in endothelial matory diseases, pregnancy or lactation, severe hypothy-
cellsbyS-nitrosylationofthioredoxin[9,10]. roidism,immunosuppressivetreatment,operationorsevere
The Rosuvastatin Impact on Ventricular Remodelling injury during the month prior to blood collection, and pa-
LipidsandCytokines(UNIVERSE),ControlledRosuvastatin tientswhodidnotprovidewritteninformedconsent.
MultinationalTrialinHeartFailure(CORONA),andEffect Initialandcontroltestsincludedfullclinicalexamination
of rosuvastatin in patients with chronic heart failure with the assessment of body mass index (BMI) and New
(GISSI-HF) trials did not indicate a significant role for York Heart Association (NYHA) class, routine laboratory
statins in HF patients, although the drug did reduce the tests, measurement of TNF-α, interleukin 6 (IL-6), and
number of cardiovascular (CV) hospitalizations in the transforminggrowth factorbeta(TGF-β) concentrations in
CORONA trial [11-13]. Although mentioned prospective bloodplasma, measurement ofN-terminal pro-brainnatri-
studiesusinghydrophilicrosuvastatinshowednobeneficial ureticpeptide(NT-proBNP),syndecan-4,cystatinC(CysC)
effectonmortality,Vrtovecetal.reportedthatatorvastatin concentration in blood serum, echocardiographic examin-
therapy reduced the incidence of sudden cardiac death in ationandtheassessmentofexercisecapacityin6-minwalk
patients with advanced CHF [14]. Correale et al. evaluated test (6MWT). The frequency of HF hospitalization and
theeffectofstatintherapyonleftventriculardysfunctionin mortalitywererecordedduringthe5-yearfollow-upperiod.
patients with CHF and showed that they had fewer read- ConsentfromtheBioethicsCommissionoftheMedical
missions for adverse events, blunted inflammatory ac- University of Lodz (No. RNN/520/10/KB) was obtained.
tivationandimprovedleftventricularperformanceassessed Written informed consent was obtained from all
by tissue Doppler imaging [15]. Metabolic and cardiac thepatients.
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Biochemicaltests relaxation time and isovolumetric contraction time
Bloodglucosewasmeasuredwithaglucosedehydrogenase by ejection time. The time of isovolumetric
method after precipitation of proteins by trichloroacetic contraction is measured from the closure of the
acid. LDL and high-density lipoprotein (HDL) fractions mitral valve to the opening of the aortic valve.
wereseparatedfromfreshserumbycombinedultracentri- The time of isovolumetric relaxation is measured
fugationandprecipitation.Lipoproteinfractioncholesterol from the closure of the aortic valve to the opening
and triglycerides were measured enzymatically. The con- of the mitral valve. The norm is ≤0.4; higher
centrationofNT-proBNPwasdeterminedusinganElecsys values indicate deteriorating efficiency of the
2010 analyzer (Roche Diagnostics, Warsaw, Poland). After myocardium [20].
the blood was taken, the material was centrifuged; the B. Rateof systolic pressurechangeintheleft ventricle
obtained serum was frozen at the temperature of −70°C (dP/dT).Thisindexdeterminestheincreasein
andstoredinthisconditionuntilthetimeofexamination. systolicpressuregeneratedbytheLVintime
The determination of NT-proBNP in blood serum was calculatedusingcontinuouswave(CW) Doppler
performed with the electroluminescence method with 2 basedonthetime ofincreaseinthespeed ofmitral
polyclonal antibodies directed against NT-proBNP within regurgitation(MR) from 1to3m/s.ValuesofdP/dT
epitope1(1–21aminoacidsequence)andepitope2(39– <400mmHg/sindicatethatthesystolicfunctionof
50amino acids).Concentration values are giveninpg/ml. theLVissignificantly impaired;normalvalues are
DeterminationofIL-6andTNF-αwasperformedwithre- >2000 mmHg/s[20,22].
agents of Beckman Coulter (Paris, France), using a sand-
wich ELISA assay. Measurement of CysC was performed Diastolic functionoftheLV wasassessed usingthe pa-
using immunonephelometric assay for the quantitative rameters of mitral inflow registered with pulsed wave
measurement of this marker in human serum and hepa- (PW) Doppler in 4-cavity apical projection and diastolic
rinizedplasma.Diazyme’sCystatinCassayisbasedonthe speed values of movement of the mitral ring registered
latex-enhanced immunoturbidimetric method. The range with tissueDopplerimaging.
of valid values for CysC measured by the immuno-
nephelometric method (N Latex Cystatin C test) is 0.53–
0.95 mg/l. Determination of syndecan 4 was performed Statisticalanalysis
withreagents ofUSCNLife ScienceInc.(Wuhan, China), The STATISTICA software package 9 (StatSoft, Poland)
using a sandwich ELISA assay [19]. Determination of was used for analysis. All values presented are the mean
TGF-β was performed with reagents of Diaclone/Gen- or median±standard deviation (SD) for continuous vari-
Probe (San Diego, USA), using an enzyme-linked im- ables and the percentage of total patients for categorical
munosorbentassay. variables. The Shapiro-Wilk test was used to assess the
normality of distribution. To compare groups Student’s
Echocardiographicassessment t test or 2-way analysis of variance (ANOVA) for con-
Echocardiography was performed using an ALOKA Alpha tinuous and discrete variables with normal distribution
6 Premier (Tokyo, Japan) with a 3–11 MHz probe. Left and non-parametric Mann-Whitney U test if the distri-
ventricular (LV) systolic function and cardiac dimensions bution was not normal were applied. For categorical var-
indexed to body surface area were determined. The heart iables chi-square test or Fisher’s test for small samples
wasimagedinparasternalshortaxisviewtoobtainLVwall was applied for comparisons. For quantitative variables
thickness and parasternal long axis view to measure ejec- (continuous and discrete) to check correlations between
tion fraction (EF), which was determined with Simpson’s variables Spearman’s rank correlation coefficient was used.
rule: EF=(LVEDV-LVESV)/LVEDV, where LVEDV is left Theassessmentoffactorsinfluencingprognosisinpatients
ventricular end-diastolic volume and LVESV is left ven- with DCM was performed using single-factor logistic re-
tricularend-systolicvolume. gression and the forward stepwise regression model, and
Leftventricularend-diastolicdiameter(LVEDD)andleft receiver operating characteristic (ROC) curves and the for-
ventricularend-systolicdiameter(LVESD)weremeasured ward stepwise regression model. Based on analysis of the
from M-mode tracings. Flow parameters were assessed in ROC curve, cut-off points were found for the measurable
Doppler examination (continuous, pulsatile and color). variables by estimating the highest product of sensitivity
Quantification of LV systolic function was also made andspecificity.Calculationsanddrawingsweremadeusing
throughapplicationof: SPSS 17.0 statistical package. The analysis of death was
plotted usingtheKaplan-Meiermethod.Dateofdeathwas
A.Themyocardial performance index(MPI),which ascertained by questioning relatives or patients’ general
reflectsglobalefficiency ofLVfunctioning.Itis practitionersand estimated ascloseaspossibleto halfyear
determinedbydividingthe sumofisovolumetric frames.Resultswereconsideredsignificantatp<0.05.
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Results Table1Characteristicsoftheanalyzedpatientswith
Baselinecharacteristicsofthepatients DCMafter5years
During 5-year observation 29% (n=20) of all 68 patients PARAMETER Mean±SDornumberofpatients(%)
died, 41% (n=28) required one re-hospitalization and Age(years) 59.0±11.0
6% (n=4) two re-hospitalizations because of HF decom- Gender(male) 40(89)
pensation. In 9% (n=6) cardiac resynchronization ther- NYHAclass
apy was applied, mitral and tricuspid valvuloplasty was
I 4(9)
performed in 1 person and heart transplantation in 2
II 22(49)
people (these patients were excluded from the analysis
III 15(33)
to avoid the imposition of the effect of statins and the
IV 4(9)
resultsofsuch procedures).
Atrialfibrillation 15(33)
Finally after 5 years we assessed 45 patients of mean
age 59±11 years (5 females and 40 males): group A– 22 Hypercholesterolemia 20(46)
patients (77% male) of mean age 63±10 years treated Anemia* 4(9)
with atorvastatin in individual dose of 10 (n=11) or Diabetesmellitusor 9(20)
20 mg (n=11), and group B – 23 patients (82% male) of abnormalglucoselevel
mean age 57±13 years without statin therapy. In 36% LVdiastolicdysfunction 4(9)
(n=16) of patients we observed dyspnea, pulmonary sPAP>40mmHg 4(9)
hemostasisin11%(n=5),andedemain9%(n=4).Body MRdegree
mass assessment revealed underweight in 4% (n=2) of 0 7(15)
patients, normal weight in 36% (n=16), overweight in I 19(43)
24% (n=11) and obesity in 36% (n=16). Chronic ob- II 15(34)
structive pulmonary disease was present in 4% (n=2)
III 4(9)
and diabetes mellitus (DM) or abnormal glucose level in
TRdegree
20% (n=9) of patients. The detailed characteristics of
0 23(51)
thepatientsarepresentedinTable1.
I 14(32)
II 8(17)
Theinfluenceatorvastatintreatmentoninflammatory
PHARMACOLOGICALTREATMENT
andclinicalparameters
In group A compared to group B, IL-6 concentration Loopdiuretics 41(91)
wasconsiderablylower(14.96±4.76vs19.02±3.94pg/ml, Spironolactone/eplerenone 39(87)
p=0.011) after five years of treatment with atorvastatin. vBeta-blockers 40(88)
TNF-α levels were also significantly reduced in the statin ACEinhibitors 41(91)
groupthaninGroupB(19.10±6.39vs27.53±7.39pg/ml, Sartans(ARBs) 4(9)
p=0.001). Also uric acid (UA) concentration was lower
Digoxin 15(34)
in the atorvastatin group(5.28±0.48 vs 6.53±0.46 mg/dl,
Acenocoumarol/warfarin 9(20)
p=0.001). No significant differences concerning NT-
Amiodarone 4(8)
proBNP concentration, echocardiographic parameters of
Statins 22(49)
the left ventricle, distance on 6MWT and in functional
Insulin 2(4)
classification according to NYHA were observed between
Oralhypoglycemics 4(9)
examinedgroups.Thedetailedcomparisonbetweengroups
AandBispresentedinTable2. *Anemia:Hb(g/dL)<13inmenand<12inwomen.
ABBREVIATIONS:ACEinhibitors–angiotensinconvertingenzymeinhibitors;
ARBangiotensinreceptorblocker;MRmitralregurgitation;NYHANewYork
Patientswithandwithoutatorvastatintherapy– heartassociation;sPAPsystolicpulmonaryarterypressure;TR
tricuspidregurgitation.
comparingchangesovertime
In the statin group after 5 years a decrease in NT-
proBNPconcentration compared with initial values from Group B. Only in the atorvastatin group a significant re-
1425.28±1264.48 to 1098.01±1483.86 pg/ml (p=0.045) ductions of total cholesterol (from 207±71 to 183±
and a decrease in LVdD and LVsD from 7.15±0.90 to 69 mg/dL) and LDL cholesterol (from 116±36 to 80±
6.67±0.88 cm (p=0.001) and from 5.87±0.92 to 5.17± 25mg/dL)wereobserved.
0.97 (p=0.001), respectively, were achieved. The signifi- In the control group a significant increase in TNF-α
cant increase of LVEF from 32.0±6.4 to 38.8±8.8% (p= levels from 12.70±12.78 to 27.50±7.39 pg/ml (p=0.006)
0.0164)wasalsoobservedinGroupA.Therewerenosig- andanincreaseinbodymassindex(BMI)from29.6±4.5
nificant changes in the range of these parameters in to31.0±4.4(p=0.033)werefound.
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Table2Comparisonofselectedparametersinpatients Table2Comparisonofselectedparametersinpatients
withDCMfromgroupA(atorvastatingroup)andgroupB withDCMfromgroupA(atorvastatingroup)andgroupB
(withoutstatin)after5-yearfollow-up (withoutstatin)after5-yearfollow-up(Continued)
PARAMETER GroupA(n=22) GroupB(n=23) p Clinicalstateofpatients
Mean±SD Mean±SD
6-MWT(m) 419.3±116.0 376.7±114.3 ns
BMI 28.9±4.3 31.0±4.4 ns*
NYHAclass(No.ofpatients[%])
Waistcircumference(cm) 98.3±12.9 96.9±13.5 ns
I 1(5) 3(13) ns
SystolicRR(mmHg) 114.7±13.0 117.5±7.7 ns
II 12(54) 10(44)
DiastolicRR(mmHg) 71.5±7.7 77.3±5.3 ns
III 8(36) 7(30)
Heartrate 77±9 69±4 ns
IV 1(5) 3(13)
Biochemicalparameters
*ns–notstatisticallysignificant.
Whitebloodcells(*103/μl) 6.9±1.4 7.3±1.4 ns ABBREVIATIONS:6MWT6-minutewalktest;BMIbodymassindex;Na
sodium;Kpotassium;HDLhigh-densitylipoprotein;LDLlow-density
Hemoglobin(g/dl) 14.6±1.4 14.5±1.3 ns lipoprotein;ASPATaspartatetransaminase;ALATalaninetransaminase;CRP
Na(mmol/l) 138±4 138±3 ns C-reactiveprotein;NT-proBNPN-terminalpro-brainnatriureticpeptide;TNF
tumornecrosisfactor;TGFbeta–transforminggrowthfactorbeta;GFRMDRD
K(mmol/l) 4.4±0.4 4.5±0.5 ns glomerularfiltrationrateusingmodificationofdietinrenaldiseaseformula;
LVdDleftventriculardiastolicdiameter;LVsDleftventricularsystolicdiameter;
Totalcholesterol(mg/dl) 178±69 202±30 0.02 LVEFleftventricularejectionfraction;LAleftatrium;RVdDrightventricular
HDLcholesterol(mg/dl) 52±18 48±9 ns diastolicdiameter;LVEdVleftventricularend-diastolicvolume;LVsVleft
ventricularsystolicvolume;NYHA;NewYorkheartassociation.
LDLcholesterol(mg/dl) 78±25 123±27 0.001
Triglycerides(mg/dl) 201±212 153±37 ns Safetyandtoleranceofatorvastatintherapy
No patients had symptoms of myopathy. There were no
ASPAT(U/l) 23.6±6.3 26.2±9.6 ns
significant changes in aminotransferases activities be-
ALAT(U/l) 23.5±7.4 26.3±10.7 ns
tweeninvestigated groupsofpatients.
Urea(mg/dl) 30.80±14.00 39.33±7.84 ns
Creatinine(mg/dl) 0.92±0.27 1.00±0.32 ns
Uricacid(mg/dl) 5.28±0.48 6.53±0.46 0.001 Hospitalizationandsurvivalassessment
Thefollowing factorsinfluencedtheriskofHFhospitali-
CRP(mg/l) 1.4±1.1 2.7±2.5 ns
zations on the basis of single-factor logistic regression:
GRFMDRD(ml/min) 792±22 71±19 ns
leg edema, hepatomegaly, no beta-blocker therapy, NT-
Biomarkers
proBNP,LVEF,LVsDandresult ofthe6-MWT(Table 3).
NT-proBNP(pg/ml) 1098.00±1483.86 1151.24±1371.00 ns
On the basis of single-factor logistic regression statistical
TNF-alpha(pg/ml) 19.10±6.40 27.53±7.39 0.001 analysis we found that: no statin therapy, leg edema,
Interleukin6(pg/ml) 14.90±4.70 19.00±3.94 0.01 hepatomegaly, no beta-blocker therapy, renal failure, re-
Syndecan4(ng/ml) 4.40±3.10 5.21±4.00 ns hospitalizations, lower BMI, LVEF, higher NT-proBNP,
LVsD, LVdD, MR degree, significantly influenced the risk
CystatinC(mg/l) 1.17±0.39 1.00±0.18 ns
ofdeath(Table4).
TGF-beta(pg/ml) 470.19±166.50 463.00±156.78 ns Thesurvivalofpatientswas87.7%(95%CI:79.2–96.2%),
Echocardiographicparameters 67.9% (95%CI: 55.7–80.2%), and 63.1% (95%CI: 50.0–
LVdD(cm) 6.6±0.8 6.4±1.8 ns 76.2%)after1,2,and5years,respectively(Figure1).Based
LVsD(cm) 5.1±0.9 5.1±1 ns on a comparison of curves using the log-rank test, the
LVEF(%) 38.4±8.8 33.9±11.5 ns probability of survival to 5 years was significantly higher
inthe group takingalowdoseofstatin (p=0.005;hazard
LAdiameter(cm) 4.7±0.8 8.0±10.5 ns
ratio[HR]3.48;95%Cl1.42–8.56)(Figure2).
RVdD(cm) 2.9±0.4 3.0±0.6 ns
According to the multivariate regression analysis we
LVEdV(ml) 187.0±37.0 191.6±72.9 ns
found that NT-proBNP (odds ratio [OR] 1.00, p=0.007)
LVsV(ml) 118.9±41.0 104.0±41.5 ns and LVdD (OR 2.96, p=0.025)werethe independentrisk
TEIindex 0.7±0.2 0.5±0.4 ns factorsofdeath,and6-MWT(OR0.99,p=0.001)wasthe
Mitralregurgitation 569.5±294.1 392.5±83.0 ns only independent risk factors of re-hospitalization for
dP/dT(mmHg/s) worsening heart failure. On the basis of ROC curve ana-
lysiswefoundthatNT-proBNPvalues≥1826pg/ml,LVEF
≤30%,BMI≤25.5,andMR≥1.5weresignificantpredictors
of both re-hospitalization and increased mortality in this
groupofpatients.
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Table3Predictorsofre-hospitalizationsinsingle-factorlogisticregression
Categoricalvariable Withre-hospitalization(%) Withoutre-hospitalization(%) p
legedema 91 9 0.009
hepatomegaly 88 11 0.03
Nobeta-blockertherapy 98 0 0.006
Quantitativevariable Withre-hospitalization(median;Q25–Q75) Withoutre-hospitalization(median;Q25–Q75) p
BMI2* 25;24–30 30;26–32 0.04
NT-proBNP1 1848;931–3248 895;511–2026 0.02
NT-proBNP2 1852;775–4000 745;360–1680 0.005
LVEF1 27;22–31 33;28–38 0.02
LVEF2 30;24–32 34;29–40 0.02
LVsD2 6;5.2–6.4 5.3;4.4–5.6 0.001
MR1 1.5;1–2 1;0–1 0.03
MR2 1;1–2 1;0–1 0.03
6-MWT1 350;290–405 438;350–490 0.01
6-MWT2 370;290–450 480;395–595 0.001
*1–forvariablesassessedafterinclusion;2–forvariablesassessedafter2months.
Q25–Q75:quartiles25%and75%.
ABBREVIATIONS:BMIbodymassindex;NT-proBNPN-terminalpro-brainnatriureticpeptide;LVEFleftventricularejectionfraction;LVsDleftventricularsystolic
diameter;MRmitralregurgitation;6MWT6minutewalktest.
Discussion cholesterol is reduced, but also that of the derivatives of
Statins act by inhibiting the enzyme 3-hydroxy-3- mevalonic acid, including isoprenoids. These compounds
methylglutaryl coenzyme A (HMG-CoA) reductase, a participate in protein isoprenylation that links lipid frag-
key step in the synthesis of cholesterol. The pleiotropic ments with intracellular proteins [23]. In limiting the pro-
effectsofstatinsmaybe connectedwiththisbasicmech- duction of isoprenoids, statins block the function of
anism. In this mechanism, not only the synthesis of cytoplasmic regulatory proteins – GTP-ases from the Rho
Table4Predictorsofdeathinsingle-factorlogisticregression
Categoricalvariable Death(%) Survival(%) p
Nostatintreatment 78 21 0.006
Legedema 72 27 0.027
Hepatomegaly 66 33 0.009
Nobeta-blockertherapy 87.5 12.5 0.001
Renalfailure 80 20 0.025
Re-hospitalizations 81 18 0.001
Quantitativevariable Withdeath(median;Q25–Q75) Withoutdeath(median;Q25–Q75) p
BMI1 24;24–26 30;25–32 0.002
BMI2 24;23–26 30;25–32 0.003
NT-proBNP1* 2771;1500–5013 980;500–2130 0.001
NT-proBNP2 2900;1296–4421 766;470–1680 0.001
LVEF1 27;21–29 32;26–38 0.01
LVEF2 30;22–31 32;28–40 0.03
LVsD2 6.2;5.3–6.7 5.3;4.5–5.9 0.01
LVdD2 7.6;6.7–8.4 6.6;6.0–7.2 0.003
MR1 2;1–3 1;0–1 0.001
MR2 2;1–3 1;0–1 0.001
*1–forvariablesassessedafterinclusion;2–forvariablesassessedafter2months.
Q25–Q75:quartiles25%and75%.
ABBREVIATIONS:BMIbodymassindex;NT-proBNPN-terminalpro-brainnatriureticpeptide;LVEFleftventricularejectionfraction;LVsDleftventricularsystolic
diameter;LVdDleftventriculardiastolicdiameter;MRmitralregurgitation.
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Figure1Kaplan-MeiercurvesprobabilityofsurvivalinpatientswithDCMafter5-yearfollow-up.*DCM–dilatedcardiomyopathy.
protein family, such as Ras, Rac1 and Rap. This results in chemokines, improve autonomic function, and reverse
increasedangiogenesisandmyocardialperfusion,decreased myocardialremodeling[27,28].
myocardial apoptosis, and improvement in endothelial and Because of the pleiotropic effect of statins, there have
cardiac function [24]. The deteriorating circulatory insuffi- been attempts to use these drugs in the treatment of
ciency is characterized by an increased amount of free DCM of nonischemic etiology. The present prospective,
radicals, which may inactivate nitric oxide (NO) [25,26]. randomizedstudyevaluatedtheeffectsofasmallatorva-
Therefore, additional advantages of Rho protein inhibition statin dose in 5-year observation on the parameters of
are also connected with increased endothelial synthesis of inflammation, left ventricular function, hospitalizations
NO and reduced expression of endothelin-1, which has a and mortality in CHF patients with DCM who have
positive effect on endothelial function [25,26]. In addition, alreadyreceived standardHF therapy. In theatorvastatin
statins inhibit the synthesis of inflammatory cytokines and group compared with the group without statin IL-6 and
Figure2Probabilityof5-yearsurvivalinpatientswithDCMtreatedandnottreatedwithatorvastatinusingKaplan-Meiermethod.
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TNF-α concentrations were considerably lower. Also, patients (p=0.004). Among secondary efficacy parame-
UA concentration was lower in the atorvastatin group ters, the quality-of-life index showed a trend suggesting
than in the group without statin therapy. No significant the benefit of statin therapy. These results suggest a posi-
differences concerning NT-proBNP concentration, echo- tive anti-inflammatory effect of atorvastatin in patients
cardiographic parameters of the left ventricle, distance with DCM. In the research of Gurguna et al. [37], the
in the 6-min walk test and in functional classification effectiveness of 12 weeks’ therapy with fluvastatin,
according to NYHA were observed between the exam- 80 mg/day, wasassessedconcerningthe concentrationof
ined groups. In the statin group after 5 years a decrease inflammatory cytokines and LV function in patients with
in NT-proBNP concentration compared with initial cardiac insufficiency and DCM as well as with cardiac
values and a decrease in LVdD and LVsD were achieved. insufficiency caused by coronary thrombosis. In both
LVEF significantly increased also in the atorvastatin groups, a considerable improvement of ventricular func-
group. Based on a comparison of curves using the log- tion and clinical symptoms of cardiac insufficiency was
rank test, the probability of survival to 5 years is higher achieved,aswellasadecreaseintheconcentrationofIL-6
inthegroupreceiving alowdose ofatorvastatin. and TNF-alpha [37]. In the study by Horwicha et al. [38],
According to studies, hyperuricemia is an independent statin therapy was related to a higher survival rate without
prognostic marker in chronic and in acute heart failure the necessity of urgent transplant in patients with cardiac
(AHF) [29,30]. Hyperuricemia can produce additional insufficiencyofischemicoriginaswellasofnon-ischaemic
adverse effects on the cardiovascular system and can origin (91 vs 72%, p<0.001 and 81 vs 63%, p<0.001, re-
mediate the immune response [31,32]. Hyperuricemia in spectively) [38]. Sola et al. [39] evaluated the influence of
patientswithheartfailure isassociatedwithhigherlevels atorvastatin (20 mg/day) on vascular indicators of inflam-
of serum markers of inflammation (C-reactive protein mation and echocardiographic indicators in 89 patients
[CRP], IL-6, and neutrophil count) [33] and higher levels with dilated cardiomyopathy of nonischemic origin in
of markers of endothelial activation, such as the soluble NYHAclassIItoIV,withLVEF<35%.Inthegrouptreated
intercellular adhesion molecule-1, and inflammatory with atorvastatin, considerable reduction of end diastolic
markers such as IL-6, TNF-α, and its receptors [34,35]. and end systolic volume ofthe LV wasobtained compared
AlthoughUAlevelhasbeenassociatedwithanincreased with the group treated with placebo [39]. In the statin
risk of cardiovascular events, it is unclear whether UA group they observed higher LVEF and a considerable de-
can provide greater prognostic information than NT- crease in the concentration of hsCRP, TNF-α receptor 2,
proBNP in advanced HF with nonischemic DCM. In the andIL-6,togetherwithanincreaseofsuperoxidedismutase
study of Kim et al. UA and NT-proBNP values (E-SOD) activity in erythrocytes, which meant that oxida-
were obtained from 122 DCM patients. Development of tive stress and the inflammatory process decreased signifi-
clinical events during follow-up was defined as the com- cantly within the 12-month observation. A significant
posite of cardiac death and readmission for heart failure. improvementofclinicalconditionofpatientsintheatorva-
During follow-up UA and NT-proBNP values were sig- statin group was also observed (NYHA class in this group
nificantly higher in patients with events. On multivariate 2.2±0.3 compared with 2.9±0.3 in the placebo group,
analysis, UA remained the only independent predictor p=0.001) [39]. In the study by Node et al. [40], 53 pa-
of prognosis [35]. The authors’ findings demonstrated tients with symptomatic DCM of nonischemic origin
that UA value could be an informative predictor in (NYHA class II and III) with LVEF <40% were assigned
nonischemic DCM. In our study we observed lower UA to a group receiving 10 mg of simvastatin or to a pla-
concentration in the group treated with atorvastatin, cebo group for 14 weeks. Patients treated with statin
which perhaps may be connected with better prognosis had considerably lower functional class according to
in these patients. In DCM, an immunological component NYHA and higher LVEF compared with patients from
may play a role, so immunomodulatory effects of statins the placebo group. The concentrations of TNF-alpha,
may be more advantageous. The study of Wojnicz et al. IL-6andBNPwerealsosignificantlylowerinthesimva-
[36] evaluatedthesafety, tolerability,andefficacyofstatin statin group. The results of our study showing de-
therapyinpatientswithheartfailuresecondarytoinflam- creased IL-6 and TNF-α concentrations are in accord
matory DCM and moderately elevated low-density lipo- with Gurguna et al. [37], Horwich et al.[38], Sola et al.
protein cholesterol levels. Seventy-four patients were [39] and Node et al. [40]. We also observed a decrease
randomized to receive atorvastatin or conventional treat- in NT-proBNPconcentration compared to initial values
ment for HF. After 6 months of therapy, the predefined and a decrease in LVdD and LVsD in the group treated
primary efficacy end point (an increase of >5% in the ab- withatorvastatin.
soluteleftventricularejectionfractionand≥2selectedcri- On the other hand, Bleske et al. [41] randomly assigned
teria by echocardiography and a decrease in NYHA 15 patients with DCM of nonischemic origin in functional
functional class) was significant in the statin-treated class I to III according to NYHA to a group treated with
Bielecka-Dabrowaetal.LipidsinHealthandDisease2013,12:47 Page9of12
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80 mg of atorvastatin or to a placebo group for 12 weeks. deaths due to rapid ventricular arrhythmias account
Although treatment was found to be safe and associated for ~50–80% of all deaths in patients with idiopathic
withconsiderablereductionofLDLcholesterol,theauthors DCM. This reduction of deaths might be caused, in part,
didnotobserveasignificantdifferencebetweenatorvastatin by a reduction in arrhythmic sudden death [46,47].
and placebo concerning NT-proBNP, hsCRP, TNF-alpha Confirmation of this thesis can be found in the study by
and indicators of endothelial activation: vascular adhesion Xian-Zhi et al. [48], where early and intensive atorva-
molecule-1, intracellular adhesive molecule-1 and P- statin therapy significantly decreased the recurrence of
selectin [41]. In the study carried out by Krum et al. [42], ventricular premature beat or non-sustained ventricular
the influence of rosuvastatin 40 mg in 86 patients with tachycardia.
systolic heart failure (LVEF <40%) of ischemic or nonisch- ThestudybyBuberetal.[49]wasperformedinasubset
emic etiology was assessed (68 patients with DCM). The of 821participants in the Multicenter Automatic Defibril-
primary end point was change in LVEF by radionuclide lator Implantation Trial with Cardiac Resynchronization
ventriculogram. Secondary end points included changes in Therapy(MADIT-CRT)trialwithadiagnosisofheartfail-
echocardiographic parameters, neurohormonal and inflam- ure other than ischemic. In this analysis of data covering
matory markers, Packer composite score, death and HF 821 patients, 499 of them received statins. Multivariate
hospitalization. Despite being safe and effective at decreas- analysis showed that time-dependent statin therapy was
ing plasma cholesterol, high-dose rosuvastatin did not independently associated with a significant 77% reduction
beneficiallyalterparametersofLVremodeling[42]. in the risk of fast ventricular tachyarrhythmias (VT/VF)
In our study we observed better survival in the atorva- or death (p<0.001) and with a significant 46% reduction
statin group of patients with DCM. The UNIVERSE and intheriskofappropriateimplantablecardioverterdefibril-
CORONA studies using rosuvastatin showed no benefi- lator shocks (p=0.01).Consistentwiththese findings, the
cial effect on mortality in patients with mainly ischemic cumulative probability of fast VT/VF or death at 4 years
chronic HF [11,12]. In the post-hoc analysis of the of follow-up was significantly lower among patients who
Eplerenone Post-Acute Myocardial Infarction Heart were treated with statins (11%) as compared with study
Failure Efficacy and Survival Study (EPHESUS) [43], the patientswhowerenottreatedwithstatins(19%; p=0.006
initiation of statin therapy mainly during hospital stay for the overall difference during follow-up). The study
for acute HF complicating acute myocardial infarction demonstrated that the use of statins is associated with a
was associated with a lower risk of all-cause death. In a significantreductioninlife-threateningarrhythmiasinpa-
post-hoc analysis performed in 6632 patients included in tientswithnonischemicheartfailure[49].
the EPHESUS trial, 47% of patients had a statin pre- One of the potential explanations why recent pro-
scribed at baseline. During a mean follow-up of 16±7 spective studies using hydrophilic rosuvastatin have not
months, all-cause death occurred in 12% of patients tak- shown any beneficial effect on mortality [13,50-52] may
ing and in 18% of patients not taking a statin (p<0.001). be connected with the observation that metabolic and
The risk of all-cause death was 20% lower in patients on cardiac effects may differ between the lipophilic and
statin. The reduction of all-cause death appears to be hydrophilic statins. It may be suggested that one of the
mainly attributable to a lower rate of cardiovascular beneficial mechanisms of statins could be to rapidly affect
death, especiallysuddendeathandstroke[43]. signaling pathways in cell membranes of the myocardium
The GISSI-HF trial [13] is the only large prospective and/or the autonomic nervous system, thereby protecting
study with some relevance to DCM because rosuvastatin patients from life-threatening arrhythmias. This assump-
was examined in a mixed population with heart failure. tionwouldbeinlinewithdatashowingstatinstoimprove
Rosuvastatin 10 mg/day did not affect clinical outcomes autonomic neural control and increase electrical stability
(death, hospitalization for cardiovascular reasons) in pa- ofthemyocardium[13,48-52].Thehighlylipophilicstatins
tients with CHF of any cause. However, the number of suchatorvastatinandsimvastatinbecomeeasilyembedded
patients with DCM was small [13]. Treatment with into the membrane, having overlapping locations in the
rosuvastatinwassafe[13]. hydrocarbon core adjacent to the phospholipid head
Todeterminewhether statintherapyimprovessurvival groups[48].Gaoetal.reportedthatlipophilicsimvastatin
in patients with heart failure secondary to nonischemic therapy in pacing-induced CHF inhibited NADPH oxida-
DCM, data from 1024 patients (NYHA functional class tiveactivityintherostralventrolateralmedullaandreduced
III and IV) with LVEF ≤0.35, who were enrolled in the thecentralsympathoexcitatoryresponseinassociationwith
BEST (Beta-blocker Evaluation of Survival Trial) trial improvement in LV function [53]. Activation of the sym-
were analyzed [44,45]. Statin therapy was independently pathetic nerve system is one of the important prognostic
associated with decreased all-cause mortality (HR 0.38, predictors for CHF patients [54]. Tsutamoto et al. ran-
95%CI 0.18–0.82, p=0.0134) and cardiovascular death domized 63 stable outpatients with DCM to atorvastatin
(HR 0.42, 95%CI 0.18–0.95, p=0.037) [45]. Sudden (n=32) or rosuvastatin (n=31) therapy. They evaluated
Bielecka-Dabrowaetal.LipidsinHealthandDisease2013,12:47 Page10of12
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cardiac sympathetic nerve activity by cardiac 123I-metaio manuscript,JRdraftedthemanuscript,MBconceivedofthestudy,
dobenzylguanidine(MIBG)scintigraphy,hemodynamicpa- participatedinitsdesign,andcoordination,andpreparedthefinalversionof
themanuscript.Allauthorsreadandapprovedthefinalmanuscript.
rameters and neurohumoral factors before and after
6monthsoftreatment[55].
Acknowledgment
The level of plasma oxidized LDL (oxLDL), a bio- WewouldliketokindlythanktoProfessorStefanD.Anker(CharitéHospital,
marker of oxidative stress in the failing heart, is an inde- Berlin,Germany)forhissubstantialsuggestionsonthispaper.Thestudywas
financedfromaJUVENTUSPLUSgrant2011(No.IP2010002770)ofthePolish
pendent prognostic predictor in CHF patients [56]. The
MinistryofScienceandHigherEducation.
clinical studies suggested that lipophilic statins improve
cardiac sympathetic activity by reducing oxidative stress Authordetails
1DepartmentofHypertension,ChairofNephrologyandHypertension,
[57,58]. Mason et al. reported that the antioxidant ef-
MedicalUniversityofLodz,Lodz,Poland.2DepartmentofClinical
fects of an active metabolite of atorvastatin were stron- Biochemistry,RoyalFreeCampus,UniversityCollegeLondonMedicalSchool,
ger than those of rosuvastatin [59]. Therefore, the UniversityCollegeLondon(UCL),London,UK.3BioMedicalDepartmentof
InternalMedicineandMedicalSpecialties,UniversityofPalermo,Palermo,
increase in LVEF observed in the atorvastatin group
Italy.4Euro-MediterraneanInstituteofScienceandTechnology,Palermo,Italy.
may be partly related to an improvement of the oxida- 5AppliedCachexiaResearch,DepartmentofCardiology,CharitéMedical
tivestressinthemyocardium.Liet al.[60]exploredthe School,CampusVirchow-Klinikum,Berlin,Germany.6Departmentof
Nephrology,HypertensionandFamilyMedicine,ChairofNephrologyand
effect of early statin therapy (atorvastatin and simva-
Hypertension,MedicalUniversityofLodz,Lodz,Poland.
statin) on mortality in patients with nonischemic DCM.
Atotalof315patientswithnonischemicDCMwereen- Received:23March2013Accepted:31March2013
Published:8April2013
rolled. The median follow-up period was 45.1 months.
By single-factor analysis, they found that the follow-up
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