Primary prevention of diastolic dysfunction in the normal heart: The "Eyes Wide Shut" on a statin pleiotropic effect?

Atherosclerosis216 (2011) 272–274

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Atherosclerosis

j o u r n al ho m e p age :w w w . e l s e v i e r . c o m / l o c a t e / a t h e r o s c l e r o s i s

Invited

commentary

Primary

prevention

of

diastolic

dysfunction

in

the

normal

heart:

The

“Eyes

Wide

Shut”

on

a

statin

pleiotropic

effect?

Daniel

E.

Monopoli

,

Maria

G.

Modena,

Giuseppe

M.

Sangiorgi

DepartmentofCardiology,UniversityHospitalofModenaViadelPozzo71Modena,MO,41124,Italy

a

r

t

i

c

l

e

i

n

f

o

Articlehistory:

Received29January2011 Accepted31January2011 Available online 12 February 2011

As defined by Braunwald’s textbook of Cardiology, diastole includestheperiodoftimeduringwhichthemyocardiumlosesits capacitytoshortenandreturnstoanunstressedlength[1], accord-ingly,diastolicdysfunctionoccurswhenthisprocessisprolonged, slowed,orincomplete[2].Diastolicdysfunctionoftheleft ven-tricle(DDLV) isthusapathologicalconditionthatmayprogress tocongestiveheartfailure(HF).Generally,twoformsofHFhave beenidentified;i.e.,HeartFailurewithNormalEjectionFraction (HFNEF)andHeartFailurewithReducedEjectionFraction(HFREF) Theformer,alsorecognisedasHeartFailurewithPreservedEjection Fraction(HFPEF)–adefinitionwhichprobablybetterdelineates thefactthatsystolic functionisnot completelynormalin such patientsbutonlyapparentlypreserved[3]iscurrentlyobserved inabout50%ofHFpatients[4,5].Itusuallyinvolvestheolderand thefemalepopulation,inparticularthosewithahistoryof hyper-tension[5–8],anditsincidenceandprevalencehasincreasedwith worseningmorbidityandmortality[5,9].Conversely,patientswith HFREFaremorelikelytobeyounger,maleandtohaveanischaemic aetiologycomparedwithHFNEFpatients[5].TheEuropean Soci-etyofCardiology(ESC)recentlyunderlinedtheclinicalimportance andcomplexityofHFNEF,andissuednewdefinitioncriteria,based onclinicalsignsand/orsymptomsofHF,echocardiographicand biologicalparameters[10].

Inthiscontext,diastolicdysfunctionreferstomechanicaland functionalabnormalitiespresentduringrelaxationandfillingofthe leftventricle(LV),suchasaprolongedisovolumicLVrelaxation, slowLVfilling,andincreaseddiastolicLVstiffness[11];whereas HFNEFreferstotheclinicalsyndromeinwhichpatientswithHF havelittleornoventriculardilatation,preservedEF,and signifi-cant,oftendominant,diastolicdysfunction.Diastolicdysfunction canthus,bequantifiedwithindicesofLVpressuredeclineand fill-ing.Abnormalpressuredeclineischaracterizedbydecreasedpeak

∗ Correspondingauthor.Tel.:+390594225729;fax:+390594222843. E-mailaddress:danielmonopoli@libero.it(D.E.Monopoli).

-dP/dt,prolongedisovolumictimeconstant(),andincreased iso-volumicrelaxationtime.Abnormalfillingischaracterizedbyslow andincompletefilling,increasedatrialcontributiontofilling,and increasedchamberstiffness,whichcanbecausedbyabnormalities inbothcardiomyocytesandextracellularmatrix(ECM) [11–14]. Changesintheamount,composition,andgeometryofsuchECM proteins,suchascollagenandelastin,canalterLV stiffnessand causesdecreasedordelayedrelaxation,sloworincomplete fill-ing,andincreaseddiastolicstiffness,leadingtothedevelopment ofHFNEF[12].Indeed,stiffnessoftheECMislargelydeterminedby tissuecollagenamount,whichinturndependsontheregulatory mechanismsofitssynthesisanddegradation,relativequantityof collagentypeI,anddegreeofcollagencross-linking[11].Moreover, cardiacinflammationcanalsocontributetodiastolicdysfunction bytriggeringtheaccumulationofECMthroughtheinductionof col-lagengeneexpressionandinhibitionofcardiacdegradationsystem

[15].

Modernevidence-basedtherapyforHFhasshownan improve-ment in prognosisofpatients affectedbyHFwithreduced left ventricularejectionfraction(HFREF).Ourgroupreportedthe ben-eficialpharmacologicaleffectofthecombinationofanaldosterone inhibitorwithanangiotensin-convertingenzymeinhibitorlimiting thesynthesisofcollagenandreducingthepost-infarct remodel-ing[16].Onthecontrary,theprognosisofpatientswithHFNEFhas remainedunchangeddespitetheuseofsameclasspharmacological agents[5,17–21].

The 3-hydroxy-3-methylgutaryl-CoA reductase inhibitors (statins) are well-known potent lipid lowering agents. Addi-tionally to their primary effects, statins have been shown to have several pleiotropic effects on the cardiovascular system

[22], including antiinflammatory,antioxidative, and endothelial protectiveeffects.Controversialresultshavebeenreportedwith statinadministrationin HFNEF.Someexperimentaland clinical studieshavesuggestedabeneficialeffectafterstatintherapyin HFNEF [23–27].Fukuta and co-authors werethe firstto report that inpatientswithHFPEFstatins wasassociatedtoimproved

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D.E.Monopolietal./Atherosclerosis216 (2011) 272–274 273

survival[23].Conversely,anotherstudyinanimalmodelshowed noeffect ontheprogression of HFneither onsurvival, despite the attenuation of myocardial fibrosis and improved diastolic stiffnessobservedinthegrouptreatedwithstatins[28].Moreover, arecentprospectivetrialbyGissi-HF-Investigatorsdidnotshow differencesinsurvivalbetweendailystatintherapyincomparison toplaceboin patientswithchronicHF,includingpatientswith preservedsystolicfunction[29].

InthisissueoftheJournal,Lermanandassociatesperformeda studyinwhichthreegroupsofpigs(n=6each)weresacrificedafter 12weeksofnormaldiet,hypercholesterolemic(HC)diet,andHC dietwithsimvastatin(80mg/day)treatment,respectively.Cardiac functionwasassessedbyelectron beamcomputed tomography andmyocardialvascularfractionbymicro-computedtomography. Histologic evaluations included collagen content quantification by Sirius Redstaining and a hydroxyoproline-based assay. The authorsobservedthatLDLserumconcentrationwassignificantly higher in HC diet group, and in HC diet treated with simvas-tatincomparedtonormaldietgroup.Cardiacearlydiastolicfilling wasreducedinHCdietgroupcomparedwithnormaldietgroup and“preserved”inHCdietwithsimvastatintreatmentgroup.In addition, myocardial vascular fractionand myocardial collagen contentwas higher in HC groupbut not in normal diet group andinHCdietwithsimvastatingroup.Immunoblottingshowed anincreaseinmyocardialexpressionofb-FGF,VEGFandTGF-␤1 inHCdietgroupcomparedwithnormalgroupwhilethe expres-sionwasattenuated inthe HCdietwithsimvastatintreatment group.

How we can we move from bench to bedside after read-ingthestudydonebyLerman andco-authors?First,this study provides additional evidences that experimental hypercholes-terolemialeadstodiastolicdysfunctionduetoincreasemyocardial collagencontent,especiallyintheperivascularcompartment,along withupregulationofpro-fibroticandproangiogeneticpathways. Second,asalsostatedbytheauthors,thepresentstudyshowsfor thefirsttimeinalargesizeanimalmodel,thatadministrationof astatinpreventsthesemyocardialmorphologicalchanges inde-pendentlyofanylipid-loweringeffect.Theseresultsrepresentan evidencetosupportthemodelofhypercholesterolemia-induced diastolicdysfunctionasareactiveprocessamenabletothe non-lipid-loweringpropertiesofstatins.Third,thenon-lipid-lowering properties of statinsalready reportedin both animal and clin-ical studies of LV hypertrophy are touhgt to result from mild statin-inducedreductionofbloodpressure,alterationsin myocar-dialgrowthregulatorysignaltransductionpathways,changesin inflammatory or immune-mediated systems,or increased arte-rialcompliance[30,31].Statinsmayalterarterialcomplianceby changing the composition of the vascular wallor by changing endothelialresponsetolocalandcirculatingvasoactivecompounds andneurohormones[32].Thepresentstudysuggestsanother lipid-independentproperty,administrationofstatinscouldpreventthe increaseinmyocardialcollagencontentatthebottomofdiastolic dysfunction.

Albeitthisstudyopensanewhorizoninthefieldofdiastolic dysfunctionpreventionshowingononeside the“indirect” role ofhypercholesterolemiainpromotingdiastolicdysfunctionand, ontheotherside,theabilityofsinvastatinforpreservingnormal diastolicfunctionthroughamechanismofactionindependentof cholesterolreduction,itishardtobelievethatlipidlowering ther-apywillbeclinicallyrelevantinnormalizingLVstructuralchanges orLV functionin patientswith HFNEF [32].Finally, we should keepinmindthattheseresultsarebasedonanimalmodels,and atthismomentshouldbeappliedwithcautiontohuman.Given theimportantpublichealthimpactofdiastolicdysfunction,large prospectiveclinicaltrialsshouldbeperformedtoevaluatethe ther-apeuticpotentialofstatinsinthisimportantfieldofprevention.–

onlyinthiswaywecouldlookdeeplyintothistopicwith“eyes wideopened”.

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