OnNovember26ththeESCWGCoronaryPathophysiology&Microcirculationtogetherwiththe German National Centre for Cardiovascular Research (DZHK, partner site Berlin)organizeda joint symposium to exchangeknowledge and stimulate interactionbetweenbasic and clinical scientists in the field of CoronaryPathophysiology and Microcirculation. The one-dayjointmeetingwasheldinthehistoricHarnack-HausinBerlin. The meeting was nicely built around fourinteractivescientificsessions,coveringawidearrayoftopics, but with a special emphasis on experimentaland clinical research of both large and small vesselsand their biology in health and in disease states, inparticularacutecoronarysyndromesandheartfailure.Belowisasummaryofeachofthesessions,duringwhicheachlecturewasfollowedbyalivelydiscussion.ThemeetingwasagreatsuccessandsetsanexcellentexampleofhowsynergisticinteractioncanbecreatedbyESCbodiesandnationalcardiovascularresearchinstitutionswhenjoiningforces!

Session1:Title: AcuteCoronarySyndrome:TheImportanceofBothLargeandSmallVesselsChairs: HolgerGerhardt&DirkDunckerThis session included six lectures thatassessed experimentaland clinicalaspects of acute coronarysyndromescoveringnotonlylargeepicardialcoronaryarterypathology,suchasplaquerupture,butalsotheinvolvementofthecoronarymicrovascularcompartment,includingmicrovascularno-reflow.Overallthissessionrevealedseveralimportantnovelinsightsintothepathophysiology,diagnosisandtreatmentofacutecoronarysyndrome.Lina Badimon: Tissue Factor: Yin/Yang in the Circulation Spanning from Thrombosis toAngiogenesis.BeyonditsroleascofactorofFactorVIIatotriggerthecoagulationcascadeandinducethrombosisonatherosclerotic plaques, TF has non-haemostatic functions as a multi-faceted signalling receptor

involvedintheregulationofangiogenesis.TFnaturallyoccursintwodifferentvariants:fulllengthTF(flTF)andalternativelysplicedTF(asTF).flTFisa~45=47kDaintegralmembrane protein that can be released from the cell membrane in the form ofmicrovesicles,whereasasTF isaprotein thatlacksa transmembranedomainandcanthusbesecretedinasolubleform.Recently,wehavedemonstratedthatmicrovascularendothelial cells (mECs) release TF in a highly regulated fashion to promotemicrovascularnetworks.Further,Wnt5a-releasedbymonocytesinteractwithFZD5inthe membrane of mECs to trigger intracellular signalling through the noncanonical

pathwaywithincreasedintracellularCa2+releaseandNF-κBactivation,whichinturnupregulatedTFexpressionandinducesangiogenesis.TFcanalsoexertangiogeniceffectsbypromotingmobilizationandtransdifferentiationofMointoECLcells.Indeed,weobservedthatTFsecretedfrommECs,mightpromote monocyte/ECL transdifferentiation and tube-like formation with specific upregulation ofsurfaceVECmarkerssuchas:VE-Cadherin,vWFandeNOSexpressionanddownregulationofmonocytecell-specificmarkerCD14.This transdifferentiationprocess is likelymediatedbyTF/β1-integrinTFinteraction.Insummary,wehavediscoverednovelmechanismstriggeredbyTF(flTFaswellasasTF)that promote angiogenesis and microvessel formation, beyond the well-known effects of TF oncoagulationandthrombusformation.DimitrisTousoulis:NewInsightsinPlaqueVulnerability:fromDiagnosistoTreatmentPlaqueruptureisthemaincauseofacutecoronarysyndromes.Intheclinicalpracticeachallengeistotreatthevulnerablepatientratherthanvulnerableplaquebecausethincapfibroatheromasareoftenmultiple and affect several arterial beds and often persist for yearswithout causingsignificant events. Moreover, statin treatment and other preventive measures havebeguntomodify thediseaseprocess,andplaquerupturedeclinesasacauseofacutecoronary syndromes (ACS), while erosion is on the rise. According to the recentguidelines of the ESC, an ACS it is possible to occur without underlying significantstenosis(MINOCA).TheprevalenceofMINOCAisabout5-10%incontemporaryclinicalpractice.ThereareepicardialcausesofMINOCAsuchaspositiveremodellingandplaqueerosion, as well as microvascular causes such as unstable microvascular angina, Takotsubocardiomyopathy,myocarditisandcardio-embolism.ThecurrenttreatmentofACSinNSTEMIpatientsincludesstatins,betablockersanddualantiplatelettherapy(DAPT).DAPTdurationisdependentonseveralfactorsandimportantscoreshavebeenintroducedsuchasPRECISE-DAPTandDAPTtoidentifythepatientswhoneedlongerantiplatelettreatment.Inconclusion,thevulnerablepatientratherthevulnerable plaque is important to be treated.MINOCA is common in ACS patients and the optimaldurationofantiplatelettreatmentiscontroversial.

Ulf Landmesser: Clinical translational studies: Novel Pathophysiological Mechanisms inCoronaryDiseaseCoronary disease and its clinical manifestations as acute coronary syndromes and/or ischemiccardiomyopathyremainamajorcauseofmorbidityandmortality.Giventhatcoronarydiseasedevelops

sub-clinicallyoverseveraldecades,moreeffectiveandearlierpreventionstrategiescaninthefuturesubstantiallyreducetheburdenofcoronarydisease,i.e.supportthestrategyofmaintainingcardiovascularhealth.Geneticstudieshavestronglysupportedthecausalroleof lipoproteins, inparticularLDLcholesterol fordevelopmentandprogressionofcoronarydisease, andhavehighlighted the conceptof “LDLburden”over timeas thecriticaldeterminantfortheclinicalmanifestationofcoronarydisease.Therefore,earlierandmoreintenseLDLcholesterolloweringinpatientswithclinicalmanifestACVDcan

markedlyreducecardiovascularrisk.RecentlythelargesthumansiRNA-basedtreatmentstudy,ORION-1,hasbeencompletedanddemonstratedthatasinglesubcutaneousPCSK9-siRNAcouldreduceLDLcholesterollevelsby50%overaperiodof>6month.Theseapproachesarefurtherdevelopedandwillprovide a highly effective and attractive treatment approach for prevention of coronary disease.Moreover,weandothershaveobtaineddatasuggestinganimportantroleofmicrobiome-dependentmetabolites,suchasTMAO,forprogressionofatheroscleroticcardiovasculardisease–andtargetingthegut microbiome is being developed as a novel preventive treatment. Finally, high resolutionintracoronaryimagingbyopticalcoherencetomographycanidentifydifferentmechanismsleadingtoacute coronary syndromes, e.g. plaque rupture or plaque erosion, and translational studies haveprovidednovelinsightsabouttheroleoftheimmunesysteminthesediverseacuteevents,andtargetedimmunomodulationmayprovideanothernoveltreatmentstrategyinpreventionofcoronarydisease.EdinaCenko:SexDifferencesinOutcomesafterSTEMIinYoungerPatients:ISASCTCStudiesAlthoughST-segmentelevationmyocardialinfarction(STEMI)mainlyoccursinindividuals>60years,younger adults canbe affected aswell. Previous studieshave shown that there are trends towardsdecreases in both the proportion and absolute number of acuteMIs in both sexes.However,womencontinuetobeathigherriskofearlymortalityafterSTEMI,eveninthe current eraof improvedevidence-based treatments andpercutaneous coronaryintervention (PCI). These data imply that women and physicians all need greaterawarenessthatMIdooccurinyoungmiddle-agedwomen.AcuteMIsisoftenperceivedassomethingthataffectsolderwomen,yetmoreyoungwomenthaneverbeforeareatrisk. Previousworkhas suggested that the reason for thedifferences inoutcome islikelymultifactorialandmaypartiallybeexplainedbysomeofthefollowingfactors:adisproportionateburdenofcoronaryriskfactorsandcomorbidities,theabsenceofchestpainatpresentation,delayedpresentationand/orreperfusioninSTEMI,under-diagnosisofMIatfirstmedicalcontact,andunderuseof acute medications. While these hypotheses may be true, recent studies pointed out that theproportionofwomenpresentingwithin2hoursaftersymptomonsetwasgreaterintheyoungerthaninoldercohorts. Inaddition,sexdifferences inadministrationofadjunctivemedical therapiesweregreaterintheolderthanintheyoungercohort.Thus,thereisnotanyoneoftheabovementionedfactorsabletoexplaintheincreaseinmortalityintheyoungwomen.Disparitiesalonecouldnotaccountforthegapinmortalityacrosssexes.Thereareprofounddifferencesingeneticsandhormonesbetweensexes.Unlesstheeffectsofsexarestudied,wewillcontinuetohavegapsintheknowledgeofpotentialdifferentmechanismsleadingyoungwomenandmentodieafteracutecoronarysyndromes,whichmayresultinmissedopportunitiesforimplementingabetterhealthinourcommunity.Womenshouldbeencouragedto participate in trials. Balancing the sexes aswell aspowering studies todetect sex differences iswarrantedinfutureresearch.

OliviaManfrini:PathophysiologyofCoronaryNo-Reflow:ExperimentalandClinicalAspectsInthelastfewyears,severalexperimentalandclinicalstudies(randomizedclinicaltrial,observationalstudies and meta-analysis) explored strategies on the prevention and treatment of no-reflow

phenomenon.Onthebasisofitspathogenicmechanisms(ischemicinjury,reperfusioninjury, distal micro-embolization and individual predisposition), We elucidated theresultscomingfromantiplateletandanti-coagulantagents,vasodilatorsandstatins,aswell as thrombectomy and distal protection devises, which are the treatment andpreventiveoptionsmostinvestigated,butwithdifferentcriteriaandtechniqueforitsassessment.Conventionalcriteriatodefineaclinicallyrelevantno-reflowphenomenon

areneededtostandardizetheresultsofclinicalstudies.Anyhow,antiplateletagentsandstatinshadproved,withoutanycontroversy,beneficialeffectsbothonno-reflowandpatientoutcomeevaluatedby30-daymajoradversecardiovascularevents.Vagalnervestimulationgivespromisingresultsinanimalmodels,butthisawaitsconfirmationinclinicaltrials.Raffaele Bugiardini: Late PCI in STEMI Patients and Outcomes: Heterogeneity of TreatmentEffectsPrimary percutaneous intervention (PCI)within 12 hours after symptom onset has been shown toimprovesurvival,andreducetheriskofrecurrentmyocardialinfarction,andstrokeinpatientswithSTsegmentelevationmyocardial infarction(STEMI).However,approximately30%ofpeople with STEMI do not undergo cardiac catheterization within 12 hours fromsymptom onset. Many patients are referred to hospital without catheterizationfacilities and are managed acutely in a non-invasive manner. The impact of amechanicalreperfusionstrategybeyonda12-hourcut-offisstillunsettled.ThereisgeneralagreementthatPCIcouldbedonelaterthan12hoursaftersymptomonsetifthere is clinical and/or electrocardiographic evidence of ongoing ischemia, orcardiogenicshock.Thereis,instead,noconsensusastowhetherlatePCIbeyondthe12hourslimitisalso beneficial in relatively stable patients especially if these patients were not previously givenfibrinolysis. Uncertainty stems from a paucity of evidence supporting benefits of revascularizationcomparedwithroutinemedicaltreatment(RMT).TheprincipalfindingsoftheISACS-TCregistrywerethatclinicallystablepatientswithSTEMImaybenefitofPCIbeyondthe12-hourcut-off.Thisassociationis substantiallymodifiedbypatientdelay toPCIwith improvement in survival concentratedamongpatientsundergoingPCIbetween25and48hoursaftersymptomonset.ThefindingsoftheISACS-TCregistrymayprospectivelyrepresentapotentialnewtreatmentparadigmforpatientswhofailatimely,within12hours,reperfusiontherapy,andareinstableconditions.Inthesepatients,aninitialwatchandwaitapproach seems tobe a valid strategy to achievebetteroutcomes. In addition, there are someethicalissueonacquiringavalidinformedconsentthatcanbeimprovedwaiting12to24hoursmore.IntheacutephaseofSTEMI,patientstypicallyaredistressedandprefertoleavealltreatmentdecisionstothephysician.AlthoughdistressmaybepresentregardlessofwhetherPCIisperformedwithin24hours or 48 hours form symptom onset, introducing a “time break” could help patients to betterunderstandtheclinical risksandbenefitsofPCIbygiving themtheopportunity fordiscussionwith(other)physiciansortheirfamily.

Session2Title: VascularBiologyinHealthandDiseaseChairs: UlfLandmesser&OliviaManfriniThissessionincludedfourhighlydiverselecturesthataddressedexperimentalaswellasclinicalaspectsofthephysiologyandbiologyofbothlargeandsmallbloodvesselsinhealthandindiseaseconditionssuchashypertensionandatherosclerosis.CorDeWit:ThePhysiologicFunctionoftheEndothelialMuscarinicReceptorMuscarinicacetylcholinereceptors(AChMR)mediatecellularresponsesuponreleaseofacetylcholine(ACh) from parasympathetic nerves. In addition, ACh is the prototypical agonist stimulating

endothelium-dependent dilation, but most blood vessels lack parasympatheticinnervation,raisingthequestionastothephysiologicfunctionofendothelialAChMR.Inhispresentation,CordeWitpresentedresultsofstudiesperformedinmicelackingtheendothelialmuscarinicreceptor(AChMR3).ThemicrovasculardilationuponAChwasselectivelyattenuatedinthesemice.Nevertheless,arterialpressureremainedunalteredand cardiachypertrophywasnot founddespite life-longdeletionof this receptor inendothelial cells. These results leave the physiologic function of these endothelial

receptorsstillobscuredespitetheirroleinthemediationofthewell-knownpowerfuldilatoryeffectofAChinthemicrocirculation.AkosKoller:RegulationofCoronaryMicrovascularTonebyPericardialFluidPericardial fluid (PF) is a ~ 15-50 ml viscous, pale yellow fluid layer between the layers of thepericardium.TheprimaryfunctionofPFistoensureaproperfrictionbetweenthepericardiumandtheheart, but inpathological conditions it can elicit pericardial tamponade leading toincreasesinsystemicandpulmonaryvenouspressures,tachycardia,reducedejectionfractionandreducedcoronarybloodflow.PFcontainsbiologicallyactivesubstances,which couldoriginate from theblood, cardiac interstitial space and/orpericardialmembranes.Thesemoleculesmayreflectthefunctionofthecardiacmuscleandexertvasomotor activity. Recently we have found a positive correlation between theelevatedlevelsofasymmetricdimethylarginine(ADMA)inthePFandtheindicesofcardiachypertrophy.ADMAcanreducetheroleofnitricoxide(NO),leadtoactivationofRASandoxidativestress,whichmaypromotethesynthesisofendothelin(ET1)inthePF.ET1,cancausearrhythmia,sub-epicardialischaemiaandST-elevation.Correspondingly,wehavefoundthatPFof [CoronaryArteryBypassGraft (CABG) andValveReplacement (VR)patients] elicited substantialconstrictor responses in isolated arteries (constriction), which were significantly reduced by anendothelin receptor antagonist. Since pericardial fluid can freely circulate in the pericardial sac,vasomotormolecules,variouscytokine,andcellscancirculateinitandmodulatethetoneofcoronaryarteries,thuscoronarybloodflow,butalsocardiaccontractilityandremodelling.MariaDorobantu: TheLongandWindingRoadofHypertensiontoHeartFailureRevealedbyBiomarkersEventhoughheartfailure(HF)isaglobalpublichealthproblem,itsdiagnosisisoftenquitechallenging,especially in the initial stages. Biomarkers are useful instruments which could facilitate the early

diagnosis and prompt therapy initiation in a patient-tailoredmanner. Substantialadvancementshavebeenmade in recent years, so reasonablypricedomics-basedtechnologieshavepermittedonthedotidentificationofawidearrayofbiomarkers.Butnotallbiomarkerscanbeusedintoclinicsasthesemustbeprecise,sensitiveandspecific for the pathology investigated. HF is characterized by a systemicinflammatoryresponse,myocardialfibrosisandincreasedmyocytestressleadingtoorgandamage.Inviewofthat,thesebiomarkersarecategorizedintomarkersrelatedtofibrosis,inflammation,myocytestressandmicroRNAs.Theassessmentbymultiple

biomarker strategy is recommended in case of early-stage HF patients. In addition to validatedbiomarkers, such as natriuretic peptides (for cardiac decompensation), high-sensitivity cardiactroponins,suppressoroftumorigenicity2,galectin-3(relatedtomyocardialinjury/fibrosis),thereare

somenewmarkerswaiting toprove theirprognosis value (procollagen type IIIN-terminalpeptide,matrixmetalloproteinases).Thevalidationofbiomarkersishinderedbylowstatisticalpowerandpoorreproducibilityof results.Hence, furtherresearch shouldaddresskey issuesrelated tovalidationofemergingbiomarkersbyusingpreciseandrobustoutcomesanduseofmultibiomarkerstrategiestostreamlinetheriskstratification,diagnosisandprognosis.

TeresaPadro:ExtracellularMatrixRemodellingandPlaqueVulnerabilityLipidrichatheroscleroticplaqueswithlowcontentinsmoothmusclecells(VSMC)arevulnerableandassociated with acute coronary syndromes. The matrisome-fraction (functional non-structuralproteins)ofthevascularextracellularmatrix(ECM)isthoughttoregulateprogressionof theatherosclerotic lesions.Under the title “Extracellularmatrixremodellingandplaquevulnerability”,TeresaPadropresentedresultsonproteomicstudiesprovidingevidenceofadistinctmatrisome-signatureintheECMofadvancedplaquesinhumanarteries.Resultsofinvitrocellcultureandmechanisticstudieshighlighttherelevanceof the ECM (matrisome)-VSMC interactome as key mediator of LDL-induceddetrimental effects on the VSMC phenotype and function, such as cytoskeletondynamics and cell migration capacity, directly involved in vascular remodelling related toatheroscleroticplaquegrowinganddestabilization.DmitryTsvetkov:PerivascularFatTissueandImplicationsforResistantHypertensionHypertensionisthemostimportantsinglecontributortotheglobalburdenofcardiovasculardisease

and mortality. In his presentation titled ‘Perivascular adipose tissue (PVAT):Implicationsforresistanthypertension’,DmitryTsvetkovdiscussedtherecentresultsofexperimentalstudiesonvasculartoneregulationbyPVAT.Theanti-contractileeffectofPVATisanimportantmechanisminthemodulationofvasculartoneinperipheralarteries.Recent evidencehas implicatedapossible role ofXE991-sensitive voltage-gatedKV(KCNQ)channelsinthisprocess,withKV7.3-7.5channelsrepresentingmostlikelycandidates.Thus,activatingthesechannelsinvascularsmoothmusclecellsmight

representapotentialnoveldrugtargetfortreatmentofresistanthypertension.

Session3Title: NovelImagingModalities:ApplicationsinCardiovascularMedicineChairs: AxelR.Pries&AkosKollerInthissessionthepotentialuseofnovelimagingmodalitiesindiscoveringnovelmechanisms-whichcouldnothavebeendonewithothermethods -havebeenpresentedby fourspeakers.Overall, thissessiondemonstratedthatnovelimagingmodalitiesareavailableandalreadyusedinbasicandappliedsciencesandtheyarewaitingtobeintroducedintheclinicalarenaforabetterdiagnosisandtreatmentsofpatientswithcardiovasculardiseases.BenjaminJudkewitz:TransparentDanionellatranslucidaasageneticallytractablevertebratebrainmodelNeuronalnetworksofa translucentorganismallowthevisualizationof the interconnectionsamongvarioussensesandneuralcentres.Understandinghowdistributedneuronalcircuitsintegratesensory

informationandgeneratebehaviourisacentralgoalofneuroscience.However,ithasbeendifficulttostudyneuronalnetworksatsingle-cell resolutionacrosstheentireadult brain in vertebrates because of their size and opacity. We addressed thischallengebyintroducingthefishDanionellatranslucidatoneuroscienceasapotentialmodelorganism.Thisteleostremainssmallandtransparenteveninadulthood,whenneuralcircuitsandbehaviourhavematured.Despitehavingthesmallestknownadultvertebratebrain,D.translucidadisplaysarichsetofcomplexbehaviours, includingcourtship, shoaling, schooling, and acoustic communication. In order to carry out

optical measurements and perturbations of neural activity with genetically encoded tools, weestablished CRISPR–Cas9 genome editing and Tol2 transgenesis techniques.We showed that thesefeatures makeD. translucida a promising model organism for the study of adult vertebrate brainfunctionatsingle-cellresolution.JensDreier:MonitoringmicrovascularperfusionvariationswithlaserspecklecontrastTheresearchgroupTranslationinStrokeResearch(TSR)attheCSBinvestigateshumanischemicstrokewith subdural electrocorticography (ECoG), brain tissuepartial pressureof oxygen (pbtO2), regionalcerebral blood flow and serial magnetic resonance imaging (Dreier, J.P., et al.Neuron 86, 902-922(2015)).Usingthisapproach,wefoundthatterminalspreadingdepolarization(SD)isthekeyprocessleadingtoirreversibleinjuryinhumanstroke(Luckl,J.,etal.Brain141,1734-1752(2018)).Inaprocessofreversetranslationfrom‘bedside’to‘bench’,we are studying whether disturbed capillary flow patterns could contribute toterminalSDbecausetheyfavourinversehemodynamicresponsestoSD(Dreier,J.P.Nat. Med 17, 439-447 (2011)). This potential therapeutic target is tackled in therodentbrainusingmicroelectrodetechnologiescombinedwitheitherlaserspecklecontrast analysis imaging or a novel system integrating diffuse reflectance spectroscopy and laser-Dopplerflowmetrytodeterminetimecoursesoftheabsoluteperfusionlevel,speedresolvedperfusion,redbloodcelloxygensaturation,pbtO2,extracellularionconcentrationsandECoG.IngolfSack:InvivomultimodalmechanicalimagingoftheheartandaortaThe heart being themotor of blood circulation propels blood through the systemic andpulmonarycirculationbyperiodiccontractionanddilatationofthefourcardiacchambers.Thismechanicalaction

canbedescribedbyaseriesoftime-dependentphysicalparameterssuchasvolume,strain, shear modulus and pressure. Unfortunately, those parameters cannot bemeasured in-vivo by morphological imaging alone but require the application ofexternalstress.Elastographyusesstresswavesinducedbyexternallyplacedactuatorsto palpate remotely the heart, the aorta or surrounding tissues. Induced tissuedeformations canbemeasuredbymotion-sensitivemagnetic resonance imagingorultrasoundtechniques.Inthistalk,approachesincardiacandaorticelastographywerepresented, highlighting promising applications and discussing current limitations.

Notwithstanding their current limitations, cardiac MRI and ultrasound elastography have alreadyrevealedthebasicmechano-functionalpropertiesofthelivingheartandhavedemonstratedimportantclinicalapplications.Therewith theypave theway for furtherdevelopmentsofcardiacelastography

towardsquantitativebiomarkersofthemechanicalfunctionofcardiacandaortictissue.AxelPries:ImagingmodalitiesinstudiesofmicrovascularnetworksThere is tremendous future potential for imagingmodalities in studies of microvascular networks,whichareresponsibleforabout80%ofperipheralvascularresistance,andwhichareusuallytreatedasa “blackbox”by clinicians. Coronarymicrovascularnetworksplay thekey role indetermining blood flow distribution in the heart. The importance ofpathophysiological events in the coronary microcirculation for relevant clinicalconditions including angina in patients with normal or near normal coronaryangiograms(microvascularangina) is increasinglyrecognized.Suchconditionsaretypically defined and analysed by non-invasive imaging approaches. While thedevelopmentofclinicalimagingmodalitieswasverydynamicandsuccessfuloverthelastdecades,theylackthespatialresolutiontodefinepathophysiologicalmechanismsonthemicrovascularlevel.Thus,acalibrationwithhighresolution(optical)imagingapproachesinexperimentalsettingsisneeded.Thiswillrequirethetargetedinteractionofresearchersfromtheclinical,themedicalimagingandtheexperimentalimagingfields.

Session4Title: TheRoleofMicrovascularDysfunctioninHeartFailureChairs: BurkertPieske&MariaDorobantuThissessionconsistedoffourlecturesontheroleofcoronarymicrovasculardysfunctioninheartfailure.Thespeakerspresentedsoliddatacomingfrombothpreclinicalandclinicalstudies,demonstratingthatcoronarymicrovasculardysfunctionisanimportantpathophysiologicalfactorinbothheartfailurewithpreserved ejection fraction (HFpEF) and in heart failurewith reduced ejection fraction (HFrEF). InHFpEF,thecoronarymicrovasculardysfunctionispromotedbythepro-inflammatorymilieuresultingfromtheclusteringofseveralrisk factors, suchashypertension,dyslipidaemiaandhyperglycaemia.ThisrecentparadigmonthepathophysiologyofHFpEFisconstantlygettingconfirmationfromthemostrecentresearch. In thiscontext, coronarymicrocirculation isanattractive therapeutic target for thetreatmentofcardiovasculardiseaseandfutureprospectivestudiesareneededtoestablishtheroleofmicrocirculation-targetedtherapiesonthepatients’outcomes.CarstenTschöpe:MyocardialMicrovascularInflammatoryEndothelialActivationinHFpEFFollowingtheparadigmofPaulusandTschöpe(JACC2014),whichpostulatesthatendothelialactivation

triggeredbyacomorbidity-drivensystemicinflammatorystateunderliessubsequentcardiac remodelling in HFpEF, this presentation outlined how endothelialinflammationanddysfunctiongoalongwithendothelialoxidativestressandcoronarymicrovascular dysfunction, which in turn induces cardiomyocyte hypertrophy andstiffening as well as cardiac fibrosis. Transdifferentiation of endothelial cells intofibroblasts, a phenomenon called endothelial-to-mesenchymal transition, herebycontributestocardiacfibrogenesisandvascular(capillary)rarefaction.Thus,globalmyocardialischaemiaduetocoronarymicrovasculardysfunctioncontributestothe

cardiacpathologyinHFpEF.DirkDuncker:MicrovascularDysfunctionandHeartFailure:LessonsfromLargeAnimalModelsThe contribution of coronary microvascular dysfunction to a variety of cardiovascular diseases,including ischemic heart disease, cardiac hypertrophy and heart failure is beingincreasingly recognized. In this presentation the results of translational studiespertaining to coronary microvascular dysfunction in swine models of systolicdysfunction (post-infarct remodelling) and diastolic dysfunction (co-morbidities,including diabetes mellitus, dyslipidaemia) and chronic kidney disease) werediscussed.Theresultsfromthesestudiesindicatethatmicrovasculardysfunctionisakey feature of these pathophysiological states, resulting in perturbations inmyocardialoxygenbalanceduringexercise.These findingslendfurthersupporttothenotionthatthecoronarymicrocirculationrepresentsanincreasinglyimportanttherapeutictargetforthetreatmentofcardiovasculardisease.VeraRegitz-Zagrosek: SexDifferences inMicrovascularDiseasewith a Focus on the CellularLevelandEffectsofOestrogen.Tounderstandsexdifferencesinmicrovasculardysfunctionandplaqueerosion,weanalysedoestrogeneffectsinthecellsinvolved.Oestradiol(E2)activatedsignallingandgeneexpressioninendothelialcells

(HUVEC) inasex-specificmanner.Tostudy theeffectofE2on thedevelopmentofcardiacfibrosisweusedisolatedratcardiacfibroblasts.E2decreasedcollagenIandIIImRNAandproteininfemalecellsviaoestrogenreceptor(ER)alphaandincreasedit inmales via ER beta.Moreover, E2 regulated collagen I and III in a sex-specificmannerin3DEngineeredConnectiveTissues(CVR2018).Cardiomyocyte-specificER-alphaoverexpressioninmiceinducedcardiachypertrophyinbothsexes,butlymph-angiogenesis and capillary angiogenesis in females only. Female ER-alphaoverexpressors with MI develop less fibrosis thanWT females or males withMI.

Finally,theystudiedsexdifferencesinbonemarrow-derivedmacrophages.Afterpolarizationintoapro-inflammatoryphenotypewithLPSandINF-gamma,themRNAexpressionofNF-kB,IL-1-betaandTNF-alphaincreasedinmale,butnotinfemalemacrophages,indicatingthatLPSandINF-gammapromotea

pro-inflammatory phenotype only in themale cells. In summary, sex-specific E2/ERmediated generegulation induces sexdifferences in cardiac fibrosis, endothelial celland immune cell functionandangiogenesis.DanijelaTrifunovic:MicrovascularDysfunctionandHFpEF–FromaClinician’sPerspectiveRecently, coronarymicrovascular dysfunction (CMD) has been regarded as one of themain causalmechanisms in HFpEF. The novel paradigm suggests that a progressive clustering of risk factors(hypertension, dyslipidaemia, dysglycaemia, and oestrogen loss) promote a pro-inflammatory and pro-oxidative state, rendering the coronary microvasculaturevulnerable to repeated episodes ofmyocardial ischaemia,whichmay lead to leftventriculardiastolicdysfunction,andultimately thedevelopmentofheart failure.Coronaryflowreserve(CFR)isreducedinpatientswithaorticstenosis,hypertrophiccardiomyopathyandinhypertensivepatientswithLVhypertrophy,andcorrelateswithNT-proBNP,troponinandE/e’.Moreover,impairedCFRisanindependentandstrong predictor of future risk of HFpEF hospitalization in patients without significant epicardialcoronaryarterydisease(CAD).Nevertheless,furtherresearchisneededtoestablishwhetherCMDiscausal forventricularremodellinganddiastolicdysfunctionorwhetherventricularremodellinganddiastolicdysfunctionarecausalforCMD.