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InGeniousHyperCare

Integratinggenomics,clinicalresearchandcareinhypertensionGenetic,genomicsandproteomicsoftransitionfromhypertensiontoheartfailureExcellenceinphenotyping.CirculatingmarkersofLVgrowthanddysfunctionJRPB3JRPB31IschemicheartdiseaseHHD=LVH±

asymptomaticdysfunctionAorticvalvestenosisAtrialfibrillationPATHWAYSTOHEARTFAILUREINARTERIALHYPERTENSIONStageAHFStageBHFStageCHFHBP±otherriskfactors*HeartFailure[*DM,MetS,Ob…]IschemicHHD=LVH±Aorticval2Thethreemajorcausesofheartfailurearehypertensiveheartdisease(HHD),ischemicheartdiseaseassociatedwithpriormyocardialinfarction(s),andidiopathicdilatedcardiomyopathy.Becausetheprevalenceofhypertensionisincreasingglobally,heartfailuresecondarytoHHDwillsoonbecomethemostcommoncauseofheartfailure.

(BerkBCetal,JClinInvest2007;117:568-575)CLINICALANDEPIDEMIOLOGICALRELEVANCEOFHYPERTENSIVEHEARTDISEASEHHDwasoneofthe15leadingcausesofdeathandburdenofdiseasein2002.HHDisprojectedtomoveuptwoplaces(fromposition13thtoposition11th)intherankingfor2030

(MathersCD&LoncarD,PlosMed2006;3:2011-2030)ThereisanimportantneedforphysicianstodetectHHD,understanditsmechanisms,andassessadequatelytreatmentoptionsavailableInthisconceptualframeworkthedevelopmentofbiomarkersforHHDcanbeofgreatinterestThethreemajorcausesofhear3【高血压英文课件】Diapositiva-14【高血压英文课件】Diapositiva-15NATURALHISTORYOFHYPERTENSIVEHEARTDISEASECMgrowthandmyocardialfibrosisCMdeath,dysfunctionandenergeticfailureandcollagenmatrixdisruptionHighBPLVH±dysfunctionHeartfailure(DíezJetal,NatClinPractCardiovascMed2005;2:209-216)NATURALHISTORYOFHYPERTENSIV6MULTIFACETEDMETHODOLOGICALAPPROACHTOIDENTIFYANDEVALUATEBIOMARKERSOFHHDHypertensivepatientswithoutLVHwithLVH±LVdysfunctionwithLVHandheartfailurewithoutischemicheartdiseasehypertrophiccardiomyopathyaorticstenosisstudiedbeforeandafterTXEndomyocardialbiopsyformolecularandhistomorphologicalstudiesEchocardiographicstudyforcharacterizationofLVmass,functionandmorphologyPeripheralandcoronarybloodsamplingfordeterminationofbiomarkers(ELISA)MULTIFACETEDMETHODOLOGICALAP7CARDIOTROPHIN-1SYNTHESISANDSIGNALINGINTHEHEART(Yamauchi-TakiharaKetal,IntJExpPathol2000;81:1-16;HeinrichPCetal,BiochemJ2003;374(pt1):1-20)CT-1Bloodgp130LIF-RSignalingpathwaysHypertrophySOCSSTAT3ERK5CardiomyocyteFibroblastCardiomyocyteMechanicalandhumoralstimuliCT-1CT-1CT-1InterstitiumCARDIOTROPHIN-1SYNTHESISAND8CARDIOTROPHIN-1ASABIOMARKEROFCARDIOMYOCYTEGROWT?HighBPLVH±dysfunctionHeartfailure(LópezBetal,JHypertens2005;23:625-632;GonzálezAetal,JHypertens2005;23:2297-2304;GonzálezAetal,JHypertens2007,inpress)PlasmaCT-1TimeofevolutionControlreferenceinterval41fmol/mLCARDIOTROPHIN-1ASABIOMARKER9FIBRILLARCOLLAGENTYPEIMETABOLISMINTHEHEART(AdaptedfromLópezBetal.JHypertens

2005:23:1445-1451)ProcollagentypeIDNASynthesisFibroblastMechanicalandhumoralstimuliProcollagentypeICollagentypeIBigtelopeptideDegradationproductsPICPMMP-1&TIMP-1PINPProteinasesLysiloxidaseGelatinasesCITPDepositionofcollagentypeIfibersInterstitiumPICPBloodFIBRILLARCOLLAGENTYPEIMETA10C-TERMINALPROPEPTIDEOFPROCOLLAGENTYPEIASABIOMARKEROFCOLLAGENMATRIXINCREASE?(QuerejetaRetal,Circulation2000;101:1729-1735-QuerejetaRetal,Circulation2004;110:1263-1268--LópezBetal,JACC2006;48:89-96)HighBPLVH±dysfunctionHeartfailureSerumPICPTimeofevolutionControlreferenceinterval71μg/LC-TERMINALPROPEPTIDEOFPROCO11ANNEXINA5SYNTHESISANDSECRETIONINTHEHEART(CamorsEetal,CardiovascRes2005;65:793-802)CardiomyocyteDeathligandsFADDECdeathsignalsICdeathsignalsDeathreceptorsCaspasesEXECUTIONOFDEATHCa2+C8cytcBcl-2Bcl-2AnxA5AnxA5AnxA5AnxA5BloodAnxA5AnxA5BloodANNEXINA5SYNTHESISANDSECRE12ANNEXINA5ASABIOMARKEROFCARDIOMYOCYTEAPOPTOSIS?(RavassaSetal,EurHeartJ,submitted)HighBPLVH±dysfunctionHeartfailurePlasmaAnxA5TimeofevolutionControlreferenceinterval8.3ng/mLANNEXINA5ASABIOMARKEROFC13FIBRILLARCOLLAGENTYPEIMETABOLISMINTHEHEART(AdaptedfromLópezBetal.JHypertens

2005:23:1445-1451)ProcollagentypeIDNASynthesisFibroblastMechanicalandhumoralstimuliProcollagentypeICollagentypeIBigtelopeptideDegradationproductsPICPMMP-1&TIMP-1PINPProteinasesLysiloxidaseGelatinasesCITPDepositionofcollagentypeIfibersInterstitiumBloodMMP-1&TIMP-1FIBRILLARCOLLAGENTYPEIMETA14THEMATRIXMETALLOPROTEINASE1ANDTISSUEINHIBITOROFMMP-1RATIOASABIOMARKEROFCOLLAGENMATRIXDISRUPTION?(QuerejetaRetal,Circulation2004;110:1263-1268-LópezBetal,JAmCollCardiol2006;48:89-96)HighBPLVH±dysfunctionHeartfailureSerumMMP-1toTIMP-1ratioTimeofevolutionControlreferenceinterval11THEMATRIXMETALLOPROTEINASE115CIRCULATINGBIOMARKERSINTHEDIAGNOSTICASSESSMENTOFHHDPlasmaorserumconcentrationTimeofevolutionControlreferenceintervalAnxA5MMP-1:TIMP-1CT-1PICPHighBPLVH±dysfunctionHeartfailureBNPCIRCULATINGBIOMARKERSINTHE16CIRCULATINGBIOMARKERSINTHETHERAPEUTICEVALUATIONOFHHDPlasmaorserumconcentrationTimeofevolutionControlreferenceinterval(LópezBetal,Circulation2001;104:286-91;LópezBetal,JAmCollCardiol2004;43:20-28-35;

GonzálezAetal,JHypertens2005;23:2297-304)HighBPLVH±dysfunctionHeartfailurePICPCT-1PICPCIRCULATINGBIOMARKERSINTHE17THEINGENIOUSHYPERCARENETWORKOpportunityforvalidationofcurrentbiomarkersHBPHHDHHDHF

Pathophysiological

Identification

ExperimentalcriteriamodelsCriteriaofusefulness

Evaluation

CriteriaofappliabilityasdiagnostictoolsastherapeutictargetsGenotypingandValidationLargegenomicstudiesclinicalstudies

Genes/proteinsTHEINGENIOUSHYPERCARENETWOR18Biomarkersofcardiomyocytechanges

IL-6,IGF-1,LIF,oncostatinM,neuregulin

FAS,FAS-l,TNFα,CFLAR Calsequestrin,osteoprotegerin CD36Biomarkersofcollagenmatrixchanges

Osteopontin,thrombospondin,TGF-ßRIII,CTGF Relaxin MMP-2,MMP-9,TIMP-4,MTCBP-1Biomarkersofgeneralmediatorschanges

IL-1α,MCP-1 MPO,SOD,nitrotyrosin,8-OH-2deoxyguanosineTHEINGENIOUSHYPERCARENETWORKOpportunityforexplorationofnewcandidatebiomarkersBiomarkersofcardiomyocytech19TheZeptosensproteomicplatformincorporatesachip-basedtechnologytoperformhighthroughputmultiplexedanalysisofhundredsofbiologicalsamplesonasingleexperiment.

TheTriturusEIAAnalyzerisanopenandautomatedELISAimmunoassayanalyzerwhichperformsavarietyofdifferenttestsonaseriesofsamplesandprocessseveralbatchessimultaneouslyTHEINGENIOUSHYPERCARENETWORKOpportunityforincorporationofhighperformancemethodologiesforbiomarkersdeterminationTheZeptosensproteomicplatf20(KietselaerBLetal,JNuclMed2007;48:562-567)Dual-isotopeimagingusing201TlforLVcontourdetectionand,simultaneously,99mTc-annexinA5inapatientwithdilatedcardiomyopathyandrapiddeteriorationofLVfunctionpresentingwithfocalupatkeinapexandlateralwall,andslightseptaluptakeTHEINGENIOUSHYPERCARENETWORKOpportunityfordevelopmentofcombinedbio-imagingmarkers(KietselaerBLetal,JNuclM21InGeniousHyperCare

Integratinggenomics,clinicalresearchandcareinhypertensionGenetic,genomicsandproteomicsoftransitionfromhypertensiontoheartfailureExcellenceinphenotyping.CirculatingmarkersofLVgrowthanddysfunctionJRPB3JRPB322IschemicheartdiseaseHHD=LVH±

asymptomaticdysfunctionAorticvalvestenosisAtrialfibrillationPATHWAYSTOHEARTFAILUREINARTERIALHYPERTENSIONStageAHFStageBHFStageCHFHBP±otherriskfactors*HeartFailure[*DM,MetS,Ob…]IschemicHHD=LVH±Aorticval23Thethreemajorcausesofheartfailurearehypertensiveheartdisease(HHD),ischemicheartdiseaseassociatedwithpriormyocardialinfarction(s),andidiopathicdilatedcardiomyopathy.Becausetheprevalenceofhypertensionisincreasingglobally,heartfailuresecondarytoHHDwillsoonbecomethemostcommoncauseofheartfailure.

(BerkBCetal,JClinInvest2007;117:568-575)CLINICALANDEPIDEMIOLOGICALRELEVANCEOFHYPERTENSIVEHEARTDISEASEHHDwasoneofthe15leadingcausesofdeathandburdenofdiseasein2002.HHDisprojectedtomoveuptwoplaces(fromposition13thtoposition11th)intherankingfor2030

(MathersCD&LoncarD,PlosMed2006;3:2011-2030)ThereisanimportantneedforphysicianstodetectHHD,understanditsmechanisms,andassessadequatelytreatmentoptionsavailableInthisconceptualframeworkthedevelopmentofbiomarkersforHHDcanbeofgreatinterestThethreemajorcausesofhear24【高血压英文课件】Diapositiva-125【高血压英文课件】Diapositiva-126NATURALHISTORYOFHYPERTENSIVEHEARTDISEASECMgrowthandmyocardialfibrosisCMdeath,dysfunctionandenergeticfailureandcollagenmatrixdisruptionHighBPLVH±dysfunctionHeartfailure(DíezJetal,NatClinPractCardiovascMed2005;2:209-216)NATURALHISTORYOFHYPERTENSIV27MULTIFACETEDMETHODOLOGICALAPPROACHTOIDENTIFYANDEVALUATEBIOMARKERSOFHHDHypertensivepatientswithoutLVHwithLVH±LVdysfunctionwithLVHandheartfailurewithoutischemicheartdiseasehypertrophiccardiomyopathyaorticstenosisstudiedbeforeandafterTXEndomyocardialbiopsyformolecularandhistomorphologicalstudiesEchocardiographicstudyforcharacterizationofLVmass,functionandmorphologyPeripheralandcoronarybloodsamplingfordeterminationofbiomarkers(ELISA)MULTIFACETEDMETHODOLOGICALAP28CARDIOTROPHIN-1SYNTHESISANDSIGNALINGINTHEHEART(Yamauchi-TakiharaKetal,IntJExpPathol2000;81:1-16;HeinrichPCetal,BiochemJ2003;374(pt1):1-20)CT-1Bloodgp130LIF-RSignalingpathwaysHypertrophySOCSSTAT3ERK5CardiomyocyteFibroblastCardiomyocyteMechanicalandhumoralstimuliCT-1CT-1CT-1InterstitiumCARDIOTROPHIN-1SYNTHESISAND29CARDIOTROPHIN-1ASABIOMARKEROFCARDIOMYOCYTEGROWT?HighBPLVH±dysfunctionHeartfailure(LópezBetal,JHypertens2005;23:625-632;GonzálezAetal,JHypertens2005;23:2297-2304;GonzálezAetal,JHypertens2007,inpress)PlasmaCT-1TimeofevolutionControlreferenceinterval41fmol/mLCARDIOTROPHIN-1ASABIOMARKER30FIBRILLARCOLLAGENTYPEIMETABOLISMINTHEHEART(AdaptedfromLópezBetal.JHypertens

2005:23:1445-1451)ProcollagentypeIDNASynthesisFibroblastMechanicalandhumoralstimuliProcollagentypeICollagentypeIBigtelopeptideDegradationproductsPICPMMP-1&TIMP-1PINPProteinasesLysiloxidaseGelatinasesCITPDepositionofcollagentypeIfibersInterstitiumPICPBloodFIBRILLARCOLLAGENTYPEIMETA31C-TERMINALPROPEPTIDEOFPROCOLLAGENTYPEIASABIOMARKEROFCOLLAGENMATRIXINCREASE?(QuerejetaRetal,Circulation2000;101:1729-1735-QuerejetaRetal,Circulation2004;110:1263-1268--LópezBetal,JACC2006;48:89-96)HighBPLVH±dysfunctionHeartfailureSerumPICPTimeofevolutionControlreferenceinterval71μg/LC-TERMINALPROPEPTIDEOFPROCO32ANNEXINA5SYNTHESISANDSECRETIONINTHEHEART(CamorsEetal,CardiovascRes2005;65:793-802)CardiomyocyteDeathligandsFADDECdeathsignalsICdeathsignalsDeathreceptorsCaspasesEXECUTIONOFDEATHCa2+C8cytcBcl-2Bcl-2AnxA5AnxA5AnxA5AnxA5BloodAnxA5AnxA5BloodANNEXINA5SYNTHESISANDSECRE33ANNEXINA5ASABIOMARKEROFCARDIOMYOCYTEAPOPTOSIS?(RavassaSetal,EurHeartJ,submitted)HighBPLVH±dysfunctionHeartfailurePlasmaAnxA5TimeofevolutionControlreferenceinterval8.3ng/mLANNEXINA5ASABIOMARKEROFC34FIBRILLARCOLLAGENTYPEIMETABOLISMINTHEHEART(AdaptedfromLópezBetal.JHypertens

2005:23:1445-1451)ProcollagentypeIDNASynthesisFibroblastMechanicalandhumoralstimuliProcollagentypeICollagentypeIBigtelopeptideDegradationproductsPICPMMP-1&TIMP-1PINPProteinasesLysiloxidaseGelatinasesCITPDepositionofcollagentypeIfibersInterstitiumBloodMMP-1&TIMP-1FIBRILLARCOLLAGENTYPEIMETA35THEMATRIXMETALLOPROTEINASE1ANDTISSUEINHIBITOROFMMP-1RATIOASABIOMARKEROFCOLLAGENMATRIXDISRUPTION?(QuerejetaRetal,Circulation2004;110:1263-1268-LópezBetal,JAmCollCardiol2006;48:89-96)HighBPLVH±dysfunctionHeartfailureSerumMMP-1toTIMP-1ratioTimeofevolutionControlreferenceinterval11THEMATRIXMETALLOPROTEINASE136CIRCULATINGBIOMARKERSINTHEDIAGNOSTICASSESSMENTOFHHDPlasmaorserumconcentrationTimeofevolutionControlreferenceintervalAnxA5MMP-1:TIMP-1CT-1PICPHighBPLVH±dysfunctionHeartfailureBNPCIRCULATINGBIOMARKERSINTHE37CIRCULATINGBIOMARKERSINTHETHERAPEUTICEVALUATIONOFHHDPlasmaorserumconcentrationTimeofevolutionControlreferenceinterval(LópezBetal,Circulation2001;104:286-91;LópezBetal,JAmCollCardiol2004;43:20-28-35;

GonzálezAetal,JHypertens2005;23:2297-304)HighBPLVH±dysfunctionHeartfailurePICPCT-1PICPCIRCULATINGBIOMARKERSINTHE38THEINGENIOUSHYPERCARENETWORKOpportunityforvalidationofcurrentbiomarkersHBPHHDHHDHF

Pathophysiological

Identification

ExperimentalcriteriamodelsCriteriaofusefulness

Evaluation

CriteriaofappliabilityasdiagnostictoolsastherapeutictargetsGenotypingandValidationLargegenomicstudiesclinicalstudies

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