1、InGenious HyperCare Integrating genomics,clinical research and care in hypertensionGenetic,genomics and proteomics of transition from hypertension to heart failureExcellence in phenotyping.Circulating markers of LV growth and dysfunctionIschemicheart diseaseHHD=LVH asymptomaticdysfunctionAortic valv
2、estenosisAtrialfibrillationPATHWAYS TO HEART FAILURE IN ARTERIAL HYPERTENSIONStage A HF Stage B HF Stage C HFHBP other risk factors*Heart Failure*DM,MetS,ObThe three major causes of heart failure are hypertensive heart disease(HHD),ischemic heart disease associated with prior myocardial infarction(s
3、),and idiopathic dilated cardiomyopathy.Because the prevalence of hypertension is increasing globally,heart failure secondary to HHD will soon become the most common cause of heart failure.(Berk BC et al,J Clin Invest 2007;117:568-575)CLINICAL AND EPIDEMIOLOGICAL RELEVANCE OF HYPERTENSIVE HEART DISE
4、ASEHHD was one of the 15 leading causes of death and burden of disease in 2002.HHD is projected to move up two places(from position 13th to position 11th)in the ranking for 2030(Mathers CD&Loncar D,Plos Med 2006;3:2011-2030)There is an important need for physicians to detect HHD,understandits mechan
5、isms,and assess adequately treatment options availableIn this conceptual framework the development ofbiomarkers for HHDcan be of great interestNATURAL HISTORY OF HYPERTENSIVE HEART DISEASECM growth andmyocardial fibrosisCM death,dysfunction and energetic failureand collagen matrix disruptionHigh BPL
6、VH dysfunctionHeart failure(Dez J et al,Nat Clin Pract Cardiovasc Med 2005;2:209-216)MULTIFACETED METHODOLOGICAL APPROACH TO IDENTIFY AND EVALUATE BIOMARKERS OF HHDHypertensive patientswithout LVH with LVH LV dysfunctionwith LVH and heart failurewithoutischemic heart diseasehypertrophic cardiomyopat
7、hyaortic stenosisstudiedbefore and after TXEndomyocardialbiopsy formolecular andhistomorphologicalstudiesEchocardiographic studyfor characterization of LV mass,function and morphologyPeripheral and coronary blood samplingfor determinationof biomarkers(ELISA)CARDIOTROPHIN-1 SYNTHESIS AND SIGNALING IN
8、 THE HEART(Yamauchi-Takihara K et al,Int J Exp Pathol 2000;81:1-16;Heinrich PC et al,Biochem J 2003;374(pt 1):1-20)CT-1Bloodgp130LIF-RSignaling pathwaysHypertrophySOCSSTAT3ERK5CardiomyocyteFibroblastCardiomyocyteMechanical andhumoral stimuliCT-1CT-1CT-1InterstitiumCARDIOTROPHIN-1 AS A BIOMARKER OF C
9、ARDIOMYOCYTE GROWT?High BP LVH dysfunction Heart failure(Lpez B et al,J Hypertens 2005;23:625-632;Gonzlez A et al,J Hypertens 2005;23:2297-2304;Gonzlez A et al,J Hypertens 2007,in press)Plasma CT-1Time of evolutionControlreferenceinterval41 fmol/mLFIBRILLAR COLLAGEN TYPE I METABOLISM IN THE HEART(Ad
10、apted fromLpez B et al.J Hypertens 2005:23:1445-1451)Procollagen type IDNASynthesisFibroblastMechanical andhumoral stimuliProcollagen type ICollagen type IBig telopeptideDegradation productsPICPMMP-1&TIMP-1PINPProteinasesLysil oxidaseGelatinasesCITP Deposition of collagen type I fibersInterstitiumPI
11、CPBloodC-TERMINAL PROPEPTIDE OF PROCOLLAGEN TYPE I AS A BIOMARKER OF COLLAGEN MATRIX INCREASE?(Querejeta R et al,Circulation 2000;101:1729-1735-Querejeta R et al,Circulation 2004;110:1263-1268-Lpez B et al,JACC 2006;48:89-96)High BP LVH dysfunction Heart failureSerum PICPTime of evolutionControlrefe
12、renceinterval71 g/LANNEXIN A5 SYNTHESIS AND SECRETION IN THE HEART(Camors E et al,Cardiovasc Res 2005;65:793-802)CardiomyocyteDeath ligandsFADDEC death signalsIC death signalsDeath receptorsCaspasesEXECUTIONOF DEATHCa2+C8cyt cBcl-2Bcl-2Anx A5Anx A5Anx A5Anx A5BloodAnx A5Anx A5BloodANNEXIN A5 AS A BI
13、OMARKER OF CARDIOMYOCYTE APOPTOSIS?(Ravassa S et al,Eur Heart J,submitted)High BP LVH dysfunction Heart failurePlasma AnxA5Time of evolutionControlreferenceinterval8.3 ng/mLFIBRILLAR COLLAGEN TYPE I METABOLISM IN THE HEART(Adapted fromLpez B et al.J Hypertens 2005:23:1445-1451)Procollagen type IDNAS
14、ynthesisFibroblastMechanical andhumoral stimuliProcollagen type ICollagen type IBig telopeptideDegradation productsPICPMMP-1&TIMP-1PINPProteinasesLysil oxidaseGelatinasesCITP Deposition of collagen type I fibersInterstitiumBloodMMP-1&TIMP-1THE MATRIX METALLOPROTEINASE 1 AND TISSUE INHIBITOR OF MMP-1
15、 RATIO AS A BIOMARKER OF COLLAGEN MATRIX DISRUPTION?(Querejeta R et al,Circulation 2004;110:1263-1268-Lpez B et al,J Am Coll Cardiol 2006;48:89-96)High BP LVH dysfunction Heart failureSerum MMP-1 to TIMP-1ratioTime of evolutionControlreferenceinterval11CIRCULATING BIOMARKERS IN THE DIAGNOSTIC ASSESS
16、MENT OF HHDPlasma or serum concentration Time of evolutionControlreferenceintervalAnxA5MMP-1:TIMP-1CT-1PICPHigh BP LVH dysfunction Heart failureBNPCIRCULATING BIOMARKERS IN THE THERAPEUTIC EVALUATION OF HHDPlasma or serum concentration Time of evolutionControlreferenceinterval(Lpez B et al,Circulati
17、on 2001;104:286-91;Lpez B et al,J Am Coll Cardiol 2004;43:20-28-35;Gonzlez A et al,J Hypertens 2005;23:2297-304)High BP LVH dysfunction Heart failurePICPCT-1PICPTHE INGENIOUS HYPERCARE NETWORKOpportunity for validation of current biomarkers HBP HHD HHD HF Pathophysiological Identification Experiment
18、al criteria models Criteria of usefulness Evaluation Criteria of appliability as diagnostic tools as therapeutic targets Genotyping and Validation Large genomic studies clinical studies Genes/proteinsBiomarkers of cardiomyocyte changesIL-6,IGF-1,LIF,oncostatin M,neuregulinFAS,FAS-l,TNF,CFLARCalseque
19、strin,osteoprotegerinCD36Biomarkers of collagen matrix changesOsteopontin,thrombospondin,TGF-RIII,CTGF RelaxinMMP-2,MMP-9,TIMP-4,MTCBP-1Biomarkers of general mediators changesIL-1,MCP-1MPO,SOD,nitrotyrosin,8-OH-2deoxyguanosineTHE INGENIOUS HYPERCARE NETWORKOpportunity for exploration of new candidat
20、e biomarkers The Zeptosens proteomic platform incorporates a chip-based technology to perform high throughput multiplexed analysis of hundreds of biological samples on a single experiment.The Triturus EIA Analyzer is an openand automated ELISA immunoassayanalyzer which performs a variety ofdifferent
21、 tests on a series of samples andprocess several batches simultaneouslyTHE INGENIOUS HYPERCARE NETWORKOpportunity for incorporation of high performance methodologiesfor biomarkers determination(Kietselaer BL et al,J Nucl Med 2007;48:562-567)Dual-isotope imaging using 201Tl for LV contour detection and,simultaneously,99mTc-annexin A5 in a patient with dilated cardiomyopathy and rapid deterioration of LVfunction presenting with focal upatke in apex and lateral wall,and slight septal uptakeTHE INGENIOUS HYPERCARE NETWORKOpportunity for development of combined bio-imaging markers
