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 dysfunction.Ischemicheart diseaseHHD = LVH asymptomaticdysfunctionAortic
2、 valvestenosisAtrialfibrillationPATHWAYS TO HEART FAILURE IN ARTERIAL HYPERTENSIONStage A HF Stage B HF Stage C HFHBP other risk factors * Heart Failure* DM, MetS, Ob.The three major causes of heart failure are hypertensive heart disease (HHD), ischemic heart disease associated with prior myocardial
3、 infarction(s), 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 HYPER
4、TENSIVE HEART DISEASEHHD 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 H
5、HD, understandits mechanisms, and assess adequately treatment options availableIn this conceptual framework the development ofbiomarkers for HHDcan be of great interest.DEFINITION AND CRITERIA TO BE ACCOMPLISHED BY A BIOMARKER A biomarker is a characteristic that is objectively measured and evaluate
6、d as anindicator of normal biological processes, pathologic processes, or pharmacologicalresponses to a therapeutic intervention(NIH, Biomarkers Definiton Working Group, 2001)A biomarker must accomplish several criteriarelated to its technical measurement in blood. Feasible measurement. Highly sensi
7、tive and specific . Able to be reproduced and standardized. With low inherent error in the measurement related to its bio-physiological sense. Changes in its blood level must parallel changes in its tissueexpression and must be associated with the assessed process related to its clinical validity. C
8、hanges in its blood level must reflect changes in patients clinical status. Changes in its blood level must reflect changes in patients prognosis.STEPS IN THE PROCESS OF DEVELOPMENT OF BIOMARKERS FOR HYPERTENSIVE HEART DISEASE HBP HHD HHD HF Pathophysiological Identification Experimental criteria mo
9、dels Criteria of usefulness Evaluation Criteria of appliability as diagnostic tools as therapeutic targets Genotyping and Validation Large genomic studies clinical studies Genes/proteins.NATURAL HISTORY OF HYPERTENSIVE HEART DISEASECM growth andmyocardial fibrosisCM death, dysfunction and energetic
10、failureand collagen matrix disruptionHigh BPLVH 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 failurewithout
11、ischemic heart diseasehypertrophic cardiomyopathyaortic stenosisstudiedbefore and after TXEndomyocardialbiopsy formolecular andhistomorphologicalstudiesEchocardiographic studyfor characterization of LV mass, function and morphologyPeripheral and coronary blood samplingfor determinationof biomarkers(
12、ELISA).CARDIOTROPHIN-1 SYNTHESIS AND SIGNALING IN 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-
13、1CT-1Interstitium.CARDIOTROPHIN-1 AS A BIOMARKER OF CARDIOMYOCYTE 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
14、fmol/mL.FIBRILLAR COLLAGEN TYPE I METABOLISM IN THE HEART(Adapted fromLpez B et al. J Hypertens 2005:23:1445-1451)Procollagen type IDNASynthesisFibroblastMechanical andhumoral stimuliProcollagen type ICollagen type IBig telopeptideDegradation productsPICPMMP-1 & TIMP-1PINPProteinasesLysil oxidaseGel
15、atinasesCITP Deposition of collagen type I fibersInterstitiumPICPBlood.C-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
16、 BP LVH dysfunction Heart failureSerum PICPTime of evolutionControlreferenceinterval71 g/L.ANNEXIN 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 cB
17、cl-2Bcl-2Anx A5Anx A5Anx A5Anx A5BloodAnx A5Anx A5Blood.ANNEXIN A5 AS A BIOMARKER OF CARDIOMYOCYTE APOPTOSIS?(Ravassa S et al, Eur Heart J, submitted)High BP LVH dysfunction Heart failurePlasma AnxA5Time of evolutionControlreferenceinterval8.3 ng/mL.FIBRILLAR COLLAGEN TYPE I METABOLISM IN THE HEART(
18、Adapted 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 fibersInterstit
19、iumBloodMMP-1 & TIMP-1.THE MATRIX METALLOPROTEINASE 1 AND TISSUE INHIBITOR OF MMP-1 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-1ratioTi
20、me of evolutionControlreferenceinterval11.CIRCULATING BIOMARKERS IN THE DIAGNOSTIC ASSESSMENT OF HHDPlasma or serum concentration Time of evolutionControlreferenceintervalAnxA5MMP-1:TIMP-1CT-1PICPHigh BP LVH dysfunction Heart failureBNP.CIRCULATING BIOMARKERS IN THE THERAPEUTIC EVALUATION OF HHDPlas
21、ma or serum concentration Time of evolutionControlreferenceinterval(Lpez B et al, Circulation 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-1PICP.THE INGENIOUS HYPERCARE NETWORKOpportunity
22、for validation of current biomarkers HBP HHD HHD HF Pathophysiological Identification Experimental criteria models Criteria of usefulness Evaluation Criteria of appliability as diagnostic tools as therapeutic targets Genotyping and Validation Large genomic studies clinical studies Genes/proteins.Bio
23、markers of cardiomyocyte changesIL-6, IGF-1, LIF, oncostatin M, neuregulinFAS, FAS-l, TNF, CFLARCalsequestrin, osteoprotegerinCD36Biomarkers of collagen matrix changesOsteopontin, thrombospondin, TGF-RIII , CTGF RelaxinMMP-2, MMP-9, TIMP-4, MTCBP-1Biomarkers of general mediators changesIL-1, MCP-1MP
24、O, SOD, nitrotyrosin, 8-OH-2deoxyguanosineTHE INGENIOUS HYPERCARE NETWORKOpportunity for exploration of new candidate biomarkers .The Zeptosens proteomic platform incorporates a chip-based technology to perform high throughput multiplexed analysis of hundreds of biological samples on a single experi
25、ment. The Triturus EIA Analyzer is an openand automated ELISA immunoassayanalyzer which performs a variety ofdifferent tests on a series of samples andprocess several batches simultaneouslyTHE INGENIOUS HYPERCARE NETWORKOpportunity for incorporation of high performance methodologiesfor biomarkers de
26、termination .(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 .
