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InGenious HyperCare Integrating genomics, clinical research and care in hypertension Genetic, genomics and proteomics o

InGenious HyperCare Integrating genomics, clinical research and care in hypertension Genetic, genomics and proteomics of transition from hypertension to heart failure Excellence in phenotyping. Circulating markers of LV growth and dysfunction. JRP B3. Atrial fibrillation. Ischemic

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InGenious HyperCare Integrating genomics, clinical research and care in hypertension Genetic, genomics and proteomics o

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  1. InGenious HyperCare Integrating genomics, clinical research and care in hypertension Genetic, genomics and proteomics of transition from hypertension to heart failure Excellence in phenotyping. Circulating markers of LV growth and dysfunction JRP B3

  2. Atrial fibrillation Ischemic heart disease HBP ± other risk factors * Heart Failure HHD = LVH ± asymptomatic dysfunction Aortic valve stenosis [* DM, MetS, Ob…] PATHWAYS TO HEART FAILURE IN ARTERIAL HYPERTENSION Stage A HF Stage B HF Stage C HF

  3. CLINICAL AND EPIDEMIOLOGICAL RELEVANCE OF HYPERTENSIVE HEART DISEASE There is an important need for physicians to detect HHD, understand its mechanisms, and assess adequately treatment options available In this conceptual framework the development of biomarkers for HHD can be of great interest The three major causes of heart failure are hypertensive heart disease (HHD), ischemic heart disease associated with prior myocardial 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) HHD 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)

  4. DEFINITION AND CRITERIA TO BE ACCOMPLISHED BY A BIOMARKER A biomarker is a characteristic that is objectively measured and evaluated as an indicator of normal biological processes, pathologic processes, or pharmacological responses to a therapeutic intervention A biomarker must accomplish several criteria related to its technical measurement in blood . Feasible measurement . Highly sensitive 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 tissue expression and must be associated with the assessed process related to its clinical validity . Changes in its blood level must reflect changes in patient’s clinical status . Changes in its blood level must reflect changes in patient’s prognosis (NIH, Biomarkers Definiton Working Group, 2001)

  5. HBP HHD HHD HF PathophysiologicalIdentificationExperimental 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 STEPS IN THE PROCESS OF DEVELOPMENT OF BIOMARKERS FOR HYPERTENSIVE HEART DISEASE

  6. Heart failure LVH ± dysfunction High BP CM growth and myocardial fibrosis CM death, dysfunction and energetic failure and collagen matrix disruption NATURAL HISTORY OF HYPERTENSIVE HEART DISEASE (Díez J et al, Nat Clin Pract Cardiovasc Med 2005;2:209-216)

  7. MULTIFACETED METHODOLOGICAL APPROACH TO IDENTIFY AND EVALUATE BIOMARKERS OF HHD Echocardiographic study for characterization of LV mass, function and morphology Endomyocardial biopsy for molecular and histomorphological studies Peripheral and coronary blood sampling for determination of biomarkers (ELISA) Hypertensive patients without LVH with LVH ± LV dysfunction with LVH and heart failure without ischemic heart disease hypertrophic cardiomyopathy aortic stenosis studied before and after TX

  8. Mechanical and humoral stimuli Fibroblast Cardiomyocyte CT-1 CT-1 CT-1 Interstitium CT-1 Blood Cardiomyocyte gp130 LIF-R Signaling pathways SOCS STAT3 ERK5 Hypertrophy 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)

  9. High BP LVH ± dysfunction Heart failure Plasma CT-1 41 fmol/mL Control reference interval Time of evolution CARDIOTROPHIN-1 AS A BIOMARKER OF CARDIOMYOCYTE GROWT? (López B et al, J Hypertens 2005;23:625-632; González A et al, J Hypertens 2005;23:2297-2304; González A et al, J Hypertens 2007, in press)

  10. FIBRILLAR COLLAGEN TYPE I METABOLISM IN THE HEART Mechanical and humoral stimuli DNA Synthesis Fibroblast Procollagen type I Procollagen type I PICP Interstitium PICP PINP Proteinases Collagen type I Blood Lysil oxidase Deposition of collagen type I fibers MMP-1 & TIMP-1 CITP Big telopeptide Gelatinases Degradation products (Adapted from López B et al. J Hypertens 2005:23:1445-1451)

  11. C-TERMINAL PROPEPTIDE OF PROCOLLAGEN TYPE I AS A BIOMARKER OF COLLAGEN MATRIX INCREASE? High BP LVH ± dysfunction Heart failure Serum PICP 71 μg/L Control reference interval Time of evolution (Querejeta R et al, Circulation 2000;101:1729-1735 - Querejeta R et al, Circulation 2004;110:1263-1268 -- López B et al, JACC 2006;48:89-96)

  12. Blood Anx A5 Anx A5 EC death signals Death ligands Death receptors Bcl-2 Anx A5 FADD Ca2+ C8 cyt c Bcl-2 Caspases EXECUTION OF DEATH Anx A5 IC death signals Cardiomyocyte Anx A5 Anx A5 Blood ANNEXIN A5 SYNTHESIS AND SECRETION IN THE HEART (Camors E et al, Cardiovasc Res 2005;65:793-802)

  13. High BP LVH ± dysfunction Heart failure Plasma AnxA5 8.3 ng/mL Control reference interval Time of evolution ANNEXIN A5 AS A BIOMARKER OF CARDIOMYOCYTE APOPTOSIS? (Ravassa S et al, Eur Heart J, submitted)

  14. FIBRILLAR COLLAGEN TYPE I METABOLISM IN THE HEART Mechanical and humoral stimuli DNA Synthesis Fibroblast Procollagen type I Procollagen type I Interstitium PICP PINP Proteinases Collagen type I Lysil oxidase Blood Deposition of collagen type I fibers MMP-1 & TIMP-1 MMP-1 & TIMP-1 CITP Big telopeptide Gelatinases Degradation products (Adapted from López B et al. J Hypertens 2005:23:1445-1451)

  15. THE MATRIX METALLOPROTEINASE 1 AND TISSUE INHIBITOR OF MMP-1 RATIO AS A BIOMARKER OF COLLAGEN MATRIX DISRUPTION? High BP LVH ± dysfunction Heart failure Serum MMP-1 to TIMP-1 ratio 11 Control reference interval Time of evolution (Querejeta R et al, Circulation 2004; 110:1263-1268 - López B et al, J Am Coll Cardiol 2006;48:89-96)

  16. High BP LVH ± dysfunction Heart failure MMP-1:TIMP-1 AnxA5 PICP CT-1 Plasma or serum concentration BNP Control reference interval Time of evolution CIRCULATING BIOMARKERS IN THE DIAGNOSTIC ASSESSMENT OF HHD

  17. High BP LVH ± dysfunction Heart failure PICP PICP Plasma or serum concentration Control reference interval CT-1 Time of evolution CIRCULATING BIOMARKERS IN THE THERAPEUTIC EVALUATION OF HHD (López B et al, Circulation 2001;104:286-91; López B et al, J Am Coll Cardiol 2004;43:20-28-35;González A et al, J Hypertens 2005;23:2297-304)

  18. THE INGENIOUS HYPERCARE NETWORK Opportunity for validation of current biomarkers HBP HHD HHD HF PathophysiologicalIdentificationExperimental 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

  19. THE INGENIOUS HYPERCARE NETWORK Opportunity for exploration of new candidate biomarkers Biomarkers of cardiomyocyte changes IL-6, IGF-1, LIF, oncostatin M, neuregulin FAS, FAS-l, TNFα, CFLAR Calsequestrin, osteoprotegerin CD36 Biomarkers of collagen matrix changes Osteopontin, thrombospondin, TGF-ßRIII , CTGF Relaxin MMP-2, MMP-9, TIMP-4, MTCBP-1 Biomarkers of general mediators changes IL-1α, MCP-1 MPO, SOD, nitrotyrosin, 8-OH-2deoxyguanosine

  20. THE INGENIOUS HYPERCARE NETWORK Opportunity for incorporation of high performance methodologies for biomarkers determination 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 open and automated ELISA immunoassay analyzer which performs a variety of different tests on a series of samples and process several batches simultaneously

  21. THE INGENIOUS HYPERCARE NETWORK Opportunity for development of combined bio-imaging markers Dual-isotope imaging using 201Tl for LV contour detection and, simultaneously, 99mTc -annexin A5 in a patient with dilated cardiomyopathy and rapid deterioration of LV function presenting with focal upatke in apex and lateral wall, and slight septal uptake (Kietselaer BL et al, J Nucl Med 2007;48:562-567)

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