高血压英文ppt精品课件pathways to heart failure in arterial

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 Ischemic heart disease HHD = LVH asymptomatic dysfunction Aortic valve stenosis Atrial fibrillation PATHWAYS TO HEART FAILURE IN ARTERIAL HYPERTENSION Stage A HF Stage B HF Stage C HF HBP 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 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 HYPERTENSIVE HEART DISEASE 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 3:2011-2030) 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 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 (NIH, Biomarkers Definiton Working Group, 2001) 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 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 models 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 DISEASE CM growth and myocardial fibrosis CM death, dysfunction and energetic failure and collagen matrix disruption High BP LVH dysfunction Heart failure (Dez J et al, Nat Clin Pract Cardiovasc Med 2005;2:209-216) MULTIFACETED METHODOLOGICAL APPROACH TO IDENTIFY AND EVALUATE BIOMARKERS OF HHD 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 Endomyocardial biopsy for molecular and histomorphological studies Echocardiographic study for characterization of LV mass, function and morphology Peripheral and coronary blood sampling for determination of biomarkers (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-1 Blood gp130 LIF-R Signaling pathways Hypertrophy SOCS STAT3 ERK5 Cardiomyocyte FibroblastCardiomyocyte Mechanical and humoral stimuli CT-1 CT-1 CT-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-1 Time of evolution Control reference interval 41 fmol/mL FIBRILLAR COLLAGEN TYPE I METABOLISM IN THE HEART (Adapted from Lpez B et al. J Hypertens 2005:23:1445-1451) Procollagen type I DNA SynthesisFibroblast Mechanical and humoral stimuli Procollagen type I Collagen type I Big telopeptide Degradation products PICP MMP-1 101:1729-1735 - Querejeta R et al, Circulation 2004;110:1263-1268 - Lpez B et al, JACC 2006;48:89-96) High BP LVH dysfunction Heart failure Serum PICP Time of evolution Control reference interval 71 g/L ANNEXIN A5 SYNTHESIS AND SECRETION IN THE HEART (Camors E et al, Cardiovasc Res 2005;65:793-802) Cardiomyocyte Death ligands FADD EC death signals IC death signals Death receptors Caspases EXECUTION OF DEATH Ca2+ C8 cyt c Bcl-2 Bcl-2 Anx A5 Anx A5 Anx A5 Anx A5 Blood Anx A5 Anx A5 Blood ANNEXIN A5 AS A BIOMARKER OF CARDIOMYOCYTE APOPTOSIS? (Ravassa S et al, Eur Heart J, submitted) High BP LVH dysfunction Heart failure Plasma AnxA5 Time of evolution Control reference interval 8.3 ng/mL FIBRILLAR COLLAGEN TYPE I METABOLISM IN THE HEART (Adapted from Lpez B et al. J Hypertens 2005:23:1445-1451) Procollagen type I DNA SynthesisFibroblast Mechanical and humoral stimuli Procollagen type I Collagen type I Big telopeptide Degradation products PICP MMP-1 110:1263-1268 - Lpez B et al, J Am Coll Cardiol 2006;48:89-96) High BP LVH dysfunction Heart failure Serum MMP-1 to TIMP-1 ratio Time of evolution Control reference interval 11 CIRCULATING BIOMARKERS IN THE DIAGNOSTIC ASSESSMENT OF HHD Plasma or serum concentration Time of evolution Control reference interval AnxA5 MMP-1:TIMP-1 CT-1 PICP High BP LVH dysfunction Heart failure BNP CIRCULATING BIOMARKERS IN THE THERAPEUTIC EVALUATION OF HHD Plasma or serum concentration Time of evolution Control reference interval (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 failure PICP CT-1 PICP THE INGENIOUS HYPERCARE NETWORK Opportunity 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 Biomarkers of cardiomyocyte changes IL-6, IGF-1, LIF, oncostatin M, neuregulin FAS, FAS-l, TNF, CFLAR Calsequestrin, osteoprotegerin CD36 Biomarkers of collagen matrix changes Osteopontin, thrombospondin, TGF-RIII , CTGF Relaxin MMP-2, MMP-9, TIMP-4, MTCBP-1 Biomarkers of general mediators changes IL-1, MCP-1 MPO, SOD, nitrotyrosin, 8-OH-2deoxyguanosine THE INGENIOUS HYPERCARE NETWORK Opportunity for exploration of new candidate biomarkers The Zeptosens proteomic platform incorporates a chip-based technology to perform high throughput multiplexed analysis of hundreds