心血管病理英文版.ppt

Click to edit Master title style,Click to edit Master text styles,Second level,Third level,Fourth level,Fifth level,*,*,文档仅供参考，不能作为科学依据，请勿模仿；如有不当之处，请联系网站或本人删除。,Aims,Anatomy and physiology of the cardiovascular system,Cardiomyopathies,Molecular pathology for cardiomyopathy,Cardiovascular System,Circulation,Heart,Aorta,Artery,Arteiole,Vein,Venule,Capillary,Pulmonary,The double pump,Four Chambers,Cardiovascular Pathology:the study of,diseases,of,heart,and,blood vessels,.,Molecular Pathology,Heart Index-Normal Heart,Heart rate,Heart rhythm,Heart Size,Wall thickness,Heart weight,Chamber volume,Heart rate vs.body size?,75 vs 600,Heart Index-Normal Heart,Heart rate,Heart rhythm,Heart rate vs.body size?,75 vs 600,Camels and bats represent the two extremes of the scale,with most other mammals falling somewhere in between.,Heart Index,EF,dP/dT max,dP/dT min,Echocardiography,Hemodynamics,Electricity conduction,Muscle,Smooth muscle,Striated muscle:,Cardiac muscle,Skeletal muscle,Sarcomere,Costamere,Myosin,Z-disc,Titin,Nebulin,Striated,Muscle,Mouse adult cardiomyocytes,Cardiomyocyte,Sarcomeres,Heart Diseases,Myocardial infarction,Carditis,Cardiomyopathies,Neoplasia,Congenital heart disease,Cardiomyopathy:Cardio+Myo+Pathy,Dilated 1:2500-3000,Hypertrophic 1:500,Restricted,ARVC(Arrhythmogenic right ventricle cardiomyopathy),Stress cardiomyopathy(broken heart syndrome),Peripartum cardiomyopathy,McNally EM,et al.,J Clin Invest,2013,Cardiomyopathies,Cardiomyopathy,Hypertrophic,Dilated,LDB3,Autosomal,Dominant,50 genes,McNally EM,et al.,J Clin Invest,2013,Maron BJ,et al.,JACC,2012,Hypertrophic,Cardiomyopathy,Myosin,Myosin binding,Protein C,75%,Maron BJ,et al.,JACC,2012,Genetic Testing and Heart Disease,Maron BJ,et al.,JACC,2012,The power of HCM mutational analysis,albeit a more limited role than initially envisioned,lies most prominently in screening family members at risk for developing disease and excluding unaffected relatives,which is,information,not achievable otherwise.Genetic testing also allows expansion of the broad HCM disease spectrum and diagnosis of HCM phenocopies with different natural history and treatment options,but is,not a reliable strategy for predicting prognosis,.,Genetic Testing and Heart Disease,Ho Carolyn Y.,Circulation,2012,How to do basic cardiac research?,Cypher/ZASP/LDB3,Huang C et al.,J Biol Chem,2003,Zhou Q,JBC 1999,Zhou Q,JCB 2001,Zheng M,et al.,Hum Mol Genet,2009,Cypher/,ZASP/,LDB3,Zheng M,et al.,Hum Mol Genet,2009,Echocardiography(Cardiac MRI),LVIDd,LVPWd,IVSd,Fraction shortening,Zheng M,et al.,Hum Mol Genet,2009,Cypher/,ZASP/,LDB3,What is basic cardiac research?,How a animal model represents human cardiomyopathy?,Zheng M,et al.,Hum Mol Genet,2009,Cypher/,ZASP/,LDB3,Cypher/ZASP/LDB3 and Z lines,Zhou Q,JBC 1999,Zhou Q,JCB 2001,Zheng M,HMG 2009,Zheng M,JMCB 2009,Cheng H,HMG 2011,Cheng H,Cir Res 2010,Peter A,2011,Lin C,JBC 2013,Mu Y,JAHA 2015,Cypher KO,Cypher Cardiac,Cypher Long,Cypher Short,ENH,Cypher ENH Double,Cypher L ENH Double,Cypher S ENH Double,Cypher Mutation,Cypher L-Flag,Cypher S-Flag,Cell Signaling and Heart Disease,Nicol RL,et al.,Annu.Rev.Genomics Hum.Genet.2000.,?,gp130,Signaling,Nicol RL,et al.,Annu.Rev.Genomics Hum.Genet.2000.,GPCR Signaling,Nicol RL,et al.,Annu.Rev.Genomics Hum.Genet.2000.,MAPK Signaling,Nicol RL,et al.,Annu.Rev.Genomics Hum.Genet.2000.,Ca,2+,Signaling,miRNAs and Heart Development,Akiko Hata.Annu Rev Physiol,2013,Akiko Hata.Annu Rev Physiol,2013,miRNAs and Heart Hypertrophy,PKA and AKAPs in the Heart,Scott JD et al.,Annu Rev Pharmacol Toxicol,2013,cAMP,AKAPs in the Heart,Kapiloff MS.Mol Pharmacol.2002,62(2):193-9.,Cypher(LDB3)=AKAP,LTCC,Calcium Cycling and Signaling,Calcium induced calcium release,Na/Ca exchanger,:NCX,the Ca transporter in the heart that is largely responsible for extruding the Ca that enters via ICa.,excitation-contraction coupling,:,Ca-dependent contractile activation:Ca-force interaction,Contraction,CaMKII,Ling H,Gray CB,Zambon AC,Grimm M,Gu Y,Dalton ND,Purcell NH,Peterson K,Brown JH,.,CaMKII,Mediates Myocardial Ischemia/Reperfusion Injury Through NF-B,.,Cir Res,2013,CaMKII,deletion protected the heart against I/R damage as evidenced by decreased,infarct,size,attenuated apoptosis and improved functional recovery,Ling H,Zhang T,Pereira L,Means CK,Cheng H,Gu Y,Dalton ND,Peterson KL,Chen J,Bers D,Brown JH,.,Requirement,for Ca2+/calmodulin-dependent kinase II in the transition from pressure overload-induced cardiac hypertrophy to heart failure in mice,.,J Clin Invest.2009,Strikingly,while KO mice showed preserved hypertrophy after 6-week TAC,CaMKIIdelta deficiency significantly ameliorated phenotypic changes associated with the transition to heart failure,such as chamber dilation,ventricular dysfunction,lung edema,cardiac fibrosis,and apoptosis.,Martin ML,Blaxall BC.Cardiac Intercellular Communication:Are Myocytes and Fibroblasts Fair-Weather Friends?J Cardiovasc Transl Res.2012,Cell and Cell Interaction,in the Heart,Fibrosis,Liver,Heart,Kidney,Lung,Heart Beating and Nucleus,NLS,NES,Ketema M,Sonnenberg A.Nesprin-3:a versatile connector,between the nucleus and the cytoskeleton.Biochem Soc Trans.,2011 Dec;39(6):1719-24.,?,Nucleus Anchoring,LINC complex(Linker of nucleoskeleton and cytoskeleton),C-terminal KASH domain(Klarsicht,Anc1,Syne homology),SUN domain,Laminopathy:mutations in A-type nuclear lamins(,LMNA,),Nuclear receptor,More,Towbin BD,Meister P,Gasser SM.,The nuclear envelope-a scaffold for silencing?Curr Opin Genet Dev.2009 19(2):180-6.,(Nuclear lamina preferentially interacts with silent genes),Chen CY,Chi YH,Mutalif RA,Starost MF,Myers TG,Anderson SA,Steward CL and Jeang KT.,Accumulation of the inner nuclear envelope protein Sun1 is pathogenic in progeric and dystrophic laminopathies.,(2012).Cell 149,565577.(SUN1 is overexpressed in all three laminopathymodels,and,in each case,dialing SUN1 back down rescues organismal and/or,cellular,defects.)(,?,),Heart Beating and Nucleus,Cardiac Regeneration-fish,Cardiac Regeneration-mammal,Porrello ER,Mahmoud AI,Simpson E,Hill JA,Richardson JA,Olson EN,Sadek HA.Transient regenerative potential of the neonatal mouse heart.Science.2011 Feb 25;331(6020):1078-80.,Mahmoud AI,Porrello ER.Turning back the cardiac regenerative clock:lessons from the neonate.Trends Cardiovasc Med.2012 Jul;22(5):128-33.doi:10.1016/j.tcm.2012.07.008.Epub 2012 Aug 14.,Cardiac Regeneration and Stem Cell Therapy,For acute myocardial infarction and,chronic ischemia,long-term mortality after 1,and 5 years,respectively,is signicantly,reduced.A few studies also indicate benecial,effects for chronic dilated cardiomyopathy.,Cardiac Conduction System,AV block,Long QT,Left bundle block,Arrhythmia,Long QT Syndrome,Kramer DB and,Zimetbaum PJ,Cardio Rev,2011,A,Duration(ms),QRS,QJ,*,Duration(ms),B,WT,KO,*,P0.01,Animal Model,KO,WT,Anterior,Posterior,C,Atrial pacing 120 ms,Cardiac Optical Mapping,D,KO,WT,Activation time(ms),Intrinsic rhythm,E,KO,WT,Atrial pacing at CL=120 ms,Activation time(ms),Animal Model,Basic Research Questionnaires,Animal vs.Human,Size,Life span,Stress,Open fields,Cardiac development,Cardiac regeneration,Stem cell therapy,Vasculature,The main cellular components of the walls of vessels are:,endothelial cells,smooth muscle cells,pericytes(the cells normally arranged along capillaries and venules),(,Pericytes,have role as supportive and connective elements,),a),serve as a,barrier,b),regulate thrombosis,thrombolysis and platelet adherence,c),influate vascular tone and blood flow,d),metabolize hormones,e),regulate immune and inflammatory reactions,f),modify lipoptoteins in the artery wall,g),regulate the growth of other cell types,including smooth muscle cells.,Pober JS et al.,Annu Rev Pathol Mech Dis 2009,Endothelial Cells,The term,endothelial dysfunction,is often used to describe several types of potentially reversible changes in the functional state of endothelial cells that occur in response to environmental stimuli.,Endothelial Dysfunction,Smooth Muscle Cells,a,),to mediate vasoconstriction,b),to mediate vasodilatation,c),to synthesize the collagen,elastin,and proteoglycans,d),to elaborate the growth factors and cytokines,e),to proliferate,and,f),to migrate to the intima.,Vascular Diseases,A,),Congenital anomalies,B),Atherosclerosis,C),Hypertensive vascular disease,D),Inflammatory disease Arteritides(Vasculitides),E),Raynaud disease,F),Aneurysms a dissections,Atherosclerosis,Atherosclerosis significantly contributes to serious morbidity and mortality approximately half or more of all deaths.,It primarily affects elastic arteries(e.g.,aorta,carotid and iliac arteries)and large and medium sized muscular arteries(e.g.,coronary and popliteal arteries).,The disease often begins in childhood,but symptoms are not usually evident until middle age.,Symptomatic atherosclerotic disease is most often localized to the arteries supplying the heart,brain,kidneys,lower extremities,and small intestine.,Myocardial infarction(heart attack),cerebral infarction(stroke),and aortic aneurysms are the major consequences of this disease.,There are also other important consequences such as gangrene of the legs,mesenteric occlusions,sudden cardiac death,chronic ischemic heart disease,and ischemic encephalopathy.,Kathryn J.Moore and Ira Tabas.Cell 2011,Macrophages and Atherosclerosis,monocyte-endothelial interactions,apoB-LPs,Risk Factors,Age(advanced age),sex(male,postmenopausal women,the protective effect of estrogens),genetics(polygenic familiar predisposition,genetic abberrations in lipoprotein metabolism resulting in excessively high blood lipid levels),diet,life style,personal habit.There are 6 major well-accepted conditions such as:,hyperlipidemia,hypertension,smoking,diabetes mellitus,elevated plasma homocysteine,factors affecting hemostasis and thrombosis.,Pathogenesis of atherosclerosis,The contemporary view of the pathogenesis:,Atherosclerosis is a chronic inflammatory response of arterial wall initiated by some form of endothelial injury!,There are described the following steps:,a),chronic endothelial injury,b),insudation of lipoproteins(mainly LDL and VLDL)into the vessel wall,c),modification of such lipoproteins by oxidation,d),adhesion of blood monocytes to the endothelium,e),migration of monocytes into the intima and their transforamtion into macrophages and foam cells,f),adhesion of platelets to focal areas of denudation or to adherent leukocytes,Lee S et al.,Cir Res.2012,Lee S et al.,Cir Res.2012,Endothelial Barrier,Dejana E et al.,Dev Cell.2009,miRNAs and Vasculature,Akiko Hata.Ann Rev Physiol.2013,Angiogenesis and Tumor,谢谢大家！,Taking Home message,Heart,EC coupling,Ca induced Ca release,Cardiac conduction system,Cadiomyopathy,atherosclerosis,