1、Cardiovascular Pathology(心血管病理)Aims1.Anatomy and physiology of the cardiovascular system2.Cardiomyopathies3.Molecular pathology for cardiomyopathyCardiovascular SystemCirculationHeartAortaArteryArteioleVeinVenuleCapillaryPulmonaryThe double pumpFour ChambersCardiovascular Pathology:the study of dise
2、ases of heart and blood vessels.Molecular PathologyHeart Index-Normal HeartHeart rateHeart rhythmHeart SizeWall thicknessHeart weightChamber volumeHeart rate vs.body size?75 vs 600Heart Index-Normal HeartHeart rateHeart rhythmHeart rate vs.body size?75 vs 600Camels and bats represent the two extreme
3、s of the scale,with most other mammals falling somewhere in between.Heart IndexEFdP/dT maxdP/dT minEchocardiographyHemodynamicsElectricity conductionMuscleSmooth muscleStriated muscle:Cardiac muscleSkeletal muscleSarcomereCostamereMyosinZ-discTitinNebulinStriated MuscleMouse adult cardiomyocytesCard
4、iomyocyteSarcomeresHeart Diseases Myocardial infarction Carditis Cardiomyopathies Neoplasia Congenital heart diseaseCardiomyopathy:Cardio+Myo+PathyDilated 1:2500-3000Hypertrophic 1:500RestrictedARVC(Arrhythmogenic right ventricle cardiomyopathy)Stress cardiomyopathy(broken heart syndrome)Peripartum
5、cardiomyopathyMcNally EM,et al.J Clin Invest,2013CardiomyopathiesCardiomyopathyHypertrophicDilatedLDB3AutosomalDominant 50 genesMcNally EM,et al.J Clin Invest,2013Maron BJ,et al.JACC,2012HypertrophicCardiomyopathyMyosinMyosin binding Protein C 75%Maron BJ,et al.JACC,2012Genetic Testing and Heart Dis
6、easeMaron BJ,et al.JACC,2012The 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
7、 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 DiseaseHo Carolyn Y.Circulation,2012How to do basic cardiac research?Cypher/ZASP
8、/LDB3Huang C et al.J Biol Chem,2003Zhou Q,JBC 1999Zhou Q,JCB 2001Zheng M,et al.Hum Mol Genet,2009Cypher/ZASP/LDB3Zheng M,et al.Hum Mol Genet,2009Echocardiography(Cardiac MRI)LVIDdLVPWdIVSdFraction shorteningZheng M,et al.Hum Mol Genet,2009Cypher/ZASP/LDB31.What is basic cardiac research?2.How a anim
9、al model represents human cardiomyopathy?Zheng M,et al.Hum Mol Genet,2009Cypher/ZASP/LDB3Cypher/ZASP/LDB3 and Z linesZhou Q,JBC 1999Zhou Q,JCB 2001Zheng M,HMG 2009Zheng M,JMCB 2009Cheng H,HMG 2011Cheng H,Cir Res 2010Peter A,2011Lin C,JBC 2013Mu Y,JAHA 2015Cypher KOCypher CardiacCypher LongCypher Sho
10、rtENHCypher ENH DoubleCypher L ENH DoubleCypher S ENH DoubleCypher MutationCypher L-FlagCypher S-FlagCell Signaling and Heart DiseaseNicol RL,et al.,Annu.Rev.Genomics Hum.Genet.2000.?gp130SignalingNicol RL,et al.,Annu.Rev.Genomics Hum.Genet.2000.GPCR SignalingNicol RL,et al.,Annu.Rev.Genomics Hum.Ge
11、net.2000.MAPK SignalingNicol RL,et al.,Annu.Rev.Genomics Hum.Genet.2000.Ca2+SignalingmiRNAs and Heart DevelopmentAkiko Hata.Annu Rev Physiol,2013Akiko Hata.Annu Rev Physiol,2013miRNAs and Heart HypertrophyPKA and AKAPs in the HeartScott JD et al.,Annu Rev Pharmacol Toxicol,2013cAMP,AKAPs in the Hear
12、tKapiloff MS.Mol Pharmacol.2002,62(2):193-9.Cypher(LDB3)=AKAPLTCCCalcium Cycling and SignalingCalcium induced calcium releaseNa/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 contracti
13、le activation:Ca-force interactionContractionCaMKIILing 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,2013CaMKII deletion protected the heart against I/R damage as evidenced by decreased infarct s
14、ize,attenuated apoptosis and improved functional recoveryLing 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 Cli
15、n 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 M
16、L,Blaxall BC.Cardiac Intercellular Communication:Are Myocytes and Fibroblasts Fair-Weather Friends?J Cardiovasc Transl Res.2012Cell and Cell Interactionin the HeartFibrosisLiverHeartKidneyLungHeart Beating and NucleusNLSNESKetema M,Sonnenberg A.Nesprin-3:a versatile connector between the nucleus and
17、 the cytoskeleton.Biochem Soc Trans.2011 Dec;39(6):1719-24.?Nucleus AnchoringLINC complex(Linker of nucleoskeleton and cytoskeleton)C-terminal KASH domain(Klarsicht,Anc1,Syne homology)SUN domainLaminopathy:mutations in A-type nuclear lamins(LMNA)Nuclear receptorMore1.Towbin BD,Meister P,Gasser SM.Th
18、e nuclear envelope-a scaffold for silencing?Curr Opin Genet Dev.2009 19(2):180-6.(Nuclear lamina preferentially interacts with silent genes)2.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 pro
19、geric 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 NucleusCardiac Regeneration-fishCardiac Regeneration-mammal1.Porrello ER,Mahmoud AI
20、,Simpson E,Hill JA,Richardson JA,Olson EN,Sadek HA.Transient regenerative potential of the neonatal mouse heart.Science.2011 Feb 25;331(6020):1078-80.2.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/
21、j.tcm.2012.07.008.Epub 2012 Aug 14.Cardiac Regeneration and Stem Cell TherapyFor acute myocardial infarction andchronic ischemia,long-term mortality after 1 and 5 years,respectively,is significantly reduced.A few studies also indicate beneficial effects for chronic dilated cardiomyopathy.Cardiac Con
22、duction SystemAV blockLong QTLeft bundle block ArrhythmiaLong QT SyndromeKramer DB and Zimetbaum PJ,Cardio Rev,2011-0.8-0.6-0.4-0.200.20.40.60.8-0.6-0.4-0.200.20.40.60.811.2ADuration(ms)QRSQJ*Duration(ms)B0102030401201020304012WTKO*P0.01Animal ModelKOWTAnteriorPosteriorCAtrial pacing 120 msCardiac O
23、ptical MappingD01234567KOWTActivation time(ms)Intrinsic rhythmE0123456789KOWTAtrial pacing at CL=120 msActivation time(ms)Animal ModelBasic Research QuestionnairesAnimal vs.Human1.Size2.Life span3.StressOpen fields1.Cardiac development2.Cardiac regeneration3.Stem cell therapyVasculatureThe main cell
24、ular 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 v
25、ascular 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 2009Endothelial CellsThe term endothelial dysfuncti
26、on 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 DysfunctionSmooth Muscle Cellsa)to mediate vasoconstriction,b)to mediate vasodilatation,c)to synthesize the collagen,e
27、lastin,and proteoglycans,d)to elaborate the growth factors and cytokines,e)to proliferate,and f)to migrate to the intima.Vascular DiseasesA)Congenital anomaliesB)AtherosclerosisC)Hypertensive vascular diseaseD)Inflammatory disease Arteritides(Vasculitides)E)Raynaud diseaseF)Aneurysms a dissectionsAt
28、herosclerosisAtherosclerosis 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 diseas
29、e 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 ao
30、rtic 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 2011Macrophages and Atherosclero
31、sismonocyte-endothelial interactionsapoB-LPs Risk FactorsAge(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,per
32、sonal 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 inflamm
33、atory 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 th
34、e 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 leukocytesLee S et al.,Cir Res.2012Lee S et al.,Cir Res.2012Endothelial BarrierDejana E et al.,Dev Cell.2009miRNAs and VasculatureAkiko Hata.Ann Rev Physiol.2013Angiogenesis and TumorTaking Home message1.Heart2.EC coupling3.Ca induced Ca release4.Cardiac conduction system5.Cadiomyopathy6.atherosclerosis
