张清泉,庄涛,孙云甫

• 1:同济大学 心律失常教育部重点实验室
• 2:同济大学医学院附属东方医院

摘要(Abstract)：

<正>心脏起搏传导系统是一种特殊的心肌组织,负责产生和传播电脉冲,在控制和协调心脏的收缩中起着至关重要的作用。起搏传导系统的形成和功能异常将导致心律失常,甚至心脏猝死[1-3]。窦房结功能障碍(sinus node dysfunction,SND)或病态窦房结综合征(sick sinus syndrome)是一种常见的老年相关性疾病,表现为窦性心动过缓,停搏,

关键词(KeyWords)：

Abstract:

Keywords:

基金项目(Foundation): 国家自然科学基金项目(31071280,81171069)

作者(Author): 张清泉,庄涛,孙云甫

参考文献(References)：

• [1]Dobrzynski H,Boyett MR,Anderson RH.New insights into pacemaker activity:promoting understanding of sick sinus syndrome[J].Circulation,2007,115(14):1921-1932.
• [2]Gourdie RG,Harris BS,Bond J,et al.Development of the cardiac pacemaking and conduction system[J].Birth Defects Res C Embryo Today,2003,69(1):46-57.
• [3]Lamas GA,Lee KL,Sweeney MO,et al.Ventricular pacing or dual-chamber pacing for sinus-node dysfunction[J].N Engl J Med,2002,346(24):1854-1862.
• [4]Hirota A,Fujii S,Kamino K.Optical monitoring of spontaneous electrical activity of8-somite embryonic chick heart[J].Jpn J Physiol,1979,29(5):635-639.
• [5]Kamino K,Hirota A,Fujii S.Localization of pacemaking activity in early embryonic heart monitored using voltage-sensitive dye[J].Nature,1981,290(5807):595-597.
• [6]Gourdie RG,Mima T,Thompson RP,et al.Terminal diversification of the myocyte lineage generates Purkinje fibers of the cardiac conduction system[J].Development,1995.121(5):1423-1431.
• [7]Buckingham M,Meilhac S,Zaffran S.Building the mammalian heart from two sources of myocardial cells[J].Nat Rev Genet,2005,6(11):826-835.
• [8]Christoffels VM,Mommersteeg MT,Trowe MO,et al.Formation of the venous pole of the heart from an Nkx2-5-negative precursor population requires Tbx18[J].Circ Res,2006,98(12):1555-1563.
• [9]Hoogaars WM,Engel A,Brons JF,et al.Tbx3controls the sinoatrial node gene program and imposes pacemaker function on the atria[J].Genes Dev,2007,21(9):1098-1112.
• [10]Sun Y,Liang X,Najafi N,et al.Islet1is expressed in distinct cardiovascular lineages,including pacemaker and coronary vascular cells[J].Dev Biol,2007,304(1):286-296.
• [11]Wiese C,Grieskamp T,Airik R,et al.Formation of the sinus node head and differentiation of sinus node myocardium are independently regulated by Tbx18and Tbx3[J].Circ Res,2009,104(3):388-397.
• [12]Chen PS,Joung B,Shinohara T,et al.The initiation of the heart beat[J].Circ J,2010,74(2):221-225.
• [13]Robinson RB,Siegelbaum SA.Hyperpolarization-activated cation currents:from molecules to physiological function[J].Annu Rev Physiol,2003,65:453-480.
• [14]Garcia-Frigola C,Shi Y,Evans SM.Expression of the hyperpolarization-activated cyclic nucleotide-gated cation channel HCN4during mouse heart development[J].Gene Expr Patterns,2003,3(6):777-783.
• [15]Moosmang S,Stieber J,Zong X,et al.Cellular expression and functional characterization of four hyperpolarization-activated pacemaker channels in cardiac and neuronal tissues[J].Eur J Biochem,2001,268(6):1646-1652.
• [16]Ludwig A,Zong X,Jeglitsch M,et al.A family of hyperpolar-ization-activated mammalian cation channels[J].Nature,1998,393(6685):587-591.
• [17]Laish-Farkash A,Glikson M,Brass D,et al.A novel mutation in the HCN4gene causes symptomatic sinus bradycardia in moroccan jews[J].J Cardiovasc Electrophysiol,2010,21(12):1365-1372.
• [18]Milanesi R,Baruscotti M,Gnecchi-Ruscone T,et al.Familial sinus bradycardia associated with a mutation in the cardiac pacemaker channel[J].N Engl J Med,2006,354(2):151-157.
• [19]Nof E,Luria D,Brass D,et al.Point mutation in the HCN4cardiac ion channel pore affecting synthesis,trafficking,and functional expression is associated with familial asymptomatic sinus bradycardia[J].Circulation,2007,116(5):463-470.
• [20]Schulze-Bahr E,Neu A,Friederich P,et al.Pacemaker channel dysfunction in a patient with sinus node disease[J].J Clin Invest,2003,111(10):1537-1545.
• [21]Ueda K,Hirano Y,Higashiuesato Y,et al.Role of HCN4channel in preventing ventricular arrhythmia[J].J Hum Genet.,2009,54(2):115-121.
• [22]Ueda K,Nakamura K,Hayashi T,et al.Functional charac-terization of a trafficking-defective HCN4mutation,D553N,associated with cardiac arrhythmia[J].J Biol Chem,2004,279(26):27194-27198.
• [23]Stieber J,Herrmann S,Feil S,et al.The hyperpolarization-activated channel HCN4is required for the generation of pacemaker action potentials in the embryonic heart[J].Proc Natl Acad Sci U S A,2003,100(25):15235-15240.
• [24]Herrmann S,Stieber J,St ckl G,et al.HCN4provides a'depo-larization reserve and is not required for heart rate acceleration in mice[J].EMBO J,2007,26(21):4423-4432
• [25]Koushik SV,Wang J,Rogers R,et al.Targeted inactivation of the sodium-calcium exchanger(Ncx1)results in the lack of a heartbeat and abnormal myofibrillar organization[J].FASEB J,2001,15(7):1209-1211.
• [26]Mangoni ME,Couette B,Marger L,et al.Voltage-dependent calcium channels and cardiac pacemaker activity:from ionic currents to genes[J].Prog Biophys Mol Biol,2006,90(1-3):38-63.
• [27]Sasse P,Zhang J,Cleemann L,et al.Intracellular Ca2+oscillations,a potential pacemaking mechanism in early embryonic heart cells[J].J Gen Physiol,2007,130(2):133-144.
• [28]Yang HT,Tweedie D,Wang S,et al.The ryanodine receptor modulates the spontaneous beating rate of cardiomyocytes during development[J].Proc Natl Acad Sci U S A,2002,99(14):9225-9230.
• [29]Cho CH,Kim SS,Jeong MJ,et al.The Na+-Ca2+exchanger is essential for embryonic heart development in mice[J].Mol Cells,2000,10(6):712-722.
• [30]Cho CH,Lee SY,Shin HS,et al.Partial rescue of the Na+-Ca2+exchanger(NCX1)knock-out mouse by transgenic expression of NCX1[J].Exp Mol Med,2003,35(2):125-135.
• [31]Mangoni ME,Couette B,Bourinet E,et al.Functional role of L-type Cav1.3Ca2+channels in cardiac pacemaker activity[J].Proc Natl Acad Sci U S A,2003,100(9):5543-5548.
• [32]Platzer J,Engel J,Schrott-Fischer A,et al.Congenital deafness and sinoatrial node dysfunction in mice lacking class D L-type Ca2+channels[J].Cell,2000,102(1):89-97.
• [33]Takeshima H,Komazaki S,Hirose K,et al.Embryonic lethality and abnormal cardiac myocytes in mice lacking ryanodine receptor type2[J].EMBO J,1998,17(12):3309-3316.
• [34]Periasamy M,Reed TD,Liu LH,et al.Impaired cardiac performance in heterozygous mice with a null mutation in the sarco(endo)plasmic reticulum Ca2+-ATPase isoform2(SERCA2)gene[J].J Biol Chem,1999,274(4):2556-2562.
• [35]Christoffels VM,Smits GJ,Kispert A,et al.Development of the pacemaker tissues of the heart[J].Circ Res,2010,106(2):240-254.
• [36]Milan DJ,Giokas AC,Serluca FC,et al.Notch1b and neure-gulin are required for specification of central cardiac conduction tissue[J].Development,2006,133(6):1125-1132.
• [37]Patel R,Kos L.Endothelin-1and Neuregulin-1convert embr-yonic cardiomyocytes into cells of the conduction system in the mouse[J].Dev Dyn,2005,233(1):20-28.
• [38]Rentschler S,Zander J,Meyers K,et al.Neuregulin-1promotes formation of the murine cardiac conduction system[J].Proc Natl Acad Sci U S A,2002,99(16):10464-10469.
• [39]Jay PY,Harris BS,Maguire CT,et al.Nkx2-5mutation causes anatomic hypoplasia of the cardiac conduction system[J].J Clin Invest,2004,113(8):1130-1137.
• [40]Ismat FA,Zhang M,Kook H,et al.Homeobox protein Hop functions in the adult cardiac conduction system[J].Circ Res,2005,96(8):898-903.
• [41]Moskowitz IP,Kim JB,Moore ML,et al.A molecular pathway including Id2,Tbx5,and Nkx2-5required for cardiac conduction system development[J].Cell,2007,129(7):1365-1376.
• [42]Benson DW,Silberbach GM,Kavanaugh-McHugh A,et al.Mutations in the cardiac transcription factor NKX2.5affect diverse cardiac developmental pathways[J].J Clin Invest,1999,104(11):1567-1573.
• [43]Bruneau BG,Nemer G,Schmitt JP,et al.A murine model of Holt-Oram syndrome defines roles of the T-box transcription factor Tbx5in cardiogenesis and disease[J].Cell,2001,106(6):709-721.
• [44]Li QY,Newbury-Ecob RA,Terrett JA,et al.Holt-Oram syndrome is caused by mutations in TBX5,a member of the Brachyury(T)gene family[J].Nat Genet,1997,15(1):21-29.
• [45]Pashmforoush M,Lu JT,Chen H,et al.Nkx2-5pathways and congenital heart disease;loss of ventricular myocyte lineage specification leads to progressive cardiomyopathy and complete heart block[J].Cell,2004,117(3):373-386.
• [46]Schott JJ,Benson DW,Basson CT,et al.Congenital heart disease caused by mutations in the transcription factor NKX2-5[J].Science,1998,281(5373):108-111.
• [47]Hoogaars WM,Tessari A,Moorman AF,et al.The transcriptional repressor Tbx3delineates the developing central conduction system of the heart[J].Cardiovasc Res,2004,62(3):489-499.
• [48]Mommersteeg MT,Hoogaars WM,Prall OW,et al.Molecular pathway for the localized formation of the sinoatrial node[J].Circ Res,2007,100(3):354-362.
• [49]Blaschke RJ,Hahurij ND,Kuijper S,et al.Targeted mutation reveals essential functions of the homeodomain transcription factor Shox2in sinoatrial and pacemaking development[J].Circulation,2007,115(14):1830-1838.
• [50]Espinoza-Lewis RA,Yu L,He F,et al.Shox2is essential for the differentiation of cardiac pacemaker cells by repressing Nkx2-5[J].Dev Biol,2009,327(2):376-385.
• [51]Liu H,Chen CH,Espinoza-Lewis RA,et al.Functional redun-dancy between human SHOX and mouse Shox2genes in the regulation of sinoatrial node formation and pacemaking function[J].J Biol Chem,2011,286(19):17029-17038.
• [52]Kapoor N,Liang W,Marbán E,et al.Direct conversion of quiescent cardiomyocytes to pacemaker cells by expression of Tbx18[J].Nat Biotechnol,2013,31(1):54-62.
• [53]Cai CL,Liang X,Shi Y,et al.Isl1identifies a cardiac progen-itor population that proliferates prior to differentiation and contributes a majority of cells to the heart[J].Dev Cell,2003,5(6):877-889.
• [54]Moretti A,Caron L,Nakano A,et al.Multipotent embryonic isl1+progenitor cells lead to cardiac,smooth muscle,and endothelial cell diversification[J].Cell,2006,127(6):1151-1165.
• [55]Sizarov A,Devalla HD,Anderson RH,et al.Molecular analysis of patterning of conduction tissues in the developing human heart[J].Circ Arrhythm Electrophysiol,2011,4(4):532-542.
• [56]de Pater E,Clijsters L,Marques SR,et al.Distinct phases of cardiomyocyte differentiation regulate growth of the zebrafish heart[J].Development,2009,136(10):1633-1641.
• [57]Hoffmann S,Berger IM,Glaser A,et al.Islet1is a direct tran-scriptional target of the homeodomain transcription factor Shox2and rescues the Shox2-mediated bradycardia[J].Basic Res Cardiol,2013,108(2):339.