摘要
背景与目的：左室舒张功能障碍是肥厚型心肌病的主要临床特点。既往研究表明肥厚型心肌病存在心肌结构与功能的高度异质性。本研究目的就是运用单心动周期实时三维超声评估肥厚型心肌病左室局部心肌的舒张功能。
方法：69例窦性心律且左室射血分数>45%的肥厚型心肌病患者(平均年龄50.4+10.3岁,49个男性)及50例年龄与性别相匹配的正常对照人群一起入组,进行二维超声及三维超声的舒张功能的研究。实时三维超声的主要评估参数包括：收缩末容积(ESV),舒张末容积(EDV),每搏量(SV),射血分数(EF),收缩/舒张末球形指数(ESSI/EDSI),舒张失同步指数(DDI),舒张末离散差(DISPED)其中包括了舒张晚期失同步指数(DDI-late),舒张早期失同步指数(DDI-early),舒张末离散差(DISPED-late)舒张早期离散差(DISPED-early)及标准17节段的容积-时间曲线。将患者按传统的二维超声舒张功能的分级标准分为三组：第一组舒张功能轻度受损(23例),第二组舒张功能假性正常(37例),第三组舒张功能限制性充盈(9例)。
结果：1)用传统二维超声与实时三维超声比较ESV、EDV、SV、LVEF,结果示二维超声测量EDV(二维93.1±17.5m1,三维88.9+18.2m1,P<.0001),ESV(二维37.8±8.9ml,三维33.08±9.9ml,P<.0001),LVEF(二维63.2±6.8%,三维59.1±6.4%,P<.0001)均明显高于三维。2)正常对照组左室17节段的容积-时间曲线相对同步、规则,而肥心病患者的节段曲线紊乱,失同步明显。DDI和DISPED会随着舒张功能不全的等级的改变而改变。在舒张晚期,DDI-late和DISPED-late在舒张功能严重不全(限制性充盈)中才表现出异常升高(7.95±2.75,26.76±17.19,P<.0001),而在轻度(轻度受损)及中度(假性正常)组中均与正常对照组无差异。但在舒张早期,DDI-early和DISPED-early在轻度(8.57±2.24,25.44+6.31,P<.0001)及中度舒张功能不全(9.56±4.66,35.42±14.19,P<.0001)中均已明显高于正常组。3)并且异常节段曲线不仅出现在肥厚的节段,也会出现在正常节段。
结论：在肥厚型心肌病中左室的整体失同步显示增加,可能是由于局部心肌节段舒张功能的异常造成的,尤其在早期舒张,失同步更为明显。提示肥厚型心肌病局部心肌的功能改变是导致整体舒张功的异常的原因,这种早期的临床损伤可以通过实时三维超声来评估。
背景与目的：心肌肌球蛋白结合蛋白C(MYBPC3)是肥厚型心肌病(HCM)主要致病基因,MYBPC3基因突变引起的HCM占20-25%。既往研究表明MYBPC3突变表现型有自己的特点,主要表现为发病晚、肥厚程度轻、心源性猝死少及预后好。但MYBPC3在国内的致病情况及相关临床表型还没有确切报道。本研究目的就是运用二维及三维超声对MYBPC3基因突变引起的肥厚型心肌病进行基因型及临床表型的相关分析。
方法：对48例肥厚型心肌病患者(平均年龄48±12岁,男性31例)进行全基因扫描,聚合酶链反应扩增其MYBPC3基因35个外显子片断,双脱氧末端终止法测序。对阳性结果家系中其他成员及健康对照组同一位置筛查,确定突变。并对先证者及家系成员进行二维及三维超声的临床表型分析。主要二维超声评估参数包括组织多普勒(TDI)二尖瓣室间隔侧壁收缩期最大运动速度Sa,舒张早期最大运动速度Ea,舒张晚期最大运动速度Aa,二尖瓣频谱舒张早期充盈峰值流速E/室间隔侧壁舒张早期最大运动速度Ea,实时三维超声的主要评估舒张失同步指数(DDI)。根据家系成员基因阳性与表型阳性与否,将入选家系成员分为二组：基因阳性/表型阳性(G+/LVH+)组,基因阳性/表型阴性(G+/LVH-)组。
结果：1)在48个散发肥厚型心肌病患者中发现9个MYBPC3基因突变,来自7个家系,有2个先证者同时有2个位点的突变,MYBPC3基因突变的检出率为15%。2)根据基因阳性与表型阳性分组,G+/LVH+组有16例,G+/LVH-组有22例,二维TDI结果示：在G+/LVH+组中,室间隔及侧壁Sa、Ea、Aa均明显减低(P<0.0001),平均室间隔和侧壁E/Ea明显均增高(13.4±3.0,8.1±3.6P<0.0001)。而在G+/LVH-组中,只有室间隔Ea明显减低(8.5±1.7P<0.0001),平均室间隔E/Ea明显均增高(6.6±2.4P<0.0001),而侧壁Sa、Ea、Aa及E/Ea与正常对照无明显差异。三维超声DDI在G+/LVH+组中较对照是明显增高的(9.1±3.4P<0.0001),而在G+/LVH-组,DDI与正常对照无明显差异。
结论：MYBPC3基因突变在本研究中检出率为15%,提示MYBPC3基因突变也是中国肥厚型心肌病发病的主要致病基因之一。在表型阳性的患者中,已出现明显的舒张功能不全,而在表型阴性的患者中,虽然总体舒张功能正常,但已经开始出现局部舒张功能的异常,这也证实了舒张功能异常是肥厚型心肌病的一种早期病理改变,MYBPC3基因突变可能会导致局部心肌舒张功能的障碍。
Background:Left ventricular (LV) diastolic dysfunction has been considered a characteristic of hypertrophic cardiomyopathy (HCM). Previous studies have shown heterogeneity of myocardial function in HCM. The aim of this studyt is to assess LV regional diastolic function in patients with HCM by using single-beat real-time three-dimensional echocardiography (RT-3DE).
Methods:Sixty-nine patients with HCM (LV ejection fraction≥45%) together with sixty age-and gender-matched normal controls were studied by two-dimensional echocardiography (2DE) and RT-3DE. The parameters analyzed by RT-3DE included the following:end diastolic volume(EDV), end systolic vlume(ESV), stroke(SV), ejection fraction(LVEF), end systolic/diastolic sphericity index (ESSI/EDSI), diastolic dyssynchrony index (DDI), dispersion end diastole (DISPED), including late(DDI-late) and early(DDI-early) diastole, dispersion end diastole (DISPED-late), dispersion early diastole (DISPED-early), and normalized segmental volume-time curves (17segments). Patients were divided into three groups according to Diastolic dysfunction criterion as previously described. Group1=impaired relaxation(n=23), Group2=pseudonormal filling(n=37), Group3=restrictive filling(n=9).
Results:1) We compared the measurements of left ventricular function acquired by2DE and RT-3DE. A significant decrease in the EDV (93.1±17.5ml in2DE versus88.9±18.2ml in RT3DE, P<.0001) coupled with ESV (37.8±8.9ml in2DE versus33.08±9.9ml in RT3DE, P<.0001) resulted in a significant increase in the LVEF in2DE (63.2±6.8%versus59.1±6.4%, P<.0001).2) Normal subjects had relatively uniform volumetric curves for all LV segments. In HCM patients, the segmental volumetric curves were dyssynchronous. DDI and DISPED were increased with degree of diastolic dysfunction. In end diastole, DDI-late and DISPED-late were abnormal in severe diastolic dysfunction (7.95±2.75,26.76±17.19, P<.0001), while they were normal in mild diastolic dysfunction. However, in early diastole, DDI-early and DISPED-early were increased in mild (8.57±2.24,25.44±6.31, P<.0001) and moderate (9.56±4.66,35.42±14.19, P<.0001) diastolic dysfunction. And abnormal volumetric segments not only occurred in the hypertrophic regions but also in normal regions.
Conclusions:Dyssynchrony in HCM was significantly increased due to regional diastolic dysfunction, especially in early diastole, suggesting that regional myocardial changes in HCM can lead to the global diastolic dysfunction. This preclinical lesion can be recognized by single-beat RT-3DE.
Background:Myosin binding protein C3(MyBPC3) mutations are one of the most causes of hypertrophic cardiomyopathy(HCM). In previous studies, Mutations in MyBPC3are responsible for15-20%of cases of familial HCM and were generally associated with mild and age-related penetrance disease. Its prevalence varies between populations. However, the links between mutations in MyBPC3and changes of cardiac functions in Chinese patients with hypertrophic cardiomyopathy remain unclear. Our objectives were to determine the associated Mutations in MyBPC3in China and clinical characteristics in MyBPC3mutations in our patients using2-dimensional and real-time3-dimensional echocardiography(2DE and RT-3DE).
Methods:48patients (age48±12years;31male) with HCM underwent genetic screening of MyBPC3. Following PCR amplification, direct sequencing of amplicons was performed. A variant was based on absence of the mutation in200healthy adult controls. HCM proband and families with identified MyBPC3mutations which were divided into group:genotyped HCM patients (genotype-positive G+/LVH+), mutation carriers without LVH (G+/LVH-)and matched normal control subjects (n=30)were examined with2DE including TDI and RT-3DE. TDI included:Septal and lateral TDI-derived systolic(Sa) and early(Ea) and late diastolic(Aa) mitral annular velocities, and Septal and lateral E/Ea. DDI in RT-3DE.
Results:1) Nine mutations in MyBPC3were identified in7of the48index cases(15%).7HCM families with identified MyBPC3mutations which were divided into group:genotyped HCM patients (genotype-positive G+/LVH+, n=16), mutation carriers without LVH (G+/LVH-, n=22).2) Septal and lateral TDI-derived systolic(Sa) and early(Ea) and late diastolic(Aa) mitral annular velocities were significantly lower and Septal and lateral E/Ea were increased in the G+/LVH+subjects compared with the controls(13.4±3.0,8.1±3.6P<.0001). However, in G+/LVH-subjects, septal Ea were significantly lower(8.5±1.7P<.0001) and E/Ea were increased(6.6±2.4P<0.0001), while lateral TDI were no difference compared with the controls. DDI derived from3DE were markedly higher in the G+/LVH+subjects than the other groups(9.1±3.4P<.0001). There was no difference between G+/LVH-subjects and controls.
Conclusions: MyBPC3genes is predominant causing mutations for HCM and account for15%of the genotyped patients in China. Severe hypertrophy and diastolic dysfunction of the disease are compatible with the presence of mutations in MyBPC3. Signs of regional diastolic abnormalities and LV remodelling are suggested to be a primary response to the mutations of MyBPC3expression.
引文
[1]Brock R. Functional obstruction of the left ventricle(acquired aortic subvalvular stenosis). Guys Hosp Rep 1957;106:221-238.
[2]Teare D. Asymmetrical hypertrophy of the heart in young adults. Br Heart J 1958; 20:1-8.
[3]Maron BJ, Shirani J, Poliac LC, Mathenge R, Roberts WC, Mueller FO. Sudden death in young competitive athletes:Clinical, demographic, and pathological profiles. JAMA 1996; 276:199-204.
[4]Maron BJ, Towbin JA, Thiene G, Antzelevitch C, Corrado D, Arnett D, Moss AJ, Seidman CE, Yong JB. Contemporary definitions and classification of the cardiomyopathies:an American Heart Association Scientific Statement from the Council on Clinical Cardiology, Heart Failure and Transplantation Committee; Quality of Care and Outcomes Research and Functional Genomics and Translational Biology Interdisciplinary Working Groups; and Council on Epidemiology and Prevention. Circulation 2006; 113:1807-1816.
[5]Hershberger RE, Cowan J, Morales A, Siegfried JD. Progress with genetic cardiomyopathies:screening, counseling, and testing in dilated, hypertrophic, and arrhythmogenic right ventricular dysplasia/cardiomyopathy. Circ Heart Fail 2009; 2:253-261.
[6]Alcalai R, Seidman JG, Seidman CE. Genetic basis of hypertrophic cardiomyopa-thy:from bench to the clinics. J Cardiovase Electro-physiol 2008; 19:104-110.
[7]Keren A,syrris P,Mckenna WJ.Hypertrophic cardiomyopathy:the genetic determinants of clinical disease expression. nat.clin.pract.cardiovasc.med 2008;53: 158-168.
[8]Debold EP,Schmitt JP,Patlak JB.Hypertrophic and dilated cardiomyopathy mutations differentially affect the molecular force generation of mouse alpha-cardiac myosin in the laser trap assay.Am J Physiol Heart Circ Physiol 2007;293:284-91.
[9]Szczesna-CordaryD, JoneM, Moore JR.Myosin regulatory light chain E22K mutation results in decreased cardiac intra-cellular calcium and force transients. FASEB J 2007;21:3974-85.
[10]Baudenbacher F,Schober T,Pinto JR.Myofilament Ca2+ sensitization causes susceptibility to cardiac arrhythmia in mice. J Clin Invest 2008;118:3893-903.
[11]Geisterfer-Lowrance AAT, Kass S, Tanigawa G, Vosberg HP, McKenna W, Seidman CE, Seidman JG, A molecular basis for familial hypertrophic cardiomyopathy:a β cardiac myosin heavy chain gene missense mutation. Cell 1990; 62:999-1006.
[12]Richard P, Charron P, Carrier L, Ledeuil C, Cheav T, Picherau C, et al. Hypertrophic cardiomyopathy:distribution of disease genes, spectrum of mutations, and implications for a molecular diagnosis strategy. Circulation 2003; 107:2227-2232.
[13]Soor GS, Luk A, Ahn E, Abraham JR, Woo A, Ralph-Edwards A, et al. Hypertrophic cardiomyopathy:current understanding and treatment objectives. J Clin Pathol 2009;62:226-235.
[14]Maron BJ. Hypertrophic cardiomyopathy:a systematic review. JAMA 2002;287:1308-1320.
[15]Poliac LC, Barron ME, Maron BJ. Hypertrophic cardiomyopathy. Anesthesiology 2006;104:183-192.
[16]Marian AJ. Contemporary treatment of hypertrophic cardiomyopathy. Tex Heart Inst J 2009; 36:194-204.
[17]Marian AJ. Hypertrophic cardiomyopathy:from genetics go treatment. Eur J Clin Invest 2010;40:360-369.
[1]齐建光,杜军保.线粒体心肌病临床诊断和基因研究进展.中国实用儿科杂志,2005：20：374-276.
[19]Marian AJ, Roberts R. The molecular genetic basis for hypertrophic cardiomyopathy. JMol Cell Cardiol 2001;33:655-670.
[20]Marian AJ. Genetic determinants of cardiac hypertrophy. Curr Opin Cardiol 2008; 23:199-205.
[21]李文,马沛然,汪翼,韩秀珍,丘厚兴.线粒体DNA点突变与心肌病关系的研究.山东医药,1998；38：3-4.
[22]Morita H, Rehm HL, Menesses A, McDonough B, Roberts AE, Kucherlapati R et al. Shared genetic causes of cardiac hypertrophy in children and adults. N Engl J Med 2008; 358:1899-1908.
[23]Seidman CE, Seidman JG. Molecular genetic studies of famililial hypertrophic cardiomyopathy. Basic Res Cardiol 1998; 93:13-16.
[24]Tanjore R, RangaRaju A, Vadapalli S, Remersu S, Narsimhan C, Nallari P. Genetic variations of β-MYH7 in hypertrophic cardiomyopathy and dilated cardiomyopathy. Indian J Hum Genet 2010; 16:67-71.
[25]Purushotham G, Madhumohan K, Anwaruddin M, Nagarajaram H, Hariram V, Narasimhan C, et al. The MYH7 p.R787H mutation causes hypertrophic cardiomyopathy in two unrelated families. Exp Clin Cardiol 2010;14:el-e4.
[26]王虎,邹玉宝,宋雷,王继征,孙凯,宋晓东,高硕,张禅那,惠汝太.心脏肌球蛋白重链基因c.1273 G>A突变与肥厚型心肌病的关联分析.遗传,2009,31：485-488.
[27]Maron BN, Nichols PF, Pickle LW, et al. Patterns of inheritance in hypertrophic cardiomyopathy:assessment by M-mode and two-dimensional echocardiography. Am J Cardiol 1984;53:1087-1094.
[28]Oakley CE, Chamoun J, Brown LJ, et al. Myosin binding protein C:Enigmatic regulator of cardiac contraction. Int J Biochem Cell Biol 2007;39:2161-2166.
[29]27 Thierfelder L, Watkins H, MacRae C, Lamas R, McKenna W, Vosberg HP et al. a-tropomyoisn and cardiac troponin T mutations cause familial hypertrophic cardiomyopathy:a disease of the sarcomere. Cell 1994;77:701-712.
[30]28Mogensen J, Klausen IC, Pedersen AK, Egeblad H, Bross P, Kruse TA, et al. a-cardiac actin is a novel disease gene in familial hypertrophic cardiomyopathy. J Clin Invest 1999; 103:R39-R43.
[31]29 Satoh M, Takahashi M, Sakamoto T, Hiroe M, Marumo F, Kimura A. Stuctural analysis of the titin gene in hypertrophic cardiomyopathy:identification of a novel disease gene. Biochem Biophys Res Commun 1999; 262:411-417.
[32]30 Geier C, Perrot A, Ozcelik C, Binner P, Counsell D, Hoffmann K, et al. Mutations in the human muscle LIM protein gene in families with hypertrophic cardiomyopathy. Circulation 2003; 107; 1390-1395.
[33]31Hsyshi T, Arimura T, Itoh-Satoh M, Ueda K, Hohda S, Inagaki N, et al. Tcap gene mutations in hypertrophic cardiomyopathy and dilated cardiomyopathy. J Am Coll Cardiol 2004; 44:2192-2201.
[34]32 Osio A, Tan LL, Chen SN, Lombardi R, Nagueh SF, Shete S, et al. Myozenin 2 is a novel gene for human hypertrophic cardiomyopathy. Circ Res 2007; 100:766-768.
[35]33Vasile VC, Ommen SR, Edwards WD, Ackeman MJ. Amissense mutation in a ubiquitously expressed protein, vinculin, confers susceptibility to hypertrophic cardiomyopathy. Biochem Biophys Res Commun 2006; 345:998-1003.
[36]Winegrad S. Cardiac myosin binding protein C. Circ Res 1999; 84:1117-1126.
[37]Vikstrom KL, Leinwand LA. Contractile protein mutations and heart disease. Curr Opin Cell Biol 1996; 8:97-105.
[38]Oliva-Sandoval MJ, Ruiz-Espejo F, Monserrat L, Hermida-Prieto M, et al. Insights into genotype-phenotype correlation in hypertrophic cardiomyopathy. Findings from 18 Spanish families with a single mutation in MYBPC3. Heart 2010;96:1980-1984.
[39]Ehlermann P, Weichenhan D, Zehelein J, Steen H, Pribe R, Zeller R, et al. Adverse events in families with hypertrophic or dilated cardiomyopathy and mutations in the MYBPC3 gene. BMC Med Genet 2008; 9:95.
[40]Bos JM,Towbin JA,Ackerman MJ. Diagnostic,prognostic,and therapcutic implications of genetic testing for hypertrophic cardiomyopathy.J Am.C oll.Cardiol 2009;54:201--211.
[41]Niimura H,Patton KK,Mckenna WJ.Sarcomere protein gene mutations in hypertrophic cardiomyopathy of the elderly.Circulation 2002; 105:446-51.
[42]Libin Wang,Jonathan G,Seidman PhD. Narrative Review:Harnessing Molecular Genetics for the Diagnosis and Management of Hypertrophic cardiomyopathy. Phsiology in Medicine 2010; 152:513-520.
[43]Chirstiaans I, Lekanne dit Deprez RH, Van Langen IM. Ventricular fibrillation in MYH7-related hypertrophic cardiomyopathy before onset of ventricular hypertrophy. Heart Rhythm 2009;6:1366-1369.
[44]Olivotto I,Girolami F, Ackerman MJ. Myofilament protein gene mutation screening and outcome of patients with hypertrophic cardiomyopathy. Mayo Clin. Proc 2008;83:530-638.
[45]Girolami F, Ho CY, Semsarian C, et al. Clinical features and outcome of hypertrophic cardiomyopathy associated with triple sarcomere protein gene mutations. J Am Coll Cardiol 2010;55:1444-53.
[46]Shackleton S, Lloyd DJ, Jackson SN. LMNA, encoding lamin A/C, is mutated in partial lipodystrophy. Nat. Genet 2000;24(2):153-156.
[47]Maron BJ, Roberts WC, Arad M. Clinical outcome and phenotypic expression in LAMP2 cardiomyopathy. JAMA 2009;301:1253-9.
[48]Hershberger RE, Lindenfeld J, Mestroni L.Genetic evaluation of cardiomyopathy a Heart Failure Society of America practice guideline. J. Card. Fail 2009; 15(2): 83-97.
[49]Arad M, Penas-Lado M, Monserrat L. Gene mutations in apical hypertrophic cardiomyopathy. Circulation 2005;112:2805-11.
[50]Zeidan Z, Buck T, Barkhausen J, et al. Real-time three-dimensional echocardiography for improved evalation of diastolic function using volume-time curves. Herz 2002;27(3):237.
[51]Navin CN, Joseph K, Robe Eol, et al. Examination protocol for three-dimensional echocardiography. Echocardiogr 2004;21(8):763-766.
[52]Jenkins C, Bricknell K, Hanekom L, et al. Reproducibility and accuracy of echocardiographic measurements of left ventricular parameters using real-time three-dimensional echocardiography. J Am Coll Cardiol 2004;44:878-86.
[53]Kuhl HP, Schreckenberg M, Rulands D, et al. High-resolusion transthoracic real-time three-dimensional echocardiography quantitation of cardiac volumes and function using semi-automatic border detection and comparison with cardiac magnetic resonance imaging. J Am Coll Cardiol 2004;43:2083-90.
[54]Mor-Avi V, Jenkins C, Kuhl HP, et al. Real-time 3-dimensional echocardiographic quantification of left ventricular volumes:multicenter study for validation with magnetic resonance imaging and investigation of sources of error. J Am Coll Cardiol Img 2008; 1:413-23.
[55]Chen G, Sun K, Huang G, et al. In vitro validation of right ventricular volume and mass messurement by real-time three-dimensional echocardiography. Echocardiogr 2006;23:395-399.
[56]Anwarf AM, Soliman 01, Nemes A, et al. Value of assessment of tricuspid annulus:real-time three-dimensional echocardiography and magnetic resonance imaging.Int J Cardiovasc Imaging 2007;23:701-705.
[57]Lang RM, Bierig M, Devereux RB, et al. Recommendations for chamber quantification. Eur J Echocardiogr 2006;7:79-108.
[58]Gordon EP, Schnittger I, Fitzgerald PJ, et al. Reproducibility of left ventricular volumes by two-dimensional echocardiography. J Am Coll Cardiol 1983;2:506-13.
[59]Shinta T, McCaahy PM, White RD, et al. Initial clinical experience of real-time three-dimensional echocardiography in patients with ischemic and idiopathic dilated cardiomyopathy. Am J Cardiol 1999;84:1068-1073.
[60]Qin JX, Jones M,Shiota T, et al. Validation of real -time three- dimensional echocardiography for quantifying left ventricular volumes in the presence of a left ventricular aneurysm:in vitro and in vivo studies. J Am Coll Cardiol 2000;36:900-907.
[61]邓斌华,谢明星.实时三维超声心动图在心脏定量中的研究进展.心血管病学进展2008;2 9：96-99.
[62]Devereux RB, Wachtell K, Gerdts E, et al. Prognostic significance of left ventricular mass change during treatment of hypertension. JAMA 2004;292:1-7.
[63]Gottdiener JS, Bednarz J, Devereux R, et al. American Society of Echocardio-graphy recommendations for use of echocardiography in clinical trials. J Am Soc Echocardiogr 2004; 17:1086-1119.
[64]Krenning BJ, Kirschbaum SW, Soliman 01, et al. Comparison of contrast agent-enhanced versus non-contrast agent-enhanced real-time three-dimensional echocardiography for analysis of left ventricular systolic function. Am J Cardiol 2007;100:1485-9.
[65]Saul GM, Hugh EM, Michael JW, et al. Left ventricular mass reliability of M mode and 2 dimensional echocardiographic formulas. Hypertension 2002; 40:673-678.
[66]Gottdiener JS, Livengood SV, Meyer PS, et al. Should echocardiography be performed to assess effect of antihypertensive theraphy? Test-retest reliability of echocardiography for measurement of left ventricular mass and function. JACC 1955;25:424-430.
[67]Teupe C, Takeuchi M, Yao JF, et al. Determination of left ventricular mass by three dimensional echocardiography:in vitro validation of a novel quantification method using multiple equi angular rotational planes for rapid measurements. Int Cardiovasc Imaging 2002; 18:161-167.
[68]Annemien E van den B, Danielle RV, Boudewijn JK, et al. Comparison of real-time three dimensional echocardiography to magnetic resonance imaging for assessment of left ventricular mass. A m J Cardiol 2006;97:113-117.
[69]Moravi V, Sugeng L, Weinert L, et al. Fast measurement of left ventricular mass with real time three dimensional echocardiography. Circulation 2004; 110:1814-1818.
[70]Jenkins C, Bricknell K, Chan J, et al. Comparison of two and three dimensional echocardiography with sequential magnetic resonance imaging for evaluating left ventriculalr volume and ejection fraction over time in patients with healed myocardial infarction. Am J Cardiol 2007;99:300-306.
[71]Hiroki Oe, Takeshi Hozume, Kotaro Arai, et al. Comparison of accurate measurement of left ventricular mass in patients with hypertrophied hearts by real time three dimensional echocardiography versus magnetic resonance imaging. Am J Cardiol 2005;95:1263-1267.
[72]Gutierrez Chico JL, Zamorano JL, LP de Isla, et al. Comparison of left ventricular volumes and ejection fractions measured by three dimensoional echocardiography versus by two dimensional echocardiography and cardiac magnetic resonance in patients with various cardiomyopathies. Am J Cardiol 2005;95:809-813.
[73]Kotaro A, Takeshi H, Yoshiki M, et al. Accuracy of measurement of left ventricular volume and ejection fraction by new real tiem three dimensional echocardiography in patients with wall motion abnormalities secondary to myocardial infarction. Am J Cardiol 2004;94:552-558.
[74]Zeidan Z, Erbel R, Barkhausen J, et al. Analysis of global systolic and diastolic left ventricular performance using volume time curves by real time three dimensional echocardiography. J Am Soc Echocardiogr 2003; 16:29-37.
[75]Annemien E van den B, Danielle RV, Boudewijn JK, et al. Real time transthoracic three dimensional echocardiographic assessment of left ventricular volume and ejection fraction in congenital heart disease. J Am Soc Echocardiogr 2006; 19:1-6.
[76]Pepi M, Tamborini G, Maltagliati A, et al. Head-to-head comparison of two- and three-dimensional transthoracic and transesophageal echocardiography in the localization of mitral valve prolapse. J Am Coll Cardiol 2006; 48:2524-30.
[77]Chung ES, Leon AR, Tavazzi L, et al. Results of the Predictors of Response to CRT(PROSPECT) Trial. Circulation 2008; 117:2608-16.
[78]Kapetanakis S, Kearney MT, Siva A, et al. Real-time three-dimensional echocardiography:a novel technique to quantify global left ventricular mechanical dyssynchrony. Circulation 2005; 112:992-1000.
[79]Marsan NA, Bleeker GB, Ypenburg C, et al. Real-time three-dimensional echocardiography as a novel approach to assess left ventricular and left atrium reverse remodeling and to predict response to cardiac resynchronization therapy. Heart Rhythm 2008; 5:1257-64.
[80]吴雪英,吴莹,孙雅萍,等.实时三维超声心动图在心脏再同步化治疗中的应用.中华超声影像学杂志2007,16：952-954.
[81]Rossi A, Cicoira M, Zanolla L, et al. Determinants and prognostic value of left atrial volume in patients with dilated cardiomyopathy. J Am Coll Cardiol 2002; 40:1425.
[82]Abhayaratna WP, Seward JB, Appleton CP, et al. Left atrial size:physiologic determinants and clinical applications. J Am Coll Cardiol 2006;47:2357-2363.
[1]Maron BJ, Pelliccia A. The heart of trained athletes:cardiac remodeling and the risks of sports, including sudden death. Circulation 2006; 114:1633-1644.
[2]Ho CY, Sweitzer NK, McDonough B, et al. Assessment of diastolic function with Doppler tissue imaging to predict genotype in preclinical hypertrophic cardiomyopathy. Circulation 2002;105:2992-2997.
[3]De Marchi SF, Allemann Y, Seiler C. Relaxation in hypertrophic cardiomyopathy and hypertensive heart disease:relations between hypertrophy and diastolic function. Heart 2000;83:678-684.
[4]Marsan NA, Tops LF, Nihoyannopoulos P, Holman ER, Bax JJ. Real-time three dimensional echocardiography:current and future clinical applications. Heart 2009; 95:1881-1890.
[5]Kato TS, Izawa H, Komamura K, et al. Heterogeneity of regional systolic function detected by tissue Doppler imaging is linked to impaired global left ventricular relaxation in hypertrophic cardiomyopathy. Heart 2008; 94:1302-1306.
[6]Wigle ED, Sasson Z, Henderson MA, et al. Hypertrophic cardiomyopathy:the importance of the site and the extent of hypertrophy. Prog Cardiovasc Dis 1985; 28: 1-83.
[7]Klues HG, Schiffers A, Maron BJ. Phenotypic spectrum and patterns of left ventricular hypertrophy in hypertrophic cardiomyopathy:morphologic observations and significance as assessed by two-dimensional echocardiography in 600 patients. J Am Coll Cardiol 1995;26:1699-1708.
[8]Nagueh SF, Appleton CP, Gillebert TC, et al. Recommendations for the evaluation of left ventricular diastolic function by echocardiography. J Am Soc Echocardiogr 2009;22:107-133.
[9]Daneshvar D, Wei J, Tolstrup K, et al. Diastolic dysfunction:improved understanding using emerging imaging techniques. Am Heart J 2010; 160:394-404.
[10]Schiller NB, Shah PM, Crawford M, DeMaria A, Devereux R, Feigenbaum H, et al. Recommendations for quantitation of the left ventricle by two-dimensional echocardiography. American Society of Echocardiography Committee on Standards, Subcommittee on Quantitation of Two-Dimensional Echocardiograms. J Am Soc Echocardiogr 1989;2:358-2367.
[11]Quinones MA, Otto CM, Stoddard M, et al. Recommendations for quantification of Doppler echocardiography:a report from the Doppler Quantification Task Force of the Nomenclature and Standards Committee of the American Society of Echocardio-graphy. JAm Soc Echocardiogr 2002;15:167-184.
[12]Zoghbi WA, Enriquez-Sarano M, Foster E,et al. Recommendations for evaluation of the severity of native valvular regurgitation with two-dimensional and Doppler echocardiography. J Am Soc Echocardiogr 2003; 16:777-802.
[13]Cerqueira MD, Weissman NJ, Dilsizian V, et al. Standardized myocardial segmentation and nomenclature for tomographic imaging of the heart:a statement for healthcare professionals from the Cardiac Imaging Committee of the Council on Clinical Cardiology of the American Heart Association. Circulation 2002; 105: 539-542.
[14]Spirito P, Bellone P, Harris KM, et al. Magnitude of left ventricular hypertrophy and risk of sudden death in hypertrophic cardiomyopathy. N Engl J Med 2000;342:1778-1785.
[15]van den Bosch AE, Robbers-Visser D, Krenning BJ, et al. Real-time transthor-acic three-dimensional echocardiographic assessment of left ventricular volume and ejection fraction in congenital heart disease. J Am Soc Echocardiogr 2006; 19:1-6.
[16]Del Pasqua A, Sanders SP, de Zorzi A, et al. Impact of three-dimensional echocardiography in complex congenital heart defect cases:the surgical view. Pediatr Cardiol 2009;30:293-300.
[17]Mor-Avi V, Jenkins C, Kuhl HP, et al. Real-time 3-dimensional echocardio-graphic quantification of left ventricular volumes:multicenter study for validation with magnetic resonance imaging and investigation of sources of error. J Am Coll Cardiol Img 2008; 1:413-423.
[18]Bicudo LS, Tsutsui JM, Shiozaki A, et al. Value of real time three-dimensional echocardiography in patients with hypertrophic cardiomyopathy:comparison with two-dimensional echocardiography and magnetic resonance imaging. Echocardiogr 2008;25:717-726.
[19]De Keulenaer GW, Brutsaert DL. Systolic and diastolic heart failure:different phenotypes of the same disease? Eur J Heart Fail 2007;9:136-143.
[20]Carasso S, Yang H, Woo A, et al. Diastolic myocardial mechanics in hypertrophic cardiomyopathy. J Am Soc Echocardiogr 2010;23:164-171.
[21]Afonso LC, Bernal J, Bax JJ, et al. Echocardiography in hypertrophic cardiomyopathy:the role of conventional and emerging technologies. JACC: Cardiova Imag 2008; 1:787-800.
[22]Williams LK, Frenneaux MP, Steeds RP. Echocardiography in hypertrophic cardiomyopathy diagnosis, prognosis, and role in management. Eur J Echocardiogr 2009;10:ⅲ9-14.
[23]Motoyasu M, Kurita T, Onishi K, et al.Correlation between late gadolinium enhancement and diastolic function in hypertrophic cardiomyopathy assessed by magnetic resonance imaging. Circ J2008;72:378-83.
[24]Wang J, Buergler JM, Veerasamy K, et al. Delayed untwisting:the mechanistic link between dynamic obstruction and exercise tolerance in patients with hypertrophic obstructive cardiomyopathy. JAm Coll Cardiol 2009;54:1326-34.
[25]Dong SJ, MacGregor JH, Crawley AP, et al. Left ventricular wall thickness and regional systolic function in patients with hypertrophic cardiomyopathy. A three-dim-ensional tagged magnetic resonance imaging study. Circulation 1994;90:1200-1209.
[26]Betocchi S, Hess OM, Losi MA, Nonogi H, Krayenbuehl HP. Regional left ventricular mechanics in hypertrophic cardiomyopathy. Circulation 1993;88:2206-2214.
[27]Oki T, Mishiro Y, Yamada H, et al. Detection of left ventricular regional relaxa-tion abnormalities and asynchrony in patients with hypertrophic cardiomyopathy with the use of tissue Doppler imaging. Am Heart J 2000; 139:497-502.
[28]ten Berg J, Steggerda RC, Siebelink HM. Myocardial disease:The patient with hypertrophic cardiomyopathy. Heart 2010;96:1764-1772.
[1]Nishimura RA, Holmes DR. Clinical Preactice. Hypertrophic obstructive cardiomyopathy. N Engl J Med 2004; 350:1320-1327.
[2]Zou Y, Song L, Wang Z. Prevalence of idiopathic hypertrophic cardiomyopathy in China:a population-based echocardiographic analysis of 8080 adults. Am J Med 2004; 116:14-18.
[3]Wang L, Seidman JG, Seidman CE. Narrative review:harnessing molecular genetics for the diagnosis and management of hypertrophic cardiomyopathy. Ann Intern Med 2010; 152:513-520.
[4]Garca-castro M, Coto E, Reguero JR. Mutations in sarcomeric genes MYH7, MYBPC3, TNNT2, TNNI3, and TPM1 in patients with hypertrophic cardiomyopathy. Rev Esp Cardiol 2009; 62:48-56.
[5]Flavigny J, Robert P, Camelin JC, Schwartz K, Carrier L, Berrebi-Bertrand I. Biomolecular interactions between human recombinant h-MyHC and cMyBPC3 implicated in familial hypertrophic cardiomyopathy. Cardiovasc Res 2003; 60:388-396.
[6]Maron BJ, Niimura H, Casey SA et al. Development of left ventricular hypertrophy in adults with hypertrophic cardiomyopathy caused by cardiac myosin binding protein C gene mutations. J Am Coll Cardiol 2001; 38:315-321.
[7]Cerqueira MD, Weissman NJ, Dilsizian V et al. Standardized myocardial segmentation and nomenclature for tomographic imaging of the heart:a statement for healthcare professionals from the Cardiac Imaging Committee of the council on clinical cardiology of the American Heart Association. Circulation 2002; 105:539-542.
[8]Elliott P, McKenna WJ. Hypertrophic cardiomyopathy. Lancet 2004; 363:1881-1891.
[9]Van Driest SL, Ommen SR, Tajik AJ, Gersh BJ, Ackerman MJ. Sarcomeric genotyping in hypertrophic cardiomyopathy. Mayo Clin Proc 2005; 80:463-468.
[10]Van Driest SL, Vasile VC, Ommen SR et al. Myosin binding protein C mutations and compound heterozygosity in hypertrophic cardiomyopathy. J Am Coll Cardiol 2004;44:1903-1910.
[11]Barefield D, Sadayappan S. Phosphorylation and function of cardiac myosin binding protein-C in health and disease. J Mol Cell Cardiol 2010; 48:866-875.
[12]Oakley CE, Chamoun J, Brown LJ, Hambly BD. Myosin binding protein-C: Enigmatic regulator of cardiac contraction. Int J Biochem Cell B 2007; 39:2161-2166.
[13]Geisterfer-Lowrance AA, Christe M, Conner DA et al. A mouse model of familial hypertrophic cardiomyopathy. Science 1996; 272:731-734.
[14]Michele DE, Gomez CA, Hong KE et al. Cardiac dysfunction in hypertrophic cardiomyopathy mutant tropomyosin mice is trans-gene-dependent,hypertrophy-independent, and improved by beta-blockade. Circ Res 2002; 91:255-262.
[15]Nagueh SF, Bachinski LL, Meyer D et al. Tissue Doppler imaging consistently detects myocardial abnormalities in patients with hypertrophic cardiomyopathy and provides a novel means for an early diagnosis before and independently of hypertrophy. Circulation 2001; 104:128-130.
[16]Miches M, Soliman OI, Kofflard MJ, Hoedemaekers YM, Dooijes D, Majoor-Krakauer D, ten Cate FJ. Diastolic abnormalities as the first feature of hypertrophic cardiomyopathy in Dutch myosin-binding protein C founder mutations. JACC Cardiovasc Imaging 2009; 2:58-64.
[17]Marsan NA, Tops LF, Nihoyannopoulos P, Holman ER, Bax JJ. Real-time three dimensional echocardiography:current and future clinical applications. Heart 2009; 95:1881-1890.
[18]Afonso LC, Bernal J, Bax JJ et al. Echocardiography in hypertrophic cardiomyopathy. JACC:Cardiovasc Imag 2008; 1:787-800.
[19]Spirito P, Maron BJ. Relation between extent of left ventricular hypertrophy and diastolic filling abnormalities in hypertrophic cardiomyopathy. J Am Coll Cardiol 1990; 15:808-813.
[20]McKenna WJ, Stewart JT, Nihoyannopoulos P, McGinty F, Davies MJ. Hypertrophic cardiomyopathy without hypertrophy:two families with myocardial disarray in the absence of increased myocardial mass. Br Heart J 1990; 63:287-290.
[21]Van Driest SL, Jaeger MA, Ommen SR et al. Comprehensive analysis of the beta-myosin heavy chain gene in 389 unrelated patients with hypertrophic cardio-myopathy. J Am Coll Cardiol 2004; 44:602-610.
[22]Richard P, Charron P, Carrier L et al. Hypertrophic cardiomyopathy:distribution of disease genes, spectrum of mutations, and implications for a molecular diagnosis strategy. Circulation 2003; 107:227-232.
[23]Pohlmann L, Kroger I, Vignier N et al. Cardiac myosin-binding protein C is required for complete relaxation in intact myocytes. Circ Res 2007; 101:928-938.
[1]Alcalai R,Seidman JG, Seidman CE. Genetic basis of hypertrophic cardio-myopathy.from bench to the clinics. J Cardiovase Electro-physiol 2008;19:104-110.
[2]Keren A,syrris P,Mckenna WJ.Hypertrophic cardiomyopathy:the genetic determi-nants of clinical disease expression. Nat.clin.pract.cardiovasc.med 2008;53:158-168.
[3]Debold EP,Schmitt JP,Patlak JB.Hypertrophic and dilated cardiomyopathy muta-tions differentially affect the molecular force generation of mouse alpha-cardiac myosin in the laser trap assay.Am J Physiol Heart Circ Physiol 2007;293:284-291.
[4]Szczesna-CordaryD, JoneM, Moore JR.Myosin regulatory light chain E22K muta-tion results in decreased cardiac intra-cellular calcium and force transients. FASEB J 2007;21:3974-3985.
[5]Baudenbacher F,Schober T,Pinto JR.Myofilament Ca2+ sensitization causes susceptibility to cardiac arrhythmia in mice.J Clin Invest 2008; 118:3893-903.
[6]Bos JM,Towbin JA,Ackerman MJ. Diagnostic,prognostic,and therapcutic implica-tions of genetic testing for hypertrophic cardiomyopathy. J Am.C oll.Cardiol 2009; 54:201-211.
[7]Niimura H,Patton KK,Mckenna WJ.Sarcomere protein gene mutations in hyper-trophic cardiomyopathy of the elderly.Circulation 2002; 105:446-451.
[8]Libin Wang,Jonathan G,Seidman PhD. Narrative Review:Harnessing Molecular Genetics for the Diagnosis and Management of Hypertrophic cardiomyopathy. Phsiology in Medicine 2010; 152:513-520.
[9]Chirstiaans I, Lekanne dit Deprez RH, Van Langen IM. Ventricular fibrillation in MYH7-related hypertrophic cardiomyopathy before onset of ventricular hypertrop hy. Heart Rhythm.2009;6:1366-1369.
[10]Olivotto I,Girolami F, Ackerman MJ. Myofilament protein gene mutation screening and outcome of patients with hypertrophic cardiomyopathy. Mayo Clin. Proc.2008;83:530-638.
[11]Girolami F, Ho CY, Semsarian C, et al. Clinical features and outcome of hypertrophic cardiomyopathy associated with triple sarcomere protein gene mutations. JAm Coll Cardiol 2010; 55:1444-1453.
[12]Shackleton S, Lloyd DJ, Jackson SN. LMNA, encoding lamin A/C, is mutated in partial lipodystrophy. Nat. Genet 2000;24(2):153-156.
[13]Maron BJ, Roberts WC, Arad M.Clinical outcome and phenotypic expression in LAMP2 cardiomyopathy. JAMA 2009;301:1253-9.
[14]Hershberger RE, Lindenfeld J, Mestroni L.Genetic evaluation of cardiomyopathy a Heart Failure Society of America practice guideline. J. Card. Fail 2009;15(2): 83-97.
[15]Arad M, Penas-Lado M, Monserrat L. Gene mutations in apical hypertrophic cardiomyopathy. Circulation.2005;112:2805-2811.
[16]Maron BJ. Hypertrophic cardiomyopathy:a systematic review. JAMA 2002;287: 1308-1320.
[17]Olivotto I, Girolami F, Ackerman MJ. Myofilament protein gene mutation screening and outcome of patients with hypertrophic cardiomyopathy. Mayo Clin Proc 2008; 83:630-638.
[18]Lombardi R, Rodriguez G, Chen SN. Resolution of established cardiac hypertrophy and fibrosis and prevention of systolic dysfunction in a transgenic rabbit model of human cardiomyopathy through thiol-sensitive mechanisms. Circulation 2009;119:1398-1407.
[19]Spirito P, Autore C. Management of hypertrophic cardiomyopathy. BMJ 2006; 332:1251-1255.
[20]Penicka M, Gregor P, Kerekes R. Candesartan use in Hypertrophic And Non-obstructive Cardiomyopathy Estate(CHANCE) Study Investigators. The effects of candesartan on left ventricular hypertrophy and function in nonobstructive hypertrophic cardiomyopathy:apilot, randomized study. JMol Diagn 2009;11:35-41.
[21]Ho CY, Sweitzer NK, McDonough B. Assessment of diastolic function with Doppler tissue imaging to predict genotype in preclinical hypertrophic cardio-myopathy. Circulation 2002;105:2992-2997.