左室舒张功能减退的实验研究及在胸外科围术期的临床应用
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摘要
一大鼠压力负荷诱导的左室舒张功能减退模型的建立及机制探讨
[目的]研究并确立左室舒张功能减退大鼠模型的建立方法,初步探讨其发生机制。
[方法]成年8周龄Wistar大鼠80只,随机均分为对照组和实验组。实验组40只,经腹腔注射10%水合氯醛(3ml/100mg)麻醉后,左上腹手术切口,进入腹腔,暴露并游离腹主动脉,确定左肾动脉分支,在其上方,将腹主动脉同8号针头(直径0.8mm)一同用丝线扎紧,然后抽出针头,环缩腹主动脉管腔。对照组40只,麻醉后施行开腹及游离腹主动脉,不做环缩。术后观察两组动物的饮食、活动能力、对外界反应能力等情况；记录出现活动能力明显下降、咳嗽和呼吸困难的时间。分别在饲养2周,4周,6周和8周时,随机抽取相同数量的对照组和实验组动物,进行血流动力学检测。由右颈总动脉插管,经聚乙烯塑料导管连接BL-410生物机能实验系统(成都泰盟科技有限公司)检测平均动脉压(MAP)、左心室收缩压(LVSP)、左心室舒张末压(LVEDP)、左心室压上升最大速率(+dp/dtmax)、左心室压下降最大速率(-dp/dtmax)。对比分析各时间点对照组和试验组数据,评价其差异。检测完毕后处死大鼠,取左心室组织,称重并计算左室重量指数(LVMI),对比分析各时间点实验组和对照组的差异。取部分左室心肌组织-80℃冰箱储存,在观察终点,统一采用RT-PCR方法,检测心室肌肌浆网膜钙离子泵(sarcoplasmic reticulum Ca2+—ATPase, SERCA2a)和受磷蛋白(PLB)的mRNA表达水平,对比分析各时间点对照组和试验组表达水平的差异性。剩余心肌组织福尔马林固定,在观察终点统一包埋、切片,HE染色观察心肌形态学变化,计数左室乳头肌水平横断面每高倍视野心肌细胞个数,对比分析各时间点实验组和对照组的差异。综合血流动力学和心肌形态学结果,作为成功模型的评价标准。所有数据均由SPSS13.0统计软件包处理。计量资料以均数±标准差表示,采用t检验；统计结果以P<0.05为有统计学差异,P<0.01为有显著统计差异。
[结果](1)实验组和对照组一般情况：术后第1周各组动物出现精神萎靡、活动减少、摄食及饮水量减少情况,一周后上述情况好转。2周时和4周时,活动进食情况,实验组与对照组无明显差异。6周时,实验组开始有动物出现活动量减少,饮食减少,体重比对照组轻(298.11±50.85vs334.29±46.09)g(P<0.05)。6周后,实验组逐渐出现咳嗽,呼吸加快症状(78.36±14.54vs46.77±11.49)g(P<0.05),活动量明显下降。在观察终点8周末,实验组对外界反映迟钝,不思进食,体重低于对照组(289.58±45.23vs349.56±38.24)g(P<0.05),有部分动物出现死亡(20%)。术后实验组大鼠死亡4只,成活率90%,2只在术后1天内死亡,2只在术后6周以后出现呼吸困难后死亡。对照组无死亡。
(2)左室压力负荷增高在各实验组稳定存在,各时间点实验组的平均动脉压(MAP)和左室收缩压(LVSP)高于对照组：MAP,2周(127.56±20.39vs90.33±15.23)mmHg(P<0.01)4周(128.415±14.03vs92.23±11.68)mmHg(P<0.01),6周(130.25±16.36vs93.85±12.34)mmHg(P<0.01)8周(115.37±13.35vs96.68±16.54)mmHg(P<0.05)；LVSP,2周(149.39±18.34vs109.76±14.40)mmHg(P<0.05)4周(156.73±15.03vs108.34±17.57)mmHg(P (3)舒张功能指标出现进行性改变：2周时,实验组较对照组,-dp/dtmax下降(4.32±0.27vs5.13±0.21)(P<0.05),其他无差异；4周时,实验组较对照组,-dp/dtmax明显下降(3.64±0.30vs5.33±0.28)(P<0.01),LVEDP明显升高(15.45±2.56vs5.90±2.46)mmHg(P<0.01),其他无差异；6周时,实验组较对照组,-dp/dtmax明显下降(3.42±0.32vs5.29±0.34)(P<0.01),LVEDP明显升高(19.89±3.28vs5.67±2.58)mmHg(P<0.01),;8周时,实验组较对照组,-dp/dtmax明显下降(2.04±0.31vs5.41±0.39)(P<0.01),LVEDP明显升高(24.34±4.08vs5.67±2.58)mmHg(P<0.01).
(4)收缩功能指标在6周时出现下降,8周时出现明显下降：6周时,实验组较对照组+dp/dtmax降低(5.98±0.31vs6.34±0.38)(P<0.05)；8周时+dp/dtmax明显降低(4.50±0.21vs6.21±0。31)(P<0.01)；
(5)左室重量指数(LVMI)情况：与对照组相比,实验组2周时无差异,4周时升高(2.69±0.18vs2.33±0.20),6周时升高(2.65±0.21vs2.42±0.16)(P<0.05),8周时明显升高(2.96±0.18vs2.39±0.19)(P<0.01)。
(5)病理学检查显示心肌进行性损害：各对照组及2周实验组,心肌细胞完整,排列整齐；4周实验组,心肌细胞肥大,间隙略增宽,偶见点状坏死,间质轻度水肿；6周实验组,心肌细胞明显肥大,细胞核大而深染、横断面积增大,散在点状心肌细胞坏死,高倍视野心肌细胞计数少于对照组(19.78±3.36vs25.34±5.04)个/Hp(P<0.05)；8周实验组,可见心肌细胞明显增大,排列紊乱,间隙增宽,片状心肌细胞坏死,高倍视野心肌细胞计数少于对照组(18.16±3.24vs28.35±3.25)个/Hp(P<0.05),并可见大量炎症细胞浸润。
(6)PLB的mRNA表达量对照组和实验组无统计学差异,SERCA2a的mRNA表达量在4至8周组表达量降低：4周时,实验组低于对照组(CT值28.15±0.84vs26.14±0.51)(P<0.05)；6周时,实验组低于对照组(CT值29.02±1.27vs26.50±0.89)(P<0.05)；8周时,实验组明显低于对照组(CT值32.09±1.38vs27.25±1.24)(P<0.01)。
[结论]8周龄Wistar大鼠肾上腹主动脉缩窄后8周观察期内,左室舒张功能随时间出现进行性减退。其中,2周时表现为左室主动松弛性受损,4周时表现为充盈压升高,6周时表现为限制性充盈障碍,8周时出现心力衰竭表现。影响心肌钙循环的主要因素——SERCA2a表达受抑制可能主要在左室舒张功能减退中后期起作用。
二超声及心衰标志物和血流动力学在评价左室舒张功能进行性减退模型时的相关性
[目的]探讨超声检查评价大鼠左室舒张功能进行性减退的可行性；探讨血清NT-proBNP水平与舒张功能进行性减退的相关性；确立评价左室舒张功能进行性减退模型的非血流动学方法。
[方法]采用肾上腹主动脉方法建立左室舒张功能减退的大鼠模型30只,并设立对照组30只。分别在术后2周、4周及6周时,随机抽取相同数量的对照组和实验组大鼠,应用飞利浦心悦iE33彩色多普勒超声仪,选取S12-4高频探头对其行心脏超声检查。舒张功能指标包括：血流频谱多普勒记录二尖瓣舒张早期血流峰值速度(E)、舒张早期峰值运动速度(Em)、舒张晚期峰值运动速度(Am)；计算Em/Am和E/Em。收缩功能指标包括：左室射血分数(LVEF)、左室短轴缩短率(FS)、二尖瓣瓣环处心肌组织的收缩期峰值运动速度(Sm)和心排量(CO)。心脏结构指标：左室后壁厚度(LVPWD)、室间隔厚度(IVSD)、左室舒张末期内径(LVEDD)、左室收缩末期内径(LVESD)、左房收缩末期内径(LADs)。按已有公式计算左室重量(LVmass)。超声检查后,即刻行血流动力学监测,检测方法同第一部分。检测指标包括平均动脉压(MAP)、左心室收缩压(LVSP)、左心室舒张末压(LVEDP)、左心室压上升最大速率(+dp/dtmax)、左心室压下降最大速率(-dp/dtmax)。血流动力学检测前经右颈总动脉抽血lml,离心后取上清,-80℃冰箱储存,在观察终点,统一采取ELISA法检测血清NT-proBNP水平。所有数据均由SPSS13.0统计软件包处理。计量资料以均数±标准差表示,采用t检验；统计结果以P<0.05为有统计学差异,P<0.01为有显著统计学差异。两个变量之间比较应用直线相关分析,并对相关系数r进行显著性检验,P<0.05为有统计学意义。
[结果](1)血流动力学检测结果提示2周时表现为左室主动松弛性受损,4周时表现为充盈压升高,6周时表现为限制性充盈障碍。
(2)超声检查中舒张功能指标显示左室舒张功能进行性减退：2周时,实验组和对照组相比,Em减慢(8.12±0.58vs9.65±0.65)(P<0.05)。4周时,实验组与对照组相比,E增快(114.7±5.8vs91.9±6.7)cm/s(P<0.05),Em减慢(7.51±3.78vs10.54±3.89)cm/s(P<0.05)；Am减慢(5.83±2.34vs6.86±2.88)cm/s(P<0.05)；Em/Am减小(1.29±0.11vs1.53±0.12)(P<0.05)；E/Em增大(11.08±1.12vs14.20±0.87)(P<0.05)；6周时,实验组与对照组相比,E增快(118.6±6.9vs89.5±7.2)(P<0.05)；Em明显减慢(6.23±1.43vs9.64±2.36)cm/s(P<0.01)；Am减慢(5.25±2.13vs6.23±2.02) cm/s (P<0.05); Em/Am明显减小(1.18±0.14vs1.54±0.24)(P<0.01)；E/Em明显增大(15.06±2.10vs10.84±1.20)(P<0.01)。
(3)超声检查中收缩功能指标在6周及8周出现下降：在6周时,与对照组相比,LVEF降低(88.65±8.02vs93.98±6.92)%(P<0.05)；FS降低(57.23±5.02vs6135±6.31)%(P<0.05)；Sm降低(7.45±2.87vs8.46±2.98)cm/s(P<0.05)。
(4)2维及M型超声检查结果显示,实验组心室肌逐渐增厚,左房内径逐渐增大：2周时,实验组与对照组相比,各组数据无差异；4周时实验组与对照组相比,LVPWD增厚(2.50±0.31vs2.15±0.27)mm(P<0.05);LADs增宽(3.25±0.32vs2.84±0.14)mm(P<0.05)；6周时,实验组与对照组相比,LVPWD明显增厚(2.82±0.40vs2.30±0.26)mm(P<0.01);LVEDD变大(6.57±0.37vs5.82±0.39)mm(P<0.05);IVSD增厚(2.39±0.28vs2.06±0.13)mm(P<0.05);LADs明显增宽(3.43±0.32vs2.79±0.41)mm(P<0.01)。
(5)评价舒张功能的无创超声指标与有创血流动力学指标相关性良好：E与LVEDP呈正相关(r=0.873,P<0.000,Em与LVEDP呈负相关(r=-0.676,P<0.001),E/Em与LVEDP呈正相关(r=0.703,P<0.001),E与-dp/dtmax呈负相关(r=-0.690,P<0.001),Em与-dp/dtmax呈正相关(r=0.762,P<0.001),E/Em与-dp/dtmax呈负相关(r=-0.839,P<0.000)。LVmass和实际测得LVM呈正相关(r=0.923,P<0.000)。
(6)血清NT-proBNP水平随时间逐渐升高：在2周(81.14±22.10vs79.47±20.83)(pg/ml)(P<0.05)和4周(101.48±49.68vs87.54±25.34)(pg/ml)(P<0.05)升高,6周(117.24±31.82vs73.35±37.56)(pg/ml)明显升高(P<0.01)；NT-proBNP与LVEDP呈正相关(r=0.590,P<0.000)；NT-proBNP与-dp/dtmax呈负相关(r=-0.601,P<0.000)。
[结论]在评价左室舒张功能进行性减退大鼠模型时,超声心动检查指标和血流动力学指标相关性良好,可准确评价大鼠左室舒张功能；通过对超声指标E、EM以及E/Em的分析,可判断大鼠左室充盈的状态,并对左室舒张功能不全程度进行分级；大鼠血清NT-proBNP水平和左室舒张功能减退程度相关,可用于大鼠左室舒张功能减退程度的评价。
三左室舒张功能不全在胸外科围术期的研究
[目的]联合超声心动和6分钟步行试验(6MWT),对胸外科术前患者的左室舒张功能进行评价；探讨胸部手术对不同级别左室舒张功能不全患者术后心功能的影响；探讨左室舒张功能不全患者在胸部术后相关并发症的发病率与术前左室舒张功能不全级别的关系；初步探讨血清NT-proBNP水平与左室舒张功能不全级别的相关性,以及在胸外科围术期的变化对其诊断心力衰竭阈值的影响。
[方法]2010年3月至2011年3月,对我科行择期或限期胸部手术的,具有一项或多项导致左室舒张功能不全危险因素的住院患者进行术前超声检查,筛选出165例左室舒张功能不全患者,并根据超声指标对其进行分组：A组75例(1级左室舒张功能不全＼松弛功能受损性充盈异常；E/A<1)；B组58例(2级左室舒张功能不全＼假性正常化；1≤E/A<1.5且E/Em>15或者Em<7cm/s), C组32例(3级左室舒张功能不全\限制性充盈异常；E/A≥2,或1.5≤E/A<2且E/Em>15或者Em<7cm/s)。(危险因素包括①年龄≥60岁；②合并高血压病；③合并糖尿病；④合并高脂血症,⑤合并轻度肺通气功能障碍；⑥具有Ⅰ Ⅱ级(NYHA)心功能不全症状的。排除标准：①Ⅲ、Ⅳ级心功能状态的；②合并缺血性心肌病患者中近一月有不稳定型心绞痛或心肌梗死的；③合并重症肌无力、脑血管疾病、下肢血管及运动系统疾病；④心律失常的；⑤肝肾功能严重不全的)。各组患者在术前1周之内进行6分钟步行试验(6MWT),在6MWT运动前、运动后即刻进行超声检查,对比分析心功能指标在试验前后的差异,并分析心功能指标的变化幅度(△1)在不同分级组间的差异。在术后第3天和第8天,分别进行超声检查,对比分析心功能指标在手术前(同运动前)和手术后的差异,并分析心功能指标的变化幅度(△2)在不同分级组间的差异。对心功能指标运动前后变化幅度△l和手术前后变化幅度△2进行相关性分析。超声检查指标包括：反映舒张功能的二尖瓣血流舒张早期峰值速度(E)、二尖瓣心房收缩期血流峰值速度(A)、E/A值、二尖瓣环舒张早期峰值运动速度(Em)二尖瓣环舒张晚期峰值运动速度(Am)、以及E/Em；反映收缩功能的左室射血分数(LVEF)、二尖瓣环收缩期峰值运动速度Sm；反映心脏形态的左室壁厚度(LVWD,=LVPWD+IVSD)、左室舒张末前后径(LVEDD)、左房收缩末前后径(LADs)。各组患者在超声检查当天清晨,取空腹血2m1,常温下离心后取上清,置-80℃冰箱储存,在研究终点统一应用ELISA法检测血清NT-proBNP水平；术前血清NT-proBNP水平和术前E/A、Em、E/Em分别进行相关性分析；对比分析所有患者术前与术后3天、术后8天血清NT-proBNP水平的差异；术后连续监测患者生命体征、监测动脉血氧分压(Pa02)、动脉乳酸值和尿量,记录术后监护时间及速尿的用量,对比分析各级别组之间的差异。计算术后各组心力衰竭(HF)、呼吸衰竭、肝肾功能衰竭、心律失常的发病率,并作各级别组之间的对比分析。所有数据均由SPSS13.0统计软件包处理。计量资料以均数±标准差表示,采用t检验和成组设计的方差分析；计数资料采用X2检验；统计结果以P<0.05为有统计学差异；P<0.01为有显著统计学差异。两个变量之间比较应用直线相关分析,并对相关系数r进行显著性检验,P<0.05为有统计学意义。
[结果]6MWT运动后超声检查显示左室舒张功能在B组有下降,在C组有明显下降：E在A组(84.2±15.5vs67.0±11.4),B组(88.7±21.9vs72.3±23.1)和C组(103.9±22.4vs88.4±19.4)均增快(P<0.05)；E/A在C组增大(1.91±0.22vs1.72±0.21)(P<0.05)；Em在A组增快(5.16±1.74vs4.23±1.79)(P<0.05)；E/Em值在B组(19.29±2.34vs17.31±2.17)(P<0.05)和C组(25.34±2.37vs23.23±3.01)(P<0.01)升高；△1Em随级别升高而降低(0.93±0.23vs0.41±0.12vs0.14±0.04)(P<0.05),△1E/Em随级别升高而升高(0.53±0.22vs1.98±0.29vs2.11±0.27)(P<0.05)。各组6MWT后收缩功能有所升高：LVEF在A组(68.4±14.3vs60.8±11.3),B组(70.1±9.2vs63.2±13.2)和C组(67.7±11.1=vs62.2±10.3)均增加(P<0.05)；Sm在A组(8.35±1.19vs7.02±1.21),B组(8.36±1.39vs7.15±1.43)和C组(8.03±1.47vs6.92±1.02)均增快(P<0.05)；△1LVEF随级别升高而降低(7.6±2.3vs6.9±3.1vs5.5±2.1)(P<0.05)。术后3天超声检查显示左室舒张功能较术前均有降低,收缩功能在B组和C组出现降低：E在A组(79.3±14.6vs67.0±11.4)、B组(86.5±17.2vs72.3±23.1)和C组(102.3±16.8vs88.4±19.4)均增快(P<0.05)；E/A在B组(1.52±0.39vs1.23±0.21)和C组(2.13±0.33vs1.72±0.21)均升高(P<0.05)；Em在B组(3.87±1.65vs4.43±1.83)和C组(3.64±1.38vs4.31±1.27)均降低(P<0.05)；E/Em在A组(19.34±1.83vs17.06±2.03)(P<0.05)、B组(20.23±1.93vs17.31±2.17)(P<0.01)及C组(28.43±3.44vs23.23±3.01)(P<0.01)均升高(P<0.05)；△2E/A随级别升高而升高(-0.06±0.02vs0.29±0.08vs0.41±0.07)(P<0.05)、△2E/Em随级别升高而升高(0.51±0.28vs2,01±0.29vs2.16±0.21)(P<0.05)；LVEF在C组出现下降(56.6±13.4vs62.2±10.3)；Sm在B组(6.05±1.77vs7.15±1.43)(P<0.05)和C组(5.47±1.3vs26.92±1.02)(P<0.05)均出现下降；A2LVEF随级别升高而降低(-2.6±0.7vs-3.4±1.1vs-5.64±1.8)和A2Sm随级别升高而降低(-0.044±0.02vs-1.10±0.21vs-1.45±0.17)(P<0.05)。术后8天A组恢复术前左室舒张功能状态,B组和C组仍低于术前水平：收缩功能在各组均恢复术前水平：E在B组(80.2±18.9vs72.3±23.1)和C组(98.3±17.4vs88.4±19.4)仍增快(P<0.05),在A组同术前无差异；E/A在B组(1.41±0.24vs1.23±0.21)和C组(2.09±0.29vs1.72±0.21)升高(P<0.05)；Em只在C组(3.79±1.76vs4.31±1.27)仍降低(P<0.05)；E/Emm在B组(19.83±2.01vsl7.31±2.17)及C组(27.46±2.01vs23.23±3.01)仍升高(P<0.05)。收缩功能指标LVEF和Sm同术前无差异；心功能指标在运动前后的变化幅度△1和在手术前后(3d)的变化幅度△2相关性良好：△1E/Em和△2E/Em正相关(r=0.893,P<0.000)；△1E/A和△2E/A呈正相关(r=0.731,P<0.001)；△1Emm和△2Emm呈正相关(r=0.785,P<0.001)；收缩指标无相关性。血清NT-proBNP水平：术前水平和E/Em呈正相关(r=0.0.782,P<0.000)；术前组间存在差异,随分级升高而增高(79.32±25.43vs89.54±18.16vs96.35±16.22)。术后3天总体水平均比术前高(107.43±22.34vs88.55±12.46)(P<0.05),且升高幅度随术前舒张功能不全级别升高而更加显著,A组(97.65±22.45vs79.32±25.43)(P<0.05),B组(108.43±23.82vs89.54±18.16)(P<0.05),C组(125.56±17.62vs96.35±16.22)(P<0.01)；术后8天同术前无差异。术后并发症的发病率：心衰发病率C组较A组(28.4%vs13.3%)(P<0.05)和B组(28.2%vs15.5%)高；呼吸衰竭发病率C组较A组(21.9%vs13.3%)(P<0.01)和B组(21.9%vs13.8%)(P<0.01)高；心律失常发生率B组较A组增高(24.1%vs17.3)(P<0.05),C组较A组高(21.8%vs17.3)(P<0.01)。
[结论]6MWT运动后,左室舒张功能在2、3级左室舒张功能不全患者进一步下降,且在3级下降的更明显；左室舒张功能在手术后早期(3d)明显下降,下降程度随术前左室舒张功能不全级别升高而增加；在术后晚期(8d),术前为1级舒张功能不全的可恢复至术前水平；左室收缩功能在术前2、3级左室舒张功能不全患者的手术后早期(3d)下降,在术后晚期(8d)可恢复；术前3级舒张功能不全患者术后更易并发心力衰竭、呼吸衰竭和心律失常；6MWT前后舒张功能变化程度与术后早期舒张功能的变化相关；血清NT-proBNP水平随左室舒张功能不全级别升高而增大；术后早期血清NT-proBNP水平在各级别普遍上升,其升高程度随术前舒张功能分级升高而增加,提示3级左室舒张功能不全患者术后心功能衰竭的风险大。
Part one. The establishment of the pressure overload in rats induced reduction of left ventricular diastolic function model.
Objective:Research and establish the methods of animal model which concerned with the reduction of left ventricular diastolic function.
Methods:The researchers used eighty8-week-old Wistar rats and randomly divided them into control and experimental group. Each group got40rats. The experimental group made an anesthesia by giving intraperitoneal injection of10%chloral hydrate (3ml/100mg). Then exposing and freeing the abdominal aorta through the left upper abdominal incision into the abdominal cavity. After determining the branch of the left renal artery, fastening the abdominal aorta together with the8Gauge needled (diameter0.8mm) by a silk thread. Reaching the abdominal aortic lumen constricted lumen after the needle was picked out. The control group made the anesthesia and then just implemented the free abdominal aorta without constricted part. After the operation, the researcher observed the animal's diet, activity, their ability of responding to the outside world, etc. Recording their significant declined time in activity, cough, and difficult breathing. In keeping the2nd week, the4th week, the6th and the8th week, giving the animal hemodynamic among the same number of rats which were randomly selected from the control group and experimental group. With the right common carotid artery, the researchers connected the BL-410biological and functional experimental system (Chengdu Tai Meng Technology Co. Ltd.) through the poly plastic tube.Then the researchers gave the mean arterial blood pressure test (MAP), left ventricular systolic pressure (LVSP), left ventricular end diastolic pressure (LVEDP), left ventricular pressure increase rate (+dp/dtmax), left ventricular pressure decline rate (-dp/dtmax). After test, the rats sacrificed, and then their left ventricular tissue were picked, weighted and calculated the left ventricular mass index (LVMI). The cardiac tissue were kept in a-80℃refrigerator. In the endpoint, unified by RT-PCR method to detect the ventricular SERCA and PLB mRNA, and compared the control group at each time point and experimental group which had differences in expression levels. The remaining10%of myocardial tissue was fixed in formalin. Then embedded in a unified endpoint and sliced. HE myocardial morphological changes were observed, and the number of myocardial cells per high power field in the cross-section of left ventricular papillary muscles was counted. The researchers consolidated the result of the hemodynamic and myocardial morphology as an evaluation criterion of a successful model. Statistical Package for all data handled by SPSS13.0. Measurement data as mean±standard deviation, using t test; statistics to P<0.05as significantly different, P<0.01as significant statistical difference.
Results:General observation:after one week, each group appeared apathetic, reduced activity, feeding and water intake reduction. Those situations were improved after a week. In the2nd and4th week, there is no significant difference between the experimental group and control group in the activities of eating situations. At the6th week, animals in the experimental group turned to be less active, less diet, and less weight than the control group (298.11±50.85vs.334.29±46.09)(P<0.05). After the6th week, animals in experimental group gradually got the symptoms about cough, breathing speed up and activity decreased significantly. At the endpoint of the8th week, animals in the experimental group reflected slowly to the outside world, had no interest in eating. Some animal died (20%), and their weight is less than the control group (289.58±45.23vs.349.56±38.24)(P<0.05). After the operation, the rats in experimental group died four, and the survival rate was90%. Among them, two died within1day after surgery and two died of breathing difficulties after8weeks. There is no death in the control group. According to the hemodynamic monitoring results, at each time point the experimental group had a higher sustainment on the MAP and LVSP. And the diastolic function parameters in this group appeared progressive change. What's more, the systolic function parameters declined at the6th week. At the2nd week, comparing with the control group, the experimental group's-dp/dtmax decreased (4.32±0.27vs.5.13±0.21)(P<0.05), and there is no other difference; at the4th week, the experimental group's-dp/dtmax decreased dramatically (3.64±0.30vs.5.33±0.28)(P<0.01), the LVEDP increased significantly (15.45±2.56vs.5.90±2.46)(P<0.01), and there is no other difference; at the6th week, the experimental group's-dp/dtmax decreased obviously (3.42±0.32vs.5.29±0.34)(P <0.01), while the LVEDP increased significantly (19.89±3.28vs.5.67±2.58)(P <0.01), and the+dp/dtmax decreased (5.98±0.31vs.6.34±0.38)(P<0.05); at the8th week, in the experimental group the-dp/dtmax decreased dramatically (2.04±0.31vs.5.41±0.39)(P<0.01), and the LVEDP increased significantly (24.34±4.08vs.5.67±2.58)(P<0.01), and the+dp/dtmax decreased obviously (4.50+0.21vs.6.21±0.31)(P<0.01). The LVMI conditions:compared with the control group, the experimental group had no difference in2weeks; in the4th week it increased (2.69±0.18vs.2.33±0.20); in the6th week it increased significantly (2.65±0.21vs.2.42±0.16); in the8th week, it increased dramatically (2.96±2.39±0.19)(P<0.01). The Pathological examination revealed progressive myocardial damage:in the control group and the experimental group within2weeks, the myocardial cell was integrity and arranged in order; in the4-week-experimental group, the cardiac hypertrophy occurred and the gap widened slightly, what's more, the occasionally spotty necrosis and interstitial edema happened; in the6-week-experimental group, there was obviously cardiac hypertrophy, and the nuclei was so big that got infection, what's more the cross-sectional area increased and there was scattered punctate myocardial necrosis, then the myocardial cell in the high power field was less than the control group(19.78±3.36vs.25.34±5.04)(P<0.05); in the8-week-experimental group, showing myocardial cells significantly increased and the arrangement was disordered, then the gap widened and the showing sheet myocardial necrosis occurred, what's more, the myocardial cell in the high power field was less than the control group(18.16±3.24vs.28.35±3.25)(P<0.05). There were large amount of inflammatory cells. PLB expression showed that there was no significant difference in control and experimental groups. According to the SERCA2a expression, in the2nd week the experimental group and control group had no significant difference; in the4th week, the experimental group was less than the control group (CT value of28.15±0.84vs.26.14±0.51)(P<0.05); in the6th week, the experimental group was less than the control group (CT value of29.02±1.27vs26.50±0.89)(P<0.05); in the8th week, the experimental group was less than the control group (CT value of32.09±1.38vs.27.25±1.24)(P<0.01)
Conclusion:8-week-old Wistar rats'left ventricular diastolic function declined within2-8weeks after having the upper kidney abdominal aortic coartation. The2nd showed impaired LV active relaxation; the4th week was the stage that the filling pressure was increased; in the6th week was the stage that the restrictive filling barriers; In the8th week, the heart failure performed. The main factor of effecting the myocardial calcium cycling-SERCA2a expression may be mainly the inhibition of left ventricular diastolic dysfunction in the late term.
Part Two. The correlation between hemodynamic with Ultrasound or Markers of heart failure during evaluat left ventricular diastolic function in the model
Objective:To discuss the evaluation of ultrasonic grading in left ventricular diastolic function of the feasibility of reduction; discuss the serum NT-proBNP levels and diastolic function of the decreased correlation; to establish non-hemodynamic methods to evaluate the left ventricular diastolic function of the reduction model of.
Methods:Using upper renal abdominal aortic coarctation method to establish the left ventricular diastolic dysfunction in a30-rat-model, and establish the control group in other30ones. After2weeks,4weeks and6weeks of reduction in abdominal aortic rings, the researchers used the application of Philips iE33color Doppler to select S12-4high-frequency probe and then made the echocardiography to the rats in the experimental group and control group. The researchers used2-D ultrasound, M-mode ultrasound recording of left ventricular posterior wall thickness (LVPWD), interventricular septum thickness (IVSD), left ventricular end diastolic diameter (LVEDD), left ventricular end systolic diameter (LVESD), left a trial end systolic diameter (LADs), Left ventricular ejection fraction (LVEF), left ventricular fractional shortening (FS) and cardiac output (CO); and calculated the left ventricular mass(LVmass) according to the formula; then the researchers used the mitral diastolic flow Doppler spectrum Early peak flow velocity (E); Doppler tissue imaging (DTI) at the mitral annulus peak systolic myocardial tissue velocity (Sm), peak early diastolic velocity (Em), late diastolic peak velocity (Am); calculation of Em/Am and E/Em. After the ultrasound examination, the researchers immediately made the hemodynamic monitoring with the method that the first part mentioned. The Detection indicators included mean arterial pressure (MAP), left ventricular systolic pressure (LVSP), left ventricular end diastolic pressure (LVEDP), left ventricular pressure increase rate (+dp/dtmax), left ventricular pressure decline rate (-dp/dtmax). The researchers drew lml blood before the hemodynamic via the right common carotid artery, and then got the supernatant after centrifugation. Keeping it in a-80℃refrigerator to store and in the end point, the researchers unified to ELISA, detect serum NT-pro BNP levels. Statistical Package for all data handled by SPSS13.0. Measurement data as mean±standard deviation, using t test; statistics to P<0.05as significantly different, P<0.01as significant statistical difference.
Results:Hemodynamic results suggested that the establishment of model is successful. The2-dimensional and M-mode ultrasound examination showed that the experimental group got the gradually thickened ventricular and the left atria diameter increased. Specifically speaking, in the2nd week, there is no difference in the experimental group and control group between the various sets of data; in the4th week compared with the control group, the experimental group's LVPWD thickened (2.50±0.31vs.2.15±0.27) mm,(P<0.05); LADs broadened (3.25±0.32vs.2.84±0.14) mm,(P<0.05); in the6th week, the experimental group's LVPWD became significantly thicker (2.82±0.40vs.2.30±0.26) mm,(P<0.01); LVEDD turned larger (6.57±0.37vs.5.82±0.39) mm,(P<0.05); IVSD thickened (2.39±0.28vs.2.06±0.13) mm,(P<0.05); LADs was obviously enlarged (3.43±0.32vs.2.79±0.41) mm,(P<0.01). The detection of left ventricular diastolic function indicators could appear on behalf of progressive reduction of left ventricular diastolic changes. Specifically speaking, in the2nd week, compared with the control group, the experimental group's Em slow (8.12±0.58vs.9.65±0.65),(P<0.05). In the4th week, the experimental group's E increased faster (114.7±5.8vs.91.9±6.7) cm/s,(P<0.05), Em slowed (7.51±3.78vs.10.54±3.89) cm/s,(P<0.05); Am slowed (5.83±2.34vs.6.86±2.88) cm/s,(P<0.05); Em/Am decreased (1.29±0.11vs.1.53±0.12),(P<0.05); E/Em increased (11.08±1.12vs14.20±0.87)(P<0.05); in the6th week, the experimental group's E increased faster (118.6±6.9vs.89.5±7.2) (P<0.05); Em was significantly slower (6.23±1.43vs.9.64±2.36) cm/s,(P<0.01); Am slow (5.25±2.13vs.6.23±2.02) cm/s,(P<0.05); Em/Am was significantly reduced Small (1.18±0.14vs.1.54±0.24),(P<0.01); E/Em was significantly increased (15.06±2.10vs10.84±1.20)(P<0.01). The detection of left ventricular systolic function indexes declined at the6th week. Specifically speaking, in the6th week, compared with the control group, the experimental group's LVEF decreased (88.65±8.02vs.93.98±6.92)%,(P<0.05); FS decreased (57.23±5.02vs.61.35±6.31)%,(P<0.05); Sm lower (7.45±2.87vs.8.46±2.98) cm/s,(P<0.05). The echocardiography which represented the diastolic function and hemodynamic indexes correlated well. E and LVEDP was positively correlated (r=0.873, P<0.000), Em was a negative correlation with LVEDP (r=-0.676, P<0.001), E/Em was positively correlated with LVEDP (r=0.703, P<0.001), E and-dp/dtmax negative correlation (r=-0.690, P<0.001), Em and-dp/dtmax was positively correlated (r=0.762, P <0.001), E/Em and-dp/dtmax negative correlation (r=-0.839, P<0.000). There was a positive correlation between the LVmass and the actual measured LVM (r=0.923, P <0.000).The Serum NT-proBNP levels in the2nd and4th week increased significantly and elevated in the6th week; NT-pro BNP was positively correlated with LVEDP (r=0.590, P<0.000); NT-pro BNP was negatively correlated with-dp/dtmax (r=-0.601, P<0.000).
Results:The correlation between the Echocardiography and hemodynamic was good, so it could be an accurate assessment of left ventricular diastolic function; through analyzing echocardiography, the left ventricular filling could be determined in the different states; the correlation between the serum NT-pro BNP levels and left ventricular diastolic function decreased degree could be used for assessing the degree of ventricular diastolic function.
Part three. The research of diastolic dysfunction during perioperative of thoracic surgery
Objective:Combined echocardiography and6-minute walking test (6MWT), to evauate left ventricular diastolic function of thoracic surgery patients; Discuss the different effect in patients of thoracic surgery on different degree of left ventricular diastolic dysfunction; Discuss the relationship between postoperative complications with degrees of left ventricular diastolic dysfunction in thoracic surgery patients; Preliminary discuss the correlation between serum NT-proBNP levels and left ventricular diastolic dysfunction degree, the change during perioperative impact threshold value of the diagnosis.
Methods:From March2010to March2011, the patients in the our department who would be done thoracic surgery operation, with one or more risk factors for diastolic dysfunction, be evaluated by ultrasound to screened which with left ventricular diastolic dysfunction. On selected cases(165), the researchers grouped them according to echocardiography:group A75cases (impaired relaxation of the filling abnormalities,E/A<1), grade B58cases (pseudo-normalization,1≤E/A<1.5and E/Em>15or Em<7cm/s), group C32cases (restrictive filling abnormalities, E/A≥2, or1.5≤E/A<2and E/Em>15or Em<7cm/s).(Those risk factors included:①age≥60;②patients with hypertension;③diabetes;④hyperlipidemia,⑤combined with mild pulmonary dysfunction;⑥has Ⅰ, Ⅱ grade (NYHA) heart failure symptoms. If the following conditions appeared, the case would be excluded:①Ⅲ, Ⅳ-level cardiac function;②combined in ischemic cardiomyopathy patients with unstable angina in January near or myocardial infarction;③myasthenia gravis, cerebrovascular disease, Lower extremity vascular and motor system diseases;④arrhythmia;⑦serious insufficiency of liver and kidney function.). Patients in each group had6-minute walking test (6MWT) in one week before surgery and the researchers analyzed the differences among the groups in6-minute walk distance (6MWD) and got the diastolic function indices and some correlation. Giving the ultrasound before and immediately after the exercise, the researchers compared the cardiac function differences before and after the test and tested the amplitude index (△1) classification by pair wise differences between groups. In the3rd and8th day after the operation, the researchers went the ultrasound respectively and made the difference analysis between these results and the results of preoperative ultrasonography, then tested the difference between the indicators before and after the change range (△2). Madding the correlation analysis of△1and△2. The ultrasound parameters included:mitral valve blood Early diastolic peak flow velocity (E), atrial systolic mitral valve blood flow peak velocity (A), E/A value, peak early diastolic mitral annulus velocity (Em) peak late diastolic mitral annulus velocity (Am), peak systolic velocity of mitral annular Sm and E/Em, left ventricular ejection fraction (LVEF),the left ventricular wall thickness (LVWD,=LVPWD+IVSD), left ventricular end diastolic diameter before and after (LVEDD), left atrial end-systolic diameter before and after (LADs). Going on the ultrasound examination to the patients in each group on the same day in the morning, taking fasting blood2ml and the supernatant after centrifugation at room temperature, setting to-80℃refrigerator storage. The researchers tested the serum levels of NT-pro BNP with the uniform application in the study endpoint by the ELISA and made the correlation analysis, then compared all patients' serum NT-proNP level differences with the3rd day and the8th day after the surgery; postoperative continuous monitoring of patient vital signs; monitor the arterial oxygen tension (Pa02), arterial lactate concentration and urine volume, record the time and postoperative care the amount of furosemide, compared the differences between the groups at all levels. Then the researchers calculated heart failure (HF), respiratory failure, kidney failure, the incidence of arrhythmia in each group after the surgery and made the comparative analysis for all levels between the groups. Statistical Package for all data handled by SPSS13.0. Measurement data as mean±standard deviation, using t test; statistics to P<0.05as significantly different, P<0.01as significant statistical difference.
Results:After6MWT, ultrasound examination showed left ventricular diastolic function decreased in group B, significantly decreased in group C:E are faster,(P<0.05); E/A increased in group C (1.91±0.22vsl.72±0.21)(P<0.05); Em faster in group A (5.16±1.74vs.4.23±1.79)(P<0.05); E/Em values in group B (19.29±2.34vs.17.31±2.17)(P<0.05) and group C (25.34±2.37vs.23.23±3.01)(P<0.01) were increased; LVEF and Sm in all groups were significantly higher (P<0.05);△1Em there are differences in various groups (0.93±0.23vs0.41±0.12vs.0.14±0.04)(P<0.05),△1iE/Em there are differences in various groups (0.53±0.22vs.1.98±0.29vs.2.11±0.27)(P<0.05); Ultrasound examination showed that after3days compared with preoperative left ventricular diastolic function were decreased, systolic function in group B group and C decreased:E in all groups were faster (P<0.05); E/A in group B and C were higher (P<0.05); Em in group B and group C were lower (P<0.05); E/Em were significantly increased in all groups (P<0.05); LVEF decline in group C(56.6±13.4vs.62.2±10.3)(P<0.05); Sm in group B (6.05±1.77vs.7.15±1.43)(P<0.05) and group C (5.47±1.3vs.26.92±1.02)(P<0.05) are declining;△2LVEF,△2E/A,△2E/Em were differences among the groups (P<0.05).△1E/Em and△2E/Em the best correlation (r=0.893, P<0.000);△1E/A and△2E/A positive correlation (r=0.731, P<0.001);△1Em and△2Em was positively correlated (r=0.785, P<0.001); Serum NT-pro BNP levels and preoperative E/Em was a positive correlation, the best correlation (r=0.782, P<0.000); Serum NT-pro BNP preoperative differences between groups, with the rise of higher grade (79.32±25.43vs.89.54±18.16vs.96.35±16.22)(P<0.05). Heart failure incidence of grade group C more than group A (28.4%vs.13.3%)(P<0.05) and group B (28.2%vs.15.5%); the incidence of respiratory failure group C more than group A (21.9%vs.13.3%)(P<0.01) and group B (21.9%vs.13.8%)(P<0.01); arrhythmias group B more than group A (24.1%vs.17.3)(P<0.05), group C more than group A (21.8%vs.17.3)(P<0.01).
Conclusion:The patients with left ventricular diastolic heart failure after the surgery were further aggravated in the left ventricular diastolic dysfunction, and it increased level of preoperative functional class was significantly improved and more;6MWT joint Doppler ultrasound could predict the increscent of the degree of diastolic dysfunction after surgery, and played the role of high-risk patients can be expected to further risk of heart failure; the elevated levels of serum NT-proBNP with left ventricular diastolic dysfunction grade increased, and the monitoring of serum NT-pro BNP could contributed to the diagnostic classification of diastolic function; the Serum NT-pro BNP levels increased preoperative, and the functional class improved, when give the diagnosis of CHF, the diagnostic threshold should be improved; patients with diastolic dysfunction in the chest surgery period got a high risk of heart failure and respiratory failure.
[目的]研究并确立左室舒张功能减退大鼠模型的建立方法,初步探讨其发生机制。
[方法]成年8周龄Wistar大鼠80只,随机均分为对照组和实验组。实验组40只,经腹腔注射10%水合氯醛(3ml/100mg)麻醉后,左上腹手术切口,进入腹腔,暴露并游离腹主动脉,确定左肾动脉分支,在其上方,将腹主动脉同8号针头(直径0.8mm)一同用丝线扎紧,然后抽出针头,环缩腹主动脉管腔。对照组40只,麻醉后施行开腹及游离腹主动脉,不做环缩。术后观察两组动物的饮食、活动能力、对外界反应能力等情况；记录出现活动能力明显下降、咳嗽和呼吸困难的时间。分别在饲养2周,4周,6周和8周时,随机抽取相同数量的对照组和实验组动物,进行血流动力学检测。由右颈总动脉插管,经聚乙烯塑料导管连接BL-410生物机能实验系统(成都泰盟科技有限公司)检测平均动脉压(MAP)、左心室收缩压(LVSP)、左心室舒张末压(LVEDP)、左心室压上升最大速率(+dp/dtmax)、左心室压下降最大速率(-dp/dtmax)。对比分析各时间点对照组和试验组数据,评价其差异。检测完毕后处死大鼠,取左心室组织,称重并计算左室重量指数(LVMI),对比分析各时间点实验组和对照组的差异。取部分左室心肌组织-80℃冰箱储存,在观察终点,统一采用RT-PCR方法,检测心室肌肌浆网膜钙离子泵(sarcoplasmic reticulum Ca2+—ATPase, SERCA2a)和受磷蛋白(PLB)的mRNA表达水平,对比分析各时间点对照组和试验组表达水平的差异性。剩余心肌组织福尔马林固定,在观察终点统一包埋、切片,HE染色观察心肌形态学变化,计数左室乳头肌水平横断面每高倍视野心肌细胞个数,对比分析各时间点实验组和对照组的差异。综合血流动力学和心肌形态学结果,作为成功模型的评价标准。所有数据均由SPSS13.0统计软件包处理。计量资料以均数±标准差表示,采用t检验；统计结果以P<0.05为有统计学差异,P<0.01为有显著统计差异。
[结果](1)实验组和对照组一般情况：术后第1周各组动物出现精神萎靡、活动减少、摄食及饮水量减少情况,一周后上述情况好转。2周时和4周时,活动进食情况,实验组与对照组无明显差异。6周时,实验组开始有动物出现活动量减少,饮食减少,体重比对照组轻(298.11±50.85vs334.29±46.09)g(P<0.05)。6周后,实验组逐渐出现咳嗽,呼吸加快症状(78.36±14.54vs46.77±11.49)g(P<0.05),活动量明显下降。在观察终点8周末,实验组对外界反映迟钝,不思进食,体重低于对照组(289.58±45.23vs349.56±38.24)g(P<0.05),有部分动物出现死亡(20%)。术后实验组大鼠死亡4只,成活率90%,2只在术后1天内死亡,2只在术后6周以后出现呼吸困难后死亡。对照组无死亡。
(2)左室压力负荷增高在各实验组稳定存在,各时间点实验组的平均动脉压(MAP)和左室收缩压(LVSP)高于对照组：MAP,2周(127.56±20.39vs90.33±15.23)mmHg(P<0.01)4周(128.415±14.03vs92.23±11.68)mmHg(P<0.01),6周(130.25±16.36vs93.85±12.34)mmHg(P<0.01)8周(115.37±13.35vs96.68±16.54)mmHg(P<0.05)；LVSP,2周(149.39±18.34vs109.76±14.40)mmHg(P<0.05)4周(156.73±15.03vs108.34±17.57)mmHg(P
(4)收缩功能指标在6周时出现下降,8周时出现明显下降：6周时,实验组较对照组+dp/dtmax降低(5.98±0.31vs6.34±0.38)(P<0.05)；8周时+dp/dtmax明显降低(4.50±0.21vs6.21±0。31)(P<0.01)；
(5)左室重量指数(LVMI)情况：与对照组相比,实验组2周时无差异,4周时升高(2.69±0.18vs2.33±0.20),6周时升高(2.65±0.21vs2.42±0.16)(P<0.05),8周时明显升高(2.96±0.18vs2.39±0.19)(P<0.01)。
(5)病理学检查显示心肌进行性损害：各对照组及2周实验组,心肌细胞完整,排列整齐；4周实验组,心肌细胞肥大,间隙略增宽,偶见点状坏死,间质轻度水肿；6周实验组,心肌细胞明显肥大,细胞核大而深染、横断面积增大,散在点状心肌细胞坏死,高倍视野心肌细胞计数少于对照组(19.78±3.36vs25.34±5.04)个/Hp(P<0.05)；8周实验组,可见心肌细胞明显增大,排列紊乱,间隙增宽,片状心肌细胞坏死,高倍视野心肌细胞计数少于对照组(18.16±3.24vs28.35±3.25)个/Hp(P<0.05),并可见大量炎症细胞浸润。
(6)PLB的mRNA表达量对照组和实验组无统计学差异,SERCA2a的mRNA表达量在4至8周组表达量降低：4周时,实验组低于对照组(CT值28.15±0.84vs26.14±0.51)(P<0.05)；6周时,实验组低于对照组(CT值29.02±1.27vs26.50±0.89)(P<0.05)；8周时,实验组明显低于对照组(CT值32.09±1.38vs27.25±1.24)(P<0.01)。
[结论]8周龄Wistar大鼠肾上腹主动脉缩窄后8周观察期内,左室舒张功能随时间出现进行性减退。其中,2周时表现为左室主动松弛性受损,4周时表现为充盈压升高,6周时表现为限制性充盈障碍,8周时出现心力衰竭表现。影响心肌钙循环的主要因素——SERCA2a表达受抑制可能主要在左室舒张功能减退中后期起作用。
二超声及心衰标志物和血流动力学在评价左室舒张功能进行性减退模型时的相关性
[目的]探讨超声检查评价大鼠左室舒张功能进行性减退的可行性；探讨血清NT-proBNP水平与舒张功能进行性减退的相关性；确立评价左室舒张功能进行性减退模型的非血流动学方法。
[方法]采用肾上腹主动脉方法建立左室舒张功能减退的大鼠模型30只,并设立对照组30只。分别在术后2周、4周及6周时,随机抽取相同数量的对照组和实验组大鼠,应用飞利浦心悦iE33彩色多普勒超声仪,选取S12-4高频探头对其行心脏超声检查。舒张功能指标包括：血流频谱多普勒记录二尖瓣舒张早期血流峰值速度(E)、舒张早期峰值运动速度(Em)、舒张晚期峰值运动速度(Am)；计算Em/Am和E/Em。收缩功能指标包括：左室射血分数(LVEF)、左室短轴缩短率(FS)、二尖瓣瓣环处心肌组织的收缩期峰值运动速度(Sm)和心排量(CO)。心脏结构指标：左室后壁厚度(LVPWD)、室间隔厚度(IVSD)、左室舒张末期内径(LVEDD)、左室收缩末期内径(LVESD)、左房收缩末期内径(LADs)。按已有公式计算左室重量(LVmass)。超声检查后,即刻行血流动力学监测,检测方法同第一部分。检测指标包括平均动脉压(MAP)、左心室收缩压(LVSP)、左心室舒张末压(LVEDP)、左心室压上升最大速率(+dp/dtmax)、左心室压下降最大速率(-dp/dtmax)。血流动力学检测前经右颈总动脉抽血lml,离心后取上清,-80℃冰箱储存,在观察终点,统一采取ELISA法检测血清NT-proBNP水平。所有数据均由SPSS13.0统计软件包处理。计量资料以均数±标准差表示,采用t检验；统计结果以P<0.05为有统计学差异,P<0.01为有显著统计学差异。两个变量之间比较应用直线相关分析,并对相关系数r进行显著性检验,P<0.05为有统计学意义。
[结果](1)血流动力学检测结果提示2周时表现为左室主动松弛性受损,4周时表现为充盈压升高,6周时表现为限制性充盈障碍。
(2)超声检查中舒张功能指标显示左室舒张功能进行性减退：2周时,实验组和对照组相比,Em减慢(8.12±0.58vs9.65±0.65)(P<0.05)。4周时,实验组与对照组相比,E增快(114.7±5.8vs91.9±6.7)cm/s(P<0.05),Em减慢(7.51±3.78vs10.54±3.89)cm/s(P<0.05)；Am减慢(5.83±2.34vs6.86±2.88)cm/s(P<0.05)；Em/Am减小(1.29±0.11vs1.53±0.12)(P<0.05)；E/Em增大(11.08±1.12vs14.20±0.87)(P<0.05)；6周时,实验组与对照组相比,E增快(118.6±6.9vs89.5±7.2)(P<0.05)；Em明显减慢(6.23±1.43vs9.64±2.36)cm/s(P<0.01)；Am减慢(5.25±2.13vs6.23±2.02) cm/s (P<0.05); Em/Am明显减小(1.18±0.14vs1.54±0.24)(P<0.01)；E/Em明显增大(15.06±2.10vs10.84±1.20)(P<0.01)。
(3)超声检查中收缩功能指标在6周及8周出现下降：在6周时,与对照组相比,LVEF降低(88.65±8.02vs93.98±6.92)%(P<0.05)；FS降低(57.23±5.02vs6135±6.31)%(P<0.05)；Sm降低(7.45±2.87vs8.46±2.98)cm/s(P<0.05)。
(4)2维及M型超声检查结果显示,实验组心室肌逐渐增厚,左房内径逐渐增大：2周时,实验组与对照组相比,各组数据无差异；4周时实验组与对照组相比,LVPWD增厚(2.50±0.31vs2.15±0.27)mm(P<0.05);LADs增宽(3.25±0.32vs2.84±0.14)mm(P<0.05)；6周时,实验组与对照组相比,LVPWD明显增厚(2.82±0.40vs2.30±0.26)mm(P<0.01);LVEDD变大(6.57±0.37vs5.82±0.39)mm(P<0.05);IVSD增厚(2.39±0.28vs2.06±0.13)mm(P<0.05);LADs明显增宽(3.43±0.32vs2.79±0.41)mm(P<0.01)。
(5)评价舒张功能的无创超声指标与有创血流动力学指标相关性良好：E与LVEDP呈正相关(r=0.873,P<0.000,Em与LVEDP呈负相关(r=-0.676,P<0.001),E/Em与LVEDP呈正相关(r=0.703,P<0.001),E与-dp/dtmax呈负相关(r=-0.690,P<0.001),Em与-dp/dtmax呈正相关(r=0.762,P<0.001),E/Em与-dp/dtmax呈负相关(r=-0.839,P<0.000)。LVmass和实际测得LVM呈正相关(r=0.923,P<0.000)。
(6)血清NT-proBNP水平随时间逐渐升高：在2周(81.14±22.10vs79.47±20.83)(pg/ml)(P<0.05)和4周(101.48±49.68vs87.54±25.34)(pg/ml)(P<0.05)升高,6周(117.24±31.82vs73.35±37.56)(pg/ml)明显升高(P<0.01)；NT-proBNP与LVEDP呈正相关(r=0.590,P<0.000)；NT-proBNP与-dp/dtmax呈负相关(r=-0.601,P<0.000)。
[结论]在评价左室舒张功能进行性减退大鼠模型时,超声心动检查指标和血流动力学指标相关性良好,可准确评价大鼠左室舒张功能；通过对超声指标E、EM以及E/Em的分析,可判断大鼠左室充盈的状态,并对左室舒张功能不全程度进行分级；大鼠血清NT-proBNP水平和左室舒张功能减退程度相关,可用于大鼠左室舒张功能减退程度的评价。
三左室舒张功能不全在胸外科围术期的研究
[目的]联合超声心动和6分钟步行试验(6MWT),对胸外科术前患者的左室舒张功能进行评价；探讨胸部手术对不同级别左室舒张功能不全患者术后心功能的影响；探讨左室舒张功能不全患者在胸部术后相关并发症的发病率与术前左室舒张功能不全级别的关系；初步探讨血清NT-proBNP水平与左室舒张功能不全级别的相关性,以及在胸外科围术期的变化对其诊断心力衰竭阈值的影响。
[方法]2010年3月至2011年3月,对我科行择期或限期胸部手术的,具有一项或多项导致左室舒张功能不全危险因素的住院患者进行术前超声检查,筛选出165例左室舒张功能不全患者,并根据超声指标对其进行分组：A组75例(1级左室舒张功能不全＼松弛功能受损性充盈异常；E/A<1)；B组58例(2级左室舒张功能不全＼假性正常化；1≤E/A<1.5且E/Em>15或者Em<7cm/s), C组32例(3级左室舒张功能不全\限制性充盈异常；E/A≥2,或1.5≤E/A<2且E/Em>15或者Em<7cm/s)。(危险因素包括①年龄≥60岁；②合并高血压病；③合并糖尿病；④合并高脂血症,⑤合并轻度肺通气功能障碍；⑥具有Ⅰ Ⅱ级(NYHA)心功能不全症状的。排除标准：①Ⅲ、Ⅳ级心功能状态的；②合并缺血性心肌病患者中近一月有不稳定型心绞痛或心肌梗死的；③合并重症肌无力、脑血管疾病、下肢血管及运动系统疾病；④心律失常的；⑤肝肾功能严重不全的)。各组患者在术前1周之内进行6分钟步行试验(6MWT),在6MWT运动前、运动后即刻进行超声检查,对比分析心功能指标在试验前后的差异,并分析心功能指标的变化幅度(△1)在不同分级组间的差异。在术后第3天和第8天,分别进行超声检查,对比分析心功能指标在手术前(同运动前)和手术后的差异,并分析心功能指标的变化幅度(△2)在不同分级组间的差异。对心功能指标运动前后变化幅度△l和手术前后变化幅度△2进行相关性分析。超声检查指标包括：反映舒张功能的二尖瓣血流舒张早期峰值速度(E)、二尖瓣心房收缩期血流峰值速度(A)、E/A值、二尖瓣环舒张早期峰值运动速度(Em)二尖瓣环舒张晚期峰值运动速度(Am)、以及E/Em；反映收缩功能的左室射血分数(LVEF)、二尖瓣环收缩期峰值运动速度Sm；反映心脏形态的左室壁厚度(LVWD,=LVPWD+IVSD)、左室舒张末前后径(LVEDD)、左房收缩末前后径(LADs)。各组患者在超声检查当天清晨,取空腹血2m1,常温下离心后取上清,置-80℃冰箱储存,在研究终点统一应用ELISA法检测血清NT-proBNP水平；术前血清NT-proBNP水平和术前E/A、Em、E/Em分别进行相关性分析；对比分析所有患者术前与术后3天、术后8天血清NT-proBNP水平的差异；术后连续监测患者生命体征、监测动脉血氧分压(Pa02)、动脉乳酸值和尿量,记录术后监护时间及速尿的用量,对比分析各级别组之间的差异。计算术后各组心力衰竭(HF)、呼吸衰竭、肝肾功能衰竭、心律失常的发病率,并作各级别组之间的对比分析。所有数据均由SPSS13.0统计软件包处理。计量资料以均数±标准差表示,采用t检验和成组设计的方差分析；计数资料采用X2检验；统计结果以P<0.05为有统计学差异；P<0.01为有显著统计学差异。两个变量之间比较应用直线相关分析,并对相关系数r进行显著性检验,P<0.05为有统计学意义。
[结果]6MWT运动后超声检查显示左室舒张功能在B组有下降,在C组有明显下降：E在A组(84.2±15.5vs67.0±11.4),B组(88.7±21.9vs72.3±23.1)和C组(103.9±22.4vs88.4±19.4)均增快(P<0.05)；E/A在C组增大(1.91±0.22vs1.72±0.21)(P<0.05)；Em在A组增快(5.16±1.74vs4.23±1.79)(P<0.05)；E/Em值在B组(19.29±2.34vs17.31±2.17)(P<0.05)和C组(25.34±2.37vs23.23±3.01)(P<0.01)升高；△1Em随级别升高而降低(0.93±0.23vs0.41±0.12vs0.14±0.04)(P<0.05),△1E/Em随级别升高而升高(0.53±0.22vs1.98±0.29vs2.11±0.27)(P<0.05)。各组6MWT后收缩功能有所升高：LVEF在A组(68.4±14.3vs60.8±11.3),B组(70.1±9.2vs63.2±13.2)和C组(67.7±11.1=vs62.2±10.3)均增加(P<0.05)；Sm在A组(8.35±1.19vs7.02±1.21),B组(8.36±1.39vs7.15±1.43)和C组(8.03±1.47vs6.92±1.02)均增快(P<0.05)；△1LVEF随级别升高而降低(7.6±2.3vs6.9±3.1vs5.5±2.1)(P<0.05)。术后3天超声检查显示左室舒张功能较术前均有降低,收缩功能在B组和C组出现降低：E在A组(79.3±14.6vs67.0±11.4)、B组(86.5±17.2vs72.3±23.1)和C组(102.3±16.8vs88.4±19.4)均增快(P<0.05)；E/A在B组(1.52±0.39vs1.23±0.21)和C组(2.13±0.33vs1.72±0.21)均升高(P<0.05)；Em在B组(3.87±1.65vs4.43±1.83)和C组(3.64±1.38vs4.31±1.27)均降低(P<0.05)；E/Em在A组(19.34±1.83vs17.06±2.03)(P<0.05)、B组(20.23±1.93vs17.31±2.17)(P<0.01)及C组(28.43±3.44vs23.23±3.01)(P<0.01)均升高(P<0.05)；△2E/A随级别升高而升高(-0.06±0.02vs0.29±0.08vs0.41±0.07)(P<0.05)、△2E/Em随级别升高而升高(0.51±0.28vs2,01±0.29vs2.16±0.21)(P<0.05)；LVEF在C组出现下降(56.6±13.4vs62.2±10.3)；Sm在B组(6.05±1.77vs7.15±1.43)(P<0.05)和C组(5.47±1.3vs26.92±1.02)(P<0.05)均出现下降；A2LVEF随级别升高而降低(-2.6±0.7vs-3.4±1.1vs-5.64±1.8)和A2Sm随级别升高而降低(-0.044±0.02vs-1.10±0.21vs-1.45±0.17)(P<0.05)。术后8天A组恢复术前左室舒张功能状态,B组和C组仍低于术前水平：收缩功能在各组均恢复术前水平：E在B组(80.2±18.9vs72.3±23.1)和C组(98.3±17.4vs88.4±19.4)仍增快(P<0.05),在A组同术前无差异；E/A在B组(1.41±0.24vs1.23±0.21)和C组(2.09±0.29vs1.72±0.21)升高(P<0.05)；Em只在C组(3.79±1.76vs4.31±1.27)仍降低(P<0.05)；E/Emm在B组(19.83±2.01vsl7.31±2.17)及C组(27.46±2.01vs23.23±3.01)仍升高(P<0.05)。收缩功能指标LVEF和Sm同术前无差异；心功能指标在运动前后的变化幅度△1和在手术前后(3d)的变化幅度△2相关性良好：△1E/Em和△2E/Em正相关(r=0.893,P<0.000)；△1E/A和△2E/A呈正相关(r=0.731,P<0.001)；△1Emm和△2Emm呈正相关(r=0.785,P<0.001)；收缩指标无相关性。血清NT-proBNP水平：术前水平和E/Em呈正相关(r=0.0.782,P<0.000)；术前组间存在差异,随分级升高而增高(79.32±25.43vs89.54±18.16vs96.35±16.22)。术后3天总体水平均比术前高(107.43±22.34vs88.55±12.46)(P<0.05),且升高幅度随术前舒张功能不全级别升高而更加显著,A组(97.65±22.45vs79.32±25.43)(P<0.05),B组(108.43±23.82vs89.54±18.16)(P<0.05),C组(125.56±17.62vs96.35±16.22)(P<0.01)；术后8天同术前无差异。术后并发症的发病率：心衰发病率C组较A组(28.4%vs13.3%)(P<0.05)和B组(28.2%vs15.5%)高；呼吸衰竭发病率C组较A组(21.9%vs13.3%)(P<0.01)和B组(21.9%vs13.8%)(P<0.01)高；心律失常发生率B组较A组增高(24.1%vs17.3)(P<0.05),C组较A组高(21.8%vs17.3)(P<0.01)。
[结论]6MWT运动后,左室舒张功能在2、3级左室舒张功能不全患者进一步下降,且在3级下降的更明显；左室舒张功能在手术后早期(3d)明显下降,下降程度随术前左室舒张功能不全级别升高而增加；在术后晚期(8d),术前为1级舒张功能不全的可恢复至术前水平；左室收缩功能在术前2、3级左室舒张功能不全患者的手术后早期(3d)下降,在术后晚期(8d)可恢复；术前3级舒张功能不全患者术后更易并发心力衰竭、呼吸衰竭和心律失常；6MWT前后舒张功能变化程度与术后早期舒张功能的变化相关；血清NT-proBNP水平随左室舒张功能不全级别升高而增大；术后早期血清NT-proBNP水平在各级别普遍上升,其升高程度随术前舒张功能分级升高而增加,提示3级左室舒张功能不全患者术后心功能衰竭的风险大。
Part one. The establishment of the pressure overload in rats induced reduction of left ventricular diastolic function model.
Objective:Research and establish the methods of animal model which concerned with the reduction of left ventricular diastolic function.
Methods:The researchers used eighty8-week-old Wistar rats and randomly divided them into control and experimental group. Each group got40rats. The experimental group made an anesthesia by giving intraperitoneal injection of10%chloral hydrate (3ml/100mg). Then exposing and freeing the abdominal aorta through the left upper abdominal incision into the abdominal cavity. After determining the branch of the left renal artery, fastening the abdominal aorta together with the8Gauge needled (diameter0.8mm) by a silk thread. Reaching the abdominal aortic lumen constricted lumen after the needle was picked out. The control group made the anesthesia and then just implemented the free abdominal aorta without constricted part. After the operation, the researcher observed the animal's diet, activity, their ability of responding to the outside world, etc. Recording their significant declined time in activity, cough, and difficult breathing. In keeping the2nd week, the4th week, the6th and the8th week, giving the animal hemodynamic among the same number of rats which were randomly selected from the control group and experimental group. With the right common carotid artery, the researchers connected the BL-410biological and functional experimental system (Chengdu Tai Meng Technology Co. Ltd.) through the poly plastic tube.Then the researchers gave the mean arterial blood pressure test (MAP), left ventricular systolic pressure (LVSP), left ventricular end diastolic pressure (LVEDP), left ventricular pressure increase rate (+dp/dtmax), left ventricular pressure decline rate (-dp/dtmax). After test, the rats sacrificed, and then their left ventricular tissue were picked, weighted and calculated the left ventricular mass index (LVMI). The cardiac tissue were kept in a-80℃refrigerator. In the endpoint, unified by RT-PCR method to detect the ventricular SERCA and PLB mRNA, and compared the control group at each time point and experimental group which had differences in expression levels. The remaining10%of myocardial tissue was fixed in formalin. Then embedded in a unified endpoint and sliced. HE myocardial morphological changes were observed, and the number of myocardial cells per high power field in the cross-section of left ventricular papillary muscles was counted. The researchers consolidated the result of the hemodynamic and myocardial morphology as an evaluation criterion of a successful model. Statistical Package for all data handled by SPSS13.0. Measurement data as mean±standard deviation, using t test; statistics to P<0.05as significantly different, P<0.01as significant statistical difference.
Results:General observation:after one week, each group appeared apathetic, reduced activity, feeding and water intake reduction. Those situations were improved after a week. In the2nd and4th week, there is no significant difference between the experimental group and control group in the activities of eating situations. At the6th week, animals in the experimental group turned to be less active, less diet, and less weight than the control group (298.11±50.85vs.334.29±46.09)(P<0.05). After the6th week, animals in experimental group gradually got the symptoms about cough, breathing speed up and activity decreased significantly. At the endpoint of the8th week, animals in the experimental group reflected slowly to the outside world, had no interest in eating. Some animal died (20%), and their weight is less than the control group (289.58±45.23vs.349.56±38.24)(P<0.05). After the operation, the rats in experimental group died four, and the survival rate was90%. Among them, two died within1day after surgery and two died of breathing difficulties after8weeks. There is no death in the control group. According to the hemodynamic monitoring results, at each time point the experimental group had a higher sustainment on the MAP and LVSP. And the diastolic function parameters in this group appeared progressive change. What's more, the systolic function parameters declined at the6th week. At the2nd week, comparing with the control group, the experimental group's-dp/dtmax decreased (4.32±0.27vs.5.13±0.21)(P<0.05), and there is no other difference; at the4th week, the experimental group's-dp/dtmax decreased dramatically (3.64±0.30vs.5.33±0.28)(P<0.01), the LVEDP increased significantly (15.45±2.56vs.5.90±2.46)(P<0.01), and there is no other difference; at the6th week, the experimental group's-dp/dtmax decreased obviously (3.42±0.32vs.5.29±0.34)(P <0.01), while the LVEDP increased significantly (19.89±3.28vs.5.67±2.58)(P <0.01), and the+dp/dtmax decreased (5.98±0.31vs.6.34±0.38)(P<0.05); at the8th week, in the experimental group the-dp/dtmax decreased dramatically (2.04±0.31vs.5.41±0.39)(P<0.01), and the LVEDP increased significantly (24.34±4.08vs.5.67±2.58)(P<0.01), and the+dp/dtmax decreased obviously (4.50+0.21vs.6.21±0.31)(P<0.01). The LVMI conditions:compared with the control group, the experimental group had no difference in2weeks; in the4th week it increased (2.69±0.18vs.2.33±0.20); in the6th week it increased significantly (2.65±0.21vs.2.42±0.16); in the8th week, it increased dramatically (2.96±2.39±0.19)(P<0.01). The Pathological examination revealed progressive myocardial damage:in the control group and the experimental group within2weeks, the myocardial cell was integrity and arranged in order; in the4-week-experimental group, the cardiac hypertrophy occurred and the gap widened slightly, what's more, the occasionally spotty necrosis and interstitial edema happened; in the6-week-experimental group, there was obviously cardiac hypertrophy, and the nuclei was so big that got infection, what's more the cross-sectional area increased and there was scattered punctate myocardial necrosis, then the myocardial cell in the high power field was less than the control group(19.78±3.36vs.25.34±5.04)(P<0.05); in the8-week-experimental group, showing myocardial cells significantly increased and the arrangement was disordered, then the gap widened and the showing sheet myocardial necrosis occurred, what's more, the myocardial cell in the high power field was less than the control group(18.16±3.24vs.28.35±3.25)(P<0.05). There were large amount of inflammatory cells. PLB expression showed that there was no significant difference in control and experimental groups. According to the SERCA2a expression, in the2nd week the experimental group and control group had no significant difference; in the4th week, the experimental group was less than the control group (CT value of28.15±0.84vs.26.14±0.51)(P<0.05); in the6th week, the experimental group was less than the control group (CT value of29.02±1.27vs26.50±0.89)(P<0.05); in the8th week, the experimental group was less than the control group (CT value of32.09±1.38vs.27.25±1.24)(P<0.01)
Conclusion:8-week-old Wistar rats'left ventricular diastolic function declined within2-8weeks after having the upper kidney abdominal aortic coartation. The2nd showed impaired LV active relaxation; the4th week was the stage that the filling pressure was increased; in the6th week was the stage that the restrictive filling barriers; In the8th week, the heart failure performed. The main factor of effecting the myocardial calcium cycling-SERCA2a expression may be mainly the inhibition of left ventricular diastolic dysfunction in the late term.
Part Two. The correlation between hemodynamic with Ultrasound or Markers of heart failure during evaluat left ventricular diastolic function in the model
Objective:To discuss the evaluation of ultrasonic grading in left ventricular diastolic function of the feasibility of reduction; discuss the serum NT-proBNP levels and diastolic function of the decreased correlation; to establish non-hemodynamic methods to evaluate the left ventricular diastolic function of the reduction model of.
Methods:Using upper renal abdominal aortic coarctation method to establish the left ventricular diastolic dysfunction in a30-rat-model, and establish the control group in other30ones. After2weeks,4weeks and6weeks of reduction in abdominal aortic rings, the researchers used the application of Philips iE33color Doppler to select S12-4high-frequency probe and then made the echocardiography to the rats in the experimental group and control group. The researchers used2-D ultrasound, M-mode ultrasound recording of left ventricular posterior wall thickness (LVPWD), interventricular septum thickness (IVSD), left ventricular end diastolic diameter (LVEDD), left ventricular end systolic diameter (LVESD), left a trial end systolic diameter (LADs), Left ventricular ejection fraction (LVEF), left ventricular fractional shortening (FS) and cardiac output (CO); and calculated the left ventricular mass(LVmass) according to the formula; then the researchers used the mitral diastolic flow Doppler spectrum Early peak flow velocity (E); Doppler tissue imaging (DTI) at the mitral annulus peak systolic myocardial tissue velocity (Sm), peak early diastolic velocity (Em), late diastolic peak velocity (Am); calculation of Em/Am and E/Em. After the ultrasound examination, the researchers immediately made the hemodynamic monitoring with the method that the first part mentioned. The Detection indicators included mean arterial pressure (MAP), left ventricular systolic pressure (LVSP), left ventricular end diastolic pressure (LVEDP), left ventricular pressure increase rate (+dp/dtmax), left ventricular pressure decline rate (-dp/dtmax). The researchers drew lml blood before the hemodynamic via the right common carotid artery, and then got the supernatant after centrifugation. Keeping it in a-80℃refrigerator to store and in the end point, the researchers unified to ELISA, detect serum NT-pro BNP levels. Statistical Package for all data handled by SPSS13.0. Measurement data as mean±standard deviation, using t test; statistics to P<0.05as significantly different, P<0.01as significant statistical difference.
Results:Hemodynamic results suggested that the establishment of model is successful. The2-dimensional and M-mode ultrasound examination showed that the experimental group got the gradually thickened ventricular and the left atria diameter increased. Specifically speaking, in the2nd week, there is no difference in the experimental group and control group between the various sets of data; in the4th week compared with the control group, the experimental group's LVPWD thickened (2.50±0.31vs.2.15±0.27) mm,(P<0.05); LADs broadened (3.25±0.32vs.2.84±0.14) mm,(P<0.05); in the6th week, the experimental group's LVPWD became significantly thicker (2.82±0.40vs.2.30±0.26) mm,(P<0.01); LVEDD turned larger (6.57±0.37vs.5.82±0.39) mm,(P<0.05); IVSD thickened (2.39±0.28vs.2.06±0.13) mm,(P<0.05); LADs was obviously enlarged (3.43±0.32vs.2.79±0.41) mm,(P<0.01). The detection of left ventricular diastolic function indicators could appear on behalf of progressive reduction of left ventricular diastolic changes. Specifically speaking, in the2nd week, compared with the control group, the experimental group's Em slow (8.12±0.58vs.9.65±0.65),(P<0.05). In the4th week, the experimental group's E increased faster (114.7±5.8vs.91.9±6.7) cm/s,(P<0.05), Em slowed (7.51±3.78vs.10.54±3.89) cm/s,(P<0.05); Am slowed (5.83±2.34vs.6.86±2.88) cm/s,(P<0.05); Em/Am decreased (1.29±0.11vs.1.53±0.12),(P<0.05); E/Em increased (11.08±1.12vs14.20±0.87)(P<0.05); in the6th week, the experimental group's E increased faster (118.6±6.9vs.89.5±7.2) (P<0.05); Em was significantly slower (6.23±1.43vs.9.64±2.36) cm/s,(P<0.01); Am slow (5.25±2.13vs.6.23±2.02) cm/s,(P<0.05); Em/Am was significantly reduced Small (1.18±0.14vs.1.54±0.24),(P<0.01); E/Em was significantly increased (15.06±2.10vs10.84±1.20)(P<0.01). The detection of left ventricular systolic function indexes declined at the6th week. Specifically speaking, in the6th week, compared with the control group, the experimental group's LVEF decreased (88.65±8.02vs.93.98±6.92)%,(P<0.05); FS decreased (57.23±5.02vs.61.35±6.31)%,(P<0.05); Sm lower (7.45±2.87vs.8.46±2.98) cm/s,(P<0.05). The echocardiography which represented the diastolic function and hemodynamic indexes correlated well. E and LVEDP was positively correlated (r=0.873, P<0.000), Em was a negative correlation with LVEDP (r=-0.676, P<0.001), E/Em was positively correlated with LVEDP (r=0.703, P<0.001), E and-dp/dtmax negative correlation (r=-0.690, P<0.001), Em and-dp/dtmax was positively correlated (r=0.762, P <0.001), E/Em and-dp/dtmax negative correlation (r=-0.839, P<0.000). There was a positive correlation between the LVmass and the actual measured LVM (r=0.923, P <0.000).The Serum NT-proBNP levels in the2nd and4th week increased significantly and elevated in the6th week; NT-pro BNP was positively correlated with LVEDP (r=0.590, P<0.000); NT-pro BNP was negatively correlated with-dp/dtmax (r=-0.601, P<0.000).
Results:The correlation between the Echocardiography and hemodynamic was good, so it could be an accurate assessment of left ventricular diastolic function; through analyzing echocardiography, the left ventricular filling could be determined in the different states; the correlation between the serum NT-pro BNP levels and left ventricular diastolic function decreased degree could be used for assessing the degree of ventricular diastolic function.
Part three. The research of diastolic dysfunction during perioperative of thoracic surgery
Objective:Combined echocardiography and6-minute walking test (6MWT), to evauate left ventricular diastolic function of thoracic surgery patients; Discuss the different effect in patients of thoracic surgery on different degree of left ventricular diastolic dysfunction; Discuss the relationship between postoperative complications with degrees of left ventricular diastolic dysfunction in thoracic surgery patients; Preliminary discuss the correlation between serum NT-proBNP levels and left ventricular diastolic dysfunction degree, the change during perioperative impact threshold value of the diagnosis.
Methods:From March2010to March2011, the patients in the our department who would be done thoracic surgery operation, with one or more risk factors for diastolic dysfunction, be evaluated by ultrasound to screened which with left ventricular diastolic dysfunction. On selected cases(165), the researchers grouped them according to echocardiography:group A75cases (impaired relaxation of the filling abnormalities,E/A<1), grade B58cases (pseudo-normalization,1≤E/A<1.5and E/Em>15or Em<7cm/s), group C32cases (restrictive filling abnormalities, E/A≥2, or1.5≤E/A<2and E/Em>15or Em<7cm/s).(Those risk factors included:①age≥60;②patients with hypertension;③diabetes;④hyperlipidemia,⑤combined with mild pulmonary dysfunction;⑥has Ⅰ, Ⅱ grade (NYHA) heart failure symptoms. If the following conditions appeared, the case would be excluded:①Ⅲ, Ⅳ-level cardiac function;②combined in ischemic cardiomyopathy patients with unstable angina in January near or myocardial infarction;③myasthenia gravis, cerebrovascular disease, Lower extremity vascular and motor system diseases;④arrhythmia;⑦serious insufficiency of liver and kidney function.). Patients in each group had6-minute walking test (6MWT) in one week before surgery and the researchers analyzed the differences among the groups in6-minute walk distance (6MWD) and got the diastolic function indices and some correlation. Giving the ultrasound before and immediately after the exercise, the researchers compared the cardiac function differences before and after the test and tested the amplitude index (△1) classification by pair wise differences between groups. In the3rd and8th day after the operation, the researchers went the ultrasound respectively and made the difference analysis between these results and the results of preoperative ultrasonography, then tested the difference between the indicators before and after the change range (△2). Madding the correlation analysis of△1and△2. The ultrasound parameters included:mitral valve blood Early diastolic peak flow velocity (E), atrial systolic mitral valve blood flow peak velocity (A), E/A value, peak early diastolic mitral annulus velocity (Em) peak late diastolic mitral annulus velocity (Am), peak systolic velocity of mitral annular Sm and E/Em, left ventricular ejection fraction (LVEF),the left ventricular wall thickness (LVWD,=LVPWD+IVSD), left ventricular end diastolic diameter before and after (LVEDD), left atrial end-systolic diameter before and after (LADs). Going on the ultrasound examination to the patients in each group on the same day in the morning, taking fasting blood2ml and the supernatant after centrifugation at room temperature, setting to-80℃refrigerator storage. The researchers tested the serum levels of NT-pro BNP with the uniform application in the study endpoint by the ELISA and made the correlation analysis, then compared all patients' serum NT-proNP level differences with the3rd day and the8th day after the surgery; postoperative continuous monitoring of patient vital signs; monitor the arterial oxygen tension (Pa02), arterial lactate concentration and urine volume, record the time and postoperative care the amount of furosemide, compared the differences between the groups at all levels. Then the researchers calculated heart failure (HF), respiratory failure, kidney failure, the incidence of arrhythmia in each group after the surgery and made the comparative analysis for all levels between the groups. Statistical Package for all data handled by SPSS13.0. Measurement data as mean±standard deviation, using t test; statistics to P<0.05as significantly different, P<0.01as significant statistical difference.
Results:After6MWT, ultrasound examination showed left ventricular diastolic function decreased in group B, significantly decreased in group C:E are faster,(P<0.05); E/A increased in group C (1.91±0.22vsl.72±0.21)(P<0.05); Em faster in group A (5.16±1.74vs.4.23±1.79)(P<0.05); E/Em values in group B (19.29±2.34vs.17.31±2.17)(P<0.05) and group C (25.34±2.37vs.23.23±3.01)(P<0.01) were increased; LVEF and Sm in all groups were significantly higher (P<0.05);△1Em there are differences in various groups (0.93±0.23vs0.41±0.12vs.0.14±0.04)(P<0.05),△1iE/Em there are differences in various groups (0.53±0.22vs.1.98±0.29vs.2.11±0.27)(P<0.05); Ultrasound examination showed that after3days compared with preoperative left ventricular diastolic function were decreased, systolic function in group B group and C decreased:E in all groups were faster (P<0.05); E/A in group B and C were higher (P<0.05); Em in group B and group C were lower (P<0.05); E/Em were significantly increased in all groups (P<0.05); LVEF decline in group C(56.6±13.4vs.62.2±10.3)(P<0.05); Sm in group B (6.05±1.77vs.7.15±1.43)(P<0.05) and group C (5.47±1.3vs.26.92±1.02)(P<0.05) are declining;△2LVEF,△2E/A,△2E/Em were differences among the groups (P<0.05).△1E/Em and△2E/Em the best correlation (r=0.893, P<0.000);△1E/A and△2E/A positive correlation (r=0.731, P<0.001);△1Em and△2Em was positively correlated (r=0.785, P<0.001); Serum NT-pro BNP levels and preoperative E/Em was a positive correlation, the best correlation (r=0.782, P<0.000); Serum NT-pro BNP preoperative differences between groups, with the rise of higher grade (79.32±25.43vs.89.54±18.16vs.96.35±16.22)(P<0.05). Heart failure incidence of grade group C more than group A (28.4%vs.13.3%)(P<0.05) and group B (28.2%vs.15.5%); the incidence of respiratory failure group C more than group A (21.9%vs.13.3%)(P<0.01) and group B (21.9%vs.13.8%)(P<0.01); arrhythmias group B more than group A (24.1%vs.17.3)(P<0.05), group C more than group A (21.8%vs.17.3)(P<0.01).
Conclusion:The patients with left ventricular diastolic heart failure after the surgery were further aggravated in the left ventricular diastolic dysfunction, and it increased level of preoperative functional class was significantly improved and more;6MWT joint Doppler ultrasound could predict the increscent of the degree of diastolic dysfunction after surgery, and played the role of high-risk patients can be expected to further risk of heart failure; the elevated levels of serum NT-proBNP with left ventricular diastolic dysfunction grade increased, and the monitoring of serum NT-pro BNP could contributed to the diagnostic classification of diastolic function; the Serum NT-pro BNP levels increased preoperative, and the functional class improved, when give the diagnosis of CHF, the diagnostic threshold should be improved; patients with diastolic dysfunction in the chest surgery period got a high risk of heart failure and respiratory failure.
引文
[1]Zile MR, Brutsaert DL. New concepts in diastolic dysfunction and diastplic heart failure:part Ⅰ. Circulation.2002,1053-8.
[2]Rihal CS, Nishimura RA, Hatle LK, et al.Systolic and diastolic dysfunction in patients with clinical diagnosis of dilated cardiomyopathy [J].Relation to symptoms and prognosis. Circulation,1994,90:2772-2779.
[3]Fox JM, Maurer MS.Ventriculovascular coupling in systolic and diastolic heart failure.Curr Heart Fail Rep,2005,2(4):204-211.
[4]Vasan RS, Levy D. Defining diastolic heart failure:a call for standardized diagnostic criteria. Circulation 2000,101:2118-2121.
[5]Gottdiener J S, Kitzman DW, Aurigemma GP, et al.Left atrial volume,geometry and function in systolic and diastolic heart failure of persons> or=65 years of age (the cardiovascular health study). [J].Am J Cardiol,2006,97 (1):83-89.
[6]Waggoner AD, Bierig SM. Tissue Doppler imaging:a useful echocardiographic method for the cardiac sonographer to assess systolic and diastolic ventricular function. J Am Soc Echocardiogr,2002,15 (5):478-482.
[7]Nikitin NP, Witte KK, Thackray SD, et al. Longitudinal ventricular function: normal values of atrioventricular annular and myocardial velocities measured with quantitative two-dimensional color Doppler tissue imaging. J Am Soc Echocardiogr,2003,16 (9):906-921.
[8]Bruch C,Schmermund A, Bartel T, et al. Tissue Doppler imaging:A new technique for assessment of pseudonormalization of the mitral inflow pattern. Echocardiography,2000,17:539-546.
[9]Lazar M, Frnaz RE, Christina S, et al. Diastolic heart failure[J].Cardiovasc Res, 2000,45:813-825.
[10]Rienstra M, Van Gelder IC,Van den Berg MP, et al. Natriuretic peptides in Patients with atrial fibrillation and advanced chronic heart failure:determinants and prognostic value of(NT-)ANP and (NT-Pro)BNP[J]. Europace, 2006,Jul,8(7):482-487.
[11]Schou M, Gustafsson F, Nielsen PH,et al. Unexplained week-to-week variation in BNP and NT-proBNP is low in chronic heart failure Patients during steady state[J]. Eur J Heart Fail,2007Jan,9(l):68-74.
[12]Power JM, Tonkin AM. Large animal models of heart failure[J]. Aust N Z J Med.1999,29(3):395-402.
[13]Munagala VK, Hart CY, Bumett JC Jr, et al. Ventricular structure and function in aged dogs with renal hypertension:a model of experimental diastolic heart failure[J].Cireulation.2005:111 (9):1128-1135.
[14]Desjardins GS, Mueller RW, Cauchy MJ. A pressure overload model of congestive heart failure in rats [J]. Cardiovasc Res,1988,22 (10):696-702.
[15]Ostman-Smith. Reduction by oral propranolol treatment of left ventricular hypertrophy secondary to pressure- overload in the rat [J].British Journal of Phannaeology.1995,116:2703-9.
[16]Annmarie D, Michael L, Pucci A, et al. Contribution of constrictor prostanoids to the calcium-dependent basal tone in the aorta from rats with aortic coarctation induced hypertension:relationship to nitric oxide[J].the Journal of Pharmacology and Experimental Therapeutics.1997,283:75-81.
[17]Donatella S, Andrea S, Emilio M, et al. Myocardial remodeling and arrhymogenesis in moderate cardiac hypertrophy in rats[J].Am J Physiol Heart Cire Physiol.2001,280:142-150.
[18]Mariela MG, Bridget B, Carlos MF, et al. Increased hypothalamic angiotensin-(1-7) levels in rats with aortic coarctation-induced hypertension[J]. NIH Public Aeeess.2007,28(8):1580-1585.
[19]Bezerra SM, dos Santos CM, et al. Chronic AT(1) receptor blockade alters autonomic balance and sympathetic responses in hypertension [J].HyPertension. 2001:38:569-575.
[20]Massart PE, Donckier J, Kyselovic J, et al. Carvedilol and lacidipine prevent cardiac hypertrophy and endothdin-1 geneover expression after aortic banding[J]. Hypertension,1999; 34:1197-1201.
[21]Bouloumie A, Bauersachs J, Linz W, et al. Endothelial dysfunction coincides with anenhanced natric oxide synthase expression and superoxide anion production 1 J J. Hypertension,1997:30:934-941.
[22]Rodriguez IB, Quiroz Y, Kim CH, et al. Hypertension induced by aortic coarctation above the renal arteries is associated with immune cell infiltration of the kidneys[J]. Am J Hypertens.2005,18(11):1449-1456.
[23]Kuo WW,Chu CY, Wu CH, et al. The profile of cardiac cytochrome coxidase(COX) expression in an accelerated cardiac-hypertrophy model[J]. J Biomed Sci.2005,12(4):601-610.
[24]WangLJ, HeJG,MaH, et al.Chronic administration of angiotensin-(1-7) attenuates pressure-overload left ventricular hypertrophy and fibrosis in rats[J]. Di Yi Jun Yi Da Xue Xue Bao.2005 May;25(5):481-487.
[25]SilvaR,Nikitin NP, Bhandari S, et al. Atherosclerotic renovascular disease in chronic heart failure:should we intervene[J]. Eur Heart J.2005,26(16):1596-1605.
[26]MurPhy TP,Rundbaek JH, Cooper C, et al. Chronic renal ischemia:implications for cardiovascular disease risk[J]. J Vasc Interv Radiol.2002,13(12):1187-1198.
[27]Zanchetti A, Stella A. Cardiovascular disease and the kidney:an epidemiologic overview[J]. J Cardiovasc Phannaeol.1999,33 SuPl 1:1-6.
[28]Del Gaudio A, Ussia G, Panettiere P, et al. Role of the kidneys in the genesis of arterial hypertension caused by coarctations of the abdominal aorta [J]. Minerva Chir. 1986,41 (14):1099-1104.
[29]Schirger JA, Chen HH, Jougasaki M, et al. Endothelin A receptor antagonism in experimental congestive heart failure results in augmentation of the renin-angiotensin system and sustained sodium retention[J]. Cireulation.2004,109(2):249-254.
[30]Holtz J, Finekh M. Pathophysiology of cardiorenal regulatory mechanisms in heart failure[J].Z Kardiol.1991,80Suppl 2:1-10.AmCollCardiol.2004:43(11):2097-2101.
[31]Hay I, Rich J, Feber P, et al. Role of impaired myocardial relaxation in the production of elevated left ventricular filling pressure[J]. Am J Physiol Heart Cire Physiol.2005,288(3):1203-1208.
[32]Schannwell CM, Schoebel FC, Marx R, et al. Prognostic relevance of left ventricular diastolic function parameters in dilated cardiomyopathy[J].Z Kardiol.2001,90(4):269-279.
[33]Chopra M, Shanna AC. Distinct cardiodynamic and molecular characteristics during early and late stages of sepsis- induced myoeardial dysfunetion[J]. Life Sci.2007,81(4):306-316.
[34]Givertz MM, Andreou C, Conrad CH, et al. Direct myocardial effects of levosimendan in humans with left ventricular dysfunction:alteration of force-frequency and relaxation-frequency relationships [J]. Cireulation.
[35]Frank KF, Bolck B, Erdmann E, et al. Sarcoplasmic reticulum Ca2-ATPase modulates cardiac contraction and relaxation [J].Cardiovasc Res,2003,57:20-27.
[36]Periasamy M, Huke S. SERCA pump level is a critical determinant of Ca2+ homeostasis and cardiac contractilit y[J]. J Mol CellCardiol,2001,33:1053-1063.
[37]Schmidt U,Hajjar RJ,Kim CS,et al.Human heart failure:cAMP stimulation of SRCa2+-ATPase activity and phosphorylation level of phospholamban.Am J physiol.1999,277:H474-480.
[38]Babu GJ, Periasamy M. Transgenic mouse models for cardiac dysfunction by a specific gene manipulation [J]. Methods Mol Med,2005,112:3652377.
[39]Weisser-Thomas J, Kubo H, Hefner CA, et al. The Na+/Ca2+ exchanger/SR Ca2+ ATPase transport capacity regulates the contractility of normal and hypertrophied feline ventricular myocytes [J]. J Card Fail,2005,11:380-387.
[40]Lavine SJ, Lavine JA. The effect of acute hypertension on left ventricular diastolic pressures in a canine model of left ventricular dysfunction with a preserved ejection fraction and elevated left ventricular filling pressures[J]. J Am Soc Eehocardiogr.2006,19(11):1350-1358.
[41]Schwammenthal E, Popescu BA, Popescu AC, et al. Association of left ventricular filling parameters assessed by pulsed wave Doppler and color M-mode Doppler echocardiography with left ventricular pathology, pulmonary congestion, and left ventricular end-diastolic pressure[J]. Am J Cardiol.2004:94(4):488-491.
[42]Yasuyuki Tsujita, Takahiro Kato, Mark A. Sussman. Evaluation of Left Ventrieular Function in Cardiomyopathic Mice by Tissue Doppler Molecular Cardiologv of China, February 2008. Vol.8 No.1 (Serial No.38 and Color M-Mode Doppler Echocardiography. Echocardiography 2005,22:245-253.
[43]Nagueh S, Sun H, Kopelen H, et al. Hemodynamic determinants of the mitral annulus diastolic velocities by tissue Doppler. Journal of the Amrican College of Cardiology,2001,37:278-285.
[44]Moe G, Angus C,Howard R, et al. Pathophysiological role of changing atrial size and pressure in modulation of atrial natriuretic factor during evolving experimental heart failure. Cardiovascular Research,1990,24:570-577.
[45]Abhayaratna WP,Seward JB,Appleton CP et al. Left atrial size:Physiologic determinants and clinical applications. Journal of the American College of Cardiology,2006,47:2357-2363.
[46]Iwanaga Y, Nishi I, Furuichi S, et al. B-type natriuretic pep tide strongly reflects diastolic wall stress in patients with chronic heart failure[J]. JACC,2006,47 (4): 742-748.
[47]Maisel AS, Krishnaswamy, Nowak RM, et al. Reqid measurement of B-type natriuretic peptide in the emergency diagnosis of heart failure[J]. N Eng J Med, 2002,347(3):161-167.
[48]Senni M,Rodeheffer R,Tribouilloy,et al. Use of echocardiography in the management of congestive heart failure in the community. J Am Coll Cardiol.1999 Jan;33(1):164-70.
[49]Zile MR, Brutsaert DL. New concepts in diastolic dysfunction and diastolic heart failure:Part Ⅰ:diagnosis, prognosis, and measurements of diastolic function. Circulation.2002 Mar 19,105(11):1387-93.
[50]ZileMR, BaieuCF, Gaaseh WH. Diastolic heart failure abnormalities in active relaxation and passive stiffness of the left ventricle[J].N Engl J Med.2004,350(19):1953-1959.
[51]Smulders YM, Stehouwer CD, Bronzwaer JG, et al. Diastolic heart failure [J]. Ned Tijdsehr Geneeskd.2003,147(50):2467-2470.
[52]He KL, Dickstein M, Sabbah HN, et al. Mechanisms of heart failure with well preserved ejection fraction in dogs following limited coronary microembolization[J]. Cardiovase Res.2004,64(1):72-83.
[53]Federmann M, Hess OM. Differentiation between systolic and diastolic dysfunction [J]. Eur Heart J.1994,15Suppl D:2-6.
[54]胡佳文,邓兵.舒张性心力衰竭研究进展.[J]2008,2(137),17-19.
[55]Lorell BH. Diastolic dysfunction in pressure-overload hypertrophy and its modification by angiotensin II:current concepts[J]. Basic Res Cardiol.1992,87 SuPP12:163-172.
[56]Klapholz M, Maurer M, Lowe AM, et al. Hospitalization for heart failure in the presence of a normal left ventricular ejection fraction:results of the New York Heart Failure Registry. Am Coll Cardiol.2004 Apr 21;43(8):1432-8.
[57]Appleton CP. Hemodynamic determinants of Doppler pulmonary venous flow velocity components:new insights from studies in lightly sedated normal dogs. J Am Coll Cardiol.1997 Nov 15;30(6):1562-74.
[58]Cohen GI, Pietrolungo JF, Thomas JD, et al. A practical guide to assessment of ventricular diastolic function using Doppler echocardiography [J]. J Am Coll Cardiol,1996,27(7):1753-1760.
[59]Sohn DW, Chai IH, Lee DJ,et al. Assessment of mitral annulus velocity by Doppler tissue imaging in the evaluation of left ventricular diastolic function. J Am Coll Cardiol.1997 Aug;30(2):474-80.
[60]Garcia MJ, Thomas JD, Klein AL.et al.New Doppler echocardiographic applications for the study of diastolic function. Am Coll Cardiol.1998 Oct, 32(4):865-75..
[61]Vitarelli A, Conde Y, Cimino E, et al. Assessment of ascending aorta distensibility after successful coarctation repair by strain doppler echocardiography [J]. J Am Soc Echocardiogr,2008, [Epub ahead of print].742-748.
[62]Khankirawatana B, Khankirawatana S, Peterson B,et al. Peak atrial systolic mitral annular velocity by Doppler tissue reliably predicts left atrial systolic function. J Am Soc Echocardiogr.2004 Apr;17(4):353-60.
[63]Nagueh SF, Sun H, Kopelen HA, et al.Hemodynamic determinants of the mitral annulus diastolic velocities by tissue Doppler. J Am Coll Cardiol.2001 Jan,37(1): 278-85.
[64]Gibson DG, Francis DP. Clinical assessment of left ventricular diastolic function [J]. Heart,2003,89(2):231-238.
[65]Nishimura R,Tajik AJ. The Vasalva maneuver:3 centuries later. Mayo Clin Proc. 2004 Apr;79(4):577-8.
[66]Hurrell DG, Nishimura RA, Ilstrup DM, et al. Utility of preload alteration in assessment of left ventricular filling pressure by Doppler echocardiography:a simultaneous catheterization and Doppler echocardiographic study[J]. JAm Coll Cardiol,1997,30(2):459-467.
[67]Brun P, Tribouilloy C, Duval AM,et al.Left ventricular flow propagation during early filling is related to wall relaxation:a color M-mode Doppler analysis. J Am Coll Cardiol.1992 Aug;20(2):420-32.
[68]Garcia MJ, Smedira NG, Greenberg NL,Color M-mode Doppler flow propagation velocity is a preload insensitive index of left ventricular relaxation:animal and human validation. J Am Coll Cardiol.2000 Jan;35(1):201-8.
[69]Takatsuji H, Mikami T, Urasawa K, et al.A new approach for evaluation of left ventricular diastolic function:spatial and temporal analysis of left ventricular filling flow propagation by color M-mode Doppler echocardiography. J Am Coll Cardiol. 1996 Feb;27(2):365-71.
[70]De Boeck BW, Oh JK, Vandervoort PM, et al. Colour M-mode velocity propagation:a glance at intra-ventricular pressure gradients and early diastolic ventricular performance. Eur J Heart Fail.2005 Jan;7(1):19-28.
[71]M(?)ller JE, S(?)ndergaard E, Seward JB,, et al. Ratio of left ventricular peak E-wave velocity to flow propagation velocity assessed by color M-mode Doppler echocardiography in first myocardial infarction:prognostic and clinical implications[J]. J Am Coll Cardiol,2000,35(2):363-370。
[72]Steine K, Stugaard M, Smiseth O A. Mechanisms of retarded apical filling in acute ischemic left ventricular failure[J]. Circulation,1999,99(15):2048-2054.
[73]合田亚希子,等.舒张功能障碍的诊断日本医学介绍,2007,18(5)[J],193-196
[74]M(?)ller JE, Poulsen SH, S(?)ndergaard E, et al. Preload dependence of color M-mode Doppler flow propagation velocity in controls and in patients with left ventricular dysfunction. J Am Soc Echocardiogr.2000 Oct;13(10):902-9.
[75]Takeda K,Chang S-M, Nagueh S, etal. Dependence of flow propagation velocity on cardiac size:Observations from patients with dilated cardiomyopathy and hypertrophic cardiomyopathy. J of the American college of Cardiology, 2002,39:383A-384A.
[76]Gonzalez-Vilchez F, Ares M, Ayuela J, et al.Combined use of pulsed and color M-mode Doppler echocardiography for the estimation of pulmonary capillary wedge pressure:an empirical approach based on an analytical relation. J Am Coll Cardiol. 1999 Aug;34(2):515-23.
[77]Gonzdlez-Vilchez F, Ayuela J, Ares M, et al. Comparison of Doppler echocardiography, color M-mode Doppler, and Doppler tissue imaging for the estimation of pulmonary capillary wedge pressure. J Am Soc Echocardiogr.2002 Oct;15(10 Pt2):1245-50.
[78]Firstenberg MS, Levine BD, Garcia MJ, et al. Relationship of echocardiographic indices to pulmonary capillary wedge pressures in healthy volunteers. JAm Coll Cardiol.2000 Nov 1;36(5):1664-9.
[79]Guyatt GH, Sullivan MJ, Thomp son PJ, et al. The 6-minute walk test:a newmeasure of exercise capacity in patients with chronic heart failure [J]. Can Med A ssoc J,1985,132 (8):919-923.
[80]Task force for the diagnosis and treatment of chronic heart failure. European society of cardiology. Guidelines for the diagnosis and treatment of chronic heart failure[J]. Eur Heart J,2001,22 (17):1527-1560.
[81]GualeniA,Aloia A, GentiliniA, et al. Effects of maximally tolerated oral therapy on the six2minute walking test in patients with chronic congestive heart failure secondary to either ischemic or idiopathic dilated cardiomyopathy[J]. Am J Car2 diol,1998,81 (11):1370-1372.
[82]Cahalin LP,MathierMA, Semigran MJ, et al. The six2minute walk test predicts peak oxygen up take survival in patients with advanced heart failure [J]. Chest,1996, 110 (2):325-330.
[83]Enright PL,McBurnieMA,B ittnerV, et al. The 62minute walk, a quick measure of functional status in elderly adults[J]. Chest,2003,123 (2):387-398.
[84]Opasich C, Pinna GD,Michaier MA, et al. Rep reducibility of the six2minute walking test in chronic congestive heart failure patients:practical implications [J]. Am J Cardiol,1998,81 (12):1497-1500.
[85]ATS statement. Guidelines for the six-minute walk test [J]. Am J Respir Crit CareMed,2002,166 (1):111-117.
[86]Enright PL. The 6 minute walk test[J]. Respir Care,2003,48 (8):783-785.
[87]Gottdiener J S, Kitzman DW, Aurigemma GP, et al. Left atrial volume, geometry, and function in systolic and diastolic heart failure of persons> or=65 years of age (the cardiovascular health study) [J].Am J Cardiol,2006,97 (1):83-89.
[88]Bttencourt P, Ferreira A, Dias P, et al. Evaluation of brain natriretic peptide in dianosis of heart failure[J]. Cardiology,2000,93:19-25.
[89]Mikkelsen KV, Bie PM(?)ller JE, et al. Neurehormonal activation and diagnostic value of cardiac peptides in patients with suspected mild heart failure [J]. Int J Cardiol.2006 Jun 28;110(3):324-33.
[90]Tschope C, Kasner M, Westerm annD, et al. The role of NT-proBNP in the diagnostic of isolated diastolic dysfunction correlation with echocardiographic and invasive measurements [J]. Eur Heart J,2005,26:2277-2284.
[1]Tokushima T, Reid CL, Gardin JM. Left ventricular diastolic function in the elderly. Am J Geriatr Cardiol,2001,10:20-29.
[2]Appleton CP,Hatle LK,Popp RI. Relation of transmitral flow velocity patterms to left ventricular diastolic function:New insights from a combined hemodynamic and Doppler echocardiographic study(Reprinted from the Journal of the American College of Cardiology, August,1988) Journal of the American College of Cardiology,1999,34(6):1659-1662.
[3]Vasan RS, Levy D. Defining diastolic heart failure:a call for standardized diagnostic criteria. Circulation 2000,101:2118-2121.
[4]Mariell Jessup, William T. Abraham, Donald E. Casey et al.2009 Focused Update Incorporated Into the ACC/AHA 2005 Guidelines for the Diagnosis and Management of Heart Failure in Adults. Circulation,2009,119:e391-e479.
[5]Chinali M, de Simone 131 Roman MJ, et al. Left atrial systolic force and cardiovascular outcome-The Strong Heart Study. American Journal of Hypertension, 2005,18(12):1570-1576.
[6]马志敏；李继敏；舒张功能障碍和舒张性心力衰竭的新观点 中国医药导刊2003,5(5)：332-334
[7]Babu GJ, Periasamy M. Transgenic mouse models for cardiac dysfunction by a specific gene manipulation [J]. Methods Mol Med,2005,112:365-377.
[8]Weisser-Thomas J, Kubo H, Hefner CA, et al. The Na+/Ca2+exchanger/SR Ca2+ATPase transport capacity regulates the contractility of normal and hypertrophied feline ventricular myocytes [J]. J Card Fail,2005,11:380-387.
[9]Mihra S, Sabbah HN, Rastogi S, et al. Reduced sarcoplasmic reticulum Ca2+ uptake and increased Na+-Ca2+exchanger expression in left ventricle myocardium of dogs with progression of heart failure[J]. Heart Vessels,2005,20:23-32.
[10]Stull LB, Matteo RG, Sweet WE, et al. Changes in calcium cy2 cling precede cardiac dysfunction during autoimmune myocarditis in mice[J]. J Mol Cell Cardiol,2001,33:449-460
[ll]Miyamoto Ml, del Monte F, Schmidt U, et al. Adenoviral gene transfer of SERCA2a improves left ventricular function in aortic-banded rats in transition to heart failure, Proc Natl Acad Sci USA.2000 Jan 18;97(2):793-8
[12]del Monte F,Hajjar PJ. Targeting calcium cycling proteins in heart failure through gene transfer. Journal of Physiology-London,2003,546(1):49-61.
[13]Marks AR, Reiken S, Marx SO. Progression of heart failure-Is protein kinase A hyperphosphorylation of the ryanodine receptor a contributing factor? [J] Circulation,2002,105(3):272-275.
[14]Reiken S, Gaburjakova M, Guatimosim S, et al. Protein kinase A phosphorylation of the cardiac calcium release channel(ryanodine receptor)in normal and failing hearts-Role of phosphatases and response to isoproterenol. Journal of Biological Chemistry,2003.278(1):444-453.
[15]Armoundas AA, Hobai IA, Tomaselli GF, et al. Role of sodium-calcium-exchanger in modulating the action potential of ventricular myocytes from normal and failing hearts. Circulation Research,2003,93(1):46-53.
[16]Weisser-Thomas J, Piacentino V Gaughan JP,et al. Calcium entry via Na/Ca exchange during the action potential directly contributes to contraction of failing human ventricular myocytes. Cardiovascular Research,2003,57(4):974-985.
[17]Hasenfuss G, Pieske B. Calcium cycling in congestive heart failure. Journal of Molecular and Cellular Cardiology,2002,34(8):951-969.
[18]Paulus WJ, Brutsaert DL, Gillebert TC, et al. How to diagnose diastolic heart failure. European Heart Journal,1998,19(7):990-1003.
[19]Wu YM, Bell sP,Trombitas K et al. Changes in titin isoform expression in pacing-induced cardiac failure give rise to increased passive muscle stiffness. Circulation,2002,106(11):1384-1389.
[20]Warren CM, Jordan MC, Roos KP,et al. Titin isoform expression in normal and hypertensive myocardium. Cardiovascular Research,2003,59(1):86-94.
[21]Cazolla O, Freiburg A, Helmes M, et al.Differential expression of cardiac titin isoforms and modulation of cellular stiffness. Circ Res.2000; 86:59-67.
[22]Jalil JE, Doering CW, Janicki JS, et al. Fibrillar collagen and myocardial s tiffness in the intact hypertrophied rat left ventricle. Circ Res.1989; 64:1041-1050.
[23]rutsaert DL, Fransen P, Andries LJ, et al. Cardiac endothelium and myo cardial function. Cardiovasc Res.1998; 38:281-290.
[24]Paulus WJ. Beneficial effects of nitric oxide on cardiac diastolic function: "the flip side of the coin." Heart Failure Rev.2000; 5:337-344.
[25]Tian R, Nascimben L, Ingwall JS, et al. Failure to maintain a low ADP concentration impairs diastolic function in hypertrophied rat hearts. Circulation, 1997,96(4):1313-1319.
[26]徐晤,夏勇,陈建辉,等.左室测压和造影对冠心病介入治疗前后左心室功能变化的评价.临床心血管病杂志,2006,22(2)：116.117.
[27]Little WC, Downes TR. Clinical evaluation of left ventricular diastolic performance. Progress in Cardiovascular Diseases,1990,32(4):273-290.
[28]Silber HA, Gottliebson WM, Lohmann DP,et al. A rapid hemodynamic monitor of acute ischemia during cardiac procedures:Changes in relaxation via a continuous left ventricular pressure-derivative loop. Journal of Surgical Research,2006, 134(1):107-113.
[29]Starling MR, Montgomery DG Mancini GB, et al. Load independence of the rate ofisovolumic relaxation in man. Circulation,1987,76(6):1274-81.
[30]Dick T. Diastolic Function:The Necessary Basics. Journal of Diagnostic Medical Sonography,2006,22:99-108.
[31]Appleton cP,Hatle LK,Popp RI. Relation of transmitral flow velocity patterns to left ventricular diastolic function:New insights from a combined hemodynamic and Doppler echocardiographic study(Reprinted from the Journal of the American College of Cardiology,August,1988). Journal of the American College ofCardiology,1999,34(6):1659-1662.
[32]Cohen GI, Pietrolungo IF,Thomas JD, et al. A practical guide to assessment of ventricular diastolic function using Doppler echocardio- graphy. J Am Coil Cardiol, 1996,27(7):1753-60.
[33]Kitzman DWj Sheikh KH, Beere PA, et al. Age-related alteration of Doppler left ventricular filling indexes in normal subjects are independent of left ventricular mass, heart rate, contractility and loading condition. JACC,1991,18(5): 1243.1250.
[34]高峻,李治安,王新房,等.多普勒组织成像探测二尖瓣环E/A比率评价左室舒张功能价值的探讨.中国超声医学杂志,2000,16(11)：849.853.
[35]Vitarelli A, Conde Y, Cimino E, et al. Assessment of ascending aorta distensibility after successful coarctation repair by strain doppler echocardiography [J]. J Am Soc Echocardiogr,2008, [Epub ahead of print].742-748.
[36]Sohn DW, Chai IH, Lee DJ,et al.Assessment of mitral annulus velocity by Doppler tissue imaging in the evaluation of left ventricular diastolic function. J Am Coll Cardiol.1997 Aug;30(2):474-80.
[37]Khankirawatana B, Khankirawatana S, Peterson B,et al. Peak atrial systolic mitral annular velocity by Doppler tissue reliably predicts left atrial systolic function. J Am Soc Echocardiogr.2004 Apr;17(4):353-60. [J]. J Am Soc Echocardiogr,2008, [Epub ahead of print].742-748.
[38]Nagueh SF, Sun H, Kopelen HA, et al.Hemodynamic determinants of the mitral annulus diastolic velocities by tissue Doppler. J Am Coll Cardiol.2001 Jan,37(1): 278-85.
[39]Gibson DG, Francis DP. Clinical assessment of left ventricular diastolic function [J]. Heart,2003,89(2):231-238.
[40]Vinlcius LB, Otavio DC, Luiz PR, et al. Tissue Doppler imaging in the evaluation of the regional diastolic function in chagas' disease[J]. Eur J Echocardiogr,2001,2(2):94-99。
[41]Ueno Y, Nakamura Y, Ohbayashi Y, et al. Evaluation of left ventricular systolic and diastolic global function:peak positive and negative myocardial velocity gradients in M-mode Doppler tissue imaging[J]. Echocardiography,2002,19(1): 15-25
[42]J Waggoner AD, Bierlg SM. Tissue Doppler imaging:a useful echocardiographic method for the cardiac sonographer to assess systolic and diastolic ventricular function[J]. J Am Soc Eehecardiogr,2001,14(12):1143.1152
[43]Garcia MJ, Thomas JD, Klein AL. New Doppler echocardiography applications for the study of diastolic function. JAm Coil Cardiol,1998,32(4):865.
[44]Takatsuji H, Mikami T, Urasawa K et al. A new approach for evaluation of left ventricular diastolic function:spatial and temporal analysis of left ventricular filling flow propagation by color M-mode Doppler echocardiography. J Am Coil Cardiol, 1996,27(2):365-71.
[45]Schindera ST, Mehwald PS, Sahn DL, et al. Accuracy of real-time three-dimensional echocardiography for quantifying right ventricular volume:static and pulsatile flow studies in an anatomic in vitro model. [J] Ultrasound Med,2002,21(10):1069-1075.
[2]Rihal CS, Nishimura RA, Hatle LK, et al.Systolic and diastolic dysfunction in patients with clinical diagnosis of dilated cardiomyopathy [J].Relation to symptoms and prognosis. Circulation,1994,90:2772-2779.
[3]Fox JM, Maurer MS.Ventriculovascular coupling in systolic and diastolic heart failure.Curr Heart Fail Rep,2005,2(4):204-211.
[4]Vasan RS, Levy D. Defining diastolic heart failure:a call for standardized diagnostic criteria. Circulation 2000,101:2118-2121.
[5]Gottdiener J S, Kitzman DW, Aurigemma GP, et al.Left atrial volume,geometry and function in systolic and diastolic heart failure of persons> or=65 years of age (the cardiovascular health study). [J].Am J Cardiol,2006,97 (1):83-89.
[6]Waggoner AD, Bierig SM. Tissue Doppler imaging:a useful echocardiographic method for the cardiac sonographer to assess systolic and diastolic ventricular function. J Am Soc Echocardiogr,2002,15 (5):478-482.
[7]Nikitin NP, Witte KK, Thackray SD, et al. Longitudinal ventricular function: normal values of atrioventricular annular and myocardial velocities measured with quantitative two-dimensional color Doppler tissue imaging. J Am Soc Echocardiogr,2003,16 (9):906-921.
[8]Bruch C,Schmermund A, Bartel T, et al. Tissue Doppler imaging:A new technique for assessment of pseudonormalization of the mitral inflow pattern. Echocardiography,2000,17:539-546.
[9]Lazar M, Frnaz RE, Christina S, et al. Diastolic heart failure[J].Cardiovasc Res, 2000,45:813-825.
[10]Rienstra M, Van Gelder IC,Van den Berg MP, et al. Natriuretic peptides in Patients with atrial fibrillation and advanced chronic heart failure:determinants and prognostic value of(NT-)ANP and (NT-Pro)BNP[J]. Europace, 2006,Jul,8(7):482-487.
[11]Schou M, Gustafsson F, Nielsen PH,et al. Unexplained week-to-week variation in BNP and NT-proBNP is low in chronic heart failure Patients during steady state[J]. Eur J Heart Fail,2007Jan,9(l):68-74.
[12]Power JM, Tonkin AM. Large animal models of heart failure[J]. Aust N Z J Med.1999,29(3):395-402.
[13]Munagala VK, Hart CY, Bumett JC Jr, et al. Ventricular structure and function in aged dogs with renal hypertension:a model of experimental diastolic heart failure[J].Cireulation.2005:111 (9):1128-1135.
[14]Desjardins GS, Mueller RW, Cauchy MJ. A pressure overload model of congestive heart failure in rats [J]. Cardiovasc Res,1988,22 (10):696-702.
[15]Ostman-Smith. Reduction by oral propranolol treatment of left ventricular hypertrophy secondary to pressure- overload in the rat [J].British Journal of Phannaeology.1995,116:2703-9.
[16]Annmarie D, Michael L, Pucci A, et al. Contribution of constrictor prostanoids to the calcium-dependent basal tone in the aorta from rats with aortic coarctation induced hypertension:relationship to nitric oxide[J].the Journal of Pharmacology and Experimental Therapeutics.1997,283:75-81.
[17]Donatella S, Andrea S, Emilio M, et al. Myocardial remodeling and arrhymogenesis in moderate cardiac hypertrophy in rats[J].Am J Physiol Heart Cire Physiol.2001,280:142-150.
[18]Mariela MG, Bridget B, Carlos MF, et al. Increased hypothalamic angiotensin-(1-7) levels in rats with aortic coarctation-induced hypertension[J]. NIH Public Aeeess.2007,28(8):1580-1585.
[19]Bezerra SM, dos Santos CM, et al. Chronic AT(1) receptor blockade alters autonomic balance and sympathetic responses in hypertension [J].HyPertension. 2001:38:569-575.
[20]Massart PE, Donckier J, Kyselovic J, et al. Carvedilol and lacidipine prevent cardiac hypertrophy and endothdin-1 geneover expression after aortic banding[J]. Hypertension,1999; 34:1197-1201.
[21]Bouloumie A, Bauersachs J, Linz W, et al. Endothelial dysfunction coincides with anenhanced natric oxide synthase expression and superoxide anion production 1 J J. Hypertension,1997:30:934-941.
[22]Rodriguez IB, Quiroz Y, Kim CH, et al. Hypertension induced by aortic coarctation above the renal arteries is associated with immune cell infiltration of the kidneys[J]. Am J Hypertens.2005,18(11):1449-1456.
[23]Kuo WW,Chu CY, Wu CH, et al. The profile of cardiac cytochrome coxidase(COX) expression in an accelerated cardiac-hypertrophy model[J]. J Biomed Sci.2005,12(4):601-610.
[24]WangLJ, HeJG,MaH, et al.Chronic administration of angiotensin-(1-7) attenuates pressure-overload left ventricular hypertrophy and fibrosis in rats[J]. Di Yi Jun Yi Da Xue Xue Bao.2005 May;25(5):481-487.
[25]SilvaR,Nikitin NP, Bhandari S, et al. Atherosclerotic renovascular disease in chronic heart failure:should we intervene[J]. Eur Heart J.2005,26(16):1596-1605.
[26]MurPhy TP,Rundbaek JH, Cooper C, et al. Chronic renal ischemia:implications for cardiovascular disease risk[J]. J Vasc Interv Radiol.2002,13(12):1187-1198.
[27]Zanchetti A, Stella A. Cardiovascular disease and the kidney:an epidemiologic overview[J]. J Cardiovasc Phannaeol.1999,33 SuPl 1:1-6.
[28]Del Gaudio A, Ussia G, Panettiere P, et al. Role of the kidneys in the genesis of arterial hypertension caused by coarctations of the abdominal aorta [J]. Minerva Chir. 1986,41 (14):1099-1104.
[29]Schirger JA, Chen HH, Jougasaki M, et al. Endothelin A receptor antagonism in experimental congestive heart failure results in augmentation of the renin-angiotensin system and sustained sodium retention[J]. Cireulation.2004,109(2):249-254.
[30]Holtz J, Finekh M. Pathophysiology of cardiorenal regulatory mechanisms in heart failure[J].Z Kardiol.1991,80Suppl 2:1-10.AmCollCardiol.2004:43(11):2097-2101.
[31]Hay I, Rich J, Feber P, et al. Role of impaired myocardial relaxation in the production of elevated left ventricular filling pressure[J]. Am J Physiol Heart Cire Physiol.2005,288(3):1203-1208.
[32]Schannwell CM, Schoebel FC, Marx R, et al. Prognostic relevance of left ventricular diastolic function parameters in dilated cardiomyopathy[J].Z Kardiol.2001,90(4):269-279.
[33]Chopra M, Shanna AC. Distinct cardiodynamic and molecular characteristics during early and late stages of sepsis- induced myoeardial dysfunetion[J]. Life Sci.2007,81(4):306-316.
[34]Givertz MM, Andreou C, Conrad CH, et al. Direct myocardial effects of levosimendan in humans with left ventricular dysfunction:alteration of force-frequency and relaxation-frequency relationships [J]. Cireulation.
[35]Frank KF, Bolck B, Erdmann E, et al. Sarcoplasmic reticulum Ca2-ATPase modulates cardiac contraction and relaxation [J].Cardiovasc Res,2003,57:20-27.
[36]Periasamy M, Huke S. SERCA pump level is a critical determinant of Ca2+ homeostasis and cardiac contractilit y[J]. J Mol CellCardiol,2001,33:1053-1063.
[37]Schmidt U,Hajjar RJ,Kim CS,et al.Human heart failure:cAMP stimulation of SRCa2+-ATPase activity and phosphorylation level of phospholamban.Am J physiol.1999,277:H474-480.
[38]Babu GJ, Periasamy M. Transgenic mouse models for cardiac dysfunction by a specific gene manipulation [J]. Methods Mol Med,2005,112:3652377.
[39]Weisser-Thomas J, Kubo H, Hefner CA, et al. The Na+/Ca2+ exchanger/SR Ca2+ ATPase transport capacity regulates the contractility of normal and hypertrophied feline ventricular myocytes [J]. J Card Fail,2005,11:380-387.
[40]Lavine SJ, Lavine JA. The effect of acute hypertension on left ventricular diastolic pressures in a canine model of left ventricular dysfunction with a preserved ejection fraction and elevated left ventricular filling pressures[J]. J Am Soc Eehocardiogr.2006,19(11):1350-1358.
[41]Schwammenthal E, Popescu BA, Popescu AC, et al. Association of left ventricular filling parameters assessed by pulsed wave Doppler and color M-mode Doppler echocardiography with left ventricular pathology, pulmonary congestion, and left ventricular end-diastolic pressure[J]. Am J Cardiol.2004:94(4):488-491.
[42]Yasuyuki Tsujita, Takahiro Kato, Mark A. Sussman. Evaluation of Left Ventrieular Function in Cardiomyopathic Mice by Tissue Doppler Molecular Cardiologv of China, February 2008. Vol.8 No.1 (Serial No.38 and Color M-Mode Doppler Echocardiography. Echocardiography 2005,22:245-253.
[43]Nagueh S, Sun H, Kopelen H, et al. Hemodynamic determinants of the mitral annulus diastolic velocities by tissue Doppler. Journal of the Amrican College of Cardiology,2001,37:278-285.
[44]Moe G, Angus C,Howard R, et al. Pathophysiological role of changing atrial size and pressure in modulation of atrial natriuretic factor during evolving experimental heart failure. Cardiovascular Research,1990,24:570-577.
[45]Abhayaratna WP,Seward JB,Appleton CP et al. Left atrial size:Physiologic determinants and clinical applications. Journal of the American College of Cardiology,2006,47:2357-2363.
[46]Iwanaga Y, Nishi I, Furuichi S, et al. B-type natriuretic pep tide strongly reflects diastolic wall stress in patients with chronic heart failure[J]. JACC,2006,47 (4): 742-748.
[47]Maisel AS, Krishnaswamy, Nowak RM, et al. Reqid measurement of B-type natriuretic peptide in the emergency diagnosis of heart failure[J]. N Eng J Med, 2002,347(3):161-167.
[48]Senni M,Rodeheffer R,Tribouilloy,et al. Use of echocardiography in the management of congestive heart failure in the community. J Am Coll Cardiol.1999 Jan;33(1):164-70.
[49]Zile MR, Brutsaert DL. New concepts in diastolic dysfunction and diastolic heart failure:Part Ⅰ:diagnosis, prognosis, and measurements of diastolic function. Circulation.2002 Mar 19,105(11):1387-93.
[50]ZileMR, BaieuCF, Gaaseh WH. Diastolic heart failure abnormalities in active relaxation and passive stiffness of the left ventricle[J].N Engl J Med.2004,350(19):1953-1959.
[51]Smulders YM, Stehouwer CD, Bronzwaer JG, et al. Diastolic heart failure [J]. Ned Tijdsehr Geneeskd.2003,147(50):2467-2470.
[52]He KL, Dickstein M, Sabbah HN, et al. Mechanisms of heart failure with well preserved ejection fraction in dogs following limited coronary microembolization[J]. Cardiovase Res.2004,64(1):72-83.
[53]Federmann M, Hess OM. Differentiation between systolic and diastolic dysfunction [J]. Eur Heart J.1994,15Suppl D:2-6.
[54]胡佳文,邓兵.舒张性心力衰竭研究进展.[J]2008,2(137),17-19.
[55]Lorell BH. Diastolic dysfunction in pressure-overload hypertrophy and its modification by angiotensin II:current concepts[J]. Basic Res Cardiol.1992,87 SuPP12:163-172.
[56]Klapholz M, Maurer M, Lowe AM, et al. Hospitalization for heart failure in the presence of a normal left ventricular ejection fraction:results of the New York Heart Failure Registry. Am Coll Cardiol.2004 Apr 21;43(8):1432-8.
[57]Appleton CP. Hemodynamic determinants of Doppler pulmonary venous flow velocity components:new insights from studies in lightly sedated normal dogs. J Am Coll Cardiol.1997 Nov 15;30(6):1562-74.
[58]Cohen GI, Pietrolungo JF, Thomas JD, et al. A practical guide to assessment of ventricular diastolic function using Doppler echocardiography [J]. J Am Coll Cardiol,1996,27(7):1753-1760.
[59]Sohn DW, Chai IH, Lee DJ,et al. Assessment of mitral annulus velocity by Doppler tissue imaging in the evaluation of left ventricular diastolic function. J Am Coll Cardiol.1997 Aug;30(2):474-80.
[60]Garcia MJ, Thomas JD, Klein AL.et al.New Doppler echocardiographic applications for the study of diastolic function. Am Coll Cardiol.1998 Oct, 32(4):865-75..
[61]Vitarelli A, Conde Y, Cimino E, et al. Assessment of ascending aorta distensibility after successful coarctation repair by strain doppler echocardiography [J]. J Am Soc Echocardiogr,2008, [Epub ahead of print].742-748.
[62]Khankirawatana B, Khankirawatana S, Peterson B,et al. Peak atrial systolic mitral annular velocity by Doppler tissue reliably predicts left atrial systolic function. J Am Soc Echocardiogr.2004 Apr;17(4):353-60.
[63]Nagueh SF, Sun H, Kopelen HA, et al.Hemodynamic determinants of the mitral annulus diastolic velocities by tissue Doppler. J Am Coll Cardiol.2001 Jan,37(1): 278-85.
[64]Gibson DG, Francis DP. Clinical assessment of left ventricular diastolic function [J]. Heart,2003,89(2):231-238.
[65]Nishimura R,Tajik AJ. The Vasalva maneuver:3 centuries later. Mayo Clin Proc. 2004 Apr;79(4):577-8.
[66]Hurrell DG, Nishimura RA, Ilstrup DM, et al. Utility of preload alteration in assessment of left ventricular filling pressure by Doppler echocardiography:a simultaneous catheterization and Doppler echocardiographic study[J]. JAm Coll Cardiol,1997,30(2):459-467.
[67]Brun P, Tribouilloy C, Duval AM,et al.Left ventricular flow propagation during early filling is related to wall relaxation:a color M-mode Doppler analysis. J Am Coll Cardiol.1992 Aug;20(2):420-32.
[68]Garcia MJ, Smedira NG, Greenberg NL,Color M-mode Doppler flow propagation velocity is a preload insensitive index of left ventricular relaxation:animal and human validation. J Am Coll Cardiol.2000 Jan;35(1):201-8.
[69]Takatsuji H, Mikami T, Urasawa K, et al.A new approach for evaluation of left ventricular diastolic function:spatial and temporal analysis of left ventricular filling flow propagation by color M-mode Doppler echocardiography. J Am Coll Cardiol. 1996 Feb;27(2):365-71.
[70]De Boeck BW, Oh JK, Vandervoort PM, et al. Colour M-mode velocity propagation:a glance at intra-ventricular pressure gradients and early diastolic ventricular performance. Eur J Heart Fail.2005 Jan;7(1):19-28.
[71]M(?)ller JE, S(?)ndergaard E, Seward JB,, et al. Ratio of left ventricular peak E-wave velocity to flow propagation velocity assessed by color M-mode Doppler echocardiography in first myocardial infarction:prognostic and clinical implications[J]. J Am Coll Cardiol,2000,35(2):363-370。
[72]Steine K, Stugaard M, Smiseth O A. Mechanisms of retarded apical filling in acute ischemic left ventricular failure[J]. Circulation,1999,99(15):2048-2054.
[73]合田亚希子,等.舒张功能障碍的诊断日本医学介绍,2007,18(5)[J],193-196
[74]M(?)ller JE, Poulsen SH, S(?)ndergaard E, et al. Preload dependence of color M-mode Doppler flow propagation velocity in controls and in patients with left ventricular dysfunction. J Am Soc Echocardiogr.2000 Oct;13(10):902-9.
[75]Takeda K,Chang S-M, Nagueh S, etal. Dependence of flow propagation velocity on cardiac size:Observations from patients with dilated cardiomyopathy and hypertrophic cardiomyopathy. J of the American college of Cardiology, 2002,39:383A-384A.
[76]Gonzalez-Vilchez F, Ares M, Ayuela J, et al.Combined use of pulsed and color M-mode Doppler echocardiography for the estimation of pulmonary capillary wedge pressure:an empirical approach based on an analytical relation. J Am Coll Cardiol. 1999 Aug;34(2):515-23.
[77]Gonzdlez-Vilchez F, Ayuela J, Ares M, et al. Comparison of Doppler echocardiography, color M-mode Doppler, and Doppler tissue imaging for the estimation of pulmonary capillary wedge pressure. J Am Soc Echocardiogr.2002 Oct;15(10 Pt2):1245-50.
[78]Firstenberg MS, Levine BD, Garcia MJ, et al. Relationship of echocardiographic indices to pulmonary capillary wedge pressures in healthy volunteers. JAm Coll Cardiol.2000 Nov 1;36(5):1664-9.
[79]Guyatt GH, Sullivan MJ, Thomp son PJ, et al. The 6-minute walk test:a newmeasure of exercise capacity in patients with chronic heart failure [J]. Can Med A ssoc J,1985,132 (8):919-923.
[80]Task force for the diagnosis and treatment of chronic heart failure. European society of cardiology. Guidelines for the diagnosis and treatment of chronic heart failure[J]. Eur Heart J,2001,22 (17):1527-1560.
[81]GualeniA,Aloia A, GentiliniA, et al. Effects of maximally tolerated oral therapy on the six2minute walking test in patients with chronic congestive heart failure secondary to either ischemic or idiopathic dilated cardiomyopathy[J]. Am J Car2 diol,1998,81 (11):1370-1372.
[82]Cahalin LP,MathierMA, Semigran MJ, et al. The six2minute walk test predicts peak oxygen up take survival in patients with advanced heart failure [J]. Chest,1996, 110 (2):325-330.
[83]Enright PL,McBurnieMA,B ittnerV, et al. The 62minute walk, a quick measure of functional status in elderly adults[J]. Chest,2003,123 (2):387-398.
[84]Opasich C, Pinna GD,Michaier MA, et al. Rep reducibility of the six2minute walking test in chronic congestive heart failure patients:practical implications [J]. Am J Cardiol,1998,81 (12):1497-1500.
[85]ATS statement. Guidelines for the six-minute walk test [J]. Am J Respir Crit CareMed,2002,166 (1):111-117.
[86]Enright PL. The 6 minute walk test[J]. Respir Care,2003,48 (8):783-785.
[87]Gottdiener J S, Kitzman DW, Aurigemma GP, et al. Left atrial volume, geometry, and function in systolic and diastolic heart failure of persons> or=65 years of age (the cardiovascular health study) [J].Am J Cardiol,2006,97 (1):83-89.
[88]Bttencourt P, Ferreira A, Dias P, et al. Evaluation of brain natriretic peptide in dianosis of heart failure[J]. Cardiology,2000,93:19-25.
[89]Mikkelsen KV, Bie PM(?)ller JE, et al. Neurehormonal activation and diagnostic value of cardiac peptides in patients with suspected mild heart failure [J]. Int J Cardiol.2006 Jun 28;110(3):324-33.
[90]Tschope C, Kasner M, Westerm annD, et al. The role of NT-proBNP in the diagnostic of isolated diastolic dysfunction correlation with echocardiographic and invasive measurements [J]. Eur Heart J,2005,26:2277-2284.
[1]Tokushima T, Reid CL, Gardin JM. Left ventricular diastolic function in the elderly. Am J Geriatr Cardiol,2001,10:20-29.
[2]Appleton CP,Hatle LK,Popp RI. Relation of transmitral flow velocity patterms to left ventricular diastolic function:New insights from a combined hemodynamic and Doppler echocardiographic study(Reprinted from the Journal of the American College of Cardiology, August,1988) Journal of the American College of Cardiology,1999,34(6):1659-1662.
[3]Vasan RS, Levy D. Defining diastolic heart failure:a call for standardized diagnostic criteria. Circulation 2000,101:2118-2121.
[4]Mariell Jessup, William T. Abraham, Donald E. Casey et al.2009 Focused Update Incorporated Into the ACC/AHA 2005 Guidelines for the Diagnosis and Management of Heart Failure in Adults. Circulation,2009,119:e391-e479.
[5]Chinali M, de Simone 131 Roman MJ, et al. Left atrial systolic force and cardiovascular outcome-The Strong Heart Study. American Journal of Hypertension, 2005,18(12):1570-1576.
[6]马志敏；李继敏；舒张功能障碍和舒张性心力衰竭的新观点 中国医药导刊2003,5(5)：332-334
[7]Babu GJ, Periasamy M. Transgenic mouse models for cardiac dysfunction by a specific gene manipulation [J]. Methods Mol Med,2005,112:365-377.
[8]Weisser-Thomas J, Kubo H, Hefner CA, et al. The Na+/Ca2+exchanger/SR Ca2+ATPase transport capacity regulates the contractility of normal and hypertrophied feline ventricular myocytes [J]. J Card Fail,2005,11:380-387.
[9]Mihra S, Sabbah HN, Rastogi S, et al. Reduced sarcoplasmic reticulum Ca2+ uptake and increased Na+-Ca2+exchanger expression in left ventricle myocardium of dogs with progression of heart failure[J]. Heart Vessels,2005,20:23-32.
[10]Stull LB, Matteo RG, Sweet WE, et al. Changes in calcium cy2 cling precede cardiac dysfunction during autoimmune myocarditis in mice[J]. J Mol Cell Cardiol,2001,33:449-460
[ll]Miyamoto Ml, del Monte F, Schmidt U, et al. Adenoviral gene transfer of SERCA2a improves left ventricular function in aortic-banded rats in transition to heart failure, Proc Natl Acad Sci USA.2000 Jan 18;97(2):793-8
[12]del Monte F,Hajjar PJ. Targeting calcium cycling proteins in heart failure through gene transfer. Journal of Physiology-London,2003,546(1):49-61.
[13]Marks AR, Reiken S, Marx SO. Progression of heart failure-Is protein kinase A hyperphosphorylation of the ryanodine receptor a contributing factor? [J] Circulation,2002,105(3):272-275.
[14]Reiken S, Gaburjakova M, Guatimosim S, et al. Protein kinase A phosphorylation of the cardiac calcium release channel(ryanodine receptor)in normal and failing hearts-Role of phosphatases and response to isoproterenol. Journal of Biological Chemistry,2003.278(1):444-453.
[15]Armoundas AA, Hobai IA, Tomaselli GF, et al. Role of sodium-calcium-exchanger in modulating the action potential of ventricular myocytes from normal and failing hearts. Circulation Research,2003,93(1):46-53.
[16]Weisser-Thomas J, Piacentino V Gaughan JP,et al. Calcium entry via Na/Ca exchange during the action potential directly contributes to contraction of failing human ventricular myocytes. Cardiovascular Research,2003,57(4):974-985.
[17]Hasenfuss G, Pieske B. Calcium cycling in congestive heart failure. Journal of Molecular and Cellular Cardiology,2002,34(8):951-969.
[18]Paulus WJ, Brutsaert DL, Gillebert TC, et al. How to diagnose diastolic heart failure. European Heart Journal,1998,19(7):990-1003.
[19]Wu YM, Bell sP,Trombitas K et al. Changes in titin isoform expression in pacing-induced cardiac failure give rise to increased passive muscle stiffness. Circulation,2002,106(11):1384-1389.
[20]Warren CM, Jordan MC, Roos KP,et al. Titin isoform expression in normal and hypertensive myocardium. Cardiovascular Research,2003,59(1):86-94.
[21]Cazolla O, Freiburg A, Helmes M, et al.Differential expression of cardiac titin isoforms and modulation of cellular stiffness. Circ Res.2000; 86:59-67.
[22]Jalil JE, Doering CW, Janicki JS, et al. Fibrillar collagen and myocardial s tiffness in the intact hypertrophied rat left ventricle. Circ Res.1989; 64:1041-1050.
[23]rutsaert DL, Fransen P, Andries LJ, et al. Cardiac endothelium and myo cardial function. Cardiovasc Res.1998; 38:281-290.
[24]Paulus WJ. Beneficial effects of nitric oxide on cardiac diastolic function: "the flip side of the coin." Heart Failure Rev.2000; 5:337-344.
[25]Tian R, Nascimben L, Ingwall JS, et al. Failure to maintain a low ADP concentration impairs diastolic function in hypertrophied rat hearts. Circulation, 1997,96(4):1313-1319.
[26]徐晤,夏勇,陈建辉,等.左室测压和造影对冠心病介入治疗前后左心室功能变化的评价.临床心血管病杂志,2006,22(2)：116.117.
[27]Little WC, Downes TR. Clinical evaluation of left ventricular diastolic performance. Progress in Cardiovascular Diseases,1990,32(4):273-290.
[28]Silber HA, Gottliebson WM, Lohmann DP,et al. A rapid hemodynamic monitor of acute ischemia during cardiac procedures:Changes in relaxation via a continuous left ventricular pressure-derivative loop. Journal of Surgical Research,2006, 134(1):107-113.
[29]Starling MR, Montgomery DG Mancini GB, et al. Load independence of the rate ofisovolumic relaxation in man. Circulation,1987,76(6):1274-81.
[30]Dick T. Diastolic Function:The Necessary Basics. Journal of Diagnostic Medical Sonography,2006,22:99-108.
[31]Appleton cP,Hatle LK,Popp RI. Relation of transmitral flow velocity patterns to left ventricular diastolic function:New insights from a combined hemodynamic and Doppler echocardiographic study(Reprinted from the Journal of the American College of Cardiology,August,1988). Journal of the American College ofCardiology,1999,34(6):1659-1662.
[32]Cohen GI, Pietrolungo IF,Thomas JD, et al. A practical guide to assessment of ventricular diastolic function using Doppler echocardio- graphy. J Am Coil Cardiol, 1996,27(7):1753-60.
[33]Kitzman DWj Sheikh KH, Beere PA, et al. Age-related alteration of Doppler left ventricular filling indexes in normal subjects are independent of left ventricular mass, heart rate, contractility and loading condition. JACC,1991,18(5): 1243.1250.
[34]高峻,李治安,王新房,等.多普勒组织成像探测二尖瓣环E/A比率评价左室舒张功能价值的探讨.中国超声医学杂志,2000,16(11)：849.853.
[35]Vitarelli A, Conde Y, Cimino E, et al. Assessment of ascending aorta distensibility after successful coarctation repair by strain doppler echocardiography [J]. J Am Soc Echocardiogr,2008, [Epub ahead of print].742-748.
[36]Sohn DW, Chai IH, Lee DJ,et al.Assessment of mitral annulus velocity by Doppler tissue imaging in the evaluation of left ventricular diastolic function. J Am Coll Cardiol.1997 Aug;30(2):474-80.
[37]Khankirawatana B, Khankirawatana S, Peterson B,et al. Peak atrial systolic mitral annular velocity by Doppler tissue reliably predicts left atrial systolic function. J Am Soc Echocardiogr.2004 Apr;17(4):353-60. [J]. J Am Soc Echocardiogr,2008, [Epub ahead of print].742-748.
[38]Nagueh SF, Sun H, Kopelen HA, et al.Hemodynamic determinants of the mitral annulus diastolic velocities by tissue Doppler. J Am Coll Cardiol.2001 Jan,37(1): 278-85.
[39]Gibson DG, Francis DP. Clinical assessment of left ventricular diastolic function [J]. Heart,2003,89(2):231-238.
[40]Vinlcius LB, Otavio DC, Luiz PR, et al. Tissue Doppler imaging in the evaluation of the regional diastolic function in chagas' disease[J]. Eur J Echocardiogr,2001,2(2):94-99。
[41]Ueno Y, Nakamura Y, Ohbayashi Y, et al. Evaluation of left ventricular systolic and diastolic global function:peak positive and negative myocardial velocity gradients in M-mode Doppler tissue imaging[J]. Echocardiography,2002,19(1): 15-25
[42]J Waggoner AD, Bierlg SM. Tissue Doppler imaging:a useful echocardiographic method for the cardiac sonographer to assess systolic and diastolic ventricular function[J]. J Am Soc Eehecardiogr,2001,14(12):1143.1152
[43]Garcia MJ, Thomas JD, Klein AL. New Doppler echocardiography applications for the study of diastolic function. JAm Coil Cardiol,1998,32(4):865.
[44]Takatsuji H, Mikami T, Urasawa K et al. A new approach for evaluation of left ventricular diastolic function:spatial and temporal analysis of left ventricular filling flow propagation by color M-mode Doppler echocardiography. J Am Coil Cardiol, 1996,27(2):365-71.
[45]Schindera ST, Mehwald PS, Sahn DL, et al. Accuracy of real-time three-dimensional echocardiography for quantifying right ventricular volume:static and pulsatile flow studies in an anatomic in vitro model. [J] Ultrasound Med,2002,21(10):1069-1075.