扩张型心肌病和心律失常心肌组织和心电重构的研究
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摘要
背景 心肌重构和心电重构是多种心血管疾病发生、发展的病理
生理学基础。
目的 本研究前三部分在探讨DCM心室重构的基础上，从自身
免疫抗体角度揭示组织重构过程中出现的电活动紊乱；论文第四
部分建立了快速右心房起搏致房颤兔模型，在深入研究电重构产
生机理的同时探讨电活动紊乱引发心房组织重构、纤维化，以及
慢性期引致心室心肌病的机制，最终将心肌组织重构与心电重构
有机结合。
内容与方法
（1）：合成β1AR和M2R抗原多肽片段，建立ELISA法测定扩
张型心肌病（DCM）和各种原发性心律失常患者循环血中抗β
1AR、抗M2R自身抗体滴度
（2）：半定量RT-PCR法测定目的基因表达的mRNA水平
（3）：放射免疫法测定血清/组织中ANP、NO、AngⅡ含量
（4）：双抗夹心ELISA法检测心肌损伤指标cTnⅠ
（5）：乳鼠心肌细胞培养，高血压、糖尿病合并DCM大鼠模型
及快速右心房起搏致房颤兔模型的建立
结果
1、（1）DCM患者抗β1AR、抗M2R自身抗体的P/N值与阳
性率均显著高于正常对照组，且两种抗体间存在正相关；室
性心律失常（VA）或DCM伴VA者抗β1和M2受体抗体
显著高于正常者和不伴有心律失常的DCM患者；（2）DCM
患者中抗β1AR抗体阳性组的QT离散度显著高于抗体阴性
组，心源性猝死和室性心律失常组QT离散度明显延长；
（3）45例临床资料完整的DCM患者中，NYHAⅢ～Ⅳ级
者抗体阳性率显著高于NYHAⅠ～Ⅱ级者。抗体阳性组
LVEDV、LVESV、EF、FS明显减低，并伴有不同程度的心
腔（LV、LA）扩大；（4）DCM患者血清ANP和NO水平
显著高于正常对照组，抗体阳性者差别更显著，且ANP和
NO水平的升高与心功能下降（NYHA评分低）相关联；（5）
南京医科大学博士学位论文D
。DCM患者外周血白细胞p l－ImLvA水平显著下降，抗 pl ARI
自身抗体阳性组和心功能 Ill～IV级组 pl AR表达略低于抗
体阴性和。。功能I～II级组，而pl－mRNA水平与患者6－受
体阻滞剂的应用未观察到明显的相关性；（6）随访DCM患D
者应用pl－受体阻滞剂（倍他乐克）治疗后1，3，6，12月，D
EF、F S在1个月时即有明显升高，LVEDV、LVESV于3
个月时开始回降，6个月后 LA、SV亦有显著差异，直到 12 D
个月方出现NYHA的显著改善。l
2、1：40滴度抗p l－受体自身抗体阳性的 DCM患者血清干预 D
培养乳鼠。肌细胞48刁2小时后，。G肌细胞搏动频率显著D
增加，上清液中cTnl无升高，NO、ANP浓度均有不同程
度的减低。比索洛尔可桔抗抗体的致。。动过速和降低 NO、l
ANP的作用。单纯比索洛尔干预培养细胞可显著降低 cTnl
水平，轻度升高NO和ANP。抗61受体自身抗体阳性的DCM D
患者血清对培养乳鼠心肌细胞ANP和pl－AR表达无显著影D
响，却可上调 ATI 的表达，比索洛尔干预可上调 pl－AR D
IInRNA并逆转 ATI表达的升高，单纯比索洛尔可降低 ANPI
l 和 ATI mRNA水平。l
D3、4个月高血压、糖尿病大鼠出现明显的血压升高、高血糖高D
D 尿糖和左室肥厚，肌浆网钙泵活力下降，SERCAZ表达减低，
胞膜61－和D3－I受体表达上调，ATI、RyRZ和L－CaZ－通道
D 一A改变不显著。培多普利（ACEI）可降低血压、逆转
D DCM大鼠的左室肥厚和上调的 pl一、IP3J受体，降低 ATI、
RyRZ－mRNA水平，不影响 SERCA、L（a》通道表达；比
D 索洛尔可降低血压，逆转m3J上调，降低 ATI、RyRZ、L－
Ca‘”通道表达，对pl＼ SEmAm洲A改变无影响。
D4、右。。房快速起搏致房颤兔模型中，血浆ANP显著升高，约
l 在1小时达峰值，右心房组织ANP含量和表达同步呈先抑
l 后扬；Angll含量迅速、持续升高，ATI表达的上调要迟于
Ansll；早期 SERCA活力、表达和 RyRZ表达均降低，L（a》
l 通道表达略有增高；晚期 SERCA活力和表达一致升高，RyRZ
l 表达仍减低，Lcaz”通道则显著降低。与右心房不同，左室
组织 ANP除表达在 1。J、时呈一过性增高外改变不明显；Angll
南京医科大学博士学位论文D
含量和 ATI表达呈显著同步升高；SERCA活力持续降低，l
但表达于早期显著升高后晚期迅速大幅度下降，RyM和 L－l
CaZ”通道持?
Cardiac and Electrical Remodeling in
Dilated Cardiomyopathy and Arrhythmias
Abstract
Background Ventricular and electrical remodeling were the pathophysiologic basis for the onset and development of various cardiovascular diseases. In the former three parts of this study, we aimed to investigate the correlation between autoimmune antibodies and electrical disturbance in the procession of ventricular remodeling. In the last part, the mechanism of atrial remodeling, fibrosis and atrial fibrillation(AF)-induced cardiomyopathy were further studied as well as electrical remodeling in AF on the model of right atriapacing induced AF rabbits. Therefore, ventricular remodeling and electrical remodeling were combined efficiently.
Methods
(1): Using sythetic 24-mer peptide to establish ELISA technique to determine the titer of anti- ~ 1 and anti-M2R autoantibodies in patients with DCM or primary arrhythmia.
(2): Semi-quantitative RT-PCR method was applied to estimate the gene expression (messenger RNA) level.
(3): Serum or tissue ANP, NO and AngII concentration were determined by radio-immune method.
(4): Double antibodies sandwich ELISA was applied to estimate cardiac injury marker cTnI level.
(5): Establish three model: cultured neonatal cardiomyocyte, hypertension-diabetes and DCM rats, right-atria pacing induced AF rabbits.
Results
1. (1 )The P/N value and positive rate of anti- ~ 1 and anti-M2R autoantibodies in DCM patients increased markedly than healthy group, and there was an positive-relation between two antibodies; The autoantibodies showed remarkable augment in patients with
I0
primary ventricular arrhythmias (PVA) or DCM patients with PVA
than healthy persons or DCM patients without any arrhythmias; (2)
QT dispersion was much longer in cardiogenic sudden death and
ventricular arrhythmias population. In DCM grouP, patients with
ani- D l-autoantibody had significan longer QT dispersion than
patients without this antibody; (3) In 45 DCM cases with Whole
clinical data, the anti D l auoantibody positive rate showed
significant higher in NYHA III~IV grouP than in NYHA I~II
grouP. In positive anibody grouP, LVEDV LVESV EF and FS
markedly decreased, togather with various degree of chamber
dilation (LV LA); (4) The serum ANP and NO concentration
increased significanly in DCM patients, especially with
autoanibodies, and this tendency was associated with decreased
heart function (NYHA class III--IV); (5) The D l messenger RNA
eXPression were downregulated in peripheral white blood ceIls in
DCM patients and had slight decrease in patients with positive
ani- fi l-antibody and worse heart function W III--IV) than
in patients with negative antibody and NYHA I~II. No
significance was observed in different heart function and the
treatment withD -blocker; (6) In DCM patients, the effect of
tfeatment with Betaloc were correlated with the time (l,3,6,l2
months) of theraPy. EF and FS had been remarkably improved as
early as one month after administration of Betaloc, LVEDV and
LVESV began to reverse at three months later, LA and SV also
showed significance at six months, heart function (N'YHA class)
had significant imProved till twelve months.
2. l:40 titer of ani 0 l autoanibody positive serum from DCM
patients were put into cultured neonatal cardiomyocytes, after
48--72 hours, the myocardial beating rate increased significantly,
and no cTnI augment was observed, together with decreased NO
and ANP level in culture fluid. Bisoprolol could markedly
decrease cTnI level and slightly increase NO and ANP
concentfation. No alteration of Aam and 0 l-unA except
l l
. 1
mcreased ATl eXPression were observed in grouP interfere with 0
l-anibody, and Bisoprolol could increase 0 1-AR eXPression and
reversed the upregulation of ATl-mRNA. Solely aPplying
BisoProlol could decrease the mRNA level of ANP and ATl.
3. In 2KlC hyPertension, diabetic and dilated cardiomyopathy rats,
there were significant increase of blood pressure (BP), blood
生理学基础。
目的 本研究前三部分在探讨DCM心室重构的基础上，从自身
免疫抗体角度揭示组织重构过程中出现的电活动紊乱；论文第四
部分建立了快速右心房起搏致房颤兔模型，在深入研究电重构产
生机理的同时探讨电活动紊乱引发心房组织重构、纤维化，以及
慢性期引致心室心肌病的机制，最终将心肌组织重构与心电重构
有机结合。
内容与方法
（1）：合成β1AR和M2R抗原多肽片段，建立ELISA法测定扩
张型心肌病（DCM）和各种原发性心律失常患者循环血中抗β
1AR、抗M2R自身抗体滴度
（2）：半定量RT-PCR法测定目的基因表达的mRNA水平
（3）：放射免疫法测定血清/组织中ANP、NO、AngⅡ含量
（4）：双抗夹心ELISA法检测心肌损伤指标cTnⅠ
（5）：乳鼠心肌细胞培养，高血压、糖尿病合并DCM大鼠模型
及快速右心房起搏致房颤兔模型的建立
结果
1、（1）DCM患者抗β1AR、抗M2R自身抗体的P/N值与阳
性率均显著高于正常对照组，且两种抗体间存在正相关；室
性心律失常（VA）或DCM伴VA者抗β1和M2受体抗体
显著高于正常者和不伴有心律失常的DCM患者；（2）DCM
患者中抗β1AR抗体阳性组的QT离散度显著高于抗体阴性
组，心源性猝死和室性心律失常组QT离散度明显延长；
（3）45例临床资料完整的DCM患者中，NYHAⅢ～Ⅳ级
者抗体阳性率显著高于NYHAⅠ～Ⅱ级者。抗体阳性组
LVEDV、LVESV、EF、FS明显减低，并伴有不同程度的心
腔（LV、LA）扩大；（4）DCM患者血清ANP和NO水平
显著高于正常对照组，抗体阳性者差别更显著，且ANP和
NO水平的升高与心功能下降（NYHA评分低）相关联；（5）
南京医科大学博士学位论文D
。DCM患者外周血白细胞p l－ImLvA水平显著下降，抗 pl ARI
自身抗体阳性组和心功能 Ill～IV级组 pl AR表达略低于抗
体阴性和。。功能I～II级组，而pl－mRNA水平与患者6－受
体阻滞剂的应用未观察到明显的相关性；（6）随访DCM患D
者应用pl－受体阻滞剂（倍他乐克）治疗后1，3，6，12月，D
EF、F S在1个月时即有明显升高，LVEDV、LVESV于3
个月时开始回降，6个月后 LA、SV亦有显著差异，直到 12 D
个月方出现NYHA的显著改善。l
2、1：40滴度抗p l－受体自身抗体阳性的 DCM患者血清干预 D
培养乳鼠。肌细胞48刁2小时后，。G肌细胞搏动频率显著D
增加，上清液中cTnl无升高，NO、ANP浓度均有不同程
度的减低。比索洛尔可桔抗抗体的致。。动过速和降低 NO、l
ANP的作用。单纯比索洛尔干预培养细胞可显著降低 cTnl
水平，轻度升高NO和ANP。抗61受体自身抗体阳性的DCM D
患者血清对培养乳鼠心肌细胞ANP和pl－AR表达无显著影D
响，却可上调 ATI 的表达，比索洛尔干预可上调 pl－AR D
IInRNA并逆转 ATI表达的升高，单纯比索洛尔可降低 ANPI
l 和 ATI mRNA水平。l
D3、4个月高血压、糖尿病大鼠出现明显的血压升高、高血糖高D
D 尿糖和左室肥厚，肌浆网钙泵活力下降，SERCAZ表达减低，
胞膜61－和D3－I受体表达上调，ATI、RyRZ和L－CaZ－通道
D 一A改变不显著。培多普利（ACEI）可降低血压、逆转
D DCM大鼠的左室肥厚和上调的 pl一、IP3J受体，降低 ATI、
RyRZ－mRNA水平，不影响 SERCA、L（a》通道表达；比
D 索洛尔可降低血压，逆转m3J上调，降低 ATI、RyRZ、L－
Ca‘”通道表达，对pl＼ SEmAm洲A改变无影响。
D4、右。。房快速起搏致房颤兔模型中，血浆ANP显著升高，约
l 在1小时达峰值，右心房组织ANP含量和表达同步呈先抑
l 后扬；Angll含量迅速、持续升高，ATI表达的上调要迟于
Ansll；早期 SERCA活力、表达和 RyRZ表达均降低，L（a》
l 通道表达略有增高；晚期 SERCA活力和表达一致升高，RyRZ
l 表达仍减低，Lcaz”通道则显著降低。与右心房不同，左室
组织 ANP除表达在 1。J、时呈一过性增高外改变不明显；Angll
南京医科大学博士学位论文D
含量和 ATI表达呈显著同步升高；SERCA活力持续降低，l
但表达于早期显著升高后晚期迅速大幅度下降，RyM和 L－l
CaZ”通道持?
Cardiac and Electrical Remodeling in
Dilated Cardiomyopathy and Arrhythmias
Abstract
Background Ventricular and electrical remodeling were the pathophysiologic basis for the onset and development of various cardiovascular diseases. In the former three parts of this study, we aimed to investigate the correlation between autoimmune antibodies and electrical disturbance in the procession of ventricular remodeling. In the last part, the mechanism of atrial remodeling, fibrosis and atrial fibrillation(AF)-induced cardiomyopathy were further studied as well as electrical remodeling in AF on the model of right atriapacing induced AF rabbits. Therefore, ventricular remodeling and electrical remodeling were combined efficiently.
Methods
(1): Using sythetic 24-mer peptide to establish ELISA technique to determine the titer of anti- ~ 1 and anti-M2R autoantibodies in patients with DCM or primary arrhythmia.
(2): Semi-quantitative RT-PCR method was applied to estimate the gene expression (messenger RNA) level.
(3): Serum or tissue ANP, NO and AngII concentration were determined by radio-immune method.
(4): Double antibodies sandwich ELISA was applied to estimate cardiac injury marker cTnI level.
(5): Establish three model: cultured neonatal cardiomyocyte, hypertension-diabetes and DCM rats, right-atria pacing induced AF rabbits.
Results
1. (1 )The P/N value and positive rate of anti- ~ 1 and anti-M2R autoantibodies in DCM patients increased markedly than healthy group, and there was an positive-relation between two antibodies; The autoantibodies showed remarkable augment in patients with
I0
primary ventricular arrhythmias (PVA) or DCM patients with PVA
than healthy persons or DCM patients without any arrhythmias; (2)
QT dispersion was much longer in cardiogenic sudden death and
ventricular arrhythmias population. In DCM grouP, patients with
ani- D l-autoantibody had significan longer QT dispersion than
patients without this antibody; (3) In 45 DCM cases with Whole
clinical data, the anti D l auoantibody positive rate showed
significant higher in NYHA III~IV grouP than in NYHA I~II
grouP. In positive anibody grouP, LVEDV LVESV EF and FS
markedly decreased, togather with various degree of chamber
dilation (LV LA); (4) The serum ANP and NO concentration
increased significanly in DCM patients, especially with
autoanibodies, and this tendency was associated with decreased
heart function (NYHA class III--IV); (5) The D l messenger RNA
eXPression were downregulated in peripheral white blood ceIls in
DCM patients and had slight decrease in patients with positive
ani- fi l-antibody and worse heart function W III--IV) than
in patients with negative antibody and NYHA I~II. No
significance was observed in different heart function and the
treatment withD -blocker; (6) In DCM patients, the effect of
tfeatment with Betaloc were correlated with the time (l,3,6,l2
months) of theraPy. EF and FS had been remarkably improved as
early as one month after administration of Betaloc, LVEDV and
LVESV began to reverse at three months later, LA and SV also
showed significance at six months, heart function (N'YHA class)
had significant imProved till twelve months.
2. l:40 titer of ani 0 l autoanibody positive serum from DCM
patients were put into cultured neonatal cardiomyocytes, after
48--72 hours, the myocardial beating rate increased significantly,
and no cTnI augment was observed, together with decreased NO
and ANP level in culture fluid. Bisoprolol could markedly
decrease cTnI level and slightly increase NO and ANP
concentfation. No alteration of Aam and 0 l-unA except
l l
. 1
mcreased ATl eXPression were observed in grouP interfere with 0
l-anibody, and Bisoprolol could increase 0 1-AR eXPression and
reversed the upregulation of ATl-mRNA. Solely aPplying
BisoProlol could decrease the mRNA level of ANP and ATl.
3. In 2KlC hyPertension, diabetic and dilated cardiomyopathy rats,
there were significant increase of blood pressure (BP), blood
引文
1．南宁地区心血管病协作组，广西南宁地区66632例人口心肌病调查报告。广西医学院学报，1979，9：57
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3．李运有，张寄南，马文珠，等。抗β肾上腺素能受体自身抗体在不同病因心脏病中的意义。中华医学杂志，1992，72：584-586
4．张寄南，苏恩本。心力衰竭与心肌肾上腺素能受体。基础医学与临床，1997，17：260-264
5．彭应用，马叔平，王吉梅，等。QT间期离散度在扩张型心肌病严重心功能不全患者预后中的意义。中国循环杂志，1996，11：551－554
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