增龄引起犬心房电及结构重构与钙通道离子分子改变和心房颤动机制研究
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摘要
目的：增龄是一个正常的生理衰老过程,但它却引起了心房肌细胞电生理特性的改变。对增龄导致心房电重构和结构重构及其相关的钙电流离子分子机制的全面了解,有助于明确增龄引起房颤的原因和影响因素,为房颤的治疗提供新的思路。本研究课题包括：1)测量成年、老年犬体表心电图P波时限、P波离散度等电生理指标；采用程序刺激,测量两组犬心房不同部位(右左心房、左右心耳和肺静脉)有效不应期(ERP). ERP离散度、不应期频率白适应性特征,比较成年、老年犬心房组织电生理特性的差别；2)应用MAS SON染色法观察心肌细胞胶原容积指数,以确定心房纤维化程度,TUNEL法检测心房肌细胞凋亡,应用电镜观察各组心房肌细胞超微结构,计算其凋亡指数,观察增龄引起心房电生理改变过程中伴随的细胞凋亡、结构重构与心房钙离子(Ca2+)通道电重构过程之间的相关性；3)通过全细胞膜片钳技术和方法,观察成年、老年犬不同部位心房肌细胞的L-型电压依赖钙通道电流(ICa-L)的电流密度、通道激活和失活特性,分析其变化规律及钙离子电流调控适应机制；4)通过分子生物学方法,检测成年、老年犬心房不同部位心房肌细胞L-型电压依赖钙通道αl亚单位(CaV1.2)、L-型Ca2+释放通兰尼碱受体(RYR2)、肌浆网钙调控-Ca2+ATP酶(SERCA2)>钙激活蛋白酶-I(Calpain I)、磷酸受钠蛋白(PLN1)等各目标基因在mRNA和蛋白质水平的表达变化,并分析各目标基因在m.RNA和蛋白质表达水平与心房电生理变化的相关机制。探索增龄在房颤发生中的地位和作用。为临床更好的防治房颤提供理论依据。方法：1)本课题第一部分：17只犬分为两组：成年犬7只,老年犬10只。两组犬均采用以下方法进行相关研究：苯妥英钠(20mg/kg,静脉注射)麻醉后,获取犬标准12导体表心电图。经胸超声测量犬双侧心房、双侧心室大小及左心室射血分数(LVEF)。分别于双侧股静脉及颈内静脉置入鞘管,开胸暴露心脏后,将6F十极电极头端缝合固定于左心耳(LAA)、左上肺静脉(LSPV)和左下肺静脉(LIPV)及右心耳(RAA)、右上肺静脉(RSPV)和右下肺静脉(RIPV)。S1S2程序刺激测定高位右心房(HRA),冠状静脉窦近段(CSp)、远段(CSd), LAA、RAA, LSPV, LIPV, RSPV, RIPV等部位的ERP。每一部位重复起搏测量3次取平均值并记录。分别在LAA、RAA以1000次/分高频刺激诱发房颤,如上述刺激无法诱发房颤,则予迷走神经干1000次/分高频刺激诱发房颤。上述研究结束后开胸取出心脏,采用MASSON三色染色法观察心房肌纤维胶原容积指数,TUNEL法检测心房肌凋亡细胞；2)本课题第二部分：对7只成年犬14个心房心肌细胞、10只老年犬16个心房心肌细胞的数据进行研究。采用全膜片钳技术记录心房肌细胞ICa-L动作电位时限(APD)、动作电位2相平台期电压和幅度,心房肌细Ica-L特性。3)本课题第三部分：对17犬左心耳组织,提取总RNA、并进行SERCA2, CaV1.2, RYR2, PLN1等的mRNA纯度测定,逆转录反应生成cDNA,以cDNA为模板进行荧光PCR鉴定以明确所分析SERCA2, CaV1.2, RYR2, PLN1基因及蛋白为所研究的目标基因和蛋白。结果：1)老年犬体表心电图P波时限以及P波离散度较成年犬明显增加(P<0.05)。老年犬LVEF较成年犬降低,但双侧心房大小及左右心室舒张末期内径两组间比较无明显差异。以S1S2300ms基础周长进行程序刺激测定的ERP在两组动物间的比较：ERP在RAA及CSp老年犬较成年犬明显延长(P<0.05),在LAA及CSd老年犬较成年犬明显缩短。尽管两组间ERP在LIPV, RSPV, RIPV无明显差异,但老年犬ERP在LSPV较成年犬明显缩短。心房不同部位和肺静脉ERP离散度老年犬较成年犬明显增大(P<0.05),老年犬与成年犬相比LAA, CSd和LSPV的ERP频率自适应性性明显下降(P<0.05),但LIPV, RSPV, RIPV的ERP频率自适应性两组间有变化但未达到统计学差别(P>0.05)；2)两组犬心房肌纤维中胶原容积分数比较,老年犬心房肌纤维中的胶原容积分数明显高于成年犬(P<0.05)。老年犬心房肌凋亡细胞即凋亡指数较成年犬明显增加(P<0.05)；3)通过研究发现成年犬和老年犬比较,心房肌细胞APD成年犬为(320.0±7.9ms),而老年犬明显延长,为(340.5±10.1ms),差别有统计学意义(P<0.05)。动作电位2相平台期电压,老年犬组为(-9.5±1.7mv),与成年犬(-6.4±1.1mv),相比明显降低,差别有统计学意义(P<0.05)。对7只成年犬的14个心房心肌细胞、10只老年犬的16个心房心肌细胞的数据进行了统计分析。老年犬较成年犬心房肌细胞ICa-L密度明显降低(-14.04±0.82pA/pF比-8.11±0.54pA/pF,P<0.05),差异有统计学意义；4)对两组犬基因表达参数比较发现：成年犬CaV1.2为2.38±0.4,老年犬为0.9±0.35,CaV1.2,基因表达明显下调,两组比较差异有有统计学意义(P<0.05)；成年犬Ca2+释放通兰尼碱受体(RYR2)基因为1.49±1.69,老年犬为4.39±4.68,两组比较差异有统计学意义(P<0.05)；两组犬SERCA2基因表达、Calpain-I及PLN1基因表达比较差异无有统计学意义；5)、对两组犬蛋白表达参数比较发现：成年犬CaV1.2蛋白为0.29±0.12,老年犬为0.13±0.10,CaV1.2蛋白表达明显下调,两组比较差异有有统计学意义(P<0.05)；成年犬Ca2+释放通道RYR2蛋白为0.08±0.36,老年犬为0.18±0.21,两组比较差异有有统计学意义(P<0.05); SERCA2、Calpain-I及PLN1蛋白表达两组比较差异无有统计学意义。结论：我们的研究显示：1)老年犬心肌细胞ERP延长及ERP离散度的增加,心房肌细胞APD延长,动作电位2相平台期电压降低,心房肌细胞ICa-L密度降低等电生理特性的变化,增龄引起的上述心房肌细胞电生理特性的改变是导致心房肌细胞Ca2+通道电重构的电生理基础；2)增龄引起心房肌细胞胶原容积分数增加导致心房纤维化进展,增龄引起心房肌凋亡细胞增加,这些改变是增龄引起心房肌细胞解剖重构的病理基础；3)老年犬心房肌细胞CaV1.2基因表达下调、钙离子释放通RYR2基因表达下调,SERCA2基因和Calpain-I及PLN1基因表达无明显改变；老年犬心房肌细胞CaV1.2蛋白表达下调、Ca2+释放通RYR2蛋白质表达上调,SERCA2蛋白和Calpain-I及PLN1蛋白表达无明显改变；上述各目标基因在mRNA和蛋白质表达水平改变是增龄引起心房ERP延长和频率自适应性降低等电生理特性变化的原因。增龄导致上述这些电生理特性改变以及组织病理学改变和钙通道离子、分子的改变可能是老年相关性房颤的潜在机制之一
Objectives:The goal of the present study was to determine weather the changes of P-wave duration, dispersion of P-wave effective refractory (ERP) period and dispersion of ERP in adult and aged normal canine. Explore the underling mechanism that aging-associated changes in the atrial actionpotential (AP) and atrial myocardial current of L-type calcium channel, provide a substrate for abnormal conduction and arrhythmogenesis, particularly atrial fibrillation (AF). Methods:1) Two groups of mongrels either sex weighing 18～26kg (19.6±5.8)kg were investigated:seven adult (2～2.5years) and ten old (> 8years). Animals were anesthetized with sodium pentobarbital (20mg/kgi.v.). Twelve-lead ECG measurements were made on conscious dogs resting quietly using electrocardiogram. Echocardiograms were performed to exclude the structural heart disease. Dual atrium and ventriaular size, the left ventricular ejection fraction (LVEF) were also measured by echocardiogram. A right cervical vein cutdown was then a 6-Fr quadripolar electrode catheter was inserted into the high right atria (HRA) and a multipolar catheters were placed at the coronary sinus (CS). The chest was opened through the fourth intercostal space. After left lateral thoracotomy, the pericardium was incised to expose the heart. A multielectrod catheters was secured to left atrial appendage (LAA), left superior pulmonary vein (LSPV) or left inferior pulmonary vein (LIPV), Similar electrode catheters were secured to right atrial appendage (RAA), right superior pulmonary vein (RSPV) and right inferior pulmonary vein (RIPV) through a right thoracotomy approach at the fourth intercostal space. The effective refractory period (ERP) of HRA, coronary sinus proximal (CSp), coronary sinus distal (CSd), LAA or RAA, LSPV, LIPV, RSPV, RIPV were measured in sequence at an atrial pacing of S1S2. The measurements were repeated 3 times and then averaged.To induce AF, atrial burst pacing was delivered through quadripolar electrode by a high-frequenc pacing in the RAA at a rate of 1000 bpm. If AF was not induced, a high-frequenc stimulats in the cervical vagosympathetic at a rate of 1000 bpm.We averaged the time of the duration of AF induced at 3 procedures in all dogs of each group.2) The current of L-type calcium channel was recorded by patch clamp technique in the whole cell mode. Action potential duration (APD), amplitude of action potential plateau, Ica-L peak current density were measurements.3) We measured the mRNA gene and protein expression levels of L-type Ca channelα1 subunit (CaV1.2), sarcoplasmic reticulum Ca+-ATPase (SECRA2), Calpain I, ryanodine receptor (RyR-2) in atrial myocardial tissue from two groups of 17 dogs. Results:1) P-wave duration and dispersion of P-wave were both longer in aged animals (P<0.05). The LVEF was significantly lower in aged than adult groupswhereas differences in left atrial dimensionLAD), right atrial dimension (RAD), left ventricular diastolic dimension (LVDd), right ventricular diastolicdimension (RVDd) between the two groups failed to achieve statistical significance.The ERP of RAA and CSp measured during atrial-programmed stimulation was significantly longer in the aged than in the adult dogs (P<0.05). However, the ERP of LAA and CSd was significantly shorter in the aged than in the adult dogs. Although significant shorter of ERP in LIPV, RSPV, RIPV was not observed, the ERP of LSPV was significantly shorter in the aged than in the adult dogs. Compared with adult dogs the dERP of different site of atrium and pulmonary veins (PVs) were increased in aged dogs (P<0.05). Compared with adult dogs a rate dependency of ERP in LAA, CSd and LSPV was significantly shorter in the aged dogs (P <0.05). Although shorter of rate dependency of ERP in LIPV, RSPV, RIPV was observed, but there are not significantly shorter in the aged than adult dogs. (P>0.05).2) Ica-L peak current density was (-14.04±0.82pA/pF), in adult group compared with (-8.11±0.54pA/pF, P<0.05) in the aged group and action potential duration to 90% repolarization (APD90) of aged group was significantly decreased. Left、right atrium transverse diameter gradually increased, but have no significant difference (P>0.05).3) The mRNA gene expression levels of CaV1.2 was significantly lower in the aged doges (0.9±0.35) than in the adult dogs (2.38±0.4, P<0.05), The mRNA gene expression levels of RYR2 was significantly higher in the aged doges (4.39±4.68) than in the adult dogs (1.49±1.69, P<0.05), There were not significantly different gene expression levels of SECRA2> PLN1 and Calpain I in two groups; The protein expression levels of CaV1.2 was significantly lower in the aged doges (0.13±0.10) than in the adult dogs (0.29±0.12, P<0.05), The prorein expression levels of RYR2 was significantly higher in the aged doges (0.18±0.21) than in the adult dogs (0.08±0.36, P<0.05), There were not significantly different protein expression levels of SECRA2, PLN1and Calpain I in two groups. Connclusions:The pesent study demonstrated the change of ERP, dERP.APD, Ica-L peak current density in two groups dogs. There are have a structural remodeling and electrical remodeling presented in aged doges. The gene and ion channel protein expression levels was different in two groups. These aging-related changes of atrial myocyte electrical and structural properties and molecular changes in aged dogs play a impotrant role in the predisposition to developing and maintaining AF due to aging.
Objectives:The goal of the present study was to determine weather the changes of P-wave duration, dispersion of P-wave effective refractory (ERP) period and dispersion of ERP in adult and aged normal canine. Explore the underling mechanism that aging-associated changes in the atrial actionpotential (AP) and atrial myocardial current of L-type calcium channel, provide a substrate for abnormal conduction and arrhythmogenesis, particularly atrial fibrillation (AF). Methods:1) Two groups of mongrels either sex weighing 18～26kg (19.6±5.8)kg were investigated:seven adult (2～2.5years) and ten old (> 8years). Animals were anesthetized with sodium pentobarbital (20mg/kgi.v.). Twelve-lead ECG measurements were made on conscious dogs resting quietly using electrocardiogram. Echocardiograms were performed to exclude the structural heart disease. Dual atrium and ventriaular size, the left ventricular ejection fraction (LVEF) were also measured by echocardiogram. A right cervical vein cutdown was then a 6-Fr quadripolar electrode catheter was inserted into the high right atria (HRA) and a multipolar catheters were placed at the coronary sinus (CS). The chest was opened through the fourth intercostal space. After left lateral thoracotomy, the pericardium was incised to expose the heart. A multielectrod catheters was secured to left atrial appendage (LAA), left superior pulmonary vein (LSPV) or left inferior pulmonary vein (LIPV), Similar electrode catheters were secured to right atrial appendage (RAA), right superior pulmonary vein (RSPV) and right inferior pulmonary vein (RIPV) through a right thoracotomy approach at the fourth intercostal space. The effective refractory period (ERP) of HRA, coronary sinus proximal (CSp), coronary sinus distal (CSd), LAA or RAA, LSPV, LIPV, RSPV, RIPV were measured in sequence at an atrial pacing of S1S2. The measurements were repeated 3 times and then averaged.To induce AF, atrial burst pacing was delivered through quadripolar electrode by a high-frequenc pacing in the RAA at a rate of 1000 bpm. If AF was not induced, a high-frequenc stimulats in the cervical vagosympathetic at a rate of 1000 bpm.We averaged the time of the duration of AF induced at 3 procedures in all dogs of each group.2) The current of L-type calcium channel was recorded by patch clamp technique in the whole cell mode. Action potential duration (APD), amplitude of action potential plateau, Ica-L peak current density were measurements.3) We measured the mRNA gene and protein expression levels of L-type Ca channelα1 subunit (CaV1.2), sarcoplasmic reticulum Ca+-ATPase (SECRA2), Calpain I, ryanodine receptor (RyR-2) in atrial myocardial tissue from two groups of 17 dogs. Results:1) P-wave duration and dispersion of P-wave were both longer in aged animals (P<0.05). The LVEF was significantly lower in aged than adult groupswhereas differences in left atrial dimensionLAD), right atrial dimension (RAD), left ventricular diastolic dimension (LVDd), right ventricular diastolicdimension (RVDd) between the two groups failed to achieve statistical significance.The ERP of RAA and CSp measured during atrial-programmed stimulation was significantly longer in the aged than in the adult dogs (P<0.05). However, the ERP of LAA and CSd was significantly shorter in the aged than in the adult dogs. Although significant shorter of ERP in LIPV, RSPV, RIPV was not observed, the ERP of LSPV was significantly shorter in the aged than in the adult dogs. Compared with adult dogs the dERP of different site of atrium and pulmonary veins (PVs) were increased in aged dogs (P<0.05). Compared with adult dogs a rate dependency of ERP in LAA, CSd and LSPV was significantly shorter in the aged dogs (P <0.05). Although shorter of rate dependency of ERP in LIPV, RSPV, RIPV was observed, but there are not significantly shorter in the aged than adult dogs. (P>0.05).2) Ica-L peak current density was (-14.04±0.82pA/pF), in adult group compared with (-8.11±0.54pA/pF, P<0.05) in the aged group and action potential duration to 90% repolarization (APD90) of aged group was significantly decreased. Left、right atrium transverse diameter gradually increased, but have no significant difference (P>0.05).3) The mRNA gene expression levels of CaV1.2 was significantly lower in the aged doges (0.9±0.35) than in the adult dogs (2.38±0.4, P<0.05), The mRNA gene expression levels of RYR2 was significantly higher in the aged doges (4.39±4.68) than in the adult dogs (1.49±1.69, P<0.05), There were not significantly different gene expression levels of SECRA2> PLN1 and Calpain I in two groups; The protein expression levels of CaV1.2 was significantly lower in the aged doges (0.13±0.10) than in the adult dogs (0.29±0.12, P<0.05), The prorein expression levels of RYR2 was significantly higher in the aged doges (0.18±0.21) than in the adult dogs (0.08±0.36, P<0.05), There were not significantly different protein expression levels of SECRA2, PLN1and Calpain I in two groups. Connclusions:The pesent study demonstrated the change of ERP, dERP.APD, Ica-L peak current density in two groups dogs. There are have a structural remodeling and electrical remodeling presented in aged doges. The gene and ion channel protein expression levels was different in two groups. These aging-related changes of atrial myocyte electrical and structural properties and molecular changes in aged dogs play a impotrant role in the predisposition to developing and maintaining AF due to aging.
引文
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