心律失常的临床和遗传学基础及治疗相关的并发症
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摘要
背景：AMP激活蛋白激酶(AMPK)由α、β和γ三个亚单位组成。编码γ2亚单位的PRKAG2基因突变与遗传性心室预激、传导系统紊乱和心肌肥厚有关。其心肌肥厚常常类似肥厚性心肌病的表现。
目的：本研究的目的是在呈现左室肥厚(LVH)的人群中找出PRKAG2心脏综合征的患者。
方法和结果：研究入选了19名有无法解释LVH且相互之间并无血缘关系的患者作为研究对象。所有对象均进行了临床和遗传学评估。结果,有4名患者存在心动过缓,但其中仅仅一位19岁的男性有心室预激的表现。这名患者在3年后出现了充血性心力衰竭。对他进行电生理研究发现房室附加旁路和房室传导阻滞共存。心室组织学分析可见细胞内大量糖原累积、肌纤维紊乱和间质纤维化。对其DNA进行直接测序发现在PRKAG2基因第1453核苷酸位点处一个碱基由A转变为G(c.1453A>G),这导致PRKAG2基因编码产物的第485位氨基酸残基由赖氨酸转变为谷氨酸(p.Lys485Glu, K485E)。K485在不同物种之间是高度保守的。在该患者的其他家庭成员及215个健康对照人群中没有发现K485E突变。为了评价残基K485在AMPK结构和功能中的作用,我们对其进行了计算机模型预测。静电学演算表明K485与AMPKβ亚单位的保守性残基D248相互之间形成盐桥,这对调节酶的功能是至关重要的。K485E突变破坏了两者之间的连接。结论：我们在一名年轻的患者身上发现了一个新生的新的PRKAG2突变,他的病情进展提示PRKAG2心脏综合征需要更多的医学关注。对于合并无法解释的左室肥厚、心室预激、传导系统缺陷和／或早发心力衰竭的患者进行PRKAG2基因遗传学筛查是极其重要的。
背景：先天性长QT综合征(long QT syndrome, LQTS)是遗传性致心律失常疾病,特征为基础心电图QT间期延长伴高发的致命性心律失常风险。LQT2是由于编码快速延迟整流钾电流α亚单位的KCNH2基因突变引起钾电流减少所致。现行治疗LQT2的药物主要是β受体阻滞剂。但是,维拉帕米对LQT2的疗效尚不清楚。
目的：本研究的目的是阐明维拉帕米对LQT2的疗效及其相关的作用机制。
方法：我们评价了一位高度疑似LQT2的先证者在应用维拉帕米治疗前后其心电图QT间期的变化以及心律失常的发生情况。我们也对患者及其家庭成员进行了遗传学检测已明确基因型别。而且,我们利用兔左室楔形心肌块技术评价了维拉帕米对LQT2模型心内外膜动作电位持续时间(APD90),跨壁复极离散度(TDR)和尖端扭转型室速(TdP)发作的影响。E-4031(0.5μmol/L)被用于构建LQT2模型。
结果：我们在先证者基因组DNA中发现了一个位于KCNH2跨膜孔区的D609N突变。这个突变也同样存在于先证者子代中,但未在其他家庭成员中发现该突变。在先证者接受维拉帕米治疗后,其心电图QT间期逐渐缩短,心律失常发作次数也明显较少。在LQT2模型上,我们观察到E-4031优先延长内膜APD90,所以导致QT间期延长和TDR增加,引起早期后除极(EAD)和TdP发作。维拉帕米(0.5～2.5μmol/L)对LQT2模型内外膜APD90产生剂量依赖性的缩短,且缩短内膜APD90的作用更强,所以减少QT间期和TDR,抑制EAD和TdP的发作。
结论：我们的资料表明维拉帕米通过减少TDR抑制LQT2模型TdP的发作。研究提示维拉帕米可以作为治疗LQT2的一种药物选择。
背景：心脏损伤后综合征(Postcardiac injury syndrome, PCIS)是各种心脏损伤后出现的并发症,但是心脏小穿孔是一个常常被忽略的病因。我们报道了一系列因为射频消融导致心脏穿孔所诱发的PCIS病例。
方法和结果：在1728例射频导管消融手术中,21名(1.2%)患者发生了超声确认的心脏穿孔,所有穿孔的患者均不需要外科干预治疗。其中,6名(6/21,28.6%)患者诊断为心脏穿孔并发PCIS,因为他们除了呈现心包积液/填塞外,也出现了胸腔积液(6/6,100%)和发热(4/6,66.7%)。4名(4/6,66.7%)并发PCIS和4名(4/15,26.7%)未并发PCIS的患者进行了心包穿刺引流,但是在穿孔后头24小时的引流量两者之间没有显著差异(441.3±343.9ml vs.182.5±151.3ml,P=0.248)。在6个PCIS患者中,胸腔积液分别在消融术后3小时至4天被检测到(中位数：2天),主要表现为双侧(4/6,66.7%),单侧均位于左侧。与未并发PCIS的穿孔患者相比,有PCIS的患者平均年龄更大(64.8±7.3岁vs.45.9±14.8岁,P=0.0078),更可能伴发高血压(66.7%vs.6.7%,P=0.0114),而且住院时间明显延长(34.2±15.8天)。
结论：在导管消融过程中出现心脏小穿孔的患者,超过25%可能发展PCIS。这类PCIS易发生在老年和伴发有高血压的患者,临床特征为早期出现的胸腔积液。
Introduction: The major structure elements of the AMP activated protein kinase(AMPK), are α, β, and γ sunbunits. Mutations in PRKAG2have been associated witha cardiac syndrome including inherited ventricular preexcitation, conduction disorderand hypertrophy mimicking hypertrophic cardiomyopathy. The aim of the presentstudy was to identify PRKAG2syndrome among patients presenting with leftventricular hypertrophy (LVH).
Methods and Results: Nineteen unrelated subjects with unexplained LVH wereclinically and genetically evaluated. Among4patients with bradycardia,manifestations of preexcitation were only found in a19year old male who alsodeveloped congestive heart failure3years later. Electrophysiological study of thiscase, identified the coexistence of an AV accessory pathway and AV conduction defect.Histological analysis of his ventricular tissue isolated by biopsy confirmed excessiveglycogen accumulation, prominent myofibrillar disarray and interstitial fibrosis.Direct sequencing of his DNA revealed a heterozygous mutation in PRKAG2consisting of an A to G transition at nucleotide1453(c.1453A>G), predicting asubstitution of a glutamic acid for lysine at residue485(p.Lys485Glu, K485E).Lys485is highly conserved among species and the mutation was absent in hisunaffected family members and in215healthy controls. To assess the role of K485inthe structure and function of the protein, computational modeling calculations andconservation analyses were performed. Electrostatic calculations indicate that K485forms a salt bridge with the conserved D248residue in the AMPK β subunit, which iscritical for proper regulation of the enzyme, and the K485E mutant disrupts theconnection.
Conclusions: Our study identifies a novel de novo PRKAG2mutation in a young, inwhich progression of the disease warrants close medical attention. It also underlines the importance of molecular screening of PRKAG2gene in patients with unexplainedLVH, ventricular preexcitation, conduction defect, and/or early onset of heart failure.
Background: Congenital long QT syndrome (LQTS) is a hereditary arrhythmogenicdisease characterized by a prolongation of the QT interval at basal ECG and by a highrisk of life threatening arrhythmias. Loss of function mutations in KCNH2gene whichencodes the α subunit of the rapidly activating delayed rectifier potassium current (IKr)is responsible for LQT2. Current pharmacological treatments for LQT2primarilyinclude the use of β adrenoreceptor antagonists. However, the therapeutic effects ofverapamil on LQT2remain unclear.
Objective: To investigate the clinical effectiveness of verapamil on LQT2patientsand its electrophysiologic mechanism by which verapamil suppresses torsades depointes (TdP) in a developed left ventricular wedge model of LQT2.Methods: The clinical course was evaluated in a suspected LQT2proband before andafter administration of verapamil by intravenous and oral routes. Genetic screeningfor KCNH2gene was examined in the proband and her family members.Transmembrane action potentials of epicardial (Epi) and endocardial (Endo) cellswere recorded simultaneously at a basic cycle length of2000ms from an arteriallyperfused wedge of rabbit left ventricle together with a transmural ECG. E4031(0.5mol/L) was used to block IKr(LQT2model). We examined the effect of verapamilon action potential duration (APD), transmural dispersion of repolarization (TDR)and the development of TdP in LQT2model of LQTS.
Results: In the LQTS patient with TdP, we identified the D609N mutation in thetransmembrane pore region of KCNH2. The proband’s son carried the same mutationand showed prolonged corrected QT interval. The symptomatic ventriculararrhythmias of the proband were effectively suppressed by oral verapamil therapy. InLQT2models, E4031preferentially prolonged APD in Endo rather than Epi, therebydramatically increasing the QT interval and TDR. Spontaneous or Programmed electrical stimulation induced early afterdepolarization (EAD) was observed in Endo,and subsequent TdP occurred. Verapamil (0.5to2.5mol/L) dose dependentlyabbreviated APD in Endo more than in Epi, thereby significantly decreasing the QTinterval, TDR, and suppressing EAD and TdP.
Conclusions: Our data suggest that verapamil prevents TdP in LQT2Model of theLQTS by reducing TDR. These results indicate a possible therapeutic role ofverapamil in the treatment of LQT2patients.
Background: Postcardiac injury syndrome (PCIS) is a complication of a variety ofcardiac injuries, of which small heart perforation is the etiology that is oftenunrecognized. We reported a series of patients with PCIS secondary to cardiacperforation during catheter ablation procedures.
Methods and Results: Out of1728radiofrequency catheter ablation procedures,21patients (1.2%) were complicated by echo defined cardiac perforation not requiringsurgical intervention. Among them,6patients (6/21,28.6%) were diagnosed withPCIS secondary to cardiac perforation because they also developed pleural effusions(6/6,100%) and fever (4/6,66.7%) in addition to pericardial effusion/tamponade.Four patients with PCIS (4/6,66.7%) and four patients without PCIS (4/15,26.7%)underwent pericardial drainage but the drainage volume during the first24hours wasnot significantly different (441.3±343.9ml vs.182.5±151.3ml, P=0.248). In the6PCIS patients, pleural effusion was detected from3hours to4days (median:2days)after ablation procedure, predominantly bilateral (66.7%) or left sided if unilateral.Patients with PCIS were older (64.8±7.3yrs vs.45.9±14.8yrs, P=0.0078), weremore likely accompanied by hypertension (66.7%vs.6.7%, P=0.0114) and had aprolonged hospital stay (34.2±15.8days).
Conclusions: More than25%of patients with small cardiac perforation duringcatheter ablation may develop PCIS which can be masked by pericardialeffusion/tamponade. This kind of PCIS is more likely associated with elder orhypertensive patients and is usually characterized by early onset of pleural effusion.
目的：本研究的目的是在呈现左室肥厚(LVH)的人群中找出PRKAG2心脏综合征的患者。
方法和结果：研究入选了19名有无法解释LVH且相互之间并无血缘关系的患者作为研究对象。所有对象均进行了临床和遗传学评估。结果,有4名患者存在心动过缓,但其中仅仅一位19岁的男性有心室预激的表现。这名患者在3年后出现了充血性心力衰竭。对他进行电生理研究发现房室附加旁路和房室传导阻滞共存。心室组织学分析可见细胞内大量糖原累积、肌纤维紊乱和间质纤维化。对其DNA进行直接测序发现在PRKAG2基因第1453核苷酸位点处一个碱基由A转变为G(c.1453A>G),这导致PRKAG2基因编码产物的第485位氨基酸残基由赖氨酸转变为谷氨酸(p.Lys485Glu, K485E)。K485在不同物种之间是高度保守的。在该患者的其他家庭成员及215个健康对照人群中没有发现K485E突变。为了评价残基K485在AMPK结构和功能中的作用,我们对其进行了计算机模型预测。静电学演算表明K485与AMPKβ亚单位的保守性残基D248相互之间形成盐桥,这对调节酶的功能是至关重要的。K485E突变破坏了两者之间的连接。结论：我们在一名年轻的患者身上发现了一个新生的新的PRKAG2突变,他的病情进展提示PRKAG2心脏综合征需要更多的医学关注。对于合并无法解释的左室肥厚、心室预激、传导系统缺陷和／或早发心力衰竭的患者进行PRKAG2基因遗传学筛查是极其重要的。
背景：先天性长QT综合征(long QT syndrome, LQTS)是遗传性致心律失常疾病,特征为基础心电图QT间期延长伴高发的致命性心律失常风险。LQT2是由于编码快速延迟整流钾电流α亚单位的KCNH2基因突变引起钾电流减少所致。现行治疗LQT2的药物主要是β受体阻滞剂。但是,维拉帕米对LQT2的疗效尚不清楚。
目的：本研究的目的是阐明维拉帕米对LQT2的疗效及其相关的作用机制。
方法：我们评价了一位高度疑似LQT2的先证者在应用维拉帕米治疗前后其心电图QT间期的变化以及心律失常的发生情况。我们也对患者及其家庭成员进行了遗传学检测已明确基因型别。而且,我们利用兔左室楔形心肌块技术评价了维拉帕米对LQT2模型心内外膜动作电位持续时间(APD90),跨壁复极离散度(TDR)和尖端扭转型室速(TdP)发作的影响。E-4031(0.5μmol/L)被用于构建LQT2模型。
结果：我们在先证者基因组DNA中发现了一个位于KCNH2跨膜孔区的D609N突变。这个突变也同样存在于先证者子代中,但未在其他家庭成员中发现该突变。在先证者接受维拉帕米治疗后,其心电图QT间期逐渐缩短,心律失常发作次数也明显较少。在LQT2模型上,我们观察到E-4031优先延长内膜APD90,所以导致QT间期延长和TDR增加,引起早期后除极(EAD)和TdP发作。维拉帕米(0.5～2.5μmol/L)对LQT2模型内外膜APD90产生剂量依赖性的缩短,且缩短内膜APD90的作用更强,所以减少QT间期和TDR,抑制EAD和TdP的发作。
结论：我们的资料表明维拉帕米通过减少TDR抑制LQT2模型TdP的发作。研究提示维拉帕米可以作为治疗LQT2的一种药物选择。
背景：心脏损伤后综合征(Postcardiac injury syndrome, PCIS)是各种心脏损伤后出现的并发症,但是心脏小穿孔是一个常常被忽略的病因。我们报道了一系列因为射频消融导致心脏穿孔所诱发的PCIS病例。
方法和结果：在1728例射频导管消融手术中,21名(1.2%)患者发生了超声确认的心脏穿孔,所有穿孔的患者均不需要外科干预治疗。其中,6名(6/21,28.6%)患者诊断为心脏穿孔并发PCIS,因为他们除了呈现心包积液/填塞外,也出现了胸腔积液(6/6,100%)和发热(4/6,66.7%)。4名(4/6,66.7%)并发PCIS和4名(4/15,26.7%)未并发PCIS的患者进行了心包穿刺引流,但是在穿孔后头24小时的引流量两者之间没有显著差异(441.3±343.9ml vs.182.5±151.3ml,P=0.248)。在6个PCIS患者中,胸腔积液分别在消融术后3小时至4天被检测到(中位数：2天),主要表现为双侧(4/6,66.7%),单侧均位于左侧。与未并发PCIS的穿孔患者相比,有PCIS的患者平均年龄更大(64.8±7.3岁vs.45.9±14.8岁,P=0.0078),更可能伴发高血压(66.7%vs.6.7%,P=0.0114),而且住院时间明显延长(34.2±15.8天)。
结论：在导管消融过程中出现心脏小穿孔的患者,超过25%可能发展PCIS。这类PCIS易发生在老年和伴发有高血压的患者,临床特征为早期出现的胸腔积液。
Introduction: The major structure elements of the AMP activated protein kinase(AMPK), are α, β, and γ sunbunits. Mutations in PRKAG2have been associated witha cardiac syndrome including inherited ventricular preexcitation, conduction disorderand hypertrophy mimicking hypertrophic cardiomyopathy. The aim of the presentstudy was to identify PRKAG2syndrome among patients presenting with leftventricular hypertrophy (LVH).
Methods and Results: Nineteen unrelated subjects with unexplained LVH wereclinically and genetically evaluated. Among4patients with bradycardia,manifestations of preexcitation were only found in a19year old male who alsodeveloped congestive heart failure3years later. Electrophysiological study of thiscase, identified the coexistence of an AV accessory pathway and AV conduction defect.Histological analysis of his ventricular tissue isolated by biopsy confirmed excessiveglycogen accumulation, prominent myofibrillar disarray and interstitial fibrosis.Direct sequencing of his DNA revealed a heterozygous mutation in PRKAG2consisting of an A to G transition at nucleotide1453(c.1453A>G), predicting asubstitution of a glutamic acid for lysine at residue485(p.Lys485Glu, K485E).Lys485is highly conserved among species and the mutation was absent in hisunaffected family members and in215healthy controls. To assess the role of K485inthe structure and function of the protein, computational modeling calculations andconservation analyses were performed. Electrostatic calculations indicate that K485forms a salt bridge with the conserved D248residue in the AMPK β subunit, which iscritical for proper regulation of the enzyme, and the K485E mutant disrupts theconnection.
Conclusions: Our study identifies a novel de novo PRKAG2mutation in a young, inwhich progression of the disease warrants close medical attention. It also underlines the importance of molecular screening of PRKAG2gene in patients with unexplainedLVH, ventricular preexcitation, conduction defect, and/or early onset of heart failure.
Background: Congenital long QT syndrome (LQTS) is a hereditary arrhythmogenicdisease characterized by a prolongation of the QT interval at basal ECG and by a highrisk of life threatening arrhythmias. Loss of function mutations in KCNH2gene whichencodes the α subunit of the rapidly activating delayed rectifier potassium current (IKr)is responsible for LQT2. Current pharmacological treatments for LQT2primarilyinclude the use of β adrenoreceptor antagonists. However, the therapeutic effects ofverapamil on LQT2remain unclear.
Objective: To investigate the clinical effectiveness of verapamil on LQT2patientsand its electrophysiologic mechanism by which verapamil suppresses torsades depointes (TdP) in a developed left ventricular wedge model of LQT2.Methods: The clinical course was evaluated in a suspected LQT2proband before andafter administration of verapamil by intravenous and oral routes. Genetic screeningfor KCNH2gene was examined in the proband and her family members.Transmembrane action potentials of epicardial (Epi) and endocardial (Endo) cellswere recorded simultaneously at a basic cycle length of2000ms from an arteriallyperfused wedge of rabbit left ventricle together with a transmural ECG. E4031(0.5mol/L) was used to block IKr(LQT2model). We examined the effect of verapamilon action potential duration (APD), transmural dispersion of repolarization (TDR)and the development of TdP in LQT2model of LQTS.
Results: In the LQTS patient with TdP, we identified the D609N mutation in thetransmembrane pore region of KCNH2. The proband’s son carried the same mutationand showed prolonged corrected QT interval. The symptomatic ventriculararrhythmias of the proband were effectively suppressed by oral verapamil therapy. InLQT2models, E4031preferentially prolonged APD in Endo rather than Epi, therebydramatically increasing the QT interval and TDR. Spontaneous or Programmed electrical stimulation induced early afterdepolarization (EAD) was observed in Endo,and subsequent TdP occurred. Verapamil (0.5to2.5mol/L) dose dependentlyabbreviated APD in Endo more than in Epi, thereby significantly decreasing the QTinterval, TDR, and suppressing EAD and TdP.
Conclusions: Our data suggest that verapamil prevents TdP in LQT2Model of theLQTS by reducing TDR. These results indicate a possible therapeutic role ofverapamil in the treatment of LQT2patients.
Background: Postcardiac injury syndrome (PCIS) is a complication of a variety ofcardiac injuries, of which small heart perforation is the etiology that is oftenunrecognized. We reported a series of patients with PCIS secondary to cardiacperforation during catheter ablation procedures.
Methods and Results: Out of1728radiofrequency catheter ablation procedures,21patients (1.2%) were complicated by echo defined cardiac perforation not requiringsurgical intervention. Among them,6patients (6/21,28.6%) were diagnosed withPCIS secondary to cardiac perforation because they also developed pleural effusions(6/6,100%) and fever (4/6,66.7%) in addition to pericardial effusion/tamponade.Four patients with PCIS (4/6,66.7%) and four patients without PCIS (4/15,26.7%)underwent pericardial drainage but the drainage volume during the first24hours wasnot significantly different (441.3±343.9ml vs.182.5±151.3ml, P=0.248). In the6PCIS patients, pleural effusion was detected from3hours to4days (median:2days)after ablation procedure, predominantly bilateral (66.7%) or left sided if unilateral.Patients with PCIS were older (64.8±7.3yrs vs.45.9±14.8yrs, P=0.0078), weremore likely accompanied by hypertension (66.7%vs.6.7%, P=0.0114) and had aprolonged hospital stay (34.2±15.8days).
Conclusions: More than25%of patients with small cardiac perforation duringcatheter ablation may develop PCIS which can be masked by pericardialeffusion/tamponade. This kind of PCIS is more likely associated with elder orhypertensive patients and is usually characterized by early onset of pleural effusion.
引文
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2. Blair E, Redwood C, Ashrafian H, Oliveira M, Broxholme J, Kerr B, SalmonA, Ostman Smith I, Watkins H. Mutations in the gamma(2) subunit ofamp activated protein kinase cause familial hypertrophic cardiomyopathy:Evidence for the central role of energy compromise in disease pathogenesis.Human molecular genetics.2001;10:12151220.
3. Gollob MH, Green MS, Tang AS, Gollob T, Karibe A, Ali Hassan AS, AhmadF, Lozado R, Shah G, Fananapazir L, Bachinski LL, Roberts R. Identificationof a gene responsible for familial wolff parkinson white syndrome. The NewEngland journal of medicine.2001;344:18231831.
4. Gollob MH, Green MS, Tang AS, Roberts R. Prkag2cardiac syndrome:Familial ventricular preexcitation, conduction system disease, and cardiachypertrophy. Current opinion in cardiology.2002;17:229234.
5. Arad M, Benson DW, Perez Atayde AR, McKenna WJ, Sparks EA, Kanter RJ,McGarry K, Seidman JG, Seidman CE. Constitutively active amp kinasemutations cause glycogen storage disease mimicking hypertrophiccardiomyopathy. The Journal of clinical investigation.2002;109:357362.
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