Familial atrial septal defect and atrioventricular conduction disturbance associated with a point mutation in the cardiac homeobox gene CSX/NKX2-5 in a Japanese patient

Atrial septal defect (ASD) is the most common form of congenital cardiac defect in humans. Recently, point mutations in the cardiac homeobox gene CSX/NKX2-5 have been reported to cause the autosomal dominant form of familial ASD. Notably, all the affected patients exhibit atrioventricular conduction disturbance and some of them died suddenly. The first case of familial ASD with a mutation of the CSX/NKX2-5 gene in a Japanese patient is reported here. Identification of CSX/NKX2-5 mutations in ASD patients would be very important because the existence of such mutations may predict sudden cardiac death.     

基因突变在先天性房间隔缺损和室间隔缺损发育形成中的作用研究

对于先天性房间隔缺损、室间隔缺损通过外科和介入手术治疗可大大提高患者生存率,但对其发育畸形的根本原因仍属于探索阶段。目前现有的研究表明,先天性心脏病是由于控制人体心脏发育的基因在时间(发育阶段)和空间(组织特异性)上的表达调控失误而引起的。现即从现有的基因水平研究对基因突变在先天性房间隔缺损和室间隔缺损发育形成中的作用研究作一综述,为从基因方面早期筛检、诊断、治疗先天性房间隔缺损、室间隔缺损提供参考。     

Scar formation in the cardiac conduction system of a patient with Takayasu's arteritis.

An autopsied case of Takayasu's arteritis associated with complete atrioventricular (AV) block is described for the first time. The findings of scar formation and diffuse infiltration of lymphocytes into the cardiac conduction system, particularly the AV node, were similar to those in patients with connective tissue diseases or congenital complete heart block. The degree of AV block progressed with aggravation of the disease. These findings suggest that complete AV block may have been induced by acquired autoimmunity involving the cardiac conduction system.     

Molecular mechanism of cardiac hypertrophy and development

Congestive heart failure is a major issues for cardiologists and to fully understand heart failure, it is important to understand the mechanism of the development of cardiac hypertrophy. Hemodynamic overload, namely mechanical stress, is a major cause of cardiac hypertrophy and to dissect the signaling pathways from mechanical stress to cardiac hypertrophy, an in-vitro device by which mechanical stress can be imposed on cardiac myocytes of neonatal rats cultured in serum-free conditions has been developed. Passively stretching cardiac myocytes cultured on silicone membranes induced various hypertrophic responses, such as activation of the phosphorylation cascades of many protein kinases, expression of specific genes and an increase in protein synthesis. During this process, secretion and production of vasoactive peptides, such as angiotensin II and endothelin-1, were increased and they played critical roles in the induction of these hypertrophic responses. Candidates for the 'mechanoreceptor' that receives the mechanical stress and converts it into intracellular biochemical signals have been recently demonstrated. Gene therapy and cell transplantation are hopeful strategies for the treatment of heart failure and require an understanding of how normal cardiac myocytes are differentiated. A key gene that plays a critical role in cardiac development has been isolated. The cardiac homeobox-containing gene Csx is expressed in the heart and the heart progenitor cells from the very early developmental stage, and targeted disruption of the murine Csx results in embryonic lethality because of the abnormal looping morphogenesis of the primary heart tube. With a cardiac zinc finger protein GATA4, Csx induces cardiomyocyte differentiation of teratocarcinoma cells as well as upregulation of cardiac genes. Mutations of human CSX cause various congenital heart diseases including atrial septal defect, ventricular septal defect, tricuspid valve abnormalities and atrioventricular block.     

Clinical characteristics and diagnosis of double-orifice left atrioventricular valve associated with other congenital heart disease

Four cases of double-orifice left atrioventricular (AV) valve are reported. Three of the four patients with double-orifice left AV valve had other associated congenital heart diseases, and the fourth had double-orifice left AV valve alone. A patient with associated ventricular septal defect, who presented with pulmonary congestion and hypertension, suffered from severe heart failure. However, these symptoms improved with the spontaneous closure of the ventricular septal defect. The patient with double-orifice left AV valve alone showed no cardiac symptoms. Two-dimensional and Doppler echocardiography did not detect the double-orifice left AV valve in two of the four patients. More recently, the echocardiographic technique has allowed a noninvasive and more frequent detection of this abnormality. But both of these patients had left-to-right atrial shunt and subsequent reduced transmitral flow and left ventricular volume, which may have made it difficult to detect the morphological and hemodynamic characteristics of double-orifice left AV valve. Careful and repeated echocardiographic observation of mitral configuration is required to determine the presence of double-orifice left AV valve when heart disease is associated with a left-to-right atrial shunt.     

First-degree heart block in the fetus of an anti-SSA/Ro-positive mother: reversal after a short course of dexamethasone treatment

Isolated congenital heart block is almost invariably associated with the presence of antibodies to SSA/Ro and SSB/La antigens in the maternal circulation. Once established, third-degree congenital heart block is permanent. However, a lesser degree of autoantibody-associated heart block in a fetus can be reversed if it is recognized and treated early enough with fluorinated glucocorticosteroids. The only method available clinically for the recognition of first-degree heart block in a fetus is measurement of the mechanical PR interval by pulsed Doppler echocardiography. This is the first report of a fetus in whom a diagnosis of first-degree heart block and the consequent decision to intervene were based solely on this technique. In addition, the first-degree heart block resolved completely after only 2 weeks of dexamethasone treatment, and the heart rhythm remained stable throughout the remainder of the pregnancy despite early discontinuation of therapy due to oligohydramnios.     

Signs of first-degree heart block occur in one-third of fetuses of pregnant women with anti-SSA/Ro 52-kd antibodies

OBJECTIVE: To prospectively investigate the development of fetal heart block in anti-SSA/Ro 52-kd-positive women, and to evaluate the usefulness of serial Doppler echocardiography in detecting early signs of congenital heart block. METHODS: Twenty-four women with anti-SSA/Ro 52-kd antibodies and consequently increased risk for fetal heart block were followed up weekly, between 18 and 24 weeks of gestation, with two Doppler echocardiographic methods designed to estimate the time delay between hemodynamic events caused by atrial and ventricular depolarizations. Two hundred eighty-four women with normal pregnancies served as controls. Anti-Ro 52-kd, anti-Ro 60-kd, and anti-La antibodies were investigated by immunoblotting and enzyme-linked immunosorbent assay using recombinant proteins. RESULTS: In anti-Ro 52-kd-positive women, fetal atrioventricular (AV) time intervals were longer and heart rates were slightly lower compared with those in controls. Eight of 24 fetuses had signs of first-degree block. One of these fetuses had progression to complete block, and another showed recovery from second-degree block to first-degree block with betamethasone treatment. In the remaining 6 fetuses, spontaneous normalization occurred before or shortly after birth. Fetuses with normal AV time intervals at 18-24 weeks had normal electrocardiographic results at birth. CONCLUSION: Anti-Ro 52-kd-positive pregnant women frequently carry fetuses with Doppler echocardiographic signs of first-degree AV block. These blocks revert spontaneously in the majority of fetuses, but progression to a more severe degree of block may occur in some. Serial Doppler echocardiographic measurement of AV time intervals is suggested as a useful method for surveillance of these high-risk pregnancies.     

Rare cardiac defect in Holt-Oram syndrome

Holt-Oram syndrome is an autosomal dominant condition associated with skeletal malformations of the upper limbs, and congenital heart disease. Approximately 40% of cases represent new mutations. Defective development of the embryonic radial ray (e.g. aplasia, hypoplasia, fusion, other anomalous development) results in a wide spectrum of phenotypes, including triphalangeal or absent thumbs, foreshortened arms and phocomelia. The syndrome is associated with defective development of cardiac structures that results in atrial septal defect (ASD), most commonly the secundum type, heart block of varying degrees, or both. We report a rare cardiac defect patent ductus arteriosus (PDA) and ventricular septal defect (VSD) in a case of Holt-Oram syndrome.     

Conduction disorders after cardiac surgery with extracorporeal circulation

Two-hundred-fifty-eight patients who had cardiac surgery with extracorporeal circulation were studied to determine the frequency and significance of conduction disturbances. Fifty-eight (34%) developed new postoperative conduction defects. Seventeen patients developed new conduction alterations after coronary artery bypass graft. The most common disturbance was transient bifascicular block (right bundle branch block and anterior subdivision block of the left bundle branch of His) (p less than 0.01). After valvular surgery twenty-one patients developed conduction defects. Of those the most common disturbance was high degree AV block (57%). The authors found no relation between the AV block and the number of valves operated on or type of valvular surgery. After congenital heart surgery, twenty patients developed conduction defects. The most common defect was high degree AV block. The frequency of complete heart block was higher after the closure of atrial septal defects (P less than 0.01). None of the conduction defects were related to the amount of time the patient was exposed to extracorporeal circulation or to postoperative myocardial infarction. All conduction defects were transient except complete heart block in some patients with ventricular septal defect surgery. In this study there were no hemodynamic complications or mortality associated with the conduction disturbances.     

Early ECG Abnormalities Associated with Transcatheter Closure of Atrial Septal Defects Using the Amplatzer® Septal Occluder

Conduction abnormalities and arrhythmias may occur in patients following secundum atrial septal defect (ASD) closure using the Amplatzer® septal occluder (ASO). Therefore, the aim of this study was to prospectively perform ambulatory ECG monitoring to assess the electrocardiographic effects of transcatheter closure (TCC) of ASD using the ASO device.From 5/97 to 3/99, 41 patients with secundum ASD, underwent TCC using the ASO device at a median age of 9.2[emsp4 ]y. (0.5–87[emsp4 ]y.) and median weight of 34[emsp4 ]kg (5.6–88[emsp4 ]kg.). Ambulatory Holter monitoring was performed pre- and immediately post TCC. Holter analysis included heart rate (HR), ECG intervals, supraventricular ectopy (SVE), ventricular ectopy (VE), and AV block.No change in baseline rhythm was noted in 37 patients (90%). Changes in AV conduction occurred in 3 patients (7%), including intermittent second degree AV block type II, and complete AV dissociation post closure. SVE was noted in 26 patients (63%) post closure, ranging from 5–2207 supraventricular premature beats (SVPB), including 9 patients (23%) with non-sustained supraventricular tachycardia (SVT), 3 of whom had short runs of SVT prior to closure. A significant increase in post-closure number of SVPB per hour (p=0.047) was noted. No significant difference was noted in PR interval, ventricular premature beats per hour, or QRS duration. Conclusions: Based on ambulatory ECG analysis, TCC of ASD with the ASO device is associated with an acute increase in SVE and a small risk of AV conduction abnormalities, including complete heart block. Long term follow-up studies will be necessary to determine late arrhythmia prevalence and relative frequency compared with standard surgical ASD repair.     

Quantitative trait loci modifying cardiac atrial septal morphology and risk of patent foramen ovale in the mouse

Atrial septal defect (ASD) is a common congenital heart disease (CHD) occurring in 5 to 7 per 10,000 live births. Mutations in 5 human genes (NKX2.5, TBX5, GATA4, MYHC, ACTC) are known to cause dominant ASD, but these account for a minority of cases. Human and mouse data suggest that ASD exists in an anatomical continuum with milder septal variants patent foramen ovale (PFO) and atrial septal aneurysm, strongly associated with ischemic stroke and migraine. We have previously shown in inbred mice that the incidence of PFO strongly correlates with length of the interatrial septum primum, defining a quantitative trait underlying PFO risk. To better understand genetic causation of atrial septal abnormalities, we mapped quantitative trait loci (QTL) influencing septal morphology using mouse strains (QSi5 and 129T2/SvEms) maximally informative for PFO incidence and 3 quantitative septal anatomical traits including septum primum length. [QSi5x129T2/SvEms]F2 intercross animals (n=1437) were phenotyped and a whole genome scan performed at an average 17-cM interval. Statistical methodology scoring PFO as a binary phenotype was developed as a confirmatory mapping technique. We mapped 7 significant and 6 suggestive QTL modifying quantitative phenotypes, with 4 supported by binary analysis. Quantitative traits, although strongly associated with PFO (P<0.001), correlated poorly with each other and in all but 1 case QTL for different traits were nonoverlapping. Thus, multiple anatomical processes under separate genetic control contribute to risk of PFO. Our findings demonstrate the feasibility of modeling the genetic basis of common CHD using animal genetic and genomic technologies.     

Cardiac septal and valvular dysmorphogenesis in mice heterozygous for mutations in the homeobox gene Nkx2-5

Heterozygous mutations in the cardiac homeobox gene, NKX2-5, underlie familial cases of atrial septal defect (ASD) with severe atrioventricular conduction block. In this study, mice heterozygous for Nkx2-5-null alleles were assessed for analogous defects. Although ASD occurred only rarely, atrial septal dysmorphogenesis was evident as increased frequencies of patent foramen ovale and septal aneurysm, and decreased length of the septum primum flap valve. These parameters were compounded by genetic background effects, and in the 129/Sv strain, septal dysmorphogenesis bordered on ASD in 17% of Nkx2-5 heterozygotes. In a proportion of neonatal heterozygotes, as well as in adults with ASD, we found that the size of the foramen ovale was significantly enlarged and altered in shape, potentially exposing the normally thin septum primum to excessive hemodynamic forces. Therefore, defective morphogenesis of the septum secundum may be one contributing factor in the generation of patent foramen ovale, septal aneurysm, and certain ASDs. Mild prolongation of P-R interval in females and an increased frequency of stenotic bicuspid aortic valves were also features of the Nkx2-5 heterozygous phenotype. Our data demonstrate that the complex effects of Nkx2-5 haploinsufficiency in mice are weaker but convergent with those in humans. As in the mouse, the phenotype of human NKX2-5 mutations may be modulated by interacting alleles.     

经食道超声心图评价成人先天性房间隔缺损

目的：探讨经食道超声心动图评价成人先天性心脏病的价值。方法：我们用经食道超声心动图（TEE）诊断成人先天性心脏病173例,156例经心导管和／或手术证实。结果：在131例经手术和／或心导管证实的房间隔缺损（ASD）的病例,经胸超声心动图（TTE）显示ADS109例,TEE显示ASD128例,TTE诊断房间隔缺损的敏感性为83％,TEE诊断房间隔缺损的敏感性为98％,值得注意的是,10例静脉窦型ASD,TTE仅能显示3例,而TEE能观察到所有的10例,且所有的TEE检查的病例,能清晰地观察到与静脉窦型ASD相关的部分肺静脉异位引流,3例冠状静脉窦部位的小ASD,TTE显示2例,但TEE未能显示,结论：TEE探查ADS明显优于TTE,尤其是静脉窦型ASD,但靠近冠状静脉窦部位的小ASD,TEE并不比TTE检查优越,同时TEE对其他先天性心脏病异常结构的观察也提供大量的附加信息。     

纽扣式补片术治疗成人先天性心脏病113例

目的 :评价纽扣式补片术治疗成人先天性心脏病的疗效及总结其经验。方法 :采用经导管纽扣式补片治疗先天性心脏病 113例 ,其中房间隔缺损 (ASD) 45例 ,动脉导管未闭 (PDA) 45例 ,室间隔缺损 (VSD) 2 3例。结果 :ASD、PDA、VSD成功率分别为 10 0 % (4 5/45例 )、95.6 % (4 3/45例 )和 83.0 % (19/2 3例 ) ,总成功率为 94 .6 %。手术并发症主要见于 VSD患者 ,束支传导阻滞发生率为 2 6 .4 3% (6 /2 3例 )。结论 :纽扣式补片术治疗成人先天性心脏病成功率高 ,即时疗效显著 ,并发症少 ,是一种安全的介入治疗方法     

Spread of heart diseases seen in an open-access paediatric echocardiography clinic

All patients <13 years of age referred to the open-access paediatric echocardiography clinic at the Sultan Qaboos University Hospital, Muscat, Oman, during the five years from 1994 to 1998 were analysed. Among the 2633 patients studied, 1543 (58.6%) were normal, 845 (32.1%) had congenital heart disease, and 245 (9.3%) had acquired heart disease. The major congenital heart diseases identified were secundum atrial septal defect (22.5%), ventricular septal defect (22.5%), patent ductus arteriosus (15.7%), mitral valve prolapse (10.7%), pulmonary stenosis (9.7%) and atrioventricular septal defect (4.5%). Fifty-eight percent of the congenital heart diseases were identified in the first year of life. Among the acquired heart diseases, rheumatic heart disease (30.2%) and cardiac involvement secondary to haemoglobinopathies (16.7%), dilated cardiomyopathy (16.3%) and hypertrophic cardiomyopathy (12.7%) were significant. Although the presence of specific cardiac symptoms was associated with a high yield of abnormalities, such disorders were also discovered in a significant number of children with isolated cardiac murmur. The referral source did not influence significantly the frequency of heart diseases diagnosed in this study. Open-access echocardiography is important in early detection of heart disease in the paediatric population.