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.     

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.     

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.     

Electrocardiographic changes and arrhythmias following percutaneous atrial septal defect and patent foramen ovale device closure

Objectives: To compare pre‐ and post‐procedure electrocardiograms (ECGs) in a large cohort of patients after percutaneous closure of atrial septal defect (ASD) and patent foramen ovale (PFO). Background: Percutaneous device closure of ASD or PFO is commonplace. Conduction and rhythm anomalies associated with percutaneous device placement have been reported. Methods: We reviewed records for all patients who underwent percutaneous device closure of ASD or PFO at our institution from 1999 to 2008. Pre‐procedure ECG and Holter studies were compared to available short term (<2 months after placement) and intermediate follow‐up (>2 months) ECG or Holter. Results: Pre‐ and post‐procedural ECGs were available in 610 patients (305 females, average age 50 ± 18.1 years, range 1–91 years, 384 PFO, 184 ASD, 42 with multiple defects, mean device size 16 mm, range 5–38 mm). We report an incidence of 5.2% (32/610) of arrhythmias in the 4 months following device placement, including 29 patients with atrial tachyarrhythmias (ATs, 22 fibrillation, 7 flutter), 1 with junctional tachycardia, and 2 with heart block. Among other findings, the average P‐wave duration was increased on intermediate follow‐up as compared to early follow‐up (P < 0.001). Development of new‐onset 1st degree AV Block after the procedure was associated with an increased risk of ATs post‐procedure (P < 0.0001). Conclusion: We report a low risk of clinically significant post‐procedure arrhythmias after device placement. Clinically significant heart block occurred in only two patients (0.3%). Changes in several markers of atrial conduction were found, suggesting an effect of device closure on intra‐atrial conduction. © 2011 Wiley‐Liss, Inc.     

Coronary angiography in patients undergoing transcatheter closure of interatrial shunt

We evaluate the yield and safety of coronary angiography (CA) in adult patients who underwent cardiac catheterization for percutaneous transcatheter closure of secundum atrial septal defect (ASD) or patent foramen ovale (PFO). Out of 268 patients, 180 were adults; 82 were adults with ASD and 98 were adults with PFO. CA was performed in 23 patients who were suspected for coronary artery disease. Of these patients, 5 (21.7%) had coronary angiographic findings that altered the planned treatment strategy. No complications associated with coronary angiography were observed. CA should be considered a part of cardiac catheterization in selected patients referred for transcatheter closure of secundum ASD or PFO.     

Transient atrioventricular block after open-heart surgery for congenital heart disease

The records of 22 patients with transient atrioventricular (AV) block after open-heart surgery for congenital heart disease from 1972 to 1978 were reviewed to determine the natural history of this entity. Preoperatively, no patient had AV block; 3 had right bundle branch block (BBB), 1 had left BBB and 5 had nonspecific intraventricular conduction delay. Complete AV block developed in 20 patients and Mobitz II AV block in 2. Transient AV block occurred intraoperatively in 14 patients and within 48 hours postoperatively in 8; AV block persisted for greater than or equal to 48 hours postoperatively in all patients, for a mean of 7.3 days (range 2 to 28). During a follow-up of 5.5 years (range 2.5 to 10), late AV block developed in 2 patients. None of the 18 patients whose escape QRS complex morphology during AV block was similar to the final QRS complex during normal sinus rhythm or atrial fibrillation with AV conduction had late AV block, whereas 2 of the 4 in whom it differed did (p less than 0.01). There was no difference in the escape rate between the 2 groups. Thus, late development of high-grade AV block is infrequent among patients with transient postoperative AV block. An escape QRS complex during postoperative AV block that differs from the QRS complex seen on recovery of normal sinus rhythm or atrial fibrillation with anterograde conduction may identify those at high risk of late AV block.     

Role of intracardiac echocardiographic guidance in transcatheter closure of atrial septal defects and patent foramen ovale using the Amplatzer device

Transesophageal echocardiography (TEE) has been successfully used for guiding transcatheter device closure of secundum atrial septal defect (ASD) and patent foramen ovale (PFO). However, the use of TEE for device closure requires general anesthesia. Experience with intracardiac echocardiographic (ICE) guidance to close ASD and PFO is limited. One hundred eleven patients (76 female/35 male) with secundum ASD (82 patients) and PFO (29 patients) associated with a stroke underwent an attempt of transcatheter closure of their defects under ICE guidance using the new AcuNav catheter. The median age of patients was 40 years (range 2.5-80.7) and the median weight was 66 kg (range 12.7-128 kg). The median two-dimensional size of secundum defects as measured by ICE was 17 mm (range 3-32 mm). The median balloon stretched diameter of the ASDs was 22 mm (range 4-36 mm). Five patients had more than one defect that required placement of two devices to close the defects. The median Qp/QS ratio for patients with secundum ASD was 2.1 (range 1-18). ICE provided adequate views of the defects and surrounding structures and the various stages of device deployment. All patients had successful device placement, including the patients who received simultaneous two devices with immediate complete closure of the defects in 100 patients, whereas four and seven patients had trivial and small residual shunt, respectively. The median fluoroscopy time was 10.2 minutes (range 3.7-38.4 minutes) and the median total procedure time was 60 minutes (range 28-180 minutes). There were no complications related to the use of the AcuNav catheter. We conclude that ICE provided unique images of the atrial communications and facilitated device closure of secundum ASD and PFO in children and adults. We believe ICE should replace TEE as a guiding imaging tool for ASD and PFO device closure, thus eliminating the need for general anesthesia.     

Incidence of atrial fibrillation following transcatheter closure of atrial septal defects in adults

Transcatheter closure of secundum atrial septal defect (ASD) and patent foramen ovale (PFO) has become a routine procedure. Little is known about the effect of atrial septal device implantation on the occurrence of atrial fibrillation (AF). We evaluated the frequency of AF occurring after transcatheter PFO and ASD closure in a large population. From 1994 until 2007 a total of 1,062 patients underwent transcatheter closure of an interatrial communication. New-onset AF was defined by 12-lead electrocardiogram or Holter monitoring in patients without a history of AF at baseline. Of the 1,062 patients, 822 had a PFO and 240 had an ASD. During a median follow up of 20 months, new-onset AF was documented in 8% of patients. New-onset AF occurred in 7% of patients after PFO closure and in 12% of patients with underlying ASD. The annual incidence of new-onset AF was 2.5% and 4.1% in patients with PFO and ASD, respectively. Generally, patients with new-onset AF were older than those without AF. Device type or size did not influence the occurrence of AF. In the group of patients with PFO, residual shunt was more common in patients with AF compared with the non-AF group. In conclusion, AF is more common after PFO and ASD closure compared with the general population; although device type or size did not impact the occurrence of AF, residual shunt may influence the occurrence of AF after intervention in patients with underlying PFO.     

Platypnea-orthodeoxia: management by transcatheter buttoned device implantation.

Dyspnea and arterial desaturation on upright position in elderly subjects is described as platypnea-orthodeoxia syndrome (POS) and in some patients it is due to right-to-left shunt across the atrial septal defect (ASD)/patent foramen ovale (PFO). Surgical closure of ASD/PFO has been the only available treatment option. Buttoned device has been used for occlusion of ostium secundum ASD, PFO associated with presumed paradoxical embolism and cerebrovascular accidents and ASD/PFO in association with other congenital heart defects causing right-to-left shunt. The objective of this article is to describe the use of buttoned device in effectively occluding ASD/PFO to relieve hypoxemia of POS. During a 4-year period ending January 2000, 10 patients, ages 71 +/- 9 (range 60-83) years with POS underwent buttoned device closure of their ASD/PFO. Echocardiographic and balloon-stretched atrial defect sizes were 8 +/- 3 mm and 12 +/- 3 mm, respectively. The ASD/PFO were occluded with devices ranging in size from 25 to 40 mm delivered via 9 French, long, blue Cook sheaths; eight had an additional 25- or 35-mm occluder placed on the right atrial side. The oxygen saturation increased (P < 0.001) from 76 +/- 7% (range 69-86%) to 95 +/- 2% (range 92-98%). No complications were encountered. Relief of symptoms was seen in all patients. Follow-up of 1-36 months (median 12 months) revealed persistent improvement of symptoms. Buttoned device occlusion of ASD/PFO to relieve hypoxemia of POS is feasible, safe, and effective and is an excellent alternative to surgery. Cathet Cardiovasc Intervent 2001;54:77-82.     

Spontaneous transition of 2:1 atrioventricular block to 1:1 atrioventricular conduction during atrioventricular nodal reentrant tachycardia: evidence supporting the intra-Hisian or infra-Hisian area as the site of block

INTRODUCTION: The incidence of spontaneous transition of 2:1 AV block to 1:1 AV conduction during AV nodal reentrant tachycardia has not been well reported. Among previous studies, controversy also existed about the site of the 2:1 AV block during AV nodal reentrant tachycardia. METHODS AND RESULTS: In patients with 2:1 AV block during AV nodal reentrant tachycardia, the incidence of spontaneous transition of 2:1 AV block to 1:1 AV conduction and change of electrophysiologic properties during spontaneous transition were analyzed. Among the 20 patients with 2:1 AV block during AV nodal reentrant tachycardia, a His-bundle potential was absent in blocked beats during 2:1 AV block in 8 patients, and the maximal amplitude of the His-bundle potential in the blocked beats was the same as that in the conducted beats in 4 patients and was significantly smaller than that in the conducted beats in 8 patients (0.49 +/- 0.25 mV vs 0.16 +/- 0.07 mV, P = 0.007). Spontaneous transition of 2:1 AV block to 1:1 AV conduction occurred in 15 (75%) of 20 patients with 2:1 AV block during AV nodal reentrant tachycardia. Spontaneous transition of 2:1 AV block to 1:1 AV conduction was associated with transient right and/or left bundle branch block. The 1:1 AV conduction with transient bundle branch block was associated with significant His-ventricular (HV) interval prolongation (66 +/- 19 ms) compared with 2:1 AV block (44 +/- 6 ms, P < 0.01) and 1:1 AV conduction without bundle branch block (43 +/- 6 ms, P < 0.01). CONCLUSION: The 2:1 AV block during AV nodal reentrant tachycardia is functional; the level of block is demonstrated to be within or below the His bundle in a majority of patients with 2:1 AV block during AV nodal reentrant tachycardia, and a minority are possibly high in the junction between the AV node and His bundle.     

Torsades de pointes complicating atrioventricular block: Evidence for a genetic predisposition

BACKGROUND: The prevalence of genetic risk factors has not been systematically evaluated in the setting of complete atriventricular (AV) block complicated by long QT syndrome (LQTS). OBJECTIVE: This study was performed to determine to what extent acquired LQTS in the context of AV block has a genetic substrate. METHODS: Among 420 recipients of pacemakers implanted over a 3-year period, we identified retrospectively 29 patients with complete AV block and a QT interval >600 ms in duration. A second study group included 22 randomly selected patients who had AV block and a QT interval <600 ms. Normal controls were 100 consecutive individuals without medical history. Genetic studies screening for HERG, KCNQ1 KCNE1, KCNE2, and SCN5A mutations were performed. RESULTS: We identified four mutations on genes encoding potassium channels in five patients with AV block and acquired LQTS. These mutations were not found among patients with AV block and a QT interval <600 ms in duration or in healthy volunteers. Functional expression of three HERG mutations (R328C, R696C, and R1047L) had a dominant negative effect on wild-type I(Kr). One KCNE2 mutation (R77W) identified in a patient treated with flecainide did not alter I(Kr). CONCLUSIONS: This study showed that complete AV block complicated by LQTS was associated with HERG mutations in 17% of cases. Further studies are needed to identify factors, genetic or environmental, which may be implicated in bradycardia-related abnormalities of ventricular repolarization.     

Early-mid term follow-up results of percutaneous closure of the interatrial septal defects with occlutech figulla devices: a single center experience

Background: Percutaneous closure of secundum type atrial septal defect (ASD) and patent foramen ovale (PFO) has gained widespread use in recent years. Herein, we evaluated the safety and efficacy of the Occlutech® Figulla devices for PFO and ASD closure in a reference tertiary center. Methods: All 143 patients (46.9% male, mean age 39.3 ± 12.2 years) who underwent transcatheter PFO (n = 85) and ASD (n = 58) closure with Occlutech® Figulla devices between February 2009 and October 2011 were included in this study. An echocardiographic follow‐up examination was performed at the 1st, 6th, and 12th month visits. Results: The devices were successfully implanted in all 143 patients (100%). In‐hospital periprocedural complications were device embolization (0.7%; 1 ASD patient), atrial fibrillation (1.4%; 1 ASD and 1 PFO patients), supraventricular tachycardia (0.7%; 1 PFO patient), and vascular access hematoma (0.7%; 1 ASD patient). Among ASD patients, 2 patients had trivial (jet width <1 mm in diameter) and 1 patient had small (1–2 mm) residual shunts before hospital discharge, which disappeared after the 6‐month visit. During the mean 15.4 ± 9.6 months follow‐up, all patients were asymptomatic and no ischemic stroke, cardiac perforation, device erosion, embolization, thrombus formation, or malposition of the device was observed. Conclusions: Percutaneous PFO and secundum type ASD closure with the novel Occlutech® Figulla Occluder devices without left atrial central pin and with significantly reduced meshwork was safe, feasible, and effective. (J Interven Cardiol 2012;25:375–381)     

相同基因型而不同表现型的PRKAG2基因突变一家系报道

目的 位于7号染色体上的腺苷一磷酸激活的蛋白激酶γ^2调节亚单位基因（PRKAG2基因）调节代谢通路。报道一个具有PRKAG2基因突变而临床表现型不同的家系。方法 使用DNA直接测序法,对一个具有多种形式心律失常的患者家系（13例患者）进行PRKAG2外显子及外显子和内含子拼接部位序列筛查寻找基因突变。结果 心电图显示患者家系存在窦性心动过缓、短PR间期、完全性右束支传导阻滞、房室传导阻滞和房性心动过速。其中3例患者在年轻时发生猝死,没有1例有预激综合征（预激）表现,只有1例有心肌肥厚。DNA测序结果显示,该家系所有患者皆有一个PRKAG2错义突变（R302Q）。这个基因突变以前曾描述并与预激和左室肥厚有关。结论 PRKAG2基因突变不仅导致预激而且与多种临床表现型有关。完全性右束支传导阻滞、窦性心动过缓、短PR间期应该高度怀疑有PRKAG2基因突变的可能。     

Five-year clinical and echocardiographic evaluation of the Das AngelWings atrial septal occluder

Background

The late outcome of patients treated with atrial septal occluder devices remains incompletely defined. The purpose of this study was to assess the late outcome (range 4-7 years postprocedure) of patients in whom the Das AngelWings septal occluder device was implanted in the atrial septum. We report the clinical and echocardiographic outcome, at an average of 5 years following the procedure, of patients treated with the Das AngelWings device used to close either a secundum atrial septal defect (ASD) or a patent foramen ovale (PFO).

Methods

Thirty-two patients underwent successful percutaneous closure of an atrial septal closure, patent foramen ovale, or fenestration in the lateral tunnel of their Fontan with the Das AngelWings device between June 1995 and March 1998 at Duke University Medical Center. Two of the 32 patients were lost to follow-up. The remaining 30 patients were divided into 3 groups based on indication for device implantation. Group 1 consisted of 14 patients with a secundum ASD and predominantly left-to-right atrial shunting. Group 2 consisted of 8 patients who had a PFO and who suffered a thromboembolic event. Group 3 (compassionate use) consisted of 10 patients with multiple comorbid medical problems with predominantly right-to-left shunting at the atrial level causing hypoxemia. Eight of the patients in group 3 were severely ill at the time of device implantation. The 2 remaining patients in group 3 underwent AngelWings implantation for closure of right-to-left shunting through a Fontan fenestration. Mean follow-up was 59 months.

Results

There was no device embolization. No patient in the ASD or PFO/stroke group had a clinical complication. By radiographic examination, 2 of 27 patients had evidence of fracture of the nitinol framework at 2-year follow-up. Residual shunting was present in 44% at 24 hours, 20% at 1 year, and 18.8% at 2 years by use of Doppler color flow imaging and/or microcavitation echocardiographic studies. Mild mitral regurgitation caused by the AngelWings device occurred in 1 patient.One patient in the compassionate use group had a subsequent neurologic event. Five of the 10 patients in the compassionate use group died of comorbid illnesses in follow-up, none directly related to device complications.

Conclusion

The late clinical outcome of secundum ASD and PFO/stroke patients in this study demonstrates that Das AngelWings closure of the atrial septum is effective and safe. These data are encouraging with respect to the expanding use of other percutaneously implanted ASD occlusion devices, although late clinical safety and efficacy data are needed for the specific devices being implanted.     

Percutaneous treatment of atrial septal aneurysm

Among a total number of 203 patients with atrial septal defects (ASD) or patent foramen ovale (PFO) who were treated by percutaneous closure, we selected 29 (19 with ASD and 10 with PFO) who fulfilled the criteria for atrial septal aneurysm. Eight patients had functional class II or III dyspnea, and 12 had a history of previous cerebrovascular accident (38%). Seven of the patients with ASD, had a single defect and 12 had multiple defects; 14 received a single occluder and 5 patients needed 2 or 3 devices. Follow-up transthoracic ultrasound study at 6 months showed the defect to be successfully closed in all 29 patients. After a mean follow-up time of 31 +/- 19 months, all patients were alive and symptom-free. Patients with atrial septal aneurysm and associated ASD or PFO can be successfully treated with Amplatzer septal occluders.