Heart-Stroke Team: A multidisciplinary assessment of patent foramen ovale-associated stroke.

INTRODUCTION: Patent foramen ovale (PFO) closure prevents recurrent ischemic stroke in selected patients with a cryptogenic stroke. Trial results tend to be generalized to daily practice, often extending original trial inclusion criteria. This may result in unnecessary closure without benefit, but with risk of complications. We therefore introduced a standardized and structured evaluation by an interdisciplinary Heart-Stroke Team (HST). Our aim was to investigate the proportion of actual PFO closure of all referred patients with a cryptogenic stroke, after evaluation by the HST. PATIENTS AND METHODS: We conducted a single-center, retrospective cohort study. Patients with an assumed cryptogenic ischemic stroke or transient ischemic attack (TIA) and a PFO who were referred for PFO closure were analyzed. As part of the HST approach, all patients underwent a standardized work-up, first to demonstrate the ischemic event on neuroimaging, second to evaluate all potential causes of stroke and finally, to assess the possible relation between the PFO and stroke. Outcome was the proportion of patients treated with PFO closure after referral. RESULTS: A total of 195 patients were included. In 124 patients (64%) PFO closure was advised. Fourty-two (22%) patients had a clear alternative cause of stroke and in 13 (7%) patients the initial stroke diagnosis could not be confirmed. CONCLUSION: After careful analysis of patients referred for PFO closure a relationship between the PFO and stroke could not be demonstrated in 32% of referrals, and 3% preferred best medical treatment over percutaneous closure. This stresses the need for a complete neurovascular work-up and multidisciplinary assessment.

Time course and interrelationship of dysrhythmias in patients with surgically repaired atrial septal defect.

BACKGROUND: Atrial fibrillation (AF) and other supraventricular tachycardias (SVTs) are known complications after surgical repair of atrial septal defect (ASD), but sinus node dysfunction (SND) and complete atrioventricular conduction block (cAVB) may also occur. OBJECTIVE: The aim of this study was to examine time course and interrelationship of various dysrhythmias in patients with ASD. METHODS: Adult patients (N = 95) with surgically repaired secundum ASD (n = 40), partial atrioventricular septal defect (n = 37) or sinus venosus defect (n = 18), and documented SND, cAVB, AF, and/or other SVT were included. The median age at repair was 13 years (interquartile range [IQR] 6-45 years), and patients were followed for 26 years (IQR 15-37 years) after ASD repair. RESULTS: SND was observed in 34 patients (36%), cAVB in 14 (14%), AF in 48 (49%), and SVT in 44 (45%); 37 patients (39%) had ≥2 dysrhythmias. All dysrhythmias presented most often after ASD repair (P < .01), with a median duration of 12 years (IQR 17 days - 32 years) to 16 years (IQR 4 - 28 years) between repair and onset. Development of SND and cAVB late after ASD repair was not related to a redo procedure in 100% and 60% of patients, respectively. SND preceded atrial tachyarrhythmias in 50% (P = .31) and SVT preceded AF in 68% (P = .09) of patients with both dysrhythmias. CONCLUSION: A substantial number of dysrhythmias presented (very) late after ASD repair. In most patients, development of late SND and cAVB was not related to redo procedures. In patients with multiple dysrhythmias, a specific order of appearance was not observed.

Corrigendum: Candidate Gene Resequencing in a Large Bicuspid Aortic Valve-Associated Thoracic Aortic Aneurysm Cohort: SMAD6 as an Important Contributor.

[This corrects the article on p. 400 in vol. 8, PMID: 28659821.].

Candidate Gene Resequencing in a Large Bicuspid Aortic Valve-Associated Thoracic Aortic Aneurysm Cohort: SMAD6 as an Important Contributor.

Bicuspid aortic valve (BAV) is the most common congenital heart defect. Although many BAV patients remain asymptomatic, at least 20% develop thoracic aortic aneurysm (TAA). Historically, BAV-related TAA was considered as a hemodynamic consequence of the valve defect. Multiple lines of evidence currently suggest that genetic determinants contribute to the pathogenesis of both BAV and TAA in affected individuals. Despite high heritability, only very few genes have been linked to BAV or BAV/TAA, such as NOTCH1, SMAD6, and MAT2A. Moreover, they only explain a minority of patients. Other candidate genes have been suggested based on the presence of BAV in knockout mouse models (e.g., GATA5, NOS3) or in syndromic (e.g., TGFBR1/2, TGFB2/3) or non-syndromic (e.g., ACTA2) TAA forms. We hypothesized that rare genetic variants in these genes may be enriched in patients presenting with both BAV and TAA. We performed targeted resequencing of 22 candidate genes using Haloplex target enrichment in a strictly defined BAV/TAA cohort (n = 441; BAV in addition to an aortic root or ascendens diameter ≥ 4.0 cm in adults, or a Z-score ≥ 3 in children) and in a collection of healthy controls with normal echocardiographic evaluation (n = 183). After additional burden analysis against the Exome Aggregation Consortium database, the strongest candidate susceptibility gene was SMAD6 (p = 0.002), with 2.5% (n = 11) of BAV/TAA patients harboring causal variants, including two nonsense, one in-frame deletion and two frameshift mutations. All six missense mutations were located in the functionally important MH1 and MH2 domains. In conclusion, we report a significant contribution of SMAD6 mutations to the etiology of the BAV/TAA phenotype.