Markus Schwerzmann

Recurrent rearrangements of chromosome 1q21.1 and variable pediatric phenotypes

BACKGROUND Duplications and deletions in the human genome can cause disease or predispose persons to disease. Advances in technologies to detect these changes allow for the routine identification of submicroscopic imbalances in large numbers of patients. METHODS We tested for the presence of microdeletions and microduplications at a specific region of chromosome 1q21.1 in two groups of patients with unexplained mental retardation, autism, or congenital anomalies and in unaffected persons. RESULTS We identified 25 persons with a recurrent 1.35-Mb deletion within 1q21.1 from screening 5218 patients. The microdeletions had arisen de novo in eight patients, were inherited from a mildly affected parent in three patients, were inherited from an apparently unaffected parent in six patients, and were of unknown inheritance in eight patients. The deletion was absent in a series of 4737 control persons (P=1.1x10(-7)). We found considerable variability in the level of phenotypic expression of the microdeletion; phenotypes included mild-to-moderate mental retardation, microcephaly, cardiac abnormalities, and cataracts. The reciprocal duplication was enriched in nine children with mental retardation or autism spectrum disorder and other variable features (P=0.02). We identified three deletions and three duplications of the 1q21.1 region in an independent sample of 788 patients with mental retardation and congenital anomalies. CONCLUSIONS We have identified recurrent molecular lesions that elude syndromic classification and whose disease manifestations must be considered in a broader context of development as opposed to being assigned to a specific disease. Clinical diagnosis in patients with these lesions may be most readily achieved on the basis of genotype rather than phenotype.

Relation between Directly Detected Patent Foramen Ovale and Ischemic Brain Lesions in Sport Divers

Scuba diving involves a risk for neurologic injuries caused by decompression sickness, arterial gas embolism, anoxia, and the toxic effects of high partial pressure of breathing gases (1). Most neuroimaging studies for detection of ischemic brain lesions have been performed in divers with acute decompression-related injuries of the central nervous system (2, 3). However, as a recent study has shown (4), most divers may be neurologically asymptomatic despite an increased prevalence of brain lesions compared with nondiving controls. Reul and colleagues (4) found 80% of all brain lesions in a subgroup of 27% of divers, possibly those with patent foramen ovale who had paradoxical arterial gas embolism during decompression (4). Knauth and coworkers (5) used transcranial Doppler ultrasonography to detect a right-to-left shunt in 87 sport divers; they reported that multiple brain lesions on magnetic resonance imaging (MRI) occurred exclusively in those with a large right-to-left shunt, which was presumed to be a patent foramen ovale (5). Detection of intravenously injected echocontrast bubbles in the cerebral vasculature is not specific for a patent foramen ovale; moreover, compared with transesophageal echocardiography, detection of these bubbles has been found to be only 68% sensitive in detecting a patent foramen ovale (6). We used MRI and transesophageal echocardiography to determine the prevalence of decompression illness symptoms and ischemic brain lesions in relation to a patent foramen ovale in sport divers. Methods Participants Cranial MRI and contrast transesophageal echocardiography were performed in 52 sport divers and 52 healthy nondiving controls. Divers at three diving clubs from three different areas in Switzerland were informed about our study. We enrolled the first 57 divers who responded, had 200 or more dives using compressed air, and adhered to decompression tables. Claustrophobia prohibited 5 divers from having cranial MRI. For the control group, healthy nondiving persons from the hospital staff were asked to participate in the study. The study was approved by the institutional ethics committee, and participants gave informed consent. Health Status, Diving Habits, and Accidents Before examining the participants, we used a questionnaire to ask them about their medical and diving history. Diving history included average diving depth; number of dives to a depth of 40 m or greater; and occurrence of symptoms of decompression illness, which included symptoms of decompression sickness and of arterial gas embolism (7). Signs of spinal decompression illness were limb weakness, cutaneous sensory level, and impaired bowel or bladder control; signs of cerebral decompression illness were blurred vision, dysarthria, hemiplegia, or loss of consciousness. Onset of symptoms in arterial gas embolism is much faster than in decompression sickness, often occurring within minutes after surfacing or during decompression (7). Diagnostic Imaging Magnetic resonance imaging was done by using a 1.5-T Magnetom Vision system (Siemens, Erlangen, Germany) equipped with a head coil. The imaging protocol included T1-weighted, T2-weighted, and proton densityweighted imaging. Images were reviewed independently by two neuroradiologists blinded to study group and to whether a patent foramen ovale was present. A lesion was counted if it was hyperintense on proton densityweighted and T2-weighted images. After MRI, transesophageal echocardiography was done by using an Acuson Sequoia C256 system (Sequoia, Mountain View, California) equipped with a multiplane, 3.5- to 7-MHz probe. Echocontrast tests (Physiogel [Braun, Emmenbruecke, Switzerland] with air in a 9:1 ratio) were performed in the transversal and longitudinal image plane by injection of 2 mL of contrast into an antecubital vein. Direct shunting of contrast bubbles into the left atrium through the foramen ovale was detected by applying the Valsalva maneuver. Statistical Analysis Assuming a non-normal distribution of data, we compared continuous data by using the Wilcoxon rank-sum test or the KruskalWallis test. Adjustment for multiple testing was done by using the Bonferroni method. Between-group comparison of categorical data was done by using logistic regression for dichotomous outcomes and Poisson regression for count data. Values are expressed as the mean (SD) or as odds or incidence ratios with 95% CIs. A Pvalue less than 0.05 was considered statistically significant. Results Thirteen of 52 divers (25%) and 9 of 52 controls (17%) had a patent foramen ovale (odds ratio, 1.47 [95% CI, 0.78 to 2.23]; P>0.2). Divers were older and smoked more than controls (Table). Diving habits were similar among the two groups of divers (Table). Table. Participant Characteristics Spinal or cerebral symptoms of decompression sickness occurred in 4 of 13 divers with and 4 of 39 divers without a patent foramen ovale (odds ratio, 3.0 [CI, 1.4 to 7.2]; P=0.03) (Figure). Arterial gas embolism occurred in 4 of 13 divers with and 2 of 39 divers without patent foramen ovale (odds ratio, 6.0 [CI, 2.4 to 12.6]; P=0.007) (Figure). In a logistic regression model, patent foramen ovale increased the risk for decompression illness events in divers by 4.5-fold (risk ratio, 4.5 [CI, 1.2 to 18.0]; P=0.03) during all dives. Figure. Decompression sickness events and ischemic brain lesions in divers and nondivers. Top. white bars gray bars Bottom. There were 41 ischemic brain lesions in 19 divers and 7 lesions in 6 controls (odds ratio, 5.8 [CI, 3.7 to 9.4]; P=0.003). Among divers with and those without patent foramen ovale, 16 and 25 ischemic lesions were detected, respectively (1.23 2.0 and 0.64 1.22 ischemic brain lesions per person); in contrast, 2 and 5 ischemic lesions were detected in controls with and those without patent foramen ovale (0.22 0.44 and 0.12 0.63 lesion per person) (P<0.001 for all groups) (Figure). In a Poisson regression model, diving increased the incidence of 1 or more ischemic brain lesions by fivefold (incidence ratio, 5.2 [CI, 1.2 to 22]; P=0.03). Almost twice as many ischemic brain lesions were seen in divers with patent foramen ovale than in those without patent foramen ovale (incidence ratio, 1.8 [CI, 0.94 to 3.35]; P=0.07) (Figure). Discussion Neurologic injuries related to decompression illness in divers are due to regional gas nucleation that predominantly occurs in fat-containing tissue (decompression sickness) or invasion of gas into the systemic circulation (arterial gas embolism). Both of these conditions may manifest as ischemic lesions in the central nervous system. In our study, 14 decompression illness events took place in 9 of 52 divers (17%). Of these 9 divers, only 2 had one or more ischemic brain lesions on MRI. Therefore, the presence of ischemic brain lesions does not appear to correlate with neurofunctional manifestations of decompression events; instead, it may primarily depend on the global burden of decompression dives. The frequency of asymptomatic divers with ischemic brain lesions in our study (19 of 43 [44%]) is similar to that in a study by Reul and colleagues (27 of 52 [52%]) (4). That study and a neuroimaging magnetic resonance study in professional divers (8) appear to be the only published controlled trials to date, and their findings were discordant: Reul and colleagues (4) observed an increased number of ischemic brain lesions compared with nondiving controls, whereas Todnem and associates (8) found a similar number of lesions. This discrepancy may be related to variable frequency in the occurrence of a patent foramen ovale, a condition that has been implicated as a factor in the pathophysiology of diving-related brain damage but never investigated in a controlled fashion together with cerebral MRI (5, 9, 10). In 1986, Wilmshurst and associates (11) suggested that atrial septal defect and patent foramen ovale may be relevant to paradoxical gas embolism among scuba divers (11). Subsequent studies did not include a control group, cerebral neuroimaging, or transesophageal echocardiography for diagnosis of patent foramen ovale. In a study by Germonpre and colleagues (12), a control group of asymptomatic divers was compared with 37 matched divers who had decompression sickness, but neuroimaging was not performed. The prevalence of patent foramen ovale was 60% among divers with decompression sickness and 36% among those without decompression sickness (P=0.06). However, these data and those of Knauth and coworkers (5) do not indicate whether it is diving or the presence of a patent foramen ovale plus diving that causes brain damage. We found that presence of a patent foramen ovale rather than diving itself is responsible for a higher prevalence of clinical events. However, the absolute frequency of decompression sickness or arterial gas embolism is quite low, and from an epidemiologic point of view, clinical problems related to diving in persons with patent foramen ovale are not an important issue. Because half of divers with ischemic brain lesions are asymptomatic even after almost 1000 dives, the risk of diving is related to the potential for neurologic long-term effects of these lesions. In addition, patent foramen ovale in divers was associated with a higher prevalence of ischemic brain lesions. Our study has some limitations. Selection bias of divers with more frequent events of decompression illness events could have occurred, thus creating a tendency toward more brain lesions in divers. However, this is unlikely because the prevalence of patent foramen ovale in divers and controls did not differ significantly and the frequency of patent foramen ovale in divers was lower than that observed in the general population (13). Controls were selected from the hospital staff rather than the general population. This may have accounted for the statistical difference in age between all groups and the trend toward more smokers among divers. Because of the small

Ventricular arrhythmias and sudden death in adults after a Mustard operation for transposition of the great arteries

AIMS To examine the prevalence of sustained ventricular tachycardia (VT) and sudden death (SD) in adults with atrial repair of transposition of the great arteries (TGA) and to determine associated risk factors. METHODS AND RESULTS In a single-centre review, we studied the outcome of 149 adults (mean age 28 +/- 7 years) who had undergone a Mustard operation for TGA. During a mean follow-up of 9 +/- 6 years, sustained VT and/or SD occurred in 9% (13/149) of the cohort. Sustained VT/SD was more likely to occur in patients with associated anatomic lesions [hazard ratio (HR) 4.9, 95% CI 1.5-16.0], with NYHA class >or=III (HR 9.8, 95% CI 3.0-31.6) and with an impaired subaortic right ventricular (RV) ejection fraction (EF) (HR 2.2, 95% CI 1.2-4.0 per 10% decrease in EF). There was an inverse correlation between the RV-EF and both age and QRS duration. Patients with a QRS duration >or=140 ms were at highest risk of sustained VT/SD (HR 13.6, 95% CI 2.9-63.4). Atrial tachyarrhythmia was detected in 66 (44%) patients, but was not a statistically significant predictor of sustained VT/SD in our adult population (HR 2.7, 95% CI 0.6-13.0). CONCLUSION Sustained VT/SD in adults after a Mustard operation for TGA are more common than previously described. Age, systemic ventricular function, and QRS duration are interrelated and are associated with VT/SD. A QRS duration >or=140 ms helps to identify the high risk patient.

Assessment of Systemic Right Ventricular Function in Patients With Transposition of the Great Arteries Using the Myocardial Performance Index Comparison With Cardiac Magnetic Resonance Imaging

Background—Assessment of systemic right ventricular (RV) function is a key point in the follow-up of patients with transposition of the great arteries (TGA). Current echocardiographic assessment of RV function is at best an estimate, and cardiac magnetic resonance (CMR) is considered the gold standard. However, this technique is expensive, has limited availability, and requires significant expertise to acquire and interpret the images. The myocardial performance index (MPI) has recently been studied for assessment of pulmonary RV function and shows promise as a simple yet powerful tool for assessing patients with RV dysfunction of various origins. We set out to compare MPI and CMR assessment of systemic RV function in patients with TGA. Methods and Results—Data from patients with TGA (11 with congenitally corrected TGA, 18 with surgically corrected TGA) who had CMR within 6 months of their echocardiogram were reviewed. The average systemic RV ejection fraction (RVEF) by CMR was 39.4±11.4%, and the systemic RVMPI for this group was 0.56±0.21. There was a strong negative correlation between the systemic RVMPI and systemic RVEF by CMR (r=−0.82, P<0.01). The systemic RVEF can be estimated from this formula: RVEF=65%−(45.2×MPI). Conclusions—MPI can be used in patients with systemic RVs to assess global function and to estimate an EF with good accuracy.

Percutaneous closure of patent foramen ovale: impact of device design on safety and efficacy

Objective: To compare the safety and efficacy of percutaneous closure of patent foramen ovale (PFO) with the Amplatzer PFO occluder (Amplatzer) or the PFO STAR device (STAR) in patients with presumed paradoxical embolism. Methods: Implantation characteristics, procedural complications, residual shunt, and recurrence of thromboembolic events were recorded prospectively in 100 consecutive patients undergoing percutaneous PFO closure with the STAR (n  =  50) or Amplatzer (n  =  50) devices between 1998 and 2001. The study was not randomised. Device implantation was successful in all cases. Results: There were more procedural complications in the STAR than in the Amplatzer group (8/50 v 1/50, p  =  0.01). More than one device placement attempt was an independent predictor of procedural complications (odds ratio (OR) 8.5, 95% confidence interval (CI) 1.3 to 55.8; p  =  0.03). A residual shunt six months after PFO closure, assessed by transoesophageal contrast echocardiography, occurred more often in the STAR than the Amplatzer group (17/50 v 3/50, p  =  0.004), and was predicted in the STAR group by the use of a device with a 5 mm as opposed to a 3 mm disc connector (OR 6.1, 95% CI 1.1 to 34.0; p  =  0.04). The actuarial risk of recurrent thromboembolic events after 3.5 years was 16.8% (95% CI 7.6% to 34.6%) in the STAR and 2.7% (95% CI 0.4% to 17.7%) in the Amplatzer group after three years (p  =  0.08). Conclusions: Percutaneous PFO closure with the Amplatzer PFO occluder had fewer procedural complications and was more likely to be complete than with the STAR device. These findings underline the importance of device design for successful percutaneous PFO closure.

Cerebrovascular accidents in adult patients with congenital heart disease

Objective To investigate the prevalence and characteristics of cerebrovascular accidents (CVA) in a large population of adults with congenital heart disease (CHD). Methods and results In a retrospective analysis of aggregated European and Canadian databases a total population of 23 153 patients with CHD was followed up to the age of 16–91 years (mean 36.4 years). Among them, 458 patients (2.0%) had one or more CVA, with an estimated event rate of 0.05% per patient-year. Permanent neurological sequelae were noted in 116 patients (25.3%). The prevalence of CVA in selected diagnostic categories was as follows: open atrial septal defect 93/2351 (4.0%); closed atrial or ventricular septal defect 57/4035 (1.4%); corrected tetralogy of Fallot 52/2196 (2.4%); Eisenmenger physiology 24/467 (5.1%); other cyanotic 50/215 (23.3%); mechanical prostheses (29/882 (3.3%). Associated conditions in patients with CVA were absence of sinus rhythm (25%), transvenous pacemakers (7%), endocarditis (2%), cardiac surgery (11%) and catheter intervention (2%), but with the exception of absent sinus rhythm these were not significantly more prevalent in patients with CVA. Conclusion CVA are a major contributor to morbidity in this young population despite absence of classical cardiovascular risk factors. Although the prevalence of CVA in patients with CHD appears low, it is 10–100 times higher than expected in control populations of comparable age. Residua occur in a strong minority of patients. The subjects at highest risk are those patients with CHD with cyanotic lesions, in whom the prevalence is over 10-fold above the average.

Quality of life of grown-up congenital heart disease patients after congenital cardiac surgery §

BACKGROUND Due to better early and long-term outcome, the increasing population of grown-ups with congenital heart disease (GUCH) brings up unexpected quality of life (QoL) issues. The cardiac lesion by itself is not always the major problem for these patients, since issues pertaining to QoL and psychosocial aspects often predominate. This study analyses the QoL of GUCH patients after cardiac surgery and the possible impact of medical and psychosocial complications. PATIENTS AND METHODS A questionnaire package containing the SF-36 health survey (health related QoL), the HADS test (anxiety/depression aspects) and an additional disease specific questionnaire was sent to 345 patients (mean 26+/-11 years) operated for isolated transposition of the great arteries (TGA), tetralogy of Fallot (TOF), and ventricular septal defect (VSD). The scores were compared with age- and gender-matched standard population data and in relation to the underlying congenital heart disease (CHD). RESULTS In all SF-36 and HADS health dimensions the GUCH patients showed excellent scores (116+/-20), which are comparable to the standard population (100+/-15), regardless of the initial CHD (p=0.12). Eighty-two percent of the patients were found to be in NYHA class I and 83% patients declared that they do not consider their QoL to be limited by their malformation. Complications like reoperations (p=0.21) and arrhythmias (p=0.10) do not show significant impact on the QoL. The additional questionnaire revealed that 76% of adult patients have a fulltime job, 18% receive a full or partial disability pension, 21% reported problems with insurances, most of them regarding health insurances (67%), and 4.4% of adult patients declared to have renounced the idea of having children due to their cardiac malformation. CONCLUSION QoL in GUCH patients following surgical repair of isolated TOF, TGA and VSD is excellent and comparable to standard population, this without significant difference between the diagnosis groups. However, these patients are exposed to a high rate of complications and special psychosocial problems, which are not assessed by standardized questionnaires, such as the SF-36 and HADS. These findings highlight the great importance for a multidisciplinary and specialized follow-up for an adequate management of these complex patients.

Canadian Cardiovascular Society 2009 Consensus Conference on the management of adults with congenital heart disease: Complex congenital cardiac lesions

With advances in pediatric cardiology and cardiac surgery, the population of adults with congenital heart disease (CHD) has increased. In the current era, there are more adults with CHD than children. This population has many unique issues and needs. They have distinctive forms of heart failure and their cardiac disease can be associated with pulmonary hypertension, thromboemboli, complex arrhythmias and sudden death. Medical aspects that need to be considered relate to the long-term and multisystemic effects of single ventricle physiology, cyanosis, systemic right ventricles, complex intracardiac baffles and failing subpulmonary right ventricles. Since the 2001 Canadian Cardiovascular Society Consensus Conference report on the management of adults with CHD, there have been significant advances in the field of adult CHD. Therefore, new clinical guidelines have been written by Canadian adult CHD physicians in collaboration with an international panel of experts in the field. Part III of the guidelines includes recommendations for the care of patients with complete transposition of the great arteries, congenitally corrected transposition of the great arteries, Fontan operations and single ventricles, Eisenmengers syndrome, and cyanotic heart disease. Topics addressed include genetics, clinical outcomes, recommended diagnostic workup, surgical and interventional options, treatment of arrhythmias, assessment of pregnancy risk and follow-up requirements. The complete document consists of four manuscripts, which are published online in the present issue of The Canadian Journal of Cardiology. The complete document and references can also be found at www.ccs.ca or www.cachnet.org.

Long-Term Results after Fluoroscopy Guided Closure of Patent Foramen Ovale for Secondary Prevention of Paradoxical Embolism

Objectives: To carry out long-term follow-up after percutaneous closure of patent foramen ovale (PFO) in patients with cryptogenic stroke. Design: Prospective cohort study. Setting: Single tertiary care centre. Participants: 525 consecutive patients (mean (SD) age 51 (12) years; 56% male). Interventions: Percutaneous PFO closure without intraprocedural echocardiography. Main outcome measures: Freedom from recurrent embolic events. Results: A mean (SD) of 1.7 (1.0) clinically apparent embolic events occurred for each patient, and 186 patients (35%) had >1 event. An atrial septal aneurysm was associated with the PFO in 161 patients (31%). All patients were followed up prospectively for up to 11 years. The implantation procedure failed in two patients (0.4%). There were 13 procedural complications (2.5%) without any long-term sequelae. Contrast transoesophageal echocardiography at 6 months showed complete closure in 86% of patients, and a minimal, moderate or large residual shunt in 9%, 3% and 2%, respectively. Patients with small occluders (<30 mm; n = 429) had fewer residual shunts (small 11% vs large 27%; p<0.001). During a mean (SD) follow-up of 2.9 (2.2) years (median 2.3 years; total 1534 patient-years), six ischaemic strokes, nine transient ischaemic attacks (TIAs) and two peripheral emboli occurred. Freedom from recurrent stroke, TIA, or peripheral embolism was 98% at 1 year, 97% at 2 years and 96% at 5 and 10 years, respectively. A residual shunt (hazard ratio = 3.4; 95% CI 1.3 to 9.2) was a risk factor for recurrence. Conclusions: This study attests to the long-term safety and efficacy of percutaneous PFO closure guided by fluoroscopy only for secondary prevention of paradoxical embolism in a large cohort of consecutive patients.

Late Results After Percutaneous Closure of Patent Foramen Ovale for Secondary Prevention of Paradoxical Embolism Using the Amplatzer PFO Occluder Without Intraprocedural Echocardiography: Effect of Device Size

OBJECTIVES We sought to assess the safety and clinical efficacy of patent foramen ovale (PFO) closure under fluoroscopic guidance only, without intraprocedural echocardiography. BACKGROUND Percutaneous PFO closure has been shown to be safe and feasible using several devices. It is generally performed using simultaneously fluoroscopic and transesophageal or intracardiac echocardiographic guidance. Transesophageal echocardiography requires sedation or general anesthesia and intubation to avoid aspiration. Intracardiac echocardiography is costly and has inherent risks. Both lengthen the procedure. The Amplatzer PFO Occluder (AGA Medical Corporation, Golden Valley, Minnesota) can be safely implanted without echocardiographic guidance. METHODS A total of 620 patients (51 +/- 12 years; 66% male) underwent PFO closure using the Amplatzer PFO Occluder for secondary prevention of presumed paradoxical embolism. Based on size and mobility of the PFO and the interatrial septum, an 18-mm device was used in 50 patients, a 25-mm device in 492, and a 35-mm device in 78. RESULTS All procedures were successful, with 5 procedural complications (0.8%): 4 arteriovenous fistulae requiring elective surgical correction, and 1 transient ischemic attack. Contrast transesophageal echocardiography at 6 months showed complete closure in 91% of patients, whereas a minimal, moderate, or large residual shunt persisted in 6%, 2%, and 1%, respectively. During a mean follow-up period of 3.0 +/- 1.9 years (median: 2.6 years; total patient-years: 1,871), 5 ischemic strokes, 8 transient ischemic attacks, and no peripheral emboli were reported. Freedom from recurrent ischemic stroke, transient ischemic attack, or peripheral embolism was 99% at 1 year, 99% at 2 years, and 97% at 5 years. CONCLUSIONS The Amplatzer PFO Occluder affords excellent safety and long-term clinical efficacy of percutaneous PFO closure without intraprocedural echocardiography.