Felix Berger

Mutations in Sarcomere Protein Genes in Left Ventricular Noncompaction

Background— Left ventricular noncompaction constitutes a primary cardiomyopathy characterized by a severely thickened, 2-layered myocardium, numerous prominent trabeculations, and deep intertrabecular recesses. The genetic basis of this cardiomyopathy is still largely unresolved. We speculated that mutations in sarcomere protein genes known to cause hypertrophic cardiomyopathy and dilated cardiomyopathy may be associated with left ventricular noncompaction. Methods and Results— Mutational analysis in a cohort of 63 unrelated adult probands with left ventricular noncompaction and no other congenital heart anomalies was performed by denaturing high-performance liquid chromatography analysis and direct DNA sequencing of 6 genes encoding sarcomere proteins. Heterozygous mutations were identified in 11 of 63 samples in genes encoding &bgr;-myosin heavy chain (MYH7), &agr;-cardiac actin (ACTC), and cardiac troponin T (TNNT2). Nine distinct mutations, 7 of them in MYH7, 1 in ACTC, and 1 in TNNT2, were found. Clinical evaluations demonstrated familial disease in 6 of 11 probands with sarcomere gene mutations. MYH7 mutations segregated with the disease in 4 autosomal dominant LVNC kindreds. Six of the MYH7 mutations were novel, and 1 encodes a splice-site mutation, a relatively unique finding for MYH7 mutations. Modified residues in &bgr;-myosin heavy chain were located mainly within the ATP binding site. Conclusions— We conclude that left ventricular noncompaction is within the diverse spectrum of cardiac morphologies triggered by sarcomere protein gene defects. Our findings support the hypothesis that there is a shared molecular etiology of different cardiomyopathic phenotypes.

Comparison of results and complications of surgical and amplatzer device closure of atrial septal defects

OBJECTIVES Results and complications of surgical versus transcatheter treatment of atrial septal defect in the current era are compared. METHODS All consecutive patients with a secundum atrial septal defect and a pulmonary/systemic flow ratio of 1.5:1 or more who presented between May 1997 and June 1998 were enrolled in this study. All patients except those who initially had defects not feasible for interventional occlusion were catheterized to allow interventional closure of the defects. All patients in whom interventional closure could not be performed underwent surgical closure. RESULTS Sixty-one patients underwent surgery at a median age of 20 years (0.5-74 years) and 61 had the defect closed with an Amplatzer device (AGA Medical Corporation, Golden Valley, Minn) at a median age of 12 years (0.8-77.7 years) (P >.2). Hospital stay in surgically treated patients was 8 days (6-19 days) versus 3 days (3-14 days) in interventionally treated patients (P <.001). Atrial septal defect and shunt sizes were larger in the surgical group ( P <.001). Closure rates in the 2 groups were identical (98%). One patient (68 years) in the surgical group had a perforated duodenal ulcer that necessitated an operation 8 days after closure of the atrial septal defect, and 1 (26 years) had an infected lateral thoracotomy wound necessitating plastic surgery. Embolization of the Amplatzer device to the left ventricle was observed in 1 patient (29 years). The device could be retrieved from the heart, but vascular surgery was required to extract it from the femoral artery. CONCLUSIONS As complete closure rates and complications are identical, but duration of hospital stay is shorter with less morbidity, we prefer implantation of an Amplatzer septal occluder to surgery wherever possible.

Percutaneous pulmonary valve implantation: two-centre experience with more than 100 patients

AIMS Dysfunction of valved conduits in the right ventricular outflow tract (RVOT) limits durability and enforces repeated surgical interventions. We report on our combined two-centre experience with percutaneous pulmonary valve implantation (PPVI). METHODS AND RESULTS One hundred and two patients with RVOT dysfunction [median weight: 63 kg (54.2-75.9 kg), median age: 21.5 years (16.2-30.1 years), diagnoses: TOF/PA 61, TAC 14, TGA 9, other 10, AoS post-Ross-OP 8] were scheduled for PPVI since December 2006. Percutaneous pulmonary valve implantation was performed in all patients. Pre-stenting of the RVOT was done in 97 patients (95%). The median peak systolic RVOT gradient decreased from 37 mmHg (29-46 mmHg) to 14 mmHg (9-17 mmHg, P < 0.001) and the ratio RV pressure/AoP decreased from 62% (53-76%) to 36% (30-42%, P < 0.0001). The median end-diastolic RV-volume index (MRI) decreased from 106 mL/m(2) (93-133 mL/m(2)) to 90 mL/m(2) (71-108 mL/m(2), P = 0.001). Pulmonary regurgitation was significantly reduced in all patients. One patient died due to compression of the left coronary artery. The incidence of stent fractures was 5 of 102 (5%). During follow-up [median: 352 days (99-390 days)] one percutaneous valve had to be removed surgically 6 months after implantation due to bacterial endocarditis. In 8 of 102 patients, a repeated dilatation of the valve was done due to a significant residual systolic pressure gradient, which resulted in a valve-in-valve procedure in four. CONCLUSION This study shows that PPVI is feasible and it improves the haemodynamics in a selected patient collective. Apart from one coronary compression, the rate of complications at short-term follow-up was low. Percutaneous pulmonary valve implantation can be performed by experienced interventionalists with similar results as originally published. The intervention is technically challenging and longer clinical follow-up is needed.

Transcatheter closure as standard treatment for most interatrial defects: experience in 200 patients treated with the Amplatzer Septal Occluder.

To judge whether an Amplatzer Septal Occluder can be used as standard therapy instead of surgery for closure of atrial septal defects we report our experiences in 200 patients. Of these patients, 127 had an atrial septal defect with haemodynamically significant left-to-right shunt, 68 patients a persistent oval foramen after presumed paradoxical embolism, and 5 had a fenestration after Fontan-repair. Mean age was 29.8 years (0.8 to 77.7 years). Body weight ranged from 6.9 to 120.0 kg (mean 51.5 kg). After diagnostic cardiac catheterization, and balloon-sizing of the defect, we implanted Amplatzer Septal Occluders with stents of 4 to 28 mm diameter. Follow-up studies were obtained after 48 hours, and one, six, and twelve months. Transcatheter closure of the atrial septal defect proved successful in all without any relevant residual shunts. In particular, complete closure was achieved in all patients after presumed paradoxical embolism. The mean period of follow-up is 9.5 months, with a range from 0.4 to 23.5 months, giving a total of 1898 patient months. The occlusion rate after three month was 98.1%. A trivial haemodynamically insignificant residual shunt remained in 1.9% of the patients. Fluoroscopy times ranged from 0 to 43.5 minutes, with a median of 8.7 minutes. The excellent results in the short and medium term in children and adults have resulted in using this device routinely at the present time for closure of central atrial septal defects up to a diameter of 28 mm. Final judgement, however, is only possible after long-term follow-up.

Percutaneous Tricuspid Valve Replacement in Congenital and Acquired Heart Disease

OBJECTIVES This study sought to describe the first human series of percutaneous tricuspid valve replacements in patients with congenital or acquired tricuspid valve (TV) disease. BACKGROUND Percutaneous transcatheter heart valve replacement of the ventriculoarterial (aortic, pulmonary) valves is established. Although there are isolated reports of transcatheter atrioventricular heart valve replacement (hybrid and percutaneous), this procedure has been less frequently described; we are aware of no series describing this procedure for TV disease. METHODS We approached institutions with significant experience with the Melody percutaneous pulmonary valve (Medtronic, Inc., Minneapolis, Minnesota) to collect data where this valve had been implanted in the tricuspid position. Clinical and procedural data were gathered for 15 patients. Indications for intervention included severe hemodynamic compromise and perceived high surgical risk; all had prior TV surgery and significant stenosis and/or regurgitation of a bioprosthetic TV or a right atrium-to-right ventricle conduit. RESULTS Procedural success was achieved in all 15 patients. In patients with predominantly stenosis, mean tricuspid gradient was reduced from 12.9 to 3.9 mm Hg (p < 0.01). In all patients, tricuspid regurgitation was reduced to mild or none. New York Heart Association functional class improved in 12 patients. The only major procedural complication was of third-degree heart block requiring pacemaker insertion in 1 patient. One patient developed endocarditis 2 months after implant, and 1 patient with pre-procedural multiorgan failure did not improve and died 20 days after the procedure. The remaining patients have well-functioning Melody valves in the TV position a median of 4 months after implantation. CONCLUSIONS In selected cases, patients with prior TV surgery may be candidates for percutaneous TV replacement.

Incidence of atrial flutter/fibrillation in adults with atrial septal defect before and after surgery

BACKGROUND There is controversy about the benefit of surgical repair for atrial septal defect in adults, especially its effect on the incidence of supraventricular dysrhythmias, atrial flutter and fibrillation. We studied their incidence before and after operation. METHODS We examined surface and 24-hour Holter electrocardiograms before, early (between 3 and 7 days), and late (more than 6 months) after operation, performed at age 42.2 years (range, 18.5 to 74.9 years), in 211 adults with atrial septal defect. Patients were arbitrarily divided into three groups: age 18 to 40 years (n = 101), age 40 to 60 years (n = 83), and age more than 60 years (n = 27). All consecutive patients operated on between January 1988 and December 1996 and having a pulmonary to systemic flow ratio of 1.5:1 or greater were included in this study. RESULTS The age of patients without arrhythmias before or after atrial septal defect closure (39+/-13 years) was significantly lower than that of patients with flutter (54+/-12 years) or fibrillation (59+/-8 years). The incidence of atrial flutter was influenced by surgical repair as atrial flutter converted to sinus rhythm late after operation in 10 of 18 patients. However, there was no change in the incidence of atrial fibrillation before (n = 28) and after (n = 21) operation. CONCLUSIONS Our data show that surgical correction of atrial septal defect leads to regression of the incidence of atrial flutter but not fibrillation. Thus, surgical repair of atrial septal defect to abolish supraventricular tachyarrhythmias in adults is warranted, but in patients with fibrillation, it may have to be combined with a Maze operation in the future.

First Experiences With the HeartWare Ventricular Assist System in Children

PURPOSE The purpose of this study is to describe initial experience with a new continuous flow, ventricular assist system in the pediatric population. DESCRIPTION Seven children (aged 6 to 16 years) received implantation of a novel third-generation, continuous flow, ventricular assist device (HeartWare, HeartWare Inc, Miami Lakes, FL) as a bridge to cardiac transplantation. EVALUATION All children were in terminal heart failure despite inotropic support, and signs of renal or hepatic impairment developed. Six children had dilatative cardiomyopathy and 1 had congenital heart disease (hypoplastic left heart, total cavopulmonary connections with extracardiac conduit). Six patients have been successfully bridged to transplantation. Median support time was 75 days (range, 1 to 136 days). One child is still under continuous mechanical support. None of the patients suffered a thromboembolic event or an infection. CONCLUSIONS The HeartWare assist system can be successfully used as a bridge to transplantation in children and adolescents with end-stage heart failure.

Masked left ventricular restriction in elderly patients with atrial septal defects: A contraindication for closure?

The impact of an atrial septal defect in the elderly with reduced diastolic elasticity of the left ventricle is unclear. We studied the hemodynamic changes during balloon occlusion of atrial septal defects in patients over 60 years of age. In 18 patients (61–78 years old; median, 70), the left atrial pressure and the mitral valve inflow was measured during complete balloon occlusion of the defect and after deflation of the balloon. In seven patients, the left atrial pressure and the E/A ratio of the mitral valve inflow increased markedly (P = 0.02). Mean atrial pressures reached values of 27 mm Hg and the v‐wave peak values of 55 mm Hg. Two patients received a transcatheter device closure and developed congestive heart failure. In the elderly, an atrial septal defect can have a decompressive impact on the left ventricle. Therefore, caution appears to be warranted if atrial septal closure is planned. Cathet Cardiovasc Intervent 2001;52:177–180.

Assessment of Diffuse Myocardial Fibrosis in Rats Using Small-Animal Look-Locker Inversion Recovery T1 Mapping

Background— The concentration of gadopentetate dimeglumine in myocardium and blood can be assessed from T1 measurements and can be used to calculate the extracellular volume (ECV) of the myocardium. We hypothesized that diffuse myocardial fibrosis in a small-animal model could be quantitatively assessed by measuring myocardial ECV using small-animal Look-Locker inversion recovery T1 mapping. Methods and Results— Sprague-Dawley rats (n=10) were subjected to continuous angiotensin-2 (AT2) infusion for 2 weeks via a subcutaneously implanted minipump system. Magnetic resonance imaging (MRI) was performed both before and after AT2 infusion. The MRI protocol included multislice cine imaging and before-and-after contrast small-animal Look-Locker inversion recovery T1 mapping and late gadolinium enhancement imaging. Myocardial ECV was calculated from hematocrit and T1 values of blood and myocardium. During the course of AT2 infusion, the mean±SD systolic blood pressure increased from 122±10.9 to 152±27.5 mm Hg (P=0.003). Normalized heart weight was significantly higher in AT2-treated animals than in control littermates (P=0.033). Cine MRI documented concentric left ventricular hypertrophy. Postcontrast myocardial T1 times were shortened after treatment (median [interquartile range], 712 [63] versus 820 [131] ms; P=0.002). Myocardial ECV increased from 17.2% (4.3%) before to 23.0% (6.2%) after AT2 treatment (P=0.031), which was accompanied by perivascular fibrosis and microscarring on myocardial histological analysis. There was a moderate level of correlation between ECV and collagen volume fraction, as assessed by histological analysis (r=0.69, P=0.013). Conclusions— In a small-animal model of left ventricular hypertrophy, contrast-enhanced T1 mapping can be used to detect diffuse myocardial fibrosis by quantification of myocardial ECV.

Sarcomere Gene Mutations in Isolated Left Ventricular Noncompaction Cardiomyopathy Do Not Predict Clinical Phenotype

Background— Left ventricular noncompaction of the myocardium (LVNC) has been recognized as a cardiomyopathy with a genetic etiology. Mutations in genes encoding sarcomere proteins were shown to be associated with LVNC. We evaluated the potential clinical impact of genetic analysis of sarcomere genes in patients with LVNC. Methods and Results— We identified 5 mutations in cardiac myosin-binding protein C (MYBPC3) and 2 mutations in &agr;-tropomyosin (TPM1) in a cohort of unrelated adult probands with isolated LVNC. The mutations in MYBPC3 and TPM1 and in 6 other previously reported sarcomere genes in this cohort resulted in a total of 18 (29%) heterozygous mutations in 63 probands. &bgr;-myosin heavy chain (MYH7) was the most prevalent disease gene and accounts for 13% of cases, followed by MYBPC3 (8%). Comparing sarcomere mutation-positive and mutation-negative LVNC probands showed no significant differences in terms of average age, myocardial function, and presence of heart failure or tachyarrhythmias at initial presentation or at follow-up. Familial disease was found in 16 probands of whom 8 were sarcomere mutation positive. Nonpenetrance was detected in 2 of 8 mutation-positive families with LVNC. Conclusions— Mutations in sarcomere genes account for a significant (29%) proportion of cases of isolated LVNC in this cohort. The distribution of disease genes confirms genetic heterogeneity and opens new perspectives in genetic testing in patients with LVNC and their relatives at high risk of inheriting the cardiomyopathy. The presence or absence of a sarcomere gene mutation in LVNC cannot be related to the clinical phenotype.