Matthias Greutmann

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.

Cardiac outcomes in young adult survivors of the arterial switch operation for transposition of the great arteries.

OBJECTIVES We sought to determine cardiac outcomes in young adults with complete transposition of the great arteries (TGA) after the arterial switch operation (ASO). BACKGROUND Although cardiac outcomes in the pediatric population with TGA after ASO have been well described, outcomes in the adult population have not to our knowledge been studied. METHODS We determined late survival in all operative survivors with TGA after ASO performed before 1991 at our local pediatric referring hospital. In the subset of adults (n = 65) followed in our adult congenital cardiac clinic, we examined cardiac outcomes in adulthood. RESULTS Survival of the 132 infants discharged from hospital after ASO was 97% (70% confidence interval [CI]: 95.0% to 98.1%) at 20 years. In the 65 patients (mean age 21 +/- 3 years, 62% male) followed at our institution, 17% (11 of 65) had at least 1 clinically significant cardiac lesion, including ventricular dysfunction, valvular dysfunction, or arrhythmias. Residual lesions were more common in those who had had cardiac reinterventions in childhood (odds ratio: 10.7, 95% CI: 2.1 to 55). In adulthood, 5 patients (8%) had arrhythmia requiring treatment and 7 patients (11%) required reinterventions (5 reoperations and 2 pacemaker implantations). Intervention for aortic valve regurgitation and aortic root dilation were not observed. Exercise capacity was reduced in most adults (82%) after ASO. CONCLUSIONS Although most adults after ASO are well, and few have residual defects, there are subgroups, particularly those who needed further cardiac intervention in childhood, who are at higher risk for ventricular and valve dysfunction and arrhythmias.

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.

B-Type Natriuretic Peptide in Pregnant Women With Heart Disease

OBJECTIVES The objectives of this study were to examine: 1) B-type natriuretic peptide (BNP) response to pregnancy in women with heart disease; and 2) the relationship between BNP levels and adverse maternal cardiac events during pregnancy. BACKGROUND Pregnancy imposes a hemodynamic stress on the heart. BNP might be a useful biomarker to assess the ability of the heart to adapt to the hemodynamic load of pregnancy. METHODS This was a prospective study of women with structural heart disease seen at our center. Serial clinical data and plasma BNP measurements were obtained during the first trimester, third trimester, and after delivery (>6 weeks). RESULTS Seventy-eight pregnant women were studied; 66 women with heart disease (age 31 ± 5 years), and 12 healthy women (age 33 ± 5 years). During pregnancy, the median peak BNP level was higher in women with heart disease compared with control subjects (median 79, interquartile range 51 to 152 pg/ml vs. median 35, interquartile range 21 to 43 pg/ml, p < 0.001). In women with heart disease, those with subaortic ventricular dysfunction had higher BNP levels (p = 0.03). A BNP >100 pg/ml was measured in all women with events during pregnancy (n = 8). Sixteen women had increased BNP levels during pregnancy but did not have clinical events. None of the women with BNP ≤100 pg/ml had events. BNP ≤100 pg/ml had a negative predictive value of 100% for identifying events during pregnancy. CONCLUSIONS Many pregnant women with heart disease have increased BNP levels during pregnancy. Incorporating serial BNP levels in into clinical practice can be helpful, specifically in adjudicating suspected adverse cardiac events during pregnancy.

Adverse Left Ventricular Mechanics in Adults With Repaired Tetralogy of Fallot

Left ventricular (LV) dysfunction is a predictor of adverse outcomes in patients with repaired tetralogy of Fallot (TOF). However, the mechanisms for LV dysfunction are not well understood. The aim of the study was to determine whether the prolonged QRS duration of right branch bundle block was associated with adverse LV mechanics. Seventy-five patients (mean age 31 +/- 2 years) with repaired TOF were studied. LV and right ventricular (RV) volumes and ejection fractions (EFs) were assessed using cardiac magnetic resonance imaging. Vector velocity imaging was used to assess longitudinal strain and intraventricular dyssynchrony. Prolonged QRS duration was associated with increased RV and LV dimensions (p = 0.01) and decreased function (RVEF r = -0.60, p <0.001 and LVEF r = -0.77, p <0.001). In addition, prolonged QRS duration was associated with heterogeneous ventricular mechanical activation and reduced strain in the lateral and septal left ventricle walls. Degree of intraventricular dyssynchrony correlated with LVEF (r = -0.59, p <0.001), QRS duration (r = 0.74, p <0.001), and septal strain (r = 0.70, p <0.001). In conclusion, LV dysfunction and dyssynchrony were observed in patients with TOF and were associated with QRS duration. It was possible that abnormal LV mechanics in combination with RV dysfunction may explain the relation between QRS duration and adverse cardiac outcomes.

Fine Mapping of the 1p36 Deletion Syndrome Identifies Mutation of PRDM16 as a Cause of Cardiomyopathy

Deletion 1p36 syndrome is recognized as the most common terminal deletion syndrome. Here, we describe the loss of a gene within the deletion that is responsible for the cardiomyopathy associated with monosomy 1p36, and we confirm its role in nonsyndromic left ventricular noncompaction cardiomyopathy (LVNC) and dilated cardiomyopathy (DCM). With our own data and publically available data from array comparative genomic hybridization (aCGH), we identified a minimal deletion for the cardiomyopathy associated with 1p36del syndrome that included only the terminal 14 exons of the transcription factor PRDM16 (PR domain containing 16), a gene that had previously been shown to direct brown fat determination and differentiation. Resequencing of PRDM16 in a cohort of 75 nonsyndromic individuals with LVNC detected three mutations, including one truncation mutant, one frameshift null mutation, and a single missense mutant. In addition, in a series of cardiac biopsies from 131 individuals with DCM, we found 5 individuals with 4 previously unreported nonsynonymous variants in the coding region of PRDM16. None of the PRDM16 mutations identified were observed in more than 6,400 controls. PRDM16 has not previously been associated with cardiac disease but is localized in the nuclei of cardiomyocytes throughout murine and human development and in the adult heart. Modeling of PRDM16 haploinsufficiency and a human truncation mutant in zebrafish resulted in both contractile dysfunction and partial uncoupling of cardiomyocytes and also revealed evidence of impaired cardiomyocyte proliferative capacity. In conclusion, mutation of PRDM16 causes the cardiomyopathy in 1p36 deletion syndrome as well as a proportion of nonsyndromic LVNC and DCM.

Comparison of two different speckle tracking software systems: does the method matter?

Background: Echocardiographic speckle tracking strain has gained clinical importance. However, the comparability of measurements between different software systems is not well defined. Methods: In 47 healthy subjects left ventricular (LV) two‐dimensional (2D) peak strain and time to peak strain (TTP) generated by EchoPAC (2DS) and velocity vector imaging (VVI) were compared. For each type of strain (longitudinal [LS], circumferential [CS], and radial strain [RS]) we compared global, anatomical level and segmental values. Results: When comparing 2DS to VVI, Pearson correlation coefficients (r) of global LS, CS, and RS were 0.68, 0.44, and 0.59, respectively (all P < 0.05). Correlation of global TTP was higher: 0.81(LS), 0.80 (CS), and 0.68 (RS), all P < 0.01. Segmental peak strain differed significantly between 2DS and VVI in 8/18 (LS), 17/18 (CS), and 15/18 (RS) LV segments (P < 0.05). However, segmental TTP significantly differed only in 5/18 (LS), 7/18 (CS), and 4/18 (RS) of LV segments. Similar strain gradients were found for both systems: apical strain was higher than basal and midventricular strain in LS and CS, with a reversed pattern for RS (P < 0.05). Conclusion: TTP strain as well as strain gradients were comparable between VVI and 2DS, but most peak strain values were not. The software‐dependency of peak strain values must be considered in clinical application. Further studies comparing the diagnostic and prognostic accuracy of strain values generated by different software systems are mandatory. (Echocardiography 2011;28:539‐547)

Transcatheter aortic valve implantation for high risk patients With severe aortic stenosis using the Edwards Sapien balloon‐expandable bioprosthesis: A single centre study with immediate and medium‐term outcomes

Background: Transcatheter aortic valve implantation (TCAVI) is an emerging alternative therapy to open‐heart surgery in high‐risk patients with symptomatic aortic stenosis. Methods: Between January 2007 and May 2009, 46 patients underwent TCAVI with the 23 mm or 26 mm Edwards Sapien bioprosthesis via either the transapical (TA‐AVI) or transfemoral (TF‐AVI) approach. All patients had an estimated operative mortality risk of >15%. Results: A total of 46 patients (30 TA‐AVI, 16 TF‐AVI) with a mean aortic valve area (AVA) of 0.63 ± 0.2 cm2 and mean gradient of 54 ± 16 mm Hg were treated. Predicted operative mortality was 25.3% by logistic Euroscore and 8.7% by Society of Thoracic Surgeons risk score. Procedural success was 93% in the TA‐AVI group and 88% in the TF‐AVI group. There was one intraprocedural death in the TA‐AVI group. Overall 30‐day mortality was 6.5% (2‐TA‐AVI, 1‐TF‐AVI). Four patients (9.5%) died from noncardiac causes after 30 days. Successful TCAVI was associated with a significant increase in AVA from 0.6 ± 0.1 cm2 to 1.6 ± 0.6 cm2 in the TA‐AVI group and 0.6 ± 0.1 cm2 to 1.4 ± 0.2 cm2 in the TF‐AVI group at a mean follow up of 7.4 ± 4.4 and 8.3 ± 5.0 months, respectively. At discharge, there was significant improvement in AVA (P < 0.0001), transaortic mean gradient (P < 0.0001), and mitral regurgitation (P = 0.01). At medium term follow up, the valve area was maintained and there was significant improvement in NYHA class in both groups (P < 0.0001). Conclusion: At medium term follow‐up, both transcatheter approaches demonstrated good valve durability with no cardiac‐related mortality post hospital discharge.

Predictors of Adverse Outcome in Adolescents and Adults With Isolated Left Ventricular Noncompaction

Isolated left ventricular noncompaction is a rare form of primary cardiomyopathy. Although increasingly diagnosed, data on the outcomes are limited. To define the predictors of adverse outcomes, we performed a retrospective analysis of a prospectively defined cohort of consecutive patients (age >14 years) diagnosed with left ventricular noncompaction at a single center. The baseline characteristics included presentation with a cardiovascular complication (i.e., decompensated heart failure, systemic embolic event, or sustained ventricular arrhythmia). The primary end point was survival free from cardiovascular death or transplantation. The predictors of survival were evaluated using the Kaplan-Meier method and Cox proportional hazards analysis. A total of 115 patients were included, 77% of whom were symptomatic at diagnosis. Compared to the asymptomatic patients, the symptomatic patients were significantly older and had larger left ventricular cavities and worse left ventricular ejection fraction. Of the 115 patients, 49 (43%) presented with a cardiovascular complication. During a median follow-up of 2.7 years (range 0.1 to 19.4), none of the asymptomatic patients died or underwent transplantation compared to 31% (27 of 88) of the symptomatic patients (p = 0.001). The major determinants of cardiovascular death or transplantation were presentation with a cardiovascular complication (hazard ratio 20.6, 95% confidence interval 4.9 to 87.5, p <0.0001) or New York Heart Association class III or greater (hazard ratio 8.8, 95% confidence interval 3.2 to 24.0, p <0.0001). Left ventricular dilation and systolic dysfunction were less strong predictors. In conclusion, in patients with left ventricular noncompaction, New York Heart Association class III or greater and cardiovascular complications at presentation are strong predictors for adverse outcome.

Generalised muscle weakness in young adults with congenital heart disease

Background In patients with heart failure from acquired cardiomyopathy, respiratory and skeletal muscle weakness is common and is an independent predictor for adverse events. Despite a different underlying pathology, many young adults with congenital heart disease (CHD) develop a syndrome comparable to heart failure from acquired cardiomyopathy and may be at risk for a similar skeletal muscle weakness. Objectives To assess respiratory and skeletal muscle strength in adults with complex CHD. Methods Respiratory and skeletal muscle function was assessed in 51 adults; 41 with complex CHD (16 tetralogy of Fallot, 11 univentricular anatomy with Fontan operation and 14 with subaortic right ventricles) and 10 controls. Maximal inspiratory (MIPs) and expiratory (MEPs) pressures, handgrip strength, lung volumes and aerobic capacity (peak VO2) were measured. Results In patients with CHD (age 34±13 years), average% predicted MIPs, MEPs and handgrip strength were lower than in controls (77±27% vs 106±28%, 85±32% vs 116±41% and 72±15% vs 93±14%, respectively, p≤0.01). There was no significant difference in muscle weakness between CHD subgroups. In 39% of patients with CHD, the handgrip strength, and in 22%, respiratory muscle strength was <70% predicted. These patients had a significantly lower peak VO2 (50±12% vs 64±14% predicted, p=0.008). Conclusion Respiratory and skeletal muscle weakness is common in young adults with complex CHD and similar to that found in older adults with advanced heart failure from acquired heart disease.