Identification of a novel TPM1 mutation in a family with left ventricular noncompaction and sudden death.

Left ventricular noncompaction (LVNC) is a cardiomyopathy morphologically characterized by 2-layered myocardium, numerous prominent trabeculations, and deep intertrabecular recesses communicating with the left ventricular cavity. The purpose of this study was to investigate patients with LVNC for possible disease causing mutations. We screened 4 genes (TAZ, LDB3, DTNA and TPM1) in 51 patients with LVNC for mutations by polymerase chain reaction and direct DNA sequencing. A novel missense substitution in exon 1 of TPM1 (c.109A>G: p.Lys37Glu) was identified in three affected members of a family with isolated LVNC. The substitution brings about a change in amino acid charge at a highly conserved residue and could result in aberrant mRNA splicing. This variant was not identified in 200 normal control samples. Pathologic analysis of a right ventricular myocardial specimen from the proband's maternal aunt revealed endocardial and subendocardial fibrosis with prominent elastin deposition, as well as the presence of adipose tissue between muscle layers, pathologic changes that are distinct from those seen in patients with HCM or DCM. Screening of the proband and her mother for variants in other sarcomeric protein-encoding candidate genes, MYH7, MYBPC3, TNNT2, TNNI3, ACTC, MYL2, and MYL3, did not identify any other non-synonymous variants or variants in splice donor-acceptor sequences that were potentially disease causing. We conclude TPM1 is a potential candidate disease-causing gene for isolated LVNC, especially in patients experiencing sudden death.

Successful cardiac resynchronization therapy in a 3-year-old girl with isolated left ventricular non-compaction and narrow QRS complex: a case report.

Cardiac resynchronization therapy (CRT) is a new method of treatment for refractory heart failure. However, for children, its indication, efficacy, and long-term prognosis remain unclear. This study describes the use of CRT for a 3-year-old girl with intractable heart failure caused by isolated left ventricular non-compaction (LVNC) with narrow QRS complex. Echocardiography showed diffuse hypokinetic left ventricular (LV) wall motion (ejection fraction =29.3%) with dyssynchrony between the apex, posterior and lateral walls, where numerous prominent trabeculations existed, and severe mitral regurgitation. Biventricular resynchronization using epicardial pacing leads was performed under general anesthesia. Pacing sites for optimal synchronization in the ventricular walls where chosen using tissue Doppler imaging, and AV delay was adjusted to achieve maximal systolic blood pressure and maximal cardiac output. Over a follow-up period of 2 years, she exhibited significant and sustained improvement in LV function and clinical symptoms. BNP levels decreased from 1,960 to 82 pg/ml. QRS duration (103 ms) on ECG did not change after CRT. We conclude that pediatric CRT provides a highly useful adjunct for the treatment of heart failure, even in patients with a narrow QRS duration, and might improve the prognosis of patients with LVNC.

SCN5A variants in Japanese patients with left ventricular noncompaction and arrhythmia.

Left ventricular noncompaction (LVNC) is a genetically heterogenous disorder. Mutations in the human cardiac sodium channel alpha-subunit gene (SCN5A) are involved in the pathophysiology of cardiac arrhythmias and cardiomyopathies. This study was performed to compare the frequency of SCN5A variants in LVNC patients with or without arrhythmias, and to investigate the relationship between variants and disease severity. DNA was isolated from the peripheral blood of 62 Japanese probands with LVNC, comprising 17 familial cases and 45 sporadic cases. Blood samples were screened for variants in SCN5A using single-strand conformational polymorphism analysis (SSCP) and DNA sequencing. Seven variants, rs6599230:G > A, c.453C > T, c.1141-3C > A, rs1805124:A > G (p.H558R), rs1805125:C > T (p.P1090L), c.3996C > T, and rs1805126:T > C were identified in 7 familial and 12 sporadic cases. The frequency of SCN5A variants was significantly higher in the patients with arrhythmias than those without (50% vs 7%: P = 0.0003), suggesting these variants represent a risk factor for arrhythmia and supporting the hypothesis that genes encoding ion channels are involved in LVNC pathophysiology. The LVNC patients with heart failure also had high occurrence of SCN5A variants, suggesting the presence of SCN5A variants and/or arrhythmias increase the severity of LVNC.

Neutrophil-derived S100A12 is profoundly upregulated in the early stage of acute Kawasaki disease.

Neutrophil-derived S100A12 is strongly upregulated during the acute stage of Kawasaki disease and decreases significantly in response to intravenous immune globulin (IVIG) treatment, whereas in nonresponders, serum concentrations increases after initial treatment. Decreased S100A12 expression in neutrophils was detected initially in nonresponders but increased significantly after IVIG treatment, suggesting delayed inflammatory response of neutrophils in nonresponders. Furthermore, in vitro S100A12 secretion increased with tumor necrosis factor-alpha (TNF-alpha) stimulation, whereas intracellular levels were lower in neutrophils with the higher TNF-alpha dose, suggesting intracellular depletion. S100A12 expression in neutrophils appears to reflect responsiveness to IVIG treatment and is possibly involved in the pathophysiology of acute vasculitis.

Surgical management of multiple ventricular septal defects: the role of the felt sandwich technique.

OBJECTIVE: Recently, the felt sandwich technique has been widely used to close muscular ventricular septal defects. We evaluated the early and midterm results of our strategy (a combination of the sandwich technique and direct closures) and assessed the role of the sandwich technique in the treatment of multiple ventricular septal defects. METHODS: Twenty-nine consecutive patients underwent an operation for multiple ventricular septal defects and associated cardiac malformations. They included 17 boys and 12 girls with a median age of 6.0 months. Thirteen patients had 4 or more ventricular septal defects (Swiss cheese septum). RESULTS: There was no surgical or follow-up mortality, and no reoperations were required. There were no cases of heart block and no significant residual shunts in the latest follow-up study. Two patients with Swiss cheese septum had postoperative congestive heart failure. Three muscular ventricular septal defects were closed with the sandwich technique in these 2 patients, whereas 1 or fewer ventricular septal defects were closed with the sandwich technique in the other 27 patients. Seven (77.8%) of 9 patients who underwent the sandwich procedure had septal dysfunction, whereas 5 (25.0%) of the other 20 patients showed septal dysfunction (P < .05). CONCLUSIONS: The outcome of the surgical repair of multiple ventricular septal defects was satisfactory. Although the sandwich technique is simple and effective, the use of numerous felt patches disturbed the movement of the interventricular septum. An effort should be made to close the muscular ventricular septal defect directly to avoid postoperative cardiac dysfunction. Large apical ventricular septal defects, especially those located just underneath the moderator band, are considered suitable for the sandwich technique.

Novel LAMP-2 mutation in a family with Danon disease presenting with hypertrophic cardiomyopathy.

Danon disease is an X-linked dominant multisystem disorder that includes hypertrophic cardiomyopathy with skeletal myopathy, and results from mutations in the gene encoding the lysosome-associated membrane protein-2 (LAMP-2). To date, over 20 different mutations in LAMP2 have been identified. Three members of a family, a male proband (18 years old) and 2 sisters (15 and 20 years old) were studied. Their mother had been diagnosed with dilated cardiomyopathy at the age of 39 years, and died from advanced heart failure at the age of 43 years. The proband developed marked concentric hypertrophy at the age of 5 years and DNA analyses revealed a novel hemizygous frameshift mutation (c.573delA) in exon 5. The 2 affected sisters were also heterozygous for the same mutation. Functional analyses of this novel LAMP2 mutation are mandatory.

Characterization of ventricular myocardial performance in the fetus by tissue Doppler imaging.

BACKGROUND: Clinically useful indices of fetal cardiac function have not been fully delineated for tissue Doppler imaging (TDI). METHODS AND RESULTS: In the present study, 56 pregnancies between the 17(th) and 38(th) weeks of gestation included 38 normal fetuses, 6 cases of hydrops fetalis (HF), and 12 of intrauterine growth retardation (IUGR). Peak velocity in early diastole (E) was measured by pulsed-wave Doppler and the peak annular velocities in systole (Sa) and early diastole (Ea) were measured by TDI. The ratio between flow velocity and annular velocity in early diastole (E/Ea) and the ratio of the Sa of right ventricle to that of the left ventricle (RVSa/LVSa) were estimated. In all fetuses with HF, LVSa was <2 cm/s and LVE/Ea was >13. RVSa/LVSa in the HF group was significantly higher than that in the normal group, and RVSa/LVSa in the IUGR group was significantly lower than that in the normal group. CONCLUSIONS: A combination of low LVSa and high LVE/Ea shows reduced global myocardial performance of the LV, and would be one of the useful indices for quantitative assessment in high-risk pregnancies. Changes in the RVSa/LVSa ratio may reflect afterload changes in both ventricles and compensatory cardiovascular mechanisms occurring during the process of placental insufficiency and heart failure.

Impaired neuroanatomic development in infants with congenital heart disease.

OBJECTIVES: We performed a regional volumetric study of the brain using 3-dimensional magnetic resonance imaging in infants with congenital heart disease to search for variables in anatomic development of the brain that may be associated with functional impairment. METHODS: Forty infants with congenital heart disease-17 infants with single ventricle physiology, 5 with transposition of great arteries, and 18 with ventricular septal defect-were studied prospectively by 3-dimensional magnetic resonance imaging of the brain several months after heart surgery. RESULTS: The global volume of gray matter was significantly reduced in the patients with congenital heart disease compared with normal controls (P < .001), whereas no significant difference in the volume of white matter was observed. Further, the decrease in gray matter volume was more apparent in the frontal lobe than in the temporal lobe, especially in infants with single ventricle physiology or transposition of the great arteries. Multivariate analysis revealed that preoperative hypoxia is strongly associated with decreased frontal gray matter volume (P < .01), as well as a diagnosis of hypoplastic left heart syndrome (P < .05). Of note, frontal gray matter volume, which includes the motor area, correlated weakly with psychomotor developmental index scores (P < .01). CONCLUSIONS: Brain developmental impairment occurs in many infants with congenital heart disease, especially in those who have preoperative hypoxia and critical congenital heart disease. This quantitative volumetric study encourages larger scale and longitudinal follow-up to elucidate the significance of impaired neuroanatomic development on functional outcome.

Assessment of variables affecting flow propagation velocity of the left ventricle in healthy children.

BACKGROUND: The purpose of the present study was to establish the normal values of flow propagation velocity (FPV) in healthy children and examine the variables that affect FPV in clinical situations. METHODS: Two hundred and thirty- five healthy children and adolescents were assessed (aged 0-22.6 years, mean age 7.4 +/- 5.4 years; male, n = 142; female, n = 93). FPV was obtained from an apical four-chamber view and determined as the slope of aliasing velocity of early diastolic transmitral flow on the color M-mode using Aloka SSD-5500 with 5.0 MHz transducer. Aliasing velocity was set at 50-70% of the peak transmitral flow velocity. Peak transmitral flow velocities in early diastole (E) and during atrial contraction (A), and the ratio of early to late peak velocity (E/A) were obtained. Tei index was also measured for analysis of general left ventricular performance. Left ventricular mass index (LVMI) was obtained from conventional echo measurement. E, E/A, Tei index and LVMI were compared with FPV in healthy subjects. RESULTS: FPV obtained from all subjects ranged from 23.7 to 96.0 cm/s (61.3 +/- 13.6 cm/s). Normal value of FPV was less dependent on age, body size, heart rate and left ventricular dimension. In contrast, although there was no significant correlation between FPV and ejection fraction, statistically significant correlation was found between FPV, LVMI (P = 0.0008) and Tei index (P = 0.025). CONCLUSIONS: FPV is independent of age, body size and heart rate and is useful to assess left ventricular relaxation in children.

Acute Kawasaki disease is associated with reverse regulation of soluble receptor for advance glycation end products and its proinflammatory ligand S100A12.

OBJECTIVE: Receptor for advanced glycation end products (RAGE) serves as a pattern recognition receptor for several endogenous ligands that are potent inducers of inflammation. By activating endothelial cells and leukocytes, RAGE augments recruitment of leukocytes to sites of inflammation, which is a key process, especially in vasculitis. Soluble RAGE (sRAGE) acts as a naturally occurring inhibitor of RAGE by neutralizing proinflammatory ligands, e.g., S100A12. This neutrophil-derived protein has been reported to be associated with Kawasaki disease (KD) and to provoke proinflammatory responses. The aim of this study was to investigate circulating sRAGE in an acute inflammatory disorder and to compare these data directly with concentrations of the proinflammatory RAGE ligand S100A12. METHODS: Serum concentrations of sRAGE and S100A12 were analyzed by specific enzyme-linked immunosorbent assays in 50 children with KD, and additionally in 39 patients with juvenile idiopathic arthritis (JIA). In 28 of the patients with KD, levels were analyzed longitudinally over the course of the disease. RESULTS: Patients with KD and those with systemic-onset JIA had decreased levels of sRAGE during active disease, especially those patients with KD who were more severely affected and not responding to treatment. In addition, the level of sRAGE correlated negatively with the level of proinflammatory S100A12. After intravenous immunoglobulin (IVIG) therapy in patients with KD, the S100A12:sRAGE ratio was significantly different between responders and nonresponders. CONCLUSION: Inverse regulation of both sRAGE and its proinflammatory ligand S100A12 seems to be a relevant molecular mechanism promoting systemic inflammation. Calculating the S100A12:sRAGE ratio might help to detect patients with KD who are at risk of being unresponsive to IVIG therapy.

Open heart operation in a child with congenital heart disease and hereditary spherocytosis.

An 18-month-old girl with hereditary spherocytosis underwent closure of the ventricular septal defect, commissurotomy of the pulmonary valve, and patch angioplasty of the pulmonary trunk without previous splenectomy. No serious complications as a result of hemolysis occurred in the perioperative period. Open heart surgery can therefore be safely performed in young children with congenital heart disease and hereditary spherocytosis who have not previously undergone splenectomy.

Expression of myeloid-related protein-8 and -14 in patients with acute Kawasaki disease.

OBJECTIVES: This study investigated patients with acute Kawasaki disease (KD) to validate myeloid-related protein (MRP)-8/MRP-14 as a marker of disease activity and severity of coronary artery lesion development. BACKGROUND: Both MRP-8 and -14, which are S100-proteins secreted by activated neutrophils and monocytes, bind specifically to endothelial cells and induce thrombogenic and inflammatory responses in a variety of disease conditions. METHODS: We investigated 61 patients with acute KD and examined sequential changes in serum levels of MRP-8/MRP-14, messenger ribonucleic acid (mRNA) expression of MRP-8 and -14 in circulating granulocytes and monocytes, and amounts of MRP-8/MRP-14 bound to circulating endothelial cells. RESULTS: The serum MRP-8/MRP-14 levels as well as mRNA expressions of MRP-8 and -14 in granulocytes were strongly upregulated during the early stage of acute KD, and decreased dramatically within 24 h of intravenous immune globulin therapy (p < 0.05) in 45 responders. In contrast, in 16 nonresponders both of these increased after the initial treatment. The number of MRP-8/MRP-14-positive circulating endothelial cells was higher in patients with acute KD than in control patients and increased significantly by 2 weeks after the onset of KD, especially in patients in whom coronary artery lesions developed. CONCLUSIONS: We show for the first time that MRP-8/MRP-14 are exclusively secreted by granulocytes in patients with acute KD, and intravenous immune globulin treatment suppresses their gene expression. Serum levels of MRP-8/MRP-14 may be useful markers of disease activity, and the levels of MRP-8/MRP-14-positive circulating endothelial cell may predict the severity of vasculitis, confirming an important role for distinct inflammatory reactions in endothelium.

Genetic analysis in patients with left ventricular noncompaction and evidence for genetic heterogeneity.

Left ventricular noncompaction (LVNC) is a cardiomyopathy characterized by numerous excessively trabeculations and deep intertrabecular recesses. This study was performed to investigate Japanese LVNC patients for disease-causing mutations in a series of selected candidate genes. DNA was isolated from the peripheral blood of 79 cases including 20 familial cases and 59 sporadic cases. DNA samples were screened for mutations in the genes encoding G4.5 (TAZ), alpha-dystrobrevin (DTNA), alpha1-syntrophin (SNTA1), FK506 Binding protein 1A (FKBP1A or FKPB12: FKBP1A), and LIM Domain Binding protein 3 (Cypher/ZASP: LDB3), using single-strand conformational polymorphism analysis and DNA sequencing. DNA variants were identified in 6 of the 79 cases, including four familial cases and two sporadic cases. A splice acceptor mutation of intron 8 in TAZ (IVS8-1G>C) was identified in one family with isolated LVNC, resulting in deletion of exon 9 from mRNA. In a sporadic case of isolated LVNC and Barth syndrome (BTHS), a 158insC in exon 2 of TAZ resulting in a frame-shift mutation was identified. A 1876G>A substitution changing an aspartic acid to asparagine (D626N) was identified in LDB3 in four members of two families with LVNC. A 163G>A polymorphism was identified in LDB3, which changed a valine to isoleucine (V55I) in one patient with isolated LVNC. In addition, in a family with nonisolated LVNC, a 362C>T mutation was identified in DTNA. LVNC, like other forms of inherited cardiomyopathy, is a genetically heterogeneous disease, associated with variable clinical symptoms and can be inherited as an autosomal or X-linked recessive disorder.

Dobutamine stress radionuclide ventriculography reveals silent myocardial dysfunction in Kawasaki disease.

Dobutamine (DOB) stress radionuclide ventriculography (RVG) is proposed for evaluating left ventricular performance in patients with Kawasaki disease (KD). Dobutamine stress RVG, up to 15 microg x kg(-1) x min(-1), was performed in 40 patients with a history of KD, some of whom had a perfusion defect (PD group) on dipyridamole stress thallium-201 myocardial imaging, some of whom had no perfusion defects (NPD group), and some of whom had no coronary artery lesions (C group). No significant differences in either systolic or diastolic indices of the left ventricle at rest were observed between the 3 groups. Although hemodynamic responses were similar in all patients after DOB stress, early diastolic index of the first third filling fraction decreased only in the PD group and was significantly lower in this group compared with the C group (p<0.01). The asynchrony index increased significantly in those patients with coronary stenosis after DOB stress (p<0.05). No serious side-effects were observed during the study. Even late after onset, patients with myocardial ischemia as a result of KD still had impaired early diastolic filling and asynchronous relaxation of the left ventricle. As an alternative to exercise testing, DOB stress RVG is a safe and promising means for serially evaluating left ventricular performance in patients with KD.

Enhanced iNOS expression in leukocytes and circulating endothelial cells is associated with the progression of coronary artery lesions in acute Kawasaki disease.

Nitric oxide (NO) serves many vasoprotective roles, but the massive release of NO causes arterial wall degeneration. We investigated whether enhanced nitric oxide synthase (iNOS) expression in peripheral blood leukocytes and circulating endothelial cells mirrors the progression of coronary arterial lesions in 55 children with acute Kawasaki disease (KD), including 24 with and 31 without coronary artery lesions (CAL). Patients were treated with i.v. gamma-globulin at the time of diagnosis and blood samples were collected before and after treatment. The cellular origin of NO synthesis was determined by flow cytometric analysis of iNOS expression in peripheral blood, and by immunohistochemical analysis of circulating endothelial cells and coronary arteries. iNOS expression in neutrophils peaked at the time of diagnosis, but did not peak in monocytes until 2 wk post onset of disease. Levels were significantly higher in both cell types in patients with CAL (p = 0.001 and p = 0.035, respectively). In addition, the number of circulating endothelial cells and levels of iNOS expression were higher in patients with CAL (p = 0.011 and p = 0.012, respectively). Immunohistochemical analysis of the coronary arteries from three patients with acute KD revealed iNOS immunoreactivity in endothelial cells, as well as infiltrating monocytes/macrophages in the aneurysms. We conclude that the expression of iNOS in peripheral blood leukocytes, as well as circulating endothelial cells, correlates with the severity of coronary arterial wall injury and the progression of CAL in patients with acute KD.