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Purpose: We previously demonstrated that the rational pediatric dosage of warfarin can be well-described by a SIZE parameter that includes an allometry exponent of weight. On the other hand, allometry alone is considered to be insufficient to predict drug clearance in neonates and infants. The primary purpose of the present study was to evaluate the effects of incorporation of the maturation process into the analysis model for the dose-response relationship of warfarin in Japanese children. In addition, we evaluated the effect of chronic heart failure (CHF) on the response to warfarin as an independent risk factor for increased anticoagulant effects., Methods: Thirty-eight patients with stable anticoagulation by warfarin were enrolled. During a mean follow-up period of 4.74 ± 3.51 years, 1092 data points including prothrombin time-international normalized ratio (PT-INR) were obtained. The data were subjected to multiple regression analysis to identify covariates related to the anticoagulant effects., Results: Two different models describing the maturation process did not improve the predictive performance for the dose-response relationship in pediatric patients. In addition to the SIZE-normalized daily dose, the vitamin K epoxide reductase complex 1 (VKORC1) genotype, and concomitant use of bosentan, CHF was identified as a covariate increasing the anticoagulant effects of warfarin to 118%., Conclusion: The SIZE parameter was useful even without incorporation of maturation models to describe the response to warfarin in pediatric patients, and our longitudinal follow-up study design with multiple observations was beneficial to detect changes within individual subjects.

• Clinical manifestations of left ventricular non-compaction (LVNC) are highly variable even in the same family, ranging from no symptoms to disabling congestive heart failure, life-threatening arrhythmias, systemic thromboemboli, and sudden cardiac death. • Myocardial dysfunction or ventricular arrhythmias are predictors of mortality both in children and adults with LVNC. • Patients with mutation were more likely to have major adverse cardiovascular events, especially those with LV systolic dysfunction having the highest risk. Left ventricular noncompaction (LVNC) is a cardiomyopathy characterized by two layered structures composed of prominent trabecular meshwork and deep intertrabecular recesses. LVNC was thought to be rare; however, heightened awareness has resulted in an increased detection of the morphological features of LVNC in routine clinical practice especially in the adult population. Although LVNC was classified as an independent primary cardiomyopathy of genetic origin by the American Heart Association in 2006, its definition, diagnostic criteria and clinical implications are still being debated. Clinical manifestations are highly variable, even in the same family, ranging from no symptoms to disabling congestive heart failure, life-threatening arrhythmias, systemic thromboemboli, and sudden cardiac death. Among phenotypic subtypes of LVNC, children with isolated LVNC with normal cardiac function had the best outcomes: children with LVNC and dilated cardiomyopathy had the worst outcomes. Myocardial dysfunction or ventricular arrhythmias are predictors of mortality in adults with LVNC. LVNC, like other forms of inherited cardiomyopathy, is genetically heterogeneous and can be inherited as an autosomal dominant or X-linked recessive disorder. It has been linked to mutations in many genes, including ZASP , TAZ/G4.5 , and those encoding sarcomeric, Z-disc, cytoskeleton proteins, and mitochondria. Disturbance of the NOTCH signaling pathway has been reported to be part of genetic pathway for LVNC as well. Although there are an increasing number of reports, genotype-phenotype correlations have been challenging and investigations are ongoing. Patients with mutations are more likely to have major adverse cardiovascular events, further, LV systolic dysfunction in mutation carriers makes them at high risk for cardiac events. Treatments focus on improvement in cardiac function and reduction of mechanical stress in patients with systolic dysfunction and on treatment of arrhythmia and implantation of an automatic implantable cardioverter-defibrillator for prevention of sudden death. Given that 20–40% of cases may be familial, family screening is recommended. [ABSTRACT FROM AUTHOR]

Kawasaki disease (KD) is an acute febrile illness of childhood characterized by systemic vasculitis, especially coronary arteritis. Aortic valve regurgitation (AVR) is a relatively common complication. There have been no reports to date of heart failure and left ventricular non-compaction (LVNC) after acute KD, although the precise etiology of this condition remains unclear. A 6-month-old boy with KD was admitted to hospital. Despite high-dose i.v. gammaglobulin for dilation of the coronary artery, moderate AVR appeared, and thereafter he developed heart failure. A rough, dense LV myocardium indicated LVNC. On genetic testing a heterogenous 163G > A substitution changing a valine to isoleucine in LIM domain binding protein 3 ( LDB3) was identified. Additional cardiac stress, such as that caused by AVR and/or KD might have triggered cardiac failure in the form of LVNC due to LDB3 mutation. [ABSTRACT FROM AUTHOR]

Objective: To investigate the morphology and genetics of a fetus at 22 weeks. This fetus demonstrated progressive fetal hydrops and cardiomegaly with retrograde flow in the pulmonary artery and progressive myocardial deterioration and heart failure. Methods: Postmortem examination, light and electron microscopy of the myocardium, karyotyping, fetal DNA analysis, screening for mutations in the G4.5 gene, α-dystrobrevin gene, FKBP 12 gene, Desmin, Syntrophin and Cypher/ZASP genes, which have been described as being associated with noncompaction ventricular myocardium, using single-strand DNA conformation polymorphism analysis and DNA sequencing. Results: The morphological diagnosis was compatible with noncompaction ventricular myocardium or spongyforme myopathy. The karyotype was normal. Mutation analysis in exons and introns of all six genes did not show any known mutation. Conclusion: Noncompaction ventricular myocardium or spongyforme myopathy may be associated with mutations in genes which have previously not been thought to be associated with this phenotype. Alternatively, this disease could be the result of abnormal cardiac hemodynamics. Copyright © 2007 S. Karger AG, Basel [ABSTRACT FROM AUTHOR]

Abstract: 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 occurence of SCN5A variants, suggesting the presence of SCN5A variants and/or arrhythmias increase the severity of LVNC. [Copyright &y& Elsevier]