Emergency Ross Procedure for Pediatric Aortic Valve Myxofibrosarcoma.

Primary cardiac tumors in children are uncommon and rarely demand surgical intervention. We report a malignant tumor arising from the aortic root in a 5-year-old boy presenting with left ventricular outflow tract obstruction and tumor embolism, its surgical management using the Ross procedure, and the unique histopathological aspects of the tumor.

Exercise in children with common congenital heart lesions: balancing benefits with risks.

Children with corrected common congenital heart lesions are often withheld from regular exercise by their parents. While there are some modest risks with exercise, they should be seen in perspective, and the life-long benefits of regular exercise on general health, mood and well-being should be emphasised.

Can an athlete have too much ticker? Hypertrophic cardiomyopathy in young athletes.

Sudden cardiac death (SCD) is an uncommon but devastating potential consequence of participation in competitive sport. It is seen in adolescent and young adult athletes. The most common cause of this, hypertrophic cardiomyopathy (HCM), is a genetic disorder responsible for more than a third of cases and is manageable. Screening is undertaken for HCM, using differing strategies in Europe and North America. Screening and early diagnosis have reduced the mortality rate but has come at a significant economic cost. The evidence and relevant arguments for and against screening are presented together with management strategies as reflected by an illustrative case.

Early developmental outcomes following major noncardiac and cardiac surgery in term infants: a population-based study.

OBJECTIVE: To ascertain developmental differences between term infants after major noncardiac surgery and cardiac surgery compared with healthy control infants in New South Wales, Australia. STUDY DESIGN: This prospective population-based cohort study enrolled infants between August 1, 2006, and December 31, 2008, who required major noncardiac surgery within the first 90 days of life. Developmental outcomes were compared in these children, cohorts of term infants requiring cardiac surgery, and healthy controls. Infants were assessed at 1 year of age using the Bayley Scales of Infant and Toddler Development, Third Edition (BSID-III). RESULTS: Of the 784 infants enrolled, 688 (90.2%) of infants alive at 1 year were assessed. Of these, 539 infants were term and were included in the present analysis. Compared with controls, the infants who underwent cardiac surgery had significantly lower (P < .001) mean scores in all 5 BSID-III subscales, and the infants who underwent noncardiac surgery had significantly lower (P < .05) mean scores in 4 of the 5 BSID-III subscales. The greatest difference was in the incidence of gross motor delay in both the cardiac surgery group (OR, 0.25; 95% CI, 0.16-0.41) and the noncardiac surgery group (OR, 0.41; 95% CI, 0.26-0.63). CONCLUSION: This unique population-based prospective study compared the developmental outcomes of infants who underwent major noncardiac surgery and cardiac surgery. Major surgery in infants was found to be significantly associated with developmental delay at 1 year of age compared with control infants. These data have important implications for interventions and clinical review in the first year of life.

A quantitative review of the profile and time course of symptom change in schizophrenia treated with clozapine.

Contemporary analyses demonstrate an early response to antipsychotic treatment in non-refractory schizophrenia. The profile of response to clozapine is unknown. We used meta-analytic and statistical procedures to examine the response profile to clozapine. We identified 19 unique, randomized, double-blind controlled clinical trials with suitable time course data, representing 1745 subjects. Individual subject data were available for 419 subjects, obtained from two industry-sponsored trials. Symptom severity scores from the BPRS or the PANSS were entered into regression analyses to estimate linear and quadratic coefficients of the rate of change of symptom severity over 4 weeks. Both linear and quadratic regression coefficients for clozapine, and for comparator antipsychotics differed significantly from zero (p ≤ 0.001), indicating early response profiles. Compared with other antipsychotic arms, for clozapine the treatment response was greater (d = -0.578, p = 0.021), and the linear coefficient was steeper (d = -0.502, p = 0.042); the quadratic coefficients indicating attenuation did not differ. Analyses of 6-week data and individual subject data from non-refractory and refractory trials were consistent with the primary findings. Somewhat surprisingly, clozapine shows an early response profile, similar in pattern but somewhat larger in magnitude than other antipsychotic drugs.

Hypoplastic left heart syndrome in context.

Hypoplastic left heart syndrome is a rare condition requiring major cardiac surgery during the neonatal period to sustain life, with subsequent procedures culminating in completion of the Fontan circulation - the common pathway for all 'single ventricle' conditions. Algorithms for care of these children are now well defined with predictable medium-term outcomes with the majority achieving a Fontan circulation. Hypoplastic left heart syndrome is one of a group of conditions that require complex surgery as a neonate and require a similar perioperative approach. Antenatal diagnosis is common in this patient subgroup, and there is a significant body of work that can be drawn on to inform parental choice.

Increased connective tissue growth factor associated with cardiac fibrosis in the mdx mouse model of dystrophic cardiomyopathy.

Cardiomyopathy contributes to morbidity and mortality in Duchenne muscular dystrophy (DMD), a progressive muscle-wasting disorder. A major feature of the hearts of DMD patients and the mdx mouse model of the disease is cardiac fibrosis. Connective tissue growth factor (CTGF) is involved in the fibrotic process in many organs. This study utilized the mdx mouse model to assess the role of CTGF and other extracellular matrix components during the development of fibrosis in the dystrophic heart. Left ventricular function of mdx and control mice at 6, 29 and 43 weeks was measured by echocardiography. Young (6 weeks old) mdx hearts had normal function and histology. At 29 weeks of age, mdx mice developed cardiac fibrosis and increased collagen expression. The onset of fibrosis was associated with increased CTGF transcript and protein expression. Increased intensity of CTGF immunostaining was localized to fibrotic areas in mdx hearts. The upregulation of CTGF was also concurrent with increased expression of tissue inhibitor of matrix metalloproteinases (TIMP-1). These changes persisted in 43 week old mdx hearts and were combined with impaired cardiac function and increased gene expression of transforming growth factor (TGF)-ß1 and matrix metalloproteinases (MMP-2, MMP-9). In summary, an association was observed between cardiac fibrosis and increased CTGF expression in the mdx mouse heart. CTGF may be a key mediator of early and persistent fibrosis in dystrophic cardiomyopathy.

Cytoplasmic CUG RNA foci are insufficient to elicit key DM1 features.

The genetic basis of myotonic dystrophy type I (DM1) is the expansion of a CTG tract located in the 3' untranslated region of DMPK. Expression of mutant RNAs encoding expanded CUG repeats plays a central role in the development of cardiac disease in DM1. Expanded CUG tracts form both nuclear and cytoplasmic aggregates, yet the relative significance of such aggregates in eliciting DM1 pathology is unclear. To test the pathophysiology of CUG repeat encoding RNAs, we developed and analyzed mice with cardiac-specific expression of a beta-galactosidase cassette in which a (CTG)(400) repeat tract was positioned 3' of the termination codon and 5' of the bovine growth hormone polyadenylation signal. In these animals CUG aggregates form exclusively in the cytoplasm of cardiac cells. A key pathological consequence of expanded CUG repeat RNA expression in DM1 is aberrant RNA splicing. Abnormal splicing results from the functional inactivation of MBNL1, which is hypothesized to occur due to MBNL1 sequestration in CUG foci or from elevated levels of CUG-BP1. We therefore tested the ability of cytoplasmic CUG foci to elicit these changes. Aggregation of CUG RNAs within the cytoplasm results both in Mbnl1 sequestration and in approximately a two fold increase in both nuclear and cytoplasmic Cug-bp1 levels. Significantly, despite these changes RNA splice defects were not observed and functional analysis revealed only subtle cardiac dysfunction, characterized by conduction defects that primarily manifest under anesthesia. Using a human myoblast culture system we show that this transgene, when expressed at similar levels to a second transgene, which encodes expanded CTG tracts and facilitates both nuclear focus formation and aberrant splicing, does not elicit aberrant splicing. Thus the lack of toxicity of cytoplasmic CUG foci does not appear to be a consequence of low expression levels. Our results therefore demonstrate that the cellular location of CUG RNA aggregates is an important variable that influences toxicity and support the hypothesis that small molecules that increase the rate of transport of the mutant DMPK RNA from the nucleus into the cytoplasm may significantly improve DM1 pathology.

Lamin A/C haploinsufficiency causes dilated cardiomyopathy and apoptosis-triggered cardiac conduction system disease.

Mutations in the lamin A/C (LMNA) gene, which encodes nuclear membrane proteins, cause a variety of human conditions including dilated cardiomyopathy (DCM) with associated cardiac conduction system disease. To investigate mechanisms responsible for electrophysiologic and myocardial phenotypes caused by dominant human LMNA mutations, we performed longitudinal evaluations in heterozygous Lmna(+/-) mice. Despite one normal allele, Lmna(+/-) mice had 50% of normal cardiac lamin A/C levels and developed cardiac abnormalities. Conduction system function was normal in neonatal Lmna(+/-) mice but, by 4 weeks of age, atrioventricular (AV) nodal myocytes had abnormally shaped nuclei and active apoptosis. Telemetric and in vivo electrophysiologic studies in 10-week-old Lmna(+/-) mice showed AV conduction defects and both atrial and ventricular arrhythmias, analogous to those observed in humans with heterozygous LMNA mutations. Isolated myocytes from 12-month-old Lmna(+/-) mice exhibited impaired contractility. In vivo cardiac studies of aged Lmna(+/-) mice revealed DCM; in some mice this occurred without overt conduction system disease. However, neither histopathology nor serum CK levels indicated skeletal muscle pathology. These data demonstrate cardiac pathology due to heterozygous Lmna mutations reflecting a 50% reduction in lamin protein levels. Lamin haploinsufficiency caused early-onset programmed cell death of AV nodal myocytes and progressive electrophysiologic disease. While lamin haploinsufficiency was better tolerated by non-conducting myocytes, ultimately, these too succumbed to diminished lamin levels leading to dilated cardiomyopathy, which presumably arose independently from conduction system disease.

Long-term cardio-respiratory consequences of heart disease in childhood.

The dynamic interaction between the heart and lungs leads to a degree of respiratory co-morbidity including both restrictive and obstructive airway abnormalities, which may be overlooked in children with congenital and acquired heart disease. The improving imaging techniques of the heart, both foetal and post-natal coupled with minimally invasive techniques for device implantation and better operative techniques for complex congenital heart disease have resulted in more children with longitudinally documented structural heart disease surviving into their adult years. Children presenting with cardiomyopathy or arrhythmias, as well as those with repaired cardiac disease, can be offered advice with regard to formal exercise testing and participation in sports, which may be particularly helpful in the adolescent years. Furthermore, through the interest of some adult cardiologists in paediatric heart disease over the past 20 years, facilities for the smooth transition of care to adult services are improving.

Cardiac electrophysiological characteristics of the mdx ( 5cv ) mouse model of Duchenne muscular dystrophy.

BACKGROUND: Duchenne muscular dystrophy (DMD) is a progressive muscle disease caused by mutations in the dystrophin gene. Cardiomyopathy, conduction abnormalities, and ventricular arrhythmias are significant complications of this disease. The mdx ( 5cv ) mouse carries a dystrophin mutation and demonstrates a more severe phenotype than the classic mdx mouse. METHODS: Comprehensive electrophysiological phenotyping was performed in adult mdx ( 5cv ) and wildtype mice, including electrocardiography (ECG), implantable Holter monitoring, intracardiac electrophysiological testing, echocardiography, and exercise treadmill testing. RESULTS: ECG performed in mdx ( 5cv ) mice revealed significantly shorter PR intervals and prominent R waves in surface lead V1. During electrophysiological testing, mdx ( 5cv ) mice exhibited longer ventricle effective refractory periods and mildly increased ventricular tachycardia inducibility. There was no evidence for cardiomyopathy or ventricular dysfunction on echocardiography. Histopathology showed no increased myocardial fibrosis. Exercise endurance was lower in mdx ( 5cv ) mice without arrhythmias or other cardiac abnormalities. CONCLUSION: Taken together at the age range examined, mdx ( 5cv ) mice exhibit discrete cardiac electrophysiological dysfunction but display no evidence of structural or contractile abnormalities. Thus, the mdx ( 5cv ) mouse recapitulates some of the electrophysiological, but not hemodynamic cardiac defects present in human DMD. In certain settings, the mdx ( 5cv ) mouse may be an appropriate subject for studying electrical pathophysiology and therapy of the cardiac complications of DMD.

Conceptual and methodological issues in the design of clinical trials of antipsychotics for the treatment of schizophrenia.

Schizophrenia is one of the most severe and disabling psychiatric disorders. Antipsychotic drugs offer considerable benefits in controlling symptoms and preventing relapse. The strategy for the present review of clinical trials was to ask 'What are the features of schizophrenia and the existing treatments of the illness that have implications for future clinical trials'? Six key facts were identified.First, schizophrenia is genetically 'complex'. Trials may benefit from designs including genetically related illnesses, by focussing on cross-cutting aspects of the phenotype such as psychosis or cognitive dysfunction, and by collecting information on possible moderators and mediators of treatment response.Second, schizophrenia affects multiple neurotransmitter systems. Multiple signalling pathways may need to be considered, with different time courses of response. Outcome measures from clinical trials could be collected at more frequent intervals, particularly in the early phase of response.Third, the clinical features used to define the illness are a mix of symptoms and social-occupational dysfunction, yet treatment response is often defined only by changes in symptoms. Multiple measures of functioning need to be collected at baseline and at the endpoint of trials. Consensus definitions for response, remission, relapse, recovery and recurrence need to be developed.Fourth, schizophrenia is often highly disabling. Linking treatment response in clinical trials to measures of quality-adjusted life-years will allow comparison with other medical illnesses using common metrics.Fifth, the general health and care of individuals with schizophrenia is often poor. 'Complex' interventions, which include, but are not limited to, antipsychotic medications, need to be designed and tested for the problems facing these patients.Finally, large gaps exist between clinical trials, practice guidelines and patterns of practice. Trials need to be designed to investigate widely used approaches such as antipsychotic polypharmacy, where actual practice diverges from evidence-based guidelines.

Outcomes following surgery for congenital heart disease in low-birthweight infants.

AIM: To describe cardiac surgery, survival and outcomes for low-birthweight (< or = 2500 g) infants undergoing surgery for congenital heart disease. METHODS: Using data from a prospectively collected population-based database of admissions to neonatal intensive care units in New South Wales and the Australian Capital Territory, we identified all low-birthweight infants undergoing cardiac surgery between 1992 and 2001. Infants with only a persistent ductus arteriosus were excluded. Two-year cardiac and neurodevelopmental outcome data were sought from hospital medical records. RESULTS: A total of 121 low-birthweight infants underwent cardiac surgery, of whom 34% had a congenital syndrome or non-cardiac birth defect. Most (81%) underwent a palliative surgical procedure in the neonatal period. There were 19 early (15.7%) and 19 late deaths giving a 2-year mortality of 31%. Factors associated with mortality included birthweight below 1500 g (P = 0.006), low weight at surgery (P = 0.028) and Apgar score at 1 min (P = 0.019). No single factor predicted 30-day mortality. By 2 years of age, 27 (33% of survivors) were known to have neurodevelopmental delay. Although 22 children are known to be developing normally, the neurodevelopmental status of 34 children was not known. CONCLUSIONS: These surgical data were comparable to previous single-institution studies. This group had a high risk of disability due to prematurity, low birthweight and associated conditions. There is a need to prospectively assess and manage neurodevelopmental outcomes in this group.

Neurodevelopmental outcomes and surgery in neonates.

A neonate requiring major surgery in 2006 has a greater prospect of survival than ever before. Increasingly, however, there is awareness that critical illness may affect later neurodevelopment. Pre-existing conditions in addition to the physiologic stresses associated with cardiac and general surgery are implicated but remain unavoidable in the case of significant structural abnormalities such as transposition of the great arteries or congenital diaphragmatic hernia. For those affected by neurodevelopmental impairment, there is a significant cost to the child, family and society. Current research focuses on the preventable causes of brain injury, before, during and after the intervention, and the rate of impairment in apparently uncomplicated procedures. In contrast to the quantity of neurodevelopmental outcome data following cardiac surgery, there remain few outcome studies dealing with non-cardiac surgery despite such intervention being two to three times more common. There appear to be compelling clinical and economic arguments for the instigation of formalised population-based developmental assessments for all infants undergoing major surgery.

Dilated cardiomyopathy resulting from high-level myocardial expression of Cre-recombinase.

BACKGROUND: Conditional gene inactivation in mice using the bacteriophage P1 Cre-loxP recombination system requires transgenic expression of Cre-recombinase driven by a tissue-specific or inducible promoter. METHODS AND RESULTS: Using the cardiac alpha-myosin-heavy-chain promoter, the most commonly used myocardial-specific transgenic promoter, we created transgenic mice expressing Cre-recombinase in the heart. Seven transgenic lines developed dilated cardiomyopathy and premature death from congestive heart failure. One founder line that survived long enough to propagate had extremely high-level Cre recombinase expression. Transgenic lines that expressed low levels remained healthy. The high-expressing strain developed heart failure over a very predictable and reproducible time course. Detailed examination of the high-expressing strain revealed important molecular, cellular, and pharmacologic hallmarks of cardiomyopathy. First, "fetal genes" such as atrial natriuretic factor and brain natriuretic protein were expressed, a marker of pathologic cardiac hypertrophy and heart failure. Second, an increased incidence of cardiac myocyte apoptosis was present. Third, treatment of mice with captopril or metoprolol, drugs that delay the progression of heart failure, improved survival. CONCLUSION: Cre-recombinase when expressed at high levels may cause organ dysfunction, which could be mistaken for an effect of conditional gene inactivation. In addition, the stereotypic cardiomyopathy and disease progression in the characterized, high-expressing transgenic strain suggests its utility as a model to study the effects of pharmacologic or genetic manipulations in heart failure.

A meta-analysis of profile and time-course of symptom change in acute schizophrenia treated with atypical antipsychotics.

The profile and time-course of symptom response in acute schizophrenia is unclear. For the present study, we hypothesized that the time-course would be nonlinear. A meta-analysis was performed using randomized, controlled clinical trials of five atypical antipsychotics reported in nine electronic databases. Studies were of subjects experiencing an acute exacerbation of illness, with multiple BPRS or PANSS data-points as outcome measures. A mixed factorial repeated-measures ANOVA was used. Twenty-one published clinical trials were identified. Reduction in total symptoms from baseline to 4 wk was associated with a linear decline in symptomatology (F=23.4, d.f.=1, 7, p=0.002) without attenuation of effect. In contrast, from baseline to 6 wk the linear symptom reduction (F=76.5, d.f.=1, 12, p<0.001) eventually flattened at the end of the trial (F=87.2, d.f.=1, 12, p<0.001). Secondary analyses showed a similar pattern for typical antipsychotics, and the same profile for risperidone and olanzapine as for atypical agents as a whole. Inclusion of LOCF data altered the results at 4 wk, but not 6 wk; completion rates had no effect on results. In conclusion, this meta-analysis confirms our hypothesis for 6-wk data. The profile of symptom change is one of linear symptom reduction until 4 wk, with a flattening of treatment effects by 6 wk. A curvilinear profile of schizophrenia symptom reduction has possible implications with respect to trial design and clinical decision-making.

Class IA phosphoinositide 3-kinase regulates heart size and physiological cardiac hypertrophy.

Class I(A) phosphoinositide 3-kinases (PI3Ks) are activated by growth factor receptors, and they regulate, among other processes, cell growth and organ size. Studies using transgenic mice overexpressing constitutively active and dominant negative forms of the p110alpha catalytic subunit of class I(A) PI3K have implicated the role of this enzyme in regulating heart size and physiological cardiac hypertrophy. To further understand the role of class I(A) PI3K in controlling heart growth and to circumvent potential complications from the overexpression of dominant negative and constitutively active proteins, we generated mice with muscle-specific deletion of the p85alpha regulatory subunit and germ line deletion of the p85beta regulatory subunit of class I(A) PI3K. Here we show that mice with cardiac deletion of both p85 subunits exhibit attenuated Akt signaling in the heart, reduced heart size, and altered cardiac gene expression. Furthermore, exercise-induced cardiac hypertrophy is also attenuated in the p85 knockout hearts. Despite such defects in postnatal developmental growth and physiological hypertrophy, the p85 knockout hearts exhibit normal contractility and myocardial histology. Our results therefore provide strong genetic evidence that class I(A) PI3Ks are critical regulators for the developmental growth and physiological hypertrophy of the heart.