Publications by authors named "Megan Sherwood"

33 Publications

Emergency Ross Procedure for Pediatric Aortic Valve Myxofibrosarcoma.

Ann Thorac Surg 2019 03 25;107(3):e183-e185. Epub 2018 Sep 25.

Heart Centre for Children, The Children's Hospital at Westmead, Westmead, New South Wales, Australia; School of Child and Adolescent Health, Sydney Medical School, University of Sydney, Sydney, Australia. Electronic address:

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.
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http://dx.doi.org/10.1016/j.athoracsur.2018.07.060DOI Listing
March 2019

Lymphangiography is a diagnostic and therapeutic intervention for patients with plastic bronchitis after the Fontan operation.

J Thorac Cardiovasc Surg 2016 08 22;152(2):e47-9. Epub 2016 Apr 22.

Heart Centre for Children, The Children's Hospital at Westmead, Sydney, New South Wales, Australia.

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http://dx.doi.org/10.1016/j.jtcvs.2016.04.051DOI Listing
August 2016

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

J Paediatr Child Health 2013 Oct 6;49(10):795-9. Epub 2013 Oct 6.

Discipline of Paediatrics and Child Health, Sydney Medical School, University of Sydney, Sydney, New South Wales, Australia; Department of Respiratory Medicine, The Children's Hospital at Westmead, Sydney, New South Wales, Australia.

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.
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http://dx.doi.org/10.1111/jpc.12388DOI Listing
October 2013

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

J Paediatr Child Health 2012 Oct 29;48(10):E156-60. Epub 2012 Jul 29.

University of New South Wales Medical School, Sydney, New South Wales, Australia.

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.
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http://dx.doi.org/10.1111/j.1440-1754.2012.02504.xDOI Listing
October 2012

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

J Pediatr 2012 Oct 10;161(4):748-752.e1. Epub 2012 May 10.

Grace Centre for Newborn Care, The Children's Hospital at Westmead, Sydney, New South Wales, Australia.

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.
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http://dx.doi.org/10.1016/j.jpeds.2012.03.044DOI Listing
October 2012

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

J Psychopharmacol 2012 Sep 30;26(9):1175-84. Epub 2012 Mar 30.

Department of Psychiatry, University of British Columbia, Vancouver, BC, Canada.

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.
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http://dx.doi.org/10.1177/0269881112440513DOI Listing
September 2012

Hypoplastic left heart syndrome in context.

J Paediatr Child Health 2012 Feb 29;48(2):E7-9. Epub 2011 Apr 29.

Heart Centre for Children, The Children's Hospital at Westmead, New South Wales, Australia.

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.
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http://dx.doi.org/10.1111/j.1440-1754.2011.02084.xDOI Listing
February 2012

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

Int J Exp Pathol 2011 Feb 1;92(1):57-65. Epub 2010 Dec 1.

Kids Heart Research and Institute for Neuroscience and Muscle Research, The Children's Hospital at Westmead, Sydney, Australia.

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)-β1 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.
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http://dx.doi.org/10.1111/j.1365-2613.2010.00750.xDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3052757PMC
February 2011

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

PLoS One 2008 18;3(12):e3968. Epub 2008 Dec 18.

Department of Biochemistry and Molecular Biology, Institute for Genetic Medicine, University of Southern California, Los Angeles, CA, USA.

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.
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http://journals.plos.org/plosone/article?id=10.1371/journal.pone.0003968PLOS
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC2597774PMC
February 2009

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

J Mol Cell Cardiol 2008 Feb 3;44(2):293-303. Epub 2007 Dec 3.

Department of Cardiology, Children's Hospital Boston, Harvard Medical School, Boston, MA 02115, USA.

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.
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http://dx.doi.org/10.1016/j.yjmcc.2007.11.008DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3011813PMC
February 2008

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

Paediatr Respir Rev 2007 Dec 17;8(4):313-21; quiz 321-2. Epub 2007 Sep 17.

Discipline of Paediatrics and Child Health, University of Sydney, Sydney, Australia.

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.
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http://dx.doi.org/10.1016/j.prrv.2007.08.006DOI Listing
December 2007

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

J Interv Card Electrophysiol 2007 Nov 17;20(1-2):1-7. Epub 2007 Oct 17.

Department of Cardiology, Children's Hospital Boston, Boston, MA 02115, USA.

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.
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http://dx.doi.org/10.1007/s10840-007-9168-zDOI Listing
November 2007

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

CNS Drugs 2007 ;21(9):699-714

Department of Psychiatry, University of British Columbia, Vancouver, British Columbia, Canada.

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.
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http://dx.doi.org/10.2165/00023210-200721090-00001DOI Listing
October 2007

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

J Paediatr Child Health 2007 May;43(5):370-5

The Children's Hospital at Westmead, New South Wales, Australia.

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.
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http://dx.doi.org/10.1111/j.1440-1754.2007.01082.xDOI Listing
May 2007

The negative impact of Alagille syndrome on survival of infants with pulmonary atresia.

J Thorac Cardiovasc Surg 2007 Apr;133(4):1094-6

Kids Heart Research and Adolph Basser Cardiac Institute, The Children's Hospital at Westmead, Sydney, Australia.

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http://dx.doi.org/10.1016/j.jtcvs.2006.12.009DOI Listing
April 2007

Neurodevelopmental outcomes and surgery in neonates.

J Paediatr Child Health 2006 Dec;42(12):749-51

Department of Neonatology, The Children's Hospital at Westmead, Westmead, Sydney, NSW, Australia.

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.
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http://dx.doi.org/10.1111/j.1440-1754.2006.00969.xDOI Listing
December 2006

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

J Card Fail 2006 Jun;12(5):392-8

Department of Medicine, Harvard Medical School, Boston, Massachusetts, USA.

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.
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http://dx.doi.org/10.1016/j.cardfail.2006.03.002DOI Listing
June 2006

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

Int J Neuropsychopharmacol 2006 Jun 5;9(3):357-66. Epub 2005 Sep 5.

Centre for Complex Disorders, Department of Psychiatry, University of British Columbia, Vancouver, BC, Canada.

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.
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http://dx.doi.org/10.1017/S1461145705005961DOI Listing
June 2006

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

Mol Cell Biol 2005 Nov;25(21):9491-502

Division of Systems Biology, Harvard Medical School, Beth Israel Deaconess Medical Center, 77 Avenue Louis Pasteur, 10th Floor, Boston, MA 02115, USA.

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.
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http://dx.doi.org/10.1128/MCB.25.21.9491-9502.2005DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC1265829PMC
November 2005

Current management of severe congenital mitral stenosis: outcomes of transcatheter and surgical therapy in 108 infants and children.

Circulation 2005 Aug 25;112(5):707-14. Epub 2005 Jul 25.

Department of Cardiology, Children's Hospital, 300 Longwood Ave, Boston, MA 02115, USA.

Background: Severe congenital mitral stenosis (MS) is a rare anomaly that is frequently associated with additional left heart obstructions. Anatomic treatments for congenital MS include balloon mitral valvuloplasty (BMVP), surgical mitral valvuloplasty (SMVP), and mitral valve replacement (MVR), although the optimal therapeutic strategy is unclear.

Methods And Results: Between 1985 and 2003, 108 patients with severe congenital MS underwent BMVP or surgical intervention at a median age of 18 months (range 1 month to 17.9 years). Anatomic subtypes of MS were "typical" congenital MS in 78 patients, supravalvar mitral ring in 46, parachute mitral valve in 28, and double-orifice mitral valve in 11, with multiple types in approximately 50% of patients. Additional left heart anomalies were present in 82 patients (76%). The first MS intervention was BMVP in 64 patients, SMVP in 33, and MVR in 11. BMVP decreased peak and mean MS gradients by a median of 33% and 38%, respectively (P<0.001), but was complicated by significant mitral regurgitation in 28%. Cross-sectional follow-up was obtained at 4.8+/-4.2 years. Overall, Kaplan-Meier survival was 92% at 1 month, 84% at 1 year, and 77% at 5 years, with 69% 5-year survival during the first decade of our experience and 87% since (P=0.09). Initial MVR and younger age were associated with worse survival. Survival free from failure of biventricular repair or mitral valve reintervention was 55% at 1 year among patients who underwent BMVP and 69% among patients who underwent supravalvar mitral ring resection initially. Among patients who underwent BMVP, survival free from failure of biventricular repair or MVR was 79% at 1 month and 55% at 5 years, with worse outcome in younger patients and those who developed significant postdilation mitral regurgitation.

Conclusions: BMVP effectively relieves left ventricular inflow obstruction in most infants and children with severe congenital MS who require intervention. However, surgical resection is preferable in patients with MS due to a supravalvar mitral ring. Five-year survival is relatively poor in patients with severe congenital MS, with worse outcomes in infants and patients undergoing MVR, but has improved in our more recent experience. Many patients have undergone second procedures for either recurrent/residual MS or mitral regurgitation resulting from dilation-related disruption of the mitral valve apparatus.
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http://dx.doi.org/10.1161/CIRCULATIONAHA.104.500207DOI Listing
August 2005

Haploinsufficiency of the cardiac transcription factor Nkx2-5 variably affects the expression of putative target genes.

FASEB J 2005 Sep 22;19(11):1495-7. Epub 2005 Jun 22.

Department of Pediatrics, Washington University School of Medicine, St. Louis, Missouri 63110, USA.

Heterozygous mutations of the cardiac transcription factor Nkx2-5 cause congenital heart disease. To elucidate the molecular pathways of transcription factor mutant phenotypes or diseases, direct targets are commonly sought in studies of homozygous null mutant animals and by heterologous promoter-reporter gene transactivation assays. The expression of putative target genes in a physiologic range of transcription factor concentration, however, is often not examined. Heterozygous Nkx2-5 knockout (Nkx2-5+/-) mice have no more than half-normal levels of Nkx2-5 protein. We therefore measured the mRNA expression of four putative targets of the cardiac transcription factor Nkx2-5 in wild-type and Nkx2-5+/- animals in a variety of developmental and pathologic states. Wild-type and Nkx2-5+/- embryonic hearts expressed similar levels of atrial natriuretic factor (ANF), brain natriuretic peptide (BNP), the RNA helicase Csm, and homeodomain only protein HOP. In the failing adult ventricle, ANF and BNP were up-regulated to the same extent in wild-type and Nkx2-5+/- myocardium. Csm and HOP were down-regulated in heart failure, and Nkx2-5+/- hearts expressed about half-normal levels in healthy and failing states. No consistent relationship existed between the expression of putative transcriptional targets and Nkx2-5 gene dosage in the physiologically relevant range. Any dependence of gene expression on Nkx2-5 gene dosage is affected by factors specific to the individual gene and the physiologic context.
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http://dx.doi.org/10.1096/fj.04-3064fjeDOI Listing
September 2005

From stem cells to viable autologous semilunar heart valve.

Circulation 2005 May;111(21):2783-91

Department of Cardiothoracic Surgery, Children's Hospital, Boston, Mass, USA.

Background: An estimated 275,000 patients undergo heart valve replacement each year. However, existing solutions for valve replacement are complicated by the morbidity associated with lifelong anticoagulation of mechanical valves and the limited durability of bioprostheses. Recent advances in tissue engineering and our understanding of stem cell biology may provide a lifelong solution to these problems.

Methods And Results: Mesenchymal stem cells were isolated from ovine bone marrow and characterized by their morphology and antigen expression through immunocytochemistry, flow cytometry, and capacity to differentiate into multiple cell lineages. A biodegradable scaffold was developed and characterized by its tensile strength and stiffness as a function of time in cell-conditioned medium. Autologous semilunar heart valves were then created in vitro using mesenchymal stem cells and the biodegradable scaffold and were implanted into the pulmonary position of sheep on cardiopulmonary bypass. The valves were evaluated by echocardiography at implantation and after 4 months in vivo. Valves were explanted at 4 and 8 months and examined by histology and immunohistochemistry. Valves displayed a maximum instantaneous gradient of 17.2+/-1.33 mm Hg, a mean gradient of 9.7+/-1.3 mm Hg, an effective orifice area of 1.35+/-0.17 cm2, and trivial or mild regurgitation at implantation. Gradients changed little over 4 months of follow-up. Histology showed disposition of extracellular matrix and distribution of cell phenotypes in the engineered valves reminiscent of that in native pulmonary valves.

Conclusions: Stem-cell tissue-engineered heart valves can be created from mesenchymal stem cells in combination with a biodegradable scaffold and function satisfactorily in vivo for periods of >4 months. Furthermore, such valves undergo extensive remodeling in vivo to resemble native heart valves.
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http://dx.doi.org/10.1161/CIRCULATIONAHA.104.498378DOI Listing
May 2005

A mouse model of cardiac rhabdomyoma generated by loss of Tsc1 in ventricular myocytes.

Hum Mol Genet 2005 Feb 15;14(3):429-35. Epub 2004 Dec 15.

Department of Medicine, Brigham and Women's Hospital and Harvard Medical School, Boston, MA 02115, USA.

Tuberous sclerosis is a hamartoma syndrome due to mutations in TSC1 or TSC2 in which cardiac rhabdomyomas are seen in approximately 60% of patients. These lesions have an unusual natural history as they are usually most prominent immediately after birth and spontaneously resolve in most cases. To develop a mouse model of this lesion, we used a conditional, floxed allele of Tsc1 and a modified myosin light chain 2v allele in which cre recombinase expression occurs in ventricular myocytes. Mice with ventricular loss of Tsc1 had a median survival of 6 months and developed a dilated cardiomyopathy with the occurrence of scattered foci of enlarged ventricular myocytes. The enlarged cells were periodic acid-Schiff positive indicating the presence of excess glycogen and expressed elevated levels of phospho-S6, similar to findings in patient rhabdomyoma cells. The observations confirm that rhabdomyomas occur through a two hit mechanism of pathogenesis. However, the mice showed no evidence of fetal/neonatal demise, and there was no evidence of proliferation in the lesions. We propose that these differences are due to the timing of loss of Tsc1 in the ventricular myocytes and/or the truncated gestational period in the mouse compared with humans, during which progestational hormones may accentuate the growth of patient rhabdomyomas.
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http://dx.doi.org/10.1093/hmg/ddi039DOI Listing
February 2005

Intermediate outcomes of atrioventricular valvuloplasty in lateral tunnel Fontan patients.

J Heart Valve Dis 2004 Nov;13(6):962-71; discussion 971

Department of Cardiac Surgery, Children's Hospital Boston, Boston, MA, USA.

Background And Aim Of The Study: Lateral tunnel Fontan operation patients with atrioventricular valve (AVV) regurgitation have an increased incidence of Fontan failure (death, take-down or transplant). The outcomes of patients undergoing AVV repair during Fontan palliation were reviewed to determine the optimal technique and timing of repair.

Methods: Hospital records for all patients with AVV regurgitation at the time of their Fontan procedure were reviewed retrospectively. Patients with staged single-ventricle palliation culminating in a lateral tunnel Fontan operation who had their first AVV repair at the Children's Hospital, Boston, were included. AVV regurgitation was graded by semi-quantitative color Doppler echocardiography on a scale of 1 to 4, as was ventricular dysfunction.

Results: Among 859 lateral tunnel Fontan patients, 27 (3%) had a total of 30 AVV repairs (18 tricuspid, six mitral, six common AVV). Of the 27 first-time AVV repairs (16 TV, six MV, five CAVV), six were performed pre-Fontan, and 21 at or after Fontan. The median age at the first AVV repair was 3 years (range: 0.6-9.4 years). Preoperatively, the median echocardiographic severity of AVV regurgitation was grade 3 (range: 2-4). At median follow up of 1.2 years (range: 0-9.5 years) the severity of AVV regurgitation was reduced significantly to median grade 2 (range: 0-4; p <0.001). No patient with initial AVV repair at the time of Fontan underwent reoperation for AVV regurgitation. In all cases, ventricular function was maintained or improved, with preoperative median systemic ventricular function grade 1.5 (range: 1 to 4) versus postoperative grade 1 (range: 1-4; p = NS). There were no Fontan failures in the intermediate term.

Conclusion: AVV regurgitation and ventricular systolic function can be maintained or improved in the intermediate term following AVV repair in single-ventricle patients.
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November 2004

Aortico-left ventricular tunnel: 35-year experience.

J Am Coll Cardiol 2004 Jul;44(2):446-50

Objectives: The purpose of this study was to review our 35 years of experience with aortico-left ventricular tunnel (ALVT), with emphasis on diagnosis, surgical details, and follow-up.

Background: Aortico-left ventricular tunnel is a rare congenital anomaly. Neonatal surgery has been advocated in all due to long-term concern of valvar aortic regurgitation (AR).

Methods: We identified 11 patients from 1963 to August 2002. Clinical, echocardiographic, catheterization, and surgical details were reviewed.

Results: Eight of 11 patients presented at less than six months old (six with congestive heart failure) and three later with a murmur, all with clinical evidence of AR. Associated lesions, most commonly aortic valve and coronary artery anomalies, were present in 45%. Catheter occlusion was considered but not performed in five. Spontaneous occlusion was documented in one. Ten had surgery (nine in our institution), seven with direct suture and two by patch closure of the aortic end of the AVLT. At follow-up (median, 5 years; 1 month to 35 years), all were asymptomatic; three had residual ALVT (one moderate, two small/trivial), with at most mild AR.

Conclusions: Aortico-left ventricular tunnel is a rare cardiac malformation with a good post-operative long-term outcome. Associated lesions occurred in 45%. Catheterization should be reserved for patients with unclear non-invasive findings or transcatheter closure. We recommend surgery for most patients. We report spontaneous closure in one patient, prompting consideration of conservative follow-up in rare small, asymptomatic AVLT.
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http://dx.doi.org/10.1016/j.jacc.2004.04.032DOI Listing
July 2004

Deletion of ribosomal S6 kinases does not attenuate pathological, physiological, or insulin-like growth factor 1 receptor-phosphoinositide 3-kinase-induced cardiac hypertrophy.

Mol Cell Biol 2004 Jul;24(14):6231-40

Beth Israel Deaconess Medical Center, Cardiovascular Division, 330 Brookline Ave., SL-408, Boston, MA 02215, USA.

Ribosomal S6 kinases (S6Ks) have been depicted as critical effectors downstream of growth factor pathways, which play an important role in the regulation of protein synthesis by phosphorylating the ribosomal protein, S6. The goal of this study was to determine whether S6Ks regulate heart size, are critical for the induction of cardiac hypertrophy in response to a pathological or physiological stimulus, and whether S6Ks are critical downstream effectors of the insulin-like growth factor 1 (IGF1)-phosphoinositide 3-kinase (PI3K) pathway. For this purpose, we generated and characterized cardiac-specific S6K1 and S6K2 transgenic mice and subjected S6K1(-/-), S6K2(-/-), and S6K1(-/-) S6K2(-/-) mice to a pathological stress (aortic banding) or a physiological stress (exercise training). To determine the genetic relationship between S6Ks and the IGF1-PI3K pathway, S6K transgenic and knockout mice were crossed with cardiac-specific transgenic mice overexpressing the IGF1 receptor (IGF1R) or PI3K mutants. Here we show that overexpression of S6K1 induced a modest degree of hypertrophy, whereas overexpression of S6K2 resulted in no obvious cardiac phenotype. Unexpectedly, deletion of S6K1 and S6K2 had no impact on the development of pathological, physiological, or IGF1R-PI3K-induced cardiac hypertrophy. These studies suggest that S6Ks alone are not essential for the development of cardiac hypertrophy.
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http://dx.doi.org/10.1128/MCB.24.14.6231-6240.2004DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC434247PMC
July 2004

Inhibition of mTOR signaling with rapamycin regresses established cardiac hypertrophy induced by pressure overload.

Circulation 2004 Jun 7;109(24):3050-5. Epub 2004 Jun 7.

Cardiovascular Division, Department of Medicine, Beth Israel Deaconess Medical Center, 330 Brookline Ave, Boston, Mass 02215, USA.

Background: Rapamycin is a specific inhibitor of the mammalian target of rapamycin (mTOR). We recently reported that administration of rapamycin before exposure to ascending aortic constriction significantly attenuated the load-induced increase in heart weight by approximately 70%.

Methods And Results: To examine whether rapamycin can regress established cardiac hypertrophy, mice were subjected to pressure overload (ascending aortic constriction) for 1 week, echocardiography was performed to verify an increase in ventricular wall thickness, and mice were given rapamycin (2 mg x kg(-1) x d(-1)) for 1 week. After 1 week of pressure overload (before treatment), 2 distinct groups of animals became apparent: (1) mice with compensated cardiac hypertrophy (normal function) and (2) mice with decompensated hypertrophy (dilated with depressed function). Rapamycin regressed the pressure overload-induced increase in heart weight/body weight (HW/BW) ratio by 68% in mice with compensated hypertrophy and 41% in mice with decompensated hypertrophy. Rapamycin improved left ventricular end-systolic dimensions, fractional shortening, and ejection fraction in mice with decompensated cardiac hypertrophy. Rapamycin also altered the expression of some fetal genes, reversing, in part, changes in alpha-myosin heavy chain and sarcoplasmic reticulum Ca2+ ATPase.

Conclusions: Rapamycin may be a therapeutic tool to regress established cardiac hypertrophy and improve cardiac function.
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http://dx.doi.org/10.1161/01.CIR.0000130641.08705.45DOI Listing
June 2004

The insulin-like growth factor 1 receptor induces physiological heart growth via the phosphoinositide 3-kinase(p110alpha) pathway.

J Biol Chem 2004 Feb 3;279(6):4782-93. Epub 2003 Nov 3.

Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, Massachusetts 02215, USA.

Insulin-like growth factor 1 (IGF1) was considered a potential candidate for the treatment of heart failure. However, some animal studies and clinical trials have questioned whether elevating IGF1 chronically is beneficial. Secondary effects of increased serum IGF1 levels on other tissues may explain these unfavorable results. The aim of the current study was to examine the role of IGF1 in cardiac myocytes in the absence of secondary effects, and to elucidate downstream signaling pathways and transcriptional regulatory effects of the IGF1 receptor (IGF1R). Transgenic mice overexpressing IGF1R in the heart displayed cardiac hypertrophy, which was the result of an increase in myocyte size, and there was no evidence of histopathology. IGF1R transgenics also displayed enhanced systolic function at 3 months of age, and this was maintained at 12-16 months of age. The phosphoinositide 3-kinase (PI3K)-Akt-p70S6K1 pathway was significantly activated in hearts from IGF1R transgenics. Cardiac hypertrophy induced by overexpression of IGF1R was completely blocked by a dominant negative PI3K(p110alpha) mutant, suggesting IGF1R promotes compensated cardiac hypertrophy in a PI3K(p110alpha)-dependent manner. This study suggests that targeting the cardiac IGF1R-PI3K(p110alpha) pathway could be a potential therapeutic strategy for the treatment of heart failure.
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http://dx.doi.org/10.1074/jbc.M310405200DOI Listing
February 2004

Phosphoinositide 3-kinase(p110alpha) plays a critical role for the induction of physiological, but not pathological, cardiac hypertrophy.

Proc Natl Acad Sci U S A 2003 Oct 24;100(21):12355-60. Epub 2003 Sep 24.

Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, MA 02215, USA.

An unresolved question in cardiac biology is whether distinct signaling pathways are responsible for the development of pathological and physiological cardiac hypertrophy in the adult. Physiological hypertrophy is characterized by a normal organization of cardiac structure and normal or enhanced cardiac function, whereas pathological hypertrophy is associated with an altered pattern of cardiac gene expression, fibrosis, cardiac dysfunction, and increased morbidity and mortality. The elucidation of signaling cascades that play distinct roles in these two forms of hypertrophy will be critical for the development of more effective strategies to treat heart failure. We examined the role of the p110alpha isoform of phosphoinositide 3-kinase (PI3K) for the induction of pathological hypertrophy (pressure overload-induced) and physiological hypertrophy (exercise-induced) by using transgenic mice expressing a dominant negative (dn) PI3K(p110alpha) mutant specifically in the heart. dnPI3K transgenic mice displayed significant hypertrophy in response to pressure overload but not exercise training. dnPI3K transgenic mice also showed significant dilation and cardiac dysfunction in response to pressure overload. Thus, PI3K(p110alpha) appears to play a critical role for the induction of physiological cardiac growth but not pathological growth. PI3K(p110alpha) also appears essential for maintaining contractile function in response to pathological stimuli.
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http://dx.doi.org/10.1073/pnas.1934654100DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC218762PMC
October 2003