[Show abstract][Hide abstract] ABSTRACT: Pulmonary arterial hypertension (PAH) is a devastating disease characterized by abnormal remodeling of small, peripheral pulmonary arteries. Germline mutations in the bone morphogenetic protein receptor type 2 (BMPR2) gene are a major risk factor for developing PAH. At present, the correlation between the BMPR2 mutation and the patient's prognosis remains controversial despite several investigations. In this study, we explored the functional effects of four BMPR2 mutations to dissect the functional significance of the BMPR2 gene defect. Cellular immunofluorescence assay of four mutants (Tyr67Cys, Thr268fs, Ser863Asn, and Gln433X) revealed that the BMPR2 protein containing Thr268fs, Ser863Asn, or Gln433X exhibited abnormal subcellular localization. The BrdU incorporation and TUNEL assay suggested that any of the BMPR2 mutations Thr268fs, Ser863Asn, or Gln433X could improve endothelial cell apoptosis and decrease cell proliferation. All of the four mutants could inhibit nitric oxide (NO) synthesis in HLMVE cells, and ET-1 levels increased in the cells transfected with mutant Ser863Asn. Our results will improve the understanding of the genotype-phenotype correlations and mechanisms associated with BMPR2 mutations.
PLoS ONE 09/2014; 9(9):e106703. · 3.53 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: Objective
Patients with inherited long QT syndrome (LQTS) are prone to torsade de pointes and sudden death (SD). Identifying affected individuals is important for SD prevention. This study aimed to determine the cause and genotype-phenotype characteristics of LQTS in a large Omani family.
Upon LQTS diagnosis of a 5-year-old girl (proband), targeted mutation screening was performed based on the gene-specific ECG pattern identified in her mother. ECG-guided family genotyping was conducted for identifying additional affected individuals.
ECGs of the proband demonstrated 2:1 AV block, incomplete right bundle branch block (IRBBB) and markedly prolonged QTc (571-638 ms) with bizarre T waves. Cardiac imaging revealed dilatation of the ascending aorta and pulmonary artery, and left ventricular non-compaction. Her parents were first cousins. Both showed mild QT prolongation, with the mother presenting a LQT2 T wave pattern and the father IRBBB. Targeted KCNH2 screening identified a novel homozygous frameshift mutation p.T1019Pfs × 38 in the proband within 72-hour. Family genotyping uncovered 3 concealed LQT2 and confirmed 11 members showing LQT2 ECG patterns as heterozygous mutation carriers. All heterozygous carriers were asymptomatic, with 71% showing normal to borderline prolonged QTc (458 ± 33 ms, range 409-522 ms).
p.T1019Pfs × 38, a novel KCNH2 mutation, has been identified in a large LQTS family in Oman. Consanguineous marriages resulted in a homozygous with severe LQTS. ECG-guided phenotyping and genotyping achieved a high efficiency. Genetic testing is essential in identifying concealed LQTS. Further investigation is warranted to determine if there is a causative relationship between homozygous p.T1019Pfs × 38 and cardiovascular anomaly.
[Show abstract][Hide abstract] ABSTRACT: Background:The effects of levosimendan(Levo) on injury patterns in the immature brain following cardiopulmonary bypass (CPB) are unknown.Methods:Eighteen 3-4 week-old anesthetised lambs, instrumented with vascular catheters, aortic and right carotid artery flow probes, were allocated to non-CPB, CPB or CPB+Levo groups(each n=6). After 120 mins CPB with 90 mins aortic cross-clamp, CPB animals received dopamine, and CPB+Levo animals both dopamine and Levo, for 4 hrs. All lambs then underwent brain MRI, followed by post-mortem brain perfusion fixation for immunohistochemical studies.Results:In CPB lambs, aortic(P<0.05) and carotid artery(P<0.01) blood flows fell by 29% and 30 % between 2-4 hr after cross clamp removal, but were unchanged in the CPB+levo group. No brain injury was detectable with MRI in either CPB or CPB+Levo lambs. However, on immunohistochemical analysis, white matter astrocyte density of both groups was higher than in non-CPB lambs (P<0.05), while white matter microglial density was higher (P<0.05), but markers of cortical oxidative stress less prevalent in CPB+Levo than CPB lambs.Conclusions:While Levo prevented early post-operative falls in cardiac output and carotid artery blood flow in a lamb model of infant CPB, this was associated with heterogenous neuroglial activation and manifestation of markers of oxidative stress.Pediatric Research (2014); doi:10.1038/pr.2014.51.
[Show abstract][Hide abstract] ABSTRACT: Multi-scale modelling is a promising tool for the study of coronary hemodynamics. A key strength of this approach is that it accounts for microvascular properties and extravascular forces that differ regionally and transmurally, as well as wave propagation effects in the conduit arteries. However, little validation of such models has been reported and no models of the newborn coronary circulation have been described. We therefore validated a multi-scale model of the left coronary circulation using high-fidelity data from nine adult sheep and nine newborn lambs, and investigated whether wave propagation effects are more prominent in adults, whose body size (and hence wave transit distance) is greater. The model consisted of a one-dimensional (1D) network of the major conduit arteries and a lumped parameter model of microvascular beds. Intramyocardial pressure was considered to arise via contraction-related myocyte thickening and transmission of ventricular cavity pressure into the heart wall. 1D network geometry from published human anatomical data was scaled using myocardial weights, while subject-specific aortic pressure/flow and ventricular pressure formed model inputs. Total vascular resistance was determined iteratively from measured mean circumflex coronary flow (CxQ), but no fitting of phasic aspects of the waveform was performed. Excellent agreement was obtained between simulated and measured CxQ waveforms in most cases. Detailed flow waveform analysis did not clearly reveal a greater prominence of wave propagation effects in adults compared with newborns. This multi-scale model is likely to be useful for investigating wave phenomena and phasic aspects of coronary flow in adults and during development.
AJP Heart and Circulatory Physiology 12/2013; · 4.01 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: Triggers and exacerbants of cirrhotic cardiomyopathy (CC) are poorly understood, limiting treatment options in patients with chronic liver diseases. Liver transplantation alone reverses some features of CC, but the physiology behind this effect has never been studied.
We aimed to determine whether reversal of liver injury and fibrosis in mouse affects cardiac parameters. The second aim was to determine whether cardiomyopathy can be induced by specifically increasing systemic bile acid (BA) levels.
6-8 week old male C57BL6J mice were fed either chow (n=5) or 3, 5-diethoxycarbonyl-1, 4-dihydroxychollidine (DDC) (n=10) for 3 weeks. At the end of 3 weeks, half the mice in the DDC fed group were randomized to chow (the reversed [REV] group). Serial ECHOs and electrocardiographic analysis was conducted weekly for 6 weeks followed by liver tissue and serum studies. Hearts were analyzed for key components of function and cell signaling. Cardiac physiologic and molecular parameters were similarly analyzed in Abcb11(-/-) mice (n=5/grp) fed 0.5% cholic acid supplemented diet for 1 week.
Mice in the REV group showed normalization of biochemical markers of liver injury with resolution of electrocardiographic and ECHO aberrations. Catecholamine resistance seen in DDC group resolved in the REV group. Cardiac recovery was accompanied by normalization of cardiac troponin-T2 as well as resolution of cardiac stress response at RNA level. Cardiovascular physiologic and molecular parameters correlated with degree of cholanemia. Cardiomyopathy was reproduced in cholanemic BA fed Abcb11(-/-) mice.
Cardiomyopathy resolves with resolution of liver injury, is associated with cholanemia, and can be induced by BA feeding. This article is protected by copyright. All rights reserved.
Liver international: official journal of the International Association for the Study of the Liver 12/2013; · 4.41 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: Most studies have not demonstrated improved survival after prenatal diagnosis of critical congenital heart disease, including hypoplastic left heart syndrome (HLHS). However, the effect of delivery near a cardiac surgical center (CSC), the recommended action after prenatal diagnosis, on HLHS mortality has been poorly investigated.
Using Texas Birth Defects Registry data, 1999-2007, which monitored >3.4 million births, we investigated the association between distance (calculated driving time) from birth center to CSC and neonatal mortality in 463 infants with HLHS. Infants with extracardiac birth defects or genetic disorders were excluded. The associations between prenatal diagnosis, CSC HLHS volume, and mortality were also examined. Neonatal mortality in infants born <10 minutes from a CSC was 21.0%, 10-90 minutes 25.2%, and >90 minutes 39.6% (p for trend <0.001). Prenatal diagnosis alone was not associated with improved survival (p=0.14). In multivariable analysis, birth >90 minutes from a CSC remained associated with increased mortality, OR 2.03 (95%CI 1.19-3.45), compared to <10 minutes. In subanalysis, birth >90 minutes from a CSC was associated with higher pre-transport mortality (OR 6.69, 95%CI 2.52-17.74) and birth 10-90 minutes with higher pre-surgical mortality (OR 4.45, 95%CI 1.17-17.00). Higher surgical mortality was associated with lower CSC HLHS volume (OR per 10 patients 0.88, 95%CI 0.84-0.91).
Infants with HLHS born far from a CSC have increased neonatal mortality, and most of this mortality is pre-surgical. Efforts to improve prenatal diagnosis of HLHS and subsequent delivery near a large volume CSC may significantly improve neonatal HLHS survival.
[Show abstract][Hide abstract] ABSTRACT: The purpose of this study was to describe patient characteristics and outcomes of heart failure (HF)-related intensive care unit (ICU) hospitalizations in children with cardiomyopathy (CM).
A query of the Pediatric Health Information System database, a large administrative and billing database of 43 tertiary children's hospitals, was performed. A total of 17,309 HF-related ICU hospitalizations from 2005 to 2010 of 14,985 children ≤18 years old were analyzed. Of those, 2,058 (12%) hospitalizations for CM-HF in 1,599 (11%) children were identified. Classification into CM subtypes was not possible owing to database limitations. The number of yearly CM-HF hospitalizations significantly increased during the study period (P = .036). Overall mortality was 11%, and cardiac transplantation occurred in 20% of hospitalizations. Mechanical circulatory support (MCS) was used in 261 (13%) of hospitalizations. Renal failure, MCS, respiratory failure, sepsis, and vasoactive medications were associated with mortality on multivariable analysis. Significant comorbidities associated with these hospitalizations included arrhythmias in 42%, renal failure in 13%, cerebrovascular disease in 6%, and hepatic impairment in 5%.
HF-related ICU hospitalizations in children with cardiomyopathy are increasing. These children are at high risk for poor outcomes with an in-hospital mortality of 11%.
Journal of cardiac failure 10/2013; 19(10):672-677. · 3.07 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: Malouf syndrome is a rare congenital disorder involving the heart, genitalia, skin and skeletal characteristics. In the present study, we report on the sporadic case of a young female with dilated cardiomyopathy, hypergonadotropic hypogonadism, a small chin, bilateral blepharoptosis, marfanoid elongated fingers and hypothyroidism. Malouf syndrome may be caused by heterozygous mutations in the lamin A/C (LMNA) gene. Genetic analyses and autopsy were performed. In spite of the patient's features, sequence analysis of the coding region of the LMNA gene including exon‑intron boundaries identified only one benign polymorphism: homozygous silent variant 1698C>T (H566). There is a possibility that the sequence analysis may have not detected intronic mutations or mutations in portions of the 5'- and 3'-untranslated regions, which would confirm the clinical diagnosis.
Molecular Medicine Reports 09/2013; · 1.48 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: We validated a multi-scale model of a left-dominant coronary circulation using high fidelity pressure and flow data acquired in adult sheep and newborn lambs. The model incorporated a one-dimensional representation of the major left conduit coronary arteries, allowing for the study of wave propagation effects. The coronary microvasculature was represented by regional instances of a lumped parameter model consisting of three transmural layers, each with two serial compartments accounting for compliance, resistance and intramyocardial pressure effects. Model inputs comprised measured aortic pressure/flow and ventricular pressure. Minimal data fitting was employed, with only measured mean coronary flow used to iteratively adjust total coronary resistance. The model was adapted to different heart sizes via allometric scaling. Excellent agreement was observed between model and experimental flow waveforms in the proximal circumflex artery, both in terms of the degree of systolic flow impediment and transient waveform features. The proposed multi-scale modelling approach is likely to be useful for studying phasic features of the coronary flow waveform, including coronary waves in different coronary anatomies and throughout development.
Conference proceedings: ... Annual International Conference of the IEEE Engineering in Medicine and Biology Society. IEEE Engineering in Medicine and Biology Society. Conference 07/2013; 2013:3857-3860.
[Show abstract][Hide abstract] ABSTRACT: Objective: Barth syndrome is an X-linked recessive disorder characterized by dilated cardiomyopathy, neutropenia, 3-methylglutaconic aciduria, abnormal mitochondria, variably expressed skeletal myopathy, and growth delay. The disorder is caused by mutations in the tafazzin (TAZ/G4.5) gene located on Xq28. We report a novel exonic splicing mutation in the TAZ gene in a patient with atypical Barth syndrome. Patient & Methods: The 4-month-old proband presented with respiratory distress, neutropenia, and dilated cardiomyopathy with reduced ejection fraction of 10%. No 3-methylglutaconic aciduria was detected on repeated urine organic acid analyses. Family history indicated that his maternal uncle died of endocardial fibroelastosis and dilated cardiomyopathy at 26 months. TAZ DNA sequencing, mRNA analysis, and cardiolipin analysis were performed. Results: A novel nucleotide substitution c.553A>G in exon 7 of the TAZ gene was identified in the proband, predicting an amino acid substitution p.Met185Val. However, this mutation created a new splice donor signal within exon 7 causing mis-splicing of the message, producing two messages that only differ in the presence/absence of exon 5; these retain intron 6 and have only 11 bases of exon 7. Cardiolipin analysis confirmed the loss of tafazzin activity. The proband's mother, maternal aunt, and grandmother carry the same mutation. Conclusions: The identification of a TAZ gene mutation, mRNA analysis, and monolysocardiolipin/cardiolipin ratio determination were important for the diagnosis and genetic counseling in this family with atypical Barth syndrome that was not found to be associated with 3-methylglutaconic aciduria.
[Show abstract][Hide abstract] ABSTRACT: OBJECTIVE: The myocardial protective effect of remote ischemic preconditioning has been demonstrated in heterogeneous groups of patients undergoing cardiac surgery. No studies have examined this technique in neonates. The present study was performed to examine the remote ischemic preconditioning efficacy in this high-risk patient group. METHODS: A preliminary, randomized, controlled trial was conducted to investigate whether remote ischemic preconditioning in cyanosed neonates undergoing cardiac surgery confers protection against cardiopulmonary bypass. Two groups of neonates undergoing cardiac surgery were recruited for the present study: patients with transposition of the great arteries undergoing the arterial switch procedure and patients with hypoplastic left heart syndrome undergoing the Norwood procedure. The subjects were randomized to the remote ischemic preconditioning or sham control groups. Remote ischemic preconditioning was induced by four 5-minute cycles of lower limb ischemia and reperfusion using a blood pressure cuff. Troponin I and the biomarkers for renal and cerebral injury were measured pre- and postoperatively. RESULTS: A total of 39 neonates were recruited-20 with transposition of the great arteries and 19 with hypoplastic left heart syndrome. Of the 39 neonates, 20 were randomized to remote ischemic preconditioning and 19 to the sham control group. The baseline demographics appeared similar between the randomized groups. The cardiopulmonary bypass and crossclamp times were not significantly different between the 2 groups. The troponin I levels were not significantly different at 6 hours after cardiopulmonary bypass nor were the postoperative inotrope requirements. Markers of renal (neutrophil gelatinase-associated lipocalin) and cerebral injury (S100b, neuron-specific enolase) were not significantly different between the 2 groups. CONCLUSIONS: Our data suggest that remote ischemic preconditioning in hypoxic neonates undergoing cardiopulmonary bypass surgery does not provide myocardial, renal, or neuronal protection. Additional studies are needed to examine the relationships among developmental age, hypoxia, and the molecular mechanisms of ischemic preconditioning.
The Journal of thoracic and cardiovascular surgery 02/2013; · 3.41 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: A writing group sponsored by the Council on Cardiopulmonary, Critical Care, Perioperative and Resuscitation, the Council on Clinical Cardiology, the Council on Cardiovascular Nursing, and the Council on Quality of Care and Outcomes Research of The American Heart Association has recently formulated a roadmap to meet the changing needs of the patient with cardiovascular disease requiring critical care. Although this roadmap has been formulated primarily to address the care needs of the adult with critical cardiovascular disease, it contains useful lessons pertinent to the care of the patient with pediatric and congenital cardiovascular disease. In this document, we have examined The Statement and applied its framework to the evolving field of pediatric cardiac critical care.
[Show abstract][Hide abstract] ABSTRACT: BACKGROUND: After repair of tetralogy of Fallot, some patients experience a low cardiac output state owing to right ventricular diastolic failure. Negative-pressure ventilation has been shown to improve cardiac output in these patients. What has not been evaluated is the effect of extubation and loading of the respiratory muscles on the distribution of cardiac output after repair of tetralogy of Fallot. METHODS: In 23 consecutive patients undergoing repair of tetralogy of Fallot, standard hemodynamic variables, central venous oxygen saturations, and near infrared spectroscopy of the brain, mesenteric, and renal circulations were monitored for 30 minutes before and after extubation. RESULTS: With extubation, the systolic blood pressure increased significantly from 96 ± 11 to 106 ± 15 mm Hg (p = 0.002) while the heart rate remained unchanged. With extubation, the central venous oxygen saturation increased significantly from 65% ± 7% to 70% ± 10% (p = 0.003). Cerebral oxygen saturations increased significantly from 67% ± 10% to 72% ± 9% (p = 0.0001), whereas mesenteric oxygenation fell significantly from 74% ± 15% to 72% ± 15% (p = 0.04). Renal oxygenation was unaffected by extubation. CONCLUSIONS: Cardiac output and cerebral oxygenation increased significantly during spontaneous respiration, the latter suggesting that the brain was in or approaching an oxygen supply-dependent state before extubation. Despite the increase in cardiac output, the presumed increase in respiratory pump perfusion, as well as the concurrent increase in cerebral perfusion, came at the expense of mesenteric perfusion. Renal oxygenation remained unchanged with extubation.
The Annals of thoracic surgery 09/2012; · 3.45 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: Clinically significant cardiovascular malformations (CVMs) occur in 5-8 per 1000 live births. Recurrent copy number variations (CNVs) are among the known causes of syndromic CVMs, accounting for an important fraction of cases. We hypothesized that many additional rare CNVs also cause CVMs and can be detected in patients with CVMs plus extracardiac anomalies (ECAs). Through a genome-wide survey of 203 subjects with CVMs and ECAs, we identified 55 CNVs >50 kb in length that were not present in children without known cardiovascular defects (n=872). Sixteen unique CNVs overlapping these variants were found in an independent CVM plus ECA cohort (n=511), which were not observed in 2011 controls. The study identified 12/16 (75%) novel loci including non-recurrent de novo 16q24.3 loss (4/714) and de novo 2q31.3q32.1 loss encompassing PPP1R1C and PDE1A (2/714). The study also narrowed critical intervals in three well-recognized genomic disorders of CVM, such as the cat-eye syndrome region on 22q11.1, 8p23.1 loss encompassing GATA4 and SOX7 and 17p13.3-p13.2 loss. An analysis of protein-interaction databases shows that the rare inherited and de novo CNVs detected in the combined cohort are enriched for genes encoding proteins that are direct or indirect partners of proteins known to be required for normal cardiac development. Our findings implicate rare variants such as 16q24.3 loss and 2q31.3-q32.1 loss, and delineate regions within previously reported structural variants known to cause CVMs.European Journal of Human Genetics advance online publication, 29 August 2012; doi:10.1038/ejhg.2012.155.
European journal of human genetics: EJHG 08/2012; · 3.56 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: In one-dimensional (1D) models of arterial networks, branch junctions are represented by flow and mechanical energy (or total pressure, i.e. p + 1/2ρu2) coupling conditions. The flow condition simply ensures conservation of mass, but the pressure condition is less trivial because pressure losses are known to occur in the vicinity of junctions, caused by regions of complex flow that depend on the vascular geometry and prevailing flow patterns. These losses are commonly ignored in 1D models under the assumption that area ratios and branching angles of arterial junctions are optimally designed. However, one setting where pressure losses are likely to be important is the junction of the ductus arteriosus (DA) with the aorta in the fetus, considering the high kinetic energy of blood in the DA , the acute angle between the aortic isthmus (Aols) and DA, and the redirection of DA blood flow towards the descending aorta (DAo, Figure 1). Previously, pressure losses have been approximated in 1D models by enforcing continuity of static (rather than total) pressure  or by using empirical loss coefficients obtained from experiments in 90 degree T-tubes . In the current study, we implemented a loss formulation described by Bassett et al  for 1D gas dynamics simulations, which unlike previous methods, can be used to model junctions with any number of branches and any orientation of branch angles, and explicitly accounts for the influence of area and flow ratios on pressure losses. Results of the model are validated against high fidelity measurements in fetal lambs.
[Show abstract][Hide abstract] ABSTRACT: Passive immunisation with palivizumab is recommended in many countries for children with haemodynamically significant cardiac disease. We trialled respiratory syncytial virus (RSV) immunoprophylaxis in such infants during 2008–2009.
We identified all RSV admissions between 2005–2009 and examined all patients with significant cardiac disease who received palivizumab in 2008–2009.
Infants with symptomatic cardiac disease had a more complicated course of RSV bronchiolitis with longer hospital stay, more frequent intensive care admission, longer intensive care stay and were more likely to receive respiratory support (all P < 0.05). One hundred seventeen infants with symptomatic cardiac disease received palivizumab. Of these, two (1.7%) required admission for RSV bronchiolitis. Overall, there was a reduction in admission of infants with symptomatic cardiac disease with RSV bronchiolitis in 2008–2009 (2% per year) compared with 2005–2007 (5–9% per year; P < 0.03). The number of patients with symptomatic cardiac disease who required intensive care for RSV bronchiolitis in the same period was unchanged, as a number presented to our service with RSV infection prior to commencing immunoprophylaxis or having had their cardiac diagnosis made in other centres.
Compared with other infants, those with haemodynamically significant cardiac disease have a more complicated course of illness with RSV bronchiolitis. In these infants, palivizumab reduced the number of hospitalisations because of RSV. Cohorting patients for maximal palivizumab use reduced overall cost. To significantly impact on intensive care admissions overall, immunoprophylaxis should be considered at a regional level.
Journal of Paediatrics and Child Health 05/2012; 48(5):395-401. · 1.19 Impact Factor