Publications by authors named "John C Galati"

37 Publications

Risk Factors for Peri-Procedural Arterial Ischaemic Stroke in Children with Cardiac Disease.

Pediatr Cardiol 2017 Oct 11;38(7):1385-1392. Epub 2017 Jul 11.

Department of Neurology, Royal Children's Hospital, Murdoch Children's Research Institute, 50 Flemington Road, Parkville, VIC, 3052, Australia.

Improved survival of children with congenital heart disease has led to increasing focus on neurodevelopmental outcome, as close to half of the infants undergoing cardiac surgery are affected by neurodevelopmental disability. Stroke is particularly important as it frequently results in permanent neurologic sequelae. The aim of this study was to investigate risk factors for peri-procedural arterial ischaemic stroke (AIS) in children with cardiac disease. A retrospective case-control analysis of children aged <18 years with radiologically confirmed AIS following a cardiac procedure admitted to the Royal Children's Hospital Melbourne between 1993 and 2010. Each case was matched with two controls with similar cardiac diagnosis, procedure type, age and date of procedure. Demographics and peri-procedural data were collected from medical records and departmental database. Fifty-two cases were identified. Multivariable analysis identified post-procedural infection (OR 6.1, CI 1.3-27, p = 0.017) and length of ICU stay (OR 4.0, CI 1.4-11, p = 0.009) as risk factors for AIS. Although the study is limited to a single-centre cohort, length of ICU stay and post-procedural infection were identified as risk factors for AIS. These findings demonstrate these factors to be important areas to focus attention for stroke prevention in children with cardiac disease.
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http://dx.doi.org/10.1007/s00246-017-1674-xDOI Listing
October 2017

No difference between aspirin and warfarin after extracardiac Fontan in a propensity score analysis of 475 patients.

Eur J Cardiothorac Surg 2016 Nov 26;50(5):980-987. Epub 2016 May 26.

Department of Cardiac Surgery, Royal Children's Hospital, Melbourne, Australia

Objectives: The most effective method of long-term thromboprophylaxis after the Fontan procedure is not clear. We compared the rates of thromboembolic events between patients receiving aspirin and warfarin after an extracardiac conduit Fontan procedure in a bi-national registry.

Methods: All patients who underwent an extracardiac conduit Fontan procedure from 1997 to 2010 in Australia and New Zealand were identified. Medication status and routine follow-up and echocardiographic data were obtained from all patients. Survival analysis with propensity score matching and adjustment was performed to determine the treatment effect of warfarin compared with that of aspirin beyond the first year of follow-up, after which time patients had settled on their long-term thromboprophylaxis strategy.

Results: Of 570 eligible patients, the data of 475 patients who were regularly followed up without mechanical valve replacement were available for analysis. Long-term thromboprophylaxis consisted of warfarin in 301 patients (63%), aspirin in 157 (33%) and none in 17 (4%). The 10-year rate of freedom from all thromboembolic events was 91% [95% confidence interval (CI) 88-94%]. Thromboembolic events beyond the first year of follow-up occurred in 18 patients (6 on aspirin and 12 on warfarin). After (i) propensity score adjustment and (ii) matching yielding 164 pairs, the hazard rates of thromboembolic events beyond the first year were not statistically different between the warfarin and aspirin groups [(i) hazard ratio (HR) 2.3, 95% CI 0.7-7.4, P = 0.2 and (ii) HR 1.5, 95% CI 0.5-4.7, P = 0.5, respectively].

Conclusions: No difference in the hazard rates of late thromboembolic events was observed between aspirin and warfarin beyond the first year after the extracardiac conduit Fontan procedure.
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http://dx.doi.org/10.1093/ejcts/ezw159DOI Listing
November 2016

Arterial ischemic stroke in children with cardiac disease.

Neurology 2015 Dec 25;85(23):2053-9. Epub 2015 Sep 25.

From the Department of Neurology (M.C., B.S., M.T.M.), Royal Children's Hospital, Murdoch Childrens Research Institute, and the Department of Paediatrics, University of Melbourne; Department of Cardiology (H.A., D.H., M.M.H.C.), Royal Children's Hospital, Heart Research Group, Murdoch Childrens Research Institute, and the Department of Paediatrics, University of Melbourne; and the Clinical Epidemiology and Biostatistics Unit (J.C.G.), Murdoch Childrens Research Institute, and the Department of Mathematics and Statistics, La Trobe University, Melbourne, Australia.

Objective: To describe the spectrum of cardiac disorders, timing in relation to interventional procedures, and outcome in children with cardiac disease and arterial ischemic stroke (AIS).

Methods: Children younger than 18 years with cardiac disease and radiologically confirmed AIS admitted to the Royal Children's Hospital Melbourne between 1993 and 2010 were retrospectively identified using ICD-9 and ICD-10 searches.

Results: Seventy-six children with cardiac disease and radiologically confirmed AIS were identified with the median age at diagnosis of 5 months (interquartile range 0-58). Cardiac lesions included cyanotic congenital heart disease (CHD) in 42 (55%), acyanotic heart disease in 24 (29%), cardiomyopathies/myocarditis in 6 (8%), infective endocarditis in 3 (4%), and primary arrhythmias in 3 (4%). Stroke occurred following cardiac procedures in 52 patients (68%): 41 post cardiac surgery (4.6 strokes per 1,000 surgical procedures) and 11 post cardiac catheterization (1.7 strokes per 1,000 catheterizations). The median time from procedure to diagnosis of stroke was 3 days (interquartile range 2-7), with 68% (95% confidence interval 58%-79%) of strokes estimated to occur within the periprocedural period. Prevalence of periprocedural stroke varied by diagnostic category, but was most common in patients with cyanotic CHD undergoing palliative surgery (22/2,256, 1%) (p < 0.005). There were 3 AIS-related deaths, and 54 survivors (84%) had persisting neurologic deficits.

Conclusions: Infants with cyanotic CHD were most frequently affected by AIS during the periprocedural period. Prospective cohort studies are required to determine effective primary and secondary prevention strategies.
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http://dx.doi.org/10.1212/WNL.0000000000002036DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4676756PMC
December 2015

Ten-year outcomes of Fontan conversion in Australia and New Zealand demonstrate the superiority of a strategy of early conversion.

Eur J Cardiothorac Surg 2016 Feb 2;49(2):530-5; discussion 535. Epub 2015 Apr 2.

Murdoch Children's Research Institute, Melbourne, VIC, Australia Department of Paediatrics, Faculty of Medicine, University of Melbourne, Melbourne, VIC, Australia The Royal Children's Hospital, Melbourne, VIC, Australia

Objective: To investigate the benefits of a strategy of early Fontan conversion.

Methods: Using the Australia and New Zealand Fontan Registry, retrospective analysis of their long-term follow-up data was performed.

Results: Between 1990 and 2014, a total of 39 patients underwent surgical conversion in 6 centres at a median age of 23.8 years (IQR: 19.3-28.2), 18.7 ± 5.0 years post-Fontan. One centre tended to perform conversion earlier: interval since first documented arrhythmia 2.9 ± 4.0 vs 4.0 ± 4.2 years, average NYHA Class 2 ± 0.4 vs 3 ± 0.9 (P = 0.008), mean number of preop anti-arrhythmics 1 ± 0.4 vs 2 ± 0.6 (P = 0.05). Two patients underwent conversion to an extracardiac conduit only, while 36 had concomitant right atrial cryoablation, of which 16 also had pacemaker implantation. Nine patients suffered major cardiac-related complications (7 low output syndrome, 3 ECMO, 3 acute renal failure, one stroke) (2/17 from the early conversion centre and 7/22 of the others; P = 0.14). Four patients died in hospital (10.3%) and 4 late after a median of 0.9 years [95% confidence interval (CI): 0.5-1] after conversion. An additional 2 patients needed transplantation at 1 and 8.8 years after conversion, respectively. The 10-year freedom from heart transplantation was 86% (95% CI: 51-97%). Outcomes from the centre with an early conversion strategy were significantly better: 8-year freedom from death or heart transplantation was 86% (95% CI: 53-96) vs 51% (95% CI: 22-74; log-rank P = 0.007). Eight additional patients required pacemaker implantation and 5 had arrhythmia recurrence.

Conclusions: Fontan conversion is associated with lasting survival outcomes up to 10 years after conversion. A strategy of surgical conversion at earlier stage of failure may be associated with better survival free from transplantation.
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http://dx.doi.org/10.1093/ejcts/ezv112DOI Listing
February 2016

Survival into adulthood of patients with atrial isomerism undergoing cardiac surgery.

J Thorac Cardiovasc Surg 2015 Jun 24;149(6):1509-13. Epub 2015 Jan 24.

Department of Cardiac Surgery, Royal Children's Hospital, Melbourne, Australia; Department of Pediatrics, University of Melbourne, Melbourne, Australia; Murdoch Children's Research Institute, Melbourne, Australia. Electronic address:

Objectives: To identify determinants of adverse outcomes in patients with atrial isomerism.

Methods: Determinants of survival were analyzed for the group as a whole as well as separately for left and right atrial isomerism.

Results: There were 78 cases with right and 104 with left atrial isomerism. Nineteen patients were not offered surgery; 49 (47%) of those with left atrial isomerism and 60 (77%) with right atrial isomerism were directed to single ventricle palliation. A total of 67 patients died. Survival to 25 years was 62% (95% confidence interval [CI], 53%-69%). Independent predictors of mortality were obstructed total anomalous pulmonary venous drainage (P < .001; hazard ratio [HR], 5.2; 95% CI, 2.7-9.7) and asplenia (P = .008; HR, 2; 95% CI, 1.2-3.3). There was no evidence that patients born in the recent era had improved survival (P = .47; HR, 1.1; 95% CI, 0.8-1.5). Survival was better for patients with left than right atrial isomerism: 18 years survival 74% (95% CI, 63%-82%) versus 50% (95% CI, 38%-60%). Independent predictors of mortality for patients with left atrial isomerism were dextrocardia (P = .009; HR, 3.0; 95% CI, 1.3-6.7) and pulmonary stenosis (P = .042; HR, 0.3; 95% CI, 0.1-0.9) and patients with right atrial isomerism, biventricular repair (P < .001; HR, 6.0; 95% CI, 2.8-13), and obstructed total anomalous pulmonary venous drainage (P < .001; HR, 4.2; 95% CI, 2.0-8.6).

Conclusions: A significant proportion of patients with isomerism still die before reaching adulthood. Only a fraction of those with obstructed pulmonary veins survive. Having biventricular repair does not confer a survival advantage to those born with right atrial isomerism.
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http://dx.doi.org/10.1016/j.jtcvs.2015.01.038DOI Listing
June 2015

Medium-term outcomes of bovine jugular vein graft and homograft conduits in children.

ANZ J Surg 2015 May 23;85(5):381-5. Epub 2015 Feb 23.

Department of Cardiac Surgery, Royal Children's Hospital, Melbourne, Victoria, Australia.

Background: The bovine jugular vein (Contegra) conduit has been described as an alternative to the homograft for right ventricle (RV) to pulmonary artery (PA) connection. We assessed the outcomes of Contegra conduits and homografts at a single institution.

Methods: We conducted a retrospective review of children (n = 249) who underwent RV-to-PA conduit (Contegra or homograft) implantation from 2001 to 2011.

Results: Median operation age was 4.8 years (2 days-18 years). Indications for surgery were as follows: primary conduit insertion (n = 131; 53%), previous conduit failure (n = 57; 23%) or Ross procedure (n = 61; 25%). There were 113 (45%) Contegra conduits and 136 (55%) homografts (92 pulmonary, 44 aortic) inserted. Early mortality was 5% (n = 12). Overall survival was 89% (95% confidence interval (CI): 84-92%) at 5 years and 87% (95% CI: 81-92%) at 10 years. Mortality was associated with smaller conduit size (P = 0.044) and syndrome diagnosis (P = 0.012). Freedom from reoperation was 85% (95% CI: 77-91%) and 75% (95% CI: 59-86%) at 5 years for homografts and Contegra conduits, respectively. Patients required conduit replacement (15%) for endocarditis (n = 4; 11%) or graft failure (n = 34; 89%). Eleven patients developed distal conduit stenosis with the majority occurring in Contegra conduits (n = 7; 64%) (P = 0.004). A larger conduit (P = 0.007) was protective against reoperation. There was no difference in reoperation between conduits (P = 0.41). Mean follow-up was 5 ± 3.2 years (96% complete). Majority of survivors (99%) were in New York Heart Association Class II/I.

Conclusion: The Contegra conduit and homograft demonstrate similar mid-term outcomes in children. Smaller conduit size is associated with higher graft failure and mortality.
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http://dx.doi.org/10.1111/ans.13018DOI Listing
May 2015

New engineering treatment of bovine pericardium confers outstanding resistance to calcification in mitral and pulmonary implantations in a juvenile sheep model.

J Thorac Cardiovasc Surg 2014 Dec 7;148(6):3194-201. Epub 2014 Aug 7.

Fremantle Heart Institute, Fremantle Hospital, School of Surgery, University of Western Australia, Perth, Western Australia, Australia; Department of Cardiothoracic Surgery, Fremantle Hospital, School of Surgery, University of Western Australia, Perth, Western Australia, Australia.

Objective: To conduct a test of noninferiority for CardioCel (Admedus, Brisbane, Australia), a chemically engineered bovine pericardium over autologous pericardium treated intraoperatively with glutaraldehyde in a chronic juvenile sheep model of pulmonary valve (PV) and mitral valve (MV) reconstruction.

Methods: We replaced the posterior leaflet of the MV and of 1 PV cusp with patches in ewes aged 10 months. There were 2 groups: CardioCel (n = 6) and control (n = 4). All valves were competent. Echocardiography was performed before euthanasia. The collected data were function, macroscopy, histology, and calcium contents. The primary end points were thickening and calcium content.

Results: All animals survived until sacrifice after 7 months. The valves had normal echo. The macroscopic aspect of the valves was excellent. Examination of the slides for both groups revealed a continuous endothelium on both sides of the patch and a layer of new collagen developed on both sides between patch and endothelium and interstitial cells and smooth muscle cell in these layers. The patch had not thickened but the 2 layers of new collagen for the PV showed a median thickening of 37% in the CardioCel group and 111% in the control group (P = .01), and for the MV a thickening of 108% and 251%, respectively, was seen (P = .01). The median calcium content in the PV was 0.24 μg/mg (range, 0.19-0.30) in the CardioCel group versus 0.34 μg/mg (range, 0.24-0.62) in controls (P = .20). In the MV it was 0.46 μg/mg (range, 0.30-1.0) in the CardioCel group and 0.47 μg/mg (range, 0.29-1.9) in controls (P = 1.0).

Conclusions: In this growing lamb model the CardioCel patch allowed accurate valve repair at both systemic and pulmonary pressure. The mechanical properties of CardioCel after 7 months were preserved with a more controlled healing than the treated autologous pericardium and without calcification.
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http://dx.doi.org/10.1016/j.jtcvs.2014.08.002DOI Listing
December 2014

Redefining expectations of long-term survival after the Fontan procedure: twenty-five years of follow-up from the entire population of Australia and New Zealand.

Circulation 2014 Sep;130(11 Suppl 1):S32-8

From the Department of Cardiac Surgery (Y.d., A.J.I.) and Department of Cardiology (R.G.W.), Royal Children's Hospital, Melbourne, Victoria, Australia; Murdoch Childrens Research Institute, Melbourne, Victoria, Australia (Y.d., A.J.I, J.C.G.); Department of Paediatrics, Faculty of Medicine, The University of Melbourne, Melbourne, Victoria, Australia (A.J.I., R.G.W.); Department of Mathematics & Statistics, La Trobe University, Melbourne, Victoria, Australia (J.C.G.); Heart Centre for Children, The Children's Hospital at Westmead, Sydney, New South Wales, Australia (R.G.W., G.F.S., D.S.W.); Department of Cardiology, Women's and Children's Hospital, Adelaide, South Australia, Australia (G.R.W.); Children's Cardiac Centre, Princess Margaret Hospital for Children, Perth, Western Australia, Australia (A.B); Paediatric Cardiology, Queensland Paediatric Cardiac Service, Mater Children's Hospital, Brisbane, Queensland, Australia (R.N.J.); Department of Cardiology, The Royal Melbourne Hospital, Melbourne, Victoria, Australia (L.E.G.); Paediatric Cardiology Services, Monash Heart, Monash Health, Melbourne, Victoria, Australia (S.H.); Department of Medicine, Monash University, Melbourne, Australia (S.H.); Adult Congenital Heart Disease Unit, The Prince Charles Hospital, Brisbane, Queensland, Australia (D.J.R.); Green Lane Paediatric and Congenital Cardiac Service, Starship Children's Hospital, Auckland, New Zealand (T.L.G.); Department of Cardiology, Royal Prince Alfred Hospital, Sydney, New South Wales, Australia (D.S.C.); Department of Medicine, The University of Sydney, New South Wales, Australia (D.S.C.); The University of Notre Dame, Sydney, New South Wales, Australia (V.F.); on behalf of the Australia and New Zealand Fontan Registry.

Background: The life expectancy of patients undergoing a Fontan procedure is unknown.

Methods And Results: Follow-up of all 1006 survivors of the 1089 patients who underwent a Fontan procedure in Australia and New Zealand was obtained from a binational population-based registry including all pediatric and adult cardiac centers. There were 203 atriopulmonary connections (AP; 1975-1995), 271 lateral tunnels (1988-2006), and 532 extracardiac conduits (1997-2010). The proportion with hypoplastic left heart syndrome increased from 1/173 (1%) before 1990 to 80/500 (16%) after 2000. Survival at 10 years was 89% (84%-93%) for AP and 97% (95% confidence interval [CI], 94%-99%) for lateral tunnels and extracardiac conduits. The longest survival estimate was 76% (95% CI, 67%-82%) at 25 years for AP. AP independently predicted worse survival compared with extracardiac conduits (hazard ratio, 6.2; P<0.001; 95% CI, 2.4-16.0). Freedom from failure (death, transplantation, takedown, conversion to extracardiac conduits, New York Heart Association III/IV, or protein-losing enteropathy/plastic bronchitis) 20 years after Fontan was 70% (95% CI, 63%-76%). Hypoplastic left heart syndrome was the primary predictor of Fontan failure (hazard ratio, 3.8; P<0.001; 95% CI, 2.0-7.1). Ten-year freedom from failure was 79% (95% CI, 61%-89%) for hypoplastic left heart syndrome versus 92% (95% CI, 87%-95%) for other morphologies.

Conclusions: The long-term survival of the Australia and New Zealand Fontan population is excellent. Patients with an AP Fontan experience survival of 76% at 25 years. Technical modifications have further improved survival. Patients with hypoplastic left heart syndrome are at higher risk of failure. Large, comprehensive registries such as this will further improve our understanding of late outcomes after the Fontan procedure.
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http://dx.doi.org/10.1161/CIRCULATIONAHA.113.007764DOI Listing
September 2014

Repair of partial atrioventricular septal defect: a 37-year experience.

Eur J Cardiothorac Surg 2015 May 2;47(5):796-802. Epub 2014 Aug 2.

Cardiac Surgery Unit, The Royal Children's Hospital, Melbourne, Australia The University of Melbourne, Melbourne, Australia Murdoch Children's Research Institute, Melbourne, Australia.

Objectives: Partial atrioventricular septal defect (pAVSD) is routinely repaired with a low mortality. However, limited data are available on the long-term follow-up of these patients. The current study was designed to determine long-term survival and morbidity of a large cohort of patients operated on at a single institution.

Methods: From 1975 to 2012, 249 consecutive patients underwent pAVSD repair at the Royal Children's Hospital. The follow-up data were obtained from hospital records, correspondence with cardiologists and primary care physicians, patient surveys and the state death registry.

Results: The early mortality rate was 1.2% (3/249), while the long-term survival rate was 96% (95% CI: 93-98%) at 10 years and 94% (95% CI: 89-97%) at 30 years. Freedom from reoperation was 84% at 10 years and 75% at 30 years. The most common reoperations were left atrioventricular valve surgery (30/249, 12.1%), resection of left ventricular outflow tract obstruction (12/249, 4.8%) and closure of residual atrial septal defects (5/249, 2.0%). Implantation of a permanent pacemaker was required in 3.2% (8/249) of patients. Despite a substantial reoperation rate, only 43% of patients older than 18 years of age were seen by a cardiologist within the most recent 2 years of the study period, compared with 80% of those younger than 18 years (P < 0.001).

Conclusions: Repair of pAVSD is performed with a low mortality and excellent long-term survival. However, a substantial reoperation rate warrants close follow-up into adulthood.
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http://dx.doi.org/10.1093/ejcts/ezu286DOI Listing
May 2015

End-to-side repair for aortic arch lesions offers excellent chances to reach adulthood without reoperation.

Ann Thorac Surg 2014 Oct 17;98(4):1405-11. Epub 2014 Jul 17.

Department of Cardiac Surgery, The Royal Children's Hospital, Melbourne, Victoria, Australia; Department of Cardiology, The Royal Children's Hospital, Melbourne, Victoria, Australia; Department of Pediatrics, University of Melbourne, Melbourne, Victoria, Australia. Electronic address:

Background: The purpose of this study was to determine the rate of reinterventions from birth to adulthood after end-to-side anastomosis technique for interrupted and hypoplastic aortic arches. Multicenter data have shown that more than half of patients require arch reintervention in the 2 decades after repair.

Methods: The follow-up of 170 consecutive patients undergoing end-to-side repair through sternotomy for interrupted aortic arch (95) or coarctation (75) in one institution between 1985 and 2012 was reviewed. Associated lesions included ventricular septal defect (143) and bicuspid aortic valve (50). One-stage repair was performed in 158 patients (93%).

Results: There were 12 hospital deaths (7%), and 4 early arch reinterventions (2 for bronchial compression). Eleven hospital survivors (7%) were lost to follow-up. After a mean of 10 ± 6 years, there were 9 late deaths. Eighteen-year survival was 93% (95% confidence interval: 87 to 96). Eight patients had bronchial compression, 5 during initial stay and 3 after hospital discharge; 2 of them required surgery. Eighteen-year freedom from arch reoperation was 87% (95% confidence interval: 76 to 93). An additional 10 patients underwent balloon dilation, for an 18-year freedom from reintervention (balloon dilation or surgery) of 77% (95% confidence interval: 65 to 85). At last follow-up, 24 patients (16%) had an echocardiographic gradient greater than 25 mm Hg. Blood pressure was recorded in 105 patients, and only 11 (10%) were hypertensive.

Conclusions: The end-to-side anastomosis technique for repair of aortic arch lesions results in a low rate of mortality, arch reoperation, and late hypertension. The development of arch obstruction requiring balloon dilation warrants continuous follow-up of these patients.
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http://dx.doi.org/10.1016/j.athoracsur.2014.05.007DOI Listing
October 2014

Impact of Blalock-Taussig shunt size on tricuspid regurgitation in hypoplastic left heart syndrome.

Ann Thorac Surg 2014 Jun 14;97(6):2123-8. Epub 2014 Apr 14.

Department of Cardiology, Royal Children's Hospital, Melbourne, Victoria, Australia; Heart Research Group, Murdoch Children's Research Institute, Melbourne, Victoria, Australia; Department of Pediatrics, University of Melbourne, Melbourne, Victoria, Australia.

Background: The prognosis for hypoplastic left heart syndrome (HLHS) has greatly improved over the past years, but there is still a significant risk of interstage mortality. Tricuspid valve regurgitation (TR) is known to be a risk factor for interstage mortality. We hypothesized that a modified Blalock-Taussig (BT) shunt with a smaller diameter would lead to a reduction in ventricular volume loading with a consequent reduction in TR.

Methods: A retrospective review of all patients with HLHS who had a Norwood procedure in our institution between 2006 and 2011 was performed. Patient demographic, echocardiographic, cardiac magnetic resonance imaging, and operative data were reviewed. The impact of BT shunt diameter on severity of TR at the time of bidirectional cavopulmonary connection (BCPC) was analyzed.

Results: Sixty-four neonates with HLHS underwent a Norwood procedure with a BT shunt. Thirty-two had a 3.5-mm BT shunt (3.5-mm group), and 32 had a 3.0-mm BT shunt (3.0-mm group). Survival to BCPC was 53 of 64 patients (83%) overall, with 25 of 32 patients (78%) in the 3.5-mm group and 28 of 32 (88%) in the 3.0-mm group (p = 0.51). The prevalence of significant TR (moderate or higher) before BCPC was 9 of 25 patients (36%) in the 3.5-mm group and 2 of 28 patients (7%) in the 3.0-mm group (odds ratio = 7.3; 95% confidence interval: 1.4-38; p = 0.018). Tricuspid valve repair was performed in 4 of 25 patients (16%) in the 3.5-mm group and 2 of 28 patients (7%) in the 3.0-mm group (p = 0.21).

Conclusions: A smaller-diameter BT shunt reduces the prevalence of significant TR at the time of BCPC. Further investigation and long-term follow-up are required to determine potential complications of this surgical strategy.
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http://dx.doi.org/10.1016/j.athoracsur.2014.02.032DOI Listing
June 2014

The extracardiac conduit Fontan procedure in Australia and New Zealand: hypoplastic left heart syndrome predicts worse early and late outcomes.

Eur J Cardiothorac Surg 2014 Sep 26;46(3):465-73; discussion 473. Epub 2014 Feb 26.

Department of Cardiac Surgery, Royal Children's Hospital, Melbourne, VIC, Australia Murdoch Childrens Research Institute, Melbourne, VIC, Australia Department of Paediatrics, Faculty of Medicine, The University of Melbourne, Melbourne, VIC, Australia.

Objectives: To identify factors associated with hospital and long-term outcomes in a binational cohort of extracardiac conduit (ECC) Fontan recipients.

Methods: All patients who underwent an ECC Fontan procedure from 1997 to 2010 in Australia and New Zealand were identified, and perioperative, follow-up, echocardiographic and reintervention data collected. Risk factors for early and late mortality, failure and adverse outcomes were analysed.

Results: A total of 570 patients were identified, and late follow-up was available in 529 patients. The mean follow-up was 6.7 years (standard deviation: 3.5) and completeness of the follow-up was 98%. There were seven hospital mortalities (1%) and 21 patients (4%) experienced early failure (death, Fontan takedown/revision or mechanical circulatory support). Prolonged length of stay occurred in 10% (57 patients), and prolonged effusions in 9% (51 patients). Overall survival at 14 years was 96% (95% confidence interval [CI]: 93-98%), and late survival for patients discharged with intact Fontan was 98% (95% CI: 94-99%). The rates of late failure (late death, transplantation, takedown, New York Heart Association class III/IV or protein-losing enteropathy) and adverse events (late failure, reoperation, percutaneous intervention, pacemaker, thromboembolic event or supraventricular tachycardia) per 100 patient-years were 0.8 and 3.8, and their 14-year freedoms were 83% (95% CI: 70-91%) and 53% (95% CI: 41-64%), respectively. After adjustment for confounders, hypoplastic left heart syndrome (HLHS) was strongly associated with prolonged effusions (OR: 2.9, 95% CI: 1.4-5.9), late failure (hazard ratio [HR]: 2.8, 95% CI: 1.1-7.5) and adverse events (HR: 3.6, 95% CI: 1.3-7.5).

Conclusions: The extracardiac Fontan procedure provides excellent survival into the second decade of life, but half of patients will suffer a late adverse event by 14 years. Patients with HLHS are at higher risk of late adverse events than other morphological groups, but their survival is still excellent.
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http://dx.doi.org/10.1093/ejcts/ezu015DOI Listing
September 2014

Surgical palliation in patients with a single ventricle and dextrocardia.

J Thorac Cardiovasc Surg 2014 Oct 16;148(4):1475-80. Epub 2014 Jan 16.

Murdoch Children's Research Institute, Victoria, Australia; Department of Cardiac Surgery, Royal Children's Hospital, Victoria, Australia; Department of Pediatrics, University of Melbourne, Melbourne, Victoria, Australia. Electronic address:

Background: Dextrocardia is found in a significant proportion of patients undergoing a single-ventricle repair. Surgical outcomes in this cohort are unclear.

Methods: The records of 41 consecutive patients with single-ventricle physiology and dextrocardia presenting in a single institution from 1990 to 2008 were reviewed. Of this cohort, 19 patients had heterotaxy syndrome. Twenty-five of the 41 patients had atrioventricular valve regurgitation (AVVR) on presentation (mild, 13; moderate, 9; severe, 3).

Results: One patient died before intervention. Initial surgical palliation was performed in 31 patients. Four patients died postoperatively and 4 interim deaths occurred between initial palliation and bidirectional cavopulmonary shunt (BCPS). Thirty of the surviving 32 patients underwent BCPS, with 2 perioperative deaths. There were 4 additional deaths before Fontan surgery. Twenty-two of the surviving 25 patients underwent a Fontan procedure. There was 1 postoperative mortality. Survival to the age of 15 years was 56% (95% confidence interval [CI], 39%-70%). Patients with moderate or severe regurgitation had higher mortality if they were managed conservatively rather than by surgery (5 of 6 vs 2 of 6; P=.24). Patients with bilateral BCPS had better operative outcomes and survival compared with peers with unilateral anastomosis (odds ratio, 27; P=.005; 95% CI, 2.7-269). The side of the systemic venous pathway did not seem to influence outcomes.

Conclusions: Surgical outcomes of single-ventricle palliation seem poor in patients with dextrocardia. Aggressive management of congenital AVVR might improve the long-term prognosis.
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http://dx.doi.org/10.1016/j.jtcvs.2013.10.077DOI Listing
October 2014

Low risk of pulmonary valve implantation after a policy of transatrial repair of tetralogy of Fallot delayed beyond the neonatal period: the Melbourne experience over 25 years.

J Am Coll Cardiol 2014 Feb 30;63(6):563-8. Epub 2013 Oct 30.

Department of Cardiac Surgery, Royal Children's Hospital, Melbourne, Australia; Department of Pediatrics of the University of Melbourne, and the Murdoch Children's Institute, Melbourne, Australia.

Objectives: The study sought to evaluate the late outcomes of a policy of transatrial repair delayed beyond the neonatal period.

Background: Long-term outcomes of transatrial repair of tetralogy of Fallot are unknown.

Methods: The records of 675 consecutive patients undergoing a transatrial repair of tetralogy of Fallot between 1980 and 2005 were reviewed, their follow-up updated and survival confirmed from national death registries. One-third (220 of 675) had undergone previous palliation. Median age at repair was 2 years in the first 8 years, and 1 year from 1988 onward. A transannular incision was performed in 75% of cases and autologous pericardium was the material used to patch this incision in 92% of cases.

Results: There were 7 hospital deaths (1%). Eight patients died during follow-up (2 sudden unexpected and 6 noncardiac deaths). Mean follow-up was 11.7 ± 6.3 years. Twenty-five years' survival was 97% (95% confidence interval [CI]: 95% to 98%). Twenty-five years' freedom from implantation of a valved conduit was 84.6% (95% CI: 77.8% to 89.5%). By multivariable analysis, prior palliation and younger age at repair were predictive of implantation of a valved conduit (hazard ratio: 2.4, 95% CI: 1.3 to 4.6, p = 0.008; hazard ratio: 0.70, 95% CI: 0.50 to 0.96, p = 0.03, respectively).

Conclusions: During long-term follow-up, transatrial repair of tetralogy of Fallot was associated with a minimal risk of sudden death and low rate of reintervention for right ventricular dilation and residual outflow tract obstruction.
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http://dx.doi.org/10.1016/j.jacc.2013.10.011DOI Listing
February 2014

Intersurgeon variability in long-term outcomes after transatrial repair of tetralogy of Fallot: 25 years' experience with 675 patients.

J Thorac Cardiovasc Surg 2014 Mar 12;147(3):880-6. Epub 2013 Dec 12.

Department of Cardiac Surgery, Royal Children's Hospital, Melbourne, Australia; Murdoch Childrens Research Institute, Melbourne, Australia; Department of Pediatrics, The University of Melbourne, Melbourne, Australia.

Objective: To compare the long-term reoperation rates among surgeons performing transatrial repair of tetralogy of Fallot.

Methods: The data set of 675 patients undergoing transatrial repair of tetralogy of Fallot at 1 institution from 1980 to 2005 was analyzed for intersurgeon differences in the reoperation rates.

Results: A follow-up period >15 years was available for 5 surgeons, allowing for comparison (541 patients; >80 patients/surgeon). The reintervention rate at 10 years varied from 8.8% (95% confidence interval [CI], 5.3%-14.5%) to 26.7% (95% CI, 14.9%-44.9%; hazard ratio, 3.4; P = .001). The procedures of 1 surgeon resulted in a reoperation rate of 10.5% at 20 years (95% CI, 5.4%-25.3%). The type of reoperation required varied among the surgeons. One surgeon had had no reoperations for pulmonary artery stenosis. Of the 5 surgeons, 2 (surgeons 2 and 5) had equivalent overall 10-year reoperation rates (24.1%, 95% CI, 12.9%-42.3%; vs 26.7%, 95% CI, 14.9%-44.9%; P = .32). Surgeon 5 had reoperation almost exclusively for right ventricular outflow tract obstruction (20.6%; 95% CI, 12.4%-33.1%) and surgeon 2 for right ventricular dilation (17.4%; 95% CI, 7.8%-36.3%). None of the patients treated by surgeon 5 required implantation of a valved conduit.

Conclusions: An analysis of the reoperation rate during the long-term follow-up of transatrial repair of tetralogy of Fallot identified variability in the outcomes among 5 surgeons. The analysis of these differences suggested that an optimal amount of opening of the right ventricular outflow tract can lead to a decreased reintervention rate. The analysis of intersurgeon variability in outcomes should be encouraged, because it will lead to improvements in cardiac surgery outcomes.
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http://dx.doi.org/10.1016/j.jtcvs.2013.11.010DOI Listing
March 2014

Trends in Fontan surgery and risk factors for early adverse outcomes after Fontan surgery: the Australia and New Zealand Fontan Registry experience.

J Thorac Cardiovasc Surg 2014 Aug 23;148(2):566-75. Epub 2013 Nov 23.

Cardiac Surgery and Cardiology Departments, Royal Children's Hospital, Melbourne, Australia; Murdoch Childrens Research Institute, Melbourne, Australia.

Objectives: This study examined changes in practice and analyzed risk factors for adverse early outcomes after Fontan surgery through use of a binational, population-based registry.

Methods: Demographic, preoperative, and perioperative data were collected from all participating institutions of the Australia and New Zealand Fontan Registry. Patient and operative characteristics were analyzed with multivariable logistic regression for impact on early mortality, early Fontan failure (death, takedown, or mechanical support), effusions (prolonging hospital stay >30 days or requiring surgical reintervention), and stay longer than 30 days.

Results: Overall mortality was 3.5% (37/1071) and declined throughout the study period, from 8% (1975-1990) to 4% (1991-2000) and 1% (2001-2010). There were no differences between the extracardiac and lateral tunnel modifications for any outcome. After 2006, the extracardiac conduit was performed exclusively, with 1.3% mortality. The proportion of patients with hypoplastic left heart syndrome rose to 17% in the current era, and this group had more effusions (odds ratio, 3.0; 95% confidence interval, 1.4-6.6) and stayed on average 2 days longer in the hospital. Hypoplastic left heart syndrome was also an independent risk factor for composite adverse early outcome (death, failure, prolonged effusions, or prolonged stay >30 days; odds ratio, 2.6; 95% confidence interval 1.4-4.8 respectively).

Conclusions: The extracardiac conduit is now the exclusive Fontan modification performed in Australia and New Zealand. Even with a higher proportion of high-risk cases, perioperative outcomes are excellent in the modern era. Hypoplastic left heart syndrome confers a higher risk of prolonged pleural effusion and early composite adverse outcome.
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http://dx.doi.org/10.1016/j.jtcvs.2013.09.074DOI Listing
August 2014

Abnormal left ventricular diastolic function at late follow-up after repair of total anomalous pulmonary venous drainage: the impact of altered ventricular loading in utero.

J Thorac Cardiovasc Surg 2014 Jul 5;148(1):238-44. Epub 2013 Oct 5.

Department of Cardiology, The Royal Children's Hospital, Melbourne, and the Department of Paediatrics, University of Melbourne, Melbourne, Australia; Heart Research Group, Murdoch Childrens Research Institute, Parkville, Australia.

Background: Assessment of diastolic function has not been described after repair of total anomalous pulmonary venous drainage (TAPVD), but studies of exercise capacity demonstrate impaired performance in this population despite normal systolic function. We postulated that diastolic impairment might contribute to this finding.

Methods: We analyzed echocardiographic variables from 28 patients with repaired TAPVD and compared these with data from 32 healthy controls (normals) and 21 subjects with repaired transposition of the great arteries (TGA).

Results: Left ventricular (LV) end-diastolic volumes were smaller in the TAPVD group (median, 50 mL/m(2) compared with a median of 64 mL/m(2) in TGA and 67 mL/m(2) in normals; P < .001 in each case). LV diastolic function in the TAPVD group was impaired. Mitral early to late ratio was increased (median, 2.7 in TAPVD compared with a median of 1.9 in TGA [P = .047] and 2.1 in normals [P = .021]). LV isovolumic relaxation time was reduced (median, 50 milliseconds in TAPVD compared with a median of 70 milliseconds in both TGA and normals; P < .001 in each case). Late diastolic and systolic tissue Doppler velocities were lower and the E/e' ratio was higher in the TAPVD group.

Conclusions: Patients with repaired TAPVD are usually regarded as having excellent outcomes, but the finding of LV diastolic dysfunction in this population warrants more careful follow-up. We postulate that the diastolic impairment in these patients is the result of relative unloading of the LV during early cardiac development. These findings may also have implications in considering therapeutic approaches for hypoplastic ventricles in attempting to achieve biventricular repair.
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http://dx.doi.org/10.1016/j.jtcvs.2013.08.045DOI Listing
July 2014

Outcomes of patients born with single-ventricle physiology and aortic arch obstruction: the 26-year Melbourne experience.

J Thorac Cardiovasc Surg 2014 Jul 24;148(1):194-201. Epub 2013 Sep 24.

Department of Cardiac Surgery, The Royal Children's Hospital; the Department of Paediatrics, University of Melbourne; and the Murdoch Childrens Research Institute, Melbourne, Australia. Electronic address:

Background: To review the long-term outcomes of patients born with single-ventricle physiology and aortic arch obstruction.

Methods: Follow-up of 70 consecutive neonates undergoing single-ventricle palliation and arch repair, excluding hypoplastic left heart syndrome, between 1983 and 2008, was reviewed. Dominant arch anomalies were coarctation (n = 48), interrupted arch (n = 10), and hypoplastic arch alone (n = 12). Neonatal Damus procedure with arch repair and shunt became the dominant approach, being performed in 1 (10%) of 10 in 1983 to 1989, 9 (32%) of 28 in 1990 to 1999, and 23 (72%) of 32 in 2000 to 2008.

Results: All patients underwent an initial procedure at a median of 6 days (range, 4-12 days): pulmonary artery banding and arch repair (n = 35); Damus, arch repair, and shunt (n = 33); and other (n = 2). Twenty-six patients died before Fontan completion. Of the 34 survivors of initial banding, 17 (50%) later required a Damus and 4 (12%) required subaortic stenosis relief. Forty patients underwent Fontan completion at a median age of 5 years (range, 4-7 years). After a mean of 5 ± 6 years after Fontan, there was 1 hospital death and 1 Fontan takedown. Overall survival was similar if patients initially underwent a Damus or pulmonary artery banding (P = .3). Overall survival at 10 years was 53% (95% confidence interval, 42%-67%).

Conclusions: Patients born with single-ventricle physiology and arch obstruction have a high risk of mortality in the first years of life. Their outcomes seem excellent once they reach Fontan status. It is likely that, in patients with single-ventricle and arch obstruction, strategies to avoid systemic outflow tract obstruction should be implemented in early life, and regular monitoring of blood pressure is warranted.
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http://dx.doi.org/10.1016/j.jtcvs.2013.07.076DOI Listing
July 2014

Favourable anatomy after end-to-side repair of interrupted aortic arch.

Heart Lung Circ 2014 Mar 30;23(3):256-64. Epub 2013 Aug 30.

Department of Cardiac Surgery, Royal Children's Hospital, Melbourne, Australia; Department of Paediatrics, University of Melbourne, Melbourne, Australia; Murdoch Children Research Institute, Melbourne, Australia. Electronic address:

Objective: To evaluate cardiovascular outcomes in patients with aortic arch repair and their possible correlation with arch geometry.

Methods: Ten patients who underwent end-to-side repair for aortic arch interruption (IAA), older than 10 years were compared to a cohort of 10 post coarctation (CoA) repair patients matched for age, sex and age at repair. Mean age at operation was 9.7±6.5 days. Patients underwent a resting and 24 h blood pressure measurements, exercise study, MRI, transthoracic echocardiography and vascular studies.

Results: Seven patients developed hypertension, two from IAA group and five from CoA group. Nine patients (45%) had gothic arch geometry, three from IAA group and six from CoA group. Despite differences in arch geometry, both groups had normal LV mass, LV function and vascular function.

Conclusion: No differences in functional or morphologic outcomes could be demonstrated between the end-to-side repair of the arch by sternotomy and the conventional coarctation repair by thoracotomy. A favourable arch geometry can be achieved after the end-to-side repair of the aortic arch. In the present study, we could not correlate adverse arch geometry with any adverse cardio-vascular outcomes. After neonatal arch repair, the contributive role of aortic arch geometry to late hypertension remains uncertain.
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http://dx.doi.org/10.1016/j.hlc.2013.08.006DOI Listing
March 2014

Outcomes of repair of complete atrioventricular septal defect in the current era.

Eur J Cardiothorac Surg 2014 Apr 20;45(4):610-7. Epub 2013 Sep 20.

Department of Cardiac Surgery, Royal Children's Hospital, Melbourne, Australia.

Objectives: We sought to evaluate the surgical outcomes of the repair of complete atrioventricular septal defects (cAVSDs) in our institution in the current era.

Methods: From 2000 to 2011, 138 patients underwent definitive repair of cAVSD. Repair was performed using a two-patch technique in 92.0% of patients and one-patch technique in 2.2%, and the ventricular septal component was closed directly in 5.8% of patients.

Results: Operative mortality was 1.4% (2 of 138). Overall mortality was 5.8% (8 of 138). Follow-up was 96% complete. Freedom from reoperation was 84.3% (95% CI 77.1-91.5%) at 8 years. Age >6 months at repair was associated with higher rates of reoperation (P = 0.001; HR 6.85; 95% CI 2.30-20.44). However, operating at <6 months of age was associated with longer intensive care unit stay (P = 0.019; median 2.7 vs 1.4 days), mechanical ventilation (P = 0.001; median 1.7 vs 0.9 days) and postoperative hospital stay (P = 0.016; median 8 vs 5 days). Moderate or greater left atrioventricular valvular regurgitation (LAVVR) at discharge was a risk factor for reoperation (P < 0.001; HR 10.85; 95% CI 3.75-31.40).

Conclusions: Repair of cAVSD carries low mortality, but a moderate reoperation rate. An optimal time for repair of the cAVSD is between 3 and 6 months of age. Repair prior to 3 months of age and the need for cleft closure were associated with a higher degree of LAVVR at discharge. Greater LAVVR at discharge is a risk factor for reoperation regardless of age at initial repair. In the current era, Down's syndrome is not a risk factor for reoperation.
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http://dx.doi.org/10.1093/ejcts/ezt444DOI Listing
April 2014

Surgical valvotomy and repair for neonatal and infant congenital aortic stenosis achieves better results than interventional catheterization.

J Am Coll Cardiol 2013 Dec 21;62(22):2134-40. Epub 2013 Aug 21.

University of Melbourne, Melbourne, Australia.

Objectives: This study sought to compare outcomes after surgical valvuloplasty and balloon dilation of the aortic valve in neonates and infants.

Background: Surgical techniques of aortic valve repair have improved and there is today controversy on the best approach to treat neonatal congenital aortic valve stenosis.

Methods: Retrospective review of data and follow-up of 123 consecutive neonates and infants (35 females, 88 males) undergoing intervention for congenital aortic stenosis.

Results: From 1977 to 2009, 123 consecutive neonates (<30 days) and infants (31 days to 1 year) underwent relief of congenital aortic stenosis. Median age at procedure was 27 days (6 to 76 days). Twenty-year survival was 80 ± 7%. Fifty-four patients required a re-intervention and freedom from re-intervention was 55 ± 6% at 10 years and 40 ± 6% at 20 years. By multivariate analysis, having the relief of stenosis by balloon valvuloplasty and undergoing initial treatment as a neonate were predictive of re-intervention. Freedom from re-intervention at 5 years was 27% after balloon valvuloplasty versus 65% after surgery. At latest follow-up, an additional 16 patients had moderate or severe stenosis and 8 had regurgitation. Freedom from re-intervention or stenosis was 39 ± 5% at 15 years. By multivariate analysis, balloon valvuloplasty (p < 0.001) and treatment as a neonate (p = 0.003) were again predictive of stenosis or re-intervention. Thirty-five patients ultimately needed a valve replacement. Significant predictor of the requirement of valve replacement was unicuspid aortic valve (p < 0.001). Freedom from valve replacement was 55 ± 7% at 20 years.

Conclusions: Surgical valvuloplasty remains the best approach to treat neonates and infants with congenital aortic stenosis. After surgery, a higher proportion of patients remain free of re-intervention than after interventional catheterization and the relief of their stenosis lasts longer.
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http://dx.doi.org/10.1016/j.jacc.2013.07.052DOI Listing
December 2013

Association of maternal and nutrient supply line factors with DNA methylation at the imprinted IGF2/H19 locus in multiple tissues of newborn twins.

Epigenetics 2013 Oct 5;8(10):1069-79. Epub 2013 Aug 5.

Department of Paediatrics; University of Melbourne; Parkville, VIC Australia; Early Life Epigenetics Group; Murdoch Childrens Research Institute (MCRI); Royal Children's Hospital; Parkville, VIC Australia.

Epigenetic events are crucial for early development, but can be influenced by environmental factors, potentially programming the genome for later adverse health outcomes. The insulin-like growth factor 2 (IGF2)/H19 locus is crucial for prenatal growth and the epigenetic state at this locus is environmentally labile. Recent studies have implicated maternal factors, including folate intake and smoking, in the regulation of DNA methylation at this locus, although data are often conflicting in the direction and magnitude of effect. Most studies have focused on single tissues and on one or two differentially-methylated regions (DMRs) regulating IGF2/H19 expression. In this study, we investigated the relationship between multiple shared and non-shared gestational/maternal factors and DNA methylation at four IGF2/H19 DMRs in five newborn cell types from 67 pairs of monozygotic and 49 pairs of dizygotic twins. Data on maternal and non-shared supply line factors were collected during the second and third trimesters of pregnancy and DNA methylation was measured via mass spectrometry using Sequenom MassArray EpiTyper analysis. Our exploratory approach showed that the site of umbilical cord insertion into the placenta in monochorionic twins has the strongest positive association with methylation in all IGF2/H19 DMRs (p<0.05). Further, evidence for tissue- and locus-specific effects were observed, emphasizing that responsiveness to environmental exposures in utero cannot be generalized across genes and tissues, potentially accounting for the lack of consistency in previous findings. Such complexity in responsiveness to environmental exposures in utero has implications for all epigenetic studies investigating the developmental origins of health and disease.
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http://dx.doi.org/10.4161/epi.25908DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3891688PMC
October 2013

MCAR is not necessary for the complete cases to constitute a simple random subsample of the target sample.

Stat Methods Med Res 2016 08 22;25(4):1527-34. Epub 2013 May 22.

Department of Mathematics and Statistics, La Trobe University, Australia.

Missing data is the norm rather than the exception in complex epidemiological studies. Complete-case analyses, which discard all subjects with some data values missing, are known to be valid under the very restrictive assumption that the response mechanism is missing completely at random (MCAR). While conditions weaker than MCAR are known under which estimators of regression coefficients are unbiased, one often comes across the view in the literature that MCAR is necessary for the complete cases to form a simple random subsample of the target sample. In this paper, we explain why this is not the case, and we distill an assumption weaker than MCAR under which the simple random subsample condition holds, which we call available at random (AAR). Moreover, we show that, unlike MCAR, AAR response mechanisms can be missing not at random (MNAR). We also suggest how approximate AAR mechanisms might arise in practice through cancellation of selection and drop-out effects, and we conclude that before pooling partially complete and complete cases into an analysis, the investigator should consider how selection might impact on the representativeness of the cases included in the pooled analysis (compared to those comprising the complete cases only).
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http://dx.doi.org/10.1177/0962280213490360DOI Listing
August 2016

Ross procedure in children: 17-year experience at a single institution.

J Am Heart Assoc 2013 Apr 19;2(2):e000153. Epub 2013 Apr 19.

Royal Children's Hospital, Melbourne, Australia.

Background: The Ross procedure in children carries substantial mortality and reoperation rate. Aortic root dilatation is of concern. To prevent dilatation of the neoaortic root, but permit normal growth, we began to apply an absorbable poly-(p-dioxanone)-filaments (PDS) band at the sino-tubular (ST)-junction.

Methods And Results: All children (n=100) who underwent Ross procedure during 1995-2012 were studied. Mean age at operation was 8.6±6.1 years (median 8.3 years, range 3 days to 18 years); 19 patients were younger than 1 year of age. The root replacement (n=91, Ross-Konno procedure in 29 patients), root inclusion (n=6), and subcoronary implantation (n=3) techniques were used. Operative mortality was 6% (6/100, 4 neonates, 2 infants). Age of <1-year at time of operation was a risk factor for early death (P<0.001). Mean follow-up time was 7.0±4.8 years (median 7.4 years, range 5 days to 16 years). Late mortality was 4.3% (4/94). Freedom from moderate or greater neoaortic valve insufficiency (AI) at 5 and 10 years was 89% and 83%, respectively. Freedom from neoaortic valve reoperation at 5 and 10 years was 96% and 86%, respectively. Aortic dilatation to Z-score >4 was greatest at the ST-junction (23%, 11/48) compared to the aortic annulus (17%, 11/66) and sinuses (14%, 7/50). Since 2001, a PDS band was placed around the ST-junction in 19 patients. Survivors with the PDS band had less AI (0 versus 20%, P=0.043) compared to survivors (n=35) without the PDS at 4.1±3 years.

Conclusions: The Ross procedure in children can be performed with acceptable results. Children younger than 1 year of age have higher mortality, but not an increased autograft reoperation rate. Stabilization of the ST-junction may reduce AI.
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http://dx.doi.org/10.1161/JAHA.113.000153DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3647280PMC
April 2013

Long-term results of a strategy of aortic valve repair in the pediatric population.

J Thorac Cardiovasc Surg 2013 Feb 13;145(2):461-7; discussion 467-9. Epub 2012 Dec 13.

Department of Cardiac Surgery, Royal Children’s Hospital, Flemington Rd, Parkville, Melbourne 3052, Victoria, Australia.

Objectives: To determine rate of reoperation subsequent to primary valve repair in a pediatric population.

Methods: Between 1996 and 2009, 142 consecutive patients underwent aortic valve repair in our institution. Median age at surgery was 9 years, with 30 being younger than age 1 year. Indication for surgery was stenosis (n = 76), regurgitation (n = 55), and both (n = 11). Forty-six patients underwent repair with no addition of patch, whereas 96 patients required addition of patches of glutaraldehyde preserved autologous pericardium for cusp extension (n = 51) and other repair (n = 45).

Results: In the early postoperative period after cusp extension repair, 2 patients had a sudden unexplained death and 1 had cardiac arrest requiring mechanical support and heart transplantation. Two additional patients with cusp extension displayed signs of coronary ischemia. After a mean follow-up of 3.4 ± 3.5 years, only 1 patient died of a noncardiac cause. Seven-year freedom from reoperation was 80% (95% confidence interval [CI], 66-89). By multivariate analysis, the only predictors of reintervention were cusp extension (hazard ratio [HR], 5.4; 95% CI, 1.7-16.8; P = .004) and infants (HR, 5.6; 95% CI, 1.7-18.4; P = .005). At final echocardiography follow-up, 23 of 119 survivors without reoperation had moderate (19%), 1 had moderate-severe (1%), and 1 had severe regurgitation (1%), whereas 12 (10%) had a moderate degree of stenosis.

Conclusions: Aortic valve repair in pediatric populations is effective in postponing reintervention. The longevity of the repair is shorter after cusp extension and when performed in infants. Caution should be used when performing tricsupidization and cusp extension of bicuspid valves because it can be responsible for mortality related to occlusion of the coronary ostia by patches.
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http://dx.doi.org/10.1016/j.jtcvs.2012.11.033DOI Listing
February 2013

The Peri/postnatal Epigenetic Twins Study (PETS).

Twin Res Hum Genet 2013 Feb 22;16(1):13-20. Epub 2012 Nov 22.

Department of Paediatrics, Royal Children's Hospital, Melbourne, Australia.

The Peri/postnatal Epigenetic Twins Study (PETS) is a longitudinal cohort of 250 pairs of Australian twins and their mothers, who were recruited mid-way through pregnancy from January 2007 to September 2009. The study is centered on the developmental origins of health and disease paradigm (DOHaD) in which an adverse intrauterine environment predisposes the individual to complex disease in later life by reducing growth in utero and adversely altering developmental plasticity. Data concerning diet and lifestyle were collected from mothers during pregnancy, and samples of plasma and serum taken at 28 weeks' gestation. We attended 75% of all births, at which time we collected multiple biological samples including placenta, cord blood, and neonatal cheek cells, the latter from 91% of pairs. Chorionicity was recorded and zygosity was determined by DNA testing where necessary. Approximately 40% of the twins are monozygotic, two-thirds of which are dichorionic. Twins were seen again at 18 months of age and repeat blood and cheek swabs taken where possible. Studies of gene expression and the epigenetic marks of DNA methylation have so far revealed that twins exhibit a wide range of epigenetic discordance at birth, that one-third of the epigenome changes significantly between birth and 18 months; shared (maternal) environment, genetic factors, and non-shared intrauterine environment contribute to an increasing proportion of epigenetic variation at birth, respectively, and affect tissues differently, and that within-pair birth weight discordance correlates with epigenetic discordance in genes associated with lipid metabolism, supporting an epigenetic mechanism for DOHaD.
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http://dx.doi.org/10.1017/thg.2012.114DOI Listing
February 2013

DNA methylation of the IGF2/H19 imprinting control region and adiposity distribution in young adults.

Clin Epigenetics 2012 Nov 13;4(1):21. Epub 2012 Nov 13.

School of Medicine and Pharmacology, University of Western Australia (UWA), Perth, WA, Australia.

Unlabelled:

Background: The insulin-like growth factor 2 (IGF2) and H19 imprinted genes control growth and body composition. Adverse in-utero environments have been associated with obesity-related diseases and linked with altered DNA methylation at the IGF2/H19 locus. Postnatally, methylation at the IGF2/H19 imprinting control region (ICR) has been linked with cerebellum weight. We aimed to investigate whether decreased IGF2/H19 ICR methylation is associated with decreased birth and childhood anthropometry and increased contemporaneous adiposity.DNA methylation in peripheral blood (n = 315) at 17 years old was measured at 12 cytosine-phosphate-guanine sites (CpGs), analysed as Sequenom MassARRAY EpiTYPER units within the IGF2/H19 ICR. Birth size, childhood head circumference (HC) at six time-points and anthropometry at age 17 years were measured. DNA methylation was investigated for its association with anthropometry using linear regression.

Results: The principal component of IGF2/H19 ICR DNA methylation (representing mean methylation across all CpG units) positively correlated with skin fold thickness (at four CpG units) (P-values between 0.04 to 0.001) and subcutaneous adiposity (P = 0.023) at age 17, but not with weight, height, BMI, waist circumference or visceral adiposity. IGF2/H19 methylation did not associate with birth weight, length or HC, but CpG unit 13 to 14 methylation was negatively associated with HC between 1 and 10 years. β-coefficients of four out of five remaining CpG units also estimated lower methylation with increasing childhood HC.

Conclusions: As greater IGF2/H19 methylation was associated with greater subcutaneous fat measures, but not overall, visceral or central adiposity, we hypothesize that obesogenic pressures in youth result in excess fat being preferentially stored in peripheral fat depots via the IGF2/H19 domain. Secondly, as IGF2/H19 methylation was not associated with birth size but negatively with early childhood HC, we hypothesize that the HC may be a more sensitive marker of early life programming of the IGF axis and of fetal physiology than birth size. To verify this, investigations of the dynamics of IGF2/H19 methylation and expression from birth to adolescence are required.
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http://dx.doi.org/10.1186/1868-7083-4-21DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3507742PMC
November 2012

Twenty-four-hour ambulatory blood pressure monitoring detects a high prevalence of hypertension late after coarctation repair in patients with hypoplastic arches.

J Thorac Cardiovasc Surg 2012 Nov 11;144(5):1110-6. Epub 2012 Sep 11.

Department of Cardiac Surgery, The Royal Children's Hospital, Department of Paediatrics, University of Melbourne, Murdoch Children's Research Institute, Melbourne, Australia.

Objectives: To determine by 24-hour blood pressure monitoring the risk of hypertension late after coarctation repair in patients with arch hypoplasia.

Methods: Sixty-two of 116 consecutive patients (age, ≥10 years) who had coarctation repair and were quoted subjectively by the surgeon or the cardiologist to have arch hypoplasia at the time of the repair underwent a transthoracic echocardiogram and 24-hour blood pressure monitoring. Median age at repair was 11 days (range, 6-48 days). Mean preoperative z score of the proximal transverse arch was -2.43 ± 0.46. Eight patients had a repair via sternotomy (6 end-to-side anastomoses, 2 patch repairs) and 54 had a conventional repair via thoracotomy.

Results: After a follow-up of 18 ± 5 years, 27% of the patients (17/62) had resting hypertension and 60% (37/62) had abnormal ambulatory blood pressure. Sensitivity of high resting blood pressure in detecting an abnormal 24-hour ambulatory blood pressure was 41%. Twenty patients had arch obstruction at last follow-up. Eighteen of them (90%) had abnormal ambulatory blood pressure. None of the patients operated on with end-to-side repair via sternotomy had reobstruction compared with 33% (18/54) of those repaired via thoracotomy.

Conclusions: Patients with a hypoplastic arch operated via thoracotomy have an alarming prevalence of hypertension. Regular follow-up with 24-hour ambulatory blood pressure monitoring is warranted, especially in patients who have had a smaller aortic arch at the time of the initial operation.
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http://dx.doi.org/10.1016/j.jtcvs.2012.08.013DOI Listing
November 2012

Comparison of methods for imputing ordinal data using multivariate normal imputation: a case study of non-linear effects in a large cohort study.

Stat Med 2012 Dec 24;31(30):4164-74. Epub 2012 Jul 24.

Clinical Epidemiology and Biostatistics Unit, Murdoch Childrens Research Institute, Melbourne, Australia.

Background: Multiple imputation is becoming increasingly popular for handling missing data, with Markov chain Monte Carlo assuming multivariate normality (MVN) a commonly used approach. Imputing categorical variables (which are clearly non-normal) using MVN imputation is challenging, and several approaches have been suggested. However, it remains unclear which approach should be preferred.

Methods: We explore methods for imputing ordinal variables using MVN imputation, including imputing as a continuous variable and as a set of indicators, and various methods for assigning imputed values to the possible categories (rounding), for estimating a non-linear association between an ordinal exposure and binary outcome. We introduce a new approach where we impute as continuous and assign imputed values into categories based on the mean indicators imputed in a separate round of imputation. We compare these approaches in a simple setting where we make 50% of data in an ordinal exposure missing completely at random, within an otherwise complete real dataset.

Results: Methods that impute the ordinal exposure as continuous distorted the non-linear exposure-outcome association by biasing the relationship towards linearity irrespective of the rounding method. In contrast, imputing using indicators preserved the non-linear association but not the marginal distribution of the ordinal variable.

Conclusions: Imputing ordinal variables as continuous can bias the estimation of the exposure-outcome association in the presence of non-linear relationships. Further work is needed to develop optimal methods for handling ordinal (and nominal) variables when using MVN imputation.
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http://dx.doi.org/10.1002/sim.5445DOI Listing
December 2012

Maternal vitamin D predominates over genetic factors in determining neonatal circulating vitamin D concentrations.

Am J Clin Nutr 2012 Jul 30;96(1):188-95. Epub 2012 May 30.

Cancer and Disease Epigenetics Group, Murdoch Childrens Research Institute, Royal Children's Hospital, Parkville, Australia.

Background: There are multiple potential regulators of neonatal vitamin D status of environmental, genetic, and epigenetic origins. The relation between these factors and circulating neonatal vitamin D has yet to be fully characterized.

Objective: The aim of this study was to examine the relative contribution of genetic factors, maternal circulating 25-hydroxyvitamin D [25(OH)D] concentrations, and the placental methylation level of the gene that encodes the primary catabolic enzyme of active vitamin D [25(OH)D-24-hydroxylase encoded by CYP24A1] to neonatal 25(OH)D concentrations.

Design: We used the classical twin study design to determine the genetic contribution to neonatal 25(OH)D. A total of 86 twin pairs (32 monozygotic and 54 dizygotic twin pairs) were included in this study. Serum 25(OH)D was measured by using a 25(OH)D kit. CYP24A1 promoter DNA methylation was measured by means of matrix-assisted laser desorption time-of-flight mass spectrometry.

Results: Maternal and neonatal 25(OH)D showed a strong association (R² = 0.19). Monozygotic and dizygotic within-pair serum 25(OH)D correlations were similar (R² = 0.71 and 0.67, respectively), which suggested no genetic effect. Placental CYP24A1 methylation did not show an association with maternal or neonatal 25(OH)D concentrations.

Conclusions: Our results suggest that maternal circulating 25(OH)D is the most significant regulator of neonatal circulating 25(OH)D concentrations, with underlying genetic factors playing a limited role. The placental methylation of the CYP24A1 promoter appears subject to a genetic influence, although no evidence of a relation between the methylation level of this gene and circulating maternal or neonatal 25(OH)D was apparent.
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http://dx.doi.org/10.3945/ajcn.112.035683DOI Listing
July 2012