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Biomedical subjects

John G Coles

Publications and source records attributed to John G Coles.

At least 19 recordsLinked to original sources
PubMed2007

Surgical outcomes in the treatment of patients with tetralogy of Fallot and absent pulmonary valve.

OBJECTIVE: Tetralogy of Fallot and absent pulmonary valve (TOF/APV) is associated with significant pulmonary artery dilatation and airway compression. Treatment of infants presenting with respiratory symptoms early in life is associated with high mortality (20-60%). We aim to report our results and identify factors associated with survival and prolonged ventilation. METHODS: We performed a retrospective review of 62 consecutive patients following repair of TOF/APV (1982-2006). Median age at repair was 1.4 years (1 day-35 years). Twenty patients required preoperative intubation. RESULTS: Sixty-one patients underwent complete repair. Thirty-three patients underwent pulmonary artery plication (n=15) or reduction (n=18). The right ventricular outflow tract (RVOT) was reconstructed with valved conduit (n=31), bioprosthetic valve (n=18), monocusp (n=8), or transannular patch (n=4). There were three perioperative and five late deaths. All perioperative deaths were in neonates and before 1995. Five- and ten-year survival was 93+/-4% and 87+/-5%. Mean ventilatory requirements for neonates, infants, and children > or =1 year were 36+/-35, 8+/-8, and 2.6+/-2.4 days (p<0.0001). On multivariable analysis, significant factors associated with prolonged ventilation were neonates (p<0.0001) and preoperative mechanical ventilation (p=0.088). Eight airway reinterventions were needed in seven infants with persistent postoperative airway compromise, pulmonary artery suspension (n=4), innominate artery suspension (n=2), and lobectomy (n=2). Freedom from RVOT reoperation was 89+/-5% and 59+/-9% at 5 and 10 years. There were no significant risk factors for time-related survival or RVOT reoperation on multivariable analysis. CONCLUSIONS: In contrast to children and adults with TOF/APV, neonates and small infants presenting with respiratory symptoms require prolonged ventilation and additional reinterventions for airway compression. Our current surgical approach which includes reduction and suspension of pulmonary arteries, reconstruction of a competent RVOT, and aggressive postoperative ventilatory management to relieve airway obstruction offers satisfactory outcomes.

Abnormalities, Multiple↗
PubMed2006

Integrin-linked kinase expression is elevated in human cardiac hypertrophy and induces hypertrophy in transgenic mice.

BACKGROUND: Although numerous signaling pathways are known to be activated in experimental cardiac hypertrophy, the molecular basis of the hypertrophic response inherent in human heart diseases remains largely unknown. Integrin-linked kinase (ILK) is a multifunctional protein kinase that physically links beta-integrins with the actin cytoskeleton, suggesting a potential mechanoreceptor role. METHODS AND RESULTS: Here, we show a marked increase in ILK protein levels in hypertrophic ventricles of patients with congenital and acquired outflow tract obstruction. This increase in ILK was associated with activation of the Rho family guanine triphosphatases, Rac1 and Cdc42, and known hypertrophic signaling kinases, including extracellular signal-related kinases (ERK1/2) and p70 S6 kinase. Transgenic mice with cardiac-specific expression of a constitutively active ILK (ILK(S343D)) or wild-type ILK (ILK(WT)) exhibited a compensated ventricular hypertrophic phenotype and displayed an activation profile of guanine triphosphatases and downstream protein kinases concordant with that seen in human hypertrophy. In contrast, transgenic mice with cardiomyocyte-restricted expression of a kinase-inactive ILK (ILK(R211A)) were unable to mount a compensatory hypertrophic response to angiotensin II in vivo. CONCLUSIONS: Taken together, these results identify ILK-regulated signaling as a broadly adaptive hypertrophic response mechanism relevant to a wide range of clinical heart disease.

Alanine↗
PubMed2006

Overexpression of integrin-linked kinase induces cardiac stem cell expansion.

OBJECTIVE: Recent evidence suggests that the adult heart contains stem cells that are capable of self-renewal as well as multilineage differentiation. However, their inherent capacity for self-renewal is limiting to cell replacement applications. Integrin-linked kinase is a multifunctional protein kinase that activates Wnt target genes implicated in the symmetric replication of embryonic stem cells. METHODS: Primary cultures derived from human fetal cardiac tissue (19-22 weeks' gestation) were grown in serum-free media and evaluated for the presence of cardiac progenitor cells. The effect of integrin-linked kinase was ascertained by adenoviral overexpression. RESULTS: Cultures infected with wild-type integrin-linked kinase yielded a significant (P = .001), approximately 5-fold increase in both the absolute number and the frequency of c-Kit-positive, myosin-negative cells. Cardiospheres, comprised on morphologically homogeneous, anchorage-independent cells, were reproducibly present at days 7 to 10 and formed derivative cardiospheres in multiple passages. Integrin-linked kinase infection of primary cardiac cell cultures resulted in a greater number of primary spheres at each cell density tested, compared with untreated and virus controls (P = .001). Secondary spheres transferred to differentiation medium and 5-aza-deoxycytodine (10 micromol/L) generated cells exhibiting biochemical evidence of differentiation into cardiomyocytes, smooth muscle cells, and endothelial cells. CONCLUSIONS: This study demonstrates that self-renewing cardiospheres generated from human fetal cardiac cells are composed of cells exhibiting the properties of stem cells, including the capacity for self-renewal and multilineage differentiation. Our results suggest that integrin-linked kinase promotes stem cell amplification and can be applied therapeutically to overcome a major limitation in the field of cardiac regenerative medicine.

Cell Proliferation↗
PubMed2006

Contemporary management of right atrial isomerism: effect of evolving therapeutic strategies.

OBJECTIVES: Infants with right atrial isomerism have poor outcomes because of a complex combination of cardiac anomalies. Aggressive management of total anomalous pulmonary venous drainage might have a positive effect on the prognosis. METHODS: Outcomes of all children with right atrial isomerism from 1994 to the present were reviewed. Management of total anomalous pulmonary venous drainage evolved from no repair or conventional surgical technique to primary sutureless repair on initial palliation. Cox survival models were used to identify variables associated with reduced survival. RESULTS: There were 55 children enrolled in the study. The median age at the initial visit was 2 days. Fifty-one patients had total anomalous pulmonary venous drainage (obstructive in 22 patients). Withdrawal of treatment occurred in 11 (20%) of 55 patients during an interval of institutional bias toward no treatment. Thirteen (24%) of 55 patients had palliations without total anomalous pulmonary venous drainage repair, and 3 (23%) of 13 survived. Thirty-one (56%) of 55 patients had operations that included total anomalous pulmonary venous drainage repair, of whom 13 (42%) of 31 underwent primary sutureless repair for total anomalous pulmonary venous drainage. Sixteen (52%) of 31 survived, and their current status 1 to 10 years (median, 5.8 years) after repair is post-Fontan (7/16 [44%]), postbidirectional Glenn (6/16 [38%]), and others (3 [20%]). In patients who underwent total anomalous pulmonary venous drainage repair (n = 31), 2 risk factors of decreased survival were identified: drainage site obstruction and infracardiac or mixed-type total anomalous pulmonary venous drainage. After adjustment, sutureless repair appeared to be associated with improved survival (hazard ratio, 0.43), but this beneficial effect did not reach significance (P = .19). CONCLUSIONS: Mortality continues to be high; however, aggressive total anomalous pulmonary venous drainage repair for right atrial isomerism has resulted in improved survival. The role of primary sutureless repair for total anomalous pulmonary venous drainage remains to be defined.

Anastomosis, Surgical↗
PubMed2006

Short and midterm results of aortic valve cusp extension in the treatment of children with congenital aortic valve disease.

BACKGROUND: We evaluated our experience with aortic valve cusp extension techniques to identify predictors of successful intraoperative repair and subsequent durability. METHODS: Twenty-two children (ages 5-18 years) underwent aortic cusp extension with autologous pericardium between 1999 and 2005. Sixteen children had previous surgical or percutaneous intervention. Ten children had bicuspid aortic valves. Cusp extensions were performed on 1 cusp in 3 patients, 2 cusps in 3, and 3 cusps in 16. Serial echocardiographic measures (n = 81) were obtained during a 5-year period and underwent blinded review. Longitudinal trajectories of ventricular and aortic valve function were modeled using mixed linear regression analysis. RESULTS: There was no hospital or late mortality. Five-year freedom from valve replacement was 75%. Comparison of preoperative and post-repair echocardiograms demonstrated reductions in aortic insufficiency (decreased in jet-width/aortic valve diameter ratio from 0.39 +/- 0.12 to 0.22 +/- 0.11; p < 0.0001), aortic stenosis (decreased in peak aortic valve gradient from 41 +/- 25 mm Hg to 29 +/- 15 mm Hg; p = 0.04), and left ventricular end-diastolic dimensions Z-score (decreased from 1.39 +/- 0.38 to 1.16 +/- 0.34; p < 0.001). During the follow-up period, post-repair jet-width and aortic valve diameter increased nonlinearly (p < 0.001). Patients with postoperative peak aortic gradients greater than 30 mm Hg had progression of aortic stenosis, whereas those with lesser postoperative peak gradients tended to regress during follow-up (p < 0.001). The decrement in Z-score of the left ventricular end-diastolic dimensions remained stable during the follow-up period. CONCLUSIONS: Aortic valve cusp extension can result in acceptable hemodynamic results with stabilization of left ventricular geometry. However, residual lesions are common and progression and regression of these lesions can be predicted based on echocardiographic data.

Adolescent↗
PubMed2006

Impact on outcomes after listing and transplantation, of a strategy to accept ABO blood group-incompatible donor hearts for neonates and infants.

BACKGROUND: Recent data suggest that ABO blood group-incompatible donor hearts are immunologically well tolerated in infants undergoing transplantation. METHODS: Competing-risks methodology was used to assess outcomes after listing and the impact of a strategy to accept heart grafts from any blood group donor for infants less than 18 months of age. RESULTS: From 1992 to 2002, there were 91 listing episodes in 84 patients (including 20 fetuses; 50% were male and 63% had congenital heart disease). Beginning in 1995, a strategy to accept ABO-incompatible organs was adopted. Competing-risks analysis showed that after 20 months 60% underwent transplantation, 18% died, and less than 1% were still listed; the remaining 21% were de-listed because of a change of surgical strategy (9%), improved clinical condition (8%), and deterioration to ineligibility (4%). Risk factors for transplantation included only a strategy to accept ABO-incompatible organs (P <.001). Risk factors for death included failure to accept ABO-incompatible organs (P =.002) and Canadian listing status 3 (P =.085) or 4 (P <.001). Multivariable parametric models were used to create competing risk predictions for outcomes specific to status and ABO-incompatible strategy. Higher status resulted in greater mortality regardless of strategy, although for any status, more patients underwent transplantation and fewer died using a strategy to accept ABO-incompatible organs. Parametric modeling of time-related freedom from death or retransplantation demonstrated no significant difference at 4 years posttransplantation (P =.78) for ABO-incompatible (74%) versus ABO-compatible transplants (72%). CONCLUSIONS: A strategy to accept ABO-incompatible donor hearts for infant transplantation significantly improves the likelihood of transplantation and reduces waiting list mortality while not adversely altering outcomes after transplantation.

ABO Blood-Group System↗
PubMed2006

Surgical repair of multiple muscular ventricular septal defects: the role of re-endocardialization strategy.

OBJECTIVE: Surgical repair of multiple muscular ventricular septal defects (Swiss cheese septum) is associated with important morbidity and mortality. We sought to examine factors associated with permanent heart block, early mortality, and time-related survival. Additionally, we evaluated a new approach, transatrial re-endocardialization of interventricular septum, to mitigate risk. METHODS: One hundred sixteen patients underwent surgery for multiple muscular ventricular septal defects (1982-2005), of whom 64 (55%) had associated cardiac anomalies. Twenty-seven consecutive patients (median age 0.54 years, range 15 days-7.2 years) underwent transatrial re-endocardialization (2002-2005). Forty-four percent had Swiss cheese septum (>4 defects). Multivariable regression analysis determined risk factors for pacemaker and survival. RESULTS: Operative mortality for the entire cohort was 9%. Risk factors for death were double-outlet right ventricle (odds ratio 44.7, P = .003), ventriculotomy (odds ratio 6.4, P = .03), and fewer multiple muscular ventricular septal defects repaired (odds ratio 4.7/defect, P = .04). Era mortalities differed: 16% for 1982 through 1990, 13% for 1990 through 1998, and 0% for 1999 through 2005, P = .006). Fourteen patients (12%) required a pacemaker. Time-related survivals at 1 and 10 years were 90% +/- 3% and 82% +/- 5%. Risk factors for death were double-outlet right ventricle (hazard ratio 8.3, P = .02) and longer bypass (hazard ratio 1.02/min, P = .02). In 27 re-endocardialization patients, a combined closure strategy to close 184 defects were applied: transatrial re-endocardialization (median 5, range 2-21), patch (median 1, range 0-4), and device (range 0-1). Post-repair ventricular function was good in 25 of 27 patients. The median number of residual defects was 1.5 (range 0-3), and median residual jet width on color Doppler was 2.3 mm (range 0-4.2 mm). One child required a pacemaker. There were no early or late deaths. CONCLUSIONS: Outcome of surgical repair of multiple muscular ventricular septal defects (Swiss cheese septum) has improved. Transatrial re-endocardialization strategy enables early complete or nearly complete obliteration of multiple muscular ventricular septal defects with minimal residual lesions (shunt, ventricular dysfunction). Long cardiopulmonary bypass duration is well tolerated. The incidence of permanent heart block has improved. Early echocardiographic and clinical outcomes are promising.

Adolescent↗
PubMed2006

First successful lower-extremity transplantation: technique and functional result.

Composite tissue transplantation has emerged as a viable alternative to prosthetics and complex reconstructive surgery. Thus far it is reserved for cases which cannot be effectively reconstructed and where it offers some benefits over prostheses. It has been used in the upper extremity with encouraging results and, most recently, in the face. This report outlines what is believed to be the first such use in the lower extremity. A normal lower limb in a 3-month-old ischiopagus twin who was not going to survive was transplanted to the appropriate pelvic position, revascularized, and reinnervated in an otherwise healthy sister. The limb survived and, because of the immune compatibility, did not require immune suppressive therapy. The return of muscle function in the transplanted limb is encouraging. The transplanted limb appears to be fully sensate. In addition to reinnervation, the limb is now spontaneously under the cortical control of the recipient.

Abdominal Muscles↗
PubMed2005

Outcomes and associated risk factors for aortic valve replacement in 160 children: a competing-risks analysis.

BACKGROUND: We sought to define patient characteristics, outcomes, and associated risk factors after aortic valve replacement (AVR) in children. METHODS AND RESULTS: Clinical records from children undergoing AVR from 1974 to 2004 at our institution were reviewed. Competing-risks methodology determined the time-related prevalence of 3 mutually exclusive end states: death, repeated replacement, and survival without subsequent AVR and their associated risk factors. Longitudinal echocardiographic data were analyzed by mixed linear-regression models. Children (n=160) underwent 198 AVRs, with 33 having >1. Competing-risks analysis predicted that 10 years from the initial AVR, 19% had died without subsequent AVR, 34% underwent a second AVR, and 47% remained alive without replacement. Risk factors for death without a second AVR included lower weight (P<0.001) and younger age at AVR (P=0.04), performance of aortic arch reconstruction together with AVR (P=0.03), and nonautograft use (P=0.03). Risk factors for a second AVR included earlier operation year (P=0.04) and implantation of a bioprosthetic or homograft valve (P=0.004). Analysis of serial echocardiographic measurements showed that pulmonary autograft use was associated with slower progression of peak aortic gradient (P=0.002), smaller left ventricular dimension (P=0.04), and decreased prevalence of aortic regurgitation (P=0.04). CONCLUSIONS: Mortality and repeated valve replacement are common after initial AVR in children, especially in younger patients and those with bioprosthetic or homograft valves. Pulmonary autograft use is associated with decreased mortality, slower gradient progression, and smaller left ventricular dimension.

Adolescent↗
PubMed2005

Postoperative chylothorax after cardiothoracic surgery in children.

BACKGROUND: The purpose of this study is to determine the incidence, risk factors, and outcomes for chylothorax in children undergoing cardiothoracic surgery. METHODS: Hospital databases were used to identify chylothorax cases. Surgical databases were used to identify all patients undergoing cardiothoracic surgery. Medical records were reviewed, including daily records of drainage volumes and management. RESULTS: From September 2000 to December 2002, there were 48 cases of chylothorax in 1,257 surgeries--an incidence of 3.8% (95% confidence interval: 2.8% to 4.8%). Overall mortality rate was similar, but cases had longer postoperative hospital stays (median, 22 versus 8 days; p < 0.001). Incidence of chylothorax was significantly higher with heart transplantation and Fontan procedures. Diagnosis was made at a median of 6 days after surgery. Duration of drainage was a median of 15 days, with 11 patients draining more than 30 days. Longer duration of drainage was associated with cavopulmonary anastomosis procedures and longer time to diagnosis of chylothorax. Nutritional management included low fat diet, enteral feeds enriched with medium-chain triglycerides, and parenteral nutrition. Five patients were treated with octreotide, 4 with thoracic duct ligation, and 1 with pleurodesis. Octreotide was associated with a variable effect on drainage. Thoracic duct ligation reduced, but did not stop drainage. CONCLUSIONS: Chylothorax increases duration of hospitalization after cardiovascular surgery in children. Early diagnosis may reduce the duration of chylothorax. Nutritional strategies remain the cornerstone for management of postoperative chylothorax. The impact of octreotide and surgical intervention is limited when reserved for patients with severe or prolonged drainage.

Adolescent↗
PubMed2005

Three-dimensional echocardiography improves the understanding of left atrioventricular valve morphology and function in atrioventricular septal defects undergoing patch augmentation.

OBJECTIVES: We sought to address the role of 3-dimensional echocardiography in the evaluation of the left atrioventricular valve in children with an atrioventricular septal defect who underwent patch augmentation of their valve for either regurgitation or left ventricular outflow tract obstruction. METHODS: Five children whose ages ranged between 4.5 and 9.2 years and who underwent patch augmentation of their left atrioventricular valve had a preoperative and postoperative transesophageal echocardiogram with 3-dimensional reconstruction to evaluate the left atrioventricular valve. The indication for operation was left atrioventricular valve regurgitation in 3 patients and left ventricular outflow tract obstruction in 2 patients. Three were rerepairs, and 2 were primary repairs. Both 3-dimensional morphology and color Doppler data were obtained. Two- and 3-dimensional findings were correlated with surgical observations through the use of direct inspection and video images obtained with a head-mounted super-VHS camera. RESULTS: In each case there was precise correlation between the 3-dimensional and surgical findings as to the cause of leaflet failure in those with regurgitation. The site that would require leaflet augmentation could be determined by means of 3-dimensional echocardiography. Three-dimensional echocardiography provided more specific detail as to the morphology and function of the left atrioventricular valve than did its 2-dimensional counterpart. CONCLUSIONS: Three-dimensional echocardiography provides detailed information about the status of the left atrioventricular valve in the atrioventricular septal defect and can aid in the planning of either primary or secondary repair.

Child↗
PubMed2005

Conventional and sutureless techniques for management of the pulmonary veins: Evolution of indications from postrepair pulmonary vein stenosis to primary pulmonary vein anomalies.

OBJECTIVE: We have previously reported a limited but favorable experience with a novel sutureless technique for surgical management of postoperative pulmonary vein stenosis occurring after repair of total anomalous pulmonary venous drainage. Because this technique requires integrity of the retrocardiac space for hemostasis, extension of the technique to the primary repair of pulmonary vein anomalies requires evaluation. This analysis reviews our experience with the sutureless technique in patients with postrepair pulmonary vein stenosis, as well as our extension of the technique into primary repair of pulmonary vein anomalies. METHODS: Retrospective univariable-multivariable analysis of all pulmonary vein stenosis procedures and sutureless pulmonary vein procedures over a 20-year period was performed. Cox proportional hazards modeling was used to identify variables associated with freedom from reoperation or death. RESULTS: Sixty patients underwent 73 procedures, with pulmonary vein stenosis present in 65 procedures. The sutureless technique was used in 40 procedures. Freedom from reoperation or death at 5 years after the initial procedure was 49%. Unadjusted freedom from reoperation or death was greater with the sutureless technique for patients with postrepair pulmonary vein stenosis ( P = .04). By using multivariable analysis, a higher pulmonary vein stenosis score was associated with greater risk of reoperation or death. After adjustment, the sutureless repair was associated with a nonsignificant trend toward greater freedom from reoperation or death ( P = .12). Despite the absence of retrocardiac adhesions, operative mortality was not increased with the sutureless technique ( P = .64). Techniques to control bleeding (intrapleural hilar reapproximation) and improve exposure (inferior vena cava division) were identified. CONCLUSION: The sutureless technique for postrepair pulmonary vein stenosis is associated with encouraging midterm results. Extension of the indications for the technique to primary repair appears safe with the development of simple intraoperative maneuvers.

Analysis of Variance↗
PubMed2005

Cardioprotective stress response in the human fetal heart.

OBJECTIVE: We propose that the fetal heart is highly resilient to hypoxic stress. Our objective was to elucidate the human fetal gene expression profile in response to simulated ischemia and reperfusion to identify molecular targets that account for the innate cardioprotection exhibited by the fetal phenotype. METHODS: Primary cultures of human fetal cardiac myocytes (gestational age, 15-20 weeks) were exposed to simulated ischemia and reperfusion in vitro by using a simulated ischemic buffer under anoxic conditions. Total RNA from treated and baseline cells were isolated, reverse transcribed, and labeled with Cy3 or Cy5 and hybridized to a human cDNA microarray for expression analysis. This analysis revealed a highly significant (false discovery rate, <3%) suppression of interleukin 6 transcript levels during the reperfusion phase confirmed by means of quantitative polymerase chain reaction (0.25 +/- 0.11-fold). Interleukin 6 signaling during ischemia and reperfusion was assessed at the protein expression level by means of Western measurements of interleukin 6 receptor, the signaling subunit of the interleukin 6 receptor complex (gp130), and signal transducer of activated transcription 3. Posttranslational changes in the protein kinase B signaling pathway were determined on the basis of the phosphorylation status of protein kinase B, mitogen-activated protein kinase, and glycogen synthase kinase 3beta. The effect of suppression of a prohypertrophic kinase, integrin-linked kinase, with short-interfering RNA was determined in an ischemia and reperfusion-stressed neonatal rat cardiac myocyte model. Endogenous secretion of interleukin 6 protein in culture supernatants was measured by enzyme-linked immunosorbent assay. RESULTS: Human fetal cardiac myocytes exhibited a significantly lower rate of apoptosis induction during ischemia and reperfusion and after exposure to staurosporine and recombinant interleukin 6 compared with that observed in neonatal rat cardiac myocytes ( P < .05 for all comparisons, analysis of variance). Exposure to exogenously added recombinant interleukin 6 increased the apoptotic rate in both rat and human fetal cardiac myocytes ( P < .05). Short-interfering RNA-mediated suppression of integrin-linked kinase, a prohypertrophy upstream kinase regulating protein kinase B and glycogen synthase kinase 3beta phosphorylation, was cytoprotective against ischemia and reperfusion-induced apoptosis in neonatal rat cardiac myocytes ( P < .05). CONCLUSIONS: Human fetal cardiac myocytes exhibit a uniquely adaptive transcriptional response to ischemia and reperfusion that is associated with an apoptosis-resistant phenotype. The stress-inducible fetal cardiac myocyte gene repertoire is a useful platform for identification of targets relevant to the mitigation of cardiac ischemic injury and highlights a novel avenue involving interleukin 6 modulation for preventing the cardiac myocyte injury associated with ischemia and reperfusion.

Adaptation, Physiological↗
PubMed2005

Biventricular repair in children with atrioventricular septal defects and a small right ventricle: anatomic and surgical considerations.

OBJECTIVE: We sought to characterize morphology and to evaluate a strategy of using biventricular repair in patients with a small right ventricle and an unbalanced atrioventricular septal defect. METHODS: Thirty-eight children with a small right ventricle and an atrioventricular septal defect underwent operative therapy. Thirty-two had biventricular repair, and 6 had single-ventricle palliation. A small right ventricle was defined on the basis of echocardiographic measurements expressed as the atrioventricular valve index (ie, right atrioventricular valve/left atrioventricular valve area) and as the ratio of right ventricular to left ventricular length. Validation of measurements in patients with a small right ventricle and an atrioventricular septal defect was achieved by comparison with balanced case-matched control subjects with atrioventricular septal defects. RESULTS: Children with a small right ventricle and an atrioventricular septal defect had a lower atrioventricular valve index (mean, 0.41 +/- 0.1 vs 0.52 +/- 0.1 [control], P < .0001) and lower right ventricular/left ventricular length ratio (0.78 +/- 0.1 vs 0.99 +/- 0.17 [control], P < .0001). Children with a small right ventricle undergoing single-ventricle palliation had the smallest right ventricular dimensions. There were 4 operative deaths. Three patients with a small right ventricle and an atrioventricular septal defect who underwent biventricular repair and had an atrioventricular valve index of less than 0.50 required early reoperation for right ventricular inadequacy. A restrictive atrial fenestration was created in 11 infants. Survival at 10 years was 87% for patients undergoing biventricular repair versus 100% for control subjects (P = .042). CONCLUSIONS: Extending the use of biventricular repair in properly selected patients with a small right ventricle and an atrioventricular septal defect is feasible. An atrial fenestration improves the physiologic tolerance to repair in selected patients. The use of biventricular repair in children with atrioventricular valve indexes of less than 0.50 requires caution.

Cardiac Surgical Procedures↗
PubMed2005

The remote ischemic preconditioning stimulus modifies gene expression in mouse myocardium.

BACKGROUND: We have recently demonstrated that remote ischemic preconditioning reduces ischemia-reperfusion injury in animal models. The mechanisms by which the remote ischemic preconditioning stimulus exerts its effect remain to be fully defined, and its effect on myocardial gene expression is unknown. We tested the hypothesis that remote ischemic preconditioning modifies myocardial gene expression immediately after the remote ischemic preconditioning stimulus (early phase) and 24 hours later (late phase). METHODS: Twenty male (C57BL/6) 10- to 12-week-old mice were randomized into 4 groups: group 1 (control, early phase; n = 5), group 2 (remote ischemic preconditioning, early phase; n = 5), group 3 (control, late phase; n = 5), and group 4 (remote ischemic preconditioning, late phase; n = 5). Groups 2 and 4 underwent remote ischemic preconditioning induced by 6 cycles of 4 minutes of occlusion and 4 minutes of reperfusion of the femoral artery. Groups 1 and 2 were killed 15 minutes after completion of sham procedure or remote ischemic preconditioning, and the hearts were removed and frozen in liquid nitrogen. Groups 3 and 4 were killed 24 hours after remote ischemic preconditioning, and the hearts were harvested in the same fashion. Gene expression was assessed by using the Affymetrix MG-430A chip (Affymetrix, Santa Clara, Calif). RESULTS: Data filtering (P < .05, analysis of variance) and hierarchic 2-way clustering identified significant differences in gene expression among the 4 groups. Genes involved in protection against oxidative stress (eg, Hadhsc, Prdx4, and Fabp4) and cytoprotection (Hsp73) were upregulated, whereas many proinflammatory genes (eg, Egr-1 and Dusp 1 and 6) were suppressed. CONCLUSION: A simple remote ischemic preconditioning stimulus modifies myocardial gene expression by upregulating cardioprotective genes and suppressing genes potentially involved in the pathogenesis of ischemia-reperfusion injury.

Animals↗
PubMed2004

The remote ischemic preconditioning stimulus modifies inflammatory gene expression in humans.

Remote ischemic preconditioning (IPC) reduces tissue injury caused by ischemia-reperfusion (IR) in distant organs. We tested the hypothesis that remote IPC (rIPC) modifies inflammatory gene transcription in humans. Using a microarray method, we demonstrated that a simple model of brief forearm ischemia suppresses proinflammatory gene expression in circulating leukocytes. Genes encoding key proteins involved in cytokine synthesis, leukocyte chemotaxis, adhesion and migration, exocytosis, innate immunity signaling pathways, and apoptosis were all suppressed within 15 min (early phase IPC) and more so after 24 h (second window IPC). Changes in leukocyte CD11b expression measured by flow cytometry mirrored this pattern, with there being a significant (P = 0.01) reduction at 24 h. The results of this study show that the rIPC stimulus modifies leukocyte inflammatory gene expression. This effect may contribute to the protective effect of IPC against IR injury and may have broader implications in other inflammatory processes. This is the first study of human gene expression following rIPC stimulus. rIPC stimulus suppressed proinflammatory gene transcription in human leukocytes.

Adult↗
PubMed2004

Gene expression profiles in children undergoing cardiac surgery for right heart obstructive lesions.

BACKGROUND: The global myocardial stress response during cardiac surgery has not been systematically studied, nor is it known whether the response of the neonatal myocardium is intrinsically different from that of older children. To determine the age-related molecular basis of this response, we conducted microarray-based differential gene expression profiling on right ventricular tissue samples acquired in patients of varying ages with right ventricular outflow tract obstruction. METHODS: We studied gene expression profiles in 24 patients during operations for lesions involving right ventricular outflow tract obstruction age stratified into group I (7 patients, aged 5 to 66 days; mean, 30 days) and group II (17 patients, aged 4 months to 12.5 years; mean, 2.8 years). Myocardial samples were taken from the right ventricular outflow tract after aortic occlusion and archived in liquid nitrogen. RNA isolation, fluorescence labeling of complementary DNA, hybridization to spotted arrays containing 19,008 characterized or unknown human complementary DNAs, and quantitative fluorescence scanning of gene-expression intensity were performed at the University of Toronto Health Network Microarray Centre. Data were analyzed with the Significance Analysis for Microarrays program. Minimum Information About Microarray Experiments-compliant, log2-normalized data sets were compared to ascertain potential statistical differences in gene expression between patient groups. RESULTS: There were no hospital deaths or major postoperative morbid events. We identified 50 transcripts differentially expressed in the neonatal group (the predicted false discovery rate was <0.8 transcripts). The neonatal pattern of gene expression (group I) was dominated by genes with literature-validated cardioprotective, antihypertrophic, and antiproliferative properties, including increases in atrial natriuretic peptide, protein phosphatase 2A, small GTPase rap1, and protein inhibitor of activated STAT protein, PIASy. Several transcripts have not been previously reported in heart. CONCLUSIONS: Neonatal myocardium has a unique pattern of gene expression, which may result from developmental (age-related) differences or reflect a more severe disease phenotype independent of age effects per se. The neonatal transcript profile seems to reflect a stress-induced protective program composed of genes with functions diametrically opposed to those expected to be related to the pathogenesis of critical right ventricular outflow tract obstruction, thus revealing a novel and compensatory antidisease transcriptional response in the neonatal heart.

Atrial Natriuretic Factor↗