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J Thorac Cardiovasc Surg 2003;126:1736-1745
© 2003 The American Association for Thoracic Surgery
Surgery for congenital heart disease |
a Division of Cardiothoracic Surgery, The Children's Hospital of Philadelphia, Philadelphia, Pa, USA
b Division of Psychology, The Children's Hospital of Philadelphia, Philadelphia, Pa, USA
c Division of Genetics, The Children's Hospital of Philadelphia, Philadelphia, Pa, USA
d Division of General Pediatrics, The Children's Hospital of Philadelphia, Philadelphia, Pa, USA
e Division of Cardiology, The Children's Hospital of Philadelphia, Philadelphia, Pa, USA
f Division of Neurology, The Children's Hospital of Philadelphia, Philadelphia, Pa, USA
g Department of Anesthesiology, Duke University Medical Center, Durham, NC, USA
h Division of Neurology, Duke University Medical Center, Durham, NC, USA
i Department of Biostatistics, University of Washington, Seattle, Wash, USA
j Division of Cardiothoracic Anesthesia, The Children's Hospital of Philadelphia, Philadelphia, Pa, USA
k Department of Medicine (Medical Genetics), University of Washington, Seattle, Wash, USA
Received for publication November 25, 2002; revisions received March 7, 2003; accepted for publication April 11, 2003.
* Address for reprints: J. William Gaynor, MD, Division of Cardiothoracic Surgery, The Children's Hospital of Philadelphia, 34th and Civic Center Blvd, Ste 8527, Philadelphia, PA, USA 19104
gaynor{at}email.chop.edu
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Abstract |
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METHODS: A single-institution prospective study of patients 
6 months of age undergoing cardiopulmonary bypass for repair of congenital heart defects was undertaken to evaluate the association between apolipoprotein E genotype and postoperative neurodevelopmental dysfunction. Developmental outcomes were evaluated at 1 year of age by using the Bayley Scales of Infant Development.
RESULTS: One-year evaluation was performed in 244 patients. After adjustment for preoperative and postoperative covariates—including gestational age, age at operation, sex, race, socioeconomic status, cardiac defect, and use of deep hypothermic circulatory arrest—the apolipoprotein E 
2 allele was associated with a worse neurologic outcome as assessed by the Psychomotor Developmental Index of the Bayley Scales of Infant Development (P = .036). Patients with the apolipoprotein E 2 allele had approximately a 7-point decrease in the Psychomotor Developmental Index.
CONCLUSIONS: Apolipoprotein E 2 allele carriers had significantly lower Psychomotor Development Index scores at 1 year of age after infant cardiac surgery. The effect was independent of ethnicity, socioeconomic status, cardiac defect, and use of deep hypothermic circulatory arrest. An effect of the apolipoprotein E 4 allele was not detected. Genetic polymorphisms that decrease neuroresiliency and impair neuronal repair after central nervous system injury are important risk factors for neurodevelopmental dysfunction after infant cardiac surgery.
The role of genetic polymorphisms that increase susceptibility to neurologic injury has not been explored in children with CHD. Apolipoprotein E (APOE) is an important regulator of cholesterol metabolism.9-12 APOE-containing lipoproteins are the primary lipid transport vehicles in the CNS. There is increasing evidence that APOE is important for neuronal repair.9,11-15 There are 3 common isoforms of APOE (E2, E3, and E4), which are encoded by 3 alleles (2, 3, and 4, respectively) and vary by single amino acid substitutions. A strong association has been validated between the APOE 4 allele and Alzheimer's disease.10 The APOE genotype has been shown to have an important role as a determinant of neurologic recovery after CNS ischemia, intracerebral hemorrhage, and traumatic brain injury.13-17 There is evidence of an association of APOE genotype with neurocognitive decline after cardiac surgery in adults.18-20 We evaluated the association between postoperative neurologic dysfunction and APOE genotype in infants undergoing cardiac surgery.
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Methods |
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Informed consent was obtained from the parent or guardian. Operations were performed by 4 cardiac surgeons with a dedicated team of cardiac anesthesiologists. Alpha-stat blood gas management was used. DHCA was used at the surgeon's discretion. The mean hematocrit after institution of CPB and hemodilution was 26% ± 3.5%. Before DHCA, patients underwent core cooling with topical hypothermia to a nasopharyngeal temperature of 18°C. Modified ultrafiltration was performed in all patients.
APOE genotype determination
Whole blood was obtained before the operation and stored at 4°C. Genomic DNA was prepared and used to determine APOE genotypes by using a previously published method.18,21
One-year neurodevelopmental examination
Children were evaluated at 12 months of age, corrected for prematurity, plus or minus 2 weeks. All study personnel were blinded to the genotype. Socioeconomic status (SES) and ethnicity were determined by parental reporting. Developmental assessment included the Bayley Scales of Infant Development, which yielded 2 scores: the Psychomotor Development Index (PDI) and the Mental Developmental Index (MDI). The MDI assesses memory, problem solving, early number concepts, generalization, vocalizations, and language and social skills. The PDI assesses control of gross muscle function, including crawling and walking, as well as fine muscle skills necessary for prehension, use of writing instruments, and imitation of hand movements. Both the MDI and PDI are normalized to a mean of 100 with an SD of 15. They yield an accurate assessment of the child's developmental status at 1 year but are not predictors of later outcome, such as IQ in adolescence. The evaluation also included medical history, growth measurements, and detailed neurologic examination assessing active and passive tone, reflexes, gross motor skills, and visual and auditory responses. Patients were evaluated by a genetic dysmorphologist. Because recognition of genetic syndromes in neonates may be difficult, some children with genetic abnormalities had been enrolled as infants. Chromosome analysis and testing for microdeletions of chromosome 22q11 were performed as indicated.
Data analysis
Patients were grouped according to cardiac diagnosis: group 1 consisted of patients with hypoplastic left heart syndrome (HLHS); group 2 consisted of patients with conotruncal defects (tetralogy of Fallot, transposition of the great arteries, truncus arteriosus, and so on); and all other defects were coded as group 3. Patients were additionally coded according to a previously described classification incorporating anatomy and perioperative physiology that has been shown to be predictive of perioperative mortality.22 Class I is 2 ventricles with no aortic arch obstruction, class II is 2 ventricles with aortic arch obstruction, class III is single ventricle with no arch obstruction, and class IV is single ventricle with arch obstruction. Patients with tetralogy of Fallot and transposition of the great arteries are in class I, whereas patients with HLHS or variants are in class IV. Results of the genetic evaluations were classified as normal if no genetic or chromosomal abnormality was demonstrated, abnormal if a specific diagnosis was confirmed, and suspect if there was evidence of a genetic syndrome that could not be confirmed. Results of the neurologic examinations were classified as normal if no abnormalities or only mild abnormalities that did not affect motor skills were found, suspect when there was a moderate degree of abnormality (ie, moderate hypotonia with generally normal reflexes and mildly abnormal motor skills), and abnormal whenever significant abnormalities of tone, reflexes, or motor skills were present.
Statistical analysis
The primary outcome was the PDI, chosen on the basis of the Boston Circulatory Arrest Study finding that use of DHCA was associated with a significant decrease in the PDI.2 Secondary measures of neurologic outcome included the MDI, head circumference at 1 year, and neuromuscular examination. The primary predictor of interest was APOE genotype. Subjects were grouped into the 2 group (22 and 32), the 33 group, and the 4 group (34 and 44). There were no 22 patients in the study population. Five 24 subjects were excluded from the analyses because the effects of the 2 and 4 alleles are opposing in Alzheimer's disease. Twelve subjects with a missing APOE genotype were also excluded. Because PDI was selected as the primary outcome, we did not make multiple comparison adjustments for analyses of the additional correlated outcomes. Baseline evaluation of APOE genotype effects used analysis of variance with 2 degrees of freedom (df), and further investigation of the APOE effects after covariate adjustment focused on separate comparisons of the 2 group versus the 33 group and the 4 group versus the 33 group.
Linear regression was used to characterize the crude and adjusted association between the 1-year outcomes PDI, MDI, and head circumference. Logistic regression was used for the categorical neuromuscular examination outcome. Suspect and abnormal neuromuscular examination groups were pooled to form a "not normal" group and thus derive a binary response variable. Three regressions were performed for each outcome. First, the marginal association between genotype and outcome was considered without adjustment for any covariates. Next, the preoperative adjusted regressions included preoperative characteristics of race (white, black, or other), sex, SES, gestational age, birth weight, head circumference percentiles, diagnostic group, and suspected or definite genetic disorder. Apgar scores were not significantly associated with outcome, and estimates of genotype effect did not substantially change with or without adjustment for Apgar score. Because 11 children were missing Apgar data, Apgar scores were dropped from the regression model rather than imputing the scores or dropping those cases. Missing percentiles of birth weight (n = 2) and head circumferences at birth (n = 24) were imputed by using the percentile at the 1-year follow-up examination. Subjects missing birth head circumference measurements were dropped from the analysis of 1-year head circumference. Finally, the preoperative and postoperative adjusted regression included these variables plus variables related to the cardiac repair. Operative variables included class (I-IV), operation, age and weight at operation, hematocrit on CPB, total support time (duration of CPB plus DHCA), number of bypass runs, and use of DHCA. The relationship between APOE genotype group and all covariates was explored by analysis of variance for quantitative traits and by 
2 analysis for categorical traits.
Interaction between genotype and major preoperative or postoperative covariates was tested by including interaction terms in the preoperative and postoperative adjusted regression analysis. Because the power to detect genotype by covariate interactions was expected to be low, fitted genotype effects for patient subsets were examined to determine whether the same general trends were manifested. Specifically, the signs of coefficients for the APOE effects were examined in subgroups on the basis of presence of a suspected or definite genetic disorder, males versus females, Caucasian children, SES, diagnostic group, support time, and use of DHCA.
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Results |
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70 in 28 patients (11%), and the PDI was 70 in 80 patients (33%). The neuromuscular examination had abnormal or suspect results in 96 patients (39%), with hypotonia in 85; hypertonia in 5; mixed tonal abnormalities in 3; and asymmetry, spastic quadriplegia, and hyperreflexia in 1 each. Head circumference at 1 year was at or below the fifth percentile in 60 patients (25%). Genetic examination results were normal in 175 patients, a definite genetic abnormality was present in 29 (12%; including 13 with 22q11 microdeletions), and 40 patients were classified as having suspect results.
No demographic or preoperative characteristics were significantly related to APOE genotype (Table 2). Although the test for differences of APOE distribution between male and female infants was not significant (P = .130), there was a trend for a deficit of 4-containing genotypes in males. Allele frequencies in Caucasian males in this sample were 2, 0.081; 3, 0.812; and 4, 0.108; for Caucasian females, they were 2, 0.075; 3, 0.769; and 4, 0.157. Allele frequencies in Caucasian subjects are expected to be 0.085 for 2, 0.768 for 3, and 0.147 for 4. The APOE genotype distribution did not significantly differ from Hardy-Weinberg proportions.21 APOE genotype frequencies are expected to vary by race.22-25 Although this variation was not statistically significant, the expected deficit of 4 alleles in Asians was seen. The distribution of male and female subjects did not differ significantly by race (P = .17; data not shown). Operative variables for the first operation and for the entire first year of life are shown in Tables 3 and 4, respectively. None was related to APOE genotype (all P > .2).
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2 group performed less well than those with the reference 33 genotype. Comparing the 2 group with the other groups pooled gave P values of .006, .041, .041, and .27 for PDI, MDI, neuromuscular examination, and head circumference, respectively (Table 7).
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2 effect on PDI remained significant after adjusting for the preoperative (P = .023) or preoperative and postoperative (P = .036) covariates (Table 7). After adjustment for covariates, the APOE 2 group had an approximately 7-point decrease in PDI score. The smaller 2 effect on MDI was not significant after preoperative (P = .09) or preoperative plus postoperative (P = .13) covariate adjustment, although the trend of poorer outcome among the 2 subjects persisted. The effect of APOE 2 on neuromuscular examination was no longer significant after preoperative (P = .18) or preoperative plus postoperative (P = .26) covariate adjustment. Head circumference at 1 year did not have a significant APOE genotype effect with or without covariate adjustment.
An APOE 4 effect was not seen for any outcome. The regression coefficients for the covariate-adjusted regression were near 0 for PDI and MDI. After covariate adjustment, nonsignificantly negative coefficients were seen for the 4 effect on PDI, MDI, and head circumference.
There was no statistically significant interaction between the pooled APOE 2 group and presence of a genetic syndrome, sex, race, SES, diagnostic group, operative class, support time, or use of DHCA in the analysis of PDI or MDI. Power to detect interactions was expected to be low in this sample size; therefore, the estimated APOE coefficients specific to covariate strata were examined for consistency. For prediction of PDI, the coefficients of the pooled group compared with the 33 reference group were negative for all strata evaluated, except for diagnostic group 1 (HLHS; 1.2; SD, 7.3) and Hispanic race (13.1; SD, 17.0). The effect of the 2 group on PDI was -4.1 (SD, 3.9) in subjects with normal genetic evaluation results and -6.9 (SD, 8.0) in subjects who were thought to have a genetic disorder. The 2 coefficient for PDI was -1.7 (SD, 5.3) in females and -10.4 (SD, 4.2) in males. The 2 coefficient for MDI analysis was negative in all strata except diagnostic group 1 (HLHS; 3.2; SD, 6.6) and class IV patients (1.7; SD, 6.0).
For the analysis of PDI and MDI, there was no significant interaction between the APOE 34 and 44 genotype groups and presence of a genetic syndrome, sex, race, SES, diagnostic group, operative class, or DHCA. For neuromuscular examination, the 2 group generally had worse examination results across the strata evaluated. A marginally significant APOE genotype x sex interaction (P = .0581) was detected in the analysis of neurologic examination. Only the 2 group males had worse examination results than the 33 genotype group (-1.8; SD, 0.8); the 2 group coefficient for females was 1.0 (SD, 0.9).
For the prediction of head circumference, a marginal APOE genotype x genetic diagnosis interaction was detected (P = .0503). The coefficient for the 2 group without evidence of a genetic disorder was -7.4 (7.2), whereas that for the 2 group with evidence of a genetic disorder was 20.0 (SD, 14.3). The 4 coefficients without and with evidence of a genetic disorder were 0.05 (SD, 5.5) and 22.9 (SD, 13.6), respectively.
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Discussion |
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2 allele to predict lower PDI at 1 year of age after infant cardiac surgery; this is independent of race, SES, cardiac defect, and use of DHCA. This finding is consistent with the hypothesis that APOE genotypes other than the common 33 predict decreased neuroresiliency after CNS injury. An APOE 4 effect is not detectable.
The gene for the human APOE is located on the long arm of chromosome 19 and codes for a 299–amino acid protein.11 The most common allele in humans is 3, and there are 2 other common alleles, 2 and 4, whose protein products differ from that of 3 by single amino acid substitutions. There are 3 homozygous genotypes (22, 33, and 44) and 3 heterozygous genotypes (23, 24, and 34). Allele frequency varies according to ethnic background.21-27
The APOE protein is the receptor ligand for low-density lipoprotein cholesterol. APOE-containing lipoproteins are the primary lipid transport vehicles in the CNS. APOE modulates lipoprotein levels by effects on clearance rate, lipolytic conversion, and very-low-density lipoprotein (VLDL) triglyceride production.11 In addition, APOE has an important role in mobilization and redistribution of cholesterol and phospholipids during remodeling of neuronal membranes. The normal function of APOE within neurons is thought to be maintenance of microtubular integrity and stabilization of the neuronal cytoskeleton.11 APOE synthesis is upregulated by astrocytes and oligodendrocytes after CNS injury or cerebral ischemia. After an injury, APOE immunoreactivity increases first in astrocytes and later in neurons. The temporal changes in localization and levels of APOE are consistent with an upregulation of APOE by astrocytes in response to injury, release into the extracellular space, and uptake by neurons. APOE immunoreactivity after global ischemia is localized to vulnerable regions such as the caudate and CA1 region of the hippocampus. Studies in APOE knockout mice have shown that APOE deficiency worsens neuronal injury after cerebral ischemia and compromises the blood-brain barrier after CNS injury.9,11,28 Mechanisms by which APOE may modify CNS injury include protection against oxidative stress, modulation of the glial response to inflammation, and a direct neurotropic effect on injured neurons.7,9,29,30
Infants undergoing cardiac surgery are at risk for CNS injury and adverse neurodevelopmental sequelae that significantly diminish the quality of life for these children and their parents.1-6 The need for early intervention, special education, and rehabilitative services results in considerable cost to society. Significant interindividual variation in outcome exists that cannot be completely explained by previously reported risk factors.3,5,6 Recent studies suggest that APOE 4 may be a risk factor for neurocognitive decline after heart surgery in adults; however, the evidence is not conclusive.18-20 The mechanisms of CNS injury during infant cardiac surgery are poorly understood and are likely different from those in adults.7 Children with CHD often have congenital CNS anomalies; in addition, many are hypoxic before and after surgery. Use of DHCA results in a period of global cerebral ischemia. Mechanisms of CNS injury in infants undergoing cardiac surgery include hypoxia/ischemia, emboli, reactive oxygen species, and inflammatory microvasculopathy.7 APOE genotype has been shown to modify the inflammatory response to CPB and is a risk factor for postoperative renal dysfunction.29,31,32
Previous studies have implicated APOE 4 as a risk factor for recovery after brain injury and for Alzheimer's disease.9-13 Few studies have focused on the 2 allele; most classified patients as 4 positive or 4 negative and did not assess the 2 allele because of its rarity. APOE 2 has been shown to adversely influence recovery after ischemic stroke and cardiac arrest and to increase the risk of intracerebral hemorrhage.12,14-17 The frequency of all 3 APOE alleles suggests some balancing selection; certain alleles are better under some conditions, and other alleles are better under other conditions.
Although this study provides strong evidence of an adverse effect of the APOE 2 allele on neurodevelopmental outcome, there are several limitations. Children with CHD are heterogeneous, and many factors besides the genetic profile affect outcome. However, the sequential analysis performed in this study adjusted for both patient and procedural factors known to affect outcome. Furthermore, no interaction of APOE genotype with these factors could be identified. In addition, the APOE 2 allele is rare, and the possibility that the APOE genotype is a surrogate for some unidentified factor cannot be excluded. There is evidence that the APOE alleles are heterogeneous within themselves, and some variants may be more strongly related to outcome than others. Full sequencing of the APOE region of 72 African American and European individuals detected many single nucleotide polymorphisms. These studies suggest that there is a substructure within the common 2, 3, and 4 alleles.33 In other words, each of these alleles is heterogeneous, although primarily in the noncoding regions. Although it is possible that an unidentified subset of the 2 alleles is associated with poor outcome, rather than the entire 2 group, a direct effect of the coding change is the most likely cause of an association. The lack of any trend toward a performance difference among carriers of the 4 allele suggests that a true 4 effect was not missed. Finally, neurodevelopmental assessment at 1 year of age is not predictive of long-term outcome. Only further evaluation of these children at an older age can determine whether APOE genotype is a risk factor for worse long-term outcome.
In summary, the APOE 2 allele predicts worse neurodevelopmental outcome at 1 year of age after infant repair of CHD. This APOE genotype-environment interaction demonstrates that genetic polymorphisms that impair neuroresiliency and CNS recovery may explain some of the interindividual variation in developmental outcome after surgery for CHD. Further studies, with more reliable and thorough testing, are necessary as the children reach school age to determine whether APOE genotype predicts a worse long-term neurodevelopmental outcome.
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Acknowledgments |
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Footnotes |
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References |
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4 allele and outcome in cerebrovascular disease. Stroke. 1998;29:1882–18874 genotype predicts a poor outcome in survivors of traumatic brain injury. Neurology. 1999;52:244–2484 allele and the pathological features in cerebral amyloid angiopathy-related hemorrhage. J Neuropathol Exp Neurol. 1999;58:711–718[Medline]This article has been cited by other articles:
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  R. G. Ohye, J. W. Gaynor, N. S. Ghanayem, C. S. Goldberg, P. C. Laussen, P. C. Frommelt, J. W. Newburger, G. D. Pearson, S. Tabbutt, G. Wernovsky, et al. Design and rationale of a randomized trial comparing the Blalock-Taussig and right ventricle-pulmonary artery shunts in the Norwood procedure. J. Thorac. Cardiovasc. Surg., October 1, 2008; 136(4): 968 - 975. [Abstract] [Full Text] [PDF]
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 B. S. Silbert, L. A. Evered, D. A. Scott, and T. F. Cowie The Apolipoprotein E {epsilon}4 Allele is not Associated With Cognitive Dysfunction in Cardiac Surgery Ann. Thorac. Surg., September 1, 2008; 86(3): 841 - 847. [Abstract] [Full Text] [PDF]
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 S. Tabbutt, A. S. Nord, G. P. Jarvik, J. Bernbaum, G. Wernovsky, M. Gerdes, E. Zackai, R. R. Clancy, S. C. Nicolson, T. L. Spray, et al. Neurodevelopmental Outcomes After Staged Palliation for Hypoplastic Left Heart Syndrome Pediatrics, March 1, 2008; 121(3): 476 - 483. [Abstract] [Full Text] [PDF]
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G. Wernovsky Improving neurologic and quality-of-life outcomes in children with congenital heart disease: Past, present, and future J. Thorac. Cardiovasc. Surg., February 1, 2008; 135(2): 240 - 242. [Full Text] [PDF]
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I. Zeltser, G. P. Jarvik, J. Bernbaum, G. Wernovsky, A. S. Nord, M. Gerdes, E. Zackai, R. Clancy, S. C. Nicolson, T. L. Spray, et al. Genetic factors are important determinants of neurodevelopmental outcome after repair of tetralogy of Fallot J. Thorac. Cardiovasc. Surg., January 1, 2008; 135(1): 91 - 97. [Abstract] [Full Text] [PDF]
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J. A. Ballweg, G. Wernovsky, R. F. Ittenbach, J. Bernbaum, M. Gerdes, P. R. Gallagher, T. E. Dominguez, E. Zackai, R. R. Clancy, S. C. Nicolson, et al. Hyperglycemia After Infant Cardiac Surgery Does Not Adversely Impact Neurodevelopmental Outcome Ann. Thorac. Surg., December 1, 2007; 84(6): 2052 - 2058. [Abstract] [Full Text] [PDF]
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J. W. Gaynor, G. Wernovsky, G. P. Jarvik, J. Bernbaum, M. Gerdes, E. Zackai, A. S. Nord, R. R. Clancy, S. C. Nicolson, and T. L. Spray Patient characteristics are important determinants of neurodevelopmental outcome at one year of age after neonatal and infant cardiac surgery J. Thorac. Cardiovasc. Surg., May 1, 2007; 133(5): 1344 - 1353. [Abstract] [Full Text] [PDF]
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C. S. Goldberg, E. L. Bove, E. J. Devaney, E. Mollen, E. Schwartz, S. Tindall, C. Nowak, J. Charpie, M. B. Brown, T. J. Kulik, et al. A randomized clinical trial of regional cerebral perfusion versus deep hypothermic circulatory arrest: Outcomes for infants with functional single ventricle J. Thorac. Cardiovasc. Surg., April 1, 2007; 133(4): 880 - 887. [Abstract] [Full Text] [PDF]
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 G. D. Williams and C. Ramamoorthy Brain monitoring and protection during pediatric cardiac surgery. Seminars in Cardiothoracic and Vascular Anesthesia, March 1, 2007; 11(1): 23 - 33. [Abstract] [PDF]
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H. P. Grocott Genetic influences on cerebral outcome after cardiac surgery. Seminars in Cardiothoracic and Vascular Anesthesia, December 1, 2006; 10(4): 291 - 296. [Abstract] [PDF]
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 M. A. Padula and A. M. Ades Neurodevelopmental Implications of Congenital Heart Disease NeoReviews, July 1, 2006; 7(7): e363 - e369. [Full Text] [PDF]
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T.-Y. Hsia and P. J. Gruber Factors Influencing Neurologic Outcome After Neonatal Cardiopulmonary Bypass: What We Can and Cannot Control Ann. Thorac. Surg., June 1, 2006; 81(6): S2381 - S2388. [Abstract] [Full Text] [PDF]
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J. R. Kaltman, G. P. Jarvik, J. Bernbaum, G. Wernovsky, M. Gerdes, E. Zackai, R. R. Clancy, S. C. Nicolson, T. L. Spray, and J. W. Gaynor Neurodevelopmental outcome after early repair of a ventricular septal defect with or without aortic arch obstruction J. Thorac. Cardiovasc. Surg., April 1, 2006; 131(4): 792 - 798. [Abstract] [Full Text] [PDF]
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H. H. Hovels-Gurich, K. Konrad, D. Skorzenski, C. Nacken, R. Minkenberg, B. J. Messmer, and M.-C. Seghaye Long-Term Neurodevelopmental Outcome and Exercise Capacity After Corrective Surgery for Tetralogy of Fallot or Ventricular Septal Defect in Infancy. Ann. Thorac. Surg., March 1, 2006; 81(3): 958 - 966. [Abstract] [Full Text] [PDF]
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J. W. Gaynor, G. Wernovsky, and R. Clancy Invited commentary. Ann. Thorac. Surg., March 1, 2006; 81(3): 967 - 967. [Full Text] [PDF]
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 M. V. Podgoreanu and D. A. Schwinn New Paradigms in Cardiovascular Medicine: Emerging Technologies and Practices: Perioperative Genomics J. Am. Coll. Cardiol., December 6, 2005; 46(11): 1965 - 1977. [Abstract] [Full Text] [PDF]
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A. H. Schultz, G. P. Jarvik, G. Wernovsky, J. Bernbaum, R. R. Clancy, J. A. D'Agostino, M. Gerdes, D. McDonald-McGinn, S. C. Nicolson, T. L. Spray, et al. Effect of congenital heart disease on neurodevelopmental outcomes within multiple-gestation births J. Thorac. Cardiovasc. Surg., December 1, 2005; 130(6): 1511 - 1516. [Abstract] [Full Text] [PDF]
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F. L. Hanley Religion, politics...deep hypothermic circulatory arrest J. Thorac. Cardiovasc. Surg., November 1, 2005; 130(5): 1236 - 1236. [Full Text] [PDF]
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