Stephen G. Miller

Does Initial Shunt Type for the Norwood Procedure Affect Echocardiographic Measures of Cardiac Size and Function During Infancy? The Single Ventricle Reconstruction Trial

Background— The Pediatric Heart Network trial comparing outcomes in 549 infants with single right ventricle undergoing a Norwood procedure randomized to modified Blalock-Taussig shunt or right ventricle–pulmonary artery shunt (RVPAS) found better 1-year transplant-free survival in those who received RVPAS. We sought to compare the impact of shunt type on echocardiographic indices of cardiac size and function up to 14 months of age. Methods and Results— A core laboratory measured indices of cardiac size and function from protocol exams: early after Norwood procedure (age 22.5±13.4 days), before stage II procedure (age 4.8±1.8 months), and at 14 months (age 14.3±1.2 months). Mean right ventricular ejection fraction was <50% at all intervals for both groups and was higher in the RVPAS group after Norwood procedure (49±7% versus 44±8%; P<0.001) but was similar by 14 months. Tricuspid and neoaortic regurgitation, diastolic function, and pulmonary artery and arch dimensions were similar in the 2 groups at all intervals. Neoaortic annulus area (4.2±1.2 versus 4.9±1.2 cm2/m2), systolic ejection times (214.0±29.4 versus 231.3±28.6 ms), neoaortic flow (6.2±2.4 versus 9.4±3.4 L/min per square meter), and peak arch velocity (1.9±0.7 versus 2.2±0.7 m/s) were lower at both interstage examinations in the RVPAS compared with the modified Blalock-Taussig shunt group (P<0.001 for all), but all were similar at 14 months. Conclusions— Indices of cardiac size and function after the Norwood procedure are similar for modified Blalock-Taussig shunt and RVPAS by 14 months of age. Interstage differences between shunt types can likely be explained by the physiology created when the shunts are in place rather than by intrinsic differences in cardiac function. Clinical Trial Registration— URL: http://www.clinicaltrials.gov. Unique identifier: NCT00115934.

Reliability of two-dimensional echocardiography in the assessment of clinically significant abnormal hemidiaphragm motion in pediatric cardiothoracic patients: Comparison with fluoroscopy.

Objective: To assess the utility and reliability of echocardiographic assessment of hemidiaphragm motion abnormalities in pediatric cardiothoracic patients. Design: Retrospective observational study, with post hoc blinded assessment of echocardiographic and fluoroscopic results. Setting: Tertiary care center. Patients: Thirty-six consecutive pediatric cardiothoracic patients with suspected hemidiaphragm paralysis were identified and included in the study. Interventions: None. Measurements and Main Results: The results of both echocardiographic and fluoroscopic studies on all patients were included. In addition, blinded review of study results were performed. The sensitivity and specificity of fluoroscopy in identifying hemidiaphragms that needed plication were 100% and 74%, respectively. The positive predictive value was 55%; negative predictive value was 100%. Comparing reported diagnoses with blinded review of the studies showed poor agreement; reviewers agreed with 89% diagnosed as normal, 44% of paralyzed, and 76% of paradoxical hemidiaphragms. The sensitivity and specificity of echo in identifying hemidiaphragms that needed plication were 100% and 81%, respectively. The positive predictive value and negative predictive value were 66% and 100%. Comparing reported diagnoses with blinded review, reviewers agreed with 97% diagnosed as normal, 81% of paralyzed, and 100% of paradoxical hemidiaphragms. Echocardiography was less accurate in discriminating between paralyzed and paradoxical diaphragm motion. Echocardiography was specific for paradoxical motion, since both patients identified by echocardiography were confirmed by fluoroscopy, but it was not sensitive. In nine patients, echo showed paralyzed motion that was identified by fluoroscopy as paradoxical. Conclusions: This study supports the use of echocardiography in the assessment of diaphragm function. When the diaphragms are clearly visualized by echo, as they are in the majority of cases, the addition of an additional fluoroscopic study adds no clinical value. The differentiation between paralyzed and paradoxical motion is unreliable by both imaging modalities.

Validation of association of the apolipoprotein E ε2 allele with neurodevelopmental dysfunction after cardiac surgery in neonates and infants.

OBJECTIVE Apolipoprotein E (APOE) genotype is a determinant of neurologic recovery after brain ischemia and traumatic brain injury. The APOE ε2 allele has been associated with worse neurodevelopmental (ND) outcome after repair of congenital heart defects (CHD) in infancy. Replication of this finding in an independent cohort is essential to validate the observed genotype-phenotype association. METHODS The association of APOE genotype with ND outcomes was assessed in a combined cohort of patients with single-ventricle CHD enrolled in the Single Ventricle Reconstruction and Infant Single Ventricle trials. ND outcome was assessed at 14 months using the Psychomotor Development Index (PDI) and Mental Development Index (MDI) of the Bayley Scales of Infant Development-II. Stepwise multivariable regression was performed to develop predictive models for PDI and MDI scores. RESULTS Complete data were available for 298 of 435 patients. After adjustment for preoperative and postoperative covariates, the APOE ε2 allele was associated with a lower PDI score (P = .038). Patients with the ε2 allele had a PDI score approximately 6 points lower than those without the risk allele, explaining 1.04% of overall PDI variance, because the ε2 allele was present in only 11% of the patients. There was a marginal effect of the ε2 allele on MDI scores (P = .058). CONCLUSIONS These data validate the association of the APOE ε2 allele with adverse early ND outcomes after cardiac surgery in infants, independent of patient and operative factors. Genetic variants that decrease neuroresilience and impair neuronal repair after brain injury are important risk factors for ND dysfunction after surgery for CHD.

Melody® pulmonary valve bacterial endocarditis: Experience in four pediatric patients and a review of the literature

The objectives of this manuscript are two‐fold: (a) to describe the clinical characteristics and management of four pediatric patients with bacterial endocarditis (BE) after Melody® pulmonary valve implantation (MPVI); and (b) to review the literature regarding Melody® pulmonary valve endocarditis.

The design and synthesis of novel α-ketoamide-based p38 MAP kinase inhibitors

We have identified a novel series of potent p38 MAP kinase inhibitors through structure-based design which due to their extended molecular architecture bind, in addition to the ATP site, to an allosteric pocket. In vitro ADME and in vivo PK studies show these compounds to have drug-like characteristics which could result in the development of an oral treatment for inflammatory conditions.

Anti-HIV-1 entry optimization of novel imidazopiperidine-tropane CCR5 antagonists

A novel series of imidazopiperidine-tropane CCR5 antagonists is described. The series was optimized for anti-HIV-1 potency using a set of phenotypic viral entry assays. This strategy resulted in the identification of several very potent (IC(50)<10nM) inhibitors of HIV-1 entry. One compound (40) was further profiled and was found to have attractive selectivity, pharmacokinetic, and antiviral properties.

Transcatheter interventions across an inferior vena cava filter

Patients who suffer from an embolic event often undergo placement of an inferior vena caval filter. Few data are available regarding treatment of this patient population with concurrent right‐to‐left shunting across an atrial communication. We report four cases of transcatheter device closure of an atrial communication across an inferior vena cava filter. Cathet Cardiovasc Intervent 2003;59:333–337.

Optimization of α-ketoamide based p38 inhibitors through modifications to the region that binds to the allosteric site

We have optimized a novel series of potent p38 MAP kinase inhibitors based on an alpha-ketoamide scaffold through structure based design that due to their extended molecular architecture bind, in addition to the ATP site, to an allosteric pocket. In vitro ADME, in vivo PK and efficacy studies show these compounds to have drug-like characteristics and have resulted in the nomination of a development candidate which is currently in phase II clinical trials for the oral treatment of inflammatory conditions.

Use of the monoplane intracardiac imaging probe in high-risk infants during congenital heart surgery.

Imaging options are limited in high‐risk infants with small or abnormal oropharyngeal anatomy during congenital heart surgery. Methods: All cases in which the monoplane intracardiac echo probe was used for transesophageal intraoperative imaging over a 15‐month period at a single institution were reviewed. Results: Eleven patients underwent intraoperative imaging using the intracardiac probe. Patient weight ranged from 1.96 kg to 4 kg. Adequate images of the anatomy relevant to the surgical repair were obtained in all cases. No adverse events related to probe use occurred. Conclusion: Transesophageal echocardiography using the monoplane intracardiac echo probe provides safe and effective imaging in patients who are not candidates for standard transesophageal echocardiography.

'Reverse' α-ketoamide-based p38 MAP kinase inhibitors

We have identified a second series of potent p38 inhibitors. As with our first generation series, these compounds are based on an alpha-ketoamide scaffold. The reversal of the ketoamide order, however, introduces more chemical flexibility and in addition results in improve potencies against p38.