Frank G. Scholl

Intracoronary gene transfer of immunosuppressive cytokines to cardiac allografts: Method and efficacy of adenovirus-mediated transduction

OBJECTIVE Allograft-targeted immunosuppressive gene therapy may inhibit recipient immune activation and provide an alternative to systemic immunosuppression. We studied the optimal technique and efficacy of intracoronary gene transfer of viral interleukin-10 and human transforming growth factor-beta 1 in a rabbit model of heterotopic heart transplantation. METHODS Replication-defective adenoviral vectors were constructed, expressing viral interleukin-10 (AdSvIL10) or transforming growth factor-beta 1 (AdCMVTGF-beta 1). Intracoronary delivery of vectors was accomplished ex vivo by either bolus injection or slow infusion. The allografts were implanted heterotopically in recipient rabbits and collected 4 days after the operation. Vector dose was 4 x 10(9) to 6 x 10(10) pfu/gm of donor heart. Transfer was confirmed by DNA amplification for both genes. Gene product expression in tissue was quantified by immunoassay and visualized by immunohistochemical staining. RESULTS Allograft viral uptake was only 9.9% +/- 2.4% with bolus injection, but increased to 80.5% +/- 6.8% at 1 ml/min infusion rate (p = 5 x 10(-14)). Uptake ratio was not affected by vector quantity or slower infusion rates. Transforming growth factor-beta 1 was consistently detected in allografts infected with AdCMVTGF-beta 1, but not with control adenovirus or AdSvIL10. Expression was proportional to infused vector quantity and reached 10 ng/gm of allograft at infused 10(10) pfu/gm. Transforming growth factor-beta 1 was also detected in recipients serum at less than 1 ng/ml. Viral interleukin-10 was detected in minor amounts only (< 1 ng/gm) in allografts infected with AdvIL10 up to 5 x 10(10) pfu/gm. Nevertheless, it was detected in recipient serum at concentrations up to 0.4 ng/ml. CONCLUSIONS Intracoronary gene transfer of immunosuppressive cytokines to cardiac allografts during cold preservation is feasible. Slow infusion is superior to bolus injection. In vivo effects on allograft rejection remain to be determined.

A Case of an Infant with Flail Tricuspid Valve Due to Spontaneous Papillary Muscle Rupture: Was Neonatal Lupus the Culprit?

A 3-month-old infant presented in extremis with a flail tricuspid valve. The authors theorized that the genesis of her papillary muscle rupture was perinatal ischemia compounded by worsening pulmonary valvular stenosis leading to excessive fiber tension. Her underlying diagnosis of autoimmune-mediated heart block with endocardial fibroelastosis and prenatal glucocorticoid steroid treatment represents potentiating factors.

Migration and infection of a pace-sense lead from an abdominal defibrillator system.

KHOO, M.S.C., et al.: Migration and Infection of a Pace‐Sense Lead from an Abdominal Defibrillator System. A 47‐year‐old man had an ICD system with epicardial and endocardial components and an abdominal generator placed in 1990 following a cardiac arrest. Ten years later his BT10 lead was amputated due to an insulation defect, and he received a new pectoral generator with transvenous leads. A few months later he developed fevers, chills, and bacteremia. Evaluation demonstrated migration of the entire BT10 lead into the right atrium. Complete surgical explantation was required and the bacteremia resolved. This case illustrates the importance of solid anchoring of distal lead components following generator removal and the potential complication of intravascular lead migration.

Variation in outcomes for benchmark operations

BACKGROUND We evaluated outcomes for common operations in The Society of Thoracic Surgeons Congenital Heart Surgery Database (STS-CHSDB) to provide contemporary benchmarks and examine variation between centers. METHODS Patients undergoing surgery from 2005 to 2009 were included. Centers with greater than 10% missing data were excluded. Discharge mortality and postoperative length of stay (PLOS) among patients discharged alive were calculated for 8 benchmark operations of varying complexity. Power for analyzing between-center variation in outcome was determined for each operation. Variation was evaluated using funnel plots and Bayesian hierarchical modeling. RESULTS Eighteen thousand three hundred seventy-five index operations at 74 centers were included in the analysis of 8 benchmark operations. Overall discharge mortality was: ventricular septal defect (VSD) repair = 0.6% (range, 0% to 5.1%), tetralogy of Fallot (TOF) repair = 1.1% (range, 0% to 16.7%), complete atrioventricular canal repair (AVC) = 2.2% (range, 0% to 20%), arterial switch operation (ASO) = 2.9% (range, 0% to 50%), ASO + VSD = 7.0% (range, 0% to 100%), Fontan operation = 1.3% (range, 0% to 9.1%), truncus arteriosus repair = 10.9% (0% to 100%), and Norwood procedure = 19.3% (range, 0% to 100%). Funnel plots revealed that the number of centers characterized as outliers were VSD = 0, TOF = 0, AVC = 1, ASO = 3, ASO + VSD = 1, Fontan operation = 0, truncus arteriosus repair = 4, and Norwood procedure = 11. Power calculations showed that statistically meaningful comparisons of mortality rates between centers could be made only for the Norwood procedure, for which the Bayesian-estimated range (95% probability interval) after risk-adjustment was 7.0% (3.7% to 10.3%) to 41.6% (30.6% to 57.2%). Between-center variation in PLOS was analyzed for all operations and was larger for more complex operations. CONCLUSIONS This analysis documents contemporary benchmarks for common pediatric cardiac surgical operations and the range of outcomes among centers. Variation was most prominent for the more complex operations. These data may aid in quality assessment and quality improvement initiatives.

Richard E. Clark Paper: Variation in Outcomes for Benchmark Operations: An analysis of the STS Congenital Heart Surgery Database

BACKGROUND We evaluated outcomes for common operations in The Society of Thoracic Surgeons Congenital Heart Surgery Database (STS-CHSDB) to provide contemporary benchmarks and examine variation between centers. METHODS Patients undergoing surgery from 2005 to 2009 were included. Centers with greater than 10% missing data were excluded. Discharge mortality and postoperative length of stay (PLOS) among patients discharged alive were calculated for 8 benchmark operations of varying complexity. Power for analyzing between-center variation in outcome was determined for each operation. Variation was evaluated using funnel plots and Bayesian hierarchical modeling. RESULTS Eighteen thousand three hundred seventy-five index operations at 74 centers were included in the analysis of 8 benchmark operations. Overall discharge mortality was: ventricular septal defect (VSD) repair = 0.6% (range, 0% to 5.1%), tetralogy of Fallot (TOF) repair = 1.1% (range, 0% to 16.7%), complete atrioventricular canal repair (AVC) = 2.2% (range, 0% to 20%), arterial switch operation (ASO) = 2.9% (range, 0% to 50%), ASO + VSD = 7.0% (range, 0% to 100%), Fontan operation = 1.3% (range, 0% to 9.1%), truncus arteriosus repair = 10.9% (0% to 100%), and Norwood procedure = 19.3% (range, 0% to 100%). Funnel plots revealed that the number of centers characterized as outliers were VSD = 0, TOF = 0, AVC = 1, ASO = 3, ASO + VSD = 1, Fontan operation = 0, truncus arteriosus repair = 4, and Norwood procedure = 11. Power calculations showed that statistically meaningful comparisons of mortality rates between centers could be made only for the Norwood procedure, for which the Bayesian-estimated range (95% probability interval) after risk-adjustment was 7.0% (3.7% to 10.3%) to 41.6% (30.6% to 57.2%). Between-center variation in PLOS was analyzed for all operations and was larger for more complex operations. CONCLUSIONS This analysis documents contemporary benchmarks for common pediatric cardiac surgical operations and the range of outcomes among centers. Variation was most prominent for the more complex operations. These data may aid in quality assessment and quality improvement initiatives.