Gary W. Raff

Short-term experience of porcine small intestinal submucosa patches in paediatric cardiovascular surgery

OBJECTIVES Surgical reconstructions or palliations of congenital heart defects often require the utilization of patches, of which the ideal material has yet to be discovered. Recently, porcine small intestinal submucosa extracellular matrix (SIS-ECM) has been advocated as an alternative to conventional synthetic or biological patch material. Here, we present our initial experience with SIS-ECM in paediatric cardiovascular reconstructions. METHODS A retrospective review of all patients <18 years of age who had SIS-ECM implanted during surgery from July 2009 to September 2011 was performed. Chart review consisted of assessment of heart defect, operative procedures, implant location, echocardiograms, reinterventions and pathology studies related to any explanted SIS-ECM. RESULTS During the study period, 37 paediatric patients had SIS-ECM implanted during a cardiovascular reconstruction. Mean length of follow-up was 411 days (range 6-757 days). SIS-ECM was implanted in 48 cardiac locations as patches for septal defects (n = 13), vascular augmentation (n = 26), outflow tract augmentation (n = 7) and valve reconstruction (n = 3). Eight of the patients required SIS-ECM patches in multiple locations. There was progressive stenosis in one RVOT patch requiring reoperation. Progressive stenosis in a near-circumferential pulmonary artery patch was present in 1 patient, requiring stent placement. All other patched structures remained patent. CONCLUSIONS SIS-ECM is suitable for the closure of septal defects. Use of SIS-ECM for the reconstructions of outflow tracts and great vessels carries a small risk of stenosis, especially in patches that form the majority of the vessel circumference. The long-term follow-up is needed to determine the risk of late stenosis.

Life-threatening coronary sinus thrombosis following catheter ablation: case report and review of literature

Coronary sinus thrombosis is an extremely rare clinical syndrome with a high fatality rate. It is associated with procedures in the right heart, including insertion of pacemaker wires, Swan-Ganz catheters, and central venous lines. Recognition is often late, and treatment options are not well characterized. We present a case of acute coronary sinus thrombosis and occlusion associated with electrophysiologic ablation for supraventricular tachycardia in an 11-year-old boy. He developed chest pain, ST elevation, a large pericardial effusion, and cardiogenic shock. Emergent cardiac catheterization and percutaneous intervention with rheolytic aspiration thrombectomy resulted in a dramatic recovery. With the advent of new technologies and procedures involving the right heart and coronary sinus, an appreciation of this potentially lethal complication and possible treatment strategies is important.

Association Between Down Syndrome and In-Hospital Death Among Children Undergoing Surgery for Congenital Heart Disease A US Population-Based Study

Background—The prevalence of Down syndrome (DS)–affected births has increased during the past 30 years; moreover, children with DS have a higher incidence of congenital heart disease compared with their peers. Whether children with DS have better or worse outcomes after repair of congenital heart disease is unclear. We sought to identify differences in in-hospital mortality after cardiac surgery in pediatric patients with and without DS using a large national database. Methods and Results—Children aged <18 years who underwent surgical intervention for congenital heart disease were identified using the Kids’ Inpatient Database (2000, 2003, 2006, and 2009). Patients were stratified using the Risk Adjustment for Congenital Heart Surgery algorithm. A total of 4231 (8.2%) of the 51 309 patients studied had a diagnosis of DS. In-hospital death for patients with DS was significantly lower than that for patients without DS overall (1.9% versus 4.3%; P<0.05) as well as within risk categories 2 (1.0% versus 1.8%; P<0.05) and 3 (2.3% versus 5.1%; P<0.05). Multivariable logistic regression showed a lower odds of death among children with DS (odds ratio=0.60; 95% confidence interval, 0.47–0.76; P<0.05) after adjusting for Risk Adjustment for Congenital Heart Surgery risk category, premature birth, major noncardiac structural anomaly, and age. Conclusions—In this large national study, children with DS who underwent repair of congenital heart disease were more likely to survive to discharge than children without DS. Future work is needed to better understand the factors underlying these differences.

PPAR-γ Regulates Carnitine Homeostasis and Mitochondrial Function in a Lamb Model of Increased Pulmonary Blood Flow

Objective Carnitine homeostasis is disrupted in lambs with endothelial dysfunction secondary to increased pulmonary blood flow (Shunt). Our recent studies have also indicated that the disruption in carnitine homeostasis correlates with a decrease in PPAR-γ expression in Shunt lambs. Thus, this study was carried out to determine if there is a causal link between loss of PPAR-γ signaling and carnitine dysfunction, and whether the PPAR-γ agonist, rosiglitazone preserves carnitine homeostasis in Shunt lambs. Methods and Results siRNA-mediated PPAR-γ knockdown significantly reduced carnitine palmitoyltransferases 1 and 2 (CPT1 and 2) and carnitine acetyltransferase (CrAT) protein levels. This decrease in carnitine regulatory proteins resulted in a disruption in carnitine homeostasis and induced mitochondrial dysfunction, as determined by a reduction in cellular ATP levels. In turn, the decrease in cellular ATP attenuated NO signaling through a reduction in eNOS/Hsp90 interactions and enhanced eNOS uncoupling. In vivo, rosiglitazone treatment preserved carnitine homeostasis and attenuated the development of mitochondrial dysfunction in Shunt lambs maintaining ATP levels. This in turn preserved eNOS/Hsp90 interactions and NO signaling. Conclusion Our study indicates that PPAR-γ signaling plays an important role in maintaining mitochondrial function through the regulation of carnitine homeostasis both in vitro and in vivo. Further, it identifies a new mechanism by which PPAR-γ regulates NO signaling through Hsp90. Thus, PPAR-γ agonists may have therapeutic potential in preventing the endothelial dysfunction in children with increased pulmonary blood flow.

L-Carnitine preserves endothelial function in a lamb model of increased pulmonary blood flow

Background:In our model of a congenital heart defect (CHD) with increased pulmonary blood flow (PBF; shunt), we have recently shown a disruption in carnitine homeostasis, associated with mitochondrial dysfunction and decreased endothelial nitric oxide synthase (eNOS)/heat shock protein (Hsp)90 interactions that contribute to eNOS uncoupling, increased superoxide levels, and decreased bioavailable nitric oxide (NO). Therefore, we undertook this study to test the hypothesis that L-carnitine therapy would maintain mitochondrial function and NO signaling.Methods:Thirteen fetal lambs underwent in utero placement of an aortopulmonary graft. Immediately after delivery, lambs received daily treatment with oral L-carnitine or its vehicle.Results:L-Carnitine–treated lambs had decreased levels of acylcarnitine and a reduced acylcarnitine:free carnitine ratio as compared with vehicle-treated shunt lambs. These changes correlated with increased carnitine acetyl transferase (CrAT) protein and enzyme activity and decreased levels of nitrated CrAT. The lactate:pyruvate ratio was also decreased in L-carnitine–treated lambs. Hsp70 protein levels were significantly decreased, and this correlated with increases in eNOS/Hsp90 interactions, NOS activity, and NOx levels, and a significant decrease in eNOS-derived superoxide. Furthermore, acetylcholine significantly decreased left pulmonary vascular resistance only in L-carnitine–treated lambs.Conclusion:L-Carnitine therapy may improve the endothelial dysfunction noted in children with CHDs and has important clinical implications that warrant further investigation.

Effects of Scaffold Material Used in Cardiovascular Surgery on Mesenchymal Stem Cells and Cardiac Progenitor Cells

BACKGROUND Polytetrafluoroethylene (PTFE) and porcine small intestinal submucosa (pSIS) are patch materials used in congenital heart surgery. Porcine SIS is an extracellular-matrix scaffold that may interact with stem or progenitor cells. To evaluate this, we determined the in vitro effects of pSIS and PTFE on human bone marrow mesenchymal stromal cells (MSCs) and cardiac progenitor cells (CPCs) in 3 areas; cell proliferation, angiogenic growth-factor production, and differentiation. METHODS Human MSCs and CPCs were seeded onto pSIS and PTFE patches. Cell-seeded patches were cultured and then assessed for cell viability and proliferation and supernatant vascular endothelial growth factor A (VEGFA) levels. Cell proliferation was quantified by MTT assay (3-[4,5-dimethylthiazol-2-yl]-2,5-diphenyltetrazolium bromide). Quantitative real-time polymerase chain reaction was performed on cell-seeded scaffolds to determine relative changes in gene expression related to angiogenesis and cardiogenesis. RESULTS The MSCs and CPCs were able to attach and proliferate on pSIS and PTFE. The proliferation rate of each cell type was similar on pSIS. Total RNA isolation was only possible from the cell-seeded pSIS patches. The MSC VEGFA production was increased by pSIS. Porcine SIS promoted an angiogenic gene profile in MSCs and an early cardiogenic profile in CPCs. CONCLUSIONS Both PTFE and pSIS allow for varying degrees of cell proliferation. Porcine SIS elicits different phenotypical responses in MSCs as compared with CPCs, which indicates that pSIS may be a bioactive scaffold that modulates stem cell activation and proliferation. These findings highlight the differences in scaffold material strategies and suggest potential advantages of bioactive approaches.

Altered lymphatics in an ovine model of congenital heart disease with increased pulmonary blood flow

Abnormalities of the lymphatic circulation are well recognized in patients with congenital heart defects. However, it is not known how the associated abnormal blood flow patterns, such as increased pulmonary blood flow (PBF), might affect pulmonary lymphatic function and structure. Using well-established ovine models of acute and chronic increases in PBF, we cannulated the efferent lymphatic duct of the caudal mediastinal node and collected and analyzed lymph effluent from the lungs of lambs with acutely increased PBF (n = 6), chronically increased PBF (n = 6), and age-matched normal lambs (n = 8). When normalized to PBF, we found that lymph flow was unchanged following acute increases in PBF but decreased following chronic increases in PBF. The lymph:plasma protein ratio decreased with both acute and chronic increases in PBF. Lymph bioavailable nitric oxide increased following acute increases in PBF but decreased following chronic increases in PBF. In addition, we found perturbations in the transit kinetics of contrast material through the pleural lymphatics of lambs with chronic increases in PBF. Finally, there were structural changes in the pulmonary lymphatic system in lambs with chronic increases in PBF: lymphatics from these lambs were larger and more dilated, and there were alterations in the expression of vascular endothelial growth factor-C, lymphatic vessel endothelial hyaluronan receptor-1, and Angiopoietin-2, proteins known to be important for lymphatic growth, development, and remodeling. Taken together these data suggest that chronic increases in PBF lead to both functional and structural aberrations of lung lymphatics. These findings have important therapeutic implications that warrant further study.

Adaptive right ventricular performance in response to acutely increased afterload in a lamb model of congenital heart disease: evidence for enhanced Anrep effect

Patients with pulmonary hypertension associated with congenital heart disease survive longer with preserved right ventricular (RV) function compared with those with primary pulmonary hypertension. The purpose of this study was to test the hypothesis that superior RV performance can be demonstrated, at baseline and when challenged with increased RV afterload, in lambs with chronic left-to-right cardiac shunts compared with control lambs. A shunt was placed between the pulmonary artery and the aorta in fetal lambs (shunt). RV pressure-volume loops were obtained 4 wk after delivery in shunt and control lambs, before and after increased afterload was applied using pulmonary artery banding (PAB). Baseline stroke volume (8.7 ± 1.8 vs. 15.8 ± 2.7 ml, P = 0.04) and cardiac index (73.0 ± 4.0 vs. 159.2 ± 25.1 ml·min(-1)·kg(-1), P = 0.02) were greater in shunts. After PAB, there was no difference in the change in cardiac index (relative to baseline) between groups; however, heart rate (HR) was greater in controls (168 ± 7.3 vs. 138 ± 6.6 beats/min, P = 0.01), and end-systolic elastance (Ees) was greater in shunts (2.63 vs. 1.31 × baseline, P = 0.02). Control lambs showed decreased mechanical efficiency (71% baseline) compared with shunts. With acute afterload challenge, both controls and shunts maintained cardiac output; however, this was via maladaptive responses in controls, while shunts maintained mechanical efficiency and increased contractility via a proposed enhanced Anrep effect-the second, slow inotropic response in the biphasic ventricular response to increased afterload, a novel finding in the RV. The mechanisms related to these physiological differences may have important therapeutic implications.

Rosiglitazone preserves pulmonary vascular function in lambs with increased pulmonary blood flow

Background:Pulmonary vascular function is impaired with increased pulmonary blood flow (PBF). We hypothesized that a peroxisome proliferator–activated receptor-γ (PPAR-γ) agonist would mitigate this effect.Methods:An aorta-to-pulmonary-artery shunt was placed in 11 fetal lambs. Lambs received the PPAR-γ agonist rosiglitazone (RG, 3 mg/kg/d, n = 6) or vehicle (n = 5) for 4 wk. Lung tissue from five normal 4-wk-old lambs was used for comparisons.Results:At 4 wk, pulmonary artery pressure (PAP) and vascular resistance (PVR) decreased with inhaled nitric oxide (NO) in RG- and vehicle-treated shunt lambs. PAP and PVR decreased with acetylcholine (Ach) in RG-treated, but not vehicle-treated, shunt lambs. In vehicle-treated shunt lambs, nicotinamide adenine dinucleotide phosphate (NADPH) oxidase activity, rac1, superoxide, and 3-nitrotyrosine (3-NT) levels were increased, and Ser1177 endothelial NO synthase (eNOS) protein was decreased as compared with normal lambs. In RG-treated shunt lambs, NOx, Ser1177 eNOS protein, and eNOS activity were increased, and NADPH activity, rac1, superoxide levels, and 3-NT levels were decreased, as compared with vehicle-treated shunt lambs. PPAR-γ protein expression was lower in vehicle-treated shunt lambs than in normal and RG-treated shunt lambs.Conclusion:The PPAR-γ agonist RG prevents the loss of agonist-induced endothelium-dependent pulmonary vascular relaxation in lambs with increased PBF, in part, due to decreased oxidative stress and/or increased NO production.BACKGROUND Pulmonary vascular function is impaired with increased pulmonary blood flow (PBF). We hypothesized that a peroxisome proliferator-activated receptor-γ (PPAR-γ) agonist would mitigate this effect. METHODS An aorta-to-pulmonary-artery shunt was placed in 11 fetal lambs. Lambs received the PPAR-γ agonist rosiglitazone (RG, 3 mg/kg/d, n = 6) or vehicle (n = 5) for 4 wk. Lung tissue from five normal 4-wk-old lambs was used for comparisons. RESULTS At 4 wk, pulmonary artery pressure (PAP) and vascular resistance (PVR) decreased with inhaled nitric oxide (NO) in RG- and vehicle-treated shunt lambs. PAP and PVR decreased with acetylcholine (Ach) in RG-treated, but not vehicle-treated, shunt lambs. In vehicle-treated shunt lambs, nicotinamide adenine dinucleotide phosphate (NADPH) oxidase activity, rac1, superoxide, and 3-nitrotyrosine (3-NT) levels were increased, and Ser1177 endothelial NO synthase (eNOS) protein was decreased as compared with normal lambs. In RG-treated shunt lambs, NOx, Ser1177 eNOS protein, and eNOS activity were increased, and NADPH activity, rac1, superoxide levels, and 3-NT levels were decreased, as compared with vehicle-treated shunt lambs. PPAR-γ protein expression was lower in vehicle-treated shunt lambs than in normal and RG-treated shunt lambs. CONCLUSION The PPAR-γ agonist RG prevents the loss of agonist-induced endothelium-dependent pulmonary vascular relaxation in lambs with increased PBF, in part, due to decreased oxidative stress and/or increased NO production.

A stepwise model for delivering medical humanitarian aid requiring complex interventions

OBJECTIVES Cardiothoracic surgeons and practitioners of cardiovascular medicine have a long history of humanitarian aid. Although this is worthwhile at multiple levels and occasionally described in some detail, few efforts have a proven algorithm with demonstrable outcomes that suggest effective educational methodology or clinical results approaching accepted standards in developed countries. METHODS Our report provides a stepwise approach to developing highly successful self-sustainable, replicable, and scalable humanitarian congenital cardiac surgical programs, and provides data to allow insight into the efficacy of our model. RESULTS This program model has evolved over 25 years, during which it has been replicated several times and scaled throughout a vast and populous country. Since 1989, Russia has undergone considerable social, political, and economic changes. Our program model proved successful throughout this time despite dynamic social, political, and medical landscapes. CONCLUSIONS The positive results of our program model indicate that these methodologies may be helpful to others attempting to address the worldwide shortage of cardiovascular care and particularly the complex interventions required in the management of congenital cardiovascular disease.