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1.  Targeted SPECT/CT Imaging of Matrix Metalloproteinase Activity in the Evaluation of Remodeling Tissue-Engineered Vascular Grafts Implanted in a Growing Lamb Model 
Objective(s)
The clinical translation of tissue-engineered vascular grafts has been demonstrated in children. The remodeling of biodegradable, cell-seeded scaffolds to functional neovessels is partially attributed to matrix metalloproteinases. Noninvasive assessment of matrix metalloproteinase activity may indicate graft remodeling and elucidate the progression of neovessel formation. Therefore, matrix metalloproteinase activity was evaluated in grafts implanted in lambs using in vivo and ex vivo hybrid imaging. Graft growth and remodeling was quantified using in vivo X-ray computed tomography angiography.
Methods
Cell-seeded and unseeded scaffolds were implanted in lambs (n=5) as inferior vena cava interposition grafts. At 2 and 6 months post-implantation, in vivo angiography assessed graft morphology. In vivo and ex vivo single photon emission tomography/X-ray computed tomography imaging was performed with a radiolabeled compound targeting matrix metalloproteinase activity at 6 months. Neotissue was examined at 6 months using qualitative histologic and immunohistochemical staining and quantitative biochemical analysis.
Results
Seeded grafts demonstrated significant luminal and longitudinal growth from 2 to 6 months. In vivo imaging revealed subjectively higher matrix metalloproteinase activity in grafts vs. native tissue. Ex vivo imaging confirmed a quantitative increase in matrix metalloproteinase activity and demonstrated higher activity in unseeded vs. seeded grafts. Glycosaminoglycan content was increased in seeded grafts vs. unseeded grafts, without significant differences in collagen content.
Conclusions
Matrix metalloproteinase activity remains elevated in tissue-engineered grafts 6 months post-implantation and may indicate remodeling. Optimization of in vivo imaging to noninvasively evaluate matrix metalloproteinase activity may assist in serial assessment of vascular graft remodeling.
doi:10.1016/j.jtcvs.2014.05.037
PMCID: PMC4747027  PMID: 24952823
2.  Preoperative Gene Expression May be Associated with Neurocognitive Decline after Cardiopulmonary Bypass 
OBJECTIVE
Despite advances in surgical techniques, neurocognitive decline (NCD) after cardiopulmonary bypass (CPB) remains a common and serious complication. We have previously demonstrated that patients with NCD have unique genetic responses 6 hours after CPB when compared with normal patients (NORM). We used genomic microarray to objectively investigate whether patients with NCD had associated preoperative gene expression profiles, and how these profiles changed up to four days after surgery.
METHODS
Cardiac surgery patients underwent neurocognitive assessments preoperatively and four days after surgery. Skeletal muscle was collected intra-operatively. Whole blood collected pre-CPB, 6 hours post-CPB, and on post-operative day four was hybridized to Affymetrix Gene Chip U133 Plus 2.0 microarrays. Gene expression in patients with NCD was compared with gene expression in the NORM group using JMP Genomics. Only genes that were commonly expressed in the two groups with a false discovery rate of 0.05 and a fold change of >1.5 were carried forward to pathway analysis using Ingenuity Pathway Analysis. Microarray gene expression was validated by Green real–time polymerase chain reaction and western blotting.
RESULTS
17 out of 42 patients developed NCD. 54,675 common transcripts were identified on microarray in each group across all time points. Preoperatively there were 140 genes that were significantly altered between the NORM and NCD groups (p < 0.05). Pathway analysis demonstrated that preoperatively patients with NCD had increased regulation in genes associated with inflammation, cell death, and neurologic dysfunction. Interestingly, the number of significantly regulated genes between the two groups changed over each time point, and decreased from 140 preoperatively, to 64, six hours after CPB, and 25, four days after surgery. There was no correlation in gene expression between the blood and skeletal muscle.
CONCLUSIONS
Patients who developed NCD post-CPB had increased differential gene expression before surgery versus patient who did not develop NCD. While significant differences in gene expression also existed post-operatively, these differences gradually decreased over time. Preoperative gene expression may be associated with neurologic injury after CPB. Further investigation into these genetic pathways may help predict patient outcome and guide patient selection.
doi:10.1016/j.jtcvs.2014.10.050
PMCID: PMC4207964  PMID: 25483902
Neurocognitive Decline; Microarray; Inflammation; Gene Expression; Cardiopulmonary Bypass
3.  Oxidant stress regulatory genetic variation in recipients and donors contributes to risk of primary graft dysfunction after lung transplantation 
Objective
Oxidant stress pathway activation during ischemia reperfusion injury may contribute to the development of primary graft dysfunction (PGD) after lung transplantation. We hypothesized oxidant stress gene variation in recipients and donors is associated with PGD.
Methods
Donors and recipients from the Lung Transplant Outcomes Group (LTOG) cohort were genotyped using the Illumina IBC chip filtered for oxidant stress pathway genes. Single nucleotide polymorphisms (SNPs) grouped into SNP-sets based on haplotype blocks within 49 oxidant stress genes selected from gene ontology pathways and literature review were tested for PGD association using a sequencing kernel association test. Analyses were adjusted for clinical confounding variables and population stratification.
Results
392 donors and 1038 recipients met genetic quality control standards. 30% of subjects developed grade 3 PGD within 72 hours. Donor NADPH Oxidase 3 (NOX3) was associated with PGD (p=0.01) with 5 individual significant loci (p-values between 0.006 and 0.03). In recipients, variation in glutathione peroxidase (GPX1) and NRF-2 (NFE2L2) was significantly associated with PGD (p=0.01 for both). The GPX1 association included 3 individual loci (p-values between 0.006 and 0.049) and the NFE2L2 association included 2 loci (p=0.03 and 0.05). Significant epistatic effects influencing PGD susceptibility were evident between three different donor blocks of NOX3 and recipient NFE2L2 (p=0.026, p=0.017 and p=0.031).
Conclusions
Our study prioritizes GPX1, NOX3, and NFE2L2 genes for future research in PGD pathogenesis, and highlights a donor-recipient interaction of NOX3 and NFE2L2 that increases PGD risk.
doi:10.1016/j.jtcvs.2014.09.077
PMCID: PMC4346512  PMID: 25439478
Primary Graft Dysfunction; Lung Transplantation; Oxidant Stress; Genes
4.  Using Genetics for Personalized Management of Heritable Thoracic Aortic Disease: How Do We Get There? 
The major diseases affecting the thoracic aorta are aortic aneurysms and acute aortic dissections (TAAD). Medical treatments can slow the enlargement of aneurysms, but the mainstay of treatment to prevent premature deaths due to dissections is surgical repair of the TAA, typically recommended when the aortic diameter reaches 5.0 – 5.5 cm. Studies on patients with acute aortic dissections indicate that up to 60% occur at aortic diameters less than 5.5 cm. Clinical predictors are thus needed to identify those at risk for dissection at aortic diameter less than 5.0 cm, and to determine the aortic diameter that justifies the risk of surgical repair to prevent an acute aortic dissection. Data from genetic studies over the past decade have established that mutations in specific genes can identify patients at risk for the disease and predict the risk of early dissection at diameters less than 5.0 cm. This information has the potential to optimize the timing of aortic surgery to prevent acute dissections.
doi:10.1016/j.jtcvs.2014.07.070
PMCID: PMC4354949  PMID: 25218541
5.  A propensity-matched analysis comparing survival after primary minimally invasive esophagectomy followed by adjuvant therapy to neoadjuvant therapy for esophagogastric adenocarcinoma 
Objectives
Prognosis for locally advanced esophagogastric adenocarcinoma (EAC) is poor with surgery alone and adjuvant therapy after open esophagectomy is frequently not tolerated. After minimally invasive esophagectomy (MIE), however, earlier return to normal function may render patients better able to receive adjuvant therapy. This study examined whether primary MIE followed by adjuvant chemotherapy impacted survival compared to propensity-matched patients treated with neoadjuvant therapy.
Methods
Patients with stage II or higher EAC treated with MIE (n=375) were identified. Using 30 pretreatment covariates, propensity for assignment to either neoadjuvant followed by MIE (n=183; 54%) or MIE as primary therapy (n=156; 46%) was calculated, generating 97 closely-matched pairs. Hazard ratios were adjusted for age, sex, BMI, smoking, comorbidity and final pathologic stage.
Results
In propensity-matched pairs, adjusted hazard ratio for death did not differ significantly for primary MIE compared to neoadjuvant (HR 0.83; 95% CI 0.60–1.16). Recurrence patterns were similar between groups and 65% of patients with IIb or greater pathologic stage received adjuvant therapy. Clinical staging was inaccurate in 37/105 (35%) patients who underwent primary MIE (n=18 upstaged and n=19 downstaged).
Conclusions
Primary MIE followed by adjuvant chemotherapy guided by pathologic findings did not negatively impact survival and allowed for accurate staging of the patient compared to clinical staging. Our data suggest that primary MIE in patients with resectable EAC may be a reasonable approach, improving stage-based prognostication and potentially minimizing overtreatment in patients with early-stage disease through accurate stage assignments. A randomized controlled trial testing this hypothesis is needed.
doi:10.1016/j.jtcvs.2014.10.044
PMCID: PMC4492295  PMID: 25454907
Neoadjuvant Therapy; Esophagectomy; Propensity Score; Surgical Procedures; Minimally Invasive; Mortality
6.  C-terminal tensin-like protein mediates invasion of human lung cancer cells and is regulated by signal transducer and activator of transcription 3 
Objectives
C-terminal tensin-like (Cten) protein, a component of focal adhesions, contributes to cell motility and invasion in multiple human cancers. Epidermal growth factor can activate signal transducer and activator of transcription 3, and both contribute to invasion through focal adhesion interactions. We hypothesize that Cten may mediate invasion of lung cancer cells provided by epidermal growth factor via signal transducer and activator of transcription 3.
Methods
Four human non–small cell lung cancer cell lines were treated with epidermal growth factor to evaluate activation of the signal transducer and activator of transcription 3 pathway and induction of Cten expression. Chemical inhibition of signal transducer and activator of transcription 3 was used to evaluate the effect on epidermal growth factor–induced Cten expression. Protein expression was quantified by Western blot. H125 and A549 cells were transduced with short-hairpin RNA via lentiviral vector to knockdown expression of Cten. An in vitro transwell invasion assay was used to assess the effects of Cten knockdown on cell invasion (n = 3 for all experiments).
Results
Stimulation of lung cancer cells with epidermal growth factor activated the signal transducer and activator of transcription 3 pathway and induced expression of Cten in all cell lines. Signal transducer and activator of transcription 3 inhibition significantly reduced epidermal growth factor–induced expression of Cten in H125 (P < .0001), H358 (P = .006), and H441 (P = .014) cells in a dose-dependent manner. Knockdown of Cten expression resulted in significant decreases in cellular invasion in both H125 (P = .0036) and A549 (P = .0006) cells.
Conclusions
These are the first findings in lung cancer to demonstrate that Cten expression mediates invasion of human lung cancer cells and is upregulated by epidermal growth factor via signal transducer and activator of transcription 3 pathway. Cten should be considered a potential therapeutic target for lung cancer.
doi:10.1016/j.jtcvs.2014.08.087
PMCID: PMC4730942  PMID: 25439778
7.  Does the Method of Radiologic Surveillance Impact Survival Following Resection of Stage I Non-Small Cell Lung Cancer? 
Objective
Controversy persists regarding appropriate radiographic surveillance strategies following lung cancer resection. We compared the impact of surveillance CT scan (CT) vs. chest radiograph (CXR) in patients who underwent resection for stage I lung cancer.
Methods
A retrospective analysis was performed of all patients undergoing resection for pathologic stage I lung cancer from January 2000–April 2013. After resection, follow-up included routine history and physical exam in conjunction with CXR or CT at the discretion of the treating physician. Identification of successive lung malignancy (i.e. recurrence at any new site or new primary) and survival were recorded.
Results
There were 554 evaluable patients with 232 undergoing routine postoperative CT and 322 receiving routine CXR. Postoperative five-year survival was 67.8% in the CT group vs. 74.8% in the CXR group (p = 0.603). Successive lung malignancy was found in 27% (63/232) of patients undergoing CT vs. 22% (72/322) receiving CXR (p = 0.19). The mean time from surgery to diagnosis of successive malignancy was 1.93 years for CT vs. 2.56 years for CXR (p = 0.046). For the CT group, 41% (26/63) of successive malignancies were treated with curative intent vs. 40% (29/72) in the CXR group (p = 0.639). Cox-proportional hazard analysis indicated imaging modality (CT vs. CXR) was not associated with survival (p = 0.958).
Conclusion
Surveillance CT may result in earlier diagnosis of successive malignancy vs. CXR in stage I lung cancer, although no difference in survival was demonstrated. A randomized trial would help determine the impact of postoperative surveillance strategies on survival.
doi:10.1016/j.jtcvs.2014.07.095
PMCID: PMC4272651  PMID: 25218540
8.  Avoiding aortic clamping during CABG reduces postoperative stroke 
Objective
The purpose of this study was to determine whether the incidence of postoperative stroke (PS) could be reduced by eliminating aortic clamping during CABG.
Methods
From 2002–2013, 12,079 patients underwent primary, isolated CABG at a single US academic institution. Aortic manipulation was completely avoided by using in-situ internal mammary arteries for inflow in 1,552 (12.9%) patients (no-touch), a clampless facilitating device (CFD) was used for proximal anastomoses in 1,548 (12.8%) patients, and aortic clamping was used in 8,979 (74.3%) patients. These strategies were assessed in a logistic regression model controlling for relevant variables.
Results
The overall incidence of PS was 1.4% (n=165), with an unadjusted incidence of 0.6% (n=10) in the no-touch group, 1.2% (n=18) in the CFD group, and 1.5% (n=137) in the clamp group (p<0.01 for no-touch vs clamp). The ratio of observed to expected stroke rate increased as the degree of aortic manipulation increased, from 0.48 in the no-touch group, to 0.61 in the CFD group, and 0.95 in the clamp group. Aortic clamping was independently associated with an increase in PS compared to a no-touch technique (AOR 2.50, p<0.01). When separated by CPB utilization, both the off-pump partial clamp and on-pump cross-clamp techniques increased the risk of PS compared to no-touch (AOR 2.52, p<0.01 and AOR 4.25, p<0.001, respectively).
Conclusion
A no-aortic touch technique has the lowest risk for postoperative stroke for patients undergoing CABG. Clamping the aorta during CABG increases the risk of PS, regardless of the severity of aortic disease.
doi:10.1016/j.jtcvs.2014.09.011
PMCID: PMC4272657  PMID: 25293356
9.  Studying Intraoperative Conversions from Video-Assisted Thoracoscopic Surgery (VATS) Lobectomy to Open Thoracotomy 
Structured abstract
Objective
To study causes and implications of intraoperative conversions to thoracotomy during VATS lobectomy.
Methods
We performed an institutional review of patients undergoing lobectomy for known or suspected lung cancer with root cause analysis of every conversion from VATS to open thoracotomy.
Results
Between 2004 and 2012, 1227 patients underwent lobectomy. Of these, 517 (42%) were completed VATS, 87 (7%) converted to open, and 623 (51%) were performed via planned thoracotomy. Patients undergoing thoracotomy were younger and had a higher incidence of prior lung cancers. Planned thoracotomy and conversion group patients had higher clinical T stage than the VATS group while the planned thoracotomy group had higher pathologic stage than the other groups. Postoperative complications were more frequent in the conversion group (46%) than VATS (23%, p<0.001), but similar to the open group (42%, p=0.56). Validating a previous classification of causes for conversion, 22/87 (25%) were due to vascular causes, 56 (64%) for anatomy (adhesions/tumor size), and 8 (9%) for lymph nodes. No specific imaging variables predicted conversion. Within the conversions, emergent (20/87, 23%) and planned (67/87, 77%) conversion groups were similar in patient- and tumor characteristics and incidence of perioperative morbidity. The conversion rate for VATS lobectomy dropped from 21/74 (28%), to 29/194 (15%), to 37/336 (11%) (p<0.001) over 3-year intervals. Over the same periods, the proportion of operations started VATS increased significantly.
Conclusions
With increasing experience, a higher proportion of lobectomy operations can be completed thoracoscopically. VATS should be strongly considered as the initial approach for the majority of patients undergoing lobectomy.
doi:10.1016/j.jtcvs.2014.08.074
PMCID: PMC4272658  PMID: 25439768
10.  Stage 1 hybrid palliation for hypoplastic left heart syndrome—assessment of contemporary patterns of use: An analysis of The Society of Thoracic Surgeons Congenital Heart Surgery Database 
Objective
Hybrid palliation is an alternative to Norwood stage 1 for the initial management of hypoplastic left heart syndrome. Contemporary multicenter hybrid use and institutional/patient factors associated with hybrid use relative to the Norwood have not been evaluated. We describe hybrid use in relation to institutional volume, patient factors, and short-term outcomes.
Methods
Infants aged 60 days or less listed in The Society of Thoracic Surgeons Congenital Heart Surgery Database (2010–2012) undergoing initial palliation of hypoplastic left heart syndrome were included. Annual institutional hybrid use rates were calculated: [hybrid procedures/(Norwood + hybrid + transplant procedures)]. In-hospital outcomes for primary hybrid and primary Norwood were compared and stratified by high (defined as ≥50%) versus low (defined as ≤10%) institutional hybrid use.
Results
Of 1728 patients (100 centers), most (n = 1496, 87%) underwent an index Norwood; 232 patients (13%) underwent an index hybrid procedure. Preoperative patient risk factors were more prevalent in patients undergoing the hybrid procedure. Only 13 of 100 institutions were high hybrid users, and these tended to have lower annual hypoplastic left heart syndrome index case volume. Unadjusted in-hospital mortality was higher for the hybrid compared with the Norwood procedure (30%vs 16%; P<.001). In-hospital mortality for the hybrid procedure was not associated with hybrid use (26%among institutions with low use vs 28%among institutions with high use). However, centers with high hybrid use had higher mortality after the Norwood (43%) compared with centers with low hybrid use (16%).
Conclusions
Few centers currently select the hybrid procedure for most infants with hypoplastic left heart syndrome. Although unadjusted in-hospital hybrid mortality is higher than Norwood mortality, potential risk factors are more prevalent among hybrid cases. Institutions with higher hybrid use have lower hypoplastic left heart syndrome case volume and higher Norwood mortality.
doi:10.1016/j.jtcvs.2014.08.020
PMCID: PMC4527867  PMID: 25266878
11.  Cardiothoracic Surgical Trials Network: Evidence-based surgery 
doi:10.1016/j.jtcvs.2015.09.122
PMCID: PMC4692154  PMID: 26519245
Cardiothoracic Surgical Network; clinical trials
12.  Building an Infrastructure for Clinical Trials in Cardiac Surgery 
doi:10.1016/j.jtcvs.2011.02.035
PMCID: PMC4687901  PMID: 21763873
13.  Lung Volume Reduction Surgery Since the National Emphysema Treatment Trial: Study of Society of Thoracic Surgeons Database 
Background:
The National Emphysema Treatment Trial (NETT) demonstrated that lung volume reduction surgery (LVRS) is an effective treatment for emphysema in select patients. With chronic lower respiratory disease being the third leading cause of death in the US, this study sought to assess practice patterns and outcomes for LVRS on a national level since the NETT.
Methods:
Aggregate statistics on LVRS reported in the Society of Thoracic Surgeons (STS) Database from January 2003 to June 2011 were analyzed to assess procedure volume, pre-operative and operative characteristics, and outcomes. Comparisons to published data from the NETT were made using chi-squared and two sided t-tests.
Results:
In 8.5 years, 538 patients underwent LVRS, with 20 to 118 cases reported in the STS database per year. When compared to NETT subjects, STS patients were younger (p<0.001), a larger proportion underwent the procedure thoracoscopically (p<0.001), and FEV1 was 31% vs. 28% of predicted (p<0.001). When mortality was compared between STS patients and all NETT subjects randomized to surgery, there were no significant differences. However, mortality was 3% higher in STS patients when compared to the non-high risk NETT subset (p=0.005).
Conclusions:
This study demonstrates the importance of patient selection and the need to develop consensus on appropriate benchmarks for mortality rates after lung volume reduction surgery. It underscores the need for dedicated centers to increasingly address the heavy burden of chronic lower respiratory disease in the US in a multi-disciplinary fashion, particularly for preoperative evaluation and postoperative management of emphysema.
doi:10.1016/j.jtcvs.2014.02.005
PMCID: PMC4130795  PMID: 24631312
Lung volume reduction; Emphysema; Outcomes; Database
14.  Myocardial Viability and Impact of Surgical Ventricular Reconstruction on Outcomes of Patients with Severe Left Ventricular Dysfunction Undergoing Coronary Artery Bypass Surgery: Results of the Surgical Treatment for Ischemic Heart Failure (STICH) Trial 
Objective
In the Surgical Treatment for Ischemic Heart Failure (STICH) trial, surgical ventricular reconstruction plus coronary artery bypass surgery was not associated with a reduction in the rate of death or cardiac hospitalization compared to bypass alone. We hypothesized that the absence of viable myocardium identifies patients with coronary artery disease and left ventricular dysfunction who have a greater benefit with coronary artery bypass graft surgery and surgical ventricular reconstruction compared to bypass alone.
Methods
Myocardial viability was assessed by single photon computed tomography in 267 of the 1,000 patients randomized to bypass or bypass plus surgical ventricular reconstruction in STICH. Myocardial viability was assessed on a per patient basis as well as regionally based on pre-specified criteria.
Results
At 3 years, there was no difference in mortality or the combined outcome of death or cardiac hospitalization between those with and those without viability, and there was no significant interaction between the type of surgery and global viability status with respect to mortality or death plus cardiac hospitalization. Furthermore, there was no difference in mortality or death plus cardiac hospitalization between those with and without anterior wall or apical scar, and no significant interaction between the presence of scar in these regions and the type of surgery with respect to mortality.
Conclusion
In patients with coronary artery disease and severe regional left ventricular dysfunction, assessment of myocardial viability does not identify patients who will derive a mortality benefit from adding surgical ventricular reconstruction to coronary artery bypass graft surgery.
doi:10.1016/j.jtcvs.2014.06.090
PMCID: PMC4250319  PMID: 25152476
15.  Differential Effects of Atorvastatin on Autophagy in Ischemic and Non-Ischemic Myocardium in Ossabaw Swine with Metabolic Syndrome 
OBJECTIVE
The perioperative administration of pleiomorphic statin drugs has been implicated in improving outcomes after cardiac surgery. Adaptive autophagy is a highly conserved cellular process that allows for the elimination of dysfunctional cell components in response to stress and survival under starving conditions. We sought to investigate the effects of the statin drug atorvastatin on autophagy in ischemic and non-ischemic myocardium utilizing a clinically relevant porcine model of metabolic syndrome.
METHODS
Male Ossabaw swine were fed a regular diet (n= 8), a high-cholesterol diet (n= 8) or a high-cholesterol diet with supplemental atorvastatin (1.5 mg/kg daily) (n= 8). After fourteen weeks all animals underwent surgical placement of an ameroid constrictor to the circumflex coronary artery to induce chronic ischemia. Non-ischemic and ischemic myocardium was harvested six months after initiation of the diet and processed for western blotting.
RESULTS
Western blot results demonstrate that in the non-ischemic myocardium a high cholesterol diet resulted in a statistically significant decrease in autophagy as indicated by an increase in mTOR and the accumulation of several essential autophagy markers including Beclin-1, LC3B-I, and LC3B-II. Atorvastatin supplementation prevented these changes, and resulted in an increase in autophagy as indicated by a decrease in autophagy flux marker P62. In the ischemic myocardium atorvastatin actually had the opposite effect, with a decrease in autophagy flux as indicated by an increase in p62 and an accumulation of LC3B-I, LCB-II and LAMP-2.
CONCLUSIONS
Atorvastatin administration has differential effects on autophagy in ischemic and non-ischemic myocardium. In the setting of metabolic syndrome, atorvastatin stimulates autophagy in non-ischemic myocardium while partly inhibiting autophagy in ischemic myocardium. The differential regulation on autophagy may, in part, explain the cardioprotective effect of statins in both ischemic and non-ischemic myocardium, and these findings may have implications in the setting of cardiac surgery.
doi:10.1016/j.jtcvs.2014.07.104
PMCID: PMC4250390  PMID: 25240527
Atorvastatin; Chronic Myocardial Ischemia; Metabolic Syndrome; Diabetes; Autophagy
16.  Targeting survival pathways to create infarct-spanning bridges of human embryonic stem cell-derived cardiomyocytes 
Background
Generating myocyte grafts that bridge across infarcts could maximize their functional impact and best utilize small numbers of stem cells. To date, however, graft survival within acute infarcts has not been feasible. To enhance intra-infarct graft viability, human embryonic-derived cardiomyocytes (hESC-CMs) were pretreated prior to implantation with cobalt protoporphyrin (CoPP), a pharmacologic inducer of cytoprotective heme oxygenase-1.
Methods
After pre-culturing with CoPP (vs. PBS), hESC-CMs were injected intramyocardially into acutely infarcted rat hearts, using directed injections to span the infarct. A further group received CoPP-pretreated hESC-CMs plus 4 weekly doses of systemic CoPP to prolong exposure to cytoprotectants. Two control groups with infarcts received vehicle-only intramyocardial injections or weekly systemic CoPP without cell therapy. Post-infarct ventricular function was gauged by echocardiography and graft size quantified at 8 weeks by histomorphometry.
Results
CoPP pre-conditioned hESC-CMs formed stable grafts deep within infarcted myocardium, while grafts without CoPP exposure survived mainly at the infarct periphery. Fractional shortening was improved at 4 and 8 weeks in all hearts receiving cell therapies (P < 0.01 vs. vehicle-only injections). CoPP treatment of both graft hESC-CMs and recipient animals resulted in the largest grafts, highest fractional shortening, preserved wall thickness, and reduced infarct dimensions.
Conclusions
Cellular therapy delivered acutely after infarction significantly improved post-infarct ventricular function at 1 and 2 months. CoPP pretreatment of cells resulted in stable hESC-CM grafts within infarcted myocardium. This design enables construction of directionally-oriented, infarct-spanning bands of new cardiomyocytes that might further improve functional restoration as engrafted myocytes proliferate and mature.
doi:10.1016/j.jtcvs.2014.06.087
PMCID: PMC4250416  PMID: 25227700
cell therapy; human embryonic stem cells; heme oxygenase-1; myocardial infarct repair; preconditioning
17.  Tumor Cells are Dislodged into the Pulmonary Vein During Lobectomy 
Objective
Intraoperative tumor shedding may facilitate tumor dissemination. Earlier studies defined shed tumor cells primarily by cytomorphological examination, and could not always distinguish normal epithelial cells from tumor cells. We sought to accurately identify tumor cells using single-cell sequencing and determine whether these cells were mobilized into the circulation during pulmonary lobectomy.
Methods
We analyzed 42 blood samples collected from the tumor-draining pulmonary vein at the end of lobectomy procedures. We used arrays of nanowells to enumerate and retrieve single EpCAM+ cells. Targeted sequencing of 10–15 cells and nested PCR of single cells detected somatic mutations in shed epithelial cells consistent with patient-matched tumor but not normal tissue.
Results
The mean of EpCAM+ cells in VATS lobectomy (no wedge) specimens (n=16) was 165 (median 115; range 0–509) but sampling cells from three patients indicated that only 0–38% of the EpCAM+ cells were tumor cells. The mean of VATS lobectomy (wedge) specimens (n=12) was 1128 (median 197; range 47– 9406) and all of the EpCAM+ cells were normal epithelial cells in two patients sampled. The mean of EpCAM+ cells in thoracotomy specimens (n=14) was 238 (median 22; range 9–2920) and 0–50% of total EpCAM+ cells were tumor cells based on four patients sampled.
Conclusion
Surgery mobilizes tumor cells into the pulmonary vein, along with many normal epithelial cells. EpCAM alone cannot differentiate between normal and tumor cells. On the other hand, single-cell genetic approaches with patient-matched normal and tumor tissue can accurately quantify the number of shed tumor cells.
doi:10.1016/j.jtcvs.2014.06.074
PMCID: PMC4356533  PMID: 25172322
18.  Expanded Level of Sympathetic Chain Removal Does Not Increase Incidence or Severity of Compensatory Hyperhidrosis Following Endoscopic Thoracic Sympathectomy 
Objective
Compensatory hyperhidrosis is a common devastating adverse effect following endoscopic thoracic sympathectomy for patients undergoing surgical treatment of primary hyperhidrosis. We sought to determine if there was a correlation in our patient population between the level and extent of sympathetic chain resection and the subsequent development of compensatory hyperhidrosis.
Methods
All patients undergoing endoscopic thoracic sympathectomy in the T2-3, T2-4, T2-5, or T2-6 levels for palmar or axillary hyperhidrosis at the University of Iowa Hospital and Clinics (n=97) between January 2004 and January 2013 were retrospectively reviewed.
Results
Differences in preoperative patient characteristics were not statistically significant between patients receiving either T2-3, T2-4, T2-5, or T2-6 level resections. Of the ninety-seven patients included in this study, twenty-eight patients (29%) experienced transient compensatory hyperhidrosis and four patients (4%) complained of severe compensatory hyperhidrosis and required further treatment. There were no operative mortalities and morbidity was similar amongst the groups.
Conclusions
Most patients had successful outcomes after undergoing extensive resection without change in incidence of compensatory hyperhidrosis. Therefore, we recommend performing a complete and adequate resection for relief of symptoms in patients with primary hyperhidrosis.
doi:10.1016/j.jtcvs.2014.06.080
PMCID: PMC4369919  PMID: 25131173
19.  Contemporary outcomes of complete atrioventricular septal defect repair: Analysis of the Society of Thoracic Surgeons Congenital Heart Surgery Database 
Objective
Contemporary outcomes data for complete atrioventricular septal defect (CAVSD) repair are limited. We sought to describe early outcomes of CAVSD repair across a large multicenter cohort, and explore potential associations with patient characteristics, including age, weight, and genetic syndromes.
Methods
Patients in the Society of Thoracic Surgeons Congenital Heart Surgery Database having repair of CAVSD (2008–2011) were included. Preoperative, operative, and outcomes data were described. Univariate associations between patient factors and outcomes were described.
Results
Of 2399 patients (101 centers), 78.4% had Down syndrome. Median age at surgery was 4.6 months (interquartile range, 3.5–6.1 months), with 11.8% (n = 284) aged ≤2.5 months. Median weight at surgery was 5.0 kg (interquartile range, 4.3–5.8 kg) with 6.3% (n = 151) <3.5 kg. Pulmonary artery band removal at CAVSD repair was performed in 122 patients (4.6%). Major complications occurred in 9.8%, including permanent pacemaker implantation in 2.7%. Median postoperative length of stay (PLOS) was 8 days (interquartile range, 5–14 days). Overall hospital mortality was 3.0%. Weight<3.5 kg and age ≤ 2.5 months were associated with higher mortality, longer PLOS, and increased frequency of major complications. Patients with Down syndrome had lower rates of mortality and morbidities than other patients; PLOS was similar.
Conclusions
In a contemporary multicenter cohort, most patients with CAVSD have repair early in the first year of life. Prior pulmonary artery band is rare. Hospital mortality is generally low, although patients at extremes of low weight and younger age have worse outcomes. Mortality and major complication rates are lower in patients with Down syndrome.
doi:10.1016/j.jtcvs.2014.05.095
PMCID: PMC4527871  PMID: 25125206
20.  Outcomes of cardiac surgery in patients less than 2.5 kg: impact of patient-dependent and patient-independent variables 
Objective
A recent STS database study showed that low weight (<2.5 kg) at surgery was associated with a high operative mortality (16%). We thought to assess outcomes after cardiac repair in patients <2.5 kg as compared to 2.5-4.5kg in an institution with a dedicated neonatal cardiac program; and to determine the potential role played by prematurity, STAT risk categories, uni/biventricular pathway, and timing of surgery.
Methods
We analyzed outcomes (hospital mortality, early reintervention, postoperative length of stay (postopLOS), mortality (at last follow-up) in patients <2.5kg at time of surgery (n=146; group1) and 2.5-4.5kg (n=622; group2), who underwent open or closed cardiac repairs from January 2006 to December 2012 at our institution. The statistical analysis was stratified by prematurity, STAT risk categories, uni/biventricular pathway and “usual”/“delayed” timing of surgery. A uni/multivariate risk analysis was performed. Mean follow-up was 21.6±25.6 months.
Results
Hospital mortality in group 1 was 10.9% (n=16) vs. 4.8% (n=30) in group 2 (p=0.007). PostopLOS and early un-planned reintervention rates were similar between the two groups. Late mortality in group 1 was 0.7% (n=1). In Group 1, early outcomes were independent of STAT risk categories, uni/biventricular pathway or timing of surgery, as opposed to group 2. Lower gestational age at birth was an independent risk factor for early mortality in group 1.
Conclusions
A dedicated multidisciplinary neonatal cardiac program yields good outcomes for neonates and infants <2.5kg independently of STAT risk categories and uni/biventricular pathway. Lower gestational age at birth was an independent risk factor for hospital mortality.
doi:10.1016/j.jtcvs.2014.07.031
PMCID: PMC4530498  PMID: 25156464
21.  Metabolic Characteristics of Human Hearts Preserved for 12 Hours by Static Storage, Antegrade Perfusion or Retrograde Coronary Sinus Perfusion 
Objective(s)
Machine perfusion of donor hearts is a promising strategy to increase the donor pool. Antegrade perfusion is effective but can lead to aortic valve incompetence and non-nutrient flow. Experience with retrograde coronary sinus perfusion of donor hearts has been limited. We tested the hypothesis that retrograde perfusion could support myocardial metabolism over an extended donor ischemic interval.
Methods
Human hearts from donors rejected or not offered for transplantation were preserved for 12 hours in University of Wisconsin Machine Perfusion Solution by: 1. Static hypothermic storage 2. Hypothermic antegrade machine perfusion or 3. Hypothermic retrograde machine perfusion. Myocardial oxygen consumption (MVO2), and lactate accumulation were measured. Ventricular tissue was collected for proton (1H) and phosphorus-31 (31P) magnetic resonance spectroscopy (MRS) to evaluate the metabolic state of the myocardium. Myocardial water content was determined at end-experiment.
Results
Stable perfusion parameters were maintained throughout the perfusion period with both perfusion techniques. Lactate/alanine ratios were lower in perfused hearts compared to static hearts (p<.001). Lactate accumulation (Antegrade 2.0±.7, Retrograde 1.7±.1 mM) and MVO2 (Antegrade 0.25±.2, Retrograde 0.26±.3 mL O2/min/100g) were similar in machine perfused groups. High energy phosphates were better preserved in both perfused groups (p<.05). Left ventricular myocardial water content was increased in retrograde perfused (80.2±.8%) compared to both antegrade perfused (76.6±.8%, p=.02) and static storage hearts (76.7±1%, p=.02).
Conclusions
In conclusion, machine perfusion by either the antegrade or the retrograde technique can support myocardial metabolism over long intervals. Machine perfusion appears promising for long term preservation of human donor hearts.
doi:10.1016/j.jtcvs.2014.02.023
PMCID: PMC4126897  PMID: 24642559
22.  Readmission following lung cancer resection is associated with a six-fold increase in 90-day postoperative mortality 
Objectives
Postoperative readmission impacts patient care and healthcare costs. There is a paucity of nation-wide data describing the clinical significance of readmission following thoracic operations. The purpose of this study was to evaluate the relationship between postoperative readmission and mortality following lung cancer resection.
Methods
Data were extracted for lung cancer resection patients from the linked SEER-Medicare registry (2006-2011), including demographics, comorbidities, socioeconomic factors, readmission within 30 days from discharge, and 90-day mortality. Readmitting facility and diagnoses were identified. A hierarchical regression model clustered at the hospital level identified predictors of readmission.
Results
We identified 11,432 lung cancer resection patients discharged alive from 677 hospitals. The median age was 74.5 years and 52% of patients received an open lobectomy. 30-day readmission rate was 12.8%, and 28.3% of readmissions were to facilities that did not perform the original operation. Readmission was associated with a six-fold increase in 90-day mortality (14.4% vs. 2.5%, p <0.001). The most common readmitting diagnoses were respiratory insufficiency, pneumonia, pneumothorax, and cardiac complications. Patient factors associated with readmission included resection type, age, prior induction chemoradiation, preoperative comorbidities including congestive heart failure and COPD, and low regional population density.
Conclusions
Factors associated with early readmission following lung cancer resection include patient comorbidities, type of operation, and socioeconomic factors. Metrics that only report readmissions to the operative provider miss one-fourth of all cases. Importantly, readmitted patients have an increased risk of death and demand maximum attention and optimal care.
doi:10.1016/j.jtcvs.2014.04.026
PMCID: PMC4201876  PMID: 24823283
Lung cancer; postoperative readmission; postoperative mortality; outcomes
23.  Technical Performance Score is Associated with Outcomes after the Norwood Procedure 
Objectives
Technical Performance Score (TPS) has been reported in a single center study to predict outcomes after congenital cardiac surgery. We sought to determine the association of TPS with outcomes in patients undergoing Norwood procedure in the Single Ventricle Reconstruction Trial.
Methods
We calculated TPS (Class 1-Optimal; Class 2-Adequate; Class 3-Inadequate) based on predischarge echocardiograms analyzed in a Core Laboratory and unplanned reinterventions that occurred prior to discharge from the Norwood hospitalization. Multivariable regression examined the association of TPS with time to first extubation, Norwood length of stay (LOS), death/transplantation, unplanned post-discharge reinterventions, and neurodevelopment at 14 months of age.
Results
Among 549 patients undergoing a Norwood procedure, 356 (65%) had an echocardiogram adequate to assess atrial septal restriction/arch obstruction or an unplanned reintervention, enabling calculation of TPS. In multivariable regression adjusting for preoperative variables, a better TPS was an independent predictor of shorter time to first extubation (p=0.019), better transplant-free survival before Norwood discharge (p<0.001; odds ratio 9.1 for Inadequate vs. Optimal score), shorter hospital LOS (p<0.001), fewer unplanned reinterventions between Norwood discharge and Stage II (p=0.004), and higher Bayley II Psychomotor Development Index at 14 months (p=0.031). TPS was not associated with transplant-free survival after Norwood discharge, unplanned reinterventions after Stage II or Bayley II Mental Development Index at 14 months.
Conclusion
TPS is an independent predictor of important outcomes after Norwood and may serve as a tool for quality improvement.
doi:10.1016/j.jtcvs.2014.05.076
PMCID: PMC4253672  PMID: 25037617
Congenital heart disease; CHD; hypoplastic left heart syndrome; outcomes
24.  Time-to-Surgery and Pre-operative Cerebral Hemodynamics Predict Post-operative White Matter Injury in Neonates with Hypoplastic Left Heart Syndrome 
Objective
Hypoxic-ischemic white mater brain injury commonly occurs in neonates with hypoplastic left heart syndrome (HLHS). Approximately half of the HLHS survivors exhibit neurobehavioral symptoms believed to be associated with this injury, though the exact timing of the injury is not known.
Methods
Neonates with HLHS were recruited for pre- and post-operative monitoring of cerebral oxygen saturation (ScO2), cerebral oxygen extraction fraction (OEF), and cerebral blood flow (CBF) using two non-invasive optical-based techniques, namely diffuse optical spectroscopy and diffuse correlation spectroscopy. Anatomical magnetic resonance imaging (MRI) scans were performed prior to and approximately one week after surgery in order to quantify the extent and timing of the acquired white matter injury. Risk factors for developing new or worsened white matter injury were assessed using uni- and multi-variate logistic regression.
Results
Thirty-seven neonates with HLHS were studied. In a univariate analysis, neonates who developed a large volume of new, or worsened, postoperative white matter injury had a significantly longer time-to-surgery (p=0.0003). In a multivariate model, longer time between birth and surgery (i.e., time-to-surgery), delayed sternal closure, and higher pre-operative CBF were predictors of post-operative white matter injury. Additionally, longer time-to-surgery and higher pre-operative CBF on morning of surgery were correlated with lower ScO2 (p=0.03 and p=0.05) and higher OEF (p=0.05 and p=0.05).
Conclusions
Longer time-to-surgery is associated with new post-operative white matter injury in otherwise healthy neonates with HLHS. The results suggest that earlier Norwood palliation may decrease the likelihood of acquiring postoperative white matter injury.
doi:10.1016/j.jtcvs.2014.05.081
PMCID: PMC4254035  PMID: 25109755
25.  Postoperative electroencephalographic seizures are associated with deficits in executive function and social behaviors at 4 years of age following cardiac surgery in infancy 
Objective
The occurrence of an electroencephalographic (EEG) seizure after surgery for complex congenital heart defects has been associated with worse neurodevelopmental (ND) outcomes. We previously identified post-operative seizures documented by 48-hour EEG monitoring in 11% of 178 neonates and infants. Evaluation at 1 year of age did not identify an adverse effect of an EEG seizure on ND outcomes. The current study was undertaken to determine if testing in the preschool period would identify deficits that become apparent as children develop.
Methods
The ND outcomes assessed at 4 years of age included cognition, language, attention, impulsivity, executive function, behavior problems, academic achievement, and visual and fine motor skills.
Results
Developmental evaluations were performed in 132 (87%) of 151 survivors. For the entire cohort, the Full-Scale IQ was 95.0 ± 18.5. IQ was 95.1 ± 18.7 for patients without a history of seizure and 93.6 ± 16.7 for those with a history of seizure. After covariate adjustment, occurrence of an EEG seizure was associated with worse executive function (P = .037) and impaired social interactions/restricted behavior (P = .05). Seizures were not significantly associated with worse performance for cognition, language, attention, impulsivity, academic achievement, or motor skills (all P > .1).
Conclusions
The occurrence of a postoperative seizure is a biomarker of brain injury. This study confirms that postoperative EEG seizures are associated with worse ND outcomes, characterized by impairments of executive function and a higher prevalence of deficits in social interactions and repetitive/restricted behaviors in preschool survivors of cardiac surgery in infancy. However, EEG seizures were not associated with worse cognitive, language, or motor skills.
doi:10.1016/j.jtcvs.2013.04.002
PMCID: PMC4617776  PMID: 23768805

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