43.10 Are Non-Emergent Cardiac Surgeries Performed During Off-Time Associated with Worse Outcome?

Posted on January 25, 2017

R. Ou1, G. Ramos1, Y. Juo1, R. J. Shemin1, P. Benharash1  1David Geffen School Of Medicine, University Of California At Los Angeles,Division Of Cardiac Surgery,Los Angeles, CA, USA

Background:

With the implementation of value-based healthcare, it is of increasing interesting to understand whether performing elective surgeries during off-time impacts surgical outcomes. In cardiac surgery, interdisciplinary coordination in the operating room is crucial. Factors such as end of day fatigue, care team transitions, and physiologic changes in patients can negatively affect coordination and precipitate adverse events in patient care. We hypothesized that “off-time” cases, including late start and weekend operations, are associated with higher postoperative mortality and major adverse events in patients receiving elective cardiac operations. 

Methods:

The institutional Society of Thoracic Surgeons (STS) database was used to identify all adult elective cardiac operations performed between January 2008 and December 2015 at a university hospital. Patients receiving transplants and extracorporeal mechanical circulatory support were excluded. ”Off-time” was defined as either operation “late starts,” i.e. an incision time after 3PM, or procedures occurring during the weekends. Univariate and multivariate logistic regression were performed to examine its impact on in-hospital mortality and major adverse events (MAE). MAE were defined as postoperative atrial fibrillation, stroke, transient ischemic attack, myocardial infarction, renal failure, surgical site infection, sepsis, prolonged respiratory support, and unplanned reoperations. Available cost data was directly obtained from the departmental BIOME database.

Results:

Of the 3,399 non-emergent cardiac operations included in the study, 468 (13.8%) were performed during off-time. After adjusting for patient and operative characteristics, cases performed off time were not associated with increased in-hospital mortality (P=0.58, CI 95%  0.99—1.02), readmissions (P=0.20, CI 95%  0.99—1.07), or MAE (P=0.10, CI 95%  0.99—1.11). Cost data were available in 1650 (48.5%) patients. Of the patients with cost data available, late start operations were associated with a 16.4% increase in total cost (P<0.01), however after adjusting for patient comorbidities this was no longer significant (P=0.17).

Conclusions:

These findings suggest that cases performed during off time are not associated with increased mortality or other complications in a tertiary-care academic medical center. Our findings should be considered during operative scheduling in order to optimize resource distribution and patient care strategies.

43.09 A Protocol to Decrease Post Operative Chylous Effusion Duration in Pediatric Patients

Posted on January 25, 2017

M. M. Winder1, D. K. Bailly3, R. J. Smout1, J. Marietta1, A. W. Eckhauser2  1Primary Childrens Hospital,Salt Lake City, UT, USA 2University Of Utah,Pediatric Cardiothoracic/Cardiothoracic Surgery/Surgery,Salt Lake City, UT, USA 3University Of Utah,Critical Care/Pediatrics,Salt Lake City, UT, USA

Introduction:  Chylothorax following pediatric cardiac surgery occurs in 2.8% of patients nationwide and leads to significant morbidity. Currently no evidence-based protocol for the treatment of chylothorax exists, which leads to wide practice variation specifically in the timing of treatments and surgical interventions. Our primary goals were to decrease variability among providers treating pediatric patients with chylothorax following cardiac surgery by developing and implementing a management protocol and to decrease time to resolution of chylothorax as demonstrated by total days of chest tube utilization.

Methods:  A chylothorax management protocol was implemented at Primary Children’s Hospital in July 2015. We included all patients aged 0-17y with chylothorac within 30 days of surgery. We excluded congenital chylothorax, Fontan patients, and those with chylothorax duration <24 hours. Retrospective analysis was completed on patients treated with chylothorax following cardiac surgery in a pre-protocol implementation cohort (July 2014 to June 2015, n = 19) and a post-protocol implementation cohort (July 2015 to March 2016, n = 13). Any patient with a diagnosis of chylothorax unrelated to cardiac surgery was excluded.

Results:  Patient characteristics including age at time of surgery, sex, race, weight on admission, RACHS categories 1-3 and 4-6 and presence of genetic abnormalities were similar pre and post protocol implementation. Protocol compliance was 92%. Following protocol implementation, duration of chest tube used decreased from 12 days to 6.2 days (p = 0.04). Time to resolution of chylothorax decreased from a mean of 7.4 days to 4.1 days (p = 0.11), with a decrease in maximum time to resolution from 30 days to 9 days (see figure). Duration of medium chain triglyceride feeds decreased from 42 days to 30 days (p=0.03). Pre and post protocol duration of mechanical ventilation (4.7 days vs. 4.5 days; p = 0.91), hospital length of stay (13.1 days vs. 14.8 days; p = 0.73, and CICU length of stay (29 days vs. 21.8 days; p =0.33) were unchanged post protocol. There were no chest tube re-insertions, readmissions, or surgical interventions related to chylothorax in either the pre- or post-protocol cohorts.

Conclusion:  Adoption of a chylothorax management protocol is feasible and in our small cohort of patients, implementation led to significantly improved duration of chest tube use and decrease from maximal time to resolution of chylothorax.

 

43.08 Lobectomy, Segmentectomy or Wedge Resection for T1a NSCLC: a Systematic Review and Meta-analysis

Posted on January 25, 2017

M. A. IJsseldijk1,2, M. Shoni3, C. Siegert5, J. Seegers2, T. Van Engelenburg2,5, T. Tsai3, A. Lebenthal3,4,5, R. Ten Broek1,2  1Radboud University Medical Center,General Surgery,Nijmegen, GELDERLAND, Netherlands 2Slingeland Hospital,Surgery,Doetinchem, GELDERLAND, Netherlands 3Brigham And Women’s Hospital,Surgery,Boston, MA, USA 4Harvard School Of Medicine,Brookline, MA, USA 5VA Boston Healthcare System,West Roxbury, MA, USA

Introduction:
The optimal treatment of small (T1a) non-small cell lung cancer (NSCLC) remains subject to debate. Lobar resection is considered the standard of care. However, recent studies indicate sublobar resection (segmentectomy or wedge resection) as a promising, parenchymal sparing treatment yielding comparable oncological outcomes. We conducted a systematic review and meta-analysis to compare oncological outcomes after lobar resections and parenchymal sparing resections in T1a NSCLC.

Methods:
We searched MEDLINE, PubMed, EMBASE, Web of Knowledge and CENTRAL to identify studies reporting overall survival (OS) or disease-free survival (DFS) following lobar resection or parenchymal sparing resections in early-stage NSCLC. Two researchers independently identified  studies and extracted data. Oncological outcomes after lobar resection and parenchymal sparing resections were compared using the Mantel-Haenszel method and outcomes were pooled for each surgical modality using the inverse variance method. 

Results:
A total of 8781 studies were identified, from which 24 articles were included. There was no difference in 5-year OS in pT1a tumors when lobar resection was compared to a lung parenchymal sparing resection (Relative Risk=0.90 (95%CI 0.80-1.02)). Moreover, there was no difference in 5-year DFS for pT1a tumors or 5-year OS for cT1a tumors between lobar surgery and a lung parenchymal sparing resection. Strikingly, there was a minor difference in 5-year DFS favoring a parenchymal sparing resection over lobar surgery for cT1a tumors.
The point estimates of 5-year OS of both comparative and non-comparative studies for pT1a tumors were 86% (95% CI: 84-89%) following lobar resection (n=1538), 83% (95%CI: 75- 91%) following segmentectomy (n = 402) and 71% (95% CI: 65 – 76%) following wedge resection (n = 65). There were no differences in pooled estimates for 5-year OS in cT1a tumors and 5-year DFS for pT1a tumors.

Conclusion:
This systematic review and meta-analysis shows that parenchymal sparing surgery in the form of segmentectomy yields equivocal results in terms of 5-year OS or DFS compared to lobar surgery for T1a NSCLC tumors. However, nodal upstaging is present in approximately 10% of patients.

 

43.07 Outcomes of Acute Renal Failure Evolved During Veno-Venous ECMO for Severe ARDS Patients

Posted on January 25, 2017

R. Devasagayaraj1, N. Cavarocchi1, H. Hirose1  1Thomas Jefferson University,Philadelphia, PA, USA

Introduction:  Patients who develop severe acute respiratory distress syndrome (ARDS) with stable hemodynamics may be placed on veno-venous extracorporeal membrane oxygenation (VV ECMO) to support respiratory recovery.  Survival outcomes remain unclear in those who develop acute kidney injury (AKI) requiring continuous veno-venous hemodialysis (CVVHD).

Methods:  A retrospective chart review (2010-2016) of patients who underwent VV ECMO for ARDS was conducted with IRB approval.  Patients supported by veno-arterial ECMO due to cardiac failure or hemodynamic instability were excluded. Analyses of patient demographics, clinical risk factors, respiratory parameters, and laboratory data were conducted.  AKI was defined by receiving CVVHD, which was used for patients with oliguria despite administration of diuretics, acute renal failure, severe metabolic acidosis, and/or uncontrollable fluid overload.  VV ECMO was performed via right internal jugular access using dual lumen ECMO cannula, while CVVHD was performed via groin access using a separate dialysis catheter.  Patients on VV ECMO were divided by development of AKI into two groups, AKI and non-AKI and survival analysis was performed.

Results: We identified 54 ARDS patients (aged 45 ± 13y, 33 males) supported by VV ECMO (mean ECMO days 12 ± 6.7) including 16 (29.6%) in AKI group and 38 (70.4%) in non-AKI group.  No patients had previous renal failure, and serum creatinine was similar between AKI and non-AKI group at the time of ECMO initiation (1.8 ± 1.1 mg/dl in AKI group vs. 1.4 ± 0.7 mg/dl in non-AKI group, p=0.194).  Survival of AKI group (56.3% [9/16]) was inferior to the non-AKI group (86.8% [33/38]), p=0.013.  At the time of initiation of ECMO, patients demographics, lung, renal, and liver functions were similar between AKI and non-AKI group.  However, at the time of decannulation of ECMO, AKI group showed higher lactate (5.2 ± 5.1 mmol/L in AKI group vs 2.1 ± 1.2 mmol/L in non-AKI group, p=0.046), metabolic acidosis (bicarbonate level, 23 ± 3.4 mmol/L vs. 27 ± 9.9 mmol/L, p=0.032), despite similar creatinine levels (1.2 ± 0.6 mg/dL vs. 1.0 ± 0.5 mg/dL, p=0.272).  AKI group showed greater incidence of complications during ECMO including liver failure (37.5% [6/16] vs. 5.2% [2/38], p=0.002) and internal hemorrhage (68.8% [11/16] vs. 21% [8/38], p<0.001). Among the survivors of ECMO, 79.2% [38/48] survived hospital stay and 43.8% [7/16] recovered renal function without need of permanent dialysis.

Conclusion: In our experience, patients initially placed on VV ECMO for single organ injury due to ARDS when complicated by AKI showed decreased survival.  Patients developing AKI are likely to develop hepato-renal syndrome and internal bleeding, all which may lead to multi-organ failure.  VV ECMO alone successfully manages patients with severe ARDS; however, other end-organ function needs careful monitoring and appropriate treatment to improve outcome.

43.06 Meta-analysis of Thromboelastography for Postoperative Hemorrhage After Cardiac Surgery

Posted on January 25, 2017

J. Parreco1, M. Eby1, A. A. Kurian1, C. Faber1, R. Kozol1  1University Of Miami,Miami, FL, USA

Introduction:
Thromboelastography (TEG) has been used since the 1940s and the first use in cardiac surgery was reported in the 1980s. The purpose of this meta-analysis was to evaluate and compare the results of implementing TEG in the routine monitoring for postoperative bleeding after cardiac surgery.

Methods:
Studies involving TEG and cardiac surgery were systematically reviewed. Studies comparing TEG to conventional assessments were included in this meta-analysis and analyzed using random or fixed effect models to determine the mean difference or odds ratio.

Results:
Six studies were identified and included 1,770 patients undergoing cardiac surgery. This included 880 patients having TEG testing performed and 890 control patients without TEG testing performed. The patients undergoing the TEG assay were less likely to require transfusions of red blood cells (RBC), plasma or platelets. For these transfusions the odds ratios (OR) with confidence interval (CI) were: 0.58 (95% CI 0.46 to 0.73, p<0.01) for RBC, 0.57 (95% CI 0.45 to 0.72, p<0.01) for plasma and 0.60 (95% CI 0.48 to 0.74, p<0.01) for platelets. The number of patients requiring reexploration for bleeding was also less in the patients having TEG testing with an OR of 0.38 (95% CI 0.22 to 0.67, p<0.01). The chest tube drainage amounts were also less in the TEG patients with a mean difference (MD) of -450.1 (95% CI -875.5 to -24.7, p=0.04).

Conclusion:
Transfusion requirements for patients undergoing cardiac surgery with TEG testing were significantly less than patients undergoing conventional assessments for postoperative hemorrhage. The rate of reexploration and chest tube drainage was also significantly less for patients undergoing TEG testing.
 

43.05 Robotic-Assisted Lobectomy Outcomes for Early vs. Late Pathologic Stages of Primary Lung Cancer

Posted on January 25, 2017

B. Montane4, F. O. Velez-Cubian2, K. Toosi4, R. Gerard4, C. C. Moodie1, J. R. Garrett1, J. P. Fontaine1,2,3, E. M. Toloza1,2,3  1Moffitt Cancer Center,Thoracic Oncology,Tampa, FL, USA 2University Of South Florida Morsani College Of Medicine,Surgery,Tampa, FL, USA 3University Of Sough Florida College Of Medicine,Oncologic Sciences,Tampa, FL, USA 4University Of South Florida,Morsani College Of Medicine,Tampa, FL, USA

Introduction:   Surgical resection is still the gold standard for early stages of primary lung cancers.  More advanced stages, including nodal involvement, are approached with a multimodality therapy.  The purpose of our investigation was to determine the surgical outcomes of robotic-assisted video-thoracoscopic (RAVT) surgery for early versus late primary lung cancer stages.

Methods:   We retrospectively analyzed perioperative outcomes of consecutive patients with primary lung cancer and who underwent RAVT lobectomy by one surgeon at our institution during a 6-year period.  Patients were grouped by pathologic stage (pStage) into 4 groups:  pStage1, pStage2, pStage3, and pStage4.  Patient characteristics, operative times, intraoperative estimated blood loss (EBL), lymph node (LN) dissection, perioperative complications, chest tube duration, hospital length of stay (LOS), and in-hospital mortality were compared among the pStage groups.  Chi-square test, Student’s t-test, and Kruskal-Wallis or Mood’s median test were used, with p≤0.05 as significant.

Results:  A total of 359 patients underwent RAVT lobectomy by one surgeon between September 2010 and May 2016.  Thirty-one patients had pulmonary metastases or benign lesions and were excluded.  A cohort of 328 patients was analyzed in our study.  Patients’ characteristics differed only by pStage4 having lower body mass index (BMI; p=0.04).  Neither overall intraoperative complications nor conversion to open lobectomy differed among pStage groups (p≥0.09), although recurrent laryngeal nerve injury was highest in pStage3 (p=0.02).  Overall postoperative complications did not differ among pStage groups (p≥0.18), with the most common postoperative complication being prolonged air leak >5 days (20.5% vs. 19.4% vs. 25.0% vs. 44.4%, respectively, for pStage1 through pStage4; p=0.57).  Median EBL and median operative times were lowest for pStage1 (150 mL, p<0.001, and 162 min, p<0.001, respectively), but chest tube duration, hospital LOS, and in-hospital mortality did not differ among pStage groups (p≥0.15).  Efficacy of LN dissection was best for pStage2 and pStage3 for numbers of individual N1 (p≤0.02) and N2 (p≤0.002) LNs harvested, respectively, but did not differ among pStage groups for numbers of LN stations assessed (p≥0.16).

Conclusions:  Robotic-assisted lobectomy is feasible not only for early stages, but also as part of multi-modality treatment for more advanced primary lung cancers.  More advanced pStage, particularly LN involvement, resulted in increased EBL and longer operative times, but did not result in increased perioperative complication risk, hospital LOS, or in-hospital mortality.  Robotic-assisted lobectomy should be considered for the surgical component for multi-modality treatment of resectable advanced-stage primary lung cancers.

43.04 Simplifying Postoperative Outcome Prediction Scores In Cardiac Surgery

Posted on January 25, 2017

Y. Juo1, N. Satou1, R. Shemin1, P. Benharash1  1University Of California – Los Angeles,Cardiac Surgery,Los Angeles, CA, USA

Introduction:
The Society of Thoracic Surgeons Predicted Risk of Mortality (STS PROM) Score is developed specifically for calculation of short-term postoperative mortality and morbidity risks. It is a composite score from 35 variables encompassing demographics, baseline comorbidities, severity/complexity of primary cardiac disease, and anatomic/technical factors for specific procedures. The calculation of PROM involves a special online calculator that is beyond the immediate reach of most surgeons in a clinical setting. Here we seek to evaluate the efficacy of simpler prediction scores such as CHADS2 and CHA2DS2-VASC in comparison with PROM score.

Methods:
All adult patients undergoing cardiac surgery at a single institution from 2008 to 2015 were identified using the institutional Society of Thoracic Surgeons database. Patients receiving transplant, ECMO and ventricular assist devices were excluded.  An area under the curve (AUC) analysis  was performed to evaluate the discriminatory abilities of STS PROM, CHADS2, and CHA2DS2-VASC scores in predicting postoperative mortality, complications, major adverse cardiac events (MACE), acute renal failure, and prolonged length of stay.

Results:
4,232 patients underwent major cardiac surgery during the study period. Most common procedures were valve replacement (n=1,356, 32.04%) and coronary artery bypass grafting (n=875, 20.67%). 30-day mortality occurred in 118 (2.79%) patients while postoperative morbidity occurred in 1,686 (39.84%) patients, including 678 (16.02%) MACE, 145 (3.43%) acute renal failures, and 482 (11.39%) prolonged length of stays. The only outcome in which STS PROM Score demonstrated a larger AUC than either CHA2DS2-VASC or CHADS2 was postoperative mortality (0.82 vs 0.65 vs 0.57, p=0.0489). There was no significant AUC difference when comparing STS PROM Score against either CHA2DS2-VASC or CHADS2 when used in prediction of postoperative complications (0.60 vs 0.57 vs 0.57, p=0.48), MACE (0.55 vs 0.53 vs 0.54, p=0.60), acute renal failure (0.74 vs 0.66 vs 0.67, p=0.37), or prolonged length of stay (0.65 vs 0.67 vs 0.64, p=0.72). 

Conclusion:
STS PROM score was superior to both CHADS2 and CHA2DS2-VASC scores in prediction of postoperative mortality. There was no significant difference in the predictive value between the three prediction scores for other postoperative morbidities Furthermore, none of the scoring systems provided satisfactory discriminatory power for the prediction of complications in view of most AUC values approximating 0.5. Further investigation is required for a more parsimonious and effective morbidity prediction score. 
 

43.03 Incidence of Cerebral Microemboli in Single-Dose vs Multi-Dose Cardioplegia in Adult Cardiac Surgery

Posted on January 25, 2017

L. Mukdad1, S. Barajas1, K. Kim1, W. Toppen1, R. Gevorgyan2, H. Laks1, P. Benharash1  1David Geffen School Of Medicine, University Of California At Los Angeles,Cardiac Surgery,Los Angeles, CA, USA 2University Of California – Los Angeles,Los Angeles, CA, USA

Introduction:  Cerebral microemboli have been associated with neurocognitive deficits after cardiac operations using cardiopulmonary bypass (CPB). Interventions by the perfusionist and alterations in flow account for a large proportion of previously unexplained microemboli. This study compared the incidence of microemboli during cardiac operations using conventional (multi-dose) and Del Nido (single-dose) cardioplegia delivery. 

Methods:  Transcranial Doppler ultrasonography was used to detect microemboli in bilateral middle cerebral arteries of 14 adult patients undergoing cardiac operations using cardiopulmonary bypass and aortic clamping. Multi-dose cardioplegia (MDC) was used in 6 patients and single-dose cardioplegia (SDC) in the remaining 8. Manual count of microemboli during cross-clamp and during administration of cardioplegia was performed. Data were analyzed using STATA 13.0 statistical software (StataCorp, College Station, TX). Categorical variables were analyzed by Fisher’s exact test and continuous variables were analyzed by the independent sample T-test for unequal sample size. An alpha of < 0.05 was considered statistically significant.

Results: Baseline preoperative characteristics were similar between groups as shown in table 1. There were no differences in the ascending aortic atheroma grade (1.2 ± 0.4 MDC vs 1.6 ± 0.7 SDC, p=0.20), bypass times (141 ± 36 min MDC vs. 171 ± 33 min SDC, p=0.18), and cross-clamp times (118 ± 32 min MDC vs. 108 ± 45 min SDC, p=0.31). Use of multi-dose cardioplegia was associated with a seven-fold increase in the number of microemboli per minute of cross-clamp time (1.65 ± 1 vs 0.24 ± .18 emboli/min SDC, p=0.002). 

Conclusion: In this prospective pilot study, we found that the use of single-dose cardioplegia led to fewer cerebral microemboli when compared to the traditional multi-dose approach. This finding deserves further investigation to evaluate the benefits of single-dose delivery vs potential reduction in myocardial protection.

 

43.01 Understanding Unplanned Readmissions After Hiatal and Paraesophageal Hernia Repairs

Posted on January 25, 2017

R. Bhagat1, E. Juarez-Colunga2, N. O. Glebova1, W. G. Henderson2, D. Fullerton1, M. J. Weyant1, J. D. Mitchell1, R. McIntyre1, R. A. Meguid1  2University Of Colorado Denver,Department Of Biostatistics & Informatics,Aurora, CO, USA 1University Of Colorado Denver,Department Of Surgery,Aurora, CO, USA

Introduction: Hospital readmissions are viewed as a marker of inferior healthcare quality & penalized with decreased reimbursement. Characteristics of unplanned readmissions after hiatal & paraesophageal hernia repairs (HPHR) are not well understood. We sought to determine the association of complications to postoperative unplanned readmission to identify opportunities for intervention.

Methods: We analyzed the ACS NSQIP database (2012-14) to characterize 30-day postoperative related, unplanned readmissions after HPHR identified by CPT code. Timing of, reason for & association between postoperative complication & unplanned readmission was analyzed.

Results: Of 23,257 patients who underwent HPHR, 17,194 (74%) were female, mean age was 55.3 years & mean length of stay (LOS) was 2.4 days. 1,281 (6%) experienced >=1 complication; death occurred in 45 (0.2%) patients. 963 (4.1%) experienced a related, unplanned readmission within 30 days of surgery. Patients who were readmitted were older (mean age 56.4 vs 55.2 years, p=0.02), had a longer mean LOS (3.2 vs 2.3 days, p<0.001), had more complex operations (mean work relative value unit with standard deviation: 20.8 (10.3) vs 18.7 (11.0), p<0.001) & more emergency operations (3.3% vs 1.9%, p=0.001). Among patients who developed >=1 postoperative complications, 55% (706/1,281) had complications while an inpatient & 8% (57/706) readmitted, 41% (532/1,281) were identified after discharge & 54% (285/532) readmitted, & 0.2% (39/1,281) had complications both as an inpatient & after discharge & 74% (29/39) readmitted. Of patients who experienced an unplanned readmission, 39% (371/963) had a documented postoperative complication, with 77% (285/371) developing their complication after discharge. Complications at readmission were mainly gastrointestinal (GI) (42%; 390/937), infectious (13%; 124/937), pulmonary (10%; 98/937) & pain (10%; 97/937). 53% of related, unplanned readmissions occurred within 7 days of discharge, & 79% within 14 days (Figure 1).

Conclusion: Related, unplanned readmission within 30 days of surgery occurred in 4% of patients undergoing HPHR. Over half of patients who developed a complication after discharge were readmitted. Patients who experienced related, unplanned readmissions underwent more complex operations & were older than those not readmitted. The most common reason for readmission was GI complication. Over half of readmissions occurred within 1 week of discharge, & nearly 80% within 2 weeks. Follow-up within the first few days after discharge from surgery may help identify patients suffering post-discharge complications & who are at risk of unplanned readmission. This may facilitate outpatient intervention targeted at common complications to prevent unplanned readmission.

36.05 Effectiveness of Local Therapy for Stage I Non-Small Cell Lung Cancer in Nonagenarians

Posted on January 25, 2017

B. N. Arnold1, D. C. Thomas1, J. E. Rosen1, M. C. Salazar1, F. C. Detterbeck1, J. D. Blasberg1, D. J. Boffa1, A. W. Kim1  1Yale University School Of Medicine,Department Of Surgery, Section Of Thoracic Surgery,New Haven, CT, USA

Introduction:  Nonagenarians are the fastest growing subset of the United States population, and non-small cell lung cancer (NSCLC) is the most common cancer in the elderly population. Stage I NSCLC is a potentially curable disease with 5-year survival approaching 50%, yet older patients undergo treatment at lower rates than younger patients. This analysis sought to describe the scope of treatment in nonagenarians with early stage NSCLC and to provide data on outcomes of these patients in order to better guide treatment decisions in this growing population of patients.

Methods:  The National Cancer DataBase was queried for all patients age 90 years and older with stage I NSCLC (tumors ≤4 cm). Patients were divided into three treatment groups: local therapy (surgery, stereotactic body radiation (SBRT)), other therapy, or no treatment. The primary outcomes were 5-year overall and relative survival. Surgery and SBRT were compared in a subset analysis.

Results: Of the 616 patients identified, 202 (33%) were treated with local therapy, 207 (34%) were treated with other therapy, and 207 (34%) underwent no treatment. Of those treated with local therapy, there were 40 (20%) lobectomies, 35 (17%) sublobar resections, and 127 (63%) patients who underwent SBRT. Of those treated with other therapy, 188 (91%) received standard radiation therapy of varying doses, 13 (6%) received combination therapy, and 6 (3%) received chemotherapy. Five-year overall survival was significantly lower with no treatment (8%) and other therapy (13%) compared to local therapy (23%) (p<0.0001). This effect remained significant after adjusting for covariates in a Cox model (HR for other therapy 1.428, 95% CI 1.11-1.83, p=0.0053; HR for no treatment 2.50, 95% CI 1.95-3.21, p<0.0001). The 5-year relative survival differed by treatment, with 81% for local therapy, 49% for other therapy, and 32% for no treatment (p<0.0001). In the subset analysis, there was no difference in overall survival between surgery (26%) and SBRT (20%) (p=0.33).

Conclusion: Nonagenarians who are managed with local therapy for stage I NSCLC (tumors ≤4 cm) have better overall survival than those who receive other therapy or no treatment, regardless of the type of local therapy. Nonagenarians with stage I lung cancer derive a benefit from treatment and should be treated with either surgery or SBRT if able to tolerate treatment.

 

35.05 Decision Analysis Supports the Use of Amylase Based Enhanced Recovery Pathway After Esophagectomy

Posted on January 25, 2017

B. Jiang2, V. P. Ho2, J. Ginsberg1, S. J. Fu1, Y. Perry1, L. Argote-Greene1, P. A. Linden1, C. W. Towe1  1University Hospitals Case Medical Center,Thoracic And Esophageal Surgery,Cleveland, OH, USA 2University Hospitals Case Medical Center,Surgery,Celeveland, OH, USA

Introduction:
A common post-operative complication after esophagectomy is anastomotic leak. Radiographic imaging of anastomotic leaks (by esophagram) is frequently inaccurate and is often performed after 5-7 days of observation. Prior study has supported the use of perianastomotic drain amylase (DA) on postoperative day 4 to identify patients at low-risk and high-risk for anastomotic leak.  . The aim of this study was to determine if decision analysis supports the use of a DA-based accelerated care pathway to decrease hospital length of stay and cost.

Methods:
We designed a decision tree model to compare costs and lengths of stay of DA leak detection versus the standard of care (esophagram) using data extracted from cohort of post-esophagectomy patients from an academic medical center that has been routinely measuring DA. We assessed the model outcome using historical cost and length of stay from retrospective review of consecutive patients undergoing elective esophagectomy. We performed a Monte Carlo simulation to assess the effects of base-case variables on model outcomes. We also performed one-way sensitivity analyses to identified thresholds where a decision alternative dominated the model (both less expensive and shorter stay than the alternative).

Results:
Using DA cutoff value of 31U/L on post-operative day 4, 38% of patients were assigned to an accelerated recovery pathway, of which 10% were found to have a leak. Patients with DA over 125U/L were defined as ‘high risk’ for leak (20% of cohort), of which 50% were diagnosed with a leak. Decision analysis demonstrated that a DA-based accelerated recovery pathway was associated with an improvement in overall LOS of 0.96 days and a cost saving of $2,773.96. Monte Carlo simulation confirmed this finding, with a median saving of 0.78 days and $2078.46.

Conclusion:
Current methodologies to detect anastomotic leaks after esophagectomy radiographically are associated with prolonged hospitalization, but drain amylase can identify patients at low risk and high risk of anastomotic leak. Decision analysis supports the use of post-operative day 4 perianastomotic DA to predict anastomotic leak to reduce hospital length of stay and cost.
 

22.10 Fluorescence Guided Surgery May Enhance Localization of Residual Disease During NSCLC Surgery

Posted on January 25, 2017

J. D. Predina1, A. Newton1, J. Keating1, O. Venegas1, S. Singhal1  1University Of Pennsylvania,Philadelphia, PA, USA

Introduction:  Postoperative cancer recurrences occur in 40% of patients undergoing resection for NSCLC.  Such recurrence rates are partially attributable to limitations in intraoperative tools that assist the surgeon in disease identification.  We hypothesized that intraoperative imaging using a fluorescent imaging agent, 5-aminolevulinic acid (5-ALA), could enhance intraoperative identification of NSCLC cancer deposits that would otherwise be missed.

Methods:  The murine NSCLC line, TC1, was cultured in vitro and exposed 1 mM concentrations of 5-ALA for 0 to 24 hours.  Fluorescence was assessed with flow cytometry.  Next, in vivo feasibility of systemic 5-ALA was tested using a small animal model of NSCLC cancer surgery (n=25).   

Results: In vitro, TC1 exhibited high levels of fluorescence after 2 hours of exposure to 5-ALA.  Additional exposure did not augment signal.  Involving in vivo studies, systemic administration of 5-ALA helped identify the presence of residual tumor cells after surgery in 17/25 resections.  The mean residual tumor size was 1.8mm, with a mean fluorescence signal-to-background ratio (SBR) of 4.1.  Of note, minimal fluorescence was noted within thoracic structures including lung parenchyma, pericardium and pleura.  

Conclusion: Systemic 5-ALA reliably accumulates in murine models of NSCLC and helps identify residual disease deposits.  This data supports additional pre-clinical studies which will set the basis for a Human Trial utilizing 5-ALA to enhance NSCLC resection.  

 

22.09 Effect of collagen substrates on oxidative stress-induced changes in SMC phenotype in BAV aortopathy.

Posted on January 25, 2017

P. G. Chan1, M. Billaud1, J. Phillippi1, T. Gleason1  1University Of Pittsburgh,Cardiothoracic Surgery,Pittsburgh, PA, USA

Introduction: Bicuspid aortic valve (BAV) is the most common congenital cardiac malformation and is associated with ascending aortopathy in form of dissection or aneurysmal disease which involve extensive collagen remodeling.  Our prior studies have uncovered that the smooth muscle cells (SMC) from the ascending aorta of BAV specimens have decreased oxidative stress defense compared to SMCs from patients with tricuspid aortic valve (TAV).  We hypothesize that oxidative stress-induced alterations in SMC phenotype can be alleviated by collagen substrates in TAV SMCs but not in BAV SMCs.

Methods: Aortic tissue was obtained from patients undergoing aortic surgery or heart transplantation with IRB approval and informed patient consent.  SMCs from TAV (n=2) and BAV (n=3) patients were harvested using previously established protocols.  SMCs were seeded at a density of 2.8×103/cm2 on tissue culture polystyrene (TCP) in the presence or absence of type 1 collagen substrate.  SMCs were cultured in the presence or absence of 20µM tert-butyl hydroperoxide (tBHP) and monitored in three random fields per well using phase contrast time-lapse microscopy in a stage-top incubation chamber for up to 12 hours.  Post-imaging, the aspect ratios (long axis/short axis) of cells (>17 cells/well) were measured at period time points as a means to assess SMC phenotype.

Results: Aspect ratio for SMCs isolated decreased in the presence of tBHP from 4.4±0.81 to 2.4±0.17 (p<0.001) for TAV SMCs and from 5.0±0.46 to 2.3±0.52 (p<0.001) for BAV SMCs.  When cultured on Type 1 collagen coated wells, TAV SMCs maintained a high aspect ratio despite exposure to oxidative stress.  TAV SMCs increased in aspect ratio on collagen to 6.2±1.55 which was relatively maintained at 4.8±0.83 (p=0.557) when exposed to tBHP.  The aspect ratio of BAV SMCs cultured on collagen was found to be decreased under tBHP treatment (3.88±0.38 vs. 2.1±0.32, p<.001) (Figure 1).

Conclusion: Oxidative stress was found to alter SMC phenotype by decreasing aspect ratio. Culture on collagen prevented oxidative stress induced alteration for TAV SMCs, but not for BAV SMCs.  These results provide further support that BAV SMCs have impaired basal oxidative stress response compared to TAV SMCs despite modulating the extracellular milieu.  Ongoing work is focused on how the extracellular matrix interplays with oxidative stress mediated effects on SMC function in BAV aortopathy.  Ultimately, with this knowledge, we hope to develop therapeutics for patients who are at risk for aneurysmal progression, delineate the molecular mechanisms associated with BAV aortopathy, and improve rupture risk predictions and recommendations for surgical or medical intervention.

22.08 Role of Cardiac Progenitor Cells in Macrophage Polarization During Fetal Cardiac Regeneration post-MI

Posted on January 25, 2017

C. Zgheib1, M. H. Hodges1, M. Allukian2, J. Xu1, K. L. Spiller3, J. H. Gorman2, R. C. Gorman2, K. W. Liechty1  1Laboratory For Fetal And Regenerative Biology, Department Of Surgery, School Of Medicine, University Of Colorado Denver – Anschutz Medical Campus And Colorado Children’s Hospital,Aurora, COLORADO, USA 2The University Of Pennsylvania School Of Medicine,Surgery,Philadelphia, PA, USA 3Drexel University, School Of Biomedical Engineering,Philadelphia, PA, USA

Introduction: Myocardial infarction (MI) remains the leading cause of death in the US. In contrast to the fibrotic response observed in adults, we have previously shown that the fetal response to MI is regenerative and is associated with increased angiogenesis and decreased inflammation. This cardiac regeneration requires both recruitment of cardiac progenitor cells (CPC) to replace lost myocardium as well as restoration of blood supply to support these recruited cells. Macrophages are also known to contribute to this repair process; however, the contribution of macrophages to tissue repair depends on their phenotype: M1 macrophages are pro-inflammatory and initiate angiogenesis; M2a macrophages are pro-fibrotic and contribute to blood vessel maturation; and M2c macrophages are pro-angiogenic, anti-inflammatory, and contribute to tissue remodeling. However, the relationship between CPCs and macrophages during the regenerative process has yet to be defined. Thus, we propose that CPCs promote fetal cardiac regeneration after MI by regulating the polarization of macrophages.

Methods: To test this hypothesis, 20% apical infarcts were created in fetal sheep by LAD ligation. Subsets of these infarcts were injected with a lentivirus containing the SDF-1α inhibitor (SDFi) transgene or an empty vector control. Hearts were harvested 3 or 30 days following infarction. Real time PCR was used to analyze the expression of macrophage phenotypes markers: IL-1β (M10, CD206 (M2a), and CD163 (M2c). 

Results: Our results revealed a significant upregulation of IL-1β, CD206, and CD163 gene expression in the fetal hearts 3 days post-MI; this upregulation returned to baseline at 30 days. In contrast, fetal hearts treated with SDFi demonstrated a significant increase in the expression of all macrophage markers 30 days post-MI, when compared to both untreated fetal hearts and treated hearts 3 days post-MI. These results suggest an early increase in the expression of M1, M2a, and M2c macrophage markers in the fetal hearts 3 days post-MI, with reversal of this upregulation following myocardial regeneration 30 days post-MI. Blocking CPC recruitment by inhibition of SDF-1α was associated with a persistent elevation in M1, M2a, and M2c gene expression, consistent with prolonged inflammation, fibrosis, and remodeling.

Conclusion: Our results suggest that following MI, CPCs promote fetal cardiac regeneration via the modulation of macrophage phenotype. Strategies to manipulate macrophage phenotype may represent a therapeutic target to promote regeneration in adult hearts after MI.

22.07 Reduced Immunogenicity Observed in Multi-Transgene Heart Xenotransplant Model with Suppressed MCP-1

Posted on January 25, 2017

J. L. Chan1, A. K. Singh1, P. C. Corcoran1, M. L. Thomas2, B. G. Lewis2, K. A. Horvath1, M. M. Mohiuddin1  1National Institutes Of Health,Cardiothoracic Surgery Research Program/National Heart, Lung And Blood Institute,Bethesda, MD, USA 2National Institutes Of Health,Division Of Veterinary Resources/Office Of Research Services,Bethesda, MD, USA

Introduction:
Considerable progress has been achieved in xenotransplantation with genetic engineering and the inclusion of additional humanized transgenes appears to be associated with improved outcomes. Monocyte chemoattractant protein-1 (MCP-1), a potent chemotactic factor, has been implicated in transplant immune interaction and rejection. We report the novel use of six-transgene cardiac xenografts and characterize their impact on MCP-1.

Methods:
Heterotopic cardiac xenotransplantations were performed on baboons with swine donor hearts expressing three-gene modifications (GTKO.CD46.TBM) or six-gene modifications (GTKO.CD46.EPCR.DAF with TFPI.CD47 or CD39.TBM). Standard immunosuppressive therapy was administered. MCP-1 levels were measured by fluorescence intensity (FI) using Luminex assay.

Results:
No significant difference in MCP-1 levels were identified preoperatively. Within 48 hours of transplantation, recipients with six-gene modifications (n=3) had a significant reduction in MCP-1 compared to the three-gene cohort (n=3) (1376FI vs. 1928FI, p=0.03). The six-gene group continued to demonstrate decreased MCP-1 in the immediate 30-day postoperative period (1403FI vs. 1916FI, p=0.02) and remained sustained after three months (1159FI vs. 1761FI, p=0.004). Analysis of additional cytokines (IFNγ, TNFα, IL-6) and transmyocardial biopsy histology paralleled findings of a reduced inflammatory response in six-gene recipients. Elevations of MCP-1 to >10% above baseline were associated with transplant rejection within 30 days (odds ratio: 7.40, p=0.01).

Conclusion:
Expression of additional humanized factors in the six-gene cardiac xenografts, including DAF (complement inhibition), CD47 (cellular immune suppression), and CD39 (effector immune modulation), is associated with suppression of MCP-1 production. Decreased MCP-1 levels observed with use of these expanded multi-transgenic donors may reflect superior inflammatory regulation, reduced immunogenicity, and improved xenotransplantation outcomes.

22.05 Calpain Inhibition Decreases Oxidative Stress Via Mitochondrial Pathways in Ischemic Myocardium

Posted on January 25, 2017

B. A. Potz1, L. A. Scrimgeour1, R. T. Clements1, F. W. Sellke1  1Brown University School Of Medicine,Cardiothoracic Surgery Research,Providence, RI, USA

Introduction: Calpain is an intracellular calcium depedent protease whose activity gets overexpressed in cells during times of stress.  Calpain overexpression has been linked to myocardial ischemic disease and organ dysfunction in patients with metabolic syndrome.  Calpain overexpression is implicated in mitochondrial damage leading to tissue oxidative stress.  The purpose of this study was to investigate the potential ability of calpain inhibition on mitochondrial impairment and oxidative stress in a swine model of chronic coronary ischemia in the setting of metabolic syndrome. 

Methods:   Yorkshire swine were divided into 3 groups, fed a high cholesterol diet for 4 weeks, then underwent surgical placement of an ameroid constrictor to their left circumflex artery. Three weeks later animals received either: no drug, high cholesterol control group (CON; n= 8); a low dose calpain inhibitor (0.12 mg/kg; LCI, n= 9); or high dose calpain inhibitor (0.25 mg/kg; HCI, n= 8).  The diets and CI was continued for 5 weeks then the heart was harvested for analysis.  OxyBlot which measures protein carbonyl content (Billerica, MA) was used to determine oxidative stress.  Western Blot was used to identify protein expression (all data was normalized to GAPDH for loading control).

Results:  Calpain inhibition was associated with decreased oxidative stress compared to the control group in the ischemic tissue. There was no change in oxidative stress between groups in the nonischemic tissue. [Figure 1A] In the ischemic myocardial tissue, calpain inhibition was associated with increased expression of the following mitochondrial proteins compared to the control group: the mitochondrial antioxidant protein superoxide dismutase 1; the electron transport chain protein succinate:quinone oxidoreductase; and  the citric acid cycle protein pyruvate dehydrogenase. There was no change in expression between groups prohibitin 1 (p=0.13) and cytochrome c (p=0.15).  [Figure 1B]

Conclusions:  In the setting of metabolic syndrome, CI improved oxidative stress in the ischemic myocardial tissue and was associated with increased expression of mitochondrial proteins involved in 1) reducing superoxide radicals and 2) promoting the citric acid cycle and the electron transport chain.  Calpain inhibition had no effect on oxidative stress in the non-ischemic myocardium. The results of the present study demonstrate the potential ability of calpain inhibition to improve myocardial oxidative stress and suggests that the mechanism through which this beneficial effect is taking place is through the mitochondria.  

22.04 Macrophages Differentially Regulate Collagen Expression in Fetal versus Adult Cardiac Fibroblasts

Posted on January 25, 2017

M. M. Hodges1, C. Zgheib1, J. Xu1, J. Hu1, K. W. Liechty1  1University Of Colorado Denver,Department Of General Surgery, Laboratory For Fetal And Regenerative Biology,Aurora, CO, USA

Introduction:  Ischemic heart disease remains the leading cause of death worldwide.  Despite tremendous advances in the medical management of ischemic cardiomyopathy, the 5-year mortality rate following a diagnosis of heart failure exceeds 50%. In our novel, ovine model of myocardial regeneration after myocardial infarction (MI), we have previously shown that the fetal response to MI is regenerative, whereas the adult response to MI is reparative and is associated with decreased angiogenesis, increased inflammation, and increased fibrosis. Macrophages have been shown to play key roles in regulation of angiogenesis and inflammation; however, the impact that macrophages have on the development of fibrosis and scar formation after MI has yet to be described. We hypothesize that macrophages differentially regulate gene expression of collagen, matrix metalloproteinases (MMP-2 and MMP-9), and transforming growth factors (TGFβ-1 and TGFβ-3) in fetal and adult cardiac fibroblasts.

Methods: To test this hypothesis, cardiac fibroblasts were isolated from the left ventricle of adult and fetal sheep. After isolation, these cardiac fibroblasts were co-cultured for 24 hours with macrophages from the RAW 264.7 cell line.  Quantitative polymerase chain reaction was used to quantify the gene expression of collagen 1α2, collagen 3α1, MMP-2, MMP-9, TGFβ-1, and TGFβ-3.

Results: When compared to adult cardiac fibroblasts, fetal cardiac fibroblasts have significantly upregulated expression of both col1α2 and col3α1, as well as significantly upregulated expression of MMP-2, MMP-9, TGFβ-1, and TGFβ-3.  After co-culture with macrophages, adult cardiac fibroblasts demonstrated significant upregulation of collagen 1α2, which was associated with a significant upregulation in TGFβ-3 and downregulation in MMP-9 gene expression. Conversely, after co-culture with macrophages, fetal cardiac fibroblasts demonstrate a significant downregulation in both col1α2 and col3α1, as well as a significant downregulation in MMP-2, MMP-9, TGFβ-1, and TGFβ-3. These results suggest a differential response of fetal and adult cardiac fibroblasts to co-culture with macrophages.  

Conclusion: Our results suggest that macrophages may play an integral role in regulating the differential responses of the fetus and adult following MI. Additionally, our results suggest that fetal cardiac fibroblasts and adult cardiac fibroblasts are characterized by baseline phenotypic differences that may further contribute to the regenerative response observed in the fetus after MI, compared to the reparative response observed in the adult after MI. A more in-depth understanding of both the phenotypic differences between adult and fetal cardiac fibroblasts, as well as the varying responses following co-culture with macrophages will enable a more complete understanding of the role macrophages play in regulating fibrosis after MI.

22.03 Role of COX-2 in Microvascular Reactivity of Peripheral Arterioles in Diabetic Patients after CPB

Posted on January 25, 2017

K. Anderson1, J. Feng1, Y. Liu1, A. K. Singh1, A. Ehsan1, F. W. Sellke1  1Rhode Island Hospital,Cardiothoracic Surgery/Surgery/Brown Medical Scholl,Providence, RI, USA

Introduction: Diabetic patients are associated with impaired peripheral microvascular function after cardiopulmonary bypass (CPB) and cardiac surgery.  We hypothesized that upregulation inducible cyclooxygenase 2 (COX-2) contributes to altered microvascular reactivity of peripheral arterioles in diabetic patients undergoing CPB and cardiac surgery.

Methods: Skeletal muscle tissue samples of diabetic (DM) and non-diabetic (ND) patients (n = 5-6/group) undergoing cardiac surgery were harvested before and after CPB.  Peripheral arterioles were dissected from the harvested skeletal muscle tissue samples. The isolated arterioles (80-180µm) were cannulated and pressurized and changes in diameter were measured with video microscopy.  In-vitro relaxation responses of pre-contracted arterioles were examined in the presence of the endothelium-dependent vasodilator bradykinin (10-10 to 10-6M) and in the presence or absence of the selective COX-2 inhibitor NS398 (10-6M). 

Results:The post-CPB protein levels of the inducible COX-2 were increased significantly compared with pre-CPB values in both DM and ND groups (P<0.05), whereas, this increase was higher in DM than that of non-diabetics (P<0.05). In the DM arterioles, not the ND vessels, bradykinin-induced relaxation response was inhibited in the presence of the specific COX-2 inhibitor NS398 at baseline (P<0.05). After CPB, bradykinin-induced relaxation response of the DM and ND arterioles was inhibited in the presence of the specific COX-2 inhibitor NS398, but this effect was more pronounced in the diabetic patients (P<0.05).

Conclusion: Diabetes and CPB are associated with upregulation in COX-2 expression/activation in human peripheral microvasculature. This alteration may lead to altered peripheral microvascular reactivity in diabetic patients undergoing cardiac surgery.

 

22.02 Both HMGB1 and DNA Released from Ischemic Myocardium Are Required to Cause Reperfusion Injury

Posted on January 25, 2017

E. J. Charles1, Y. Tian2, J. H. Mehaffey1, D. Wu1, I. L. Kron1, Z. Yang1  1University Of Virginia,Surgery,Charlottesville, VA, Virgin Islands, U.S. 2Tianjin Medical University General Hospital,Cardiovascular Surgery,Tianjin, , China

Introduction: Damage-associated molecular patterns such as high mobility group box 1 (HMGB1) and mitochondrial DNA (mtDNA) may play critical roles in mediating myocardial ischemia-reperfusion (IR) injury.  We hypothesized that HMGB1 and cell-free mtDNA collectively released from ischemia myocardium would lead to activation of splenic leukocytes and cause reperfusion injury.

Methods: Levels of HMGB1 and cell-free mtDNA were measured in plasma and cardiac perfusate obtained from C57BL6 mice (n=4-8/group) that underwent sham surgery or 10, 20, or 40-minute occlusions of the left coronary artery (LCA) without reperfusion.  Perfusate was obtained via antegrade coronary perfusion with phosphate-buffered saline. Levels were measured using SYTOX® Green florescence and Western blot. Separate C57BL6 mice (n=4-8/group) underwent 20 minutes of LCA occlusion followed by 60 minutes of reperfusion.  Resultant myocardial infarct size was measured with TTC and Phthalo blue staining.  Treated groups received recombinant HMGB1 (0.1μg/g/2μl; rtHMGB1), mtDNA obtained from naive C57BL6 mouse livers (0.5ug/g/2μl; mtDNA), or both rtHMGB1 and mtDNA (H+D) 5 minutes prior to reperfusion via external jugular vein injection.  An additional group of mice underwent splenectomy prior to LCA occlusion and received both rtHMGB1 and mtDNA (H+D+Splx).

Results: Plasma levels of HMGB1 and mtDNA were low and not significantly different between mice undergoing sham or LCA occlusion without reperfusion.  However, cardiac perfusate levels were significantly increased in ischemic hearts after 40 minutes of LCA occlusion (p<0.05 vs. other groups).  Infarct size as a percentage of left ventricular risk region after 40 minutes of LCA occlusion without reperfusion was 23.9±5.4%, compared to 0.0% after 20-minute occlusion (p<0.05). In mice undergoing 20 minutes of LCA occlusion followed by 60 minutes of reperfusion, injection of rtHMGB1 or mtDNA did not exacerbate infarct size compared to control mice (p>0.99).  However, H+D mice had significantly larger infarct size (21.2±4.9%), compared with control, rtHMGB1, and mtDNA (all p<0.01, Figure 1). This increased infarct size was attenuated by splenectomy (H+D+Splx: 5.3±2.1%, p=0.02 vs H+D).  There were no significant differences between groups in size of risk region as a percentage of left ventricular mass.

Conclusion: The release of both HMGB1 and mtDNA together from ischemic myocardium is critical to cause reperfusion injury and leads to increased infarct size.  Blocking the effects HMGB1 and/or mtDNA on splenic leukocyte activation may provide a therapeutic option for attenuating myocardial IR injury.

 

22.01 Divergent Roles of Alveolar Macrophages in Neutrophil-Driven Lung Injury

Posted on January 25, 2017

S. Chiu1, M. Akbarpour1, A. McQuattie-Pimentel2, K. Anekalla2, P. Reyfman2, A. Misharin2, H. Perlman2, G. S. Budinger2, A. Bharat1  1Northwestern University,Surgery,Chicago, IL, USA 2Northwestern University,Medicine,Chicago, IL, USA

Introduction:  Pathogen- and damage- associated molecular patterns (PAMPs and DAMPs) stimulate neutrophil recruitment and initiate injury in the lung. It has been suggested that monocytes recruit neutrophils in response to PAMPs while alveolar macrophages (AM) mediate DAMP-driven lung injury, such as ischemia-reperfusion (IR) following pulmonary transplant. Here, we utilize a novel multi-color flow panel to demonstrate that, contrary to the contemporary paradigm, AM ameliorate neutrophil infiltration following lung transplant, but are responsible for neutrophil recruitment in response to PAMPs. 

Methods:  Intratracheal instillation of lipopolysaccharide (LPS) was used to induce PAMP-driven lung injury. Murine single lung allogeneic transplant utilizing wild-type C57BL/6J and Balb/C was performed to induce DAMP-driven lung injury. Clodronate liposomes were used to deplete alveolar macrophages. EdU was injected at the time of transplant to quantify the number of cells entering S phase and undergoing cell division. Flow cytometry was used to measure cell populations and fluorescence-activated cell sorting to isolate alveolar macrophages. Next Generation RNA Sequencing was utilized to compare the transcriptomes of pre- and post-transplant AM. 

Results: After lung transplant or intratracheal LPS instillation, there was significant neutrophil infiltration at 24 hours (>3 fold increase, *p<0.001, Figure A&B). Following transplantation, donor AM proliferated in vivo, resulting in serial increase in AM cell counts (1.7 fold increase) and proportion of cells that had undergone cell division (1.6-fold increase). The increase in cell count was not due to infiltration by recipient AM, since all AM in the allograft remained of donor origin. Transcriptional profiling revealed that post-transplant AM upregulated genes involved in cell division and proliferation. However, genes responsible for activation of innate immunity, neutrophil recruitment, and pattern recognition receptor response were downregulated (Figure A). Depletion of AM in donor lungs prior to transplant lead to increased neutrophil infiltration following IR (Intact AM: 1.1 x 10^6 vs. Depleted AM: 1.5 x10^6, Figure A). In contrast, the robust neutrophil recruitment after intratracheal LPS was abrogated by depletion of AM (*p<0.001, Figure B).

Conclusion: Alveolar macrophages proliferate following lung transplant and downregulate genes involved in immune activation. Hence, they may play a role in ameliorating IR injury. Contrastingly, they augment the immune response and recruit neutrophils in response to PAMPs, demonstrating their role in pulmonary mucosal immunity.

 

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