Two Decades of Declining Medicare Reimbursement in Cardiac Surgery.

BACKGROUND: Given the uncertainty of US health care finances, an understanding of reimbursement trends has become increasingly important in the field of cardiac surgery. We aimed to assess Medicare reimbursement trends for common cardiac surgical procedures from 2000 to 2022. METHODS: Reimbursement data were extracted from the Centers for Medicare and Medicaid Services Physician Fee Schedule Look-Up Tool during the study period for 6 common cardiac operations: aortic valve replacement, mitral valve repair and replacement, tricuspid valve replacement, Bentall procedure, and coronary artery bypass grafting. Reimbursement rates were adjusted for inflation to 2022 US dollars using the Consumer Price Index. Total percentage change and compound annual growth rate were calculated. A split-time analysis was performed to assess trends before and after 2015. Least squares and linear regressions were performed. The R2 value was calculated for each procedure, and slope was used to determine change in reimbursements over time. RESULTS: Inflation-adjusted reimbursement decreased by 34.1% during the study period. The overall compound annual growth rate was -1.8%. Reimbursement trends differed by procedure (P < .001), with all reimbursements trending down (R2 > 0.62), except for mitral valve replacement (P = .21) and tricuspid valve replacement (P = .43). Coronary artery bypass grafting decreased the most (-44.4%), followed by aortic valve replacement (-40.1%), mitral valve repair (-38.5%), mitral valve replacement (-29.8%), Bentall procedure (-28.5%), and tricuspid valve replacement (-25.3%). In split-time analysis, reimbursement rates did not significantly change from 2000 to 2015 (P = .24) but decreased significantly from 2016 to 2022 (P = .001). CONCLUSIONS: Medicare reimbursement significantly decreased for most cardiac surgical procedures. These trends justify further advocacy by The Society of Thoracic Surgeons to maintain access to quality cardiac surgical care.

Lung lobectomy surgical approach and resource utilization differ by anatomic lobe in a statewide discharge registry.

Background: Anatomic lobe-specific differences with respect to pulmonary lobectomy have been suggested in the thoracic surgery literature but hard data has been lacking in larger population studies in part due to coding systems that do not distinguish pulmonary lobectomy by anatomic lobe. International Classification of Diseases, Tenth Revision (ICD-10) procedure codes, adopted in the United States in 2015, may provide novel methodologic accessibility for pulmonary lobectomy studies as they classify lobectomy operations by specific anatomic lobe. We queried the Texas Inpatient Public Use Data File (TPUDF) ICD-10 codes for both open and endoscopic approach lobectomy with a specific view to differences based on anatomic lobes. Methods: Between fourth fiscal quarter (Q4) 2015 and Q4 2017, all pulmonary lobectomy operations performed in Texas state-licensed hospitals were identified by querying the TPUDF for ICD-10 procedure codes for pulmonary lobectomy as classified by anatomic lobe. Surgical approach, additional procedures and diagnosis codes, length of hospital stay (LOS), and discharge status were recorded with aggregate values undergoing statistical analysis. Results: Right and left upper versus lower lobe resections were more prevalent however minimally invasive surgery was less commonly performed for upper than right lower lobectomy. LOS, irrespective of surgical approach, was longer for upper versus lower lobe resection as was need for transfer to additional inpatient facilities. LOS was longer and need for additional surgical or procedural interventions days after the primary procedure of lobectomy was greater for right versus left upper lobe resection, suggesting some differential properties of the right versus left pleural space. Conclusions: The marked clinical differences between anatomic lobes in the setting of pulmonary lobectomy observed in this study have the potential to translate to differences in expected hospital and health system costs and surgeon time-expenditure and experience premium that currently have no mechanism for their accounting. These findings highlight the value of ICD-10 coding for analysis of pulmonary lobectomy in administrative databases and suggest a possible path to more informed patient counseling and equitable hospital and surgeon reimbursement based on payment adjustment by anatomic lobe in pulmonary lobectomy operations.

Toward a Next-Generation Digital Chest Tube.

Chest tubes in patients who have undergone pulmonary resection with pleural air leak are painful, impair ventilatory mechanics, and increase hospital length of stay and costs. Despite these well-documented concerns, current protocols for chest tube management in this setting are not well supported by evidence. Excessive suction applied to chest tubes has been associated with prolonged air leak due to alveolar over-distension, and most practitioners intuit that suction should be minimized to the lowest level needed to maintain desired pleural apposition. Unfortunately, there is no evidence-based protocol for the establishment of minimal adequate suction. Digital suction devices in current clinical use can identify air leak resolution preventing the delay of chest tube removal but cannot guide suction minimization while an air leak persists. We recently described a monitor of lung expansion in a porcine model of pleural air leak that could detect loss of pleural apposition continuously in real-time based on electrical impedance readings obtained directly from the surface of the lung via chest tube-embedded electrodes. The value of the impedance signal was "in-range" when pleural apposition was present but became abruptly "out-of-range" when pneumothorax due to inadequate suction developed. These findings suggested that a digitally controlled suction pump system could be programmed to recognize the development of pneumothorax and automatically identify and set the minimum level of suction required to maintain pleural apposition. We present here preliminary proof of concept for this system.

Using a quality improvement initiative to reduce acute kidney injury during on-pump coronary artery bypass grafting.

INTRODUCTION: In response to a perceived high incidence of acute kidney injury following cardiopulmonary bypass at our institution, a quality improvement initiative consisting of a systematic change to a delivered oxygen (DO2) goal-directed perfusion practice was implemented. We sought to maintain DO2 > 270 mL/min/m2 to reduce the incidence of acute kidney injury. METHODS: 'The study population included all patients receiving isolated, non-emergent, on-pump coronary artery bypass grafting from January 2015 through December 2018, excluding patients requiring preoperative hemodialysis. DO2 goal-directed perfusion was instituted in February 2017. Acute kidney injury was defined using Acute Kidney Injury Network criteria. RESULTS: The pre-goal-directed perfusion cohort included 257 patients, and the post-goal-directed perfusion cohort included 226 patients. The DO2 was significantly higher in the post-goal-directed perfusion group (p < 0.001). Postoperative change in serum creatinine and incidence of acute kidney injury were significantly lower in the post-goal-directed perfusion group (p < 0.001, p = 0.001, respectively). Estimation with probit and ordered probit models support these findings. CONCLUSION: This initiative confirms previous assertions that DO2 is a critical intraoperative parameter and should direct perfusion intervention accordingly.

Agitation Techniques to Enhance Drainage of Retained Hemothorax.

Background. Retained hemothorax (RH) is a common problem in cardiothoracic and trauma surgery. We aimed to determine the optimum agitation technique to enhance thrombus dissolution and drainage and to apply the technique to a porcine-retained hemothorax. Methods. Three agitation techniques were tested: flush irrigation, ultrasound, and vibration. We used the techniques in a benchtop model with tissue plasminogen activator (tPA) and pig hemothorax with tPA. We used the most promising technique vibration in a pig hemothorax without tPA. Statistics. We used 2-sample t tests for each comparison and Cohen d tests to calculate effect size (ES). Results. In the benchtop model, mean drainages in the agitation group and control group and the ES were flush irrigation, 42%, 28%, and 2.91 (P = .10); ultrasound, 35%, 27%, and .76 (P = .30); and vibration, 28%, 19%, and 1.14 (P = .04). In the pig hemothorax with tPA, mean drainages and the ES of each agitation technique compared with control (58%) were flush irrigation, 80% and 1.14 (P = .37); ultrasound, 80% and 2.11 (P = .17); and vibration, 95% and 3.98 (P = .06). In the pig hemothorax model without tPA, mean drainages of the vibration technique and control group were 50% and 43% (ES = .29; P = .65). Discussion. In vitro studies suggested flush irrigation had the greatest effect, whereas only vibration was significantly different vs the respective controls. In vivo with tPA, vibration showed promising but not statistically significant results. Results of in vivo experiments without tPA were negative. Conclusion. Agitation techniques, in combination with tPA, may enhance drainage of hemothorax.

Minocycline reverses IL-17A/TRAF3IP2-mediated p38 MAPK/NF-κB/iNOS/NO-dependent cardiomyocyte contractile depression and death.

Minocycline, an FDA-approved second-generation semisynthetic tetracycline, exerts antioxidant, anti-apoptotic and anti-inflammatory effects, independent of its antimicrobial properties. Interleukin (IL)-17A is an immune and inflammatory mediator, and its sustained induction is associated with various cardiovascular diseases. Here we investigated (i) whether IL-17A induces cardiomyocyte contractile depression and death, (ii) whether minocycline reverses IL-17A's negative inotropic effects and (iii) investigated the underlying molecular mechanisms. Indeed, treatment with recombinant mouse IL-17A impaired adult cardiomyocyte contractility as evidenced by a 34% inhibition in maximal velocity of shortening and relengthening after 4 h (P < .01). Contractile depression followed iNOS induction at 2 h (2.13-fold, P < .01) and NO generation at 3 h (3.71-fold, P <.01). Further mechanistic investigations revealed that IL-17A-dependent induction of iNOS occurred via TRAF3IP2, TRAF6, TAK1, NF-κB, and p38MAPK signaling. 1400 W, a highly specific iNOS inhibitor, suppressed IL-17A-induced NO generation and contractile depression, where as the NO donors SNAP and PAPA-NONOate both suppressed cardiomyocyte contractility. IL-17A also stimulated cardiomyocyte IL-1ß and TNF-α secretion, however, their neutralization failed to modulate IL-17A-mediated contractile depression or viability. Further increases of IL-17A concentration and the duration of exposure enhanced IL-1ß and TNF-α secreted levels, buthad no impact on adult cardiomyocyte viability. However, when combined with pathophysiological concentrations of IL-1ß or TNF-α, IL-17A promoted adult cardiomyocyte death. Importantly, minocycline blunted IL-17A-mediated deleterious effects, indicating its therapeutic potential in inflammatory cardiac diseases.

Intrapleural Impedance Sensor Real-Time Tracking of Pneumothorax in a Porcine Model of Air Leak.

In patients with alveolar-to-pleural air leak due to recent surgery or trauma, clinicians tend to manage chest tubes with suction therapy. Nonsuction therapy is associated with shorter chest tube duration but also a higher risk of pneumothorax. We sought to develop an intrapleural electrical impedance sensor for continuous, real-time monitoring of pneumothorax development in a porcine model of air leak as a means of promoting nonsuction therapy. Using thoracoscopy, 2 chest tubes and the pleural impedance sensor were introduced into the pleural space of 3 pigs. Continuous air leak was introduced through 1 chest tube by carbon dioxide insufflation. The second chest tube was placed to suction then transitioned to no suction at increasingly higher air leaks until pneumothorax developed. Simultaneously, real-time impedance measurements were obtained from the pleural sensor. Fluoroscopy spot images were captured to verify the presence or absence of pneumothorax. Statistical Analysis Software was used throughout. With the chest tube on suction, a fully expanded lung was identified by a distinct pleural electrical impedance respiratory waveform. With transition of the chest tube to water seal, loss of contact of the sensor with the lung resulted in an immediate measurement of infinite electrical impedance. Pneumothorax resolution by restoring suction therapy was detected in real time by a return of the normal respiratory impedance waveform. Pleural electrical impedance monitoring detected pneumothorax development and resolution in real time. This simple technology has the potential to improve the safety and quality of chest tube management.

Empagliflozin reduces high glucose-induced oxidative stress and miR-21-dependent TRAF3IP2 induction and RECK suppression, and inhibits human renal proximal tubular epithelial cell migration and epithelial-to-mesenchymal transition.

Proximal tubular epithelial cells (PTEC) in the S1 segment of the kidney abundantly express sodium-glucose co-transporters (SGLT) that play a critical role in whole body glucose homeostasis. We recently reported suppression of RECK (Reversion Inducing Cysteine Rich Protein with Kazal Motifs), a membrane anchored endogenous MMP inhibitor and anti-fibrotic mediator, in the kidneys of db/db mice, a model of diabetic kidney disease (DKD), as well as in high glucose (HG) treated human kidney proximal tubule cells (HK-2). We further demonstrated that empagliflozin (EMPA), an SGLT2 inhibitor, reversed these effects. Little is known regarding the mechanisms underlying RECK suppression under hyperglycemic conditions, and its rescue by EMPA. Consistent with our previous studies, HG (25 mM) suppressed RECK expression in HK-2 cells. Further mechanistic investigations revealed that HG induced superoxide and hydrogen peroxide generation, oxidative stress-dependent TRAF3IP2 upregulation, NF-κB and p38 MAPK activation, inflammatory cytokine expression (IL-1ß, IL-6, TNF-α, and MCP-1), miR-21 induction, MMP2 activation, and RECK suppression. Moreover, RECK gain-of-function inhibited HG-induced MMP2 activation and HK-2 cell migration. Similar to HG, advanced glycation end products (AGE) induced TRAF3IP2 and suppressed RECK, effects that were inhibited by EMPA. Importantly, EMPA treatment ameliorated all of these deleterious effects, and inhibited epithelial-to-mesenchymal transition (EMT) and HK-2 cell migration. Collectively, these findings indicate that hyperglycemia and associated AGE suppress RECK expression via oxidative stress/TRAF3IP2/NF-κB and p38 MAPK/miR-21 induction. Furthermore, these results suggest that interventions aimed at restoring RECK or inhibiting SGLT2 have the potential to treat kidney inflammatory response/fibrosis and nephropathy under chronic hyperglycemic conditions, such as DKD.

RECK suppresses interleukin-17/TRAF3IP2-mediated MMP-13 activation and human aortic smooth muscle cell migration and proliferation.

Sustained inflammation and matrix metalloproteinase (MMP) activation contribute to vascular occlusive/proliferative disorders. Interleukin-17 (IL-17) is a proinflammatory cytokine that signals mainly via TRAF3 Interacting Protein 2 (TRAF3IP2), an upstream regulator of various critical transcription factors, including AP-1 and NF-κB. Reversion inducing cysteine rich protein with kazal motifs (RECK) is a membrane-anchored MMP inhibitor. Here we investigated whether IL-17A/TRAF3IP2 signaling promotes MMP-13-dependent human aortic smooth muscle cell (SMC) proliferation and migration, and determined whether RECK overexpression blunts these responses. Indeed, IL-17A treatment induced (a) JNK, p38 MAPK, AP-1, NF-κB, and CREB activation, (b) miR-21 induction, (c) miR-27b and miR-320 inhibition, (d) MMP-13 expression and activation, (e) RECK suppression, and (f) SMC migration and proliferation, all in a TRAF3IP2-dependent manner. In fact, gain of TRAG3IP2 function, by itself, induced MMP-13 expression and activation, and RECK suppression. Furthermore, treatment with recombinant MMP-13 stimulated SMC migration in part via ERK activation. Importantly, RECK gain-of-function attenuated MMP-13 activity without affecting its mRNA or protein levels, and inhibited IL-17A- and MMP-13-induced SMC migration. These results indicate that increased MMP-13 and decreased RECK contribute to IL-17A-induced TRAF3IP2-dependent SMC migration and proliferation, and suggest that TRAF3IP2 inhibitors or RECK inducers have the potential to block the progression of neointimal thickening in hyperplastic vascular diseases.

The combination of a neprilysin inhibitor (sacubitril) and angiotensin-II receptor blocker (valsartan) attenuates glomerular and tubular injury in the Zucker Obese rat.

OBJECTIVE: Diabetic nephropathy (DN) is characterized by glomerular and tubulointerstitial injury, proteinuria and remodeling. Here we examined whether the combination of an inhibitor of neprilysin (sacubitril), a natriuretic peptide-degrading enzyme, and an angiotensin II type 1 receptor blocker (valsartan), suppresses renal injury in a pre-clinical model of early DN more effectively than valsartan monotherapy. METHODS: Sixty-four male Zucker Obese rats (ZO) at 16 weeks of age were distributed into 4 different groups: Group 1: saline control (ZOC); Group 2: sacubitril/valsartan (sac/val) (68 mg kg-1 day-1; ZOSV); and Group 3: valsartan (val) (31 mg kg-1 day-1; ZOV). Group 4 received hydralazine, an anti-hypertensive drug (30 mg kg-1 day-1, ZOH). Six Zucker Lean (ZL) rats received saline (Group 5) and served as lean controls (ZLC). Drugs were administered daily for 10 weeks by oral gavage. RESULTS: Mean arterial pressure (MAP) increased in ZOC (+ 28%), but not in ZOSV (- 4.2%), ZOV (- 3.9%) or ZOH (- 3.7%), during the 10 week-study period. ZOC were mildly hyperglycemic, hyperinsulinemic and hypercholesterolemic. ZOC exhibited proteinuria, hyperfiltration, elevated renal resistivity index (RRI), glomerular mesangial expansion and podocyte foot process flattening and effacement, reduced nephrin and podocin expression, tubulointerstitial and periarterial fibrosis, increased NOX2, NOX4 and AT1R expression, glomerular and tubular nitroso-oxidative stress, with associated increases in urinary markers of tubular injury. None of the drugs reduced fasting glucose or HbA1c. Hypercholesterolemia was reduced in ZOSV (- 43%) and ZOV (- 34%) (p < 0.05), but not in ZOH (- 13%) (ZOSV > ZOV > ZOH). Proteinuria was ameliorated in ZOSV (- 47%; p < 0.05) and ZOV (- 30%; p > 0.05), but was exacerbated in ZOH (+ 28%; p > 0.05) (ZOSV > ZOV > ZOH). Compared to ZOC, hyperfiltration was improved in ZOSV (p < 0.05 vs ZOC), but not in ZOV or ZOH. None of the drugs improved RRI. Mesangial expansion was reduced by all 3 treatments (ZOV > ZOSV > ZOH). Importantly, sac/val was more effective in improving podocyte and tubular mitochondrial ultrastructure than val or hydralazine (ZOSV > ZOV > ZOH) and this was associated with increases in nephrin and podocin gene expression in ZOSV (p < 0.05), but not ZOV or ZOH. Periarterial and tubulointerstitial fibrosis and nitroso-oxidative stress were reduced in all 3 treatment groups to a similar extent. Of the eight urinary proximal tubule cell injury markers examined, five were elevated in ZOC (p < 0.05). Clusterin and KIM-1 were reduced in ZOSV (p < 0.05), clusterin alone was reduced in ZOV and no markers were reduced in ZOH (ZOSV > ZOV > ZOH). CONCLUSIONS: Compared to val monotherapy, sac/val was more effective in reducing proteinuria, renal ultrastructure and tubular injury in a clinically relevant animal model of early DN. More importantly, these renoprotective effects were independent of improvements in blood pressure, glycemia and nitroso-oxidative stress. These novel findings warrant future clinical investigations designed to test whether sac/val may offer renoprotection in the setting of DN.

Pleural electrical impedance is a sensitive, real-time indicator of pneumothorax.

BACKGROUND: Chest tube management protocols, particularly in patients with alveolar-pleural air leak due to recent surgery or trauma, are limited by concerns over safety, especially concerns about rapid and occult development of pneumothorax. A continuous, real-time monitor of pneumothorax could improve the quality and safety of chest tube management. We developed a rat model of pneumothorax to test a novel approach of measuring electrical impedance within the pleural space as a monitor of lung expansion. MATERIALS AND METHODS: Anesthetized Sprague-Dawley rats underwent right thoracotomy. A novel impedance sensor and a thoracostomy tube were introduced into the right pleural space. Pneumothorax of varying volumes ranging from 0.2 to 20 mL was created by syringe injection of air via the thoracostomy tube. Electrical resistance measurements from the pleural sensor and fluoroscopic images were obtained at baseline and after the creation of pneumothorax and results compared. RESULTS: A statistically significant, dose-dependent increase in electrical resistance was observed with increasing volume of pneumothorax. Resistance measurement allowed for continuous, real-time monitoring of pneumothorax development and the ability to track pneumothorax resolution by aspiration of air via the thoracostomy tube. Pleural resistance measurement demonstrated 100% sensitivity and specificity for all volumes of pneumothorax tested and was significantly more sensitive for pneumothorax detection than fluoroscopy. CONCLUSIONS: The electrical impedance-based pleural space sensor described in this study provided sensitive and specific pneumothorax detection, which was superior to radiographic analysis. Real-time, continuous monitoring for pneumothorax has the potential to improve the safety, quality, and efficiency of postoperative chest tube management.

Glycemic control by the SGLT2 inhibitor empagliflozin decreases aortic stiffness, renal resistivity index and kidney injury.

BACKGROUND: Arterial stiffness is emerging as an independent risk factor for the development of chronic kidney disease. The sodium glucose co-transporter 2 (SGLT2) inhibitors, which lower serum glucose by inhibiting SGLT2-mediated glucose reabsorption in renal proximal tubules, have shown promise in reducing arterial stiffness and the risk of cardiovascular and kidney disease in individuals with type 2 diabetes mellitus. Since hyperglycemia contributes to arterial stiffness, we hypothesized that the SGLT2 inhibitor empagliflozin (EMPA) would improve endothelial function, reduce aortic stiffness, and attenuate kidney disease by lowering hyperglycemia in type 2 diabetic female mice (db/db). MATERIALS/METHODS: Ten-week-old female wild-type control (C57BLKS/J) and db/db (BKS.Cg-Dock7m+/+Leprdb/J) mice were divided into three groups: lean untreated controls (CkC, n = 17), untreated db/db (DbC, n = 19) and EMPA-treated db/db mice (DbE, n = 19). EMPA was mixed with normal mouse chow at a concentration to deliver 10 mg kg-1 day-1, and fed for 5 weeks, initiated at 11 weeks of age. RESULTS: Compared to CkC, DbC showed increased glucose levels, blood pressure, aortic and endothelial cell stiffness, and impaired endothelium-dependent vasorelaxation. Furthermore, DbC exhibited impaired activation of endothelial nitric oxide synthase, increased renal resistivity and pulsatility indexes, enhanced renal expression of advanced glycation end products, and periarterial and tubulointerstitial fibrosis. EMPA promoted glycosuria and blunted these vascular and renal impairments, without affecting increases in blood pressure. In addition, expression of "reversion inducing cysteine rich protein with Kazal motifs" (RECK), an anti-fibrotic mediator, was significantly suppressed in DbC kidneys and partially restored by EMPA. Confirming the in vivo data, EMPA reversed high glucose-induced RECK suppression in human proximal tubule cells. CONCLUSIONS: Empagliflozin ameliorates kidney injury in type 2 diabetic female mice by promoting glycosuria, and possibly by reducing systemic and renal artery stiffness, and reversing RECK suppression.

TRAF3IP2 mediates TWEAK/TWEAKR-induced pro-fibrotic responses in cultured cardiac fibroblasts and the heart.

Persistent inflammation promotes development and progression of heart failure (HF). TWEAK (TNF-Related WEAK Inducer Of Apoptosis), a NF-κB- and/or AP-1-responsive proinflammatory cytokine that signals via TWEAK receptor (TWEAKR), is expressed at high levels in human and preclinical models of HF. Since the adapter molecule TRAF3IP2 (TRAF3 Interacting Protein 2) is an upstream regulator of various proinflammatory pathways, including those activated by NF-κB and AP-1, we hypothesized that targeting TRAF3IP2 inhibits TWEAK-induced proinflammatory and pro-fibrotic responses in vitro and in vivo. Consistent with the hypothesis, forced expression of TRAF3IP2 upregulated TWEAK and its receptor expression in cultured adult mouse cardiac fibroblasts (CF). Further, exogenous TWEAK upregulated TRAF3IP2 expression in a time- and dose-dependent manner, suggesting a positive-feedback regulation of TRAF3IP2 and TWEAK. TWEAK also promoted TRAF3IP2 nuclear translocation. Confirming its critical role in TWEAK signaling, silencing TRAF3IP2 inhibited TWEAK autoregulation, TWEAKR upregulation, p38 MAPK, NF-κB and AP-1 activation, inflammatory cytokine expression, MMP and TIMP1 activation, collagen expression and secretion, and importantly, proliferation and migration. Recapitulating these in vitro results, continuous infusion of TWEAK for 7 days increased systolic blood pressure (SBP), upregulated TRAF3IP2 expression, activated p38 MAPK, NF-κB and AP-1, induced the expression of multiple proinflammatory and pro-fibrotic mediators, and interstitial fibrosis in hearts of wild type mice. These proinflammatory and pro-fibrotic changes occurred in conjunction with myocardial hypertrophy and contractile dysfunction. Importantly, genetic ablation of TRAF3IP2 inhibited these TWEAK-induced adverse cardiac changes independent of increases in SBP, indicating that TRAF3IP2 plays a causal role, and thus a therapeutic target, in chronic inflammatory and fibro-proliferative diseases.

Lung transplant patients with coronary artery disease rarely die of cardiac causes.

BACKGROUND: A relative contraindication for lung transplant (LT) is coronary disease burden sufficient to cause risk of myocardial infarction after LT. We analyzed cause of death and outcomes of our LT patients with coronary artery disease (CAD). METHODS: Inpatient records from March 1, 2004, to January 31, 2015, were retrospectively examined and data of 306 LTs extracted. Twenty-five patients without coronary angiography (CA) and 7 with redo LTs were excluded. The other 274 patients were divided into 2 groups: CAD (n = 116) and no CAD (n = 158). Patients with prior revascularization or coronary stenosis >10% were placed into the CAD group. RESULTS: The CAD group was older and had more male patients, greater history of smoking and hypertension, and greater proportion of patients with interstitial lung disease than the no-CAD group. CAD patients were more likely to receive a single-lung transplant. Death of cardiac causes occurred for 2 patients (1.7%) in the CAD group and for 1 patient (0.6%) in the no-CAD group (P = 0.39). CONCLUSIONS: This analysis shows that compared with patients who have no CAD, patients with CAD have different demographic characteristics and receive more single-lung transplants. Incidence of death of cardiac causes is rare.

TRAF3IP2 mediates high glucose-induced endothelin-1 production as well as endothelin-1-induced inflammation in endothelial cells.

Hyperglycemia-induced production of endothelin (ET)-1 is a hallmark of endothelial dysfunction in diabetes. Although the detrimental vascular effects of increased ET-1 are well known, the molecular mechanisms regulating endothelial synthesis of ET-1 in the setting of diabetes remain largely unidentified. Here, we show that adapter molecule TRAF3 interacting protein 2 (TRAF3IP2) mediates high glucose-induced ET-1 production in endothelial cells and ET-1-mediated endothelial cell inflammation. Specifically, we found that high glucose upregulated TRAF3IP2 in human aortic endothelial cells, which subsequently led to activation of JNK and IKKß. shRNA-mediated silencing of TRAF3IP2, JNK1, or IKKß abrogated high-glucose-induced ET-converting enzyme 1 expression and ET-1 production. Likewise, overexpression of TRAF3IP2, in the absence of high glucose, led to activation of JNK and IKKß as well as increased ET-1 production. Furthermore, ET-1 transcriptionally upregulated TRAF3IP2, and this upregulation was prevented by pharmacological inhibition of ET-1 receptor B using BQ-788, or inhibition of NADPH oxidase-derived reactive oxygen species using gp91ds-tat and GKT137831. Notably, we found that knockdown of TRAF3IP2 abolished ET-1-induced proinflammatory and adhesion molecule (IL-1ß, TNF-α, monocyte chemoattractant protein 1, ICAM-1, VCAM-1, and E-selectin) expression and monocyte adhesion to endothelial cells. Finally, we report that TRAF3IP2 is upregulated and colocalized with CD31, an endothelial marker, in the aorta of diabetic mice. Collectively, findings from the present study identify endothelial TRAF3IP2 as a potential new therapeutic target to suppress ET-1 production and associated vascular complications in diabetes. NEW & NOTEWORTHY This study provides the first evidence that the adapter molecule TRAF3 interacting protein 2 mediates high glucose-induced production of endothelin-1 by endothelial cells as well as endothelin-1-mediated endothelial cell inflammation. The findings presented herein suggest that TRAF3 interacting protein 2 may be an important therapeutic target in diabetic vasculopathy characterized by excess endothelin-1 production.

Metformin inhibits aldosterone-induced cardiac fibroblast activation, migration and proliferation in vitro, and reverses aldosterone+salt-induced cardiac fibrosis in vivo.

The overall goals of this study were to investigate whether metformin exerts anti-fibrotic effects in aldosterone (Aldo)+salt-treated wild type mouse hearts, and determine the underlying molecular mechanisms in isolated adult cardiac fibroblasts (CF). In vitro, Aldo induced CF activation, migration, and proliferation, and these effects were inhibited by metformin. Further, Aldo induced PPM1A (Protein Phosphatase Magnesium Dependent 1A) activation and inhibited AMPK phosphorylation. At a pharmacologically relevant concentration, metformin restored AMPK activation, and inhibited Aldo-induced Nox4/H2O2-dependent TRAF3IP2 induction, pro-inflammatory cytokine expression, and CF migration and proliferation. Further, metformin potentiated the inhibitory effects of spironolactone, a mineralocorticoid receptor antagonist, on Aldo-induced collagen expression, and CF migration and proliferation. These results were recapitulated in vivo, where metformin reversed Aldo+salt-induced oxidative stress, suppression of AMPK activation, TRAF3IP2 induction, pro-inflammatory cytokine expression, and cardiac fibrosis, without significantly modulating systolic blood pressure. These in vitro and in vivo data indicate that metformin has the potential to reduce adverse cardiac remodeling in hypertensive heart disease.

Effect of inhaled tacrolimus on ischemia reperfusion injury in rat lung transplant model.

OBJECTIVE: Systemic tacrolimus therapy has been shown to protect against lung ischemia-reperfusion injury in animal models. We sought to investigate on a functional and cellular level if inhaled nanoparticle tacrolimus administered to the donor lung before procurement could similarly attenuate ischemia-reperfusion injury after lung transplant. METHODS: An isogenic orthotopic rat model of single left lung transplant was used. Donor animals were pretreated with inhaled tacrolimus (treatment group) or inhaled lactose (controls) before lung procurement. Lung grafts were subjected to 3 hours of cold ischemia followed by 4 hours of reperfusion after graft implantation. Recipient animal arterial blood gas measurement and isograft wet to dry weight ratios were obtained. Macrophage, neutrophil, and T-cell accumulation and activation in lung isografts, including γδ T-cell, T-helper, and cytotoxic T-cell subtypes were analyzed by flow cytometry. Tacrolimus levels were measured in the lung isograft using liquid chromatography/mass spectrometry. Isograft cytokine levels were measured with commercial enzyme-linked immunosorbent assay and microbead array kits. RESULTS: Oxygenation in treatment group animals was significantly higher than in controls. The presence of macrophages, neutrophils, and all T-cell subtypes in the isografts as well as isograft levels of inflammatory cytokines were all less in the treatment group versus controls, although no single variable achieved statistical significance. CONCLUSIONS: Inhaled nanoparticle tacrolimus treatment of lung donors is associated with an attenuation of ischemia-reperfusion injury on a functional and cellular level in lung transplant.

CIKS (Act1 or TRAF3IP2) mediates high glucose-induced endothelial dysfunction.

Hyperglycemia-induced endothelial dysfunction is characterized by enhanced inflammatory cytokine and adhesion molecule expression, and endothelial-monocyte adhesion. The adapter molecule CIKS (connection to IKK and SAPK/JNK; also known as Act1 or TRAF3IP2) is an upstream regulator of NF-κB and AP-1, and plays a role in inflammation and injury. Here we show that high glucose (HG; 25mM vs. 5mM d-glucose)-induced endothelial-monocyte adhesion and inhibition of endothelial cell (EC) migration were both reversed by CIKS knockdown. In EC, HG induced CIKS mRNA and protein expression via DPI-inhibitable Nox4-dependent ROS generation. Further, HG induced CIKS transcription and enhanced CIKS promoter-dependent reporter gene activation via Nox4, ROS, AP-1 and C/EBP. Coimmunoprecipitation and immunoblotting revealed CIKS/IKKß/JNK physical association under basal conditions that was enhanced by HG treatment. Importantly, CIKS knockdown inhibited HG-induced (i) IKKß and JNK phosphorylation, (ii) p65 and c-Jun nuclear translocation, and (iii) NF-κB- and AP-1-dependent proinflammatory cytokine, chemokine, and adhesion molecule expression. Similar to HG, the deleterious metabolic products of chronic hyperglycemia, AGE-HSA, AOPPs-HSA and oxLDL, also induced CIKS-dependent endothelial dysfunction. Notably, aortas from streptozotocin-induced and the autoimmune type 1 diabetic NOD and Akita mice showed enhanced DPI-inhibitable ROS generation and CIKS expression. Since CIKS mediates high glucose-induced NF-κB and AP-1-dependent inflammatory signaling and endothelial dysfunction, targeting CIKS may delay progression of vascular diseases during diabetes mellitus and atherosclerosis.

Diagnosis of anastomotic leak: electrolyte detection versus barium fluoroscopy.

BACKGROUND: We recently described a new method of diagnosing anastomotic leak using the detection of electrical changes induced by electrolyte extravasation from a surgically created gastric leak site in experimental rats. We sought to compare the sensitivity and specificity of anastomotic leak detection for this method to that of upper gastrointestinal (GI) barium fluoroscopy. METHODS: Experimental rats with a surgically created gastric leak site and controls were interrogated as to the presence of leak using either the electrolyte-gated leak detection method or upper GI barium fluoroscopy. The sensitivity and specificity of leak detection for the two methods were compared. RESULTS: The sensitivity and specificity of electrolyte-gated leak detection were both 100% (95% confidence interval 69-100%). Barium upper GI fluoroscopy misidentified one leak as a control and one control as a leak, for a sensitivity and specificity of 80% each (95% confidence interval 37-97%). No statistically significant difference was seen between electrolyte-gated leak detection and barium upper GI fluoroscopy in terms of the sensitivity and specificity of anastomotic leak detection. CONCLUSIONS: Electrolyte-gated leak detection was similarly sensitive and specific for anastomotic leak detection as upper GI barium fluoroscopy, the current standard. The electrolyte-gated method has the advantages of an inert contrast agent (normal saline) and the possibility of performing leak interrogation at the bedside. Electrolyte-gated leak detection might represent a plausible alternative to upper GI barium fluoroscopy for routine postoperative anastomotic leak surveillance after esophagectomy or other foregut surgery.