The risk of diabetic renal function impairment in the first decade after diagnosed of diabetes mellitus is correlated with high variability of visit-to-visit systolic and diastolic blood pressure: a case control study.

BACKGROUND: The variability of visit-to-visit (VVV) in systolic blood pressure (SBP) and diastolic blood pressure (DBP) is proved as a predictor of renal function deterioration in patients with non-diabetic chronic kidney disease. The purpose of this study was to investigate the relationship of the variability in SBP and the magnitude of renal function impairment for normal renal function patients in the first 10-years diagnosed with type II diabetes mellitus (DM). METHODS: We retrospectively reviewed the electronic medical records of 789 patients who were first diagnosed with diabetes mellitus during 2000-2002 and regularly followed for 10 years with a total of 53,284 clinic visits. The stages of Chronic Kidney Disease (CKD) of every patient were determined using estimated glomerular filtration rate. The occurrence of nephropathy was defined in those patients whose CKD stages elevated equal or larger than three. RESULTS: Patients were categorized according to the VVV of systolic and diastolic BP into three groups. Patients with high VVV of both SBP and DBP had a 2.44 fold (95% CI: 1.88-3.17, p < 0.001) increased risk of renal function impairment compared with patients with low VVV of both SBP and DBP. Risk of renal function impairment for patients with high VVV of either SBP or DBP had a 1.43-fold increase (95% CI: 1.08-1.89, p = 0.012) compared with patients with low VVV of both SBP and DBP. Cox regression analysis also demonstrated that every 1-year increase of DM diagnosed age significantly raised the risk of renal function impairment with a hazard ration of 1.05 (95% CI: 1.04-1.06, p < 0.001). CONCLUSIONS: Not only VVV of SBP but also VVV in DBP is correlated with diabetic nephropathy in the first decade for patients diagnosed with type 2 DM.

Electrocautery device does not provide adequate pulmonary vessel sealing in transumbilical anatomic pulmonary lobectomy.

INTRODUCTION: Safe pulmonary vessel sealing device plays a crucial role in anatomic lung resection. In 2014, we reported high rates of massive bleeding complications during transumbilical lobectomy in a canine model due to difficulty in managing the pulmonary vessel with an endostapler. In this animal survival series, we aimed to evaluate the outcome of pulmonary vessel sealing with an electrocautery device to simplify the transumbilical thoracic surgery. METHODS: Under general anesthesia, a 3-cm longitudinal incision was made over the umbilicus. Under video guidance, a bronchoscope was inserted through the incision for exploration. The diaphragmatic wound was created with an electrocautery knife and used as the entrance into the thoracic cavity. Using the transumbilical technique, anatomic lobectomy was performed with electrosurgical devices and endoscopic vascular staplers in 15 canines. RESULTS: Transumbilical endoscopic anatomic lobectomy was successfully completed in 12 of the 15 animals. Intraoperative bleeding developed in three animals during pulmonary hilum dissection, where one animal was killed due to hemodynamic instability and the other two animals required thoracotomy to complete the operation. There were five delayed bleeding and surgical mortality cases caused by inadequate vessel sealing by electrosurgical devices. Postmortem examination confirmed correct transumbilical lobectomy in the twelve animals that survived the operations. CONCLUSION: Transumbilical anatomic lobectomy is technically feasible in a canine model; however, the electrosurgical devices were not effective in sealing the pulmonary vessel in the current canine model.

Long-term outcomes after thoracoscopic resection of stage I and II thymoma: a propensity-matched study.

PURPOSE: The use of video-assisted thoracoscopic surgery (VATS) in patients with thymoma remains controversial. We sought to evaluate the perioperative and oncological outcomes after VATS resection for stage I and II thymoma and to compare the outcomes with those obtained after median sternotomy (MST). METHODS: Between 1991 and 2007, a total of 140 patients with stage I and II thymoma underwent surgery at the Chang Gung Memorial Hospital. Of them, 58 underwent MST, 61 VATS, and 21 thoracotomy. Using a propensity score based on four variables (myasthenia gravis, tumor size on CT images, age, and Masaoka stage), 48 VATS-treated patients were matched to 48 patients who received MST. Outcomes compared included perioperative complications, length of stay, tumor recurrence, and survival. RESULTS: No operative deaths occurred in this study. VATS was associated with fewer intraoperative blood loss, and more patients in the VATS group were extubated in the operating room after surgery compared with the MST group (37.5 vs. 12.5 %, respectively, P = 0.005). The mean length of stay was shorter in the VATS group than in the MST group (5.8 vs. 7 days, respectively; P = 0.008). After a median follow-up of 53 months, five patients developed recurrent tumors (four pleural and one pericardial). No statistically significant differences were found in the 5-year survival rates between the two study groups. CONCLUSIONS: VATS appears feasible for patients with stage I and II thymoma and is associated with better perioperative outcomes than MST. The oncological outcomes are also similar.

Transumbilical Thoracoscopy Versus Conventional Thoracoscopy for Lung Wedge Resection: Safety and Efficacy in a Live Canine Model.

PURPOSE: Transumbilical single-port surgery has been associated with less postoperative pain and offers better cosmetic outcomes than conventional 3-port laparoscopic surgery. This study compares the safety and efficacy of transumbilical thoracoscopy and conventional thoracoscopy for lung wedge resection. METHODS: The animals (n = 16) were randomly assigned to the transumbilical thoracoscopic approach group (n = 8) or conventional thoracoscopic approach group (n = 8). Transumbilical lung resection was performed via an umbilical incision and a diaphragmatic incision. In the conventional thoracoscopic group, lung resection was completed through a thoracic incision. For both procedures, we compared the surgical outcomes, for example, operating time and operative complications; physiologic parameters, for example, respiratory rate and body temperature; inflammatory parameters, for example, white blood cell count; and pulmonary parameters, for example, arterial blood gas levels. The animals were euthanized 2 weeks after the surgery for gross and histologic evaluations. RESULTS: The lung wedge resection was successfully performed in all animals. There was no significant difference in the mean operating times or complications between the transumbilical and the conventional thoracoscopic approach groups. With regard to the physiologic impact of the surgeries, the transumbilical approach was associated with significant elevations in body temperature on postoperative day 1, when compared with the standard thoracoscopic approach. CONCLUSIONS: This study suggests that both approaches for performing lung wedge resection were comparable in efficacy and postoperative complications.

Bronchoscopic finding determined outcome after chemoradiotherapy in esophageal cancer patients with airway invasion.

BACKGROUND: We studied whether the bronchoscopic findings could be help to predict outcome after chemoradiotherapy (CRT) in patients with airway invasion by esophageal cancer. METHOD: Between 2000 and 2010, we retrospectively investigated esophageal cancer patients with T4 disease due to airway invasion who had received CRT as first line treatment. Airway invasion is defined as infiltration of the tracheobronchial wall or protruded intraluminal growth on bronchoscopy. The total radiation dose of CRT was 60 Gy and divided into two cycles. Bronchoscopic findings were evaluated together with other clinical parameters and correlated with overall survival (OS). RESULT: There were 68 patients with a mean age of 54.5 years. After the first cycle of CRT, bronchoscopic examination showed complete regression of endobronchial lesion in 16 patients. OS was 26% at 1 year and 5% at 3 years with the median survival time (MST) of 7 months. Multivariate analysis revealed vocal cord palsy (unfavorable, OR [95% CI]:2 [1.07-3.84], P = 0.03), carina involvement (unfavorable, OR [95% CI]:2.6 [1.12-6], P = 0.025) and intraluminal tumor growth (unfavorable, OR [95% CI]:1.9 [1.1-3.3], P = 0.023) as independent factors for survival. The MST after CRT was 12.1, 6.1, 5.7 months in patients with 0, 1, 2 factors, respectively (P < 0.001). CONCLUSION: Bronchoscopic finding determined outcome after CRT in esophageal cancer patients with airway invasion.

Factors associated with proceeding to surgical intervention and recurrence of primary spontaneous pneumothorax in adolescent patients.

UNLABELLED: Primary spontaneous pneumothorax (PSP) is not uncommon, and its recurrence is often a challenging clinical problem. Surgical management and predisposing factors for the recurrence of PSP, however, have not yet been well elucidated in adolescent patients. The major aim of this study was to investigate factors associated with proceeding to surgical intervention and recurrence of PSP in adolescents. Two hundred and nineteen episodes of PSP in 171 adolescent patients were retrospectively reviewed. The clinical and radiological spectrum of PSP and factors for proceeding to surgical intervention were assessed in these 171 patients. Risk factors for the recurrence of PSP were further analyzed in 128 patients with first attack of PSP. The male-to-female ratio of the 171 PSP patients was 9:1, and the mean age was 17.6 ± 1.5 years. The median body mass index (BMI) percentile was 11 (range 2-31), and 45 (34 %) patients had underweight BMI. The incidence of recurrent PSP was high with a total recurrence rate of 21 %. Ipsilateral recurrence rate of PSP after video-assisted thoracoscopic surgery (VATS) was much less than that of the conservative treatment (4 vs. 18 %). A large-size pneumothorax with a persistent air leak was the most significant factor for proceeding to VATS surgery (P = 0.001). In addition, it was a significant factor influencing the recurrence of PSP (P = 0.014). Other factors that did not significantly affect the recurrence rate were BMI, smoking status, and the number of bullae. CONCLUSION: Adolescent PSP has a high recurrence rate of 21 % after a 2-year follow-up. A large-size pneumothorax with a persistent air leak may not only lead to surgical intervention but also the risk of a recurrence of PSP. The initial size of pneumothorax may not only guide the management process but also predict the risk of a recurrence in adolescent patients with PSP.

Feasibility of transumbilical surgical lung biopsy and pericardial window creation.

BACKGROUND: To date there are no practical platforms for performing natural orifice transluminal endoscopic surgery in the thoracic cavity. This study evaluates the feasibility of transumbilical thoracosopy for lung biopsy and pericardial window creation. METHODS: Eleven dogs (6 in the nonsurvival group and 5 in the survival group) were used for this study. A homemade metallic tube was advanced into the abdominal cavity via a 12-mm umbilical incision. The metallic tube was advanced into the thoracic cavity through a subxyphoid diaphragmatic incision under video guidance. Access to the thoracic cavity was achieved by a flexible bronchoscope via the metallic tube. Surgical lung biopsy and pericardial window creation were performed using an electrocautery loop and needle knife. The animals were euthanized 20 minutes after the surgery was complete (nonsurvival group) or 14 days postsurgery (survival group) for necropsy evaluation. RESULTS: Eight pericardial window creations and 21 of 22 preplanned lung biopsies were completed in a median time of 72.18 minutes (range 50-105 minutes). One dog in the nonsurvival group died after tension pneumothorax due to postprocedure massive air leaks. In the survival group, the postoperative period was uneventful in all 5 dogs. Autopsies revealed no signs of vital organ injury and complete healing of the diaphragmatic incision occurred in all animals. CONCLUSIONS: The study demonstrated that transumbilical thoracoscopic surgical lung biopsy and pericardial window creation is feasible. The safety and efficacy of the transumbilical approach need to be verified by a more detailed survival study.

Feasibility of endoscopic transoral thoracic surgical lung biopsy and pericardial window creation.

BACKGROUND: The thoracic cavity approach for natural orifice transluminal endoscopic surgery (NOTES) is technically challenging. The aim of this study was to evaluate the feasibility of a transoral endoscopic technique for a surgical lung biopsy and pericardial window creation METHODS: Under general anesthesia, a 12 mm incision was made over the vestibulum oris region. Under video guidance, a homemade metallic tube was introduced through the incision, extending along the pre-tracheal space to the substernal space with blunt dissection technique, and used as the entrance into the thoracic cavity. A surgical lung biopsy and a pericardial window creation were performed in 12 canines, using the transoral NOTES technique. RESULTS: The transoral endoscopic surgical lung biopsy and pericardial window creation were successfully completed in 11 of the 12 canines. Intraoperative bleeding and death from an injury to the pulmonary hilum developed in one animal during the electrosurgical excision of lung tissue. CONCLUSIONS: Transoral surgical lung biopsy and pericardial window creation in canine models is technically feasible and can be used as a novel experimental platform for studies of NOTES for intra-thoracic surgery.

Feasibility of endoscopic transoral surgical lung biopsy in a live canine model.

BACKGROUND: The feasibility of using a transoral approach to the thoracic cavity has not yet been measured in humans or animals. The present study aimed to evaluate the feasibility of transoral surgical lung biopsy (TOLB) in 10 canines. METHODS: Through an incision over the vestibulum oris, a homemade metal tube was introduced into the thoracic cavity under endoscopic guidance and used as a working channel of surgical lung biopsy. TOLB was performed on the predetermined lung lobe by using an electrocautery loop and endoscopic grasper. RESULTS: Successful surgical lung biopsy was achieved in 8 of 10 animals in a mean time of 132 minutes (range 130-190 minutes). There were no major intraoperative or postoperative complications, and all animals survived for 2 weeks after surgery. Autopsy showed no evidence of vital structure injury, mediastinitis, or empyema. CONCLUSIONS: TOLB was demonstrated to be safe and feasible in a canine model.

A rare epidermal growth factor receptor (EGFR) gene mutation in small cell lung carcinoma patients.

AIM: Activating mutations in the epidermal growth factor receptor (EGFR) are predominantly detected in pulmonary adenocarcinoma and have been reported in small cell lung cancer (SCLC) for decades. This retrospective single-center study aimed to determine the frequency and types of EGFR mutations in SCLC in Taiwan. METHODS: This study comprises a consecutive cohort of 161 patients histologically diagnosed with SCLC between January 1992 and August 2014 at the Department of Pathology in Keelung Chang Gung Memorial Hospital, Taiwan. Archived formalin-fixed paraffin-embedded sections from 71 patients were eligible for molecular analysis. EGFR mutation analysis was performed using a fully-automated IdyllaTM EGFR Mutation Test and confirmed a comparable result through Qiagen Therascreen® EGFR RGQ PCR. In addition, EGFR gene copy number was assessed in EGFR-mutated tumors by fluorescence in situ hybridization (FISH). RESULTS: Mutational status of the EGFR gene was successfully analyzed in 63 specimens by both IdyllaTM and Qiagen platforms. Both methods detected L858R point mutation in exon 21 in an 81-year-old female and a 47-year-old male non-smoker. Both tumors show no concurrent EGFR gene amplification. The overall agreement between results obtained with the Idylla™ EGFR Mutation Test and Qiagen Therascreen® EGFR RGQ PCR was 100% Conclusions. Our results showed that EGFR mutation is a rare mutation type in a consecutive series of de novo SCLC. Furthermore, the performance of Idylla™ EGFR Mutation Test and Qiagen Therascreen® EGFR RGQ PCR on archived paraffin sections of limited quantities is available with the high agreement of results.

Single-dose antimicrobial prophylaxis in transoral surgical lung biopsy: a preliminary experience.

BACKGROUND: The feasibility of the transtracheal approach to the thoracic cavity has been demonstrated, but surgical lung biopsy via the tracheal approach still remains a challenge. This study aimed to evaluate the feasibility and outcome of transoral surgical lung biopsy under a single preoperative dose of parenteral antibiotics. METHODS: Transoral thoracoscopy and surgical lung biopsy were performed for 10 anesthetized dogs after a single intravenous injection of cefazoline (20 mg/kg). A 12-mm transoral incision was created on the vestibulum, and a homemade metallic tube was advanced into the thoracic cavity via the pretracheal and substernal space under endoscopic guidance. After thoracic exploration, surgical lung biopsy was performed using an electrosurgical snare with a flexible bronchoscope inserted through the metallic tube. The resection margin of the lung was secured with a homemade endoloop. The animals were killed by day 14 after the surgery for gross and histologic evaluations. RESULTS: The thoracic cavity was evaluated and lung biopsy was performed successfully (for 3 lobes in the right lung and 2 lobes in the left lung) in 9 of the 10 dogs. Neither mortality nor intraoperative complications were observed. The average time for the transoral thoracoscopy and surgical lung biopsy was 133.5 min. Postmortem examination showed complete healing, with fibrosis and moderate adhesion over the resection margin. No evidence of either mediastinitis or intrathoracic infection was observed. CONCLUSION: This study showed the feasibility of transoral thoracoscopy and surgical lung biospy in dogs. Moreover, single-dose prophylaxis with cefazoline in transoral surgical lung biopsy was found to be effective in preventing potential infection.

Percutaneous computed tomography-guided cryotherapy of thoracic masses in nonsurgical candidates: experience in 19 patients.

BACKGROUND/PURPOSE: Percutaneous cryotherapy has become a minimally invasive treatment option for unresectable lung malignancies. We report the experience and outcomes with percutaneous computed tomography (CT)-guided cryotherapy of primary lung malignancies, as well as recurrence and metastases, in patients ineligible for surgery. METHODS: The procedure was performed after administration of local anesthesia on 23 tumors in 19 patients (10 male and 9 female patients; mean age, 58.7 years). None of the patients were surgical candidates and underwent CT-guided percutaneous cryotherapy for treatment of the malignant mass in the lung. Visualization of low-attenuation ice ball formation was performed using CT scanning after each cycle of freezing and thawing therapy. Subsequent CT scans were scheduled at 3-month intervals post-procedure to assess tumor control. RESULTS: No lethal complication, major bleeding or bronchial damage was observed in any of the 23-cryotherapy sessions performed. Three patients developed pneumothorax and one patient required chest tube insertion. Thirteen tumors (56.5%) regressed, including two complete responses, five tumors (21.7%) were stationary and the remaining five tumors (21.7%) were found to be progressing at the 3-month follow-ups. No recurrence was found in the 11 regressed tumors for 6 months, and there was also no recunence in the two tumors that completely responded up to 12 months later with a satisfactory procedure. CONCLUSION: Percutaneous cryotherapy for primary lung cancer, recurrence and metastatic lung tumors is feasible and safe for local control.

Secure closure of the tracheal incision after natural orifice transluminal endoscopic surgery with a surgical sealant (CoSeal).

BACKGROUND: To evaluate the effectiveness of surgical sealant (CoSeal) in sealing the tracheal assess sites after transtracheal thoracoscopy. METHODS: Two dogs underwent transtracheal thoracic exploration and pericardial window creation. The thoracic cavity was approached with flexible bronchoscope through a 9-mm tracheal incision. The pericardial window was performed with a needle knife via the working channel of the bronchoscope, and the tracheal assess site was closed with CoSeal using a rubber catheter. The integrity of tracheal healing was evaluated under positive pressure ventilation. RESULT: Transtracheal creation of pericardial window and closure of tracheal incision with CoSeal was successfully performed in both dogs. There was no evidence of air leaks from the chest tube during positive pressure ventilation. Autopsy revealed no injury to the mediastinum and intrathoracic structure. CONCLUSION: Endoscopic closure of tracheal access site of NOTES with CoSeal appears to be a feasible technique.

Survival of Patients with Lung Cancer in the Setting of Liver Cirrhosis: A Multicenter Propensity Score Matching Study.

PURPOSE: The survival outcome of lung cancer patients with coexisting liver cirrhosis has thus far received limited attention in the literature. In this study, we evaluated whether liver cirrhosis is an independent risk factor for the survival of patients with lung cancer. MATERIALS AND METHODS: We conducted a retrospective, multicenter, propensity-matched study of lung cancer patients with and without liver cirrhosis. To determine differences in survival, we sought to identify risk factors associated with poor outcomes using Kaplan-Meier survival analysis and Cox proportional hazards regression. RESULTS: There were no statistically significant differences in the baseline clinical characteristics of patients between the cirrhosis and non-cirrhosis groups. The median overall survival of patients with and without cirrhosis was 13.07 months (95% confidence interval [CI]: 10.56-16.84) and 13.67 months (95% CI: 10.42-16.91), respectively (p=0.76). Cox proportional hazards regression analysis revealed that liver cirrhosis was not an independent risk factor for poor outcome (hazard ratio [HR]: 1.057, 95% CI: 0.805-1.388, p=0.690). In patients with cirrhosis, lower serum albumin levels, higher Charlson Comorbidity Index score, advanced-stage lung cancer, and treatment modality were factors associated with poor outcome. Increase in serum albumin by 1 g was associated with a 30% reduction in the risk of mortality (HR: 0.700, 95% CI: 0.494-0.993, p=0.045). While every point increase in the Charlson Comorbidity Index score by 1 point was linked to a 9% higher risk of mortality (HR: 1.090, 95% CI: 1.023-1.161, p=0.007). CONCLUSION: The survival rates of lung cancer patients with and without cirrhosis did not differ significantly. Higher serum albumin levels and lower Charlson Comorbidity Index scores were associated with improved survival.

Histopathologic Findings Associated With Matrix Metalloproteinases Proceeding to Recurrence of Primary Spontaneous Pneumothorax in Adolescents.

Background: Primary spontaneous pneumothorax is potentially life-threatening, and its recurrence is always a serious problem. Pathological examination provides molecular insights into the pathophysiology of primary spontaneous pneumothorax. Objectives: To investigate the association of histopathologic features of primary spontaneous pneumothorax with matrix metalloproteinase expression and their relevance to the recurrence. Methods: A total of 217 tissue section slides in 172 adolescent patients with primary spontaneous pneumothorax were retrospectively reviewed from January 2001 to June 2020. All histopathologic features were recorded and pathologic findings related to ipsilateral recurrence and second surgery were analyzed. Serum levels of matrix metalloproteinases were prospectively measured in 25 primary spontaneous pneumothorax patients receiving surgery and 18 healthy controls. Their relevance to the histopathologic features of primary spontaneous pneumothorax related to its recurrence was also examined. Results: The major presenting histopathologic findings of primary spontaneous pneumothorax were bleb/bulla (98%) followed by fibrosis (68%). Low prevalence of the pathologic findings of granulation tissue and macrophage accumulation were significantly associated with recurrent primary spontaneous pneumothorax, whereas fibrosis was significantly higher in patients receiving more than once surgery. Furthermore, the ratios of matrix metalloproteinase-2/tissue inhibitor of metalloproteinase-1 and matrix metalloproteinase-9/tissue inhibitor of metalloproteinase-1 were significantly higher in theses pathological findings as well as multinucleated giant cells and mesothelial cell hyperplasia in comparison with healthy controls. Conclusions: Low prevalence of macrophage accumulation and granulation tissue related to the overexpression of matrix metalloproteinase-2 and-9 activities may contribute to healing impairment and primary spontaneous pneumothorax recurrence.

Polygenic Panels Predicting the Susceptibility of Multiple Upper Aerodigestive Tract Cancer in Oral Cancer Patients.

Head and neck cancer was closely related with habitual use of cigarette and alcohol. Those cancer patients are susceptible to develop multiple primary tumors (MPTs). In this study, we utilized the single nucleotide polymorphisms (SNPs) array (Affymetrix Axion Genome-Wide TWB 2.0 Array Plate) to investigate patients' risks of developing multiple primary cancers. We recruited 712 male head and neck cancer patients between Mar 1996 and Feb 2017. Two hundred and eighty-six patients (40.2%) had MPTs and 426 (59.8%) had single cancer. Four hundred and twelve normal controls were also recruited. A list of seventeen factors was extracted and ten factors were demonstrated to increase the risks of multiple primary cancers (alcohol drinking, rs118169127, rs149089400, rs76367287, rs61401220, rs141057871, rs7129229, older age, rs3760265, rs9554264; all were p value < 0.05). Polygenic scoring model was built and the area under curve to predict the risk developing MPTs is 0.906. Alcohol drinking, among the seventeen factors, was the most important risk factor to develop MPT in upper aerodigestive tract (OR: 7.071, 95% C.I.: 2.134-23.434). For those with high score in polygenic model, routine screening of upper digestive tract including laryngoscope and esophagoscope is suggested to detect new primaries early.

Cardiomyocytic apoptosis limited by bradykinin via restoration of nitric oxide after cardioplegic arrest.

BACKGROUND: Our previous studies revealed that cardioplegia-induced cardiac arrest under cardiopulmonary bypass (CPB) decreased cardiomyocytic nitric oxide and increased apoptosis. We hypothesized that pretreatment with bradykinin (BK) would improve the profile of anti-apoptotic proteins and inhibit cardiomyocytic apoptosis. MATERIALS AND METHODS: New Zealand white rabbits received total CPB. Rabbits were weaned from CPB and reperfused for 4 h. Blood was sampled at various time points. Bradykinin and/or nitric oxide synthase (NOS) inhibitors or BK-receptor antagonists were infused systemically 30 min before beginning of CPB, and continued throughout the procedure. The ascending aorta was cross-clamped for 60 min while cold crystalloid cardioplegic solution was intermittently infused into the aortic root. The hearts were harvested and studied for evidence of apoptosis and ischemia/reperfusion induced inflammation-related cytokine production by cardiomyocytes. RESULTS: Our results revealed that bradykinin supplementation during cardioplegia could prevent I/R-induced inflammatory and apoptotic effects, which could be reversed with a NOS inhibitor. BK antagonists and NOS inhibitors worsened the inflammatory and apoptotic responses of cardiomyocytes, which could be reversed with an exogenous NO donor. CONCLUSIONS: Restoring the NO concentration after cardioplegia-induced cardiac arrest (CCA) under CPB with bradykinin could modulate (1) the nuclear translocation of NF-kappaB, (2) the plasma levels of inflammation-related cytokines, (3) the Bcl-2/Bax ratio, and (4) the occurrence of apoptosis. Exogenous bradykinin administration was associated with the myocardial apoptotic response by inhibition of NF-kappaB translocation, inflammatory cytokine production, Akt activation, and elevation of the Bcl-2/Bax ratio via a NO-mediated pathway.

AMP-activated protein kinase activation during cardioplegia-induced hypoxia/reoxygenation injury attenuates cardiomyocytic apoptosis via reduction of endoplasmic reticulum stress.

Cardioplegic-induced H/R injury results in cardiomyocytic apoptosis. AMPK has been shown to reduce ER stress and the unfolded protein response (UPR). Whether AMPK activation can attenuate cardiomyocytic apoptosis after cardioplegia-induced H/R injury is unknown. Cardiomyocytes were exposed to simulated ischemia by incubation in a hypoxic chamber with intermittent cold cardioplegia solution infusion at 20-minute intervals and subsequently reoxygenated in a normoxic environment. Various doses of AMPK activators (AICAR or metformin) were given 2 days before H/R injury. The cardiomyocytes were harvested after reoxygenation for subsequent examination. With both AMPK activators, the antiapoptotic genes of ER stress and UPR, the subsequent production of proapoptotic proteins was attenuated, and the antiapoptotic proteins were elevated. The activity of the apoptotic effectors of ER stress was also reduced with AMPK activation. Moreover, TUNEL staining showed that AMPK activation significantly reduced the percentage of apoptotic cardiomyocytes after cardioplegia-induced H/R injury. Our results revealed that AMPK activation during cardioplegia-induced H/R injury attenuates cardiomyocytic apoptosis, via enhancement of antiapoptotic and reduction of proapoptotic responses, resulting from lessening ER stress and the UPR. AMPK activation may serve as a future pharmacological target to reduce H/R injury in the clinical setting.