Confined ischemia may improve remote myocardial outcome after rat cardiac arrest.

BACKGROUND: Confined ongoing ischemia after ischemia-reperfusion injury (IRI) may alter myocardial recovery. We evaluated in a rat cardiac transplantation model whether distal persistent myocardial ischemia (dMI) and remote preconditioning (RPreC) have a remote myocardial impact after IRI. MATERIAL AND METHODS: Syngeneic heterotopic cardiac transplantation was performed on 29 Fischer344 rats to induce IRI, including nine rats which underwent distal ligation of the left anterior coronary artery (LAD) to yield distal MI (IRI+ dMI). RPreC was applied by occluding the left renal artery 5 min prior to reperfusion in six rats with IRI (IRI+ RPreC) as well as in seven with distal MI (IRI+ dMI+ RPreC). Microdialysis, histology and qRT-PCR for inducible nitric oxide synthase (iNOS) and endothelial nitric oxide synthase (eNOS) were performed after graft harvesting. RESULTS: In contrast to IRI + dMI + RPreC (39 ± 7 µmol), glutamate decreased in IRI + RPreC and IRI + dMI as compared with IRI (26 ± 3 and 31 ± 8 vs 91 ± 20, µmol respectively, p < 0.007). The relative number of vacuolated intramyocardial artery nuclei decreased in IRI + dMI as compared with IRI (0.02 ± 0.01, range 0-12 vs. 0.42 ± 0.31, range 0-3.25 PSU respectively, p < 0.04). iNOS expression decreased in IRI + RPreC as compared with IRI (p < 0.04), and eNOS expression decreased in IRI + dMI + RPreC as compared with IRI + dMI (p < 0.006) along with increased glycerol release. CONCLUSIONS: dMI after IRI has a potentially beneficial myocardial impact after cardiac arrest, which is hampered by RPreC.

Myocardial infarction induces early increased remote ADAM8 expression of rat hearts after cardiac arrest.

BACKGROUND: A disintegrin and metalloproteinase-8 (ADAM8) is a potential surrogate of inflammation which has recently been associated with myocardial infarction. We evaluated in a rat cardiac transplantation model whether ischemia-reperfusion injury alone (IRI) or with early regional myocardial infarction (MI) would suffice to induce inflammatory myocardial remodeling and ADAM8 expression. MATERIAL AND METHODS: Isogenic heterotopic cardiac transplantation after cardiac arrest was performed to 48 Fischer 344 rats to induce ischemia-reperfusion injury (IRI), of which 27 rats also underwent ligation of the left anterior coronary artery (LAD) of the heart to yield MI. Histology was performed at 0.5, 24 and 48 h after transplantation. ADAM8 was evaluated by qRT-PCR after graft harvesting. RESULTS: After 0.5 and 48 h respectively, edematous intramyocardial artery nuclei and periadventitial inflammation were more prominent in MI after transplantation, as compared with IRI alone and Controls (57.0 vs 40.0 and 5.0; 1.9 vs 1.1 and 0.9, point score units, p < 0.05, respectively). The expression of ADAM-8 was increased in MI as compared with Controls (1.9 vs 1.0, 1.9 fold increase) at 48 h. In grafts with MI, ADAM8 was localized using immunohistochemistry to the vicinity of the area corresponding to the developing infarction as well as in intramyocardial arteries remote to the infarction area. CONCLUSIONS: Remote histopathological changes of ischemic cardiac grafts are associated with increased expression of ADAM8 thus emphasizing a global myocardial impact of MI.

Glutamate release predicts ongoing myocardial ischemia of rat hearts.

BACKGROUND: Glutamate metabolism is associated with myocardial ischemia-reperfusion, but it is not clear whether glutamate reveals ongoing ischemia (OI). We evaluated whether microdialysis would detect OI induced by coronary artery ligation in a rat cardiac transplantation model. MATERIAL AND METHODS: A total of 24 Fischer 344 rats underwent syngeneic heterotopic cardiac transplantation. Of these, 16 rats underwent ligation of the left anterior coronary artery (LAD) of the heart to induce ongoing ischemia (OI), of which eight grafts received intra-aortally Gabapentin (12 mg/graft), a glutamate-release inhibitor and eight grafts with transplantation only served as the control. With a microdialysis catheter samples for glucose, lactate, pyruvate, glutamate, and glycerol were analysed spectrophotometrically. Histology and aquaporin 7 evaluations were performed after graft harvesting. RESULTS: Glutamate was elevated after 15 min of reperfusion in OI as compared with Control (14.31 +/- 5.03 microM vs 6.75 +/- 2.21 microM, p = 0.05), respectively. Glycerol remained high in OI (61.89 +/- 46.13 microM to 15.84 +/- 0.85 microM, p = ns) and low in Control (12.33 +/- 3.36 microM to 5.52 +/- 0.25 microM, p = ns). Gabapentin decreased glutamate release from 7.32 +/- 1.57 microM to 2.71 +/- 0.64 microM, (p < 0.05) and resulted in decrease of glycerol levels from 24.64 +/- 4.03 microM to 10.43 +/- 2.49 microM, (p < 0.05) in OI. The expression of aquaporin 7 and histology confirmed OI. CONCLUSIONS: We suggest that glutamate release may be used as an early indicator of OI after cardiac arrest.

Real-world guideline-based treatment of lung cancer improves short- and long-term outcomes and resection rate: A population-based study.

OBJECTIVES: Recent guidelines for the treatment of lung cancer include comprehensive lists of recommendations for pre-operative risk evaluation, staging, and surgery. Our aim was to evaluate whether the implementation of these in a population-based real-world setting would improve outcomes. MATERIALS AND METHODS: All patients diagnosed with primary lung cancer in Central Finland and Ostrobothnia between January 1, 2006, and December 31, 2017, were identified from registry data (N = 2116), including patients who underwent surgical resection (n = 303). Data were divided into two periods, old and modern, according to which international guidelines were followed. RESULTS: Between surgical patients of the old and modern periods, significant changes occurred in the rate of pre-operative stair climbing tests (3.7 % vs. 68.6 %, p < 0.001), the use of positron emission computed tomography (18.7 % vs. 75.7 %, p < 0.001), and invasive staging (3.7 % vs. 26.0 %, p < 0.001). In surgery, the rate of VATS (2.2 % vs. 81.1 %, p < 0.001), segmentectomy (1.5 % vs. 27.2 %, p < 0.001), and extended resections (5.2 % vs. 13.6 %, p = 0.015) increased. However, between these periods, the rate of pneumonectomy decreased from 7.5 % to 1.2 % (p = 0.005) and bilobectomy from 9.0%-1.8% (p = 0.004). The overall resection rate increased from 10.5%-19.7 %, mainly due to a higher number of high-risk patients (12.7 % vs. 34.3 %, p < 0.001). Patients faced fewer major complications (21.6 % vs. 8.9 %, p = 0.002) and had shorter hospital stays (9 days, IQR 7-11 vs. 5 days, IQR 3-7; p < 0.001). In the modern period, patients underwent adjuvant therapy less often than in the old period (35.1 % vs. 22.5 %, p = 0.015). Recurrence-free 5-year survival rate improved, however, from 64.0%-76.8% (p < 0.001). CONCLUSIONS: The introduction of guideline-based modern patient evaluation and treatment was associated with improved short- and long-term outcomes of lung cancer surgery.

C4d Deposition Reveals Myocardial Infarction After Cardiac Arrest--Experimental Study.

BACKGROUND: The diagnosis of regional myocardial infarction (MI) after cardiac arrest and ischemia-reperfusion injury (IRI) is a major clinical challenge. OBJECTIVES: We evaluated in a rat cardiac transplantation model whether IRI alone or with MI would induce complement C4d deposition. MATERIAL AND METHODS: Isogenic heterotopic cardiac transplantation was performed in 16 Fischer 344 rats to induce IRI, of which 9 rats also underwent ligation of the left anterior coronary artery (LAD) of the heart to yield MI. Histology and qRT-PCR for endothelial nitric oxide synthase (eNOS), inducible nitric oxide synthase (iNOS) and transforming growth factor ß (TGFß) were performed after cessation of heart beat. C4d was evaluated by immunohistochemistry. RESULTS: Myocardial inflammation and C4d deposition was increased in grafts with IRI+MI as compared with IRI (0.71 vs. 0.14, PSU, respectively, p<0.04 and 80.13 vs. 20.29, PSU, respectively, p<0.02). The expression of eNOS decreased in grafts with IRI+MI as compared with IRI (p<0.05). Receiver operating characteristic (ROC) curve analysis showed that IRI+MI was associated with C4d deposition (AUC 0.837; S.E. 0.116; p=0.035; 95% C.I. 0.610-1.000). CONCLUSIONS: Increased C4d deposition may be amenable to identify early MI after cardiac arrest. Early treatment aimed towards complement activation may provide a novel means for induced MI after cardiac arrest.

Inhibition of monoamine oxidase A increases recovery after experimental cardiac arrest.

OBJECTIVES: Perioperative myocardial infarction (MI) with ischaemia-reperfusion injury (IRI) is a devastating entity occurring in 1-2% of patients after cardiac surgery. The molecular pathway leading to myocardial cellular destruction after MI may include monoamine oxidases. We experimentally investigated whether moclobemide, a monoamine oxidase inhibitor, enhances myocardial recovery after cardiac arrest and MI. METHODS: Fifty-six syngeneic Fischer rats underwent heterotopic cardiac transplantation to induce reversible IRI after cardiac arrest. Twenty-eight rats also underwent permanent ligation of the left anterior descending coronary artery to induce MI after cardiac arrest. Twenty-eight rats with or without MI were treated with subcutaneous moclobemide 10 mg/kg/day. Methods used to study myocardial recovery were microdialysis for intramyocardial metabolism, histology and quantitative reverse-transcription polymerase chain reaction for high-mobility group box-1 (HMGB1), haeme oxygenase-1 (HO-1), interleukin-6, hypoxia-inducible factor 1α and macrophages (CD68). RESULTS: Pyruvate increased in MI treated with moclobemide versus IRI with moclobemide (29.19 ± 7.64 vs 13.86 ± 8.49 µM, P = 0.028), reflecting metabolic activity after cardiac arrest and reperfusion. Myocardial inflammation increased in MI compared with IRI after 1 h (0.80 ± 0.56 vs 0, point score units [PSUs], P = 0.003), but decreased after 5 days in MI treated with moclobemide versus MI alone (0.80 ± 0.83 vs 2.00 ± 0.70, PSU, P = 0.033). Expressions of HMGB1, CD68 and HO-1 decreased in MI treated with moclobemide versus MI alone (1.33 ± 0.20 vs 1.75 ± 0.24, fold changes [FCs], P = 0.028; 5.15 ± 1.10 vs 9.59 ± 2.75, FC, P = 0.050; 10.41 ± 4.17 vs 21.28 ± 10.01, FC, P = 0.047), indicating myocardial recovery and increased cellularity of remote intramyocardial arteries. CONCLUSIONS: Moclobemide enhances myocardial recovery after cardiac arrest and MI; inhibition of remote myocardial changes may be achieved by targeting treatment against monoamine oxidase.

Sildenafil after cardiac arrest and infarction; an experimental rat model.

OBJECTIVES: Resuscitation after cardiac arrest may lead to ischemia-reperfusion injury and infarction. We evaluated whether sildenafil, a phosphodiesterase-5 inhibitor, has an impact on recovery after cardiac arrest in a rat cardiac transplantation model. DESIGN: Sixty-one Fischer344 rats underwent syngeneic heterotopic cardiac transplantation after ischemia and ligation of the left anterior coronary artery of the heart to yield myocardial infarction (IRI + MI). Of these, 22 rats received subcutaneously injected sildenafil (1 mg/kg/day) (IRI +MI + S). Twenty-three additional grafted animals with transplantation only served as controls with ischemia reperfusion injury (IRI). After 2 days, immunohistochemistry for eNOS, and RT-PCR for iNOS and Aquaporin-7 were performed after graft harvesting and histology. RESULTS: Two days after transplantation, remote intramyocardial arteries were more preserved in IRI + MI + S as compared with IRI +MI and IRI (0.74 ± 0.14, 0.56 ± 0.23 and 0.55 ± 0.22, PSU, p < 0.05, respectively). Decreased eNOS staining confirmed the presence of developing infarction in IRI + MI and IRI + MI + S. The expression of iNOS was significantly lower during IRI + MI +S as compared with IRI + MI (0.02 ± 0.01 and 1.02 ± 0.02, FC, p < 0.05). CONCLUSIONS: Administered at the onset of reperfusion and developing infarction, sildenafil has an impact on myocardial recovery after cardiac arrest and ischemia.