Koji Kagisaki

Interleukin-6 derived from hypoxic myocytes promotes neutrophil-mediated reperfusion injury in myocardium☆

BACKGROUND Reperfusion injury in the myocardium has recently been considered to be a type of inflammation, and close attention has been paid to the possible involvement of neutrophils, complement, and cytokines in the onset of this injury. Recently, it has been reported that serum levels of interleukin-6 are elevated significantly after myocardial infarction. The major site of interleukin-6 production and its exact roles are still unknown. In this study, we hypothesized that myocytes may produce interleukin-6 during hypoxia and this may play a role in neutrophil-mediated reperfusion injury. METHODS AND RESULTS In the clinical study, 20 patients who underwent coronary artery bypass grafting were divided into 2 groups: group F, in which patients were treated with a serine protease inhibitor (FUT-175, 2 mg/kg per hour) during cardiopulmonary bypass, and group C (untreated patients). In group C, myocardial interleukin-6 production, as determined by the difference between the interleukin-6 level in the cardiopulmonary bypass circuit and its level in coronary venous blood, increased significantly after reperfusion (12+/-4 pg/mL) as compared with that before aortic crossclamping (2+/-2 pg/mL). In group F, the increase in the interleukin-6 level was suppressed significantly (before aortic crossclamping, 3+/-2 pg/mL; after reperfusion, 4+/-3 pg/mL). The interleukin-6 production differed significantly between group C and group F. In the in vitro experimental study, the supernatant from myocytes exposed to 2 hours of hypoxia (group 2H) showed significantly higher levels of interleukin-6 (455+/-260 pg/mL) than that from normoxic myocytes (group N) (47+/-15 pg/mL). This interleukin-6 production was suppressed by the addition of FUT-175 (123+/-24 pg/mL). The interleukin-6 production by endothelial cells of coronary vessels did not differ between group 2H (283+/-151 pg/mL) and group N (151+/-86 pg/mL). In a coincubation system with a monolayer of endothelial cells on collagen membrane and myocytes under collagen membrane in a modified Boyden chamber, 2 hours of coincubation showed a significantly higher percent of neutrophil transendothelial migration (group 2H vs N, 78%+/-13% vs 26%+/-11%), value of chemiluminescence (22+/-8 vs 5+/-2 x 10(3) counts/3 minutes), and percent of irreversibly damaged myocytes (48%+/-17% vs 12%+/-8%) than normoxic coincubation. In contrast, anti-interleukin-6 monoclonal antibody significantly attenuated neutrophil transendothelial migration (42%+/-19%) and irreversible damage of myocytes (26%+/-15%) in 2 hours of coincubation. CONCLUSIONS Interleukin-6 is produced from myocardium during ischemia and reperfusion in patients undergoing coronary bypass grafting. This interleukin-6 may be derived from hypoxic myocytes and play a role in neutrophil-mediated reperfusion injury in myocardium.

Reduction in myocardial apoptosis associated with overexpression of heat shock protein 70.

Abstract It is reported that ischemia-reperfusion induces apoptotic cell death in myocardium. It is also demonstrated that heat shock protein 70 (HSP70) enhances myocardial tolerance. Therefore, it is hypothesized that HSP70 may play a role in the attenuation of myocardial apoptosis. To elucidate this goal, HSP70-overexpressing and control-transfected rat hearts were prepared using gene transfection by intra-coronary infusion of the hemagglutinating virus of Japan-liposome. In vivo experiment Hearts fo both groups were subjected to global ischemia, followed by reperfusion in situ. Shorter recovery time to spontaneous beating (HSP70-transfected vs control-transfected; 46.7±4.6 vs 67.5±7.0 s, p = 0.033) and lower serum CPK levels (415±27 vs 533±36 IU, p = 0.027) were observed in the HSP70-transfected group. The HSP70-transfected group also showed a lower percentage of cardiac myocytes positively stained by nick end labeling after ischemia-reperfusion (17.5±4.9 vs 40.0±5.1%, p = 0.010). In vitro experiment Cardiac myocytes isolated from the hearts of both groups (prepared separately from the in vivo eperiment) were subjected to hypoxia-reoxygenation. Flow cytometry was used to identify the cells that showed sub-G1 DNA content as apoptotic cells. Apoptotic cels as a percentage of viable cells increased more in the control-transfected group after hypoxia-reoxygenation (13.0±0.77 vs 21.9±1.18%, p < 0.0001).In conclusion, we demonstrated that apoptosis after ischemia-reperfusion was decreased in the HSP70-overexpressing heart in vivo and in vitro, leading to the suggestions that HSP70 could be associated with the reduction in myocardial apoptosis.

Impact of the Evolution of the Fontan Operation on Early and Late Mortality: A Single-Center Experience of 405 Patients Over 3 Decades

BACKGROUND Postoperative mortality has decreased in patients undergoing the Fontan operation, and the determinants of such mortality may also have changed significantly. METHODS We conducted a study intended to focus on clarifying the determinants of mortality in 405 consecutive patients who had undergone a Fontan operation (62 patients after an atriopulmonary connection, 105 after an intra-atrial rerouting, and 238 patients after an extracardiac rerouting) between 1979 and 2010. RESULTS The overall 1-year, 5-year, 10-year, and 15-year rates of survival were 87.1%, 84.6%, 83.4%, and 81.6%, respectively, and the type of procedure as well as heterotaxy syndrome, ventricular ejection fraction, and atrioventricular valve repair at the time of the Fontan operation were independent predictors of overall mortality (p < 0.05 for all). Heterotaxy syndrome and atrioventricular (AV) valve repair were independent predictors of early (less than 6 months postoperative) mortality and the type of procedure was an independent predictor of late (6 or more months postoperative) mortality (p < 0.05 to 0.01). In the era of intra-atrial rerouting, heterotaxy syndrome was the only independent predictor of total, early, and late mortality (p < 0.05 for all), whereas a low ejection fraction, AV valve repair, and repair of a total anomalous pulmonary vein connection, rather than heterotaxy syndrome, were independent predictors of total or early mortality or both (p < 0.05 for all) in the era of extracardiac rerouting. CONCLUSIONS Even in the modern era of extracardiac rerouting in the Fontan operation, a low ventricular ejection fraction, AV valve dysfunction, or a total anomalous pulmonary vein connection remain significant risk factors for mortality in patients with a single-ventricle physiology.

Long-term functional results of the one and one half ventricular repair for the spectrum of patients with pulmonary atresia/stenosis with intact ventricular septum.

OBJECTIVE To determine whether one and one half ventricular repair (1.5 VR) is definitely superior to the Fontan procedure in patients having hypoplastic right ventricle (RV) in the setting of pulmonary atresia with intact ventricular septum (PA/IVS) or its relatives, in terms of results in the longer term. METHOD Since 1987, 1.5 VR has been chosen in seven patients with PA/IVS and in six having PS with hypoplastic RV. On preoperative catheterization, right ventricular end-diastolic volume (RVEDV) was 47+/-23% of the anticipated normal value, and annular diameter of the tricuspid valve (TVD) 72+/-22% of normal (Z value being -2.4+/-2.1). Follow-up term was 3-15 (10+/-4) years. RESULTS All patients survived 1.5 VR, but one patient died of arrhythmia 9 years later. Freedom from arrhythmia was 80 and 20% at 10 and 12 years, respectively. Two patients have undergone conversion to the Fontan circulation, but none to true biventricular physiology. Consecutive catheterization (1, 5, and 10 years after 1.5 VR) demonstrated no changes in %RVEDV or %TVD. Cardiac index was 2.4+/-0.6 l/min per m(2) at either 5 or 10 years. RA pressure was 9+/-3 and 12+/-2 mmHg at 5 and 10 years, respectively. Smaller %RVEDV and %TVD were associated with episodes of atrial arrhythmia and higher RA pressure. Exercise testing showed anaerobic threshold of 16.6+/-3.4 ml/kg per min and 13.1+/-2.7 ml/kg per min at 5 and 10 years, respectively. These values were equivalent to those in patients with classical tricuspid atresia or PA/IVS undergoing the Fontan procedure, and unequivocally inferior to those in patients having PA/IVS. who could have undergone biventricular repair. CONCLUSION Although we previously expected reasonable functional results after 1.5 VR between the Fontan circulation and biventricular physiology, this was not always the case in patients having pulmonary atresia or stenosis with intact ventricular septum.

Early Detection of Cardiac Damage With Heart Fatty Acid-Binding Protein After Cardiac Operations

BACKGROUND It is still difficult to evaluate myocardial damage in the acute phase of reperfusion in cardiac operations. We investigated the clinical significance of human heart fatty acid-binding protein (HH-FABP) for detecting myocardial damage after cardiac operations earlier than creatine kinase MB isoform or troponin-T. METHODS Blood samples from 20 patients who underwent coronary artery bypass grafting were collected serially after reperfusion to measure serum levels of creatine kinase-MB, troponin-T, and HH-FABP. RESULTS Serum HH-FABP levels peaked earliest after reperfusion. In addition, the maximum serum HH-FABP level was predictable immediately after reperfusion. The maximum serum HH-FABP level correlated with the maximum serum creatine kinase-MB or troponin-T level, as well as with the aortic cross-clamp time or the maximum dose of catecholamines administered after reperfusion. CONCLUSIONS Measurements of HH-FABP allow for earlier evaluation of myocardial damage in the acute phase of reperfusion. Human heart fatty acid-binding protein may be a useful indicator of myocardial damage after cardiac operations.

Clinical evaluation of leukocyte-depleted blood cardioplegia for pediatric open heart operation

BACKGROUND Blood cardioplegia (BCP) is widely used for myocardial protection during open heart operation. However, BCP may have a chance to induce neutrophil-mediated myocardial injury during aortic cross-clamping. We clinically evaluated the myocardial protective effect of leukocyte-depleted blood cardioplegia (LDBCP) for initial and intermittent BCP administration in pediatric patients. METHODS Fifty patients undergoing open heart operation for congenital heart disease between January 1997 and March 1999 were reviewed. Twenty-five were administered LDBCP for myocardial protection during ischemic periods (LDBCP group), and the remaining 25 were given BCP without leukocyte depletion (BCP group). RESULTS The difference in plasma concentrations of malondialdehyde between coronary sinus effluent blood and arterial blood just after reperfusion in the LDBCP group (1.68 +/- 0.56 micromol/L) was significantly lower than that in the BCP group (2.35 +/- 0.62 micromol/L; p < 0.01). The LDBCP group showed significantly lower plasma concentrations of human heart fatty acid-binding protein at 50 minutes after reperfusion (LDBCP group, 103.5 +/- 38.7 IU/L; BCP group, 144.8 +/- 48.8 IU/L; p < 0.01) and the peak value of creatine kinase-MB during the first 24 postoperative hours (LDBCP group, 17.0 +/- 8.5 IU/L; BCP group, 26.0 +/- 11.6 IU/L; p < 0.01) than did the BCP group. The maximum dose of catecholamine was significantly smaller in the LDBCP group (LDBCP group, 3.20 +/- 2.18 microg x kg(-1) x min(-1); BCP group, 5.60 +/- 2.83 microg x kg(-1) x min(-1); p < 0.01). CONCLUSIONS These results suggest the usefulness of LDBCP for protection from the myocardial injury that can be induced by BCP administration during aortic cross-clamping.

Ventricular Performance in Long-Term Survivors After Fontan Operation

BACKGROUND Ventricular function and arrhythmia in patients with Fontan circulation in long-term follow-up are still unknown. METHODS We retrospectively reviewed 48 patients who survived and were followed up for more than 15 years, among 110 patients who underwent Fontan operation in our institute from 1979 to 1992. Atriopulmonary connection was performed in 26 patients and total cavopulmonary connection in 22. The patients were categorized into right ventricle, left ventricle, and biventricle groups. Follow-up cardiac catheterization and exercise test were performed routinely every 5 years post surgery. Median age at Fontan operation was 5 years. RESULTS Mean follow-up was 18.5 years. Cardiac index in the total cavopulmonary connection group was higher than in the atriopulmonary connection group at 10 and 15 years post surgery (p<0.05). Ejection fraction in the left-ventricle group was higher than in the right-ventricle group. End-diastolic volume at 5, 10, and 15 years was significantly lower than at 1 year (p<0.05). End-diastolic pressure at 10 years was significantly higher than at 1 and 5 years (p<0.05). Beyond 15 years, 6 patients developed ventricular tachycardia. The only significant risk factors for the onset of ventricular tachycardia in a multivariate analysis were age at Fontan operation and absolute age (p<0.05). CONCLUSIONS Long-term follow-up of patients demonstrated that postoperative ventricular systolic performance seemed to become steady. Ventricular tachycardia was detected 15 years post surgery, especially in older patients with older age at Fontan operation, possibly revealing a risk factor in the long-term postoperative period, thereby meriting further consideration.

Late true aneurysm after bypass grafting for long aortic coarctation

Two adolescent patients who underwent a repair of long aortic coarctation using bypass grafting with subsequent late true aneurysm formation are reported. To our knowledge, only 1 case of late true aneurysm formation after bypass grafting has been reported in the English-language literature.

Prognostic value of exercise variables in 335 patients after the Fontan operation: a 23-year single-center experience of cardiopulmonary exercise testing.

BACKGROUND The prognostic value of cardiopulmonary exercise testing (CPX) for mortality risk remains controversial in Fontan patients. PURPOSE Our goal of the present study was to clarify the prognostic value of major CPX variables and the factors determining exercise capacity in a large cohort of Fontan patients. METHODS Since 1990, heart rate (HR), oxygen uptake (VO2 ), and ventilatory equivalent for carbon dioxide production (VE/VCO2 ) at peak exercise were determined in 335 Fontan patients (18 ± 5 years old), and the CPX variables were compared with the clinical profile and events. RESULTS When compared with 209 controls, peak HR (148 ± 24 bpm), VO2 (27 ± 7 mL/kg/minute, [61 ± 15%]), and VE/VCO2 (40 ± 8 [117 ± 24%]) were markedly impaired in the Fontan patients (P < .0001). During a follow-up of 3.1 ± 2.7 years, 62 Fontan pathophysiological-associated events requiring unscheduled hospitalization (USH) occurred, and 24 patients died. All the CPX variables predicted the USH and mortality (P < .001-.0001). On multivariate analysis, in addition to use of diuretics (P = .0007) and low cardiac index (P = .0426), peak VO2 independently predicted the USH (hazard ratio: 0.95 per %, 95% confidence interval: 0.91-0.99, P = .014), while for mortality, multivariate analysis revealed that, in addition to heterotaxy syndrome (P = .0128) and year at first Fontan operation (P = .0532), peak VO2 independently predicted mortality (hazard ratio: 0.88 per %, 95% confidence interval: 0.76-0.98, P = .0217). CONCLUSION Fontan patients exhibit markedly impaired CPX variables, and all the major variables, especially peak VO2 , predicted the risk of both morbidity and mortality.

Does the off-pump Fontan procedure ameliorate the volume and duration of pleural and peritoneal effusions?

OBJECTIVE We initiated an off-pump Fontan procedure by using temporary bypass from the inferior vena cava to the atrium and advanced the procedure in selected patients by simply cross-clamping the inferior vena cava. We aimed to investigate whether the off-pump Fontan procedure could ameliorate the volume and duration of pleural and peritoneal effusion. METHODS We retrospectively reviewed 74 patients (aged <4 years) who underwent Fontan completion between January 2001 and December 2006. The patients were classified into the following two groups: a cardiopulmonary bypass group in which cardiopulmonary bypass was required (n=27) and an off-pump group in which the procedure was completed without the use of cardiopulmonary bypass (n=47). A propensity score was used to control the treatment selection bias for the use of cardiopulmonary bypass. Fourteen patients from each group were successfully matched. Both bilateral pleural and peritoneal drainage tubes were placed in all the patients. The total volume of the effusion was measured at 6, 12, 24, 48, and 72h postoperatively and was corrected for body weight (kg) and intervals (h). RESULTS Significantly reduced effusion (ml/kg/h) was noted in the off-pump group compared to the cardiopulmonary bypass group at 12h (cardiopulmonary bypass group, 8.6 [4.8-11.5]; off-pump group, 2.5 [1.2-5.4]; p=0.006) and at 48h (cardiopulmonary bypass group, 6.1 [2.6-9.9]; off-pump group, 1.4 [0.9-3.1]; p=0.008). CONCLUSIONS The off-pump Fontan procedure may reduce the volume of postoperative pleural and peritoneal effusion.