Seiichiro Murata

Coronary malperfusion due to type a aortic dissection: mechanism and surgical management

BACKGROUND Coronary malperfusion associated with aortic dissection is relatively rare, but when it occurs, it is fatal to the patient. To salvage such moribund patients, aggressive coronary revascularization concomitant with aortic repair is essential. We review the surgical results and mechanism of malperfusion in a group of 12 patients with coronary malperfusion caused by type A aortic dissection, and we discuss our surgical approach. METHODS Between March 1990 and March 2003, 12 patients (6.1%) from a total of 196 consecutive patients with acute type A aortic dissection undergoing surgery suffered coronary malperfusion associated with the dissection. There were 4 men and 8 women (mean age, 60.8 +/- 8.3 years). Nine patients had acute myocardial infarction due to dissection before surgery, and 3 patients suffered coronary malperfusion after aortic declamping. RESULTS Hospital mortality rate was 33.3% (4 patients). The mortality rate was higher than that in patients without coronary malperfusion (33.3% vs. 8.2%, p = 0.019). Three patients could not be weaned from cardiopulmonary bypass, and 1 patient died of heart failure in the intensive care unit. Involved coronary arteries included the right coronary artery (8 patients), left coronary (2 patients), and both (2 patients). Mechanisms of coronary obstruction were compression (2 patients), coronary dissection (7 patients), and coronary disruption (3 patients). Coronary artery bypass grafting was performed concomitant with aortic repair. CONCLUSIONS Acute type A aortic dissection with coronary involvement is associated with high mortality rate, aggressive coronary revascularization and early aortic repair with simple techniques are necessary to salvage these critically ill patients.

Superoxide dismutase mimetic m40401 reduces ischemia-reperfusion injury and graft coronary artery disease in rodent cardiac allografts.

Background. The oxidative stress associated with ischemia-reperfusion (I/R) of cardiac allografts leads to production of injurious cytokines and expression of proinflammatory adhesion molecules. This is one of the most important alloantigen-independent factors associated with graft coronary artery disease (GCAD). M40401 is a newly developed cell permeable superoxide dismutase mimetic, which has been shown to scavenge superoxide anion with highly specific and enhanced catalytic activity. We hypothesized that M40401 would exert a protective effect in I/R injury of cardiac allografts and ameliorate the progression of GCAD. Methods. Recipient ACI rats were pretreated with M40401 or vehicle control. PVG donor hearts were heterotopically transplanted into the abdomen of ACI recipients. Cardiac allografts were analyzed for adhesion molecule mRNA expression and tumor necrosis factor-&agr; expression after 4 hr of reperfusion. Neutrophil infiltration was detected by myeloperoxidase activity. Intercellular adhesion molecule-1, vascular cell adhesion molecule-1, and endothelial leukocyte adhesion molecule-1 mRNA were detected by reverse-transcriptase polymerase chain reaction. Immunohistochemical analysis of adhesion molecule expression was also performed. Additional grafts were procured 90 days after transplantation and assessed for the development of GCAD by computer-assisted image analysis. Results. In the M40401-treated group, adhesion molecule expression was significantly less than in the vehicle control group. Treated grafts also had lower myeloperoxidase activity and tumor necrosis factor-&agr; concentration compared with controls. Neointimal proliferation and intima to media ratios in M40401-treated allografts were significantly decreased compared with controls. Conclusions. Selective removal of superoxide anion by M40401 results in inhibition of I/R injury. Furthermore, M40401 treatment decreases the development of oxidative stress-associated GCAD. This treatment strategy may have broad cardioprotective applications for all cardiac operations in addition to cardiac transplantation.

Up-regulation of Bcl-2 through hyperbaric pressure transfection of TGF-β1 ameliorates ischemia-reperfusion injury in rat cardiac allografts

BACKGROUND Oxidative stress after ischemia-reperfusion of cardiac allografts leads to activation of cardiomyocytes and production of cytokines. Bcl-2, an inhibitor of the apoptotic pathway, also has strong antioxidant properties. Ischemia-reperfusion injury after transplantation leads to decreased bcl-2 and increased tumor necrosis factor (TNF)-alpha levels. Transforming growth factor (TGF)-beta1 is known to attenuate ischemia-reperfusion injury and inhibits apoptosis of myofibroblasts. We hypothesize that TGF-beta1, prevents bcl-2 cleavage and increased TNF-alpha production. METHODS Rat PVG donor hearts were heterotopically transplanted into ACI recipients. Donor hearts were procured and assigned to groups: (1) intracoronary TGF-beta1 (200 ng/ml) perfusion and pressure at 78 psi for 45 minutes (n = 4); (2) intracoronary TGF-beta1 perfusion and incubation for 45 minutes without pressure (n = 4), (3) saline perfusion and incubation for 45 minutes without pressure (n = 4). Hearts were procured 4 hours after transplantation and analyzed by reverse transcriptase-polymerase chain reaction for bcl-2 mRNA expression, ELISA for TNF-alpha, and for myeloperoxidase activity (MPO). RESULTS Bcl-2 decreased in untreated animals (bcl-2:G3PDH ratio = 0.85 +/- 0.73 vs 1.16 +/- 0.11, not significant [NS]), whereas TNF-alpha increased to 669.99 +/- 127.09 vs 276.84 +/- 73.65 pg/mg total protein in controls (p < 0.003). In TGF-beta(1) pressure-treated hearts, bcl-2 was up-regulated (2.49 +/- 0.6 vs 1.16 +/- 0.11, controls, p < 0.005), whereas TNF-alpha was unchanged (396.1 +/- 100.38 vs 276.84 +/- 73.65 pg/mg, NS). Hearts treated with TGF-beta1 and pressure showed significant up-regulation of bcl-2 compared with hearts treated with TGF-beta1 without pressure (2.49 +/- 0.6 vs 1.17 +/- 0.6, p < 0.02). MPO showed no differences. CONCLUSIONS Bcl-2 is down-regulated and TNF-alpha up-regulated in this model of ischemia-reperfusion injury. Furthermore, TGF-beta1 is linked to this process and ameliorates reperfusion injury by up-regulating bcl-2 and inhibiting TNF-alpha. Therapeutic overexpression of myocardial TGF-beta1 may be clinically useful to control ischemia-reperfusion injury associated with cardiac transplantation.

Effects of adenoviral up-regulation of bcl-2 on oxidative stress and graft coronary artery disease in rat heart transplants.

Background. Bcl-2 has been shown to have antioxidant properties. Early oxidative stress is an important antigen-independent factor that contributes to the development of graft coronary artery disease (GCAD). We hypothesized that adenoviral up-regulation of bcl-2 would decrease early oxidative stress and inhibit GCAD after heart transplantation. Methods. PVG rat hearts were treated with adenovirus carrying the human bcl-2 gene (AdvBcl-2) or null adenovirus (AdvNull) then transplanted into the abdomens of PVG recipients. After 4 days of reperfusion to allow adenoviral gene expression, grafts were retransplanted into ACI rat recipients and reperfused for 4 or 8 hours or 90 days (cyclosporine A 7.5 mg/kg on postoperative day [POD] 0–9). Production of tumor necrosis factor (TNF)-&agr; after 4 hours and oxidized glutathione (GSSG) after 8 hours indicated development of oxidative stress. 90-day allografts were assessed for GCAD by way of computerized morphometry. Results. Over-expression of bcl-2 at the time of allograft reperfusion was confirmed by Western blotting. Whereas AdvNull-treated hearts demonstrated elevated TNF-&agr; levels after 4 hours and increased GSSG after 8 hours of reperfusion, AdvBcl-2-treated hearts were no different from nontransplanted hearts. AdvBcl-2 treatment also resulted in decreased luminal narrowing and intima-to-media ratio at POD 90. Conclusions. Bcl-2 over-expression interrupts the development of oxidative stress in reperfused rat-heart allografts. Early up-regulation of bcl-2 also decreases GCAD, indicating the importance of early oxidative stress and the role that bcl-2 may play in the long-term function of heart transplants.

Elevated cyclic adenosine monophosphate ameliorates ischemia–reperfusion injury in rat cardiac allografts

BACKGROUND Oxidative stress after ischemia and reperfusion leads to leukocyte activation, the production of injurious cytokines, and increased expression of inflammatory adhesion molecules. This initial event is one of the most important alloantigen-independent factors associated with graft coronary artery disease (GCAD). Cyclic adenosine monophosphate (cAMP) is an important second messenger that inhibits the expression of tumor necrosis factor alpha (TNF-alpha), vascular cell adhesion molecule 1 (VCAM-1), and endothelial leukocyte adhesion molecule 1 (ELAM-1) in vitro. Its levels decrease during organ preservation. We hypothesized that augmenting allograft cAMP levels with the water-soluble adenylate cyclase activator, NKH477, could decrease ischemia-reperfusion injury and inhibit the progression of GCAD. METHODS PVG to ACI rat heterotopic cardiac allografts, treated with NKH477 solution or vehicle, were reperfused for 4 hours or 90 days after 60 minutes of ischemia. We analyzed grafts for intracellular adhesion molecule 1 (ICAM-1), VCAM-1, and ELAM-1 mRNA expression; TNF-alpha and interleukin-6 (IL-6) protein expression; and myeloperoxidase activity. We also performed immunohistochemical analysis for ICAM-1 and VCAM-1 protein expression. At post-operative Day 90, the progression of GCAD had increased morphometrically. RESULTS NKH477-treated grafts had significantly decreased levels of myeloperoxidase activity compared with controls. In this group, TNF-alpha, IL-6, and VCAM-1 protein expression was inhibited; however, ICAM-1 and ELAM-1 expression did not alter. We found no differences in the degree of development of GCAD between groups. CONCLUSION Although augmented intracellular cAMP prevented acute reperfusion injury, it was insufficient to prevent the development of GCAD. Intracellular adhesion molecule 1 and ELAM-1, whose expression NKH477 does not inhibit, may play important roles in the development of GCAD.

Impact of concomitant cardiac procedure on coronary artery surgery in hemodialysis-dependent patients

OBJECTIVE Coronary artery bypass grafting (CABG) in hemodialysis-dependent patients is associated with high mortality and morbidity rates. This retrospective study was undertaken to identify the risk factors for in-hospital mortality for hemodialysis-dependent patients. METHODS Subjects included 87 consecutive hemodialysis-dependent patients (81 men and 6 women), aged 47-82 years (mean age, 65 years), who underwent CABG. Operative procedures included CABG alone (n=77) and CABG with valve replacement, repair, or the Dor procedure (n=10). Thirty-one perioperative risk factors were subjected to univariate and multivariate analyses to identify the risk factors for hospital death. RESULTS The overall in-hospital mortality rate, including operative death, was 14.9% (13/87). Univariate analysis showed the following 7 risk factors to be statistically significant predictors of hospital death: age > or = 70 years, a concomitant cardiac procedure, left ventricular ejection fraction <30%, left ventricular end-systolic volume index >70 ml/m2, a left main lesion, emergency/urgent surgery, and anemia (hemoglobin <10 mg/dl) (p<0.05 for each predictor). Multivariate logistic regression analysis confirmed that a concomitant cardiac procedure (chi-squared = 17.080, p=0.013) and age > or = 70 years (chi-squared = 9.112, p=0.019) are statistically significant independent risk factors for hospital death. CONCLUSION A concomitant cardiac procedure and age > or = 70 years were identified as significant independent risk factors for hospital mortality after CABG for hemodialysis-dependent patients. These preoperative risk factors may help in predicting operative risks and improving clinical outcomes in hemodialysis-dependent patients undergoing CABG.

L-arginine polymers enhance coronary flow and reduce oxidative stress following cardiac transplantation in rats

Abstract Background Hearts treated with l-arginine polymers have demonstrated upregulated production of nitric oxide. The current study examined whether these polymers improved coronary flow and reduced myocardial oxidative stress after rat heart transplantation. Methods PVG donor hearts were incubated ex vivo with either 100 μmol/L l-arginine polymers 9 amino acids in length (R9) (n = 7) or phosphate-buffered saline (n = 7) for 30 minutes after arrest and then transplanted heterotopically into the abdomen of ACI recipient rats. Coronary flows were assessed using fluorescent microspheres both at baseline (30 minutes after reperfusion) and at 6 hours and compared using the paired Student t test. Evidence of oxidative stress was assessed in a separate cohort of similarly treated animals by enzyme-linked imunosorbent assay for rat tumor necrosis factor-α at 6 hours. Results Histochemistry with biotinylated l-arginine polymers demonstrated uptake of R9 into the vascular walls of treated allografts. Although all hearts experienced deterioration in coronary flow between baseline and 6 hours, the R9-treated group had a smaller reduction (29.9%, P = .10) than the phosphate-buffered saline control group (58.0%, P = .003). Tumor necrosis factor-α levels were also significantly reduced in the R9 treatment group compared with the phosphate-buffered saline category (160 ± 30 versus 205 ± 38, P = .007). Conclusion Rat cardiac allografts treated with R9 at the time of procurement exhibited less deterioration in coronary flow and a reduction in myocardial oxidative stress than the phosphate-buffered saline control group in the perioperative period. The use of arginine polymers may thus provide important myocardial protection against ischemia-reperfusion injury in both transplant and routine cardiac surgery cases.

Aortic connector for coronary revascularization in a patient with Takayasu's disease

Takayasus disease affects the aorta and its major branches including coronary arteries, some of which may require coronary artery bypass grafting (CABG). However, calcification of the aorta affected by Takayasus disease often makes proximal anastomosis of a vein graft very difficult. In addition, since the major branches of the aortic arch are also frequently affected by it, the internal mammary arteries are unsuitable for use in CABG. We report a 60-year-old woman with stenosis of the left main coronary artery and heavy aortic calcification caused by Takayasus disease whose severe angina was successfully relieved by off-pump CABG using mechanical aortic connectors for proximal vein graft anastomoses.

Bcl-2-mediated inhibition of apoptosis in rat cardiac allografts worsens development of graft coronary artery disease

BACKGROUND We hypothesized that adenovirally mediated Bcl-2 transfection of donor hearts would reduce the apoptosis that occurs during acute rejection while worsening the development of chronic graft coronary artery disease (GCAD). METHODS PVG donor hearts were treated with either AdvBcl-2 or AdvNull virus before heterotopic transplantation into ACI rats. Bcl-2 expression was assessed on post-operative day 4 (POD) 4 by western blot. Apoptosis was measured using (99m)Technetium-bound-annexin V imaging and caspase 3 activity assay. Allograft survival was determined in a separate cohort of animals. Long-term-treated animals were then assessed for measures of GCAD on POD 90. RESULTS Western blot analysis showed upregulation of Bcl-2 expression in AdvBcl-2-treated hearts. (99m)Tc-annexin V images demonstrated decreased uptake in the AdvBcl-2 group (1.41 +/- 0.33% vs 1.94 +/- 0.37%, p = 0.026). Caspase 3 activity was also significantly lower in this treatment group (0.112 +/- 0.032 vs 0.204 +/- 0.096, p = 0.049). Allograft survival was similar in both groups, respectively (7.7 +/- 1.2 vs 6.8 +/- 1.5 days, p = 0.340). GCAD, as determined by percent luminal narrowing (5.9 +/- 6.1% vs 1.6 +/- 1.5%, p = 0.039), intima-to-media ratio (5.1 +/- 5.1% vs 1.5 +/- 1.7%, p = 0.040) and percent of affected vessels (15.1 +/- 9.9% vs 5.3 +/- 4.4%, p = 0.009), was higher for the AdvBcl-2 group. CONCLUSION Treatment of cardiac allografts with AdvBcl-2 resulted in a reduction of apoptosis that did not significantly improve short-term graft survival, but worsened chronic GCAD.

Arginine polymers enhance coronary flow and reduce oxidative stress following cardiac transplantation in rats

BACKGROUND Hearts treated with l-arginine polymers have demonstrated upregulated production of nitric oxide. The current study examined whether these polymers improved coronary flow and reduced myocardial oxidative stress after rat heart transplantation. METHODS PVG donor hearts were incubated ex vivo with either 100 mumol/L l-arginine polymers 9 amino acids in length (R9) (n = 7) or phosphate-buffered saline (n = 7) for 30 minutes after arrest and then transplanted heterotopically into the abdomen of ACI recipient rats. Coronary flows were assessed using fluorescent microspheres both at baseline (30 minutes after reperfusion) and at 6 hours and compared using the paired Student t test. Evidence of oxidative stress was assessed in a separate cohort of similarly treated animals by enzyme-linked imunosorbent assay for rat tumor necrosis factor-alpha at 6 hours. RESULTS Histochemistry with biotinylated l-arginine polymers demonstrated uptake of R9 into the vascular walls of treated allografts. Although all hearts experienced deterioration in coronary flow between baseline and 6 hours, the R9-treated group had a smaller reduction (29.9%, P =.10) than the phosphate-buffered saline control group (58.0%, P =.003). Tumor necrosis factor-alpha levels were also significantly reduced in the R9 treatment group compared with the phosphate-buffered saline category (160 +/- 30 versus 205 +/- 38, P =.007). CONCLUSION Rat cardiac allografts treated with R9 at the time of procurement exhibited less deterioration in coronary flow and a reduction in myocardial oxidative stress than the phosphate-buffered saline control group in the perioperative period. The use of arginine polymers may thus provide important myocardial protection against ischemia-reperfusion injury in both transplant and routine cardiac surgery cases.