Effects of inhaled FK 506 on the suppression of acute rejection after lung transplantation: use of a rat orthotopic lung transplantation model.

BACKGROUND: FK 506 inhalant was recently developed for localized administration. We investigated its effects on acute lung allograft rejection and compared its efficacy with that of intramuscular administration of FK 506. METHODS: Rats (n = 123) with orthotopic left lung transplantation were divided into 9 groups. Six groups inhaled FK 506 (5 puffs, 10 puffs or 20 puffs per day), or were given intramuscular administration of FK 506 (0.05, 0.1 or 1.0 mg/kg/day). The other groups included rats receiving an isograft, rats with an untreated allograft, and a placebo group. All groups (n = 6 each) were monitored for 14 days post-operatively as an end-point and graft survival time was determined. The remaining animals were killed 4 days after transplantation. The histologic grade of rejection was determined for all groups (n = 6 each). With both (n = 3 each) inhalation therapy and intramuscular administration of FK 506, which showed similar degrees of effectiveness, both blood FK 506 concentration and cytokine expression in the graft and spleen were evaluated. RESULTS: FK 506 inhalation therapy extended allograft survival time and reduced histologic rejection on Day 4 in all groups. Graft survival time and histologic rejection scores at a dose of 10 puffs/day were comparable to those with 0.1 mg/kg/day of intramuscular FK 506. Trough concentrations of FK 506 in blood were detectable with 0.1 mg/kg/day of intramuscular FK 506, but not with 10 puffs/day. The messenger RNA expression levels of interferon-gamma in the lung allograft was suppressed significantly at a dose of 10 puffs/day. CONCLUSIONS: FK 506 inhalant enhances acute lung allograft survival with lower blood concentrations than when using comparable intramuscular administration.

Antiproliferative effects of NKH477, a forskolin derivative, on cytokine profile in rat lung allografts.

OBJECTIVE: NKH477 was recently identified as a water-soluble forskolin derivative and was reported to prolong survival of murine cardiac allografts. However, the mechanism of the efficacy is not clear in vivo. The aim of this study was to investigate the immunosuppressive effects of NKH477 on acute lung allograft rejection in the rat model and its mechanism of action in vivo. METHODS: Left lungs were transplanted orthotopically from Brown-Norway donors to Lewis recipients. Recipient rats were untreated or treated daily with different doses of NKH477. Grafts were excised on Day 3 or Day 5 to determine histopathological rejection and expressions of interleukin (IL)-2, IL-4, IL-10, and interferon (IFN)-gamma by enzyme-linked immunosorbent assay. The cytokine expression at Day 3 or Day 5 was also evaluated in recipient spleens by immunohistochemistry. Furthermore, mesenteric lymph node cells from recipients at Day 5 were cultured alone or stimulated with donor antigens for 72 hours to determine cell proliferation by means of thymidine incorporation. RESULTS: NKH477 significantly extended allograft survival time in a dose-dependent manner and reduced histopathological rejection. Treatment with NKH477 inhibited IFN-gamma and IL-10 expression, whereas expression of these cytokines were markedly upregulated in the untreated allografts. Expression of IL-2 and IL-10 also increased in the spleen of untreated allorecipients. NKH477 suppressed expression of both cytokines in the spleen. In addition, lymphocyte proliferation was inhibited in NKH477-treated recipients as compared with untreated recipients. CONCLUSION: These results suggest that NKH477 exerts an antiproliferative effect on lymphocytes in vivo with an altered cytokine profile in rat recipients of lung allografts.

A simple but useful method of screening for mesenteric ischemia secondary to acute aortic dissection.

BACKGROUND: In spite of recent improvements in treatment for acute aortic dissection, mesenteric ischemia secondary to aortic dissection is still challenging. We propose a simple screening method to detect mesenteric ischemia secondary to acute aortic dissection. METHODS: From 1991 to 2002, 245 patients with acute aortic dissection were admitted to our hospital. Nine (3.7%) of those were complicated with mesenteric ischemia. The clinical records of those 9 patients were retrospectively analyzed. The ratios of the diameter of the superior mesenteric vein (SMV) to that of the superior mesenteric artery (SMA) were calculated in patients with mesenteric ischemia (group M) and in patients without mesenteric ischemia (group C). Blood test data, including results of arterial blood gas analysis, in the 2 groups were also compared. RESULTS: The SMV/SMA ratios in groups M and C were 1.16 +/- 0.33 and 1.78 +/- 0.29, respectively (P=.003). A cutoff value of the SMV/SMA ratio was 1.5 (sensitivity, 88.9%; specificity, 88.9%) with an odds ratio of 64.0. Although there were differences between the 2 groups in glutamate oxaloacetate transaminase, lactate dehydrogenase, creatine phosphate kinase, pH, and lactate values, the measurement of lactate was especially useful (P=.002). CONCLUSIONS: The combination of the SMV/SMA ratio and lactate concentration is a useful screening method to detect mesenteric ischemia secondary to acute aortic dissection.

Direct-vision retrosternal dissection using the Kent retractor for sternal re-entry.

Repeat median sternotomy is still associated with high morbidity and mortality from catastrophic hemorrhage or myocardial injury. To overcome these problems, we devised a new technique of sternal re-entry using the Kent retractor set (Takasago Ika Kogyo, Tokyo, Japan), which increases the safety of retrosternal dissection and sternal redivision.

Minimally ischemic off-pump coronary artery bypass grafting: active perfusion-assist with nitroglycerin-supplemented blood.

During off-pump coronary artery bypass surgery, concern remains about possible myocardial injury associated with the transient occlusion and stabilization of the target vessels. To try to minimize myocardial ischemia and achieve hemodynamic stability, we used a coronary perfusion catheter combined with the perfusion-assisted direct coronary artery bypass system, which enables active and modified coronary perfusion of the target vessel throughout the duration of multiple grafting.

Simultaneous aortic and mitral valve replacement: predictors of adverse outcome.

BACKGROUND AND AIM OF THE STUDY: Uncertainties remain regarding the influence of several preoperative and intraoperative factors on outcome after double (simultaneous aortic and mitral) valve replacement (DVR). METHODS: Between 1981 and 1999, 132 patients (58 males, 74 females; mean age 53.8 years) underwent DVR with either aortic and mitral bileaflet mechanical valves in 81 patients, aortic tilting disk valve and mitral bileaflet valve in 36, and aortic tilting disk and mitral biological valve in 15. The mean duration of follow up was 7.6 years; cumulative follow up was 860 patient-years (pt-yr). RESULTS: Early mortality was 9.9% (n = 13). Late death occurred in 21 patients (linearized rate 2.4%/pt-yr; freedom rate at 10 years 77.6 +/- 5.4%) including cardiac-related death in 16 patients (linearized rate 1.9%/pt-yr; freedom rate at 10 years 86.9 +/- 4.5%) and valve-related death in 11 (linearized rate 1.3%/pt-yr; freedom rate at 10 years 87.7 +/- 4.3%). Late morbidity included 30 cases of thromboembolism (linearized rate 3.5%/pt-yr; freedom rate at 10 years 70.2 +/- 6.1%), seven bleeding (linearized rate 0.8%/pt-yr; freedom rate at 10 years 95.6 +/- 2.2%), 22 reoperations (linearized rate 2.6%/pt-yr; freedom rate at 10 years 79.4 +/- 5.1%), three prosthetic valve endocarditis, 13 structural valve deterioration, and two paravalvular leakage. Independent determinants of early and late mortality and morbidity, except for valve reoperation, were preoperative patient-related factors of NYHA class IV, left ventricular ejection fraction < or = 40%, mean right atrial pressure > or = 15 mmHg, and mean pulmonary artery wedge pressure > or = 25 mmHg. However, late valve reoperation and all valve-related complications were influenced by a valve-related factor, namely mitral bioprosthesis. CONCLUSION: Earlier surgical management before the development of severe heart failure, myocardial dysfunction and hemodynamic deterioration would improve the results of DVR. Mitral bioprosthesis combined with a mechanical aortic valve should be avoided as it increases the risk of reoperation.

Ten year clinical experience with the CarboMedics heart valve implants.

We reviewed the histories of 144 patients who underwent heart valve replacement with the CarboMedics prosthesis from 1990 to 2000. There were 74 males and 70 females, with a mean age of 52 years, including 69 aortic valve replacements, 48 mitral valve replacements, and 27 double (aortic and mitral) valve replacements. The mean duration of follow-up was 6.5 years. Early mortality was 7.6% (11 patients). Late deaths occurred in 14 patients, including cardiac-related late deaths in 9 and valve-related deaths in 3. The survival rate including early deaths was 84.7 +/- 3.2% at 5 years and 78 +/- 4.1% at 10 years. Preoperative New York Heart Association Class IV (p = 0.0001) was found to be a significant predictor of cardiac-related late death. Freedom rate from complications at 10 years were embolism 84.7 +/- 4.2% (linearized rate 1.8% per patient year), valve thrombosis 92.7 +/- 2.7% (linearized rate 0.8% per patient year), bleeding 95.6 +/- 2.6% (linearized rate 0.4% per patient year), reoperation 85.9 +/- 4% (linearized rate 1.5% per patient year), valve endocarditis 98.7 +/- 1.3% (linearized rate 0.1% per patient year), and nonstructural dysfunction 90 +/- 3.5% (linearized rate 1% per patient year). There was no structural deterioration. The early and long-term results with the CarboMedics heart valve implantation were acceptable, but valve thrombosis remains a concern in the present study. Further investigation for optimal anticoagulation therapy is necessary to reduce the incidence of valve thrombosis as well as embolic and bleeding complications.