Hideto Shimpo

Inhibition of Toll-like Receptor 4 With Eritoran Attenuates Myocardial Ischemia-Reperfusion Injury

Background— We previously reported that the functional mutation of Toll-like receptor 4 (TLR4) in C3H/HeJ mice subjected to myocardial ischemia-reperfusion (MI/R) injury resulted in an attenuation of myocardial infarction size. To investigate the ligand-activating TLR4 during MI/R injury, we evaluated the effect of eritoran, a specific TLR4 antagonist, on MI/R injury, with the goal of defining better therapeutic options for MI/R injury. Methods and Results— C57BL/6 mice received eritoran (5 mg/kg) intravenously 10 minutes before 30 minutes of in situ of transient occlusion of the left anterior descending artery, followed by 120 minutes of reperfusion. Infarct size was measured using triphenyltetrazoliumchloride staining. A c-Jun NH2-terminal kinase (JNK) activation was determined by Western blotting, nuclear factor (NF)-&kgr;B activity was detected by gel-shift assay, and cytokine expression was measured by ribonuclease protection assay. Mice treated with eritoran developed significantly smaller infarcts when compared with mice treated with vehicle alone (21.0±6.4% versus 30.9±13.9%; P=0.041). Eritoran pretreatment resulted in a reduction in JNK phosphorylation (eritoran versus vehicle: 3.98±0.81 versus 7.01±2.21-fold increase; P=0.020), less nuclear NF-&kgr;B translocation (2.70±0.35 versus 7.75±0.60-fold increase; P=0.00007), and a decrease in cytokine expression (P<0.05). Conclusions— We conclude that inhibition of TLR4 with eritoran in an in situ murine model significantly reduces MI/R injury and markers of an inflammatory response.

Elevated Levels of High-Sensitivity C-Reactive Protein and Serum Amyloid-A Late After Kawasaki Disease: Association Between Inflammation and Late Coronary Sequelae in Kawasaki Disease

Background—Coronary sequelae that persist after Kawasaki disease (KD) have been associated with obstructive changes of the lesions and coronary vascular events in adolescents and young adults. However, little is known about the association between sequelae late after KD and inflammatory markers, which are potential mediators and markers for atherogenesis. Methods and Results—Cross-sectional study was performed to test the hypothesis that coronary sequelae are associated with elevated levels of inflammatory markers in patients late after KD (mean time interval after the onset, 10 years, 10 months). Levels of high-sensitivity C-reactive protein (CRP), serum amyloid-A (SAA), interleukin-6, and soluble intercellular adhesion molecule-1 were measured in the 4 groups (n=80): the referent group (n=15) and KD subgroups with normal coronary arteries from the onset (n=27); with regressed aneurysms (n=18); and with coronary artery lesions, such as persistent aneurysms, stenosis, and occlusion (n=20). CRP levels were significantly elevated in a KD subgroup with coronary artery lesions compared with the referent or other KD subgroups, as analyzed by ANOVA and ANCOVA after adjustment for a confounding factor body mass index. Levels of CRP, SAA, and interleukin-6 were positively correlated. Stepwise regression and logistic regression analyses support the association between the persistence of coronary artery lesions and the levels of CRP and SAA. Conclusions—Results demonstrate that the persistence of coronary lesions late after KD was independently associated with levels of CRP and SAA, suggesting that inflammation may be a novel functional aspect of coronary artery diseases late after KD.

Prospective evaluation of three different diagnostic criteria for disseminated intravascular coagulation

There are three different diagnostic score systems for disseminated intravascular coagulation (DIC) established by the Japanese Ministry Health and Welfare (JMHW), the International Society on Thrombosis and Haemostasis (ISTH) and the Japanese Association for Acute Medicine (JAAM). The JMHW criteria are still used in Japan. In the present study, all three diagnostic criteria were used to prospectively evaluate 413 patients with different underlying diseases of DIC who were treated at the Mie University Hospital (JMHW, n= 166; ISTH, n=143; JAAM, n=291). The odds ratio (95% confidence interval) for death was 1.88 (1.22 - 2.90) in JMHW, 2.55 (1.65 - 3.95) in ISHT and 1.99 (1.19 - 3.32) in JAAM. The platelet count, prothrombin time, fibrin and fibrinogen degradation products and fibrinogen were significantly important for diagnosis of DIC by all three diagnostic criteria. Haemostatic molecular markers were significantly high in all patients and were useful for the diagnosis of DIC. The JAAM diagnostic criteria displayed a high sensitivity for DIC and the ISTH overt-DIC diagnostic criteria displayed a high specificity for DIC. All three diagnostic criteria for DIC were related to a poor patient outcome.

Long-Term Follow-up After Carpentier-Edwards Ring Annuloplasty for Tricuspid Regurgitation

BACKGROUND Use of flexible rings for tricuspid ring annuloplasty is becoming popular. This study was undertaken to evaluate Carpentier-Edwards (C-E) rigid ring annuloplasty for tricuspid regurgitation (TR), secondary to mitral valve disease and clinical outcome on a long-term basis. METHODS From December 1985 to March 1996, 45 patients with secondary TR underwent C-E ring annuloplasty. Thirty-nine patients (95.1%) were in New York Heart Association (NYHA) functional class III or IV. The mean follow-up was 96.7+/-48.5 months or 362.6 patient-years. RESULTS There were three in-hospital and nine late deaths that were not related to tricuspid annuloplasty. Actuarial survival at 10 years was 68.3%. Echocardiographic studies showed that TR was well controlled within grade 2+ in all survivors. Residual pulmonary hypertension (PH) was recognized in 9 of 21 patients (42.9%) with preoperative PH, however, no TR was seen in 6 patients. A TR grade of 2+ was observed in 3 patients. Thirty of the total survivors (96.8%) were in NYHA class I and II, but 1 patient was in NYHA class III. The actuarial rate of freedom from tricuspid valve reoperation after 10 years was 97.5%. CONCLUSIONS C-E ring annuloplasty is acceptable for repair of secondary TR and improvement in clinical status on a long-term basis.

In Vivo Plaque Composition and Morphology in Coronary Artery Lesions in Adolescents and Young Adults Long After Kawasaki Disease. A Virtual Histology–Intravascular Ultrasound Study

Background— Coronary artery lesions (CALs) late after Kawasaki disease were characterized by endothelial dysfunction and low-grade inflammation, surrogate markers for atherosclerosis. We tested the hypothesis that CALs in patients long after Kawasaki disease are accompanied by atheroma-like features, as assessed by virtual histology–intravascular ultrasound, a new method to assess coronary plaque composition and morphology in vivo. Methods and Results— Virtual histology–intravascular ultrasound was performed in 13 Japanese Kawasaki disease patients (median age, 18.3 years; interquartile range, 16.9 to 23.3 years) an interval after Kawasaki disease (median, 15.9 years; interquartile range, 14.3 to 21.9 years). We investigated 6 sites with localized stenosis, 15 sites with an aneurysm, 29 sites with a regressed aneurysm, and 50 sites with a normal coronary segment. Plaque components were categorized into 4 parts: fibrous, fibrofatty, necrotic core, and dense calcium areas. Qualitatively, the normal segment had no or trivial intravascular ultrasound–visible plaque area, whereas the CAL exhibited a heterogeneous plaque area with the 4 components in different amounts and proportions. Quantitatively, a combined group of CALs had a higher absolute value of fibrous, dense calcium, and necrotic core areas than the normal segment. In further analyses of 3 subtypes of CALs, localized stenosis, an advanced lesion, exhibited higher absolute and relative values of dense calcium and necrotic core areas and a lower relative value of the fibrous area than regressed and persistent aneurysms. Conclusion— The present limited but initial virtual histology–intravascular ultrasound findings give new insight into the potential role of atherogenesis in the evolution of CALs in adolescents and young adults long after Kawasaki disease and therefore warrant further investigation.

Silicone-coated polypropylene hollow-fiber oxygenator : Experimental evaluation and preliminary clinical use

BACKGROUND A membrane oxygenator consisting of a microporous polypropylene hollow fiber with a 0.2-microm ultrathin silicone layer (cyclosiloxane) was developed. Animal experimental and preliminary clinical studies evaluated its reliability in bypass procedures. METHODS Five 24-hour venoarterial bypass periods were conducted on dogs using the oxygenator (group A). In 5 controls, bypass periods were conducted using the same oxygenator without silicone coating (group B). As a preliminary clinical study, 14 patients underwent cardiopulmonary bypass with the silicone-coated oxygenator. RESULTS Eight to 16 hours (mean, 12.2 hours) after initiation of bypass, plasma leakage occurred in all group B animals, but none in group A. The O2 and CO2 transfer rates after 24 hours in group A were significantly higher than at termination of bypass in group B (p < 0.005 and p < 0.03, respectively). Scanning electron microscopy of silicone-coated fibers after 24 hours of bypass revealed no damage to the silicone coating of the polypropylene hollow fibers. In the clinical study, the oxygenator showed good gas transfer, acceptable pressure loss, low hemolysis, and good durability. CONCLUSIONS This oxygenator is more durable and offers greater gas transfer capabilities than the previous generation of oxygenators.

Ultrafiltration of the priming blood before cardiopulmonary bypass attenuates inflammatory response and improves postoperative clinical course in pediatric patients.

ABSTRACT The priming solution using in cardiopulmonary bypass (CPB) for infants undergoing cardiac surgery includes considerable amounts of stored blood. Our objective was to test the hypothesis that ultrafiltration (UF) of the stored blood before CPB reduces the unfavorable effects of stored blood and the production of inflammatory cytokines. Fifty pediatric patients with congenital heart defects took part in this study. The patients were randomly divided into two groups: the UF (27 pediatric patients who received UF) and control (23 pediatric patients who did not receive UF) groups. UF was performed with a polysulphone ultrafiltrator before CPB. Blood samples were collected immediately before, during, and 1 h after CPB. The levels of cytokines (TNF‐&agr;, IL‐1&bgr;, IL‐8), NH3, and bradykinin were determined. The serum concentrations of NH3 and bradykinin decreased significantly after UF. Compared with the control group, the UF group had significantly lower cytokine production. Water balance in UF group was better than that of control group. The UF group received significantly less inotropic support and shorter duration of ventilator support and ICU stay. We conclude that removal of bradykinin and a decrease in the levels of NH3, potassium, and pH play a significant role in reducing water retention and postoperative lung injury. UF of the blood used to prime the circuit for CPB is a safe and efficient method for use in open heart surgery in small pediatric patients.

Biocompatibility of silicone-coated oxygenator in cardiopulmonary bypass

BACKGROUND This study was designed to analyze the biocompatibility of silicone-coated oxygenators using inflammatory response as the outcome measure, and to investigate whether the silicone-coated oxygenators perform better in terms of postoperative organ dysfunction. METHODS The 32 patients who underwent cardiopulmonary bypass (CPB) were divided into 3 groups: group A (n = 10), heparin-coated circuit with silicone-coated oxygenator; group B (n = 11), whole heparin-coated circuit; and group C (n = 11), whole untreated circuit. The plasma concentrations of the proinflammatory markers, made of inflammatory cytokines (tumor necrosis factor-alpha, interleukin-1beta, interleukin-6, interleukin-8), terminal complement complex (C5b-9), and polymorphonuclear elastase (PMN-E), were measured by enzyme-linked immunosorbant assay. RESULTS All proinflammatory markers were significantly lower in groups A and B than in group C, especially C5b-9 and PMN-E concentrations, which were significantly lower in group A than in group B. The alveolar-arterial oxygen gradients (A-aDO2) and the respiratory index were significantly better in group A than in group C. In group B, however, only the A-aDO2 was significantly better than in group C. The duration of intubation and the length of stay in the intensive care unit stay were significantly shorter in groups A and B than in group C. CONCLUSIONS Silicone-coated oxygenators are biocompatible and prevent postoperative organ dysfunction.

Coronary artery aneurysm in a patient with Marfan syndrome

True aneurysm of the coronary artery in Marfan syndrome is very rare. We present a patient with Marfan syndrome who had aneurysms from the ascending aorta to the thoracoabdominal aorta and a large aneurysm of the left main coronary artery after an original Bentall operation. Prosthetic graft replacement of total aorta, coronary artery bypass grafting, and removal of the aneurysm of the left main coronary artery were successfully performed.

Immunohistochemical diagnosis of methylthioadenosine phosphorylase (MTAP) deficiency in non-small cell lung carcinoma

Methylthioadenosine phosphorylase (MTAP) is involved in the metabolism of purines and converts methylthioadenosine (MTA) to adenine. It is abundant in all normal tissues but is deficient in various tumors. Here, we investigated MTAP deficiency in clinical samples of lung cancer using immunohistochemistry (IHC), and compared these results with those obtained by real-time PCR. Seventy-five samples were obtained from patients who underwent operations for non-small cell lung cancer (NSCLC). MTAP genetic analysis, using real-time PCR, and IHC were carried out on the samples. Methylation-specific primers were used to analyze methylation of the MTAP promoter, using DNA treated with sodium bisulfite. Sixty-nine of 75 samples were compared using both IHC and real-time PCR. The IHC results were consistent with those of real-time PCR in 56 samples. Of 62 positive samples tested by real-time PCR, only 49 (79%) were MTAP-positive by IHC. Seven samples were MTAP-negative by real-time PCR and IHC. In 13 samples of PCR (+) and IHC (-), six samples showed that the promoter region of MTAP was methylated. IHC is an accurate and useful diagnostic method for detecting MTAP deficiency in NSCLC, and the frequency of MTAP deficiency was found to be relatively high. The metabolic alterations diagnosed by IHC could be exploited for selective chemotherapy.