BACKGROUND:The long-term mortality of end-stage renal disease (ESRD) patients is still unsatisfactory. Therefore, long-term risk assessments in ESRD patients undergoing cardiac surgery are needed. Recently, sarcopenia is major concern in cardiac surgery because of its association with poor long-term survival. However, the impact of sarcopenia on the long-term survival of ESRD patients undergoing cardiac surgery is not well understood. METHODS:Eighty-two ESRD patients who underwent elective cardiac surgery were enrolled. Sarcopenia was identified based on noncontrast abdominal computed tomography. The impact of preoperative and intraoperative factors on long-term survival was investigated. RESULTS:Forty-three patients (52%) were diagnosed with sarcopenia. The in-hospital mortality rate was 4.9%. The 5-year overall survival rate was 48%. The multivariate analyses revealed that STS score ≥ 4 (odds ratio, 6.0; confidence interval, 2.5-14.7; p < 0.01) and presence of sarcopenia (odds ratio, 2.4; confidence interval, 1.3-4.5; p  =  0.03) were independent risk factors for overall survival. The 5-year survival rates of low-risk (Society of Thoracic Surgeons score of < 4) patients without sarcopenia, low-risk with sarcopenia, more than intermediate-risk (Society of Thoracic Surgeons score of ≥ 4) without sarcopenia, and more than intermediate-risk with sarcopenia groups were 80%, 51%, 50%, and 26%, respectively. CONCLUSIONS:Among the ESRD patients, the low risk without sarcopenia group showed an excellent long-term survival, in contrast to more than intermediate-risk patients with sarcopenia, who can expect poor long-term survival. Preoperative assessment of sarcopenia in addition to the surgical risk score can be useful in developing a therapeutic strategy.

Cardiac tissue is composed of cardiomyocytes, vascular cells, fibroblasts, and extracellular matrix (ECM). Myocardial cell death due to cellular injury, such as acute myocardial infarction, triggers a multistage repair response in which the damaged tissue is replaced by a fibrotic scar, mainly composed of ECM produced by myofibroblasts. In the heart, it is believed that most myofibroblasts are transdifferentiated from resident cardiac fibroblasts. Although the initial reparative fibrosis is critical to prevent ventricular wall rupture, an excessive fibrotic response is detrimental. This is because sustained activation of myofibroblasts leads to excessive ECM deposition, which reduces cardiac contractile properties and disturbs cardiac electrical signaling, resulting in heart failure. Therefore, myofibroblast regulation may be a potential target for heart failure therapy. In this section, we discuss cardiac fibrosis with a focus on myofibroblasts and present our work on 2,5-dimethylecoxib which is a promising new anti-fibrotic agent. We hope that our discussion of the relationship between cardiac fibrosis and myofibroblasts will lead to the development of new anti-fibrotic agents and the treatment of heart failure.

We previously reported that 2,5-dimethylcelecoxib (DM-C), a derivative of celecoxib, lacks cyclooxygenase-2 inhibitory effects and suppresses cardiac remodeling by activating glycogen synthase kinase-3 (GSK-3). However, it remains unclear whether DM-C attenuates fibroblast-to-myofibroblast transformation (FMT), which plays a key role in cardiac fibrosis. Therefore, we evaluated the effect of DM-C on FMT using a cryoinjury-induced myocardial infarction (CMI) mouse model. We found that DM-C attenuated the deterioration of left ventricular ejection fraction after CMI by decreasing cardiac fibrosis. Analysis of the expression level of α-smooth muscle actin (α-SMA), a marker for myofibroblasts, indicated that DM-C decreased FMT at the cardiac injury site. To investigate the mechanism by which DM-C attenuated FMT, fibroblasts obtained from the heart were stimulated with TGF-β to induce FMT, and the effect of DM-C was analyzed. DM-C suppressed the expression of α-SMA and the phosphorylation levels of Smad 2/3 and GSK-3, indicating that DM-C suppressed α-SMA expression by inhibiting the transforming growth factor (TGF)-β signaling pathway via activation of GSK-3. DM-C decreased the expression of collagen, connective tissue growth factor (CTGF) and Snail, which are also known to accelerate cardiac fibrosis. These results suggested that DM-C attenuated cardiac fibrosis by suppressing FMT at the injured site after CMI by inhibiting the TGF-β signaling pathway via activation of GSK-3. Thus, DM-C has potential against cardiac disease as a novel anti-fibrotic agent.

外科教育におけるoff the job training (off-JT)の重要性は広く認識されており，2017年より心臓血管外科専門医取得に際し30時間以上のoff-JTを義務付けている。U-40 Basic Lecture Courseは，若手心臓血管外科医を対象に基本的な手術手技を学ぶ機会を提供するべく毎年開催されている。U-40 Advanced Lecture Courseは，若手心臓血管外科医を対象に，より高度なレクチャー，ハンズオンセミナーを受ける機会を提供するために開始された。しかし，COVID-19の感染拡大以降，ハンズオンセミナーを開催する機会が非常に限られているのが現状である。その中で，ハイブリッドハンズオンセミナーを開催した。本稿では，このハイブリッドハンズオンセミナーの詳細について報告する。

Systemic sclerosis (SSc) is a connective tissue disorder characterized by the development of skin fibrosis. No topical treatment for the skin manifestations of SSc has been developed. We previously reported that celecoxib, a selective inhibitor of COX-2, and/or its derivative DM-celecoxib suppressed cardiac and renal fibrosis. Therefore, the effect of celecoxib on the SSc fibrosis was investigated. In in-vivo study, bleomycin was injected s.c. into a single location of the hair less mouse Hos:HR1 every 3 days for 10 days to induce scleroderma. For the treatment of celecoxib, celecoxib was dissolved into acetone and topically applied, whereas control mice received acetone only. Ten days after the first injection, skin section was obtained and histological analysis were performed. To clarify the mechanism of celecoxib action, normal human skin fibroblast cell line NB1RGB was stimulated with TGF-β to induced fibroblast-myofibroblast transformation and the effects of celecoxib on the expression of α-SMA was analyzed. We found that topical application of celecoxib significantly decreased skin thickness and the expression of α-SMA in bleomycin-induced scleroderma model mice. Consistent with these results, celecoxib inhibited the expression of α-SMA induced by TGF-β in NB1RGB cells. Further studies are now conducting to clarify the action of celecoxib.

We previously reported the 2,5-dimethylcelecoxib (DM-C) attenuated cardiac remodeling in different types of cardiac hypertrophy model. However, it remains unclear whether DM-celecoxib attenuates fibroblast-to-myofibroblast transformation (FMT) which plays the key role in cardiac fibrosis after myocardial infarction (MI). Therefore, we investigated the effect of DM-C on FMT using cryoinjury induced myocardial infarction (CMI) mouse model and TGF-β1-stimulated cardiac fibroblasts. We found that DM-celecoxib attenuated deterioration of left ventricular ejection fraction after CMI by decreasing cardiac fibrosis. Analysis of the expression level of α-smooth muscle actin, a marker for myofibroblast, indicated that DM-celecoxib decreased FMT in cardiac injured site. In the cardiac fibroblasts, DM-celecoxib suppressed expression of α-SMA and phosphorylation levels of Smad 2/3 and GSK-3, indicating that DM-celecoxib suppressed α-SMA expression by inhibiting TGF-β signaling pathway via activation of GSK-3. These results suggested that DM-celecoxib attenuated cardiac fibrosis via suppressing fibroblast-to-myofibroblast transformation in injured site after CMI by suppressing TGF-β signaling pathway via activation of GSK-3. Thus, DM-celecoxib has a potential as a novel anti-fibrotic agent after MI in clinical setting.

Myocardial ischemia/reperfusion (MI/R) injury leads to aggravated cardiac remodeling and heart failure. Previously, we reported that 2,5-dimethylelcelecoxib (DMC), a derivative of celecoxib without cyclooxygenase-2 inhibition, prevents cardiac remodeling in a non-ischemic cardiac fibrosis model. In this study, we examined whether DMC inhibited myocardial remodeling associated with MI/R injury. The left anterior descending coronary artery was ligatured for 0.5 hours and subsequently subjected to reperfusion for MI/R injury in male C57 BL/6 mice. Vehicle or DMC was administered orally (DMC: 150 mg/kg) immediately after awakening and followed by feeding (DMC: 1000 ppm). Echocardiographic evaluation showed significant improvement of left ventricular ejection fraction in the DMC-treated group compared to the Vehicle-treated group at 1-4 weeks after MI/R injury. In MI/R-injured hearts, protein expression of alpha-smooth muscle actin (myofibroblast marker) was significantly reduced by DMC treatment, as were mRNA expressions of fibronectin, connective tissue growth factor, and matrix metalloproteinase-9, 3 days after injury. Masson trichrome staining indicated that DMC significantly reduced cardiac fibrosis area 4 weeks after MI/R injury. This study revealed that DMC decreased myofibroblast appearance, and suppressed fibrosis and cardiac dysfunction associated with MI/R injury. DMC might be useful for preventing the development of heart failure associated with reperfusion therapy for acute myocardial infarction.

The U-40 generation of surgeons are practicing through trial and error, and form various careers. At the 51st Annual Meeting of the Japanese Society of Cardiovascular Surgery, U-40 Special Project, we looked back on the U-40 generation and more senior doctors to see what kind of future visions, problems and careers they have had. We conducted a questionnaire for the purpose of visualizing the future prospects of the U-40 generation. In this article, we report the results. Jpn. J. Cardiovasc. Surg. 51 ( 1 ) : U1 - U10 ( 2022 )

日本心臓血管外科学会U-40コラムでは，専門医制度をテーマにしてU-40世代を対象にアンケートを実施し，専門医取得に際した現状や課題などについて報告してきた．新専門医制度の導入にあたり，新たにoff the job trainingと体外循環技術の参加型実習が義務付けられた．第5回目の今号では，U-40世代の人工心肺を中心とした体外循環研修の現状，研修プログラムの是非などについてアンケートを実施したので，その結果と考察について報告する．

Secretion of extracellular matrix by myofibroblasts, transform from fibroblasts and express alpha smooth muscle actin (aSMA), lead to cardiac fibrosis and progress cardiac remodeling. We previously reported the 2,5-dimethylcelecoxib (DM-C) attenuated cardiac remodeling in different type of cardiac hypertrophy models. However, as the effect of DM-C on myofibroblasts transformation and cardiac remodeling after myocardial infarction (MI) are still unclear, we tried to clarify these points. In in vitro study, dermal fibroblasts from SD rat were used for analysis of myofibroblast transformation. In in vivo study, cryoinjury-induced MI (CMI) mouse model was used. In vitro studies showed that DM-C significantly suppressed the expression of aSMA and the phosphorylation levels of Akt, GSK-3 b and Smad2/3, all of them were elevated by TGF-b treatment. In vivo studies showed that the expression of aSMA and fibrosis area were decreased in DM-C group compared with control group. Further, evaluation of the cardiac function revealed that DM-C-treatment alleviated the reduction of the ejection fraction. These results suggest that DM-C attenuates cardiac remodeling after CMI by inhibiting fibrosis via suppression of the myofibroblast transformation. Therefore, DM-C has potential as the novel drug for treatment of cardiac remodeling after MI.

Mesenchymal stem cells (MSCs) are an attractive cell source for tissue regeneration and repair. However, their low differentiation efficacy currently impedes the development of MSC therapy. In this study, we investigated the effects of differentiation-inducing factor-1 (DIF-1) on the differentiation efficacy of bone marrow-derived MSCs (BM-MSCs) into adipogenic or osteogenic lineages. BM-MSCs were obtained from Sprague-Dawley rats. DIF-1 alone neither affected cell surface antigen expression nor induced adipogenic or osteogenic differentiation. However, DIF-1 significantly enhanced the effects of adipogenic differentiation stimuli, which were evaluated as the number of oil red-O positive cells and the expression of adipocyte differentiation markers. In contrast, DIF-1 significantly attenuated the effects of osteogenic differentiation stimuli, which were evaluated as alizarin red-S positive calcium deposition, and the expression of osteoblast differentiation markers. We further investigated the mechanism by which DIF-1 affects MSC differentiation efficacy and found that glycogen synthase kinase-3 was the main factor mediating the action of DIF-1 on the adipogenic differentiation of BM-MSCs, whereas it was only partially involved in osteogenic differentiation. These results suggest that DIF-1 supports MSC differentiation toward the desired cell fate by enhancing the differentiation efficacy.

We investigated how cardiovascular surgeons get a day off.

Mesenchymal stem cells (MSCs) are an attractive cell source for tissue regeneration and repair. However, their low differentiation efficacy currently impedes the development of MSC therapy. Therefore, in this study, we investigated the effects of differentiation-inducing factor-1 (DIF-1) on the differentiation efficacy of bone marrow-derived MSCs (BM-MSCs) into adipogenic or osteogenic lineages. BM-MSCs, which were obtained from Sprague-Dawley rats, were positive for the MSC markers (CD29, CD73, and CD90). DIF-1 alone neither affected cell surface antigen expression nor induced adipogenic or osteogenic differentiation. However, DIF-1 significantly enhanced the effects of adipogenic differentiation stimuli, which were evaluated as the number of oil red-O positive cells and the expression of adipocyte differentiation markers (peroxisome proliferator-activated receptor gamma, adipocyte fatty acid-binding protein, and adiponectin). In contrast, DIF-1 significantly attenuated the effects of osteogenic differentiation stimuli, which were evaluated as alizarin red-S positive calcium deposition, and the expression of osteoblast differentiation markers alkaline phosphatase, runt-related transcription factor 2, and osteopontin. We further investigated the mechanism by which DIF-1 affects MSC differentiation efficacy and found that glycogen synthase kinase-3 was the main factor mediating the action of DIF-1 on the adipogenic differentiation of BM-MSCs, whereas it was only partially involved in osteogenic differentiation. These results suggest that DIF-1 supports MSC differentiation toward the desired cell fate by enhancing the differentiation efficacy.

Background Aortic dilatation may occur in some patients even after complete repair of tetralogy of Fallot (TOF). The progression rate of the aortic diameter is so slow, and the incidence of aortic dissection is so low that it is suspected that frequent imaging of the aorta may not be necessary. Case presentation We describe an asymptomatic 41-year-old man with hypertension in whom aortic dilatation was accidentally discovered 39 years after TOF repair. He underwent ambulatory follow-up without any difficulty for 21 years after the repair. Contrast-enhanced computed tomography revealed significant aortic dilatation (maximum diameter of 88 mm at the sinus of Valsalva), and echocardiography revealed severe aortic regurgitation, which seemed to progress during the last 18 years without any evaluation or follow-up. The Bentall procedure was successfully performed using a valved graft, under deep hypothermic circulatory arrest with antegrade cerebral perfusion, and his postoperative course was uneventful. Histopathological examination of ascending aorta specimens revealed severe cystic medial degeneration. Conclusions Keeping in mind that a patient with rapid progression of the aortic dilatation after TOF repair exist, periodic follow-up for evaluation of the aorta is essential in patients with TOF.

Atypical hemolytic uremic syndrome (aHUS) is a thrombotic microangiopathy (TMA)-related disease that manifests as a triad of microangiopathic hemolytic anemia, thrombocytopenia, and acute kidney injury (AKI) and is caused by uncontrolled activation of the complement system. We report the case of a 61-year-old woman with acute type A aortic dissection that subsequently developed into aHUS. The hematologic disorders underlying aHUS improved after treatment with the complement inhibitor eculizumab. It is important to consider aHUS when a patient clinically develops a triad of microangiopathic hemolytic anemia, thrombocytopenia, and an increasing creatinine level following cardiovascular surgery.

Aortic stenosis (AS) is the most common valvular heart disease and is most frequently recognized among elderly people. Surgical aortic valve replacement (SAVR) is the most effective therapy, but its indication is sometimes difficult, and is impossible for high operative risk patients. Transcatheter aortic valve replacement (TAVR) was recently approved in Japan for high risk and inoperable patients with severe AS. TAVR is a less invasive method because it does not require a cardiopulmonary bypass and is associated with excellent surgical outcomes. In Western countries, the indication of TAVR has already been extended to moderate operative risk patients with severe AS, and is going to be further extended to low risk patients. The number of patients undergoing TAVR is increasing progressively, and there are effective alternative therapies for patients with severe AS. Selection of these surgical methods will be important in the near future. In regard to low operative risk patients especially, not only operative mortality, but also long-tern mortality and morbidity and quality of life should be taken into consideration. It is considered that some comorbidities in AS patients will be revealed to have an impact on surgical outcomes at the time when these surgical methods are selected. In this review, we examine end-stage renal disease on hemodialysis, functional tricuspid regurgitation, and sigmoid septum, and give an outline of what influence SAVR and TAVR have on the surgical outcomes of severe AS patients.

Background: Recent retrospective studies have shown that salvage surgery can improve survival with acceptable adverse events, and this procedure has been adapted for lung cancer. However, there are no reports demonstrating the efficacy of salvage surgery combined with aortic resection. Case presentation: A 73-year-old man had received definitive concurrent chemoradiotherapy (carboplatin/paclitaxel, 70Gy) for lung cancer originated from the left upper lobe and infiltrating the thoracic aorta (cT4N1M0 stage IIIA). Although the tumor has shrunk significantly (ycT4N0M0 stage IIIA), radiation pneumonitis occurred. Due to the steroid therapy, radiation pneumonitis was relieved; however, re-enlargement of the primary tumor was observed during steroid tapering. Nonetheless, the lymphatic and distant metastases were controlled. Moreover, aortic invasion was localized to the periphery of the third branch, and the tumor was considered to be resectable. Intraoperatively, we observed macroscopic evidence of aortic invasion in the periphery of the third branch; thus, left upper lobectomy combined with descending aorta resection was performed under partial extracorporeal circulation. The patient is currently active without any recurrence 21months post-surgery. Conclusions: No clear consensus exists regarding salvage surgery combined with aortic resection for primary lung cancer. However, we believe that this surgery may improve the survival of carefully selected patients.

We report a case of a 55-year-old male who had been diagnosed with mitral regurgitation and atrial septal defect 5 years earlier. He was referred to our institution because of worsening of mitral regurgitation accompanied by exertional dyspnea. As an echocardiography showed atrioventricular valve regurgitation and ostium primum atrial septal defect, but without ventricular septal defect, he was diagnosed as having partial atrioventricular septal defect (pAVSD). An operation was performed through median sternotomy. The anterior atrioventricular leaflet had a cleft and thickening with calcification. Suturing the cleft could not control the regurgitation. Incomplete coaptation was seen at the edge of the anastomosis site of the cleft, where the severe calcification had been identified. A rough zone including a part of the chordae tendineae was sutured in order to compensate for the gap. The atrioventricular septal defect was closed with an autologous pericardial patch. He was discharged uneventfully on the 24th postoperative day and has been followed up without complications for 1.5 years.

僧帽弁輪乾酪性石灰化（caseous calcification of mitral annulus : CCMA）は僧帽弁の腫瘤性変化を特徴とする稀な疾患であるが，血行動態に影響を与えることが少ないことからその手術報告はきわめて少ない．今回，われわれは虚血性心臓病（IHD）を基礎に僧帽弁閉鎖不全症（MR）を合併し，心不全が急性増悪したCCMA症例に対し僧帽弁置換術（MVR）および冠動脈バイパス手術（CABG）を行った．症例は67歳女性で急激に増悪した心不全の精査で僧帽弁後尖の腫瘤性病変を伴った高度MRと左冠動脈主幹部を含む3枝病変を認めた．僧帽弁逆流の制御と冠血行再建を目的に生体弁によるMVRおよびCABGを施行した．僧帽弁後尖の腫瘤性病変は弁輪に達しており，弁尖切除後に自己心膜による弁輪形成を必要とした．病理診断で僧帽弁後尖の腫瘤は乾酪性石灰化病変であった．術中所見を中心に報告する．