Validation of a Five-Year Prognostic Model Using 123I-metaiodobenzylguanidine Scintigraphy in Patients with Heart Failure.

Background: 123I-metaiodobenzylguanidine (MIBG) scintigraphy evaluates the severity and prognosis of patients with heart failure. A prognostic model has been proposed using a multicenter study data of 123I-MIBG scintigraphy. We evaluated the usefulness of the model using a database. Methods: The study included 208 patients with noncompensated heart failure requiring hospitalization. 123I-MIBG scintigraphy and echocardiography were performed predischarge and 6 months postdischarge. The 5-year mortality rate was calculated by the model and classified into tertiles. Results: In 208 patients, 56 cardiac deaths occurred within the observation period (median, 4.83 years). In the evaluation of predischarge parameters, the predicted 5-year mortality was 15.5% ± 5.0%, 33.5% ± 3.9%, and 51.2% ± 8.2%, and 11 (16.2%), 18 (27.3%), and 27 (36.5%) cardiac deaths occurred in groups 1, 2, and 3, respectively. At the 6-month postdischarge evaluation, the estimated mortality was 8.2% ± 2.2%, 18.5% ± 4.8%, and 43.0% ± 12.1%, and 6 (9.4%), 21 (29.2%), and 29 (40.3%) cardiac deaths occurred, respectively. The predischarge Kaplan-Meier survival analysis showed significant difference between groups 1 and 3 (P value 0.014). Moreover, the 6-month postdischarge evaluation showed significant difference between group 1 and 2, and between groups 1 and 3 (P value 0.016, <0.001, respectively). For groups 1 and 3, the 6-month postdischarge difference was more significant than the predischarge difference (Chi-square 16.7 and 8.1, respectively). Conclusions: The prognostic model using 123I-MIBG scintigraphy was useful in predicting mortality risk in patients with heart failure. The estimated mortality at 6 months postdischarge was more useful than the predischarge estimation for heart failure hospitalization.

Pyothorax and Constrictive Pericarditis after Chemoradiotherapy for Esophageal Cancer: A Case Report.

A 75-year-old man underwent chemoradiotherapy for advanced esophageal cancer. After nine years, he was hospitalized for left pyothorax. Consequently, the patient underwent drainage and window opening surgery. He experienced cardiopulmonary arrest but was resuscitated. Based on cardiac catheterization data, the patient was diagnosed with constrictive pericarditis. Unfortunately, extracorporeal circulation did not improve his condition, and he ultimately died. An autopsy revealed adhesion between the pericardium and pleura, especially the pericardium in contact with the left thoracic cavity, which was markedly thickened. This suggests that constrictive pericarditis, a latent complication of chemoradiotherapy, is aggravated by pyothorax.

Brugada phenocopy with altered ST-segment elevation in pericardial diffuse large B-cell lymphoma and effusive-constrictive pericarditis: a case report.

Background: Cardiac lymphoma is a rare disease. Effusive-constrictive pericarditis can be a characteristic of pericardial involvement in patients with this disease. Conversely, a phenotype with electrocardiogram changes similar to those of Brugada syndrome is called Brugada phenocopy, and these changes improve after treatment. Case summary: A 71-year-old man was transported to our hospital with chest pain, hypotension, and ST-segment elevation in V1 and V2 leads during maintenance dialysis for renal failure. After arrival at the hospital, his ST-segment elevation disappeared, and emergency coronary angiography scan revealed no significant coronary artery stenoses or obstructions. His computed tomography and echocardiography scans revealed pericardial effusion and an intrapericardial mass. Further, his blood pressure dropped and ST-segment elevation recurred during dialysis after 7 days. Thus, pericardiocentesis was performed, but haemodynamic improvement was insufficient, and right catheterization findings suggested effusive-constrictive pericarditis. Meanwhile, flow cytometry of the pericardial fluid suggested the diagnosis of B-cell lymphoma; however, radical chemoradiotherapy was impossible because of cardiogenic shock. The patient died on Day 17. Further, autopsy revealed diffuse large B-cell lymphoma with pericardial and myocardial infiltration. Discussion: Cardiac lymphoma is rare but can be associated with effusive-constrictive pericarditis, which may be difficult to manage even with pericardial drainage. In such cases, radical treatment, including chemotherapy, should be promptly considered, if possible. Our patient presented with Brugada-type electrocardiogram but no syncope or family history, suggesting Brugada phenocopy and not true Brugada syndrome due to cardiac lymphoma. Notably, temporary improvement in ST-segment elevation was observed despite the absence of treatment.

Characterization of thraustochytrid-specific sterol O-acyltransferase: modification of DGAT2-like enzyme to increase the sterol production in Aurantiochytrium limacinum mh0186.

IMPORTANCE: Since the global market for sterols and vitamin D are grown with a high compound annual growth rate, a sustainable source of these compounds is required to keep up with the increasing demand. Thraustochytrid is a marine oleaginous microorganism that can synthesize several sterols, which are stored as SE in lipid droplets. DGAT2C is an unconventional SE synthase specific to thraustochytrids. Although the primary structure of DGAT2C shows high similarities with that of DGAT, DGAT2C utilizes sterol as an acceptor substrate instead of diacylglycerol. In this study, we examined more detailed enzymatic properties, intracellular localization, and structure-activity relationship of DGAT2C. Furthermore, we successfully developed a method to increase sterol and provitamin D3 productivity of thraustochytrid by more than threefold in the process of elucidating the function of the DGAT2C-specific N-terminal region. Our findings could lead to sustainable sterol and vitamin D production using thraustochytrid.

Simultaneous structural replacement of the sphingoid long-chain base and sterol in budding yeast.

The basic structures of membrane lipids that compose biomembranes differ among species; i.e., in mammals, the primary structure of long-chain base (LCB), the common backbone of ceramides and complex sphingolipids, is sphingosine, whereas, in yeast Saccharomyces cerevisiae, it is phytosphingosine, and S. cerevisiae does not have sphingosine. In addition, the sterol, which is coordinately involved in various functions with complex sphingolipids, is cholesterol in mammals, while in yeast it is ergosterol. Previously, it was found that yeast cells are viable when the structure of LCBs is replaced by sphingosine by supplying an exogenous LCB to cells lacking LCB biosynthesis. Here, we characterized yeast cells having sphingosine instead of phytosphingosine (sphingosine cells). Sphingosine cells exhibited a strong growth defect when biosynthesis of ceramides or complex sphingolipids was inhibited, indicating that, in the sphingosine cells, exogenously added sphingosine is required to be further metabolized. The sphingosine cells exhibited hypersensitivity to various environmental stresses and had abnormal plasma membrane and cell wall properties. Furthermore, we also established a method for simultaneous replacement of both LCB and sterol structures with those of mammals (sphingosine/cholesterol cells). The multiple stress hypersensitivity and abnormal plasma membrane and cell wall properties observed in sphingosine cells were also observed in sphingosine/cholesterol cells, suggesting that simultaneous replacement of both LCB and sterol structures with those of mammals cannot prevent these abnormal phenotypes. This is the first study to our knowledge showing that S. cerevisiae can grow even if LCB and sterol structures are simultaneously replaced with mammalian types.

Single coronary artery diagnosed in the perinatal period: A case report.

OBJECTIVE: Having a single coronary artery (SCA) is a rare congenital anomaly in which a single artery arises from the aorta. Although most cases of SCA are asymptomatic and incidental, its effects during the perinatal period remain unknown. Herein, we report a case of pregnant woman with suspected SCA, based on transthoracic echocardiography (TTE) findings. CASE REPORT: A 33-year-old multiparous woman presented with preterm premature rupture of the membrane at 29 weeks gestation. The patient's preoperative electrocardiogram (ECG) showed slight ST changes. TTE showed dilated right coronary artery and hypoplastic left coronary artery. Cesarean section was performed at 30 weeks of gestation due to non-reassuring fetal status. Although poor oxygenation was observed postoperatively, the patient was managed appropriately. She was diagnosed with SCA based on coronary computed tomographic angiography findings one month after delivery. CONCLUSION: Pregnant women with SCA require careful perinatal care.

Impaired biosynthesis of ergosterol confers resistance to complex sphingolipid biosynthesis inhibitor aureobasidin A in a PDR16-dependent manner.

Complex sphingolipids and sterols are coordinately involved in various cellular functions, e.g. the formation of lipid microdomains. Here we found that budding yeast exhibits resistance to an antifungal drug, aureobasidin A (AbA), an inhibitor of Aur1 catalyzing the synthesis of inositolphosphorylceramide, under impaired biosynthesis of ergosterol, which includes deletion of ERG6, ERG2, or ERG5 involved in the final stages of the ergosterol biosynthesis pathway or miconazole; however, these defects of ergosterol biosynthesis did not confer resistance against repression of expression of AUR1 by a tetracycline-regulatable promoter. The deletion of ERG6, which confers strong resistance to AbA, results in suppression of a reduction in complex sphingolipids and accumulation of ceramides on AbA treatment, indicating that the deletion reduces the effectiveness of AbA against in vivo Aur1 activity. Previously, we reported that a similar effect to AbA sensitivity was observed when PDR16 or PDR17 was overexpressed. It was found that the effect of the impaired biosynthesis of ergosterol on the AbA sensitivity is completely abolished on deletion of PDR16. In addition, an increase in the expression level of Pdr16 was observed on the deletion of ERG6. These results suggested that abnormal ergosterol biosynthesis confers resistance to AbA in a PDR16-dependent manner, implying a novel functional relationship between complex sphingolipids and ergosterol.

Drug-coated balloons for the treatment of stent edge restenosis.

BACKGROUND: Drug-coated balloon (DCB) is a device for treating patients with in-stent restenosis; however, there are scant data on its efficacy for stent edge restenosis (SER). This study aimed to investigate the clinical outcomes of DCB use for treating SER compared with new-generation drug-eluting stent (DES) implantation. METHOD: From December 2013 to January 2019, patients who underwent DES implantation or DCB for SER were enrolled. Clinical outcomes were analyzed, and propensity score with matching was conducted. The primary outcome was target-vessel revascularization (TVR). The secondary outcomes were the incidence of all-cause mortality, major adverse cardiovascular events (MACE), and target lesion revascularization (TLR). RESULT: A total of 291 patients with SER were included: 160 were treated with DCB, and 131 with new-generation DES. DCB treatment for SER treatment was associated with a lower risk of TVR than DES [hazard ratio, 0.549; 95% confidence interval (CI), 0.339-0.891] at a median follow-up of 1080 days (interquartile range; 729-1080 days). Propensity score matching (PSM) was performed to adjust for baseline clinical and lesion characteristics. After PSM, no significant difference in the risk of TVR was observed (hazard ratio, 0.965; 95% CI, 0.523-1.781). Similarly, the risk for all-cause death (hazard ratio, 0.507; 95% CI, 0.093-2.770), MACE (hazard ratio: 0.812; 95% CI, 0.451-1.462), and TLR (hazard ratio: 0.962; 95% CI, 0.505-1.833) were comparable between the two groups. CONCLUSION: DCB treatment efficacy for SER was similar to that of new-generation DES after PSM. DCB is a significant alternative to obtain comparable results with new-generation DES for the treatment of SER.

Acute pulmonary thromboembolism after messenger RNA vaccination against coronavirus disease 2019: A case report.

Vaccine-induced immune thrombotic thrombocytopenia (VITT) is defined as thrombosis after inoculation of adenovirus vector vaccines against severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2). VITT rarely occurs with messenger RNA vaccines, and the use of heparin for VITT is also controversial. A 74-year-old female patient with no risk factors for thrombosis was brought to our hospital after loss of consciousness. Nine days before admission, she had received the third vaccine against SARS-CoV-2 (mRNA1273, Moderna). Immediately after transport, cardiopulmonary arrest occurred, prompting extracorporeal membrane oxygenation (ECMO). Pulmonary angiography showed translucent images of both pulmonary arteries, resulting in the diagnosis of acute pulmonary thromboembolism. Unfractionated heparin was administered, but D-dimer subsequently became negative. Pulmonary thrombosis remained in large volume, indicating that heparin was ineffective. Treatment was shifted to anticoagulant therapy using argatroban, which increased D-dimer level and improved respiratory status. The patient was successfully weaned from ECMO and ventilator. Anti-platelet factor 4 antibody examined after treatment initiation showed negative results; however, VITT was considered as an underlying condition because of the time of onset after vaccination, the ineffectiveness of heparin, and the absence of other causes of thrombosis. In case heparin is not effective, argatroban can be an alternative therapy against thrombosis. Learning objective: During the coronavirus disease 2019 pandemic, treatment with vaccine against severe acute respiratory syndrome coronavirus 2 has been widely performed. Vaccine-induced immune thrombotic thrombocytopenia is the most common thrombosis after adenovirus vector vaccines. However, thrombosis can also occur after messenger RNA vaccination. Though commonly used for thrombosis, heparin may be ineffective. Non-heparin anticoagulants should be considered.

Assays and Utilization of Enzymes Involved in Glycolipid Metabolism in Bacteria and Fungi.

Microbial glycosphingolipid (GSL)-degrading enzymes with unique specificity are useful tools for GSL research. On the other hand, some microbial glycolipids, not only GSLs but also steryl glucosides, are closely related to pathogenicity, and, thus, the metabolism of microbial glycolipids is attracting attention as a target for antibiotics. This chapter describes the assays and utilization of microbial enzymes useful for glycolipid research and those involved in pathogenicity or host immune reactions.

Oozing-type rupture caused by right ventricular intramural hematoma after right ventricular infarction.

An 81-year-old man was admitted to the hospital because of decreased level of consciousness. He had bradycardia (27 beats/min). Electrocardiography showed ST-segment elevation in leads II, III, and aVF and ST-segment depression in leads aVL, V1. Transthoracic echocardiography (TTE) visualized reduced motion of the left ventricular (LV) inferior wall and right ventricular (RV) free wall. Coronary angiography revealed occlusion of the right coronary artery. A primary percutaneous coronary intervention was successfully performed with temporary pacemaker backup. On the third day, the sinus rhythm recovered, and the temporary pacemaker was removed. On the fifth day, a sudden cardiac arrest occurred. Extracorporeal cardiopulmonary resuscitation was performed. TTE showed a high-echoic effusion around the right ventricle, indicating a hematoma. The drainage was ineffective. He died on the eighth day. An autopsy showed the infarcted lesion and an intramural hematoma in the RV. However, no definite perforation of the myocardium was detected. The hematoma extended to the epicardium surface, indicative of oozing-type RV rupture induced by RV infarction. The oozing-type rupture induced by RV infarction might develop asymptomatically without influence on the vital signs of the patient. Frequent echocardiographic evaluation is essential in cases of RV infarction taking care of silent oozing-type rupture. Learning objective: Inferior left ventricular infarction sometimes complicates right ventricular (RV) infarction. The typical manifestations of RV infarction include low blood pressure, low cardiac output, and elevated right atrium pressure. Although the frequency is low, fatal complications of oozing-type RV rupture might progress asymptomatically. Frequent echocardiographic screening is necessary to detect them.

Long-term outcomes of intermediate coronary stenosis in patients undergoing hemodialysis after deferred revascularization based on fractional flow reserve.

OBJECTIVES: This study aimed to assess the long-term outcomes of patients undergoing hemodialysis (HD) after deferred revascularization based on fractional flow reserve (FFR). BACKGROUND: FFR is a practical technique for assessing the functional severity of intermediate coronary stenosis. Prior research has revealed a satisfactory outcome in patients after the deferral of percutaneous coronary intervention for coronary lesions based on FFR measurement. However, little research has been conducted focusing on patients undergoing HD. METHODS: The retrospective study comprised 225 consecutive patients with FFR assessment and deferred revascularization between January 2016 and December 2019. Based on a deferral cutoff FFR value of >0.80, we assessed the differences in all-cause death, major adverse cardiac events (MACEs), and target vessel failure (TVF) between the HD (n = 69) and non-HD groups (n = 156) during a mean ± standard deviation routine follow-up of 32.2 ± 13.4 months. RESULTS: Although the HD group had significantly higher rates of diabetes mellitus than the non-HD group (53.6% vs. 37.2%, p = 0.021), there were no significant differences in sex, left ventricular ejection fraction, or other risk factors between the groups, nor with respect to stenosis diameter or mean FFR. The HD group had a significantly higher incidence of TVF than the non-HD group (34.8% vs. 14.1%, p < 0.001), as well as a significantly higher risk of all-cause death and MACEs. CONCLUSIONS: The study revealed that deferred revascularization in coronary lesions with an FFR value of >0.80 in patients undergoing HD was associated with poor outcomes. Therefore, it is important to carefully monitor patients with intermediate coronary stenosis undergoing HD.

Significance of mitochondrial fatty acid ß-oxidation for the survivability of Aurantiochytrium limacinum ATCC MYA-1381 during sugar starvation.

Thraustochytrids are marine protists that accumulate large amounts of palmitic acid and docosahexaenoic acid in lipid droplets. Random insertional mutagenesis was adopted for Aurantiochytrium limacinum ATCC MYA-1381 to search for genes that regulate lipid metabolism in thraustochytrids. A mutant strain, M17, was selected because of its significant decrease in myristic acid, palmitic acid, and triacylglycerol contents and cell growth defect. Genome analysis revealed that the gene encoding for mitochondrial electron-transfer flavoprotein ubiquinone oxidoreductase (ETFQO) was lacking in the M17 strain. This mutant strain exhibited a growth defect at the stationary phase, possibly due to stagnation of mitochondrial fatty acid ß-oxidation and branched-chain amino acid degradation, both of which were caused by lack of ETFQO. This study shows the usability of random insertional mutagenesis to obtain mutants of lipid metabolism in A. limacinum and clarifies that ETFQO is integral for survival under sugar starvation in A. limacinum.

Loss of tolerance to multiple environmental stresses due to limitation of structural diversity of complex sphingolipids.

Structural diversity of complex sphingolipids is important for maintenance of various cellular functions; however, the overall picture of the significance of this structural diversity remains largely unknown. To investigate the physiological importance of the structural diversity of complex sphingolipids, we here constructed a complex sphingolipid structural diversity disruption library in budding yeast, which comprises 11 mutants including with combinations of deletions of sphingolipid-metabolizing enzyme genes. The sensitivity of the mutants to various environmental stresses revealed that the more the structural variation of complex sphingolipids is limited, the more stress sensitivity tends to increase. Moreover, it was found that in mutant cells with only one subtype of complex sphingolipid, Slt2 MAP kinase and Msn2/4 transcriptional factors are essential for maintenance of a normal growth and compensation for reduced tolerance of multiple stresses caused by loss of complex sphingolipid diversity. Slt2 and Msn2/4 are involved in compensation for impaired integrity of cell walls and plasma membranes caused by loss of complex sphingolipid diversity, respectively. From these findings, it was suggested that loss of structural diversity of complex sphingolipids affects the environment of the cell surface, including both plasma membranes and cell walls, which could cause multiple environmental stress hypersensitivity.

Functions and applications of glycolipid-hydrolyzing microbial glycosidases.

Glycolipids are important components of cell membranes in several organisms. The major glycolipids in mammals are glycosphingolipids (GSLs), which are composed of ceramides. In mammals, GSLs are degraded stepwise from the non-reducing end of the oligosaccharides via exo-type glycosidases. However, endoglycoceramidase (EGCase), an endo-type glycosidase found in actinomycetes, is a unique enzyme that directly acts on the glycosidic linkage between oligosaccharides and ceramides to generate intact oligosaccharides and ceramides. Three molecular species of EGCase, namely EGCase I, EGCase II, and endogalactosylceramidase, have been identified based on their substrate specificity. EGCrP1 and EGCrP2, which are homologs of EGCase in pathogenic fungi, were identified as the first fungal glucosylceramide- and sterylglucoside-hydrolyzing glycosidases, respectively. These enzymes are promising targets for antifungal drugs against pathogenic fungi. This review describes the functions and properties of these microbial glycolipid-degrading enzymes, the molecular basis of their differential substrate specificity, and their applications.

Crosstalk between protein kinase A and the HOG pathway under impaired biosynthesis of complex sphingolipids in budding yeast.

Complex sphingolipids are important components of the lipid bilayer of budding yeast Saccharomyces cerevisiae, and a defect of the biosynthesis causes widespread cellular dysfunction. In this study, we found that mutations causing upregulation of the cAMP/protein kinase A (PKA) pathway cause hypersensitivity to the defect of complex sphingolipid biosynthesis caused by repression of AUR1 encoding inositol phosphorylceramide synthase, whereas loss of PKA confers resistance to the defect. Loss of PDE2 encoding cAMP phosphodiesterase or PKA did not affect the reduction in complex sphingolipid levels and ceramide accumulation caused by AUR1 repression, suggesting that the change in sensitivity to the AUR1 repression due to the mutation of the cAMP/PKA pathway is not caused by exacerbation or suppression of the abnormal metabolism of sphingolipids. We also identified PBS2 encoding MAPKK in the high-osmolarity glycerol (HOG) pathway as a multicopy suppressor gene that rescues the hypersensitivity to AUR1 repression caused by deletion of IRA2, which causes hyperactivation of the cAMP/PKA pathway. Since the HOG pathway has been identified as one of the rescue systems against the growth defect caused by the impaired biosynthesis of complex sphingolipids, it was assumed that PKA affects activation of the HOG pathway under AUR1-repressive conditions. Under AUR1-repressive conditions, hyperactivation of PKA suppressed the phosphorylation of Hog1, MAPK in the HOG pathway, and transcriptional activation downstream of the HOG pathway. These findings suggested that PKA is possibly involved in the avoidance of excessive activation of the HOG pathway under impaired biosynthesis of complex sphingolipids.

Acute myocarditis associated with COVID-19 vaccination: A case report.

Recently, new vaccine platforms-including mRNA vaccines for coronavirus disease 2019 (COVID-19) have been given emergency use authorization in Japan. Here, we present a rare case of myocarditis following a COVID-19 vaccine. In this case, myocarditis was confirmed by cardiac magnetic resonance imaging, endomyocardial biopsy, and troponin levels. The degree of myocardial inflammation in the endomyocardial biopsy samples was mild and the patient's clinical course was not severe. Although the pathology of myocarditis in this case was mild, further investigation would be needed. .

PUFA synthase-independent DHA synthesis pathway in Parietichytrium sp. and its modification to produce EPA and n-3DPA.

The demand for n-3 long-chain polyunsaturated fatty acids (n-3LC-PUFAs), such as docosahexaenoic acid (DHA) and eicosapentaenoic acid (EPA), will exceed their supply in the near future, and a sustainable source of n-3LC-PUFAs is needed. Thraustochytrids are marine protists characterized by anaerobic biosynthesis of DHA via polyunsaturated fatty acid synthase (PUFA-S). Analysis of a homemade draft genome database suggested that Parietichytrium sp. lacks PUFA-S but possesses all fatty acid elongase (ELO) and desaturase (DES) genes required for DHA synthesis. The reverse genetic approach and a tracing experiment using stable isotope-labeled fatty acids revealed that the ELO/DES pathway is the only DHA synthesis pathway in Parietichytrium sp. Disruption of the C20 fatty acid ELO (C20ELO) and ∆4 fatty acid DES (∆4DES) genes with expression of ω3 fatty acid DES in this thraustochytrid allowed the production of EPA and n-3docosapentaenoic acid (n-3DPA), respectively, at the highest level among known microbial sources using fed-batch culture.

Oxygen plasma modulates glucosinolate levels without affecting lipid contents and composition in Brassica napus seeds.

Rapeseed contains high levels of glucosinolates (GSLs), playing pivotal roles in defense against herbivores and pests. As their presence in rapeseed reduces the value of the meal for animal feeding, intensive efforts to reduce them produced low-seed GSL cultivars. However, there is no such variety suitable for the south part of Japan. Here, we tested the effects of cold oxygen plasma (oxygen CP) on seed germination and GSL and lipid content, in 3 rapeseed cultivars. According to the cultivars, oxygen CP slightly stimulated seed germination and modified the GSL levels, and decreased GSL levels in Kizakinonatane but increased those in Nanashikibu. In contrast, it negligibly affected the lipid content and composition in the 3 cultivars. Thus, oxygen CP modulated seed GSL levels without affecting seed viability and lipid content. Future optimization of this technique may help optimize rapeseed GSL content without plant breeding.