Search

Mitochondrial DNA m.3243A > G mutation causes mitochondrial encephalopathy, lactic acidosis, and stroke-like episodes (MELAS) and its associated multi-organ disorders, including diabetes. To clarify associations between m.3243A > G organ heteroplasmy and clinical phenotypes, including the age at death, we combined genetic and pathological examinations from seven unreported and 36 literature cases of autopsied subjects. Clinical characteristics of subjects were as follows: male, 13; female, 28; unknown, 2; the age at death, 36.9 ± 20.2 [4-82] years; BMI, 16.0 ± 2.9 [13.0-22.3]; diabetes, N = 21 (49%), diabetes onset age 38.6 ± 14.2 years; deafness, N = 27 (63%); stroke-like episodes (StLEp), N = 25 (58%); congestive heart failure (CHF), N = 15 (35%); CHF onset age, 51.3 ± 14.5 years. Causes of death (N = 32) were as follows: cardiac, N = 13 (41%); infection, N = 8 (25%); StLEp, N = 4 (13%); gastrointestinal, N = 4 (13%); renal, N = 2 (6%); hepatic, N = 1 (2%). High and low heteroplasmies were confirmed in non-regenerative and regenerative organs, respectively. Heteroplasmy of the liver, spleen, leukocytes, and kidney for all subjects was significantly associated with the age at death. Furthermore, the age at death was related to juvenile-onset (any m.3243A > G-related symptoms appeared before 20) and stroke-like episodes. Multiple linear regression analysis with the age at death as an objective variable showed the significant contribution of liver heteroplasty and juvenile-onset to the age at death. m.3243A > G organ heteroplasmy levels, particularly hepatic heteroplasmy, are significantly associated with the age at death in deceased cases., Competing Interests: Declaration of Competing Interest The authors have no competing interests to disclose except Daisuke Chujo, who received honoraria from Eli Lilly Japan K.K., research funding from Sanofi and Novo Nordisk Pharma Ltd., and subsides or donations from Novo Nordisk Pharm Ltd., (Copyright © 2023 The Authors. Published by Elsevier Inc. All rights reserved.)

Recent studies have reported that patients with autoimmune hyperchylomicronemia caused by glycosylphosphatidylinositol-anchored high-density lipoprotein binding protein 1 (GPIHBP1) autoantibodies are associated with rheumatoid arthritis, systemic lupus erythematosus, Sjogren's syndrome, Hashimoto's thyroiditis, Basedow's disease, and immune thrombocytopenia. We report a rare case of hyperchylomicronemia due to GPIHBP1 autoantibodies and fluctuating thyroid autoimmune disease. A 28-year-old woman, diagnosed with Hashimoto's thyroiditis at 26 years of age, started taking 50 µg/day of levothyroxine sodium. She had an episode of acute pancreatitis at 27 years of age; her serum triglyceride (TG) level was 1291 mg/dL at that time. The patient was referred to our hospital because her hyperchylomicronemia (hypertriglyceridemia) did not improve on treatment with pemafibrate and eicosapentaenoic acid (EPA). Serum total cholesterol and TG levels were 237 mg/dL and 2535 mg/dL, respectively, while plasma pre-heparin lipoprotein lipase (LPL) mass was 15 ng/mL (26.5-105.5 ng/mL). We diagnosed her as Basedow's disease based on autoimmune antibodies and ultrasound examination. Targeted exome sequencing revealed no pathogenic variants in the LPL or GPIHBP1 genes. The serum GPIHBP1 autoantibody level was 686.0 U/mL (<58.4 U/mL) and GPIHBP1 mass was 301.9 pg/mL (570.6-1625.6 pg/mL). The patient showed hyperchylomicronemia during periods of hypothyroidism and hyperthyroidism, whereas GPIHBP1 autoantibodies were positive during episode of hyperchylomicronemia but negative during periods of normal TG levels. Based on these findings, the patient was diagnosed with hyperchylomicronemia due to GPIHBP1 autoantibodies and treated with rituximab. GPIHBP1 autoantibodies remained undetectable and TG levels were controlled at approximately 200 mg/dL., Competing Interests: Conflict of interest None., (Copyright © 2022. Published by Elsevier Inc.)

Objective: To investigate the mechanisms underlying the effect of repetitive transcranial magnetic stimulation (rTMS) on post-stroke hemiplegia, we assessed alterations in cerebral glucose metabolism., Methods: Five post-stroke hemiplegic patients (three targeted for upper limb impairment and two targeted for lower limb impairment) aged 62.6 ± 6.1 years (mean ± standard deviation) with a duration since stroke onset of 3.5 ± 3.8 years participated in this preliminary study. Cerebral glucose metabolism was measured twice-before and after rTMS with intensive rehabilitation-using positron emission tomography with [18F]fluorodeoxyglucose. The Asymmetry Index (AI) was calculated to assess laterality of metabolism between the lesional and contralesional motor areas. The alteration rates of AI (%ΔAI) were compared between participants in whom rTMS was effective and ineffective., Results: Two of the three upper-limb-targeted patients and one of the two lower-limb-targeted patients showed motor function improvements following rTMS treatment. All three patients who responded to rTMS had improved laterality of cerebral glucose metabolism in motor areas, commonly in the precentral gyrus, with an %ΔAI of approximately 10%. In contrast, the two patients who did not respond to rTMS had no improvements in laterality., Conclusions: These results suggest for the first time that improved glucose metabolism is associated with improved motor function after a combination of rTMS and intensive rehabilitation., (© 2021. Fondazione Società Italiana di Neurologia.)

Homozygous familial hypercholesterolemia (HoFH) is a rare genetic disorder, and a genetic analysis is important to make a definitive diagnosis. A comprehensive genetic analysis using next generation sequencing (NGS) and whole exome sequencing (WES) is feasible. However, the application of NGS in the assessment of genomic structural variations is generally limited, and a substantial number of control samples are needed for such assessments. Thus, NGS alone is unlikely to detect genomic structural variations in a "singleton." We present the case of a patient with compound HeFH (heterozygous FH), whose causative mutations in the LDLR gene could not be identified by WES, necessitating the application of the multiplex ligation-dependent probe amplification (MLPA) technique.

The coronavirus infection 2019 (COVID-19) pandemic has led to the development of mRNA vaccines with proven efficacy. However, it remains unclear whether patients who developed pericarditis after the first COVID-19 mRNA would be fit to receive the second vaccination. Herein, we present the case of a 64-year-old man who visited our emergency department with substernal chest discomfort that began 4 days after his first mRNA COVID-19 vaccination. Acute pericarditis was diagnosed based on symptoms and ST-segment elevation on an electrocardiogram. Chest pain improved 2 days after treatment.Since there are no guidelines on whether to administer an additional vaccination to a patient who developed pericarditis after the initial vaccination, we considered whether or not to administer the additional vaccination. We informed the patient about the risks and benefits and decided to administer the second dose. He did not experience any major adverse reactions. The indications for the second vaccination need to be thoroughly considered.

Introduction: Familial hypercholesterolaemia (FH) is an autosomal-dominant inherited genetic disease. It carries an extremely high cardiovascular risk associated with significantly elevated low-density lipoprotein (LDL) cholesterol. The diagnostic rate of this disease in some European nations is quite high, due to the presence of multiple prospective registries. On the other hand, few data-and in particular multicentre data-exist regarding this issue among Japanese subjects. Therefore, this study intends to assemble a multicentre registry that aims to comprehensively assess cardiovascular risk among Japanese FH patients while taking into account their genetic backgrounds., Methods and Analysis: The Hokuriku-plus FH registry is a prospective, observational, multicentre cohort study, enrolling consecutive FH patients who fulfil the clinical criteria of FH in Japan from 37 participating hospitals mostly in Hokuriku region of Japan from April 2020 to March 2024. A total of 1000 patients will be enrolled into the study, and we plan to follow-up participants over 5 years. We will collect clinical parameters, including lipids, physical findings, genetic backgrounds and clinical events covering atherosclerotic and other important events, such as malignancies. The primary endpoint of this study is new atherosclerotic cardiovascular disease (ASCVD) events. The secondary endpoints are as follows: LDL cholesterol, secondary ASCVD events and the occurrence of other diseases including hypertension, diabetes and malignancies., Ethics and Dissemination: This study is being conducted in compliance with the Declaration of Helsinki, the Ethical Guidelines for Medical and Health Research Involving Human Subjects, and all other applicable laws and guidelines in Japan. This study protocol has been approved by the Institutional Review Board at Kanazawa University. We will disseminate the final results at international conferences and in a peer-reviewed journal., Trial Registration Number: UMIN000038210., Competing Interests: Competing interests: None declared., (© Author(s) (or their employer(s)) 2020. Re-use permitted under CC BY-NC. No commercial re-use. See rights and permissions. Published by BMJ.)

A 69-year-old woman presented with appetite loss, fatigue, and a low-grade fever. She had been receiving certolizumab pegol for rheumatoid arthritis for six years. Computed tomography of the chest showed multiple micronodules in both lungs and bilateral hilar and mediastinal lymphadenopathy. An ophthalmic examination showed the findings of uveitis. Lymphocytosis with an increased CD4/CD8 ratio was seen in the bronchoalveolar lavage fluid. Video-assisted thoracoscopic biopsy specimens obtained from the right lung and a right hilar lymph node showed noncaseous epithelioid cell granulomas. Anti-tumor necrosis factor-α-induced sarcoidosis was diagnosed, and she was successfully treated with cessation of certolizumab pegol and systemic corticosteroid therapy.

Aim: Coronary computed tomography angiography (CCTA)-derived fractional flow reserve (FFR CT ) accurately diagnoses ischemic lesions of intermediate stenosis severity. However, significant determinants of FFR CT have not been fully evaluated., Methods: This was a sub-analysis of the Treatment of Alogliptin on Coronary Atherosclerosis Evaluated by Computed Tomography-Based Fractional Flow Reserve trial. Thirty-nine diabetic patients (117 vessels) with intermediate coronary artery stenosis [percent diameter stenosis (%DS) ＜70%] in whom FFR CT was measured were included in this study. CCTA-defined, vessel-based volumetric and morphological characteristics of plaques were examined to determine their ability to predict FFR CT ., Results: Patient-based, multivariate linear regression analysis showed that hemoglobinA1c, triglycerides, and the estimated glomerular filtration rate were significant independent factors associated with FFR CT . Vessel-based, univariate linear regression analysis showed that the total atheroma volume (r=－0.233, p=0.01) and the percentage atheroma volume (PAV) (r=－0.284, p=0.002) as well as %DS (r=－0.316, p=0.006) were significant determinants of FFR CT . Among the plaque components, significant negative correlations were observed between FFR CT and low- (r=－0.248, p=0.007) or intermediate-attenuation plaque volume (r=－0.186, p=0.045), whereas calcified plaque volume was not associated with FFR CT . In the left anterior descending coronary artery (LAD), the plaque volume of each component was associated with FFR CT ., Conclusions: Plaque volume, PAV, and %DS were significant determinants of FFR CT . Plaque morphology, particularly in LAD, was associated with FFR CT in diabetic patients with intermediate coronary artery stenosis.

Increasing the urine flow rate (UFR) reduces the toxic effect of contrast media. Use of the RenalGuard system enables the achievement of a high UFR by maintaining intravascular volume and prevents the development of contrast-induced acute kidney injury (CI-AKI). However, the efficacy and safety of RenalGuard system have not yet been evaluated in Japan. This multicenter prospective study evaluated the efficacy and safety of the RenalGuard therapy in preventing CI-AKI development in 60 Japanese patients with renal dysfunction [estimated glomerular filtration rate (eGFR) < 45 mL/min/1.73 m 2 ] undergoing catheter procedures. Baseline eGFR and Mehran's CIN (contrast-induced nephropathy) risk score were 35.1 ± 8.5 mL/min/1.73 m 2 and 11.7 ± 4.3, respectively. Regardless of this high-risk profile, the incidence of CI-AKI was 8.6% (5/58) compared with the 26.1% incidence estimated by the CIN risk score. Moreover, two-sided 95% (Fisher's) exact confidence interval was 2.9-19.0 and its upper limit (i.e., 19.0) was less than the prespecified threshold incidence of 25.0. Univariate logistic regression analysis demonstrated that the UFR during catheter procedure was one of the most important factor associated with CI-AKI (odds ratio 0.99, confidence interval 0.98-1.00, p = 0.03). In conclusion, RenalGuard therapy may prevent CI-AKI development in Japanese patients with renal dysfunction. Further large-scale prospective multicenter studies are necessary to confirm our findings.

Recently, fractional flow reserve (FFR) derived from coronary computed tomography angiography (CCTA) (FFR CT ) has been developed. However, FFR CT cannot be calculated for all patients from CCTA datasets. The purpose of the present study, therefore, was to evaluate the predictors that results in cases being inappropriate for FFR CT processing. This study was a sub-analysis of the TRACT trial, from which 50 patients were divided into 2 groups according to FFR CT measurability (measurable [group M] or not measurable [group N]) using CCTA examination at baseline. Thirty-nine (78%) patients comprised group M and 11 (22%) comprised group N. Heart rate at CCTA examination (72 beats/min vs. 63 beats/min; p = 0.007) and Agatston score (665 vs. 33; p = 0.002) in group N were significantly higher than those in group M. Multivariate logistic regression analyses revealed that heart rate at CCTA examination (OR 1.348 [95% CI 1.167-1.556]; p < 0.001) and Agatston score (OR 1.002 [95% CI 1.000-1.003]; p = 0.004) were significant, independent factors associated with non-measurability of FFR CT . The frequency of poor image quality was highest in patients with heart rate > 65 beats/min and Agatston score > 400 (p < 0.0001). In conclusions, high heart rate at the time of CCTA examination and higher Agatston score were associated with poor image quality that resulted in cases being inappropriate for FFR CT processing. Heart rate control at CCTA examination is necessary to acquire good-quality images required for computing FFR CT .

Background: Little data exist regarding the clinical application of whole exome sequencing (WES) for the molecular diagnosis of severe hypertriglyceridemia (HTG)., Methods: WES was performed for 28 probands exhibiting severe HTG (≥1000 mg/dl) without any transient causes. We evaluated recessive and dominant inheritance models in known monogenic HTG genes, followed by disease-network gene prioritization and copy number variation (CNV) analyses to identify causative variants and a novel genetic mechanism for severe HTG., Results: We identified possible causative variants for severe HTG, including three novel variants, in nine probands (32%). In the recessive inheritance model, we identified two homozygous subjects with lipoprotein lipase (LPL) deficiency and one subject harboring compound heterozygous variants in both LPL and APOA5 genes (hyperchylomicronemia). In the dominant inheritance model, we identified probands harboring deleterious heterozygous variants in LPL, glucokinase regulatory protein, and solute carrier family 25 member 40 genes, possibly associated with this extreme HTG phenotype. However, gene prioritization and CNV analyses did not validate the novel genes associated with severe HTG., Conclusions: In 28 probands with severe HTG, we identified potential causative variants within nine genes associated with rare Mendelian dyslipidemias. Clinical WES may be feasible for such extreme cases, potentially leading to appropriate therapies., (Copyright © 2018 Elsevier B.V. All rights reserved.)

A 71-year-old woman with congenital rubella syndrome (CRS) presented with prolonged cough. No physical findings suggested the presence of any connective tissue diseases. Chest computed tomography showed ground-glass opacities and consolidations in the bilateral lower lobes. She had elevated serum Krebs von den Lungen-6, hypoxemia and positive serum anti-Jo-1 antibody. Bronchoalveolar lavage fluid revealed lymphocytosis with a decreased CD4/CD8 ratio. A transbronchial lung biopsy specimen revealed organizing pneumonia. Based on a diagnosis of interstitial pneumonia with autoimmune features (IPAF), systemic corticosteroids were administered, and a good outcome was obtained. A possible relationship between CRS and IPAF is herein discussed.

Background: The use of coronary computed tomography angiography (CCTA) for noninvasive anatomic detection of coronary artery disease is increasing. Recently, fractional flow reserve (FFR) assessment using routinely acquired CCTA datasets (FFR CT ) has been developed. However, there are no reports about changes in coronary atherosclerosis, composition, and FFR CT in patients with type 2 diabetes., Methods: This prospective, multicenter, observational trial evaluated changes in coronary atherosclerosis after alogliptin therapy in patients with type 2 diabetes. Fifty-one patients with type 2 diabetes who underwent CCTA examination and having intermediate coronary artery stenosis were treated with 25 mg of alogliptin. After 48 weeks, CCTA examination was repeated. The primary endpoint was changes in FFR CT , and the secondary endpoint was changes in total atheroma volume (TAV) from the baseline to the 48-week follow-up., Results: The FFR CT decreased from the baseline to follow-up, but not significantly. A significant increase in TAV (from 658.5 mm 3 to 668.9 mm 3 , p  = 0.048) was observed. Vessel volume tended to increase, whereas percentage atheroma volume and lumen volume did not change. A significant negative correlation was observed between percentage change in TAV and change in FFR CT ( r  = -0.185, p  = 0.048). A significant increase in calcified plaques ( p  = 0.01) and a decrease in intermediate-attenuation plaques ( p  = 0.006) was observed., Conclusions: In Japanese patients with diabetes and intermediate coronary artery stenosis, alogliptin could not improve FFR CT or reduce atheroma volume, whereas the plaque composition changed. A progression of atheroma volume was associated with a reduction in FFR CT .

Hypercholesterolemia, particularly an increase in low-density lipoprotein cholesterol (LDL-C) levels, contributes substantially to the development of coronary artery disease and the risk for cardiovascular events. As the first-line pharmacotherapy, statins have been shown to reduce both LDL-C levels and cardiovascular events. However, despite intensive statin therapy, a sizable proportion of statin-treated patients are unable to achieve the recommended target LDL-C levels, and not all patients can avoid future cardiovascular events. Proprotein convertase subtilisin/kexin type 9 (PCSK9) plays a key role in cholesterol homeostasis by enhancing the degradation of hepatic low-density lipoprotein receptor (LDLR). Owing to its importance in lipid metabolism, PCSK9 has emerged as a novel pharmacological target for lowering LDL-C levels. In this review, the potential role of circulating PCSK9 as a new biomarker of lipid metabolism is described. Next, previous studies evaluating the effects of lipid-modifying pharmacological agents, particularly statins, on circulating PCSK9 concentrations are summarized. Statins decrease hepatic intracellular cholesterol, resulting in increased LDLRs as well as increased PCSK9 protein. There is a clear dose-response effect of statin treatment on PCSK9 level, as increasing doses of statins also increase the level of circulating PCSK9. Finally, the available therapeutic strategies to inhibit PCSK9 are present. Monoclonal antibodies against PCSK9, in combination with statins, are one of the most promising and novel approaches to achieve further reduction of LDL-C levels and reduce the risk of cardiovascular events.

Activated factor-X (FXa) plays an important role not only in the coagulation cascade, but also in pro-inflammatory responses. However, few data exist regarding the anti-inflammatory effect of FXa inhibitors in clinical practice. The aim of this study was to evaluate the anti-inflammatory and anti-atherosclerotic effects of FXa inhibitors in Japanese patients with non-valvular atrial fibrillation (NVAF). Eighty-three patients with NVAF were treated with FXa inhibitors from March 2013 to March 2015 at our institution. Of these, 55 patients who were not pretreated with warfarin or dabigatran (rivarixaban in 23 patients and apixaban in 32) were included in this study. We measured various inflammatory and coagulation markers at baseline and at 6 months after treatment. Plasma concentrations of pentraxin 3 (PTX3) (from 2.45 ± 1.31 to 1.97 ± 1.00 ng/mL, p = 0.0009) and fibrin and fibrinogen degradation products (FDP) D-dimer (from 1.18 ± 0.70 to 0.74 ± 0.32 μg/mL, p < 0.0001) decreased, while those of TM (from 2.9 ± 0.8 to 3.2 ± 0.9 FU/mL, p = 0.003) increased significantly at 6 months. Interestingly, change of each marker denoted the same tendency in both rivaroxaban and apixaban. In conclusion, the present study suggests that FXa inhibitors have not only an anti-coagulant effect but also anti-inflammatory effects in patients with NVAF. Further large-scale prospective study is necessary to evaluate whether changes in these markers will be associated with a lower risk for future cardiovascular events.