Language：English   Publisher：Scientific Reports  

Vascular calcification, which is a major complication of diabetes mellitus, is an independent risk factor for cardiovascular disease. Osteogenic differentiation of vascular smooth muscle cells (VSMCs) is one of the key mechanisms underlying vascular calcification. Emerging evidence suggests that macrophage-derived extracellular vesicles (EVs) may be involved in calcification within atherosclerotic plaques in patients with diabetes mellitus. However, the role of macrophage-derived EVs in the progression of vascular calcification is largely unknown. In this study, we investigated whether macrophage-derived EVs contribute to the osteogenic differentiation of VSMCs under high glucose conditions. We isolated EVs that were secreted by murine peritoneal macrophages under normal glucose (EVs-NG) or high glucose (EVs-HG) conditions. miRNA array analysis in EVs from murine macrophages showed that miR-17-5p was significantly increased in EVs-HG compared with EVs-NG. Prediction analysis with miRbase identified transforming growth factor β receptor type II (TGF-β RII) as a potential target of miR-17-5p. EVs-HG as well as miR-17-5p overexpression with lipid nanoparticles inhibited the gene expression of Runx2, and TGF-β RII. Furthermore, we demonstrated that VSMCs transfected with miR-17-5p mimic inhibited calcium deposition. Our findings reveal a novel role of macrophage-derived EVs in the negative regulation of osteogenic differentiation in VSMCs under high glucose conditions.

DOI： 10.1038/s41598-024-67006-9

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Language：English   Publisher：The Japanese Circulation Society  

<p><b><i>Background:</i></b> Coronavirus disease 2019 (COVID-19) has impacted on cardiovascular disease. However, it remains unclear whether the COVID-19 pandemic has impacted on disease severity and patients’ prognosis of acute myocardial infarction (AMI) in Japan.</p><p><b><i>Methods and Results:</i></b> We retrospectively accumulated data from the Japanese Registry of All Cardiac and Vascular Diseases–Diagnosis Procedure Combination (JROAD-DPC) study (April 2019 to March 2021). Patients were divided into a before COVID-19 pandemic group or a during COVID-19 pandemic group. The proportion of patients who presented with cardiogenic shock (Killip class IV) was compared between groups, in association with 30-day mortality as the primary outcome. Killip class IV AMI significantly increased in the during COVID-19 pandemic group (15.7% vs. 14.5% in the before pandemic group, P<0.0001). The 30-day mortality was higher in the during COVID-19 pandemic group (9.6% vs. 9.2% in the before COVID-19 pandemic group, P=0.049). However, there was no significant difference in the adjusted 30-day mortality in each Killip class between the before and during COVID-19 pandemic groups.</p><p><b><i>Conclusions:</i></b> During the early stage of the COVID-19 pandemic in Japan, 30-day mortality of AMI increased, mainly because of the increase of Killip class IV AMI patients. However, irrespective of the COVID-19 pandemic, the adjusted 30-day mortality of each Killip classification group was unchanged.</p>

DOI： 10.1253/circrep.cr-24-0011

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Language：English   Publisher：The Japanese Circulation Society  

<p>The 87^thAnnual Meeting of the Japanese Circulation Society (JCS2023) was held in March 2023 in Fukuoka, Japan, marking the first in-person gathering after the COVID-19 pandemic. With the theme of “New Challenge With Next Generation” the conference emphasized the development of future cardiovascular leaders and technologies such as artificial intelligence (AI). Notable sessions included the Mikamo Lecture on heart failure and the Mashimo Lecture on AI in medicine. Various hands-on sessions and participatory events were well received, promoting learning and networking. Post-event surveys showed high satisfaction among participants, with positive feedback on face-to-face interactions and the overall experience. JCS2023, attended by 17,852 participants, concluded successfully, marking a significant milestone in post-pandemic meetings, and advancing cardiovascular medicine.</p>

DOI： 10.1253/circj.cj-24-0127

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Language：English   Publishing type：Research paper (scientific journal)   Publisher：Japan Atherosclerosis Society  

<p> <b>Aim:</b> Several clinical trials using intravascular ultrasound (IVUS) evaluation have demonstrated that intensive lipid-lowering therapy by statin or a combination therapy with statin and ezetimibe results in significant regression of coronary plaque volume. However, it remains unclear whether adding ezetimibe to statin therapy affects coronary plaque composition and the molecular mechanisms of plaque regression. We conducted this prospective IVUS analysis in a subgroup from the CuVIC trial.</p><p><b>Methods:</b> The CuVIC trial was a prospective randomized, open, blinded-endpoint trial conducted among 11 cardiovascular centers, where 260 patients with coronary artery disease who received coronary stenting were randomly allocated into either the statin group (S) or the combined statin and ezetimibe group (S＋E). We enrolled 79 patients (S group, 39 patients; S＋E group, 40 patients) in this substudy, for whom serial IVUS images of nonculprit lesion were available at both baseline and after 6–8 months of follow-up.</p><p><b>Results:</b> After the treatment period, the S＋E group had significantly lower level of low-density lipoprotein cholesterol (LDL-C; 80.9±3.7 vs. 67.7±3.8 mg/dL, <i>p</i>=0.0143). Campesterol, a marker of cholesterol absorption, and oxysterols (β-epoxycholesterol, 4β-hydroxycholesterol, and 27-hydroxycholesterol) were also lower in the S＋E group. IVUS analyses revealed greater plaque regression in the S＋E group than in the S group (−6.14% vs. −1.18% for each group, <i>p</i>=0.042). It was noteworthy that the lowering of campesterol and 27-hydroxycholesterol, but not LDL-C, had a significant positive correlation with plaque regression.</p><p><b>Conclusions:</b> Compared with statin monotherapy, ezetimibe in combination with statin achieved significantly lower LDL-C, campesterol, and 27-hydroxycholesterol, which resulted in greater coronary plaque regression.</p>

DOI： 10.5551/jat.63507

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Language：English   Publisher：(一社)日本動脈硬化学会  

冠動脈ステント留置術を受けた冠動脈疾患の患者をスタチン(S)またはSとエゼチミブの併用(S+E)で治療するCuVIC試験から、治療前と6～8ヵ月追跡調査後の非責任病変の血管内超音波(IVUS)画像が得られた79症例(S群39名、S+E群40名)を抽出し解析した。治療期間後のS+E群のLDL-コレステロール(LDL-C)値はS群と比べて有意に低かった。S+E群ではコレステロール吸収のマーカーであるcampesterol、オキシステロール(β-epoxycholesterol、4β-hydroxycholesterol、27-hydroxycholesterol)も低かった。IVUS解析でS+E群のプラーク退縮率はS群と比べて大きかった。campesterolおよび27-hydroxycholesterolの低下はプラーク退縮と正相関し、LDL-Cの低下は相関しなかった。

Language：English   Publisher：The Japanese Circulation Society  

<p><b><i>Background:</i></b> Recent revisions of clinical guidelines by the Japanese Circulation Society, American Heart Association/American College of Cardiology, and European Society of Cardiology updated the management of antithrombotic strategies for patients with atrial fibrillation (AF) undergoing percutaneous coronary intervention (PCI). However, the extent to which these guidelines have been implemented in real-world daily clinical practice is unclear.</p><p><b><i>Methods and Results:</i></b> We conducted surveys on the status of antithrombotic therapy for patients with AF undergoing PCI every 2 years from 2014 to 2022 in 14 cardiovascular centers in Japan. The primary use of drug-eluting stents increased from 10% in 2014 to 95–100% in 2018, and the use of direct oral anticoagulants increased from 15% in 2014 to 100% in 2018, in accordance with the revised practice guidelines. In patients with acute coronary syndrome, the duration of triple therapy within 1 month was approximately 10% until 2018, and increased to >70% from 2020. In patients with chronic coronary syndrome, the duration of triple therapy within 1 month was approximately 10% until 2016, and >75% from 2018. Since 2020, the most common timing of discontinuation of dual antiplatelet therapy to transition to anticoagulation monotherapy during the chronic phase of PCI has been 1 year after PCI.</p><p><b><i>Conclusions:</i></b> Japanese interventional cardiologists have updated their treatment strategies for patients with AF undergoing PCI according to revisions of clinical practice guidelines.</p>

DOI： 10.1253/circrep.cr-23-0047

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Language：English   Publishing type：Research paper (scientific journal)   Publisher：Nutrients  

Oxysterols have been implicated in the pathogenesis of cardiovascular diseases. Serum levels of oxysterols could be positively correlated with cholesterol absorption and synthesis. However, physiological regulation of various serum oxysterols is largely unknown. The aim of this study was to investigate the relationship between clinical factors and cholesterol metabolism markers, and identify oxysterols associated with cholesterol absorption and synthesis in patients with coronary artery disease. Subjects (n = 207) who underwent coronary stenting between 2011 and 2013 were studied cross-sectionally. We measured lipid profiles including serum oxysterols. As for the serum biomarkers of cholesterol synthesis and absorption, oxysterol levels were positively correlated with campesterol and lathosterol. Covariance structure analysis revealed that dyslipidemia and statin usage had a positive correlation with “cholesterol absorption”. Statin usage also had a positive correlation with “cholesterol synthesis”. Several oxysterols associated with cholesterol absorption and/or synthesis. In conclusion, we elucidated the potential clinical factors that may affect cholesterol metabolism, and the associations between various oxysterols with cholesterol absorption and/or synthesis in patients with coronary artery disease.

DOI： 10.3390/nu15132997

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Language：English   Publisher：CJC Open  

DOI： 10.1016/j.cjco.2022.11.009

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Language：English   Publishing type：Research paper (scientific journal)   Publisher：Scientific Reports  

Emerging evidence suggests that 7-ketocholesterol (7-KC), one of the most abundant dietary oxysterols, causes inflammation and cardiovascular diseases. Here we show the deteriorating effects of dietary 7-KC on myocardial ischemia–reperfusion (IR) injury and detailed the molecular mechanisms. A high-fat high-cholesterol diet containing 7-KC (7KWD) for 3 weeks increased the plasma 7-KC level compared with high-fat high-cholesterol diet in mice. In wild-type mice but not in CCR2−/− mice, dietary 7-KC increased the myocardial infarct size after IR. Flow cytometry revealed that the ratio of Ly-6Chigh inflammatory monocytes to total monocytes was increased in the 7KWD group. Unbiased RNA sequencing using murine primary macrophages revealed that 7-KC regulated the expression of transcripts related to inflammation and cholesterol biosynthesis. We further validated that in vitro, 7-KC induced endoplasmic reticulum stress, mitochondrial reactive oxygen species production, and nuclear factor-kappa B activation, which are associated with increased mRNA levels of proinflammatory cytokines. Administration of N-acetyl-l-cysteine or siRNA-mediated knockdown of PKR-like endoplasmic reticulum kinase or endoplasmic reticulum oxidase 1α suppressed the levels of 7-KC-induced inflammation. Dietary 7-KC exacerbates myocardial IR injury through monocyte/macrophage-mediated inflammation. Endoplasmic reticulum stress and oxidative stress are involved in the 7-KC-induced proinflammatory response in macrophages.

DOI： 10.1038/s41598-022-19065-z

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Language：English   Publisher：Japan Atherosclerosis Society  

<p><b>Aims:</b> Previous studies suggested that implantation with a 1st-generation DES was associated with coronary endothelial dysfunction, which was associated with Rho-kinase activation. Second-generation drug-eluting stents (DESs) may preserve coronary endothelial function in stented coronary arteries; however, because of methodological limitations, further study is needed to clarify the association between 2 ^nd-generation DESs and coronary endothelial dysfunction. </p><p><b>Methods:</b> We retrospectively analysed the CuVIC trial database, where we identified 112 patients who underwent coronary stenting in the left coronary arteries with either a bare metal stent (BMS, <i>n</i>=53) or 2^nd-generation DES (<i>n</i>=59). We compared vasomotions of target vessels with stents and non-target vessels without stents. Furthermore, we measured the Rho-kinase activation detected in mononucleocytes from aortic and coronary sinus blood. </p><p><b>Results:</b> ACh-induced vasoconstrictive responses of target vessels were not enhanced with a 2^nd-generation DES (45±21% vs. 44±20%, <i>P</i>=0.56, paired <i>t</i>-test), but significantly enhanced in the coronary arteries with a BMS (50±18% vs. 42±20%, <i>P</i>=0.002). Rho-kinase activation did not differ between patients with a BMS and 2^nd-generation DES. In the target vessels with a BMS, large late lumen loss and acute coronary syndrome (ACS) at the index percutaneous coronary intervention (PCI) were associated with ACh-induced enhanced coronary vasoconstrictive responses. </p><p><b>Conclusions:</b> Evaluation of ACh-induced vasomotion of target vessels comparing with non-target vessels revealed that 2^nd-generation DESs were not associated with coronary endothelial dysfunction in target vessels, nor activation of Rho-kinase in the coronary sinus blood 6-8 months after stenting. </p>

DOI： 10.5551/jat.61366

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