DOI： 10.1253/circj.cj-24-0076

PubMed

DOI： 10.1016/j.jacep.2023.10.017

DOI： 10.1016/j.jaccas.2023.102160

Publishing type：Research paper (scientific journal)   International / domestic magazine：International journal  

BACKGROUND: Sex disparities in the association between epicardial adipose tissue volume (EATV) and cardiovascular disease have been reported. The sex-dependent effects of EATV on left atrial (LA) size have not been elucidated. METHODS: Consecutive 247 subjects (median 65 [interquartile range 57, 75] years; 67% of men) who underwent multi-detector computed tomography without significant coronary artery disease or moderate to severe valvular disease were divided into two groups: patients with sinus rhythm (SR) or atrial fibrillation (AF). Sex differences in the association between the EATV index (EATVI) (mL/m2) and LA volume index (LAVI) in 63 SR (28 men and 35 women) and 184 AF (137 men and 47 women) patients were evaluated using univariate and multivariate regression analyses. RESULTS: In overall that includes both men and women, the relationship between EATVI and LAVI was not significantly correlated for patients with SR and AF. The relationship between EATVI and LAVI differed between men and women in both SR and AF groups. In SR patients, there was a positive relationship between EATVI and LAVI in men, but not in women. In contrast, in patients with AF, a negative relationship was found between EATVI and LAVI in women, whereas no association was found in men. CONCLUSIONS: We evaluated sex differences in the association between EATVI and LAVI in patients with either SR or AF, and found a positive relationship in men with SR and a negative relationship in women with AF. This is the first report to evaluate sex differences in the relationship between EATVI and LAVI, suggesting that EAT may play a role, at least in part, in sex differences in the etiology of AF.

DOI： 10.1186/s12872-023-03569-1

PubMed

DOI： 10.1093/eurheartj/ehad695

DOI： 10.1007/s10840-023-01687-6

DOI： 10.1007/s00380-024-02358-w

Publishing type：Research paper (scientific journal)   International / domestic magazine：Domestic journal  

<p>We herein report the case of a 46-year-old woman with Takayasu arteritis (TA), severe stenosis in the left main coronary artery (LMCA), and severe aortic regurgitation. Prednisolone and tacrolimus were initiated as TA treatments. Two months after initiating medical therapy, the aortic regurgitation severity improved to a moderate grade, although there was no obvious improvement in LMCA stenosis. Thus, after confirming the resolution of inflammation, we performed coronary artery bypass grafting alone without any aortic valve intervention. In TA patients with severe LMCA stenosis, surgical management of the coronary artery should therefore be considered only after successfully administering anti-inflammatory therapy. </p>

DOI： 10.2169/internalmedicine.3032-23

PubMed

Publishing type：Research paper (scientific journal)   International / domestic magazine：Domestic journal  

Reduced exercise tolerance is one of the hallmarks of patients with cardiac amyloidosis (CA), but detailed biological responses during exercise were not investigated. The purpose of this study was to compare the cardiopulmonary exercise test (CPX) parameters between CA patients and propensity-matched heart failure patients. This was a single-center, retrospective, observational study of patients diagnosed with CA. The control group was extracted by propensity score matching from patients who underwent CPX for chronic heart failure during the same period. Clinical data including assessment of biological responses during CPX were compared between the patients with CA (CA group, n = 16) and the control group (non-CA group, n = 16). Echocardiography suggested more impaired diastolic function in the CA group than in the non-CA group. There was no significant difference between groups in the fraction of end-tidal carbon dioxide (FETCO2) at rest. However, the difference between the FETCO2 at rest and the FETCO2 at the respiratory compensation point (ΔFETCO2) was significantly smaller in the CA group than in the non-CA group (0.40% ± 0.37% vs. 0.82% ± 0.33%; p = 0.002). Only in the CA group, there was a significant negative correlation between the ΔFETCO2 and the E/e' ratio on echocardiography (r = - 0.521; p = 0.039) and the serum high-sensitivity troponin T concentration (r = - 0.501; p = 0.048). In conclusion, patients with CA may find it difficult to increase cardiac output during exercise due to severe diastolic dysfunction.

DOI： 10.1007/s00380-023-02342-w

PubMed

International / domestic magazine：Domestic journal  

DOI： 10.1007/s12928-023-00973-4

PubMed

DOI： 10.1186/s12933-023-01928-y

DOI： 10.1186/s12933-023-01856-x

DOI： 10.1038/s41598-023-37183-0

DOI： 10.1016/j.ijcha.2023.101279

Publishing type：Research paper (scientific journal)   International / domestic magazine：International journal  

Background Sterile inflammation caused by metabolic disorders impairs endothelial function; however, the underlying mechanism by which hyperglycemia induces inflammation remains obscure. Recent studies have suggested that stimulator of interferon genes (STING), a key cytosolic DNA sensor in the innate immune system, contributes to the pathogenesis of inflammatory diseases. This study examines the role of the STING in endothelial dysfunction in streptozotocin-induced diabetic mice. Methods and Results Injection of streptozotocin promoted the expression of STING and DNA damage markers in the aorta of wild-type mice. Streptozotocin elevated blood glucose and lipid levels in both wild-type and STING-deficient mice, which showed no statistical differences. Genetic deletion of STING ameliorated endothelial dysfunction as determined by the vascular relaxation in response to acetylcholine (P<0.001) and increased endothelial nitric oxide synthase phosphorylation in the aorta (P<0.05) in STZ-injected mice. Endothelium-independent vascular response to sodium nitroprusside did not differ. Treatment with a direct STING agonist, cyclic GMP-AMP, or mitochondrial DNA increased inflammatory molecule expression (eg, VCAM1 and IFNB) and decreased endothelial nitric oxide synthase phosphorylation in human umbilical vein endothelial cells, partially through the STING pathway. Cyclic GMP-AMP significantly impaired endothelial function of aortic segments obtained from wild-type mice, which was ameliorated in the presence of C-176, a STING inhibitor, or a neutralizing interferon-β antibody. Furthermore, the administration of C-176 ameliorated endothelial dysfunction in STZ-induced diabetic mice (P<0.01). Conclusions The DNA damage response regulated by STING impairs endothelial function. STING signaling may be a potential therapeutic target of endothelial dysfunction caused by hyperglycemia.

DOI： 10.1161/JAHA.123.030084

PubMed

DOI： 10.1016/j.jccase.2023.07.002

DOI： 10.1007/s10554-023-02917-8

Publishing type：Research paper (scientific journal)   International / domestic magazine：Domestic journal  

Histopathological examination has revealed that stents on severely calcified plaques were associated with delayed vascular healing. Although atherectomy devices can increase the number of malapposed struts, tissue responses to implanted drug eluting stents in atherectomy patients remain largely unknown. This retrospective observational study included 30 patients who underwent atherectomy and everolimus-eluting stent (EES) deployment for severely calcified coronary lesions (biodegradable polymer EES (BP-EES), n = 15; durable polymer EES (DP-EES), n  = 15). Optical coherence tomography was carried out at baseline and follow-up, and struts with acute stent malapposition (ASM) were categorized as struts on modified calcium (mod-Ca), non-modified calcium (non-mod-Ca), or non-calcium (non-Ca). Adequate vascular healing, defined as ASM resolution with neointimal coverage, was compared between the BP-EES and DP-EES groups. Multivariate linear regression analysis using a generalized estimated equation revealed that BP-EES use was associated with significantly better adequate vascular healing compared with DP-EES (odds ratio [OR]: 3.691, 95% confidence interval [CI] 1.175-11.592, P = 0.025). adequate vascular healing was associated with the underlying plaque morphology (mod-Ca vs non-mod-Ca: OR 2.833, 95% CI 1.491-5.384, P = 0.001; non-Ca vs non-mod-Ca: OR 1.248, 95% CI 0.440-3.543, P = 0.677). This study demonstrates that drug-eluting stent selection and calcium modification are possible factors affecting vascular healing of malapposed struts in severely calcified lesions.

DOI： 10.1007/s12928-023-00965-4

PubMed

International / domestic magazine：International journal  

KEY CLINICAL MESSAGE: Contrast defects in veins are often diagnosed as benign thrombi, but depending on the patient's background it is necessary to differentiate between tumor thrombi. It is difficult to differentiate between these using contrast-enhanced CT alone, but with angioscopy it is easy to visually distinguish between a benign and tumor thrombi. ABSTRACT: Contrast-enhanced computer tomography (CT) performed on a male patient being treated for de-differentiated chondrosarcoma revealed contrast defects in the pulmonary artery and right femoral vein, and a diagnosis of pulmonary artery thromboembolism and venous thromboembolism was made, and oral anticoagulant therapy was started. However, a follow-up CT showed that the contrast defect had extended to the inferior vena cava. Observation using an angioscope revealed that it was not a benign thrombi but a tumor.

DOI： 10.1002/ccr3.7975

PubMed

DOI： 10.1002/jcu.23514

DOI： 10.1016/S2589-7500(23)00107-3

Publishing type：Research paper (scientific journal)   International / domestic magazine：Domestic journal  

The Mediterranean diet, which is characterized by high consumption of olive oil, prevents cardiovascular disease. Meanwhile, olive mill wastewater (OMWW), which is obtained as a byproduct during olive oil production, contains various promising bioactive components such as water-soluble polyphenols. Hydroxytyrosol (HT), the major polyphenol in OMWW, has anti-oxidative and anti-inflammatory properties; however, the atheroprotective effects of OMWW and HT remain to be fully understood. Here, we investigated the effect of OMWW and HT on atherogenesis. Male 8-week-old apolipoprotein E-deficient mice were fed a western-type diet supplemented with OMWW (0.30%w/w) or HT (0.02%w/w) for 20 weeks. The control group was fed a non-supplemented diet. OMWW and HT attenuated the development of atherosclerosis in the aortic arch as determined by Sudan IV staining (P < 0.01, respectively) without alteration of body weight, plasma lipid levels, and blood pressure. OMWW and HT also decreased the production of oxidative stress (P < 0.01, respectively) and the expression of NADPH oxidase subunits (e.g., NOX2 and p22phox) and inflammatory molecules (e.g. IL-1β and MCP-1) in the aorta. The results of in vitro experiments demonstrated that HT inhibited the expression of these molecules that were stimulated with LPS in RAW264.7 cells, murine macrophage-like cells. OMWW and HT similarly attenuated atherogenesis. HT is a major component of water-soluble polyphenols in OMWW, and it inhibited inflammatory activation of macrophages. Therefore, our results suggest that the atheroprotective effects of OMWW are at least partially attributable to the anti-inflammatory effects of HT.

DOI： 10.1007/s00380-023-02290-5

PubMed

DOI： 10.1093/ehjci/jead081

International / domestic magazine：International journal  

DOI： 10.1093/ehjcr/ytad278

PubMed

肺静脈隔離(PVI)への左房後壁隔離(LA PWI)の追加はPVI単独よりも非発作性心房細動(AF)患者の予後を改善することが報告されている。本研究では、左房後壁内部への追加通電の必要性の予測因子を明らかするため、後ろ向きコホート研究を行った。2018年6月～2020年7月に当院で非発作性AFに対して初回のPVIとLA PWIを行った患者77例を対象とした。3Dマッピングシステムを用いて左房内の双極電位を記録した後にPVIとLA PWIを行った。天井ラインと底部ラインの作成でLA PWIが完成、もしくはライン上のgapへの追加通電で隔離が完成したA群35例(男性68.6%、平均68.2±8.3歳)と、それでは隔離できず左房後壁内部への通電が必要であったB群42例(男性78.6%、平均62.9±11.8歳)に分けた。最終的に全例でPVIが達成され、追加通電によって全例でLA PWIが達成された。A群はB群と比較して年齢が有意に高く、天井ライン上の最大電位と平均電位が有意に高かった。年齢を調整後の多変量解析では、天井ライン上の最大電位と平均電位が、後壁内部の追加通電の独立した予測因子であった。

Publishing type：Research paper (scientific journal)   International / domestic magazine：International journal  

Cardiometabolic disorders, including obesity-related insulin resistance and atherosclerosis, share sterile chronic inflammation as a major cause; however, the precise underlying mechanisms of chronic inflammation in cardiometabolic disorders are not fully understood. Accumulating evidence suggests that several coagulation proteases, including thrombin and activated factor X (FXa), play an important role not only in the coagulation cascade but also in the proinflammatory responses through protease-activated receptors (PARs) in many cell types. Four members of the PAR family have been cloned (PAR 1-4). For instance, thrombin activates PAR-1, PAR-3, and PAR-4. FXa activates both PAR-1 and PAR-2, while it has no effect on PAR-3 or PAR-4. Previous studies demonstrated that PAR-1 and PAR-2 activated by thrombin or FXa promote gene expression of inflammatory molecules mainly via the NF-κB and ERK1/2 pathways. In obese adipose tissue and atherosclerotic vascular tissue, various stresses increase the expression of tissue factor and procoagulant activity. Recent studies indicated that the activation of PARs in adipocytes and vascular cells by coagulation proteases promotes inflammation in these tissues, which leads to the development of cardiometabolic diseases. This review briefly summarizes the role of PARs and coagulation proteases in the pathogenesis of inflammatory diseases and describes recent findings (including ours) on the potential participation of this system in the development of cardiometabolic disorders. New insights into PARs may ensure a better understanding of cardiometabolic disorders and suggest new therapeutic options for these major health threats.

DOI： 10.1016/j.jjcc.2022.09.013

PubMed

Publishing type：Research paper (scientific journal)   International / domestic magazine：Domestic journal  

DOI： 10.1007/s12928-022-00902-x

PubMed

新規非ステロイド性選択的ミネラルコルチコイド受容体(MR)ブロッカーエサキセレノンが糖尿病誘発性血管機能障害に及ぼす影響について検討した。8週齢の雄性C57BL/6マウスにストレプトゾトシン(STZ)を単回投与して糖尿病モデルを作成し、エサキセレノン3mg/kg/日または賦形剤を3週間投与した。投与後、代謝パラメータ、血漿中アルドステロン、腎機能パラメータを測定し、大動脈セグメントにおける血管内皮依存性・非依存性血管反応を評価した。さらに、ヒト臍帯静脈内皮細胞(HUVECs)をin vitro評価に用いた。糖尿病モデルマウスにおいて血糖値の有意な上昇のほか、血漿中糖アルブミン、血漿脂質、血漿中アルドステロンの増加が生じており、エサキセレノン投与では血圧減少はみられず、代謝パラメータへの影響もみられなかった。STZ投与に伴い血管拡張能に障害が誘発されたが、エサキセレノン投与後、血管内皮依存性血管障害に改善が認められ、内皮非依存性血管拡張には有意な変化はみられなかった。HUVECsを用いた検討では、アルドステロンによって用量依存性にeNOS Ser1177のリン酸化が有意に減少しており、eNOS Thr495リン酸化の増大、eNOS Ser1177/eNOS Thr495リン酸化比の有意な減少が観察された。エサキセレノン投与ではeNOS Ser1177のリン酸化とeNOS Ser1177/eNOS Thr495リン酸化比の有意な増加、eNOS Thr495リン酸化の有意な減少が認められた。エサキセレノンは糖尿病誘発性血管機能障害に対して緩和作用を有することが示された。

Publishing type：Research paper (scientific journal)   International / domestic magazine：International journal  

BACKGROUND: This study aimed to investigate the association between the extent and severity of coronary atherosclerosis, epicardial adipose tissue (EAT) accumulation, and left ventricular (LV) global longitudinal strain (GLS) in patients with preserved LV ejection fraction (LVEF) and without LV regional wall motion abnormalities. METHODS: This study included 169 preserved LVEF patients without LV wall motion abnormalities who underwent coronary computed tomography (CT) angiography for the assessment of suspected coronary artery disease (CAD). The segment stenosis score (SSS) and segment involvement score (SIS) were calculated to evaluate CAD extent. The EAT volume was defined as CT attenuation values ranging from -250 to -30 HU within the pericardial sac. LVGLS was measured using echocardiography to assess subclinical LV dysfunction. RESULTS: All patients had preserved LVEF of ≥50%, and the mean LVGLS was -18.7% (-20.5% to -16.9%). Mean SSS and SIS were 2.0 (0-5) and 4.0 (0-36), respectively, while mean EAT volume was 116.1 mL (22.9-282.5 mL). Multivariate analysis using linear regression model demonstrated that LVEF (β, -17.0; 95% CI, -20.9 - -13.1), LV mass index (β, 0.03; 95% CI, 0.01-0.06), and EAT volume (β, 0.010; 95% CI, 0.0020-0.0195) were independently associated with LVGLS; however, obstructive CAD was not. The multivariate models demonstrated that SSS (Î, 0.12; 95% CI, 0.05-0.18) and SIS (Î, 0.27; 95% CI, 0.10-0.44) were correlated with deterioration of LVGLS, independent of other parameters. CONCLUSION: This study demonstrates that EAT volume and CAD extent are associated with the deterioration of LVGLS in this population.

DOI： 10.1016/j.ijcha.2023.101176

PubMed

Publishing type：Research paper (scientific journal)   International / domestic magazine：Domestic journal  

<p><b><i>Background:</i></b> Coronary intraplaque microluminal structures (MS) are associated with plaque vulnerability, and the inward progression of vascular inflammation from the adventitia towards the media and intima has also been demonstrated. Therefore, in the present study we investigated the relationships among MS, local inflammation in adjacent epicardial adipose tissue (EAT), and coronary plaque characteristics.</p><p><b><i>Methods and Results:</i></b> Optical coherence tomography (OCT) revealed MS in the left anterior descending coronary artery in 10 fresh cadaveric hearts. We sampled 30 lesions and subdivided them based on the presence of MS: MS (+) group (n=19) and MS (−) group (n=11). We measured inflammatory molecule levels in the adjacent EAT and percentage lipid volume assessed by integrated backscatter intravascular ultrasound in each lesion. The expression levels of vascular endothelial growth factor B and C-C motif chemokine ligand 2 were significantly higher in the MS (+) group than in the MS (−) group (0.9±0.7 vs. 0.2±0.2 arbitrary units (AU), P=0.04 and 1.5±0.5 vs. 0.6±0.7 AU, P=0.02, respectively). Percentage lipid volume was significantly higher in the MS (+) group than in the MS (−) group (38.7±16.5 vs. 23.7±10.9%, P=0.03).</p><p><b><i>Conclusions:</i></b> Intraplaque MS observed on OCT were associated with lipid-rich plaques and local inflammation in the adjacent EAT. Collectively, these results suggest that local inflammation in the EAT is associated with coronary plaque vulnerability via MS.</p>

DOI： 10.1253/circj.CJ-22-0299

PubMed

Publishing type：Research paper (scientific journal)   International / domestic magazine：International journal  

BACKGROUND: Mechanical stress on the heart, such as high blood pressure, initiates inflammation and causes hypertrophic heart disease. However, the regulatory mechanism of inflammation and its role in the stressed heart remain unclear. IL-1β (interleukin-1β) is a proinflammatory cytokine that causes cardiac hypertrophy and heart failure. Here, we show that NLRP3 (neural signals activate the nucleotide-binding domain, leucine-rich-containing family, pyrin domain-containing 3) inflammasome for IL-1β production to induce adaptive hypertrophy in the stressed heart. METHODS: C57BL/6 mice, knockout mouse strains for NLRP3 and P2RX7 (P2X purinoceptor 7), and adrenergic neuron-specific knockout mice for SLC17A9, a secretory vesicle protein responsible for the storage and release of ATP, were used for analysis. Pressure overload was induced by transverse aortic constriction. Various animal models were used, including pharmacological treatment with apyrase, lipopolysaccharide, 2'(3')-O-(4-benzoylbenzoyl)-ATP, MCC950, anti-IL-1β antibodies, clonidine, pseudoephedrine, isoproterenol, and bisoprolol, left stellate ganglionectomy, and ablation of cardiac afferent nerves with capsaicin. Cardiac function and morphology, gene expression, myocardial IL-1β and caspase-1 activity, and extracellular ATP level were assessed. In vitro experiments were performed using primary cardiomyocytes and fibroblasts from rat neonates and human microvascular endothelial cell line. Cell surface area and proliferation were assessed. RESULTS: Genetic disruption of NLRP3 resulted in significant loss of IL-1β production, cardiac hypertrophy, and contractile function during pressure overload. A bone marrow transplantation experiment revealed an essential role of NLRP3 in cardiac nonimmune cells in myocardial IL-1β production and cardiac phenotype. Pharmacological depletion of extracellular ATP or genetic disruption of the P2X7 receptor suppressed myocardial NLRP3 inflammasome activity during pressure overload, indicating an important role of ATP/P2X7 axis in cardiac inflammation and hypertrophy. Extracellular ATP induced hypertrophic changes of cardiac cells in an NLRP3- and IL-1β-dependent manner in vitro. Manipulation of the sympathetic nervous system suggested sympathetic efferent nerves as the main source of extracellular ATP. Depletion of ATP release from sympathetic efferent nerves, ablation of cardiac afferent nerves, or a lipophilic β-blocker reduced cardiac extracellular ATP level, and inhibited NLRP3 inflammasome activation, IL-1β production, and adaptive cardiac hypertrophy during pressure overload. CONCLUSIONS: Cardiac inflammation and hypertrophy are regulated by heart-brain interaction. Controlling neural signals might be important for the treatment of hypertensive heart disease.

DOI： 10.1161/CIRCULATIONAHA.122.060860

PubMed

DOI： 10.1016/j.jaccas.2022.10.009

PubMed

冠動脈プラーク内に観察される微小管腔構造(MS)、隣接する心外膜脂肪組織(EAT)の局所炎症、冠動脈プラークの性状の関連性を新鮮献体で調べた。新鮮献体10体(女性7名、年齢69～96歳)の左冠動脈前下行枝を対象とした。光干渉断層法(OCT)を施行してMSの評価を行った。標本として選出した30病変を、MS陽性の19病変とMS陰性の11病変に分類した。病変毎に、隣接EAT内の炎症性分子レベルの測定、および後方散乱血管内超音波法による脂質体積百分率の評価を行った。血管内皮細胞増殖因子(VEGF)BとC-Cモチーフケモカインリガンド2の発現レベルは、いずれもMS陰性の病変群に対しMS陽性の群で有意に上昇していた(0.9±0.7 vs.0.2±0.2任意単位[AU]、P=0.04、1.5±0.5 vs.0.6±0.7AU、P=0.02)。脂質体積百分率はMS陽性群で平均38.7±16.5%、MS陰性群で平均23.7±10.9%となり、MS陽性群の方が有意に高かった(P=0.03)。OCTで観察されるプラーク内MS所見は、隣接EATの局所炎症、および脂質が豊富なプラークと関連していた。総合すると、EAT内の局所炎症は、MSによって生じる冠動脈プラークの脆弱性に関連していることが示唆された。

DOI： 10.3389/fcvm.2023.1095806

Objective: The cutoff value on radiography for judging Achilles tendon xanthoma (ATX), one of the diagnostic criteria for familial hypercholesterolemia, was altered from 9 mm to 8/7.5 mm (men/women) in the new guidelines from the Japan Atherosclerosis Society. The present study investigated whether or not ATX newly identified by the revised criteria, i.e. Achilles tendon thickness (ATT) of ≥ 8 mm and < 9 mm in men, is associated with coronary lesion severity in premature coronary artery disease (CAD) patients.<br>Methods: Eighty-seven male subjects with a history of acute coronary syndrome (ACS) under 60 years old and with a maximum ATT for the right and left sides of < 9 mm were enrolled. The severity of the coronary lesions was assessed using the SYNTAX score derived from coronary angiography at the onset of ACS.<br/>Results: Nine patients (10%) had a maximum ATT ≥ 8 mm (ATX group) among the present subjects. The SYNTAX score was significantly larger in the ATX group than in the non-ATX group (18.3 ± 9.8 vs. 12.3 ± 7.3, <i>P</i> = 0.028). The ATX group also had an increased body mass index (BMI) and C-reactive protein (CRP) level. In all subjects, the maximum ATT was positively correlated with the SYNTAX score (R = 0.337, <i>P</i> = 0.001). A multiple regression analysis revealed that the presence of ATX was significantly associated with the SYNTAX score, independent of confounding factors, including the BMI and CRP.<br>Conclusions: This study demonstrated that ATX, even when mild, was associated with coronary lesion severity in premature CAD. ATX, based on new criteria, may be an independent predictor of CAD progression.<br/>

DOI： 10.7793/jcad.29.23-00010

Publishing type：Research paper (scientific journal)   International / domestic magazine：International journal  

BACKGROUND: Lung subtraction iodine mapping (LSIM)-CT is a clinically useful technique that can visualize pulmonary mal-perfusion in patients with chronic thromboembolic pulmonary disease (CTEPD). However, little is known about the associations of LSIM images with hemodynamic parameters of patients with CTEPD. This study investigates a parameter of LSIM images associated with mean pulmonary arterial pressure (mPAP) and validates the association between pulmonary vascular resistance, right atrial pressure, cardiac index, and exercise capacity in patients with CTEPD. METHODS: This single-center, prospective, observational study involved 30 patients diagnosed with CTEPD using lung perfusion scintigraphy. To examine the correlation of decreased pulmonary perfusion area (DPA) with mPAP, areas with 0-10, 0-15, 0-20, and 0-30 HU in lung subtraction images were adopted in statistical analysis. The DPA to total lung volume ratio (DPA ratio, %) was calculated as the ratio of each DPA volume to the total lung volume. To assess the correlation between DPA ratios of 0-10, 0-15, 0-20, and 0-30 HU and mPAP, Spearman's rank correlation coefficient was used. RESULTS: The DPA ratio of 0-10 HU had the most preferable correlation with mPAP than DPA ratios of 0-15, 0-20, and 0-30 HU (ρ = 0.440, P = 0.015). The DPA ratio of 0-10 HU significantly correlates with pulmonary vascular resistance (ρ = 0.445, P = 0.015). The receiver operating characteristic curve analysis indicated that the best cutoff value of the DPA ratio of 0-10 HU for the prediction of an mPAP of ≥30 mmHg was 8.5% (AUC, 0.773; 95% CI, 0.572-0.974; sensitivity, 83.3%; specificity, 75.0%). Multivariate linear regression analysis, which was adjusted for the main pulmonary arterial to ascending aortic diameter ratio and right ventricular to left ventricular diameter ratio, indicated that the DPA ratio of 0-10 HU was independently and significantly associated with mPAP (B = 89.7; 95% CI, 46.3-133.1, P < 0.001). CONCLUSION: The DPA ratio calculated using LSIM-CT is possibly useful for estimating the hemodynamic status in patients with CTEPD.

DOI： 10.3389/fcvm.2023.1237296

PubMed

Publishing type：Research paper (scientific journal)   International / domestic magazine：International journal  

BACKGROUND: Chronic kidney disease (CKD) impacts prognosis in patients undergoing transcatheter aortic valve implantation (TAVI). While estimated glomerular filtration rate (eGFR) calculated from serum creatinine [eGFR (creatinine)] is affected by body muscle mass which reflects frailty, eGFR calculated from serum cystatin C [eGFR (cystatin C)] is independent of body composition, resulting in better renal function assessment. METHODS: This study included 390 consecutive patients with symptomatic severe aortic stenosis (AS) who underwent TAVI, and measured cystatin C-based eGFR at discharge. Patients were divided into two groups, with or without CKD estimated with eGFR (cystatin C). The primary endpoint of this study was the 3-year all-cause mortality after TAVI. RESULTS: The median patient age was 84 years, and 32.8% patients were men. Multivariate Cox regression analysis indicated that eGFR (cystatin C), diabetes mellitus, and liver disease were independently associated with 3-year all-cause mortality. In the receiver-operating characteristic (ROC) curve, the predictive value of eGFR (cystatin C) was significantly higher than that of eGFR (creatinine). Furthermore, Kaplan-Meier estimates revealed that 3-year all-cause mortality was higher in the CKD (cystatin C) group than that in the non-CKD (cystatin C) group with log-rank p = 0.009. In contrast, there was no significant difference between the CKD (creatinine) and non-CKD (creatinine) groups with log-rank p = 0.94. CONCLUSIONS: eGFR (cystatin C) was associated with 3-year all-cause mortality in patients who underwent TAVI, and it was superior to eGFR (creatinine) as a prognostic biomarker.

DOI： 10.3389/fcvm.2023.1035736

PubMed

冠動脈CT血管造影(CCTA)-Wide Volume Scan(WVS)により冠動脈疾患と胸部大動脈プラークを同時に評価し、心血管予後との関連について検討した。2017年4月〜2019年11月の期間にCCTA-WVS検査により冠動脈疾患の評価と大動脈弓を含む胸部大動脈の評価を行った胸痛患者455名(男性234名、女性221名、平均65±13歳)を対象とした。CCTA-WVS所見は冠動脈石灰化スコア0、0〜100、101〜400、>400がそれぞれ42.9%、26.8%、20.6%、11.2%であった。平均2.8±0.9年の追跡期間中、445例中34例(7.6%)に主要有害事象(MACE)を認めた。吹田CVDリスクスコアで調整したCox比例ハザードモデルでは、冠動脈石灰化スコア>400と胸部大動脈プラークスコア(T3)が心血管イベント発症の独立した予測因子であった。CCTA-WVSを用いた胸部大動脈プラークスコアと冠動脈疾患の包括的評価が心血管イベントリスクの層別化に貢献できると考えられた。

DOI： 10.7759/cureus.32234

PubMed

DOI： 10.1016/j.jacasi.2022.09.005

PubMed

心外膜脂肪組織(EAT)量は冠動脈疾患や心房細動と関連するので、心不全(HF)で駆動率(EF)の低下(HFrEF)した患者におけるEAT量と右心室(RV)の収縮機能の関係を調べた。心臓MRIとCTを行った非虚血性HFの100名の患者を被験者とした。始めに患者を左心室(LV)EF50%以上と50%未満に分け、EFの保たれている(HFpEF)群14名と、HFrEF群86名とした。HFrEF群はさらにRV機能障害のある群(RVEF=45%未満)54名と、ない群(RVEF=45%以上)32名に分けた。HFrEFでRV機能障害群における体表面積(BSA)に対するEAT量は、他の群よりも有意に低かった。HFrEF群では、BSAに対するEAT量はRVEFと正相関を示したが、LVEFとは相関しなかった。RV機能障害のあるHFrEF患者は、HFpEF患者よりもEATが少なく、EATの低値がHFrEFのRV機能障害の重篤性と関連することが示された。

DOI： 10.21037/cdt-22-306

PubMed

Publishing type：Research paper (scientific journal)   International / domestic magazine：International journal  

BACKGROUND: Wide-volume scanning with 320-row multidetector computed tomography coronary angiography (CTCA-WVS) enables the assessment of the aortic arch plaque (AAP) morphology and coronary arteries without requiring additional contrast volume. This study aimed to investigate the prevalence of AAPs and their association with coronary artery disease (CAD) and major adverse cardiovascular events (MACEs) in patients who underwent CTCA-WVS. METHODS: This study included 204 patients without known CAD (mean age, 65 years; 53% men) who underwent CTCA-WVS. We evaluated the presence of aortic plaques in the ascending aorta, aortic arch, and thoracic descending aorta using CTCA-WVS. Large aortic plaques were defined as plaques of at least 4 mm in thickness. A complex aortic plaque was defined as a plaque with ulceration or protrusion. MACEs were defined as composite events of cardiovascular (CV) death, nonfatal myocardial infarction, and ischemic stroke. RESULTS: AAPs and large/complex AAPs were identified in 51% ( n = 105) and 18% ( n = 36) of the study patients, respectively. The prevalence of AAPs with large/complex morphology increased with CAD severity (2.1% in no CAD, 12% in nonobstructive CAD, and 39% in obstructive CAD). The univariate Cox hazard model demonstrated that the predictors associated with MACEs were diabetes, obstructive CAD, and large/complex AAPs. Independent factors associated with large/complex AAPs were male sex [odds ratio (OR), 2.90; P = 0.025], stroke history (OR, 3.48; P = 0.026), obstructive CAD (OR, 3.35; P = 0.011), and thoracic aortic calcification (OR, 1.77; P = 0.005). CONCLUSION: CTCA-WVS provides a comprehensive assessment of coronary atherosclerosis and thoracic aortic plaques in patients with CAD, which may improve the stratification of patients at risk for CV events.

DOI： 10.1097/MCA.0000000000001171

PubMed

DOI： 10.1111/jce.15627

PubMed

DOI： 10.1111/jce.15663

PubMed

Publishing type：Research paper (scientific journal)   International / domestic magazine：International journal  

BACKGROUND: Esaxerenone is a novel, non-steroidal selective mineralocorticoid receptor (MR) blocker. MR activation plays a crucial role in the development of cardiovascular and metabolic diseases. In this study, we investigated the effects of esaxerenone on various metabolic parameters in mice. MATERIALS AND METHODS: Esaxerenone (3 mg/kg/day) was orally administered to high-fat diet (HFD)-fed male C57BL/6 mice. Mice fed a normal diet (ND) served as controls. Glucose and insulin tolerance, plasma lipid levels, and transaminase levels were assessed as metabolic parameters. Macrophage accumulation in the adipose tissue was evaluated using histological analysis. 3T3-L1 adipocytes, HepG2 cells, and C2C12 myotubes were used for in vitro experiments. Gene expression and insulin signaling were examined using quantitative RT-PCR and western blotting, respectively. RESULTS: HFD successfully induced insulin resistance compared with that in ND. Esaxerenone ameliorated insulin resistance (P < 0.05) without altering other metabolic parameters, such as the lipid profile. Esaxerenone administration tended to decrease plasma transaminase levels compared with those in the non-treated group. In the adipose tissue, esaxerenone decreased macrophage accumulation (P < 0.05) and increased the expression levels of adiponectin and PPARγ. Aldosterone significantly decreased the expression levels of PPARγ and adiponectin in 3T3-L1 adipocytes. Furthermore, aldosterone attenuated insulin-induced Akt phosphorylation in 3T3-L1 adipocytes, HepG2 cells, and C2C12 myotubes in a dose-dependent manner (P < 0.01). These effects were ameliorated by pretreatment with esaxerenone. CONCLUSION: Esaxerenone ameliorated insulin resistance in HFD-fed mice. Reduction of inflammation and improvement in insulin signaling may underlie the beneficial effects of esaxerenone.

DOI： 10.1016/j.ejphar.2022.175190

PubMed

Publishing type：Research paper (scientific journal)   International / domestic magazine：International journal  

AIMS: Abnormal left ventricular diastolic response to preload stress can be an early marker of heart failure (HF). The aim of this study was to assess clinical course in patients with HF with preserved ejection fraction (HFpEF) who underwent preload stress echocardiography. In the subgroup analysis, we assessed the prognosis of patients with unstable signs during preload stress classified by treatment strategies. METHODS AND RESULTS: We prospectively conducted preload stress echocardiographic studies between January 2006 and December 2013 in 211 patients with HFpEF. Fifty-eight patients had abnormal diastolic reserve during preload stress (unstable impaired relaxation: unstable IR). Of 58 patients with unstable IR, 19 patients were assigned to additional therapy by increased or additional therapy and 39 patients were assigned to standard therapy. Composite outcomes were prespecified as the primary endpoint of death and hospitalization for deteriorating HF. During a median period of 6.9 years, 19 patients (33%) reached the composite outcome. Unstable group with standard therapy had significantly shorter event-free survival than stable group. Patients with uptitration of therapy had longer event-free survival than those with standard therapy group after adjustment of laboratory data (hazard ratio, 0.20, 95% confidence interval, 0.05-0.90; P = 0.036); the 10 year event-free survival in patients with and without uptitration of therapy was 93% and 51%, respectively (P = 0.023). CONCLUSIONS: Patients with unstable sign had significantly shorter event-free survival than patients with stable sign. After additional therapy, the prognosis of patients with unstable signs improved. This technique may impact decision-making for improving their prognosis.

DOI： 10.1002/ehf2.14127

PubMed

症例は71歳男性で、末梢性ポリニューロパチーに起因した四肢の痺れと歩行困難を訴えていた。心疾患の病歴は無かったが、心電図検査では低電位と第1度房室ブロックが、心エコー法では前壁中隔の高度の肥大が、心臓MRIでは左室心外膜にガドリニウム遅延造影所見が示された。遺伝子検査でトランスサイレチン遺伝子にVal30Met変異が示され、遺伝性トランスサイレチンアミロイドーシス(ATTR variant)の孤発例と診断した。ポリニューロパチーに対しタファミジス20mgでの加療を9ヵ月間続けたが、神経筋症状は消退しなかった。しかし、心エコー評価では中隔の厚が減り左室心筋重量係数は低下するなど、左室肥大の退縮を意味する所見が示された。タファミジス治療から2年後に通院が困難との理由で他院へ転院し、その後、タファミジス治療を受けつつも歩行困難のため入院となっていた。

International / domestic magazine：Domestic journal  

We performed a drug-coated balloon (DCB) angioplasty for severe pulmonary vein (PV) stenosis resulting from cryoballoon ablation for atrial fibrillation. Three and fourteen months after the angioplasty, follow-up multidetector computed tomography did not show restenosis. Lesion regression was observed at 14-month follow-up. Two years after PV angioplasty with DCB, the patient was well without any symptoms. DCB angioplasty may become an alternative effective procedure for PV stenosis. Learning objective: The usefulness and safety of drug-coated balloon angioplasty for severe pulmonary vein stenosis resulting from cryoballoon ablation for atrial fibrillation was observed at 14-month follow-up.

DOI： 10.1016/j.jccase.2022.02.009

PubMed

症例は68歳男性で、発作性心房細動の既往があり、第2世代クライオバルーンを用いた冷凍アブレーションを受けた。使用したバルーン径は28mmで、各肺静脈におけるバルーン留置時間は180秒であった。クライオバルーンの冷却温度は左上肺静脈で-55℃、左下肺静脈で-41℃、右下肺静脈で-53℃、右上肺静脈で-60℃であった。術後に肺静脈再伝導はなく、追加の冷却凝固は必要なかった。術後9ヵ月の再診で多列検出器型CT装置(MDCT)を用いた検査を施行した。左上肺静脈に中等度狭窄病変を認めた。3ヵ月後(術後12ヵ月)に再度MDCTを実施したところ、肺静脈狭窄の重症化を認めたため、血管形成術を計画した。肺静脈狭窄による症状は見られなかった。術前にクロピドグレル(75mg)を投与した。0.014インチのガイディングワイヤを挿入し、4Frマルチパーパスカテーテルを左上肺静脈へ挿入した。血管内超音波法で観察したところ、線維性およびfibro-fattyの新生内膜形成を認めた。薬剤被覆バルーンを拡張したところ、肺静脈圧較差は2mmHgに低下した。術後経過は良好で、14ヵ月後の再診で肺静脈狭窄の再発はなかった。

Publishing type：Research paper (scientific journal)   International / domestic magazine：Domestic journal  

<p> <b>Aims:</b> Pharmacological blockade of mineralocorticoid receptors (MRs) is a potential therapeutic approach to reduce cardiovascular complications since MRs play a crucial role in cardiovascular regulation. Recent studies suggest that MR antagonists affect several extrarenal tissues, including vessel function. We investigated the effect of a novel nonsteroidal selective MR blocker, esaxerenone, on diabetes-induced vascular dysfunction.</p><p><b>Methods:</b> Diabetes was induced by a single dose of streptozotocin in 8-week-old male C57BL/6 mice. Esaxerenone (3 mg/kg/day) or a vehicle was administered by gavage to diabetic mice for 3 weeks. Metabolic parameters, plasma aldosterone levels, and parameters related to renal function were measured. Endothelium-dependent or -independent vascular responses of the aortic segments were analyzed with acetylcholine or sodium nitroprusside, respectively. Human umbilical vein endothelial cells (HUVECs) were used for the in vitro study.</p><p><b>Results:</b> Induction of diabetes elevated plasma aldosterone level (<i>P</i>＜0.05) and impaired endothelium-dependent vascular relaxation (<i>P</i>＜0.05). The administration of esaxerenone ameliorated the endothelial dysfunction (<i>P</i>＜0.01) without the alteration of metabolic parameters, blood pressure, and renal function. Esaxerenone improved the eNOS^Ser1177 phosphorylation in the aorta obtained from diabetic mice (<i>P</i>＜0.05) compared with that in the vehicle-treated group. Furthermore, a major MR agonist, aldosterone, decreased eNOS^Ser1177 phosphorylation and increased eNOS^Thr495 phosphorylation in HUVECs, which recovered with esaxerenone. Esaxerenone ameliorated the endothelium-dependent vascular relaxation caused by aldosterone in the aortic segments obtained from C57BL/6 mice (<i>P</i>＜0.001).</p><p><b>Conclusion:</b> Esaxerenone attenuates the development of diabetes-induced endothelial dysfunction in mice. These results suggest that esaxerenone has potential vascular protective effects in individuals with diabetes.</p>

DOI： 10.5551/jat.63382

PubMed

Publishing type：Research paper (scientific journal)   International / domestic magazine：International journal  

BACKGROUND: In some patients with non-ischemic cardiomyopathy, left ventricular (LV) contraction is improved by optimal medical therapy, leading to LV reverse remodeling (RR). Patients with heart failure with improved ejection fraction and LVRR have a good prognosis, but the factors that predict RR are not fully understood. The relationship between body composition and cardiovascular disease has been reported. The present study aimed to assess the clinical predictors of LVRR in association with body composition. METHODS: We recruited patients who were diagnosed with non-ischemic cardiomyopathy between September 2017 and January 2020. Finally, 89 patients with a reduced LV ejection fraction were enrolled in this prospective study. Body composition, including ectopic fat, was measured in all patients using computed tomography. Echocardiography was performed 6 months after enrollment to evaluate LVRR. RESULTS: LVRR was observed in 39 patients (43.8%) after 6 months. In terms of the demographic findings, epicardial adipose tissue volume was greater in the LVRR group than in the non-LVRR group (135.2 cm3 [SD 128.4 cm3] vs. 88.9 cm3 [SD 54.6 cm3]; p = 0.040). The Kaplan-Meier analysis demonstrated that adverse cardiac events were significantly less frequent in the LVRR group than in the non-LVRR group (log-rank test, p = 0.013). The multivariate logistic regression analysis identified epicardial adipose tissue volume as an independent predictor of LVRR (odds ratio [OR]: 1.010, 95% confidence interval [CI]: 1.001-1.01; p = 0.036). CONCLUSION: Epicardial adipose tissue volume is an independent predictor of LVRR in patients with non-ischemic cardiomyopathy.

DOI： 10.1016/j.ijcard.2022.03.051

PubMed

Publishing type：Research paper (scientific journal)   International / domestic magazine：International journal  

The effects of catheter ablation on exercise tolerance and quality of life in patients with atrial fibrillation (AF) have been reported. We assessed cardiac function in more detail using the leg positive pressure (LPP) technique and found that contractile reserve is particularly important in relation to exercise tolerance and prognosis. In this study, we used the LPP technique to examine changes in contractile reserve immediately after ablation and 6 months later. We prospectively enrolled patients who underwent catheter ablation for AF at 2 institutes. We performed LPP stress echocardiography 2 to 3 days after (FU-1) and 6 months after (FU-2) ablation to examine changes in cardiac function indexes. The primary end point was improvement in contractile reserve. Ultimately, 109 patients (mean age 67.4 ± 9.6 years; 70% men) underwent 2 sessions of LPP stress echocardiography. The median CHA2DS2-VASC score was 2 (interquartile range 13). From FU-1 to FU-2, the change in the stroke volume index after the LPP maneuver increased in patients with paroxysmal and persistent AF with low CHA2DS2-VASC scores (both p <0.05). Regardless of AF subtype, contractile reserve at FU-2 improved in patients with low CHA2DS2-VASC scores compared with that at FU-1. In contrast, patients with high CHA2DS2-VASC scores had no change. In conclusion, patients with AF with a low CHA2DS2-VASC score had improved contractile reserve after ablation, whereas patients with high scores did not show any improvement. Aggressive interventions in patients with high scores may lead to better management after catheter ablation.

DOI： 10.1016/j.amjcard.2021.12.026

PubMed

Publishing type：Research paper (scientific journal)   International / domestic magazine：Domestic journal  

Sterile chronic inflammation causes cardiometabolic disorders; however, the mechanisms are not fully understood. Previous studies have demonstrated the degradation of cells/tissues in the vasculature and metabolic organs in lifestyle-associated diseases, such as diabetes and hyperlipidemia, suggesting the release and/or accumulation of nucleic acids from damaged cells. DNA is indispensable for life; however, DNA fragments, especially those from pathogens, strongly induce inflammation by the activation of DNA sensors. Growing evidence suggests that DNA-sensing mechanisms, which are normally involved in self-defense against pathogens as the innate immune system, are associated with the progression of inflammatory diseases in response to endogenous DNA fragments. There are several types of DNA sensors in our bodies. Toll-like receptor 9 (TLR9)-one of the most studied DNA sensors-recognizes DNA fragments in endosome. In addition, stimulator of interferon genes (STING), which has recently been extensively investigated, recognizes cyclic GMP-AMP (cGAMP) generated from DNA fragments in the cytosol. Both TLR9 and STING are known to play pivotal roles in host defense as the innate immune system. However, recent studies have indicated that the activation of these DNA sensors in immune cells, such as macrophages, promotes inflammation leading to the development of vascular and metabolic diseases associated with lifestyle. In this review, we discuss recent advances in determining the roles of DNA sensors in these disease contexts. Revealing a novel mechanism of sterile chronic inflammation regulated by DNA sensors might facilitate clinical interventions for these health conditions.

DOI： 10.5551/jat.RV17059

PubMed

CiNii Article

DOI： 10.1007/s10840-021-01026-7

International / domestic magazine：International journal  

DOI： 10.1016/j.jcmg.2021.09.005

PubMed

Publishing type：Research paper (scientific journal)   International / domestic magazine：International journal  

BACKGROUND: The COVID-19 pandemic has caused an unprecedented disruption in medical education. Students and lecturers had to adapt to online education. The current study aimed to investigate the level of satisfaction and future preference for online lectures among clinical clerkship students and elucidated the factors that affect these outcomes. METHODS: We selected a sample of 114 medical students undergoing clinical clerkship during the COVID-19 pandemic. We conducted onsite lectures before the pandemic and online lectures after the outbreak. A survey was conducted, and the sample included students and 17 lecturers. The average scores of total satisfaction and future preference related to online lectures were computed. RESULTS: Students' scores on total satisfaction with online lectures and their future preference were higher than those for onsite lectures. Scores on the ease of debating dimension were low and those on accessibility of lectures in online lectures were higher than those in onsite lectures. There was no difference between the two groups in the scores on the comprehensibility and ease of asking questions dimensions. Results of the multiple regression analysis revealed that accessibility determined total satisfaction, and future preference was determined by comprehensibility as well as accessibility. Contrary to students' future preferences, lecturers favored onsite lectures to online ones. CONCLUSION: Online lectures are an acceptable mode of teaching during the COVID-19 pandemic for students undergoing clinical clerkship. Online lectures are expected to become more pervasive to avoid the spread of COVID-19.

DOI： 10.1186/s12909-021-03096-7

PubMed

Publishing type：Research paper (scientific journal)   International / domestic magazine：International journal  

BACKGROUND: Although epicardial adipose tissue (EAT) is associated with coronary artery disease (CAD), it is unclear whether EAT volume (EAV) can be used to diagnose high-risk coronary plaque burden associated with coronary events. This study aimed to investigate (1) the prognostic impact of low-attenuation non-calcified coronary plaque (LAP) burden on patient level analysis, and (2) the association of EAV with LAP volume in patients without known CAD undergoing coronary computed tomography angiography (CCTA). MATERIALS AND METHODS: This retrospective study consisted of 376 patients (male, 57%; mean age, 65.2 ± 13 years) without known CAD undergoing CCTA. Percent LAP volume (%LAP, <30 HU) was calculated as the LAP volume divided by the vessel volume. EAT was defined as adipose tissue with a CT attenuation value ranging from -250 to -30 HU within the pericardial sac. The primary endpoint was a composite event of death, non-fatal myocardial infarction, and unstable angina and worsening symptoms requiring unplanned coronary revascularization >3 months after CCTA. The determinants of %LAP (Q4) were analyzed using a multivariable logistic regression model. RESULTS: During the follow-up period (mean, 2.2 ± 0.9 years), the primary endpoint was observed in 17 patients (4.5%). The independent predictors of the primary endpoint were %LAP (Q4) (hazard ratio [HR], 3.05; 95% confidence interval [CI], 1.09-8.54; p = 0.033] in the Cox proportional hazard model adjusted by CAD-RADS category. Cox proportional hazard ratio analysis demonstrated that %LAP (Q4) was a predictor of the primary endpoint, independnet of CAD severity, Suita score, EAV, or CACS. The independent determinants of %LAP (Q4) were CACS ≥218.3 (p < 0.0001) and EAV ≥125.3 ml (p < 0.0001). The addition of EAV to CACS significantly improved the area under the curve (AUC) to identify %LAP (Q4) than CACS alone (AUC, EAV + CACS vs. CACS alone: 0.728 vs. 0.637; p = 0.013). CONCLUSIONS: CCTA-based assessment of EAV, CACS, and LAP could help improve personalized cardiac risk management by administering patient-suited therapy.

DOI： 10.3389/fcvm.2022.824470

PubMed

Publishing type：Research paper (scientific journal)   International / domestic magazine：International journal  

In lifestyle-related diseases, such as cardiovascular, metabolic, respiratory, and kidney diseases, chronic inflammation plays a causal role in their pathogenesis; however, underlying mechanisms of sterile chronic inflammation are not well-understood. Previous studies have confirmed the damage of cells in these organs in the presence of various risk factors such as diabetes, dyslipidemia, and cigarette smoking, releasing various endogenous ligands for pattern recognition receptors. These studies suggested that nucleic acids released from damaged tissues accumulate in these tissues, acting as an endogenous ligand. Undamaged DNA is an integral factor for the sustenance of life, whereas, DNA fragments, especially those from pathogens, are potent activators of the inflammatory response. Recent studies have indicated that inflammatory responses such as the production of type I interferon (IFN) induced by DNA-sensing mechanisms which contributes to self-defense system in innate immunity participates in the progression of inflammatory diseases by the recognition of nucleic acids derived from the host, including mitochondrial DNA (mtDNA). The body possesses several types of DNA sensors. Toll-like receptor 9 (TLR9) recognizes DNA fragments in the endosomes. In addition, the binding of DNA fragments in the cytosol activates cyclic guanosine monophosphate (GMP)-adenosine monophosphate (AMP) synthase (cGAS), resulting in the synthesis of the second messenger cyclic GMP-AMP (cGAMP). The binding of cGAMP to stimulator of interferon genes (STING) activates NF-κB and TBK-1 signaling and consequently the production of many inflammatory cytokines including IFNs. Numerous previous studies have demonstrated the role of DNA sensors in self-defense through the recognition of DNA fragments derived from pathogens. Beyond the canonical role of TLR9 and cGAS-STING, this review describes the role of these DNA-sensing mechanism in the inflammatory responses caused by endogenous DNA fragments, and in the pathogenesis of lifestyle-related diseases.

DOI： 10.3389/fcvm.2022.881181

PubMed

Publishing type：Research paper (scientific journal)   International / domestic magazine：Domestic journal  

<p>Transthyretin amyloidosis (ATTR) variant is a life-threatening hereditary disease predominantly affecting the peripheral nervous system and heart. Tafamidis, which prevents the deposition of amyloid by stabilizing transthyretin, is available for the treatment of neuropathy and cardiomyopathy of ATTR. However, whether tafamidis could eliminate established amyloid deposits and improve cardiac function remains unknown. We reported a case of regression of left ventricular hypertrophy after tafamidis therapy in a patient with an ATTR variant. J. Med. Invest. 69 : 320-322, August, 2022</p>

DOI： 10.2152/jmi.69.320

PubMed

Publishing type：Research paper (scientific journal)   International / domestic magazine：International journal  

BACKGROUND: The choice of direct oral anticoagulants (DOACs) for venous thromboembolism (VTE) is at the physician's discretion; however, it is useful to know the differences in the clinical data of DOACs to help physicians choose. OBJECTIVE: We aimed to compare the mortality associated with the use of rivaroxaban, edoxaban, and apixaban in clinical practice. METHODS: We identified 38,245 patients with first hospitalization for VTE from the Diagnosis Procedure Combination database in the Japanese Registry of All Cardiac and Vascular Datasets (JROAD-DPC). We classified patients into three groups by DOAC (rivaroxaban and edoxaban group, rivaroxaban and apixaban group, and edoxaban and apixaban group) and compared the in-hospital mortality and bleeding risk by propensity score (PS) matching in each group. RESULTS: After PS matching, patients with rivaroxaban use had significantly lower total in-hospital mortality (1.2% vs. 2.1%; odds ratio [OR] 0.55, p = 0.012) and in-hospital mortality within 21 days (0.4% vs. 1.0%; OR 0.41, p = 0.020) and 28 days (0.7% vs. 1.3%; OR 0.53, p = 0.042) than patients with apixaban use. In the subanalysis, significant differences were only observed in patients younger than 80 years of age, patients with pulmonary embolism, and patients without heart failure. There was no significant difference in in-hospital mortality in the other groups and in the rate of bleeding events among the three groups. CONCLUSION: On PS-matched analysis, there was a difference in in-hospital mortality, especially in the rivaroxaban and apixaban group. Identifying the clinical characteristics of patients associated with each DOAC, as well as prognosis, will be useful in determining treatment strategies for VTE.

DOI： 10.1007/s40256-021-00514-5

PubMed

Publishing type：Research paper (scientific journal)   International / domestic magazine：Domestic journal  

AIMS: Various pathological processes related to diabetes cause endothelial dysfunction. Eicosanoids derived from arachidonic acid (AA) have roles in vascular regulation. Fibrates have recently been shown to attenuate vascular complications in diabetics. Here we examined the effects of pemafibrate, a selective peroxisome proliferator-activated receptor α modulator, on plasma eicosanoid levels and endothelial function in diabetic mice. METHODS: Diabetes was induced in 7-week-old male wild-type mice by a single injection of streptozotocin (150 mg/kg). Pemafibrate (0.3 mg/kg/day) was administered orally for 3 weeks. Untreated mice received vehicle. Circulating levels of eicosanoids and free fatty acids were measured using both gas and liquid chromatography-mass spectrometry. Endothelium-dependent and endothelium-independent vascular responses to acetylcholine and sodium nitroprusside, respectively, were analyzed. RESULTS: Pemafibrate reduced both triglyceride and non-high-density lipoprotein -cholesterol levels (P＜0.01), without affecting body weight. It also decreased circulating levels of AA (P＜0.001), thromboxane B2 (P＜0.001), prostaglandin E2, leukotriene B4 (P＜0.05), and 5-hydroxyeicosatetraenoic acid (P＜0.001), all of which were elevated by the induction of diabetes. In contrast, the plasma levels of 15-deoxy-Δ12,14-prostaglandin J2, which declined following diabetes induction, remained unaffected by pemafibrate treatment. In diabetic mice, pemafibrate decreased palmitic acid (PA) and stearic acid concentrations (P＜0.05). Diabetes induction impaired endothelial function, whereas pemafibrate ameliorated it (P＜0.001). The results of ex vivo experiments indicated that eicosanoids or PA impaired endothelial function. CONCLUSION: Pemafibrate diminished the levels of vasoconstrictive eicosanoids and free fatty acids accompanied by a reduction of triglyceride. These effects may be associated with the improvement of endothelial function by pemafibrate in diabetic mice.

DOI： 10.5551/jat.61101

PubMed

CiNii Article

糖尿病マウスにおいて、血漿脂質濃度、アラキドン酸(AA)由来エイコサノイド値、内皮機能に対するペマフィブラート(PF)の影響を調べた。マウスを非糖尿病対照、未処理糖尿病、PF処理糖尿病の3群に無作為に分けた。糖尿病マウスはストレプトゾトシン注入によって糖尿病を誘発させ、PFまたは溶媒のみを投与して、PF群と未処理群とした。エイコサノイドと遊離脂肪酸の血中濃度はガスクロマトグラフィー質量分析と液体クロマトグラフィー質量分析計で測定した。内皮依存性血管反応はアセチルコリン、内皮非依存性血管反応はニトロプルシドナトリウムへの反応で解析した。PFは体重への影響なしでトリグリセリド値と非HDLコレステロール値を低下させ、糖尿病誘発によって上昇したAA、トロンボキサンB2、プロスタグランジンE2、ロイコトリエンB4、5-ヒドロキシエイコサテトラエン酸の血中濃度を減少させた。15-デオキシ-Δ12,14-プロスタグランジンJ2の血漿中濃度は糖尿病誘発後に低下したが、PF処理の影響はなかった。糖尿病マウスではPFはパルミチン酸(PA)値とステアリン酸値を低下させた。糖尿病誘発によって血管内皮機能が低下したが、PFによって改善した。ex vivo実験の結果、エイコサノイドまたはPAは血管内皮機能を低下させることが示された。

塞栓源不明脳塞栓症(ESUS)の入院患者121例(男性71例)を対象に心エコー検査を実施し、左房機能の評価がESUSの原因として発作性心房細動(AF)を予測するかどうかを検討した。AFの既往、左室駆出率が30%未満、感染性心内膜炎の患者は除外した。平均追跡期間は18日で、AFは46例(38%)で新規発生した。患者をAF発症群46例(男性50%、平均80±8歳)と非AF群75例(男性64%、平均73±14歳)に分類した。患者背景はAF発症群で高血圧症が多かったが、併存症および使用薬剤に関して有意な群間差はなかった。左房機能評価で左房容積係数(LAVI)はAF発症群の方が有意に高く、左房リザーバー機能およびポンプ機能はAF発症群の方が有意に低かった。AFの発症に関するROC曲線で、標準的な臨床データに加えて左房リザーバー機能または左房ポンプ機能のパラメータを組み込んだモデルの曲線下面積(AUC)は、それぞれ0.76±0.05と0.86±0.04で、通常モデルにLAVIを組み込んだモデルのAUC(0.68±0.04)より有意に高かった(P<0.05)。

Publishing type：Research paper (scientific journal)   International / domestic magazine：International journal  

AIMS : Lifestyle-related diseases promote atherosclerosis, a chronic inflammatory disease; however, the molecular mechanism remains largely unknown. Endogenous DNA fragments released under over-nutrient condition provoke sterile inflammation through the recognition by DNA sensors. Here, we investigated the role of stimulator of interferon genes (STING), a cytosolic DNA sensor, in atherogenesis. METHODS AND RESULTS : Apolipoprotein E-deficient (Apoe-/-) mice fed a western-type diet (WTD), a hypercholesterolaemic mouse model, showed higher STING expression and markers for DNA damage such as γH2AX, p53, and single-stranded DNA (ssDNA) accumulation in macrophages in the aorta compared with wild-type (WT) mice. The level of cGAMP, a STING agonist, in the aorta was higher in Apoe-/- mice. Genetic deletion of Sting in Apoe-/- mice reduced atherosclerotic lesions in the aortic arch, lipid, and macrophage accumulation in plaques, and inflammatory molecule expression in the aorta compared with the control. Pharmacological blockade of STING using a specific inhibitor, C-176, ameliorated atherogenesis in Apoe-/- mice. In contrast, bone marrow-specific STING expression in Apoe-/- mice stimulated atherogenesis. Expression or deletion of STING did not affect metabolic parameters and blood pressure. In vitro studies revealed that STING activation by cGAMP or mitochondrial DNA accelerated inflammatory molecule expression (e.g. TNF-α or IFN-β) in mouse and human macrophages. Activation of nuclear factor-κB and TANK binding kinase 1 was involved in STING-associated vascular inflammation and macrophage activation. Furthermore, human atherosclerotic lesions in the carotid arteries expressed STING and cGAMP. CONCLUSION : Stimulator of interferon genes stimulates pro-inflammatory activation of macrophages, leading to the development of atherosclerosis. Stimulator of interferon genes signalling may serve as a potential therapeutic target for atherosclerosis.

DOI： 10.1093/eurheartj/ehab249

PubMed

Publishing type：Research paper (scientific journal)   International / domestic magazine：International journal  

BACKGROUND: The overlap time of transmitral flow can be a novel marker of subclinical left ventricular dysfunction for predicting adverse events in heart failure (HF). We aimed to (1) investigate the role of overlap time of the E-A wave in association with clinical parameters and (2) evaluate whether the overlap time could add prognostic information with respect to other conventional clinical prognosticators in HF. METHODS: We prospectively evaluated 153 patients hospitalized with HF (mean age 68 ± 15 years; 63% male). The primary endpoint was readmission following HF or cardiac death. RESULTS: During a median period of 25 months, 43 patients were readmitted or died. Overlap time appeared to be associated with worse outcomes. After adjustment for readmission scores and ratios of diastolic filling period and cardiac cycle length in a Cox proportional-hazards model, overlap time was associated with event-free survival, independent of elevated left atrial pressure based on guidelines. When overlap time was added to the model based on clinical variables and elevated left atrial pressure, the C-statistic significantly improved from 0.70 (95% CI: 0.63-0.77) to 0.77 (95% CI: 0.69-0.83, compared) (P = 0.035). CONCLUSION: This preliminary study suggested that prolonged overlap time may have potential for predicting readmission and cardiac mortality risk assessment in patients with HF.

DOI： 10.1016/j.cardfail.2021.05.018

PubMed

Publishing type：Research paper (scientific journal)   International / domestic magazine：International journal  

BACKGROUND: In patients with embolic stroke of undetermined source (ESUS), paroxysmal atrial fibrillation (AF) is often diagnosed, however, the risk of paroxysmal AF in ESUS has not been well described. Several studies have suggested a linkage between left atrial (LA) functional parameters and risk of AF in stroke patients. The aim of this study was to assess the role of LA functional parameters as predictors of latent paroxysmal AF in ESUS on admission. METHODS: Between January 2015 and December 2019, consecutive stroke patients with suspected ESUS at admission were prospectively included in this study. They were under hospital electrocardiographic monitoring for detection of new-onset AF. Various echocardiographic parameters including left atrial strain were assessed for association with new-onset AF. RESULTS: We gathered 1082 consecutive patients with ischemic stroke. After exclusions, 121 patients with suspected ESUS at admission formed the study cohort. New-onset AF was detected in 46 (38%) patients during hospital electrocardiographic monitoring (median follow-up: 18 days). LA pump and reservoir strains were significantly and independently associated with new-onset AF. Receiver operating characteristic analysis for the association with new-onset AF showed that the areas under the curve (AUCs) of clinical parameters plus one of each strain (LA pump strain: AUC: 0.86±0.04 and LA reservoir strain: AUC: 0.76±0.05) models were significantly better than plus LA volume index (AUC: 0.68±0.04, compared p-values <0.05). CONCLUSIONS: LA strain was significantly associated with new development of AF. Patients with impaired LA function at admission should be carefully monitored to find AF.

DOI： 10.1016/j.jjcc.2021.05.005

PubMed

Publishing type：Research paper (scientific journal)   International / domestic magazine：International journal  

Fish oil-derived long-chain monounsaturated fatty acids (LCMUFAs) with a carbon chain length longer than 18 units ameliorate cardiovascular risk in mice. In this study, we investigated whether LCMUFAs could improve endothelial functions in mice and humans. In a double-blind, randomized, placebo-controlled, parallel-group, multi-center study, healthy subjects were randomly assigned to either an LCMUFA oil (saury oil) or a control oil (olive and tuna oils) group. Sixty subjects were enrolled and administrated each oil for 4 weeks. For the animal study, ApoE-/- mice were fed a Western diet supplemented with 3% of either gadoleic acid (C20:1) or cetoleic acid (C22:1) for 12 weeks. Participants from the LCMUFA group showed improvements in endothelial function and a lower trimethylamine-N-oxide level, which is a predictor of coronary artery disease. C20:1 and C22:1 oils significantly improved atherosclerotic lesions and plasma levels of several inflammatory cytokines, including IL-6 and TNF-α. These beneficial effects were consistent with an improvement in the gut microbiota environment, as evident from the decreased ratio of Firmicutes and/ or Bacteroidetes, increase in the abundance of Akkermansia, and upregulation of short-chain fatty acid (SCFA)-induced glucagon-like peptide-1 (GLP-1) expression and serum GLP-1 level. These data suggest that LCMUFAs alter the microbiota environment that stimulate the production of SCFAs, resulting in the induction of GLP-1 secretion. Fish oil-derived long-chain monounsaturated fatty acids might thus help to protect against cardiovascular disease.

DOI： 10.1016/j.trsl.2021.03.016

PubMed

DOI： 10.1136/openhrt-2021-001860

PubMed

Publishing type：Research paper (scientific journal)   International / domestic magazine：International journal  

BACKGROUND: Cardiovascular diseases are the second most common cause of mortality among cancer survivors, after death from cancer. We sought to assess the impact of cancer on the short-term outcomes of acute myocardial infarction (AMI), by analysing data obtained from a large-scale database. METHODS: This study was based on the Diagnosis Procedure Combination database in the Japanese Registry of All Cardiac and Vascular Diseases and the Diagnosis Procedure Combination. We identified patients who were hospitalised for primary AMI between April 2012 and March 2017. Propensity Score (PS) was estimated with logistic regression model, with cancer as the dependent variable and 21 clinically relevant covariates. The main outcome was in-hospital mortality. RESULTS: We split 1 52 208 patients into two groups with or without cancer. Patients with cancer tended to be older (cancer group 73±11 years vs non-cancer group 68±13 years) and had smaller body mass index (cancer group 22.8±3.6 vs non-cancer 23.9±4.3). More patients in the non-cancer group had hypertension or dyslipidaemia than their cancer group counterparts. The non-cancer group also had a higher rate of percutaneous coronary intervention (cancer 92.6% vs non-cancer 95.2%). Patients with cancer had a higher 30-day mortality (cancer 6.0% vs non-cancer 5.3%) and total mortality (cancer 8.1% vs non-cancer 6.1%) rate, but this was statistically insignificant after PS matching. CONCLUSION: Cancer did not significantly impact short-term in-hospital mortality rates after hospitalisation for primary AMI.

DOI： 10.1136/openhrt-2021-001860

PubMed

Publishing type：Research paper (scientific journal)  

Background Cardiovascular diseases are the second most common cause of mortality among cancer survivors, after death from cancer. We sought to assess the impact of cancer on the short-term outcomes of acute myocardial infarction (AMI), by analysing data obtained from a large-scale database.Methods This study was based on the Diagnosis Procedure Combination database in the Japanese Registry of All Cardiac and Vascular Diseases and the Diagnosis Procedure Combination. We identified patients who were hospitalised for primary AMI between April 2012 and March 2017. Propensity Score (PS) was estimated with logistic regression model, with cancer as the dependent variable and 21 clinically relevant covariates. The main outcome was in-hospital mortality.Results We split 1 52 208 patients into two groups with or without cancer. Patients with cancer tended to be older (cancer group 73 +/- 11 years vs non-cancer group 68 +/- 13 years) and had smaller body mass index (cancer group 22.8 +/- 3.6vs non-cancer 23.9 +/- 4.3). More patients in the non-cancer group had hypertension or dyslipidaemia than their cancer group counterparts. The non-cancer group also had a higher rate of percutaneous coronary intervention (cancer 92.6% vs non-cancer 95.2%). Patients with cancer had a higher 30-day mortality (cancer 6.0% vs non-cancer 5.3%) and total mortality (cancer 8.1% vs non-cancer 6.1%) rate, but this was statistically insignificant after PS matching.Conclusion Cancer did not significantly impact short-term in hospital mortality rates after hospitalisation for primary AMI.

DOI： 10.1136/openhrt-2021-001860

Publishing type：Research paper (scientific journal)   International / domestic magazine：Domestic journal  

Infective endocarditis (IE) may be acquired in the community as community-acquired (CA) IE or in the healthcare setting. In Japan, cases of CA-methicillin-resistant Staphylococcus aureus (MRSA) infection as skin infection have been increasing. CA-MRSA strains, including the USA300 clone, have higher pathogenicity and are more destructive to tissue than healthcare-associated MRSA strains because of the toxins they produce, including arginine-catabolic mobile element (ACME) and Panton-Valentine leukocidin (PVL). However, only a few IE cases induced by USA300 have been reported. We herein report a 64-year-old man who developed CA-IE from a furuncle caused by USA300 MRSA producing PVL and ACME, which resulted in complications of meningitis.

DOI： 10.2169/internalmedicine.6902-20

PubMed

CiNii Article

症例は64歳男性で、1年前に僧帽弁逸脱のため僧帽弁形成術を施行されていた。今回、左大腿に発疹を認めて皮膚科を受診した。せつと診断され、膿培養はメチシリン耐性黄色ブドウ球菌(MRSA)陽性であった。7日間にわたりレボフロキサシン500mg/日が処方され、せつは徐々に改善した。25日後、全身性疲労と摂氏39度超の発熱が出現し、右胸に別の発疹を認めた。組織学的所見から、皮膚膿瘍が示唆された。3日後、意識消失後に転倒して救急来院した。入院後、意識レベルは改善したが、頸部痛を訴えた。腰椎穿刺の所見から、髄膜炎が示唆された。経食道心エコー検査の所見では、大動脈弁左冠尖の疣贅が強く疑われた。血液培養でMRSAが検出されたことから、髄膜炎を合併したせつによる感染性心内膜炎(IE)と診断した。IEの原因として、皮膚感染症とUSA300株MRSAによる組織破壊性市中IEが疑われた。マルチプレックスPCR検査を行い、MRSAはUSA300株であり、Panton-Valentineロイコシジンとアルギニン異化可動性元素に陽性であることを確認した。

Publishing type：Research paper (scientific journal)   International / domestic magazine：International journal  

BACKGROUND: Echocardiography requires a high degree of skill on the part of the examiner, and the skill may be more improved in larger volume centers. This study investigated trends and outcomes associated with the use and volume of echocardiographic exams from a real-world registry database of heart failure (HF) hospitalizations. METHODS: This study was based on the Diagnosis Procedure Combination database in the Japanese Registry of All Cardiac and Vascular Datasets (JROAD-DPC). A first analysis was performed to assess the trend of echocardiographic examinations between 2012 and 2016. A secondary analysis was performed to assess whether echocardiographic use was associated with in-hospital mortality in 2015. RESULTS: During this period, the use of echocardiography grew at an average annual rate of 6%. Patients with echocardiography had declining rates of hospital mortality, and these trends were associated with high hospitalization costs. In the 2015 sample, a total of 52,832 echocardiograms were examined, corresponding to 65.6% of all HF hospital admissions for that year. We found that the use and volume of echocardiography exams were associated with significantly lower odds of all-cause hospital mortality in heart failure (adjusted odds ratio (OR): 0.48 for use of echocardiography and 0.78 for the third tertile; both p < 0.001). CONCLUSIONS: The use of echocardiography was associated with decreased odds of hospital mortality in HF. The volumes of echocardiographic examinations were also associated with hospital mortality.

DOI： 10.3390/jcdd8100124

PubMed

Publishing type：Research paper (scientific journal)   International / domestic magazine：International journal  

BACKGROUND: Heart failure with recovered ejection fraction (HFrecEF) has been reported in several previous studies to have a better prognosis than heart failure with reduced ejection fraction (HFrEF). However, the factors associated with HFrecEF have not been identified. The aim of this study was to test the hypothesis that left atrial (LA) strain could help identify patients with recovered ejection fraction (EF) among those with heart failure (HF) with low EF on admission. METHODS: One hundred consecutive patients hospitalized for the first time for new-onset HF were enrolled. Patients were clinically diagnosed with HFrEF on admission (left ventricular EF < 40%) and received optimal treatment for HF. Twenty-eight patients improved to HFrecEF during 6 months of follow-up. RESULTS: Regarding clinical background, there were significantly more women and a lower rate of atrial fibrillation in the HFrecEF group than in the HFrEF group. In a multivariate logistic regression analysis, LA strain was an independent predictor of HFrecEF, even after adjustment for gender and left ventricular EF (odds ratio: 4.06; 95% CI: 2.04-8.07; P < .001). A cutoff value of 10.8% for LA strain showed high sensitivity (96%) and specificity (82%) in identifying HFrecEF in patients with HF presenting with low EF on admission. During a follow-up period of 24 ± 13 months, 31 patients (31%) had cardiovascular death or readmission for HF. Patients with reduced LA strain (<10.8%) had significantly shorter event-free survival than those with preserved LA strain (P = .02). CONCLUSIONS: LA strain is a useful indicator for predicting HFrecEF and should be considered as a routine measurement in patients with HFrEF on admission.

DOI： 10.1016/j.echo.2021.03.016

PubMed

Publishing type：Research paper (scientific journal)   International / domestic magazine：Domestic journal  

BACKGROUND: Activated factor X (FXa), which contributes to chronic inflammation via protease-activated receptor 2 (PAR2), might play an important role in atrial fibrillation (AF) arrhythmogenesis. This study aimed to assess whether PAR2 signaling contributes to AF arrhythmogenesis and whether rivaroxaban ameliorates atrial inflammation and prevents AF.Methods and Results:In Study 1, PAR2 deficient (PAR2-/-) and wild-type mice were infused with angiotensin II (Ang II) or a vehicle via an osmotic minipump for 2 weeks. In Study 2, spontaneously hypertensive rats (SHRs) were treated with rivaroxaban, warfarin, or vehicle for 2 weeks after 8 h of right atrial rapid pacing. The AF inducibility and atrial remodeling in both studies were examined. Ang II-treated PAR2-/- mice had a lower incidence of AF and less mRNA expression of collagen1 and collagen3 in the atrium compared to wild-type mice treated with Ang II. Rivaroxaban significantly reduced AF inducibility compared with warfarin or vehicle. In SHRs treated with a vehicle, rapid atrial pacing promoted gene expression of inflammatory and fibrosis-related biomarkers in the atrium. Rivaroxaban, but not warfarin, significantly reduced expression levels of these genes. CONCLUSIONS: The FXa-PAR2 signaling pathway might contribute to AF arrhythmogenesis associated with atrial inflammation. A direct FXa inhibitor, rivaroxaban, could prevent atrial inflammation and reduce AF inducibility, probably by inhibiting the pro-inflammatory activation.

DOI： 10.1253/circj.CJ-20-1006

PubMed

CiNii Article

プロテアーゼ活性化受容体2(PAR2)シグナル伝達と心房細動(AF)との関連、および活性化血液凝固第X因子(FXa)阻害薬rivaroxabanの心房炎症やAF予防への効果について検討した。PAR2欠損マウスでは、野生型マウスに比べてangiotensin II投与後のAF発生率が低く、心房でのcollagen1とcollagen3のmRNA発現が少なかった。高血圧自然発症ラットにおいて、高頻度右心房ペーシング施行8時間後のrivaroxaban投与群では、warfarin投与群や賦形剤投与群に比べてAF発生率が有意に低かった。賦形剤投与群の心房では高頻度ペーシングにより炎症および線維化関連バイオマーカーの遺伝子発現が増加したが、rivaroxaban投与群では有意に減少した。FXa-PAR2シグナル伝達経路は心房炎症と関連するAFの発生に関与している可能性があり、rivaroxabanは心房炎症を予防し、AF発生率を抑制する可能性が示された。

Publishing type：Research paper (scientific journal)   International / domestic magazine：Domestic journal  

AIM: The bioactive lipid, sphingosine-1-phosphate (S1P), has various roles in the physiology and pathophysiology of many diseases. There are five S1P receptors; however, the role of each S1P receptor in atherogenesis is still obscure. Here we investigated the contribution of S1P receptor 2 (S1P2) to atherogenesis by using a specific S1P2 antagonist, ONO-5430514, in apolipoprotein E-deficient (Apoe－/－) mice. METHODS: Apoe－/－ mice fed with a western-type diet (WTD) received ONO-5430514 (30 mg/kg/day) or vehicle. To examine the effect on atherogenesis, Sudan IV staining, histological analysis, qPCR, and vascular reactivity assay was performed. Human umbilical vein endothelial cells (HUVEC) were used for in vitro experiments. RESULTS: WTD-fed Apoe－/－ mice had significantly higher S1P2 expression in the aorta compared with wild-type mice. S1P2 antagonist treatment for 20 weeks reduced atherosclerotic lesion development (p＜0.05). S1P2 antagonist treatment for 8 weeks ameliorated endothelial dysfunction (p＜0.05) accompanied with significant reduction of lipid deposition, macrophage accumulation, and inflammatory molecule expression in the aorta compared with vehicle. S1P2 antagonist attenuated the phosphorylation of JNK in the abdominal aorta compared with vehicle (p＜0.05). In HUVEC, S1P promoted inflammatory molecule expression such as MCP-1 and VCAM-1 p＜0.001), which was attenuated by S1P2 antagonist or a JNK inhibitor (p＜0.01). S1P2 antagonist also inhibited S1P-induced JNK phosphorylation in HUVEC (p＜0.05). CONCLUSIONS: Our results suggested that an S1P2 antagonist attenuates endothelial dysfunction and prevents atherogenesis. S1P2, which promotes inflammatory activation of endothelial cells, might be a therapeutic target for atherosclerosis.

DOI： 10.5551/jat.54916

PubMed

CiNii Article

高コレステロール血症マウスモデルにおける内皮機能不全およびアテローム性動脈硬化症の発症におけるスフィンゴシン1-リン酸2型受容体(S1P2)の役割について検討した。Western-Type Diet(WTD)を与えたApoE-/-マウスにS1P2アンタゴニスト(30mg/kg/day)またはビヒクルを投与した。Sudan IV染色、組織学的解析、qPCR、血管反応性アッセイにより動脈硬化への影響について検討した。その結果、WTD食餌ApoE-/-マウスでは、野生型マウスと比較して、大動脈におけるS1P2発現が有意に高かった。また、S1P2アンタゴニストの20週間の投与により、動脈硬化病変の進展が抑制された(p<0.05)。8週間の投与では、ビヒクル群と比較して内皮機能不全の改善(p<0.05)、大動脈における脂質沈着、マクロファージの蓄積、炎症性分子の発現の減少が認められた。また、S1P2アンタゴニストはビヒクルと比較して、腹部大動脈におけるJNKリン酸化を抑制した(p<0.05)。さらに、ヒト臍帯静脈内皮細胞(HUVEC)を使用したin vitro実験を行った。その結果、HUVECにおいて、S1PはMCP-1やVCAM-1などの炎症分子の発現を促進したが(p<0.001)、S1P2アンタゴニストやJNK阻害剤により、その効果は減弱した(p<0.01)。また、S1P2アンタゴニストはHUVECにおけるS1P誘導性のJNKリン酸化を抑制した(p<0.05)。

Publishing type：Research paper (scientific journal)   International / domestic magazine：International journal  

Background The prognosis of patients with cancer-venous thromboembolism (VTE) is not well known because of a lack of registry data. Moreover, there is also no knowledge on how specific types are related to prognosis. We sought to evaluate the clinical characteristics and outcomes of patients with cancer-associated VTE, compared with a matched cohort without cancer using real-world registry data of VTE. Methods and Results This study was based on the Diagnosis Procedure Combination database in the JROAD-DPC (Japanese Registry of All Cardiac and Vascular Diseases and the Diagnosis Procedure Combination). Of 5 106 151 total patients included in JROAD-DPC, we identified 49 580 patients who were first hospitalized with VTE from April 2012 to March 2017. Propensity score was estimated with a logistic regression model, with cancer as the dependent variable and 18 clinically relevant covariates. After propensity matching, there were 25 148 patients with VTE with or without cancer. On propensity score-matched analysis with 25 148 patients with VTE, patients with cancer had higher total in-hospital mortality within 7 days (1.3% versus 1.1%, odds ratio [OR], 1.66; 95% CI, 1.31-2.11; P<0.0001), 14 days (2.5% versus 1.5%, OR, 2.07; 95% CI, 1.72-2.49; P<0.0001), and 30 days (4.8% versus 2.0%, OR, 2.85; 95% CI, 2.45-3.31; P<0.0001). On analysis for each type of cancer, in-hospital mortality in 11 types of cancer was significantly high, especially pancreas (OR, 12.96; 95% CI, 6.41-26.20), biliary tract (OR, 8.67; 95% CI, 3.00-25.03), and liver (OR, 7.31; 95% CI, 3.05-17.50). Conclusions Patients with cancer had a higher in-hospital acute mortality for VTE than those without cancer, especially in pancreatic, biliary tract, and liver cancers.

DOI： 10.1161/JAHA.120.019373

PubMed

International / domestic magazine：International journal  

DOI： 10.1186/s41232-021-00160-z

PubMed

International / domestic magazine：International journal  

BACKGROUND: To accurately diagnose and control heart failure (HF), it is important to carry out a simple assessment of elevated pulmonary arterial wedge pressure (PAWP). The aim of this study was to develop and validate an objective method for detecting elevated PAWP by applying deep learning (DL) to a chest X-ray (CXR). METHODS: We enrolled 1,013 consecutive patients with a right heart catheter between October 2009 and February 2020. We developed a convolutional neural network to identify patients with an elevated PAWP (> 18 mmHg) as the actual value of PAWP to be used in the dataset for training. In the prospective validation dataset used to detect elevated PAWP, the area under the receiver operating characteristic curve (AUC) was calculated using the DL model that evaluated the CXR. RESULTS: In the prospective validation dataset, the AUC of the DL model with CXR was not significantly different than the AUC produced by brain natriuretic peptide and the echocardiographic left ventricular diastolic dysfunction algorithm (DL model: 0.77 vs. BNP: 0.77 vs. DD algorithm: 0.70; respectively; p=NS for all comparisons), however was significantly higher than the AUC of the cardiothoracic ratio (DL model vs. CTR: 0.66, p=0.044). The model based on three parameters (BNP, DD algorithm, and CTR) was improved by adding the DL model (AUC: from 0.80 to 0.86; p=0.041). CONCLUSIONS: Applying the DL model based on a CXR (a classical, universal, and low-cost test) is useful for screening for elevated PAWP.

DOI： 10.1016/j.cjca.2021.02.007

PubMed

J-GLOBAL

Publishing type：Research paper (scientific journal)   International / domestic magazine：International journal  

OBJECTIVES: There is a high prevalence of left ventricular diastolic dysfunction (LVDD) in systemic sclerosis (SSc) which is associated with high mortality. Thus, early detection of LVDD could be important in management of SSc. We hypothesised that exercise echocardiography in SSc patients with normal resting haemodynamics may expose early phase LVDD, which could affect its prognosis, defined as cardiovascular death and unplanned hospitalisation for heart failure. METHODS: Between January 2014 and December 2018, we prospectively enrolled 140 patients with SSc who underwent 6-minute walk (6MW) stress echocardiographic studies with normal range of estimated mean pulmonary arterial pressure (mPAP) (<25 mm Hg) and mean pulmonary artery wedge pressure (mPAWP) (<15 mm Hg) at rest. We used ΔmPAP/Δcardiac output (CO) to assess pulmonary vascular reserve and ΔmPAWP/ΔCO to assess LV cardiac reserve between resting and post-6MW. RESULTS: During a median period of 3.6 years (IQR 2.0-5.1 years), 25 patients (18%) reached the composite outcome. Both ΔmPAP/ΔCO and ΔmPAWP/ΔCO in patients with events were significantly greater than in those without events (8.9±3.8 mm Hg/L/min vs 3.0±1.7 mm Hg/L/min; p=0.002, and 2.2±0.9 mm Hg/L/min vs 0.9±0.5 mm Hg/L/min; p<0.001, respectively). Patients with both impaired LV cardiac reserve (ΔmPAWP/ΔCO>1.4 mm Hg/L/min) and impaired pulmonary vascular reserve (ΔmPAP/ΔCO>3.0 mm Hg/L/min) had worse outcomes compared with those without these abnormalities (p<0.001). CONCLUSION: The 6MW stress echocardiography revealed impaired LV cardiac reserve in SSc patients with normal resting haemodynamics. Furthermore, LV cardiac reserve independently associates with clinical worsening in SSc, providing incremental prognostic utility, in addition to pulmonary vascular parameters.

DOI： 10.1136/openhrt-2020-001559

PubMed

DOI： 10.1002/joa3.12484

Publishing type：Research paper (scientific journal)   International / domestic magazine：International journal  

A broad range of chronic conditions, including heart failure (HF), have been associated with vitamin D deficiency. Existing clinical trials involving vitamin D supplementation in chronic HF patients have been inconclusive. We sought to evaluate the outcomes of patients with vitamin D supplementation, compared with a matched cohort using real-world big data of HF hospitalization. This study was based on the Diagnosis Procedure Combination database in the Japanese Registry of All Cardiac and Vascular Datasets (JROAD-DPC). After exclusion criteria, we identified 93,692 patients who were first hospitalized with HF between April 2012 and March 2017 (mean age was 79 ± 12 years, and 52.2% were male). Propensity score (PS) was estimated with logistic regression model, with vitamin D supplementation as the dependent variable and clinically relevant covariates. On PS-matched analysis with 10,974 patients, patients with vitamin D supplementation had lower total in-hospital mortality (6.5 vs. 9.4%, odds ratio: 0.67, p < 0.001) and in-hospital mortality within 7 days and 30 days (0.9 vs. 2.5%, OR, 0.34, and 3.8 vs. 6.5%, OR: 0.56, both p < 0.001). In the sub-group analysis, mortalities in patients with age < 75, diabetes, dyslipidemia, atrial arrhythmia, cancer, renin-angiotensin system blocker, and β-blocker were not affected by vitamin D supplementation. Patients with vitamin D supplementation had a lower in-hospital mortality for HF than patients without vitamin D supplementation in the propensity matched cohort. The identification of specific clinical characteristics in patients benefitting from vitamin D may be useful for determining targets of future randomized control trials.

DOI： 10.3390/nu13020335

PubMed

DOI： 10.1038/s41440-021-00752-9

Publishing type：Research paper (scientific journal)   International / domestic magazine：Domestic journal  

Adipose tissue serves not only as an energy store or a mechanical cushion, but also as an endocrine organ. Recent evidence revealed that perivascular adipose tissue is involved in vascular homeostasis and pathophysiology of adjacent arteries by producing various adipokines. Epicardial adipose tissue (EAT) is located between the surface of the heart and the visceral layer of the pericardium and surrounds the coronary arteries. Many clinical studies suggest that an increase in EAT volume is associated with coronary artery disease. It has been reported that exercise and some antidiabetic drugs can reduce EAT volume. In this review, we outline recent findings on the roles of EAT in the pathogenesis of coronary atherosclerosis.

DOI： 10.1253/circj.CJ-20-0935

PubMed

CiNii Article

Publishing type：Research paper (scientific journal)   International / domestic magazine：Domestic journal  

AIM: Synthetic vascular grafts are widely used in surgical revascularization, mainly for medium- to large-sized vessels. However, synthetic grafts smaller than 6 mm in diameter are associated with a high incidence of thrombosis. In this study, we evaluated silk fibroin, a major protein of silk, with high biocompatibility and biodegradability, as a useful material for extremely-small-diameter vascular grafts. METHODS: A small-sized (0.9 mm inner diameter) graft was braided from a silk fibroin thread. The right carotid arteries of 8- to 14-week-old male C57BL/6 mice were cut at the midpoint, and fibroin grafts (5- to 7-mm in length) were transplanted using a cuff technique with polyimide cuffs. The grafts were harvested at different time points and analyzed histologically. RESULTS: CD31＋ endothelial cells had already started to proliferate at 2 weeks after implantation. At 4 weeks, neointima had formed with α-smooth muscle actin+ cells, and the luminal surface was covered with CD31＋endothelial cells. Mac3＋ macrophages were accumulated in the grafts. Graft patency was confirmed at up to 6 months after implantation. CONCLUSION: This mouse model of arterial graft implantation enables us to analyze the remodeling process and biocompatibility of extremely-small-diameter vascular grafts. Biodegradable silk fibroin might be applicable for further researches using genetically modified mice.

DOI： 10.5551/jat.52720

PubMed

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絹フィブロインの極小径人工血管としての素材の有用性を評価した。絹フィブロイン糸から内径0.9mmのグラフトを編んだ。生後8〜14週の雄C57BL/6マウスの右頸動脈の中間点を切断して、ポリイミドカフによるカフ法を用いてフィブロイングラフトを移植した。グラフトを移植後1、2週、3、6ヵ月に採取して、免疫組織化学染色法を行って組織学的解析を実施した。移植後2週でCD31+内皮細胞が増殖し始めた。4週には平滑筋αアクチン+細胞で新生内膜が形成され、管腔側はCD31+内皮細胞で被覆された。Mac3+マクロファージがグラフト内に蓄積した。グラフト開存性は移植後6ヵ月まで確認できた。本動脈グラフト移植マウスモデルによって、極小径人工血管のリモデリング過程と生体適合性の解析が可能となった。

Publishing type：Research paper (scientific journal)   International / domestic magazine：Domestic journal  

AIM: Recent studies have demonstrated that selective sodium-glucose cotransporter 2 inhibitors (SGLT2is) reduce cardiovascular events, although their mechanism remains obscure. We examined the effect of canagliflozin, an SGLT2i, on atherogenesis and investigated its underlying mechanism. METHOD: Canagliflozin (30 mg/kg/day) was administered by gavage to streptozotocin-induced diabetic apolipoprotein E-deficient (ApoE－/－) mice. Sudan IV staining was performed at the aortic arch. Immunostaining, quantitative RT-PCR, and vascular reactivity assay were performed using the aorta. In vitro experiments using human umbilical vein endothelial cells (HUVECs) were also performed. RESULT: Canagliflozin decreased blood glucose (P＜0.001) and total cholesterol (P＜0.05) levels. Sudan IV staining showed that 12-week canagliflozin treatment decreased atherosclerotic lesions (P＜0.05). Further, 8-week canagliflozin treatment ameliorated endothelial dysfunction, as determined by acetylcholine-induced vasodilation (P＜0.05), and significantly reduced the expressions of inflammatory molecules such as ICAM-1 and VCAM-1 in the aorta at the RNA and protein levels. Canagliflozin also reduced the expressions of NADPH oxidase subunits such as NOX2 and p22phox in the aorta and reduced urinary excretion of 8-OHdG, suggesting a reduction in oxidative stress. Methylglyoxal, a precursor of advanced glycation end products, increased the expressions of ICAM-1 and p22phox in HUVECs (P＜0.05, both). Methylglyoxal also decreased the phosphorylation of eNOSSer1177 and Akt but increased the phosphorylation of eNOSThr495 and p38 MAPK in HUVECs. CONCLUSION: Canagliflozin prevents endothelial dysfunction and atherogenesis in diabetic ApoE－/－ mice. Anti-inflammatory and antioxidative potential due to reduced glucose toxicity to endothelial cells might be its underlying mechanisms.

DOI： 10.5551/jat.52100

PubMed

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カナグリフロジンが糖尿病性アポリポ蛋白質e-欠損(ApoE-/-)マウスにおいて血管内皮機能障害を改善し、アテローム形成を予防できるか検討した。ApoE-/-マウスにストレプトゾトシンを投与して糖尿病を誘発させ、カナグリフロジンを12週間または8週間にわたり強制経口投与した。ヒト臍帯静脈内皮細胞(HUVEC)を用いてin vitro検査を実施した。カナグリフロジンは血糖値と総コレステロール値を低下させた。12週間のカナグリフロジン投与では動脈硬化病変が減少し、8週間投与では血管内皮機能障害が改善し、大動脈における細胞間接着分子(ICAM)-1や血管細胞接着分子-1などの炎症性分子がRNAおよび蛋白質レベルで発現低下した。カナグリフロジンによって大動脈におけるニコチンアミドアデニンジヌクレオチドリン酸オキシダーゼ2やp22phoxが発現低下し、8-ヒドロキシデオキシグアノシンの尿中排泄量が減少し、酸化ストレスの減少が示唆された。メチルグリオキサールによってHUVECにおいてICAM-1およびp22phoxが発現亢進した。メチルグリオキサールはHUVECにおいて内皮型一酸化窒素合成酵素(eNOS)Ser1177とAktのリン酸化を減少させたが、eNOSThr495とp38マイトジェン活性化プロテインキナーゼのリン酸化を増加させた。

<p>Rupture of vulnerable atherosclerotic plaques or erosion of fibrous plaques cause thrombotic occlusion of coronary artery, leads to acute myocardial infarction or unstable angina. Both aggregation of platelets and activation of blood coagulation system play central role in thrombus formation. Blood coagulation factors, especially activated factor X and thrombin, are also involved in inflammation via activation of protease-activated receptors (PARs) expressed on vascular cells and inflammatory cells. Administration of rivaroxaban, one of direct oral anticoagulants, to apolipoprotein-E deficient (ApoE-/-) mouse attenuates progression of atherosclerotic plaque with decrease in accumulation of macrophages and expression of inflammatory cytokines. Similarly, deficiency of PAR-2 gene in bone marrow cells of ApoE-/- mouse reduces expression of inflammatory cytokines in macrophages and atherosclerotic lesion progression. A recent clinical study indicated that rivaroxaban is effective in secondary prevention of arteriosclerotic diseases when used in combination with aspirin. This effect is conceivable mainly by inhibition of thrombus formation. However, it would be possible that the anti-atherosclerotic action of rivaroxaban contributes to these favorable effects.</p>

DOI： 10.7133/jca.20-00031

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冠動脈の動脈硬化プラークが破綻すると血栓が形成され,急激な管腔閉塞により心筋梗塞や不安定狭心症の原因となる。血栓形成には,血小板と血液凝固系の両方が関与する。血液凝固因子は,血管構成細胞のプロテアーゼ活性型受容体の活性化を介して血管の炎症にも関与する。最近の臨床試験で直接経口抗凝固薬は,抗血小板薬との併用により動脈硬化疾患の二次予防に有効であった。この効果には抗炎症作用も寄与している可能性がある。(著者抄録)

Publishing type：Research paper (scientific journal)   International / domestic magazine：Domestic journal  

Advanced age, obesity, and muscle weakness are independent factors in the onset of deep vein thrombosis (DVT). Recently, an association between sarcopenia and DVT has been reported. We hypothesized that sarcopenia related factors, observed by ultrasonography, are associated with the regression effect on the thrombus following anticoagulation therapy. The present study focused on gastrocnemius muscle (GCM) thickness and the GCM's internal echogenic brightness. We examined the association with DVT regression following direct oral anticoagulants (DOACs) treatment.The prospective cohort study period was between October 2017 and August 2018. We enrolled 46 patients diagnosed with DVT by ultrasonography, who were aged >60 years old and treated with DOACs. Sarcopenia was evaluated using the Asian Working Group for Sarcopenia flowchart. The average DOACs treatment period was 94 days, and 29 patients exhibited thrombus regression. On univariate logistic regression analysis, sarcopenia, average GCM diameter index, and gastrocnemius integrated backscatter index were significantly associated with thrombus regression. In a multivariate model, only the average GCM diameter index correlated with thrombus regression.The average GCM diameter index is associated with DVT regression treated with DOACs. Considering the GCM diameter during DVT treatment can be a marker to make a decision for the treatment of DVT.

DOI： 10.1536/ihj.20-032

PubMed

CiNii Article

Publishing type：Research paper (scientific journal)   International / domestic magazine：International journal  

AIMS: Risk assessment of developing cardiac involvement in systemic sarcoidosis can be challenging because of limited data. Recently, attention has been given to left ventricular and right ventricular (LV and RV) involvement in cardiac sarcoidosis (CS) and its prevalence, relevance, and prognostic value. The aim of this study was to assess the role of biventricular strain to predict prognosis in confirmed sarcoidosis patients. METHODS AND RESULTS: LV and RV longitudinal strains (LSs) were evaluated by 2D speckle tracking in 139 consecutive confirmed sarcoidosis patients without other pre-existing structural heart diseases, and 52 age- and gender-matched control subjects. The primary endpoint was CS-related events (cardiac death or development of cardiac involvement). Sarcoidosis without cardiac involvement had significantly lower LV and RV free wall LS compared with control subjects. Basal LS had a higher area under the curve for differentiation of sarcoidosis in patients without cardiac involvement compared to control (cut-off value: -18% with 89% sensitivity and 69% specificity). During a median period of 50 months, the occurrence of CS-related events was observed in 20 patients. In a multivariate analysis, basal LV LS and RV free wall LS were associated with the events [hazard ratio (HR) 0.72, P < 0.001 and HR: 0.83, P = 0.006, respectively]. Patients with impaired biventricular function had significantly shorter event-free survival than those with preserved biventricular function (P < 0.001). CONCLUSION: Deterioration of biventricular strain was associated with CS-related events. This information might be useful for clinical evaluation and follow-up in sarcoidosis.

DOI： 10.1093/ehjci/jez235

PubMed

サルコペニア/筋肉量の減少が直接経口抗凝固薬による血栓退縮効果に及ぼす影響について検討した。直接経口抗凝固薬を服薬中の深部静脈血栓症患者46例(男性17例、女性29例、平均72±11歳)を対象とした。サルコペニアの診断にはアジアのワーキンググループによるAWGSを用いた。全患者で超音波検査を実施し、腓腹筋の筋厚値と超音波高周波信号の反射波から算出したIB値を測定した。直接経口抗凝固薬の平均治療期間は94日で、29例で血栓退縮効果を認めた。患者を血栓退縮群29例(男性41%、平均72±13歳)と非血栓退縮群17例(男性29%、平均72±9歳)の2群に分類した。性別、年齢、BMI、深部静脈血栓症の症状に有意な群間差はなかった。サルコペニアは血栓退縮群(10%)の方が非血栓退縮群(35%)より有意に少なかった(P=0.02)。腓腹筋の筋厚値は血栓退縮群の方が有意に高く、IB値は有意に低かった(いずれもP<0.001)。多変量ロジスティック回帰モデルでは腓腹筋の筋厚値が直接経口抗凝固薬による血栓退縮の唯一の予測因子であった(OR:4.104,95%CI:1.738〜9.690,P=0.001)。

Publishing type：Research paper (scientific journal)   International / domestic magazine：International journal  

Recent studies reported cardioprotective effects of sodium glucose co-transporter 2 (SGLT2) inhibitors; however, the underlying mechanisms are still obscure. Here, we investigated whether empagliflozin attenuates atherogenesis and endothelial dysfunction in diabetic apolipoprotein E-deficient (ApoE-/-) mice. Male streptozotocin (STZ) - induced diabetic ApoE-/- mice were treated with empagliflozin for 12 or 8 weeks. Empagliflozin lowered blood glucose (P < 0.001) and lipid levels in diabetic ApoE-/- mice. Empagliflozin treatment for 12 weeks significantly decreased atherosclerotic lesion size in the aortic arch (P < 0.01) along with reduction of lipid deposition (P < 0.05), macrophage accumulation (P < 0.001), and inflammatory molecule expression in plaques compared with the untreated group. Empagliflozin treatment for 8 weeks significantly ameliorated diabetes-induced endothelial dysfunction as determined by the vascular response to acetylcholine (P < 0.001). Empagliflozin reduced RNA expression of a macrophage marker, CD68, and inflammatory molecules such as MCP-1 (P < 0.05) and NADPH oxidase subunits in the aorta compared with the untreated group. Empagliflozin also reduced plasma levels of vasoconstrictive eicosanoids, prostaglandin E2 and thromboxane B2 (P < 0.001), which were elevated in diabetic condition. Furthermore, empagliflozin attenuated RNA expression of inflammatory molecules in perivascular adipose tissue (PVAT), suggesting the reduction of inflammation in PVAT. In in vitro studies, methylglyoxal (MGO), a precursor of AGEs, significantly increased the expression of inflammatory molecules such as MCP-1 and TNF-α in a murine macrophage cell line, RAW264.7. Our results indicated that empagliflozin attenuated endothelial dysfunction and atherogenesis in diabetic ApoE-/- mice. Reduction of vasoconstrictive eicosanoids and inflammation in the vasculature and PVAT may have a role as underlying mechanisms at least partially.

DOI： 10.1016/j.ejphar.2020.173040

PubMed

Publishing type：Research paper (scientific journal)   International / domestic magazine：International journal  

DOI： 10.1016/j.echo.2020.01.009

PubMed

Publishing type：Research paper (scientific journal)   International / domestic magazine：International journal  

A proper echocardiographic study requires several video clips recorded from different acquisition angles for observation of the complex cardiac anatomy. However, these video clips are not necessarily labeled in a database. Identification of the acquired view becomes the first step of analyzing an echocardiogram. Currently, there is no consensus whether the mislabeled samples can be used to create a feasible clinical prediction model of ejection fraction (EF). The aim of this study was to test two types of input methods for the classification of images, and to test the accuracy of the prediction model for EF in a learning database containing mislabeled images that were not checked by observers. We enrolled 340 patients with five standard views (long axis, short axis, 3-chamber view, 4-chamber view and 2-chamber view) and 10 images in a cycle, used for training a convolutional neural network to classify views (total 17,000 labeled images). All DICOM images were rigidly registered and rescaled into a reference image to fit the size of echocardiographic images. We employed 5-fold cross validation to examine model performance. We tested models trained by two types of data, averaged images and 10 selected images. Our best model (from 10 selected images) classified video views with 98.1% overall test accuracy in the independent cohort. In our view classification model, 1.9% of the images were mislabeled. To determine if this 98.1% accuracy was acceptable for creating the clinical prediction model using echocardiographic data, we tested the prediction model for EF using learning data with a 1.9% error rate. The accuracy of the prediction model for EF was warranted, even with training data containing 1.9% mislabeled images. The CNN algorithm can classify images into five standard views in a clinical setting. Our results suggest that this approach may provide a clinically feasible accuracy level of view classification for the analysis of echocardiographic data.

DOI： 10.3390/biom10050665

PubMed

Publishing type：Research paper (scientific journal)   International / domestic magazine：Domestic journal  

BACKGROUND: The coronary adventitia has recently attracted attention as a source of inflammation because it harbors nutrient blood vessels, termed the vasa vasorum (VV). This study assessed the link between local inflammation in adjacent epicardial adipose tissue (EAT) and coronary arterial atherosclerosis in fresh cadavers.Methods and Results:Lesion characteristics in the left anterior descending coronary artery of 10 fresh cadaveric hearts were evaluated using integrated backscatter intravascular ultrasound (IB-IVUS), and the density of the VV and levels of inflammatory molecules from the adjacent EAT were measured for each of the assessed lesions. The lesions were divided into lipid-rich, lipid-moderate, and lipid-poor groups according to percentage lipid volume assessed by IB-IVUS. Higher expression of inflammatory molecules (i.e., vascular endothelial growth factor A [VEGFA] andVEGFB) was observed in adjacent EAT of lipid-rich (n=11) than in lipid-poor (n=11) lesions (7.99±3.37 vs. 0.45±0.85 arbitrary units [AU], respectively, forVEGFA; 0.27±0.15 vs. 0.11±0.07 AU, respectively, forVEGFB; P<0.05). The density of adventitial VV was greater in lipid-rich than lipid-poor lesions (1.50±0.58% vs. 0.88±0.23%; P<0.05). CONCLUSIONS: Lipid-rich coronary plaques are associated with adventitial VV and local inflammation in adjacent EAT in fresh cadavers. This study suggests that local inflammation of EAT is associated with coronary plaque progression via the VV.

DOI： 10.1253/circj.CJ-19-0914

PubMed

CiNii Article

死後硬直していない解剖用遺体10例(男性5例、女性5例、死亡時年齢69〜96歳)の心臓を用いて、冠動脈のアテローム性動脈硬化と心外膜脂肪組織における炎症の関連について検討した。後方散乱を利用した血管内超音波エコー(IB-IVUS)により新鮮死体の左前下行枝(37病変)を評価し、心外膜脂肪組織における血管内皮増殖因子(VEGF)および栄養血管である外膜内の脈管の脈管の密度を測定した。左前下行枝病変をプラークの性状に応じて、脂質に富むプラーク(lipid rich)群11例、中等度の脂質群15例、少量の脂質群(lipid poor)11例の3群に分類した。脂質体積分率は平均で32.7±6.0%であった。心外膜脂肪組織におけるVEGF発現を定量化したところ、VEGF-AおよびVEGF-Bはいずれもlipid rich群の方がlipid poor群より有意に高かった(P<0.05)。また外膜内の脈管の脈管の密度もlipid rich群(1.50±0.58%)の方がlipid poor群(0.88±0.23%)より有意に高かった(P<0.05)。以上より、脂質に富む冠動脈プラークは心外膜脂肪組織の炎症と関連することが示唆された。

Publishing type：Research paper (scientific journal)   International / domestic magazine：International journal  

OBJECTIVES: This study investigated whether a deep convolutional neural network (DCNN) could provide improved detection of regional wall motion abnormalities (RWMAs) and differentiate among groups of coronary infarction territories from conventional 2-dimensional echocardiographic images compared with that of cardiologists, sonographers, and resident readers. BACKGROUND: An effective intervention for reduction of misreading of RWMAs is needed. The hypothesis was that a DCNN trained using echocardiographic images would provide improved detection of RWMAs in the clinical setting. METHODS: A total of 300 patients with a history of myocardial infarction were enrolled. From this cohort, 3 groups of 100 patients each had infarctions of the left anterior descending (LAD) artery, the left circumflex (LCX) branch, and the right coronary artery (RCA). A total of 100 age-matched control patients with normal wall motion were selected from a database. Each case contained cardiac ultrasonographs from short-axis views at end-diastolic, mid-systolic, and end-systolic phases. After the DCNN underwent 100 steps of training, diagnostic accuracies were calculated from the test set. Independently, 10 versions of the same model were trained, and ensemble predictions were performed using those versions. RESULTS: For detection of the presence of WMAs, the area under the receiver-operating characteristic curve (AUC) produced by the deep learning algorithm was similar to that produced by the cardiologists and sonographer readers (0.99 vs. 0.98, respectively; p = 0.15) and significantly higher than the AUC result of the resident readers (0.99 vs. 0.90, respectively; p = 0.002). For detection of territories of WMAs, the AUC by the deep learning algorithm was similar to the AUC by the cardiologist and sonographer readers (0.97 vs. 0.95, respectively; p = 0.61) and significantly higher than the AUC by resident readers (0.97 vs. 0.83, respectively; p = 0.003). From a validation group at an independent site (n = 40), the AUC by the deep learning algorithm was 0.90. CONCLUSIONS: The present results support the possibility of using DCNN for automated diagnosis of RWMAs in the field of echocardiography.

DOI： 10.1016/j.jcmg.2019.02.024

PubMed

Publishing type：Research paper (scientific journal)   International / domestic magazine：Domestic journal  

BACKGROUND: Although full-volume quantification of epicardial adipose tissue (EAT) is a predictor of LV diastolic dysfunction (LVDD), how localized EAT depots are linked to LVDD remains unclear. We evaluated the effect of local EAT depots on LV diastolic function parameters in patients with preserved LV ejection fraction (LVEF).Methods and Results:From 423 consecutive patients who underwent cardiac CT angiography, we recruited 252 with sinus rhythm and normal LVEF. The EAT volume index (EATV/body surface area) and the localized EAT thickness around the right coronary artery (EATRCA), left anterior descending artery (EATLAD), left circumflex artery (EATLCX), right ventricle (EATRV), left ventricle (EATLV), right atrium (EATRA), and left atrium (EATLA) were measured using cardiac CT. In the LVDD group (n=71), the EATV index (75±30 vs. 64±28 mL/m2, P=0.010), EATLCX(10.7±3.8 vs. 9.4±3.4 mm, P=0.008), and EATLV(2.6±1.6 vs. 2.1±1.4 mm, P=0.024) were greater than in the non-LVDD group (n=181). In contrast, EATLCXand EATLVwere markedly associated with decreased lateral e' and increased lateral E/e'. Multiple regression analysis indicated that EATLCXand EATLVwere strongly associated with LV diastolic function parameters. CONCLUSIONS: Localized EAT depots are linked to altered mitral annular motion. Further study is warranted to clarify whether localized EAT depots are functionally linked to the clinical manifestations of LVDD.

DOI： 10.1253/circj.CJ-19-0793

PubMed

CiNii Article

DOI： 10.1103/PhysRevD.101.012007

左室駆出率の保たれた患者における心エコー左室拡張機能パラメータと左室拡張機能障害(LVDD)診断に対する局所的心外膜脂肪組織(EAT)集積の影響を評価した。2012〜2015年に冠動脈疾患が疑われて心臓CTを実施した患者のうち、洞調律と正常な左室駆出率を示す患者252例(男性54%、平均66±13歳)を後ろ向きに解析した。心臓CTを実施し、EAT容積係数、局所的EAT厚として右冠動脈(EATRCA)、左前下行枝(EATLAD)、左回旋枝(EATLCX)、右室(EATRV)、左室(EATLV)、右房(EATRA)、左房(EATLA)周囲を測定した。心エコーを実施して、中隔および外側でE/e'を計算した。LVDDありが71例、LVDDなしが181例であった。EAT容積係数はLVDD群が75±30cm3/m2、非LVDD群が64±28cm3/m2、EATLCXは10.7±3.8mmと9.4±3.3mm、EATLVは2.6±1.6mmと2.1±1.4mmで、非LVDD群よりもLVDD群の方が有意に大きかった。EATLCXとEATLVは外側e'の減少と外側E/e'の増加に顕著に関連していた。重回帰分析ではEATLCXとEATLVは左室拡張機能パラメータと強く関連していた。

Publishing type：Research paper (scientific journal)   International / domestic magazine：International journal  

Diabetic patients have coagulation abnormalities, in which thrombin plays a key role. Whereas accumulating evidence suggests that it also contributes to the development of vascular dysfunction through the activation of protease-activated receptors (PARs). Here we investigated whether the blockade of thrombin attenuates endothelial dysfunction in diabetic mice. Induction of diabetes by streptozotocin (STZ) increased the expression of PAR1, PAR3, and PAR4 in the aorta. STZ-induced diabetic mice showed impairment of endothelial function, while the administration of dabigatran etexilate, a direct thrombin inhibitor, significantly attenuated endothelial dysfunction in diabetic mice with no alteration of metabolic parameters including blood glucose level. Dabigatran did not affect endothelium-independent vasodilation. Dabigatran decreased the expression of inflammatory molecules (e.g., MCP-1 and ICAM-1) in the aorta of diabetic mice. Thrombin increased the expression of these inflammatory molecules and the phosphorylation of IκBα, and decreased the phosphorylation of eNOSSer1177 in human umbilical endothelial cells (HUVEC). Thrombin significantly impaired the endothelium-dependent vascular response of aortic rings obtained from wild-type mice. Inhibition of NF-κB attenuated thrombin-induced inflammatory molecule expression in HUVEC and ameliorated thrombin-induced endothelial dysfunction in aortic rings. Dabigatran attenuated the development of diabetes-induced endothelial dysfunction. Thrombin signaling may serve as a potential therapeutic target in diabetic condition.

DOI： 10.1016/j.vph.2019.106632

PubMed

Publishing type：Research paper (scientific journal)   International / domestic magazine：International journal  

BACKGROUND: Recent studies have shown that patients with combined pre- and postcapillary pulmonary hypertension (CpcPH) had worse outcomes than those with isolated postcapillary pulmonary hypertension (IpcPH). However, the prognostic factors including right ventricular (RV) function have not been well documented. The aim of this study was to assess the differentiation of PH phenotypes, using echocardiography, and the association between RV longitudinal strain and cardiac events. METHODS AND RESULTS: We prospectively recruited consecutive patients who had undergone right heart catheterization. The primary endpoint was cardiovascular death or readmission due to heart failure. We included 137 patients with Group 2 PH. A RV longitudinal strain of 17% was sensitive (85%) and specific (70%) to determine the CpcPH. During a median period of 31 months, 43 patients experienced the primary endpoint during follow-up. In a multivariate analysis, RV longitudinal strain was associated with the primary endpoint in both CpcPH and IpcPH (HR: 0.84, P = 0.003; HR: 0.86, P = 0.001). CONCLUSIONS: Lower RV longitudinal strain was independently associated with worse outcomes in CpcPH and IpcPH. RV longitudinal strain may play a prognostic role in PH phenotypes.

DOI： 10.1016/j.cardfail.2019.08.021

PubMed

Publishing type：Research paper (scientific journal)   International / domestic magazine：International journal  

Background: It is known that epicardial adipose tissue (EAT) volume is linked to cardiac dysfunction. However, it is unclear whether EAT volume (EATV) is closely linked to abnormal LV strain. We examined the relationship between EATV and global longitudinal strain (GLS), global circumferential strain (GCS), and global radial strain (GRS) in patients with preserved LV function. Methods: Notably, 180 consecutive subjects (68 ± 12 years; 53% men) underwent 320-slice multi-detector computed tomography coronary angiography and were segregated into coronary artery disease (CAD) (≥1 coronary artery branch stenosis ≥50%) and non-CAD groups. GLS, GCS, and GRS were evaluated by 2-dimensional speckle tracking in patients with preserved left ventricular (LV) ejection fraction (LVEF) ≥50%. Results: First, GLS, but not GRS and GCS, was lower in the high EATV group though the LVEF was comparable to the low EATV group. Frequency of GLS ≤18 was higher in the high EATV group. Second, multiple regression model showed that EATV, age, male sex, and CAD, were determinants of GLS. Third, the cutoff points of EATV were comparable (~116-117 mL) in both groups. The cutoff of EATV ≥116 showed a significant correlation with GLS ≤18 in overall subjects. Conclusions: Increasing EATV was independently associated with global longitudinal strain despite the preserved LVEF and lacking obstructive CAD. Our findings suggest an additional role of EAT on myocardial systolic function by impaired LV longitudinal strain.

DOI： 10.3389/fcvm.2020.607825

PubMed

Publishing type：Research paper (scientific journal)   International / domestic magazine：International journal  

Growing evidence suggests that damage-associated molecule patterns (DAMPs) and their receptors, pattern recognition receptors (PRRs), are associated with the progression of cardiometabolic disorders, including obesity-related insulin resistance and atherosclerosis. Cardiometabolic disorders share sterile chronic inflammation as a major cause; however, the exact mechanisms are still obscure. Toll-like receptor 9 (TLR9), one of the nucleic acid-sensing TLRs, recognizes DNA fragments derived from pathogens and contributes to self-defense by activation of the innate immune system. In addition, previous studies demonstrated that TLR9 recognizes DNA fragments released from host cells, accelerating sterile inflammation, which is associated with inflammatory diseases such as autoimmune diseases. In obese adipose tissue and atherosclerotic vascular tissue, various stresses release DNA fragments and/or nuclear proteins as DAMPs from degenerated adipocytes and vascular cells. Recent studies indicated that the activation of TLR9 in immune cells including macrophages and dendritic cells by recognition of these DAMPs promotes inflammation in these tissues, which causes cardiometabolic disorders. This review discusses recent advances in understanding the role of sterile inflammation associated with TLR9 and its endogenous ligands in cardiometabolic disorders. New insights into innate immunity may provide better understanding of cardiometabolic disorders and new therapeutic options for these major health threats in recent decades.

DOI： 10.1186/s41232-020-00118-7

PubMed

Publishing type：Research paper (scientific journal)   International / domestic magazine：International journal  

Objectives: Cilnidipine, an L-/N-type calcium channel blocker (CCB), has unique organ-protective properties due to suppression of hyperactivity in the sympathetic nervous system and renin-angiotensin system (RAS). In this study, we hypothesized that cilnidipine might exert a renoprotective effect by suppressing the RAS. Methods: A total of 25 hypertensive patients receiving a RAS inhibitor were randomly assigned to a cilnidipine (n = 12) or amlodipine (n = 13) group. The effects of cilnidipine on proteinuria and angiotensin II-renin feedback were assessed. Results: After 6 months of treatment, both systolic and diastolic blood pressures were significantly reduced to a similar extent in both groups. The urine albumin-to-creatinine ratio was significantly lower in the cilnidipine group (p < 0.05) than in the amlodipine group. Amlodipine increased plasma angiotensin I and angiotensin II levels (p < 0.05), whereas cilnidipine did not. Interestingly, the cilnidipine group had a higher ratio of angiotensin-(1-7) (Ang-(1-7)) to angiotensin II in plasma than the amlodipine group (p < 0.05). Conclusions: The L-/N-type CCB cilnidipine, but not amlodipine, decreased urinary albumin excretion in hypertensive patients. Cilnidipine also increased the ratio of Ang-(1-7) to angiotensin II in plasma, which might be one factor underlying its beneficial effects.

DOI： 10.1155/2020/6653851

PubMed

International / domestic magazine：International journal  

DOI： 10.1016/j.jcmg.2019.07.002

PubMed

Publishing type：Research paper (scientific journal)   International / domestic magazine：Domestic journal  

Dipeptidyl peptidase-4 (DPP-4) inhibitors are novel antidiabetic agents with possible vascular protection effects. Endothelial dysfunction is an initiation step in atherogenesis. The purpose of this study was to investigate whether vildagliptin (Vilda) attenuates the development of endothelial dysfunction and atherosclerotic lesions in nondiabetic apolipoprotein E-deficient (ApoE-/-) mice. Eight-week-old nondiabetic ApoE-/- mice fed a Western-type diet received Vilda (50 mg/kg/day) for 20 weeks or 8 weeks. After 20 weeks of treatment, Vilda administration reduced atherogenesis in the aortic arch as determined by en face Sudan IV staining compared with the vehicle group (P < 0.05). Vilda also reduced lipid accumulation (P < 0.05) and vascular cell adhesion molecule-1 (VCAM-1) expression (P < 0.05) and tended to decrease macrophage infiltration (P = 0.05) into atherosclerotic plaques compared with vehicle. After 8 weeks of treatment, endothelium-dependent vascular reactivity was examined. Vilda administration significantly attenuated the impairment of endothelial function in nondiabetic ApoE-/- mice compared with the vehicle group (P < 0.05). Vilda treatment did not alter metabolic parameters, including blood glucose level, in both study protocols. To investigate the mechanism, aortic segments obtained from wild-type mice were incubated with exendin-4 (Ex-4), a glucagon-like peptide-1 (GLP-1) analog, in the presence or absence of lipopolysaccharide (LPS). Ex-4 attenuated the impairment of endothelium-dependent vasodilation induced by LPS (P < 0.01). Furthermore, Ex-4 promoted phosphorylation of eNOS at Ser1177 which was decreased by LPS in human umbilical endothelial cells (P < 0.05). Vilda inhibited the development of endothelial dysfunction and prevented atherogenesis in nondiabetic ApoE-/- mice. Our results suggested that GLP-1-dependent amelioration of endothelial dysfunction is associated with the atheroprotective effects of Vilda.

DOI： 10.1536/ihj.19-117

PubMed

CiNii Article

Publishing type：Research paper (scientific journal)   International / domestic magazine：Domestic journal  

BACKGROUND: Whether preoperative echocardiography improves postoperative outcomes is not well established, so we examined the value of echocardiographic assessment on the onset of postoperative heart failure (HF), and determining which patients benefitted most from undergoing echocardiography prior to major elective non-cardiac surgery.Methods and Results:We identified all patients aged 50 years and older who had major elective non-cardiac surgery, and excluded patients with previously identified severe cardiovascular disease. The primary endpoint was the onset of HF during hospitalization. A total of 806 patients were included in the analysis. During hospitalization, 49 patients (6%) reached the primary endpoint. Within the matched cohort, preoperative echocardiography was associated with a statistically significant decrease in postoperative HF (hazard ratio: 0.46, P=0.01). In subgroup analyses, age, sex, body surface area, hypertension, diabetes mellitus, prior HF, surgical type, chronic kidney disease, pulmonary disease, and malignancy influenced the association of echocardiography with postoperative HF. CONCLUSIONS: The use of echocardiography in elderly patients with certain risk factors was associated with improved postoperative outcomes. The basis for this finding remains to be determined; particularly whether echocardiography is simply a marker of a population with better outcomes or whether it leads to better management that improves outcomes.

DOI： 10.1253/circj.CJ-19-0663

PubMed

CiNii Article

ApoE欠損マウスを用いて、DPP-4阻害薬であるビルダグリプチンが血管内皮機能とアテローム性動脈硬化に及ぼす影響を検討した。ApoE欠損マウスに西洋型食餌を8週齢から28週齢まで与え、ビルダグリプチン(50mg/kg)を0.5%カルボキシメチルセルロース(CMC)水溶液に懸濁して投与した。対照群には同量のCMC水溶液を投与した。大動脈のen face sudan IV染色を実施し、ビルダグリプチン投与群でアテローム性動脈硬化の進展が有意に抑制された。またビルダグリプチン投与群ではプラーク中における脂質蓄積とVCAM-1の発現が対照群より有意に低く、マクロファージの浸潤も少なかった。非糖尿病マウスの血管内皮機能に対するビルダグリプチンの効果を検討するため、ApoE欠損マウスと野生型マウスに西洋型食餌を与えた。8週間後にApoE欠損マウスで血管内皮機能障害を認めたが、8週間のビルダグリプチン投与により血管内皮機能障害は対照群に比べて有意に改善した。ビルダグリプチン投与により血糖値を含む代謝パラメータに有意な群間差はみられなかった。

心エコー評価と術後心不全の発生率との関係性を評価し、待機的非心臓手術に先行した心エコー検査によって便益が得られる患者を明らかにした。2013年1月31日〜2015年10月31日に緊急非心臓手術を実施した50歳以上の患者を後ろ向きに調べた。入院中の心不全の発症を評価した。傾向スコアマッチング後、心エコーを実施した403例(男性41%、平均70±9歳)と心エコー非実施の403例(男性42%、平均70±9歳)を評価した。入院中に49例が心不全を発症した。術前心エコーは術後心不全の減少と有意に関連した。サブグループ解析では、年齢、性別、体表面積、高血圧、糖尿病、先行する心不全、手術型、慢性腎疾患、肺疾患、悪性腫瘍が心エコーと術後心不全の関連に影響を及ぼしていることが示された。危険因子のある高齢患者における心エコーの使用は術後転帰の改善と関連した。

DOI： 10.2169/naika.108.1607

CiNii Article

Publishing type：Research paper (scientific journal)   International / domestic magazine：International journal  

Activated factor X (FXa) plays a central role in the coagulation cascade, while it also mediates vascular function through activation of protease-activated receptors (PARs). Here, we examined whether inhibition of FXa by rivaroxaban, a direct FXa inhibitor, attenuates endothelial dysfunction in streptozotocin (STZ)-induced diabetic mice. Induction of diabetes increased the expression of a major FXa receptor, PAR2, in the aorta (P < 0.05). Administration of rivaroxaban (10 mg/kg/day) to diabetic wild-type (WT) mice for 3 weeks attenuated endothelial dysfunction as determined by acetylcholine-dependent vasodilation compared with the control (P < 0.001), without alteration of blood glucose level. Rivaroxaban promoted eNOSSer1177 phosphorylation in the aorta (P < 0.001). Induction of diabetes to PAR2-deficient (PAR2-/-) mice did not affect endothelial function and eNOSSer1177 phosphorylation in the aorta compared with non-diabetic PAR2-/- mice. FXa or a PAR2 agonist significantly impaired endothelial function in aortic rings obtained from WT mice, but not in those from PAR2-/- mice. FXa promoted JNK phosphorylation (P < 0.01) and reduced eNOSSer1177 phosphorylation (P < 0.05) in human coronary artery endothelial cells (HCAEC). FXa-induced endothelial dysfunction in aortic rings (P < 0.001) and eNOSSer1177 phosphorylation (P < 0.05) in HCAEC were partially ameliorated by a JNK inhibitor. Rivaroxaban ameliorated diabetes-induced endothelial dysfunction. Our results suggest that FXa or PAR2 is a potential therapeutic target.

DOI： 10.1038/s41598-019-47474-0

PubMed

症例は20歳男性で、気管支喘息の病歴が存在していた。嘔気、咽頭痛、下肢の皮疹が続くため来院した。受診時の診察では下肢に隆起性の紫斑を認め、また咽頭はわずかに発赤している様子が観察された。患者からは急性腹症の履歴は聴取されなかった。心拍数は98拍/分、体温は37.8℃で血液検査では白血球数上昇、フィブリノゲン高値、および抗ストレプトリジン-O抗体価陽性が示されたが血清免疫グロブリン(Ig)A濃度は基準範囲内であった。尿検査では蛋白尿(1+)と判定された。皮膚生検を施行し蛍光免疫染色の直接法にて血管中膜にIgA沈着を認めた。これらの所見からガイドラインに準拠してpossibleなIgA血管炎と診断した。アセトアミノフェン500mg/日で加療したところ2週間以内に紫斑を含む症状は完全消退し、最後の受診から1ヵ月後の時点でも患者は体調が快調であると報告していた。

症例は89歳女性で、転倒後に生じた右臀部の疼痛を主訴に当院を受診した。患者には無症候性の重症大動脈弁狭窄が存在していた。CTでは右大腿骨幹の完全骨折に加え、その受傷部、頭蓋骨、両側肩甲骨、および腰椎に骨溶解性腫瘍が多発していることが判明した。経カテーテル大動脈弁留置術、次いで骨折に対する手術を施行して成功した。血清学的検査ではEpstein-Barrウイルス(EBV)の核抗原に対するIgG、およびEBVカプシド抗原に対するIgGが陽性であったが、EBVのDNAに対するPCR検査は施行しなかった。右側頭軟部組織の生検ではCD20とB-cell lymphoma 2(BCL-2)が陽性の大型細胞がび漫性に増殖している所見が観察され、Ki-67標識指数は80%と増殖能が高いことも示された。骨髄生検は行わなかった。こうした多発病変は骨に限局していたことから高齢者EBウイルス陽性び漫性大細胞型B細胞リンパ腫による原発性骨リンパ腫(臨床ステージIV、予後リスク高)と診断した。治療法には最善の支持療法が選択され、その後は骨病変の進行が示されるとともに患者の全身状態は悪化して入院9週後に死亡した。

Publishing type：Research paper (scientific journal)   International / domestic magazine：International journal  

Background Toll-like receptor ( TLR ) 9 recognizes bacterial DNA , activating innate immunity, whereas it also provokes inflammation in response to fragmented DNA released from mammalian cells. We investigated whether TLR 9 contributes to the development of vascular inflammation and atherogenesis using apolipoprotein E-deficient ( Apoe -/-) mice. Methods and Results Tlr9-deficient Apoe -/- ( Tlr9 -/- Apoe -/-) mice and Apoe -/- mice on a Western-type diet received subcutaneous angiotensin II infusion (1000 ng/kg per minute) for 28 days. Angiotensin II increased the plasma level of double-stranded DNA, an endogenous ligand of TLR 9, in these mice. Genetic deletion or pharmacologic blockade of TLR 9 in angiotensin II-infused Apoe -/- mice attenuated atherogenesis in the aortic arch ( P<0.05), reduced the accumulation of lipid and macrophages in atherosclerotic plaques, and decreased RNA expression of inflammatory molecules in the aorta with no alteration of metabolic parameters. On the other hand, restoration of TLR 9 in bone marrow in Tlr9 -/- Apoe -/- mice promoted atherogenesis in the aortic arch ( P<0.05). A TLR 9 agonist markedly promoted proinflammatory activation of Apoe -/- macrophages, partially through p38 mitogen-activated protein kinase signaling. In addition, genomic DNA extracted from macrophages promoted inflammatory molecule expression more effectively in Apoe -/- macrophages than in Tlr9 -/- Apoe -/- macrophages. Furthermore, in humans, circulating double-stranded DNA in the coronary artery positively correlated with inflammatory features of coronary plaques determined by optical coherence tomography in patients with acute myocardial infarction ( P<0.05). Conclusions TLR 9 plays a pivotal role in the development of vascular inflammation and atherogenesis through proinflammatory activation of macrophages. TLR 9 may serve as a potential therapeutic target for atherosclerosis.

DOI： 10.1161/JAHA.118.010860

PubMed

Publishing type：Research paper (scientific journal)   International / domestic magazine：International journal  

Middle-aged marathon runners have an increased risk of developing atrial fibrillation (AF). A previous study described that repetitive marathon running was associated with left atrial (LA) dysfunction. However, whether this change is common in marathon runners and which runners are at risk of LA dysfunction remain unknown. The purpose of this study was to determine which factors could predict LA dysfunction. We prospectively examined 12 healthy amateur volunteers (9 males, 31 ± 8 years old) who participated in a full marathon. All echocardiographic measurements and speckle-tracking echocardiography were performed before and after the marathon. The endpoint was defined as reduced LA reservoir strain 1 day after the marathon (non-responder group). Seven participants were in the non-responder group. Age (35 ± 9 vs. 26 ± 2 years, p = 0.020), augmentation index (76 ± 12 vs. 55 ± 8, p = 0.002), and diastolic blood pressures (83 ± 11 vs. 70 ± 7 mmHg, p = 0.021) in the non-responder group were significantly higher compared with the responder group. In multivariate linear regression analysis, only the augmentation index was an independent predictor of reduced LA reservoir function after the marathon (β = - 0.646, p = 0.023). The augmentation index was a predictive marker for reduction in LA reservoir function after a marathon in healthy amateur volunteers.

DOI： 10.1007/s10554-018-1502-2

PubMed

Publishing type：Research paper (scientific journal)   International / domestic magazine：Domestic journal  

AIM: It is speculated that statin therapy modulates the synthesis of polyunsaturated fatty acids (PUFA), including eicosapentaenoic acid (EPA) and docosahexaenoic acid (DHA). However, the data available on the effects of statin therapy on the serum levels of PUFA and the subsequent impact on in-stent restenosis (ISR) in patients with acute coronary syndrome (ACS) are limited. METHODS: A total of 120 ACS patients who received emergent coronary stent implantation, follow-up coronary angiography to evaluate ISR, and new statin therapy were enrolled. We measured the serum levels of the PUFA and lipids at the onset of ACS and at the follow-up coronary angiography. RESULTS: The follow-up coronary angiography revealed 38 ISR cases. New statin therapy significantly reduced the serum levels of DHA and low-density lipoprotein cholesterol (LDL-C), while it did not affect EPA level. Single regression analysis revealed that a decreased serum level of LDL-C was associated with decreased DHA level. The multiple logistic regression analysis revealed that the decreased DHA level after statin therapy and low serum level of EPA on admission were determinants of prevalence of ISR. CONCLUSION: Statin therapy decreased the serum level of DHA with a parallel reduction in LDL-C level in patients with ACS. Decreased DHA level after statin therapy and low EPA level on admission are risk factors for ISR, indicating that in patients with ACS, decreased serum levels of DHA may be a residual target for the prevention of ISR.

DOI： 10.5551/jat.44735

PubMed

CiNii Article

急性冠症候群(ACS)患者における血清多価不飽和脂肪酸(PUFA)値とステント内再狭窄(ISR)に及ぼすスタチン療法の影響を調査した。2009年1月〜2017年7月に当施設で新規病変に対してステント留置による緊急経皮的冠動脈インターベンション(PCI)を実施したACS患者のデータを後ろ向きに調査した。ACS患者120例(男性74%、平均67±13歳)に緊急冠動脈ステント留置を実施し、緊急PCI後3ヵ月以降に経過観察で冠動脈造影によってISRを評価し、スタチン療法を実施した。ACS発症時と経過観察冠動脈造影時にPUFAと脂質の血清値を測定した。38例でISRが明らかになった。新規スタチン療法によって血清LDLコレステロール(C)値とドコサヘキサエン酸(DHA)が有意に減少したが、エイコサペンタエン酸(EPA)は変化しなかった。単一回帰分析では血清LDL-C値の減少がDHA値の減少と関連した。多重ロジスティック回帰分析ではスタチン療法後のDHA値の減少と入院時のEPAの低血清値がISR有病率の決定因子であった。

症例は80歳女性で、網膜中心静脈閉塞症手術のための術前心電図検査の最中に、安静時胸痛が突然出現した。高血圧の既往はあったが、高脂血症はなく、慢性心房細動のため25年間にわたり抗凝固療法を受けていた。心エコーではI、aVL、V2-6リードにJ波を伴うST上昇およびIIIとaVFリードにST低下を認めた。5分後、前胸波はcoved型からST上昇Saddleback型に変化した。心電図の所見により近位左前下行枝(LAD)の閉塞による広汎性前側急性心筋梗塞(AMI)が示唆されたが、心エコーでは壁運動異常は示されなかった。緊急冠動脈血管造影ではLADにおける狭窄または閉塞は認めなかったが、対角枝の先端の閉塞が示された。血管形成の翌日にI、aVL、V2-5リードに陰性T波を認めた。抗凝固療法の2週間後に実施した冠血管造影では対角枝の再灌流を認め、対角枝の先端は心房細動による血栓にて閉塞していたと考えられた。造影MRIの画像は前外側左心室壁に小さな梗塞を示した。AMI発症の3週間後に合併症なく退院した。

Publishing type：Research paper (scientific journal)   International / domestic magazine：Domestic journal  

Immunoglobulin A vasculitis (IgAV), formerly known as Henoch-Schönlein purpura, primarily occurs during childhood between the ages of 3 and 15 years and is the most common form of systemic vasculitis in children ; its occurrence in adults has been rarely reported. Such low incidence could be attributable to either under-diagnosis or misdiagnosis. Thus, not only pediatricians but also physicians should be able to diagnose IgAV accurately to manage the patients appropriately and avoid its associated complications. In addition, treatment of adult onset IgAV with renal involvement has not been fully established yet. We describe here a case of adult onset IgAV complicated by proteinuria and pharyngitis, which was cured by no specific treatment. J. Med. Invest. 66 : 344-346, August, 2019.

DOI： 10.2152/jmi.66.344

PubMed

CiNii Article

Publishing type：Research paper (scientific journal)   International / domestic magazine：Domestic journal  

Primary non-Hodgkin bone lymphoma (PBL) can involve solitary or multiple destructive bone lesions such as those of the femur or pelvis humerus, and some cases have osteolytic lesions. PBL is a rare disease in adults. Thus, PBL is rarely considered a differential diagnosis of the osteolytic tumor. In addition, PBL can be underdiagnosed because patients do not experience symptoms or show objective abnormalities in the early stage. Here, we reported an elderly patient with PBL in multiple bones, including the cranial and femoral bones that were fractured due to falling. J. Med. Invest. 66 : 347-350, August, 2019.

DOI： 10.2152/jmi.66.347

PubMed

CiNii Article

Publishing type：Research paper (scientific journal)   International / domestic magazine：International journal  

Background: The interactions of adipose tissue with the kidney are hypothesized to affect kidney function. Also, excessive peri-renal fat may increase the risk of cardiometabolic risk. However, the role(s) of peri-renal fat adipocytokine has never been evaluated. Objectives: To elucidate levels of adiponectin expression in peri-renal and subcutaneous adipose tissue and its determinants in human biopsied samples. Methods: A pair of subcutaneous and perirenal fat tissue samples were collected from 80 patients (men: 54; women: 26) who underwent urological operations. Subcutaneous adipose tissue (SAT) area, visceral adipose tissue (VAT) area and peri-renal adipose tissue (RAT) volume were quantified on abdominal computed tomography. Cytokine/adipocytokine expression was evaluated by real-time semi-quantitative polymerase chain reaction (qPCR). Probability was considered significant if P < 0.05. Results: Current study evaluated determinants of plasma adiponectin levels and expression levels of adiponectin in SAT and RAT in human samples. We found that: first, plasma adiponectin levels were correlated with VAT area but not with BMI, waist circumference, SAT area, and RAT volume; second, expression levels of adiponectin in SAT were correlated with BMI, waist circumference, and SAT area but not with VAT area and RAT volume; and third, expression levels of adiponectin in RAT were correlated with all adiposity indices including BMI, waist circumference, SAT area, VAT area, and RAT volume. Conclusion: This study evaluated levels of adiponectin expression in RAT and SAT and its determinants in patients who underwent urological operation. Levels of adiponectin mRNA in RAT were negatively correlated with remote fat mass in SAT and VAT and also with local fat mass in RAT, while level of adiponectin in SAT was not correlated with RAT volume. Further studies are warranted to evaluate roles of peri-renal fat mass accumulation and its pathophysiological machineries.

DOI： 10.3389/fendo.2019.00897

PubMed

Publishing type：Research paper (scientific journal)   International / domestic magazine：Domestic journal  

The culprit lesion of acute myocardial infarction could be predicted by electrocardiogram findings. However, we experienced some cases with coronary angiographic finding in the area of ST-T elevation that was different from that predicted. The lambda-like J wave could be caused by ischemia although the mechanism has not been fully elucidated. We report a case of acute myocardial infarction that showed discrepancy between ST-T elevation with lambda-like ischemic J wave in a broad area and coronary angiographical finding of diagonal branch occlusion. J. Med. Invest. 66 : 185-187, February, 2019.

DOI： 10.2152/jmi.66.185

PubMed

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PubMed

J-GLOBAL

J-GLOBAL

慢性炎症はインスリン抵抗性,動脈硬化症などの心血管代謝疾患の病態基盤となる.しかしながら,無菌性慢性炎症の基盤メカニズムの全体像は未解明である.糖尿病や脂質異常症,高血圧などの様々な生活習慣に関連したリスク因子は,代謝臓器や血管組織において,細胞や組織のダメージを誘発し,種々のパターン認識受容体に対する様々な内因性リガンドを放出させる.近年,ダメージを受けた細胞から放出されるDNA断片などの核酸は,組織内に蓄積し,内因性リガンドとして役割を果たすことが明らかになってきた.生体内には,核酸断片を認識する受容体(DNAセンサー)が存在している.DNAセンサーは,本来,病原体由来のDNA断片を認識し,強力な免疫反応を誘導することで,生体防御システムとして作用する.しかし,最近の研究によって,DNAセンサーは,自己細胞由来のミトコンドリアDNAなどの核酸断片をも認識することにより,無菌性炎症を惹起し,種々の炎症性疾患の病態に関与することが明らかになってきた.本稿では,複数あるDNAセンサーのうち,エンドソームに局在するToll様受容体9と細胞質内に存在するcyclic GMP-AMP synthase-stimulator of interferon genesが,心血管代謝疾患の病態に与える影響を概説する.(著者抄録)

冠動脈CT血管造影(CCTA)-Wide Volume Scan(WVS)により冠動脈疾患と胸部大動脈プラークを同時に評価し、心血管予後との関連について検討した。2017年4月～2019年11月の期間にCCTA-WVS検査により冠動脈疾患の評価と大動脈弓を含む胸部大動脈の評価を行った胸痛患者455名(男性234名、女性221名、平均65±13歳)を対象とした。CCTA-WVS所見は冠動脈石灰化スコア0、0～100、101～400、>400がそれぞれ42.9%、26.8%、20.6%、11.2%であった。平均2.8±0.9年の追跡期間中、445例中34例(7.6%)に主要有害事象(MACE)を認めた。吹田CVDリスクスコアで調整したCox比例ハザードモデルでは、冠動脈石灰化スコア>400と胸部大動脈プラークスコア(T3)が心血管イベント発症の独立した予測因子であった。CCTA-WVSを用いた胸部大動脈プラークスコアと冠動脈疾患の包括的評価が心血管イベントリスクの層別化に貢献できると考えられた。

J-GLOBAL

J-GLOBAL

冠動脈の動脈硬化プラークが破綻すると血栓が形成され,急激な管腔閉塞により心筋梗塞や不安定狭心症の原因となる。血栓形成には,血小板と血液凝固系の両方が関与する。血液凝固因子は,血管構成細胞のプロテアーゼ活性型受容体の活性化を介して血管の炎症にも関与する。最近の臨床試験で直接経口抗凝固薬は,抗血小板薬との併用により動脈硬化疾患の二次予防に有効であった。この効果には抗炎症作用も寄与している可能性がある。(著者抄録)

DOI： 10.1093/ehjci/jez235

Publishing type：Research paper, summary (international conference)  

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