Aims Anomalous origin of the coronary artery (AOCA) with an inter-arterial course (IAC) between the great vessels poses a risk for a life-threatening cardiovascular event. We assessed, in a registry-based study, the clinical features, treatment strategies, and prognoses of life-threatening cardiovascular events ensuant to AOCA. Methods and results Included were 65 AOCA patients (48 men/17 women, aged 41 ± 23 years) from 40 clinical centres who had experienced sudden cardiac arrest (SCA) (n = 30), acute myocardial infarction (AMI) (n = 5), angina (n = 23), or syncope (n = 7). The anomalous vessel was the right coronary artery in 72% of patients and left coronary artery in 28%; the ostium was slit-like in 42%. Coronary luminal narrowing ≥75% was absent in patients with SCA or syncope (86% and 57%, respectively), but occlusion or narrowing was seen in those with AMI (100%) or angina (52%). Age ≤40 years, male sex, sporting activity, absence of prodromal symptoms, acutely angled (≤30°) take-off from the aorta, and absence of luminal narrowing of the IAC segment were associated with SCA in this patient group. Coronary vasospasm was inducible in 12 of 17 patients without coronary narrowing. Management included surgical revascularization (n = 26) percutaneous coronary intervention (n = 9), and medical treatment (n = 26). Four SCA patients died while hospitalized; no others died during the median 5.0 (range, 1.8–7.0)-year follow-up period. Conclusions In patients with AOCA, age ≤40 years, male sex, sporting activity, and an acute take-off angle appear to be risk factors for SCA. Appropriate management can be beneficial. Confirmation in a large-scale study is warranted.

Thoracic aortic dissection (TAD) is a life-threatening vascular disease. We showed that CD44, a widely distributed cell surface adhesion molecule, has an important role in inflammation. In this study, we examined the role of CD44 in the development of TAD. TAD was induced by the continuous infusion of β-aminopropionitrile (BAPN), a lysyl oxidase inhibitor, and angiotensin II (AngII) for 7 days in wild type (WT) mice and CD44 deficient (CD44 -/-) mice. The incidence of TAD in CD44 -/mice was significantly reduced compared with WT mice (44% and 6%, p < 0.01). Next, to evaluate the initial changes, aortic tissues at 24 hours after BAPN/AngII infusion were examined. Neutrophil accumulation into thoracic aortic adventitia in CD44 -/mice was significantly decreased compared with that in WT mice (5.7 ± 0.3% and 1.6 ± 0.4%, p < 0.01). In addition, BAPN/AngII induced interleukin-6, interleukin-1β, matrix metalloproteinase-2 and matrix metalloproteinase-9 in WT mice, all of which were significantly reduced in CD44 −/− mice (all p < 0.01). In vitro transmigration of neutrophils from CD44 −/− mice through an endothelial monolayer was significantly decreased by 18% compared with WT mice (p < 0.01). Our findings indicate that CD44 has a critical role in TAD development in association with neutrophil infiltration into adventitia. open Scientific RepoRtS | (2020) 10:6869 | https://doi.org/10.1038/s41598-020-63824-9www.nature.com/scientificreports www.nature.com/scientificreports/ routes of administration including oral gavage 7,14 , subcutaneous osmotic pump infusion 15 , and subcutaneous injection 16,17 , have previously been established. In the current study, we investigated the role of CD44 in TAD induced by BAPN/AngII by comparing wild type (WT) and CD44 deficient (CD44 −/− ) mice. Results CD44 deficiency in mice decreases rates of aortic dissection.To investigate the effects of CD44 deficiency on the development of aortic dissection, WT and CD44 −/− mice were administered saline or BAPN/AngII for 7 days (Fig. 1). Saline-treated WT and CD44 −/− mice were used as controls. A slight increase in blood pressure after treatment with BAPN/AngII was observed in WT and CD44 −/− mice (Supplemental Fig. 1). Treatment with BAPN/AngII led to thoracic and abdominal aortic dissection (the presence of an intramural thrombus) and rupture. Figure 2A shows a representative image of TAD (white arrow). Histological analyses in thoracic aortae showed that intramural haematoma (black arrow) and degradation of elastin (yellow arrow) were present in the dissection area (Fig. 2B). The incidence of aortic dissection in BAPN/AngII-treated CD44 −/− mice was approximately 0.4 times as high as the incidence in BAPN/AngII-treated WT mice (69% and 26%, p = 0.01) (Fig. 2C). Furthermore, the incidence of TAD after BAPN/AngII treatment was significantly reduced in CD44 −/− mice compared with WT mice (44% and 6%, p < 0.01). However, no difference in the incidence of abdominal aortic dissection was observed (25% and 20%, p = 0.76) ( Fig. 2D). Scientific RepoRtS...

Atherosclerosis is a leading cause of morbidity and mortality in many countries. Mice are the most frequently used animal model to study the pathogenesis and molecular mechanisms of atherosclerosis. En face analyses of the aorta and cross-sections of the aortic root are the two common modes for quantifying the severity of atherosclerosis in mice. This mini-review introduces these two methods, discusses their pros and cons, and provides suggestions to optimize the quantification of atherosclerosis, thereby enhancing rigor and reproducibility in preclinical research.

Accumulating evidence has shown that oxidized low-density lipoprotein (LDL) is a useful marker for cardiovascular disease. Oxidized LDL contributes to atherogenesis in a wide range of stages, such as impairing vascular endothelial cells, promoting expression of adhesion factors of vascular endothelial cells, and facilitating monocyte migration and accumulation of lipids under the vascular endothelium by being captured by macrophages [1]. Previous studies have shown that oxidized LDL levels are elevated in patients with coronary artery disease [2,3]. Oxidized LDL levels are especially increased in acute coronary syndrome (ACS) compared with stable angina pectoris [4]. Furthermore, elevated oxidized LDL levels are predictive of future cardiovascular events in healthy men and predict an increased risk of future myocardial infarction in apparently healthy people [5]. These

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Doxorubicin (DOX)-based chemotherapy induces cardiotoxicity, which is considered the main bottleneck for its clinical application. In this study, we investigated the potential benefit of LCZ696, an angiotensin receptor–neprilysin inhibitor against DOX-induced cardiotoxicity in rats and H9c2 cells and determined whether the mechanism underlying any such effects involves its antioxidant activity. Male Sprague–Dawley rats were randomly separated into four groups, each consisting of 15 rats (DOX (1.5 mg/kg/day intraperitoneally for 10 days followed by non-treatment for 8 days); DOX + valsartan (31 mg/kg/day by gavage from day 1 to day 18); DOX + LCZ696 (68 mg/kg/day by gavage from day 1 to day 18); and control (saline intraperitoneally for 10 days). DOX-induced elevation of cardiac troponin T levels on day 18 was significantly reduced by LCZ696, but not valsartan. The DOX-induced increase in myocardial reactive oxygen species (ROS) levels determined using dihydroethidium was significantly ameliorated by LCZ696, but not valsartan, and was accompanied by the suppression of DOX-induced increase in p47phox. LCZ696 recovered the DOX-induced decrease in phosphorylation of adenosine monophosphate-activated protein kinase and increased the ratio of Bax and Bcl-2. In H9c2 cardiomyocytes, LCZ696 reduced DOX-induced mitochondrial ROS generation and improved cell viability more than valsartan. Our findings indicated that LCZ696 ameliorated DOX-induced cardiotoxicity in rat hearts in vivo and in vitro, possibly by mediating a decrease in oxidative stress.

BackgroundAbdominal aortic aneurysm (AAA) is a life-threatening disease that lacks effective preventive therapies. This study aimed to evaluate the effect of pemafibrate, a selective peroxisome proliferator-activated receptor alpha (PPARα) agonist, on AAA formation and rupture.MethodsExperimental AAA was induced by subcutaneous angiotensin II (AngII) infusion in ApoE–/– mice for 4 weeks. Pemafibrate (0.1 mg/kg/day) was administered orally. Dihydroethidium staining was used to evaluate the reactive oxygen species (ROS).ResultsThe size of the AngII-induced AAA did not differ between pemafibrate- and vehicle-treated groups. However, a decreased mortality rate due to AAA rupture was observed in pemafibrate-treated mice. Pemafibrate ameliorated AngII-induced ROS and reduced the mRNA expression of interleukin-6 and tumor necrosis factor-α in the aortic wall. Gelatin zymography analysis demonstrated significant inhibition of matrix metalloproteinase-2 activity by pemafibrate. AngII-induced ROS production in human vascular smooth muscle cells was inhibited by pre-treatment with pemafibrate and was accompanied by an increase in catalase activity. Small interfering RNA-mediated knockdown of catalase or PPARα significantly attenuated the anti-oxidative effect of pemafibrate.ConclusionPemafibrate prevented AAA rupture in a murine model, concomitant with reduced ROS, inflammation, and extracellular matrix degradation in the aortic wall. The protective effect against AAA rupture was partly mediated by the anti-oxidative effect of catalase induced by pemafibrate in the smooth muscle cells.

Key Clinical MessageA right coronary artery of anomalous origin is rare congenital anatomy that can be fatal. CT angiography is an excellent tool for its anatomical assessment. Noninvasive CT‐based fractional flow reserve measurement can additionally evaluate the functional severity of coronary stenosis and is potentially useful for evaluating coronary anomalies.