Augmented neutrophil extracellular traps formation promotes atherosclerosis development in socially defeated apoE-/- mice.

Depression is an independent risk factor of cardiovascular disease (CVD); however, the causal association remains undefined. We exposed mice to repeated social defeat (RSD) to precipitate depressive-like behaviors, and investigated the effects on atherosclerosis. Eight-week-old male apoE-/- mice were exposed to RSD by housing with a larger CD-1 mouse in a shared home cage. They were subjected to vigorous physical contact daily for 10 consecutive days and fed a high-cholesterol diet (HCD) for 6 weeks. The social interaction ratio and immobility time showed dramatic social avoidance before and after HCD feeding. Defeated mice showed higher increase in atherosclerotic lesion areas in the aortic root and entire aorta than control mice. Mean blood pressure and lipid profile were equivalent in both groups. While Ly-6G- and Mac3-positive areas in the aortic root were comparable between the groups, citrullinated histone H3 (Cit-H3)- and myeloperoxidase (MPO)-positive areas, markers of neutrophil extracellular traps (NETs), were significantly increased in the defeated mice. Treatment with DNase I completely diminished the exaggerated atherosclerosis. The proportion of peripheral blood polymorphonuclear myeloid-derived suppressor cells (PMN-MDSC), but not of inflammatory monocytes, was markedly increased. Moreover, in vitro NETs formation from bone marrow (BM) PMN-MDSC was markedly augmented, accompanied by higher expression of Nox2 gene and reactive oxygen species. Our findings demonstrate that exposure to RSD promotes atherosclerosis by augmenting NETs formation within the plaque. This provides new insight into the underlying mechanism of depression-related CVD.

Adrenergic receptor-mediated activation of FGF-21-adiponectin axis exerts atheroprotective effects in brown adipose tissue-transplanted apoE-/- mice.

Brown adipose tissue (BAT) has been found as an endocrine organ that maintains metabolic homeostasis; however, the effects on atherosclerosis remain undefined. Here, we investigated the effect of experimental BAT transplantation on atherosclerosis. Interscapular BAT was dissected from wild-type mice and transplanted into the visceral cavity of 12-week-old apoE-/- mice. Oil-red O staining of whole aortas after 3 months of a high-cholesterol diet showed a significant decrease in atherosclerotic lesion area in BAT-transplanted mice by 32% compared with the sham control mice. Lipid profiles, except for serum triglyceride level, showed no difference between the 2 groups. BAT-transplanted mice showed higher concentrations of serum noradrenalin, fibroblast growth factor 21 (FGF-21), and adiponectin. Treatment with the ß3-adrenergic receptor (AR) blocker completely abrogated the atheroprotective effects of BAT transplantation, with serum concentrations of FGF-21 and adiponectin being equivalent between the 2 groups. Homologous transplantation of BAT from apoE-/- mice also showed a significant decrease in atherosclerotic lesion area by 28% without affecting lipid profiles, while epidydimal white adipose tissue transplantation did not affect atherosclerosis. Serum and endogenous BAT concentrations of FGF-21 were significantly higher in BAT-transplanted mice than sham control mice. Concomitantly, serum adiponectin levels were elevated in BAT-transplanted mice and showed a significant inverse correlation with atherosclerotic lesion area. Our findings show for the first time that atheroprotective effect of BAT transplantation is BAT-specific and independent of lipid-lowering effect, accompanied by AR-mediated activation of the FGF-21-adiponectin axis.

Transplantation of periaortic adipose tissue inhibits atherosclerosis in apoE-/- mice by evoking TGF-ß1-mediated anti-inflammatory response in transplanted graft.

Perivascular adipose tissue (PAT) is associated with vascular homeostasis; however, its causal effect on atherosclerosis currently remains undefined. Here, we investigated the effect of experimental PAT transplantation on atherosclerosis. The thoracic periaortic adipose tissue (tPAT) was dissected from 16-week-old wild-type mice and transplanted over the infrarenal aorta of 20-week-old apoE deficient (apoE-/-) mice fed high-cholesterol diet for 3 months. Oil-red O staining after 4 weeks showed a significant 20% decrease in the atherosclerotic lesion of suprarenal aorta compared with that of sham control mice, while that of infrarenal aorta showed no difference between the two groups. TGF-ß1 mRNA expression was significantly higher in grafted tPAT than donor tPAT, accompanied by a significant increase in serum TGF-ß1 concentration, which was inversely correlated with the suprarenal lesion area (r = -0.63, P = 0.012). Treatment with neutralizing TGF-ß antibody abrogated the anti-atherogenic effect of tPAT transplantation. Immunofluorescent analysis of grafted tPAT showed that TGF-ß-positive cells were co-localized with Mac-2-positive cells and this number was significantly increased compared with donor tPAT. There was also marked increase in mRNA expression of alternatively activated macrophages-related genes. Furthermore, the percentage of eosinophils in stromal vascular fraction of donor tPAT was much higher than that in epididymal white adipose tissue, concomitant with the significantly higher protein level of IL-4. IL-4 mRNA expression levels in grafted tPAT were increased in a time-dependent manner after tPAT transplantation. Our findings show that tPAT transplantation inhibits atherosclerosis development by exerting TGF-ß1-mediated anti-inflammatory response, which may involve alternatively activated macrophages.

Maternal high-fat diet exaggerates atherosclerosis in adult offspring by augmenting periaortic adipose tissue-specific proinflammatory response.

OBJECTIVE: Maternal obesity elicits offspring's metabolic disorders via developmental modifications of visceral adipose tissue; however, its effect on atherogenesis remains undefined. Perivascular adipose tissue has recently been implicated in vascular remodeling and vasoreactivity. We hypothesize that developmental modifications of perivascular adipose tissue by maternal high-fat diet (HFD) exposure promotes atherosclerosis in adult offspring. APPROACH AND RESULTS: Eight-week-old female apolipoprotein E-deficient mice were fed an HFD or normal diet (ND) during gestation and lactation. Offspring were fed a high-cholesterol diet from 8 weeks of age. Twenty-week-old male offspring of HFD-fed dams (O-HFD) showed a 2.1-fold increase in atherosclerotic lesion of the entire aorta compared with those of ND-fed dams (O-ND). Although mRNA expressions of interleukin-6, tumor necrosis factor, and monocyte chemotactic protein-1 and accumulation of macrophages in epididymal white adipose tissue were less in O-HFD than in O-ND, thoracic periaortic adipose tissue (tPAT) showed an exaggerated inflammatory response in O-HFD. Intra-abdominal transplantation of tPAT from 8-week-old O-HFD alongside the distal abdominal aorta exaggerated atherosclerosis development of the infrarenal aorta in recipient apolipoprotein E-deficient mice compared with tPAT from O-ND (210%, P<0.01). Although macrophage accumulation was rarely detected in tPAT of 8-week-old offspring, mRNA expression and protein levels of macrophage colony-stimulating factor were markedly elevated in O-HFD (2.3-fold, 3.3-fold, respectively, P<0.05), suggesting that increased macrophage colony-stimulating factor expression contributes to the augmented accumulation of macrophages, followed by the enhanced proinflammatory response. CONCLUSIONS: Our findings demonstrate that maternal HFD exaggerates atherosclerosis development in offspring by augmenting tPAT-specific inflammatory response proceeded by an increased expression of macrophage colony-stimulating factor.

Clinical outcome of the patients with femoropopliteal artery disease after endovascular therapy: focused on drug-coated-balloon-related distal embolism detected by laser doppler flowmetry.

Several trials have shown that paclitaxel drug-coated balloons (DCBs) significantly reduce restenosis rates. However, some reports have shown distal embolisms occurring after DCBs. No study has analyzed the clinical outcomes of patients with DCB-induced distal embolism. This study aimed to investigate the clinical outcomes of DCB-induced distal embolism in patients with femoropopliteal artery disease. Between February 2018 and April 2019, consecutive patients (n = 32) who presented with de novo femoropopliteal artery disease and underwent endovascular therapy using DCB were retrospectively reviewed in a single-center study. Patients were divided into two groups based on whether distal embolism was detected using laser doppler flowmetry (DEL group) or not (non-DEL group). Baseline characteristics and 1-year clinical outcomes were compared between the groups. DEL was found in 44% of limbs (DEL group: n = 15, non-DEL group: n = 19). Below-the-knee arterial runoff ≤ 1 (p = 0.033), popliteal lesion (p = 0.044), ambulation difficulty (p = 0.021), and previous history of coronary artery disease (p = 0.013) were identified as predictive factors of DEL. Procedural factors, reference vessel diameter, lesion length, and total drug amount were not predictive of DEL. The overall target lesion restenosis (TLR) rate was 17.4% (n = 5). The TLR rate was not significantly different between the DEL and non-DEL groups (13.3% vs. 15.8%, p = 0.55). Severe calcification was the only significant factor for TLR (4.2% vs. 40.0%, p = 0.02). Among patients with femoropopliteal disease, there was no difference in 1-year clinical outcome between patients who underwent DEL and those who did not.

Social Stress Increases Vulnerability to High-Fat Diet-Induced Insulin Resistance by Enhancing Neutrophil Elastase Activity in Adipose Tissue.

Social stress (SS) has been linked to the development of cardiovascular disease (CVD), which is closely associated with insulin resistance (IR); however, the causal effect of SS on IR remains unclear. The 8-week-old male C57BL/6 mice were exposed to SS by housing with a larger CD-1 mouse in a shared home cage without physical contact for 10 consecutive days followed by high-fat diet (HFD) feeding. Control mice were housed in the same cage without a CD-1 mouse. After 6 weeks of HFD, insulin sensitivity was significantly impaired in stressed mice. While the percentage of classically activated macrophages in epididymal white adipose tissue (eWAT) was equivalent between the two groups, the percentage of lymphocyte antigen 6 complex locus G6D (Ly-6G)/neutrophil elastase (NE)-double positive cells markedly increased in stressed mice, accompanied by augmented NE activity assessed by ex vivo eWAT fluorescent imaging. Treatment with an NE inhibitor completely abrogated the insulin sensitivity impairment of stressed mice. In vitro NE release upon stimulation with a formyl peptide receptor 1 agonist was significantly higher in bone marrow neutrophils of stressed mice. Our findings show that SS-exposed mice are susceptible to the development of HFD-induced IR accompanied by augmented NE activity. Modulation of neutrophil function may represent a potential therapeutic target for SS-associated IR.

Successful bailout procedure for acute popliteal artery occlusion associated with EXOSEAL® vascular closure device: a case report.

BACKGROUND: Vascular closure devices have been widely used to achieve rapid hemostasis after percutaneous catheterization procedures via the common femoral artery. The EXOSEAL vascular closure device is a device that can deliver a bioabsorbable polyglycolic acid plug to fill the subcutaneous puncture route at the groin for rapid hemostasis, and this device has a lower risk of arterial occlusion than other vascular closure devices. CASE PRESENTATION: An 83-year-old Japanese man underwent percutaneous coronary intervention for a proximal stenosis in his left circumflex artery through a 7-Fr sheath from his right common femoral artery. We encountered acute popliteal artery occlusion associated with EXOSEAL vascular closure device. We detected the plug material of this device at the occluded lesion by intravascular ultrasound, and performed successful bailout stenting after pulling the embolus with an inflated balloon catheter up to the superficial femoral artery from the popliteal artery. CONCLUSION: Acute limb ischemia caused by an EXOSEAL vascular closure device is a very rare complication. Balloon angioplasty and stenting are considered to be effective options to deal with the plug dislodgement of an EXOSEAL vascular closure device. We must be prepared for every rare complication during endovascular treatment.

Fatal Right Ventricular Free Wall Rupture During Percutaneous Coronary Intervention for Inferior Acute Myocardial Infarction.

BACKGROUND Ventricular rupture is a complication of acute myocardial infarction (AMI) that results in hemopericardium and cardiac tamponade and has a high mortality rate. Most cases involve the left ventricular free wall, and there have been few previous reports of solitary right ventricular free wall rupture. This report is of a case of fatal right ventricular free wall rupture during percutaneous coronary intervention (PCI) for inferior acute myocardial infarction (AMI). CASE REPORT A 76-year-old woman underwent emergency coronary angiography following inferior AMI. During angiography and attempted percutaneous coronary intervention (PCI), sudden onset of cardiac arrest occurred due to cardiac tamponade. Blood was drained from the pericardium by pericardiocentesis. Despite of advanced cardiac support, the patient died. The post mortem findings showed a solitary right ventricular free wall rupture due to inferior myocardial infarction. CONCLUSIONS A rare case is presented of right ventricular free wall rupture following AMI that occurred during PCI. This case demonstrates that early diagnosis and management are required to prevent patient mortality.

A Rare Case of Isolated Idiopathic Inferior Mesenteric Artery Dissection.

BACKGROUND Isolated dissection of a mesenteric artery is very rare and usually presents with acute gastrointestinal symptoms. There have been previously published reports on the isolated dissection of the superior mesenteric artery. However, isolated dissection of the inferior mesenteric artery is rare. CASE REPORT A 43-year-old man presented with sudden onset of lower abdominal pain. Abdominal computed tomography (CT) imaging confirmed isolated dissection of the inferior mesenteric artery. To prevent exacerbation of the dissection, his systolic blood pressure was controlled to <140 mmHg, and his progress was observed for ten days while in hospital during which time the dissection stabilized. There was no extension of the dissection. After three years, the dissection had healed and did not recur. CONCLUSIONS To our knowledge, this is the first case report of isolated dissection of the inferior mesenteric artery that resolved spontaneously. This case shows the importance of blood pressure control in the management of arterial dissection.

Vulnerable neoatherosclerosis in coronary artery with whole circumference showing intravascular echo attenuation.

Neoatherosclerosis is emerging as a stent-associated problem that has not yet been fully resolved. Because in-stent restenosis with a neoatherosclerotic etiology is associated with a high risk of acute coronary syndrome and a poor survival prognosis, it is essential to precisely identify patients at risk using advanced imaging modalities.

Emergence of Ventricular Septal Rupture During Primary Coronary Intervention for Myocardial Infarction Manifested as Unexpected Coronary Blood Flow Disturbance.

BACKGROUND As primary percutaneous coronary intervention (PCI) has been commonly performed for acute myocardial infarction (AMI), we rarely encounter ventricular septal rupture (VSR), which is one of the mechanical complications of AMI. However, the associated mortality rate is still very high unless treated appropriately. CASE REPORT We encountered a very rare case of VSR that was considered to have occurred during primary PCI for AMI. The manifestation of sudden coronary flow disturbance may correspond with the emergence of VSR. We introduced a veno-arterial extracorporeal membrane oxygenation (ECMO) system for sudden hemodynamic instability. As a result, the existence of VSR under the operation of the ECMO system led to unusual hemodynamics in the heart, but the vital signs were stabilized by ECMO. VSR was surgically treated and the patient fully recovered without any neurological or physical sequelae. CONCLUSIONS Although we now encounter markedly fewer mechanical complications of AMI in this era of primary PCI, we should always be conscious of its possibility in the acute phase of myocardial infarction.

Tips of the dual-lumen microcatheter-facilitated reverse wire technique in percutaneous coronary interventions for markedly angulated bifurcated lesions.

In practical settings of percutaneous coronary intervention (PCI), we sometimes encounter difficulty in introducing a guidewire (GW) to the markedly angulated side branch (SB), and the reverse wire technique is considered as a last resort to overcome such a situation. We analyzed 12 cases that underwent PCI with dual-lumen microcatheter-facilitated reverse wire technique between January 2013 and July 2016. We retrospectively investigated the lesion's characteristics and the details of the PCI procedures, and discussed tips about the use of this technique. The SB that exhibits both a smaller take-off angle and a larger carina angle is considered to be the most suitable candidate for this technique. The first step of this technique involves the delivery of the reverse wire system to the target bifurcation. However, most cases exhibit significant stenosis proximal to the bifurcation, which often hampers the delivery of the reverse wire system. Because the sharply curved reverse wire system is easier to pass the stenosis as compared to the roundly curved system, we recommend a sharp curve should be adopted for this technique. On the other hand, it is sure that device delivery is much easier on the GW with a round curve as compared to that with a sharp curve. Therefore, it is important to modify the details of this procedure on a case-by-case basis according to the lesion's characteristics.

A rare manifestation of severe critical limb ischemia caused by solitary aorto-iliac occlusive disease.

Currently, there are more opportunities to treat patients complicated with critical limb ischemia (CLI), which is a very dismal medical condition associated with a high risk of major amputation, disability and death. Because CLI is usually caused by multi-level occlusive atherosclerotic disease, the condition of CLI induced by aorto-iliac occlusive disease (AIOD) alone is thought to be a rare pathological entity. We encountered a patient with severe CLI caused by solitary AIOD. Three vascular access routes were established and stiff guidewires retrogradely passed the occluded arteries on both sides. We deployed two self-expandable bare metal stents and complete revascularization led to wound healing. Recent improvements of catheter devices and procedural techniques related to endovascular treatment (EVT) have enabled us to safely recanalize complex vascular lesions of the lower extremities. Therefore, an EVT strategy is one of the favorable treatment options for CLI patients who are contraindicated for surgical treatments.

Successful bailout stenting strategy against lethal coronary dissection involving left main bifurcation.

Catheter-induced coronary dissection involving left main bifurcation is a rare complication during cardiac catheterization but can become lethal unless it is treated appropriately. Interventional cardiologists always have to pay attention to the risk of complications related to cardiac catheterization and prepare for determining the best bailout strategy for the situation.

Guide Catheter Extension Device Is Effective in Renal Angioplasty for Severely Calcified Lesions.

BACKGROUND The GuideLiner catheter extension device is a monorail-type "Child" support catheter that facilitates coaxial alignment with the guide catheter and provides an appropriate back-up force. This device has been developed in the field of coronary intervention, and now is becoming widely applied in the field of endovascular treatment. However, there has been no report on the effectiveness of the guide catheter extension device in percutaneous transluminal renal angioplasty (PTRA). CASE REPORT We encountered a case of atherosclerotic subtotal occlusion at the ostium of the left renal artery. Due to the severely calcified orifice and weaker back-up force provided by a JR4 guide catheter, we could not pass any guidewires through the target lesion. Therefore, we introduced a guide catheter extension device, the GuideLiner catheter, through the guide catheter and achieved good guidewire maneuverability. We finally deployed 2 balloon-expandable stents and successfully performed all PTRA procedures. CONCLUSIONS The guide catheter extension device can be effective in PTRA for severely calcified subtotal occlusion.

Bone marrow angiotensin AT2 receptor deficiency aggravates atherosclerosis development by eliminating macrophage liver X receptor-mediated anti-atherogenic actions.

BACKGROUND: Bone marrow (BM) Angiotensin II (Ang II) type 1 (AT1) receptor plays a crucial role in atherosclerosis development; however, the effect of BM Ang II type 2 (AT2) receptor on atherogenesis remains undefined. METHODS AND RESULTS: We generated BM chimera apoE-deficient (apoE(-/-)) mice whose BM cells were repopulated with AT2-deficient (Agtr2(-/-)) or wild-type (Agtr2(+/+)) cells. After 2 months of a high-cholesterol diet, the atherosclerotic lesion area was significantly increased in the apoE(-/-)/BM-Agtr2(-/-) mice compared with the apoE(-/-)/BM-Agtr2(+/+) mice (51%, P < 0.05), accompanied by an augmented accumulation of lesion macrophages. Although phenotypic polarization in BM-derived macrophages and lipopolysaccharide-induced expression of proinflammatory cytokines in thioglycollate-induced peritoneal macrophages (TGPMs) were not affected by AT2-deficiency, mRNA and protein expression levels of macrophage liver X receptor ß (LXRß) were significantly decreased in Agtr2(-/-) TGPMs compared with Agtr2(+/+) TGPMs. Anti-inflammatory effects of LXR agonist (GW3965) were markedly inhibited in Agtr2(-/-) TGPMs. Furthermore, the expression levels of ATP-binding cassette transporter ABCA1 and CCR7 were much lower in Agtr2(-/-) TGPMs than Agtr2(+/+) TGPMs, accompanied by a significantly reduced cholesterol efflux. CONCLUSIONS: Our findings demonstrate that BM-AT2 deficiency aggravates atherosclerosis, at least in part, by eliminating the anti-atherogenic properties of macrophages elicited by LXRß activation.

Transplantation of periaortic adipose tissue from angiotensin receptor blocker-treated mice markedly ameliorates atherosclerosis development in apoE-/- mice.

BACKGROUND: Perivascular adipose tissue is implicated in vasoreactivity; however, its effect on atherosclerosis remains undefined. METHODS AND RESULTS: We examined the effect of a high-cholesterol diet (HCD) on phenotypic alterations of the thoracic periaortic adipose tissue (tPAT) in apoE-deficient (apoE(-/-)) mice. Gene expression of the components of the renin angiotensin system and that of macrophage markers were significantly higher in apoE(-/-) mice fed an HCD than in those fed a chow diet (CD). These changes were absent both in angiotensin II (AngII) receptor blocker (ARB)-treated apoE(-/-) mice and in Ang II type 1 (AT1) receptor-deficient apoE(-/-) (Agtr1(-/-)/apoE(-/-)) mice. To evaluate their effect on atherosclerosis, we transplanted tPAT into apoE(-/-) mice alongside the distal abdominal aorta. Transplanted tPAT was harvested from apoE(-/-) and Agtr1(-/-)/apoE(-/-) mice fed a CD (tPAT-CD/apoE(-/-), tPAT-CD/Agtr1(-/-)/apoE(-/-)), HCD (tPAT-HCD/apoE(-/-), tPAT-HCD/Agtr1(-/-)/apoE(-/-)), or HCD in combination with ARB treatment (tPAT-HCD/ARB/apoE(-/-)). Four weeks after transplantation, a significantly increased oil red O-positive area was observed in the aorta of tPAT-HCD/apoE(-/-) mice than in tPAT-CD/apoE(-/-) mice. Such a change was absent in tPAT-HCD/ARB/apoE(-/-) and tPAT-HCD/Agtr1(-/-)/apoE(-/-) mice. CONCLUSIONS: Our findings demonstrated that AT1 receptor plays a crucial role in HCD-induced phenotypic alterations of tPAT, modulation of which could exert beneficial effects on atherosclerosis.