A novel cardiac ryanodine receptor gene (RyR2) mutation in an athlete with aborted sudden cardiac death: a case of adult-onset catecholaminergic polymorphic ventricular tachycardia.

Sudden cardiac death (SCD) in athletes <35 years of age are mostly due to congenital or acquired cardiac malformations or hypertrophic cardiomyopathy. However, ion channelopathies such as catecholaminergic polymorphic ventricular tachycardia (CPVT) or long-QT syndromes, which are less frequently observed, are also potential pathogenesis of SCD in young athletes. CPVT is an inherited arrhythmia that is induced by physical or emotional stress and may lead to ventricular fibrillation syncope or SCD. Here, we report a case of athlete woman with adult-onset CPVT and aborted SCD who has a novel missense mutation (K4392R) in the cardiac RyR2 gene.

Development of virtual reality content for learning Japan Prehospital Trauma Evaluation and Care initial assessment procedures.

Aim: The Japan Prehospital Trauma Evaluation and Care (JPTEC) is a standardized educational program for prehospital trauma care in Japan. The initial assessment in the JPTEC course comprises a training segment that includes a 30-min session. Given the limited face-to-face training due to the coronavirus disease 2019, virtual reality (VR) content has become an alternative. However, creating VR content typically requires the assistance of expert technicians. We aimed to create VR content for the initial assessment segment of the JPTEC and verify its educational effectiveness. Methods: We created VR content for learning the initial assessment of the JPTEC using our easy-to-use VR content creation system. The participants played the VR content for 15 min. The number of times they "cleared" (i.e., made a correct decision and completed the initial assessment) was recorded every 5 min. Then, a JPTEC-certified instructor tested their practical skills through face-to-face simulation. Results: The authors had no specialized skills and created the VR content in 2 days. Fourteen students used the material. They cleared the scenario 3 (3-4) times in the first 5 min in 15 min, 5 (4-5) times in the second 5 min, and 5 (5-5) times in the third 5 min (P < 0.05). All participants passed the practical evaluation. Conclusion: A shorter VR training developed using our easy-to-use VR content creation system can replace the 30-min JPTEC session on the initial assessment. This system allows for the free and easy creation of VR content.

Instructor Development Workshops for Advanced Life Support Training Courses Held in a Fully Virtual Space: Observational Study.

BACKGROUND: Various face-to-face training opportunities have been lost due to the COVID-19 pandemic. Instructor development workshops for advanced resuscitation (ie, advanced life support) training courses are no exception. Virtual reality (VR) is an attractive strategy for remote training. However, to our knowledge, there are no reports of resuscitation instructor training programs being held in a virtual space. OBJECTIVE: This study aimed to investigate the learning effects of an instructor development workshop that was conducted in a virtual space. METHODS: In this observational study, we created a virtual workshop space by using NEUTRANS (Synamon Inc)-a commercial VR collaboration service. The instructor development workshop for the advanced life support training course was held in a virtual space (ie, termed the VR course) as a certified workshop by the Japanese Association of Acute Medicine. We asked 13 instructor candidates (students) who participated in the VR course to provide a workshop report (VR group). Reports from a previously held face-to-face workshop (ie, the face-to-face course and group) were likewise prepared for comparison. A total of 5 certified instructor trainers viewed and scored the reports on a 5-point Likert scale. RESULTS: All students completed the VR course without any problems and received certificates of completion. The scores for the VR group and the face-to-face group did not differ at the level of statistical significance (median 3.8, IQR 3.8-4.0 and median 4.2, IQR 3.9-4.2, respectively; P=.41). CONCLUSIONS: We successfully conducted an instructor development workshop in a virtual space. The degree of learning in the virtual workshop was the same as that in the face-to-face workshop.

Deletion of Superoxide Dismutase 1 Blunted Inflammatory Aortic Remodeling in Hypertensive Mice under Angiotensin II Infusion.

Superoxide dismutase (SOD) is an enzyme that catalyzes the dismutation of two superoxide anions (O2·-) into hydrogen peroxide (H2O2) and oxygen (O2) and is generally known to protect against oxidative stress. Angiotensin II (AngII) causes vascular hypertrophic remodeling which is associated with H2O2 generation. The aim of this study is to investigate the role of cytosolic SOD (SOD1) in AngII-induced vascular hypertrophy. We employed C57/BL6 mice (WT) and SOD1 deficient mice (SOD1-/-) with the same background. They received a continuous infusion of saline or AngII (3.2 mg/kg/day) for seven days. The blood pressures were equally elevated at 1.5 times with AngII, however, vascular hypertrophy was blunted in SOD1-/- mice compared to WT mice (WT mice 91.9 ± 1.13 µm versus SOD1-/- mice 68.4 ± 1.41 µm p < 0.001). The elevation of aortic interleukin 6 (IL-6) and phosphorylation of pro-inflammatory STAT3 due to AngII were also blunted in SOD1-/- mice's aortas. In cultured rat vascular smooth muscle cells (VSMCs), reducing expression of SOD1 with siRNA decreased AngII induced IL-6 release as well as phosphorylation of STAT3. Pre-incubation with polyethylene glycol (PEG)-catalase also attenuated phosphorylation of STAT3 due to AngII. These results indicate that SOD1 in VSMCs plays a role in vascular hypertrophy due to increased inflammation caused by AngII, probably via the production of cytosolic H2O2.

Successful Endovascular Removal of a Perforated Inferior Vena Cava Filter Complicated by a Large Retroperitoneal Hematoma: Pitfall of Catheter-Directed Thrombolysis.

Symptomatic caval perforation is rare complication after inferior vena cava (IVC) filter insertion. A 44-year-old woman developed back pain after the placement of retrieval IVC filter during catheter-directed thrombolysis (CDT). Her computed tomography showed a large right-sided retroperitoneal hematoma. After 2 weeks, endovascular removal of the perforated filter was successfully performed without complication. Because thrombolytic agents can accelerate bleeding caused by endovascular procedures, the bleeding rate of the IVC filter deployment during CDT might be higher than expected.

Cardiac Asystole Triggered by Temporal Lobe Epilepsy with Amygdala Enlargement.

A 25-year-old previously healthy man was hospitalized for syncope. While standing, he suddenly lost consciousness, followed by a generalized tonic clonic seizure. An electrocardiogram demonstrated asystole. No cardiac abnormalities were detected on the echocardiogram, cardiac magnetic resonance imaging (MRI), positron emission tomography, or a coronary angiogram. An electrophysiological study showed normal sinus node and atrioventricular node function. An electroencephalogram revealed small spike waves in the fronto-temporal region. Brain MRI demonstrated a left-sided amygdala enlargement. To the best of our knowledge, this is the first case of temporal lobe epilepsy with an amygdala enlargement that induced cardiac asystole.

Deficiency of interleukin-1 receptor antagonist promotes neointimal formation after injury.

BACKGROUND: The cytokine interleukin (IL)-1 is an important mediator of inflammation and cardiovascular disease. Activity of this cytokine is modulated endogenously via the IL-1 receptor antagonist (IL-1Ra). The role of IL-1Ra in neointima formation after injury, however, is poorly understood. METHODS AND RESULTS: Using IL-1Ra-deficient (IL-1Ra-/-; backcrossed 8 generations into the C57BL/6J background) and wild-type (IL-1Ra+/+) mice, we investigated neointimal formation 3 weeks after femoral artery injury induced by an external vascular cuff model. Intima and media thicknesses were measured, and the intima/media ratio was calculated. The mean intimal thickness and the intima/media ratio of IL-1Ra-/- mice increased by 249% (31.8+/-2.9 microm [n=10] versus 9.1+/-0.7 microm [n=10]; P<0.0001) and 257% (2.5+/-0.2 versus 0.7+/-0.1; P<0.0001), respectively, compared with IL-1Ra+/+ mice. No significant differences were observed in the medial thickness. Control immunostaining for IL-1Ra in injured vessels localized IL-1beta and the endogenous inhibitor in the endothelium and inflammatory cells of the adventitia in IL-1Ra+/+ but not IL-1Ra-/- mice. CONCLUSIONS: The absence of IL-1Ra promotes neointimal formation in mice after injury. These results suggest that endogenous IL-1Ra may suppress other occlusive vascular responses to injury, such as atherosclerosis and restenosis after angioplasty.

Lack of interleukin-1 receptor antagonist modulates plaque composition in apolipoprotein E-deficient mice.

OBJECTIVE: Interleukin (IL)-1 plays an important role in atherosclerosis. IL-1 receptor antagonist (IL-1Ra) is an endogenous inhibitor of IL-1. However, the role of IL-1Ra in the development of atherosclerosis is poorly understood. METHODS AND RESULTS: Mice that lacked IL-1Ra (IL-1Ra-/-) were crossed with apolipoprotein E-deficient (E-/-) mice and formation of atherosclerotic lesions was analyzed after 16 weeks or 32 weeks consumption of a normal chow diet. This study focused on the comparison of atherosclerotic lesion between IL-1Ra+/+/apoE-/- (n=12) and IL-1Ra(+/-)/apoE-/- mice (n=12), because of the significantly leaner phenotype in IL-1Ra-/-/apoE-/- mice compared with the others. Interestingly, atherosclerotic lesion size in IL-1Ra+/-/apoE-/- mice at age 16 weeks was significantly increased (30%) compared with IL-1Ra+/+/apoE-/- mice (P<0.05). At 32 weeks, the differences of lesion size between these mice failed to achieve statistical significance. However, immunostaining demonstrated an 86% (P<0.0001) increase in the MOMA-2-stained lesion area of IL-1Ra+/-/apoE-/- mice. In addition, alpha-actin staining in these lesions was significantly decreased (-15%) compared with those in IL-1Ra+/+/apoE-/- mice (P<0.05). CONCLUSIONS: These results suggest an important role of IL-1Ra in the suppression of lesion development during early atherogenesis and furthermore indicate its role in the modulation of plaque composition.

IκBNS regulates interleukin-6 production and inhibits neointimal formation after vascular injury in mice.

AIMS: IκBNS regulates a subset of Toll-like receptor (TLR)-dependent genes including interleukin-6 (IL-6) by inhibiting nuclear factor-κB (NF-κB). IL-6 is an inflammatory biomarker for cardiovascular diseases. The aim of this study was to determine whether IκBNS changes arterial inflammation and intimal hyperplasia after vascular injury. METHODS AND RESULTS: We investigated neointimal formation in IκBNS-deficient (IκBNS(-/-); C57BL/6 background) and wild-type (IκBNS(+/+)) mice 2 weeks after cuff injury. The mean intimal area and the intima/media ratio of IκBNS(-/-) mice increased 89% (8066 ± 1141 vs. 4267 ± 1095 µm(2); P = 0.027) and 100% (0.72 ± 0.13 vs. 0.36 ± 0.09; P = 0.032) compared with IκBNS(+/+) mice. We observed significant up-regulation of TLR4 in injured arteries of IκBNS(-/-) mice. NF-κB activity in the intima of IκBNS(-/-) mice was 5.1-fold higher (P = 0.008) compared with IκBNS(+/+) mice at 7 days post-injury. IL-6 mRNA levels in injured arteries of IκBNS(-/-) mice were 1.8-fold higher (P = 0.002) compared with those of IκBNS(+/+) mice at 3 days post-injury. Vascular smooth muscle cells from IκBNS(-/-) mice showed a significant increase in cell migration compared with those from IκBNS(+/+) mice after IL-6 stimulation in the scratch-wound healing assay. Furthermore, anti-mouse IL-6 receptor antibody (MR16-1) significantly reduced intimal hyperplasia compared with control IgG injection in IκBNS(-/-) mice. These findings suggest that IL-6 participates in the development of neointimal hyperplasia after vascular injury in IκBNS(-/-) mice. CONCLUSION: IκBNS down-regulates TLR4 expression, NF-κB activity, and IL-6 production after vascular injury. IκBNS might suppress intimal hyperplasia caused by vascular inflammation such as atherosclerosis, and restenosis after angioplasty.

Novel TNF-α receptor 1 antagonist treatment attenuates arterial inflammation and intimal hyperplasia in mice.

AIM: Tumor necrosis factor receptor 1 (TNFR1) participates importantly in arterial inflammation in genetically altered mice; however it remains undetermined whether a selective TNFR1 antagonist inhibits arterial inflammation and intimal hyperplasia. This study aimed to determine the effect and mechanism of a novel TNFR1 antagonist in the suppression of arterial inflammation. METHODS: We investigated intimal hyperplasia in IL-1 receptor antagonist-deficient mice two weeks after inducing femoral artery injury in an external vascular cuff model. All mice received intraperitoneal injections of TNFR1 antagonist (PEG-R1antTNF) or normal saline twice daily for 14 days. RESULTS: PEG-R1antTNF treatment yielded no adverse systemic effects, and we observed no significant differences in serum cholesterol or blood pressure in either group; however, selective PEG-R1antTNF treatment significantly reduced intimal hyperplasia (19,671±4,274 vs. 11,440±3,292 µm(2); p=0.001) and the intima/media ratio (1.86±0.43 vs. 1.34±0.36; p=0.029), compared with saline injection. Immunostaining revealed that PEG-R1antTNF inhibits Nuclear factor-κB (NF-κB), suppressing smooth muscle cell (SMC) proliferation and decreasing chemokine and adhesion molecule expression, and thus decreasing intimal hyperplasia and inflammation. CONCLUSIONS: Our data suggest that PEG-R1antTNF suppresses SMC proliferation and inflammation by inhibiting NF-κB. This study highlights the potential therapeutic benefit of selective TNFR1 antagonist therapy in preventing intimal hyperplasia and arterial inflammation.

Deficiency of CuZn superoxide dismutase promotes inflammation and alters medial structure following vascular injury.

AIM: The anti-oxidant enzyme copper/zinc superoxide dismutase (CuZnSOD) metabolizes superoxide anion (O(2)(-)) in vascular cells. However, the role of CuZnSOD in vascular injury remains poorly understood. METHODS: Using CuZnSOD-deficient (CuZnSOD(-/-)) mice and wild-type (WT) mice, we investigated morphometric changes and the role of O(2)(-) in vascular remodeling after femoral artery injury induced by an external vascular cuff model. RESULTS: Three days post-injury, inflammatory cell infiltration increased significantly. Moreover, the percent positive area of tumor necrosis factor-α (TNF-α), intercellular adhesion molecule-1 (ICAM-1), and vascular cell adhesion molecule-1 (VCAM-1) in media were higher in CuZnSOD(-/-) mice than in WT mice (TNF-α: 34.8±8.4% versus 18.8±5.6%, p < 0.05, ICAM-1: 29.6±6.5% versus 11.0±2.8%, p < 0.05, VCAM-1: 23.5±7.5% versus 3.7±1.1%, p < 0.05). mRNA expression of iNOS was markedly increased in CuZnSOD(-/-) mice with cuff injury. Dihydroethidine staining revealed increased levels of vascular O(2)(-) in media from CuZnSOD(-/-) mice. Although neointimal formation remained unchanged, 14 days postinjury, we observed degeneration of the media, and the media/vessel wall ratio increased in CuZnSOD(-/-) mice (40.4±2.1% versus 26.8±1.4%, p < 0.05). Furthermore, SMemb/MHC-B-stained lesions increased markedly in CuZnSOD(-/-) mice. CONCLUSIONS: CuZnSOD-deficiency promoted inflammation, expressed adhesion molecules, and altered the structure of the media post-injury. Our results suggest that O(2)(-) participates importantly in the progression of early stage vascular inflammation, resulting in vascular remodeling in media but not neointimal formation, post-injury.

Left ventricular hypertrophy in mice with a cardiac-specific overexpression of interleukin-1.

Recent studies have identified the importance of proinflammatory cytokines in the development of left ventricular (LV) hypertrophy. However, the precise role of interleukin-1 (IL-1), one of the major proinflammatory cytokines, in the myocardium is not fully understood. In this study, we investigated the pathophysiological consequences of cardiac expression of IL-1 in vivo. We generated mice with a cardiac-specific overexpression of human IL-1alpha. We then analyzed their heart morphology and functions. Histological and echocardiographic analyses revealed concentric LV hypertrophy with preserved LV systolic function in the mice. Our results suggest that myocardial expression of IL-1 is sufficient to cause LV hypertrophy.