REGN-COV2 antibody cocktail in patients with SARS-CoV-2: Observational study from a single institution in Japan.

INTRODUCTION: A new treatment for coronavirus disease (COVID-19), REGN-COV2, a cocktail consisting of two neutralizing antibodies against severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), has been approved for patients at a risk of developing more severe disease. METHODS: We retrospectively reviewed patients recently diagnosed with COVID-19 with risk factors for severe infection, who were treated with the REGN-COV2 antibody cocktail between July and September 2021. The REGN-COV2 antibody cocktail was administered to patients within 7 days of disease onset, with an oxygen saturation of >93%, and with at least one comorbidity. We investigated the percentage of patients with COVID-19-related hospitalization or death, the duration of symptoms after treatment, and the adverse effects of treatment. RESULTS: A total of 108 patients were reviewed. Of them, 64% were aged ≥50 years, 31% had obesity, 36% had hypertension, and 18% had diabetes. In addition, 49% had multiple risk factors for severe COVID-19. Overall, 12 patients (11%) needed COVID-19-related hospitalization. No adverse effects of treatment were observed. CONCLUSIONS: This study shows that treatment with the REGN-COV2 antibody cocktail is safe and beneficial in patients at a risk of developing severe COVID-19.

Psychological Effects on Healthcare Workers during the COVID-19 Outbreak: A Single-center Study at a Tertiary Hospital in Tokyo, Japan.

Objective The present study analyzed the psychological status of healthcare workers in Japan and the influencing factors during the 2019 coronavirus disease pandemic. Methods An online survey was conducted from July 22 to August 21, 2020. A total of 328 of the 1,029 medical staff members in our university hospital participated in the study. Their mental health was assessed using the 12-item General Health Questionnaire. A multivariate regression analysis was performed to identify the factors associated with the mental health outcomes. Results Of the respondents, 78.0% reported psychological distress. Overall, we found that women, non-physicians, those who lived alone, and younger respondents had significantly greater psychological distress than their counterparts. The multivariate regression analysis showed that four factors were extracted as independent 12-item General Health Questionnaire-related factors: the lack of a sense of mission as a medical professional, the burden of the change in the quality of work, the lack of understanding about virus infectivity, and a strong sense of duty. Conclusion In summary, we found a high prevalence of psychological distress among healthcare workers during the 2019 coronavirus disease outbreak in Japan. Independent risk factors for psychological distress were the burden of the change in the quality of work, the lack of understanding about virus infectivity, a sense of responsibility, and the lack of a strong motivation and drive to help.

Heterogeneity of hemodynamic parameters in untreated primary hypertension, and individualization of antihypertensive therapy based on noninvasive hemodynamic measurements.

Noninvasive measurement of hemodynamic parameter was undertaken in 240 patients with untreated primary hypertension using impedance cardiography (ICG) in outpatient clinics. High output was defined as a cardiac index (CI) >3.6 L/minute/m(2) and high resistance was defined as the total peripheral resistance index (TPRI) >2700 dyne·s·m(2)/cm(5). Of all patients, 67% had high-resistance hypertension (high TPRI with normal or low CI), and 16% had high-output hypertension (high CI with normal TPRI). Treatment with ß-blockers for high-output hypertension and with calcium channel blockers for high-resistance hypertension reduced blood pressure equally, and restored normal hemodynamic balance, as reported in studies using invasive monitoring methods. These findings suggest that it is appropriate to use noninvasive ICG measurements to guide antihypertensive therapy. Multivariate analysis showed that female gender, tachycardia, and low body mass index (BMI) were associated with high-output hypertension, but age was not. Heterogeneity of hemodynamic parameters is thought to be one of the reasons why the efficacies of antihypertensive agents differ between patients. It may be feasible to predict which antihypertensive agent would be the most effective for a particular patient based on hemodynamic measurements or combination of gender, heart rate, and BMI.

Aldosterone blockade by Spironolactone improves the hypertensive vascular hypertrophy and remodeling in angiotensin II overproducing transgenic mice.

OBJECTIVES AND BACKGROUND: Recent evidence has revealed that aldosterone (ALDO) is produced in the vasculature, and acts directly in the cardiovascular system. This study was designed to examine the role of ALDO in the process of long-term renin-angiotensin system (RAS) induced vascular remodeling. MATERIAL AND METHOD: Hypertensive transgenic mice that overproduce angiotensin II (AngII), i.e., Tsukuba-Hypertensive-Mice (THM), were given tap water or 1% salt water and treated with or without Spironolactone (SPRL: 20mg/kg/day) for 4 weeks. We also employed A7r5 cells and investigated the effect of SPRL on the AngII mediated signal transduction in the vascular smooth muscle cells. RESULTS: Intimal hyperplasia, medial hypertrophy and degradation of medial elastic laminae were observed in the abdominal aorta, independent of blood pressure. Taking 1% salt water markedly enhanced these changes. In contrast, SPRL-treated THM showed almost complete disappearance of these intimal hyperplasia and medial hypertrophy. Osteopontin (OPN) was markedly up-regulated in the intima and media. However, it was inhibited by SPRL treatment in spite of high level of AngII. In A7r5 cells, AngII (10(-7)muM) induced OPN expression and pretreatment with MEK, PI3K, and EGFR inhibitor suppressed it. SPRL pretreatment also inhibited AngII-induced ERK and AKT phosphorylation, and resulted in the suppression of AngII-induced OPN expression. CONCLUSIONS: ALDO blockade by SPRL restores the vascular remodeling caused by the long-term RAS enhancement even in the high level of AngII, independent of blood pressure. Blocking AngII alone may not be sufficient, and direct ALDO blockade is also important to prevent vascular disease.

Delayed enhancement on computed tomography in abdominal aortic aneurysm wall.

The purpose of this study was to evaluate delayed enhancement (DE) of the aortic wall of atherosclerotic aneurysms using computed tomography and to evaluate the relationships between DE and wall thickness of abdominal aortic aneurysm (AAA), diameter of AAA, serum levels of C-reactive protein (CRP) which indicate inflammation status, and pathological findings. Computed tomographic images of atherosclerotic AAA in 110 patients were studied between July 2001 and March 2003. Computed tomography (CT) scanning included unenhanced, enhanced early, and enhanced delayed phases. Pathological findings were obtained from 19 of the 110 patients. We determined DE of the AAA wall and assessed the association between DE and AAA wall thickness, AAA diameter, serum levels of CRP, and pathological findings. Delayed enhancement on CT was demonstrated in 66 of 110 patients with atherosclerotic AAA (60.0%). Patients with DE demonstrated significantly larger AAA diameter (4.8 +/- 0.9 versus 3.9 +/- 0.6 cm, P < 0.0001) and significantly higher levels of CRP (5.0 +/- 6.0 versus 2.3 +/- 2.9 mg/l, P = 0.033) than those patients without DE. Patients with DE also had significantly thicker and more severe atheroma and a tendency toward more prominent inflammation and vascularity in pathologic findings. There was no significant difference in wall thickness between AAA with and without DE (1.44 +/- 0.7 versus 1.24 +/- 0.22 mm, P = 0.352). Delayed enhancement on CT demonstrated in over half of atherosclerotic AAA may be associated with chronic inflammation by atherosclerosis.

Comprehensive genetic analysis of relevant four genes in 49 patients with Marfan syndrome or Marfan-related phenotypes.

In order to evaluate the contribution of FBN1, FBN2, TGFBR1, and TGFBR2 mutations to the Marfan syndrome (MFS) phenotype, the four genes were analyzed by direct sequencing in 49 patients with MFS or suspected MFS as a cohort study. A total of 27 FBN1 mutations (22 novel) in 27 patients (55%, 27/49), 1 novel TGFBR1 mutation in 1 (2%, 1/49), and 2 recurrent TGFBR2 mutations in 2 (4%, 2/49) were identified. No FBN2 mutation was found. Three patients with either TGFBR1 or TGFBR2 abnormality did not fulfill the Ghent criteria, but expressed some overlapping features of MFS and Loeys-Dietz syndrome (LDS). In the remaining 19 patients, either of the genes did not show any abnormalities. This study indicated that FBN1 mutations were predominant in MFS but TGFBRs defects may account for approximately 5-10% of patients with the syndrome.

Heparin regulates transcription of endothelin-1 gene in endothelial cells.

Heparin, which is widely used as an anticoagulant, has been shown to have antiatherosclerotic and antihypertensive effects in animals and humans. These effects are mediated by the inhibition of endothelin-1 (ET-1) production in endothelial cells. To clarify the mechanism of this inhibition, we investigated the effect of heparin on transcriptional regulation of the ET-1 gene in bovine aortic endothelial cells (BAEC) cultured in fetal calf serum. ET-1 mRNA expression was significantly suppressed by heparin in a dose-dependent manner. Promoter analysis revealed that the minimum ET-1 promoter containing only the GATA and AP-1 sequences as positive cis-acting sites in the ET-1 promoter is sufficient for this suppression. Gel mobility shift assays using oligonucleotides encoding the ET-1 AP-1 and ET-1 GATA sites confirmed that both AP-1 and GATA binding activities in BAEC nuclear extract were markedly inhibited by heparin. Western blot analyses indicated that heparin completely blocked extracellular signal-regulated kinase (ERK) activation, and inhibiting ERK activity resulted in loss of heparin-dependent inhibition of the ET-1 gene. These data indicate that the ET-1 mRNA level is negatively regulated by heparin at the transcription level, through modification of AP-1 and GATA protein binding activities, which direct the ET-1 promoter in BAEC. This effect may be mediated, at least in part, through inhibition of ERK activity.

Accessory mitral valve tissue causing severe left ventricular outflow tract obstruction in an adult.

Accessory mitral valve (AMV) is a rare cause of left ventricular outflow tract (LVOT) obstruction and is extremely rare in adults. We report a case of an older adult with an AMV that caused severe LVOT obstruction. A parachute-like piece of tissue (the AMV) protruding into the LVOT during systole was first detected in a 45-year-old woman by echocardiography. Because the pressure gradient and dyspnea gradually progressed, she finally underwent a successful operation for removal when she was 48 years old.

Matrix metalloproteinase 2 is suppressed by trapidil, a CD40-CD40 ligand pathway inhibitor, in human abdominal aortic aneurysm wall.

BACKGROUND: The activation of inflammatory cells and the production of matrix metalloproteinases (MMPs) are important in the pathogenesis of abdominal aortic aneurysm (AAA). Previous studies have demonstrated that the antiplatelet agent trapidil has multiple actions, including suppression of MMP expression through the inhibition of the CD40-CD40 ligand (CD40-CD40L) pathway in cultured cells. A recent clinical study suggested that trapidil might have functions beyond its antiplatelet action. Methods and results In the present study, we performed immunohistochemical analysis and semiquantitative reverse transcription-polymerase chain reaction to evaluate the effect of trapidil on the production of MMPs in cultured aortic tissues from patients with infrarenal AAA (n = 9) and control patients with aortoiliac occlusive disease (n = 7). The tissue concentrations of both MMP-2 and MMP-9 were significantly higher in AAA walls than in control aortic walls. Both trapidil and an anti-CD154 (CD40L) antibody significantly suppressed the protein production and mRNA expression of MMP-2 but did not inhibit those of MMP-9 in organ cultures of AAA wall specimens. MMP-9 was produced by macrophages and a lot of neutrophils in AAA tissues, whereas MMP-2 was derived from macrophages. CD40 was expressed on macrophages but not on neutrophils, and this expression could explain the differential effect of trapidil on the production of MMP-2 and MMP-9. CONCLUSIONS: Trapidil, a CD40-CD40L pathway inhibitor, suppressed mRNA expression and protein production of MMP-2 in AAA tissues, suggesting a potential therapeutic approach for the prevention or treatment of AAA.

Expression of peroxisome proliferator-activated receptor-gamma in vascular smooth muscle cells is upregulated in cystic medial degeneration of annuloaortic ectasia in Marfan syndrome.

BACKGROUND: Cystic medial degeneration (CMD) is a histological abnormality that is common in annuloaortic ectasia (AAE) and aortic dissection with Marfan syndrome. Apoptosis and loss of vascular smooth muscle cells (VSMCs) is one of the features of CMD, but little is known about its pathogenesis. Peroxisome proliferator-activated receptor-gamma (PPARgamma), a transcription factor of the nuclear receptor superfamily, has been reported to show antiproliferative effects on VSMCs as well as anti-inflammatory effects on macrophages. PPARgamma agonist has been recently reported to induce apoptosis of cultured VSMCs. METHODS: We examined the histopathology of ascending aortas in AAE of Marfan patients (n=21) and control patients (n=6) at surgery. RT-PCR was performed to demonstrate expression of PPARgamma in CMD. Localization of PPARgamma was determined by double immunostaining using antibodies against PPARgamma and cell-specific markers (ie, SMCs, macrophages, and T lymphocytes). RESULTS: PPARgamma expression was upregulated in AAE samples but minimal in control samples by RT-PCR (P=0.07). Immunoreactivity against PPARgamma in numerous nuclei of VSMCs was observed in CMD lesions. Severity of CMD correlated with positive immunoreactivity of PPARgamma in medial VSMCs (P=0.03). No inflammatory cells (ie, macrophages or T lymphocytes) were detected in CMD lesions. CONCLUSION: PPARgamma expression is upregulated in SMCs of CMD without any inflammatory response. Activated PPARgamma in VSMCs might be involved in the pathogenesis of CMD in Marfan's aortas. Regulation of PPARgamma might lead to clinical implication in protection against progression of AAE.

An angiotensin-converting enzyme inhibitor, not an angiotensin II type-1 receptor blocker, prevents beta-aminopropionitrile monofumarate-induced aortic dissection in rats.

OBJECTIVE: Cystic medial degeneration (CMD) is a histologic abnormality that is common in aortic diseases such as aortic dilation, aneurysm, or dissection. Although little is known about the mechanism underlying CMD, we have previously demonstrated that angiotensin II signaling via angiotensin II type 2 receptor (AT2R) plays a central role in apoptosis of vascular smooth muscle cells (VSMCs) occurring in CMD associated with Marfan syndrome. The aim of this study is to elucidate the role of angiotensin II signaling in THE pathogenesis of aortic diseases associated with CMD. METHOD: We investigated the effects of angiotensin-converting enzyme inhibitor (ACEI), temocapril (n = 15), angiotensin II receptor type-1 (AT1R) blocker, CS-866 (n = 15), and vehicle control (n = 17) on 0.25% beta-aminopropionitrile monofumarate (BAPN)-induced aortic dissection and histopathologic findings in a rat model. RESULTS: Temocapril significantly prevented aortic dissection (P <.05), CMD (P <.01), and VSMC apoptosis (P <.01) compared with vehicle control in BAPN-fed rats. However, CS-866 did not show any preventive effect. Reversed transcriptase-polymerase chain reaction demonstrated that expression of both AT1R and AT2R was detected in control rat aortas, and that AT2R expression was significantly upregulated in the aortas of BAPN-fed rats (P <.01). Blood pressure was significantly and equally lowered in both temocapril and CS-866 groups compared with control. CONCLUSIONS: Differential expression of angiotensin II receptors and AT2R signaling are involved in the pathogenesis of CMD and aortic dissection in BAPN-fed rats. ACEIs might be of clinical value for the prevention and treatment of aortic diseases related to CMD.

A 3-hydroxy-3-methylglutaryl coenzyme A reductase inhibitor, cerivastatin, suppresses production of matrix metalloproteinase-9 in human abdominal aortic aneurysm wall.

AIM: Abdominal aortic aneurysm (AAA) is a common vascular degenerative disease. AAA wall contains inflammatory cells that produce matrix metalloproteinases (MMPs) that probably contribute to elastolysis and remodeling of the aneurysm. 3-Hydroxy-3-methylglutaryl coenzyme A reductase inhibitors (statins) have been shown to reduce the expression of various molecules (including MMPs) independently of their cholesterol-lowering effect. The aims of this study are to investigate whether statins could modulate the biology of AAA wall and have a potential therapeutic value against AAAs. METHODS: We performed immunohistochemical analysis, evaluated MMP-9 production in the aortic wall from patients with infrarenal AAA (n = 10) and control patients with aortoiliac occlusive disease (n = 8), and examined the effect of cerivastatin on MMP-9 production in the AAA wall with organ culture. RESULTS: Neutrophils and macrophages were the cellular sources of MMP-9 in the AAA wall. The tissue concentrations of both total and active MMP-9 were significantly higher in tissues from AAA walls than in control aortic walls. Cerivastatin (0.001 to 0.1 micromol/L) significantly reduced the tissue levels of both total and active MMP-9 in a concentration-dependent manner (P <.001), and the production of tissue inhibitor of MMP-1 was unaffected. Cerivastatin neither reduced the number of infiltrating neutrophils and macrophages nor enhanced apoptosis of those cells, as evaluated with terminal transferase-mediated deoxyurisine triphosphate nick end labeling. CONCLUSION: These results suggest that cerivastatin can directly modulate the biology of the AAA wall and suppress MMP-9 production in the AAA wall by inhibiting the activation of neutrophils and macrophages, indicating that statin therapy could be useful for the prevention or treatment of AAA.

The embryonic angiogenic factor Del1 accelerates tumor growth by enhancing vascular formation.

Del1 is a unique alpha v beta 3 integrin ligand that is produced by endothelial cells, and thus provides an autocrine signaling pathway in this cell type. It is expressed transiently in the embryo and mediates cell attachment, migration, and activation of cytoplasmic signaling molecules in focal contacts. Del1 also activates angiogenesis in the chick chorioallantoic membrane assay. Reexpression of this embryonic signaling molecule has now been documented in naturally occurring human tumors, where it is expressed by both tumor cells and angiogenic endothelial cells, suggesting that Del1 is important in mediating angiogenesis under pathophysiological conditions in the adult. To investigate the role of Del1 in tumor growth and angiogenesis, human 143B osteosarcoma cells and murine Lewis lung carcinoma cells were engineered to express Del1 and compared to control transfectants for their ability to produce tumors in nude or syngeneic mice, respectively. Del1 expressing tumors showed a two- to fourfold increase in capillary density and an accelerated rate of growth. Expression of Del1 also correlated with a decrease in apoptosis in tumor cells in vivo. Taken together, these data suggest that Del1 acts as an angiogenic factor in the context of solid tumor formation and that this increase in vascularization accelerates tumor growth through decreased apoptosis.