Guggulsterone, an anti-inflammatory phytosterol, inhibits tissue factor and arterial thrombosis

Background: The phytosterol guggulsterone is a potent anti-inflammatory mediator with less side effects than classic steroids. This study assesses the impact of guggulsterone on tissue factor (TF) expression and thrombus formation. Methods and results: Guggulsterone inhibited TNF-α-induced endothelial TF protein expression and surface activity in a concentration-dependent manner; in contrast, dexamethasone did not affect TNF-α-induced TF expression. Guggulsterone enhanced endothelial tissue factor pathway inhibitor and impaired plasminogen activator inhibitor-1 as well as vascular cell adhesion molecule-1 protein. Real-time polymerase chain reaction revealed that guggulsterone inhibited TNF-α-induced TF mRNA expression; moreover, it impaired activation of the MAP kinases JNK and p38, while that of ERK remained unaffected. In vivo, guggulsterone inhibited TF activity and photochemical injury induced thrombotic occlusion of mouse carotid artery. Guggulsterone also inhibited TF expression, proliferation, and migration of vascular smooth muscle cells in a concentration-dependent manner. Conclusions: Guggulsterone inhibits TF expression in vascular cells as well as thrombus formation in vivo; moreover, it impairs vascular smooth muscle cell activation. Hence, this phytosterol offers novel therapeutic options, in particular in inflammatory diseases associated with an increased risk of thrombosi

Sex hormones in SARS-CoV-2 susceptibility: key players or confounders?

Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection has a clear sex disparity in clinical outcomes. Hence, the interaction between sex hormones, virus entry receptors and immune responses has attracted major interest as a target for the prevention and treatment of SARS-CoV-2 infections. This Review summarizes the current understanding of the roles of androgens, oestrogens and progesterone in the regulation of virus entry receptors and disease progression of coronavirus disease 2019 (COVID-19) as well as their therapeutic value. Although many experimental and clinical studies have analysed potential mechanisms by which female sex hormones might provide protection against SARS-CoV-2 infectivity, there is currently no clear evidence for a sex-specific expression of virus entry receptors. In addition, reports describing an influence of oestrogen, progesterone and androgens on the course of COVID-19 vary widely. Current data also do not support the administration of oestradiol in COVID-19. The conflicting evidence and lack of consensus results from a paucity of mechanistic studies and clinical trials reporting sex-disaggregated data. Further, the influence of variables beyond biological factors (sex), such as sociocultural factors (gender), on COVID-19 manifestations has not been investigated. Future research will have to fill this knowledge gap as the influence of sex and gender on COVID-19 will be essential to understanding and managing the long-term consequences of this pandemic

Amphetamines induce tissue factor and impair tissue factor pathway inhibitor: role of dopamine receptor type 4

Aims Amphetamine intake is associated with acute vascular syndromes. Since these events are caused by arterial thrombosis and this in turn is triggered by tissue factor (TF), this study examines whether amphetamines regulate TF in human endothelial cells. Methods and results Amphetamine (10−7-10−4 mol/L) enhanced thrombin- and tumour necrosis factor (TNF)-α-induced as well as basal TF expression (P = 0.029, 0.0003, and 0.003 at maximal concentration), and TNF-α-induced plasminogen activator inhibitor (PAI)-1 expression (P = 0.003), whereas tissue factor pathway inhibitor expression was impaired (P = 0.008). Similarly, 3,4-methylenedioxymethamphetamine (10−7-10−4 mol/L) enhanced TF expression (P = 0.046). These effects were paralleled by an increased TF activity (P = 0.002); moreover, clotting time of human plasma was accelerated by supernatant from amphetamine-treated cells (P = 0.03). Amphetamine enhanced TF mRNA expression via phosphorylation of the mitogen-activated protein kinases (MAPKs) extracellular signal-regulated kinase (ERK) and p38 (P = 0.03 and 0.033), but not c-Jun NH2-terminal kinase (JNK; P = 0.81). The effect of amphetamine on TF expression was abrogated by the dopamine D4 receptor antagonists L-745,870 and L-750,667, but not D2 or D3 receptor antagonists; furthermore, L-745,870 blunted the amphetamine-induced activation of ERK and p38, but not JNK. Conclusion Amphetamines induce endothelial TF expression via stimulation of dopamine D4 receptor and activation of the MAPKs p38 and ERK. These effects occur at clinically relevant amphetamine concentrations and may account for the increased incidence of acute vascular syndromes after amphetamine consumptio

Temporal trends in mortality and provision of intensive care in younger women and men with acute myocardial infarction or stroke

BACKGROUND Timely management of acute myocardial infarction (AMI) and acute stroke has undergone impressive progress during the last decade. However, it is currently unknown whether both sexes have profited equally from improved strategies. We sought to analyze sex-specific temporal trends in intensive care unit (ICU) admission and mortality in younger patients presenting with AMI or stroke in Switzerland. METHODS Retrospective analysis of temporal trends in 16,954 younger patients aged 18 to ≤ 52 years with AMI or acute stroke admitted to Swiss ICUs between 01/2008 and 12/2019. RESULTS Over a period of 12 years, ICU admissions for AMI decreased more in women than in men (- 6.4% in women versus - 4.5% in men, p < 0.001), while ICU mortality for AMI significantly increased in women (OR 1.2 [1.10-1.30], p = 0.032), but remained unchanged in men (OR 0.99 [0.94-1.03], p = 0.71). In stroke patients, ICU admission rates increased between 3.6 and 4.1% per year in both sexes, while ICU mortality tended to decrease only in women (OR 0.91 [0.85-0.95, p = 0.057], but remained essentially unaltered in men (OR 0.99 [0.94-1.03], p = 0.75). Interventions aimed at restoring tissue perfusion were more often performed in men with AMI, while no sex difference was noted in neurovascular interventions. CONCLUSION Sex and gender disparities in disease management and outcomes persist in the era of modern interventional neurology and cardiology with opposite trends observed in younger stroke and AMI patients admitted to intensive care. Although our study has several limitations, our data suggest that management and selection criteria for ICU admission, particularly in younger women with AMI, should be carefully reassessed

Long-Term Mortality after New-Onset Atrial Fibrillation in COVID-19

Background: Atrial fibrillation (AF) has been described as a common cardiovascular manifestation in patients suffering from coronavirus disease 2019 (COVID-19) and has been suggested to be a potential risk factor for a poor clinical outcome. Methods: In this observational study, all patients hospitalized due to COVID-19 in 2020 in the Cantonal Hospital of Baden were included. We assessed clinical characteristics, in-hospital outcomes as well as long-term outcomes with a mean follow-up time of 278 (±90) days. Results: Amongst 646 patients diagnosed with COVID-19 (59% male, median age: 70 (IQR: 59-80)) in 2020, a total of 177 (27.4%) patients were transferred to the intermediate/intensive care unit (IMC/ICU), and 76 (11.8%) were invasively ventilated during their hospitalization. Ninety patients (13.9%) died. A total of 116 patients (18%) showed AF on admission of which 34 (29%) had new-onset AF. Patients with COVID-19 and newly diagnosed AF were more likely to require invasive ventilation (OR: 3.5; p = 0.01) but did not encounter an increased in-hospital mortality. Moreover, AF neither increased long-term mortality nor the number of rehospitalizations during follow-up after adjusting for confounders. Conclusions: In patients suffering from COVID-19, the new-onset of AF on admission was associated with an increased risk of invasive ventilation and transfer to the IMC/ICU but did not affect in-hospital or long-term mortality

Immunoreactivity of the SARS-CoV-2 entry proteins ACE-2 and TMPRSS-2 in murine models of hormonal manipulation, ageing, and cardiac injury

Previous work indicates that SARS-CoV-2 virus entry proteins angiotensin-converting enzyme 2 (ACE-2) and the cell surface transmembrane protease serine 2 (TMPRSS-2) are regulated by sex hormones. However, clinical studies addressing this association have yielded conflicting results. We sought to analyze the impact of sex hormones, age, and cardiovascular disease on ACE-2 and TMPRSS-2 expression in different mouse models. ACE-2 and TMPRSS-2 expression was analyzed by immunostaining in a variety of tissues obtained from FVB/N mice undergoing either gonadectomy or sham-surgery and being subjected to ischemia-reperfusion injury or transverse aortic constriction surgery. In lung tissues sex did not have a significant impact on the expression of ACE-2 and TMPRSS-2. On the contrary, following myocardial injury, female sex was associated to a lower expression of ACE-2 at the level of the kidney tubules. In addition, after myocardial injury, a significant correlation between younger age and higher expression of both ACE-2 and TMPRSS-2 was observed for lung alveoli and bronchioli, kidney tubules, and liver sinusoids. Our experimental data indicate that gonadal hormones and biological sex do not alter ACE-2 and TMPRSS-2 expression in the respiratory tract in mice, independent of disease state. Thus, sex differences in ACE-2 and TMPRSS-2 protein expression observed in mice may not explain the higher disease burden of COVID-19 among men

Gender- and age-related differences in rest and post-stress left ventricular cardiac function determined by gated SPECT

Gender- and age-related changes of left ventricular (LV) function and dimensions have not been elucidated in a large population by gated SPECT. Thus, the aim of this study was to derive male and female reference limits for left ventricular functional parameters, and determine the effect of age on LV dimensions and systolic function for this imaging modality. 1,639 (53% males) subjects without cardiovascular disease who underwent cardiac SPECT between January 2002 and June 2012 were included in this study. Mean age at presentation was 61±12years (range 18-92years). A significant effect of age (p=0.011) and gender (p<0.0001) on resting LV ejection fraction (LVEF) was observed, with an increase in LVEF with age being more pronounced in women (ΔB-coefficient: −0.088, p=0.011). Overall, mean LVEF was higher in women compared to men (70.3±8.6% vs. 64.4±7.5%, p<0.0001). LVEF after pharmacological stress with adenosine was significantly lower than at rest in both women and men (∆LVEF=1.1% in males and ∆LVEF=1.6% in females, p=0.01), which was the result of a significant increase in end-systolic volume after stress (p=0.0001). With advancing age an increase in LVEF was observed that was more pronounced in women than in men. These findings indicate that the evaluation of cardiac function and volumes of patients by gated SPECT should consider age- and gender-matched normative values

Development and validation of a prognostic model for the early identification of COVID-19 patients at risk of developing common long COVID symptoms

Background: The coronavirus disease 2019 (COVID-19) pandemic demands reliable prognostic models for estimating the risk of long COVID. We developed and validated a prediction model to estimate the probability of known common long COVID symptoms at least 60 days after acute COVID-19. Methods: The prognostic model was built based on data from a multicentre prospective Swiss cohort study. Included were adult patients diagnosed with COVID-19 between February and December 2020 and treated as outpatients, at ward or intensive/intermediate care unit. Perceived long-term health impairments, including reduced exercise tolerance/reduced resilience, shortness of breath and/or tiredness (REST), were assessed after a follow-up time between 60 and 425 days. The data set was split into a derivation and a geographical validation cohort. Predictors were selected out of twelve candidate predictors based on three methods, namely the augmented backward elimination (ABE) method, the adaptive best-subset selection (ABESS) method and model-based recursive partitioning (MBRP) approach. Model performance was assessed with the scaled Brier score, concordance c statistic and calibration plot. The final prognostic model was determined based on best model performance. Results: In total, 2799 patients were included in the analysis, of which 1588 patients were in the derivation cohort and 1211 patients in the validation cohort. The REST prevalence was similar between the cohorts with 21.6% (n = 343) in the derivation cohort and 22.1% (n = 268) in the validation cohort. The same predictors were selected with the ABE and ABESS approach. The final prognostic model was based on the ABE and ABESS selected predictors. The corresponding scaled Brier score in the validation cohort was 18.74%, model discrimination was 0.78 (95% CI: 0.75 to 0.81), calibration slope was 0.92 (95% CI: 0.78 to 1.06) and calibration intercept was -0.06 (95% CI: -0.22 to 0.09). Conclusion: The proposed model was validated to identify COVID-19-infected patients at high risk for REST symptoms. Before implementing the prognostic model in daily clinical practice, the conduct of an impact study is recommended. Keywords: Clinical prediction model; Long COVID; Prognostic factors; Stratified medicin