Division of Cardiology, Department of Medicine, Emory University, Atlanta, Georgia
The renin-angiotensin system is a central component of the physiological and pathological responses of ...cardiovascular system. Its primary effector hormone, angiotensin II (ANG II), not only mediates immediate physiological effects of vasoconstriction and blood pressure regulation, but is also implicated in inflammation, endothelial dysfunction, atherosclerosis, hypertension, and congestive heart failure. The myriad effects of ANG II depend on time (acute vs. chronic) and on the cells/tissues upon which it acts. In addition to inducing G protein- and non-G protein-related signaling pathways, ANG II, via AT 1 receptors, carries out its functions via MAP kinases (ERK 1/2, JNK, p38MAPK), receptor tyrosine kinases PDGF, EGFR, insulin receptor, and nonreceptor tyrosine kinases Src, JAK/STAT, focal adhesion kinase (FAK). AT 1 R-mediated NAD(P)H oxidase activation leads to generation of reactive oxygen species, widely implicated in vascular inflammation and fibrosis. ANG II also promotes the association of scaffolding proteins, such as paxillin, talin, and p130Cas, leading to focal adhesion and extracellular matrix formation. These signaling cascades lead to contraction, smooth muscle cell growth, hypertrophy, and cell migration, events that contribute to normal vascular function, and to disease progression. This review focuses on the structure and function of AT 1 receptors and the major signaling mechanisms by which angiotensin influences cardiovascular physiology and pathology.
vascular smooth muscle; NAD(P)H oxidase; tyrosine and nontyrosine receptor kinases; endothelial dysfunction; vascular disease
Address for reprint requests and other correspondence: K. K. Griendling, Emory Univ., Division of Cardiology, 319 WMB, 1639 Pierce Dr., Atlanta, GA 30322 (e-mail: kgriend{at}emory.edu )
The COVID-19 pandemic is a global public health crisis with considerable mortality and morbidity. A role for cytokine storm and therapeutic immunomodulation in a subgroup of patients with severe ...COVID-19 was proposed early in the pandemic. The concept of cytokine storm in COVID-19 has been criticised, given the lack of clear definition and relatively modest cytokinaemia (which may be necessary for viral clearance) compared with acute respiratory distress syndrome and bacterial sepsis. Here we consider the arguments for and against the concept of cytokine storm in COVID-19.
Several criteria have been proposed to identify the subgroup of COVID-19 patients exhibiting a cytokine storm. The beneficial effects of corticosteroids and interleukin-6 inhibition suggest that inflammation is a modifiable pathogenic component of severe COVID-19. The presence of genetic polymorphisms and pathogenic auto-autoantibodies in severe COVID-19 also suggests a significant contribution of immune dysregulation to poor outcomes.
Hyperinflammation is a key component of severe COVID-19, residing underneath the cytokine storm umbrella term, associated with poor outcomes. Better understanding of the aetiopathogenesis, with identification of biomarkers to predict treatment responses and prognosis, will hopefully enable a stratified and ultimately precision medicine approach.
•COVID-19 is caused by a highly pathogenic coronavirus named “SARS-CoV-2”.•COVID-19 pathophysiology is primarily defined by acute respiratory illness.•Several studies have revealed a possible ...neurological component to COVID-19.•Various neurological manifestations have also been reported for SARS and MERS.•Further research into the importance of neurological manifestations in COVID-19 is needed.
Central to COVID-19 pathophysiology is an acute respiratory infection primarily manifesting as pneumonia. Two months into the COVID-19 outbreak, however, a retrospective study in China involving more than 200 participants revealed a neurological component to COVID-19 in a subset of patients. The observed symptoms, the cause of which remains unclear, included impaired consciousness, skeletal muscle injury and acute cerebrovascular disease, and appeared more frequently in severe disease. Since then, findings from several studies have hinted at various possible neurological outcomes in COVID-19 patients. Here, we review the historical association between neurological complications and highly pathological coronaviruses including SARS-CoV, MERS-CoV and SARS-CoV-2. We draw from evidence derived from past coronavirus outbreaks, noting the similarities and differences between SARS and MERS, and the current COVID-19 pandemic. We end by briefly discussing possible mechanisms by which the coronavirus impacts on the human nervous system, as well as neurology-specific considerations that arise from the repercussions of COVID-19.
•We report two UK cases of cerebral venous sinus thrombosis and thrombocytopenia following first dose of the Vaxzevria vaccine (previously named COVID-19 Vaccine AstraZeneca).•The proposed ...pathophysiology is a vaccine-induced immune mechanism, supported by the detection of antibodies to platelet factor-4.•Neuroimaging revealed high clot burden with large amount of parenchymal and subarachnoid haemorrhage, leading to fatal outcomes.•Management of this condition differs from usual treatment of cerebral venous sinus thrombosis,in particular avoiding heparin and platelet transfusions.
Recent reports have highlighted rare, and sometimes fatal, cases of cerebral venous sinus thrombosis (CVST) and thrombocytopenia following the Vaxzevria vaccine. An underlying immunological mechanism similar to that of spontaneous heparin-induced thrombocytopenia (HIT) is suspected, with the identification of antibodies to platelet factor-4 (PF4), but without previous heparin exposure. This unusual mechanism has significant implications for the management approach used, which differs from usual treatment of CVST. We describe the cases of two young males, who developed severe thrombocytopenia and fatal CVST following the first dose of Vaxzevria. Both presented with a headache,with subsequent rapid neurological deterioration. One patient underwent PF4 antibody testing, which was positive. Arapid vaccinationprogramme is essential in helping to control the COVID-19 pandemic. Hence, it is vital that such COVID-19 vaccine-associated events, which at this stage appear to be very rare, are viewed through this lens.However, some cases have proved fatal. Itis critical that clinicians arealerted to the emergence of such eventstofacilitate appropriate management.Patients presenting with CVST features and thrombocytopenia post-vaccination should undergoPF4 antibody testing and be managed in a similar fashion to HIT,in particular avoiding heparin and platelet transfusions.
Cardiovascular disease (CVD) remains the leading cause of morbidity and mortality for women in the United States and worldwide. There has been no American College of Cardiology (ACC)/American Heart ...Association guideline update specifically for the prevention of CVD in women since 2011. Since then, the body of sex-specific data has grown, in addition to updated hypertension, cholesterol, diabetes, atrial fibrillation, and primary prevention guidelines. The ACC CVD in Women Committee undertook a review of the recent guidelines and major studies to summarize recommendations pertinent to women. In this update, the authors address special topics, particularly the risk factors and treatments that have led to some controversies and confusion. Specifically, sex-related risk factors, hypertension, diabetes, hyperlipidemia, anticoagulation for atrial fibrillation, use of aspirin, perimenopausal hormone therapy, and psychosocial issues are highlighted.
Currently as many as one-half of women with suspected myocardial ischemia have no obstructive coronary artery disease (CAD), and abnormal coronary reactivity (CR) is commonly found.
The authors ...prospectively investigated CR and longer-term adverse cardiovascular outcomes in women with and with no obstructive CAD in the National Heart, Lung, and Blood Institute–sponsored WISE (Women’s Ischemia Syndrome Evaluation) study.
Women (n = 224) with signs and symptoms of ischemia underwent CR testing. Coronary flow reserve and coronary blood flow were obtained to test microvascular function, whereas epicardial CR was tested by coronary dilation response to intracoronary (IC) acetylcholine and IC nitroglycerin. All-cause mortality, major adverse cardiovascular events (MACE) (cardiovascular death, myocardial infarction, stroke, and heart failure), and angina hospitalizations served as clinical outcomes over a median follow-up of 9.7 years.
The authors identified 129 events during the follow-up period. Low coronary flow reserve was a predictor of increased MACE rate (hazard ratio HR: 1.06; 95% confidence interval CI: 1.01 to 1.12; p = 0.021), whereas low coronary blood flow was associated with increased risk of mortality (HR: 1.12; 95% CI: 1.01 to 1.24; p = 0.038) and MACE (HR: 1.11; 95% CI: 1.03 to 1.20; p = 0.006) after adjusting for cardiovascular risk factors. In addition, a decrease in cross-sectional area in response to IC acetylcholine was associated with higher hazard of angina hospitalization (HR: 1.05; 95% CI: 1.02 to 1.07; p < 0.0001). There was no association between epicardial IC-nitroglycerin dilation and outcomes.
On longer-term follow-up, impaired microvascular function predicts adverse cardiovascular outcomes in women with signs and symptoms of ischemia. Evaluation of CR abnormality can identify those at higher risk of adverse outcomes in the absence of significant CAD. (Women's Ischemia Syndrome Evaluation WISE; NCT00000554)
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Abstract
Ischaemic heart disease is a leading cause of morbidity and mortality in both women and men. Compared with men, symptomatic women who are suspected of having myocardial ischaemia are more ...likely to have no obstructive coronary artery disease (CAD) on coronary angiography. Coronary vasomotor disorders and coronary microvascular dysfunction (CMD) have been increasingly recognized as important contributors to angina and adverse outcomes in patients with no obstructive CAD. CMD from functional and structural abnormalities in the microvasculature is associated with adverse cardiac events and mortality in both sexes. Women may be particularly susceptible to vasomotor disorders and CMD due to unique factors such as inflammation, mental stress, autonomic, and neuroendocrine dysfunction, which predispose to endothelial dysfunction and CMD. CMD can be detected with coronary reactivity testing and non-invasive imaging modalities; however, it remains underdiagnosed. This review focuses on sex differences in presentation, pathophysiologic risk factors, diagnostic testing, and prognosis of CMD.
Symptomatic individuals suspected of having myocardial ischemia often have no obstructive atherosclerotic narrowing of epicardial coronary arteries. Abnormal coronary vascular reactivity and, in ...particular, coronary artery vasospasm (CAS) may be an explanation in a subset of these patients. Psychological factors play an important role in ischemic heart disease, but their role in CAS is not clear; autonomic dysfunction and increased inflammation are two prevailing pathophysiological mechanisms implicated in abnormal coronary reactivity resulting from mental health conditions. Interrelationships between psychological factors, abnormal coronary reactivity, and sex/gender differences are poorly defined in the etiology of CAS. In this issue of Psychosomatic Medicine (2019;81:237-245), Hung et al. report a frequency of less than 0.1% of new-onset CAS in the Taiwanese population, with higher occurrence in women and younger individuals. Patients with CAS had a higher prevalence of previous anxiety and depression compared with those with coronary artery disease and controls, with no sex differences. In this editorial comment, we discuss the potential reasons for underreporting of CAS and the challenges regarding the use of administrative health records for psychosomatic research. In this editorial, a model is presented to explain the association between emotional stressors and mental health factors with CAS, including the role of sympathetic nervous system activation, inflammation, oxidative stress, endothelial dysfunction, and smooth muscle cell dysregulation.
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