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1.
Eur Heart J Cardiovasc Pharmacother ; 8(2): 149-156, 2022 02 16.
Article in English | MEDLINE | ID: covidwho-1706743

ABSTRACT

AIMS: Uncontrolled blood pressure (BP) increases the risk of developing heart failure (HF). The effect of spironolactone on BP of patients at risk of developing HF is yet to be determined. To evaluate the effect of spironolactone on the BP of patients at risk for HF and whether renin can predict spironolactone's effect. METHODS AND RESULTS: HOMAGE (Heart OMics in Aging) was a prospective multicentre randomized open-label blinded endpoint (PROBE) trial including 527 patients at risk for developing HF randomly assigned to either spironolactone (25-50 mg/day) or usual care alone for a maximum of 9 months. Sitting BP was assessed at baseline, Months 1 and 9 (or last visit). Analysis of covariance (ANCOVA), mixed effects models, and structural modelling equations was used. The median (percentile25-75) age was 73 (69-79) years, 26% were female, and >75% had history of hypertension. Overall, the baseline BP was 142/78 mmHg. Patients with higher BP were older, more likely to have diabetes and less likely to have coronary artery disease, had greater left ventricular mass (LVM), and left atrial volume (LAV). Compared with usual care, by last visit, spironolactone changed SBP by -10.3 (-13.0 to -7.5) mmHg and DBP by -3.2 (-4.8 to -1.7) mmHg (P < 0.001 for both). A higher proportion of patients on spironolactone had controlled BP <130/80 mmHg (36 vs. 26%; P = 0.014). Lower baseline renin levels predicted a greater response to spironolactone (interactionP = 0.041). CONCLUSION: Spironolactone had a clinically important BP-lowering effect. Spironolactone should be considered for lowering blood pressure in patients who are at risk of developing HF.


Subject(s)
Heart Failure , Spironolactone , Aged , Blood Pressure , Female , Heart Failure/diagnosis , Heart Failure/drug therapy , Heart Failure/epidemiology , Humans , Male , Mineralocorticoid Receptor Antagonists/adverse effects , Prospective Studies , Spironolactone/therapeutic use
2.
Elife ; 92020 04 27.
Article in English | MEDLINE | ID: covidwho-1344522

ABSTRACT

COVID-19 patients can present with pulmonary edema early in disease. We propose that this is due to a local vascular problem because of activation of bradykinin 1 receptor (B1R) and B2R on endothelial cells in the lungs. SARS-CoV-2 enters the cell via ACE2 that next to its role in RAAS is needed to inactivate des-Arg9 bradykinin, the potent ligand of the B1R. Without ACE2 acting as a guardian to inactivate the ligands of B1R, the lung environment is prone for local vascular leakage leading to angioedema. Here, we hypothesize that a kinin-dependent local lung angioedema via B1R and eventually B2R is an important feature of COVID-19. We propose that blocking the B2R and inhibiting plasma kallikrein activity might have an ameliorating effect on early disease caused by COVID-19 and might prevent acute respiratory distress syndrome (ARDS). In addition, this pathway might indirectly be responsive to anti-inflammatory agents.


The COVID-19 pandemic represents an unprecedented threat to global health. Millions of cases have been confirmed around the world, and hundreds of thousands of people have lost their lives. Common symptoms include a fever and persistent cough and COVID-19 patients also often experience an excess of fluid in the lungs, which makes it difficult to breathe. In some cases, this develops into a life-threatening condition whereby the lungs cannot provide the body's vital organs with enough oxygen. The SARS-CoV-2 virus, which causes COVID-19, enters the lining of the lungs via an enzyme called the ACE2 receptor, which is present on the outer surface of the lungs' cells. The related coronavirus that was responsible for the SARS outbreak in the early 2000s also needs the ACE2 receptor to enter the cells of the lungs. In SARS, the levels of ACE2 in the lung decline during the infection. Studies with mice have previously revealed that a shortage of ACE2 leads to increased levels of a hormone called angiotensin II, which regulates blood pressure. As a result, much attention has turned to the potential link between this hormone system in relation to COVID-19. However, other mouse studies have shown that ACE2 protects against a build-up of fluid in the lungs caused by a different molecule made by the body. This molecule, which is actually a small fragment of a protein, lowers blood pressure and causes fluid to leak out of blood vessels. It belongs to a family of molecules known as kinins, and ACE2 is known to inactivate certain kinins. This led van de Veerdonk et al. to propose that the excess of fluid in the lungs seen in COVID-19 patients may be because kinins are not being neutralized due to the shortage of the ACE2 receptor. This had not been hypothesized before, even though the mechanism could be the same in SARS which has been researched for the past 17 years. If this hypothesis is correct, it would mean that directly inhibiting the receptor for the kinins (or the proteins that they come from) may be the only way to stop fluid leaking into the lungs of COVID-19 patients in the early stage of disease. This hypothesis is unproven, and more work is needed to see if it is clinically relevant. If that work provides a proof of concept, it means that existing treatments and registered drugs could potentially help patients with COVID-19, by preventing the need for mechanical ventilation and saving many lives.


Subject(s)
Antiviral Agents/therapeutic use , Coronavirus Infections/drug therapy , Coronavirus Infections/pathology , Drug Development , Pneumonia, Viral/drug therapy , Pneumonia, Viral/pathology , Angioedema/drug therapy , Angioedema/metabolism , Angioedema/pathology , Anti-Inflammatory Agents/therapeutic use , Betacoronavirus/physiology , Bradykinin Receptor Antagonists/therapeutic use , COVID-19 , Coronavirus Infections/metabolism , Endothelial Cells/metabolism , Endothelial Cells/pathology , Humans , Inflammation/immunology , Inflammation/pathology , Kallikreins/metabolism , Kinins/metabolism , Lung/metabolism , Lung/pathology , Pandemics , Pneumonia, Viral/metabolism , Receptor, Bradykinin B1/metabolism , Receptor, Bradykinin B2/metabolism , Respiratory Distress Syndrome/drug therapy , Respiratory Distress Syndrome/pathology , Respiratory Distress Syndrome/prevention & control , SARS-CoV-2 , Signal Transduction
3.
Physiol Rep ; 9(11): e14800, 2021 06.
Article in English | MEDLINE | ID: covidwho-1268434

ABSTRACT

The objective of this review is to give an overview of the pathophysiological effects of the Coronavirus Disease 2019 (COVID-19) in relation to hypertension (HT), with a focus on the Renin-Angiotensin-Aldosterone System (RAAS) and the MAS receptor. HT is a multifactorial disease and a public health burden, as it is a risk factor for diseases like stroke, coronary artery disease, and heart failure, leading to 10.4 million deaths yearly. Blood pressure is regulated by the RAAS. The system consists of two counter-regulatory axes: ACE/ANG-II/AT1 R and ACE2/ANG-(1-7)/MAS. The main regulatory protein in balancing the RAAS is angiotensin-converting enzyme 2 (ACE2). The protein also functions as the main mediator of endocytosis of the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) into the host cell. SARS-CoV-2 is the cause of COVID-19 and has caused a worldwide pandemic; however, the treatment and prophylaxis of COVID-19 are limited. Several drugs and vaccines are currently being tested in clinical trials with a few already approved by EMA and FDA. HT is a major risk factor regarding the severity and fatality of COVID-19, and the RAAS plays an important role in COVID-19 infection since SARS-CoV-2 can lead to a dysregulation of the system by reducing the ACE2 expression. The exact mechanisms of HT in relation to COVID-19 remain uncertain, and more research is needed for further elucidation.


Subject(s)
Angiotensin-Converting Enzyme Inhibitors/therapeutic use , COVID-19/physiopathology , Hypertension/virology , Renin-Angiotensin System/physiology , COVID-19/epidemiology , COVID-19/virology , Humans , Hypertension/physiopathology , Pandemics , Risk Factors , SARS-CoV-2/isolation & purification
4.
Clin Respir J ; 15(8): 915-924, 2021 Aug.
Article in English | MEDLINE | ID: covidwho-1238374

ABSTRACT

BACKGROUND: Coronavirus disease 2019 (COVID-19) is an emerging, rapidly evolving pandemic, hypertension is one of the most common co-existing chronic conditions and a risk factor for mortality. Nearly one-third of the adult population is hypertensive worldwide, it is urgent to identify the factors that determine the clinical course and outcomes of COVID-19 patients with hypertension. METHODS AND RESULTS: 148 COVID-19 patients with pre-existing hypertension with clarified outcomes (discharge or deceased) from a national cohort in China were included in this study, of whom 103 were discharged and 45 died in hospital. Multivariate regression showed higher odds of in-hospital death associated with high-sensitivity cardiac troponin (hs-cTn) > 28 pg/ml (hazard ratio [HR]: 3.27, 95% confidence interval [CI]: 1.55-6.91) and interleukin-6 (IL-6) > 7 pg/ml (HR: 3.63, 95% CI:1.54-8.55) at admission. Patients with uncontrolled blood pressure (BP) (n = 52) which were defined as systolic BP ≥140 mm Hg or diastolic BP ≥90 mm Hg for more than once (≥2 times) during hospitalization, were more likely to have ICU admission (p = 0.037), invasive mechanical ventilation (p = 0.028), and renal injury (p = 0.005). A stricter BP control with the threshold of 130/80 mm Hg was associated with lower mortality. Treatment with renin-angiotensin-aldosterone system (RAAS) suppressors, including angiotensin-converting enzyme (ACE) inhibitors, angiotensin II receptor blockers (ARB), and spironolactone, was associated with a lower rate of ICU admission compared to other types of anti-hypertensive medications (8 (22.9%) vs. 25 (43.1%), p = 0.048). CONCLUSION: Among COVID-19 patients with pre-existing hypertension, elevated hs-cTn and IL-6 could help clinicians to identify patients with fatal outcomes at an early stage, blood pressure control is associated with better clinical outcomes, and RAAS suppressors do not increase mortality and may decrease the need for ICU admission.


Subject(s)
COVID-19 , Hypertension , Angiotensin Receptor Antagonists , Angiotensin-Converting Enzyme Inhibitors , China/epidemiology , Hospital Mortality , Humans , Hypertension/epidemiology , Retrospective Studies , SARS-CoV-2
5.
Int J Environ Res Public Health ; 18(9)2021 05 10.
Article in English | MEDLINE | ID: covidwho-1231487

ABSTRACT

The purpose of the research is to analyze the improvement in the physical and mental health of college students after intermittent exercises are performed by massage. The present study employed a mixed research method. An experimental study was conducted to analyze the current status of the volunteers' sports performance and body composition, and then a questionnaire was designed for the subjects' physical and mental health. The data were then analyzed using SPSS 26.0 software for statistical analysis such as t-test and ANOVA. The subjects were then interviewed to collect their opinions on the study results, and finally, the results were explored by multivariate analysis. The study found that intermittent exercise can help university students develop physical fitness and performance, improve body composition, and regulate physical and mental health. The combination of intermittent exercise with sports massages further enhanced the performance of sit-ups and standing long jump, improve blood pressure, BMI, and self-confidence, as well as reducing suicidal tendencies (experimental group > control group). However, intermittent exercise participants still experienced fatigue, headache, emotional loss, and fear of depression, and the addition of sports massage did not significantly improve flexibility and cardiorespiratory endurance (control group > experimental group).


Subject(s)
Exercise , Mental Health , Humans , Massage , Physical Fitness , Students
6.
J Hypertens ; 39(6): 1077-1089, 2021 06 01.
Article in English | MEDLINE | ID: covidwho-1219489

ABSTRACT

SUMMARY: The coronavirus disease 2019 (COVID-19) pandemic considerably affects health, wellbeing, social, economic and other aspects of daily life. The impact of COVID-19 on blood pressure (BP) control and hypertension remains insufficiently explored. We therefore provide a comprehensive review of the potential changes in lifestyle factors and behaviours as well as environmental changes likely to influence BP control and cardiovascular risk during the pandemic. This includes the impact on physical activity, dietary patterns, alcohol consumption and the resulting consequences, for example increases in body weight. Other risk factors for increases in BP and cardiovascular risk such as smoking, emotional/psychologic stress, changes in sleep patterns and diurnal rhythms may also exhibit significant changes in addition to novel factors such as air pollution and environmental noise. We also highlight potential preventive measures to improve BP control because hypertension is the leading preventable risk factor for worldwide health during and beyond the COVID-19 pandemic.


Subject(s)
COVID-19 , Hypertension/epidemiology , Life Style , Stress, Psychological , Humans , Pandemics , Risk Factors , SARS-CoV-2 , Smoking , Socioeconomic Factors
7.
Diabet Med ; 38(2): e14458, 2021 02.
Article in English | MEDLINE | ID: covidwho-1214788

ABSTRACT

Dapagliflozin (SGLT-2 inhibitor) and sotagliflozin (SGLT1/2 inhibitor) are two of the drugs of SGLT inhibitor class which have been recommended by the National Institute for Health and Care Excellence (NICE) in people with type 1 diabetes with BMI ≥27 kg/m2 . Dapagliflozin is licensed in the UK for use in the NHS while sotagliflozin may be available in future. These and possibly other SGLT inhibitors may be increasingly used in people with type 1 diabetes as new licences are obtained. These drugs have the potential to improve glycaemic control in people with type 1 diabetes with the added benefit of weight loss, better control of blood pressure and more time in optimal glucose range. However, SGLT inhibitors are associated with a higher incidence of diabetic ketoacidosis without significant hyperglycaemia. The present ABCD/Diabetes UK joint updated position statement is to guide people with type 1 diabetes and clinicians using these drugs help mitigate this risk and other potential complications. Particularly, caution needs to be exercised in people who are at risk of diabetic ketoacidosis due to low calorie diets, illnesses, injuries, starvation, excessive exercise, excessive alcohol consumption and reduced insulin administration among other precipitating factors for diabetic ketoacidosis.


Subject(s)
Diabetes Mellitus, Type 1/drug therapy , Diabetic Ketoacidosis/epidemiology , Overweight/metabolism , Sodium-Glucose Transporter 2 Inhibitors/therapeutic use , Benzhydryl Compounds/therapeutic use , Diabetes Mellitus, Type 1/complications , Diabetes Mellitus, Type 1/metabolism , Drug Therapy, Combination , Glucosides/therapeutic use , Glycosides/therapeutic use , Humans , Hypoglycemic Agents/therapeutic use , Insulin/therapeutic use , Overweight/complications , Practice Guidelines as Topic , United Kingdom
8.
Drug Discov Today ; 26(10): 2214-2220, 2021 10.
Article in English | MEDLINE | ID: covidwho-1184927

ABSTRACT

The novel severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) enters host cells by interacting with membrane-bound angiotensin-converting enzyme 2 (ACE2), a vital element in the renin-angiotensin system (RAS), which regulates blood pressure, fluid balance, and cardiovascular functions. We herein evaluate existing evidence for the molecular alterations within the RAS pathway (e.g., ACE2 and angiotensin II) during SARS-CoV-2 infection and subsequent Coronavirus Disease 2019 (COVID-19). This includes reports regarding potential effect of RAS blockade (e.g., ACE inhibitors and angiotensin II receptor blockers) on ACE2 expression and clinical outcomes in patients with co-morbidities commonly treated with these agents. The collective evidence suggests a dual role for ACE2 in COVID-19, depending on the stage of infection and the coexisting diseases in individual patients. This information is further discussed with respect to potential therapeutic strategies targeting RAS for COVID-19 treatment.


Subject(s)
COVID-19/therapy , Renin-Angiotensin System/drug effects , Angiotensin II/metabolism , Angiotensin-Converting Enzyme 2/genetics , COVID-19/drug therapy , COVID-19/physiopathology , Humans , SARS-CoV-2
9.
J Med Internet Res ; 22(12): e22493, 2020 12 03.
Article in English | MEDLINE | ID: covidwho-1186721

ABSTRACT

BACKGROUND: Automated texting platforms have emerged as a tool to facilitate communication between patients and health care providers with variable effects on achieving target blood pressure (BP). Understanding differences in the way patients interact with these communication platforms can inform their use and design for hypertension management. OBJECTIVE: Our primary aim was to explore the unique phenotypes of patient interactions with an automated text messaging platform for BP monitoring. Our secondary aim was to estimate associations between interaction phenotypes and BP control. METHODS: This study was a secondary analysis of data from a randomized controlled trial for adults with poorly controlled hypertension. A total of 201 patients with established primary care were assigned to the automated texting platform; messages exchanged throughout the 4-month program were analyzed. We used the k-means clustering algorithm to characterize two different interaction phenotypes: program conformity and engagement style. First, we identified unique clusters signifying differences in program conformity based on the frequency over time of error alerts, which were generated to patients when they deviated from the requested text message format (eg, ###/## for BP). Second, we explored overall engagement styles, defined by error alerts and responsiveness to text prompts, unprompted messages, and word count averages. Finally, we applied the chi-square test to identify associations between each interaction phenotype and achieving the target BP. RESULTS: We observed 3 categories of program conformity based on their frequency of error alerts: those who immediately and consistently submitted texts without system errors (perfect users, 51/201), those who did so after an initial learning period (adaptive users, 66/201), and those who consistently submitted messages generating errors to the platform (nonadaptive users, 38/201). Next, we observed 3 categories of engagement style: the enthusiast, who tended to submit unprompted messages with high word counts (17/155); the student, who inconsistently engaged (35/155); and the minimalist, who engaged only when prompted (103/155). Of all 6 phenotypes, we observed a statistically significant association between patients demonstrating the minimalist communication style (high adherence, few unprompted messages, limited information sharing) and achieving target BP (P<.001). CONCLUSIONS: We identified unique interaction phenotypes among patients engaging with an automated text message platform for remote BP monitoring. Only the minimalist communication style was associated with achieving target BP. Identifying and understanding interaction phenotypes may be useful for tailoring future automated texting interactions and designing future interventions to achieve better BP control.


Subject(s)
Blood Pressure/physiology , Hypertension/therapy , Monitoring, Physiologic/methods , Text Messaging/standards , Adolescent , Adult , Aged , Female , Humans , Male , Middle Aged , Phenotype , Young Adult
10.
Med (N Y) ; 2(5): 575-590.e5, 2021 05 14.
Article in English | MEDLINE | ID: covidwho-1179905

ABSTRACT

BACKGROUND: Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection appears to increase the risk of adverse pregnancy outcomes, such as pre-eclampsia in pregnant women. The mechanism(s) by which this occurs remains unclear. METHODS: We investigated the pathophysiology of SARS-CoV-2 at maternal-fetal interface in pregnant women who tested positive for the virus using RNA in situ hybridization (viral RNA), immunohistochemistry, and hematoxylin and eosin staining. To investigate whether viral infection alters the renin angiotensin system (RAS) in placenta, which controls blood pressure, we treated human trophoblasts with recombinant spike protein or a live modified virus with a vesicular stomatitis viral backbone expressing spike protein (VSV-S). FINDINGS: Viral colonization was highest in maternal decidua, fetal trophoblasts, Hofbauer cells, and in placentas delivered prematurely. We localized SARS-CoV-2 to cells expressing angiotensin-converting enzyme 2 (ACE2) and demonstrate that infected placentas had significantly reduced ACE2. In response to both spike protein and VSV-S, cellular ACE2 decreased although angiotensin II receptor type 1 (AT1R) increased with concomitant increase in soluble fms-like tyrosine kinase-1 (sFlt1). Viral infection decreased pro-angiogenic factors, AT2R, and placental growth factor, which competitively binds to sFlt1. Sera from infected pregnant women had elevated levels of sFlt1 and angiotensin II type 1-receptor autoantibodies prior to delivery, both signatory markers of pre-eclampsia. CONCLUSIONS: SARS-CoV-2 colonizes ACE2-expressing maternal and fetal cells in the placenta. Infection in pregnant women correlates with alteration of placental RAS. As RAS regulates blood pressure, SARS-CoV-2 infection may thus increase adverse hemodynamic outcomes, such as pre-eclampsia in pregnant women. FUNDING: NIH/NICHD grants R01 HD091218 and 3R01HD091218-04S1 (RADx-UP Supplement).


Subject(s)
COVID-19 , Pre-Eclampsia , Pregnancy Complications, Infectious , Angiotensin-Converting Enzyme 2 , Female , Humans , Placenta/metabolism , Placenta Growth Factor/metabolism , Pre-Eclampsia/metabolism , Pregnancy , Pregnancy Complications, Infectious/metabolism , Renin-Angiotensin System , SARS-CoV-2 , Spike Glycoprotein, Coronavirus/metabolism , Vascular Endothelial Growth Factor Receptor-1/metabolism
11.
J Nurs Scholarsh ; 53(4): 418-427, 2021 07.
Article in English | MEDLINE | ID: covidwho-1177437

ABSTRACT

PURPOSE: Secondary prevention of coronary artery disease, self-management behavior, and blood pressure control are important to cardiovascular event prevention and promotion of quality of life (QOL), but they are underutilized. The purpose of this study was to investigate the effects of a self-efficacy theory-based health information technology intervention implemented through blood control and patient self-management. DESIGN: A clinical randomized waitlist-controlled trial. METHODS: The study was conducted at a medical center in Taipei, Taiwan. A total of 60 subjects were randomly assigned to either the immediate intervention (experimental) group or the waitlist control group. The primary endpoint was systolic blood pressure at 3 months; secondary end points included self-management behavior and QOL. Treatment for the immediate intervention group lasted 3 months, while the waitlist control group received routine care for the first 3 months, at which point they crossed over to the intervention arm and received the same intervention as the experimental group for another 3 months. Both groups were evaluated by questionnaires and physiological measurements at both 3 and 6 months postadmission. The results were analyzed using generalized estimating equations. RESULTS: Systolic blood pressure significantly improved for the intervention group participants at 3 months, when there was also significant improvement in self-management behavior and QOL. There was no significant or appreciable effect of time spent in the waitlist condition, with treatments in the two conditions being similarly effective. CONCLUSION: The use of a theory-based health information technology treatment compared with usual care resulted in a significant improvement in systolic blood pressure, self-management behavior, and QOL in patients with coronary artery disease. CLINICAL RELEVANCE: This treatment would be a useful strategy for clinical care of cardiovascular disease patients, improving their disease self-management. It also may help guide further digital health care strategies during the COVID-19 pandemic.


Subject(s)
Coronary Artery Disease/therapy , Medical Informatics/methods , Psychological Theory , Self-Management/psychology , Adult , Aged , Blood Pressure , Female , Humans , Male , Middle Aged , Self Efficacy , Taiwan , Treatment Outcome , Waiting Lists
12.
Clin Sci (Lond) ; 134(21): 2851-2871, 2020 11 13.
Article in English | MEDLINE | ID: covidwho-1177131

ABSTRACT

Angiotensin converting enzyme (ACE) is well-known for its role in blood pressure regulation via the renin-angiotensin aldosterone system (RAAS) but also functions in fertility, immunity, haematopoiesis and diseases such as obesity, fibrosis and Alzheimer's dementia. Like ACE, the human homologue ACE2 is also involved in blood pressure regulation and cleaves a range of substrates involved in different physiological processes. Importantly, it is the functional receptor for severe acute respiratory syndrome (SARS)-coronavirus (CoV)-2 responsible for the 2020, coronavirus infectious disease 2019 (COVID-19) pandemic. Understanding the interaction between SARS-CoV-2 and ACE2 is crucial for the design of therapies to combat this disease. This review provides a comparative analysis of methodologies and findings to describe how structural biology techniques like X-ray crystallography and cryo-electron microscopy have enabled remarkable discoveries into the structure-function relationship of ACE and ACE2. This, in turn, has enabled the development of ACE inhibitors for the treatment of cardiovascular disease and candidate therapies for the treatment of COVID-19. However, despite these advances the function of ACE homologues in non-human organisms is not yet fully understood. ACE homologues have been discovered in the tissues, body fluids and venom of species from diverse lineages and are known to have important functions in fertility, envenoming and insect-host defence mechanisms. We, therefore, further highlight the need for structural insight into insect and venom ACE homologues for the potential development of novel anti-venoms and insecticides.


Subject(s)
Betacoronavirus/pathogenicity , Coronavirus Infections/enzymology , Peptidyl-Dipeptidase A/metabolism , Pneumonia, Viral/enzymology , Receptors, Virus/metabolism , Virus Internalization , Angiotensin-Converting Enzyme 2 , Angiotensin-Converting Enzyme Inhibitors/therapeutic use , Animals , Antiviral Agents/therapeutic use , Betacoronavirus/drug effects , COVID-19 , Coronavirus Infections/drug therapy , Coronavirus Infections/virology , Host-Pathogen Interactions , Humans , Pandemics , Peptidyl-Dipeptidase A/chemistry , Pneumonia, Viral/drug therapy , Pneumonia, Viral/virology , Protein Conformation , Receptors, Virus/chemistry , SARS-CoV-2 , Structure-Activity Relationship
13.
J Biochem ; 170(2): 299-306, 2021 Oct 11.
Article in English | MEDLINE | ID: covidwho-1153228

ABSTRACT

Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) is a novel coronavirus that has given rise to the devastating global pandemic. In most cases, SARS-CoV-2 infection results in the development of viral pneumonia and acute respiratory distress syndrome, known as 'coronavirus disease 2019' or COVID-19. Intriguingly, besides the respiratory tract, COVID-19 affects other organs and systems of the human body. COVID-19 patients with pre-existing cardiovascular disease have a higher risk of death, and SARS-CoV-2 infection itself may cause myocardial inflammation and injury. One possible explanation of such phenomena is the fact that SARS-CoV-2 utilizes angiotensin-converting enzyme 2 (ACE2) as the receptor required for viral entry. ACE2 is expressed in the cells of many organs, including the heart. ACE2 functions as a carboxypeptidase that can cleave several endogenous substrates, including angiotensin II, thus regulating blood pressure and vascular tone. It remains largely unknown if the SARS-CoV-2 infection alters the enzymatic properties of ACE2, thereby contributing to cardiovascular complications in patients with COVID-19. Here, we demonstrate that ACE2 cleavage of des-Arg9-bradykinin substrate analogue is markedly accelerated, while cleavage of angiotensin II analogue is minimally affected by the binding of spike protein. These findings may have implications for a better understanding of COVID-19 pathogenesis.


Subject(s)
Angiotensin-Converting Enzyme 2/metabolism , SARS-CoV-2/metabolism , Spike Glycoprotein, Coronavirus/metabolism , Catalysis , Humans , Protein Binding , SARS-CoV-2/genetics , Substrate Specificity
14.
Front Immunol ; 12: 630430, 2021.
Article in English | MEDLINE | ID: covidwho-1120200

ABSTRACT

C-reactive protein (CRP) is the best-known acute phase protein. In humans, almost every type of inflammation is accompanied by an increase of CRP concentration. Until recently, the only known physiological function of CRP was the marking of cells to initiate their phagocytosis. This triggers the classical complement pathway up to C4, which helps to eliminate pathogens and dead cells. However, vital cells with reduced energy supply are also marked, which is useful in the case of a classical external wound because an important substrate for pathogens is disposed of, but is counterproductive at internal wounds (e.g., heart attack or stroke). This mechanism negatively affects clinical outcomes since it is established that CRP levels correlate with the prognosis of these indications. Here, we summarize what we can learn from a clinical study in which CRP was adsorbed from the bloodstream by CRP-apheresis. Recently, it was shown that CRP can have a direct effect on blood pressure in rabbits. This is interesting in regard to patients with high inflammation, as they often become tachycardic and need catecholamines. These two physiological effects of CRP apparently also occur in COVID-19. Parts of the lung become ischemic due to intra-alveolar edema and hemorrhage and in parallel CRP increases dramatically, hence it is assumed that CRP is also involved in this ischemic condition. It is meanwhile considered that most of the damage in COVID-19 is caused by the immune system. The high amounts of CRP could have an additional influence on blood pressure in severe COVID-19.


Subject(s)
C-Reactive Protein/immunology , COVID-19/immunology , Myocardial Infarction/immunology , SARS-CoV-2/immunology , Stroke/immunology , Animals , Cell Death/immunology , Cell Hypoxia/immunology , Complement C4/immunology , Humans , Rabbits
15.
J Pharm Pharm Sci ; 24: 84-93, 2021.
Article in English | MEDLINE | ID: covidwho-1100474

ABSTRACT

Angiotensin converting enzyme 2 (ACE2) is a main receptor for SARS-CoV-2 entry to the host cell. ACE2 is one of the key enzymes in renin-angiotensin system and plays a vital role in the maintenance of cardiovascular function. ACE/ACE2 balance is critical in the regulation of blood pressure, electrolyte homeostasis, vascular and cardiac remodeling and inflammation. ACE2 was shown to be abundantly present in human epithelial cells of the lung and enterocytes of the small intestine as well as in endothelial cells of the arterial and venous vessels. ACE2 and TMPRSS2 are colocalized on the cell surface and produced a critical step host cell entry of SARS-CoV-2. TMPRSS2-cleaved ACE2 permits SARS-CoV-2 host cell entry however, ADAM17-cleaved ACE2 produces protective effects in several organs. Differently, basigin (CD147) was suggested as a putative alternate receptor for SARS-CoV-2 entry into endothelial cells. The intestinal ACE2 receptor is associated with the neutral amino acid transporter B0AT1 and ACE2 is necessary for the expression of this transporter on the luminal surface of intestinal epithelial cells. There is a good association between the localization of SARS-CoV-2 binding receptor ACE2 and the disease target organs in respiratory, cardiovascular and gastrointestinal systems. Decreased expression of ACE2, being a receptor for coronavirus, would prevent cellular entry of the virus thereby reducing progression of the infection. However, increased ACE2 expression produces beneficial health effects. Further studies are needed to clarify this conflicting situation. Currently, it is recommended to continue the therapy with ACE2-increasing drugs in patients with COVID-19.


Subject(s)
Angiotensin-Converting Enzyme 2/metabolism , COVID-19/enzymology , Endothelial Cells/enzymology , Epithelial Cells/enzymology , Receptors, Virus/metabolism , SARS-CoV-2/pathogenicity , Virus Internalization , Animals , COVID-19/virology , Endothelial Cells/virology , Epithelial Cells/virology , Host-Pathogen Interactions , Humans , Signal Transduction
16.
Can J Kidney Health Dis ; 8: 2054358121991684, 2021.
Article in English | MEDLINE | ID: covidwho-1090712

ABSTRACT

RATIONALE: Acute kidney injury is a common complication of COVID-19 and is associated with significantly increased mortality. The most frequent renal biopsy finding with SARS-CoV-2 infection is acute tubular injury; however, new onset glomerular diseases have been reported. The development of persistent urinary abnormalities in patients with COVID-19 should prompt consideration for renal biopsy to rule out glomerulonephritis. PRESENTING CONCERNS: A 30-year-old man with no prior medical history presented to the emergency department with symptoms of COVID-19 and new onset painful purpuric rash, arthralgia, and abdominal pain. SARS-CoV-2 infection was confirmed with nucleic acid testing and laboratory investigations revealed preserved renal function with dysmorphic hematuria and nephrotic range proteinuria. DIAGNOSIS: A skin biopsy of the purpuric rash was performed, which demonstrated leukocytoclastic vasculitis. Renal biopsy revealed focally crescentic and segmentally necrotizing IgA nephropathy. Overall, given the clinical syndrome of glomerulonephritis with purpuric rash, arthralgia, and abdominal pain, the presentation is most in keeping with a diagnosis of IgA vasculitis in the setting of COVID-19. INTERVENTIONS: The patient was treated conservatively for COVID-19 in the community. A 7-day course of prednisone was started for the vasculitic rash. IgA nephropathy was managed conservatively with blood pressure control and RAAS blockade with losartan. OUTCOMES: With conservative management, the patient's COVID-19 symptoms resolved completely and he did not require hospital admission. Following prednisone therapy, the patient's rash, arthralgia, and abdominal pain improved. However, despite resolution of COVID-19, hematuria and proteinuria persisted. With the initiation of RAAS blockade, renal function remained stable and proteinuria improved dramatically at 6 weeks. NOVEL FINDINGS: De novo glomerulonephritis is a renal manifestation of SARS-CoV-2 infection beyond acute tubular injury. IgA vasculitis appears to be a rare complication of COVID-19.

17.
Hypertension ; 77(3): 846-855, 2021 03 03.
Article in English | MEDLINE | ID: covidwho-1083929

ABSTRACT

Hypertension has been identified as a risk factor for coronavirus disease 2019 (COVID-19) and associated adverse outcomes. This study examined the association between preinfection blood pressure (BP) control and COVID-19 outcomes using data from 460 general practices in England. Eligible patients were adults with hypertension who were tested or diagnosed with COVID-19. BP control was defined by the most recent BP reading within 24 months of the index date (January 1, 2020). BP was defined as controlled (<130/80 mm Hg), raised (130/80-139/89 mm Hg), stage 1 uncontrolled (140/90-159/99 mm Hg), or stage 2 uncontrolled (≥160/100 mm Hg). The primary outcome was death within 28 days of COVID-19 diagnosis. Secondary outcomes were COVID-19 diagnosis and COVID-19-related hospital admission. Multivariable logistic regression was used to examine the association between BP control and outcomes. Of the 45 418 patients (mean age, 67 years; 44.7% male) included, 11 950 (26.3%) had controlled BP. These patients were older, had more comorbidities, and had been diagnosed with hypertension for longer. A total of 4277 patients (9.4%) were diagnosed with COVID-19 and 877 died within 28 days. Individuals with stage 1 uncontrolled BP had lower odds of COVID-19 death (odds ratio, 0.76 [95% CI, 0.62-0.92]) compared with patients with well-controlled BP. There was no association between BP control and COVID-19 diagnosis or hospitalization. These findings suggest BP control may be associated with worse COVID-19 outcomes, possibly due to these patients having more advanced atherosclerosis and target organ damage. Such patients may need to consider adhering to stricter social distancing, to limit the impact of COVID-19 as future waves of the pandemic occur.


Subject(s)
Blood Pressure/drug effects , COVID-19/epidemiology , Hypertension/epidemiology , Pandemics , SARS-CoV-2 , Adult , Aged , Aged, 80 and over , Antihypertensive Agents/therapeutic use , Atherosclerosis/epidemiology , COVID-19/prevention & control , Comorbidity , England/epidemiology , Female , Follow-Up Studies , Hospitalization/statistics & numerical data , Humans , Hypertension/drug therapy , Logistic Models , Male , Middle Aged , Odds Ratio , Primary Health Care/statistics & numerical data , Retrospective Studies , Risk Factors , Severity of Illness Index , Survival Analysis , Treatment Outcome
18.
Compr Physiol ; 11(1): 1575-1589, 2021 02 12.
Article in English | MEDLINE | ID: covidwho-1082844

ABSTRACT

Uncontrolled immune system activation amplifies end-organ injury in hypertension. Nonetheless, the exact mechanisms initiating this exacerbated inflammatory response, thereby contributing to further increases in blood pressure (BP), are still being revealed. While participation of lymphoid-derived immune cells has been well described in the hypertension literature, the mechanisms by which myeloid-derived innate immune cells contribute to T cell activation, and subsequent BP elevation, remains an active area of investigation. In this article, we critically analyze the literature to understand how monocytes, macrophages, dendritic cells, and polymorphonuclear leukocytes, including mast cells, eosinophils, basophils, and neutrophils, contribute to hypertension and hypertension-associated end-organ injury. The most abundant leukocytes, neutrophils, are indisputably increased in hypertension. However, it is unknown how (and why) they switch from critical first responders of the innate immune system, and homeostatic regulators of BP, to tissue-damaging, pro-hypertensive mediators. We propose that myeloperoxidase-derived pro-oxidants, neutrophil elastase, neutrophil extracellular traps (NETs), and interactions with other innate and adaptive immune cells are novel mechanisms that could contribute to the inflammatory cascade in hypertension. We further posit that the gut microbiota serves as a set point for neutropoiesis and their function. Finally, given that hypertension appears to be a key risk factor for morbidity and mortality in COVID-19 patients, we put forth evidence that neutrophils and NETs cause cardiovascular injury post-coronavirus infection, and thus may be proposed as an intriguing therapeutic target for high-risk individuals. © 2021 American Physiological Society. Compr Physiol 11:1575-1589, 2021.


Subject(s)
COVID-19 , Extracellular Traps/immunology , Hypertension/immunology , Immunity, Innate/immunology , Neutrophils/immunology , Animals , COVID-19/complications , COVID-19/immunology , Gastrointestinal Microbiome/immunology , Humans , Hypertension/physiopathology , Inflammation/immunology , Inflammation/physiopathology , Oxidative Stress/immunology , SARS-CoV-2/immunology
19.
Front Neurol ; 11: 600544, 2020.
Article in English | MEDLINE | ID: covidwho-1084539

ABSTRACT

Reports of different types of neurological manifestations of COVID-19 are rapidly increasing, including changes of posterior reversible leukoencephalopathy syndrome (PRES). Here we describe the first reported case of COVID-19 and PRES in Australia diagnosed on basis of MRI brain imaging and confirmed clinically by presence of confusion, delirium, headaches, also associated with hypertension and blood pressure variability and stable long-term kidney problems. He made full recovery as his blood pressure was controlled and clinical status was supported with appropriate supportive therapy. Although traditionally a rare condition, PRES is likely to be more common among patients with COVID-19 pathobiology there is Renin downregulation of ACE2 receptors, involvement of Renin-Angiotensin-Aldosterone system, endotheliitis, cytokine storm, and hyper-immune response. Thus we advocate clinical suspicion and early brain imaging with MRI brain among vulnerable patients with known co-morbidities, and diagnosed with COVID-19 given that hypertension and blood pressure variability are often exacerbated by acute SARS-CoV-2 immune reactions. Such acute hypertensive encephalopathy was able to be reversed with timely supportive therapy ensuring re-hydration and re-establishment of blood pressure control.

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