The association of withholding or continuing angiotensin-converting enzyme inhibitors or angiotensin 2 receptor blockers on acute kidney injury after non-cardiac surgery.

BACKGROUND: Withholding or continuing angiotensin-converting enzyme inhibitors or angiotensin 2 receptor blockers peri-operatively in non-cardiac surgery remains controversial as they may result in intra-operative hypotension and postoperative organ damage. METHODS: We included patients prescribed angiotensin-converting enzyme inhibitors or angiotensin 2 receptor blockers who underwent surgical procedures > 1 h duration under general or spinal anaesthesia from January 2012 to June 2022 in a single centre. We categorised patients by whether these drugs were withheld for 24 h before surgery. We evaluated the association of withholding these drugs before non-cardiac surgery with creatinine concentrations that increased ≥ 26.4 µmol.l-1 in the first 48 postoperative hours (acute kidney injury). We also analysed changes in creatinine concentrations and estimated glomerular filtration rates. RESULTS: Angiotensin-converting enzyme inhibitors or angiotensin 2 receptor blockers were withheld in 24,285 of 32,933 (74%) patients and continued in 8648 (26%) patients. We used propensity scores for drug discontinuation to match 8631 patient pairs who did or did not continue these drugs: acute kidney injury was recorded for 1791 (21%) patients who continued these drugs vs. 1587 (18%) who did not (OR (95%CI) 1.16 (1.08-1.25), p < 0.001). Intra-operative hypotension was recorded for 3892 (45%) patients who continued drugs vs. 3373 (39%) patients who did not (OR (95%CI) 1.28 (1.21-1.36), p < 0.001). Continuing drugs was independently associated with a mean increase in creatinine of 2.2 µmol.l-1 (p < 0.001) and a mean decrease in estimated glomerular filtration rate of 1.4 ml.min.1.73 m-2 (p < 0.001). CONCLUSIONS: Continuing angiotensin-converting enzyme inhibitors or angiotensin 2 receptor blockers 24 h before non-cardiac surgery was associated with intra-operative hypotension and postoperative acute kidney injury.

The Role of the Kinin System and the Effect of Des-Arginine9-Bradykinin on Coagulation and Platelet Function in Critically Ill COVID-19 Patients: A Secondary Analysis of a Prospective Observational Study.

The effect of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) on the coagulation system is not fully understood. SARS-CoV-2 penetrates cells through angiotensin-converting enzyme 2 (ACE2) receptors, leading to its downregulation. Des-arginine9-bradykinin (DA9B) is degraded by ACE2 and causes vasodilation and increased vascular permeability. Furthermore, DA9B is associated with impaired platelet function. Therefore, the aim of this study was to evaluate the effects of DA9B on platelet function and coagulopathy in critically ill coronavirus disease 2019 (COVID-19) patients. In total, 29 polymerase-positive SARS-CoV-2 patients admitted to the intensive care unit of the University Hospital of Giessen and 29 healthy controls were included. Blood samples were taken, and platelet impedance aggregometry and rotational thromboelastometry were performed. Enzyme-linked immunosorbent assays measured the concentrations of DA9B, bradykinin, and angiotensin 2. Significantly increased concentrations of DA9B and angiotensin 2 were found in the COVID-19 patients. A negative effect of DA9B on platelet function and intrinsic coagulation was also found. A sub-analysis of moderate and severe acute respiratory distress syndrome patients revealed a negative association between DA9B and platelet counts and fibrinogen levels. DA9B provokes inhibitory effects on the intrinsic coagulation system in COVID-19 patients. This negative feedback seems reasonable as bradykinin, which is transformed to DA9B, is released after contact activation. Nevertheless, further studies are needed to confirm our findings.

Nephrogenic diabetes insipidus in a geriatric patient affected by SARS-CoV-2: complexity of a diagnosis, complexity of a virus.

Background: Coronavirus disease 2019 (COVID-19) has an important impact on the kidney through direct and indirect damage mechanisms. Most previous studies have highlighted lesions caused by this virus in the early segments of the nephron. However, due to the antigenic characteristics of the virus, with almost ubiquitous receptors, and the molecular release it triggers, the distal segments of the nephron could also be affected. Methods: A 71 year-old-man with respiratory failure while suffering from severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) pneumonia presented with typical symptoms of diabetes insipidus after ~20 days of hospitalization. The water deprivation test led to the diagnosis of nephrogenic diabetes insipidus. The aetiological study was complex, in particular because of the patient's previous lithium therapy. Results: The sequence of pathognomonic events typical of diabetes insipidus associated with anamnestic, clinical and laboratory evidence strongly supported the diagnosis of nephrogenic diabetes insipidus due to SARS-CoV-2 rather than other aetiologies. Conclusions: The collecting duct could represent a target for SARS-CoV-2 infection, directly or indirectly, as a result of lesions of upstream portions of the nephron, which would cascade into the distal segment. Other molecules, besides angiotensin 2 converting enzyme, might be involved in facilitating the viral aggression. The complexity of the geriatric patient shows the importance of a comprehensive approach that integrates careful monitoring of clinical signs and symptoms and laboratory and instrumental tests. This is especially important in the context of SARS-CoV-2 infection and in the management of its unexpected complications.

The critical role of endothelial cell in the toxicity associated with chimeric antigen receptor T cell therapy and intervention strategies.

Chimeric antigen receptor (CAR)-T cell therapy has shown promising results in patients with hematological malignancies. However, many patients still have poor prognoses or even fatal outcomes due to the life-threatening toxicities associated with the therapy. Moreover, even after improving the known influencing factors (such as number or type of CAR-T infusion) related to CAR-T cell infusion, the results remain unsatisfactory. In recent years, it has been found that endothelial cells (ECs), which are key components of the organization, play a crucial role in various aspects of immune system activation and inflammatory response. The levels of typical markers of endothelial activation positively correlated with the severity of cytokine release syndrome (CRS) and immune effector cell-associated neurotoxic syndrome (ICANS), suggesting that ECs are important targets for intervention and toxicity prevention. This review focuses on the critical role of ECs in CRS and ICANS and the intervention strategies adopted.

Impact of Delta SARS-CoV-2 Infection on Glucose Metabolism: Insights on Host Metabolism and Virus Crosstalk in a Feline Model.

Severe Acute Respiratory Syndrome Coronavirus 2 (SARS-CoV-2) causes enhanced mortality in people with metabolic and cardiovascular diseases. Other highly infectious RNA viruses have demonstrated dependence on glucose transport and utilization, so we hypothesized that SARS-CoV-2 infection could lead to alterations in cellular and whole-body glucose metabolism. Twenty-four healthy domestic cats were intratracheally inoculated with B.1.617.2 (delta) SARS-CoV-2 and samples were collected at 4- and 12-days post-inoculation (dpi). Blood glucose and circulating cortisol concentrations were elevated at 4 and 12 dpi. Serum insulin concentration was statistically significantly decreased, while angiotensin 2 concentration was elevated at 12 dpi. SARS-CoV-2 RNA was detected in the pancreas and skeletal muscle at low levels; however, no change in the number of insulin-producing cells or proinflammatory cytokines was observed in the pancreas of infected cats through 12 dpi. SARS-CoV-2 infection statistically significantly increased GLUT protein expression in both the heart and lungs, correlating with increased AMPK expression. In brief, SARS-CoV-2 increased blood glucose concentration and cardio-pulmonary GLUT expression through an AMPK-dependent mechanism, without affecting the pancreas, suggesting that SARS-CoV-2 induces the reprogramming of host glucose metabolism. A better understanding of host cell metabolism and virus crosstalk could lead to the discovery of novel metabolic therapeutic targets for patients affected by COVID-19.

Wuhan 3 years after the outbreak of the pandemic-cardiological insights and perspectives.

In November 2019, Wuhan, a city in Central China, became the center of an outbreak of pneumonia of unknown cause, which was later named "coronavirus disease 2019" (COVID-19). COVID-19 is caused by the novel severe acute respiratory distress syndrome coronavirus 2 (SARS-CoV-2) infection. The emergence of novel SARS-CoV­2 strains and mutations exerted a serious global public health threat. Although various vaccines have been developed, specific anti-SARS-CoV­2 drugs are limited. As cardiologists, we believe that because SARS-CoV­2 can bind to the angiotensin 2 receptor on the surface of cardiomyocytes, it may also lead to cardiac injury. COVID-19-associated cardiac injury is not rare in clinical practice, and most of these cases are mild, while a few might progress to fulminant myocarditis (FM). Overactivated immune response and inflammatory storm represent the core pathogenesis of COVID-19-associated FM. Early identification and diagnosis of COVID-19-associated FM are critical for its treatment. Recently, Wuhan was hit by the Omicron variant again. We proposed managing COVID-19-associated cardiac injury according to the severity, which has had a significant effect on outcome.

Vasoplegic Syndrome after Cardiopulmonary Bypass in Cardiovascular Surgery: Pathophysiology and Management in Critical Care.

Vasoplegic syndrome (VS) is a common complication following cardiovascular surgery with cardiopulmonary bypass (CPB), and its incidence varies from 5 to 44%. It is defined as a distributive form of shock due to a significant drop in vascular resistance after CPB. Risk factors of VS include heart failure with low ejection fraction, renal failure, pre-operative use of angiotensin-converting enzyme inhibitors, prolonged aortic cross-clamp and left ventricular assist device surgery. The pathophysiology of VS after CPB is multi-factorial. Surgical trauma, exposure to the elements of the CPB circuit and ischemia-reperfusion promote a systemic inflammatory response with the release of cytokines (IL-1ß, IL-6, IL-8, and TNF-α) with vasodilating properties, both direct and indirect through the expression of inducible nitric oxide (NO) synthase. The resulting increase in NO production fosters a decrease in vascular resistance and a reduced responsiveness to vasopressor agents. Further mechanisms of vasodilation include the lowering of plasma vasopressin, the desensitization of adrenergic receptors, and the activation of ATP-dependent potassium (KATP) channels. Patients developing VS experience more complications and have increased mortality. Management includes primarily fluid resuscitation and conventional vasopressors (catecholamines and vasopressin), while alternative vasopressors (angiotensin 2, methylene blue, hydroxocobalamin) and anti-inflammatory strategies (corticosteroids) may be used as a rescue therapy in deteriorating patients, albeit with insufficient evidence to provide any strong recommendation. In this review, we present an update of the pathophysiological mechanisms of vasoplegic syndrome complicating CPB and discuss available therapeutic options.

Association Between a High Gene Expression Variant of Chymase and Increased Risk for Basal Cell Carcinoma.

BACKGROUND/AIM: Previous studies have associated certain variations in genes encoding factors of renin-angiotensin system (RAS), indirectly leading to higher angiotensin II (AngII) levels, with greater risk for basal cell carcinoma (BCC) development. Chymase (CMA1) is the main regulator of the RAS-independent AngII generation pathway and numerous studies have shown its oncogenic potential in several cancer types including BCC. In this study, we investigated the possible association between BCC pathogenesis and the functional DNA polymorphism A1903G (rs1800875) that affects expression of the CMA1 gene. PATIENTS AND METHODS: We genotyped 199 DNA samples, isolated from 100 BCC patients and 99 age, sex, and ethnicity-matched healthy controls for the CMA1 A1903G polymorphism. Genotyping was performed with PCR amplification, followed by MboI enzyme digestion and agarose gel electrophoresis of the resulted DNA fragments. RESULTS: The variant G allele that possibly increases CMA1 gene expression was not detected at a significantly different frequency between the groups of BCC patients and healthy controls. However, the AG heterozygous genotype was significantly increased in BCC patients compared with controls (p<0.001). CONCLUSION: The high expression CMA1 G allele carriers have an increased risk for BCC and elevated levels of chymase in the skin may have a carcinogenic effect.

A double-blind randomised feasibility trial of angiotensin-2 in cardiac surgery.

Acute kidney injury is common after cardiac surgery. Vasoplegic hypotension may contribute to kidney injury, and different vasopressors may have variable effects on kidney function. We conducted a double-blind, randomised feasibility trial comparing peri-operative angiotensin-2 with noradrenaline. We randomly allocated 60 patients at two centres to a blinded equipotent angiotensin-2 or noradrenaline infusion intra-operatively and for up to 48 h postoperatively, titrated to mean arterial pressure of 70-80 mmHg. Primary feasibility outcomes included consent rate, protocol adherence, infusion duration, mean arterial pressure maintenance in the target range and major adverse outcomes. Secondary outcomes included kidney injury rate. The consent rate was 47%. Protocol adherence was 100% in the angiotensin-2 group and 94% in the noradrenaline group. Study drug duration was median (IQR [range]) 217 (160-270 [30-315]) vs. 185 (135-301 [0-480]) min (p = 0.78) min intra-operatively, and 5 (0-16 [0-48]) vs. 14.5 (4.8-29 [0-48]) hours (p = 0.075) postoperatively for angiotensin-2 and noradrenaline, respectively. The mean arterial pressure target was achieved postoperatively in 25 of 28 (89%) of the angiotensin-2 group and 27 of 32 (84%) of the noradrenaline group. One participant had a stroke, one required extracorporeal support and three required renal replacement therapy, all in the noradrenaline group (p = 0.99, p = 0.99 and p = 0.1). Acute kidney injury occurred in 7 of 28 in the angiotensin-2 group vs. 12 of 32 patients in the noradrenaline group (p = 0.31). This pilot study suggests that a trial comparing angiotensin-2 with noradrenaline is feasible. Its findings justify further investigations of angiotensin-2 in cardiac surgery.

Poor Performance of Angiotensin II Enzyme-Linked Immuno-Sorbent Assays in Mostly Hypertensive Cohort Routinely Screened for Primary Aldosteronism.

Primary aldosteronism (PA) is the most common, but broadly underdiagnosed, form of hormonal hypertension. To improve screening procedures, current biochemical approaches aim to determine newly appreciated angiotensin II (Ang II) and calculate the aldosterone-to-angiotensin II ratio (AA2R). Thus, the aim of this study was to assess the diagnostic performance of these screening tests in comparison to the aldosterone-to-direct renin ratio (ADRR), which is routinely used. Cheap and available ELISA was used for Ang II measurement. To our knowledge, this is the first study of this laboratory method's usage in PA. The study cohort included 20 PA patients and 80 controls. Ang II concentrations were comparable between PA and non-PA patients (773.5 vs. 873.2 pg/mL, p = 0.23, respectively). The AA2R was statistically significantly higher in PA group when compared with non-PA (0.024 vs. 0.012 ng/dL/pg/mL, p < 0.001). However, the diagnostic performance of the AA2R was significantly worse than that of the ADRR (AUROC 0.754 vs. 0.939, p < 0.01). The sensitivity and specificity of the AA2R were 70% and 76.2%, respectively. Thus, the AA2R was not effective as a screening tool for PA. Our data provide important arguments in the discussion on the unsatisfactory accuracy of renin−angiotensin system evaluation by recently repeatedly used ELISA tests.

[Differences among renin-angiotensin system inhibitor drugs in prognosis of hypertense patients with COVID-19]. / Diferencias entre fármacos inhibidores del sistema renina-angiotensina en pacientes hipertensos ingresados por COVID-19.

Introduction: Concerns have been raised about Renin-angiotensin system inhibitors (RASi) in patients with COVID-19. Although recent trials have proved its security, evidence regarding intrinsic differences between RASi is lacking, especially in patients with arterial hypertension. Our objective was to analyse the prognosis of hypertense patients who received angiotensin converting enzyme inhibitors (ACEi) or angiotensin-2 receptor blockers (ARBs) and were hospitalized due to COVID-19. Materials and methods: 392 consecutive patients with hypertension and COVID-19 were analyse. Incidence of the combined event (death or mechanical ventilation need) was the primary endpoint. Secondary, incidence of each event and time to event were analysed. Results: 155 received ACEi and 237 ARBs. During the hospitalization, the combined event was observed in the 31,6 % of patients. No differences were observed between those previously treated with ACEi and ARBs (33.5 vs. 30.9%; p = 0.51). In the survival analysis, no differences were observed regarding time to combined event (p = 0.91). In-hospital mortality was similar in both groups (32.3 vs. 29.1%; p = 0.51), as well as the need of mechanical ventilation (3.2 vs. 5.9%; p = 0.23). Conclusions: The type of RASi was not associated with in-hospital major events in patients with arterial hypertension hospitalized due to COVID-19.

Introducción: Han surgido dudas sobre la seguridad de los fármacos inhibidores del sistema renina-angiotensina (SRA) en pacientes con enfermedad por coronavirus 2019 (COVID-19). Aunque estudios recientes han demostrado la seguridad de este grupo de fármacos, la evidencia sobre la comparativa de los diferentes fármacos inhibidores del SRA es escasa, sobre todo en pacientes hipertensos. Nuestro objetivo fue analizar el pronóstico de los pacientes hipertensos tratados con inhibidores de la enzima convertidora de angiotensina (IECA) o antagonistas del receptor de angiotensina II (ARA II) que presentaron COVID-19. Materiales y métodos: Se analizaron 582 pacientes hipertensos con COVID-19. Se registró la incidencia del evento combinado de muerte o necesidad de ventilación mecánica invasiva (VMI) durante la hospitalización. De forma secundaria, se analizó la incidencia de eventos de manera independiente y se realizó un análisis de supervivencia para analizar el tiempo hasta los eventos. Resultados: 155 pacientes recibían tratamiento previo con IECA y 237 con ARA II. Durante la hospitalización por COVID-19, se observó una incidencia del evento combinado del 31.6%. No se detectaron diferencias entre los pacientes que recibían tratamiento con IECA y los tratados con ARA II (33.5 vs. 30.9%; p = 0.51). En el análisis de supervivencia, no se hallaron diferencias en el tiempo hasta el evento combinado (p = 0.91). La mortalidad intrahospitalaria fue similar en ambos grupos (32.3 vs. 29.1%; p = 0.51), así como la necesidad de VMI (3.2 vs. 5.9%; p = 0.23). Conclusiones: El tipo de inhibidor del SRA no se asoció a diferencias pronósticas significativas entre los pacientes hipertensos ingresados con COVID-19.

Molecular and Physiological Study in Patients with Coronavirus in Thi-Qar Province Iraq.

The current study aimed to study the effect of Covid-19 disease on some physiological parameters for assessing the physiological effect of Covid-19. The current study included 100 patients, 50 males, and 50 females, whose ages ranged from 10 - 73 years infected with Covid-19 molecularly diagnosed at AL-Imam Hussein Teaching Hospital in Thi-Qar Province from April to August 2021 and 50 people as a control group. The results illustrated a significant decrease in the level of hemoglobin, lymphocyte, and platelet in the patient's group, whereas a significant increase in the count of total white blood cells (WBC) was recorded in patients compared with the control group. The results showed that the hemoglobin level, WBC, and platelet increased significantly in males compared to females, while the lymphocytes increased significantly in female patients. The results of age groups showed non-significant differences in the hematological parameters. The current results illustrated a significant increase in the level of blood urea, serum creatinine, and random blood sugar in the patient's group. According to the gender of patients, the blood urea increased significantly in the female group, while the blood sugar increased significantly in the male group. On the other hand, the serum creatinine had no significant difference. According to age groups, a significant increase in blood urea was recorded in patients over 70 years, but no differences in both creatinine and random blood sugar level were noted. The current study recorded that the concentration of CRP, ferritin, and D. Dimer was significantly higher in patients; according to gender, the level of CRP and ferritin increased non-significantly compared with a male group of patients, while D. Dimer increased significantly in the female group. According to age group, only CRP increased significantly in the first age group compared with other age groups. The sequencing analysis was performed for 10 isolated Covid-19, and the result indicates that only one isolated sample has a sequencing identity of 99,5% with Covid-19 in Iran.

A Pair of "ACEs".

The emergence of the COVID-19 viral pandemic has generated a renewed interest in pharmacologic agents that target the renin angiotensin system (RAS). Angiotensin-converting enzyme 1 (ACE1) inhibitors decrease the synthesis of angiotensin II (Ang II) from its precursor angiotensin I and inhibit the breakdown of bradykinin, while Ang II receptor blockers antagonize the action of Ang II at the receptor level downstream. The actions of both classes of drugs lead to vasodilation, a blunting of sympathetic drive and a reduction in aldosterone release, all beneficial effects in hypertension and congestive heart failure. ACE2 cleaves the vasoconstrictor Ang II to produce the anti-inflammatory cytoprotective angiotensin 1-7 (Ang 1-7) peptide, which functions through the G protein-coupled receptor MAS to counteract the pathophysiologic effects induced by Ang II via its receptors, including vasoconstriction, inflammation, hypercoagulation, and fibrosis. SARS-CoV-2 enters human cells by binding ACE2 on the cell surface, decreases ACE2 activity, competes for ACE2 receptor-binding sites, and shifts the RAS toward an overexpression of Ang II, accounting for many of the deleterious effects of the virus. Thus, there is great interest in developing recombinant ACE2 as a therapeutic for prevention or treatment of COVID-19. Notably, ACE2 is highly expressed in the oral cavity, and saliva and dorsum of the tongue are major reservoirs of SARS-CoV-2. Cost-effective methods to debulk the virus in the oral cavity may aid in the prevention of viral spread. Here we review the pharmacology of targeted small molecule inhibitors of the RAS and discuss novel approaches to employing ACE2 as a therapeutic for COVID-19.

Functional ACE2 deficiency leading to angiotensin imbalance in the pathophysiology of COVID-19.

SARS-CoV-2, the virus responsible for COVID-19, uses angiotensin converting enzyme 2 (ACE2) as its primary cell-surface receptor. ACE2 is a key enzyme in the counter-regulatory pathway of the broader renin-angiotensin system (RAS) that has been implicated in a broad array of human pathology. The RAS is composed of two competing pathways that work in opposition to each other: the "conventional" arm involving angiotensin converting enzyme (ACE) generating angiotensin-2 and the more recently identified ACE2 pathway that generates angiotensin (1-7). Following the original SARS pandemic, additional studies suggested that coronaviral binding to ACE2 resulted in downregulation of the membrane-bound enzyme. Given the similarities between the two viruses, many have posited a similar process with SARS-CoV-2. Proponents of this ACE2 deficiency model argue that downregulation of ACE2 limits its enzymatic function, thereby skewing the delicate balance between the two competing arms of the RAS. In this review we critically examine this model. The available data remain incomplete but are consistent with the possibility that the broad multisystem dysfunction of COVID-19 is due in large part to functional ACE2 deficiency leading to angiotensin imbalance with consequent immune dysregulation and endothelial cell dysfunction.

ß-Arrestin-Mediated Angiotensin II Type 1 Receptor Activation Promotes Pulmonary Vascular Remodeling in Pulmonary Hypertension.

Pulmonary arterial hypertension (PAH) is a disease of abnormal pulmonary vascular remodeling whose medical therapies are thought to primarily act as vasodilators but also may have effects on pulmonary vascular remodeling. The angiotensin II type 1 receptor (AT1R) is a G protein-coupled receptor that promotes vasoconstriction through heterotrimeric G proteins but also signals via ß-arrestins, which promote cardioprotective effects and vasodilation through promoting cell survival. We found that an AT1R ß-arrestin-biased agonist promoted vascular remodeling and worsened PAH, suggesting that the primary benefit of current PAH therapies is through pulmonary vascular reverse remodeling in addition to their vasodilation.

Facilitation of TRKB Activation by the Angiotensin II Receptor Type-2 (AT2R) Agonist C21.

Blockers of angiotensin II type 1 receptor (AT1R) exert antidepressant-like effects by indirectly facilitating the activation of the angiotensin II type 2 receptor (AT2R), which leads to increased surface expression and transactivation of tropomyosin-related kinase B receptors (TRKB). Compound 21 (C21) is a non-peptide AT2R agonist that produces neuroprotective effects. However, the behavioral effects of C21 and its involvement with the brain-derived neurotrophic factor (BDNF)-TRKB system still need further investigation. The aim of the present study was to assess the effect of C21 on the activation of TRKB and its consequences on conditioned fear. The administration of C21 (0.1-10 µM/15 min) increased the surface levels of TRKB but was not sufficient to increase the levels of phosphorylated TRKB (pTRKB) in cultured cortical neurons from rat embryos. Consistent with increased TRKB surface expression, C21 (10 µM/15 min or 3 days) facilitated the effect of BDNF (0.1 ng/mL/15 min) on pTRKB in these cells. In contextual fear conditioning, the freezing time of C21-treated (administered intranasally) wild-type mice was decreased compared to the vehicle-treated group, but no effect of C21 was observed in BDNF.het animals. We observed no effect of C21 in the elevated plus-maze test for anxiety. Taken together, our results indicate that C21 facilitated BDNF effect by increasing the levels of TRKB on the cell surface and reduced the freezing time of mice in a BDNF-dependent manner, but not through a general anxiolytic-like effect.

Insulin resistance in COVID-19 and diabetes.

BACKGROUND: The epidemiology of COVID-19 and its association with cardiometabolic disorders is poorly understood. This is a narrative review that investigates the effects of COVID-19 infection on insulin resistance in patients with diabetes. METHODS: An online search of all published literature was done via PubMed and Google Scholar using the MeSH terms "COVID-19," "SARS-CoV-2," "coronavirus," "insulin resistance," and "diabetes." Only articles that were directly applicable to insulin resistance in COVID-19 and diabetes was reviewed. RESULTS: Current data shows an increased risk of mortality in patients with diabetes and COVID-19 compared to those without diabetes. COVID-19 triggers insulin resistance in patients, causing chronic metabolic disorders that were non-existent prior to infection. CONCLUSION: Patients with diabetes are more susceptible to COVID-19 infection than those without diabetes. ACE2 expression decreases with infection, exaggerating Ang II activity with subsequent insulin resistance development, an exaggerated immune response and severe SARS-COV-2 infection.

Risk of SARS-CoV-2 infection and COVID-19 prognosis with the use of renin-angiotensin-aldosterone system (RAAS) inhibitors: a systematic review.

BACKGROUND: Angiotensin-converting-enzyme-2, being the receptor for SARS-CoV-2, is increased in the use of RAAS inhibitors. Therefore, concerns have been raised over risks of SARS-CoV-2 infection and poor prognosis of COVID-19 in persons with prior exposure to these drugs. This study aimed to systematically review available evidence for associations between exposure to RAAS inhibitors with susceptibility to SARS-CoV-2 infection and clinical outcomes in infected persons. It hopes to address the question on the effects of RAAS inhibitors on the risk of COVID-19 and its prognosis. MAIN BODY: Search was conducted in the databases of PubMed, Scopus, Cochrane, Embase and MedRxiv.org from December 2019 to May 31, 2020, using relevant keywords. Additional articles were identified through hand-searching of reference lists. Studies that reported associations between positive tests to COVID-19 and use of RAAS inhibitors, and treatment outcomes of COVID-19 patients who had exposure to RAAS inhibitors were considered eligible. The Newcastle-Ottawa scale was used to assess risk of bias in individual studies. The review was conducted in line with Preferred Regulatory Items for Systematic Reviews and Meta-Analysis (PRISMA) guidelines 2009. From the 952 studies screened and 2 studies from reference hand-searching, 18 were reviewed. Four studies evaluated the risks for SARS-CoV-2 infection among RAAS inhibitors users, and 16 (including 2 of the 4 studies) evaluated the clinical outcomes associated with previous exposure to RAAS inhibitors. CONCLUSION: Evidence does not suggest higher risks for SARS-CoV-2 infection or poor disease prognosis in the use of RAAS inhibitors. This suggests the continued use of RAAS inhibitors by patients with existing needs, which supports the position statements of American Heart Association and European societies for Cardiology. SUPPLEMENTARY INFORMATION: The online version contains supplementary material available at 10.1186/s43094-021-00224-4.

Soluble fms-like tyrosine kinase-1 and angiotensin2 target calcitonin gene-related peptide family peptides in maternal vascular smooth muscle cells in pregnancy†.

Calcitonin gene-related peptide (CALCB), adrenomedullin (ADM), and adrenomedullin2 (ADM2) are hypotensive peptides that belong to CALCB family of peptides. Goal of this study was to identify the effect of fms-like tyrosine kinase (sFLT-1) and angiotensin2 (Ang2) on the function of these peptides in OA smooth muscle cells (OASMC) and assess the sensitivity of OA for these peptides in preeclampsia (PE) and normotensive pregnancy. METHODS: Peptide function was assessed by Cyclic adenosine monophosphate (cAMP) assays and wire myograph; mRNA expression by Polymerase chain reaction (PCR) and protein-protein interaction by proximity ligation assay and co-immunoprecipitation. FINDINGS: All three peptides increased cAMP synthesis in the order of efficacy CALCB > ADM = ADM2 and vascular endothelial growth factor (VEGF) mRNA in OASMC (P < 0.05); sFLT-1 mediated decrease in cAMP synthesis (P < 0.05) is differentially rescued by all three CALCB family peptides in OASMC (P < 0.005); sFLT-1 decreased receptor activity-modifying protein (RAMP)1 and RAMP2 mRNA expression (P < 0.05); Ang2 decreased the expression of calcitonin-receptor-like receptor and RAMP1 mRNA and desensitized CALCB and ADM2 receptors in OASMC (P < 0.05); sFLT-1 increased RAMP1and Ang2 type 1 receptor (AT1R) interaction in OASMC which is inhibited in presence of all three peptides; and all three peptides relax OA in PE with enhanced ADM2 response (P < 0.05). CONCLUSION: sFLT-1 and Ang2 impair OASMC mediated functional responses of CALCB family peptides which can be inhibited by respective peptide treatment. The sensitivity of OA for CALCB, ADM, and ADM2-mediated relaxation is retained in PE.