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Abstract: Background: Acute kidney injury (AKI) is a common complication of vasodilatory shock. AKI is associated with an increased risk of death, prolonged hospital stays, and subsequent transition to chronic kidney disease. Catecholamines have historically been used as the first-line vasopressors for vasodilatory shock; however, they may adversely affect renal function and recovery. Objectives: To compare the effects of catecholamine and noncatecholamine vasopressors on AKI risk and recovery in preclinical and clinical studies of vasodilatory shock. Methods: MEDLINE, Embase, and Cochrane Central Register of Controlled Trials were systematically searched to identify studies reporting renal outcomes associated with catecholamine (norepinephrine, epinephrine, metaraminol, phenylephrine, dopamine) and noncatecholamine vasopressors (vasopressin, angiotensin II), in preclinical models or adult cohorts of vasodilatory shock. Two independent reviewers screened studies and extracted data using a prespecified form for qualitative synthesis and risk of bias assessment. Results: Of 3,504 citations, 90 studies were eligible for inclusion: 41 preclinical studies, 17 nonrandomized clinical studies, 28 randomized clinical studies, and 4 post-hoc analyses. Risk of bias was generally low in preclinical studies and low to moderate in clinical studies. In preclinical studies, catecholamine vasopressors exacerbated medullary hypoxia and intrarenal inflammation compared to noncatecholamine vasopressors. In clinical studies, catecholamines were associated with higher serum creatinine, lower urine output, and increased requirements for renal replacement therapy compared to noncatecholamine vasopressors. In patients on high-dose catecholamines, adjunctive angiotensin II was associated with improved renal replacement therapy liberation. Conclusion: Preclinical and clinical studies suggest that noncatecholamine vasopressors may confer renal benefits compared to catecholamine vasopressors. These hypothesis-generating observations suggest the need for comparative studies focused on renal outcomes. Systematic Review Registration : PROSPERO 2024 CRD42024527773., Competing Interests: RB has received research funding, consultant fees, advisory board fees, and lecturing fees from Innoviva and Viatris. The other authors report no conflicts of interest., (Copyright © 2024 by the Shock Society.)

Background: The combination of intravenous hydrocortisone and enteral fludrocortisone may reduce mortality in patients with septic shock. The optimal dose and reliability of absorption of fludrocortisone in critically ill patients are unclear., Methods: In a multi-centre, open label, phase II randomized clinical trial, intravenous hydrocortisone alone or in combination with one of three doses of enteral fludrocortisone (50 µg, 100 µg or 200 µg daily) for 7 days was compared in patients with septic shock. The primary outcome was time to shock resolution. We conducted pharmacokinetic studies to assess absorption., Results: Out of 153 enrolled patients, 38 (25%) received hydrocortisone alone, 42 (27%) received additional 50 µg, 36 (24%) received 100 µg and 37 (24%) received 200 µg fludrocortisone. Plasma concentrations of fludrocortisone were detected in 97% of patients at 3 h-median (interquartile range [IQR]) 261 (156-334) ng/L. There was no significant difference in the time to shock resolution between groups with median (IQR) of 3 (2.5-4.5), 3 (2-4), 3 (2-6) and 3 (2-5.5) days in the hydrocortisone alone, 50 µg, 100 µg and 200 µg fludrocortisone groups, respectively. The corresponding 28-day mortality rates were 9/38 (24%), 7/42 (17%), 4/36 (11%) and 4/37 (11%), respectively. There were no significant differences between groups with respect to, recurrence of shock, indices of organ failure or other secondary outcomes., Conclusions: Enteral fludrocortisone resulted in detectable plasma fludrocortisone concentrations in the majority of critically ill patients with septic shock, although they varied widely indicating differing absorption and bioavailability. Its addition to hydrocortisone was not associated with shorter time to shock resolution., Competing Interests: Declarations. Conflicts of interest: BV, JM, NH and SF are supported by a Leadership Fellowship and AB from an Ideas Grant from the National Health and Medical Research Council of Australia. BV and NH receive institutional research support from Baxter for the conduct of a clinical trial in patients with diabetic ketoacidosis. AB is supported by an Australian Research Council Future Fellowship and grants from the Translational Research Institute, Australian Infectious diseases Research Centre and Metro South health. JD, MR and LM are supported by a grant from the Hospital Research Foundation. MY is supported by a grant from the Baker Foundation and the Australian Research Council. SF has received consulting fees from RevImmune Inc and is Director of Sepsis Australia (honorary) and Asia Pacific Sepsis Alliance (honorary). All other others do not report any conflict of interest., (© 2024. Crown.)

Objectives: The relationship between renin levels, exposure to renin-angiotensin system (RAS) inhibitors, angiotensin II (ANGII) responsiveness, and outcome in patients with vasopressor-dependent vasodilatory hypotension is unknown., Design: We conducted a single-center prospective observational study to explore whether recent RAS inhibitor exposure affected baseline renin levels, whether baseline renin levels predicted ANGII responsiveness, and whether renin levels at 24 hours were associated with clinical outcomes., Setting: An academic ICU in Melbourne, VIC, Australia., Patients: Forty critically ill adults who received ANGII as the primary agent for vasopressor-dependent vasodilatory hypotension who were included in the Acute Renal effects of Angiotensin II Management in Shock study., Interventions: None., Measurements and Main Results: After multivariable adjustment, recent exposure to a RAS inhibitor was independently associated with a relative increase in baseline renin levels by 198% (95% CI, 36-552%). The peak amount of ANGII required to achieve target mean arterial pressure was independently associated with baseline renin level (increase by 46% per ten-fold increase; 95% CI, 8-98%). Higher renin levels at 24 hours after ANGII initiation were independently associated with fewer days alive and free of continuous renal replacement therapy (CRRT) (-7 d per ten-fold increase; 95% CI, -12 to -1)., Conclusions: In patients with vasopressor-dependent vasodilatory hypotension, recent RAS inhibitor exposure was associated with higher baseline renin levels. Such higher renin levels were then associated with decreased ANGII responsiveness. Higher renin levels at 24 hours despite ANGII infusion were associated with fewer days alive and CRRT-free. These preliminary findings emphasize the importance of the RAS and the role of renin as a biomarker in patients with vasopressor-dependent vasodilatory hypotension., Competing Interests: Dr. See is supported by a Jacquot Research Establishment Fellowship. Dr. Bellomo’s institution received funding from Paion, Baxter Healthcare, and Jafron Healthcare; he received funding from Viatris and Innoviva; and he disclosed the off-label product use of Giapreza. The remaining authors have disclosed that they do not have any potential conflicts of interest., (Copyright © 2024 by the Society of Critical Care Medicine and Wolters Kluwer Health, Inc. All Rights Reserved.)

Managing health care for older adults aged 75 years and older can pose unique challenges stemming from age-related physiological differences and comorbidities, along with elevated risk of delirium, frailty, disability, and polypharmacy. This review is aimed at providing a comprehensive analysis of the management of acute coronary syndromes (ACS) in older patients, a demographic substantially underrepresented in major clinical trials. Because older patients often exhibit atypical ACS symptoms, a nuanced diagnostic and risk stratification approach is necessary. We aim to address diagnostic challenges for older populations and highlight the diminished sensitivity of traditional symptoms with age, and the importance of biomarkers and imaging techniques tailored for older patients. Additionally, we review the efficacy and safety of pharmacological agents for ACS management in older people, emphasizing the need for a personalized and shared decision-making approach to treatment. This review also explores revascularization strategies, considering the implications of invasive procedures in older people, and weighing the potential benefits against the heightened procedural risks, particularly with surgical revascularization techniques. We explore the perioperative management of older patients experiencing myocardial infarction in the setting of noncardiac surgeries, including preoperative risk stratification and postoperative care considerations. Furthermore, we highlight the critical role of a multidisciplinary approach involving cardiologists, geriatricians, general and internal medicine physicians, primary care physicians, and allied health, to ensure a holistic care pathway in this patient cohort.

Background: While ample high-level evidence supports the limited use of antibiotics post-source control in intraabdominal infections, there is a paucity of available data in guiding antibiotic duration for intrathoracic infections. This study aims to analyze patient outcomes among those who have undergone surgical decortication for parapneumonic pleural empyema, comparing cases managed with infectious disease (ID) specialists against those without, and to identify predictive factors influencing antibiotic duration post-source control. We hypothesized that antibiotic duration would vary depending on the involvement of ID specialists., Methods: A retrospective chart review was completed on patients with parapneumonic pleural empyemas who underwent surgical decortication at a single tertiary center from January 2011 to March 2021. Differences in patient characteristics and outcomes for those whose antibiotics were managed by ID or not were compared with Wilcoxon two-sample tests and Fisher's exact tests. Linear regression was used to evaluate for significant factors predictive of antibiotic duration., Results: A total of 116 patients underwent surgical decortication for pleural empyema of parapneumonic etiology. ID specialists were involved with antibiotic management in 62 (53.4%) cases, while the remaining cases were not managed by ID. Demographics and patient comorbidities were similar between both groups. Growth of preoperative fluid cultures was higher in patients managed by ID (40.3% vs. 20.4%, P=0.03). Postoperatively, patients managed by ID had longer durations of antibiotics (28.7 vs. 20.9 days, P<0.001) and were more likely to be on IV antibiotics than patients not managed by ID (59.7% vs. 38.9%, P=0.04). However, postoperative outcomes were similar, including rates of disease recurrence, readmission, and 30-day mortality. Linear regression revealed length of antibiotics was significantly dependent on preoperative ventilator status [estimate: 16.346; 95% confidence interval (CI): 6.365-26.326; P=0.002], growth of preoperative pleural fluid cultures (estimate: 10.203; 95% CI: 2.502-17.904; P=0.01), and ID involvement (estimate: 8.097; 95% CI: 1.003-15.191; P=0.03)., Conclusions: Antibiotic duration for pleural empyema managed with surgical decortication is significantly dependent on ID involvement, preoperative growth of cultures, and preoperative ventilator status. However, outcomes, including disease recurrence and 30-day mortality, were similar between patients regardless of ID involvement and longer length of antibiotics, raising the question of what the adequate duration of antibiotics is for patients who receive appropriate source control for pleural empyema. Further study with randomized control trials should be conducted to provide high-level evidence regarding length of antibiotics in this patient population., Competing Interests: Conflicts of Interest: All authors have completed the ICMJE uniform disclosure form (available at https://jtd.amegroups.com/article/view/10.21037/jtd-24-61/coif). The authors have no conflicts of interest to declare, (2024 Journal of Thoracic Disease. All rights reserved.)

Background: Mineralocorticoid receptor antagonists (MRAs) have emerged as potential therapy to target the underlying arrhythmogenic substrate in atrial fibrillation (AF). Nevertheless, there have been inconsistent results on the impact of MRAs on AF., Objective: We sought to evaluate the effect of MRAs on AF incidence and progression in patients with and without heart failure., Methods: Electronic databases were searched up to September, 2022 for randomized controlled trials (RCTs) that evaluated MRA use and reported AF outcomes. Primary outcome was a composite of new-onset or recurrent AF. Safety outcomes included hyperkalemia and gynecomastia risks. A random-effects meta-analysis estimated pooled odds ratios (OR) and 95% confidence intervals (CI)., Results: 12 RCTs, comprising 11,419 patients treated with various MRAs were included [5960 (52%) on MRA]. On follow-up (6-39 months), 714 (5.5%) patients developed AF. MRA therapy was associated with a 32% reduction in the risk of new-onset or recurrent AF [OR 0.68 (95% CI 0.51-0.92), I 2  = 40%]. On subgroup analysis, the greatest benefit magnitude was demonstrated in reducing AF recurrence [OR 0.50 (95% CI 0.30-0.83)] and among patients with left ventricular dysfunction [OR 0.59 (95% CI 0.40-0.85)]. Gynecomastia, but not hyperkalemia, was associated with MRA use. Meta-regression analysis demonstrated that therapy duration was a significant interaction factor driving the effect size (P interaction  = 0.013)., Conclusion: MRA use is associated with a reduction in AF risk, especially AF progression. A prominent effect is seen in patients with heart failure, further augmented by therapy duration. Prospective trials are warranted to evaluate MRA use as upstream therapy for preventing this common arrhythmia., (© 2023. The Author(s), under exclusive licence to Springer-Verlag GmbH Germany.)

Background: Stroke increases subsequent dementia risk yet there are no specific post-stroke therapies to protect cognition. Cardiorespiratory exercise is recommended for secondary prevention of stroke and may be neuroprotective. The Post Ischaemic Stroke Cardiovascular Exercise Study (PISCES) aims to reduce post-stroke secondary neurodegeneration and cognitive decline. During the pandemic, we pivoted to a ZOom Delivered Intervention Against Cognitive decline (ZODIAC) protocol, reducing pandemic-amplified barriers to exercise., Methods: We present pandemic adaptions for a multicentre phase IIb assessor-blinded randomised controlled trial of ischaemic stroke survivors testing the efficacy and feasibility of an 8-week home-based exercise intervention delivered at 2 months post-stroke. We compare cardiorespiratory exercise (intervention arm) versus balance and stretching (active control arm). Participants are assessed with magnetic resonance imaging (MRI), fitness, blood, microbiome, and neuropsychological tests at three study visits: before and after the exercise intervention and at 12 months. Modifications to the original protocol include pre-exercise safety home visits, commercial delivery of exercise equipment to facilitate assessor blinding, and reconsideration of statistical plan to allow pooling of the studies. We have reduced in-person study visits from 27 to 3. Primary outcome remains between-group (intervention versus control) difference in brain volume change; secondary outcome is between-group difference in global cognitive ability to allow remote administration of a validated cognitive scale., Discussion: Remotely delivered exercise interventions reduce participant burden and may reduce barriers to recruitment. A decrease in the number of in-person study visits can be supported by greater information capture via self-reported questionnaires and phone surveys., Trial Registration: Prospectively ACTRN12616000942459. Registered on July 2016., (© 2024. The Author(s).)

Aims: We aimed to recruit a representative cohort of women and men with multi-morbid chronic heart disease as part of a trial testing an innovative, nurse-co-ordinated, multi-faceted intervention to lower rehospitalization and death by addressing areas of vulnerability to external challenges to their health., Methods and Results: The prospective, randomized open, blinded end-point RESILIENCE Trial recruited 203 hospital inpatients (mean age 75.7 ± 10.2 years) of whom 51% were women and 94% had combined coronary artery disease, heart failure, and/or atrial fibrillation. Levels of concurrent multi-morbidity were high (mean Charlson Index of Comorbidity Score 6.5 ± 2.7), and 8.9% had at least mild frailty according to the Rockwood Clinical Frailty Scale. Including the index admission, 19-20% of women and men had a pre-existing pattern of seasonally linked hospitalization (seasonality). Detailed phenotyping revealed that 48% of women and 40% of men had ≥3 physiological factors, and 15% of women and 16% of men had ≥3 behavioural factors likely to increase their vulnerability to external provocations to their health. Overall, 61-62% of women and men had ≥4 combined factors indicative of such vulnerability. Additional factors such as reliance on the public health system (63 vs. 49%), lower education (30 vs. 14%), and living alone (48 vs. 29%) were more prevalent in women., Conclusion: We successfully recruited women and men with multi-morbid chronic heart disease and bio-behavioural indicators of vulnerability to external provocations to their health. Once completed, the RESILIENCE TRIAL will provide important insights on the impact of addressing such vulnerability (promoting resilience) on subsequent health outcomes., Registration: ClinicalTrials.org: NCT04614428., Competing Interests: Conflict of interest: None declared., (© The Author(s) 2023. Published by Oxford University Press on behalf of the European Society of Cardiology. All rights reserved. For permissions, please e-mail: journals.permissions@oup.com.)

Early decongestion therapy with intravenous diuretics may be associated with improved outcomes in acute heart failure (AHF), however data is conflicting. This meta-analysis sought to evaluate the impact of door-to-IV diuretic (D2D) time on mortality in patients with AHF. Pooled estimates from observational studies comprising 28,124 patients, early IV diuresis (reference time 30-105 minutes) was associated with a 23% reduction in 30-day mortality in AHF (OR 0.77; 95% CI 0.64-0.93), despite no significant in-hospital death reduction (OR 0.84; 95% CI 0.57-1.24)., Competing Interests: Disclosures None reported., (Copyright © 2023 The Author(s). Published by Elsevier Inc. All rights reserved.)

Hypertension, defined as persistently elevated systolic blood pressure (SBP) >140 mmHg and/or diastolic blood pressure (DBP) at least 90 mmHg (International Society of Hypertension guidelines), affects over 1.5 billion people worldwide. Hypertension is associated with increased risk of cardiovascular disease (CVD) events (e.g. coronary heart disease, heart failure and stroke) and death. An international panel of experts convened by the International Society of Hypertension College of Experts compiled lifestyle management recommendations as first-line strategy to prevent and control hypertension in adulthood. We also recommend that lifestyle changes be continued even when blood pressure-lowering medications are prescribed. Specific recommendations based on literature evidence are summarized with advice to start these measures early in life, including maintaining a healthy body weight, increased levels of different types of physical activity, healthy eating and drinking, avoidance and cessation of smoking and alcohol use, management of stress and sleep levels. We also discuss the relevance of specific approaches including consumption of sodium, potassium, sugar, fibre, coffee, tea, intermittent fasting as well as integrated strategies to implement these recommendations using, for example, behaviour change-related technologies and digital tools., (Copyright © 2023 The Author(s). Published by Wolters Kluwer Health, Inc.)

Objective: Angiotensin-converting enzyme 2 activity reflects non-classical renin-angiotensin system upregulation. We assessed the association of urinary angiotensin-converting enzyme 2 (uACE2) activity with acute kidney injury (AKI). Design, setting and participants: A prospective observational study in which we measured uACE2 activity in 105 critically ill patients at risk of AKI. We report AKI stage 2 or 3 at 12 hours of urine collection (AKI 12h ) and AKI stage 2 or 3 at any time during intensive care unit stay in patients free from any stage of AKI at inclusion (AKI ICU ). AKI prediction was assessed using area under the receiver-operating characteristics curve (AUROC) and net reclassification indices (NRIs). Main outcome measure: AKI stage 2 or 3 at 12 hours of urine collection. Results: Within 12 hours of inclusion, 32 of 105 patients (30%) had developed AKI 12h . Corrected uACE2 activity was significantly higher in patients without AKI 12h compared with those with AKI 12h (median [interquartile range], 13 [6-24] v 7 [4-10] pmol/min/mL per mmol/L of urine creatinine; P < 0.01). A 10-unit increase in uACE2 was associated with a 28% decrease in AKI 12h risk (odds ratio [95% CI], 0.72 [0.46-0.97]). During intensive care unit admission, 39 of 76 patients (51%) developed AKI ICU . uACE2 had an AUROC for the prediction of AKI 12h of 0.68 (95% CI, 0.57-0.79), and correctly reclassified 28% of patients (positive NRI) to AKI 12h . Patients with uACE2 > 8.7 pmol/min/mL per mmol/L of urine creatinine had a significantly lower risk of AKI ICU on log-rank analysis (52% v 84%; P < 0.01). Conclusions: Higher uACE2 activity was associated with a decreased risk of AKI stage 2 or 3. Our findings support future evaluations of the role of the non-classical renin-angiotensin system during AKI., Competing Interests: None declared., (© 2020 College of Intensive Care Medicine of Australia and New Zealand.)

Background: The role of the renin-angiotensin-aldosterone axis in vasoplegia after cardiac surgery remains unclear. We tested the hypothesis that, compared with norepinephrine, infusion of angiotensin II titrated to achieve similar mean arterial pressure (MAP) would suppress plasma renin concentration (PRC) while maintaining aldosterone levels., Methods: In a double-blind, randomised controlled trial, subjects received either an infusion of angiotensin II or norepinephrine to maintain MAP 70-80 mm Hg from induction of anaesthesia. We compared PRC, aldosterone, dipeptidyl peptidase-3, and angiotensin-converting enzyme 2 activity between treatment groups, before surgery, on ICU admission, and 24 h after surgery., Results: In 60 patients (11.7% female; mean age 68 yr [11 yr]), norepinephrine increased median PRC at ICU admission (median difference [MD] 46 [inter-quartile range, IQR, 3-88] μU ml -1 ; P<0.001) but angiotensin II did not (MD -3 [IQR -62 to 35] μU ml -1 ; P=0.36). Aldosterone levels increased with both. The aldosterone:PRC ratio did not change with norepinephrine (MD -0.01 [IQR -0.14 to 0.03] μU ml -1 per ng dl -1 , P=0.76) but increased with angiotensin II (MD 0.05 [IQR 0.004-0.26] μU ml -1 per ng dl -1 , P<0.001). The upper quartile of PRC before surgery was associated with higher vasopressor requirements when norepinephrine was used to maintain MAP, but not angiotensin II. Dipeptidyl peptidase-3 levels and angiotensin-converting enzyme 2 activities were similar at all time points., Conclusions: Angiotensin II suppressed renin release while maintaining aldosterone levels compared with norepinephrine. Higher plasma renin concentration before surgery was associated with greater vasopressor requirement for norepinephrine, but not angiotensin II., Clinical Trial Registration: Australian and New Zealand Clinical Trials Registry-ACTRN12621000195853 23/02/2021., (Copyright © 2023 British Journal of Anaesthesia. Published by Elsevier Ltd. All rights reserved.)

Individual preference for morning or evening activities (chronotype), affect, hardiness, and talent are associated with a variety of performance outcomes. This longitudinal study was designed to investigate the degree to which these variables are associated with academic, physical, and military performance. Self-reported measures of chronotype, affect, and hardiness were collected from 1149 cadets from the Class of 2016 upon entry to the United States Military Academy. Talent, a composite of academic, leadership, and physical fitness scores were drawn from cadet records. Academic, military, and physical performance measures were collected at graduation 4 years later. The results indicated that a morning orientation was associated with better physical and military performance. Higher talent scores, as well as lower levels of negative affect, were associated with better performance across all three performance measures. Hardiness was only associated with military performance. The findings suggest that a morning orientation and less negative affect may result in better performance overall within a challenging and structured military environment. Future studies of chronotype shifts may provide further insight into associated performance benefits.

Background: Despite cardiovascular diseases and thrombosis being major causes of death in patients with chronic kidney disease (CKD), there remains no effective biomarker to predict thrombotic risk in this population., Objective: To evaluate global coagulation assays in patients with CKD and correlate the biomarkers to clinical outcomes., Material and Methods: Patients with eGFR<30 mL/min/1.73m 2 were recruited (n = 90) in this prospective observational study. Blood samples were collected for global coagulation assays, including thromboelastography, calibrated automated thrombogram (CAT), overall hemostatic potential (OHP) and tissue factor pathway inhibitor (TFPI)., Results: Following adjustment for age and gender, CKD subjects (mean age 66 years, 36 % female) had increased maximum amplitude on thromboelastography (70.1 vs 60.2 mm, p < 0.001), higher peak thrombin (233.2 vs 219.7 mm, p = 0.030) and increased OHP (16.1 vs 6.4 units, p < 0.001) compared to healthy controls (n = 153). TFPI was also increased in CKD patients (36.4 vs 14.5 ng/mL, p < 0.001). Compared to hemodialysis patients (n = 43), peritoneal-dialysis patients (n = 25) had more hypercoagulable parameters. Thirty-five CKD patients reported thrombotic complications - key predictors included dialysis, higher fibrinogen, reduced endogenous thrombin potential, elevated D-dimer and increased TFPI. Using the dialysis cohort, the predictive risk model based on the key predictors performed better than Framingham heart score and number of cardiovascular risk factors (Harrell's C-stat 0.862 vs 0.585 vs 0.565)., Conclusion: CKD appears to confer a hypercoagulable state compared to healthy controls. Interestingly, reduced thrombin generation and raised TFPI was paradoxically associated with increased thrombotic risks, highlighting possible complex compensatory mechanisms within the coagulation system, which may be important in predicting clinical outcomes., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2023 Elsevier Ltd. All rights reserved.)

Diminazene aceturate (DIZE), a putative angiotensin-converting enzyme 2 (ACE2) activator, elicits relaxation in various animal models. This study aimed to determine the relaxing mechanisms in internal iliac arteries utilised by DIZE in healthy and atherogenic rabbit models. Studies were conducted on internal iliac artery rings retrieved from male New Zealand White rabbits fed a 4-week healthy control (n = 24) or atherogenic diet (n = 20). To investigate pathways utilised by DIZE to promote arterial relaxation, a DIZE dose response [10 -9.0 M - 10 -5.0 M] was performed on pre-contracted rings incubated with pharmaceuticals that target: components of the renin-angiotensin system; endothelial- and vascular smooth muscle-dependent mechanisms; protein kinases; and potassium channels. ACE2 expression was quantified by immunohistochemistry analysis following a 2 hr or 4 hr DIZE incubation. DIZE significantly enhanced vessel relaxation in atherogenic rings at doses [10 -5.5 M] (p < 0.01) and [10 -5.0 M] (p < 0.0001), when compared to healthy controls. Comprehensive results from functional isometric studies determined that DIZE causes relaxation via different mechanisms depending on pathology. For the first time, we report that in healthy blood vessels DIZE exerts its direct relaxing effect through ACE2/AT 2 R and NO/sGC pathways; however, in atherogenesis this switches to MasR, arachidonic acid pathway (i.e., COX1/2, EET and DHET), MCLP, Ca 2+ activated voltage channels, AMPK and ERK1/2. Moreover, quantitative immunohistochemical analysis demonstrated that DIZE increases artery ACE2 expression in a time dependent manner. We provide a detailed investigation of DIZE's mechanisms and demonstrate for the first time that in healthy and atherogenic arteries DIZE provides beneficial effects through directly inducing relaxation, albeit via different pathways., Competing Interests: Declaration of Competing Interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2022 Elsevier Inc. All rights reserved.)

Objective: To determine whether disrupting the renin angiotensin system with angiotensin receptor blockers will improve clinical outcomes in people with covid-19., Design: CLARITY was a pragmatic, adaptive, multicentre, phase 3, randomised controlled trial., Setting: 17 hospital sites in India and Australia., Participants: Participants were at least 18 years old, previously untreated with angiotensin receptor blockers, with a laboratory confirmed diagnosis of severe acute respiratory syndrome coronavirus-2 (SARS-CoV-2) infection who had been admitted to hospital for management of covid-19., Intervention: Oral angiotensin receptor blockers (telmisartan in India) or placebo (1:1) for 28 days., Main Outcome Measures: The primary endpoint was covid-19 disease severity using a modified World Health Organization Clinical Progression Scale (WHO scale) at day 14. Secondary outcomes were WHO scale scores at day 28, mortality, intensive care unit admission, and respiratory failure. Analyses were evaluated on an ordinal scale in the intention-to-treat population., Results: Between 3 May 2020 and 13 November 2021, 2930 people were screened for eligibility, with 393 randomly assigned to angiotensin receptor blockers (of which 388 (98.7%) to telmisartan 40 mg/day) and 394 to the control group. 787 participants were randomised: 778 (98.9%) from India and nine (1.1%) from Australia. The median WHO scale score at day 14 was 1 (interquartile range 1-1) in 384 participants assigned angiotensin receptor blockers and 1 (1-1) in 382 participants assigned placebo (adjusted odds ratio 1.51 (95% credible interval 1.02 to 2.23), probability of an odds ratio of >1 (Pr(OR>1)=0.98). WHO scale scores at day 28 showed little evidence of difference between groups (1.02 (0.55 to 1.87), Pr(OR>1)=0.53). The trial was stopped when a prespecified futility rule was met., Conclusions: In patients admitted to hospital for covid-19, mostly with mild disease, not requiring oxygen, no evidence of benefit, based on disease severity score, was found for treatment with angiotensin receptor blockers, using predominantly 40 mg/day of telmisartan., Trial Registration: ClinicalTrials.gov NCT04394117., Competing Interests: Competing interests: All authors have completed the ICMJE uniform disclosure form at www.icmje.org/disclosure-of-interest/ and declare: support from the Australian government and the University of Sydney for the submitted work; no financial relationships with any organisations that might have an interest in the submitted work in the previous three years except the following: MJ is responsible for research projects that have received funding from Amgen, Baxter, CSL, Dimerix, Eli Lilly, Gambro, and Merck Sharp and Dohme; has received advisory, steering committee or speaker fees, or both, from Akebia, Amgen, Astra Zeneca, Baxter, Bayer, Boehringer Ingelheim, Cesas Linx, Chinook, CSL, Janssen, Medscape, Merck Sharp Dohme, Roche, and Vifor; CP serves on advisory boards for AstraZeneca, Boehringer Ingelheim, Merck Sharp and Dohme, and Novartis; CJ serves on advisory boards for AstraZeneca, Boehringer Ingelheim, Chiesi, GlaxoSmithKline, Novartis, and Sanofi-Genzyme; VJ has received grants from Baxter Healthcare, Biocon, and GlaxoSmithKline, and speaker fees or on the advisory board for AstraZeneca, Baxter Healthcare, NephroPlus, Sanofi; no other relationships or activities that could appear to have influenced the submitted work., (© Author(s) (or their employer(s)) 2019. Re-use permitted under CC BY. No commercial re-use. See rights and permissions. Published by BMJ.)

Among patients with chronic kidney disease (CKD), aortic stenosis (AS) is associated with a significantly higher rate of mortality. We aimed to evaluate whether diffuse myocardial fibrosis, determined using native T1 mapping, has prognostic utility in predicting major adverse cardiovascular events (MACEs), including all-cause mortality or heart failure hospitalization, in patients with CKD and severe AS who are evaluated for transcatheter aortic valve implantation. Cardiac magnetic resonance with T1 mapping using the modified Look-Locker inversion recovery technique was performed in 117 consecutive patients with severe AS and CKD (stage ≥3). Patients were followed up to determine the occurrence of MACE. The mean age of the 117 patients in the cohort was 82 ± 8 years. Native T1 was 1,055 ms (25th- to 75th percentiles 1,031 to 1,078 ms), which is higher than previously reported in healthy controls. Patients with higher T1 times were more likely to have higher N-terminal pro-B-type natriuretic peptide levels (4,122 [IQR 1,578 to 7,980] pg/ml vs 1,678 [IQR 493 to 2,851] pg/ml, p = 0.005) and a history of heart failure (33% vs 9%, p = 0.034). After median follow-up of 3.4 years, MACE occurred in 71 patients (61%). The Society of Thoracic Surgeons predicted risk of mortality score (hazard ratio [HR] 1.07, 95% confidence interval [CI] 1.02 to 1.12, p = 0.006), native T1 >1,024 ms (HR 2.10, 95% CI 1.09 to 4.06, p = 0.028), and New York Heart Association class (HR 1.56, 95% 1.09 to 2.34, p = 0.016) were independent predictors of MACE. Longer native T1 was associated with MACE occurrence in patients with CKD and severe AS., (Copyright © 2022 Elsevier Inc. All rights reserved.)

Angiotensin converting enzyme 2 (ACE2) is an endogenous negative regulator of the renin-angiotensin system, a key factor in the development of cardiovascular disease (CVD). ACE2 is also used by SARS-CoV-2 for host cell entry. Given that COVID-19 is associated with hypercoagulability, it is timely to explore the potential relationship between plasma ACE2 activity and the coagulation profile. In this cross-sectional study, ACE2 activity and global coagulation assays (GCA) including thromboelastography, thrombin, and fibrin generation were measured in adult healthy controls (n = 123; mean age 41 ± 17 years; 35% male) and in patients with cardiovascular risk factors and/or disease (n = 258; mean age 65 ± 14 years; 55% male). ACE2 activity was significantly lower in controls compared to patients with cardiovascular risk factors and/or disease (median 0.10 (0.02, 3.33) vs. 5.99 (1.95, 10.37) pmol/mL/min, p < 0.001). Of the healthy controls, 48% had undetectable ACE2 activity. Controls with detectable ACE2 had lower maximum amplitude (p < 0.001). In patients with cardiovascular risk factors and/or disease, those in the 3rd tertile were older and male (p = 0.002), with a higher Framingham grade and increased number of cardiovascular risk factors (p < 0.001). In conclusion, plasma ACE2 activity is undetectable to very low in young healthy controls with minimal clinically relevant associations to GCA. Patients with cardiovascular risk factors and/or disease have increased plasma ACE2 activity, suggesting that it may be an important biomarker of endothelial dysfunction and atherosclerosis.

Joining a function-enhanced Fc-portion of human IgG to the SARS-CoV-2 entry receptor ACE2 produces an antiviral decoy with strain transcending virus neutralizing activity. SARS-CoV-2 neutralization and Fc-effector functions of ACE2-Fc decoy proteins, formatted with or without the ACE2 collectrin domain, were optimized by Fc-modification. The different Fc-modifications resulted in distinct effects on neutralization and effector functions. H429Y, a point mutation outside the binding sites for FcγRs or complement caused non-covalent oligomerization of the ACE2-Fc decoy proteins, abrogated FcγR interaction and enhanced SARS-CoV-2 neutralization. Another Fc mutation, H429F did not improve virus neutralization but resulted in increased C5b-C9 fixation and transformed ACE2-Fc to a potent mediator of complement-dependent cytotoxicity (CDC) against SARS-CoV-2 spike (S) expressing cells. Furthermore, modification of the Fc-glycan enhanced cell activation via FcγRIIIa. These different immune profiles demonstrate the capacity of Fc-based agents to be engineered to optimize different mechanisms of protection for SARS-CoV-2 and potentially other viral pathogens., Competing Interests: Authors PMH and BW are inventors on a provisional patent filing by the Burnet Institute. The remaining authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2022 Wines, Kurtovic, Trist, Esparon, Lopez, Chappin, Chan, Mordant, Lee, Gherardin, Patel, Hartley, Pymm, Cooney, Beeson, Godfrey, Burrell, van Zelm, Wheatley, Chung, Tham, Subbarao, Kent and Hogarth.)

Cardiovascular disease remains the leading cause of death in the era of modern medicine despite major advancements in this field. Current available clinical surrogate markers and blood tests do not adequately predict individual risk of cardiovascular disease. A more precise and sophisticated tool that can reliably predict the thrombosis and bleeding risks at an individual level is required in order for clinicians to confidently recommend early interventions with a favorable risk-benefit profile. Critical to the development of this tool is the assessment and understanding of Virchow's triad and its complex interactions between hypercoagulability, endothelial dysfunction and vessel flow, a fundamental concept to the development of thrombosis. This review explores the pathophysiology of cardiovascular disease stemming from the triad of factors and how individualized risk assessment can be improved through the multimodal use of tools such as global coagulation assays, endothelial biomarkers and vessel flow assessment.

The CLARITY trial (Controlled evaLuation of Angiotensin Receptor Blockers for COVID-19 respIraTorY disease) is a two-arm, multi-centre, randomised controlled trial being run in India and Australia that investigates the effectiveness of angiotensin receptor blockers in addition to standard care compared to placebo (in Indian sites) with standard care in reducing the duration and severity of lung failure in patients with COVID-19. The trial was designed as a Bayesian adaptive sample size trial with regular planned analyses where pre-specified decision rules will be assessed to determine whether the trial should be stopped due to sufficient evidence of treatment effectiveness or futility. Here, we describe the statistical analysis plan for the trial and define the pre-specified decision rules, including those that could lead to the trial being halted. The primary outcome is clinical status on a 7-point ordinal scale adapted from the WHO Clinical Progression scale assessed at day 14. The primary analysis will follow the intention-to-treat principle. A Bayesian adaptive trial design was selected because there is considerable uncertainty about the extent of potential benefit of this treatment.Trial registrationClinicalTrials.gov NCT04394117 . Registered on 19 May 2020Clinical Trial Registry of India CTRI/2020/07/026831Version and revisionsVersion 1.0. No revisions., (© 2022. The Author(s).)