Search

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 T11,024 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.

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 .

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.

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

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.

BACKGROUND: Cardiac fibrosis in mitral valve prolapse (MVP) is implicated in the development of sudden cardiac death (SCD); however, the pattern remains poorly characterized. OBJECTIVE: The purpose of this study was to systematically quantify left and right ventricular fibrosis in individuals with isolated MVP and SCD (iMVP-SCD), whereby other potential causes of death are excluded, compared to a control cohort. METHODS: Individuals with iMVP-SCD were identified from the Victorian Institute of Forensic Medicine, Australia, and matched for age, sex, and body mass index to control cases with noncardiac death. Cardiac tissue sections were analyzed to determine collagen deposition in the left ventricular free wall (anterior, lateral, and posterior portions), interventricular septum, and right ventricle. Within the iMVP-SCD cases, the endocardial-to-epicardial distribution of fibrosis within the left ventricle was specifically characterized. RESULTS: Seventeen cases with iMVP-SCD were matched 1:1 with 17 controls, yielding 149 samples and 1788 histologic regions. The iMVP-SCD group had increased left ventricular (anterior, lateral, and posterior; all P

Global coagulation assays (GCAs) may provide a more comprehensive individual hemostatic profiling. We aim to evaluate GCAs (thromboelastography, thrombin generation) in healthy controls, and correlate results with age, gender, lipid status, tissue factor pathway inhibitor (TFPI) and P-selectin. Blood samples were collected from healthy controls (> 18 years of age) not taking anticoagulation or antiplatelet agents and without known cardiovascular disease. Thromboelastography (TEG) was performed on citrated whole blood while calibrated automated thrombogram (CAT), P-selectin (endothelial marker) and TFPI (principle inhibitor of tissue factor-initiated coagulation) were performed on platelet-poor plasma. 153 healthy controls (mean age 42 years, 98 females (64%)) were recruited. Female controls demonstrated more hypercoagulable TEG and CAT parameters while those over 50 years of age demonstrated more hypercoagulable TEG parameters despite comparable thrombin generation. Paradoxically, individuals with “flattened” thrombin curves (lower velocity index (rate of thrombin generation) despite preserved endogenous thrombin potential (amount of thrombin)) were more likely to be male (49% vs 20%, p = 0.003) with increased low-density lipoprotein cholesterol (3.3 vs 2.6 mmol/L, p = 0.003), P-selectin (54.2 vs 47.3 ng/mL, p = 0.038) and TFPI (18.7 vs 8.6 ng/ml, p = 0.001). In addition to reduced velocity index and thrombin peak, controls in the highest TFPI tertile also demonstrated a poorer lipid profile. GCAs can detect subtle changes of the hemostatic profile. Interestingly, reduced thrombin generation was paradoxically associated with increased cardiovascular risk factors, possibly attributable to increased TFPI. This finding may suggest compensation by the coagulation system in response to endothelial activation and represent a biomarker for early cardiovascular disease. A larger prospective study evaluating these assays in the cardiovascular disease population is ongoing.

Patients with atrial fibrillation (AF) have risk factors that predispose to thoracic aneurysmal disease (TAD) and atherosclerosis. In this study in patients with AF, we assessed the occurrence of incidental TAD and assessed if a validated predictive score used to predict AF, the CHARGE-AF score, was associated with greater aortic dimensions. We also assessed the prevalence of coronary calcification. We conducted a cross-sectional study of 1,000 consecutive patients with AF undergoing chest multidetector CT during evaluation for pulmonary vein isolation. A dilated aortic root or ascending aorta (AA, dimension/ body surface area >2.05 cm/m2) were found in 195 (20%). A total of 12 (1%) had significant aortic aneurysmal enlargement of > 5.0 cm. Advancing age, a bicuspid aortic valve, hypertension, and male gender were associated with increased aortic dimensions. Aortic root dimensions increased linearly (p < 0.001) and ascending aortic dimensions increased nonlinearly across CHARGE-AF deciles (p < 0.001). Nearly two-thirds (63%) had coronary calcification, 38% of whom were not on lipid-lowering therapy. In conclusion, in patients with AF undergoing gated chest CT, 1 in 5 had previously undetected TAD, with a small proportion having significantly aneurysmal dimensions approaching surgical thresholds. Risk factors previously established to increase the propensity to develop AF are also associated with increased TAD. These findings raise the need to consider a surveillance strategy for TAD in patients with AF, particularly in those with other risk factors for aortic disease. A high prevalence of coronary calcium was also detected, representing an opportunity to optimize statin therapy in patients with AF.

Retinal blood vessels provide information on the risk of cardiovascular disease (CVD). Here, we report the development and validation of deep-learning models for the automated measurement of retinal-vessel calibre in retinal photographs, using diverse multiethnic multicountry datasets that comprise more than 70,000 images. Retinal-vessel calibre measured by the models and by expert human graders showed high agreement, with overall intraclass correlation coefficients of between 0.82 and 0.95. The models performed comparably to or better than expert graders in associations between measurements of retinal-vessel calibre and CVD risk factors, including blood pressure, body-mass index, total cholesterol and glycated-haemoglobin levels. In retrospectively measured prospective datasets from a population-based study, baseline measurements performed by the deep-learning system were associated with incident CVD. Our findings motivate the development of clinically applicable explainable end-to-end deep-learning systems for the prediction of CVD on the basis of the features of retinal vessels in retinal photographs. Deep-learning models for the automated measurement of retinal-vessel calibre in retinal photographs perform comparably to or better than expert graders in associations of measurements of retinal-vessel calibre with cardiovascular risk factors.

Rationale: Whether biomarkers can identify subgroups of patients with septic shock with differential treatment responses to hydrocortisone is unknown.Objectives: To determine if there is heterogene...

Introduction: Fibrosis is significantly associated with nearly all forms of heart and kidney disease. Clinical diagnosis of fibrosis is currently reliant on conventional methods that do not have the sensitivity and specificity required for effective diagnosis. Hypothesis: An handheld portable near-infrared (NIR) spectrometer, usable intraoperatively coupled to machine learning algorithms can discriminate between fibrotic and healthy cardiac and renal tissue. We sought to validate this in an animal model. Methods: 10 Male Sprague Dawley rats (SDR) with either induced cardiac (SDR-H) and renal (SDR-K) fibrosis (n=5) compare to normal controls (n=5). Hearts from all rats were used as tissue screening in model validation as they contain a high amount of collagen. Multiple tissue samples were harvested from SDR-K ( n fibrosis = 12, n control = 4) and SDR-H ( n fibrosis = 12, n control = 4) groups. NIR spectra (1350 - 2500 nm) were acquired from all tissue sections. Results: Stained sections showed insignificant differences between the fibrotic SDR-H and their corresponding controls as collagen fibrils dominated both groups. SDR-K showed distinguishable features between examined groups. NIR absorption at 1509, 1725, 2055, and 2306 nm were found to be highly indicative of fibrosis (Figure1). PCA (57% explained variance) and PLS-DA (sensitivity: 96%) showed excellent discrimination for SDR-K groups while the heart shows no meaningful discrimination for SDR-H groups. SVM and LR analysis corroborated these results by achieving a 98% classification accuracy for SDR-K and no discrimination for SDR-H. All machine learning models were cross-validated with outcomes of histological staining to establish a robust interpretation and underpin their pathological meanings. Conclusions: NIR accurately diagnoses cardiac and renal fibrosis in rats model. There is potential for this technology to be translated into an intraoperative instrument for tissue diagnosis

Background Angiotensin converting enzyme 2 (ACE2) is expressed in the human myocardium and blood vessels and degrades the vasoconstrictor peptide angiotensin (Ang) II. Plasma ACE2 activity is elevated in patients with cardiovascular disease (CVD) and is a predictor of major adverse cardiovascular events (MACE) in obstructive coronary artery disease. However, it is unknown whether acute coronary syndrome (ACS) causes dynamic changes in plasma ACE2 activity. Purpose We investigated dynamic changes in serial troponin-T and plasma ACE2 activity in patients presenting with ACS who underwent invasive coronary angiography (ICA). Methods Consecutive patients admitted with ACS from October-November 2019 were screened. Those meeting the Fourth Universal Definition of Myocardial Infarction who had both ICA and serial troponin-T testing were included. The study was approved by the hospitals Human Research Ethics Committee. All patients had routine plasma samples taken over 3 time-points for measurement of troponin-T; the same sample was used to measure plasma ACE2 activity. Catalytic ACE2 activity was measured using a validated, sensitive quenched fluorescent substrate-based assay. Serial median troponin and ACE2 activity levels were analysed using the Friedman test for repeated measures. Results Forty-nine patients were included. The mean age of participants was 63.9±11.0 years, and 36 (74%) patients were male. Overall, 16 (36%) patients presented with ST-elevation myocardial infarction (STEMI) and 29 (74%) with non-ST-elevation myocardial infarction (NSTEMI). Twenty-nine (59%) patients had a history of hypertension and 14 (29%) a history of ischaemic heart disease; 13 (27%) with priorMI, 11 (22%) had previous PCI and 2 (4%) had prior coronary artery bypass grafting. Over the 3 time points, there was a clear rise in median troponin-T levels representing myocardial injury (p Conclusions Patients with ACS had higher plasma ACE2 levels compared to levels previously reported in healthy controls. There were no dynamic changes in ACE2 activity in the setting of ACS, despite a significant rise in troponin-T. These results suggest that plasma ACE2 levels reflect underlying endothelial dysfunction rather than acute myocardial injury or infarction. Studies are now underway to assess if plasma ACE2 activity in ACS predicts MACE. Funding Acknowledgement Type of funding sources: None. Table 1

Background and aims Endothelial dysfunction is a precursor to atherosclerosis and is implicated in the coexistence between cardiovascular disease (CVD) and chronic kidney disease (CKD). We examined whether retinal microvascular dysfunction is present in subjects with renal impairment and predictive of long-term CKD progression in patients with CVD. Methods In a single centre prospective observational study, 253 subjects with coronary artery disease and CVD risk factors underwent dynamic retinal vessel analysis. Retinal microvascular dysfunction was quantified by measuring retinal arteriolar and venular dilatation in response to flicker light stimulation. Serial renal function assessment was performed over a median period of 9.3 years using estimated GFR (eGFR). Results Flicker light-induced retinal arteriolar dilatation (FI-RAD) was attenuated in patients with baseline eGFR Conclusions Retinal arteriolar endothelial dysfunction is present in patients with CVD who have early-stage CKD, and serves as an indicator of long-term CKD progression in those with normal renal function.

A proportion of patients surviving acute coronavirus disease 2019 (COVID-19) infection develop post-acute COVID syndrome (long COVID (LC)) lasting longer than 12 weeks. Here, we studied individuals with LC compared to age- and gender-matched recovered individuals without LC, unexposed donors and individuals infected with other coronaviruses. Patients with LC had highly activated innate immune cells, lacked naive T and B cells and showed elevated expression of type I IFN (IFN-β) and type III IFN (IFN-λ1) that remained persistently high at 8 months after infection. Using a log-linear classification model, we defined an optimal set of analytes that had the strongest association with LC among the 28 analytes measured. Combinations of the inflammatory mediators IFN-β, PTX3, IFN-γ, IFN-λ2/3 and IL-6 associated with LC with 78.5-81.6% accuracy. This work defines immunological parameters associated with LC and suggests future opportunities for prevention and treatment.

A proportion of patients surviving acute COVID-19 infection develop post-COVID syndrome (long COVID) encompassing physical and neuropsychiatric symptoms lasting longer than 12 weeks. Here we studied a prospective cohort of individuals with long COVID compared to age/gender matched subjects without long COVID (from the ADAPT study), healthy donors and individuals infected with other non-SARS CoV2 human coronaviruses (the ADAPT-C study). We found highly activated innate immune cells and an absence of subsets of un-activated naïve T and B cells in peripheral blood of long COVID subjects, that did not reconstitute over time. These activated myeloid cells may contribute to the elevated levels of type I (IFN-β) and III interferon (IFN-λ1) that remained persistently high in long COVID subjects at 8 months post-infection. We found positive inter-analyte correlations that consisted of 18 inflammatory cytokines in symptomatic long COVID subjects that was not observed in asymptomatic COVID-19 survivors. A linear classification model was used to exhaustively search through all 20475 combinations of the 29 analytes measured, that had the strongest association with long COVID and found that the best 4 analytes were: IL-6, IFN-γ, MCP-1 (CCL2) and VCAM-1. These four inflammatory biomarkers gave an accuracy of 75.9%, and an F1 score of 0.759, and have also previously been associated with acute severe disease. In contrast, plasma ACE2 levels, while elevated in the serum of people previously infected with SARS-CoV-2 were not further elevated in subjects with long COVID symptoms. This work defines immunological parameters associated with long COVID and suggests future opportunities to prevention and treatment.

May Measurement Month (MMM), originally initiated as a temporary solution to address the lack of blood pressure (BP) screening programs worldwide, emerged as an effective annual campaign to increase the awareness of hypertension. MMM18, a cross-sectional survey of volunteers aged ≥18 years was carried out during May 2018 predominantly in capital cities across Australia following the standard MMM protocol. Blood pressure screening along with additional information including anthropometric data and responses to questionnaires on demographic, lifestyle, and environmental factors were collected from 3 352 individuals across Australia. After multiple imputation, 1 026 (30.6%) adult Australians had hypertension. Of the 2 936 individuals not on antihypertensive treatment, 610 (20.8%) were hypertensive, and 237 (57.1%) of the 416 individuals receiving antihypertensive treatment had uncontrolled BP. In line with MMM17 results and other previous surveys, MMM18 revealed that close to one-third of the screened population (30.6%) had hypertension, 57.1% of individuals treated with BP-lowering medication remained uncontrolled indicating suboptimal management of the condition in the majority of patients. Most importantly, only 49.0% of those with hypertension were aware of their elevated BP, highlighting lack of awareness of elevated BP in nearly half of the affected population. Elevated BP was directly associated with alcohol consumption, overweight, and obesity. Our findings demonstrate the need for (i) continued efforts to increase BP awareness in the population, (ii) optimization of BP management strategies, and (iii) tackling some of the major contributors to BP elevation, including alcohol consumption and obesity.

Endothelin-1 (ET-1) is a vasoconstrictor associated with cardiovascular disease, whereas adrenomedullin (ADM) is a vasorelaxant with cardioprotective properties. We sought to determine the relationship between plasma ET-1 and ADM with coronary circulatory function and long-term major adverse cardiovascular events (MACE).Thirty-two patients undergoing coronary angiography for chest pain were recruited. Baseline plasma ET-1 and ADM levels were measured. The index of microcirculatory resistance (IMR), coronary flow mediated dilatation (cFMD) and coronary flow reserve (CFR) were measured in a non-obstructed coronary artery. Patients were assessed for MACE over a median period of 8.8 years.Plasma ET-1 levels correlated with IMR (r = 0.57; p 0.01) and ADM levels correlated with CFR (r = 0.50; p = 0.04) and cFMD (r = 0.62; p = 0.01). After adjustment for age, gender and cardiovascular risk factors, the association between ADM and cFMD (β = 0.79; p 0.01) and between ET-1 and IMR (β = 5.7; p = 0.01) remained significant. IMR was higher, although not statistically significant, in patients with long-term MACE (17.9 ± 5.3 vs. 13.1 ± 6.0 units; p = 0.14). In patients free of MACE, cFMD (9.3 ± 7.6 vs. 2.8 ± 5.0%; p = 0.01) and plasma ADM levels (7.6 ± 5.3 vs. 4.0 ± 1.9 pmol/L; p = 0.07) were higher.Plasma ET-1 and ADM were associated with measures of coronary microvascular and coronary conduit vessel function, respectively. Increased cFMD and elevated plasma ADM were associated with a cardioprotective effect.

Classic and nonclassic renin-angiotensin systems (RAS) are 2 sides of an ubiquitous endocrine/paracrine cascade regulating blood pressure and homeostasis. Angiotensin II and angiotensin-converting enzyme (ACE) levels are associated with severity of disease in the critically ill, and are central to the physiology and the pathogenesis of circulatory shock. Angiotensin (1-7) and ACE2 act as an endogenous counterregulatory arm to the angiotensin II/ACE axis. The tissue-based RAS has paracrine effects dissociated from those of the circulating RAS. Exogenous angiotensin II or ACE2 may improve the outcome of septic shock and acute respiratory distress syndrome, respectively.

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.

Background Left ventricular non‐compaction remains a poorly described entity, which has led to challenges of overdiagnosis. We aimed to evaluate if the presence of a thin compacted myocardial layer portends poorer outcomes in individuals meeting cardiac magnetic resonance criteria for left ventricular non‐compaction . Methods and Results This was an observational, retrospective cohort study involving individuals selected from the Cleveland Clinic Foundation cardiac magnetic resonance database (N=26 531). Between 2000 and 2018, 328 individuals ≥12 years, with left ventricular non‐compaction or excessive trabeculations based on the cardiac magnetic resonance Petersen criteria were included. The cohort comprised 42% women, mean age 43 years. We assessed the predictive ability of myocardial thinning for the primary composite end point of major adverse cardiac events (composite of all‐cause mortality, heart failure hospitalization, left ventricular assist device implantation/heart transplant, ventricular tachycardia, or ischemic stroke). At mean follow‐up of 3.1 years, major adverse cardiac events occurred in 102 (31%) patients. After adjusting for comorbidities, the risk of major adverse cardiac events was nearly doubled in the presence of significant compacted myocardial thinning (hazard ratio [HR], 1.88 [95% CI, 1.18‒3.00]; P =0.016), tripled in the presence of elevated plasma B‐type natriuretic peptide (HR, 3.29 [95% CI, 1.52‒7.11]; P =0.006), and increased by 5% for every 10‐unit increase in left ventricular end‐systolic volume (HR, 1.01 [95% CI, 1.00‒1.01]; P =0.041). Conclusions The risk of adverse clinical events is increased in the presence of significant compacted myocardial thinning, an elevated B‐type natriuretic peptide or increased left ventricular dimensions. The combination of these markers may enhance risk assessment to minimize left ventricular non‐compaction overdiagnosis whilst facilitating appropriate diagnoses in those with true disease.

Global coagulation assays (GCAs) may provide a more comprehensive individual hemostatic profiling. We aim to evaluate GCAs (thromboelastography, thrombin generation) in healthy controls, and correlate results with age, gender, lipid status, tissue factor pathway inhibitor (TFPI) and P-selectin. Blood samples were collected from healthy controls ( 18 years of age) not taking anticoagulation or antiplatelet agents and without known cardiovascular disease. Thromboelastography (TEG) was performed on citrated whole blood while calibrated automated thrombogram (CAT), P-selectin (endothelial marker) and TFPI (principle inhibitor of tissue factor-initiated coagulation) were performed on platelet-poor plasma. 153 healthy controls (mean age 42 years, 98 females (64%)) were recruited. Female controls demonstrated more hypercoagulable TEG and CAT parameters while those over 50 years of age demonstrated more hypercoagulable TEG parameters despite comparable thrombin generation. Paradoxically, individuals with "flattened" thrombin curves (lower velocity index (rate of thrombin generation) despite preserved endogenous thrombin potential (amount of thrombin)) were more likely to be male (49% vs 20%, p = 0.003) with increased low-density lipoprotein cholesterol (3.3 vs 2.6 mmol/L, p = 0.003), P-selectin (54.2 vs 47.3 ng/mL, p = 0.038) and TFPI (18.7 vs 8.6 ng/ml, p = 0.001). In addition to reduced velocity index and thrombin peak, controls in the highest TFPI tertile also demonstrated a poorer lipid profile. GCAs can detect subtle changes of the hemostatic profile. Interestingly, reduced thrombin generation was paradoxically associated with increased cardiovascular risk factors, possibly attributable to increased TFPI. This finding may suggest compensation by the coagulation system in response to endothelial activation and represent a biomarker for early cardiovascular disease. A larger prospective study evaluating these assays in the cardiovascular disease population is ongoing.

SummaryThe CLARITY trial (Controlled evaLuation of Angiotensin Receptor Blockers for COVID-19 respIraTorY Disease) 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 CLARITY trial is a multi-centre, randomised controlled Bayesian adaptive 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 2020.https://clinicaltrials.gov/ct2/show/NCT04394117Clinical Trial Registry of India: CTRI/2020/07/026831Version and revisionsVersion 1.0. No revisions.

Background SARS-CoV-2 binds to membrane-bound angiotensin-converting enzyme 2 (ACE2) which may result in downregulation of membrane-bound ACE2. ACE2 is a key regulator of the renin-angiotensin system (RAS) and is responsible for degrading angiotensin II and thereby counteracting its pro-inflammatory, pro-fibrotic effects mediated through the angiotensin II type 1 receptor (AT1R). As AT1R is directly blocked by angiotensin receptor blockers (ARBs), these agents may offer a safe, low-cost solution for reducing COVID-19 respiratory outcomes. Methods and discussion CLARITY is a pragmatic, adaptive, two-arm, multi-centre, comparative effectiveness phase III randomised controlled trial that examines whether ARBs reduce COVID-19 severity among high-risk patients. Recruiting in India and Australia, the trial will compare treatment with a maximum tolerated daily dose of an ARB to standard of care. Treatment allocation is blinded in India but open-label in Australia due to interruptions to placebo supply in the latter. The primary endpoint is a 7-point ordinal scale of clinical states, ranging from no limitation of activities (category 1) to death (category 7), assessed on day 14. Secondary outcomes include the 7-point scale assessed at day 28 and 28- and 90-day mortality. The design adapts the sample size based on accumulating data via frequent interim analyses and the use of predictive probability to determine whether the current sample size is sufficient or continuing accrual would be futile. The trial commenced recruitment on 18 August 2020. Trial registration ClinicalTrials.gov, NCT04394117. Registered on 19 May 2020. Clinical Trial Registry of India: CTRI/2020/07/026831)

BackgroundAlthough it is known that winter inclusive of the Christams holiday period is associated with an increased risk of dying compared to other times of the year, very few studies have specifically examined this phenomenon within a population cohort subject to baseline profiling and prospective follow-up. In such a cohort, we sought to determine the specific characteristics of mortality occuring during the Christmas holidays. MethodsBaseline profiling and outcome data were derived from a prospective population-based cohort with longitudinal follow-up in Central Norway - the Nord-Trøndelag Health Study. From 1984-1986, 88% of the target population comprising 39,273 men and 40,353 women aged 48±18 and 50±18 years, respectively, were profiled. We examined the long-term pattern of all-cause mortality and specific causes of death according to season, month and individual days of the year to determine the number of excess (cause-specific) deaths occuring at key timepoints (including the Christmas holidays). ResultsDuring 33.5 (IQR 17.1-34.4) years follow-up, 19,879 (50.7%) men and 19,316 (49.3%) women died at age-adjusted rate of 5.3 and 4.6 deaths per 1000/annum, respectively. Each winter, there were 44 (95% CI 43-45) more all-cause deaths compared to summer, with 21 (95% CI 20-22) more deaths attributable to cardiovascular disease. Compared to any other time of the year, December 25th-27th was the deadliest; being associated with an excess of 1.3 (95% CI 1.1-1.5) all-cause and 1.0 (95% CI 0.7-1.3) cardiovascular-related deaths per day each year. Compared to the pre-Christmas/Winter period (1st-21st December), the incidence rate ratio of all-cause mortality increased to 1.22 (95% CI 1.16-1.27) and 1.17 (95% 1.11-1.22) in men and women, respectively, in the next 21 days (Christmas/New Year holiday period). All observed differences were highly significant (P

Background Although it is known that winter inclusive of the Christmas holiday period is associated with an increased risk of dying compared to other times of the year, very few studies have specifically examined this phenomenon within a population cohort subject to baseline profiling and prospective follow-up. In such a cohort, we sought to determine the specific characteristics of mortality occuring during the Christmas holidays. Methods Baseline profiling and outcome data were derived from a prospective population-based cohort with longitudinal follow-up in Central Norway - the Trøndelag Health (HUNT) Study. From 1984 to 1986, 88% of the target population comprising 39,273 men and 40,353 women aged 48 ± 18 and 50 ± 18 years, respectively, were profiled. We examined the long-term pattern of mortality to determine the number of excess (all-cause and cause-specific) deaths that occurred during winter overall and, more specifically, the Christmas holidays. Results During 33.5 (IQR 17.1–34.4) years follow-up, 19,879 (50.7%) men and 19,316 (49.3%) women died at age-adjusted rate of 5.3 and 4.6 deaths per 1000/annum, respectively. Overall, 1540 (95% CI 43–45 deaths/season) more all-cause deaths occurred in winter (December to February) versus summer (June to August), with 735 (95% CI 20–22 deaths per season) of these cardiovascular-related. December 25th–27th was the deadliest 3-day period of the year; being associated with 138 (95% CI 96–147) and 102 (95% CI 72–132) excess all-cause and cardiovascular-related deaths, respectively. Accordingly, compared to 1st–21st December (equivalent winter conditions), the incidence rate ratio of all-cause mortality increased to 1.22 (95% CI 1.16–1.27) and 1.17 (95% 1.11–1.22) in men and women, respectively, during the next 21 days (Christmas/New Year holidays). All observed differences were highly significant (P Conclusion Beyond a broader pattern of seasonally-linked mortality characterised by excess winter deaths, the deadliest time of year in Central Norway coincides with the Christmas holidays. During this time, the pattern and frequency of cardiovascular-related mortality changes markedly; contrasting with a more stable pattern of cancer-related mortality. Pending confirmation in other populations and climates, further research to determine if these excess deaths are preventable is warranted.

Background Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), the causative agent of COVID-19, enters human cells by binding of its viral protein to the aminopeptidase angiotensin-converting enzyme 2 (ACE2). This has led to speculation whether treatment with renin-angiotensin system (RAS) inhibitors was associated with an increased likelihood of a positive test for COVID-19 and risk of mortality. Aims We performed a systematic review and meta-analysis to investigate whether RAS inhibitors increased the likelihood of a positive test or death/severe illness in patients with COVID-19. Methods A systematic search of MEDLINE, PubMed and EMBASE was conducted for studies stratified by the use of angiotensin-converting enzyme inhibitors (ACEI) or angiotensin receptor blockers (ARB). Pooled analysis was performed using a random-effects model. Results Seven trials of 73 122 patients were included. Overall, 16 624 (22.7%) patients had a positive COVID-19 test and 7892 (10.8%) were on a RAS inhibitor. RAS inhibitors were not associated with higher likelihood of a positive COVID-19 test result (odds ratio (OR) 0.97 (95% CI 0.97-1.05, P = 0.48) with low heterogeneity. This was comparable when stratifying by use of each medication class. The use of RAS inhibitors was also not associated with mortality or severe illness (OR 0.89, 95% CI 0.73-1.07, P = 0.21) with moderate heterogeneity. Conclusion Use of ACEI or ARB was not associated with a heightened susceptibility for a positive diagnosis of COVID-19. Furthermore, they were not associated with increased illness severity or mortality due to COVID-19. Randomised controlled trials are needed to address definitively the potential benefits or harms of RAS inhibitors in patients with COVID-19.

Background Recent evidence from animal studies suggests that elastin degradation accelerates atherosclerosis and increases risk of plaque rupture and subsequent myocardial infarction and stroke. Desmosine is an elastin-specific degradation product. We analysed the prognostic value of plasma desmosine (pDES) in a cohort of patients with coronary artery disease (CAD). Methods Patients with CAD (n=400) undergoing elective coronary angiography were prospectively recruited over 3 years and had bloods drawn for analysis of pDES using a validated stable isotope dilution liquid chromatography-tandem mass spectrometry method. Patients were followed up for 12 months for major adverse cardiovascular events (MACE: composite of death, myocardial infarction, target vessel repeat revascularisation, target lesion revascularisation, and heart failure hospital admission). The upper limit of normal for pDES is 0.35 ng/mL. The predictive value of pDES for MACE was analysed with Cox-proportional hazards ratio (HR) model and Kaplan-Meier survival analysis. Results During follow-up, there were 36 MACE events. Median pDES level across the entire cohort was 0.3 ng/mL (IQR 0.23–0.41 ng/mL). Patients with a pDES level >0.35 ng/mL were more likely to be male and older with a mean age of 69.7±10.3 years, have a history of prior stroke or transient ischaemic attack (TIA) and COPD. In univariable analysis, a pDES level of >0.35 ng/mL was associated with an increased risk of MACE (HR 4.76, 95% CI: 2.34–9.68, p0.35 ng/mL was associated with risk of MACE after adjustment for age, sex, COPD status and previous stroke and TIA (HR 3.97; 95% CI: 1.82–8.67, p=0.001) (Figure). Conclusion Increased elastin degradation as measured by elevated pDES levels, predicts outcomes in patients with CAD independent of traditional cardiovascular risk factors and may play a role as a future biomarker in these patients. Kaplan-Meier survival analysis Funding Acknowledgement Type of funding source: None

Aims Angiotensin-converting enzyme 2 (ACE2) is the cellular entry point for severe acute respiratory syndrome coronavirus (SARS-CoV-2)—the cause of coronavirus disease 2019 (COVID-19). However, the effect of renin-angiotensin system (RAS)-inhibition on ACE2 expression in human tissues of key relevance to blood pressure regulation and COVID-19 infection has not previously been reported. Methods and results We examined how hypertension, its major metabolic co-phenotypes, and antihypertensive medications relate to ACE2 renal expression using information from up to 436 patients whose kidney transcriptomes were characterized by RNA-sequencing. We further validated some of the key observations in other human tissues and/or a controlled experimental model. Our data reveal increasing expression of ACE2 with age in both human lungs and the kidney. We show no association between renal expression of ACE2 and either hypertension or common types of RAS inhibiting drugs. We demonstrate that renal abundance of ACE2 is positively associated with a biochemical index of kidney function and show a strong enrichment for genes responsible for kidney health and disease in ACE2 co-expression analysis. Conclusion Our results indicate that neither hypertension nor antihypertensive treatment is likely to alter the expression of the key entry receptor for SARS-CoV-2 in the human kidney. Our data further suggest that in the absence of SARS-CoV-2 infection, kidney ACE2 is most likely nephro-protective but the age-related increase in its expression within lungs and kidneys may be relevant to the risk of SARS-CoV-2 infection., Graphical Abstract Graphical Abstract

Aims Endothelial dysfunction is a precursor to the development of symptomatic atherosclerosis. Retinal microvascular reactivity to flicker light stimulation is a marker of endothelial function and can be quantified in vivo. We sought to determine whether retinal microvascular endothelial dysfunction predicts long-term major adverse cardiovascular events (MACE). Methods and results In a single center prospective observational study, patients with coronary artery disease (CAD) or cardiovascular risk factors underwent dynamic retinal vessel assessment in response to flicker light stimulation and were followed up for MACE. Retinal microvascular endothelial dysfunction was quantified by measuring maximum flicker light-induced retinal arteriolar (FI-RAD) and venular dilatation (FI-RVD). In total, 252 patients underwent dynamic retinal vessel assessment and 242 (96%) had long-term follow-up. Of the 242 patients, 88 (36%) developed MACE over a median period of 8.6 years (IQR 6.0-9.1). After adjustment for traditional risk factors, patients within the lowest quintile of FI-RAD had the highest risk of MACE (OR 5.21; 95% CI 1.78, 15.28). Patients with lower FI-RAD were also more likely to die (OR 2.09; 95% CI 1.00, 4.40, per standard deviation decrease in FI-RAD). In Kaplan-Meier analysis, patients with FI-RAD responses below the cohort median of 1.4% exhibited reduced MACE-free survival (55.5 vs. 71.5%; log-rank p = 0.004). FI-RVD was not predictive of MACE. Conclusions Retinal arteriolar endothelial dysfunction is an independent predictor of MACE in patients with CAD or cardiovascular risk factors. Dynamic retinal vessel analysis may provide added benefit to traditional risk factors in stratifying patients at risk for cardiovascular events. Translational perspective Subclinical endothelial dysfunction precedes cardiovascular diseases and can be assessed non-invasively using the retinal microvascular network. Retinal arteriolar endothelial dysfunction is an independent predictor of MACE and all-cause mortality in patients with established coronary artery disease or cardiovascular risk factors. Validation studies and investigation into the lifestyle and pharmacological modifiability of endothelial dysfunction could enhance risk prediction and guide intensification of therapy.

Angiotensin converting enzyme 2 (ACE2) is the cellular entry point for severe acute respiratory syndrome coronavirus (SARS-CoV-2) - the cause of COVID-19 disease. It has been hypothesized that use of renin-angiotensin system (RAS) inhibiting medications in patients with hypertension, increases the expression of ACE2 and thereby increases the risk of COVID-19 infection and severe outcomes or death. However, the effect of RAS-inhibition on ACE2 expression in human tissues of key relevance to blood pressure regulation and COVID-19 infection has not previously been reported. We examined how hypertension, its major metabolic co-phenotypes and antihypertensive medications relate to ACE2 renal expression using information from up to 436 patients whose kidney transcriptomes were characterised by RNA-sequencing. We further validated some of the key observations in other human tissues and/or a controlled experimental model. Our data reveal increasing expression of ACE2 with age in both human lungs and the kidney. We show no association between renal expression of ACE2 and either hypertension or common types of RAS inhibiting drugs. We demonstrate that renal abundance of ACE2 is positively associated with a biochemical index of kidney function and show a strong enrichment for genes responsible for kidney health and disease in ACE2 co-expression analysis. Collectively, our data indicate that neither hypertension nor antihypertensive treatment are likely to alter individual risk of SARS-CoV-2 infection or influence clinical outcomes in COVID-19 through changes of ACE2 expression. Our data further suggest that in the absence of SARS-CoV-2 infection, kidney ACE2 is most likely nephro-protective but the age-related increase in its expression within lungs and kidneys may be relevant to the risk of SARS-CoV-2 infection.