Proteomic profiles of left atrial volume and its influence on response to spironolactone: Findings from the HOMAGE trial and STANISLAS cohort.

AIMS: High left ventricular filling pressure increases left atrial volume and causes myocardial fibrosis, which may decrease with spironolactone. We studied clinical and proteomic characteristics associated with left atrial volume indexed by body surface area (LAVi), and whether LAVi influences the response to spironolactone on biomarker expression and clinical variables. METHODS AND RESULTS: In the HOMAGE trial, where people at risk of heart failure were randomized to spironolactone or control, we analysed 421 participants with available LAVi and 276 proteomic measurements (Olink) at baseline, month 1 and 9 (mean age 73 ± 6 years; women 26%; LAVi 32 ± 9 ml/m2). Circulating proteins associated with LAVi were also assessed in asymptomatic individuals from a population-based cohort (STANISLAS; n = 1640; mean age 49 ± 14 years; women 51%; LAVi 23 ± 7 ml/m2). In both studies, greater LAVi was significantly associated with greater left ventricular masses and volumes. In HOMAGE, after adjustment and correction for multiple testing, greater LAVi was associated with higher concentrations of matrix metallopeptidase-2 (MMP-2), insulin-like growth factor binding protein-2 (IGFBP-2) and N-terminal pro-B-type natriuretic peptide (NT-proBNP) (false discovery rates [FDR] <0.05). These associations were externally replicated in STANISLAS (all FDR <0.05). Among these biomarkers, spironolactone decreased concentrations of MMP-2 and NT-proBNP, regardless of baseline LAVi (pinteraction > 0.10). Spironolactone also significantly reduced LAVi, improved left ventricular ejection fraction, lowered E/e', blood pressure and serum procollagen type I C-terminal propeptide (PICP) concentration, a collagen synthesis marker, regardless of baseline LAVi (pinteraction > 0.10). CONCLUSION: In individuals without heart failure, LAVi was associated with MMP-2, IGFBP-2 and NT-proBNP. Spironolactone reduced these biomarker concentrations as well as LAVi and PICP, irrespective of left atrial size.

Sepsis-associated acute kidney injury: recent advances in enrichment strategies, sub-phenotyping and clinical trials.

Acute kidney injury (AKI) often complicates sepsis and is associated with high morbidity and mortality. In recent years, several important clinical trials have improved our understanding of sepsis-associated AKI (SA-AKI) and impacted clinical care. Advances in sub-phenotyping of sepsis and AKI and clinical trial design offer unprecedented opportunities to fill gaps in knowledge and generate better evidence for improving the outcome of critically ill patients with SA-AKI. In this manuscript, we review the recent literature of clinical trials in sepsis with focus on studies that explore SA-AKI as a primary or secondary outcome. We discuss lessons learned and potential opportunities to improve the design of clinical trials and generate actionable evidence in future research. We specifically discuss the role of enrichment strategies to target populations that are most likely to derive benefit and the importance of patient-centered clinical trial endpoints and appropriate trial designs with the aim to provide guidance in designing future trials.

Outcomes for clinical trials involving adults with chronic kidney disease: a multinational Delphi survey involving patients, caregivers, and health professionals.

BACKGROUND: Many outcomes of high priority to patients and clinicians are infrequently and inconsistently reported across trials in CKD, which generates research waste and limits evidence-informed decision making. We aimed to generate consensus among patients/caregivers and health professionals on critically important outcomes for trials in CKD prior to kidney failure and the need for kidney replacement therapy, and to describe the reasons for their choices. METHODS: Online two-round international Delphi survey. Adult patients with CKD (all stages and diagnoses), caregivers and health professionals, who could read English, Spanish, or French were eligible. Participants rated the importance of outcomes using a Likert scale (7-9 indicating critical importance) and a best-worst scale. The scores for the two groups were assessed to determine absolute and relative importance. Comments were analysed thematically. RESULTS: In total, 1 399 participants from 73 countries completed Round 1 of the Delphi survey including 628 (45%) patients/caregivers and 771 (55%) health professionals. In Round 2, 790 participants (56% response rate) from 63 countries completed the survey including 383 (48%) patients/caregivers and 407 (52%) health professionals. The overall top five outcomes were: kidney function, need for dialysis/transplant, life participation, cardiovascular disease, and death. In the final round, patients/caregivers indicated higher scores for most outcomes (17/22 outcomes), and health professionals gave higher priority to mortality, hospitalization, and cardiovascular disease (mean difference > 0.3). Consensus was based upon the two groups yielding median scores of ≥ 7 and mean scores > 7, and the proportions of both groups rating the outcome as 'critically important' being greater than 50%. Four themes reflected the reasons for their priorities: imminent threat of a health catastrophe, signifying diminishing capacities, ability to self-manage and cope, and tangible and direct consequences. CONCLUSION: Across trials in CKD, the outcomes of highest priority to patients, caregivers, and health professionals were kidney function, need for dialysis/transplant, life participation, cardiovascular disease, and death.

Phenotyping patients with ischaemic heart disease at risk of developing heart failure: an analysis of the HOMAGE trial.

AIMS: We aim to characterize the clinical and proteomic profiles of patients at risk of developing heart failure (HF), with and without coronary artery disease (CAD) or prior myocardial infarction (MI). METHODS AND RESULTS: HOMAGE evaluated the effect of spironolactone on plasma and serum markers of fibrosis over 9 months of follow-up in participants with (or at risk of having) CAD, and raised natriuretic peptides. In this post hoc analysis, patients were classified as (i) neither CAD nor MI; (ii) CAD; or (iii) MI. Proteomic between-group differences were evaluated through logistic regression and narrowed using backward stepwise selection and bootstrapping. Among the 527 participants, 28% had neither CAD or MI, 31% had CAD, and 41% had prior MI. Compared with people with neither CAD nor MI, those with CAD had higher baseline plasma concentrations of matrix metalloproteinase-7 (MMP-7), galectin-4 (GAL4), plasminogen activator inhibitor 1 (PAI-1), and lower plasma peptidoglycan recognition protein 1 (PGLYRP1), whilst those with a history of MI had higher plasma MMP-7, neurotrophin-3 (NT3), pulmonary surfactant-associated protein D (PSPD), and lower plasma tumour necrosis factor-related activation-induced cytokine (TRANCE). Proteomic signatures were similar for patients with CAD or prior MI. Treatment with spironolactone was associated with an increase of MMP7, NT3, and PGLYRP1 at 9 months. CONCLUSIONS: In patients at risk of developing HF, those with CAD or MI had a different proteomic profile regarding inflammatory, immunological, and collagen catabolic processes.

Effect of Dialysate and Plasma Sodium on Mortality in a Global Historical Hemodialysis Cohort.

SIGNIFICANCE STATEMENT: This large observational cohort study aimed to investigate the relationship between dialysate and plasma sodium concentrations and mortality among maintenance hemodialysis patients. Using a large multinational cohort of 68,196 patients, we found that lower dialysate sodium concentrations (≤138 mmol/L) were independently associated with higher mortality compared with higher dialysate sodium concentrations (>138 mmol/L). The risk of death was lower among patients exposed to higher dialysate sodium concentrations, regardless of plasma sodium levels. These results challenge the prevailing assumption that lower dialysate sodium concentrations improve outcomes in hemodialysis patients. The study confirms that until robust evidence from randomized trials that are underway is available, nephrologists should remain cautious in reconsideration of dialysate sodium prescribing practices to optimize cardiovascular outcomes and reduce mortality in this population. BACKGROUND: Excess mortality in hemodialysis (HD) patients is largely due to cardiovascular disease and is associated with abnormal fluid status and plasma sodium concentrations. Ultrafiltration facilitates the removal of fluid and sodium, whereas diffusive exchange of sodium plays a pivotal role in sodium removal and tonicity adjustment. Lower dialysate sodium may increase sodium removal at the expense of hypotonicity, reduced blood volume refilling, and intradialytic hypotension risk. Higher dialysate sodium preserves blood volume and hemodynamic stability but reduces sodium removal. In this retrospective cohort, we aimed to assess whether prescribing a dialysate sodium ≤138 mmol/L has an effect on survival outcomes compared with dialysate sodium >138 mmol/L after adjusting for plasma sodium concentration. METHODS: The study population included incident HD patients from 875 Fresenius Medical Care Nephrocare clinics in 25 countries between 2010 and 2019. Baseline dialysate sodium (≤138 or >138 mmol/L) and plasma sodium (<135, 135-142, >142 mmol/L) concentrations defined exposure status. We used multivariable Cox regression model stratified by country to model the association between time-varying dialysate and plasma sodium exposure and all-cause mortality, adjusted for demographic and treatment variables, including bioimpedance measures of fluid status. RESULTS: In 2,123,957 patient-months from 68,196 incident HD patients with on average three HD sessions per week dialysate sodium of 138 mmol/L was prescribed in 63.2%, 139 mmol/L in 15.8%, 140 mmol/L in 20.7%, and other concentrations in 0.4% of patients. Most clinical centers (78.6%) used a standardized concentration. During a median follow-up of 40 months, one third of patients ( n =21,644) died. Dialysate sodium ≤138 mmol/L was associated with higher mortality (multivariate hazard ratio for the total population (1.57, 95% confidence interval, 1.25 to 1.98), adjusted for plasma sodium concentrations and other confounding variables. Subgroup analysis did not show any evidence of effect modification by plasma sodium concentrations or other patient-specific variables. CONCLUSIONS: These observational findings stress the need for randomized evidence to reliably define optimal standard dialysate sodium prescribing practices.

Mineralocorticoid receptor antagonist use in chronic kidney disease with type 2 diabetes: a clinical practice document by the European Renal Best Practice (ERBP) board of the European Renal Association (ERA).

Chronic kidney disease (CKD) in individuals with type 2 diabetes (T2D) represents a major public health issue; it develops in about 30%-40% of patients with diabetes mellitus and is the most common cause of CKD worldwide. Patients with CKD and T2D are at high risk of both developing kidney failure and of cardiovascular events. Renin-angiotensin system (RAS) blockers were considered the cornerstone of treatment of albuminuric CKD in T2D for more than 20 years. However, the residual risk of progression to more advanced CKD stages under RAS blockade remains high, while in major studies with these agents in patients with CKD and T2D no significant reductions in cardiovascular events and mortality were evident. Steroidal mineralocorticoid receptor antagonists (MRAs) are known to reduce albuminuria in individuals on RAS monotherapy, but their wide clinical use has been curtailed by the significant risk of hyperkalemia and absence of trials with hard renal outcomes. In recent years, non-steroidal MRAs have received increasing interest due to their better pharmacologic profile. Finerenone, the first compound of this class, was shown to effectively reduce the progression of kidney disease and of cardiovascular outcomes in participants with T2D in phase 3 trials. This clinical practice document prepared from a task force of the European Renal Best Practice board summarizes current knowledge on the role of MRAs in the treatment of CKD in T2D aiming to support clinicians in decision-making and everyday management of patients with this condition.

Hypotension in heart failure is less harmful if associated with high or increasing doses of heart failure medication: Insights from the Swedish Heart Failure Registry.

AIMS: Heart failure (HF) medication may reduce blood pressure (BP). Low BP is associated with worse outcomes but how this association is modified by HF medication has not been studied. We evaluated the association between BP and outcomes according to HF medication dose in HF with reduced ejection fraction (HFrEF). METHODS AND RESULTS: We studied HFrEF patients from the Swedish HF registry (2000-2018). Associations between systolic BP (SBP) and cardiovascular death (CVD) and/or HF hospitalization (HFH) were analysed according to doses of renin-angiotensin system (RAS) inhibitors, beta-blockers and mineralocorticoid receptor antagonists (MRA). Among 42 040 patients (median age 74.0), lower baseline SBP was associated with higher risk of CVD/HFH (adjusted hazard ratio [HR] per 10 mmHg higher SBP: 0.92, 95% confidence interval [CI] 0.92-0.93), which was less high risk under optimized RAS inhibitor and beta-blocker doses (10% decrease in event rates per 10 mmHg SBP increase in untreated patients vs. 7% decrease in patients at maximum dose, both adjusted p < 0.02). Among the 13 761 patients with repeated measurements, 9.9% reported a SBP decrease >10 mmHg when HF medication doses were increased, whereas 24.6% reported a SBP decrease >10 mmHg with stable/decreasing doses. Decreasing SBP was associated with higher risk of CVD/HFH in patients with stable (HR 1.10, 95% CI 1.04-1.17) or decreasing (HR 1.29, 95% CI 1.18-1.42) HF medication dose but not in patients with an increase in doses (HR 0.94, 95% CI 0.86-1.02). CONCLUSIONS: The association of lower SBP with higher risk of CVD/HFH is attenuated in patients with optimized HF medication. These results suggest that low or declining SBP should not limit HF medication optimization.

From Cardiorenal Syndrome to Chronic Cardiovascular and Kidney Disorder: A Conceptual Transition.

The association between cardiac and kidney dysfunction has received attention over the past two decades. A putatively unique syndrome, the cardiorenal syndrome, distinguishing five subtypes on the basis of the chronology of cardiac and kidney events, has been widely adopted. This review discusses the methodologic and practical problems inherent to the current classification of cardiorenal syndrome. The term "disorder" is more appropriate than the term "syndrome" to describe concomitant cardiovascular and kidney dysfunction and/or damage. Indeed, the term disorder designates a disruption induced by disease states to the normal function of organs or organ systems. We apply Occam's razor to the chronology-based construct to arrive at a simple definition on the basis of the coexistence of cardiovascular disease and CKD, the chronic cardiovascular-kidney disorder (CCKD). This conceptual framework builds upon the fact that cardiovascular and CKD share common risk factors and pathophysiologic mechanisms. Biological changes set in motion by kidney dysfunction accelerate cardiovascular disease progression and vice versa . Depending on various combinations of risk factors and precipitating conditions, patients with CCKD may present initially with cardiovascular disease or with hallmarks of CKD. Treatment targeting cardiovascular or kidney dysfunction may improve the outcomes of both. The portfolio of interventions targeting the kidney-cardiovascular continuum is in an expanding phase. In the medium term, applying the new omics sciences may unravel new therapeutic targets and further improve the therapy of CCKD. Trials based on cardiovascular and kidney composite end points are an attractive and growing area. Targeting pathways common to cardiovascular and kidney diseases will help prevent the adverse health effects of CCKD.

Early diagnosis of chronic kidney disease in patients with diabetes in France: multidisciplinary expert opinion, prevention value and practical recommendations.

Diabetes is the leading cause of end-stage kidney disease (ESKD), accounting for approximately 50% of patients starting dialysis. However, the management of these patients at the stage of chronic kidney disease (CKD) remains poor, with fragmented care pathways among healthcare professionals (HCPs). Diagnosis of CKD and most of its complications is based on laboratory evidence. This article provides an overview of critical laboratory evidence of CKD and their limitations, such as estimated glomerular filtration rate (eGFR), urine albumin-to-creatinine ratio (UACR), Kidney Failure Risk Equation (KFRE), and serum potassium. eGFR is estimated using the CKD-EPI 2009 formula, more relevant in Europe, from the calibrated dosage of plasma creatinine. The estimation formula and the diagnostic thresholds have been the subject of recent controversies. Recent guidelines emphasized the combined equation using both creatinine and cystatin for improved estimation of GFR. UACR on a spot urine sample is a simple method that replaces the collection of 24-hour urine. Albuminuria is the preferred test because of increased sensitivity but proteinuria may be appropriate in some settings as an alternative or in addition to albuminuria testing. KFRE is a new tool to estimate the risk of progression to ESKD. This score is now well validated and may improve the nephrology referral strategy. Plasma or serum potassium is an important parameter to monitor in patients with CKD, especially those on renin-angiotensin-aldosterone system (RAAS) inhibitors or diuretics. Pre-analytical conditions are essential to exclude factitious hyperkalemia. The current concept is to correct hyperkalemia using pharmacological approaches, resins or diuretics to be able to maintain RAAS blockers at the recommended dose and discontinue them at last resort. This paper also suggests expert recommendations to optimize the healthcare pathway and the roles and interactions of the HCPs involved in managing CKD in patients with diabetes.

Sodium polystyrene is unsafe and should not be prescribed for the treatment of hyperkalaemia: primum non nocere!

'Old-generation' potassium (K) binders [i.e. sodium (SPS) and calcium polystyrene sulfonate] are widely used, but with substantial heterogeneity across countries to treat hyperkalaemia (HK). However, there are no randomized data to support their chronic use to manage HK, nor have they been shown to have a renin-angiotensin-aldosterone system inhibitor (RAASi)-enabling effect. These compounds have poor tolerability and an unpredictable onset of action and magnitude of K lowering. Furthermore, SPS may induce fluid overload, owing to the fact that it exchanges K for sodium. Its use has also been associated with colonic necrosis, as emphasized by a black box warning from the US Food and Drug Administration. In contrast, two new K binders, patiromer and sodium zirconium cyclosilicate, have been shown to be safe and well tolerated for chronic management of HK, thereby enabling RAASi optimization, as acknowledged by the latest international cardiorenal guidelines. In view of the lack of reliable evidence regarding the efficacy and safety of the old-generation K binders compared with the placebo-controlled randomized and real-word evidence demonstrating the safety, efficacy and RAASi-enabling effect of the new K binders, clinicians should now use these new K binders to treat HK (primum non nocere!).

Role of aldosterone in mid- and long-term left ventricular remodelling after acute myocardial infarction: The REMI study.

AIMS: Whether aldosterone levels after myocardial infarction (MI) are associated with mid- and long-term left ventricular (LV) remodelling in the era of systematic use of renin-angiotensin system inhibitors is uncertain. We prospectively investigated the relationship between aldosterone levels and mid- and long-term LV remodelling in patients with acute MI. METHODS AND RESULTS: Plasma aldosterone was measured in 119 patients successfully treated by primary percutaneous coronary angioplasty for a first acute ST-elevation MI (STEMI) 2-4 days after the acute event. LV volumes were assessed by cardiac magnetic resonance (CMR) and transthoracic echocardiography (TTE) in the same timeframe and 6 months later. LV assessment was repeated by TTE 3-9 years after MI (n = 80). The median aldosterone level at baseline was 23.1 [16.8; 33.1] pg/ml. In the multivariable model, higher post-MI aldosterone concentration was significantly associated with more pronounced increase in LV end-diastolic volume index (TTE: ß ± standard error [SE]: 0.113 ± 0.046, p = 0.015; CMR: ß ± SE: 0.098 ± 0.040, p = 0.015) and LV end-systolic volume index (TTE: ß ± SE: 0.083 ± 0.030, p = 0.008; CMR: ß ± SE: 0.064 ± 0.032, p = 0.048) at 6-month follow-up, regardless of the method of assessment. This result was consistent also in patients with a LV ejection fraction (LVEF) >40%. The association between baseline plasma aldosterone and adverse LV remodelling did not persist at the 3-9-year follow-up evaluation. CONCLUSION: Aldosterone concentration in the acute phase was associated with adverse LV remodelling in the medium term, even in the subgroup of patients with LVEF >40%, suggesting a potential role of the mineralocorticoid system in post-MI adverse remodelling. Plasma aldosterone was no longer associated with LV remodelling in the long term (NCT01109225).

Impact of disease duration on proteomic bioprofile and prognosis in rheumatoid arthritis patients.

OBJECTIVES: Cardiovascular disease worsens the prognosis of rheumatoid arthritis (RA) and vice-versa. Inflammation may be a common pathway for both conditions. It is expected that a longer RA duration leads to a greater inflammatory cumulative exposure burden; however, studies on the association between RA disease duration and outcomes are scarce. Our aim is to compare the characteristics, biomarker expression and outcomes according to the duration of RA. METHODS: Prospective cohort study including 399 RA patients, with detailed clinical, echocardiographic, and proteomic phenotyping that were compared across tertiles of RA disease duration. Cox proportional models were used to study the association of disease duration with cardiovascular outcomes. RESULTS: RA duration tertiles were: tertile 1 with median of 3.2; tertile 2 with median of 8.8; and tertile 3 with median of 21.8 years. Compared to tertile 1, patients in tertile 3 were older, had more erosive disease, more frequent echocardiographic alterations, lower haemoglobin and walked a shorter distance on the 6MWT. Natriuretic peptides, cathepsin L1, galectin 9, matrix metalloproteinase-12, adrenomedullin and tumour necrosis factor receptor 11A were higher in patients with longer disease duration. Compared to patients in tertile 1, those in tertile 3 had higher risk of a subsequent cardiovascular hospitalisation or cardiovascular death (HR 2.71, 95%CI 1.06-6.92, p=0.04). CONCLUSIONS: RA patients with longer disease duration had more organ damage and worse outcomes than those with shorter disease duration. Biomarker expression suggested that patients with longer RA duration had activation of pathways related to inflammation, extracellular matrix organisation, fibrosis and congestion.

NGAL is a Novel Target in Hypertension by Modulating the NCC-Mediated Renal Na Balance.

BACKGROUND: The expression of NGAL/lcn2 (neutrophil gelatinase-associated lipocalin) is directly modulated by mineralocorticoid receptor activation but its role in blood pressure control is unclear. METHODS: a potential relationship between NGAL plasma levels, systolic blood pressure and urinary Na excretion was assessed in the STANISLAS cohort. The specific role of NGAL/lcn2 in salt-sensitive hypertension was studied using lcn2-knockout mice (lcn2 KO) fed with low-Na diet (0Na). RESULTS: we show that NGAL plasma levels positively correlate with systolic blood pressure, whereas they negatively correlate with urinary Na excretion in subjects of the STANISLAS cohort. Prolonged feeding of lcn2 KO mice with a 0Na diet induced lower systolic blood pressure than that of the control group (wildtype), suggesting a role for NGAL/lcn2 in Na-balance homeostasis. Short-term or prolonged 0Na increased Na-Cl cotransporter (NCC) phosphorylation in the cortex of wildtype mice, which was prevented in lcn2 KO mice. Recombinant mouse lcn2 injections in lcn2 KO mice induced NCC phosphorylation in the kidney cortex, associated with decreased urinary Na excretion. Ex vivo experiments using kidney slices from lcn2 KO mice showed increased NCC phosphorylation by recombinant murine lcn2. In addition, recombinant murine lcn2 induced activation of CamK2ß (calcium/calmodulin-dependent protein kinase II ß subunit) phosphorylation in lcn2 KO mice and in kidney slices, providing an underlying mechanism involved in lcn2-induced NCC phosphorylation. Indeed, the inhibition of CamK2ß prevented NCC phosphorylation induced by recombinant lcn2 in kidney slices. CONCLUSIONS: we highlight a novel role of NGAL/lcn2 as a modulator of the activity of the renal sodium transporter NCC affecting salt-sensitive blood pressure.

Budget Impact Analysis of Expanding Gliflozin Coverage in the CKD Population: A French Perspective.

INTRODUCTION: Gliflozins have historically been indicated for type 2 diabetes in France. However, their efficacy has recently been demonstrated in heart failure and chronic kidney disease (CKD), with positive recommendations by Haute Autorité de Santé for gliflozin therapies in these indications. The study objective was to investigate the 5-year budget impact associated with the introduction of gliflozins in addition to standard therapy in people with CKD and elevated albuminuria, regardless of diabetes status, from the perspective of the French healthcare system. METHODS: A budget impact model was developed to estimate the 5-year implications of incorporating gliflozins in the treatment of patients with CKD in France, using efficacy data from the Dapagliflozin and Prevention of Adverse Outcomes in Chronic Kidney Disease (DAPA-CKD) trial. Direct medical costs associated with drug acquisition and management, treatment-related adverse events, dialysis and kidney transplantation, and adverse clinical outcomes were considered. Market share forecasts were estimated from historical data and expert opinions. Event rates were derived from trial data, while cost data were sourced from published estimates. RESULTS: The introduction of gliflozins was estimated to be cost saving compared to the no gliflozins scenario, with an expected cumulative 5-year budget impact of -€650 million, driven by slowed disease progression in patients treated with gliflozins, with fewer patients cumulatively progressing to end-stage kidney disease (84,526 vs. 92,062). This, in addition to fewer hospitalisations for heart failure and deaths from any cause, led to substantial medical care cost offsets (kidney-related: - €894 million; hospitalisation for heart failure: - €14.3 million; end-of-life care: - €17.3 million) to the additional drug acquisition (€273 million) and treatment-related adverse events costs (€2.98 million). CONCLUSION: In concert with early diagnosis and proactive management of CKD, the expansion of the gliflozin indications into the French CKD population presents the opportunity to reduce the substantial burden associated with cardio-renal complications which outweighs the additional cost of the new treatment. INFOGRAPHIC.

Effect of weight-adjusted intermediate-dose versus fixed-dose prophylactic anticoagulation with low-molecular-weight heparin on venous thromboembolism among noncritically and critically ill patients with COVID-19: the COVI-DOSE trial, a multicenter, randomised, open-label, phase 4 trial.

Background: Venous thromboembolism is a major complication of coronavirus disease 2019 (COVID-19). We hypothesized that a weight-adjusted intermediate dose of anticoagulation may decrease the risk of venous thromboembolism COVID-19 patients. Methods: In this multicenter, randomised, open-label, phase 4, superiority trial with blinded adjudication of outcomes, we randomly assigned adult patients hospitalised in 20 French centers and presenting with acute respiratory SARS-CoV-2. Eligible patients were randomly assigned (1:1 ratio) to receive an intermediate weight-adjusted prophylactic dose or a fixed-dose of subcutaneous low-molecular-weight heparin during the hospital stay. The primary outcome corresponded to symptomatic deep-vein thrombosis (fatal) pulmonary embolism during hospitalization (COVI-DOSE ClinicalTrials.gov number: NCT04373707). Findings: Between May 2020, and April 2021, 1000 patients underwent randomisation in medical wards (noncritically ill) (80.1%) and intensive care units (critically ill) (19.9%); 502 patients were assigned to receive a weight-adjusted intermediate dose, and 498 received fixed-dose thromboprophylaxis. Symptomatic venous thromboembolism occurred in 6 of 502 patients (1.2%) in the weight-adjusted dose group and in 10 of 498 patients (2.1%) in the fixed-dose group (subdistribution hazard ratio, 0.59; 95% CI, 0.22-1.63; P = 0.31). There was a twofold increased risk of major or clinically relevant nonmajor bleeding: 5.9% in the weight-adjusted dose group and 3.1% in the fixed-dose group (P = 0.034). Interpretation: In the COVI-DOSE trial, the observed rate of thromboembolic events was lower than expected in patients hospitalized for COVID-19 infection, and the study was unable to show a significant difference in the risk of venous thromboembolism between the two low-molecular-weight-heparin regimens. Funding: French Ministry of Health, CAPNET, Grand-Est Region, Grand-Nancy Métropole.

Layer myocardial strain is the most heritable echocardiographic trait.

AIMS: Myocardial deformation assessed by strain analysis represents a significant advancement in our assessment of cardiac mechanics. However, whether this variable is genetically heritable or whether all/most of its variability is related to environmental factors is currently unknown. We sought to determine the heritability of echocardiographically determined cardiac mechanics indices in a population setting. METHODS AND RESULTS: A total of 1357 initially healthy subjects (women 51.6%; 48.2 ± 14.1 years) were included in this study from 20-year follow-up after the fourth visit of the longitudinal familial STANISLAS cohort (Lorraine, France). Data were acquired using state-of-the-art cardiac ultrasound equipment, using acquisition and measurement protocols recommended by the EACVI (European Association of Cardiovascular Imaging)/ASE (American Society of Echocardiography)/Industry Task Force. Layer-specific global longitudinal strain (GLS) and global circumferential strain (full-wall, subendocardial, and subepicardial) and conventional structural and functional cardiac parameters and their potential heritability were assessed using restricted maximum likelihood analysis, with genetic relatedness matrix calculated from genome-wide association data. Indices of longitudinal/circumferential myocardial function and left ventricular (LV) ejection fraction had low heritability (ranging from 10% to 20%). Diastolic and standard LV function parameters had moderate heritability (ranging from 20% to 30%) except for end-systolic and end-diastolic volumes (30% and 45%, respectively). In contrast, global longitudinal subendocardial strain (GLSEndo)/global longitudinal subepicardial strain (GLSEpi) ratio had a high level of heritability (65%). Except for GLSEndo/GLSEpi ratio, a large percentage of variance remained unexplained (>50%). CONCLUSIONS: In our population cohort, GLSEndo/GLSEpi ratio had a high level of heritability, whereas other classical and mechanical LV function parameters did not. Given the increasing recognition of GLSEndo/GLSEpi ratio as an early/sensitive imaging biomarker of systolic dysfunction, our results suggest the possible existence of individual genetic predispositions to myocardial decline.

Shared Heritability of Blood Pressure and Pulse Wave Velocity: Insights From the STANISLAS Cohort.

BACKGROUND: Pulse wave velocity (PWV) is a marker of arterial stiffness, which is intrinsically highly correlated with blood pressure (BP). However, the interplay of PWV and BP heritability has not been extensively studied. This study aimed to estimate the heritability of PWV and BP and determine the genetic correlation between PWV and BP. METHODS: The heritability of PWV and BP was estimated in 1080 subjects from the STANISLAS (Suivi Temporaire Annuel Non-Invasif de la Santé des Lorrains Assurés Sociaux) cohort with at least one relative using a linear mixed model within one frequentist and one Bayesian framework implemented, respectively, in the Gaston and MCMCglmm R packages. Then their genetic correlations were also estimated. RESULTS: The heritability estimations for PWV were within the same range of the heritability of systolic BP and diastolic BP (23%, 19%, and 27%, respectively). Daytime heritability of BP was higher than nighttime BP. In addition, phenotypic correlations between PWV and systolic BP/diastolic BP were, respectively, 0.34 and 0.23, whereas nonsignificant genetic correlations were 0.08 and 0.22 respectively, indicating that PWV and diastolic BP shared more polygenic codeterminants than PWV and systolic BP. CONCLUSIONS: Our results suggest that the heritability of PWV is >20% and within the same range as BP heritability. It also suggests that the link between PWV and BP goes beyond phenotypic association: PWV and BP (in particular diastolic BP) share common genetic determinants. This genetic interdependence of PWV and BP appears largely polygenic.

Protein Biomarkers of New-Onset Heart Failure: Insights From the Heart Omics and Ageing Cohort, the Atherosclerosis Risk in Communities Study, and the Framingham Heart Study.

BACKGROUND: We sought to identify protein biomarkers of new-onset heart failure (HF) in 3 independent cohorts (HOMAGE cohort [Heart Omics and Ageing], ARIC study [Atherosclerosis Risk in Communities], and FHS [Framingham Heart Study]) and assess if and to what extent they improve HF risk prediction compared to clinical risk factors alone. METHODS: A nested case-control design was used with cases (incident HF) and controls (without HF) matched on age and sex within each cohort. Plasma concentrations of 276 proteins were measured at baseline in ARIC (250 cases/250 controls), FHS (191/191), and HOMAGE cohort (562/871). RESULTS: In single protein analysis, after adjusting for matching variables and clinical risk factors (and correcting for multiple testing), 62 proteins were associated with incident HF in ARIC, 16 in FHS, and 116 in HOMAGE cohort. Proteins associated with incident HF in all cohorts were BNP (brain natriuretic peptide), NT-proBNP (N-terminal pro-B-type natriuretic peptide), eukaryotic translation initiation factor 4E-BP1 (4E-binding protein 1), hepatocyte growth factor (HGF), Gal-9 (galectin-9), TGF-alpha (transforming growth factor alpha), THBS2 (thrombospondin-2), and U-PAR (urokinase plasminogen activator surface receptor). The increment in C-index for incident HF based on a multiprotein biomarker approach, in addition to clinical risk factors and NT-proBNP, was 11.1% (7.5%-14.7%) in ARIC, 5.9% (2.6%-9.2%) in FHS, and 7.5% (5.4%-9.5%) in HOMAGE cohort, all P<0.001), each of which was a larger increase than that for NT-proBNP on top of clinical risk factors. Complex network analysis revealed a number of overrepresented pathways related to inflammation (eg, tumor necrosis factor and interleukin) and remodeling (eg, extracellular matrix and apoptosis). CONCLUSIONS: A multiprotein biomarker approach improves prediction of incident HF when added to natriuretic peptides and clinical risk factors.