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Congestion is a cardinal sign of heart failure (HF). In the past, it was seen as a homogeneous epiphenomenon that identified patients with advanced HF. However, current evidence shows that congestion in HF varies in quantity and distribution. This updated view advocates for a congestive-driven classification of HF according to onset (acute vs. chronic), regional distribution (systemic vs. pulmonary), compartment of distribution (intravascular vs. extravascular), and clinical vs. subclinical. Thus, this review will focus on the utility of circulating biomarkers for assessing and managing the different fluid overload phenotypes. This discussion focused on the clinical utility of the natriuretic peptides, carbohydrate antigen 125 (also called mucin 16), bio-adrenomedullin and mid-regional pro-adrenomedullin, ST2 (also known as interleukin-1 receptor-like 1), cluster of differentiation 146, troponin, C-terminal pro-endothelin-1, and parameters of haemoconcentration. The utility of circulation biomarkers on top of clinical evaluation, haemodynamics, and imaging needs to be better determined by dedicated studies. Some multiparametric frameworks in which these tools contribute to management are proposed.

This study used the ECOSSE model (v. 5.0.1) to simulate soil respiration (Rs) fluxes estimated from ecosystem respiration (Reco) for eight European permanent grassland (PG) sites with varying grass species, soils, and management. The main aim was to evaluate the strengths and weaknesses of the model in estimating Rs from grasslands, and to gain a better understanding of the terrestrial carbon cycle and how Rs is affected by natural and anthropogenic drivers. Results revealed that the current version of the ECOSSE model might not be reliable for estimating daily Rs fluxes, particularly in dry sites. The daily estimated and simulated Rs ranged from 0.95 to 3.1 g CO2-C m−2, and from 0.72 to 1.58 g CO2-C m−2, respectively. However, ECOSSE could still be a valuable tool for predicting cumulative Rs from PG. The overall annual relative deviation (RD) value between the cumulative estimated and simulated annual Rs was 11.9%. Additionally, the model demonstrated accurate simulation of Rs in response to grass cutting and slurry application practices. The sensitivity analyses and attribution tests revealed that increased soil organic carbon (SOC), soil pH, temperature, reduced precipitation, and lower water table (WT) depth could lead to increased Rs from soils. The variability of Rs fluxes across sites and years was attributed to climate, weather, soil properties, and management practices. The study suggests the need for additional development and application of the ECOSSE model, specifically in dry and low input sites, to evaluate the impacts of various land management interventions on carbon sequestration and emissions in PG.

Background Secretion of cardioprotective B-type natriuretic peptide 1–32 (BNP1-32) is increased proportionately with cardiac dysfunction, but its measurement in plasma is difficult. Therefore, less specific BNP and amino-terminal proBNP (NT-proBNP) assays that detect the precursor molecule proBNP alongside BNP or NT-proBNP metabolites were developed to reflect BNP1-32 secretion and are now mandated in the diagnosis of heart failure (HF). We compared the diagnostic performance of 2 widely used clinical assays: the Roche proBNPII assay, and Abbott BNP assay, against our recently developed in-house assays that measure either intact BNP1-32 or NT-proBNP. Methods EDTA plasma samples obtained from patients presenting with breathlessness (n = 195, 60 [31%] with clinically adjudicated HF) were assayed using the Roche NT-proBNP and our specific in-house BNP1-32 and NTBNP assays. A subset (n = 75) were also assessed with the Abbott BNP assay. Results Roche NT-proBNP was highly correlated with BNP1-32 and NTBNP (Spearman rho = 0.92 and 0.90, respectively, both Ps Conclusions Since all assays exhibited similar performance in the diagnosis of HF, currently mandated assays provide a reliable proxy for circulating concentrations of active BNP1-32 in HF diagnosis.

Iron deficiency (ID) is highly prevalent in patients with heart failure (HF) but its impact on prognosis in HF with preserved ejection fraction (HFpEF) remains unclear. We assessed whether ID defined by soluble transferrin receptor (sTfR) criteria is independently associated with all-cause mortality in patients with HFpEF, and evaluated its comparative prognostic performance to ID definitions in common clinical use.Data were analyzed from 788 patients (36% HFpEF) in a prospective multicenter HF cohort study. Baseline plasma samples were analyzed with respect to 4 definitions of ID: sTfR of ≥1.59 mg/L (IDID defined by sTfR criteria is independently associated with all-cause mortality in patients with HFpEF. Poor concordance between ID definitions suggests that iron biomarkers do not reflect the same pathological process in the complex relationship between iron and HF. Therefore, which definition should guide iron replacement needs further evaluation.

In patients with heart failure, the beneficial effects of drug and device therapies counteract to some extent ongoing cardiac damage. According to the net balance between these two factors, cardiac geometry and function may improve (reverse remodelling, RR) and even completely normalize (remission), or vice versa progressively deteriorate (adverse remodelling, AR). RR or remission predict a better prognosis, while AR has been associated with worsening clinical status and outcomes. The remodelling process ultimately involves all cardiac chambers, but has been traditionally evaluated in terms of left ventricular volumes and ejection fraction. This is the second part of a review paper by the Study Group on Biomarkers of the Heart Failure Association of the European Society of Cardiology dedicated to ventricular remodelling. This document examines the proposed criteria to diagnose RR and AR, their prevalence and prognostic value, and the variables predicting remodelling in patients managed according to current guidelines. Much attention will be devoted to RR in patients with heart failure with reduced ejection fraction because most studies on cardiac remodelling focused on this setting. © 2022 European Society of Cardiology.

Background and Objectives:There is an increasing awareness of the “Heart-Brain Connection”, whereby cardiovascular function is connected with cognition. Diffusion MRI studies reported higher brain free-water (FW) was associated with cerebrovascular disease (CeVD) and cognitive impairment. In current work, we investigated whether higher brain FW was related to blood cardiovascular biomarkers and whether FW mediated the associations between blood biomarkers and cognition.Methods:Participants recruited from two Singapore memory clinics between 2010 and 2015 underwent collection of blood samples and neuroimaging at baseline and longitudinal neuropsychological assessments up to 5 years. We examined the associations of blood cardiovascular biomarkers (high-sensitivity cardiac troponin-T (hs-cTnT), N-terminal pro-hormone B-type natriuretic peptide (NT-proBNP), growth/differentiation factor 15 (GDF-15)) with brain white matter (WM) and cortical grey matter (GM) FW derived from diffusion-MRI using whole brain voxel-wise general linear regression. We then assessed the relationships among baseline blood biomarkers, brain-FW, and cognitive decline using path models.Results:308 older adults (76 no cognitive impairment, 134 cognitive impairment no dementia, and 98 Alzheimer’s disease dementia and vascular dementia; mean [SD] age: 72.1 [8.3]) were included. We found that blood cardiovascular biomarkers were associated with higher FW in widespread WM regions and in specific GM networks including the default mode, executive control, and somatomotor networks at baseline (p< 0.01, family-wise error corrected). Baseline FW in widespread WM and network-specific GM fully mediated the associations of blood biomarkers with longitudinal cognitive decline over 5 years. Specifically, in GM, higher FW in the default mode network mediated the relationship with memory decline (hs-cTnT: β=-0.115, SE=0.034,p=0.001; NT-proBNP: β=-0.154, SE=0.046,p=0.001; GDF-15: β=-0.073, SE=0.027,p=0.006); in contrast, higher FW in the executive control network was responsible for executive function decline (hs-cTnT: β=-0.126, SE=0.039,p=0.001; NT-proBNP: β=-0.110, SE=0.038,p=0.004; GDF-15: β=-0.117, SE=0.035,p=0.001). Similar full mediation effects of brain FW were also identified for baseline cognition.Discussion:Results suggested a role of brain-FW in linking cardiovascular dysfunction to cognitive decline. These findings provide new evidence for brain-heart interactions, paving the way for prediction and monitoring of domain-specific cognitive trajectory.

This study used the ECOSSE model (v. 5.0.1) to simulate soil respiration (Rs) flux-es estimated from ecosystem respiration (Reco) for eight European permanent grassland (PG) sites with varying grass species, soils, and management. The main aim was to evaluate the strengths and weaknesses of the model in estimating Rs from grasslands, and to gain a better understanding of the terrestrial carbon cycle and how Rs is affect-ed by natural and anthropogenic drivers. Results revealed that the current version of the ECOSSE model may not be reliable for estimating daily Rs fluxes, particularly in dry sites. However, it could still be a valuable tool for predicting cumulative Rs from PG. Additionally, the model demonstrated accurate simulation of Rs in response to grass cutting and slurry application practices. The sensitivity analyses and attribution tests revealed that increased soil organic carbon (SOC), soil pH, temperature, reduced precipitation, and lower water table (WT) depth could lead to increased Rs from soils. The variability of Rs fluxes across sites and years was attributed to climate, weather, soil properties, and management practices. The study suggests the need for additional development and application of the ECOSSE model, specifically in dry and low input sites, to evaluate the impacts of various land management interventions on carbon sequestration and emissions in PG.

BACKGROUNDCompared to patients with hypertension only (HTN), those with hypertension and diabetes (HTN/DM) have worse prognosis. We aimed to characterize morphological differences between HTN and HTN/DM using cardiovascular magnetic resonance (CMR); and compare differentially expressed proteins associated with myocardial fibrosis using high throughput multiplex assays.METHODSAsymptomatic patients underwent CMR: 438 patients with HTN (60±8 years; 59% males) and 167 age- and sex-matched patients with HTN/DM (60±10 years; 64% males). Replacement myocardial fibrosis was defined as non-ischemic late gadolinium enhancement on CMR. Extracellular volume (ECV) fraction was used as a marker of diffuse myocardial fibrosis. A total of 184 serum proteins (Olink Target CVD II and III panels) were measured to identify unique signatures associated with myocardial fibrosis in all patients.RESULTSDespite similar left ventricular (LV) mass (P=0.344) and systolic blood pressure (P=0.086), patients with HTN/DM had increased concentricity and worse multi-directional strain (PCONCLUSIONSAdverse cardiac remodeling was observed in patients with HTN/DM. The novel proteomic signatures and associated biological activities of increased immune and inflammatory response may partly explain these observations.CLINICAL PERSPECTIVESMyocardial fibrosis is a hallmark of heart failure and predicts worse cardiovascular outcomes in patients with hypertension. There is increasing interest to target the myocardial interstitium to improve diagnosis, risk stratification and to discover novel therapies. Our study demonstrates that myocardial fibrosis is a heterogeneous pathology resulting from cardiac disease-specific biology. In hypertensive patients, concomitant diabetes mellitus accelerates adverse cardiac remodeling. This observation endorses the importance to consider early risk stratification by imaging and/or biomarker profiling in these patients. Whether patients with hypertension and diabetes would derive incremental anti-fibrotic benefits from therapies targeting inflammation/immune activate require further investigations.

AimsIn bradycardia patients treated with dual-chamber pacing, we aimed to evaluate whether pacing with atrioventricular (AV) delay management [AV hysteresis (AVH)], compared with standard pacing with fixed AV delays, reduces unnecessary ventricular pacing percentage (VPP) and is associated with better clinical outcomes. Main study endpoints were the incidence of heart failure hospitalizations (HFH), persistent atrial fibrillation (AF), and cardiac death.Methods and resultsData from two identical prospective observational studies, BRADYCARE I in the USA and BRADYCARE II in Europe, Africa, and Asia, were pooled. Overall, 2592 patients (75 ± 10 years, 45.1% female, 50% with AVH) had complete clinical and device data at 1-year follow-up and were analysed. Primary pacing indication was sinus node disease (SND) in 1177 (45.4%), AV block (AVB) in 974 (37.6%), and other indications in 441 (17.0%) patients. Pacing with AVH, compared with standard pacing, was associated with a lower 1-year incidence of HFH [1.3% vs. 3.1%, relative risk reduction (RRR) 57.5%, P = 0.002] and of persistent AF (5.3% vs. 7.7%, RRR = 31.1%, P = 0.028). Cardiac mortality was not different between groups (1.0% vs. 1.4%, RRR = 27.8%, P = 0.366). Pacing with AVH, compared with standard pacing, was associated with a lower (P < 0.001) median VPP in all patients (7% vs. 75%), in SND (3% vs. 44%), in AVB (25% vs. 98%), and in patients with other pacing indications (3% vs. 47%).ConclusionCardiac pacing with AV delay management via AVH is associated with reduced 1-year incidence of HFH and persistent AF, most likely due to a reduction in VPP compared to standard pacing.

BackgroundHeart failure (HF) and diabetes epidemiologically share a bidirectional relationship, with each increasing the incidence and worsening the prognosis of the other. Global longitudinal strain (GLS) measured by feature tracking cardiovascular magnetic resonance (CMR) has prognostic value in HF. However, this has not been established in HF patients with diabetes.ObjectivesThis study aimed to assess the prognostic value of GLS in HF patients with diabetes.MethodsConsecutive patients (n=315) with HF from six tertiary cardiac centres in Singapore underwent CMR at 3T, including GLS, late gadolinium enhancement (LGE), native T1 mapping, and extracellular volume fraction (ECV) mapping. The primary outcome was a composite of all-cause mortality or HF hospitalisation.ResultsCompared to those without diabetes (n=156), the diabetes group (n=159) had a higher prevalence of LGE (76 vs 60%, pConclusionCompared to heart failure patients without diabetes, those with diabetes have worse CMR markers of fibrosis and adverse prognosis. GLS is a powerful and independent prognostic marker in heart failure patients with diabetes.

Upregulated expression of microRNA (miR)-221 is associated with downregulation of p27 and subsequent increased cell proliferation in a variety of human cancers. It is unknown whether miR-221 mimics could trigger neoplastic cellular proliferation. In vitro, we demonstrated miR-221 significantly downregulates the expression of P27 and increases proliferation of H9c2 and cardiac fibroblasts. The knockdown of PUM1 but not PUM2 abolished such effects by miR-221, as verified by RT-qPCR and western blot, direct binding of p27 3′ UTR by luciferase reporter assay and cell proliferation by Ki67. In vivo expression of P27 in the rat liver, heart, kidney, spleen, and muscle were not affected by miR-221 at 1 and 4 mg/kg and concurrently full-length (FL) PUM1 (140 kDa) was not detected. Instead, isoforms of 105 and 90 kDa were observed and generated through alternative RNA slicing verified by cDNA cloning and sequencing and cathepsin K cleavage confirmed by studies with the inhibitor odanacatib. This is the first study to address the possible pro-proliferative effects of miR-221 mimic therapeutics in cardiovascular applications. Loss of FL PUM1 expression is a key factor abrogating miR-221-mediated p27 regulation, although other concurrent mechanisms cannot be excluded. Our findings provide essential insights into the context-dependent nature of miRNA functionality., Graphical Abstract, miR-221 mimics deploy therapeutics for cardioprotection and prevention of cardiac fibrosis without triggering neoplastic cellular proliferation due to loss of full-length (FL) PUM1. Loss of FL PUM1 expression is a key factor abrogating miR-221-mediated p27 regulation. This finding provides essential insights into the context-dependent nature of miRNA functionality.

OBJECTIVES This study sought to estimate and compare the aggregate treatment benefit of pharmacological therapy for heart failure (HF) with reduced ejection fraction. BACKGROUND The estimated treatment effects of various combinations of contemporary HF medical therapies are not well characterized. METHODS We performed a systematic network meta-analysis, using MEDLINE/EMBASE and the Cochrane Central Register of Controlled Trials for randomized controlled trials published between January 1987 and January 2020. We included angiotensin-converting enzyme inhibitors, angiotensin receptor blockers, beta-blockers (BB), mineralocorticoid receptor antagonists (MRAs), digoxin, hydralazine-isosorbide dinitrate, ivabradine, angiotensin receptor-neprilysin inhibitors (ARNi), sodium glucose cotransporter-2 inhibitors (SGLT2i), vericiguat, and omecamtiv-mecarbil. The primary outcome was all-cause death. We estimated the life-years gained in 2 HF populations (BIOSTAT-CHF [BIOlogy Study to TAilored Treatment in Chronic Heart Failure] and ASIAN-HF [Asian Sudden Cardiac Death in Heart Failure Registry]). RESULTS We identified 75 relevant trials representing 95,444 participants. A combination of ARNi, BB, MRA, and SGLT2i was most effective in reducing all-cause death (HR: 0.39; 95% CI: 0.31-0.49); followed by ARNi, BB, MRA, and vericiguat (HR: 0.41; 95% CI: 0.32-0.53); and ARNi, BB, and MRA (HR: 0.44; 95% CI: 0.36-0.54). Results were similar for the composite outcome of cardiovascular death or first hospitalization for HF (HR: 0.36; 95% CI: 0.29-0.46 for ARNi, BB, MRA, and SGLT2i; HR: 0.44; 95% CI: 0.35-0.56 for ARNi, BB, MRA, and omecamtiv-mecarbil; and HR: 0.43; 95% CI: 0.34-0.55 for ARNi, BB, MRA, and vericiguat). The estimated additional number of life-years gained for a 70-year-old patient on ARNi, BB, MRA, and SGLT2i was 5.0 years (2.5-7.5 years) compared with no treatment in secondary analyses. CONCLUSIONS In patients with HF with reduced ejection fraction, the estimated aggregate benefit is greatest for a combination of ARNi, BB, MRA, and SGLT2i. (J Am Coll Cardiol HF 2022;10:73-84) (c) 2022 by the American College of Cardiology Foundation.

AIMS: Chronic obstructive pulmonary disease (COPD) is a frequent comorbidity in patients with heart failure (HF). We assessed the influence of COPD on circulating levels and prognostic value of three HF biomarkers: N-terminal pro-B-type natriuretic peptide (NT-proBNP), high-sensitivity troponin T (hs-TnT), and soluble suppression of tumorigenesis-2 (sST2).METHODS: Individual data from patients with chronic HF, known COPD status, NT-proBNP and hs-TnT values (n = 8088) were analysed. A subgroup (n = 3414) had also sST2 values.RESULTS: Patients had a median age of 66 years (interquartile interval 57-74), 77% were men and 82% had HF with reduced ejection fraction. NT-proBNP, hs-TnT and sST2 were 1207 ng/l (487-2725), 17 ng/l (9-31) and 30 ng/ml (22-44), respectively. Patients with COPD (n = 1249, 15%) had higher NT-proBNP (P = 0.042) and hs-TnT (P CONCLUSIONS: Among patients with HF, those with COPD have higher NT-proBNP and hs-TnT, but not sST2. All these biomarkers yield prognostic significance regardless of the COPD status.

Background: Echocardiography is the diagnostic modality for assessing cardiac systolic and diastolic function to diagnose and manage heart failure. However, manual interpretation of echocardiograms can be time consuming and subject to human error. Therefore, we developed a fully automated deep learning workflow to classify, segment, and annotate two-dimensional (2D) videos and Doppler modalities in echocardiograms. Methods: We developed the workflow using a training dataset of 1145 echocardiograms and an internal test set of 406 echocardiograms from the prospective heart failure research platform (Asian Network for Translational Research and Cardiovascular Trials; ATTRaCT) in Asia, with previous manual tracings by expert sonographers. We validated the workflow against manual measurements in a curated dataset from Canada (Alberta Heart Failure Etiology and Analysis Research Team; HEART; n=1029 echocardiograms), a real-world dataset from Taiwan (n=31 241), the US-based EchoNet-Dynamic dataset (n=10 030), and in an independent prospective assessment of the Asian (ATTRaCT) and Canadian (Alberta HEART) datasets (n=142) with repeated independent measurements by two expert sonographers. Findings: In the ATTRaCT test set, the automated workflow classified 2D videos and Doppler modalities with accuracies (number of correct predictions divided by the total number of predictions) ranging from 0·91 to 0·99. Segmentations of the left ventricle and left atrium were accurate, with a mean Dice similarity coefficient greater than 93% for all. In the external datasets (n=1029 to 10 030 echocardiograms used as input), automated measurements showed good agreement with locally measured values, with a mean absolute error range of 9–25 mL for left ventricular volumes, 6–10% for left ventricular ejection fraction (LVEF), and 1·8–2·2 for the ratio of the mitral inflow E wave to the tissue Doppler e' wave (E/e' ratio); and reliably classified systolic dysfunction (LVEF

BackgroundHeart Rate Score (HRSc), the percent of all atrial paced and sensed event in the largest 10 bpm rate histogram bin of a pacemaker, predicts survival in patients with cardiac devices. No correlation between HRSc and development of atrial fibrillation (AF) has been reported.ObjectiveTo evaluate the relationship between pacemaker post-implantation HRSc and newly-developed AF incidence.MethodsPatients with dual-chamber pacemakers, implanted 2013-2017, with ALTITIUDE remote monitoring data with ≥600,000 beats of histogram data collected at baseline were included (N=34,543). HRSc was determined from the post-implantation histogram data during the initial 3 months. Patients were excluded if they had AF, defined as atrial high-rate episodes >5 minutes or >1% of right atrial beats >170 bpm during the initial 3-months post-implantation. New AF, after the baseline period, was defined by each of the following: >1%, >10% or >25% of atrial beats >170 bpm or Atrial Tachycardia Response (ATR) events >24 hr.ResultsPatients were followed a median of 2.8 (1.0-4.0) years. Patients with initial HRSc≥70% were older, had higher %RA pacing, had lower %RV pacing and were more likely programmed with rate-response vs subjects with HRScConclusionHRSc predicts subsequent AF independent of well-known risk factors in pacemaker patients.

AimsIn acute coronary syndrome (ACS) patients without advanced renal dysfunction [estimated glomerular filtration rate (eGFR) < 30 mL/min/1.73 m2], early (within 24 h of admission) angiotensin-converting enzyme inhibitor/angiotensin receptor blocker (ACEI/ARB) is the guideline-directed medical therapy. The clinical efficacy of early ACEI/ARB therapy among ACS patients with advanced renal dysfunction remains unclear.Methods and resultsAmong 184 850 ACS patients hospitalized from July 2014 to December 2018 in the Chinese National Electronic Disease Surveillance System Platform (CNEDSSP) cohort and 113 650 ACS patients enrolled from November 2014 to December 2019 in the Improving Care for Cardiovascular Disease in China-ACS Project (CCC-ACS) cohort, we identified 3288 and 3916 ACS patients with admission eGFR < 30 mL/min/1.73 m2 [2647 patients treated with ACEI/ARB (36.7%)], respectively. After 1:1 propensity score matching (PSM) in each cohort, Kaplan–Meier analysis showed that early ACEI/ARB use was associated with a 39% [hazard ratio (HR): 0.61, 95% confidence interval (95% CI): 0.45–0.82] and a 34% (HR: 0.66, 95% CI: 0.46–0.95) reduction in in-hospital mortality in CNEDSSP and CCC-ACS cohorts, respectively, which was consistent in multiple sensitivity analyses. A random effect meta-analysis of the two cohorts after PSM revealed a 32% reduction (risk ratio: 0.68, 95% CI: 0.55–0.84) in in-hospital mortality among ACEI/ARB users.ConclusionsBased on two nationwide cohorts in China in contemporary practice, we demonstrated that ACEI/ARB therapy initiated within 24 h of admission is associated with a reduction in in-hospital mortality in ACS patients with advanced renal dysfunction.Clinical trial registrationCCC-ACS project was registered at URL: https://www.clinicaltrials.gov. (Unique identifier: NCT02306616).

Background: We aimed to assess if discordance between patient-reported Kansas City Cardiomyopathy Questionnaire (KCCQ)-overall summary (os) score and physician-assessed New York Heart Association (NYHA) class is common among patients with heart failure (HF) with reduced or preserved ejection fraction, and determine its association with outcomes. Methods: A total of 4818 patients with HF were classified according to KCCQ-os score (range 0–100, dichotomized by median value 71.9 into high [good] versus low [bad]) and NYHA class (I/II [good] or III/IV [bad]) as concordant good (low NYHA class, high KCCQ-os score), concordant bad (high NYHA class, low KCCQ-os score), discordant worse NYHA class (high NYHA class, high KCCQ-os score), and discordant worse KCCQ-os score (low NYHA class, low-KCCQ-os score). The composite of HF hospitalization or death at 1 year was compared across groups. Results: There were 2070 (43.0%) concordant good, 1099 (22.8%) concordant bad, 331 (6.9%) discordant worse NYHA class, and 1318 (27.4%) discordant worse KCCQ-os score patients. Compared with concordant good, adverse outcomes were the highest in concordant bad (HR, 2.7 [95% CI, 2.2–3.5]) followed by discordant worse KCCQ-os score (HR, 1.8 [95% CI, 1.4–2.2]) and discordant worse NYHA class (HR, 1.5 [95% CI, 1.0–2.3]); with no modification by HF phenotype (preserved versus reduced ejection fraction, P interaction =0.52). At 6 months, 1403 (48%) experienced clinically significant improvement in KCCQ-os score (≥5 points increase over 6 months). Patients with improved KCCQ-os at 6 months (HR, 0.65 [95% CI, 0.47–0.92]) had better outcomes and the association was not modified by HF phenotype ( P interaction =0.40). Conclusions: One-third of patients with HF had discordance between patient-reported and clinician-assessed health status, largely attributable to worse patient-reported outcomes. Such discordance, particularly in those with discordantly worse KCCQ, should alert physicians to an increased risk of HF hospitalization and death, and prompt further assessment for potential drivers of worse patient-reported outcomes relative to physicians’ assessment.

Background Carotid artery stiffness is associated with cognitive impairment and dementia, but the underlying mechanisms remain unknown. We examined the associations of carotid artery stiffness with cerebral small‐vessel disease markers, cognition, and dementia subtypes in a memory clinic cohort. Methods and Results A total of 272 participants underwent carotid ultrasonography, 3 Tesla brain magnetic resonance imaging, and neuropsychological assessment. Carotid ultrasonography was used to assess β‐index, pressure‐strain elastic modulus, and pulse‐wave velocity‐β. Brain magnetic resonance images were graded for cerebral small‐vessel disease markers, including white matter hyperintensities, lacunes, and cerebral microbleeds. Participants were classified as having no cognitive impairment, cognitive impairment and no dementia, or dementia subtyped as Alzheimer disease and vascular dementia. Cognition was assessed using National Institute of Neurological Disorders and Stroke–Canadian Stroke Network harmonization battery. After adjusting for age, sex, cardiovascular risk factors, and diseases, multivariable models showed that β‐index ( β =0.69; P =0.002), elastic modulus ( β =0.78; P β =0.80; P Conclusions In memory clinic patients, carotid artery stiffness was associated with white matter hyperintensities and lacunes, impairment in global and domain‐specific cognition, and causative subtypes of dementia, particularly vascular. The effects of carotid stiffness on cognition were not independent of, and were partially mediated by, cerebral small‐vessel disease.

Supplemental Digital Content is available in the text., Objective: While the risk of acute coronary events has been associated with biological variability of circulating cholesterol, the association with variability of other atherogenic lipids remains less understood. We evaluated the longitudinal variability of 284 lipids and investigated their association with asymptomatic coronary atherosclerosis. Approach and Results: Circulating lipids were extracted from fasting blood samples of 83 community-sampled symptom-free participants (age 41–75 years), collected longitudinally over 6 months. Three types of coronary plaque volume (calcified, lipid-rich, and fibrotic) were quantified using computed tomography coronary angiogram. We first deconvoluted between-subject (CVg) and within-subject (CVw) lipid variabilities. We then tested whether the mean lipid abundance was different across groups categorized by Framingham risk score and plaques phenotypes (lipid-rich, fibrotic, and calcified). Finally, we investigated whether visit-to-visit variability of each lipid was associated with plaque burden. Most lipids (72.5%) exhibited higher CVg than CVw. Among the lipids (n=145) with 1.2-fold higher CVg than CVw, 26 species including glycerides and ceramides were significantly associated with Framingham risk score and the 3 plaque phenotypes (false discovery rate

Despite their limitations, unfractionated heparin (UFH) and bivalirudin remain standard-of-care parenteral anticoagulants for percutaneous coronary intervention (PCI). We discovered novel direct thrombin inhibitors (DTIs) from tick salivary transcriptomes and optimised their pharmacologic activity. The most potent, ultravariegin, inhibits thrombin with a Ki of 4.0 pM, 445-fold better than bivalirudin. Unexpectedly, despite their greater antithrombotic effect, variegin/ultravariegin demonstrated less bleeding, achieving a 3-to-7-fold wider therapeutic index in rodent thrombosis and bleeding models. When used in combination with aspirin and ticagrelor in a porcine model, variegin/ultravariegin reduced stent thrombosis compared with antiplatelet therapy alone but achieved a 5-to-7-fold lower bleeding time than UFH/bivalirudin. Moreover, two antibodies screened from a naïve human antibody library effectively reversed the anticoagulant activity of ultravariegin, demonstrating proof-of-principle for antidote reversal. Variegin and ultravariegin are promising translational candidates for next-generation DTIs that may reduce peri-PCI bleeding in the presence of antiplatelet therapy., Bleeding complications limits the use of effective antithrombotics therapeutics. Here, the authors developed next-generation direct thrombin inhibitors with low bleeding risks as safe peri-percutaneous coronary intervention anticoagulants when used in combination with antiplatelets.

Patients with cancer are at increased risk of myocardial infarction (MI) and stroke. Guidelines do not address lipid profile targets for these patients. Within the lipid profiles, we hypothesized that patients with cancer develop MI or stroke at lower low density lipoprotein cholesterol (LDL-C) concentrations than patients without cancer and suffer worse outcomes. We linked nationwide longitudinal MI, stroke and cancer registries from years 2007–2017. We identified 42,148 eligible patients with MI (2421 prior cancer; 39,727 no cancer) and 43,888 eligible patients with stroke (3152 prior cancer; 40,738 no cancer). Median LDL-C concentration was lower in the prior cancer group than the no cancer group at incident MI [2.43 versus 3.10 mmol/L, adjusted ratio 0.87 (95% CI 0.85–0.89)] and stroke [2.81 versus 3.22 mmol/L, adjusted ratio 0.93, 95% CI 0.91–0.95)]. Similarly, median triglyceride and total cholesterol concentrations were lower in the prior cancer group, with no difference in high density lipoprotein cholesterol. Prior cancer was associated with higher post-MI mortality [adjusted hazard ratio (HR) 1.48, 95% CI 1.37–1.59] and post-stroke mortality (adjusted HR 1.95, 95% CI 1.52–2.52). Despite lower LDL-C concentrations, patients with prior cancer had worse post-MI and stroke mortality than patients without cancer.

We address the problem of making single-point decisions in large partially observable games, where players interleave observation, deliberation, and action. We present information set generation as a key operation needed to reason about games in this way. We show how this operation can be used to implement an existing decision-making algorithm. We develop a constraint satisfaction algorithm for performing information set generation and show that it scales better than the existing depth-first search approach on multiple non-trivial games.

Objectives The goal of this study was to assess the predictive power of N-terminal pro–B-type natriuretic peptide (NT-proBNP) and the decision cutoffs in heart failure (HF) across body mas...

Aims The importance of iron deficiency (ID) in heart failure with preserved ejection fraction (HFpEF) is unknown. In HF with reduced ejection fraction (HFrEF), ID is reported as an independent predictor of mortality in HF although not all published studies agree. Different definitions of ID have been assessed, and the natural history of untreated ID not established, which may explain the conflicting results. This study aimed to assess the relationship between ID and mortality in HFpEF, clarify which definition of ID correlates best with outcomes in HFrEF, and determine the prognostic importance of change in ID status over time. Methods and results Analyses were conducted on data from 1563 patients participating in a prospective international cohort study comparing HFpEF with HFrEF. Plasma samples from baseline and 6 month visits were analysed for the presence of ID. Two ID definitions were evaluated: IDFerritin = ‘ferritin

This chapter describes an epitope-directed approach to generate antipeptide monoclonal antibodies to multiple nonoverlapping protein sites using a cocktail of fusion peptides as immunogen. It provides a step-by-step protocol on how antigenic peptides on a target protein can be identified by in silico prediction and discusses considerations for final peptide selection. Each antigenic peptide (10-20 amino acids long) is displayed as three-copy inserts on the surface exposed loop of a thioredoxin scaffold protein. The corresponding DNA coding sequence specifying the tripeptide insert flanked by Gly-Ser-Gly-Ser-Gly linkers is cloned in-frame into the Rsr II site of the thioredoxin gene in the pET-32a vector. The presence of a C-terminal polyhistidine tag (His

Background: The TOPCAT trial (Treatment of Preserved Cardiac Function Heart Failure With an Aldosterone Antagonist Trial) suggested clinical benefits of spironolactone treatment among patients with heart failure with preserved ejection fraction enrolled in the Americas. However, a comprehensive assessment of biologic pathways impacted by spironolactone therapy in heart failure with preserved ejection fraction has not been performed. Methods: We conducted aptamer-based proteomic analysis utilizing 5284 modified aptamers to 4928 unique proteins on plasma samples from TOPCAT participants from the Americas (n=164 subjects with paired samples at baseline and 1 year) to identify proteins and pathways impacted by spironolactone therapy in heart failure with preserved ejection fraction. Mean percentage change from baseline was calculated for each protein. Additionally, we conducted pathway analysis of proteins altered by spironolactone. Results: Spironolactone therapy was associated with proteome-wide significant changes in 7 proteins. Among these, CARD18 (caspase recruitment domain-containing protein 18), PKD2 (polycystin 2), and PSG2 (pregnancy-specific glycoprotein 2) were upregulated, whereas HGF (hepatic growth factor), PLTP (phospholipid transfer protein), IGF2R (insulin growth factor 2 receptor), and SWP70 (switch-associated protein 70) were downregulated. CARD18, a caspase-1 inhibitor, was the most upregulated protein by spironolactone (−0.5% with placebo versus +66.5% with spironolactone, P Conclusions: Proteomic analysis in the TOPCAT trial revealed proteins and pathways altered by spironolactone, including the caspase inhibitor CARD18 and multiple pathways that involved collagens. In addition to effects on fibrosis, our studies suggest potential antiapoptotic effects of spironolactone in heart failure with preserved ejection fraction, a hypothesis that merits further exploration.

The approval of the first small interfering RNA (siRNA) drug Patisiran by FDA in 2018 marks a new era of RNA interference (RNAi) therapeutics. MicroRNAs (miRNA), an important post-transcriptional gene regulator, are also the subject of both basic research and clinical trials. Both siRNA and miRNA mimics are ~21 nucleotides RNA duplexes inducing mRNA silencing. Given the well performance of siRNA, researchers ask whether miRNA mimics are unnecessary or developed siRNA technology can pave the way for the emergence of miRNA mimic drugs. Through comprehensive comparison of siRNA and miRNA, we focus on (1) the common features and lessons learnt from the success of siRNAs; (2) the unique characteristics of miRNA that potentially offer additional therapeutic advantages and opportunities; (3) key areas of ongoing research that will contribute to clinical application of miRNA mimics. In conclusion, miRNA mimics have unique properties and advantages which cannot be fully matched by siRNA in clinical applications. MiRNAs are endogenous molecules and the gene silencing effects of miRNA mimics can be regulated or buffered to ameliorate or eliminate off-target effects. An in-depth understanding of the differences between siRNA and miRNA mimics will facilitate the development of miRNA mimic drugs.

Background. Each year, approximately 5000 New Zealanders are admitted to hospital with first-time acute coronary syndrome (ACS). The Multi-Ethnic New Zealand Study of Acute Coronary Syndromes (MENZACS) is a prospective longitudinal cohort study embedded within the All New Zealand Acute Coronary Syndrome Quality Improvement (ANZACS-QI) registry in six hospitals. The objective of MENZACS is to examine the relationship between clinical, genomic, and cardiometabolic markers in relation to presentation and outcomes post-ACS. Methods. Patients with first-time ACS are enrolled and study-specific research data is collected alongside the ANZACS-QI registry. The research blood samples are stored for future genetic/biomarker assays. Dietary information is collected with a food frequency questionnaire and information about physical activity, smoking, and stress is also collected via questionnaire. Detailed family history, ancestry, and ethnicity data are recorded on all participants. Results. During the period between 2015 and 2019, there were 2015 patients enrolled. The mean age was 61 years, with 60% of patients aged Conclusion. MENZACS represents a cohort with optimal contemporary management and will be a significant epidemiological bioresource for the study of environmental and genetic factors contributing to ACS in New Zealand’s multi-ethnic environment. The study will utilise clinical, nutritional, lifestyle, genomic, and biomarker analyses to explore factors influencing the progression of coronary disease and develop risk prediction models for health outcomes.

Mark Richards, an atmospheric physicist and senior teaching fellow at Imperial College London, explains why he founded the Blackett Lab Family – the UK’s first national network of Black physicists – in 2020.

The approval of new heart failure (HF) therapies has slowed over the past two decades in part due to the high costs of conducting large randomized clinical trials that are needed to adequately power major clinical endpoint studies. Several biomarkers have been identified reflecting different elements of HF pathophysiology, with possible applications in diagnosis, risk stratification, treatment monitoring, and even in the design of clinical trials. Biomarkers could potentially be used to refine study inclusion criteria to enable enrolment of patients who are more likely to respond to a therapeutic intervention, despite being at sufficient risk to meet pre-determined study endpoint rates. When there is a close relationship between biomarker levels and clinical endpoints, changes in biomarker levels after a given treatment can act as a surrogate endpoint, potentially reducing the duration and cost of a clinical trial. Natriuretic peptides have been widely used in clinical trials with a variable amount of added value, which such variation being probably due to the absence of a close pathophysiological connection to the study drug. Notable exceptions to this include sacubitril/valsartan and vericiguat. Future studies should seek to adopt unbiased approaches for discovery of true companion diagnostics; with -omics-based tools, biomarkers might be more precisely selected for use in clinical trials to identify responses that closely reflect the biological effects of the drug under investigation. Finally, biomarkers associated with cardiac damage and remodelling, such as cardiac troponin, could be employed as safety endpoints provided that standardization between different assays is achieved. © 2022 European Society of Cardiology.

Hydrogen sulfide (H2S) and substance P (SP) are known from animal models and in vitro studies as proinflammatory mediators. In this study, peripheral blood concentrations of H2S and SP were measured in patients with Escherichia coli or Klebsiella pneumoniae bacteraemia. Fifty patients were recruited from general wards at Christchurch Hospital, during 2020–2021. Samples from age- and sex-matched healthy subjects previously recruited as controls for studies of cardiovascular disease were used as controls. The concentrations of H2S were higher than controls on day 0, day 1, and day 2, and SP was higher than controls on all 4 days. The concentrations of H2S were highest on day 0, whereas SP concentrations were higher on day 2 than other days. Interleukin-6 and C-reactive protein were significantly higher on day 0 and day 1, respectively. The concentrations of H2S and SP did not differ between 15 non-septic (SIRS 0-1) and the 35 septic subjects (SIRS ≥ 2). Substance P concentrations were higher in subjects with abdominal infection than urinary tract infections on day 0 (p = 0.0002) and day 1 (p = 0.0091). In conclusion, the peak H2S concentrations precede the SP peak in patients with Gram-negative bacteraemia, but this response varies with the site of infection.

Different associations between epicardial adipose tissue (EAT) and cardiac function have been suggested in patients with heart failure with preserved (HFpEF) versus reduced and mildly reduced ejection fraction (HFrEF/HFmrEF). However, few studies have directly compared the association between EAT and left atrial (LA) and left ventricular (LV) function in patients with HFpEF and HFrEF/HFmrEF.We studied EAT thickness using transthoracic echocardiography in a multicentre cohort of 149 community-dwelling controls without heart failure, 99 patients with HFpEF, and 366 patients with HFrEF/HFmrEF. EAT thickness was averaged from parasternal long-axis and short-axis views, respectively, and off-line speckle tracking analysis was performed to quantify LA and LV function. Data were validated in an independent cohort of 626 controls, 243 patients with HFpEF, and 180 patients with HFrEF/HFmrEF. For LV function, LV global longitudinal strain (GLS) was measured in both derivation and validation cohorts. For LA function, LAGLS at reservoir, contractile and conduit phase were measured in the derivation cohort, and only LAGLS at reservoir phase was measured in the validation cohort. In the derivation cohort, EAT thickness was lower in HFrEF/HFmrEF (7.3 ± 2.5 mm) compared to HFpEF (8.3 ± 2.6 mm, p 0.05) and controls (7.9 ± 1.8 mm, p 0.05). Greater EAT thickness was associated with better LV and contractile LA function in HFrEF/HFmrEF, but not in HFpEF (p for interaction0.05). These findings were confirmed in the validation cohort, where EAT thickness was lower in HFrEF/HFmrEF (6.7 ± 1.4 mm) compared to HFpEF (9.6 ± 2.8 mm; p 0.05) and controls (7.7 ± 2.3 mm; p 0.05). Greater EAT thickness was associated with better LV and reservoir LA function in patients with HFrEF/HFmrEF but worse LV and reservoir LA function in patients with HFpEF (p for interaction0.05). Thickened EAT (EAT thickness10 mm) was associated with LA dysfunction (LAGLS at reservoir phase23%) in HFpEF, but not in HFrEF/HFmrEF.Epicardial adipose tissue thickness is greater in patients with HFpEF than HFrEF/HFmrEF. Increased EAT thickness is associated with worse LA and LV function in HFpEF but the opposite in HFrEF/HFmrEF.

Severe acute respiratory syndrome coronavirus-2 (SARS-CoV-2) inactivation is an important step toward enhanced biosafety in testing facilities and affords a reduction in the biocontainment level necessary for handling virus-positive biological specimens. Virus inactivation methods commonly employ heat, detergents, or combinations thereof. In this work, we address the dearth of information on the efficacy of SARS-CoV-2 inactivation procedures in plasma and their downstream impact on immunoassays. We evaluated the effects of heat (56 °C for 30 min), detergent (1-5% Triton X-100), and solvent-detergent (SD) combinations [0.3-1% tri