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BackgroundMyeloperoxidase (MPO), a neutrophil-derived enzyme, is associated with oxidative stress and inflammation, which contribute to the pathophysiology of heart failure with preserved ejection fraction (HFpEF). Bioactive MPO causes vascular dysfunction and accumulation of serum uric acid (SUA). We investigated the association of plasma MPO and SUA with echocardiographic variables in a populational setting.MethodsThis was a cross-sectional analysis of the fourth visit of the STANISLAS cohort (N=1677 participants, age 49±14 years, 48% male), a population of initially healthy individuals. Participants were divided into four groups according to median plasma MPO and SUA levels. Adjusted linear regression models were used to assess the relationship of plasma MPO and SUA with echocardiographic markers.ResultsParticipants with high MPO and high SUA were older, had more diabetes, a higher body mass index, lower estimated glomerular filtration rate and higher systolic blood pressure. In multivariable regression analyses, compared with patients with low MPO and low SUA, they had decreased left atrial reservoir strain (mean±SE=−1.43±0.62, p=0.022), decreased mitral annular e’ velocity (mean±SE=−0.60±0.16, p<0.001) and more impaired left ventricular systolic global longitudinal strain (mean±SE=0.50±0.23, p=0.029). In contrast, high MPO with low SUA was not associated with impaired diastolic function.ConclusionsIn a population setting, high MPO and SUA, indicative of high bioactive MPO, were associated with early markers of diastolic dysfunction, suggesting a potential role of the MPO pathway in the early development of HFpEF.

BackgroundDiagnosing heart failure with preserved ejection fraction (HFpEF) remains challenging, particularly in older adults. While the Heart Failure Association (HFA)-PEFF and H2FPEF Scores offer structured diagnostic approaches, their clinical utility is still debated. This study aims to compare the diagnostic accuracy of HFpEF Scores versus inclusion criteria used in sodium-glucose cotransporter-2 inhibitors (SGLT2i) trials, age-adjusted N-terminal pro B-type natriuretic peptide (NT-proBNP) thresholds and the universal definition of heart failure (HF).MethodsDiagnostic tools were assessed using sex-weighted and age-weighted propensity score adjustment in individuals aged 60–80 years from two established HFpEF cohorts (MEtabolic Road to DIAstolic Heart Failure (MEDIA), n=297; Karolinska-Rennes (KaRen), n=174) and two community-based cohorts without HF (Suivi Temporaire Annuel Non-Invasif de la Santé des Lorrains Assurés Sociaux (STANISLAS), n=461; Malmö, n=1030).ResultsHFA-PEFF and H2FPEF Scores classified a large proportion of participants in both community-based cohorts (up to 81% in Malmö) and HFpEF cohorts (up to 75% in MEDIA) in the intermediate-likelihood category, requiring further diagnostic evaluation. Their diagnostic discrimination ranged from moderate to good. The universal definition of HF, SGLT2i trial criteria and NT-proBNP age-adjusted thresholds showed diagnostic performance comparable to HFA-PEFF Scores in the HFpEF cohorts and correctly excluded almost all individuals in the community cohorts. The universal definition of HF demonstrated a diagnostic discrimination higher than H2FPEF and comparable to HFA-PEFF, with the most balanced performance in terms of sensitivity and specificity.ConclusionsUsing scores, a substantial proportion of HFpEF individuals fall into the intermediate likelihood category, highlighting diagnostic uncertainty. Simpler tools, such as the universal definition of HF, demonstrate comparable or even superior diagnostic and rule-out performances for HFpEF, emphasising the need for more practical and reliable approaches to HFpEF diagnosis.

Background Arterial stiffness is a major prognostic factor of cardiovascular (CV) morbi-mortality in kidney transplant (KT) patients. Preclinical studies have demonstrated that the vascular toxicity of calcineurin inhibitors (CNI) is mediated through the activation of the mineralocorticoid receptor (MR) in vascular smooth muscle cells. Additionally, the role of MR in contributing to arterial stiffness is well documented in non-transplanted individuals. This study aims to investigate the impact of MR antagonist treatment on the progression of arterial stiffness in KT patients on cyclosporine. Methods This is a randomized, open-label, single-center, cross-over trial involving 36 stable KT patients who have been transplanted for at least 1 year and are maintained on cyclosporine therapy. After a 4-week run-in period, participants will be randomly assigned to one of two groups. Group A will receive eplerenone at a dose of 50 mg daily for 6 months, followed by a 6-month period without treatment. There will be an 8-week washout phase between the treatment and non-treatment periods. Group B will start with 6 months without treatment, followed by the same 8-week washout phase, and then receive eplerenone for 6 months. The primary outcome is to assess the effect of 6 months of eplerenone on arterial stiffness, measured through pulse wave velocity (PWV) using the Sphygmocor® method at the start and end of each treatment period. Secondary outcomes will include changes in (1) central and peripheral blood pressure profiles, (2) intima-media thickness, (3) left ventricular mass, (4) biomarkers of oxidative stress and endothelial dysfunction, and (5) renal graft function markers, such as proteinuria and creatinine levels. Additionally, the incidence of hyperkalemia and episodes of acute renal failure will be monitored. Discussion CNI are a key component of immunosuppressive therapy in KT patients. By limiting vascular toxicity through MR blockade, CV risk in these patients may be reduced. Trial registration ClinicalTrials.gov identifier: NCT04450953. EudraCT number 2019-004243-74.

Vascular Ehlers-Danlos syndrome is a rare severe disease that causes arterial dissections and ruptures that can lead to early death. No preventive treatment has yet been validated. Our aim was to assess the ability of celiprolol, a β1-adrenoceptor antagonist with a β2-adrenoceptor agonist action, to prevent arterial dissections and ruptures in vascular Ehlers-Danlos syndrome. Our study was a multicentre, randomised, open trial with blinded assessment of clinical events in eight centres in France and one in Belgium. Patients with clinical vascular Ehlers-Danlos syndrome were randomly assigned to 5 years of treatment with celiprolol or to no treatment. Randomisation was done from a centralised, previously established list of sealed envelopes with stratification by patients' age (≤32 years or >32 years). 33 patients were positive for mutation of collagen 3A1 (COL3A1). Celiprolol was administered twice daily and uptitrated every 6 months by steps of 100 mg to a maximum of 400 mg per day. The primary endpoints were arterial events (rupture or dissection, fatal or not). This study is registered with ClinicalTrials.gov, number NCT00190411. 53 patients were randomly assigned to celiprolol (25 patients) or control groups (28). Mean duration of follow-up was 47 (SD 5) months, with the trial stopped early for treatment benefit. The primary endpoints were reached by five (20%) in the celiprolol group and by 14 (50%) controls (hazard ratio [HR] 0·36; 95% CI 0·15–0·88; p=0·040). Adverse events were severe fatigue in one patient after starting 100 mg celiprolol and mild fatigue in two patients related to dose uptitration. We suggest that celiprolol might be the treatment of choice for physicians aiming to prevent major complications in patients with vascular Ehlers-Danlos syndrome. Whether patients with similar clinical presentations and no mutation are also protected remains to be established. French Ministry of Health, Programme Hospitalier de Recherche Clinique 2001.

There is limited evidence regarding intra-observer and inter-observer variations in echocardiographic measurements of diastolic function. This study aimed to assess this reproducibly within a population-based cohort study. Sixty subjects in sinus rhythm were randomly selected among 4th visit participants of the STANISLAS Cohort (Lorraine region, France). This 4th examination systematically included M-mode, 2-dimensional, DTI and pulsed-wave Doppler echocardiograms. Reproducibility of variables was studied by intra-class correlation coefficients (ICC) and Bland Altman plots. Our population was on average middle-aged (50 ± 14 y), overweight (BMI = 26 ± 6 kg/m2) and non-smoking (87%) with a quarter of the participants having self-declared hypertension or treated with anti-hypertensive medication(s). Intra-observer ICC were > 0.90 for all analyzed parameters except for left ventricular ejection fraction (LVEF) which was 0.89 (0.81-0.93). The mean relative intra-observer differences were small and limits of agreement of relative differences were narrow for all considered parameters (<5% and <15% respectively). Inter-observer ICC were > 0.90 for all analyzed parameters except for LVEF (ICC = 0.87) and both mitral and pulmonary A wave duration (0.83 and 0.73 respectively). The mean relative inter-observer differences were <5% for all parameters except for pulmonary A wave duration (mean difference = 6.5%). Limits of agreement of relative differences were narrow (<15%), except for mitral A wave duration and velocity (both <20%) as well as left ventricular mass and pulmonary A wave duration (both <30%). Intra-observer agreements with regard to the presence and severity of diastolic dysfunction were excellent (Kappa = 0.93 (0.83-1.00) and 0.88 (0.75-0.99), respectively). In this validation study within the STANISLAS cohort, diastolic function echocardiographic parameters were found to be highly reproducible. Diastolic dysfunction consequently appears as a highly effective clinical and research tool.

Higher serum bilirubin has been associated with poorer prognosis in patients with heart failure (HF). We examined the association between serum bilirubin and clinical outcomes in patients with clinical signs of HF and/or left ventricular systolic dysfunction after acute myocardial infarction (MI). A total of 7,467 patients from the High-Risk Myocardial Infarction Database Initiative with an available baseline total bilirubin concentration were studied. The association between baseline bilirubin concentrations and the composite outcome of cardiovascular mortality (CVM), nonfatal stroke, nonfatal MI or hospitalization for HF, CVM, and all-cause mortality were assessed using Cox proportional hazards models. An interaction with time was observed with associations present only in the first 90 days after randomization. The median (percentile25-75) baseline total bilirubin concentration was 11 (8 to 14) µmol/L and was above the “normal” range (>17.1 µmol/L) in 1,053 (14.1%) patients. In multivariable analysis, with adjustment for baseline characteristics (demographic, co-morbidities, Killip score, left ventricular ejection fraction, and laboratory variables), patients with a bilirubin concentration of >17.1 µmol/L had a significantly higher risk of all the studied outcomes at 90 days (e.g., CVM: adjusted hazard ratio 1.45, 95% confidence interval 1.14 to 1.86, p = 0.003). The addition of bilirubin to a validated survival model modestly improved the risk reclassification to predict 90-day events (continuous net reclassification improvement for CVM 6.4%, 95% confidence interval 0.7% to 9.6%, p = 0.04). In patients with MI complicated with HF and/or systolic dysfunction, bilirubin concentration is an independent predictor of mortality and may improve risk stratification.

Patients with rheumatoid arthritis (RA) are at higher risk for having underdiagnosed heart failure, however there are no recommendations regarding echocardiographic screening. We aimed to determine the prevalence of subclinical ventricular dysfunction in RA applying current echocardiographic guidelines, its association with patients’ characteristics, biomarkers and prognostic parameters and compare the 2016 guidelines to the recommendations from 2009. Prospective study of RA patients without known heart disease, categorized as preserved ventricular function (PVF), systolic dysfunction (SD), isolated diastolic dysfunction (DD) or indeterminate diastolic function (IDF) as per the 2016 echocardiography guidelines—or any ventricular dysfunction (AVD) comprehending the last 3. The median age was 58 years and 78% were females. The majority had PVF (73%), followed by DD (13%), IDF (11%) and SD (4%). Concordance with the 2009 echocardiographic guidelines was low. Compared with PVF, AVD patients were older (65 vs 55 years, p < 0.001), had a higher prevalence of hypertension and dyslipidaemia (56% vs 38%, p = 0.003 and 60% vs 41%, p = 0.002, respectively). In multivariable analysis, age (particularly > 57 years) was the only independent predictor of AVD or DD. AVD was significantly associated with higher NT-proBNP and lower distance in 6-min walk test. There were no significant independent associations between characteristics of RA disease and ventricular function. A total of 17% of RA patients without known cardiovascular disease presented subclinical systolic or diastolic dysfunction, which was associated with older age. The echocardiographic screening may have clinical value in identifying subclinical ventricular dysfunction, especially in older RA patients.

To investigate the influence of increasing age on clinical presentation, treatment and long-term outcome in patients with inducible paroxysmal supraventricular tachycardia (SVT) without pre-excitation syndromes. Clinical and electrophysiological study (EPS) data, as well as long-term clinical outcome (mean follow-up 2.4±4.0 years) were collected in patients referred for regular tachycardia with inducible SVT during EPS without pre-excitation. Among 1960 referred patients, 301 patients (15.4%) were aged ≥70 (70-97). In this subset, anticoagulants were prescribed in 49 patients following an erroneous diagnosis of atrial tachycardia and 14 were previously erroneously diagnosed with ventricular tachycardia because of wide QRS. Ablation was performed more frequently in patients ≥70 despite more frequent failure and complications. During follow-up, higher risks of AF, stroke, pacemaker implantation and death were observed in patients ≥70 whereas SVT recurrences were similar in both age groups. In multivariable analysis, age ≥70 was independently associated with higher risks of SVT-related adverse events prior to ablation (OR = 1.93, 1.41-2.62, p<0.001), conduction disturbances (OR = 11.27, 5.89-21.50, p<0.001), history of AF (OR = 2.18, 1.22-3.90, p = 0.009) and erroneous diagnosis at baseline (OR = 9.14, 5.93-14.09, p<0.001) as well as high rates of procedural complications (OR = 2.13, 1.19-3.81, p = 0.01) and ablation failure (OR = 1.68, 1.08-2.62, p = 0.02). In contrast, age ≥70 was not significantly associated with a higher risk of AF in multivariable analysis. A sizeable proportion of patients with inducible SVT without pre-excitation syndromes are elderly. These patients exhibit higher risks of erroneous tachycardia diagnosis prior to EPS as well as failure and/or complication of ablation, but similar risk of SVT recurrence. These results support performing transesophageal EPS in most patients and intracardiac EPS in selected patients. EPS may furthermore prove useful in elderly patients with regular tachycardia, mainly by avoiding treatment based on an erroneous diagnosis.

Background Carotid Intima Media Thickness (IMT) and stiffness are associated with cardiovascular events. The study aims were to perform a head-to-head comparison of the Wall Track System (WTS) and ART.LAB for carotid IMT, distension and diameter echotracking measurements as well as inter- and intra-observer reproducibility. Methods Echotracking measurements were performed with WTS and ART.LAB in 188 participants from the STANISLAS Cohort (mean age 47 ± 14 years). Inter-observer reproducibility analysis was performed in 60 patients consecutively included among the STANISLAS Cohort and two other ongoing cohorts, in whom measurements were successively performed by three operators. Results The relative differences between WTS and ART.LAB in artery diameter measurements were minimal (mean difference -1.8%) while the differences in IMT and distension measurements were 6.1% and 4.3%, respectively. The Bland and Altman plots for diameter, distension and intima media thickness showed no measurement bias between ART.LAB and WTS. The internal reproducibility for carotid diameter was good with the two devices (≈2% SD). The ART.LAB performed ≈2-fold better than WTS for IMT internal reproducibility (5% vs. 12.5%, p < 0.0001) and distension internal reproducibility (6.3% vs. 12.4%, p < 0.0001). The inter- and intra-observer reproducibility for carotid diameter and IMT was good for both devices. Complete results were obtained in 1:50 min in ART.LAB and 11:13 min with WTS. Conclusion ART.LAB and WTS show good agreement, with good inter- and intra-observer reproducibility with the two devices. Nevertheless, internal reproducibility of ART.LAB is better and measurements are easier to perform, favouring this device for carotid intima media thickness and stiffness measurements. Highlights Our results show a good agreement between ART.LAB and WTS echotracking devices. In our hands, internal reproducibility of ART.LAB is better than WTS. Carotid stiffness and thickness measurements are easier/quicker with ART.LAB than with WTS.

Aims Biomarkers reflecting myocardial fibrosis and inflammation have been individually associated with left ventricular hypertrophy (LVH) and diastolic dysfunction (DD). However, the added value of a fibrosis‐inflammation multimarker approach in a populational setting is yet to be studied. We evaluated the value of a multimarker approach to detect LVH and DD in a large population‐based cohort. Methods and results In a prespecified analysis (BioSe‐PreIC study) of the 4th visit of the STANISLAS cohort (1705 subjects, 47 ± 14 years, 47.4% men), we evaluated the ability of brain natriuretic peptide (BNP), Galectin‐3 (GAL3), N‐terminal propeptide of procollagen type III (P3NP), and soluble ST2 to predict LVH (LV mass > 116/100 g/m2 for men/women) and DD using discrimination (C‐index) and reclassification analysis (NRI). Participants with LVH and/or DD had significantly higher levels of BNP, GAL3, and ST2. Overall, the predictive value of clinical variables for LVH and/or DD was good (C‐index ranging from 0.76 to 0.82) and the addition of BNP, Gal3, P3NP, and ST2 moderately but significantly improved predictive value (delta C‐index = 0.03, P = 0.03 for LVH and 0.01, P = 0.01 for DD) and reclassification (NRI = 25.3, P = 0.02 for LVH and NRI = 32.7 for DD, P < 0.0001). Gal3, P3NP, and ST2 significantly improved predictive value (delta C‐index = 0.01, P = 0.01) and reclassification (NRI = 31.3, P < 0.0001) for DD of top of clinical variables and BNP. Conclusions As the measurement of Gal3, P3NP, and ST2 results in marginal (even if significant) increase in the prediction of DD/LVH on top of routine evaluation, their systematic use should not be promoted in unselected healthy individuals to screen for preclinical DD. Further research is needed to determine whether a more personalized medicine approach combing proteomic and clinical scoring can amplify the added value of biomarkers to identify preclinical DD.