Search

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/m 2 ). 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/m 2 ). 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 (p interaction  > 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 (p interaction  > 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., (© 2024 The Authors. European Journal of Heart Failure published by John Wiley & Sons Ltd on behalf of European Society of Cardiology.)

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: β ± standard error [SE]: 0.113 ± 0.046, p = 0.015; CMR: β ± SE: 0.098 ± 0.040, p = 0.015) and LV end-systolic volume index (TTE: β ± SE: 0.083 ± 0.030, p = 0.008; CMR: β ± 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)., (© 2023 The Authors. European Journal of Heart Failure published by John Wiley & Sons Ltd on behalf of European Society of Cardiology.)

Aims: Spironolactone is currently used in a large proportion of patients with heart failure and preserved ejection fraction (HFpEF), yet its effect on cardiac structure and function in a large population has not been well established. The aim of this study was to evaluate the impact of spironolactone on key echocardiographic parameters in HFpEF., Methods and Results: An individual-patient-data meta-analysis of three randomized trials (HOMAGE, Aldo-DHF, and TOPCAT) was performed comparing spironolactone (9-12 month exposure) to placebo (or control) for the changes in left atrial volume index (LAVi), left ventricular mass index (LVMi), interventricular septum (IVS) thickness, E/e' ratio, and left ventricular ejection fraction (LVEF) among patients with stage B (HOMAGE) or C (Aldo-DHF and TOPCAT) HFpEF. Analysis of covariance was used to test the effect of spironolactone on echocardiographic changes. A total of 984 patients were included in this analysis: 452 (45.9%) from HOMAGE, 398 (40.4%) from Aldo-DHF, and 134 (13.6%) from TOPCAT. The pooled-cohort patient's median age was 71 (66-77) years and 39% were women. Median LAVi was 29 (24-35) ml/m 2 , LVMi 100 (84-118) g/m 2 , IVS thickness 12 (10-13) mm, E/e' ratio 11 (9-13), and LVEF 64 (59-69)%. Spironolactone reduced LAVi by -1.1 (-2.0 to -0.1) ml/m 2 (p = 0.03); LVMi by -3.6 (-6.4 to -0.8) g/m 2 (p = 0.01); IVS thickness by -0.2 (-0.3 to -0.1) mm (p = 0.01); E/e' ratio by -1.3 (-2.4 to -0.2) (p = 0.02); and increased LVEF by 1.7 (0.8-2.6)% (p < 0.01). No treatment-by-study heterogeneity was found except for E/e' ratio with a larger effect in Aldo-DHF and TOPCAT (interaction p < 0.01)., Conclusions: Spironolactone improved cardiac structure and function of patients with HFpEF., (© 2022 European Society of Cardiology.)

Aims: In people at risk of heart failure (HF) enrolled in the Heart 'OMics' in AGEing (HOMAGE) trial, spironolactone reduced circulating markers of collagen synthesis, natriuretic peptides, and blood pressure and improved cardiac structure and function. In the present report, we explored factors associated with dyskalaemia., Methods and Results: The HOMAGE trial was an open-label study comparing spironolactone (up to 50 mg/day) versus standard care in people at risk for HF. After randomization, serum potassium was assessed at 1 and 9 months and was defined as low when ≤3.5 mmol/L (hypokalaemia) and high when ≥5.5 mmol/L (hyperkalaemia). Multivariable logistic regression models were constructed to identify clinical predictors of dyskalaemia. A total of 513 participants (median age 74 years, 75% men, median estimated glomerular filtration rate 71 mL/min/1.73 m 2 ) had serum potassium available and were included in this analysis. At randomization, 88 had potassium < 4.0 mmol/L, 367 had potassium 4.0-5.0 mmol/L, and 58 had potassium > 5.0 mmol/L. During follow-up, on at least one occasion, a serum potassium < 3.5 mmol/L was observed in 6 (1.2%) and <4.0 mmol/L in 46 (9%) participants, while a potassium > 5.0 mmol/L was observed in 38 (8%) and >5.5 mmol/L in 5 (1.0%) participants. The median (percentile 25-75 ) increase in serum potassium with spironolactone during the study was 0.23 (0.16; 0.29) mmol/L. Because of the low incidence of dyskalaemia, for regression analysis, hypokalaemia and hyperkalaemia thresholds were set at <4.0 and >5.0 mmol/L, respectively. The occurrence of a serum potassium > 5.0 mmol/L during follow-up was positively associated with the presence of diabetes mellitus {odds ratio [OR]: 1.21 [95% confidence interval (CI) 2.14; 3.79]} and randomization to spironolactone (OR: 2.83 [95% CI 1.49; 5.37]). Conversely, the occurrence of a potassium concentration < 4.0 mmol/L was positively associated with the use of thiazides (OR: 2.39 [95% CI 1.32; 4.34]), blood urea concentration (OR: 2.15 [95% CI 1.34; 3.39] per 10 mg/dL), and history of hypertension (OR: 2.32 [95% CI 1.02; 5.29]) and negatively associated with randomization to spironolactone (OR: 0.30 [95% CI 0.18; 0.52])., Conclusions: In people at risk for developing HF and with relatively normal renal function, spironolactone reduced the risk of hypokalaemia and, at the doses used, was not associated with the occurrence of clinically meaningful hyperkalaemia., (© 2022 The Authors. ESC Heart Failure published by John Wiley & Sons Ltd on behalf of European Society of Cardiology.)

Aims: Procollagen type I C-terminal propeptide (PICP) and procollagen type III N-terminal propeptide (PIIINP) are markers reflecting collagen synthesis in cardiac fibrosis. However, they may be influenced by the presence of non-cardiac comorbidities (e.g. ageing, obesity, renal impairment). Understanding the associations between markers of collagen synthesis and abnormalities of cardiac structure and function is important to screen for myocardial fibrosis and monitor the antifibrotic effect of medications., Methods and Results: The HOMAGE (Heart 'OMics' in AGEing) trial showed that spironolactone decreased serum PICP concentrations and improved cardiac remodelling over 9 months in a population at risk of developing heart failure (HF). We evaluated the associations between echocardiographic variables, PICP, PIIINP and galectin-3 at baseline and during the course of the trial. Among 527 individuals (74 ± 7 years, 26% women), median serum concentrations of PICP, PIIINP and galectin-3 were 80.6 μg/L (65.1-97.0), 3.9 μg/L (3.1-5.0), and 16.1 μg/L (13.5-19.7), respectively. After adjustment for potential confounders, higher serum PICP was significantly associated with left ventricular hypertrophy, left atrial enlargement, and greater ventricular stiffness (all p &lt; 0.05), whereas serum PIIINP and galectin-3 were not (all p &gt; 0.05). In patients treated with spironolactone, a reduction in serum PICP during the trial was associated with a decrease in E/e' (adjusted-beta = 0.93, 95% confidence interval 0.14-1.73; p = 0.022)., Conclusions: In individuals at high risk of developing HF, serum PICP was associated with cardiac structural and functional abnormalities, and a decrease in PICP with spironolactone was correlated with improved diastolic dysfunction as assessed by E/e'. In contrast, no such associations were present for serum PIIINP and galectin-3., (© 2022 European Society of Cardiology.)

Aims: Left ventricular ejection fraction (LVEF) can provide haemodynamic information and may influence the response to spironolactone and other heart failure (HF) therapies. We aimed to study patient characteristics and circulating protein associations with LVEF, and whether LVEF influenced the response to spironolactone., Methods and Results: HOMAGE enrolled patients aged >60 years at high risk of developing HF with a LVEF ≥45%. Overall, 527 patients were randomized to either spironolactone or standard of care for ≈9 months, and 276 circulating proteins were measured using Olink® technology. A total of 364 patients had available LVEF determined by the Simpson's biplane method. The respective LVEF tertiles were: tertile 1: <60% (n = 122), tertile 2: 60%-65% (n = 121), and tertile 3: >65% (n = 121). Patients with a LVEF >65% had smaller left ventricular chamber size and volumes, and lower natriuretic peptide levels. Compared to patients with a LVEF <60%, those with LVEF >65% had higher levels of circulating c-c motif chemokine ligand-23 and interleukin-8, and lower levels of tissue plasminogen activator, brain natriuretic peptide (BNP), S100 calcium binding protein A12, and collagen type I alpha 1 chain (COL1A1). Spironolactone significantly reduced the circulating levels of BNP and COL1A1 without significant treatment-by-LVEF heterogeneity: BNP change β = -0.36 log 2 and COL1A1 change β = -0.16 log 2 (p < 0.0001 for both; interaction p > 0.1 for both). Spironolactone increased LVEF from baseline to month 9 by 1.1% (p = 0.007)., Conclusion: Patients with higher LVEF had higher circulating levels of chemokines and inflammatory markers and lower levels of stretch, injury, and fibrosis markers. Spironolactone reduced the circulating levels of natriuretic peptides and type 1 collagen, and increased LVEF., (© 2022 European Society of Cardiology.)

Aims: The HOMAGE randomized trial found that spironolactone reduced left atrial volume index (LAVI), E:A ratio, and a marker of collagen type I synthesis (procollagen type I C-terminal propeptide) in patients at risk of heart failure (HF). Previous trials showed that patients with HF, preserved ejection fraction and low serum collagen type I C-terminal telopeptide to matrix metalloproteinase-1 ratio (CITP:MMP-1), associated with high collagen cross-linking, had less improvement in diastolic function with spironolactone. We evaluated the interaction between serum CITP:MMP-1 and spironolactone on cardiac function in the HOMAGE trial., Methods and Results: Patients at risk of HF were randomized to spironolactone (n = 260) or not (n = 255). Blood sampling and echocardiography were done at baseline, one and nine months. CITP:MMP-1 was used as an indirect measure of collagen cross-linking. Higher baseline CITP:MMP-1 (i.e. lower collagen cross-linking) was associated with greater reductions in LAVI with spironolactone at both one (p = 0.003) and nine (p = 0.01) months, but no interaction was observed for E:A ratio. Spironolactone reduced LAVI after one and nine months only for those patients in the third tertile of CITP:MMP-1 (estimated lowest collagen cross-linking) [mean differences spiro/control : -1.77 (95% confidence interval, CI -2.94 to -0.59) and -2.52 (95% CI -4.46 to -0.58) mL/m 2 ; interaction p across-tertiles  = 0.005; interaction p third tertile  = 0.008] with a similar trend for N-terminal pro-B-type natriuretic peptide which was consistently reduced by spironolactone only in the lowest collagen cross-linking tertile [mean differences spiro/control : -0.47 (95% CI -0.66 to -0.28) and -0.31 (95% CI -0.59 to -0.04) ng/L; interaction p across-tertiles  = 0.09; interaction p third tertile  < 0.001]., Conclusions: These findings suggest that, for patients at risk of HF, the effects of spironolactone on left atrial remodelling may be more prominent in patients with less collagen cross-linking (indirectly assessed by serum CITP:MMP-1)., (© 2021 The Authors. European Journal of Heart Failure published by John Wiley & Sons Ltd on behalf of European Society of Cardiology.)

Objectives: This study sought to identify homogenous echocardiographic phenotypes in community-based cohorts and assess their association with outcomes., Background: Asymptomatic cardiac dysfunction leads to a high risk of long-term cardiovascular morbidity and mortality; however, better echocardiographic classification of asymptomatic individuals remains a challenge., Methods: Echocardiographic phenotypes were identified using K-means clustering in the first generation of the STANISLAS (Yearly non-invasive follow-up of Health status of Lorraine insured inhabitants) cohort (N = 827; mean age: 60 ± 5 years; men: 48%), and their associations with vascular function and circulating biomarkers were also assessed. These phenotypes were externally validated in the Malmö Preventive Project cohort (N = 1,394; mean age: 67 ± 6 years; men: 70%), and their associations with the composite of cardiovascular mortality (CVM) or heart failure hospitalization (HFH) were assessed as well., Results: Three echocardiographic phenotypes were identified as "mostly normal (MN)" (n = 334), "diastolic changes (D)" (n = 323), and "diastolic changes with structural remodeling (D/S)" (n = 170). The D and D/S phenotypes had similar ages, body mass indices, cardiovascular risk factors, vascular impairments, and diastolic function changes. The D phenotype consisted mainly of women and featured increased levels of inflammatory biomarkers, whereas the D/S phenotype, consisted predominantly of men, displayed the highest values of left ventricular mass, volume, and remodeling biomarkers. The phenotypes were predicted based on a simple algorithm including e', left ventricular mass and volume (e'VM algorithm). In the Malmö cohort, subgroups derived from e'VM algorithm were significantly associated with a higher risk of CVM and HFH (adjusted HR in the D phenotype = 1.87; 95% CI: 1.04 to 3.37; adjusted HR in the D/S phenotype = 3.02; 95% CI: 1.71 to 5.34)., Conclusions: Among asymptomatic, middle-aged individuals, echocardiographic data-driven classification based on the simple e'VM algorithm identified profiles with different long-term HF risk. (4th Visit at 17 Years of Cohort STANISLAS-Stanislas Ancillary Study ESCIF [STANISLASV4]; NCT01391442)., Competing Interests: Funding Support and Author Disclosures The STANISLAS Cohort visit 4 was sponsored by the Nancy CHRU and was funded in part by the Programme Hospitalier de Recherche Clinique Interrégional. Biomarker studies are co-funded by the French National Research Agency Fighting Heart Failure (ANR-15-RHU-0004) and FEDER Lorraine, and all French co-authors are supported by the French Programme d'investissements d'avenir project “Lorraine Université d’Excellence” GEENAGE (ANR-15-IDEX-04-LUE) programs, and the Contrat de Plan Etat Région Lorraine and FEDER IT2MP. The research leading to these results also received support from the European Union Commission’s Seventh Framework program under grant 305507 (Heart OMics in Aging). Support was also provided from the “EXPERT” ERA-CVD 2016 and MR-Focus (both grants managed by the French National Research Agency). Drs. Girerd, Rossignol, and Zannad are supported by the French National Research Agency Fighting Heart Failure (ANR-15-RHU-0004), the French PIA project Lorraine Université d’Excellence GEENAGE (ANR-15-IDEX-04-LUE) programs, and the Contrat de Plan Etat Région Lorraine and FEDER IT2MP. Dr Girerd is a consultant for Novartis, AstraZeneca, and Boehringer Ingelheim. Dr Rossignol has received grants and personal fees from AstraZeneca, Bayer, CVRx, Fresenius, and Novartis; and personal fees from Grunenthal, Servier, Stealth Peptides, Vifor Fresenius Medical Care Renal Pharma, Idorsia, NovoNordisk, Ablative Solutions, G3P, Corvidia, and Relypsa. Dr Zannad has received personal fees from Boehringer Ingelheim, Janssen, Novartis, Boston Scientific, Amgen, CVRx, AstraZeneca, Vifor Fresenius, Cardior, Cereno Pharmaceutical, Applied Therapeutics, Merck Sharpe and Dohme, Bayer, and Cellprothera outside the submitted work; and has received other support from CVCT and Cardiorenal, outside the submitted work. Dr Ferreira is a consultant for Boehringer Ingelheim. Dr Magnusson is supported by grants from the Medical Faculty of Lund University; Skane University Hospital; the Crafoord Foundation; the Ernhold Lundstroms Research Foundation; the Region Skane; the Hulda and Conrad Mossfelt Foundation; the Southwest Skanes Diabetes Foundation; the Kockska Foundation; the Research Funds of Region Skåne; the Swedish Heart and Lung Foundation; and the Wallenberg Center for Molecular Medicine, Lund University. All other authors have reported that they have no relationships relevant to the contents of this paper to disclose., (Copyright © 2022 The Authors. Published by Elsevier Inc. All rights reserved.)

Introduction: Chest X-ray (CXR) widely used, but the prognostic value of congestion quantification using CXR remains uncertain. The main objective of the present study was to assess whether initial quantification of lung congestion evaluated by CXR [and its interplay with estimated plasma volume status (ePVS)] in patients with worsening heart failure (WHF) is associated with in-hospital and short-term clinical outcome., Methods: We studied 117 patients hospitalized for WHF in the ICALOR HF disease management program. Pulmonary congestion was estimated using congestion score index (CSI, range 0 to 3) evaluated from 6 lung areas on CXR. Systemic congestion was assessed by ePVS. Logistic regression analysis was used to assess length of stay and the composite of all-cause death or HF re-hospitalization at 90 days., Results: Patients were divided according to the median of admission CSI (median = 2.20) and ePVS (median = 5.38). Higher CSI was significantly associated with higher pulmonary arterial systolic pressure in multivariable models. Multivariable models showed patients with high CSI/high ePVS had a 6-day longer length of stay [OR (95% CI) = 6.78 (1.82-29.79), p < 0.01] and 5-fold higher risk of 90-day composite outcome [OR (95% CI) = 5.13 (1.26-25.11) p = 0.03] compared to patients with low CSI/low ePVS, while other configurations (either isolated high CSI or high ePVS) yielded neutral associations. Furthermore, CSI and ePVS significantly improved reclassification on top of clinical covariates for the composite outcome [Net reclassification index = 37.3% (0.52-87.0), p = 0.046]., Conclusion: An admission assessment of pulmonary and systemic congestion in WHF patients using CSI and ePVS can identify a cluster of high-risk patients at short-term outcomes., (Copyright © 2019 Elsevier B.V. All rights reserved.)

Background: End-stage renal disease is associated with cardiac remodeling, which is partly reversible after kidney transplantation (KT). We aimed to determine the association of cardiovascular comorbidities or kidney-related factors with cardiac reverse remodeling after KT., Methods: We performed echocardiography in 56 patients (aged 48 ± 15 years, mean ± SD) before and 24 months after undergoing their first KT. Echocardiograms were reviewed using a standardized process with blinding for the patient characteristics and evaluation timing. Multivariable linear regression analysis was used to evaluate the association between comorbidities and changes in cardiac structure and systolic/diastolic function., Results: Left ventricular mass index (LVMI) and diastolic parameters did not change significantly, while left ventricular ejection fraction (LVEF) increased from 63.9 to 69.6% (p = 0.046). Multivariable analysis revealed associations of histories of valvular heart disease with a smaller reduction in LVMI (β = -27.3, p = 0.04), of coronary artery disease or heart failure with a smaller increase in LVEF (β = 7.17, p = 0.02), and of diabetes mellitus with less improvement in E wave (β = -0.19, p = 0.05), e' (β = 4.15, p = 0.046), and E/e' (β = -5.00, p < 0.01)., Conclusion: Cardiovascular comorbidities were -associated with less improvement in cardiac structure and function following KT. Our findings suggest that patients with CV comorbidities may experience limited "favorable" reverse cardiac remodeling following KT., (© 2020 S. Karger AG, Basel.)

Background: Global longitudinal strain (GLS), derived from speckle-tracking echocardiography (STE), is a widely used and reproducible left ventricular deformation parameter; assessment of multilayer strain components has also become possible. However, its association with comorbidities/symptoms in low-risk populations without cardiac disease remains understudied. We report reference ranges for longitudinal deformation and their association with cardiovascular risk factors and dyspnea in a large population-based cohort., Methods: We studied 1,243 subjects without cardiac disease (47 ± 14 years, 47.4% men; 13.8% with dyspnea) enrolled at the fourth visit of the STANISLAS Cohort (Lorraine, France). Clinical evaluation included a comprehensive dyspnea questionnaire. Multilayer GLS (full-wall, subendocardial, and subepicardial) and strain rate (systolic, early, and late diastolic) were evaluated by GLS STE acquisition and measurement protocols as per recommendations by the European Association of Cardiovascular Imaging, American Society of Echocardiography, and Industry Task Force., Results: Full-wall GLS was 23.4% ± 2.7% (mean ± SD) with a subendocardial/subepicardial ratio of 1.2 ± 0.1. Age, gender, smoking status, and body mass index were significantly associated with strain variables, whereas diabetes, dyslipidemia, and hypertension/systolic blood pressure were not. Specifically, there were reductions in diastolic strain rate with aging but no differences in GLS. After propensity score matching, subjects with dyspnea had lower global endocardial strain (-23.48 ± 2.70 vs -23.02 ± 2.81; P = .043) and lower global subendocardial/subepicardial strain ratio (P = .034), whereas transmural strain and classical echocardiographic measurements were unrelated to dyspnea., Conclusions: Higher body mass index was found to be significantly associated with impaired strain variables in a low-risk population without cardiac disease. In addition, lower global endocardial strain and lower global subendocardial/subepicardial strain ratio were significantly associated with dyspnea contrary to other echocardiographic variables., (Copyright © 2019 American Society of Echocardiography. Published by Elsevier Inc. All rights reserved.)

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 (percentile 25-75 ) 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., (Copyright © 2018. Published by Elsevier Inc.)

Introduction: 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., Methods: 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., Results: 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)., Conclusion: 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.