Publications by authors named "Kevin Duarte"

59 Publications

Evidence of a Blood Pressure Reduction During the COVID-19 Pandemic and Associated Lockdown Period: Insights from e-Health Data.

Telemed J E Health 2021 Jun 8. Epub 2021 Jun 8.

Department of Internal Medicine and ESH Excellence Centre, Saint-Joseph Hospital, Paris, France.

p p
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1089/tmj.2021.0006DOI Listing
June 2021

Perceived risk profile and treatment optimization in heart failure: an analysis from BIOlogy Study to TAilored Treatment in chronic heart failure.

Clin Cardiol 2021 Jun 7;44(6):780-788. Epub 2021 May 7.

Université de Lorraine, INSERM, Centre d'Investigations Cliniques Plurithématique 1433, Inserm U1116, CHRU de Nancy and F-CRIN INI-CRCT, Nancy, France.

Background: Achieving target doses of angiotensin-converting-enzyme inhibitor/angiotensin-receptor blockers (ACEi/ARB) and beta-blockers in heart failure with reduced ejection fraction (HFrEF) is often underperformed. In BIOlogy Study to TAilored Treatment in chronic heart failure (BIOSTAT-CHF) study, many patients were not up-titrated for which no clear reason was reported. Therefore, we hypothesized that perceived-risk profile might influence treatment optimization.

Methods: We studied 2100 patients with HFrEF (LVEF≤40%) to compare the clinical characteristics and adverse events associated with treatment up-titration (after a 3-month titration protocol) between; a) patients not reaching target doses for unclear reason; b) patients not reaching target doses due to symptoms and/or side effects; c) patients reaching target doses.

Results: For ACEi/ARB, (a), (b) and (c) was observed in 51.3%, 25.9% and 22.7% of patients, respectively. For beta-blockers, (a), (b) and (c) was observed in 67.5%, 20.2% and 12.3% of patients, respectively. By multinomial logistic regression analysis for ACEi/ARB, patients in group (a) and (b) had lower blood pressure and poorer renal function, and patients in group (a) were older and had lower ejection fraction. For beta-blockers, patients in group (a) and (b) had more severe congestion and lower heart rate. At 9 months, adverse events (i.e., hypotension, bradycardia, renal impairment, and hyperkalemia) occurred similarly among the three groups.

Conclusions: Patients in whom clinicians did not give a reason why up-titration was missed were older and had more co-morbidities. Patients in whom up-titration was achieved did not have excess adverse events. However, from these observational findings, the pattern of subsequent adverse events among patients in whom up-titration was missed cannot be determined.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1002/clc.23576DOI Listing
June 2021

Co-culture of exogenous oligodendrocytes with unmyelinated cerebella: Revisiting ex vivo models and new tools to study myelination.

Glia 2021 Aug 2;69(8):1916-1931. Epub 2021 Apr 2.

Institut du Cerveau - Paris Brain Institute - ICM, Inserm, CNRS, AP-HP, Hôpital de la Pitié Salpêtrière, Sorbonne Université, Paris, France.

Common in vitro models used to study the mechanisms regulating myelination rely on co-cultures of oligodendrocyte precursor cells (OPCs) and neurons. In such models, myelination occurs in an environment that does not fully reflect cell-cell interactions and environmental cues present in vivo. To avoid these limitations while specifically manipulating oligodendroglial cells, we developed a reliable ex vivo model of myelination by seeding OPCs on cerebellar slices, deprived of their endogenous oligodendrocytes. We showed that exogenous OPCs seeded on unmyelinated cerebella, efficiently differentiate and form compact myelin. Spectral confocal reflectance microscopy and electron microscopy analysis revealed that the density of compacted myelin sheaths highly increases all along the culture. Importantly, we defined the appropriate culture time frame to study OPC differentiation and myelination, using accurate quantification resources we generated. Thus, this model is a powerful tool to study the cellular and molecular mechanisms of OPC differentiation and myelination. Moreover, it is suitable for the development and validation of new therapies for myelin-related disorders such as multiple sclerosis and psychiatric diseases.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1002/glia.24001DOI Listing
August 2021

Soluble triggering receptor expressed on myeloid cells-1 is a marker of organ injuries in cardiogenic shock: results from the CardShock Study.

Clin Res Cardiol 2021 Mar 7. Epub 2021 Mar 7.

Université de Lorraine, CHRU de Nancy, Médecine Intensive et Réanimation Central, INSERM U1116, Nancy, France.

Aims: Optimal outcome after cardiogenic shock (CS) depends on a coordinated healing response in which both debris removal and extracellular matrix tissue repair play a crucial role. Excessive inflammation can perpetuate a vicious circle, positioning leucocytes as central protagonists and potential therapeutic targets. High levels of circulating Triggering Receptor Expressed on Myeloid cells-1 (TREM-1), were associated with death in acute myocardial infarction confirming excessive inflammation as determinant of bad outcome. The present study aims to describe the association of soluble TREM-1 with 90-day mortality and with various organ injuries in patients with CS.

Methods And Results: This is a post-hoc study of CardShock, a prospective, multicenter study assessing the clinical presentation and management in patients with CS. At the time of this study, 87 patients had available plasma samples at either baseline, and/or 48 h and/or 96-120 h for soluble TREM-1 (sTREM-1) measurements. Plasma concentration of sTREM-1 was higher in 90-day non-survivors than survivors at baseline [median: 1392 IQR: (724-2128) vs. 621 (525-1233) pg/mL, p = 0.008), 48 h (p = 0.019) and 96-120 h (p = 0.029). The highest tertile of sTREM-1 at baseline (threshold: 1347 pg/mL) was associated with 90-day mortality with an unadjusted HR 3.08 CI 95% (1.48-6.42). sTREM-1 at baseline was not associated to hemodynamic parameters (heart rate, blood pressure, use of vasopressors or inotropes) but rather with organ injury markers: renal (estimated glomerular filtration rate, p = 0.0002), endothelial (bio-adrenomedullin, p = 0.018), myocardial (Suppression of Tumourigenicity 2, p = 0.002) or hepatic (bilirubin, p = 0.008).

Conclusion: In CS patients TREM-1 pathway is highly activated and gives an early prediction of vital organ injuries and outcome.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1007/s00392-021-01823-0DOI Listing
March 2021

Risk stratification with echocardiographic biomarkers in heart failure with preserved ejection fraction: the media echo score.

ESC Heart Fail 2021 Jun 3;8(3):1827-1839. Epub 2021 Mar 3.

Inserm, Centre d'Investigations Cliniques-Plurithématique 1433, Inserm U1116, CHRU Nancy, Université de Lorraine, and F-CRIN INI-CRCT (Cardiovascular and Renal Clinical Trialists), Nancy, France.

Aims: Echocardiographic predictors of outcomes in heart failure with preserved ejection fraction (HFpEF) have not been systematically or independently validated. We aimed at identifying echocardiographic predictors of cardiovascular events in a large cohort of patients with HFpEF and to validate these in an independent large cohort.

Methods And Results: We assessed the association between echocardiographic parameters and cardiovascular outcomes in 515 patients with heart failure with preserved left ventricular (LV) ejection fraction (>50%) in the MEtabolic Road to DIAstolic Heart Failure (MEDIA) multicentre study. We validated out findings in 286 patients from the Karolinska-Rennes Prospective Study of HFpEF (KaRen). After multiple adjustments including N-terminal pro-brain natriuretic peptide (NT-proBNP), the significant predictors of death or cardiovascular hospitalization were pulmonary arterial systolic pressure > 40 mmHg, respiratory variation in inferior vena cava diameter > 0.5, E/e' > 9, and lateral mitral annular s' < 7 cm/s. The combination of these four variables differentiated patients with <10% vs. >35% 1 year risk. Adding these four echocardiographic variables on top of clinical variables and NT-proBNP yielded significant net reclassification improvement (33.8%, P < 0.0001) and increase in C-index (5.3%, a change from 72.2% to 77.5%, P = 0.015) of similar magnitude as the addition of NT-proBNP on top of clinical variables alone. In the KaRen cohort, these four variables yielded a similar improvement in net reclassification improvement (22.3%, P = 0.014) and C-index (4.0%, P = 0.029).

Conclusions: Use of four simple echocardiographic parameters (within the MEDIA echo score), indicative of pulmonary hypertension, elevated central venous pressure, LV diastolic dysfunction, and LV long-axis systolic dysfunction, independently predicted prognosis and improved risk stratification additionally to clinical variables and NT-proBNP in HFpEF. This finding was validated in an independent cohort.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1002/ehf2.13251DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8120404PMC
June 2021

Head-to-head comparison of clustering methods for heterogeneous data: a simulation-driven benchmark.

Sci Rep 2021 Feb 18;11(1):4202. Epub 2021 Feb 18.

Centre d'Investigations Cliniques Plurithématique 1433, INSERM 1116, CHRU de Nancy, Université de Lorraine, Nancy, France.

The choice of the most appropriate unsupervised machine-learning method for "heterogeneous" or "mixed" data, i.e. with both continuous and categorical variables, can be challenging. Our aim was to examine the performance of various clustering strategies for mixed data using both simulated and real-life data. We conducted a benchmark analysis of "ready-to-use" tools in R comparing 4 model-based (Kamila algorithm, Latent Class Analysis, Latent Class Model [LCM] and Clustering by Mixture Modeling) and 5 distance/dissimilarity-based (Gower distance or Unsupervised Extra Trees dissimilarity followed by hierarchical clustering or Partitioning Around Medoids, K-prototypes) clustering methods. Clustering performances were assessed by Adjusted Rand Index (ARI) on 1000 generated virtual populations consisting of mixed variables using 7 scenarios with varying population sizes, number of clusters, number of continuous and categorical variables, proportions of relevant (non-noisy) variables and degree of variable relevance (low, mild, high). Clustering methods were then applied on the EPHESUS randomized clinical trial data (a heart failure trial evaluating the effect of eplerenone) allowing to illustrate the differences between different clustering techniques. The simulations revealed the dominance of K-prototypes, Kamila and LCM models over all other methods. Overall, methods using dissimilarity matrices in classical algorithms such as Partitioning Around Medoids and Hierarchical Clustering had a lower ARI compared to model-based methods in all scenarios. When applying clustering methods to a real-life clinical dataset, LCM showed promising results with regard to differences in (1) clinical profiles across clusters, (2) prognostic performance (highest C-index) and (3) identification of patient subgroups with substantial treatment benefit. The present findings suggest key differences in clustering performance between the tested algorithms (limited to tools readily available in R). In most of the tested scenarios, model-based methods (in particular the Kamila and LCM packages) and K-prototypes typically performed best in the setting of heterogeneous data.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1038/s41598-021-83340-8DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7892576PMC
February 2021

Hemodynamic and anti-inflammatory effects of early esmolol use in hyperkinetic septic shock: a pilot study.

Crit Care 2021 01 7;25(1):21. Epub 2021 Jan 7.

INSERM CIC1433, Nancy University Hospital, 54000, Nancy, France.

Background: Several studies have shown that heart rate control with selective beta-1 blockers in septic shock is safe. In these trials, esmolol was administered 24 h after onset of septic shock in patients who remained tachycardic. While an earlier use of beta-blockers might be beneficial, such use remains challenging due to the difficulty in distinguishing between compensatory and non-compensatory tachycardia. Therefore, the Esmosepsis study was designed to study the effects of esmolol aimed at reducing the heart rate by 20% after the initial resuscitation process in hyperkinetic septic shock patients on (1) cardiac index and (2) systemic and regional hemodynamics as well as inflammatory patterns.

Methods: Nine consecutive stabilized tachycardic hyperkinetic septic shock patients treated with norepinephrine for a minimum of 6 h were included. Esmolol was infused during 6 h in order to decrease the heart rate by 20%. The following data were recorded at hours H0 (before esmolol administration), H1-H6 (esmolol administration) and 1 h after esmolol cessation (H7): systolic arterial pressure, diastolic arterial pressure, mean arterial pressure, central venous pressure, heart rate, PICCO transpulmonary thermodilution, sublingual and musculo-cutaneous microcirculation, indocyanine green clearance and echocardiographic parameters, diuresis, lactate, and arterial and venous blood gases.

Results: Esmolol was infused 9 (6.4-11.6) hours after norepinephrine introduction. Esmolol was ceased early in 3 out of 9 patients due to a marked increase in norepinephrine requirement associated with a picture of persistent cardiac failure at the lowest esmolol dose. For the global group, during esmolol infusion, norepinephrine infusion increased from 0.49 (0.34-0.83) to 0.78 (0.3-1.11) µg/min/kg. The use of esmolol was associated with a significant decrease in heart rate from 115 (110-125) to 100 (92-103) beats/min and a decrease in cardiac index from 4.2 (3.1-4.4) to 2.9 (2.5-3.7) l/min/m. Indexed stroke volume remained unchanged. Cardiac function index and global ejection fraction also markedly decreased. Using echocardiography, systolic, diastolic as well as left and right ventricular function parameters worsened. After esmolol cessation, all parameters returned to baseline values. Lactate and microcirculatory parameters did not change while the majority of pro-inflammatory proteins decreased in all patients.

Conclusion: In the very early phase of septic shock, heart rate reduction using fast esmolol titration is associated with an increased risk of hypotension and decreased cardiac index despite maintained adequate tissue perfusion (NCT02068287).
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1186/s13054-020-03445-wDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7791811PMC
January 2021

Estimated plasma volume status in heart failure: clinical implications and future directions.

Clin Res Cardiol 2021 Jan 6. Epub 2021 Jan 6.

Centre d'Investigations Cliniques Plurithématique, INSERM 1433, CHRU de Nancy, Inserm 1116 and INI-CRCT (Cardiovascular and Renal Clinical Trialists) F-CRIN Network, Université de Lorraine, Nancy, France.

Congestion is one of the main predictors of poor outcome in patients with heart failure (HF). Assessing and monitoring congestion is essential for optimizing HF therapy. Among the various available methods, serial measurements of estimated plasma volume (ePVS) using routine blood count and/or body weight (e.g., the Strauss, Duarte, Hakim formulas) may be useful in HF management. Further prospective study is warranted to determine whether ePVS can help optimize decongestion therapy (loop diuretics, mineralocorticoid receptor antagonists, SGLT2i) in various HF settings. This narrative review summarizes the recent evidence supporting the association of ePVS with clinical congestion and outcome(s) and discusses future directions for monitoring ePVS in HF.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1007/s00392-020-01794-8DOI Listing
January 2021

Diagnostic performance of congestion score index evaluated from chest radiography for acute heart failure in the emergency department: A retrospective analysis from the PARADISE cohort.

PLoS Med 2020 11 11;17(11):e1003419. Epub 2020 Nov 11.

Université de Lorraine, Inserm, Centre d'Investigations Cliniques-1433, and Inserm, CHRU Nancy, F-CRIN INI-CRCT, Nancy, France.

Background: Congestion score index (CSI), a semiquantitative evaluation of congestion on chest radiography (CXR), is associated with outcome in patients with heart failure (HF). However, its diagnostic value in patients admitted for acute dyspnea has yet to be evaluated.

Methods And Findings: The diagnostic value of CSI for acute HF (AHF; adjudicated from patients' discharge files) was studied in the Pathway of dyspneic patients in Emergency (PARADISE) cohort, including patients aged 18 years or older admitted for acute dyspnea in the emergency department (ED) of the Nancy University Hospital (France) between January 1, 2015 and December 31, 2015. CSI (ranging from 0 to 3) was evaluated using a semiquantitative method on CXR in consecutive patients admitted for acute dyspnea in the ED. Results were validated in independent cohorts (N = 224). Of 1,333 patients, mean (standard deviation [SD]) age was 72.0 (18.5) years, 686 (51.5%) were men, and mean (SD) CSI was 1.42 (0.79). Patients with higher CSI had more cardiovascular comorbidities, more severe congestion, higher b-type natriuretic peptide (BNP), poorer renal function, and more respiratory acidosis. AHF was diagnosed in 289 (21.7%) patients. CSI was significantly associated with AHF diagnosis (adjusted odds ratio [OR] for 0.1 unit CSI increase 1.19, 95% CI 1.16-1.22, p < 0.001) after adjustment for clinical-based diagnostic score including age, comorbidity burden, dyspnea, and clinical congestion. The diagnostic accuracy of CSI for AHF was >0.80, whether alone (area under the receiver operating characteristic curve [AUROC] 0.84, 95% CI 0.82-0.86) or in addition to the clinical model (AUROC 0.87, 95% CI 0.85-0.90). CSI improved diagnostic accuracy on top of clinical variables (net reclassification improvement [NRI] = 94.9%) and clinical variables plus BNP (NRI = 55.0%). Similar diagnostic accuracy was observed in the validation cohorts (AUROC 0.75, 95% CI 0.68-0.82). The key limitation of our derivation cohort was its single-center and retrospective nature, which was counterbalanced by the validation in the independent cohorts.

Conclusions: In this study, we observed that a systematic semiquantified assessment of radiographic pulmonary congestion showed high diagnostic value for AHF in dyspneic patients. Better use of CXR may provide an inexpensive, widely, and readily available method for AHF triage in the ED.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1371/journal.pmed.1003419DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7657510PMC
November 2020

Prognostic value for long-term graft survival of estimated glomerular filtration rate and proteinuria quantified at 3 months after kidney transplantation.

Clin Kidney J 2020 Oct 26;13(5):791-802. Epub 2020 Apr 26.

Department of Nephrology and Kidney Transplantation, Nancy University Hospital, Vandoeuvre-lès-Nancy, France.

Background: The estimated glomerular filtration rate (eGFR) measured at 1 year is the usual benchmark applied in kidney transplantation (KT). However, acting on earlier eGFR values could help in managing KT during the first post-operative year. We aimed to assess the prognostic value for long-term graft survival of the early (3 months) quantification of eGFR and proteinuria following KT.

Methods: The 3-, 6- and 12-month eGFR using the Modified Diet in Renal Disease equation (eGFR) was determined and proteinuria was measured in 754 patients who underwent their first KT between 2000 and 2010 (with a mean follow-up of 8.3 years) in our centre. Adjusted associations with graft survival were estimated using a multivariable Cox model. The predictive accuracy was estimated using the C-index and net reclassification index. These same analyses were measured in a multicentre validation cohort of 1936 patients.

Results: Both 3-month eGFR and proteinuria were independent predictors of return to dialysis (all P < 0.05) and there was a strong correlation between eGFR at 3 and 12 months (Spearman's ρ = 0.76). The predictive accuracy of the 3-month eGFR was within a similar range and did not differ significantly from the 12-month eGFR in either the derivation cohort [C-index 62.6 (range 57.2-68.1) versus 66.0 (range 60.1-71.9), P = 0.41] or the validation cohort [C-index 69.3 (range 66.4-72.1) versus 71.7 (range 68.7-74.6), P = 0.25].

Conclusion: The 3-month eGFR was a valuable predictor of the long-term return to dialysis whose predictive accuracy was not significantly less than that of the 12-month eGFR in multicentre cohorts totalling >2500 patients. Three-month outcomes may be useful in randomized controlled trials targeting early therapeutic interventions.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1093/ckj/sfaa044DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7577768PMC
October 2020

Sex differences in circulating proteins in heart failure with preserved ejection fraction.

Biol Sex Differ 2020 08 24;11(1):47. Epub 2020 Aug 24.

Université de Lorraine, INSERM, Centre d'Investigation Clinique et Plurithématique 1433, INSERM U1116, CHRU de Nancy, F-CRIN INI-CRCT (Cardiovascular and Renal Clinical Trialists), Nancy, France.

Background: Many patients with heart failure with preserved ejection fraction (HFpEF) are women. Exploring mechanisms underlying the sex differences may improve our understanding of the pathophysiology of HFpEF. Studies focusing on sex differences in circulating proteins in HFpEF patients are scarce.

Methods: A total of 415 proteins were analyzed in 392 HFpEF patients included in The Metabolic Road to Diastolic Heart Failure: Diastolic Heart Failure study (MEDIA-DHF). Sex differences in these proteins were assessed using adjusted logistic regression analyses. The associations between candidate proteins and cardiovascular (CV) death or CV hospitalization (with sex interaction) were assessed using Cox regression models.

Results: We found 9 proteins to be differentially expressed between female and male patients. Women expressed more LPL and PLIN1, which are markers of lipid metabolism; more LHB, IGFBP3, and IL1RL2 as markers of transcriptional regulation; and more Ep-CAM as marker of hemostasis. Women expressed less MMP-3, which is a marker associated with extracellular matrix organization; less NRP1, which is associated with developmental processes; and less ACE2, which is related to metabolism. Sex was not associated with the study outcomes (adj. HR 1.48, 95% CI 0.83-2.63), p = 0.18.

Conclusion: In chronic HFpEF, assessing sex differences in a wide range of circulating proteins led to the identification of 9 proteins that were differentially expressed between female and male patients. These findings may help further investigations into potential pathophysiological processes contributing to HFpEF.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1186/s13293-020-00322-7DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7444077PMC
August 2020

Association between right-sided cardiac function and ultrasound-based pulmonary congestion on acutely decompensated heart failure: findings from a pooled analysis of four cohort studies.

Clin Res Cardiol 2020 Aug 8. Epub 2020 Aug 8.

INSERM, Centre d'Investigations Cliniques 1433, CHRU de Nancy, Inserm 1116 and INI-CRCT (Cardiovascular and Renal Clinical Trialists) F-CRIN Network, Institut Lorrain du cœur et des, Université de Lorraine, 4, rue du Morvan, Vandoeuvre-Les-Nancy, 54500, Nancy, France.

Background: Right ventricular (RV) dysfunction and RV-pulmonary artery (PA) uncoupling are associated with the development of pulmonary congestion during exercise. However, there is limited information regarding the association between these right-sided cardiac parameters and pulmonary congestion in acutely decompensated heart failure (HF).

Methods: We performed an individual patient meta-analysis from four cohort studies of hospitalized patients with HF who had available lung ultrasound (B-lines) data on admission and/or at discharge. RV function was assessed by tricuspid annular plane systolic excursion (TAPSE), RV-PA coupling was defined as the ratio of TAPSE to PA systolic pressure (PASP).

Results: Admission and discharge cohort included 319 patients (75.8 ± 10.1 years, 46% women) and 221 patients (77.9 ± 9.0 years, 47% women), respectively. Overall, higher TAPSE was associated with higher ejection fraction, lower PASP, b-type natriuretic peptide and B-line counts. By multivariable analysis, worse RV function or RV-PA coupling was associated with higher B-line counts on admission and at discharge, and with a less reduction in B-line counts from admission to discharge. Higher B-line counts at discharge were associated with a higher risk of the composite of all-cause mortality and/or HF re-hospitalization [adjusted-HR 1.13 (1.09-1.16), p < 0.001]. Furthermore, the absolute risk increase related to high B-line counts at discharge was higher in patients with lower TAPSE.

Conclusions: In patients with acutely decompensated HF, impaired RV function and RV-PA coupling were associated with severe pulmonary congestion on admission, and less resolution of pulmonary congestion during hospital stay. Worse prognosis related to residual pulmonary congestion was enhanced in patients with RV dysfunction. TAPSE, tricuspid annular plane systolic excursion; PASP, pulmonary artery systolic pressure.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1007/s00392-020-01724-8DOI Listing
August 2020

Improved cardiovascular risk prediction in patients with end-stage renal disease on hemodialysis using machine learning modeling and circulating microribonucleic acids.

Theranostics 2020 9;10(19):8665-8676. Epub 2020 Jul 9.

Institute of Molecular and Translational Therapeutic Strategies (IMTTS), Hannover Medical School, Hannover, Germany.

To test whether novel biomarkers, such as microribonucleic acids (miRNAs), and nonstandard predictive models, such as decision tree learning, provide useful information for medical decision-making in patients on hemodialysis (HD). Samples from patients with end-stage renal disease receiving HD included in the AURORA trial were investigated (n=810). The study included two independent phases: phase I (matched cases and controls, n=410) and phase II (unmatched cases and controls, n=400). The composite endpoint was cardiovascular death, nonfatal myocardial infarction or nonfatal stroke. miRNA quantification was performed using miRNA sequencing and RT-qPCR. The CART algorithm was used to construct regression tree models. A bagging-based procedure was used for validation. In phase I, miRNA sequencing in a subset of samples (n=20) revealed miR-632 as a candidate (fold change=2.9). miR-632 was associated with the endpoint, even after adjusting for confounding factors (HR from 1.43 to 1.53). These findings were not reproduced in phase II. Regression tree models identified eight patient subgroups with specific risk patterns. miR-186-5p and miR-632 entered the tree by redefining two risk groups: patients older than 64 years and with hsCRP<0.827 mg/L and diabetic patients younger than 64 years. miRNAs improved the discrimination accuracy at the beginning of the follow-up (24 months) compared to the models without miRNAs (integrated AUC [iAUC]=0.71). The circulating miRNA profile complements conventional risk factors to identify specific cardiovascular risk patterns among patients receiving maintenance HD.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.7150/thno.46123DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7392028PMC
May 2021

Circulating plasma proteins and new-onset diabetes in a population-based study: proteomic and genomic insights from the STANISLAS cohort.

Eur J Endocrinol 2020 Sep;183(3):285-295

Université de Lorraine, INSERM, Centre d'Investigations Cliniques Plurithématique 1433, INSERM 1116, CHRU de Nancy, FCRIN INI-CRCT, Nancy, France.

Objective: Determining the factors associated with new-onset pre-diabetes and type 2 diabetes mellitus (T2D) is important for improving the current prevention strategies and for a better understanding of the disease.

Design: To study the factors (clinical, circulating protein and genetic) associated with new onset pre-diabetes and T2D in an initially healthy (without diabetes) populational familial cohort with a long follow-up (STANISLAS cohort).

Methods: A total of 1506 participants attended both the visit 1 and visit 4, separated by ≈20 years. Over 400 proteins, GWAS and genetic associations were studied using models adjusted for potential confounders. Both prospective (V1 to V4) and cross-sectional (V4) analyses were performed.

Results: People who developed pre-diabetes (n = 555) and/or T2D (n = 73) were older, had higher BMI, blood pressure, glucose, LDL cholesterol, and lower eGFR. After multivariable selection, PAPP-A (pappalysin-1) was the only circulating protein associated with the onset of both pre-diabetes and T2D with associations persisting at visit 4 (i.e. ≈20 years later). FGF-21 (fibroblast growth factor 21) was a strong prognosticator for incident T2D in the longitudinal analysis, but not in the cross-sectional analysis. The heritability of the circulating PAPP-A was estimated at 44%. In GWAS analysis, the SNP rs634737 was associated with PAPP-A both at V1 and V4. External replication also showed lower levels of PAPP-A in patients with T2D.

Conclusions: The risk of developing pre-diabetes and T2D increases with age and with features of the metabolic syndrome. Circulating PAPP-A, which has an important genetic component, was associated with both the development and presence of pre-diabetes and T2D.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1530/EJE-20-0246DOI Listing
September 2020

Prognostic Value of Dynamic Changes in Pulmonary Congestion During Exercise Stress Echocardiography in Heart Failure With Preserved Ejection Fraction.

Circ Heart Fail 2020 06 16;13(6):e006769. Epub 2020 Jun 16.

Division of Cardiology, University of Perugia School of Medicine, Italy (E.C., G.A.).

Background: Patients with heart failure (HF) with preserved ejection fraction (HFpEF) typically develop dyspnea and pulmonary congestion upon exercise. Lung ultrasound is a simple diagnostic tool, providing semiquantitative assessment of extravascular lung water through B-lines. It has been shown that patients with HFpEF develop B-lines upon submaximal exercise stress echocardiography; however, whether exercise-induced pulmonary congestion carries prognostic implications is unknown. This study aimed at evaluating the prognostic value of B-line assessment during exercise in patients with HFpEF.

Methods: Sixty-one New York Heart Association class I to II patients with HFpEF underwent standard echocardiography, lung ultrasound (28-scanning point method), and BNP (B-type natriuretic peptide) assessment during supine exercise echocardiography (baseline and peak exercise). The primary end point was a composite of cardiovascular death or HF hospitalization at 1 year.

Results: B-lines, E/e', and BNP significantly increased during exercise (<0.001 for all). By multivariable analysis, both peak (hazard ratio, 1.50 [95% CI, 1.21-1.85], <0.001), and change (hazard ratio 1.34 [95% CI, 1.12-1.62], =0.002) B-lines were retained as independent predictors of outcome (hazard ratios per 1 B-line increment), along with BNP and E/e' ratio. Importantly, adding peak B-line on top of a clinical model significantly improved prognostic accuracy (C-index increase, 0.157 [0.056-0.258], =0.002) and net reclassification (continuous net reclassification improvement, 0.51 [0.09-0.74], =0.016), with similar results for B-line change.

Conclusions: Detection of exercise-induced pulmonary congestion by lung ultrasound is an independent predictor of outcome in patients with HFpEF; its use may help refining the routine risk stratification of these patients on top of well-established clinical variables.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1161/CIRCHEARTFAILURE.119.006769DOI Listing
June 2020

Use of the Win Ratio in Cardiovascular Trials.

JACC Heart Fail 2020 06;8(6):441-450

British Heart Foundation Cardiovascular Research Centre, University of Glasgow, Glasgow, United Kingdom. Electronic address:

Objectives: The purpose of this study was to compare the win ratio (WR) with the corresponding hazard ratios (HRs) and 1/HR.

Background: The primary outcome in many cardiovascular trials is a composite that includes nonfatal and fatal events. The time-to-first event analysis gives equal statistical weighting to each component event. The WR, which takes into account the clinical importance and timing of the outcomes, has been suggested as an alternative approach.

Methods: Cox proportional hazards models and WR.

Results: In the these trials (n = 16) the WR and HR differed only slightly. For example, in the PARADIGM-HF (sacubitril/valsartan vs. enalapril), the primary outcome of time to first heart failure hospitalization (HFH) or cardiovascular death (CVD) and use of the Cox model gave a 1/HR of 1.25 (95% confidence interval [CI]: 1.12 to 1. 41; z-score = 4.8). Using WR for testing this composite in the hierarchical order of CVD and HFH gave a WR of 1.27 (95% CI: 1.15 to 1.39; z-score = 4.7), reflecting an effect similar to that of sacubitril/valsartan therapy on CVD and HFH. In the DIG (digoxin vs. placebo) trial, the outcome of time-to-first HFH or CVD using Cox gave a 1/HR of 1.18 (95% CI: 1.10 to 1.27; z-score = 4.5). Using the WR for testing this composite in the hierarchical order of CVD and HFH gave a WR of 1.14 (95% CI: 1.05 to 1.20; z-score = 3.1), reflecting a larger effect of digoxin on HFH than on CVD. Several other trials and endpoints including patient-reported measurements were studied.

Conclusions: In 16 large cardiovascular outcome trials, HR and WR provided similar estimates of treatment effects. The WR allows prioritization of fatal outcomes and the hierarchical testing of broader composite endpoints including patient-reported outcomes. In this way, the WR allows for the incorporation of patient-centered and other outcomes, while prioritizing the competing risk of death and hospital admission.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1016/j.jchf.2020.02.010DOI Listing
June 2020

Reduced Diuretic Dose in Patients Treated With Eplerenone: Data From the EPHESUS Trial.

Circ Heart Fail 2020 05 1;13(5):e006597. Epub 2020 May 1.

Universite de Lorraine, Clinical Investigation Center 1433, French Clinical Research Infrastructure Network Investigation Network Initiative-Cardiovascular and Renal Clinical Trialists, Centre Hospitalier Regional et Universitaire de Nancy, INSERM Unite 1116 (J.P.F., K. Duarte, N.G., R.F., S.T., F.Z., P.R.).

Background: Loop diuretics are used for congestion relief, and dose adaptations are usually a consequence of the clinicians' clinical judgement about the congestive status of the patient. In EPHESUS (Eplerenone in Patients With Systolic Dysfunction After Myocardial Infarction), many patients required diuretics for congestion relief. We thus hypothesized that blinded allocation to eplerenone would lead clinicians to reduce loop diuretics, as a consequence of the improvement in patients' status.

Methods: Cox and mixed-effects models were used over a median follow-up of 1.3 years in 6632 patients.

Results: A total of 6632 patients were included; at baseline, 3352 (50.5%) did not have diuretics, 2195 (33.1%) had diuretic doses between 1 and 40 mg/day, and 1085 (16.4%) had diuretic doses >40 mg/day. Patients with higher furosemide equivalent doses had a worse clinical status. Both baseline and follow-up incremental loop diuretic doses were associated with worse prognosis. Eplerenone treatment was associated with lower prescribed loop diuretic doses throughout the follow-up; lower doses were observed at 90 days and decreased further at 180 days and beyond. Eplerenone treatment led to a mean furosemide equivalent dose reduction of -2.2 mg/day (-2.9 to -1.6) throughout the follow-up. Eplerenone was effective in reducing morbidity and mortality regardless of the baseline loop diuretic dose used: hazard ratio for the outcome of cardiovascular death or heart failure hospitalization was 0.83 ([95% CI, 0.75-0.92]; for interaction, 0.54).

Conclusions: Eplerenone treatment led to a loop diuretic dose reduction during follow-up without evidence of treatment effect modification by loop diuretics. These findings suggest that eplerenone reduces congestive signs and symptoms, which enables clinicians to reduce loop diuretic doses.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1161/CIRCHEARTFAILURE.119.006597DOI Listing
May 2020

Impact of Uric Acid on Hypertension Occurrence and Target Organ Damage: Insights From the STANISLAS Cohort With a 20-Year Follow-up.

Am J Hypertens 2020 09;33(9):869-878

Université de Lorraine, INSERM CIC-P 1433, CHRU de Nancy, INSERM U1116, FCRIN INI-CRCT (Cardiovascular and Renal Clinical Trialists), Nancy, France.

Background: Recent studies have shown that hyperuricemia may be associated with incident hypertension (HTN). We examined whether serum uric acid (SUA) is a predictor of HTN and target organ damage (TOD) 20 years later in initially healthy middle-aged individuals.

Methods: Participants from the Suivi Temporaire Annuel Non-Invasif de la Santé des Lorrains Assurés Sociaux (STANISLAS) a single-center familial longitudinal cohort study (961 initially healthy adults and 570 children) underwent clinical and laboratory measurements at baseline and after approximately 20 years. Blood pressure (BP: using ambulatory BP measurements), urine albumin-to-creatinine ratio, estimated glomerular filtration rate (eGFR), left ventricular hypertrophy (LVH), diastolic dysfunction, and carotid-femoral pulse wave velocity (PWV) were measured at the end of follow-up.

Results: In the parent population, higher baseline or last SUA levels and higher change in SUA (ΔUA) were significantly associated with an increased risk of HTN development, even after adjusting for known HTN risk factors (all P < 0.01). Higher baseline SUA was marginally associated with an increased risk of having high carotid-femoral PWV (P = 0.05). The association of SUA with BP increase was body mass index dependent (the increase in BP being greater in leaner subjects; interactionp < 0.05), and the association of SUA with eGFR decline was age dependent (the decline in eGFR being greater in older subjects; interactionp < 0.05). There was no significant association between SUA and diastolic dysfunction or LVH. In the whole population (i.e. including children), a significant association between SUA at baseline and the risk of HTN and higher carotid-femoral PWV was also found (both P < 0.02).

Conclusions: Increased SUA is associated with the development of HTN and vascular/renal TOD in initially healthy midlife subjects.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1093/ajh/hpaa030DOI Listing
September 2020

Prognostic impact of plasma volume estimated from hemoglobin and hematocrit in heart failure with preserved ejection fraction.

Clin Res Cardiol 2020 Nov 6;109(11):1392-1401. Epub 2020 Apr 6.

Centre d'Investigations Cliniques 1433, Université de Lorraine, INSERM, CHRU de Nancy, Inserm 1116 and INI-CRCT (Cardiovascular and Renal Clinical Trialists) F-CRIN Network, Institut Lorrain du cœur Et des, Vaisseaux Louis Mathieu, 4, rue du Morvan, 54500, Vandoeuvre-Les-Nancy, Nancy, France.

Background: Plasma volume (PV) estimated from Duarte's formula (based on hemoglobin/hematocrit) has been associated with poor prognosis in patients with heart failure (HF). There are, however, limited data regarding the association of estimated PV status (ePVS) derived from hemoglobin/hematocrit with clinical profiles and study outcomes in patients with HF and preserved ejection fraction (HFpEF).

Methods And Results: Patients from North and South America enrolled in the Treatment of Preserved Cardiac Function Heart Failure with an Aldosterone Antagonist trial (TOPCAT) with available hemoglobin/hematocrit data were studied. The association between ePVS (Duarte formula and Hakim formula) and the composite of cardiovascular mortality, HF hospitalization, or aborted cardiac arrest was assessed. Among 1747 patients (age 71.6 years; males 50.1%), mean ePVS derived from Duarte formula was 4.9 ± 1.0 mL/g. Higher Duarte-derived ePVS was associated with prior HF admission, diabetes, more severe congestion, poor renal function, higher natriuretic peptide level, and E/e'. After adjustment for potential covariates including natriuretic peptide, higher Duarte-derived ePVS was associated with an increased rate of the primary outcome [highest vs. lowest ePVS quartile: adjusted-HR (95%CI) = 1.79 (1.28-2.50), p < 0.001]. Duarte-derived ePVS improved prognostic performance on top of clinical and routine variables (including natriuretic peptides) (NRI = 11, p < 0.001), whereas Hakim-derived ePVS did not (p = 0.59). The prognostic value of Duarte-derived ePVS was not modified by renal function (P interaction > 0.10 for all outcomes).

Conclusion: ePVS from Duarte's formula was associated with congestion status and improved risk stratification regardless of renal function. Our findings suggest that Duarte-derived ePVS is a useful congestion variable in patients with HFpEF.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1007/s00392-020-01639-4DOI Listing
November 2020

Covariate adjusted reanalysis of the I-Preserve trial.

Clin Res Cardiol 2020 Nov 25;109(11):1358-1365. Epub 2020 Mar 25.

BHF Cardiovascular Research Centre, University of Glasgow, 126 University Place, Glasgow, G12 8TA, UK.

Background: The CHARM-Preserved trial suggested that the renin-angiotensin system (RAS) inhibitor candesartan might have been beneficial in heart failure with preserved ejection fraction (HFpEF); however, this hypothesis was not supported by the findings of I-Preserve with irbesartan.

Aims: To re-analyse the results of I-Preserve, adjusting for imbalances in baseline variables that may have influenced the trial outcomes.

Methods: Cox proportional hazards models with covariate adjustment for baseline variables, including age, sex, medical history, physiological and laboratory variables.

Results: In I-Preserve, 763 (37.0%) participants in the placebo group and 742 (35.9%) in the irbesartan group experienced the primary composite outcome (death from any cause or hospitalization for heart failure, myocardial infarction, unstable angina, arrhythmia, or stroke). The prespecified analysis of this outcome, stratifying for the use of ACEi at baseline, gave a hazard ratio (HR) of 0.95 (95% confidence interval, 0.86-1.05); p = 0.35. Adjusting the effect of treatment for key prognostic baseline variables, gave a HR of 0.89 (0.80-0.99); p = 0.033. Similar findings were observed for the composite of cardiovascular death or HF hospitalization.

Conclusion: Adjusting for imbalances in baseline variables that influence outcomes (or the response to therapy or both) can improve the power around the estimate of the effect of treatment and may alter its statistical significance. Along with the CHARM-Preserved results, these findings suggest that angiotensin-receptor blockers may have a modest effect in HFpEF.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1007/s00392-020-01632-xDOI Listing
November 2020

Association of Dietary Patterns Derived Using Reduced-Rank Regression With Subclinical Cardiovascular Damage According to Generation and Sex in the STANISLAS Cohort.

J Am Heart Assoc 2020 04 21;9(7):e013836. Epub 2020 Mar 21.

CarMeN Laboratory Centre de Recherche en Nutrition Humaine Rhône-Alpes Univ-Lyon Université Claude Bernard Lyon1 Hospices Civils de Lyon F-CRIN/FORCE Network Pierre Bénite, Lyon France.

Background The diet impact on cardiovascular diseases has been investigated widely, but the association between dietary patterns (DPs) and subclinical cardiovascular damage remains unclear. More informative DPs could be provided by considering metabolic syndrome components as intermediate markers. This study aimed to identify DPs according to generation and sex using reduced-rank regression (RRR) with metabolic syndrome components as intermediate markers and assess their associations with intima-media thickness, left ventricular mass, and carotid-femoral pulse-wave velocity in an initially healthy population-based family study. Methods and Results This study included 1527 participants from the STANISLAS (Suivi Temporaire Annuel Non-Invasif de la Santé des Lorrains Assurés Sociaux) cohort fourth examination. DPs were derived using reduced-rank regression according to generation (G1: age ≥50 years; G2: age <50 years) and sex. Associations between DPs and cardiovascular damage were analyzed using multivariable linear regression models. Although identified DPs were correlated between generations and sex, qualitative differences were observed: whereas only unhealthy DPs were found for both men generations, healthy DPs were identified in G2 ("fruity desserts") and G1 ("fiber and w3 oil") women. The "alcohol," "fast food and alcohol," "fried, processed, and dairy products," and "meat, starch, sodas, and fat" DPs in G1 and G2 men and in G1 and G2 women, respectively, were associated with high left ventricular mass (β [95% CI], 0.23 [0.10-0.36], 0.76 [0.00-1.52], 1.71 [0.16-3.26], and 1.80 [0.45-3.14]). The "alcohol" DP in G1 men was positively associated with carotid-femoral pulse-wave velocity (0.22 [0.09-0.34]). Conclusions The DPs that explain the maximum variation in metabolic syndrome components had different associations with subclinical cardiovascular damage across generation and sex. Our results indicate that dietary recommendations should be tailored according to age and sex. Clinical Trial Registration URL: http://www.clinicaltrials.gov. Unique identifier: NCT01391442.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1161/JAHA.119.013836DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7428593PMC
April 2020

Clinical determinants and prognostic implications of renin and aldosterone in patients with symptomatic heart failure.

ESC Heart Fail 2020 06 13;7(3):953-963. Epub 2020 Mar 13.

INSERM, Centre d'Investigations Cliniques Plurithématique 1433, Inserm U1116, CHRU de Nancy and F-CRIN INI-CRCT, Université de Lorraine, Nancy, France.

Aims: Activation of the renin-angiotensin-aldosterone system plays an important role in the pathophysiology of heart failure (HF) and has been associated with poor prognosis. There are limited data on the associations of renin and aldosterone levels with clinical profiles, treatment response, and study outcomes in patients with HF.

Methods And Results: We analysed 2,039 patients with available baseline renin and aldosterone levels in BIOSTAT-CHF (a systems BIOlogy study to Tailored Treatment in Chronic Heart Failure). The primary outcome was the composite of all-cause mortality or HF hospitalization. We also investigated changes in renin and aldosterone levels after administration of mineralocorticoid receptor antagonists (MRAs) in a subset of the EPHESUS trial and in an acute HF cohort (PORTO). In BIOSTAT-CHF study, median renin and aldosterone levels were 85.3 (percentile = 28-247) μIU/mL and 9.4 (percentile = 4.4-19.8) ng/dL, respectively. Prior HF admission, lower blood pressure, sodium, poorer renal function, and MRA treatment were associated with higher renin and aldosterone. Higher renin was associated with an increased rate of the primary outcome [highest vs. lowest renin tertile: adjusted-HR (95% CI) = 1.47 (1.16-1.86), P = 0.002], whereas higher aldosterone was not [highest vs. lowest aldosterone tertile: adjusted-HR (95% CI) = 1.16 (0.93-1.44), P = 0.19]. Renin and/or aldosterone did not improve the BIOSTAT-CHF prognostic models. The rise in aldosterone with the use of MRAs was observed in EPHESUS and PORTO studies.

Conclusions: Circulating levels of renin and aldosterone were associated with both the disease severity and use of MRAs. By reflecting both the disease and its treatments, the prognostic discrimination of these biomarkers was poor. Our data suggest that the "point" measurement of renin and aldosterone in HF is of limited clinical utility.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1002/ehf2.12634DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7261568PMC
June 2020

Myocardial reperfusion reverses the J-curve association of cardiovascular risk and diastolic blood pressure in patients with left ventricular dysfunction and heart failure after myocardial infarction: insights from the EPHESUS trial.

Eur Heart J 2020 05;41(17):1673-1683

Centre d'Investigation Clinique Plurithématique Pierre Drouin-INSERM CHU de Nancy, Nancy, France.

Aims: The described association of low diastolic blood pressure (DBP) with increased cardiovascular outcomes could be due to reduced coronary perfusion or is simply due to reverse causation. If DBP is physiologically relevant, coronary reperfusion after myocardial infarction (MI) might influence DBP-risk association.

Methods And Results: The relation of achieved DBP with cardiovascular death or cardiovascular hospitalization, cardiovascular death, and all-cause death was explored in 5929 patients after acute myocardial infarction (AMI) with impaired left ventricular function, signs and symptoms of heart failure, or diabetes in the EPHESUS trial according to their reperfusion status. Cox regression models were used to assess the impact of reperfusion status on the association of DBP and systolic blood pressure (SBP) with outcomes in an adjusted fashion. In patients without reperfusion, lower DBP <70 mmHg was associated with increased risk for all-cause death [adjusted hazard ratios (HRs) 1.80, 95% confidence interval (CI) 1.41-2.30; P < 0.001], cardiovascular death (HR 1.70, 95% CI 1.3-3.22; P < 0.001), cardiovascular death or cardiovascular hospitalization (HR 1.54, 95% CI 1.26-1.87; P < 0.001). In patients with reperfusion, the risk increase at low DBP was not observed. At low SBP, risk increased independently of reperfusion. A sensitivity analysis in the subgroup of patients with optimal SBP of 120-130 mmHg showed again risk reduction of reperfusion at low DBP. Adding the treatment allocation to eplerenone or placebo into the models had no effects on the results.

Conclusion: Patients after AMIs with a low DBP had an increased risk, which was sensitive to reperfusion therapy. Low blood pressure after MI identifies in patients with particular higher risk. These data support the hypothesis that low DBP in patients with stenotic coronary lesions is associated with risk, potentially involving coronary perfusion pressure and the recommendations provided by guidelines suggesting lower DBP boundaries for these high-risk patients.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1093/eurheartj/ehaa132DOI Listing
May 2020

Enhanced clinical phenotyping by mechanistic bioprofiling in heart failure with preserved ejection fraction: insights from the MEDIA-DHF study (The Metabolic Road to Diastolic Heart Failure).

Biomarkers 2020 Mar 16;25(2):201-211. Epub 2020 Feb 16.

CHRU de Nancy, F-CRIN INI-CRCT (Cardiovascular and Renal Clinical Trialists), INSERM U1116, Centre d'Investigation Clinique et Plurithématique 1433, INSERM, Université de Lorraine, Nancy, France.

Heart failure with preserved ejection fraction (HFpEF) is a heterogeneous syndrome for which clear evidence of effective therapies is lacking. Understanding which factors determine this heterogeneity may be helped by better phenotyping. An unsupervised statistical approach applied to a large set of biomarkers may identify distinct HFpEF phenotypes. Relevant proteomic biomarkers were analyzed in 392 HFpEF patients included in Metabolic Road to Diastolic HF (MEDIA-DHF). We performed an unsupervised cluster analysis to define distinct phenotypes. Cluster characteristics were explored with logistic regression. The association between clusters and 1-year cardiovascular (CV) death and/or CV hospitalization was studied using Cox regression. Based on 415 biomarkers, we identified 2 distinct clusters. Clinical variables associated with cluster 2 were diabetes, impaired renal function, loop diuretics and/or betablockers. In addition, 17 biomarkers were higher expressed in cluster 2 1. Patients in cluster 2 those in 1 experienced higher rates of CV death/CV hospitalization (adj. HR 1.93, 95% CI 1.12-3.32,  = 0.017). Complex-network analyses linked these biomarkers to immune system activation, signal transduction cascades, cell interactions and metabolism. Unsupervised machine-learning algorithms applied to a wide range of biomarkers identified 2 HFpEF clusters with different CV phenotypes and outcomes. The identified pathways may provide a basis for future research.Clinical significanceMore insight is obtained in the mechanisms related to poor outcome in HFpEF patients since it was demonstrated that biomarkers associated with the high-risk cluster were related to the immune system, signal transduction cascades, cell interactions and metabolismBiomarkers (and pathways) identified in this study may help select high-risk HFpEF patients which could be helpful for the inclusion/exclusion of patients in future trials.Our findings may be the basis of investigating therapies specifically targeting these pathways and the potential use of corresponding markers potentially identifying patients with distinct mechanistic bioprofiles most likely to respond to the selected mechanistically targeted therapies.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1080/1354750X.2020.1727015DOI Listing
March 2020

Association of estimated plasma volume status with hemodynamic and echocardiographic parameters.

Clin Res Cardiol 2020 Aug 31;109(8):1060-1069. Epub 2020 Jan 31.

INSERM, Centre d'Investigations Cliniques 1433, CHRU de Nancy, Inserm 1116 and INI-CRCT (Cardiovascular and Renal Clinical Trialists) F-CRIN Network, Université de Lorraine, 4, rue du Morvan, 54500, Vandoeuvre-Les-Nancy, France.

Background: Estimated plasma volume status (ePVS) has diagnostic and prognostic value in patients with heart failure (HF). However, it remains unclear which congestion markers (i.e., biological, imaging, and hemodynamic markers) are preferentially associated with ePVS. In addition, there is evidence of sex differences in both the hematopoietic process and myocardial structure/function.

Method And Results: Patients with significant dyspnea (NYHA ≥ 2) underwent echocardiography and lung ultrasound within 4 h prior to cardiac catheterization. Patients were divided according to tertiles based on sex-specific ePVS thresholds calculated from hemoglobin and hematocrit measurements using Duarte's formula. Among the 78 included patients (median age 74.5 years; males 69.2%; HF 48.7%), median ePVS was 4.1 (percentile = 3.7-4.9) mL/g in males (N = 54) and 4.8 (4.4-5.3) mL/g in females (N = 24). Patients with the highest ePVS had more frequently HF, higher NT-proBNP, larger left atrial volume, and higher E/e' (all p values < 0.05), but no difference in inferior vena cava diameter or pulmonary congestion assessed by lung ultrasound (all p values > 0.10). In multivariable analysis, higher E/e' and lower diastolic blood pressure were significantly associated with increased ePVS. The association between ePVS and congestion variables was not sex-dependent except for left-ventricular end-diastolic pressure, which was only correlated with ePVS in females (Spearman Rho = 0.53, p < 0.01 in females and Spearman Rho = - 0.04, p = 0.76 in males; p = 0.08).

Conclusion: ePVS is associated with E/e' regardless of sex, while only associated with invasively measured left-ventricular end-diastolic pressure in females. These results suggest that ePVS is preferably associated with left-sided hemodynamic markers of congestion.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1007/s00392-020-01599-9DOI Listing
August 2020

Biomarkers in patients with heart failure and central sleep apnoea: findings from the SERVE-HF trial.

ESC Heart Fail 2020 04 17;7(2):503-511. Epub 2020 Jan 17.

Inserm CIC-P 1433, CHRU de Nancy, Inserm U1116, French Clinical Research Infrastructure Network Investigation Network Initiative-Cardiovascular and Renal Clinical Trialists, Université de Lorraine, Nancy, France.

Aims: The Treatment of Sleep-Disordered Breathing with Predominant Central Sleep Apnoea by Adaptive Servo Ventilation in Patients with Heart Failure trial investigated the effects of adaptive servo-ventilation (ASV) (vs. control) on outcomes of 1325 patients with heart failure and reduced ejection fraction (HFrEF) and central sleep apnoea (CSA). The primary outcome (a composite of all-cause death or unplanned HF hospitalization) did not differ between the two groups. However, all-cause and cardiovascular (CV) mortality were higher in the ASV group. Circulating biomarkers may help in better ascertain patients' risk, and this is the first study applying a large set of circulating biomarkers in patients with both HFrEF and CSA.

Methods And Results: Circulating protein-biomarkers (n = 276) ontologically involved in CV pathways, were studied in 749 (57% of the trial population) patients (biomarker substudy), to investigate their association with the study outcomes (primary outcome, CV death and all-cause death). The mean age was 69 ± 10 years, and > 90% were male. The groups (ASV vs. control and biomarker substudy vs. no biomarker) were well balanced. The "best" clinical prognostic model included male sex, systolic blood pressure < 120 mmHg, diabetes, loop diuretic, cardiac device, 6-min walking test distance, and N-terminal pro BNP as the strongest prognosticators. On top of the "best" clinical prognostic model, the biomarkers that significantly improved both the discrimination (c-index) and the net reclassification index (NRI) of the model were soluble suppression of tumorigenicity 2 for the primary outcome; neurogenic locus notch homolog protein 3 (Notch-3) for CV-death and all-cause death; and growth differentiation factor 15 (GDF-15) for all-cause death only.

Conclusions: We studied 276 circulating biomarkers in patients with HFrEF and central sleep apnoea; of these biomarkers, three added significant prognostic information on top of the best clinical model: soluble suppression of tumorigenicity 2 (primary outcome), Notch-3 (CV and all-cause death), and GDF-15 (all-cause death).
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1002/ehf2.12521DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7160494PMC
April 2020

Predictors of sudden cardiac death in high-risk patients following a myocardial infarction.

Eur J Heart Fail 2020 05 16;22(5):848-855. Epub 2020 Jan 16.

BHF Cardiovascular Research Centre, University of Glasgow, Glasgow, UK.

Aims: To develop a risk model for sudden cardiac death (SCD) in high-risk acute myocardial infarction (AMI) survivors.

Methods And Results: Data from the Effect of Carvedilol on Outcome After Myocardial Infarction in Patients With Left Ventricular Dysfunction trial (CAPRICORN) and the Valsartan in Acute Myocardial Infarction Trial (VALIANT) were used to create a SCD risk model (with non-SCD as a competing risk) in 13 202 patients. The risk model was validated in the Eplerenone Post-AMI Heart Failure Efficacy and Survival Study (EPHESUS). The rate of SCD was 3.3 (95% confidence interval 3.0-3.5) per 100 person-years over a median follow-up of 2.0 years. Independent predictors of SCD included age > 70 years; heart rate ≥ 70 bpm; smoking; Killip class III/IV; left ventricular ejection fraction ≤30%; atrial fibrillation; history of prior myocardial infarction, heart failure or diabetes; estimated glomerular filtration rate < 60 mL/min/1.73 m ; and no coronary reperfusion or revascularisation therapy for index AMI. The model was well calibrated and showed good discrimination (C-statistic = 0.72), including in the early period after AMI. The observed 2-year event rates increased steeply with each quintile of risk score (1.9%, 3.6%, 6.2%, 9.0%, 13.4%, respectively).

Conclusion: An easy to use SCD risk score developed from routinely collected clinical variables in patients with heart failure, left ventricular systolic dysfunction or both, early after AMI was superior to left ventricular ejection fraction. This score might be useful in identifying patients for future trials testing treatments to prevent SCD early after AMI.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1002/ejhf.1694DOI Listing
May 2020

Cardiovascular risk associated with serum potassium in the context of mineralocorticoid receptor antagonist use in patients with heart failure and left ventricular dysfunction.

Eur J Heart Fail 2020 08 9;22(8):1402-1411. Epub 2020 Jan 9.

University of Michigan School of Medicine, Ann Arbor, MI, USA.

Background: To assess the prognostic value of mineralocorticoid receptor antagonist (MRA) initiation and change in serum potassium (K ) during follow-up in patients post-acute myocardial infarction with left ventricular dysfunction or chronic heart failure (HF) and reduced ejection fraction (HFrEF).

Methods And Results: Risk scores for predicting cardiovascular death (primary outcome), hospitalization for HF and all-cause death were developed. K and other relevant time-updated clinical and biological variables were added to conventional prognostic factors when constructing these new models. EPHESUS (n = 6632) was the derivation cohort, while EMPHASIS-HF (chronic HF, n = 2737) was used as external validation cohort. The final cardiovascular death risk score included medical history, clinical and biological parameters (e.g. K , below or above the normal range of 4-5 mmol/L, estimated glomerular filtration rate, and anaemia), as well as aspects of treatment (any diuretic usage, MRA use or discontinuation, and beta-blocker use). The risk score performed well in both the derivation and validation cohorts and outperformed the MAGGIC score. A web-based calculator was created to allow easy determination of the risk score (http://cic-p-nancy.fr/CardiovascularriskscoreCalculator/).

Conclusion: Adding time-updated variables, including K and MRA treatment, improved risk prediction of cardiovascular death (on top of the MAGGIC score) in patients with HF eligible for renin-angiotensin system inhibitors and MRA therapy. This new risk score including MRA usage and K may be of value in helping physicians to better use MRAs, avoid unnecessary and potentially detrimental permanent discontinuations, and therefore improving cardiovascular outcomes in patients with chronic HFrEF or HF after acute myocardial infarction with left ventricular dysfunction.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1002/ejhf.1724DOI Listing
August 2020

PAK3 mutations responsible for severe intellectual disability and callosal agenesis inhibit cell migration.

Neurobiol Dis 2020 03 14;136:104709. Epub 2019 Dec 14.

Department of Cognition and Behavior, Paris-Saclay Institute of Neuroscience (Neuro-PSI CNRS, UMR 9197), Paris-Sud and Paris-Saclay Universities, Orsay, France. Electronic address:

Corpus callosum agenesis (CCA) is a brain malformation associated with a wide clinical spectrum including intellectual disability (ID) and an etiopathological complexity. We identified a novel missense G424R mutation in the X-linked p21-activated kinase 3 (PAK3) gene in a boy presenting with severe ID, microcephaly and CCA and his fetal sibling with CCA and severe hydrocephaly. PAK3 kinase is known to control synaptic plasticity and dendritic spine dynamics but its implication is less characterized in brain ontogenesis. In order to identify developmental functions of PAK3 impacted by mutations responsible for CCA, we compared the biochemical and biological effects of three PAK3 mutations localized in the catalytic domain. These mutations include two "severe" G424R and K389N variants (responsible for severe ID and CCA) and the "mild" A365E variant (responsible for nonsyndromic mild ID). Whereas they suppressed kinase activity, only the two severe variants displayed normal protein stability. Furthermore, they increased interactions between PAK3 and the guanine exchange factor αPIX/ARHGEF6, disturbed adhesion point dynamics and cell spreading, and severely impacted cell migration. Our findings highlight new molecular defects associated with mutations responsible for severe clinical phenotypes with developmental brain defects.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1016/j.nbd.2019.104709DOI Listing
March 2020