Zohra Lamiral

BACKGROUND: Patients with chronic kidney disease (CKD) are at high risk of cardiovascular complications. We have shown that Ngal (neutrophil gelatinase–associated lipocalin)/lcn2 is involved in aldosterone-induced cardiac remodeling and inflammation. Here, we investigated the role of Ngal in the progression of cardiorenal syndrome. METHODS: CKD was induced in rats via 5/6 nephrectomy in wild-type and Ngal knockout rats. Cardiorenal functions were assessed 3 months after subtotal nephrectomy or sham operation. Cardiac fibroblasts were isolated from wild-type rats and incubated with or without rNgal (recombinant Ngal) and Gal-3 (galectin-3). RESULTS: Cardiac perfusion was less impaired in CKD Ngal knockout than in CKD wild type. Left ventricle interstitial fibrosis was more severe in CKD wild type than in sham but was blunted in CKD Ngal knockout rats. Levels of Gal-3, Col1 (collagen 1), Ccl2 (C-C motif chemokine ligand 2), and IL-6 (interleukin-6) were high in cardiac fibroblasts incubated with rNgal. A similar pattern was observed in cells treated with recombinant Gal-3. Both Ngal and Gal-3 induced activation of the Tlr4 (toll-like receptor 4)-Myd88 (myeloid differentiation primary response 88) pathway. The effects of rNgal were blunted by concomitant treatment with Gal-3 or Tlr4 inhibitors, suggesting that Gal-3 contributes to Ngal-induced cardiac fibrosis and inflammation by activating the Tlr4-Myd88 pathway. In both MEDIA-DHF (Metabolic Road to Diastolic Heart Failure) and BIOSTAT-CHF (Biology Study to Tailored Treatment in Chronic Heart Failure) cohorts, elevated levels of Ngal and Gal-3 were associated with advanced diastolic dysfunction and adverse clinical outcomes, particularly among patients with impaired renal function. CONCLUSIONS: In CKD rats, Ngal was involved in cardiac remodeling via a Gal-3/Tlr4-dependent pathway, increasing inflammation and fibrosis, and correlated to cardiac outcomes in the MEDIA-DHF and BIOSTAT-CHF cohorts.

Background: Heart failure with preserved ejection fraction (HFpEF) is characterized by chronic low‐grade inflammation, which influences endothelial function, affecting glycocalyx integrity, barrier permeability, and cell adhesion. The role of endothelial glycocalyx shedding in the onset and progression of HFpEF remains poorly understood. Our aim was to investigate the association of glycocalyx degradation biomarkers, hyaluronan and syndecan‐1, with patient characteristics and clinical outcomes in HFpEF and at population level. Methods: Circulating hyaluronan and syndecan‐1 concentrations were assessed in a population‐based cohort (STANISLAS [Suivi Temporaire Annuel Non‐Invasif de la Santé des Lorrains Assurés Sociaux], n=959) and a cohort with HFpEF (NETDiamond [New Targets in Diastolic Heart Failure: From Comorbidities to Personalized Medicine], n=86). Results: Hyaluronan levels increased with age in both the population cohort and the cohort with HFpEF. Higher hyaluronan concentrations were associated in adjusted analyses with features of adverse cardiac remodeling (higher left atrial volume index and left ventricular mass index) in both cohorts and with higher peak early mitral inflow velocity/peak early diastolic mitral annular velocity in the cohort with HFpEF. Syndecan‐1 was negatively associated with left ventricular mass index in the population cohort but not in the cohort with HFpEF where a positive association with features of adverse cardiac remodeling was found. In HFpEF, higher concentrations of both hyaluronan and syndecan‐1 were significantly associated with increased rates of cardiovascular events. Conclusions: Hyaluronan increases with age and is consistently associated with adverse cardiac remodeling across the spectrum of cardiovascular risk. In HFpEF, a manifestation of advanced cardiovascular disease, both hyaluronan and syndecan‐1 associate with a higher risk of events. These findings suggest that glycocalyx degradation markers provide clinically relevant information across different stages of disease. Whether such markers may serve as therapeutic targets should be further explored.

Background: Heart failure with preserved ejection fraction (HFpEF) is a multifaceted syndrome, likely stemming from comorbidity‐induced inflammation resulting in endothelial dysfunction. Endothelial glycocalyx degradation's role in the development and prognosis of HFpEF remains largely unexplored. Our study aimed at exploring the association between glycocalyx degradation and diastolic dysfunction and determining whether glycocalyx degradation can predict clinical outcomes in patients with HFpEF. Methods: Perlecan and thrombomodulin concentrations were assessed in individuals deemed healthy (STANISLAS [Suivi Temporaire Annuel Non‐Invasif de la Santé des Lorrains Assurés Sociaux (Annual Noninvasive Temporary Monitoring of the Health of Insured Lorrainers)] cohort, n=1705) and patients with HFpEF (MEDIA‐DHF [Metabolic Road to Diastolic Heart Failure], n=460 and BIOSTAT‐CHF [Biology Study to Tailored Treatment in Chronic Heart Failure], n=556) to evaluate endothelial glycocalyx degradation. Results: In patients with HFpEF, perlecan but not thrombomodulin was increased compared with controls ( P P =0.73). In adjusted analysis, perlecan was associated with peak early mitral inflow velocity/peak early diastolic mitral annular velocity ratio and thrombomodulin with peak early diastolic mitral annular velocity in control individuals, whereas perlecan and thrombomodulin were associated with peak early mitral inflow velocity/peak early diastolic mitral annular velocity and left atrial volume index in patients with HFpEF (all P P =0.026) and BIOSTAT‐CHF cohorts (adjusted HR, 2.12 [95% CI, 1.49–3.03]; P P =0.004) but not in MEDIA‐DHF. Conclusions: Higher circulating levels of the endothelial glycocalyx degradation biomarkers like perlecan and, to a lesser extent, thrombomodulin are associated with features of diastolic dysfunction in population and HFpEF settings and predict poor outcome in patients with HFpEF. These results suggest that glycocalyx degradation may be an early step in the pathological processes leading to HFpEF and gain further prognostic value in later stages (ie, overt HFpEF). Registration: URL: https://clinicaltrials.gov/ ; Unique identifiers: NCT01391442, https://clinicaltrials.gov/study/NCT01391442?cond=stanislas&rank=1 ; NCT02446327; URL: https://cordis.europa.eu ; BIOSTAT‐CHF ID: 242209.

Assessing VAC is especially useful in heart failure and valvular heart disease, but less is known about VAC in the pathophysiology of CV disease risk in younger individuals. In young individuals without overt CV disease, we showed descriptive data regarding VAC, determined by PWV/GLS ratio, and explored the associations of VAC with clinical CV disease risk factors. Worse VAC, reflected by higher values of PWV/GLS, associated with high blood pressure and smoking in young adults.

Background: Atrial fibrillation (AF) leads to the development of cardiac remodeling/diastolic dysfunction and vice versa. We intended to determine whether cardiac remodeling/diastolic dysfunction is present at early stages of AF. Methods: We studied 175 patients with paroxysmal AF, compared with 175 matched control subjects, who had available echocardiography data to investigate the association between echocardiographic variables and AF from the STANISLAS cohort. Results: In this study (mean age 55 years; 70.3% male), patients with paroxysmal AF had greater left ventricular mass compared to matched controls (p < 0.05). Patients with paroxysmal AF were also likely to have larger left atrial volume and a higher peak tricuspid regurgitation velocity, leading to higher prevalence (though p < 0.05). Multivariable conditional logistic regression models showed that paroxysmal AF was significantly associated with increased left ventricular mass and left atrial enlargement (all-p < 0.001), but not with e’ and deceleration time of E wave (all-p > 0.1). Conclusions: Left ventricular mass and left atrial enlargement rather than diastolic dysfunction (as evaluated by echocardiography) were associated with paroxysmal AF irrespective of body mass index, blood pressure and renal function. These findings suggest that cardiac remodeling may occur very early in the natural history of AF.

Background Loop diuretics are the mainstay of congestion treatment in patients with heart failure (HF). We assessed the association between baseline loop diuretic use and outcome. We also compared the increment in risk related to diuretic dose with conventional prognostic enrichment criteria used in the EMPHASIS-HF trial, which included patients with systolic HF and mild symptoms, such as prior hospitalization and elevated natriuretic peptides. Methods Individual analyses were performed according to baseline loop diuretic usage (furosemide-equivalent dose > 40 mg, 1–40 mg, and no furosemide), and according to enrichment criteria adopted in the trial [i.e. recent hospitalization (< 30 days or 30 to 180 days prior to randomization) due to HF or other cardiovascular cause, or elevated natriuretic peptides]. The primary endpoint was a composite of cardiovascular death or HF hospitalization. Results Loop diuretic usage at baseline (HR for > 40 mg furosemide-equivalent dose = 3.16, 95% CI 2.43–4.11; HR for 1–40 mg = 2.06, 95% CI 1.60–2.65) was significantly associated with a higher risk for the primary endpoint in a stepwise manner when compared to no baseline loop diuretic usage. In contrast, the differences in outcome rates were more modest when using history of hospitalization and/or BNP: all HR ranged from 1 (reference, non-HF related CV hospitalization > 30 days) to 2.04 (HF hospitalization < 30 days). The effect of eplerenone on the primary endpoint was consistent across subgroups in both analyses (P for interaction ≥ 0.2 for all). Conclusions Loop diuretic usage (especially at doses > 40 mg) identified patients at higher risk than history of HF hospitalization and/or high BNP blood concentrations. Graphic abstract

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.

The quality of phantom images was previously shown to be higher on digital (Vereos Philips®) compared to analog PET (Ingenuity Philips®) cameras. This study aimed to determine the extent to which this difference still remains significant on normal brain 18F-FDG PET images. Relative noise and contrast as well as border sharpness (a spatial resolution index) of central (striata) and peripheral (occiput) gray-matter structures were compared between 10 sets of normal brain 18F-FDG PET images recorded and reconstructed on digital and analog last-generation PET cameras, together with a subjective visual analysis of image quality provided by experienced physicians. Compared with analog PET, digital PET provided marked improvements in image quality parameters. The median relative noise was decreased (− 22%), while gray/white-matter contrast was increased (+ 27%/+ 41% for central/peripheral gray-matter structures), with these results being consistent with visual analysis. In addition, a clear enhancement in image sharpness was further documented for digital PET owing to the possible use of a 1-mm3 voxel size (+ 24%/+ 21%). On normal brain 18F-FDG images and compared with a last-generation analog PET, the fully digital PET camera offers marked improvements in image noise and contrast, as well as significant potential for further enhancing spatial resolution.