Dietary inflammatory potential and arterial stiffness in a French cohort: Insights from the STANISLAS study.

BACKGROUND AND AIMS: Chronic inflammation plays a key role in arterial stiffness pathogenesis. Dietary components can display anti- or pro-inflammatory properties. Nonetheless, the association between the diet's overall inflammatory potential and arterial stiffness is unclear. This study aimed to assess the association between the diet's overall inflammatory potential and arterial stiffness assessed by carotid-femoral pulse wave velocity (cfPWV). METHODS AND RESULTS: This cross-sectional study included 1307 participants from the STANISLAS family cohort study. Dietary data were collected using a validated food frequency questionnaire. The adapted dietary inflammatory index (ADII) score was calculated to assess the inflammatory potential of the participants' diet. The association of ADII score quartile with cfPWV was assessed using IPW-weighted linear mixed models with random family effect. The median (Q1-Q3) ADII score was 0.45 (-1.57, 2.04). Participants exhibiting higher ADII scores demonstrated elevated energy intake, dietary saturated fat, and ultra-processed foods. Conversely, individuals with lower ADII scores exhibited higher vitamins and omega intakes, and a higher diet quality, as assessed by the DASH score. Despite these observations from the descriptive analyses, ADII score quartiles were not significantly associated with cfPWV (ß(95% CI) were 0.01 (-0.02,0.04) for Q2, 0.02 (-0.01,0.05) for Q3, and 0.02 (-0.01,0.05) for Q4 compared to Q1). CONCLUSION: In this cross-sectional study, participants had a relatively modest consumption of pro-inflammatory foods, no substantial associations were observed between the diet inflammatory potential and arterial stiffness. Further longitudinal studies in larger cohorts are needed to better understand the link between inflammatory diet and arterial stiffness.

Potassium canrenoate in brain-dead organ donors: a randomised controlled clinical trial protocol (CANREO-PMO).

INTRODUCTION: Ischaemia/reperfusion injuries (IRIs) are associated with poorer survival of kidney grafts from expanded criteria donors. Preclinical studies have shown that mineralocorticoid receptor antagonists (MRAs) prevent acute and chronic post-ischaemic renal dysfunction by limiting IRI. However, data concerning the safety of MRAs in brain-dead donor patients are scarce. We seek to investigate the tolerance of MRAs on the haemodynamics in this population. METHODS AND ANALYSIS: CANREO-PMO is a randomised, controlled, single-centre, double-blind study. Brain-dead organ donors hospitalised in intensive care are randomised 1:1 after consent to receive 200 mg potassium canrenoate or its matching placebo every 6 hours until organ procurement. The primary outcome is a hierarchical composite endpoint that includes: (1) cardiocirculatory arrest, (2) the impossibility of kidney procurement, (3) the average hourly dose of norepinephrine/epinephrine between randomisation and departure to the operating room, and (4) the average hourly volume of crystalloids and/or colloids received. Thirty-six patients will be included. The secondary endpoints evaluated among the graft recipients are the: (1) vital status of the kidney graft recipients and serum creatinine level with estimated glomerular filtration rate (GFR) according to Chronic Kidney Disease Epidemiology Collaboration (CKD-EPI) at 3 months after renal transplantation, (2) percentage of patients dependent on dialysis and/or with an estimated GFR <20 mL/min/1.73 m2 at 3 months, (3) vital status of the kidney graft recipients at 3 months, and (4) vital status of the kidney graft recipients and creatinine levels (in µmol/L), with the estimated GFR according to CKD-EPI (in mL/min/1.73 m2), at 1 year, 3 years and 10 years after transplantation. ETHICS AND DISSEMINATION: This trial has full ethical approval (Comité de Protection des Personnes: CPP Ouest II-ANGERS, France), and the written consent of relatives will be obtained. Results will be reported at conferences, peer-reviewed publications and using social media channels. TRIAL REGISTRATION NUMBER: NCT04714710.

Association between eating behaviour and 13-year cardiovascular damages in the initially healthy STANISLAS cohort.

AIMS: Several dimensions of eating behaviour (EB), such as restrained eating (RE), appear to be cross-sectionally associated with certain cardiovascular (CV) diseases and metabolic risk factors although little is known regarding longitudinal associations. This study aimed to assess the associations between EB and CV damage or metabolic syndrome after 13 years, in initially healthy individuals. METHODS AND RESULTS: This study included 1109 participants from the familial STANISLAS (Suivi Temporaire Annuel Non-Invasif de la Santé des Lorrains Assurés Sociaux) cohort study. Emotional eating (EmE), RE, and external eating were assessed using the Dutch Eating Behaviour Questionnaire. Metabolic syndrome and CV damages such as carotid-femoral pulse-wave velocity (cfPWV), left ventricular mass, carotid intima-media thickness, and diastolic dysfunction (DD) were measured after a period of 13 years. Mixed model analysis with a family random effect and adjustment for age, sex, education, temporal gap, physical activity, metabolic factors at baseline, and the onset of CV disease during follow-up, and mediation analysis were performed in adults and adolescents separately. Among adults, EmE was associated with a 38% increased risk of DD 13 years later [odds ratio = 1.38 (1.05; 1.83)]. Stress level mediated 31.9% of this association (P = 0.01). Emotional eating was positively associated with cfPWV (ß=0.02 [0.01; 0.04]). External eating was slightly associated with lower cfPWV (ß=-0.03 [-0.05; -0.01]). No associations were observed between EB dimensions and metabolic syndrome. Energy intake was not found to be a mediator of any associations. CONCLUSION: Our results suggest that CV prevention should also take into account EB and include emotion regulation skills teaching.

The association of three dimensions of eating behaviour [emotional eating, restrained eating, and external eating] with 13 years later cardiovascular damages have been investigated in the initially healthy STANISLAS (Suivi Temporaire Annuel Non-Invasif de la Santé des Lorrains Assurés Sociaux) cohort. Emotional eating was associated with higher pulse-wave velocity and an increased risk of diastolic dysfunction. External eating was associated with lower pulse-wave velocity. Stress level was found to be a mediator of the association found between emotional eating and diastolic dysfunction.

Fatty acid desaturase genetic variations and dietary omega-3 fatty acid intake associate with arterial stiffness.

Aims: Long-chain polyunsaturated fatty acids (PUFAs) generate diverse bioactive lipid mediators, which tightly regulate vascular inflammation. The effects of omega-3 PUFA supplementation in cardiovascular prevention however remain controversial. In addition to direct dietary intake, fatty acid desaturases (FADS) determine PUFA levels. Increased arterial stiffness represents an independent predictor of mortality and cardiovascular events. The aim of the present study was to determine the association of PUFA intake, FADS1 genotype, and FADS expression with arterial stiffness. Methods and results: A cross-sectional population-based cohort study of 1464 participants without overt cardiovascular disease was conducted. Dietary intake was assessed using a food frequency questionnaire. Arterial stiffness was assessed by carotid-femoral pulse wave velocity (cfPWV), and the FADS1 locus variant was determined. Blood cell transcriptomics was performed in a subset of 410 individuals. Pulse wave velocity was significantly associated with the FADS1 locus variant. Differential associations between PWV and omega-3 PUFA intake were observed depending on the FADS1 genotype. High omega-3 PUFA intake attenuated the FADS1 genotype-dependent associations. Carriers of the minor FADS1 locus variant exhibited increased expression of FADS2, which is associated with PWV. Conclusion: Taken together, these findings point to FADS1 genotype-dependent associations of omega-3 PUFA intake on subclinical cardiovascular disease. These findings may have implications for identifying responders and non-responders to omega-3 PUFA supplementation and open up for personalized dietary counselling in cardiovascular prevention.

Quality of Beverage Intake and Cardiometabolic and Kidney Outcomes: Insights From the STANISLAS Cohort.

Background and Aims: Beverages are an important aspect of diet, and their quality can possibly affect health. The Healthy Beverage Index (HBI) has been developed to take into account these effects. This study aimed to highlight the relationships between health and beverage quality by assessing the association of the HBI and its components with kidney and cardiometabolic (CM) outcomes in an initially healthy population-based familial cohort. Methods: This study included 1,271 participants from the STANISLAS cohort. The HBI, which includes 10 components of habitual beverage consumption, was calculated. Associations of the HBI and its components with estimated glomerular filtration rate (eGFR), albuminuria, hypertriglyceridemic waist (HTG waist), metabolic syndrome (MetS), carotid-femoral pulse wave velocity (cfPWV), carotid intima-media thickness (cIMT), and left ventricular mass (LV mass) were analyzed using multivariable linear or logistic regression models. Results: The median HBI score was 89.7 (78.6-95) out of 100 points. While the overall HBI score was not significantly associated with any of the studied outcomes, individual HBI components were found differently associated with the outcomes. cfPWV and cIMT were lower in participants who did not meet the full-fat milk criteria (p = 0.03 and 0.001, respectively). In men, higher cfPWV was observed for the "low Fat milk" (p = 0.06) and "alcohol" (p = 0.03) non-adherence criteria. Odds of HTG waist were higher with the non-adherence to sugar-sweetened beverages criteria (p < 0.001). eGFR was marginally higher with non-adherence to the coffee/tea criteria (p = 0.047). Conclusions: In this initially healthy population, HBI components were differently associated with kidney and cardiometabolic outcomes, despite a good overall HBI score. Our results highlight specific impacts of different beverage types and suggest that beverages could have an impact on kidney and cardiometabolic health.

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

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 (ß [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.

Protocol for a multicentre randomised controlled trial evaluating the effects of moderate hypothermia versus normothermia on mortality in patients with refractory cardiogenic shock rescued by venoarterial extracorporeal membrane oxygenation (VA-ECMO) (HYPO-ECMO study).

INTRODUCTION: Venoarterial extracorporeal membrane oxygenation (VA-ECMO) is widely used to support the most severe forms of cardiogenic shock (CS). Nevertheless, despite extracorporeal membrane oxygenation (ECMO) use, mortality still remains high (50%). Moderate hypothermia (MH) (33°C-34°C) may improve cardiac performance and decrease ischaemia-reperfusion injuries. The use of MH during VA-ECMO is strongly supported by experimental and preliminary clinical data. METHODS AND ANALYSIS: The Hypothermia-Extracorporeal Membrane Oxygenation (HYPO-ECMO) study is a multicentre, prospective, controlled randomised trial between an MH group (33°C≤T°C≤34°C) and normothermia group (36°C≤T°C≤37°C). The primary endpoint is all-cause mortality at day 30 following randomisation. The study will also assess as secondary endpoints the effects of targeted temperature management strategies on (1) mortality rate at different time points, (2) organ failure and supportive treatment use and (3) safety. All intubated adults with refractory CS supported with VA-ECMO will be screened. Exclusion criteria are patients having undergone cardiac surgery for heart transplantation or left or biventricular assist device implantation, acute poisoning with cardiotoxic drugs, pregnancy, uncontrolled bleeding and refractory cardiac arrest.Three-hundred and thirty-four patients will be randomised and followed up to 6 months to detect a 15% difference in mortality. Data analysis will be intention to treat. The differences between the two study groups in the risk of all-cause mortality at day 30 following randomisation will be studied using logistic regression analysis adjusted for postcardiotomy setting, prior cardiac arrest, prior myocardial infarction, age, vasopressor dose, Sepsis-related Organ Failure Assessment (SOFA) score and lactate at randomisation. ETHICS AND DISSEMINATION: Ethics approval has been granted by the Comité de Protection des Personnes Est III Ethics Committee. The trial has been approved by the French Health Authorities (Agence Nationale de la Sécurité du Médicament et des Produits de Santé). Dissemination of results will be performed via journal articles and presentations at national and international conferences. Since this study is also the first step in the constitution of an 'ECMO Trials Group', its results will also be disseminated by the aforementioned group. TRIAL REGISTRATION NUMBER: NCT02754193.

EPURE Transplant (Eplerenone in Patients Undergoing Renal Transplant) study: study protocol for a randomized controlled trial.

BACKGROUND: Despite advances in immunosuppressive therapy, kidney graft survival has failed to improve during the last decades. Ischemia/reperfusion injury (IRI) is one of the main pathophysiological mechanisms underlying delayed graft function, which is associated with poor long-term graft survival. Due to organ shortage, the proportion of grafts from expanded criteria donors (ECDs) is ever growing. These grafts may particularly benefit from IRI prevention. In preclinical models, mineralocorticoid receptor antagonists (MRAs) have been shown to efficiently prevent IRI. This study aims to assess the effect of MRA administration in the early phase of kidney transplantation (KT) among recipients of ECD grafts on mid-term graft function. METHODS/DESIGN: This is a multicenter, double-blind, placebo-controlled, randomized clinical trial. Patients on hemodialysis and undergoing a single or a dual KT from an ECD will be eligible for inclusion. We plan to randomize 132 patients. Included patients will be randomized (1:1) to receive either eplerenone 25 mg every 12 h during 4 days (the first dose being administered just prior to KT) or placebo. The primary outcome is graft function at 3 months, assessed by glomerular filtration rate (GFR, in mL/min/1.73m2) measured using iohexol clearance. Secondary outcomes include (1) proportion of patients with either dialysis dependency or a GFR < 30 mL/min/1.73m2 at 3 months, (2) proportion of patients with immediate, slow, or delayed graft function, (3) proteinuria at 3 months, (4) occurrence of hyperkalemia during the first week following KT, (5) length of hospital stay for the KT, and (6) occurrence of biopsy-proven acute rejection in the first 3 months following KT. Estimated GFR, graft, and patient survival will also be collected at 1, 3, and 10 years via the national database of organ recipients. DISCUSSION: Improvement of ECD grafts is a public health priority, since better ECD outcomes could eventually limit organ shortage. MRA administration in the early phase of KT may prevent IRI and subsequently improve mid-term graft function. The trial will also assess the safety of MRA administration in this population, primarily the absence of threatening hyperkalemia. TRIAL REGISTRATION: ClinicalTrials.gov, NCT02490904 . Registered on 1 July 2015.

Obesity and metabolic features associated with long-term developing diastolic dysfunction in an initially healthy population-based cohort.

BACKGROUND: Diastolic dysfunction (DD) is increasingly common. However, its metabolic determinants are poorly known. This study aims to determine which metabolic and inflammatory features predict DD in initially healthy adults. METHODS: We prospectively analyzed the association between metabolic features and DD in 728 initially healthy adults aged 30-60 from Eastern France enrolled in the STANISLAS population-based cohort. Clinical and biological cardiovascular features were collected at baseline (1994-1995). DD was assessed twenty years later (2011-2016) by echocardiography using current international guidelines. For replication purposes, 1463 subjects from the Malmö Preventive Project cohort were analyzed. RESULTS: In the STANISLAS cohort, 191 subjects (26.2%) developed DD. In age-sex-adjusted logistic models, significant predictors of DD were body mass index (BMI, odds ratio for 1-standard-deviation increase (OR) 1.28, 95% CI 1.08-1.52), waist circumference (WC, OR 1.48, 95% CI 1.18-1.84), waist-hip ratio (OR 1.53, 95% CI 1.16-2.02), systolic blood pressure (OR 1.19, 95% CI 1.00-1.43) and triglycerides (TG, OR 1.18, 95% CI 1.00-1.40). Subjects with elevated WC (> 80th percentile) and TG (> 50th percentile) had a twofold higher DD risk (age-sex-adjusted odds ratio 2.00, 95% CI 1.20-3.31, P = 0.008), whereas no such interplay was observed for BMI. In the Malmö cohort, BMI was similarly associated with DD; participants with both elevated BMI and TG were at higher DD risk (age-sex-adjusted odds ratio 1.61, 95% CI 1.18-2.20, P = 0.002). CONCLUSIONS: Subjects with elevated WC and TG may have a higher long-term DD risk. Prevention targeting visceral obesity may help reduce the incidence of DD.

A fragment-based approach to understanding inhibition of 1-deoxy-D-xylulose-5-phosphate reductoisomerase.

The inhibition of 1-deoxy-D-xylulose-5-phosphate reductoisomerase (DXR) by fosmidomycin was studied by using a kinetic assay based on the consumption of NADPH and synthetic substrate. Fosmidomycin is a slow tight-binding inhibitor of DXR that shows strong negative cooperativity (absolute value(h) = 0.3) in binding. Cooperativity is displayed during the initial (weak, K0.5 = 10 microM) binding event and does not change as the binding tightens to the equilibrium value of 0.9 nM over a period of seconds to minutes. A series of fosmidomycin fragments was examined, but all showed much weaker inhibition, in the mM range. A series of cyclic fosmidomycin analogues was also synthesised and tested, but these showed high-microM binding at best. None of the synthetic compounds showed time-dependent inhibition. We concluded that the slow tight-binding behaviour, and perhaps also cooperativity, are mediated by significant reorganisation of the active site upon fosmidomycin binding. This makes the rational design of new inhibitors of DXR difficult at best.