STANISLAS Cohort Research Articles

Association of ventricular-arterial coupling with biomarkers involved in heart failure pathophysiology-the STANISLAS cohort.

Impaired left ventricular-arterial coupling (VAC) has been shown to correlate with worse prognosis in cardiac diseases and heart failure (HF). The extent of the relationship between VAC and circulating biomarkers associated with HF has been scarcely documented. We aimed to explore associations of VAC with proteins involved in HF pathophysiology within a large population-based cohort of middle-aged individuals. In the forth visit of the STANISLAS family cohort, involving 1309 participants (mean age 48 ± 14 years; 48% male) from parent and children generations, we analysed the association of 32 HF-related proteins with non-invasively assessed VAC using pulse wave velocity (PWV)/global longitudinal strain (GLS) and arterial elastance (Ea)/ventricular end-systolic elastance (Ees). Among the 32 tested proteins, fatty acid-binding protein adipocyte 4, interleukin-6, growth differentiation factor 15, matrix metalloproteinase (MMP)-1, and MMP-9 and adrenomedullin were positively associated with PWV/GLS whereas transforming growth factor beta receptor type 3, MMP-2 and N-terminal pro-B-type natriuretic peptide (NT-proBNP) were negatively associated. In multivariable models, only MMP-2 and NT-proBNP were significantly and inversely associated with PWV/GLS in the whole population and in the parent generation. Higher levels of NT-proBNP were also negatively associated with Ea/Ees in the whole cohort but this association did not persist in the parent subgroup. Elevated MMP-2 and NT-proBNP levels correlate with better VAC (lower PWV/GLS), possibly indicating a compensatory cardiovascular response to regulate left ventricular pressure amidst cardiac remodelling and overload.

Advanced myocardial deformation echocardiography for evaluation of the athlete's heart: Functional and mechanistic analysis

BackgroundAssessment of the athlete's heart is challenging because of a phenotypic overlap between reactive physiological adaptation and pathological remodelling. The potential value of myocardial deformation remains controversial in identifying early cardiomyopathy. AimTo identify the echocardiographic phenotype of athletes using advanced two-dimensional speckle tracking imaging, and to define predictive factors of subtle left ventricular systolic dysfunction. MethodsIn total, 191 healthy male athletes who underwent a preparticipation medical evaluation at Nancy University Hospital between 2013 and 2020 were included. Clinical and echocardiographic data were compared with 161 healthy male subjects from the STANISLAS cohort. Borderline global longitudinal strain value was defined as<17.5%. ResultsAthletes demonstrated lower left ventricular ejection fraction (57.9±5.3% vs. 62.6±6.4%; P<0.01) and lower global longitudinal strain (17.5±2.2% vs. 21.1±2.1%; P<0.01). No significant differences were found between athletes with and without a borderline global longitudinal strain value regarding clinical characteristics, structural echocardiographic features and exercise capacity. A borderline global longitudinal strain value was associated with a lower endocardial global longitudinal strain (18.8±1.2% vs. 22.7±1.9%; P=0.02), a lower epicardial global longitudinal strain (14.0±1.1% vs. 16.6±1.2%; P<0.01) and a higher endocardial/epicardial global longitudinal strain ratio (1.36±0.07 vs. 1.32±0.06; P<0.01). No significant difference was found regarding mechanical dispersion (P=0.46). ConclusionsBorderline global longitudinal strain value in athletes does not appear to be related to structural remodelling, mechanical dispersion or exercise capacity. The athlete's heart is characterized by a specific myocardial deformation pattern with a more pronounced epicardial layer strain impairment.

Proteomic profiles of left atrial volume and its influence on response to spironolactone: Findings from the HOMAGE trial and STANISLAS cohort.

High left ventricular filling pressure increases left atrial volume and causes myocardial fibrosis, which may decrease with spironolactone. We studied clinical and proteomic characteristics associated with left atrial volume indexed by body surface area (LAVi), and whether LAVi influences the response to spironolactone on biomarker expression and clinical variables. In the HOMAGE trial, where people at risk of heart failure were randomized to spironolactone or control, we analysed 421 participants with available LAVi and 276 proteomic measurements (Olink) at baseline, month 1 and 9 (mean age 73 ± 6 years; women 26%; LAVi 32 ± 9 ml/m2). Circulating proteins associated with LAVi were also assessed in asymptomatic individuals from a population-based cohort (STANISLAS; n = 1640; mean age 49 ± 14 years; women 51%; LAVi 23 ± 7 ml/m2). In both studies, greater LAVi was significantly associated with greater left ventricular masses and volumes. In HOMAGE, after adjustment and correction for multiple testing, greater LAVi was associated with higher concentrations of matrix metallopeptidase-2 (MMP-2), insulin-like growth factor binding protein-2 (IGFBP-2) and N-terminal pro-B-type natriuretic peptide (NT-proBNP) (false discovery rates [FDR] <0.05). These associations were externally replicated in STANISLAS (all FDR <0.05). Among these biomarkers, spironolactone decreased concentrations of MMP-2 and NT-proBNP, regardless of baseline LAVi (pinteraction > 0.10). Spironolactone also significantly reduced LAVi, improved left ventricular ejection fraction, lowered E/e', blood pressure and serum procollagen type I C-terminal propeptide (PICP) concentration, a collagen synthesis marker, regardless of baseline LAVi (pinteraction > 0.10). In individuals without heart failure, LAVi was associated with MMP-2, IGFBP-2 and NT-proBNP. Spironolactone reduced these biomarker concentrations as well as LAVi and PICP, irrespective of left atrial size.

Abstract 129: Ngal Is A Novel Target In Hypertension By Modulating The Ncc-mediated Renal Na Balance

Background: The expression of neutrophil gelatinase-associated lipocalin (NGAL/lcn2) is directly modulated by mineralocorticoid receptor activation but its role in blood pressure control is unclear. Methods: a potential relationship between NGAL plasma levels, systolic blood pressure and urinary Na excretion was assessed in the STANISLAS cohort. The specific role of NGAL/lcn2 in salt-sensitive hypertension was studied using lcn2-depleted mice (lcn2 KO) fed with low Na diet (0Na). Results: we show that NGAL plasma levels positively correlate with systolic blood pressure (SBP), whereas they negatively correlate with urinary Na excretion in subjects of the STANISLAS cohort. Prolonged feeding of lcn2 KO mice with a 0Na diet induced lower SBP than that of the control group (WT), suggesting a role for NGAL/lcn2 in Na-balance homeostasis. Short-term or prolonged 0Na increased Na-Cl cotransporter (NCC) phosphorylation in the cortex of WT mice, which was prevented in lcn2 KO mice. Recombinant mouse lcn2 injections in lcn2 KO mice induced NCC phosphorylation in the kidney cortex, associated with decreased urinary Na excretion. Ex-vivo experiments using kidney slices from lcn2 KO mice showed increased NCC phosphorylation by recombinant murine lcn2. In addition, recombinant murine lcn2 induced activation of CamK2β phosphorylation in lcn2 KO mice and in kidney slices, providing an underlying mechanism involved in lcn2-induced NCC phosphorylation. Indeed, the inhibition of CamK2β prevented NCC phosphorylation induced by recombinant lcn2 in kidney slices. Conclusion: we highlight a novel role of NGAL/lcn2 as a modulator of the activity of the renal sodium transporter NCC affecting salt-sensitive blood pressure

NGAL is a Novel Target in Hypertension by Modulating the NCC-Mediated Renal Na Balance.

The expression of NGAL/lcn2 (neutrophil gelatinase-associated lipocalin) is directly modulated by mineralocorticoid receptor activation but its role in blood pressure control is unclear. a potential relationship between NGAL plasma levels, systolic blood pressure and urinary Na excretion was assessed in the STANISLAS cohort. The specific role of NGAL/lcn2 in salt-sensitive hypertension was studied using lcn2-knockout mice (lcn2 KO) fed with low-Na diet (0Na). we show that NGAL plasma levels positively correlate with systolic blood pressure, whereas they negatively correlate with urinary Na excretion in subjects of the STANISLAS cohort. Prolonged feeding of lcn2 KO mice with a 0Na diet induced lower systolic blood pressure than that of the control group (wildtype), suggesting a role for NGAL/lcn2 in Na-balance homeostasis. Short-term or prolonged 0Na increased Na-Cl cotransporter (NCC) phosphorylation in the cortex of wildtype mice, which was prevented in lcn2 KO mice. Recombinant mouse lcn2 injections in lcn2 KO mice induced NCC phosphorylation in the kidney cortex, associated with decreased urinary Na excretion. Ex vivo experiments using kidney slices from lcn2 KO mice showed increased NCC phosphorylation by recombinant murine lcn2. In addition, recombinant murine lcn2 induced activation of CamK2β (calcium/calmodulin-dependent protein kinase II β subunit) phosphorylation in lcn2 KO mice and in kidney slices, providing an underlying mechanism involved in lcn2-induced NCC phosphorylation. Indeed, the inhibition of CamK2β prevented NCC phosphorylation induced by recombinant lcn2 in kidney slices. we highlight a novel role of NGAL/lcn2 as a modulator of the activity of the renal sodium transporter NCC affecting salt-sensitive blood pressure.

Layer myocardial strain is the most heritable echocardiographic trait.

Myocardial deformation assessed by strain analysis represents a significant advancement in our assessment of cardiac mechanics. However, whether this variable is genetically heritable or whether all/most of its variability is related to environmental factors is currently unknown.We sought to determine the heritability of echocardiographically determined cardiac mechanics indices in a population setting. A total of 1357 initially healthy subjects (women 51.6%; 48.2 ± 14.1 years) were included in this study from 20 years follow-up after the 4th visit of the longitudinal familial STANISLAS cohort (Lorraine, France). Data were acquired using state-of-the-art cardiac ultrasound equipment, using acquisition and measurement protocols recommended by the EACVI/ASE/Industry Task Force. Layer-specific global longitudinal strain (GLS) and global circumferential strain (GCS) (full-wall, subendocardial and subepicardial) and conventional structural and functional cardiac parameters and their potential heritability were assessed using restricted maximum likelihood analysis, with genetic relatedness matrix calculated from genome-wide association data. Indices of longitudinal/circumferential myocardial function and left ventricular (LV) ejection fraction had low heritability (ranging from 10 to 20%). Diastolic and standard LV function parameters had moderate heritability (ranging from 20 to 30%) except for end-systolic and end-diastolic volumes (respectively 30 and 45%). In contrast, GLSEndo/GLSEpi ratio had a high level of heritability (65%). Except for GLSendo/GLSepi ratio, a large percentage of variance remained unexplained (greater than 50%). In our population cohort, GLSendo/GLSepi ratio had a high level of heritability whereas other classical and mechanical LV function parameters did not. Given the increasing recognition of GLSendo/GLSepi ratio as an early/sensitive imaging biomarker of systolic dysfunction, our results suggest the possible existence of individual genetic predispositions to myocardial decline.

Birth weight and hypertension: nature or nurture?

Birth weight and hypertension: nature or nurture?

Advanced myocardial deformation echocardiography for the athlete's heart evaluation: Functional and mechanistic analysis

Echocardiographic assessment of the athlete's heart remains challenging because of a phenotypic overlap between reactive physiological adaptation and pathological remodelling. The lower range of normal values of left ventricle systolic ejection fraction (LVEF) and global longitudinal strain (GLS) in athletes makes it difficult to differentiate changes related to adaptive remodelling or indicative of early cardiomyopathy. This study sought to identify echocardiographic phenotype of endurance athletes using 2D speckle tracking imaging with a multi-layer approach and to define predictive factors of subtle LV systolic dysfunction. Healthy male athletes who underwent a pre-participation medical evaluation at the University Hospital of Nancy between 2013 and 2020 were included. Clinical and echocardiographic data were compared with healthy men from the STANISLAS cohort. Subtle LV dysfunction was defined as a GLS < 17.5%. A total of 191 athletes and 161 control subjects were studied. Athletes demonstrated lower LVEF (57.9% vs. 62.6%; P < 0.01) and lower GLS (17.8% vs. 21.1%; P < 0.01). No significant differences were found between athletes with and without subtle LV dysfunction regarding clinical characteristics, structural echocardiographic features, and exercise capacity. Athletes with subtle LV dysfunction exhibited a lower endocardial GLS (18.8% vs. 22.7%; P < 0.02), a lower epicardial GLS (14.0% vs. 16.6%; P < 0.01) and a greater endocardial/epicardial GLS ratio (1.36 vs. 1.32; P < 0.01). No significant difference was found regarding mechanical dispersion (P = 0.46). The endurance athlete's heart is characterized by a specific myocardial deformation pattern with a greater endocardial/epicardial GLS ratio. Subtle LV dysfunction seems mainly driven by a decreased epicardial GLS and not related to exercise capacity, structural remodelling or mechanical dispersion (Fig. 1).

Ventricular–arterial coupling (VAC) in a population-based cohort of middle-aged individuals: The STANISLAS cohort

Background and aimsData exploring normal values of different ventricular–arterial coupling (VAC) parameters and their association with anthropometric and cardiovascular (CV) factors are scarce. We aim to report values of two different methods of VAC assessment according to age and sex and explore their association with CV factors within a large population-based cohort of middle-aged individuals. MethodsFor 1333 (mean age 48 ± 14) individuals participating in the 4th visit of the STANISLAS cohort, VAC was assessed by two methods [1]: arterial elastance (Ea)/end-systolic elastance (Ees) and [2] Pulse wave velocity (PWV)/Global longitudinal strain (GLS). ResultsThe mean values of Ea/Ees and PWV/GLS were 1.06 ± 0.20 and 0.42 ± 0.12, respectively. The two methods of VAC assessment were poorly correlated (Pearson's correlation coefficient r = 0.14 (0.08; 0.19)). Increased PWV/GLS was associated with older age and a higher degree of cardiovascular risk factors (i.e., BMI, blood pressure, LDL, diabetes, hypertension) in the whole population as well as in the parent generation. In contrast, higher Ea/Ees were associated with decreasing age, and lower prevalence of risk factors in the whole cohort but neutrally associated with risk factors in the parent generation. ConclusionsHigher PWV/GLS is significantly associated with CV factors regardless of age. In contrast, worse Ea/Ees is associated with a better CV risk profile when considering individuals aged 30 to 70 but neutrally associated with CV factors when considering only older patients. These results may suggest that PWV/GLS should preferably be used to explore VAC. In addition, age-individualized threshold of Ea/Ees should be used.

Birth weight and subclinical cardiovascular and renal damage in a population-based study (the STANISLAS cohort study).

Although preterm-born and low-birth-weight individuals have an increased risk of cardiovascular diseases in adulthood, little is known regarding early cardiovascular and renal damage (CVRD) or hypertension in adulthood. Our study investigated the association of birth weight with early CVRD markers as well as the heritability of birth weight in an initially healthy family-based cohort. This study was based on 1028 individuals from the familial longitudinal STANISLAS cohort (399 parents/629 children) initiated in 1993-1995, with a fourth examination conducted in 2011-2016. Analyses performed at the fourth visit included pulse-wave velocity, central pressure, ambulatory blood pressure, hypertension status, diastolic dysfunction/distensibility, left ventricular mass indexed (LVMI), carotid intima-media thickness and kidney damage. The family structure of the cohort allowed birth weight heritability estimation. Mean (±SD) birth weight was 3.3 ± 0.6 kg. Heritability was moderate (42-44%). At the fourth visit, individuals were 37 years old (32.0-57.0), 56% were women and 13% had antihypertensive treatment. Birth weight was strongly and negatively associated with hypertension [odds ratio (OR) 95% confidence interval (CI) 0.61 (0.45-0.84)]. A nonlinear association was found with LVMI, participants with a birth weight greater than 3 kg having a higher LVMI. A positive association ( β 95% CI 5.09 (1.8-8.38)] was also observed between birth weight and distensibility for adults with normal BMI. No associations were found with other CVRD. In this middle-aged population, birth weight was strongly and negatively associated with hypertension, and positively associated with distensibility in adults with normal BMI and with LVMI for higher birth weights. No associations were found with other CVRD markers.

Associations of childhood adiposity with adult intima-media thickness and inflammation: a 20-year longitudinal population-based cohort.

The associations between childhood adiposity and adult increased carotid intima-media thickness (cIMT) have been well established, which might be corroborated by the association between adiposity in children and inflammation in adults. However, longitudinal data regarding biological pathways associated with childhood adiposity are lacking. The current study included participants from the STANISLAS cohort who had adiposity measurements at age 5-18 years [ N = 519, mean (SD) age, 13.0 (2.9) years; 46.4% male], and who were measured with cIMT, vascular-related and metabolic-related proteins at a median follow-up of 19 ± 2 years. BMI, waist-to-height ratio and waist circumference were converted to age-specific and sex-specific z -scores. A minority of children were overweight/obese (16.2% overweight-BMI z -score >1; 1.3% obesity- z -score >2). Higher BMI, waist-height ratio and waist circumference in children were significantly associated with greater adult cIMT in univariable analysis, although not after adjusting for C-reactive protein. These associations were more pronounced in those with consistently high adiposity status from childhood to middle adulthood. Participants with higher adiposity during childhood (BMI or waist-height ratio) had higher levels of insulin-like growth factor-binding protein-1, protein-2, matrix metalloproteinase-3, osteopontin, hemoglobin and C-reactive protein in adulthood. Network analysis showed that IL-6, insulin-like growth factor-1 and fibronectin were the key proteins associated with childhood adiposity. In a population-based cohort followed for 20 years, higher BMI or waist-to-height ratio in childhood was significantly associated with greater cIMT and enhanced levels of proteins reflective of inflammation, supporting the importance of inflammation as progressive atherosclerosis in childhood adiposity.

Impact of smoking on cardiovascular risk and premature ageing: Findings from the STANISLAS cohort

Background and aimsSmoking may lead to premature ageing, but the impact on the cardiovascular system and circulating proteins needs further investigation. In the present study, we aim to understand the impact of smoking on heart and vessels and circulating biomarkers of multiple domains including cardiovascular damage, premature ageing and cancer-related pathways. MethodsThe STANISLAS Cohort is a longitudinal familial cohort with detailed cardiovascular examination and biomarker assessment. This study included all the participants enrolled in the fourth visit of the STANISLAS Cohort for whom information on smoking habits was available (n = 1696). We assessed pulse wave velocity, intima-media thickness, echocardiographic parameters and a total of 460 proteins to study the association of circulating plasma proteins with smoking status (never vs. past vs. current smoking) while adjusting for potential confounders. ResultsCurrent smokers were approximately 18 years younger but had higher left ventricular mass index (LVMi) and similar pulse wave velocity (PWV), carotid intima media thickness (cIMT), frequency of hypertension, diabetes and carotid plaques compared to the much older never smokers. After multivariate selection, 25 proteins were independently associated with current or past smoking. Current smoking was strongly associated with higher levels of EDIL-3, CCL11, TNFSF13B, KIT, and lower levels of IL-12B and PLTP (p < 0.0001) while past smoking was associated with FGF-21, CHIT1, and lower levels of CXCL10, IL1RL2 and RAGE (p < 0.01). ConclusionsCurrent smoking is associated with signs of early onset of cardiovascular ageing and protein biomarkers that regulate inflammation, endothelial function, metabolism, oncological processes and apoptosis.

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.

Abstract 12100: Exploration of Proteomic Risk Markers for Incident Heart Failure and Cardiac Remodeling in Three European Population-Based Cohorts

Introduction: Several biomarkers have been linked with incident heart failure (HF), but the pathophysiology of HF is complex and multifactorial. Hypothesis: We explored 92 biomarkers’ associations with left ventricular hypertrophy (LVH), prevalent LV diastolic dysfunction (LVDD), and incident HF in three European population-based cohorts. Methods: Profiling of 92 biomarkers was carried out in 1737 participants from the echocardiography subsample of the population-based cohort study, the Malmö Preventive Project (mean age 67 years, 29% women). The final study sample consisted of 1681 subjects for analyses of incident HF (n=130), and 1530 subjects for analyses of LVDD (n=109) and LVH (n=498). Multivariable Cox regression analyses excluding subjects with prevalent HF were carried out for incident HF. Multivariable logistic regression analyses excluding subjects with reduced or mid-range LV ejection fraction (&lt;50%) were carried out for LVDD and LVH. Replication analyses of significant findings were carried out in the HOMAGE (562 cases of incident HF, 871 controls) and STANISLAS cohorts (304 cases of LVDD and 1668 controls; and 245 cases of LVH and 1681 controls). Results: In the multivariable model adjusted for clinical risk factors, six proteins were associated with incident HF (median follow-up time 12.6, interquartile range 10.9-13.6 years): ST2 (hazard ratio (HR) 1.40; 95% confidence interval (1.03-1.91); p=0.031), GDF-15 (HR 1.33 (1.00-1.77); p=0.048), AZU1 (HR 1.42 (1.10-1.82); p=0.006), MPO (HR 1.48 (1.02-2.15); p=0.041), Gal-4 (HR 1.37 (1.02-1.85); p=0.038) and NT-proBNP (HR 1.98 (1.66-2.36); p=2.1x10 -14 ) in the discovery cohort. In the replication cohort, ST2, GDF15, NT-proBNP and Gal-4 also displayed significant associations with incident HF. In analyses of DD, none of the associated proteins in the discovery cohort (AZU1; TR; PCSK9 and NT-proBNP) were replicated in the STANISLAS cohort. Among AZU1, PGLYRP1, and NT-proBNP, NT-proBNP was the only protein that was significantly associated with LVH in both cohorts. Conclusions: We replicated the association of ST2, GDF-15, NT-proBNP and Gal-4 with incident HF, whereas NT-proBNP was the only biomarker that was associated with LVH as well as incident HF in discovery and replication cohorts.

Isolated diastolic hypertension and target organ damage: Findings from the STANISLAS cohort.

BackgroundIsolated diastolic hypertension (IDH) is defined as diastolic blood pressure (DBP) ≥80 mmHg and systolic blood pressure (SBP) <130 mmHg according to 2017 ACC/AHA guidelines. The effective cardiovascular risk linked to IDH is debated.HypothesisIDH might contribute marginally to hypertension‐related target organ damage (TOD) development.MethodsIn this cross‐sectional analysis 1605 subjects from the STANISLAS cohort, a large familiar longitudinal study from Eastern France, were included. Participants were categorized according to average values at 24‐h ABP recording as having normal BP (SBP < 130/DBP < 80 mmHg); combined hypertension (SBP ≥130/DBP ≥80 mmHg or on antihypertensive treatment); IDH (SBP <130/DBP >80 mmHg); isolated systolic hypertension (ISH: SBP ≥130/DBP <80 mmHg). The association between hypertension status and TOD was assessed by multivariable‐adjusted logistic models.ResultsUsing normotension as reference, IDH was not significantly associated with NTproBNP levels (adjusted odds ratio [OR] 1.04 [95%CI 0.82;1.32], p = .750), microalbuminuria (OR 0.99 [0.69; 1.42], p = .960), diastolic dysfunction (OR 1.53 [0.88; 2.68], p = .130), left ventricular (LV) mass index (OR per 10 g/m2 increase 1.07 [0.95; 1.21], p = .250), LV longitudinal strain (global: OR 1.07 [0.99; 1.14], p = .054; subendocardial: OR 1.06 [0.99; 1.13], p = .087), carotid intima media thickness (OR 1.27 [0.79; 2.06], p = .320), reduced ankle‐brachial index (<0.9; OR 1.59 [0.19; 13.55], p = .670) and pulse wave velocity (PWV; OR 1.07 [0.93; 1.23], p = .360). In contrast, combined hypertension and ISH were independently associated with LV mass index and PWV increase (all p ≤ .01).ConclusionsIDH was not significantly associated with TOD. Further studies are needed to clarify the clinical role of IDH. Registration: URL: https://www.clinicaltrials.gov; Unique identifier: NCT01391442.

Machine Learning-Derived Echocardiographic Phenotypes Predict Heart Failure Incidence in Asymptomatic Individuals

ObjectivesThis study sought to identify homogenous echocardiographic phenotypes in community-based cohorts and assess their association with outcomes. BackgroundAsymptomatic cardiac dysfunction leads to a high risk of long-term cardiovascular morbidity and mortality; however, better echocardiographic classification of asymptomatic individuals remains a challenge. MethodsEchocardiographic phenotypes were identified using K-means clustering in the first generation of the STANISLAS (Yearly non-invasive follow-up of Health status of Lorraine insured inhabitants) cohort (N = 827; mean age: 60 ± 5 years; men: 48%), and their associations with vascular function and circulating biomarkers were also assessed. These phenotypes were externally validated in the Malmö Preventive Project cohort (N = 1,394; mean age: 67 ± 6 years; men: 70%), and their associations with the composite of cardiovascular mortality (CVM) or heart failure hospitalization (HFH) were assessed as well. ResultsThree echocardiographic phenotypes were identified as “mostly normal (MN)” (n = 334), “diastolic changes (D)” (n = 323), and “diastolic changes with structural remodeling (D/S)” (n = 170). The D and D/S phenotypes had similar ages, body mass indices, cardiovascular risk factors, vascular impairments, and diastolic function changes. The D phenotype consisted mainly of women and featured increased levels of inflammatory biomarkers, whereas the D/S phenotype, consisted predominantly of men, displayed the highest values of left ventricular mass, volume, and remodeling biomarkers. The phenotypes were predicted based on a simple algorithm including e′, left ventricular mass and volume (e′VM algorithm). In the Malmö cohort, subgroups derived from e′VM algorithm were significantly associated with a higher risk of CVM and HFH (adjusted HR in the D phenotype = 1.87; 95% CI: 1.04 to 3.37; adjusted HR in the D/S phenotype = 3.02; 95% CI: 1.71 to 5.34). ConclusionsAmong asymptomatic, middle-aged individuals, echocardiographic data-driven classification based on the simple e′VM algorithm identified profiles with different long-term HF risk. (4th Visit at 17 Years of Cohort STANISLAS-Stanislas Ancillary Study ESCIF [STANISLASV4]; NCT01391442)

Genetics of severe hypercholesterolemia in the general population: Insights from the STANISLAS cohort

Background: Severe hypercholesterolemia (SH) is a common condition characterized by increased levels of total and low-density lipoprotein cholesterol (LDLc). Methods: The aim of this study is to screen for prevalence of hypercholesterolemia, perform heritability estimation of circulating lipoproteins and study the association between SH cases and surrogate cardiovascular disease markers among participants of STANISLAS cohort. Gene candidate analyses were utilized to investigate the association between lipid levels, SH and polymorphisms from the three commonly reported genes (APOB, LDLR and PCSK9). Results: Participants with SH (n=102; 6.9%) were older (58 vs. 51yr), had higher total cholesterol (290 vs. 209mg/dL), LDLc (206 vs. 136mg/dL) and triglycerides (114 vs. 88 mg/dL). Despite smoking less, they had carotid plaques more frequently (21.2 vs. 9.3%), higher cIMT (676 vs. 597µm), and had more frequent family history cardiovascular disease. The circulating lipid levels have an important heritability: LDLc 51.6%, HDLc 66.6%, total cholesterol 49.8%, and triglycerides 41.4%. The SNPs located in LDLR gene present the strongest association with LDLc levels: rs55997232, rs17242395, rs1010679, and rs11668477. Conclusion: In a healthy cohort, participants with SH had premature vascular damage. LDLc had an important component of heritability and SNPs linked to the LDLR gene presented a strong association with LDLc. These findings reinforce the need for an early identification and treatment of SH subjects, which is mostly polygenic.

Cardiac Remodeling and Diastolic Dysfunction in Paroxysmal Atrial Fibrillation.

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 <10% in the AF group) of diastolic dysfunction (all-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.

Circulating multimarker approach to identify patients with preclinical left ventricular remodelling and/or diastolic dysfunction

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

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

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. 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). 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. 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. 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.