Prevention Of Renal And Vascular End-Stage Disease Study Research Articles

Association of baseline and longitudinal changes in insulin-like growth factor-binding protein-7 with the risk of incident heart failure: Data from the PREVEND study.

Senescence is a major risk factor for heart failure (HF), and insulin-like growth factor-binding protein-7 (IGFBP7) has been identified as an important senescence-inducing factor. The aim of this study was to examine the value of baseline and repeat IGFBP7 measurements in predicting future HF among community-dwelling Dutch adults from the Prevention of Renal and Vascular End-stage Disease (PREVEND) study. Individuals without prevalent HF who attended PREVEND visits 2 and 4 median of 5.1 years apart (25th-75th percentile, 4.9-5.2) with measurements of IGFBP7 were included. We used Cox proportional hazards models to investigate the association between IGFBP7 and HF incidence. A total of 6125 participants attending visit 2 (mean ± standard deviation [SD] age 53.1 ± 12.2 years; 3151 [51.4%] men) were followed for a median of 8.4 (7.8-8.9) years, and 194 participants (3.2%) developed incident HF. Median baseline IGFBP7 concentration was 87.0 (75.1-97.3) ng/ml, and baseline IGFBP7 levels were significantly associated with risk for incident HF (HF risk factors adjusted hazard ratio [HR] per 1 SD change in log-transformed IGFBP7: 1.22, 95% confidence interval [CI] 1.03-1.46). Baseline IGFBP7 was also significantly associated with incident HF in individuals with N-terminal pro-B-type natriuretic peptide <125 ng/L. Among 3879 participants attending both visits 2 and 4 (mean ± SD age 57.5 ± 11.3 years; 1952 [50.3%] men), 93 individuals developed HF (after visit 4) during a median follow-up of 3.2 (2.8-3.9) years. Median increase in IGFBP7 concentration between visits was 0.68 (-7.09 to 8.36) ng/ml, and changes in IGFBP7 levels were significantly associated with risk for incident HF (HF risk factors adjusted HR per 1 SD change in log-transformed IGFBP7: 1.68, 95% CI 1.19-2.36). Both baseline as well as repeat IGFBP7 measurements provide information about the risk of developing HF.

Enhanced chronic inflammation and increased branched chain amino acids in adrenal disorders: a cross-sectional study.

Patients with adrenal hormone excess demonstrate increased cardiovascular risk and mortality. We aimed to determine the impact of adrenal disorders on the inflammation marker GlycA, total branched-chain amino acids (BCAA), ketone bodies and the gut microbiome-derived metabolites trimethylamine N-oxide (TMAO) and betaine. We conducted a single-center cross-sectional study of patients with nonfunctioning adenomas (NFA), mild autonomous cortisol secretion (MACS), primary aldosteronism (PA), Cushing syndrome (CS), pheochromocytoma/paragangliomas (PPGL), other benign or malignant adrenal masses, and adrenocortical carcinoma (ACC) between January 2015 and July 2022 (n=802). Referent subjects included participants of the PREVEND (Prevention of Renal and Vascular End-stage Disease) study (n=5241). GlycA, BCAA, ketone bodies, TMAO, and betaine were measured using nuclear magnetic resonance spectroscopy. Multivariable logistic analyses were adjusted for age, sex, BMI, smoking, hypertension, diabetes mellitus and statin therapy. In age-and sex-adjusted comparison to referent subjects, increased GlycA was noted in all patient categories, increased BCAA in NFA, MACS, CS, PA and ACC, increased TMAO in patients with other malignant adrenal masses, increased betaine in NFA and MACS, and increased ketone bodies in NFA, CS and ACC. Essentially similar findings were observed in fully adjusted analysis and after exclusion of subjects with diabetes and cardiovascular disease. Patients with functioning and non-functioning adrenal masses demonstrated increased GlycA and BCAA, biomarkers associated with adverse cardiometabolic disorders and mortality. Patients with NFA demonstrated an adverse metabolic profile similar to patients with MACS and CS.

Plasma Calprotectin Levels Associate With New-Onset Hypertension in the General Population: A Prospective Cohort Study.

Low-grade systemic inflammation is a relevant pathogenic mechanism underlying the development of hypertension. In this study, we hypothesized that plasma calprotectin levels, as a biomarker of neutrophil-mediated inflammation, is associated with developing new-onset hypertension in the general population. Plasma calprotectin levels were determined in 3524 participants who participated in the PREVEND (Prevention of Renal and Vascular End-Stage Disease) study, a prospective population-based cohort study. Plasma calprotectin levels were studied for associations with the risk of new-onset hypertension, defined as systolic blood pressure of at least 140 mm Hg, diastolic blood pressure of at least 90 mm Hg, or the first recorded use of antihypertensives. Participants with hypertension at baseline were excluded. Median plasma calprotectin levels were 0.48 (0.34-0.66) mg/L, and median systolic blood pressure was 117 (109-126) mm Hg. Plasma calprotectin levels were significantly associated with the risk of new-onset hypertension (hazard ratio [HR], per doubling 1.30 [95% CI, 1.21-1.41]; P<0.001), also after adjustment for age and sex (HR, 1.26 [95% CI, 1.16-1.37]; P<0.001), but not after additional adjustment for potentially confounding factors, including baseline systolic blood pressure (HR, 1.00 [95% CI, 0.90-1.11]; P=0.996). Stratified analyses showed significant effect modification by sex (Pinteraction=0.023) and urinary albumin excretion (Pinteraction=0.004), with higher HRs in men (compared with women) and in individuals with higher urinary albumin excretion (>9.3 mg per 24 hours) compared with lower urinary albumin excretion (≤9.3 mg per 24 hours). Higher plasma calprotectin levels are associated with an increased risk of new-onset hypertension in the general population. This association is dependent on baseline systolic blood pressure and is particularly prominent in men compared with women.

Cell-free, high-density lipoprotein-specific phospholipid efflux assay predicts incident cardiovascular disease.

BACKGROUNDCellular cholesterol efflux capacity (CEC) is a better predictor of cardiovascular disease (CVD) events than HDL-cholesterol (HDL-C) but is not suitable as a routine clinical assay.METHODSWe developed an HDL-specific phospholipid efflux (HDL-SPE) assay to assess HDL functionality based on whole plasma HDL apolipoprotein-mediated solubilization of fluorescent phosphatidylethanolamine from artificial lipid donor particles. We first assessed the association of HDL-SPE with prevalent coronary artery disease (CAD): study I included NIH severe-CAD (n = 50) and non-CAD (n = 50) participants, who were frequency matched for sex, BMI, type 2 diabetes mellitus, and smoking; study II included Japanese CAD (n = 70) and non-CAD (n = 154) participants. We also examined the association of HDL-SPE with incident CVD events in the Prevention of Renal and Vascular End-stage Disease (PREVEND) study comparing 340 patients with 340 controls individually matched for age, sex, smoking, and HDL-C levels.RESULTSReceiver operating characteristic curves revealed stronger associations of HDL-SPE with prevalent CAD. The AUCs in study I were as follows: HDL-SPE, 0.68; apolipoprotein A-I (apoA-I), 0.62; HDL-C, 0.63; and CEC, 0.52. The AUCs in study II were as follows: HDL-SPE, 0.83; apoA-I, 0.64; and HDL-C, 0.53. Also longitudinally, HDL-SPE was significantly associated with incident CVD events independent of traditional risk factors with ORs below 0.2 per SD increment in the PREVEND study (P < 0.001).CONCLUSIONHDL-SPE could serve as a routine clinical assay for improving CVD risk assessment and drug discovery.TRIAL REGISTRATIONClinicalTrials.gov NCT01621594.FUNDINGNHLBI Intramural Research Program, NIH (HL006095-06).

Fibrotic Marker Galectin-3 Identifies Males at Risk of Developing Cancer andHeartFailure.

Cancer and heart failure (HF) are the leading causes of death in the Western world. Shared mechanisms such as fibrosis may underlie either disease entity, furthermore it is unknown whether this relationship is sex-specific. We sought to investigate how fibrosis-related biomarker galectin-3 (gal-3) aids in identifying individuals at risk for new-onset cancer and HF, and how this differs between sexes. Gal-3 was measured at baseline and at 4-year follow-up in 5,786 patients of the PREVEND (Prevention of Renal and Vascular Endstage Disease) study. The total follow-up period was 11.5 years. An increase of≥50% in gal-3 levels between measurements was considered relevant. We performed sex-stratified log-rank tests and Cox regression analyses overall and by sex to evaluate the association of gal-3 over time with both new-onset cancer and new-onset HF. Of the 5,786 healthy participants (50% males), 399 (59% males) developed new-onset cancer, and 192 (65%males) developed new-onset HF. In males, an increase in gal-3 was significantly associated with new-onset cancer (both combined and certain cancer-specific subtypes), after adjusting for age, body mass index, hypertension, smoking status, estimated glomerular filtration rate, diabetes mellitus, triglycerides, coronary artery disease, and C-reactive protein (HR: 1.89; 95% CI: 1.32-2.71; P< 0.001). Similar analyses demonstrated an association with new-onset HF in males (HR: 1.77; 95% CI: 1.07-2.95; P=0.028). In females, changes in gal-3 over time were neither associated with new-onset cancer nor new-onset HF. Gal-3, a marker of fibrosis, is associated with new-onset cancer and new-onset HF in males, but not in females.

Trajectories of renal biomarkers and new-onset heart failure in the general population: Findings from the PREVEND study.

Renal dysfunction is one of the most critical risk factors for developing heart failure (HF). However, the association between repeated measures of renal function and incident HF remains unclear. Therefore, this study investigated the longitudinal trajectories of urinary albumin excretion (UAE) and serum creatinine and their association with new-onset HF and all-cause mortality. Using group-based trajectory analysis, we estimated trajectories of UAE and serum creatinine in 6881 participants from the Prevention of Renal and Vascular End-stage Disease (PREVEND) study and their association with new-onset HF and all-cause death during the 11-years of follow-up. Most participants had stable low UAE or serum creatinine. Participants with persistently higher UAE or serum creatinine were older, more often men, and more often had comorbidities, such as diabetes, a previous myocardial infarction or dyslipidaemia. Participants with persistently high UAE had a higher risk of new-onset HF or all-cause mortality, whereas stable serum creatinine trajectories showed a linear association for new-onset HF and no association with all-cause mortality. Our population-based study identified different but often stable longitudinal patterns of UAE and serum creatinine. Patients with persistently worse renal function, such as higher UAE or serum creatinine, were at a higher risk of HF or mortality.

Clustering of cardiovascular and renal comorbidities and risk of incident atrial fibrillation in the community-based PREVEND cohort

Abstract Funding Acknowledgements Type of funding sources: Foundation. Main funding source(s): The PREVEND study is supported by the Dutch Kidney Foundation and the Netherlands Heart Foundation. Background Atrial fibrillation (AF) is a condition that occurs in the presence of comorbidities. With the accumulation of comorbidities over time, certain comorbidities may more often occur together than others, i.e. clustering of comorbidities. Acknowledging clustering of certain comorbidities may have implications for diagnosing previously unrecognized comorbidities, and clusters of comorbidities may carry differential risks of diseases, like AF. Albeit that the individual cardiovascular risk factors and comorbidities are well known, information on the impact of clustering of these on incident AF is sparse. Purpose We aimed to investigate the presence of clusters of cardiovascular and renal comorbidities and study the association between comorbidity clusters and incident AF. Methods We used the community-based Prevention of Renal and Vascular ENd-stage Disease (PREVEND) cohort in which 8,592 individuals participated. We excluded individuals with prior AF or missing ECG data, leaving 8,265 individuals for analysis. Atrial fibrillation was diagnosed if either AF or atrial flutter was present on a 12-lead ECG during one of the study visits, or at an outpatient visit or hospitalization. Latent class analysis was performed to assess clustering of 10 cardiovascular and renal comorbidities. The optimum number of classes was determined by the number of classes for which the Bayesian information criterion (BIC) reached a minimum value. As secondary analysis, latent class analysis was repeated with additionally including age, sex, and ethnicity. Kaplan-Meier analysis was performed to calculate the cumulative probability of incident AF, stratified by the latent classes. Results In the total population, the mean age was 48.9±12.6 years and 50.2% were women. During 9.2±2.1 years of follow-up, 251 individuals (3.0%) developed AF. Latent class analysis resulted in a model with three clusters as the optimal model, with one cluster being young (44.5±10.8 years) and healthy, carrying a low (1.0%) risk of incident AF; one cluster being older (63.0±8.4 years) and multimorbid, carrying a high (16.2%) risk of incident AF and a third middle-aged (57.0±11.3 years), obese and hypertensive cluster carrying an intermediate risk (5.9%) of incident AF. When adding age, sex and ethnicity to the latent class analysis, similar results were observed. Conclusion We identified three clusters of individuals in the community-based PREVEND cohort. The three clusters contained different amounts of comorbidities carrying different risks of incident AF. However, there were no differences between clusters regarding specific combination(s) of comorbidities.

OR12-4 Metabolic Profiling in Adrenal Tumors Demonstrates Enhanced Chronic Inflammation, Branched Chain Amino Acids and Ketone Bodies, Biomarkers that Predict High Cardiometabolic Risk

Abstract Background Patients with adrenal hormone excess demonstrate an increased cardiovascular risk and mortality. We aimed to determine the impact of adrenal hormone excess on the metabolic profile that included plasma lipoproteins, total branched-chain amino acids (BCAA), ketone bodies, and GlycA (a proinflammatory glycoprotein biomarker). Method: We conducted a single-center cross-sectional study of consecutive patients with adrenal adenomas, Cushing syndrome (CS), and pheochromocytoma/paragangliomas (PPGL) between January 2015 and May 2021. Adrenal adenomas comprised nonfunctioning adenomas (NFA), adenomas with mild autonomous cortisol secretion (MACS), and primary aldosteronism (PA). Malignant and other benign tumors were excluded. Collected fasting plasma samples were measured using nuclear magnetic resonance spectroscopy for lipoproteins, BCCA, ketone bodies and GlycA. The results were compared to referent subjects from PREVEND (Prevention of Renal and Vascular End-stage Disease) study. Lipoprotein Insulin Resistance Index (LP-IR) which predicts incident diabetes was calculated based on 6 lipoprotein parameters. Results NFA (n=166, median age 60.1years, 63.3% women), MACS (n=158 (median age 61.8 years, 62. 0% women), CS (n=101, median age 43.8 years, 85.1% women), PA (n=71 (median age 55.8 years, 31. 0% women), PPGL (n=43, median age 55.5 years, 46.5% women) was diagnosed in 539 patients. Referent subjects (n=6540) were younger with a median age of 48.4, 50.2% women. When compared to referent subjects, and after age and sex-adjustment, GlycA was highest in patients with CS (OR 3.3, 95% CI 2.8-3.8), followed by PPGL (OR 2.3, 95%CI 1.8-2.9), MACS (OR 2, 95%CI 1.7-2.3), NFA (OR 1.9, 95%CI 1.7-2.2), and PA (OR 1.5, 95%CI 1.2-1.8). When compared to referent subjects, and after sex- and age adjustment, all patient groups demonstrated increase in BCAA: CS (OR 2.7 (95%CI 2.3-3.2), PPGL (OR 2.3, 95% CI 1.8-2.9), NFA (OR 2.4, 95% CI 2.1-2.7), PA (OR 2. 0, 95%CI 1.7-2.5), MACS (OR 2.2, 95% CI 1.7-2.6). Total ketone bodies were increased in patients with cortisol excess (OR of 1.4, 95%CI 1.2-1.5 in CS, and OR of 1.2, 95%CI 1-1.3 in MACS) and NFA (OR 1.2, 95%CI 1.1-1.3), but not in PA or PPGL. All patient groups except PPGL were more likely to have a higher LP-IR score. When compared to referent subjects, the highest sex- and age-adjusted LP-IR increase was in patients with CS (OR 1.9 (95%CI 1.5-2.2), followed by MACS (OR 1.4, 95% CI 1.2-1.7), PA (OR 1.4, 95%CI 1.1-1.8), and NFA (OR 1.4, 95% CI 1.2-1.7). Conclusion Patient with adrenal adenomas and PPGL demonstrate an increase in GlycA, BCAA, and ketone bodies - biomarkers associated with adverse cardiometabolic disorders and mortality. All patients except those with PPGL also demonstrated a higher LP-IR index that was reported to predict incident diabetes. Patients with NFA demonstrated an adverse metabolic profile similar to patients with MACS. Presentation: Sunday, June 12, 2022 11:45 a.m. - 12:00 p.m.

Surviving in scrubs: sexism, sexual harassment, and assault in the primary care workforce

<h3>Summary</h3> <h3>Background and objectives</h3> There is a need for prediction scores that identify individuals at increased risk for developing progressive chronic kidney disease (CKD). Therefore, this study was performed to develop and validate a “renal risk score” for the general population. <h3>Design, setting, participants, &amp; measurements</h3> For this study we used data from the PREVEND (Prevention of Renal and Vascular ENdstage Disease) study, a prospective population-based cohort study with a median follow-up of 6.4 years. Participants with two or three consecutive estimated GFR (eGFR) measurements during follow-up were included. Participants within the group who had the most renal function decline (top 20% of the total population) and had an eGFR value &lt;60 ml/min per 1.73 m² during follow-up were defined as having progressive CKD. Possible predictors for progressive CKD were selected on the basis of univariable logistic regression analyses. <h3>Results</h3> A final prediction model was built using backward logistic regression analysis. Besides baseline eGFR, the model contained age, urinary albumin excretion, systolic BP, C-reactive protein, and known hypertension. The area under the receiver operating characteristic (ROC) curve was 0.84. We performed internal validation by using a bootstrapping procedure. As expected, after the regression coefficients were corrected for optimism, the area under the ROC curve was still 0.84. For clinical use we divided all predictors in meaningful clinical categories to develop a score chart. The area under the ROC curve was 0.83, indicating the high discriminative value of this model. <h3>Conclusions</h3> Given the high internal validity of this renal risk score, this score can be helpful to identify individuals at increased risk for progressive CKD.

Fibroblast Growth Factor 23 and Risk of New Onset Heart Failure With Preserved or Reduced Ejection Fraction: The PREVEND Study.

BackgroundThe role of fibroblast growth factor 23 (FGF23) in the development of new‐onset heart failure (HF) with reduced (HFrEF) or preserved ejection fraction (HFpEF) in the general population is unknown. Therefore, we set out to investigate associations of C‐terminal FGF23 with development of new‐onset HF and, more specifically, with HFrEF or HFpEF in a large, prospective, population‐based cohort.Methods and ResultsWe studied 6830 participants (aged 53.8±12.1 years; 49.7% men; estimated glomerular filtration rate, 93.1±15.7 mL/min per 1.73 m2) in the community‐based PREVEND (Prevention of Renal and Vascular End‐Stage Disease) study who were free of HF at baseline. Cross‐sectional multivariable linear regression analysis showed that ferritin (standardized β, −0.24; P<0.001) and estimated glomerular filtration rate (standardized β, −0.13; P<0.001) were the strongest independent correlates of FGF23. Multivariable Cox proportional hazard regression was used to study the association between baseline FGF23 and incident HF, HFrEF (ejection fraction ≤40%) or HFpEF (ejection fraction ≥50%). After median follow‐up of 7.4 [IQR 6.9–7.9] years, 227 individuals (3.3%) developed new‐onset HF, of whom 132 had HFrEF and 88 had HFpEF. A higher FGF23 level was associated with an increased risk of incident HF (fully adjusted hazard ratio, 1.29 [95% CI, 1.06–1.57]) and with an increased risk of incident HFrEF (fully adjusted hazard ratio, 1.31 [95% CI, 1.01–1.69]). The association between FGF23 and incident HFpEF lost statistical significance after multivariable adjustment (hazard ratio, 1.22 [95% CI, 0.87–1.71]).ConclusionsHigher FGF23 is independently associated with new‐onset HFrEF in analyses fully adjusted for cardiovascular risk factors and other potential confounders. The association between FGF23 and incident HFpEF lost statistical significance upon multivariable adjustment.

Association of Cardiometabolic Disease With Cancer in the Community

BackgroundObesity and cardiometabolic dysfunction have been associated with cancer risk and severity. Underlying mechanisms remain unclear. ObjectivesThe aim of this study was to examine associations of obesity and related cardiometabolic traits with incident cancer. MethodsFHS (Framingham Heart Study) and PREVEND (Prevention of Renal and Vascular End-Stage Disease) study participants without prevalent cancer were studied, examining associations of obesity, body mass index (BMI), waist circumference, visceral adipose tissue (VAT) and subcutaneous adipose tissue depots, and C-reactive protein (CRP) with future cancer in Cox models. ResultsAmong 20,667 participants (mean age 50 years, 53% women), 2,619 cancer events were observed over a median follow-up duration of 15 years. Obesity was associated with increased risk for future gastrointestinal (HR: 1.30; 95% CI: 1.05-1.60), gynecologic (HR: 1.62; 95% CI: 1.08-2.45), and breast (HR: 1.32; 95% CI: 1.05-1.66) cancer and lower risk for lung cancer (HR: 0.62; 95% CI: 0.44-0.87). Similarly, waist circumference was associated with increased risk for overall, gastrointestinal, and gynecologic but not lung cancer. VAT but not subcutaneous adipose tissue was associated with risk for overall cancer (HR: 1.22; 95% CI: 1.05-1.43), lung cancer (HR: 1.92; 95% CI: 1.01-3.66), and melanoma (HR: 1.56; 95% CI: 1.02-2.38) independent of BMI. Last, higher CRP levels were associated with higher risk for overall, colorectal, and lung cancer (P < 0.05 for all). ConclusionsObesity and abdominal adiposity are associated with future risk for specific cancers (eg, gastrointestinal, gynecologic). Although obesity was associated with lower risk for lung cancer, greater VAT and CRP were associated with higher lung cancer risk after adjusting for BMI.

Atrial fibrillation detected at screening is not a benign condition: outcomes in screen-detected versus clinically detected atrial fibrillation. Results from the Prevention of Renal and Vascular End-stage Disease (PREVEND) study

AimsIt is unknown whether screen-detected atrial fibrillation (AF) carries cardiovascular risks similar to clinically detected AF. We aimed to compare clinical outcomes between individuals with screen-detected and clinically detected incident...

Triglyceride-rich lipoprotein and LDL particle subfractions and their association with incident type 2 diabetes: the PREVEND study

BackgroundTriglyceride-rich lipoproteins particles (TRLP) and low density lipoprotein particles (LDLP) vary in size. Their association with β-cell function is not well described. We determined associations of TRLP and LDLP subfractions with β-cell function, estimated as HOMA-β, and evaluated their associations with incident T2D in the general population.MethodsWe included 4818 subjects of the Prevention of Renal and Vascular End-Stage Disease (PREVEND) study without T2D at baseline. TRLP and LDLP subfraction concentrations and their average sizes were measured using the LP4 algorithm of the Vantera nuclear magnetic resonance platform. HOMA-IR was used as measure of insulin resistance. HOMA-β was used as a proxy of β-cell function.ResultsIn subjects without T2D at baseline, very large TRLP, and LDL size were inversely associated with HOMA-β, whereas large TRLP were positively associated with HOMA-β when taking account of HOMA-IR. During a median follow-up of 7.3 years, 263 participants developed T2D. In multivariable-adjusted Cox regression models, higher concentrations of total, very large, large, and very small TRLP (reflecting remnants lipoproteins) and greater TRL size were associated with an increased T2D risk after adjustment for relevant covariates, including age, sex, BMI, HDL-C, HOMA-β, and HOMA-IR. On the contrary, higher concentrations of large LDLP and greater LDL size were associated with a lower risk of developing T2D.ConclusionsSpecific TRL and LDL particle characteristics are associated with β-cell function taking account of HOMA-IR. Moreover, TRL and LDL particle characteristics are differently associated with incident T2D, even when taking account of HOMA-β and HOMA-IR.

Atrial fibrillation detected at screening is not a benign condition - a comparison of clinical outcomes in screen-detected vs. hospital-detected atrial fibrillation

Abstract Funding Acknowledgements Type of funding sources: Public grant(s) – National budget only. Main funding source(s): Dutch Heart Foundation Background Screening for atrial fibrillation (AF) improves detection of AF. However, it is unknown whether AF detected at screening carries risks similar to clinically detected AF, and if it should be treated similarly. Purpose We aimed to compare clinical outcomes in individuals with screen-detected vs. hospital-detected incident AF. Methods We studied 8265 individuals (mean age 49 ± 13 years, 50% women) without prevalent AF from the population-based PREVEND (Prevention of Renal and Vascular End-Stage Disease) cohort study. By design, 70% of PREVEND participants had urinary albumin concentration ≥10 mg/l. AF was considered screen-detected when first detected on a 12-lead electrocardiogram (ECG) during one of the PREVEND study visits, and hospital-detected when first detected on a hospital ECG. Using Cox regression models with screen-detected and hospital-detected AF as time-varying covariates, we studied the association of screen-detected vs. hospital-detected AF with mortality, incident heart failure (HF), and incident cardiovascular (CV) events. Results During a mean follow-up of 9.7 years, 265 participants (3.2%) developed incident AF (mean age 62 ± 9 years, 30% women, 65% hypertension, 23% obesity, 9% diabetes, 15% history of myocardial infarction, 3% history of stroke, 2% prevalent HF). Of all incident AF cases, 60 (23%) were screen-detected and 205 (77%) hospital-detected. Baseline characteristics were generally comparable between participants with screen-detected and hospital-detected AF. A larger proportion of incident AF was screen-detected in men (26%) compared to women (15%). In univariabe analysis, both screen-detected and hospital-detected AF were strongly associated with death, incident HF, and incident CV events. After multivariable adjustment, hospital-detected AF was significantly associated with death (HR 2.95, 95% CI 2.18-4.00), incident HF (HR 3.98, 95% CI 2.49-6.34), and incident CV events (HR 1.92, 95% CI 1.21-3.06). Screen-detected AF was significantly associated with death (HR 2.21, 95% CI 1.09-4.47) and incident HF (HR 4.90, 95% CI 2.28-10.57), but not with incident CV events (HR 1.12, 95% CI 0.46-2.71). Conclusions In a population-based cohort enriched for microalbuminuria, almost a quarter of incident AF cases was first detected through ECG screening. Compared to hospital-detected AF, screen-detected AF was similarly associated with adverse outcomes. Although randomised trials are needed, this study highlights that AF screening may help decrease the general burden of CV disease.

Interleukin 6 and Development of Heart Failure With Preserved Ejection Fraction in the General Population.

BackgroundThe cause of heart failure with preserved ejection fraction (HFpEF) is poorly understood, and specific therapies are lacking. Previous studies suggested that inflammation plays a role in the development of HFpEF. Herein, we aimed to investigate in community‐dwelling individuals whether a higher plasma interleukin 6 (IL‐6) level is associated with an increased risk of developing new‐onset heart failure (HF) over time, and specifically HFpEF.Methods and ResultsWe performed a case‐cohort study based on the PREVEND (Prevention of Renal and Vascular End‐Stage Disease) study, a prospective general population‐based cohort study. We included 961 participants, comprising 200 participants who developed HF and a random group of 761 controls. HF with reduced ejection fraction or HFpEF was defined on the basis of the left ventricular ejection fraction of ≤40% or >40%, respectively. In Cox proportional hazard regression analyses, IL‐6 levels were statistically significantly associated with the development of HF (hazard ratio [HR], 1.28; 95% CI, 1.02–1.61; P=0.03) after adjustment for key risk factors. Specifically, IL‐6 levels were significantly associated with the development of HFpEF (HR, 1.59; 95% CI, 1.16–2.19; P=0.004), whereas the association with HF with reduced ejection fraction was nonsignificant (HR, 1.05; 95% CI, 0.75–1.47; P=0.77). In sensitivity analyses, defining HFpEF as left ventricular ejection fraction ≥50%, IL‐6 levels were also significantly associated with the development of HFpEF (HR, 1.47; 95% CI, 1.04–2.06; P=0.03) after adjustment for key risk factors.ConclusionsIL‐6 is associated with new‐onset HFpEF in community‐dwelling individuals, independent of potential confounders. Our findings warrant further research to investigate whether IL‐6 might be a novel treatment target to prevent HFpEF.

High-Density Lipoprotein Anti-Inflammatory Capacity and Incident Cardiovascular Events.

The role of high-density lipoprotein (HDL) function in cardiovascular disease represents an important emerging concept. The present study investigated whether HDL anti-inflammatory capacity is prospectively associated with first cardiovascular events in the general population. HDL anti-inflammatory capacity was determined as its ability to suppress TNFα (tumor necrosis factor α)-induced VCAM-1 (vascular cell adhesion molecule-1) mRNA expression in endothelial cells in vitro (results expressed as achieved percent reduction by individual HDL related to the maximum TNFα effect with no HDL present). In a nested case-control design of the PREVEND (Prevention of Renal and Vascular End Stage Disease) study, 369 cases experiencing a first cardiovascular event (combined end point of death from cardiovascular causes, ischemic heart disease, nonfatal myocardial infarction, and coronary revascularization) during a median of 10.5 years of follow-up were identified and individually matched to 369 controls with respect to age, sex, smoking status, and HDL cholesterol. Baseline samples were available in 340 cases and 340 matched controls. HDL anti-inflammatory capacity was not correlated with HDL cholesterol or hsCRP (high-sensitivity C-reactive protein). HDL anti-inflammatory capacity was significantly lower in cases compared with controls (31.6% [15.7-44.2] versus 27.0% [7.4-36.1]; P<0.001) and was inversely associated with incident CVD in a fully adjusted model (odds ratio [OR] per 1 SD, 0.74 [CI, 0.61-0.90]; P=0.002). Furthermore, this association was approximately similar with all individual components of the cardiovascular disease end point. The HDL anti-inflammatory was not correlated with cholesterol efflux capacity (r=-0.02; P>0.05). When combining these 2 HDL function metrics in 1 model, both were significantly and independently associated with incident cardiovascular disease in a fully adjusted model (efflux: OR per 1 SD, 0.74; P=0.002; anti-inflammatory capacity: OR per 1 SD, 0.66; P<0.001). Adding HDL anti-inflammatory capacity improved risk prediction by the Framingham risk score, with a model likelihood-ratio statistic increase from 10.50 to 20.40 (P=0.002). The HDL anti-inflammatory capacity, reflecting vascular protection against key steps in atherogenesis, was inversely associated with incident cardiovascular events in a general population cohort, independent of HDL cholesterol and HDL cholesterol efflux capacity. Adding HDL anti-inflammatory capacity to the Framingham risk score improves risk prediction.

Cardiovascular Risk Factors Are Associated With Future Cancer

BackgroundThe extent to which co-occurrence of cardiovascular disease (CVD) and cancer is due to shared risk factors or other mechanisms is unknown. ObjectivesThis study investigated the association of standard CVD risk factors, CVD biomarkers, pre-existing CVD, and ideal cardiovascular (CV) health metrics with the development of future cancer. MethodsThis study prospectively followed Framingham Heart Study and PREVEND (Prevention of Renal and Vascular End-Stage Disease) study participants free of cancer at baseline and ascertained histology-proven cancer. This study assessed the association of baseline CV risk factors, 10-year atherosclerotic (ASCVD) risk score, established CVD biomarkers, prevalent CVD, and the American Heart Association (AHA) Life’s Simple 7 CV health score with incident cancer using multivariable Cox models. Analyses of interim CVD events with incident cancer used time-dependent covariates. ResultsAmong 20,305 participants (mean age 50 ± 14 years; 54% women), 2,548 incident cancer cases occurred over a median follow-up of 15.0 years (quartile 1 to 3: 13.3 to 15.0 years). Traditional CVD risk factors, including age, sex, and smoking status, were independently associated with cancer (p < 0.001 for all). Estimated 10-year ASCVD risk was also associated with future cancer (hazard ratio [HR]: 1.16 per 5% increase in risk; 95% confidence interval [CI] 1.14 to 1.17; p < 0.001). The study found that natriuretic peptides (tertile 3 vs. tertile 1; HR: 1.40; 95% CI: 1.03 to 1.91; p = 0.035) were associated with incident cancer but not high-sensitivity troponin (p = 0.47). Prevalent CVD and the development of interim CV events were not associated with higher risk of subsequent cancer. However, ideal CV health was associated with lower future cancer risk (HR: 0.95 per 1-point increase in the AHA health score; 95% CI: 0.92 to 0.99; p = 0.009). ConclusionsCVD risk, as captured by traditional CVD risk factors, 10-year ASCVD risk score, and natriuretic peptide concentrations are associated with increased risk of future cancer. Conversely, a heart healthy lifestyle is associated with a lower risk of future cancer. These data suggest that the association between CVD and future cancer is attributable to shared risk factors.

Urinary excretion of epidermal growth factor and rapid loss of kidney function.

Lower urinary excretion of the kidney tubule-specific biomarker epidermal growth factor (uEGF) is associated with increased risk of renal function [glomerular filtration rate (GFR)] loss in diabetes and in patients with established chronic kidney disease (CKD). We investigated whether uEGF is associated with rapid GFR decline or incident CKD in the general population. Subjects without CKD or diabetes were recruited from the general population in Tromso, Norway [Renal Iohexol Clearance Survey (RENIS); N = 1249] and Groningen, the Netherlands [Prevention of REnal and Vascular END-stage disease (PREVEND); N = 4534], with a median follow-up of 5.6 and 7.4 years, respectively. GFR was measured by iohexol clearance in the RENIS and estimated using the CKD Epidemiology Collaboration creatinine-cystatin C equation in the PREVEND study. Rapid GFR decline was defined as an annual GFR loss >3.0 mL/min/1.73 m2 and in sensitivity analyses as subjects with the 10% steepest GFR slope within each cohort. Lower baseline uEGF excretion was associated with rapid GFR loss in both cohorts {RENIS, odds ratio [OR] per 1 μg/mmol lower uEGF 1.42 [95% confidence interval (CI) 1.06-1.91], P = 0.02; PREVEND, OR 1.29 [95% CI 1.10-1.53], P < 0.01}, adjusted for baseline GFR, albumin:creatinine ratio and conventional CKD risk factors. Similar results were obtained using the outcome of the 10% steepest GFR slope in each cohort. Lower uEGF levels were associated with incident CKD in the combined analysis of both cohorts. Lower uEGF levels are associated with increased risk of rapid GFR loss and incident CKD in the general population. This finding, together with previous findings in CKD and high-risk populations, supports that uEGF may serve as a broadly applicable biomarker representing the tubular component of the current glomerulus-centric clinical risk assessment system.

High Betaine, a Trimethylamine N-Oxide Related Metabolite, Is Prospectively Associated with Low Future Risk of Type 2 Diabetes Mellitus in the PREVEND Study.

Background: Gut microbiota-related metabolites, trimethylamine-N-oxide (TMAO), choline, and betaine, have been shown to be associated with cardiovascular disease (CVD) risk. Moreover, lower plasma betaine concentrations have been reported in subjects with type 2 diabetes mellitus (T2DM). However, few studies have explored the association of betaine with incident T2DM, especially in the general population. The goals of this study were to evaluate the performance of a newly developed betaine assay and to prospectively explore the potential clinical associations of betaine and future risk of T2DM in a large population-based cohort. Methods: We developed a high-throughput, nuclear magnetic resonance (NMR) spectroscopy procedure for acquiring spectra that allow for the accurate quantification of plasma/serum betaine and TMAO. Assay performance for betaine quantification was assessed and Cox proportional hazards regression was employed to evaluate the association of betaine with incident T2DM in 4336 participants in the Prevention of Renal and Vascular End-Stage Disease (PREVEND) study. Results: Betaine assay results were linear (y = 1.02X − 3.75) over a wide range of concentrations (26.0–1135 µM). The limit of blank (LOB), limit of detection (LOD) and limit of quantitation (LOQ) were 6.4, 8.9, and 13.2 µM, respectively. Coefficients of variation for intra- and inter-assay precision ranged from 1.5–4.3% and 2.5–5.5%, respectively. Deming regression analysis of results produced by NMR and liquid chromatography coupled to tandem mass spectrometry(LC-MS/MS) revealed an R2 value of 0.94 (Y = 1.08x – 1.89) and a small bias for higher values by NMR. The reference interval, in a cohort of apparently healthy adult participants (n = 501), was determined to be 23.8 to 74.7 µM (mean of 42.9 ± 12.6 µM). In the PREVEND study (n = 4336, excluding subjects with T2DM at baseline), higher betaine was associated with older age and lower body mass index, total cholesterol, triglycerides, and hsCRP. During a median follow-up of 7.3 (interquartile range (IQR), 5.9–7.7) years, 224 new T2DM cases were ascertained. Cox proportional hazards regression models revealed that the highest tertile of betaine was associated with a lower incidence of T2DM. Hazard ratio (HR) for the crude model was 0.61 (95% CI: 0.44–0.85, p = 0.004). The association remained significant even after adjusting for multiple clinical covariates and T2DM risk factors, including fasting glucose. HR for the fully-adjusted model was 0.50 (95% CI: 0.32–0.80, p = 0.003). Conclusions: The newly developed NMR-based betaine assay exhibits performance characteristics that are consistent with usage in the clinical laboratory. Betaine levels may be useful for assessing the risk of future T2DM.

Concentration of Branched-Chain Amino Acids Is a Strong Risk Marker for Incident Hypertension.

The potential role of branched-chain amino acids (BCAAs) in the pathogenesis of cardiometabolic diseases is increasingly recognized, but the association of BCAAs with incident hypertension remains unknown. The aim of the present study was to explore the association of BCAAs with incident hypertension in a prospective population-based cohort study. We measured plasma concentrations of BCAAs by means of nuclear magnetic resonance spectroscopy in 4169 participants from the PREVEND (Prevention of Renal and Vascular End-stage Disease) study. We estimated the risk of incident hypertension using multivariable-adjusted Cox regression models. After a median follow-up of 8.6 years, incident hypertension was ascertained in 924 subjects. Cox regression analyses revealed a significant association between BCAAs and incident hypertension. The hazard ratio per one SD of BCAAs was 1.11 (95% CI, 1.02-1.20; P=0.01) after full adjustment for multiple clinical variables. Likewise, the fully adjusted association remained significant when evaluated as categorical variable (hazard ratio for upper quartile with lowest quartile as reference category, 1.36; 95% CI, 1.11-1.68; P=0.003). Furthermore, the net reclassification improvement assessment improved after addition of BCAAs to a traditional risk model (P<0.001). This prospective study revealed that high plasma concentrations of BCAAs are associated with an increased risk of newly developed hypertension. The association remained after adjusting for age, sex, body mass index, and lipid profile.