Prospective Investigation Of The Vasculature In Uppsala Seniors Research Articles

An association between heart rate variability and incident heart failure in an elderly cohort.

Early identification of individuals at risk of developing heart failure (HF) may improve poor prognosis. A dominant sympathetic activity is common in HF and associated with worse outcomes; however, less is known about the autonomic balance before HF. A low frequency/high frequency (L-F/H-F) ratio, index of heart rate variability, and marker of the autonomic balance predict the development of HF and may improve the performance of the HF prediction model when added to traditional cardiovascular (CV) risk factors. Individuals in the PIVUS (Prospective Investigation of the Vasculature in Uppsala Seniors) study (n = 1016, all aged 70 years) were included. Exclusion criteria were prevalent HF, electrocardiographic QRS duration ≥130 millisecond, major arrhythmias, or conduction blocks at baseline. The association between the L-F/H-F ratio and incident HF was assessed using Cox proportional hazard analysis. The C-statistic evaluated whether adding the L-F/H-F-ratio to traditional CV risk factors improved the discrimination of incident HF. HF developed in 107/836 study participants during 15 years of follow-up. A nonlinear, inverse association between the L-F/H-F ratio and incident HF was mainly driven by an L-F/H-F ratio of <30. The association curve was flat for higher values (hazard ratio, HR for the total curve = 0.78 [95% confidence interval, CI: 0.69-0.88, p < .001]; HR = 2 for L-F/H-F ratio = 10). The traditional prediction model improved by 3.3% (p < .03) when the L-F/H-F ratio was added. An L-F/H-F ratio of <30 was related to incident HF and improved HF prediction when added to traditional CV risk factors.

A short P-wave duration is associated with incident heart failure in the elderly: a 15 years follow-up cohort study.

Early identification of patients at risk of congestive heart failure (HF) may alter their poor prognosis. The aim was therefore to test whether simple electrocardiographic variables, the P-wave and PR-interval, could predict incident HF. The PIVUS (Prospective Investigation of the Vasculature in Uppsala Seniors) study (1016 individuals all aged 70 years, 50% women) was used to identify predictors of HF. Subjects with prevalent HF, QRS duration ≥ 130 ms, atrial tachyarrhythmias, implanted pacemaker/defibrillator, second- and third-degree atrioventricular block or delta waves at baseline were excluded. Cox proportional hazard analysis was used to relate the PR interval, P-wave duration (Pdur) and amplitude (Pamp), measured in lead V1, to incident HF. Adjustment was performed for gender, RR-interval, beta-blocking agents, systolic blood pressure, body mass index and smoking. Out of 836 subjects at risk, 107 subjects were diagnosed with HF during a follow-up of 15 years. In the multivariate analysis, there was a strong U-shaped correlation between Pdur in lead V1 and incident HF (P = 0.0001) which was significant for a Pdur < 60 ms [HR = 2.75; 95% CI: 1.87-4.06, at Pdur 40 ms] but not for prolonged Pdur. There was no significant relationship between incident HF and the PR-interval or the Pamp. A Pdur < 60 ms improved discrimination by 3.7% when added to the traditional risk factors including sex, RR-interval, beta-blocking agents, systolic blood pressure, BMI and smoking (P = 0.048). A short Pdur, an easily measured parameter on the ECG, may potentially be a useful marker of future HF, enabling its early detection and prevention, thus improving outcomes.

Short P-Wave Duration Is Associated with Incident Atrial Fibrillation.

Atrial fibrillation (AF) is common and increases the risk for stroke and heart failure (HF). The early identification of patients at risk may prevent the development of AF and improve prognosis. This study, therefore, aimed to test the effect of the association between P-wave and PR-interval on the ECG and incident AF.The PIVUS (Prospective Investigation of the Vasculature in Uppsala Seniors) study (1016 individuals all aged 70 years; 50% women) was used to identify whether the ECG variables P-wave duration (Pdur) and PR-duration in lead V1 were related to new-onset AF. Exclusion criteria were prevalent AF, QRS-duration ≥ 130 milliseconds (msec), atrial tachyarrhythmias and implanted pacemaker/defibrillator. Cox proportional-hazards models were used for analyses. Adjustments were made for gender, RR-interval, beta-blocking agents, systolic blood pressure, body mass index, and smoking.Of 877 subjects at risk, 189 individuals developed AF during a 15-year follow-up. There was a U-shaped relationship between the Pdur and incident AF (P = 0.017) following multiple adjustment. Values below 60 msec were significantly associated with incident AF, with a hazard ratio of 1.55 (95% confidence interval 1.15-2.09) for a Pdur ≤ 42 msec. There was no significant relationship between incident AF and the PR-interval.A short Pdur derived from the ECG in V1 may be a useful marker for new-onset AF, enabling the early identification of at-risk patients.

Changes in plasma levels of per- and polyfluoroalkyl substances (PFAS) are associated with changes in plasma lipids - A longitudinal study over 10 years

BackgroundAssociations between per- and polyfluoroalkyl substances (PFAS), mainly PFOS and PFOA, and increased blood lipids have been reported primarily from cross-sectional studies. The aim of the present study was to investigate associations between multiple PFAS and blood lipids in a longitudinal fashion. MethodsA total of 864 men and women aged 70 years and free from lipid medication were included from the Prospective Investigation of the Vasculature in Uppsala Seniors (PIVUS) study from Uppsala Sweden, 614 and 404 of those were reinvestigated at age 75 and 80. At all three occasions, eight PFAS were measured in plasma using ultra-performance liquid chromatography-tandem mass spectrometry (UPLC-MS/MS). Total cholesterol, triglycerides, low-density lipoprotein cholesterol (LDL-C) and high-density lipoprotein cholesterol (HDL-C) were also measured in plasma at all three occasions. Mixed-effects linear regression models were used to examine the relationship between the changes in PFAS levels and changes in lipid levels. ResultsChanges in plasma levels of six out of the eight investigated PFAS were positively associated with changes in plasma lipids after adjustment for sex, change in body mass index (BMI), smoking, physical activity, statin use (age was the same in all subjects), and correction for multiple testing. For example, changes in perfluorodecanoic acid (PFDA) were positively associated with the changes in total cholesterol (β: 0.23, 95% confidence interval (CI): 0.14 to 0.32), triglycerides (β: 0.08, 95% CI: 0.04–0.12) and HDL-cholesterol (β: 0.08, 95% CI: 0.04–0.11). ConclusionIn this longitudinal study with three measurements over 10 years of both plasma PFAS and lipids, changes in six out of the eight investigated PFAS were positively associated with changes in plasma lipids, giving further support for a role of PFAS exposure in human lipid metabolism.

High Serum-Induced AhRL Is Associated with Prevalent Metabolic Syndrome and Future Impairment of Glucose Tolerance in the Elderly.

BackgroundHigh circulating levels of dioxins and dioxin-like chemicals, acting via the aryl hydrocarbon receptor (AhR), have previously been linked to diabetes. We now investigated whether the serum AhR ligands (AhRL) were higher in subjects with metabolic syndrome (MetS) and in subjects who had developed a worsened glucose tolerance over time.MethodsSerum AhRL at baseline was measured by a cell-based AhRL activity assay in 70-year-old subjects (n=911) in the Prospective Investigation of the Vasculature in Uppsala Seniors (PIVUS) study. The main outcome measures were prevalent MetS and worsening of glucose tolerance over 5 years of follow-up.ResultsAhRL was significantly elevated in subjects with prevalent MetS as compared to those without MetS, following adjustment for sex, smoking, exercise habits, alcohol intake and educational level (P=0.009). AhRL at baseline was higher in subjects who developed impaired fasting glucose or diabetes at age 75 years than in those who remained normoglycemic (P=0.0081). The odds ratio (OR) of AhRL for worsening glucose tolerance over 5 years was 1.43 (95% confidence interval [CI], 1.13 to 1.81; P=0.003, continuous variables) and 2.81 (95% CI, 1.31 to 6.02; P=0.008, in the highest quartile) adjusted for sex, life style factors, body mass index, and glucose.ConclusionThese findings support a large body of epidemiologic evidence that exposure to AhR transactivating substances, such as dioxins and dioxin-like chemicals, might be involved in the pathogenesis of MetS and diabetes development. Measurement of serum AhRL in humans can be a useful tool in predicting the onset of metabolic disorders.

Cardiovascular-related proteins and the abdominal visceral to subcutaneous adipose tissue ratio

Background and aimsAn increased amount of visceral adipose tissues has been related to atherosclerosis and future cardiovascular events. The present study aims to investigate how the abdominal fat distribution links to plasma levels of cardiovascular-related proteins. Method and resultsIn the Prospective investigation of Obesity, Energy and Metabolism (POEM) study (n = 326, all aged 50 years), abdominal visceral (VAT) and subcutaneous (SAT) adipose tissue volumes were quantified by MRI. Eighty-six cardiovascular-related proteins were measured by the proximity extension assay (PEA). Similar investigations were carried out in the Prospective Investigation of the Vasculature in Uppsala Seniors (PIVUS) study (n = 400, all aged 75 years).In the discovery dataset (POEM), 10 proteins were related to the VAT/SAT-ratio using false discovery rate <.05. Of those, Cathepsin D (CTSD), Interleukin-1 receptor antagonist protein (IL-1RA) and Growth hormone (GH) (inversely) were related to the VAT/SAT-ratio in the validation in PIVUS following adjustment for sex, BMI, smoking, education level and exercise habits (p < 0.05). In a secondary analysis, a meta-analysis of the two samples suggested that 15 proteins could be linked to the VAT/SAT-ratio following adjustment as above and Bonferroni-correction of the p-value. ConclusionThree cardiovascular-related proteins, cathepsin D, IL-1RA and growth hormone, were being associated with the distribution of abdominal adipose tissue using a discovery/validation approach. A meta-analysis of the two samples suggested that also a number of other cardiovascular-related proteins could be associated with an unfavorable abdominal fat distribution.

A cross-omics integrative study of metabolic signatures of chronic obstructive pulmonary disease

BackgroundChronic obstructive pulmonary disease (COPD) is a common lung disorder characterized by persistent and progressive airflow limitation as well as systemic changes. Metabolic changes in blood may help detect COPD in an earlier stage and predict prognosis.MethodsWe conducted a comprehensive study of circulating metabolites, measured by proton Nuclear Magnetic Resonance Spectroscopy, in relation with COPD and lung function. The discovery sample consisted of 5557 individuals from two large population-based studies in the Netherlands, the Rotterdam Study and the Erasmus Rucphen Family study. Significant findings were replicated in 12,205 individuals from the Lifelines-DEEP study, FINRISK and the Prospective Investigation of the Vasculature in Uppsala Seniors (PIVUS) studies. For replicated metabolites further investigation of causality was performed, utilizing genetics in the Mendelian randomization approach.ResultsThere were 602 cases of COPD and 4955 controls used in the discovery meta-analysis. Our logistic regression results showed that higher levels of plasma Glycoprotein acetyls (GlycA) are significantly associated with COPD (OR = 1.16, P = 5.6 × 10− 4 in the discovery and OR = 1.30, P = 1.8 × 10− 6 in the replication sample). A bi-directional two-sample Mendelian randomization analysis suggested that circulating blood GlycA is not causally related to COPD, but that COPD causally increases GlycA levels. Using the prospective data of the same sample of Rotterdam Study in Cox-regression, we show that the circulating GlycA level is a predictive biomarker of COPD incidence (HR = 1.99, 95%CI 1.52–2.60, comparing those in the highest and lowest quartile of GlycA) but is not significantly associated with mortality in COPD patients (HR = 1.07, 95%CI 0.94–1.20).ConclusionsOur study shows that circulating blood GlycA is a biomarker of early COPD pathology.

Effect of new statin treatment on carotid artery intima-media thickness: A real-life observational study over 10 years

Background and aimsRandomized clinical trials (RCT) have shown statin treatment to slow down the increase in carotid artery intima-media thickness (IMT) seen with ageing. However, those RCTs usually have a limited follow-up (1–3 years). Here an observational study was used to investigate the real-life effect of new statin treatment over a 10-year follow-up. MethodsIn the Prospective Investigation of the Vasculature in Uppsala Seniors (PIVUS) study, 954 individuals all aged 70 years at baseline were investigated regarding carotid artery IMT three times during 10 years (n = 771 at age 75, and n = 591 at age 80). ResultsAt age 70, 503 subjects were statin-naïve and did not receive statin during the 10-year follow-up period (the never-statin group), while 197 subjects were statin-naïve but received statins during the follow-up period (the received-statin group). Low-density lipoprotein (LDL)-cholesterol increased over time in the never-statin group (+0.1 mmol/l, p = 0.0012), but decreased in the group receiving statin treatment (−1.1 mmol/l, p < 0.0001). The never-statin group increased significantly in IMT over the 10 years (+0.07 mm, p < 0.0001), while the numerical increase seen in the received-statin group was not significant (+0.02 mm, p = 0.22) A significant difference in the change in IMT over time was seen between the received-statin group and the never-statin group (p < 0.0001 for interaction between time and group, adjusted for a propensity score). ConclusionsThis real-life observational study showed that new statin treatment reduced the increase in IMT seen over 10 years compared to subjects not treated with statins.

Evaluation of time delay between discovery of a high blood pressure in a health screening survey and hypertension diagnosis

Purpose Early treatment of hypertension is important to reduce adverse cardiovascular outcomes. The aim of this study was to investigate the time delay from detection of a high blood pressure in a health screening survey to hypertension diagnosis in primary care. Materials and methods Seventy years old inhabitants in the Uppsala County were randomly invited to the Prospective Investigation of the Vasculature in Uppsala Seniors (PIVUS) study. We found 409 individuals without antihypertensive treatment with a blood pressure >140/90 mmHg, being the average of three recordings measured after 30 min rest in a supine position. These individuals were recommended to ask their primary care physician to further investigate this finding. Results During 10 years of follow-up, 285 of them (70%) received a hypertension diagnosis. The mean time to diagnosis was 5 (SD 2) years. The chance of receiving a diagnosis of hypertension during the follow-up period in this group with elevated blood pressure at baseline was related to the systolic blood pressure (OR 1.04 per 1 mmHg, 95%CI 1.02–1.04), the BMI (OR 1.06 per 1 kg/m2, 95%CI 1.01–1.12), and statin use (OR 3.76, 95%CI 1.35–10.3) at the health survey, but was not significantly related to sex, prevalence of diabetes, or use of salicylic acid. No significant interaction between sex and systolic blood pressure regarding hypertension diagnosis was observed. Conclusion In conclusion, when an elevated blood pressure was discovered in elderly persons at a health screening, 70% of those received a hypertension diagnosis within 10 years, with a mean time to diagnosis of 5 years. Health care actions should be enforced to shorten this time lag both in terms of information to the individuals, as well as the handling of this patient group in primary care.

Changes in Proteomic Profiles are Related to Changes in BMI and Fat Distribution During 10 Years of Aging.

This study investigated howchanges in 84 proteins over a 10-year period of aging were related to changes in measures of body fat and distribution over the same period. Cardiovascular candidate proteins were measured using the proximal extension assay technique, along with BMI and waist-hip ratio (WHR), at ages 70, 75, and 80 in 1,016 participants of the Prospective Investigation of the Vasculature in Uppsala Seniors(PIVUS) cohort. Associations of changes in plasma protein levels, BMI, and WHR over time were analyzed using linear mixed models. Changes in 19 and 16 proteins were significantly associated with changes in BMI and WHR, respectively (P < 0.00059), over the investigated 10-year period. Leptin and fatty acid-binding protein 4 were among the proteins most strongly associated with changes in both BMI and WHR. Four of the proteins significantly tracked with change in BMI (P < 0.00059) but not WHR (P > 0.05): endothelial cell-specific molecule 1, pentraxin-related protein PTX3, ST2protein(also known as interleukin-1 receptor-like 1), and spondin-1. Five proteins tracked with change in WHR (P < 0.00059) but not BMI (P > 0.05): caspase-8, cathepsin L1, oxidized low-density lipoprotein receptor 1, interleukin-6 receptor subunit alpha, and C-C motif chemokine 20. This is the first large longitudinal study of how changes in plasma protein signatures are associated with changes in measures of body fat and distribution over 10 years of aging.

A Multi-Cohort Metabolomics Analysis Discloses Sphingomyelin (32:1) Levels to be Inversely Related to Incident Ischemic Stroke

Background and PurposeTo search for novel pathophysiological pathways related to ischemic stroke using a metabolomics approach. MethodsWe identified 204 metabolites in plasma by liquid chromatography mass spectrometry in 3 independent population-based samples (TwinGene, Prospective Investigation of the Vasculature in Uppsala Seniors (PIVUS) and Uppsala Longitudinal Study of Adult Men). TwinGene was used for discovery and the other 2 samples were meta-analyzed as replication. In PIVUS, traditional cardiovascular (CV) risk factors, multiple markers of subclinical CV disease, markers of coagulation/fibrinolysis were measured and analyzed in relation to top metabolites. ResultsIn TwinGene (177 incident cases, median follow-up 4.3 years), levels of 28 metabolites were associated with incident ischemic stroke at a false discover rate (FDR) of 5%. In the replication (together 194 incident cases, follow-up 10 and 12 years, respectively), only sphingomyelin (32:1) was significantly associated (HR .69 per SD change, 95% CI .57-0.83, P value = .00014; FDR <5%) when adjusted for systolic blood pressure, diabetes, smoking, low density lipoportein (LDL)- and high density lipoprotein (HDL), body mass index (BMI) and atrial fibrillation. In PIVUS, sphingomyelin (32:1) levels were significantly related to both LDL- and HDL-cholesterol in a positive fashion, and to serum triglycerides, BMI and diabetes in a negative fashion. Furthermore, sphingomyelin (32:1) levels were related to vasodilation in the forearm resistance vessels, and inversely to leukocyte count (P < .0069 and .0026, respectively). ConclusionsAn inverse relationship between sphingomyelin (32:1) and incident ischemic stroke was identified, replicated, and characterized. A possible protective role for sphingomyelins in stroke development has to be further investigated in additional experimental and clinical studies.

The metabolites urobilin and sphingomyelin (30:1) are associated with incident heart failure in the general population.

AimsWe aimed to investigate whether metabolomic profiling of blood can lead to novel insights into heart failure pathogenesis or improved risk prediction.Methods and resultsMass spectrometry‐based metabolomic profiling was performed in plasma or serum samples from three community‐based cohorts without heart failure at baseline (total n = 3924; 341 incident heart failure events; median follow‐up ranging from 4.6 to 13.9 years). Cox proportional hazard models were applied to assess the association of each of the 206 identified metabolites with incident heart failure in the discovery cohorts Prospective Investigation of the Vasculature in Uppsala Seniors (PIVUS) (n = 920) and Uppsala Longitudinal Study of Adult Men (ULSAM) (n = 1121). Replication was undertaken in the independent cohort TwinGene (n = 1797). We also assessed whether metabolites could improve the prediction of heart failure beyond established risk factors (age, sex, body mass index, low‐density and high‐density lipoprotein cholesterol, triglycerides, lipid medication, diabetes, systolic and diastolic blood pressure, blood pressure medication, glomerular filtration rate, smoking status, and myocardial infarction prior to or during follow‐up). Higher circulating urobilin and lower sphingomyelin (30:1) were associated with incident heart failure in age‐adjusted and sex‐adjusted models in the discovery and replication sample. The hazard ratio for urobilin in the replication cohort was estimated to 1.29 per standard deviation unit, 95% confidence interval (CI 1.03–1.63), and for sphingomyelin (30:1) to 0.72 (95% CI 0.58–0.89). Results remained similar after further adjustment for established heart failure risk factors in meta‐analyses of all three cohorts. Urobilin concentrations were inversely associated with left ventricular ejection fraction at baseline in the PIVUS cohort (β = −0.70, 95% CI −1.03 to −0.38). No major improvement in risk prediction was observed when adding the top 2 metabolites (C‐index 0.787, 95% CI 0.752–0.823) or nine Lasso‐selected metabolites (0.790, 95% CI 0.754–0.826) to a modified Atherosclerosis Risk in Communities heart failure risk score model (0.780, 95% CI 0.745–0.816).ConclusionsOur metabolomic profiling of three community‐based cohorts study identified associations of circulating levels of the haem breakdown product urobilin, and sphingomyelin (30:1), a cell membrane component involved in signal transduction and apoptosis, with incident heart failure.

Longitudinal effects of aging on plasma proteins levels in older adults - associations with kidney function and hemoglobin levels.

BackgroundA targeted proteomics chip has been shown to be useful to discover novel associations of proteins with cardiovascular disease. We investigated how these proteins change with aging, and whether this change is related to a decline in kidney function, or to a change in hemoglobin levels.Material and methodsIn the Prospective Investigation of the Vasculature in Uppsala Seniors (PIVUS) study, including 1,016 participants from the general population aged 70 at baseline, 84 proteins were measured at ages 70, 75, 80. At these occasions, glomerular filtration rate (eGFR) was estimated and the hemoglobin levels were measured.ResultsSixty-one of the 84 evaluated proteins changed significantly during the 10-year follow-up (multiple testing-adjusted alpha = 0.00059), most showing an increase. The change in eGFR was inversely related to changes of protein levels for the vast majority of proteins (74%). The change in hemoglobin was significantly related to the change in 40% of the evaluated proteins, with no obvious preference of the direction of these relationships.ConclusionThe majority of evaluated proteins increased with aging in adults. Therefore, normal ranges for proteins might be given in age-strata. The increase in protein levels was associated with the degree of reduction in eGFR for the majority of proteins, while no clear pattern was seen for the relationships between the proteins and the change in hemoglobin levels. Studies on changes in urinary proteins are warranted to understand the association between the reduction in eGFR and increase in plasma protein levels.

Small Vessel Disease on Neuroimaging in a 75-Year-Old Cohort (PIVUS): Comparison With Cognitive and Executive Tests.

Background and Purpose: Signs of small vessel disease (SVD) are commonly seen on magnetic resonance imaging (MRI) of the brain in cognitively healthy elderly individuals, and the clinical relevance of these are often unclear. We have previously described three different MRI manifestations of SVD as well as cerebral perfusion in a longitudinal study of non-demented 75-year-old subjects. The purpose of the present study was to evaluate the relationship of these findings to cognition and executive function at age 75 and changes after 5 years.Methods: In all, 406 subjects from the Prospective Investigation of the Vasculature in Uppsala Seniors (PIVUS) study were examined with MRI of the brain at age 75 years. Two-hundred and fifty of the subjects were re-examined 5 years later. White matter hyperintensities (WMHs) and lacunar infarcts (LIs) were assessed on both occasions, but microbleeds (MBs) and perfusion only at age 75. Cognitive function was screened by the Mini Mental State Examination (MMSE). Trail Making Test A and B (TMT-A and TMT-B) were performed at baseline and at follow-up at age 80.Results: At baseline, 93% performed >27 points in the MMSE. The TMT-B at age 75 was significantly related to WMH visual scoring after adjustment for sex, education and cerebrovascular disease risk factors (+80 s (95% CI 0.3–161 s), P < 0.05 for grade 2–3 vs. grade 0). Neither MMSE nor TMT-A was significantly related to WMH scoring. There was no relation between any test performance and WMH volume, white matter volume, number of MBs or brain perfusion at age 75. Subjects who had sustained a new LI (n = 26) showed a greater increase of the time to perform TMT-A at the 5-year follow-up (+25 s vs. +4 s in LI-free subjects, P = 0.003). Changes in MMSE or TMT-A and -B test performance between ages 75 and 80 were not related to changes in WMH scoring or volume during the 5 years follow-up, or to brain perfusion at age 75.Conclusion: In this cognitively healthy community-based population, moderate-severe WMHs and incident LIs on brain MRI in individuals aged 75–80 years were associated with a mild impairment of processing speed and executive function.

High serum levels of p,p’-DDE are associated with an accelerated decline in GFR during 10 years follow-up

Over the past 20 years, the global incidence of chronic kidney disease (CKD) has been increasing and organochlorine pesticides (such as DDT) is a suspected etiological factor. The present study examines the associations between low level background exposure to p,p’-DDE (1-dichloro-2,2-bis (p-chlorophenyl) ethylene), the main DDT metabolite, and kidney function during a 10-year follow-up. Data was analysed from the Prospective Investigation of the Vasculature in Uppsala Seniors (PIVUS) study (n = 1016, 50% women, all aged 70 years). Serum levels of p,p’-DDE was measured by gas chromatography coupled to high-resolution mass spectrometry (GC/HRMS) at baseline (i.e. age of 70 years). Glomerular filtration rate (GFR) was estimated using serum creatinine and cystatin C at 70, 75 and 80 years of age. A significant decline in GFR was seen during the 10-year follow-up (−24 ml/min/1.73 m2, p < 0.0001). A significant negative interaction was seen between baseline p,p’-DDE levels and change in GFR over time (p < 0.0001) following adjustment for sex, systolic blood pressure, diabetes, BMI, smoking and education level at age 70. Subjects with the lowest levels of p,p’-DDE levels at age 70 showed the lowest decline in GFR over 10 years, while subjects with the highest p,p’-DDE levels showed the greatest decline.Baseline levels of p,p’-DDE were related to an accelerated reduction in GFR over 10 years suggesting a nephrotoxic effect of DDT/p,p’-DDE. These findings support a potential role for DDT in the epidemic of CKD of unknown etiology (CKDu) in agricultural communities of Sri Lanka and Central America where DDT was previously used.

Changes in plasma levels of perfluoroalkyl substances (PFASs) are related to increase in carotid intima-media thickness over 10 years \u2013 a longitudinal study

BackgroundIt has previously been reported that the environmental contaminants perfluoroalkyl substances (PFASs) are linked to atherosclerosis in cross-sectional studies. Since cross-sectional studies could be subject to reverse causation, the purpose of this study was to analyze if the longitudinal changes in PFASs during a 10-year follow-up were related to the change in carotid artery intima-media thickness (IMT, ultrasound) during the same period.MethodsIn the Prospective Investigation of the Vasculature in Uppsala Seniors (PIVUS) study, 1016 individuals were investigated at age 70; 826 of them were reinvestigated at age 75 and 602 at age 80 years. Eight different PFASs were measured in plasma by ultra-performance liquid chromatography-tandem mass spectrometry (HPLC-MS/MS), and IMT was measured at all three time points. Random-effects mixed regression models were used to examine the associations over time.ResultsIMT increased 0.058 mm during the 10-year period (p < 0.0001). Following adjustment for baseline values of PFASs (age 70) and sex, the changes in plasma levels of 6 of the 8 measured PFASs were significantly related to the change in IMT over the 10-year follow-up period in a positive fashion (p < 0.0062 using Bonferroni correction for 8 tests). Further adjustment for traditional cardiovascular (CV) risk factors (HDL and LDL cholesterol, smoking, systolic blood pressure, statin use, fasting glucose and serum triglycerides) affected these relationships only marginally.ConclusionThe change in plasma levels of several PFASs during 10 years was positively related to increase in IMT seen during the same period, giving prospective evidence that PFASs might interfere with the atherosclerotic process.

Circulating levels of perfluoroalkyl substances and left ventricular geometry of the heart in the elderly

AimsSome persistent organic pollutants (POPs) such as hexachlorobenzene (HCB) and some polychlorinated biphenyls (PCBs) have been shown to interfere with myocardial function and geometry. We therefore investigated if also another group of POPs: per- and polyfluoroalkyl substances (PFASs) were associated with alterations in left ventricular geometry. Methods801 subjects aged 70 years were investigated in a cross-sectional study within the scope of the Prospective Investigation of the Vasculature in Uppsala Seniors (PIVUS) study. Eight PFASs were detected in >75% of participants´ plasma by ultra-performance liquid chromatograph/tandem mass spectrometry. Left ventricular geometry was determined by echocardiography. Multivariable linear regression was used to investigate the associations between PFASs and left ventricular geometry of the heart after exclusion of subjects with previous myocardial infarction (n = 72). ResultsWhen adjusting for multiple comparisons, none of the eight PFASs evaluated were significantly related to left ventricular mass. However, perfluorononanoic acid (PFNA), perfluorodecanoic acid (PFDA), and perfluoroundecanoic acid (PFUnDA) were related to relative wall thickness (RWT) in a negative fashion (p < 0.0021). Besides being inversely related to RWT, PFNA was also positively related to left ventricular end-diastolic volume (LVEDD) (p < 0.0021). These analyses were adjusted for traditional cardiovascular risk factors. ConclusionIn this cross-sectional study, several of the PFASs evaluated, especially PFNA, were related to myocardial geometry: a reduction in relative wall thickness and an increase in left ventricular diameter following adjustment for traditional cardiovascular risk factors, suggesting a role for PFASs in cardiac remodeling.

Proteomic profiling of endothelium-dependent vasodilation.

As endothelial dysfunction is an early event in atherosclerosis formation, we investigated if proteins previously related to cardiovascular disease also were related to endothelial function using a novel targeted proteomics approach. In the Prospective Investigation of the Vasculature in Uppsala Seniors (PIVUS) study (n = 850-970, all aged 70 years), endothelium-dependent vasodilation (EDV) in the forearm was assessed by intra-arterial infusion of acetylcholine. Flow-mediated vasodilation (FMD) was investigated in the brachial artery by ultrasound. The same investigations were carried out in the Prospective investigation of Obesity, Energy and Metabolism (POEM) study (n = 375-461, all aged 50 years). After strict quality control, 84 cardiovascular-related proteins measured by the proximity extension assay were studied in relation to EDV and FMD in PIVUS (discovery sample) and POEM (validation sample). Of the 15 proteins being significantly related to EDV in PIVUS (false discovery rate <0.025), seven could be replicated in POEM at nominal significance and same effect direction when adjusted for sex and storage time. Of those, only cathepsin D remained significant following further adjustment for traditional cardiovascular risk factors (beta, -0.08; 95% confidence interval, -0.16, -0.01; P = 0.033; change in ln-transformed EDV per 1-SD increase in protein level). No protein was significantly related to FMD. Using a discovery/validation approach in two samples, our results indicate an inverse association between plasma cathepsin D levels and endothelial-dependent vasodilation.

Relationships between serum-induced AhR bioactivity or mitochondrial inhibition and circulating polychlorinated biphenyls (PCBs)

Metabolic syndrome and mitochondrial dysfunction have been linked to elevated serum levels of persistent organic pollutants (POPs). However, it is not clear which specific POPs contribute to aryl hydrocarbon receptor (AhR)-dependent bioactivity or inhibit mitochondrial function in human subjects. Here, we measured the cumulative bioactivity of AhR ligand mixture (AhR bioactivity) and the effects on mitochondrial function (ATP concentration) in recombinant Hepa1c1c7 cells incubated with raw serum samples obtained from 911 elderly subjects in the Prospective Investigation of the Vasculature in Uppsala Seniors (PIVUS) cohort. Plasma concentrations of 30 POPs and plastic chemicals have previously been determined in the same PIVUS subjects. Linear regression analysis demonstrated that total toxic equivalence (TEQ) values and polychlorinated biphenyls (PCBs) were significantly correlated with AhR bioactivity (positively) and ATP concentration (negatively). Serum AhR bioactivities were positively associated with some PCBs, regardless of their dioxin-like properties, but only dioxin-like PCBs stimulated AhR bioactivity. By contrast, PCBs mediated a reduction in ATP content independently of their dioxin-like properties. This study suggests that AhR bioactivity and ATP concentrations in serum-treated cells may be valuable surrogate biomarkers of POP exposure and could be useful for the estimation of the effects of POPs on human health.

The effect of drinking water contaminated with perfluoroalkyl substances on a 10-year longitudinal trend of plasma levels in an elderly Uppsala cohort

BackgroundIn 2012, drinking water contaminated with per- and polyfluoroalkyl substances (PFASs), foremost perfluorooctanesulfonic acid (PFOS) and perfluorohexanesulfonic acid (PFHxS) at levels over 20ng/L and 40ng/L, respectively, was confirmed in Uppsala, Sweden. ObjectivesWe assessed how a longitudinally sampled cohort's temporal trend in PFAS plasma concentration was influenced by their residential location and determined the plausible association or disparity between the PFASs detected in the drinking water and the trend in the study cohort. MethodsThe Prospective Investigation of the Vasculature in Uppsala Seniors (PIVUS) cohort provided plasma samples three times from 2001 to 2014. Individuals maintaining the same zip code throughout the study (n = 399) were divided into a reference (no known PFAS exposure), low, intermediate and high exposure area depending on the proportion of contaminated drinking water received. Eight PFASs detected in the majority (75%) of the cohort's plasma samples were evaluated for significant changes in temporal PFAS concentrations using a random effects (mixed) model. ResultsPFHxS plasma concentrations continued to significantly increase in individuals living in areas receiving the largest percentage of contaminated drinking water (p < 0.0001), while PFOS showed an overall decrease. The temporal trend of other PFAS plasma concentrations did not show an association to the quality of drinking water received. ConclusionsThe distribution of contaminated drinking water had a direct effect on the trend in PFHxS plasma levels among the different exposure groups, resulting in increased concentrations over time, especially in the intermediate and high exposure areas. PFOS and the remaining PFASs did not show the same relationship, suggesting other sources of exposure influenced these PFAS plasma trends.