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Objective: The pathophysiology of hypertension remains incompletely understood. We investigated associations of circulating metabolites with longitudinal blood pressure (BP) changes in the Prospective Investigation of the Vasculature in Uppsala Seniors cohort and validated the findings in the Uppsala Longitudinal Study of Adult Men cohort. Approach and Results: Circulating metabolite levels were assessed with liquid- and gas-chromatography coupled to mass spectrometry among persons without BP-lowering medication at baseline. We studied associations of baseline levels of metabolites with changes in BP levels and the clinical BP stage between baseline and a follow-up examination 5 years later. In the discovery cohort, we investigated 504 individuals that contributed with 757 observations of paired BP measurements. The mean baseline systolic and diastolic BPs were 144 (19.7)/76 (9.7) mm Hg, and change in systolic and diastolic BPs were 3.7 (15.8)/−0.5 (8.6) mm Hg over 5 years. The metabolites associated with diastolic BP change were ceramide, triacylglycerol, total glycerolipids, oleic acid, and cholesterylester. No associations with longitudinal changes in systolic BP or BP stage were observed. Metabolites with similar structures to the 5 top findings in the discovery cohort were investigated in the validation cohort. Diacylglycerol (36:2) and monoacylglycerol (18:0), 2 glycerolipids, were associated with diastolic BP change in the validation cohort. Conclusions: Circulating baseline levels of ceramide, triacylglycerol, total glycerolipids, and oleic acid were positively associated with longitudinal diastolic BP change, whereas cholesterylester levels were inversely associated with longitudinal diastolic BP change. Two glycerolipids were validated in an independent cohort. These metabolites may point towards pathophysiological pathways of hypertension.

Established risk factors for left ventricular hypertrophy (LVH) are hypertension, diabetes, and obesity. However, as these risk factors explain only part of the variation in left ventricular mass, we investigated whether persistent organic pollutants (POPs) might also play a role in LVH, because exposure to polychlorinated biphenyl 126 induced cardiac growth in rats.In the Prospective Investigation of the Vasculature in Uppsala Seniors (PIVUS), left ventricular mass index (LVMI), relative wall thickness (RWT), and geometric groups of LVH, were determined by echocardiography and 21 POPs were measured by high-resolution chromatography coupled to high-resolution mass spectrometry (HRGC/HRMS) in 1016 individuals aged 70 years. All individuals with a history of myocardial infarction were excluded from analysis (n = 72).Several of the POPs were related to abnormal left ventricular geometry before adjustment for established risk factors, but lost in significance following adjustment. However, the pesticide hexachlorobenzene (HCB) levels were significantly related to RWT, and concentric left ventricular remodeling, also following adjustment for sex, blood pressure, antihypertensive treatment, diabetes, and BMI (P 0.0001).In this cross-sectional study, circulating levels of HCB were related to increased wall thickness of the left ventricle and concentric left ventricular remodeling, independently of LVH risk factors, suggesting a role of this environmental contaminant in abnormal growth of the left ventricle.

Background: Exposure to PCBs and dioxin to experimental animals increase blood pressure. We therefore investigated if circulating levels of persistent organic pollutants (POPs) were related to hypertension in a population-based sample. Methods: 1016 subjects aged 70 years were investigated in the Prospective Investigation of the Vasculature in Uppsala Seniors (PIVUS) study. Hypertension was defined as either use of antihypertensive treatment or blood pressure > 140/90 mmHg. Twenty-one different POPs, including 16 PCBs, three pesticides (HCB, DDE and TNK), one dioxin (OCDD) and one brominated compound (BDE47) were analyzed by high-resolution chromatography coupled to high-resolution mass spectrometry (HRGC/ HRMS) at age 70. Results: 732 subjects (72%) showed hypertension. When the POPs were treated as continuous variables and adjusted for gender only, several of the PCBs with a low number of chlorine atoms (PCB74, 99, 105, 118 and 138) were related to prevalent hypertension. Also the OC pesticides, HCB, TNK, pp-DDE, and the brominated compound BDE47 were related to hypertension. The strongest of these associations were seen for pp-DDE (OR 1.35 for a SD change, 95%CI 1.17-1.56, p Conclusion: In this cross-sectional analysis of an elderly population, high levels of circulating levels of pp-DDE were associated with prevalent hypertension, further strengthening the experimental findings that POPs might influence blood pressure.

Background: When reporting circulating levels of persistent organic pollutants (POPs), usually lipid-normalized values are given. However, animal experiments and some human data support the view that exposure to POPs might change lipid values. The aim of the present study is to investigate if POP levels could predict future change in lipids levels. Methods: In the population-based Prospective Investigation of the Vasculature in Uppsala Seniors (PIVUS) study, lipids were measured at age 70 and at age 75 in 598 subjects without lipid-lowering medication. Twenty-one different POPs, including 16 PCBs, three pesticides (HCB, DDE and TNK), one dioxin (OCDD) and one brominated compound (BDE47) were analyzed by high-resolution chromatography coupled to high-resolution mass spectrometry (HRGC/ HRMS) at age 70. Results: Strong relationships were seen between the baseline levels of PCBs 194, 206 and 209 and the degree of increase in total serum cholesterol and LDL-cholesterol during the 5 year follow-up. These relationships were generally stronger when lipid-normalized levels were used compared to wet-weight based levels. On the contrary, both HCB and TNK levels were inversely related to the change in LDL-cholesterol, with strongest associations found using wet-weight based levels. PCBs 194, 206 and 209 were inversely related to the change in HDL-cholesterol. None of the POPs were related to the change in serum triglycerides. Conclusion: POPs are related to the future change in lipids. This might explain why POP exposure previously has been linked to atherosclerosis and future cardiovascular disease. It might also question the use of lipid-normalization when studying relationships between POPs and metabolic diseases.