Cohort profile: the Hortega Study for the evaluation of non-traditional risk factors of cardiometabolic and other chronic diseases in a general population from Spain.

PURPOSE: The Hortega Study is a prospective study, which investigates novel determinants of selected chronic conditions with an emphasis on cardiovascular health in a representative sample of a general population from Spain. PARTICIPANTS: In 1997, a mailed survey was sent to a random selection of public health system beneficiaries assigned to the University Hospital Rio Hortega's catchment area in Valladolid (Spain) (n=11 423, phase I), followed by a pilot examination in 1999-2000 of 495 phase I participants (phase II). In 2001-2003, the examination of 1502 individuals constituted the Hortega Study baseline examination visit (phase III, mean age 48.7 years, 49% men, 17% with obesity, 27% current smokers). Follow-up of phase III participants (also termed Hortega Follow-up Study) was obtained as of 30 November 2015 through review of health records (9.5% of participants without follow-up information). FINDINGS TO DATE: The Hortega Study integrates baseline information of traditional and non-traditional factors (metabolomic including lipidomic and oxidative stress metabolites, genetic variants and environmental factors, such as metals), with 14 years of follow-up for the assessment of mortality and incidence of chronic diseases. Preliminary analysis of time to event data shows that well-known cardiovascular risk factors are associated with cardiovascular incidence rates, which add robustness to our cohort. FUTURE PLANS: In 2020, we will review updated health and mortality records of this ongoing cohort for a 5-year follow-up extension. We will also re-examine elder survivors to evaluate specific aspects of ageing and conduct geolocation to study additional environmental exposures. Stored biological specimens are available for analysis of new biomarkers. The Hortega Study will, thus, enable the identification of novel factors based on time to event data, potentially contributing to the prevention and control of chronic diseases in ageing populations.

Mortality and cardiovascular disease burden of uncontrolled diabetes in a registry-based cohort: the ESCARVAL-risk study.

BACKGROUND: Despite the epidemiological evidence about the relationship between diabetes, mortality and cardiovascular disease, information about the population impact of uncontrolled diabetes is scarce. We aimed to estimate the attributable risk associated with HbA1c levels for all-cause mortality and cardiovascular hospitalization. METHODS: Prospective study of subjects with diabetes mellitus using electronic health records from the universal public health system in the Valencian Community, Spain 2008-2012. We included 19,140 men and women aged 30 years or older with diabetes who underwent routine health examinations in primary care. RESULTS: A total of 11,003 (57%) patients had uncontrolled diabetes defined as HbA1c ≥6.5%, and, among those, 5325 participants had HbA1c ≥7.5%. During an average follow-up time of 3.3 years, 499 deaths, 912 hospitalizations for coronary heart disease (CHD) and 786 hospitalizations for stroke were recorded. We observed a linear and increasingly positive dose-response of HbA1c levels and CHD hospitalization. The relative risk for all-cause mortality and CHD and stroke hospitalization comparing patients with and without uncontrolled diabetes was 1.29 (95 CI 1.08,1.55), 1.38 (95 CI 1.20,1.59) and 1.05 (95 CI 0.91, 1.21), respectively. The population attributable risk (PAR) associated with uncontrolled diabetes was 13.6% (95% CI; 4.0-23.9) for all-cause mortality, 17.9% (95% CI; 10.5-25.2) for CHD and 2.7% (95% CI; - 5.5-10.8) for stroke hospitalization. CONCLUSIONS: In a large general-practice cohort of patients with diabetes, uncontrolled glucose levels were associated with a substantial mortality and cardiovascular disease burden.

A gene-environment interaction analysis of plasma selenium with prevalent and incident diabetes: The Hortega study.

BACKGROUND: Selenium and single-nucleotide-polymorphisms in selenoprotein genes have been associated to diabetes. However, the interaction of selenium with genetic variation in diabetes and oxidative stress-related genes has not been evaluated as a potential determinant of diabetes risk. METHODS: We evaluated the cross-sectional and prospective associations of plasma selenium concentrations with type 2 diabetes, and the interaction of selenium concentrations with genetic variation in candidate polymorphisms, in a representative sample of 1452 men and women aged 18-85 years from Spain. RESULTS: The geometric mean of plasma selenium levels in the study sample was 84.2µg/L. 120 participants had diabetes at baseline. Among diabetes-free participants who were not lost during the follow-up (N=1234), 75 developed diabetes over time. The multivariable adjusted odds ratios (95% confidence interval) for diabetes prevalence comparing the second and third to the first tertiles of plasma selenium levels were 1.80 (1.03, 3.14) and 1.97 (1.14, 3.41), respectively. The corresponding hazard ratios (95% CI) for diabetes incidence were 1.76 (0.96, 3.22) and 1.80 (0.98, 3.31), respectively. In addition, we observed significant interactions between selenium and polymorphisms in PPARGC1A, and in genes encoding mitochondrial proteins, such as BCS1L and SDHA, and suggestive interactions of selenium with other genes related to selenoproteins and redox metabolism. CONCLUSIONS: Plasma selenium was positively associated with prevalent and incident diabetes. While the statistical interactions of selenium with polymorphisms involved in regulation of redox and insulin signaling pathways provide biological plausibility to the positive associations of selenium with diabetes, further research is needed to elucidate the causal pathways underlying these associations.

Renal function and attributable risk of death and cardiovascular hospitalization in patients with cardiovascular risk factors from a registry-based cohort: the Estudio Cardiovascular Valencia-risk study.

BACKGROUND: Information about the attributable risk associated with renal dysfunction in patients with cardiovascular risk factors is lacking. OBJECTIVE: We aimed to estimate the attributable risk associated with chronic kidney disease Epidemiology Collaboration-estimated glomerular filtration rate (eGFR), for all-cause mortality, and cardiovascular hospitalization. DESIGN, SETTING, AND PARTICIPANTS: Prospective study of study participants with cardiovascular risk factors in 2008-2012. We included 52 007 cardiovascular disease-free men and women aged 30 years or older with hypertension, diabetes, or dyslipidemia, who underwent routine health examinations in primary care. RESULTS: A total of 6639 (12.8%) patients had eGFR below 60 ml/min per 1.73 m and among them 1782 (3.4%) had 45 ml/min per 1.73 m or lower. During an average follow-up time of 3.2 years, 54.12 deaths, 99.98 coronary heart disease (CHD) hospitalizations, and 90.64 stroke hospitalizations/10 000 person-years were recorded. The population attributable risks associated with having a GFR lower than 60 ml/min per 1.73 m were 6.9% (95% confidence interval = 2.07, 10.65) for all-cause mortality, 6.8% (4.3, 9.4) for CHD hospitalization, and 4.1% (1.02, 7.00) for stroke hospitalization. Participants with increasing number of cardiovascular risk factors displayed increasing population attributable risks associated to a GFR less than 60 ml/min per 1.73 m for all-cause mortality and CHD (P heterogeneity 0.002 and 0.05, respectively). CONCLUSION: In a large general practice cohort of patients with cardiovascular disease risk factors, decreasing eGFR levels were associated with additional attributed risk of mortality and cardiovascular disease. Our findings underscore that intensified efforts are needed to reduce the cardiovascular disease burden associated to chronic kidney disease.

Impact of hypertension on mortality and cardiovascular disease burden in patients with cardiovascular risk factors from a general practice setting: the ESCARVAL-risk study.

OBJECTIVE: To estimate the attributable risk associated to hypertension for all-cause mortality and cardiovascular hospitalization endpoints in a prospective study of patients with at least one cardiovascular risk factors participating in the Estudio Cardiovascular Valencia-risk project, we also evaluated the attributable risk associated with other risk factors and risk factor clustering. METHODS: Prospective electronic health recording-based study in a Mediterranean population that included 52 007 cardiovascular disease-free men and women aged 30 years or older (mean age 62.6 year) with hypertension (79.0%), diabetes mellitus (37.3%), or dyslipidemia (88.2%), who underwent routine health examinations. All-cause mortality and hospitalization records for coronary heart disease (CHD) or stroke were collected. RESULTS: During an average follow-up time of 3.2 years, 928 deaths and 1682 and 1529 hospitalizations for CHD and stroke, respectively, were recorded. In both men and women, hypertension significantly increased the multiadjusted rates of death and CHD and stroke hospitalizations. Hypertension was associated with a substantial amount of avoidable deaths both in men and women, population attributable risks were 41.81 (95% confidence interval 28.02, 53.24)% and 37.84 (5.74, 61.51)%, respectively. Similarly, the population attributable risk of hospitalization for CHD and stroke associated to hypertension was among the highest in both the sexes as compared with the impact of the other main cardiovascular risk factors. Increasing cardiovascular risk factors clustering was associated with increasing burden of disease. CONCLUSION: Our results highlight the relevance of hypertension as main risk factor for mortality and cardiovascular events in a real-life setting. Although our data support the ongoing need of cardiovascular risk factors prevention, intensified actions for primary prevention of hypertension show potential to largely reduce the burden of cardiovascular disease.

Do genes modify the association of selenium and lipid levels?

The interaction of selenium, a component of antioxidant selenoproteins, with genetic variation in lipid-related pathways has not been evaluated earlier as a potential determinant of blood lipid levels. We aimed at evaluating the effects of gene-environment interactions between plasma levels of selenium and polymorphisms in lipid metabolic pathways on plasma lipid levels in a study population from Spain (N=1,315). We observed statistically significant associations between plasma selenium and lipid levels (differences in total, low-density lipoprotein [LDL]-cholesterol, and triglycerides comparing the 80th with the 20th percentiles of plasma selenium levels were, respectively, 12.0 (95% confidence interval 6.3, 17.8), 8.9 (3.7, 14.2), and 9.0 (2.9, 15.2) mg/dl). We also found statistically significant interactions at the Bonferroni-corrected significance level (p=0.0008) between selenium and rs2290201 in FABP4 for total and LDL cholesterol levels and rs1800774 in CETP for elevated LDL cholesterol. Other polymorphisms showed statistically significant differential associations of plasma selenium levels and lipids biomarkers at the nominal p-value of 0.05. Reported statistical interactions with genes involved in lipid transport and transfer provide biological support to the positive associations of selenium with lipids shown in cross-sectional studies and lead to the hypothesis that selenium and lipid levels share common biological pathways that need to be elucidated in mechanistic studies.

Cadmium exposure and clinical cardiovascular disease: a systematic review.

Mounting evidence supports that cadmium, a toxic metal found in tobacco, air and food, is a cardiovascular risk factor. Our objective was to conduct a systematic review of epidemiologic studies evaluating the association between cadmium exposure and cardiovascular disease. Twelve studies were identified. Overall, the pooled relative risks (95% confidence interval) for cardiovascular disease, coronary heart disease, stroke, and peripheral arterial disease were: 1.36 (95% CI: 1.11, 1.66), 1.30 (95% CI: 1.12, 1.52), 1.18 (95% CI: 0.86, 1.59), and 1.49 (95% CI: 1.15, 1.92), respectively. The pooled relative risks for cardiovascular disease in men, women and never smokers were 1.29 (1.12, 1.48), 1.20 (0.92, 1.56) and 1.27 (0.97, 1.67), respectively. Together with experimental evidence, our review supports the association between cadmium exposure and cardiovascular disease, especially for coronary heart disease. The number of studies with stroke, heart failure (HF) and peripheral arterial disease (PAD) endpoints was small. More studies, especially studies evaluating incident endpoints, are needed.