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1.
Eur J Prev Cardiol ; 28(12): 1376-1385, 2021 Oct 13.
Artigo em Inglês | MEDLINE | ID: mdl-34647588

RESUMO

AIMS: The purpose of this study was to analyse the association of leisure-time physical activity of different intensities at baseline, and cardiovascular disease incidence, cardiovascular disease mortality and all-cause mortality in a population-based sample of 60-year-old men and women with and without established metabolic syndrome, for more than 20 years of follow-up. A secondary aim was to study which cardiometabolic factors may mediate the association between physical activity and long-term outcomes. METHODS: A total of 3693 participants (53% women) underwent physical examination and laboratory tests, completed an extensive questionnaire at baseline 1997-1999 and were followed until their death or until 31 December 2017. First-time cardiovascular disease events and death from any cause were ascertained through regular examinations of national registers. RESULTS: Metabolic syndrome prevalence was 23.0%. In metabolic syndrome participants, light physical activity attenuated cardiovascular disease incidence (hazard ratio = 0.71; 95% confidence interval 0.50-1.00) compared to sedentary (reference) after multi-adjustment. Moderate/high physical activity was inversely associated with both cardiovascular disease and all-cause mortality, but became non-significant after multi-adjustment. Sedentary non-metabolic syndrome participants had lower cardiovascular disease incidence (0.47; 0.31-0.72) but not significantly different cardiovascular disease (0.61; 0.31-1.19) and all-cause mortality (0.92; 0.64-1.34) compared to sedentary metabolic syndrome participants. Both light and moderate/high physical activity were inversely associated with cardiovascular disease and all-cause mortality in non-metabolic syndrome participants (p<0.05). There were significant variations in several central cardiometabolic risk factors with physical activity level in non-metabolic syndrome participants. Fibrinogen mediated the protective effects of physical activity in non-metabolic syndrome participants. CONCLUSION: Physical activity of different intensities attenuated cardiovascular risk and mortality in 60-year old men and women with metabolic syndrome during a 20-year follow-up.

2.
Circulation ; 144(12): 916-929, 2021 Sep 21.
Artigo em Inglês | MEDLINE | ID: mdl-34543072

RESUMO

BACKGROUND: Early detection of coronary atherosclerosis using coronary computed tomography angiography (CCTA), in addition to coronary artery calcification (CAC) scoring, may help inform prevention strategies. We used CCTA to determine the prevalence, severity, and characteristics of coronary atherosclerosis and its association with CAC scores in a general population. METHODS: We recruited 30 154 randomly invited individuals age 50 to 64 years to SCAPIS (the Swedish Cardiopulmonary Bioimage Study). The study includes individuals without known coronary heart disease (ie, no previous myocardial infarctions or cardiac procedures) and with high-quality results from CCTA and CAC imaging performed using dedicated dual-source CT scanners. Noncontrast images were scored for CAC. CCTA images were visually read and scored for coronary atherosclerosis per segment (defined as no atherosclerosis, 1% to 49% stenosis, or ≥50% stenosis). External validity of prevalence estimates was evaluated using inverse probability for participation weighting and Swedish register data. RESULTS: In total, 25 182 individuals without known coronary heart disease were included (50.6% women). Any CCTA-detected atherosclerosis was found in 42.1%; any significant stenosis (≥50%) in 5.2%; left main, proximal left anterior descending artery, or 3-vessel disease in 1.9%; and any noncalcified plaques in 8.3% of this population. Onset of atherosclerosis was delayed on average by 10 years in women. Atherosclerosis was more prevalent in older individuals and predominantly found in the proximal left anterior descending artery. Prevalence of CCTA-detected atherosclerosis increased with increasing CAC scores. Among those with a CAC score >400, all had atherosclerosis and 45.7% had significant stenosis. In those with 0 CAC, 5.5% had atherosclerosis and 0.4% had significant stenosis. In participants with 0 CAC and intermediate 10-year risk of atherosclerotic cardiovascular disease according to the pooled cohort equation, 9.2% had CCTA-verified atherosclerosis. Prevalence estimates had excellent external validity and changed marginally when adjusted to the age-matched Swedish background population. CONCLUSIONS: Using CCTA in a large, random sample of the general population without established disease, we showed that silent coronary atherosclerosis is common in this population. High CAC scores convey a significant probability of substantial stenosis, and 0 CAC does not exclude atherosclerosis, particularly in those at higher baseline risk.

3.
Lancet Planet Health ; 5(9): e620-e632, 2021 09.
Artigo em Inglês | MEDLINE | ID: mdl-34508683

RESUMO

BACKGROUND: Long-term exposure to outdoor air pollution increases the risk of cardiovascular disease, but evidence is unclear on the health effects of exposure to pollutant concentrations lower than current EU and US standards and WHO guideline limits. Within the multicentre study Effects of Low-Level Air Pollution: A Study in Europe (ELAPSE), we investigated the associations of long-term exposures to fine particulate matter (PM2·5), nitrogen dioxide (NO2), black carbon, and warm-season ozone (O3) with the incidence of stroke and acute coronary heart disease. METHODS: We did a pooled analysis of individual data from six population-based cohort studies within ELAPSE, from Sweden, Denmark, the Netherlands, and Germany (recruited 1992-2004), and harmonised individual and area-level variables between cohorts. Participants (all adults) were followed up until migration from the study area, death, or incident stroke or coronary heart disease, or end of follow-up (2011-15). Mean 2010 air pollution concentrations from centrally developed European-wide land use regression models were assigned to participants' baseline residential addresses. We used Cox proportional hazards models with increasing levels of covariate adjustment to investigate the association of air pollution exposure with incidence of stroke and coronary heart disease. We assessed the shape of the concentration-response function and did subset analyses of participants living at pollutant concentrations lower than predefined values. FINDINGS: From the pooled ELAPSE cohorts, data on 137 148 participants were analysed in our fully adjusted model. During a median follow-up of 17·2 years (IQR 13·8-19·5), we observed 6950 incident events of stroke and 10 071 incident events of coronary heart disease. Incidence of stroke was associated with PM2·5 (hazard ratio 1·10 [95% CI 1·01-1·21] per 5 µg/m3 increase), NO2 (1·08 [1·04-1·12] per 10 µg/m3 increase), and black carbon (1·06 [1·02-1·10] per 0·5 10-5/m increase), whereas coronary heart disease incidence was only associated with NO2 (1·04 [1·01-1·07]). Warm-season O3 was not associated with an increase in either outcome. Concentration-response curves indicated no evidence of a threshold below which air pollutant concentrations are not harmful for cardiovascular health. Effect estimates for PM2·5 and NO2 remained elevated even when restricting analyses to participants exposed to pollutant concentrations lower than the EU limit values of 25 µg/m3 for PM2·5 and 40 µg/m3 for NO2. INTERPRETATION: Long-term air pollution exposure was associated with incidence of stroke and coronary heart disease, even at pollutant concentrations lower than current limit values. FUNDING: Health Effects Institute.


Assuntos
Poluição do Ar , Doença das Coronárias , Acidente Vascular Cerebral , Adulto , Poluição do Ar/efeitos adversos , Doença das Coronárias/induzido quimicamente , Doença das Coronárias/epidemiologia , Exposição Ambiental/efeitos adversos , Exposição Ambiental/análise , Humanos , Incidência , Estudos Multicêntricos como Assunto , Acidente Vascular Cerebral/epidemiologia
4.
PLoS Med ; 18(9): e1003763, 2021 09.
Artigo em Inglês | MEDLINE | ID: mdl-34547017

RESUMO

BACKGROUND: We aimed to investigate the association of serum pentadecanoic acid (15:0), a biomarker of dairy fat intake, with incident cardiovascular disease (CVD) and all-cause mortality in a Swedish cohort study. We also systematically reviewed studies of the association of dairy fat biomarkers (circulating or adipose tissue levels of 15:0, heptadecanoic acid [17:0], and trans-palmitoleic acid [t16:1n-7]) with CVD outcomes or all-cause mortality. METHODS AND FINDINGS: We measured 15:0 in serum cholesterol esters at baseline in 4,150 Swedish adults (51% female, median age 60.5 years). During a median follow-up of 16.6 years, 578 incident CVD events and 676 deaths were identified using Swedish registers. In multivariable-adjusted models, higher 15:0 was associated with lower incident CVD risk in a linear dose-response manner (hazard ratio 0.75 per interquintile range; 95% confidence interval 0.61, 0.93, P = 0.009) and nonlinearly with all-cause mortality (P for nonlinearity = 0.03), with a nadir of mortality risk around median 15:0. In meta-analyses including our Swedish cohort and 17 cohort, case-cohort, or nested case-control studies, higher 15:0 and 17:0 but not t16:1n-7 were inversely associated with total CVD, with the relative risk of highest versus lowest tertile being 0.88 (0.78, 0.99), 0.86 (0.79, 0.93), and 1.01 (0.91, 1.12), respectively. Dairy fat biomarkers were not associated with all-cause mortality in meta-analyses, although there were ≤3 studies for each biomarker. Study limitations include the inability of the biomarkers to distinguish different types of dairy foods and that most studies in the meta-analyses (including our novel cohort study) only assessed biomarkers at baseline, which may increase the risk of misclassification of exposure levels. CONCLUSIONS: In a meta-analysis of 18 observational studies including our new cohort study, higher levels of 15:0 and 17:0 were associated with lower CVD risk. Our findings support the need for clinical and experimental studies to elucidate the causality of these relationships and relevant biological mechanisms.

5.
BMC Neurol ; 21(1): 306, 2021 Aug 09.
Artigo em Inglês | MEDLINE | ID: mdl-34372806

RESUMO

BACKGROUND: Pro-inflammatory processes underlie ischemic stroke, albeit it is largely unknown if they selectively associate with the risk of atherothrombotic or cardioembolic ischemic stroke. Here we analyze whether pro-inflammatory interleukin (IL) 6 trans-signaling, is associated with the risk of ischemic stroke and underlying atrial fibrillation (AF). METHODS: During a 20-year follow-up, 203 incident ischemic strokes were recorded from national registers in the cohort of 60-year-old men and women from Stockholm (n = 4232). The risk of ischemic stroke associated with circulating IL6 trans-signaling, assessed by a ratio between the pro-inflammatory binary IL6:sIL6R complex and the inactive ternary IL6:sIL6R:sgp130 complex (B/T ratio), was estimated by Cox regression and expressed as hazard ratio (HR) with a 95% confidence interval (CI) in the presence or absence of AF. Risk estimates were adjusted for cardiovascular risk factors and anticoagulant treatment. In a secondary analysis, the association of IL6 trans-signaling with the risk of incident AF (n = 279) was analyzed. RESULTS: B/T ratio > median was associated with increased risk of ischemic stroke in study participants without AF (adjusted HR 1.49; 95% CI 1.08-2.06), while an association could not be demonstrated in the presence of AF. Moreover, the B/T ratio was not associated with the risk of AF (HR 0.96; 95% CI 0.75-1.24). CONCLUSIONS: Pro-inflammatory IL6 trans-signaling, estimated by the B/T ratio, is associated with ischemic stroke in individuals without AF. These findings suggest that the B/T ratio could be used to assess the risk of non-AF associated ischemic stroke.


Assuntos
Isquemia Encefálica , AVC Isquêmico , Fibrilação Atrial/complicações , Fibrilação Atrial/epidemiologia , Isquemia Encefálica/epidemiologia , Feminino , Humanos , Incidência , Interleucina-6 , Masculino , Pessoa de Meia-Idade , Medição de Risco , Fatores de Risco
6.
Sci Rep ; 11(1): 7866, 2021 04 12.
Artigo em Inglês | MEDLINE | ID: mdl-33846368

RESUMO

The relationship between intake of saturated fats and subclinical atherosclerosis, as well as the possible influence of genetic variants, is poorly understood and investigated. We aimed to investigate this relationship, with a hypothesis that it would be positive, and to explore whether genetics may modulate it, using data from a European cohort including 3,407 participants aged 54-79 at high risk of cardiovascular disease. Subclinical atherosclerosis was assessed by carotid intima-media thickness (C-IMT), measured at baseline and after 30 months. Logistic regression (OR; 95% CI) was employed to assess the association between high intake of food rich in saturated fat (vs. low) and: (1) the mean and the maximum values of C-IMT in the whole carotid artery (C-IMTmean, C-IMTmax), in the bifurcation (Bif-), the common (CC-) and internal (ICA-) carotid arteries at baseline (binary, cut-point ≥ 75th), and (2) C-IMT progression (binary, cut-point > zero). For the genetic-diet interaction analyses, we considered 100,350 genetic variants. We defined interaction as departure from additivity of effects. After age- and sex-adjustment, high intake of saturated fat was associated with increased C-IMTmean (OR:1.27;1.06-1.47), CC-IMTmean (OR:1.22;1.04-1.44) and ICA-IMTmean (OR:1.26;1.07-1.48). However, in multivariate analysis results were no longer significant. No clear associations were observed between high intake of saturated fat and risk of atherosclerotic progression. There was no evidence of interactions between high intake of saturated fat and any of the genetic variants considered, after multiple testing corrections. High intake of saturated fats was not independently associated with subclinical atherosclerosis. Moreover, we did not identify any significant genetic-dietary fat interactions in relation to risk of subclinical atherosclerosis.


Assuntos
Aterosclerose , Espessura Intima-Media Carotídea , Gorduras na Dieta/efeitos adversos , Predisposição Genética para Doença , Idoso , Aterosclerose/epidemiologia , Aterosclerose/etiologia , Aterosclerose/genética , Estudos de Coortes , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Fatores de Risco
7.
Eur J Nutr ; 60(1): 123-134, 2021 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-32206896

RESUMO

BACKGROUND/AIM: The association between alcohol consumption and subclinical atherosclerosis is still unclear. Using data from a European multicentre study, we assess subclinical atherosclerosis and its 30-month progression by carotid intima-media thickness (C-IMT) measurements, and correlate this information with self-reported data on alcohol consumption. METHODS: Between 2002-2004, 1772 men and 1931 women aged 54-79 years with at least three risk factors for cardiovascular disease (CVD) were recruited in Italy, France, Netherlands, Sweden, and Finland. Self-reported alcohol consumption, assessed at baseline, was categorized as follows: none (0 g/d), very-low (0 - 5 g/d), low (> 5 to ≤ 10 g/d), moderate (> 10 to ≤ 20 g/d for women, > 10 to ≤ 30 g/d for men) and high (> 20 g/d for women, > 30 g/d for men). C-IMT was measured in millimeters at baseline and after 30 months. Measurements consisted of the mean and maximum values of the common carotids (CC), internal carotid artery (ICA), and bifurcations (Bif) and whole carotid tree. We used quantile regression to describe the associations between C-IMT measures and alcohol consumption categories, adjusting for sex, age, physical activity, education, smoking, diet, and latitude. RESULTS: Adjusted differences between median C-IMT values in different levels of alcohol consumption (vs. very-low) showed that moderate alcohol consumption was associated with lower C-IMTmax[- 0.17(95%CI - 0.32; - 0.02)], and Bif-IMTmean[- 0.07(95%CI - 0.13; - 0.01)] at baseline and decreasing C-IMTmean[- 0.006 (95%CI - 0.011; - 0.000)], Bif-IMTmean[- 0.016(95%CI - 0.027; - 0.005)], ICA-IMTmean[- 0.009(95% - 0.016; - 0.002)] and ICA-IMTmax[- 0.016(95%: - 0.032; - 0.000)] after 30 months. There was no evidence of departure from linearity in the association between alcohol consumption and C-IMT. CONCLUSION: In this European population at high risk of CVD, findings show an inverse relation between moderate alcohol consumption and carotid subclinical atherosclerosis and its 30-month progression, independently of several potential confounders.


Assuntos
Aterosclerose , Espessura Intima-Media Carotídea , Consumo de Bebidas Alcoólicas , Aterosclerose/epidemiologia , Aterosclerose/etiologia , Feminino , Finlândia , França , Humanos , Itália/epidemiologia , Masculino , Países Baixos , Fatores de Risco , Suécia
8.
Vasc Med ; 26(1): 3-10, 2021 02.
Artigo em Inglês | MEDLINE | ID: mdl-33350884

RESUMO

Interleukin (IL) 6 contributes to atherosclerotic plaque development through IL6 membrane-bound (IL6R and gp130) and soluble (sIL6R and sgp130) receptors. We investigated IL6 receptor expression in carotid plaques and its correlation with circulating IL6 and soluble receptor levels. Plasma samples and carotid plaques were obtained from 78 patients in the Biobank of Karolinska Endarterectomies study. IL6, sIL6R, and sgp130 were measured in plasma and IL6, IL6R, sIL6R, GP130, and sGP130-RAPS (sGP130) gene expression assessed in carotid plaques. Correlations between plaque IL6 signaling gene expression and plasma levels were determined by Spearman's correlation. Differences in plasma and gene expression levels between patients with (n = 53) and without (n = 25) a history of a cerebral event and statin-treated (n = 65) and non-treated (n = 11), were estimated by Kruskal-Wallis. IL6 and its receptors were all expressed in carotid plaques. There was a positive, borderline significant, moderate correlation between plasma IL6 and sIL6R and the respective gene expression levels (rho 0.23 and 0.22, both p = 0.05). IL6R expression was higher in patients with a history of a cerebrovascular event compared to those without (p = 0.007). Statin-treated had higher IL6R, sIL6R, and sGP130 expression levels and plasma sIL6R compared to non-treated patients (all p < 0.05). In conclusion, all components of the IL6 signaling pathways are expressed in carotid artery plaques and IL6 and sIL6R plasma levels correlate moderately with IL6 and sIL6R. Our data suggest that IL6 signaling in the circulation might mirror the system activity in the plaque, thus adding novel perspectives to the role of IL6 signaling in atherosclerosis.


Assuntos
Artérias Carótidas/metabolismo , Estenose das Carótidas/metabolismo , Receptor gp130 de Citocina/metabolismo , Interleucina-6/metabolismo , Placa Aterosclerótica , Receptores de Interleucina-6/metabolismo , Idoso , Biomarcadores/metabolismo , Artérias Carótidas/cirurgia , Estenose das Carótidas/sangue , Estenose das Carótidas/genética , Estenose das Carótidas/terapia , Estudos Transversais , Receptor gp130 de Citocina/sangue , Receptor gp130 de Citocina/genética , Endarterectomia das Carótidas , Feminino , Humanos , Inibidores de Hidroximetilglutaril-CoA Redutases/uso terapêutico , Interleucina-6/sangue , Interleucina-6/genética , Masculino , Receptores de Interleucina-6/sangue , Receptores de Interleucina-6/genética , Transdução de Sinais
9.
Genes (Basel) ; 11(11)2020 10 22.
Artigo em Inglês | MEDLINE | ID: mdl-33105679

RESUMO

Non-alcoholic fatty liver disease (NAFLD) and atherosclerosis-related cardiovascular diseases (CVD) share common metabolic pathways. We explored the association between three NAFLD-associated single nucleotide polymorphisms (SNPs) rs738409, rs10401969, and rs1260326 with sub-clinical atherosclerosis estimated by the carotid intima-media thickness (c-IMT) and the inter-adventitia common carotid artery diameter (ICCAD) in patients free from clinically overt NAFLD and CVD. The study population is the IMPROVE, a multicenter European study (n = 3711). C-IMT measures and ICCAD were recorded using a standardized protocol. Linear regression with an additive genetic model was used to test for association of the three SNPs with c-IMT and ICCAD. In secondary analyses, the association of the three SNPs with c-IMT and ICCAD was tested after stratification by alanine aminotransferase levels (ALT). No associations were found between rs738409, rs1260326, rs10401969, and c-IMT or ICCAD. Rs738409-G and rs10401969-C were associated with ALT levels (p < 0.001). In patients with ALT levels above 28 U/L (highest quartile), we observed an association between rs10401969-C and c-IMT measures of c-IMTmax and c-IMTmean-max (p = 0.018 and 0.021, respectively). In conclusion, NAFLD-associated SNPs do not associate with sub-clinical atherosclerosis measures. However, our results suggest a possible mediating function of impaired liver function on atherosclerosis development.


Assuntos
Aterosclerose/genética , Artérias Carótidas/fisiologia , Hepatopatia Gordurosa não Alcoólica/genética , Polimorfismo de Nucleotídeo Único/genética , Idoso , Alanina Transaminase/sangue , Substituição de Aminoácidos/genética , Espessura Intima-Media Carotídea , Feminino , Estudos de Associação Genética , Humanos , Masculino
10.
Br J Sports Med ; 54(21): 1294-1299, 2020 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-32680841

RESUMO

OBJECTIVE: To evaluate long-term risk of first cardiovascular (CV) events, CV deaths and all-cause deaths in community-dwelling participants of a cardiovascular disease (CVD) prevention programme delivered in a primary care setting. METHODS: Individuals who visited a primary healthcare service in Sollentuna (Sweden) and agreed to participate in the programme between 1988 and 1993 were followed. They had at least one CV risk factor but no prior myocardial infarction and received support to increase physical activity using the programme Physical Activity on Prescription and to adopt health-promoting behaviours including cooking classes, weight reduction, smoking cessation and stress management. Participants (n=5761) were compared with a randomly selected, propensity score-matched reference group from the general population in Stockholm County (n=34 556). All individuals were followed in Swedish registers until December 2011. RESULTS: In the intervention group and the reference group there were 698 (12.1%) and 4647 (13.4%) first CV events, 308 (5.3%) and 2261 (6.5%) CV deaths, and 919 (16.5%) and 6405 (18.5%) all-cause deaths, respectively, during a mean follow-up of 22 years. The HR (95% CI) in the intervention group compared with the reference group was 0.88 (0.81 to 0.95) for first CV events, 0.79 (0.70 to 0.89) for CV deaths and 0.83 (0.78 to 0.89) for all-cause deaths. CONCLUSIONS: Participation in a CVD prevention programme in primary healthcare focusing on promotion of physical activity and healthy lifestyle was associated with lower risk of CV events (12%), CV deaths (21%) and all-cause deaths (17%) after two decades. Promoting physical activity and healthy living in the primary healthcare setting may prevent CVD.


Assuntos
Doenças Cardiovasculares/prevenção & controle , Exercício Físico , Promoção da Saúde/organização & administração , Estilo de Vida Saudável , Atenção Primária à Saúde/organização & administração , Prevenção Primária , Adulto , Doenças Cardiovasculares/mortalidade , Causas de Morte , Feminino , Seguimentos , Humanos , Estudos Longitudinais , Masculino , Pessoa de Meia-Idade , Suécia/epidemiologia
11.
Eur J Prev Cardiol ; : 2047487320916596, 2020 Apr 10.
Artigo em Inglês | MEDLINE | ID: mdl-32276576

RESUMO

AIMS: The purpose of this study was to analyse the association of leisure-time physical activity of different intensities at baseline, and cardiovascular disease incidence, cardiovascular disease mortality and all-cause mortality in a population-based sample of 60-year-old men and women with and without established metabolic syndrome, for more than 20 years of follow-up. A secondary aim was to study which cardiometabolic factors may mediate the association between physical activity and long-term outcomes. METHODS: A total of 3693 participants (53% women) underwent physical examination and laboratory tests, completed an extensive questionnaire at baseline 1997-1999 and were followed until their death or until 31 December 2017. First-time cardiovascular disease events and death from any cause were ascertained through regular examinations of national registers. RESULTS: Metabolic syndrome prevalence was 23.0%. In metabolic syndrome participants, light physical activity attenuated cardiovascular disease incidence (hazard ratio = 0.71; 95% confidence interval 0.50-1.00) compared to sedentary (reference) after multi-adjustment. Moderate/high physical activity was inversely associated with both cardiovascular disease and all-cause mortality, but became non-significant after multi-adjustment. Sedentary non-metabolic syndrome participants had lower cardiovascular disease incidence (0.47; 0.31-0.72) but not significantly different cardiovascular disease (0.61; 0.31-1.19) and all-cause mortality (0.92; 0.64-1.34) compared to sedentary metabolic syndrome participants. Both light and moderate/high physical activity were inversely associated with cardiovascular disease and all-cause mortality in non-metabolic syndrome participants (p<0.05). There were significant variations in several central cardiometabolic risk factors with physical activity level in non-metabolic syndrome participants. Fibrinogen mediated the protective effects of physical activity in non-metabolic syndrome participants. CONCLUSION: Physical activity of different intensities attenuated cardiovascular risk and mortality in 60-year old men and women with metabolic syndrome during a 20-year follow-up.

13.
Circ Res ; 126(5): 571-585, 2020 02 28.
Artigo em Inglês | MEDLINE | ID: mdl-31893970

RESUMO

RATIONALE: PCSKs (Proprotein convertase subtilisins/kexins) are a protease family with unknown functions in vasculature. Previously, we demonstrated PCSK6 upregulation in human atherosclerotic plaques associated with smooth muscle cells (SMCs), inflammation, extracellular matrix remodeling, and mitogens. OBJECTIVE: Here, we applied a systems biology approach to gain deeper insights into the PCSK6 role in normal and diseased vessel wall. METHODS AND RESULTS: Genetic analyses revealed association of intronic PCSK6 variant rs1531817 with maximum internal carotid intima-media thickness progression in high-cardiovascular risk subjects. This variant was linked with PCSK6 mRNA expression in healthy aortas and plaques but also with overall plaque SMA+ cell content and pericyte fraction. Increased PCSK6 expression was found in several independent human cohorts comparing atherosclerotic lesions versus healthy arteries, using transcriptomic and proteomic datasets. By immunohistochemistry, PCSK6 was localized to fibrous cap SMA+ cells and neovessels in plaques. In human, rat, and mouse intimal hyperplasia, PCSK6 was expressed by proliferating SMA+ cells and upregulated after 5 days in rat carotid balloon injury model, with positive correlation to PDGFB (platelet-derived growth factor subunit B) and MMP (matrix metalloprotease) 2/MMP14. Here, PCSK6 was shown to colocalize and cointeract with MMP2/MMP14 by in situ proximity ligation assay. Microarrays of carotid arteries from Pcsk6-/- versus control mice revealed suppression of contractile SMC markers, extracellular matrix remodeling enzymes, and cytokines/receptors. Pcsk6-/- mice showed reduced intimal hyperplasia response upon carotid ligation in vivo, accompanied by decreased MMP14 activation and impaired SMC outgrowth from aortic rings ex vivo. PCSK6 silencing in human SMCs in vitro leads to downregulation of contractile markers and increase in MMP2 expression. Conversely, PCSK6 overexpression increased PDGFBB (platelet-derived growth factor BB)-induced cell proliferation and particularly migration. CONCLUSIONS: PCSK6 is a novel protease that induces SMC migration in response to PDGFB, mechanistically via modulation of contractile markers and MMP14 activation. This study establishes PCSK6 as a key regulator of SMC function in vascular remodeling. Visual Overview: An online visual overview is available for this article.


Assuntos
Miócitos de Músculo Liso/metabolismo , Pró-Proteína Convertases/genética , Serina Endopeptidases/genética , Remodelação Vascular , Animais , Artérias Carótidas/metabolismo , Artérias Carótidas/patologia , Movimento Celular , Proliferação de Células , Células Cultivadas , Masculino , Metaloproteinases da Matriz/genética , Metaloproteinases da Matriz/metabolismo , Camundongos , Camundongos Endogâmicos C57BL , Miócitos de Músculo Liso/fisiologia , Polimorfismo de Nucleotídeo Único , Pró-Proteína Convertases/metabolismo , Proteínas Proto-Oncogênicas c-sis/metabolismo , Ratos , Ratos Sprague-Dawley , Serina Endopeptidases/metabolismo , Transcriptoma
14.
Genes Immun ; 21(2): 100-108, 2020 02.
Artigo em Inglês | MEDLINE | ID: mdl-31932740

RESUMO

The genes regulating circulating levels of soluble gp130 (sgp130), the antagonist of the inflammatory response in atherosclerosis driven by interleukin 6, are largely unknown. Aims of the present study were to identify genetic loci associated with circulating sgp130 and to explore the potential association between variants associated with sgp130 and markers of subclinical atherosclerosis. The study is based on IMPROVE (n = 3703), a cardiovascular multicentre study designed to investigate the determinants of carotid intima media thickness, a measure of subclinical atherosclerosis. Genomic DNA was genotyped by the CardioMetaboChip and ImmunoChip. About 360,842 SNPs were tested for association with log-transformed sgp130, using linear regression adjusted for age, gender, and population stratification using PLINK v1.07. A p value of 1 × 10-5 was chosen as threshold for significance value. In an exploratory analysis, SNPs associated with sgp130 were tested for association with c-IMT measures. We identified two SNPs significantly associated with sgp130 levels and 24 showing suggestive association with sgp130 levels. One SNP (rs17688225) on chromosome 14 was positively associated with sgp130 serum levels (ß = 0.03 SE = 0.007, p = 4.77 × 10-5) and inversely associated with c-IMT (c-IMTmean-max ß = -0.001 SE = 0.005, p = 0.0342). Our data indicate that multiple loci regulate sgp130 levels and suggest a possible common pathway between sgp130 and c-IMT measures.


Assuntos
Aterosclerose/sangue , Aterosclerose/genética , Receptor gp130 de Citocina/sangue , Receptor gp130 de Citocina/genética , Idoso , Aterosclerose/patologia , Biomarcadores/sangue , Espessura Intima-Media Carotídea , Feminino , Frequência do Gene , Loci Gênicos , Predisposição Genética para Doença , Variação Genética , Humanos , Interleucina-6/sangue , Interleucina-6/genética , Masculino , Pessoa de Meia-Idade , Polimorfismo de Nucleotídeo Único , Fatores de Risco
15.
Eur J Prev Cardiol ; 27(2): 122-129, 2020 01.
Artigo em Inglês | MEDLINE | ID: mdl-31438723

RESUMO

BACKGROUND: Interleukin 6 trans-signalling is independently associated with the risk of cardiovascular events. The aim of this study was to investigate if interleukin 6 trans-signalling can identify individuals at risk for cardiovascular events (coronary artery disease and ischaemic stroke) among those at-low-intermediate risk. METHODS: In a cohort of 60-year-olds (n = 4232, incident cardiovascular events n = 525), interleukin 6 trans-signalling was estimated by a ratio between the pro-inflammatory interleukin 6: soluble interleukin 6 receptor binary receptor complex and the inactivated interleukin 6: soluble interleukin 6 receptor: sgp130 ternary complex (B/T ratio). Risk associated with B/T ratio >median was investigated in individuals with low-density lipoprotein cholesterol ≤4.0 (mmol/l) and in those at low-intermediate risk according to the Framingham risk score (FRS) using Cox regression and expressed as hazard ratio and 95% confidence interval. Difference in time to event (years; 95% confidence interval) was analysed with quantile regression. The interaction between low-density lipoprotein cholesterol and B/T ratio was estimated on the additive scale. Incremental discriminatory value of the B/T ratio if low-density lipoprotein cholesterol ≤4.0 was compared to that of the FRS and interleukin 6. RESULTS: B/T ratio >median was associated with increased cardiovascular event risk when low-density lipoprotein cholesterol ≤4.0 (hazard ratio 1.59; 95% confidence interval 1.24-2.05) or FRS ≤ 10%, >10-≤20% (hazard ratio 1.27; 95% confidence interval 1.00-1.61 and hazard ratio 1.78; 95% confidence interval 1.36-2.34, respectively). B/T ratio >median and low-density lipoprotein cholesterol ≤4.0 were associated with early cardiovascular events, particularly ischaemic stroke. No interaction was observed between low-density lipoprotein cholesterol and the B/T ratio, both factors increasing cardiovascular event risk by 60%. In the presence of low-density lipoprotein cholesterol ≤4.0, the B/T ratio slightly improved discrimination measures. CONCLUSIONS: Interleukin 6 trans-signalling increases cardiovascular event risk in middle-aged men and women otherwise classified at low-intermediate cardiovascular risk.


Assuntos
Doenças Cardiovasculares/sangue , Interleucina-6/sangue , Receptores de Interleucina-6/sangue , Biomarcadores/sangue , Doenças Cardiovasculares/diagnóstico , Doenças Cardiovasculares/epidemiologia , LDL-Colesterol/sangue , Feminino , Fatores de Risco de Doenças Cardíacas , Humanos , Incidência , Masculino , Pessoa de Meia-Idade , Valor Preditivo dos Testes , Prognóstico , Estudos Prospectivos , Medição de Risco , Transdução de Sinais , Suécia/epidemiologia
16.
Eur J Nutr ; 59(5): 2089-2097, 2020 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-31350637

RESUMO

PURPOSE: Fatty acid composition in blood and adipose tissue (AT) is a useful biomarker of dietary fat quality. However, circulating saturated fatty acids (SFA) and monounsaturated fatty acids (MUFA) have been proposed to also reflect carbohydrate-induced de novo lipogenesis (DNL) and stearoyl-CoA desaturase (SCD) activity. We aimed to test the hypothesis that high carbohydrate intake is related to SFA and MUFA in serum or AT in a Swedish population. METHODS: Fatty acid composition was measured in serum phospholipids (PL) and AT by gas chromatography in 63-year-old men (n = 299). Carbohydrate and alcohol intake was assessed (validated 7-day food records) in relation to total SFA, 16:0 (palmitate), 16:1 (palmitoleate), and estimated SCD activity (16:1n-7/16:0-ratio) in serum PL and in AT, respectively. RESULTS: Total carbohydrate intake was inversely associated with 16:0 in PL (P = 0.005), independently of BMI. Disaccharides were non-linearly (restricted cubic splines) and weakly associated with 16:1 and SCD activity in PL (nonlinear trend, P ≤ 0.02) but not AT. Carbohydrate intake and SCD expression were not associated (P ≥ 0.08, n = 81). Alcohol intake was, however, linearly associated with 16:0 in PL (P < 0.001), and with 16:1 (P < 0.001) and SCD activity (P ≤ 0.005) in both PL and AT. CONCLUSIONS: Higher carbohydrate intake from sugar-rich foods or beverages was not clearly reflected by higher SFA or SCD activity in serum PL or AT. Alcohol was, however, associated with higher SFA and MUFA.


Assuntos
Ácidos Graxos , Fosfolipídeos , Tecido Adiposo , Carboidratos da Dieta , Ácidos Graxos Monoinsaturados , Humanos , Masculino , Pessoa de Meia-Idade , Estearoil-CoA Dessaturase , Suécia
17.
Data Brief ; 23: 103789, 2019 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-31372435

RESUMO

Data presented in this article are related to the research article entitled "A priori-defined Mediterranean-like dietary pattern predicts cardiovascular events better in north Europe than in Mediterranean countries" [Veglia et al., 2018]. Data contain information about the incidence of cardiovascular events in a high-risk European population (IMPROVE study) [Baldassarre et al., 2010, 2012, 2013]. Combined vascular events, as well as cardio- and cerebro-vascular events were stratified according to a priori-defined simple Mediterranean Diet (MD) score, based on just seven nutritional items (minimal adherence was 0 and maximal adherence was 7).

18.
Sci Rep ; 9(1): 7339, 2019 05 14.
Artigo em Inglês | MEDLINE | ID: mdl-31089183

RESUMO

CADM2 has been associated with a range of behavioural and metabolic traits, including physical activity, risk-taking, educational attainment, alcohol and cannabis use and obesity. Here, we set out to determine whether CADM2 contributes to mechanisms shared between mental and physical health disorders. We assessed genetic variants in the CADM2 locus for association with phenotypes in the UK Biobank, IMPROVE, PROCARDIS and SCARFSHEEP studies, before performing meta-analyses. A wide range of metabolic phenotypes were meta-analysed. Psychological phenotypes analysed in UK Biobank only were major depressive disorder, generalised anxiety disorder, bipolar disorder, neuroticism, mood instability and risk-taking behaviour. In UK Biobank, four, 88 and 172 genetic variants were significantly (p < 1 × 10-5) associated with neuroticism, mood instability and risk-taking respectively. In meta-analyses of 4 cohorts, we identified 362, 63 and 11 genetic variants significantly (p < 1 × 10-5) associated with BMI, SBP and CRP respectively. Genetic effects on BMI, CRP and risk-taking were all positively correlated, and were consistently inversely correlated with genetic effects on SBP, mood instability and neuroticism. Conditional analyses suggested an overlap in the signals for physical and psychological traits. Many significant variants had genotype-specific effects on CADM2 expression levels in adult brain and adipose tissues. CADM2 variants influence a wide range of both psychological and metabolic traits, suggesting common biological mechanisms across phenotypes via regulation of CADM2 expression levels in adipose tissue. Functional studies of CADM2 are required to fully understand mechanisms connecting mental and physical health conditions.


Assuntos
Transtornos de Ansiedade/genética , Transtorno Bipolar/genética , Moléculas de Adesão Celular/genética , Transtorno Depressivo Maior/genética , Obesidade/genética , Afeto , Idoso , Feminino , Predisposição Genética para Doença , Variação Genética , Humanos , Masculino , Pessoa de Meia-Idade , Neuroticismo , Polimorfismo de Nucleotídeo Único , Locos de Características Quantitativas , Assunção de Riscos
19.
Circulation ; 139(21): 2422-2436, 2019 05 21.
Artigo em Inglês | MEDLINE | ID: mdl-30971107

RESUMO

BACKGROUND: Global dietary recommendations for and cardiovascular effects of linoleic acid, the major dietary omega-6 fatty acid, and its major metabolite, arachidonic acid, remain controversial. To address this uncertainty and inform international recommendations, we evaluated how in vivo circulating and tissue levels of linoleic acid (LA) and arachidonic acid (AA) relate to incident cardiovascular disease (CVD) across multiple international studies. METHODS: We performed harmonized, de novo, individual-level analyses in a global consortium of 30 prospective observational studies from 13 countries. Multivariable-adjusted associations of circulating and adipose tissue LA and AA biomarkers with incident total CVD and subtypes (coronary heart disease, ischemic stroke, cardiovascular mortality) were investigated according to a prespecified analytic plan. Levels of LA and AA, measured as the percentage of total fatty acids, were evaluated linearly according to their interquintile range (ie, the range between the midpoint of the first and fifth quintiles), and categorically by quintiles. Study-specific results were pooled using inverse-variance-weighted meta-analysis. Heterogeneity was explored by age, sex, race, diabetes mellitus, statin use, aspirin use, omega-3 levels, and fatty acid desaturase 1 genotype (when available). RESULTS: In 30 prospective studies with medians of follow-up ranging 2.5 to 31.9 years, 15 198 incident cardiovascular events occurred among 68 659 participants. Higher levels of LA were significantly associated with lower risks of total CVD, cardiovascular mortality, and ischemic stroke, with hazard ratios per interquintile range of 0.93 (95% CI, 0.88-0.99), 0.78 (0.70-0.85), and 0.88 (0.79-0.98), respectively, and nonsignificantly with lower coronary heart disease risk (0.94; 0.88-1.00). Relationships were similar for LA evaluated across quintiles. AA levels were not associated with higher risk of cardiovascular outcomes; in a comparison of extreme quintiles, higher levels were associated with lower risk of total CVD (0.92; 0.86-0.99). No consistent heterogeneity by population subgroups was identified in the observed relationships. CONCLUSIONS: In pooled global analyses, higher in vivo circulating and tissue levels of LA and possibly AA were associated with lower risk of major cardiovascular events. These results support a favorable role for LA in CVD prevention.


Assuntos
Ácido Araquidônico/sangue , Doenças Cardiovasculares/sangue , Dieta Saudável , Gorduras na Dieta/sangue , Ácido Linoleico/sangue , Prevenção Primária/métodos , Comportamento de Redução do Risco , Idoso , Biomarcadores/sangue , Doenças Cardiovasculares/diagnóstico , Doenças Cardiovasculares/mortalidade , Doenças Cardiovasculares/prevenção & controle , Gorduras na Dieta/administração & dosagem , Feminino , Humanos , Ácido Linoleico/administração & dosagem , Masculino , Pessoa de Meia-Idade , Valor Nutritivo , Estudos Observacionais como Assunto , Fatores de Proteção , Recomendações Nutricionais , Medição de Risco , Fatores de Risco
20.
Occup Environ Med ; 76(4): 201-207, 2019 04.
Artigo em Inglês | MEDLINE | ID: mdl-30804165

RESUMO

BACKGROUND: There is limited evidence from longitudinal studies on transportation noise from different sources and development of ischaemic heart disease (IHD) and stroke. OBJECTIVES: This cohort study assessed associations between exposure to noise from road traffic, railway or aircraft and incidence of IHD and stroke. METHODS: In a cohort of 20 012 individuals from Stockholm County, we estimated long-term residential exposure to road traffic, railway and aircraft noise. National Patient and Cause-of-Death Registers were used to identify IHD and stroke events. Information on risk factors was obtained from questionnaires and registers. Adjusted HR for cardiovascular outcomes related to source-specific noise exposure were computed using Cox proportional hazards regression. RESULTS: No clear or consistent associations were observed between transportation noise and incidence of IHD or stroke. However, noise exposure from road traffic and aircraft was related to IHD incidence in women, with HR of 1.11 (95% CI 1.00 to 1.22) and 1.25 (95% CI 1.09 to 1.44) per 10 dB Lden, respectively. For both sexes taken together, we observed a particularly high risk of IHD in those exposed to all three transportation noise sources at≥45 dB Lden, with a HR of 1.57 (95% CI 1.06 to 2.32), and a similar tendency for stroke (HR 1.42; 95% CI 0.87 to 2.32). CONCLUSION: No overall associations were observed between transportation noise exposure and incidence of IHD or stroke. However, there appeared to be an increased risk of IHD in women exposed to road traffic or aircraft noise as well as in those exposed to multiple sources of transportation noise.


Assuntos
Incidência , Isquemia Miocárdica/epidemiologia , Ruído dos Transportes/efeitos adversos , Acidente Vascular Cerebral/epidemiologia , Adulto , Estudos de Coortes , Feminino , Humanos , Estudos Longitudinais , Masculino , Pessoa de Meia-Idade , Isquemia Miocárdica/etiologia , Ruído/efeitos adversos , Fatores de Risco , Acidente Vascular Cerebral/etiologia , Suécia/epidemiologia
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