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- Marklund, Matti, et al.
(författare)
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Biomarkers of Dietary Omega-6 Fatty Acids and Incident Cardiovascular Disease and Mortality : An Individual-Level Pooled Analysis of 30 Cohort Studies
- 2019
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Ingår i: Circulation. - : American Heart Association. - 0009-7322 .- 1524-4539. ; 139:21, s. 2422-2436
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Tidskriftsartikel (refereegranskat)abstract
- 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, 15198 incident cardiovascular events occurred among 68659 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.
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| 3. |
- Rykaczewska, Urszula, et al.
(författare)
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PCSK6 Is a Key Protease in the Control of Smooth Muscle Cell Function in Vascular Remodeling
- 2020
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Ingår i: Circulation Research. - : LIPPINCOTT WILLIAMS & WILKINS. - 0009-7330 .- 1524-4571. ; 126:5, s. 571-585
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Tidskriftsartikel (refereegranskat)abstract
- 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.
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| 4. |
- Stenestrand, Ulf, 1961-
(författare)
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Improving outcome in acute myocardial infarction
- 2002
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Doktorsavhandling (övrigt vetenskapligt/konstnärligt)abstract
- Background: Despite common guidelines there are vanatlons in the treatment of acute myocardial infarction (AMI) between hospitals in Sweden. Uncertainties remain regarding the efficacy of early statin therapy and early revascularisation in AMI patients. In the elderly patients also the role of fibrinolytic therapy has been questioned.Methods: We created a national quality assurance register named RIKS-HIA including all patients admitted to participating hospitals' ICCU. The database accumulates information about baseline characteristics, interventions, complications and outcome in consecutive patients. The merging of the database with the Cause of Death Register provides opportunity to compare the effects of treatments on long-term outcome. Multivariate Cox regression analysis and propensity score was used to evaluate outcome in AMI patients of the studied interventions, and to compare activity level between different hospitals.Results: After patient characteristics were taken into account there were still significant differences between the hospitals in some treatment modalities that remained over time. There was no correlation between hospital size and activity level. In 19 599 in-hospital survivors after their first registry-recorded AMI at an age below 80 years early statin treatment was associated with a 25 % relative risk reduction of I-year mortality. In 21 912 patients with first registry-recorded AMI younger than 80 years and alive at day 14, early revascularisation was associated with a 50 % relative reduction of I-year mortality. For both therapies the effects were homogeneous among all subgroups based on age, gender, baseline characteristics, previous disease manifestations and medication. Fibrinolytic therapy in ST-segment elevation myocardial infarction patients 75 years of age and older showed a net benefit of 13% in outcome when non-fatal intracranial haemorrhage and I-year survival were analysed.Conclusion: The results indicates the need of continuous quality assurance, and strategies to reduce the differences in AMI therapy between hospitals. They lend support to early statin and early revascularisation regimens in AMI patients. Fibrinolytic therapy is recommended also in the elderly patients.
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| 5. |
- Bergström, Göran, 1964, et al.
(författare)
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Prevalence of Subclinical Coronary Artery Atherosclerosis in the General Population
- 2021
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Ingår i: Circulation. - Philadelphia : American Heart Association. - 0009-7322 .- 1524-4539. ; 144:12, s. 916-929
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Tidskriftsartikel (refereegranskat)abstract
- 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.
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| 6. |
- Söderberg, Stefan, 1957-
(författare)
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Leptin : a risk marker for cardiovascular disease
- 1999
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Doktorsavhandling (övrigt vetenskapligt/konstnärligt)abstract
- A major cause of morbidity and early death in the Western societies is cardiovascular disease (CVD) secondary to atherosclerotic disease. Metabolic aberrations have been linked to CVD. Particular combinations of these so-called risk markers are common and (central) obesity, Type 2 diabetes, impaired glucose tolerance, hypertension, dyslipidemia, dysfibrinolysis and hyperinsulinemia are often associated. This has been entitled the Insulin Resistance Syndrome (1RS), due to underlying insulin resistance. Moreover, aberrations in circulating levels of androgens and IGF-binding proteins are associated with 1RS.The main hypothesis in this thesis was that increased levels of leptin, the recently discovered adipocyte derived hormone in combination with obesity may be an important factor in the link between 1RS and the development of CVD.The association between leptin levels and variables associated with the Insulin Resistance Syndrome was studied in a healthy sample (n=163) of middle-aged men and women from the northern Sweden MONICA health survey. Central obesity was associated with high levels of leptin and insulin in men and women. In contrast, central obesity was linked to low testosterone levels in men, whereas in women, central obesity was associated with high testosterone but low SHBG levels. Furthermore, in males and postmenopausal women central obesity was a major determinant for circulating leptin. Leptin levels were associated with biochemical androgenicity in non-obese men and women. The direction of this association was dependent on gender and body fat distribution. Specifically, testosterone was inversely associated to leptin in non-obese men and in normal weight women whereas testosterone was positively associated to leptin in non-obese women. In contrast, adiposity and insulin levels, but not testosterone, were associated to leptin in obese men and women. Similarly, leptin was associated to IGFBP-1 and proinsulin in non-obese men and premenopausal women. Hyperleptinemia was significantly associated to high PAI-1 levels in men and in centrally obese women. In a multivariate model, high leptin levels predicted PAI-1 levels in men but not in women. Finally, leptin levels were related to blood pressure in obese men.The impact of hyperleptinemia on future risk for development of CVD was tested in a nested case-referent study based on the MONICA and the Västerbotten Intervention Program surveys. It was found that hyperleptinemia and high total cholesterol levels were associated with increased risk for development of myocardial infarction whereas high levels of apolipoprotein A-l were protective. Hyperleptinemia together with hypertension remained as significant risk markers for hemorrhagic stroke whereas hypertension alone predicted ischemic stroke. The combinations of hyperleptinemia on one hand and low apolipoprotein A- 1 and high blood pressure on the other were associated with a pronounced increased risk for myocardial infarction and hemorrhagic stroke, respectively.In conclusion, hyperleptinemia is independently associated with several risk markers for CVD included in the insulin resistance syndrome. Furthermore, high leptin levels predict the development of CVD.
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