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- Hageman, S., et al.
(författare)
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SCORE2 risk prediction algorithms: new models to estimate 10-year risk of cardiovascular disease in Europe
- 2021
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Ingår i: European Heart Journal. - : Oxford University Press (OUP). - 0195-668X .- 1522-9645. ; 42:25, s. 2439-2454
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Tidskriftsartikel (refereegranskat)abstract
- Aims The aim of this study was to develop, validate, and illustrate an updated prediction model (SCORE2) to estimate 10-year fatal and non-fatal cardiovascular disease (CVD) risk in individuals without previous CVD or diabetes aged 40-69 years in Europe. Methods and results We derived risk prediction models using individual-participant data from 45 cohorts in 13 countries (677 684 individuals, 30 121 CVD events). We used sex-specific and competing risk-adjusted models, including age, smoking status, systolic blood pressure, and total- and HDL-cholesterol. We defined four risk regions in Europe according to country-specific CVD mortality, recalibrating models to each region using expected incidences and risk factor distributions. Region-specific incidence was estimated using CVD mortality and incidence data on 10 776 466 individuals. For external validation, we analysed data from 25 additional cohorts in 15 European countries (1 133 181 individuals, 43 492 CVD events). After applying the derived risk prediction models to external validation cohorts, C-indices ranged from 0.67 (0.65-0.68) to 0.81 (0.76-0.86). Predicted CVD risk varied several-fold across European regions. For example, the estimated 10-year CVD risk for a 50-year-old smoker, with a systolic blood pressure of 140 mmHg, total cholesterol of 5.5 mmol/L, and HDL-cholesterol of 1.3 mmol/L, ranged from 5.9% for men in low- risk countries to 14.0% for men in very high-risk countries, and from 4.2% for women in low-risk countries to 13.7% for women in very high-risk countries. Conclusion SCORE2-a new algorithm derived, calibrated, and validated to predict 10-year risk of first-onset CVD in European populations-enhances the identification of individuals at higher risk of developing CVD across Europe.
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| 2. |
- Zegeye, Mulugeta M, 1986-, et al.
(författare)
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IL-6 as a Mediator of the Association Between Traditional Risk Factors and Future Myocardial Infarction : A Nested Case-Control Study
- 2021
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Ingår i: Arteriosclerosis, Thrombosis and Vascular Biology. - : Lippincott Williams & Wilkins. - 1079-5642 .- 1524-4636. ; 41:4, s. 1570-1579
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Tidskriftsartikel (refereegranskat)abstract
- OBJECTIVE: Studies elucidating the importance of IL (interleukin)-6 trans-signaling associated with risk of future myocardial infarction (MI) are scarce. Additionally, whether elevation in IL-6 explains part of the association between traditional risk factors and future MI has not been explored.Approach and Results: We conducted a nested case-control study including a total of 584 participants (292 cases and 292 controls) from Västerbotten Intervention Programme and MONICA (Multinational Monitoring of Trends and Determinants in Cardiovascular Disease) cohorts. At baseline, plasma cholesterol levels were measured, and clinical characteristics of participants were collected. In this study, we measured the plasma concentration of IL-6, sIL-6R (soluble IL-6 receptor), and sgp130 (soluble-gp130). To estimate extent of IL-6 trans-signaling, we estimated plasma concentration of a novel biomarker, the IL-6 binary complex. IL-6 binary complex concentration was significantly elevated in participants who experienced MI compared with those who did not. Univariate analyses showed that a 2-fold increase in IL-6 binary complex was associated with 2.45× higher risk of future MI (95% CI relative risk, 1.65-3.66, P<0.001). Receiver operating characteristics analyses revealed that the predictive performance of IL-6 binary complex (area under the curve, 0.614) was equivalent to that of IL-6 (area under the curve, 0.603). Furthermore, using Process mediation analyses tool, we found statistically significant indirect effect of smoking and hypertension on future MI that is mediated through increased IL-6 binary complex or plasma IL-6.CONCLUSIONS: IL-6 and IL-6 binary complex concentration in plasma were significantly associated with future MI. Our data additionally imply that both the elevated plasma IL-6, and the IL-6 binary complex concentration could partly explain, and, thus, might hypothetically be functionally associated with the increased risk of MI in smokers and hypertensive participants.
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| 3. |
- Zegeye, Mulugeta M, 1986-, et al.
(författare)
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Soluble LDL-receptor is induced by TNF-α and inhibits hepatocytic clearance of LDL-cholesterol
- 2023
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Ingår i: Journal of Molecular Medicine. - : Springer. - 0946-2716 .- 1432-1440. ; 101:12, s. 1615-1626
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Tidskriftsartikel (refereegranskat)abstract
- Defective LDL-C clearance and hence its elevation in the circulation is an established risk factor for cardiovascular diseases (CVDs) such as myocardial infarction (MI). A soluble LDL-receptor (sLDL-R) has been detected in human plasma which correlates strongly with circulating LDL-C and classical conditions that promote chronic inflammation. However, the mechanistic interplay between sLDL-R, inflammation, and CVDs remains to be investigated. Here, we report that stimulation of HepG2 cells with TNF-α induces the release of sLDL-R into culture supernatants. In addition, TNF-α induces gene expression of peptidases ADAM-17 and MMP-14 in HepG2 cells, and inhibiting these peptidases using TMI 1 significantly reduces the TNF-α induced sLDL-R release. We found that a soluble form of recombinant LDL-R (100 nM) can strongly bind to LDL-C and form a stable complex (KD = E-12). Moreover, incubation of HepG2 cells with this recombinant LDL-R resulted in reduced LDL-C uptake in a dose-dependent manner. In a nested case-control study, we found that baseline sLDL-R in plasma is positively correlated with plasma total cholesterol level. Furthermore, a twofold increase in plasma sLDL-R was associated with a 55% increase in the risk of future MI [AOR = 1.55 (95% CI = 1.10-2.18)]. Nevertheless, mediation analyses revealed that a significant proportion of the association is mediated by elevation in plasma cholesterol level (indirect effect β = 0.21 (95% CI = 0.07-0.38). Collectively, our study shows that sLDL-R is induced by a pro-inflammatory cytokine TNF-α via membrane shedding. Furthermore, an increase in sLDL-R could inhibit hepatic clearance of LDL-C increasing its half-life in the circulation and contributing to the pathogenesis of MI. KEY MESSAGES: TNF-α causes shedding of hepatocytic LDL-R through induction of ADAM-17 and MMP-14. sLDL-R binds strongly to LDL-C and inhibits its uptake by hepatocytic cells. Plasma sLDL-R is positively correlated with TNF-α and cholesterol. Plasma sLDL-R is an independent predictor of myocardial infarction (MI). Plasma cholesterol mediates the association between sLDL-R and MI.
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