| 1. |
- Clark, DW, et al.
(författare)
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Associations of autozygosity with a broad range of human phenotypes
- 2019
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Ingår i: Nature communications. - : Springer Science and Business Media LLC. - 2041-1723. ; 10:1, s. 4957-
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Tidskriftsartikel (refereegranskat)abstract
- In many species, the offspring of related parents suffer reduced reproductive success, a phenomenon known as inbreeding depression. In humans, the importance of this effect has remained unclear, partly because reproduction between close relatives is both rare and frequently associated with confounding social factors. Here, using genomic inbreeding coefficients (FROH) for >1.4 million individuals, we show that FROH is significantly associated (p < 0.0005) with apparently deleterious changes in 32 out of 100 traits analysed. These changes are associated with runs of homozygosity (ROH), but not with common variant homozygosity, suggesting that genetic variants associated with inbreeding depression are predominantly rare. The effect on fertility is striking: FROH equivalent to the offspring of first cousins is associated with a 55% decrease [95% CI 44–66%] in the odds of having children. Finally, the effects of FROH are confirmed within full-sibling pairs, where the variation in FROH is independent of all environmental confounding.
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| 2. |
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| 5. |
- Locke, Adam E, et al.
(författare)
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Genetic studies of body mass index yield new insights for obesity biology.
- 2015
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Ingår i: Nature. - : Springer Science and Business Media LLC. - 0028-0836 .- 1476-4687. ; 518:7538, s. 197-401
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Tidskriftsartikel (refereegranskat)abstract
- Obesity is heritable and predisposes to many diseases. To understand the genetic basis of obesity better, here we conduct a genome-wide association study and Metabochip meta-analysis of body mass index (BMI), a measure commonly used to define obesity and assess adiposity, in up to 339,224 individuals. This analysis identifies 97 BMI-associated loci (P < 5 × 10(-8)), 56 of which are novel. Five loci demonstrate clear evidence of several independent association signals, and many loci have significant effects on other metabolic phenotypes. The 97 loci account for ∼2.7% of BMI variation, and genome-wide estimates suggest that common variation accounts for >20% of BMI variation. Pathway analyses provide strong support for a role of the central nervous system in obesity susceptibility and implicate new genes and pathways, including those related to synaptic function, glutamate signalling, insulin secretion/action, energy metabolism, lipid biology and adipogenesis.
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| 6. |
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| 7. |
- den Ruijter, H. M., et al.
(författare)
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Common carotid intima-media thickness does not add to Framingham risk score in individuals with diabetes mellitus: the USE-IMT initiative
- 2013
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Ingår i: Diabetologia. - : Springer Science and Business Media LLC. - 1432-0428 .- 0012-186X. ; 56:7, s. 1494-1502
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Tidskriftsartikel (refereegranskat)abstract
- The aim of this work was to investigate whether measurement of the mean common carotid intima-media thickness (CIMT) improves cardiovascular risk prediction in individuals with diabetes. We performed a subanalysis among 4,220 individuals with diabetes in a large ongoing individual participant data meta-analysis involving 56,194 subjects from 17 population-based cohorts worldwide. We first refitted the risk factors of the Framingham heart risk score on the individuals without previous cardiovascular disease (baseline model) and then expanded this model with the mean common CIMT (CIMT model). The absolute 10 year risk for developing a myocardial infarction or stroke was estimated from both models. In individuals with diabetes we compared discrimination and calibration of the two models. Reclassification of individuals with diabetes was based on allocation to another cardiovascular risk category when mean common CIMT was added. During a median follow-up of 8.7 years, 684 first-time cardiovascular events occurred among the population with diabetes. The C statistic was 0.67 for the Framingham model and 0.68 for the CIMT model. The absolute 10 year risk for developing a myocardial infarction or stroke was 16% in both models. There was no net reclassification improvement with the addition of mean common CIMT (1.7%; 95% CI -1.8, 3.8). There were no differences in the results between men and women. There is no improvement in risk prediction in individuals with diabetes when measurement of the mean common CIMT is added to the Framingham risk score. Therefore, this measurement is not recommended for improving individual cardiovascular risk stratification in individuals with diabetes.
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| 8. |
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| 9. |
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| 10. |
- Frazier-Wood, Alexis C., et al.
(författare)
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Genetic variants associated with subjective well-being, depressive symptoms, and neuroticism identified through genome-wide analyses
- 2016
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Ingår i: Nature Genetics. - : Nature Research (part of Springer Nature). - 1061-4036 .- 1546-1718. ; 48, s. 624-
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Tidskriftsartikel (refereegranskat)abstract
- Very few genetic variants have been associated with depression and neuroticism, likely because of limitations on sample size in previous studies. Subjective well-being, a phenotype that is genetically correlated with both of these traits, has not yet been studied with genome-wide data. We conducted genome-wide association studies of three phenotypes: subjective well-being (n = 298,420), depressive symptoms (n = 161,460), and neuroticism (n = 170,911). We identify 3 variants associated with subjective well-being, 2 variants associated with depressive symptoms, and 11 variants associated with neuroticism, including 2 inversion polymorphisms. The two loci associated with depressive symptoms replicate in an independent depression sample. Joint analyses that exploit the high genetic correlations between the phenotypes (vertical bar(p) over cap vertical bar approximate to 0.8) strengthen the overall credibility of the findings and allow us to identify additional variants. Across our phenotypes, loci regulating expression in central nervous system and adrenal or pancreas tissues are strongly enriched for association.
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| 11. |
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| 12. |
- Bots, Michiel L., et al.
(författare)
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Common Carotid Intima-Media Thickness Measurements Do Not Improve Cardiovascular Risk Prediction in Individuals With Elevated Blood Pressure The USE-IMT Collaboration
- 2014
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Ingår i: Hypertension. - 1524-4563. ; 63:6, s. 1173-1181
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Tidskriftsartikel (refereegranskat)abstract
- Carotid intima-media thickness (CIMT) is a marker of cardiovascular risk. It is unclear whether measurement of mean common CIMT improves 10-year risk prediction of first-time myocardial infarction or stroke in individuals with elevated blood pressure. We performed an analysis among individuals with elevated blood pressure (ie, a systolic blood pressure 140 mm Hg and a diastolic blood pressure 90 mm Hg) in USE-IMT, a large ongoing individual participant data meta-analysis. We refitted the risk factors of the Framingham Risk Score on asymptomatic individuals (baseline model) and expanded this model with mean common CIMT (CIMT model) measurements. From both models, 10-year risks to develop a myocardial infarction or stroke were estimated. In individuals with elevated blood pressure, we compared discrimination and calibration of the 2 models and calculated the net reclassification improvement (NRI). We included 17 254 individuals with elevated blood pressure from 16 studies. During a median follow-up of 9.9 years, 2014 first-time myocardial infarctions or strokes occurred. The C-statistics of the baseline and CIMT models were similar (0.73). NRI with the addition of mean common CIMT was small and not significant (1.4%; 95% confidence intervals, -1.1 to 3.7). In those at intermediate risk (n=5008, 10-year absolute risk of 10% to 20%), the NRI was 5.6% (95% confidence intervals, 1.6-10.4). There is no added value of measurement of mean common CIMT in individuals with elevated blood pressure for improving cardiovascular risk prediction. For those at intermediate risk, the addition of mean common CIMT to an existing cardiovascular risk score is small but statistically significant.
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| 13. |
- Wang, X., et al.
(författare)
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Clustering of cardiovascular risk factors and carotid intima-media thickness: The USE-IMT study
- 2017
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Ingår i: Plos One. - : Public Library of Science (PLoS). - 1932-6203. ; 12:3
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Tidskriftsartikel (refereegranskat)abstract
- Background The relation of a single risk factor with atherosclerosis is established. Clinically we know of risk factor clustering within individuals. Yet, studies into the magnitude of the relation of risk factor clusters with atherosclerosis are limited. Here, we assessed that relation. Individual participant data from 14 cohorts, involving 59,025 individuals were used in this cross-sectional analysis. We made 15 clusters of four risk factors (current smoking, overweight, elevated blood pressure, elevated total cholesterol). Multilevel age and sex adjusted linear regression models were applied to estimate mean differences in common carotid intima-media thickness (CIMT) between clusters using those without any of the four risk factors as reference group. Compared to the reference, those with 1, 2, 3 or 4 risk factors had a significantly higher common CIMT: mean difference of 0.026 mm, 0.052 mm, 0.074 mm and 0.114 mm, respectively. These findings were the same in men and in women, and across ethnic groups. Within each risk factor cluster (1, 2, 3 risk factors), groups with elevated blood pressure had the largest CIMT and those with elevated cholesterol the lowest CIMT, a pattern similar for men and women. Clusters of risk factors relate to increased common CIMT in a graded manner, similar in men, women and across race-ethnic groups. Some clusters seemed more atherogenic than others. Our findings support the notion that cardiovascular prevention should focus on sets of risk factors rather than individual levels alone, but may prioritize within clusters.
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| 14. |
- Eikendal, Anouk L M, et al.
(författare)
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Common Carotid Intima-Media Thickness Relates to Cardiovascular Events in Adults Aged
- 2015
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Ingår i: Hypertension. - 1524-4563. ; 65:4, s. 707-707
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Tidskriftsartikel (refereegranskat)abstract
- Although atherosclerosis starts in early life, evidence on risk factors and atherosclerosis in individuals aged <45 years is scarce. Therefore, we studied the relationship between risk factors, common carotid intima-media thickness (CIMT), and first-time cardiovascular events in adults aged <45 years. Our study population consisted of 3067 adults aged <45 years free from symptomatic cardiovascular disease at baseline, derived from 6 cohorts that are part of the USE-IMT initiative, an individual participant data meta-analysis of general-population-based cohort studies evaluating CIMT measurements. Information on risk factors, CIMT measurements, and follow-up of the combined end point (first-time myocardial infarction or stroke) was obtained. We assessed the relationship between risk factors and CIMT and the relationship between CIMT and first-time myocardial infarction or stroke using a multivariable linear mixed-effects model and a Cox proportional-hazards model, respectively. During a follow-up of 16.3 years, 55 first-time myocardial infarctions or strokes occurred. Median CIMT was 0.63 mm. Of the risk factors under study, age, sex, diastolic blood pressure, body mass index, total cholesterol, and high-density lipoprotein cholesterol related to CIMT. Furthermore, CIMT related to first-time myocardial infarction or stroke with a hazard ratio of 1.40 per SD increase in CIMT, independent of risk factors (95% confidence interval, 1.11-1.76). CIMT may be a valuable marker for cardiovascular risk in adults aged <45 years who are not yet eligible for standard cardiovascular risk screening. This is especially relevant in those with an increased, unfavor-able risk factor burden.
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| 15. |
- Gijsberts, Crystel M, et al.
(författare)
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Race/Ethnic Differences in the Associations of the Framingham Risk Factors with Carotid IMT and Cardiovascular Events.
- 2015
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Ingår i: PLoS ONE. - : Public Library of Science (PLoS). - 1932-6203. ; 10:7
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Tidskriftsartikel (refereegranskat)abstract
- Clinical manifestations and outcomes of atherosclerotic disease differ between ethnic groups. In addition, the prevalence of risk factors is substantially different. Primary prevention programs are based on data derived from almost exclusively White people. We investigated how race/ethnic differences modify the associations of established risk factors with atherosclerosis and cardiovascular events.
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| 16. |
- Den Ruijter, Hester M., et al.
(författare)
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Common Carotid Intima-Media Thickness Measurements in Cardiovascular Risk Prediction A Meta-analysis
- 2012
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Ingår i: JAMA: The Journal of the American Medical Association. - : American Medical Association (AMA). - 1538-3598. ; 308:8, s. 796-803
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Tidskriftsartikel (refereegranskat)abstract
- Context The evidence that measurement of the common carotid intima-media thickness (CIMT) improves the risk scores in prediction of the absolute risk of cardiovascular events is inconsistent. Objective To determine whether common CIMT has added value in 10-year risk prediction of first-time myocardial infarctions or strokes, above that of the Framingham Risk Score. Data Sources Relevant studies were identified through literature searches of databases (PubMed from 1950 to June 2012 and EMBASE from 1980 to June 2012) and expert opinion. Study Selection Studies were included if participants were drawn from the general population, common CIMT was measured at baseline, and individuals were followed up for first-time myocardial infarction or stroke. Data Extraction Individual data were combined into 1 data set and an individual participant data meta-analysis was performed on individuals without existing cardiovascular disease. Results We included 14 population-based cohorts contributing data for 45 828 individuals. During a median follow-up of 11 years, 4007 first-time myocardial infarctions or strokes occurred. We first refitted the risk factors of the Framingham Risk Score and then extended the model with common CIMT measurements to estimate the absolute 10-year risks to develop a first-time myocardial infarction or stroke in both models. The C statistic of both models was similar (0.757; 95% CI, 0.749-0.764; and 0.759; 95% CI, 0.752-0.766). The net reclassification improvement with the addition of common CIMT was small (0.8%; 95% CI, 0.1%-1.6%). In those at intermediate risk, the net reclassification improvement was 3.6% in all individuals (95% CI, 2.7%-4.6%) and no differences between men and women. Conclusion The addition of common CIMT measurements to the Framingham Risk Score was associated with small improvement in 10-year risk prediction of first-time myocardial infarction or stroke, but this improvement is unlikely to be of clinical importance. JAMA. 2012;308(8):796-803 www.jama.com
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| 17. |
- Peters, S. A. E., et al.
(författare)
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Increased age, high body mass index and low HDL-C levels are related to an echolucent carotid intima-media : the METEOR study
- 2012
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Ingår i: Journal of Internal Medicine. - : Wiley. - 0954-6820 .- 1365-2796. ; 272:3, s. 257-266
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Tidskriftsartikel (refereegranskat)abstract
- Introduction. Echolucent plaques are related to a higher cardiovascular risk. Studies to investigate the relationship between echolucency and cardiovascular risk in the early stages of atherosclerosis are limited. We studied the relationship between cardiovascular risk factors and echolucency of the carotid intimamedia in low-risk individuals.Methods. Data were analysed from the Measuring Effects on Intima-Media Thickness: an Evaluation of Rosuvastatin (METEOR) study, a randomized placebo-controlled trial including 984 individuals which showed that rosuvastatin attenuated the rate of change of carotid intimamedia thickness (CIMT). In this post hoc analysis, duplicate baseline ultrasound images from the far wall of the left and right common carotid arteries were used for the evaluation of the echolucency of the carotid intimamedia, measured by grey-scale median (GSM) on a scale of 0256. Low GSM values reflect echolucent, whereas high values reflect echogenic structures. The relationship between baseline GSM and cardiovascular risk factors was evaluated using linear regression models.Results. Mean baseline GSM (+/- SD) was 84 +/- 29. Lower GSM of the carotid intimamedia was associated with older age, high body mass index (BMI) and low levels of high-density lipoprotein cholesterol (HDL-C) [beta -4.49, 95% confidence interval (CI) -6.50 to -2.49; beta -4.51, 95% CI -6.43 to -2.60; beta 2.45, 95% CI 0.47 to 4.42, respectively]. Common CIMT was inversely related to GSM of the carotid intimamedia (beta -3.94, 95% CI -1.98 to -5.89).Conclusion. Older age, high BMI and low levels of HDL-C are related to echolucency of the carotid intimamedia. Hence, echolucency of the carotid intimamedia may be used as a marker of cardiovascular risk profile to provide more information than thickness alone.
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| 18. |
- Peters, S A E, et al.
(författare)
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Manual or semi-automated edge detection of the maximal far wall common carotid intima-media thickness : a direct comparison
- 2012
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Ingår i: Journal of Internal Medicine. - : Wiley. - 0954-6820 .- 1365-2796. ; 271:3, s. 247-256
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Tidskriftsartikel (refereegranskat)abstract
- Background: Automated edge detection is thought to be superior to manual edge detection in quantification of the far wall common carotid intima-media thickness (CIMT), yet published evidence making a direct comparison is not available. Methods: Data were used from the METEOR study, a randomized placebo-controlled trial among 984 individuals showing that rosuvastatin attenuated the rate of change of 2 year change in CIMT among low-risk individuals with subclinical atherosclerosis. For this post hoc analysis, CIMT images of the far wall of the common carotid artery were evaluated using manual and semi-automated edge detection and reproducibility, relation to cardiovascular risk factors, rates of change over time and effects of lipid-lowering therapy were assessed. Results: Reproducibility was high for both reading methods. Direction, magnitude and statistical significance of risk factor relations were similar across methods. Rate of change in CIMT in participants assigned to placebo was 0.0066 mm per year (SE: 0.0027) for manually and 0.0072 mm per year (SE: 0.0029) for semi-automatically read images. The effect of lipid-lowering therapy on CIMT changes was -0.0103 mm per year (SE: 0.0032) for manual reading and -0.0111 mm per year (SE: 0.0034) for semi-automated reading. Conclusion: Manual and semi-automated readings of the maximal far wall of the common CIMT images both result in high reproducibility, show similar risk factor relations, rates of change and treatment effects. Hence, choices between semi-automated and manual reading software for CIMT studies likely should be based on logistical and cost considerations rather than differences in expected data quality when the choice is made to use far wall common CIMT measurements.
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| 21. |
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| 22. |
- van der Laan, Sander W., et al.
(författare)
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Cystatin C and Cardiovascular Disease : A Mendelian Randomization Study
- 2016
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Ingår i: Journal of the American College of Cardiology. - : Elsevier BV. - 0735-1097 .- 1558-3597. ; 68:9, s. 934-945
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Tidskriftsartikel (refereegranskat)abstract
- BACKGROUND Epidemiological studies show that high circulating cystatin C is associated with risk of cardiovascular disease (CVD), independent of creatinine-based renal function measurements. It is unclear whether this relationship is causal, arises from residual confounding, and/or is a consequence of reverse causation. OBJECTIVES The aim of this study was to use Mendelian randomization to investigate whether cystatin C is causally related to CVD in the general population. METHODS We incorporated participant data from 16 prospective cohorts (n = 76,481) with 37,126 measures of cystatin C and added genetic data from 43 studies (n = 252,216) with 63,292 CVD events. We used the common variant rs911119 in CST3 as an instrumental variable to investigate the causal role of cystatin C in CVD, including coronary heart disease, ischemic stroke, and heart failure. RESULTS Cystatin C concentrations were associated with CVD risk after adjusting for age, sex, and traditional risk factors (relative risk: 1.82 per doubling of cystatin C; 95% confidence interval [CI]: 1.56 to 2.13; p = 2.12 x 10(-14)). The minor allele of rs911119 was associated with decreased serum cystatin C (6.13% per allele; 95% CI: 5.75 to 6.50; p = 5.95 x 10(-211)), explaining 2.8% of the observed variation in cystatin C. Mendelian randomization analysis did not provide evidence fora causal role of cystatin C, with a causal relative risk for CVD of 1.00 per doubling cystatin C (95% CI: 0.82 to 1.22; p = 0,994), which was statistically different from the observational estimate (p = 1.6 x 10(-5)). A causal effect of cystatin C was not detected for any individual component of CVD. CONCLUSIONS Mendelian randomization analyses did not support a causal role of cystatin C in the etiology of CVD. As such, therapeutics targeted at lowering circulating cystatin C are unlikely to be effective in preventing CVD.
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| 23. |
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| 24. |
- Goncalves, Isabel, et al.
(författare)
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Detecting the vulnerable plaque in patients.
- 2015
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Ingår i: Journal of Internal Medicine. - : Wiley. - 1365-2796 .- 0954-6820. ; 278:5, s. 520-530
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Forskningsöversikt (refereegranskat)abstract
- Atherosclerosis is a systemic condition that eventually evolves into vulnerable plaques and cardiovascular events. Pathology studies reveal that rupture-prone atherosclerotic plaques have a distinct morphology, namely a thin, inflamed fibrous cap covering a large lipidic and necrotic core. With the fast development of imaging techniques in the last decades, detecting vulnerable plaques thereby identifying individuals at high risk for cardiovascular events has become of major interest. Yet, in current clinical practice, there is no routine use of any vascular imaging modality to assess plaque characteristics as each unique technique has its pros and cons. This review describes the techniques that may evolve into screening tool for the detection of the vulnerable plaque. Finally, it seems that plaque morphology has been changing in the last decades leading to a higher prevalence of 'stable' atherosclerotic plaques, possibly due to the implementation of primary prevention strategies or other approaches. Therefore, the nomenclature of vulnerable plaque lesions should be very carefully defined in all studies.
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| 25. |
- Lind, Lars, et al.
(författare)
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Effect of Rosuvastatin on the Echolucency of the Common Carotid Intima-Media in Low-Risk Individuals : the METEOR Trial
- 2012
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Ingår i: Journal of the American Society of Echocardiography. - : Elsevier BV. - 0894-7317 .- 1097-6795. ; 25:10, s. 1120-1127.e1
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Tidskriftsartikel (refereegranskat)abstract
- Background:The echolucency of the carotid intima-media is related to increased cardiovascular risk factor levels, morbidity, and mortality. The aim of this study was to assess the effect of statins on the echolucency of the common carotid intima-media in a low-risk population.Methods:Data from the Measuring Effects on Intima-Media Thickness: An Evaluation of Rosuvastatin study were used. Ultrasound images from the far walls of the left and right common carotid arteries were used for evaluation of the echolucency of the carotid intima-media, measured by grayscale median (GSM). Low GSM values reflect echolucent structures, whereas high values reflect echogenic structures. The primary end point was the difference in the annual rate of change in GSM between rosuvastatin and placebo.Results:Two-year change in GSM did not significantly differ between rosuvastatin and placebo in the total population, with a mean difference in the rate of change in GSM of 1.13 (95% confidence interval, -1.00 to 3.25). The effect of rosuvastatin differed across quintiles of baseline GSM values (P for interaction = .01). In the lowest quintile (n = 175) (i.e., in those with the most echolucent intima-media), the difference in the rate of change in GSM between rosuvastatin and placebo was 4.18 (95% confidence interval, -0.23 to 8.58). Increases in GSM were significantly related to decreasing low-density lipoprotein cholesterol levels in the lowest quintile (beta = 0.76; 95% confidence interval, 0.26 to 1.25).Conclusions:Treatment with rosuvastatin did not affect the echolucency of the arterial wall in all low-risk individuals. However, a potential effect of rosuvastatin on the echolucency of the common carotid intima-media is most likely to be found in individuals with echolucent arterial walls at baseline.
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| 26. |
- Meershoek, A. J. A., et al.
(författare)
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Meta-analysis of the outcomes of treatment of internal carotid arterynear occlusion
- 2019
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Ingår i: British Journal of Surgery. - : John Wiley & Sons. - 0007-1323 .- 1365-2168. ; 106:6, s. 665-671
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Tidskriftsartikel (refereegranskat)abstract
- Background: Guidelines recommend treating patients with an internal carotid artery near occlusion (ICANO) with best medical therapy (BMT) based on weak evidence. Consequently, patients with ICANO were excluded from randomized trials. The aim of this individual‐patient data (IPD) meta‐analysis was to determine the optimal treatment approach.Methods: A systematic search was performed in MEDLINE, EMBASE and the Cochrane Library databases in January 2018. The primary outcome was the occurrence of any stroke or death within the first 30 days of treatment, analysed by multivariable mixed‐effect logistic regression. The secondary outcome was the occurrence of any stroke or death beyond 30 days up to 1 year after treatment, evaluated by Kaplan–Meier survival analysis.Results: The search yielded 1526 articles, of which 61 were retrieved for full‐text review. Some 32 studies met the inclusion criteria and pooled IPD were available from 11 studies, including some 703 patients with ICANO. Within 30 days, any stroke or death was reported in six patients (1·8 per cent) in the carotid endarterectomy (CEA) group, five (2·2 per cent) in the carotid artery stenting (CAS) group and seven (4·9 per cent) in the BMT group. This resulted in a higher 30‐day stroke or death rate after BMT than after CEA (odds ratio 5·63, 95 per cent c.i. 1·30 to 24·45; P = 0·021). No differences were found between CEA and CAS. The 1‐year any stroke‐ or death‐free survival rate was 96·1 per cent for CEA, 94·4 per cent for CAS and 81·2 per cent for BMT.Conclusion: These data suggest that BMT alone is not superior to CEA or CAS with respect to 30‐day or 1‐year stroke or death prevention in patients with ICANO. These patients do not appear to constitute a high‐risk group for surgery, and consideration should made to including them in future RCTs of internal carotid artery interventions.
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| 27. |
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