22 results on '"Freiberg JJ"'
Search Results
2. Remnant Cholesterol and Myocardial Infarction in Normal Weight, Overweight, and Obese Individuals from the Copenhagen General Population Study.
- Author
-
Varbo A, Freiberg JJ, and Nordestgaard BG
- Subjects
- Aged, Body Mass Index, Denmark epidemiology, Female, Humans, Male, Middle Aged, Myocardial Infarction blood, Myocardial Infarction complications, Risk Factors, Body Weight, Cholesterol blood, Myocardial Infarction epidemiology, Obesity blood, Obesity complications, Overweight blood, Overweight complications, Population Surveillance
- Abstract
Background: We tested whether high remnant cholesterol is associated with high myocardial infarction risk, independent of whether an individual is normal weight, overweight, or obese., Methods: A total of 106216 individuals from the Copenhagen General Population Study were followed for up to 11 years, during which 1565 experienced a myocardial infarction. Individuals were grouped by clinically meaningful remnant cholesterol concentrations of <0.5 mmol/L (19 mg/dL), 0.5 to 0.99 mmol/L (19-38 mg/dL), 1.0 to 1.49 mmol/L (39-58 mg/dL), and ≥1.5 mmol/L (58 mg/dL), and by body mass index (BMI) of <18.5 kg/m
2 (underweight), 18.5 to 24.9 kg/m2 (normal weight), 25 to 29.9 kg/m2 (overweight), and ≥30 kg/m2 (obese)., Results: Median calculated remnant cholesterol was 0.40 mmol/L [interquartile range (IQR), 0.30-0.55 mmol/L] [15 mg/dL (12-21 mg/dL)] for underweight, 0.50 mmol/L (IQR, 0.37-0.71 mmol/L) [19 mg/dL (14-27 mg/dL)] for normal weight, 0.70 mmol/L (IQR, 0.49-1.00 mmol/L) [27 mg/dL (19-39 mg/dL)] for overweight, and 0.85 mmol/L (IQR, 0.61-1.20 mmol/L) [(33 mg/dL (24-46 mg/dL)] for obese individuals. On continuous scales, remnant cholesterol was positively correlated with BMI until reaching a plateau of approximately 1 mmol/L (39 mg/dL) at BMI >35 kg/m2 . R2 from an unadjusted linear regression for the correlation between calculated remnant cholesterol and BMI was 12%. Stepwise higher remnant cholesterol was associated with stepwise higher myocardial infarction risk in a similar pattern for normal weight, overweight, and obese individuals. When compared with individuals with remnant cholesterol <0.5 mmol/L (19 mg/dL), individuals with remnant cholesterol ≥1.5 mmol/L (58 mg/dL) had hazard ratios for myocardial infarction of 2.0 (95% CI, 1.3-3.2) for normal weight, 1.9 (95% CI, 1.4-2.6) for overweight, and 2.3 (95% CI, 1.4-3.5) for obese individuals. Directly measured remnant cholesterol increased 0.91 mmol/L (95% CI, 0.89-0.94 mmol/L) [35 mg/dL (34-36 mg/dL)] per 1 mmol/L (39 mg/dL) increase in calculated remnant cholesterol., Conclusions: Remnant cholesterol and BMI were positively correlated; however, high remnant cholesterol was associated with higher myocardial infarction risk across the examined BMI subcategories, indicating that remnant cholesterol is a risk factor for myocardial infarction independent of overweight and obesity., (© 2017 American Association for Clinical Chemistry.)- Published
- 2018
- Full Text
- View/download PDF
3. Reply to: "Appropriate use of cholesterol-lowering therapy".
- Author
-
Langsted A, Freiberg JJ, and Nordestgaard BG
- Subjects
- Cholesterol, Humans, Medical Overuse, Anticholesteremic Agents, Cardiovascular Diseases, Diabetes Mellitus
- Published
- 2017
- Full Text
- View/download PDF
4. Extent of undertreatment and overtreatment with cholesterol-lowering therapy according to European guidelines in 92,348 Danes without ischemic cardiovascular disease and diabetes in 2004-2014.
- Author
-
Langsted A, Freiberg JJ, and Nordestgaard BG
- Subjects
- Adult, Aged, Aged, 80 and over, Biomarkers blood, Cardiovascular Diseases etiology, Denmark, Down-Regulation, Dyslipidemias blood, Dyslipidemias complications, Dyslipidemias diagnosis, Female, Humans, Male, Middle Aged, Risk Assessment, Risk Factors, Time Factors, Treatment Outcome, Anticholesteremic Agents therapeutic use, Cardiovascular Diseases prevention & control, Cholesterol blood, Dyslipidemias drug therapy, Guideline Adherence trends, Health Services Misuse trends, Medical Overuse trends, Practice Guidelines as Topic, Practice Patterns, Physicians' trends
- Abstract
Background and Aims: We estimated the extent of undertreatment and overtreatment with cholesterol-lowering therapy according to European guidelines in individuals in the Danish general population without ischemic cardiovascular disease and diabetes., Methods: We examined 92,348 such individuals aged 35-100 years recruited from 2004 through 2014 in the Copenhagen General Population Study. Each individual was assigned their 10-year risk of fatal cardiovascular disease according to the European SCORE chart based on age, sex, smoking, total cholesterol, and systolic blood pressure. European guidelines recommend cholesterol-lowering therapy definitely at ≥10% risk and LDL cholesterol ≥1.8 mmol/L, definitely at 5-9% risk and LDL cholesterol ≥2.5 mmol/L, possibly at 1-4% risk and LDL cholesterol ≥3 mmol/L, but not at <1% risk., Results: 3858 individuals had ≥10% risk, 16,255 had 5-9% risk, 49,131 had 1-4% risk, and 23,104 had <1% 10-year risk of fatal cardiovascular disease. In these groups, 81%, 86%, 93%, and 99% did not receive cholesterol-lowering therapy. Definite undertreatment and overtreatment according to guidelines were found in 19% and 0.2% or in 187,660 and 1570 per million 35-100 year olds without ischemic cardiovascular disease and diabetes. If definite and possible undertreatment and overtreatment were combined, the corresponding numbers were 52% and 3% or 519,416 and 29,194 per million., Conclusions: In the Danish general population, ∼190,000 per million 35-100 year olds without ischemic cardiovascular disease and diabetes are not treated to LDL cholesterol goals according to European guidelines. Conversely, ∼1600 per million received cholesterol-lowering therapy without endorsement in European guidelines., (Copyright © 2016 Elsevier Ireland Ltd. All rights reserved.)
- Published
- 2017
- Full Text
- View/download PDF
5. Extreme nonfasting remnant cholesterol vs extreme LDL cholesterol as contributors to cardiovascular disease and all-cause mortality in 90000 individuals from the general population.
- Author
-
Varbo A, Freiberg JJ, and Nordestgaard BG
- Subjects
- Cardiovascular Diseases blood, Denmark epidemiology, Fasting, Humans, Risk Factors, Cardiovascular Diseases mortality, Cause of Death, Cholesterol blood, Cholesterol, LDL blood
- Abstract
Background: Increased nonfasting remnant cholesterol, like increased LDL cholesterol, is causally associated with increased risk for ischemic heart disease (IHD). We tested the hypothesis that extreme concentrations of nonfasting remnant and LDL cholesterol are equal contributors to the risk of IHD, myocardial infarction (MI), and all-cause mortality., Methods: We compared stepwise increasing concentrations of nonfasting remnant and LDL cholesterol for association with risk of IHD, MI, and all-cause mortality in approximately 90 000 individuals from the Danish general population. During up to 22 years of complete follow-up, 4435 participants developed IHD, 1722 developed MI, and 8121 died., Results: Compared with participants with nonfasting remnant cholesterol <0.5 mmol/L (19.3 mg/dL), hazard ratios for IHD ranged from 1.3 (95% CI 1.1-1.5) for remnant cholesterol of 0.5-0.99 mmol/L (19.3-38.2 mg/dL) to 2.4 (1.9-2.9) for remnant cholesterol of ≥1.5 mmol/L (58 mg/dL) (P for trend <0.001). Compared with participants with LDL cholesterol <3.0 mmol/L (115.8 mg/dL), hazard ratios for IHD ranged from 1.3 (1.1-1.5) for LDL cholesterol of 3-3.99 mmol/L (115.8-154 mg/dL) to 2.3 (1.9-2.8) for LDL cholesterol of ≥5 mmol/L (193 mg/dL) (P < 0.001). Corresponding hazard ratios for MI ranged from 1.8 (1.4-2.3) to 3.4 (2.5-4.8) for remnant cholesterol (P < 0.001), and from 1.7 (1.4-2.2) to 4.7 (3.5-6.3) for LDL cholesterol (P < 0.001). Nonfasting remnant cholesterol concentrations were associated stepwise with all-cause mortality ranging from hazard ratio 1.0 (0.9-1.1) to 1.6 (1.4-1.9) (P < 0.001), whereas LDL cholesterol concentrations were associated with decreased all-cause mortality risk in a U-shaped pattern, with hazard ratios from 0.8 (0.7-0.8) to 0.9 (0.8-1.0) (P = 0.002). After mutual adjustment, LDL cholesterol best predicted MI, and remnant cholesterol best predicted all-cause mortality., Conclusions: Both lipoproteins were associated equally with risk of IHD and MI; however, only nonfasting remnant cholesterol concentrations were associated stepwise with increased all-cause mortality risk., (© 2015 American Association for Clinical Chemistry.)
- Published
- 2015
- Full Text
- View/download PDF
6. Authors' response to Young and Hopkins: vitamin D and lung function.
- Author
-
Afzal S, Lange P, Bojesen SE, Freiberg JJ, and Nordestgaard BG
- Subjects
- Female, Humans, Male, Lung physiopathology, Pulmonary Disease, Chronic Obstructive physiopathology, Vitamin D analogs & derivatives
- Published
- 2014
- Full Text
- View/download PDF
7. Plasma 25-hydroxyvitamin D, lung function and risk of chronic obstructive pulmonary disease.
- Author
-
Afzal S, Lange P, Bojesen SE, Freiberg JJ, and Nordestgaard BG
- Subjects
- Aged, Cohort Studies, Female, Forced Expiratory Volume physiology, Humans, Male, Middle Aged, Pulmonary Disease, Chronic Obstructive blood, Spirometry, Vital Capacity physiology, Vitamin D blood, Lung physiopathology, Pulmonary Disease, Chronic Obstructive physiopathology, Vitamin D analogs & derivatives
- Abstract
Background: 25-hydroxyvitamin D (25(OH)D) may be associated with lung function through modulation of pulmonary protease-antiprotease imbalance, airway inflammation, lung remodelling and oxidative stress. We examined the association of plasma 25(OH)D levels with lung function, lung function decline and risk of chronic obstructive pulmonary disease (COPD)., Methods: Plasma 25(OH)D was measured in 10 116 participants in the Copenhagen City Heart Study and in 8391 participants in the Copenhagen General Population Study. In the former study, up to three measurements of lung function spanning 20 years allowed analyses of lung function decline., Results: In both cohorts, forced vital capacity in % of predicted was 7% lower and forced expiratory volume in 1 s in % of predicted was 7-10% lower for lowest versus highest decile of 25(OH)D (ptrend≤1×10(-28)). In prospective analyses, participants in the lower versus higher 25(OH)D quintiles had a faster decline in forced expiratory volume in 1 s % predicted (pinteraction=1×10(-7)) and forced vital capacity % predicted (pinteraction=8×10(-8)). In cross-sectional analyses, multivariable adjusted ORs for COPD were 2.30 (95% CI 1.55 to 3.41) and 3.06 (1.97 to 4.76) for lowest versus highest quintile in the Copenhagen City Heart Study using Global Initiative for Chronic Obstructive Lung Disease (GOLD) and lower limit of normal criteria. The corresponding ORs were 1.82 (1.13 to 2.92) and 2.23 (1.35 to 3.69) in the Copenhagen General Population Study. In prospective analyses, corresponding multivariable adjusted HRs for developing COPD were 1.58 (1.05 to 2.40) and 2.00 (1.19 to 3.36)., Conclusions: We observed a novel association of lower plasma 25(OH)D levels with faster decline in lung function and with a higher risk of COPD in prospective analyses.
- Published
- 2014
- Full Text
- View/download PDF
8. Short telomere length, cancer survival, and cancer risk in 47102 individuals.
- Author
-
Weischer M, Nordestgaard BG, Cawthon RM, Freiberg JJ, Tybjærg-Hansen A, and Bojesen SE
- Subjects
- Age Factors, Aged, Denmark epidemiology, Female, Follow-Up Studies, Humans, Incidence, Linear Models, Male, Middle Aged, Multivariate Analysis, Neoplasms mortality, Neoplasms pathology, Odds Ratio, Prospective Studies, Risk Assessment, Risk Factors, Survival Analysis, Survival Rate, Telomere Shortening, Leukocytes pathology, Neoplasms epidemiology, Neoplasms genetics, Telomere pathology
- Abstract
Background: Recent meta-analyses have suggested that short telomere length was associated with increased risk of cancer. We therefore tested the hypotheses that short telomere length was associated with increased risk of cancer and with increased risk of early death after cancer., Methods: We measured leukocyte telomere length in a prospective study of 47 102 Danish general population participants from the Copenhagen City Heart Study and the Copenhagen General Population Study. Participants were followed for up to 20 years for cancer diagnosis and death. Follow-up was 100% complete. All statistical tests were two-sided., Results: Telomere length decreased linearly with increasing age (P <.001). During follow-up, we observed 3142 first cancers and, among these individuals, 1730 deaths. Decreasing quartiles of telomere length were associated with decreasing survival after cancer (log-rank P <.001). Multivariable-adjusted hazard ratios of early death were 1.31 (95% confidence interval [CI] = 1.14 to 1.52) in individuals in the quartile and 1.43 (95% CI = 1.13 to 1.80) in individuals in the decile with the shortest telomeres vs the longest. Unadjusted hazard ratios of cancer risk were 1.74 (95% CI = 1.58 to 1.93) and 2.00 (95% CI = 1.70 to 2.35) in individuals in the quartile and decile with the shortest vs longest telomeres; however, multivariable adjustment changed these hazard ratios to 0.98 (95% CI = 0.88 to 1.08) and 0.95 (95% CI = 0.80 to 1.11), mainly because of age adjustment., Conclusions: Short telomere length is associated with reduced survival after cancer but not with cancer risk. The latter contrasts with findings from recent meta-analyses.
- Published
- 2013
- Full Text
- View/download PDF
9. Only a fraction of patients with ischaemic diseases or diabetes are treated to recommended target values for plasma lipids.
- Author
-
Siggaard-Andersen N, Freiberg JJ, and Nordestgaard BG
- Subjects
- Aged, Aged, 80 and over, Brain Ischemia blood, Cholesterol, LDL blood, Cross-Sectional Studies, Denmark, Diabetes Mellitus blood, Female, Humans, Hyperlipidemias blood, Intermittent Claudication blood, Male, Middle Aged, Myocardial Ischemia blood, Practice Guidelines as Topic, Triglycerides blood, Cholesterol blood, Guideline Adherence statistics & numerical data, Hyperlipidemias drug therapy, Hypolipidemic Agents therapeutic use
- Abstract
Introduction: We tested the hypothesis that individuals in the general population with and without ischaemic cardiovascular disease, or with diabetes, are treated to recommended target values for plasma lipids., Material and Methods: We used the Copenhagen General Population Study in which 69,354 individuals were examined cross-sectionally from 2004 through 2010. Among this population, 1,521 had previously had myocardial infarction, 2,372 other ischaemic heart disease, 542 ischaemic stroke, 2,086 claudicatio intermittens and 2,155 had diabetes., Results: The fraction of participants using lipid-lowering therapy among those with myocardial infarction was 70%, other ischaemic heart disease 44%, ischaemic stroke 60%, claudicatio intermittens 33%, diabetes 48%, and for those without ischaemic cardiovascular disease 8%. Among those with myocardial infarction with and without lipid-lowering therapy, 41% and 84%, respectively, had not reached a total cholesterol < 4.5 mmol/l, 30% and 79%, respectively, had not reached a low-density lipoprotein cholesterol < 2.5 mmol/l, and 46% and 48%, respectively, had not reached triglycerides < 1.7 mmol/l. In those with other ischaemic cardiovascular disease, with diabetes or without ischaemic cardiovascular disease, a similar or larger fraction of individuals did not reach guideline lipid targets., Conclusion: Large fractions of individuals with ischaemic cardiovascular disease or diabetes are not treated with lipid-lowering therapy. Even among many of those treated, plasma total cholesterol, low-density lipoprotein cholesterol and triglycerides are not treated to guideline targets.
- Published
- 2012
10. Short telomere length, myocardial infarction, ischemic heart disease, and early death.
- Author
-
Weischer M, Bojesen SE, Cawthon RM, Freiberg JJ, Tybjærg-Hansen A, and Nordestgaard BG
- Subjects
- Adult, Age Factors, Aged, Aging genetics, Denmark epidemiology, Female, Follow-Up Studies, Genetic Predisposition to Disease, Humans, Male, Middle Aged, Phenotype, Proportional Hazards Models, Prospective Studies, Real-Time Polymerase Chain Reaction, Risk Assessment, Risk Factors, Time Factors, Myocardial Infarction genetics, Myocardial Infarction mortality, Myocardial Ischemia genetics, Myocardial Ischemia mortality, Telomere Shortening
- Abstract
Objective: We tested the hypothesis that short telomere length is associated with increased risk of myocardial infarction, ischemic heart disease, and early death., Methods and Results: We measured leukocyte telomere length in 2 prospective studies of 19 838 Danish general population participants from the Copenhagen City Heart Study and the Copenhagen General Population Study. Participants were followed for up to 19 years for incident myocardial infarction (n=929), ischemic heart disease (n=2038), and death (n=4342). Follow-up was 100% complete. Telomere length decreased linearly with increasing age in women and men in both studies (P=7×10(-74) to P=3×10(-125)). Multifactorially adjusted hazard ratios were 1.10 (95% CI 1.01-1.19) for myocardial infarction, 1.06 (1.00-1.11) for ischemic heart disease, and 1.09 (1.05-1.13) for early death per 1000-base pair decrease in telomere length. The multifactorially adjusted hazard ratios for the shortest versus the longest decile of telomere length were 1.49 (1.07-2.07) for myocardial infarction, 1.24 (1.01-1.53) for ischemic heart disease, and 1.25 (1.07-1.46) for early death., Conclusion: Short telomere length is associated with only modestly increased risk of myocardial infarction, ischemic heart disease, and early death.
- Published
- 2012
- Full Text
- View/download PDF
11. Nonfasting cholesterol and triglycerides and association with risk of myocardial infarction and total mortality: the Copenhagen City Heart Study with 31 years of follow-up.
- Author
-
Langsted A, Freiberg JJ, Tybjaerg-Hansen A, Schnohr P, Jensen GB, and Nordestgaard BG
- Subjects
- Adult, Biomarkers blood, Denmark epidemiology, Epidemiologic Methods, Female, Humans, Hypercholesterolemia complications, Hypercholesterolemia epidemiology, Male, Middle Aged, Myocardial Infarction epidemiology, Myocardial Infarction etiology, Myocardial Ischemia epidemiology, Myocardial Ischemia etiology, Sex Factors, Cholesterol blood, Myocardial Infarction blood, Triglycerides blood
- Abstract
Objectives: We compared the ability of very high levels of nonfasting cholesterol and triglycerides to predict risk of myocardial infarction and total mortality., Design: Prospective study from 1976 to 1978 until 2007., Setting: Danish general population., Participants: Randomly selected population of 7581 women and 6391 men, of whom 768 and 1151 developed myocardial infarction and 4398 and 4416 died, respectively. Participation rate was 72%, and follow-up was 100% complete. Less than 2% of participants were taking lipid-lowering therapy., Results: Compared to women with cholesterol <5 mmol L(-1) , multivariate-adjusted hazard ratios for myocardial infarction ranged from 1.3 [95% confidence interval (CI): 0.9-1.8] for a cholesterol level of 5.0-5.99 mmol L(-1) to 2.5 (95%CI: 1.6-4.0) for cholesterol ≥ 9 mmol L(-1) (trend: P < 0.0001). Compared with women with nonfasting triglycerides <1 mmol L(-1) , hazard ratios for myocardial infarction ranged from 1.5 (95%CI: 1.2-1.8) for triglycerides of 1.0-1.99 mmol L(-1) to 4.2 (95%CI: 2.5-7.2) for triglycerides ≥ 5 mmol L(-1) (p<0.0001). In men, corresponding hazard ratios ranged from 1.2 (95%CI: 1.0-1.5) to 5.3 (95%CI: 3.6-8.0) for cholesterol (P < 0.0001) and from 1.3 (95%CI: 1.0-1.6) to 2.1 (95%CI: 1.5-2.8) for triglycerides (P < 0.0001). Increasing cholesterol levels were not consistently associated with total mortality in women (trend: P = 0.39) or men (P = 0.02). By contrast, compared with women with triglycerides <1 mmol L(-1) , multivariate-adjusted hazard ratios for total mortality ranged from 1.1 (95%CI: 1.0-1.2) for triglycerides of 1.0-1.99 mmol L(-1) to 2.0 (95%CI: 1.5-2.9) for triglycerides ≥5 mmol L(-1) (trend: P < 0.0001); corresponding hazard ratios in men ranged from 1.1 (95%CI: 1.0-1.2) to 1.5 (95%CI: 1.2-1.7) (P < 0.0001)., Conclusions: Stepwise increasing levels of nonfasting cholesterol and nonfasting triglycerides were similarly associated with stepwise increasing risk of myocardial infarction, with nonfasting triglycerides being the best predictor in women and nonfasting cholesterol the best predictor in men. Even more surprisingly, only increasing levels of nonfasting triglycerides were associated with total mortality, whereas increasing cholesterol levels were not., (© 2010 The Association for the Publication of the Journal of Internal Medicine.)
- Published
- 2011
- Full Text
- View/download PDF
12. Clinical relevance of non-fasting and postprandial hypertriglyceridemia and remnant cholesterol.
- Author
-
Nordestgaard BG and Freiberg JJ
- Subjects
- Cardiovascular Diseases etiology, Dietary Fats administration & dosage, Female, Humans, Hypertriglyceridemia diagnosis, Male, Postprandial Period, Risk Factors, Sex Factors, Time Factors, Cholesterol blood, Hypertriglyceridemia complications, Triglycerides blood
- Abstract
Non-fasting triglycerides are measured at any time within up to 8 h (14 h) after any normal meal, while postprandial triglycerides are measured at a fixed time point within up to 8 h (14 h) of a standardised fat tolerance test. The simplest possible way of evaluating remnant cholesterol is non-fasting/postprandial total cholesterol minus low-density lipoprotein (LDL) cholesterol minus high-density lipoprotein (HDL) cholesterol. Elevated levels of non-fasting/postprandial triglycerides directly correlate with elevated remnant cholesterol. In the general population, 38% of men have non-fasting/postprandial triglycerides > 2mmol/L (>176 mg/dL) while 45% of men have non-fasting/postprandial triglyceride levels of 1-2 mmol/L (89-176 mg/dL); corresponding fractions in women are 20% and 47%. Also, 31% of men have remnant cholesterol levels > 1mmol/L (>39 mg/dL) while 46% of men have remnant cholesterol levels of 0.5-1 mmol/L (19-39 mg/dL); corresponding fractions in women are 15% and 43%. Non-fasting triglycerides ≥5 mmol/L vs. <1 mmol/L marked a 17 and 5 fold increased risk of myocardial infarction, a 5 and 3 fold increased risk of ischemic stroke, and a 4 and 2 fold increased risk of early death in women and men in the general population. As all cells can degrade triglycerides it is biologically unlikely that it is the triglyceride molecules themselves that cause atherosclerosis and cardiovascular disease. However, elevated remnant cholesterol may lead to cholesterol entrapment in the arterial intima and consequently to accelerated atherosclerosis and cardiovascular disease.
- Published
- 2011
- Full Text
- View/download PDF
13. Novel mutations in leukotriene C4 synthase and risk of cardiovascular disease based on genotypes from 50,000 individuals.
- Author
-
Freiberg JJ, Tybjaerg-Hansen A, and Nordestgaard BG
- Subjects
- Adult, Aged, Aged, 80 and over, Case-Control Studies, Cross-Sectional Studies, Denmark, Female, Genetic Predisposition to Disease, Genetic Variation, Genotype, Heterozygote, Humans, Ischemia pathology, Male, Middle Aged, Odds Ratio, Prospective Studies, Risk Factors, Sex Factors, Stroke pathology, Cardiovascular Diseases genetics, Glutathione Transferase genetics, Mutation
- Abstract
Background: Atherosclerosis is an inflammatory condition where cysteinyl leukotrienes have been identified to play an important role. Furthermore, cysteinyl leukotrienes may also affect thrombus formation. Using prospective, cross-sectional and case-control designs, we tested the hypothesis that hitherto unknown genetic variation, likely to affect the function of leukotriene C(4) synthase, is associated with risk of venous thromboembolism, ischemic stroke and myocardial infarction., Methods and Results: Resequencing the gene coding for leukotriene C(4) synthase in an extreme risk population with more than 1500 individuals revealed 17 new mutations, of which four are likely to change protein function (211G>A (minor allele frequency, 0.0001), IVS3 + 1G>A (0.002), 374G>A (0.0006) and 451_453+10del (0.0007)). Based on genotyping 50,000 individuals, age and sex adjusted odds ratios for venous thromboembolism were 2.0 (95% CI, 1.3-3.5) for IVS3+1G>A heterozygotes vs. wild type, and 1.9 (1.5-2.7) for any mutation heterozygote vs. wild type. Corresponding values were 2.0 (1.3-3.2) and 1.5 (1.1-2.1) for ischemic stroke, and 1.0 (0.8-1.3) and 1.2 (1.0-1.4) for myocardial infarction., Conclusions: Four novel mutations that are likely to change the function of leukotriene C(4) synthase were associated with increased risk of venous thromboembolism and ischemic stroke. These findings need confirmation in other independent studies. In addition, the mechanism behind these findings deserves further investigation., (© 2010 International Society on Thrombosis and Haemostasis.)
- Published
- 2010
- Full Text
- View/download PDF
14. Risk factors for near-term myocardial infarction in apparently healthy men and women.
- Author
-
Nordestgaard BG, Adourian AS, Freiberg JJ, Guo Y, Muntendam P, and Falk E
- Subjects
- Aged, Biomarkers blood, Case-Control Studies, Female, Humans, Male, Risk Factors, Time Factors, Myocardial Infarction blood
- Abstract
Background: Limited information is available regarding risk factors for the near-term (4 years) onset of myocardial infarction (MI). We evaluated established cardiovascular risk factors and putative circulating biomarkers as predictors for MI within 4 years of measurement., Methods: We conducted a matched, nested case-control study (252 cases and 499 controls) drawing on 45 735 men and women participating in the Copenhagen City Heart Study and the Copenhagen General Population Study. Established risk factors and 17 putative biomarkers, including inflammation-sensitive plasma proteins (C-reactive protein, fibrinogen, alpha(l)-antitrypsin, complement 3), apolipoproteins (A1, B, E, B/A1 ratio), markers of iron overload (iron, transferrin, transferrin saturation), creatinine, alkaline phosphatase, gamma-glutamyl transpeptidase, and leukocytes (lymphocyte count, neutrophil count, neutrophil/lymphocyte ratio) were assessed., Results: Among women and men, only 13% and 50%, respectively, of those with near-term MI were classified as high risk by Framingham risk score at baseline. After adjustment for established risk factors, odds ratios for near-term MI, which compared highest to lowest quintiles, were 2.87(95% CI 1.51-5.48; P = 0.001) for alpha(l)-antitrypsin, 2.84(1.42-5.67; P = 0.003) for C-reactive protein, 1.97(1.09-3.57; P = 0.03) for creatinine, 1.99(1.09-3.65; P = 0.03) for fibrinogen, and 0.37(0.19-0.73; P = 0.004) for iron. The corresponding odds ratio for all biomarkers combined was 7.24 (3.28-16.0; P < 0.001)., Conclusions: We identified 5 biomarkers associated with increased near-term risk of MI independently of established risk factors. All putative biomarkers combined explained a 7-fold increase in the odds of near-term MI.
- Published
- 2010
- Full Text
- View/download PDF
15. Missense polymorphisms in BRCA1 and BRCA2 and risk of breast and ovarian cancer.
- Author
-
Dombernowsky SL, Weischer M, Freiberg JJ, Bojesen SE, Tybjaerg-Hansen A, and Nordestgaard BG
- Subjects
- Breast Neoplasms epidemiology, Female, Humans, Incidence, Ovarian Neoplasms epidemiology, Polymerase Chain Reaction, Risk Factors, Breast Neoplasms genetics, Genes, BRCA1, Genes, BRCA2, Genetic Predisposition to Disease, Ovarian Neoplasms genetics, Polymorphism, Genetic
- Abstract
Purpose: BRCA1 and BRCA2 are key tumor suppressors with a role in cellular DNA repair, genomic stability, and checkpoint control. Mutations in BRCA1 and BRCA2 often cause hereditary breast and ovarian cancer; however, missense polymorphisms in these genes pose a problem in genetic counseling, as their impact on risk of breast and ovarian cancer is unclear., Experimental Design: We resequenced BRCA1 and BRCA2 in 194 women with a familial history of breast and/or ovarian cancer and identified nine possibly biologically relevant polymorphisms (BRCA1 Gln356Arg, Pro871Leu, Glu1038Gly, Ser1613Gly, and Met1652Ile. BRCA2 Asn289His, Asn372His, Asp1420Tyr, and Thr1915Met). [corrected] We evaluated risk of breast and/or ovarian cancer by these polymorphisms in a prospective study of 5,743 women from the general population followed for 39 years and in a case-control study of 1,201 breast cancer cases and 4,120 controls., Results: We found no association between heterozygosity or homozygosity for any of the nine polymorphisms and risk of breast and/or ovarian cancer in either study. We had 80% power to exclude hazard/odds ratios for heterozygotes and/or homozygotes for all nine missense polymorphisms above 1.3 to 3.3 in the prospective study, and above 1.2 to 3.2 in the case-control study., Conclusions: Heterozygosity and homozygosity of any of the examined nine BRCA1 and BRCA2 missense polymorphisms cannot explain the increased risk of breast and/or ovarian cancer observed in families with hereditary breast and/or ovarian cancer. Therefore, genetic counseling of such families safely can disregard findings of these missense polymorphisms.
- Published
- 2009
- Full Text
- View/download PDF
16. [Fasting and nonfasting lipids--secondary publication].
- Author
-
Langsted A, Freiberg JJ, and Nordestgaard BG
- Subjects
- Adult, Aged, Aged, 80 and over, Apolipoproteins blood, Cardiovascular Diseases etiology, Cholesterol blood, Cholesterol, HDL blood, Cholesterol, LDL blood, Cross-Sectional Studies, Eating physiology, Female, Humans, Male, Middle Aged, Predictive Value of Tests, Prospective Studies, Reference Values, Risk Factors, Triglycerides blood, Fasting blood, Lipids blood
- Abstract
We tested the hypotheses that lipid levels change minimally in response to normal food intake and that nonfasting levels predict cardiovascular events. The maximum changes after normal food intake from fasting levels were as follows: total cholesterol -0.2 mmol/l, LDL cholesterol -0.2 mmol/l, HDL cholesterol -0.1 mmol/l, and for triglycerides +0.3 mmol/l. Highest versus lowest tertile of nonfasting total cholesterol, LDL cholesterol, and triglycerides, and lowest versus highest tertile of nonfasting HDL cholesterol predicted a 1.7-to 2.2-fold increased risk of cardiovascular events.
- Published
- 2009
17. [Nonfasting triglycerides and risk of ischemic stroke--secondary publication].
- Author
-
Freiberg JJ, Tybjaerg-Hansen A, Jensen JS, and Nordestgaard BG
- Subjects
- Adult, Aged, Aged, 80 and over, Brain Ischemia blood, Brain Ischemia epidemiology, Cross-Sectional Studies, Denmark epidemiology, Female, Humans, Male, Middle Aged, Proportional Hazards Models, Risk Factors, Stroke epidemiology, Stroke blood, Triglycerides blood
- Abstract
The role of triglycerides in the risk of ischemic stroke remains controversial. We tested the hypothesis that increased levels of nonfasting triglycerides are associated with ischemic stroke in the general population. Men with a nonfasting triglyceride level 5 mmol/l had a multivariable, adjusted hazard ratio for ischemic stroke of 2.5 (95% confidence interval: 1.3-4.8) compared with men with a nonfasting triglyceride level < 1 mmol/l. The corresponding value in women was 3.8 (1.3-11). We conclude that the level of nonfasting triglycerides is associated with risk of ischemic stroke.
- Published
- 2009
18. Nonfasting hyperlipidemia and cardiovascular disease.
- Author
-
Nordestgaard BG, Langsted A, and Freiberg JJ
- Subjects
- Animals, Cardiovascular Diseases diagnosis, Cardiovascular Diseases prevention & control, Hematologic Tests methods, Humans, Hyperlipidemias diagnosis, Hyperlipidemias prevention & control, Risk Factors, Cardiovascular Diseases blood, Fasting blood, Hyperlipidemias blood
- Abstract
Most humans are in the nonfasting or postprandial state in the majority of a 24 hour cycle; however, lipids, lipoproteins, and apolipoproteins are usually measured in the fasting state. Recent studies demonstrate that these values at most change minimally in response to normal food intake, changes that are clinically unimportant. Also, elevated levels of nonfasting triglycerides as a marker of elevated remnant lipoprotein cholesterol associate strongly with increased risk of myocardial infarction, ischemic stroke, and early death. The mechanism behind these findings likely involves entrance of remnant lipoproteins into the arterial intima with subsequent retention leading to atherogenesis, while low HDL cholesterol levels may be an innocent bystander. Finally, nonfasting levels of total cholesterol, non-HDL cholesterol, LDL cholesterol, apolipoprotein B, triglycerides, HDL cholesterol, apolipoprotein A1, total cholesterol/HDL cholesterol, and apolipoprotein B/apolipoprotein A1 all associate with increased risk of cardiovascular disease. These new data open the possibility that nonfasting rather than fasting lipid profiles can be used for cardiovascular risk prediction. If implemented, this would simplify blood sampling for lipid measurements for millions of patients worldwide. Furthermore, the results also highlight the need for randomized double-blind trials of new and established drugs to reduce nonfasting triglycerides and remnant lipoprotein cholesterol, with the ultimate aim of reducing risk of cardiovascular disease and early death.
- Published
- 2009
- Full Text
- View/download PDF
19. Leukotriene C4 synthase and ischemic cardiovascular disease and obstructive pulmonary disease in 13,000 individuals.
- Author
-
Freiberg JJ, Dahl M, Tybjaerg-Hansen A, Grande P, and Nordestgaard BG
- Subjects
- Adult, Asthma complications, Asthma enzymology, Asthma epidemiology, Asthma genetics, Denmark epidemiology, Female, Genotype, Humans, Incidence, Ischemic Attack, Transient complications, Ischemic Attack, Transient enzymology, Ischemic Attack, Transient epidemiology, Ischemic Attack, Transient genetics, Lung Diseases, Obstructive epidemiology, Lung Diseases, Obstructive genetics, Male, Middle Aged, Myocardial Ischemia epidemiology, Myocardial Ischemia genetics, Stroke complications, Stroke enzymology, Stroke epidemiology, Stroke genetics, Glutathione Transferase genetics, Lung Diseases, Obstructive complications, Lung Diseases, Obstructive enzymology, Myocardial Ischemia complications, Myocardial Ischemia enzymology
- Abstract
Ischemic cardiovascular disease and obstructive pulmonary disease involve inflammation. Leukotrienes may be important pro-inflammatory mediators. We tested the hypothesis that the (-1072)G > A and (-444)A > C promoter polymorphisms of leukotriene C4 synthase confer risk of transient ischemic attack (TIA), ischemic stroke, ischemic heart disease (IHD), asthma, and chronic obstructive pulmonary disease (COPD). We genotyped individuals from the Danish general population, the Copenhagen City Heart Study, and Danish patients with IHD/coronary atherosclerosis, the Copenhagen Ischemic Heart Disease Study. We used prospective (n = 10,386), cross-sectional (n = 10,386), and case-control (n = 2392 + 5012) designs. Allele frequency was 0.07 for (-1072)A and 0.29 for (-444)C. Cumulative incidence for TIA was higher for (-1072)AA versus GG genotype (log-rank: p < 0.001), and lower for (-444)CC versus AA genotype (log-rank: p = 0.03). Cumulative incidence for ischemic stroke was also lower for (-444)CC versus AA genotype (log-rank: p = 0.04). Multifactorially adjusted hazard ratios for TIA were 5.2(95% CI:1.9-14) for (-1072)AA versus GG genotype, and 0.4(0.2-1.0) for (-444)CC versus AA genotype. Corresponding values were 1.9 (0.7-5.2) and 0.7 (0.5-1.0) for ischemic stroke, and 0.8 (0.4-1.6) and 1.0 (0.9-1.2) for IHD. In the case-control study, corresponding multifactorially adjusted odds ratios for IHD/coronary atherosclerosis were 0.5 (0.2-1.3) and 1.2 (1.0-1.5). These genotypes were not associated with risk of asthma or COPD. Leukotriene C4 synthase promoter genotypes influence risk of TIA and ischemic stroke, but not risk of IHD/coronary atherosclerosis, asthma, or COPD.
- Published
- 2009
- Full Text
- View/download PDF
20. Nonfasting triglycerides and risk of ischemic stroke in the general population.
- Author
-
Freiberg JJ, Tybjaerg-Hansen A, Jensen JS, and Nordestgaard BG
- Subjects
- Adult, Aged, Aged, 80 and over, Brain Ischemia blood, Brain Ischemia epidemiology, Cross-Sectional Studies, Denmark epidemiology, Female, Humans, Lipids blood, Longitudinal Studies, Male, Middle Aged, Proportional Hazards Models, Risk Factors, Stroke blood, Stroke epidemiology, Triglycerides blood
- Abstract
Context: The role of triglycerides in the risk of ischemic stroke remains controversial. Recently, a strong association was found between elevated levels of nonfasting triglycerides, which indicate the presence of remnant lipoproteins, and increased risk of ischemic heart disease., Objective: To test the hypothesis that increased levels of nonfasting triglycerides are associated with ischemic stroke in the general population., Design, Setting, and Participants: The Copenhagen City Heart Study, a prospective, Danish population-based cohort study initiated in 1976, with follow-up through July 2007. Participants were 13,956 men and women aged 20 through 93 years. A cross-sectional study included 9637 individuals attending the 1991-1994 examination of the prospective study., Main Outcome Measures: Prospective study: baseline levels of nonfasting triglycerides, other risk factors at baseline and at follow-up examinations, and incidence of ischemic stroke. Cross-sectional study: levels of nonfasting triglycerides, levels of remnant cholesterol, and prevalence of ischemic stroke., Results: Of the 13,956 participants in the prospective study, 1529 developed ischemic stroke. Cumulative incidence of ischemic stroke increased with increasing levels of nonfasting triglycerides (log-rank trend, P < .001). Men with elevated nonfasting triglyceride levels of 89 through 176 mg/dL had multivariate-adjusted hazard ratios (HRs) for ischemic stroke of 1.3 (95% CI, 0.8-1.9; 351 events); for 177 through 265 mg/dL, 1.6 (95% CI, 1.0-2.5; 189 events); for 266 through 353 mg/dL, 1.5 (95% CI, 0.9-2.7; 73 events); for 354 through 442 mg/dL, 2.2 (95% CI, 1.1-4.2; 40 events); and for 443 mg/dL or greater, 2.5 (95% CI, 1.3-4.8; 41 events) vs men with nonfasting levels less than 89 mg/dL (HR, 1.0; 85 events) (P < .001 for trend). Corresponding values for women were 1.3 (95% CI, 0.9-1.7; 407 events), 2.0 (95% CI, 1.3-2.9; 135 events), 1.4 (95% CI, 0.7-2.9; 26 events), 2.5 (95% CI, 1.0-6.4; 13 events), and 3.8 (95% CI, 1.3-11; 10 events) vs women with nonfasting triglyceride levels less than 89 mg/dL (HR, 1.0; 159 events) (P < .001 for trend). Absolute 10-year risk of ischemic stroke ranged from 2.6% in men younger than 55 years with nonfasting triglyceride levels of less than 89 mg/dL to 16.7% in men aged 55 years or older with levels of 443 mg/dL or greater. Corresponding values in women were 1.9% and 12.2%. In the cross-sectional study, men with a previous ischemic stroke vs controls had nonfasting triglyceride levels of 191 (IQR, 131-259) mg/dL vs 148 (IQR, 104-214) mg/dL (P < .01); corresponding values for women were 167 (IQR, 121-229) mg/dL vs 127 (IQR, 91-181) mg/dL (P < .05). For remnant cholesterol, corresponding values were 38 (IQR, 26-51) mg/dL vs 29 (IQR, 20-42) mg/dL in men (P < .01) and 33 (IQR, 24-45) mg/dL vs 25 (IQR, 18-35) mg/dL in women (P < .05)., Conclusion: In this study population, nonfasting triglyceride levels were associated with risk of ischemic stroke.
- Published
- 2008
- Full Text
- View/download PDF
21. Heterogeneity and weak coupling may explain the synchronization characteristics of cells in the arterial wall.
- Author
-
Jacobsen JC, Aalkjaer C, Matchkov VV, Nilsson H, Freiberg JJ, and Holstein-Rathlou NH
- Subjects
- Animals, Calcium Signaling, Cytosol metabolism, Gap Junctions, Guanosine Monophosphate chemistry, Membrane Potentials, Models, Biological, Oscillometry, Rats, Rats, Wistar, Arteries pathology, Calcium metabolism, Muscle, Smooth, Vascular metabolism, Myocytes, Smooth Muscle cytology
- Abstract
Vascular smooth muscle cells (SMCs) exhibit different types of calcium dynamics. Static vascular tone is associated with unsynchronized calcium waves and the developed force depends on the number of recruited cells. Global calcium transients synchronized among a large number of cells cause rhythmic development of force known as vasomotion. We present experimental data showing a considerable heterogeneity in cellular calcium dynamics in the vascular wall. In stimulated vessels, some SMCs remain quiescent, whereas others display waves of variable frequency. At the onset of vasomotion, all SMCs are enrolled into synchronized oscillation. Simulations of coupled SMCs show that the experimentally observed cellular recruitment, the presence of quiescent cells and the variation in oscillation frequency may arise if the cell population is phenotypically heterogeneous. In this case, quiescent cells can be entrained at the onset of vasomotion by the collective driving force from the synchronized oscillations in the membrane potential of the surrounding cells. Partial synchronization arises with an increase in the concentration of cyclic guanosine monophosphate, but in a heterogeneous cell population complete synchronization also requires a high-conductance pathway that provides strong coupling between the cells.
- Published
- 2008
- Full Text
- View/download PDF
22. Promotor polymorphisms in leukotriene C4 synthase and risk of ischemic cerebrovascular disease.
- Author
-
Freiberg JJ, Tybjaerg-Hansen A, Sillesen H, Jensen GB, and Nordestgaard BG
- Subjects
- Adult, Aged, Aged, 80 and over, Carotid Artery Diseases genetics, Carotid Artery Diseases physiopathology, Case-Control Studies, Cerebrovascular Disorders physiopathology, Cross-Sectional Studies, Cysteine physiology, Female, Follow-Up Studies, Gene Frequency, Genetic Predisposition to Disease genetics, Glutathione Transferase physiology, Humans, Leukotrienes physiology, Linkage Disequilibrium genetics, Male, Middle Aged, Predictive Value of Tests, Prospective Studies, Risk Factors, Stroke physiopathology, Venous Thrombosis genetics, Venous Thrombosis physiopathology, Cerebrovascular Disorders genetics, Glutathione Transferase genetics, Polymorphism, Genetic genetics, Stroke genetics
- Abstract
Objective: Cysteinyl leukotrienes are involved in inflammation and possibly in early carotid atherosclerosis. We tested the hypothesis that the -444 A/C and -1072 G/A polymorphisms of the leukotriene C(4) synthase associate with risk of ischemic cerebrovascular disease., Methods and Results: We genotyped 10 592 individuals from the Danish general population, the Copenhagen City Heart Study. During 24 years of follow-up, 557 individuals developed ischemic cerebrovascular disease. The allele frequency was 0.07 for -1072 A and 0.29 for -444 C. Cumulative incidence for ischemic cerebrovascular disease was higher for -1072 AA versus GG genotype (log-rank: P=0.002), and lower for -444 CC versus AA genotype (log-rank: P=0.008). Combined genotypes showed corresponding cumulative incidence differences (log-rank: P=0.003). Multifactorially adjusted hazard ratios for ischemic cerebrovascular disease were 2.8(1.4 to 5.7) for -1072 AA versus GG genotype, 0.6(0.4 to 0.9) for -444 CC versus AA genotype, 2.5(1.2 to 5.4) for combined AA-AA versus GG-AA genotype, and 0.6(0.4 to 0.9) for combined GG-CC versus GG-AA genotype. Genotype did not associate with risk of deep venous thrombosis or severe carotid atherosclerosis, or with levels of platelets and coagulation factors., Conclusions: Leukotriene C(4) synthase -1072 AA genotype predict increased risk, whereas -444 CC genotype predict decreased risk of ischemic cerebrovascular disease.
- Published
- 2008
- Full Text
- View/download PDF
Catalog
Discovery Service for Jio Institute Digital Library
For full access to our library's resources, please sign in.