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1.
Neurology ; 2019 Aug 30.
Artigo em Inglês | MEDLINE | ID: mdl-31471504

RESUMO

OBJECTIVE: To test the hypothesis that the associations of body mass index (BMI) and BMI-related risk factors with risk of stroke have attenuated over time using cohorts recruited from the general population over 4 decades. METHODS: We undertook prospective studies of 2 cohorts enrolled in 1976 to 1978 (13,567 participants from the Copenhagen City Heart Study) and 2003 to 2015 (107,040 participants from the Copenhagen General Population Study). Each cohort was recruited randomly from the Danish general population 20 to 100 years of age. Participants were followed up from the date of examination to date of emigration, death, or stroke event, whichever occurred first. Follow-up ended in March 2017. We did not lose track of any individual. BMI and blood pressure were modeled with splines and in categories. Main outcome was incident stroke, including ischemic stroke, intracerebral hemorrhage, and subarachnoid hemorrhage. RESULTS: The crude incidence of stroke declined in extreme categories of BMI and blood pressure from 1977 to 2017. The multivariable-adjusted hazard ratios for stroke in participants with BMI ≥30 vs 18.5 to 24.9 kg/m2 were 1.4 (95% confidence interval 1.2-1.6) in the 1976-1978 cohort and 1.1 (1.0-1.2) in the 2003-2015 cohort (p = 0.008 for 1976-1978 vs 2003-2015). The corresponding hazard ratios (confidence intervals) in participants with blood pressure ≥160/100 vs <140/90 mm Hg were 2.1 (1.9-2.3) and 1.5 (1.4-1.7), respectively (p < 0.001). Similar secular trends were observed for diabetes mellitus but were not obvious for other risk factors. CONCLUSION: The associations of high BMI and high blood pressure with higher risk of stroke were attenuated across 2 Danish cohorts enrolled from 1976 through 2015.

2.
J Am Coll Cardiol ; 74(11): 1465-1476, 2019 Sep 17.
Artigo em Inglês | MEDLINE | ID: mdl-31514949

RESUMO

BACKGROUND: Low-density lipoprotein cholesterol (LDL-C) is causally associated with a high risk of coronary artery disease. Whether this also holds for a spectrum of peripheral vascular diseases is unknown. OBJECTIVES: The purpose of this study was to determine whether high LDL-C causally relates to risk of retinopathy, neuropathy, chronic kidney disease (CKD), and peripheral arterial disease (PAD) in the general population. METHODS: One-sample Mendelian randomization (MR) of 116,419 Danish individuals, 2-sample MR on summary-level data from the Global Lipid Genetics Consortium (GLGC) (n = 94,595) and the UK Biobank (n = 408,455), and meta-analysis of randomized statin trials (n = 64,134) were performed. RESULTS: Observationally, high LDL-C did not associate with high risk of retinopathy or neuropathy. There were stepwise increases in risk of CKD and PAD with higher LDL-C (both p for trend <0.001), with hazard ratios of 1.05 (95% confidence interval [CI]: 0.97 to 1.13) for CKD, and 1.41 (95% CI: 1.23 to 1.62) for PAD in individuals with LDL-C above the 95th percentile versus below the 50th percentile. In genetic, causal analyses in the Copenhagen studies, the risk ratio of disease for a 1 mmol/l higher LDL-C was 1.06 (95% CI: 0.24 to 4.58) for retinopathy, 1.05 (95% CI: 0.64 to 1.72) for neuropathy, 3.83 (95% CI: 2.00 to 7.34) for CKD, and 2.09 (95% CI: 1.30 to 2.38) for PAD. Summary-level data from the GLGC and the UK Biobank for retinopathy, neuropathy, and PAD gave similar results. For CKD, a 1-mmol/l lower LDL-C conferred a higher eGFR of 1.95 ml/min/1.73 m2 (95% CI: 1.88 to 2.02 ml/min/1.73 m2) observationally, 5.92 ml/min/1.73 m2 (95% CI: 4.97 to 6.86 ml/min/1.73 m2) genetically, and 2.69 ml/min/1.73 m2 (95% CI: 1.48 to 3.94 ml/min/1.73 m2) through statin therapy. CONCLUSIONS: High LDL-C was not causally associated with risk of retinopathy and neuropathy; however, high LDL-C was observationally and genetically associated with high risks of PAD and CKD, suggesting that LDL-C is causally involved in the pathogenesis of these diseases.

3.
Thorax ; 74(10): 934-940, 2019 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-31481635

RESUMO

BACKGROUND: Individual susceptibility to exacerbations in chronic obstructive pulmonary disease (COPD) is likely influenced by genetic factors; however, most such variance is unexplained. We hypothesised that ß2-adrenergic receptor genotypes, Gly16Arg (rs1042713, c.46G>A) and Gln27Glu (rs1042714, c.79C>G) influence risk of severe exacerbations in COPD. METHODS: Among 96 762 individuals in the Copenhagen General Population Study, we identified 5262 with COPD (forced expiratory volume in one second divided by forced vital capacity, FEV1/FVC, below 0.7, FEV1 less than 80% of predicted value, age above 40 years and no asthma) who had genotyping performed. Severe exacerbations were defined as acute admissions due to COPD during 5 years of follow-up (mean 3.4 years). 923 individuals with COPD diagnosed similarly in the Copenhagen City Heart Study (CCHS) were used for replication analyses. RESULTS: We recorded 461 severe exacerbations in 5262 subjects. The HRs for severe exacerbations were 1.62 (95% CI 1.30 to 2.03, p=0.00002) for 16Gly/Arg heterozygotes and 1.41 (1.04 to 1.91, p=0.03) for 16Arg homozygotes, compared with 16Gly homozygotes. HRs were 1.35 (1.03 to 1.76, p=0.03) for 27Gln/Glu heterozygotes and 1.49 (1.12 to 1.98, p=0.006) for 27Gln homozygotes, compared with 27Glu homozygotes. Similar trends were observed in the CCHS. Among 27Gln homozygotes only, HRs were 5.20 (1.81 to 14.9, p=0.002) for 16Gly/Arg heterozygotes and 4.03 (1.40 to 11.6, p=0.01) for 16Arg homozygotes, compared with 16Gly homozygotes. CONCLUSION: Common ß2-adrenergic receptor genotypes influence risk of severe exacerbations in COPD, potentially mainly by genetic influence of the 16Arg allele in rs1042713.

5.
BMC Med ; 17(1): 160, 2019 Aug 30.
Artigo em Inglês | MEDLINE | ID: mdl-31466528

RESUMO

BACKGROUND: Randomised control trials and genetic analyses have demonstrated that vitamin D or 25-hydroxyvitamin D (25[OH]D) levels may not play a causal role in the development of cardiovascular disease. However, it is unclear if 25(OH)D is causally associated with cause-specific vascular disease and lipids. Therefore, we examined the causal association of 25(OH)D with myocardial infarction, stroke, ischaemic heart disease, ischaemic stroke, subarachnoid haemorrhage, intracerebral haemorrhage, and lipid levels among both Chinese and Europeans. METHODS: We used a Mendelian randomisation (MR) design in the China Kadoorie Biobank, the Copenhagen City Heart Study, and the Copenhagen General Population Study. The 25(OH)D-related genetic variants in the CYP2R1 and DCHR7 genes were genotyped in 99,012 Chinese adults and 106,911 Danish adults. RESULTS: In Chinese adults, plasma 25(OH)D levels were not significantly associated with cause-specific vascular disease or mortality, with the exception of intracerebral haemorrhage (HR, 1.09 [95% CI, 1.01,1.18] per 25 nmol/L higher plasma 25(OH)D). In Europeans, plasma 25(OH)D levels were inversely associated with all types of vascular diseases and mortality. However, MR analysis did not demonstrate causal associations of genetically increased 25(OH)D levels with cause-specific vascular diseases, or mortality in both Chinese and European adults. In addition, each 25 nmol/L higher 25(OH)D was observationally associated with lower total cholesterol and low-density lipoprotein cholesterol levels, but higher high-density lipoprotein cholesterol levels. Likewise, MR analysis showed that 25(OH)D levels were not causally associated with lipids in both Chinese and European adults after Bonferroni correction. CONCLUSIONS: We found no evidence to support that genetically increased 25(OH)D was associated with a lower risk of ischaemic stroke, intracerebral haemorrhage, subarachnoid haemorrhage, and lipid levels in both Chinese and European adults. These results suggest that the inverse associations of vitamin D with vascular disease could be the result of confounding.

6.
AIDS ; 2019 Aug 01.
Artigo em Inglês | MEDLINE | ID: mdl-31373917

RESUMO

: Abnormal electrocardiograms (ECG) are associated with increased risk of arrhythmias and sudden cardiac death. We aimed to investigate the prevalence and associated risk factors of prolonged QTc and major ECG abnormalities, in persons living with HIV (PLWH) and uninfected controls. DESIGN: PLWH aged ≥40 were recruited from the Copenhagen comorbidity in HIV infection (COCOMO) study and matched on sex and age to uninfected controls from the Copenhagen General Population Study. METHODS: ECGs were categorized according to Minnesota Code Manual of ECG Findings definition of major abnormalities. A QT interval corrected for heart rate (QTc) >440ms in males and >460ms in females was considered prolonged. Pathologic Q-waves were defined as presence of major Q-wave abnormalities. RESULTS: ECGs were available for 745 PLWH and 2,977 controls. Prolonged QTc was prevalent in 9% of PLWH and 6% of controls, p = .052. Pathologic Q-waves were more common in PLWH (6%) than in controls (4%), p = .028. There was no difference in prevalence of major ECG abnormalities between PLWH and controls, p = .987.In adjusted analyses, HIV was associated with a 3.6ms[1.8-5.4] longer QTc interval, p < .001, and HIV was independently associated with prolonged QTc (adjusted odds ratio: 1.59 [1.14-2.19]), p = .005. HIV was borderline associated to pathologic Q-waves after adjusting, p = .051. CONCLUSION: HIV was associated with higher odds ratio of prolonged QTc after adjustment for cardiovascular risk factors, but analyses were not adjusted for QT-prolonging medication. Although evidence indicated more pathologic Q-waves in PLWH, the risk seemed to be associated mainly with an adverse risk profile.

8.
Artigo em Inglês | MEDLINE | ID: mdl-31385593

RESUMO

Objective Prolonged seated immobility during long-distance flights is related to an increased risk of venous thromboembolism (VTE), but little, if anything, is known about the risk related to sedentary work. The objective of this paper was to examine the risk of VTE according to sitting posture at work. Methods This prospective study includes a total of 78 936 participants from the Copenhagen City Heart Study and the Copenhagen General Population Study, all without previous thromboembolic events and aged <65 years. An assessment of the number of hours spent in sitting position at work was assigned each participant at baseline using a job exposure matrix. VTE was identified through national patient registries. Survival analyses were performed to determine the risk of VTE according to sedentary position at work with adjustment for a range of known determinants including lifestyle and coagulation factors. Results During the follow-up period of 582 411 person years (mean follow-up, 7.4 years) 911 participants experienced their first VTE event. Multivariable adjusted analyses showed no difference in risk of VTE between occupational sitting ≥6.5 hours/day and occupational sitting ≤3.5 hours/day (hazard ratio 1.11, 95% confidence interval 0.92-1.34). Conclusion This study does not support the hypothesis that sedentary work is a risk factor for VTE in the general population. Whether certain occupations with particularly high exposure to immobilized sitting positions are associated with thromboembolic events is not addressed.

9.
J Infect Dis ; 2019 Aug 15.
Artigo em Inglês | MEDLINE | ID: mdl-31414119

RESUMO

BACKGROUND: Prior to the introduction of combination antiretroviral therapy (cART), cytopenias were common in people with HIV (PWH), but it is unknown if well-controlled HIV infection is a risk factor for cytopenia. In this study we aimed to determine if HIV infection is an independent risk factor for anemia, neutropenia, lymphocytopenia, and thrombocytopenia. METHODS: PWH with undetectable viral replication and absence of chronic hepatitis infection (n=796) were recruited from the Copenhagen Comorbidity in HIV infection (COCOMO) study and matched uninfected controls from the Copenhagen General Population Study (n=2388). Hematology was analyzed in venous blood samples. Logistic regression analyses adjusted for age, sex, ethnicity, smoking status, alcohol, and hs-CRP were performed to determine possible associations between HIV and cytopenias. RESULTS: PWH had a higher prevalence of anemia (6.9% vs. 3.4%, P<.001), neutropenia (1.3% vs. 0.2%, P<.001), and thrombocytopenia (5.5% vs. 2.7%, P<.001) than uninfected controls. HIV was independently associated with anemia adjusted odds ratio (aOR) 2.0 (95%CI: 1.4-3.0), neutropenia aOR 6.3 (95%CI: 2.0-19.6) and thrombocytopenia aOR 2.7 (95%CI: 1.8-4.2). No association was found between HIV and lymphocytopenia. CONCLUSIONS: Cytopenia is rare in PWH and well-controlled virus, but HIV remains a risk factor for anemia, neutropenia and thrombocytopenia and requires ongoing attention and monitoring.

10.
J Am Coll Cardiol ; 74(1): 54-66, 2019 Jul 09.
Artigo em Inglês | MEDLINE | ID: mdl-31272552

RESUMO

BACKGROUND: High lipoprotein(a) is associated with increased risk of myocardial infarction and aortic valve stenosis. Previous studies have examined the association of lipoprotein(a) and risk of stroke; however, the results are conflicting. OBJECTIVES: The purpose of this study was to test if high lipoprotein(a) is associated with high risk of ischemic stroke observationally and causally from human genetics. METHODS: The study included 49,699 individuals from the Copenhagen General Population Study and 10,813 individuals from the Copenhagen City Heart Study with measurements of plasma lipoprotein(a), LPA kringle-IV type 2 number of repeats, and LPA rs10455872. The endpoint of ischemic stroke was ascertained from Danish national health registries and validated by medical doctors. RESULTS: Compared with individuals with lipoprotein(a) levels <10 mg/dl (<18 nmol/l: first to 50th percentile), the multivariable-adjusted hazard ratio for ischemic stroke was 1.60 (95% confidence interval [CI]:1.24 to 2.05) for individuals with lipoprotein(a) levels >93mg/dl (>199 nmol/L: 96th to 100th percentile). In observational analyses for a 50 mg/dl (105 nmol/l) higher lipoprotein(a) level the age- and sex-adjusted hazard ratio for ischemic stroke was 1.20 (95% CI: 1.13 to 1.28), while the corresponding age- and sex-adjusted genetic causal risk ratio for KIV-2 number of repeats was 1.20 (95% CI: 1.02 to 1.43) and for rs10455872 was 1.27 (95% CI: 1.06 to 1.51). The highest absolute 10-year risk of ischemic stroke was 17% in active smoking individuals >70 years of age with hypertension and lipoprotein(a) levels >93 mg/dl (>199 nmol/l: 96th to 100th percentile). In the Copenhagen City Heart Study, risk estimates for high levels of lipoprotein(a) were in the same direction but did not reach statistical significance. CONCLUSIONS: In a large contemporary general population study, high plasma levels of lipoprotein(a) were associated with increased risk of ischemic stroke both observationally and causally from human genetics.

11.
Curr Vasc Pharmacol ; 17(5): 515-537, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-31309820

RESUMO

Postprandial hypertriglyceridaemia, defined as an increase in plasma triglyceride-containing lipoproteins following a fat meal, is a potential risk predictor of atherosclerotic cardiovascular disease and other chronic diseases. Several non-modifiable factors (genetics, age, sex and menopausal status) and lifestyle factors (diet, physical activity, smoking status, obesity, alcohol and medication use) may influence postprandial hypertriglyceridaemia. This narrative review considers the studies published over the last decade that evaluated postprandial hypertriglyceridaemia. Additionally, the genetic determinants of postprandial plasma triglyceride levels, the types of meals for studying postprandial triglyceride response, and underlying conditions (e.g. familial dyslipidaemias, diabetes mellitus, metabolic syndrome, non-alcoholic fatty liver and chronic kidney disease) that are associated with postprandial hypertriglyceridaemia are reviewed; therapeutic aspects are also considered.

12.
Respir Med ; 155: 141-147, 2019 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-31362177

RESUMO

BACKGROUND: Differences in previous exacerbation history may influence prognosis of chronic obstructive pulmonary disease (COPD). We hypothesized that prognosis differs between individuals with a history of only medically treated exacerbations (moderate exacerbations) and those with a history of hospitalised exacerbations (severe exacerbations). METHODS: We included 98 614 adults from the Copenhagen General Population Study and assessed risk of moderate and severe exacerbations, pneumonia hospitalisation, and respiratory and all-cause mortality from 2003 until 2013 according to exacerbation history. RESULTS: Among 6545 individuals with COPD, 6290 had no exacerbations in the preceding year, 109 had one moderate exacerbation, 108 had two or more moderate exacerbations, and 38 had one or more severe exacerbations. During 9.4 years of follow-up, we observed 926 moderate and 244 severe exacerbations, 477 pneumonias, and 707 deaths, including 69 from respiratory disease. Compared to individuals without previous exacerbations, lung function and symptom adjusted hazard ratios (HRs) for future moderate exacerbation were 4.68 (95% confidence interval:3.31-6.62) for individuals with one previous moderate exacerbation, 21 (13-33) for individuals with two or more previous moderate exacerbations, and 5.30 (3.44-8.15) for individuals with one or more previous severe exacerbations. Corresponding HRs were 1.62(0.78-3.34), 1.29(0.57-2.89), and 5.43 (2.56-12) for severe exacerbation, 1.86(1.06-3.27), 1.74(1.01-2.99), and 4.85 (2.94-8.02) for pneumonia, 0.53(0.10-2.99), 1.65(0.53-5.17), and 2.98 (1.14-7.83) for respiratory mortality, and 1.34(0.79-2.29), 1.57(1.00-2.47), and 1.49 (0.85-2.62) for all-cause mortality, respectively. CONCLUSION: Individuals with COPD and a history of hospitalised exacerbations carried the poorest prognosis compared to those with a history of only medically treated exacerbations, suggesting difference in risk profile.

13.
J Thromb Haemost ; 2019 Jul 15.
Artigo em Inglês | MEDLINE | ID: mdl-31309714

RESUMO

BACKGROUND: It is unclear whether high platelet count or high hematocrit predict risk of thrombosis in individuals from the general population. OBJECTIVES: We tested the hypothesis that individuals from the general population with high platelet count or high hematocrit have high risk of arterial and venous thrombosis. METHODS: We prospectively followed 108 521 individuals from The Copenhagen General Population Study for a median of 8 years. Platelet count and blood hematocrit were measured at study entry. RESULTS AND CONCLUSION: Multivariable adjusted hazard ratios for individuals with platelet counts in the top 5 percentiles (>398 × 109 /L) vs in the 25th-75th percentiles (231-316 × 109 /L) were 1.77 (95% confidence interval [CI], 1.38-2.24) for arterial thrombosis in the brain (38 and 26 events/10 000 person-years) and 0.82 (95%, 0.61-1.11) for arterial thrombosis in the heart (23 and 28 events/10 000 person-years). For individuals with hematocrit values in the top 5 percentiles (women/men: >45/>48%) vs the 25th-75th percentiles (women/men: 38.1-42/41.1-45%), hazard ratios were 1.27 (95% CI, 0.91-1.75) for arterial thrombosis in the brain (40 and 26 events/10 000 person-years) and 1.46 (95% CI, 1.06-2.00) for arterial thrombosis in the heart (43 and 25 events/10 000 person-years). Neither high platelet count nor high hematocrit was associated with risk of venous thromboembolism. When excluding individuals with myeloproliferative neoplasia from the main analyses, results on risk of thrombosis were similar. In this prospective study, high platelet counts were associated with 1.8-fold risk of arterial thrombosis in the brain, whereas high hematocrit was associated with 1.5-fold risk of arterial thrombosis in the heart.

14.
J Clin Lipidol ; 13(3): 374-392, 2019 May - Jun.
Artigo em Inglês | MEDLINE | ID: mdl-31147269

RESUMO

Lipoprotein(a) [Lp(a)] is a well-recognized, independent risk factor for atherosclerotic cardiovascular disease, with elevated levels estimated to be prevalent in 20% of the population. Observational and genetic evidence strongly support a causal relationship between high plasma concentrations of Lp(a) and increased risk of atherosclerotic cardiovascular disease-related events, such as myocardial infarction and stroke, and valvular aortic stenosis. In this scientific statement, we review an array of evidence-based considerations for testing of Lp(a) in clinical practice and the utilization of Lp(a) levels to inform treatment strategies in primary and secondary prevention.

15.
J Am Coll Cardiol ; 73(24): 3102-3114, 2019 Jun 25.
Artigo em Inglês | MEDLINE | ID: mdl-31221259

RESUMO

BACKGROUND: Reduced low-density lipoprotein (LDL) cholesterol due to inhibition of proprotein convertase subtilisin/kexin 9 (PCSK9) reduces cardiovascular events and may therefore also reduce cardiovascular and all-cause mortality. OBJECTIVES: This study tested the hypothesis that genetically low LDL cholesterol due to PCSK9 variation is causally associated with low cardiovascular and all-cause mortality in the general population. METHODS: A total of 109,566 individuals from the Copenhagen General Population Study and the Copenhagen City Heart Study were genotyped for PCSK9 R46L (rs11591147), R237W (rs148195424), I474V (rs562556), and E670G (rs505151). During a median follow-up of 10 years (range 0 to 42 years) and 1,247,225 person-years, there were 3,828 cardiovascular deaths and 16,373 deaths from any cause. Results were validated using data on 431,043 individuals from the UK Biobank. RESULTS: An increasing number of weighted PCSK9 alleles were associated with stepwise lower LDL cholesterol of up to 0.61 mmol/l (24 mg/dl; 18.2%; p for trend <0.001) and with lower cardiovascular mortality (p = 0.001), but not with lower all-cause mortality (p = 0.11). In causal, genetic analyses, a 0.5-mmol/l (19.4-mg/dl) lower LDL cholesterol was associated with risk ratios for cardiovascular and all-cause mortality of 0.79 (95% confidence interval [CI]: 0.63 to 0.99; p = 0.04) and 1.02 (95% CI: 0.94 to 1.12; p = 0.63) in the Copenhagen studies, 0.79 (95% CI: 0.58 to 1.08; p = 0.14) and 0.98 (95% CI: 0.87 to 1.10; p = 0.75) in the UK Biobank, and of 0.79 (95% CI: 0.65 to 0.95; p = 0.01) and 1.01 (95% CI: 0.94 to 1.08; p = 0.85), respectively, in studies combined. CONCLUSIONS: Genetically low LDL cholesterol due to PCSK9 variation was causally associated with low risk of cardiovascular mortality, but not with low all-cause mortality in the general population.

16.
Cardiovasc Diabetol ; 18(1): 71, 2019 Jun 04.
Artigo em Inglês | MEDLINE | ID: mdl-31164165

RESUMO

In the era of precision medicine, treatments that target specific modifiable characteristics of high-risk patients have the potential to lower further the residual risk of atherosclerotic cardiovascular events. Correction of atherogenic dyslipidemia, however, remains a major unmet clinical need. Elevated plasma triglycerides, with or without low levels of high-density lipoprotein cholesterol (HDL-C), offer a key modifiable component of this common dyslipidemia, especially in insulin resistant conditions such as type 2 diabetes mellitus. The development of selective peroxisome proliferator-activated receptor alpha modulators (SPPARMα) offers an approach to address this treatment gap. This Joint Consensus Panel appraised evidence for the first SPPARMα agonist and concluded that this agent represents a novel therapeutic class, distinct from fibrates, based on pharmacological activity, and, importantly, a safe hepatic and renal profile. The ongoing PROMINENT cardiovascular outcomes trial is testing in 10,000 patients with type 2 diabetes mellitus, elevated triglycerides, and low levels of HDL-C whether treatment with this SPPARMα agonist safely reduces residual cardiovascular risk.

17.
Eur Heart J ; 40(33): 2813-2824, 2019 Sep 01.
Artigo em Inglês | MEDLINE | ID: mdl-31236578

RESUMO

AIMS: To determine whether plasma apoE levels and APOE genotype are associated with all-cause and cause-specific mortality. METHODS AND RESULTS: Using a prospective cohort design with 105 949 white individuals from the general population, we tested the association between plasma apoE at study enrolment and death during follow-up, and whether this was independent of APOE genotype. We confirmed the well-known association between APOE genotypes and mortality. For all-cause, cardiovascular, and cancer mortality, high levels of apoE were associated with increased risk, while for dementia-associated mortality low levels were associated with increased risk. For the highest vs. the fifth septile of plasma apoE, hazard ratios (HRs) were 1.20 (95% confidence interval 1.12-1.28) for all-cause mortality, 1.28 (1.13-1.44) for cardiovascular mortality, and 1.18 (1.05-1.32) for cancer mortality. Conversely, for the lowest vs. the fifth septile the HR was 1.44 (1.01-2.05) for dementia-associated mortality. Results were similar in analyses restricted to APOE ɛ33 carriers. Examining genetically determined plasma apoE, a 1 mg/dL increase conferred risk ratios of 0.97 (0.92-1.03) for cardiovascular mortality and 1.01 (0.95-1.06) for cancer mortality, while a 1 mg/dL decrease conferred a risk ratio of 1.70 (1.36-2.12) for dementia-associated mortality. CONCLUSION: High plasma levels of apoE were associated with increased all-cause, cardiovascular, and cancer mortality, however of a non-causal nature, while low levels were causally associated with increased dementia-associated mortality.

19.
Eur Respir J ; 2019 Jun 27.
Artigo em Inglês | MEDLINE | ID: mdl-31248954

RESUMO

A normal spirometry is often used to preclude airway disease in individuals with unspecific respiratory symptoms. We tested the hypothesis that chronic respiratory symptoms are associated with respiratory hospitalisations and death in individuals with normal spirometry without known airway disease.We included 108 246 randomly chosen individuals aged 20-100 from a Danish population-based cohort study. Normal spirometry was defined as a pre-bronchodilator forced expiratory volume in 1 s(FEV1)/forced vital capacity(FVC)≥0.70. Chronic respiratory symptoms included dyspnoea, chronic mucus hypersecretion, wheezing, and cough. Individuals with known airway disease, i.e. chronic obstructive pulmonary disease and/or asthma, were excluded (n=10 291). We assessed risk of hospitalisations due to exacerbations of airway disease and pneumonia, and respiratory and all-cause mortality from 2003 through 2018.52 999 had normal spirometry without chronic respiratory symptoms and 30 890 had normal spirometry with chronic respiratory symptoms. During follow-up, we observed 1037 hospitalisations with exacerbation of airway disease, 5743 hospitalisations with pneumonia, and 8750 deaths, of which 463 were due to respiratory disease. Compared to individuals with normal spirometry without chronic respiratory symptoms, multivariable adjusted hazard ratios for individuals with normal spirometry with chronic respiratory symptoms were 1.62(95% confidence interval:1.20-2.18) for exacerbation hospitalisations, 1.26(1.17-1.37) for pneumonia hospitalisations, 1.59(1.22-2.06) for respiratory mortality, and 1.19(1.13-1.25) for all-cause mortality. There was a positive dose-response relationship between number of symptoms and risk of outcomes. Results were similar after 2 years follow-up, for never-smokers alone, and for each symptom separately.Chronic respiratory symptoms are associated with respiratory hospitalisations and death in individuals with normal spirometry without known airway disease.

20.
Curr Atheroscler Rep ; 21(8): 30, 2019 May 20.
Artigo em Inglês | MEDLINE | ID: mdl-31111240

RESUMO

PURPOSE OF REVIEW: High lipoprotein(a) levels are observationally and causally, from human genetics, associated with increased risk of cardiovascular disease including myocardial infarction and aortic valve stenosis. The European Atherosclerosis Society recommends screening for elevated lipoprotein(a) levels in high-risk patients. Different therapies have been suggested and some are used to treat elevated lipoprotein(a) levels such as niacin, PCSK9 inhibitors, and CETP inhibitors; however, to date, no randomized controlled trial has demonstrated that lowering of lipoprotein(a) leads to lower risk of cardiovascular disease. RECENT FINDINGS: Synthetic oligonucleotides can be used to inactivate genes involved in disease processes. To lower lipoprotein(a), two antisense oligonucleotides have been developed, one targeting apolipoprotein B and one targeting apolipoprotein(a). Mipomersen is an antisense oligonucleotide targeting apolipoprotein B and thereby reducing levels of all apolipoprotein B containing lipoproteins in the circulation. Mipomersen has been shown to lower lipoprotein(a) by 20-50% in phase 3 studies. AKCEA-APO(a)-LRx is the most recent antisense oligonucleotide targeting apolipoprotein(a) and thereby uniquely targeting lipoprotein(a). It has been tested in a phase 2 study and has shown to lower lipoprotein(a) levels by 50-80%. The treatment of elevated lipoprotein(a) levels with the newest antisense oligonucleotides seems promising; however, no improvement in cardiovascular disease risk has yet been shown. However, a phase 3 study of AKCEA-APO(a)-LRx is being planned with cardiovascular disease as outcome, and results are awaited with great anticipation.

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