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Single nucleotide polymorphism (SNP) interactions are the key to improving polygenic risk scores. Previous studies reported several significant SNP-SNP interaction pairs that shared a common SNP to form a cluster, but some identified pairs might be false positives. This study aims to identify factors associated with the cluster effect of false positivity and develop strategies to enhance the accuracy of SNP-SNP interactions. The results showed the cluster effect is a major cause of false-positive findings of SNP-SNP interactions. This cluster effect is due to high correlations between a causal pair and null pairs in a cluster. The clusters with a hub SNP with a significant main effect and a large minor allele frequency (MAF) tended to have a higher false-positive rate. In addition, peripheral null SNPs in a cluster with a small MAF tended to enhance false positivity. We also demonstrated that using the modified significance criterion based on the 3 p-value rules and the bootstrap approach (3pRule + bootstrap) can reduce false positivity and maintain high true positivity. In addition, our results also showed that a pair without a significant main effect tends to have weak or no interaction. This study identified the cluster effect and suggested using the 3pRule + bootstrap approach to enhance SNP-SNP interaction detection accuracy.
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Herança Multifatorial , Polimorfismo de Nucleotídeo Único , Humanos , Herança Multifatorial/genética , Frequência do Gene , Estudo de Associação Genômica Ampla/métodos , Análise por Conglomerados , Modelos Genéticos , Epistasia GenéticaRESUMO
AIMS: Thoracic aortic diameter is modulated by various factors including both physiological and pathological mechanisms. The aim of this study was to explore the determinants of thoracic aortic size focusing on arterial blood pressure and physical activity in normotensive and hypertensive individuals. METHODS: Ascending and descending aortic diameters were measured in participants of the Copenhagen General Population Study using thoracic CT angiography. To assess the relation between arterial blood pressure and thoracic aortic diameters, individuals with diabetes, hypercholesterolemia, smoking, and prescribed antihypertensive medication were excluded. Intensity of physical activity was recorded based on self-reported questionnaire data. RESULTS: A total of 1214 normotensive and 284 hypertensive individuals were examined. In all individuals, male sex, older age, and body surface area were associated with higher diameters of the ascending and descending aorta (Pâ<â0.01). In normotensive individuals, hard physical activity >â4âh/week was independently associated with higher thoracic aortic diameters (ascending ß:1.09[0.52;1.66] and descending ß: 0.47[0.14;0.80], both Pâ<â0.01), whereas higher systolic blood pressure was not associated with thoracic aortic diameters (ascending Pâ=â0.12 and descending pâ=â0.33). In hypertensive individuals, higher systolic blood pressure (per 10âmmHg) was independently associated with higher thoracic aortic diameters (ascending ß: 0.55[0.17;0.94] and descending ß: 0.23[0.10;0.37] mm/10âmmHg, both Pâ<â0.01), whereas hard physical activity was not associated with higher aortic diameters (ascending Pâ=â0.11 and descending Pâ=â0.51). CONCLUSION: In normotensive individuals hard physical activity, and in hypertensive individuals increasing systolic blood pressure are factors each independently associated with larger thoracic aortic size. These findings suggest a context sensitive mode of aortic vascular response to size modulating adaptation.
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BACKGROUND: Pre-eclampsia is a pregnancy related disorder associated with hypertension and vascular inflammation, factors that are also involved in the pathological pathway of aortic dilatation and aneurysm development. It is, however, unknown if younger women with previous pre-eclampsia have increased aortic dimensions. We tested the hypothesis that previous pre-eclampsia is associated with increased aortic dimensions in younger women. METHODS: The study was a cross-sectional cohort study of women with previous pre-eclampsia, aged 40-55, from the PRECIOUS population matched by age and parity with women from the general population. Using contrast-enhanced CT, aortic diameters were measured in the aortic root, ascending aorta, descending aorta, at the level of the diaphragm, suprarenal aorta, and infrarenal aorta. RESULTS: 1355 women (684 with previous pre-eclampsia and 671 from the general population), with a mean (standard deviation) age of 46.9 (4.4) were included. The pre-eclampsia group had larger mean (standard deviation) aortic diameters (mm) in all measured segments from the ascending to the infrarenal aorta (ascending: 33.4 (4.0) vs. 31.4 (3.7), descending: 23.9 (2.1) vs. 23.3 (2.0), diaphragm: 20.8 (1.8) vs. 20.4 (1.8), suprarenal: 22.9 (1.9) vs. 22.0 (2.0), infrarenal: 19.3 (1.6) vs. 18.6 (1.7), p â< â0.001 for all, also after adjustment for age, height, parity, menopause, dyslipidemia, smoking and chronic hypertension. Guideline-defined ascending aortic aneurysms were found in 8 vs 2 women (p â= â0.12). CONCLUSIONS: Women with previous pre-eclampsia have larger aortic dimensions compared with women from the general population. Pre-eclampsia was found to be an independent risk factor associated with a larger aortic diameter.
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A diagnosis of chronic obstructive pulmonary disease (COPD) is mainly considered in individuals with more than 10 pack-years of smoking. We tested the hypothesis that low smoking exposure, below the critical threshold of 10 pack-years, increases risk of COPD and leads to poor prognosis.We followed non-obstructive adult smokers from the Copenhagen City Heart Study for COPD, defined as forced expiratory volume in one second [FEV1]/forced vital capacity [FVC]<0.70 and FEV1<80% predicted, and for related clinical outcomes. First, we followed individuals for 5years according to baseline smoking for risk of developing COPD, and hereafter for up to four decades for severe exacerbations and death.In 6098 non-obstructive smokers, 1781(29%) developed COPD after 5 years follow-up; 23% in individuals with <10pack-years of smoking at baseline, 26% in those with 10-19.9pack-years, 30% in those with 20-39.9pack-years, and 39% in those with ≥40pack-years. During four decades follow-up, we recorded 620 exacerbations and 5573 deaths. Compared to individuals without COPD with <10pack-years of smoking, multivariable adjusted hazard ratios (HRs) for exacerbations were 1.94(95% confidence interval:1.36-2.77) in those without COPD with ≥10pack-years, 2.83(1.72-4.66) in those with COPD with <10pack-years, 4.34(2.93-6.43) in COPD with 10-19.9pack-years, 4.39(2.98-6.47) in COPD with 20-39.9pack-years, and 4.98(3.11-7.97) in COPD with ≥40pack-years. Corresponding HRs for all-cause mortality were 1.20(1.10-1.32), 1.33(1.14-1.56), 1.59(1.40-1.80),1.81(1.62-2.03), and 1.81(1.55-2.10), respectively.Low smoking exposure below the critical threshold of 10 pack-years increases risk of COPD in middle-aged adults within 5 years, and these individuals have increased risk of severe exacerbation and early death over four decades.
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OBJECTIVE: To investigate the contributions of low-grade inflammation measured by C-reactive protein (CRP), hyperglycaemia, and type 2 diabetes to risk of ischemic heart disease (IHD) and cardiovascular disease (CVD) death in the general population, and whether hyperglycaemia and high CRP are causally related. RESEARCH DESIGN AND METHODS: Observational and bidirectional, one-sample Mendelian randomization (MR) analyses in 112,815 individuals from the Copenhagen General Population Study and the Copenhagen City Heart Study, and bidirectional, two-sample MR with summary level data from two publicly available consortia, CHARGE and MAGIC. RESULTS: Observationally, higher plasma CRP was associated with stepwise higher risk of IHD and CVD death, with hazard ratios and 95% confidence intervals (95%CI) of 1.50 (1.38, 1.62) and 2.44 (1.93, 3.10) in individuals with the 20% highest CRP concentrations. The corresponding hazard ratios for elevated plasma glucose were 1.10 (1.02, 1.18) and 1.22 (1.01, 1.49), respectively. Cumulative incidences of IHD and CVD death were 365% and 592% higher, respectively, in individuals with both type 2 diabetes and plasma CRP ≥ 2 mg/L compared to individuals without either. Plasma CRP and glucose were observationally associated (ß-coefficient: 0.02 (0.02, 0.03), p = 3 × 10- 20); however, one- and two-sample MR did not support a causal effect of CRP on glucose (-0.04 (-0.12, 0.32) and - 0.03 (-0.13, 0.06)), nor of glucose on CRP (-0.01 (-0.08, 0.07) and - 0.00 (-0.14, 0.13)). CONCLUSIONS: Elevated concentrations of plasma CRP and glucose are predictors of IHD and CVD death in the general population. We found no genetic association between CRP and glucose, or vice versa, suggesting that lowering glucose pharmacologically does not have a direct effect on low-grade inflammation.
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Biomarcadores , Glicemia , Proteína C-Reativa , Doenças Cardiovasculares , Diabetes Mellitus Tipo 2 , Fatores de Risco de Doenças Cardíacas , Hiperglicemia , Análise da Randomização Mendeliana , Humanos , Diabetes Mellitus Tipo 2/diagnóstico , Diabetes Mellitus Tipo 2/sangue , Diabetes Mellitus Tipo 2/mortalidade , Diabetes Mellitus Tipo 2/epidemiologia , Diabetes Mellitus Tipo 2/genética , Proteína C-Reativa/análise , Proteína C-Reativa/metabolismo , Biomarcadores/sangue , Hiperglicemia/sangue , Hiperglicemia/epidemiologia , Hiperglicemia/diagnóstico , Hiperglicemia/mortalidade , Hiperglicemia/genética , Medição de Risco , Glicemia/metabolismo , Masculino , Dinamarca/epidemiologia , Doenças Cardiovasculares/mortalidade , Doenças Cardiovasculares/genética , Doenças Cardiovasculares/diagnóstico , Doenças Cardiovasculares/epidemiologia , Doenças Cardiovasculares/sangue , Feminino , Pessoa de Meia-Idade , Incidência , Regulação para Cima , Isquemia Miocárdica/sangue , Isquemia Miocárdica/genética , Isquemia Miocárdica/epidemiologia , Isquemia Miocárdica/diagnóstico , Isquemia Miocárdica/mortalidade , Idoso , Prognóstico , Mediadores da Inflamação/sangue , Predisposição Genética para Doença , Fatores de RiscoRESUMO
Cardiovascular disease (CVD) remains the leading cause of morbidity and mortality worldwide and challenges the capacity of health care systems globally. Atherosclerosis is the underlying pathophysiological entity in two-thirds of patients with CVD. When considering that atherosclerosis develops over decades, there is potentially great opportunity for prevention of associated events such as myocardial infarction and stroke. Subclinical atherosclerosis has been identified in its early stages in young individuals; however, there is no consensus on how to prevent progression to symptomatic disease. Given the growing burden of CVD, a paradigm shift is required-moving from late management of atherosclerotic CVD to earlier detection during the subclinical phase with the goal of potential cure or prevention of events. Studies must focus on how precision medicine using imaging and circulating biomarkers may identify atherosclerosis earlier and determine whether such a paradigm shift would lead to overall cost savings for global health.
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Aterosclerose , Diagnóstico Precoce , Medicina de Precisão , Humanos , Aterosclerose/diagnóstico , Medicina de Precisão/métodos , Biomarcadores/sangueRESUMO
AIM: Due to aging populations the incidence of aortic valve stenosis (AVS) is increasing steeply. Since no medical therapy is available but only surgical interventions, it is highly warranted to identify modifiable risk factors for early prevention. The aim of the study was to investigate the associations of cardiovascular risk factors with AVS and to create 10-year absolute risk scores for use in primary prevention. METHODS: In the Copenhagen General Population Study (N=93,979) lifestyle data, biochemical measures, and confounders were assessed at baseline. Risk factors with the strongest association with aortic valve stenosis from Cox regression analyses were included in ten-year risk prediction models. Ten-year absolute risk scores were conducted using the method of Fine-Gray proportional sub-hazards models, accounting for competing events. RESULTS: 1,132 individuals developed AVS during follow-up. Of well-known cardiovascular risk factors, those that associated with AVS included increasing levels of remnant cholesterol, triglycerides, lipoprotein(a), systolic blood pressure, and body mass index, low adherence to Danish dietary guidelines, current smoking, high alcohol consumption, lipid-lowering therapy and diabetes mellitus. Ten-year absolute risk scores increased when compiling the most important risk factors for AVS; age, sex, body mass index, systolic blood pressure, lipoprotein(a), and diabetes. Ten-year absolute risk increased from <1% to 19%. CONCLUSIONS: The presence of cardiovascular risk factors is associated with AVS, supporting that this disease, at least partly, may be modifiable through lifestyle changes. Risk charts combining cardiovascular risk factors have the potential to identify high-risk individuals, offering opportunities for preventive strategies. (Word count 245).
This study investigates the impact of common cardiovascular risk factors on aortic valve stenosis (AVS) and introduces a risk score to predict the likelihood of developing AVS within ten years. We identified strong links between AVS and several risk factors, including lipid traits, high blood pressure, obesity, smoking, increased alcohol intake, low adherence to dietary guidelines, and diabetes. A ten-year risk score combining age, sex, body mass index, blood pressure, the lipid trait lipoprotein(a), and diabetes estimates an individual's future risk of AVS, which can range from 1% to 19%. Such risk scores enable identification of individuals at highest risk, where early prevention is most effective.
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BACKGROUND: Historically, lipids and lipoproteins were measured in the fasting state for cardiovascular risk prediction; however, since 2009 use of nonfasting lipid profiles has increased substantially worldwide. For patients, nonfasting lipid profiles are convenient and avoid any risk of hypoglycemia. For laboratories, blood sampling in the morning and extra visits for patients who have not fasted are avoided. For patients, clinicians, hospitals, and society, nonfasting sampling allows same-day visits with first blood sampling followed by a short wait for test results before clinical consultation. Therefore, nonfasting compared to fasting lipid profiles will save money and time and may improve patient compliance with cardiovascular prevention programs. CONTENT: We report on the progression of endorsement and implementation of nonfasting lipid profiles for cardiovascular risk prediction worldwide and summarize the recommendations from major medical societies and health authorities in different countries. We also describe practical advantages and disadvantages for using nonfasting lipid profiles. Further, we include a description of why fasting has been the standard historically, the barriers against implementation of nonfasting lipid profiles, and finally we suggest the optimal content of a nonfasting lipid profile. SUMMARY: Lipid, lipoprotein, and apolipoprotein concentrations vary minimally in response to normal food intake and nonfasting lipid profiles are equal or superior to fasting profiles for cardiovascular risk prediction. Major guidelines and consensus statements in Europe, the United States, Canada, Brazil, Japan, India, and Australia now endorse use of nonfasting lipid profiles in some or all patients; however, there are still gaps in endorsement and implementation of nonfasting lipid profiles worldwide.
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Jejum , Lipídeos , Humanos , Jejum/sangue , Lipídeos/sangue , Doenças Cardiovasculares/sangue , Lipoproteínas/sangueRESUMO
BACKGROUND AND AIMS: The PROMINENT trial, a cardiovascular outcome trial of the triglyceride- and remnant cholesterol-lowering agent pemafibrate, has shown neutral results despite reduction in plasma triglycerides and remnant cholesterol. We tested the hypothesis that absolute mass changes in remnant cholesterol, LDL cholesterol, and apolipoprotein B explain the results of the PROMINENT trial. METHODS: Among 108,431 individuals from the Copenhagen General Population Study (CGPS), those who met the key inclusion criteria of the PROMINENT trial were analyzed to mimic the trial design. Endpoint atherosclerotic cardiovascular disease (ASCVD) was cardiovascular death, myocardial infarction, ischemic stroke, and coronary revascularization as defined in PROMINENT. RESULTS: In the PROMINENT trial, treatment with pemafibrate resulted in -7 mg/dL (-0.18 mmol/L; -18 %) change in remnant cholesterol, +10 mg/dL (+0.26 mmol/L; +12 %) LDL cholesterol, and +5 mg/dL (+0.05 g/L; +5 %) apolipoprotein B. In the CGPS mimicking PROMINENT, the estimated hazard ratios for ASCVD were 0.97 (95 % confidence interval: 0.94-0.99) for a -7 mg/dL (-0.18 mmol/L) change in remnant cholesterol, 1.04 (1.01-1.07) for a +10 mg/dL (+0.26 mmol/L) change in LDL cholesterol, and 1.02 (1.01-1.03) for a +5 mg/dL (+0.05 g/L) change in apolipoprotein B. When combining absolute changes in remnant cholesterol, LDL cholesterol, and apolipoprotein B, the estimated hazard ratio for ASCVD was 1.05 (0.96-1.14) in the CGPS mimicking PROMINENT compared to 1.03 (0.91-1.15) in the PROMINENT trial. CONCLUSIONS: Absolute mass changes in remnant cholesterol, LDL cholesterol, and apolipoprotein B can explain results of the PROMINENT trial. The 3 mg/dL (0.08 mmol/L) higher total atherogenic cholesterol together with 5 mg/dL (0.05 g/L) higher apolipoprotein B seem to explain the trend toward more ASCVD in the pemafibrate arm.
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LDL-Colesterol , Colesterol , Triglicerídeos , Humanos , LDL-Colesterol/sangue , Feminino , Masculino , Pessoa de Meia-Idade , Colesterol/sangue , Idoso , Triglicerídeos/sangue , Resultado do Tratamento , Dinamarca/epidemiologia , Biomarcadores/sangue , Apolipoproteína B-100/sangue , Doenças Cardiovasculares/sangue , Doenças Cardiovasculares/epidemiologia , Doenças Cardiovasculares/prevenção & controle , Aterosclerose/sangue , Aterosclerose/epidemiologia , Apolipoproteínas B/sangue , Adulto , Hipolipemiantes/uso terapêutico , Benzoxazóis , Butiratos , LipoproteínasRESUMO
BACKGROUND: Elevated apoB-containing lipoproteins (=remnants+LDLs [low-density lipoproteins]) are a major risk factor for atherosclerotic cardiovascular disease, including peripheral artery disease (PAD) and myocardial infarction. We tested the hypothesis that remnants and LDL both explain part of the increased risk of PAD conferred by elevated apoB-containing lipoproteins. For comparison, we also studied the risk of chronic limb-threatening ischemia and myocardial infarction. METHODS: apoB, remnant cholesterol, and LDL cholesterol were measured in 93â 461 individuals without statin use at baseline from the Copenhagen General Population Study (2003-2015). During up to 15 years of follow-up, 1207 had PAD, 552 had chronic limb-threatening ischemia, and 2022 had myocardial infarction in the Danish National Patient Registry. Remnant and LDL cholesterol were calculated from a standard lipid profile. Remnant and LDL particle counts were additionally measured with nuclear magnetic resonance spectroscopy in 25â 347 of the individuals. Results were replicated in 302â 167 individuals without statin use from the UK Biobank (2004-2010). RESULTS: In the Copenhagen General Population Study, multivariable adjusted hazard ratios for risk of PAD per 1 mmol/L (39 mg/dL) increment in remnant and LDL cholesterol were 1.9 (95% CI, 1.5-2.4) and 1.1 (95% CI, 1.0-1.2), respectively; corresponding results in the UK Biobank were 1.7 (95% CI, 1.4-2.1) and 0.9 (95% CI, 0.9-1.0), respectively. In the association from elevated apoB to increased risk of PAD, remnant and LDL cholesterol explained 73% (32%-100%) and 8% (0%-46%), respectively; corresponding results were 63% (30%-100%) and 0% (0%-33%) for risk of chronic limb-threatening ischemia and 41% (27%-55%) and 54% (38%-70%) for risk of myocardial infarction; results for remnant and LDL particle counts corroborated these findings. CONCLUSIONS: PAD risk conferred by elevated apoB-containing lipoproteins was explained mainly by elevated remnants, while myocardial infarction risk was explained by both elevated remnants and LDL.
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Apolipoproteína B-100 , Biomarcadores , LDL-Colesterol , Colesterol , Lipoproteínas , Doença Arterial Periférica , Adulto , Idoso , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Apolipoproteína B-100/sangue , Biomarcadores/sangue , Colesterol/sangue , LDL-Colesterol/sangue , Dinamarca/epidemiologia , Isquemia/sangue , Isquemia/epidemiologia , Isquemia/diagnóstico , Infarto do Miocárdio/epidemiologia , Infarto do Miocárdio/sangue , Infarto do Miocárdio/diagnóstico , Doença Arterial Periférica/epidemiologia , Doença Arterial Periférica/sangue , Doença Arterial Periférica/diagnóstico , Estudos Prospectivos , Sistema de Registros , Medição de Risco , Fatores de Risco , Fatores de Tempo , TriglicerídeosRESUMO
BACKGROUND AND AIMS: Apolipoprotein E (apoE) plays a crucial role in cholesterol metabolism, and high levels of apoE in plasma are associated with cardiovascular disease and all-cause mortality. We aimed to assess if HIV is independently associated with high plasma apoE and to determine HIV-related risk factors for high plasma apoE. METHODS: We included 661 people with HIV (PWH) from the Copenhagen Comorbidity in HIV (COCOMO) study with available measurement of plasma apoE. COCOMO participants were frequency matched 1:1 on age and sex with controls from the Copenhagen General Population Study. High plasma apoE was defined as levels above the 90th percentile (66.2 mg/L). The association between HIV and high plasma apoE was assessed using logistic regression models. Among PWH, both linear and logistic regression models were used to determine HIV-specific risk factors for high plasma apoE. RESULTS: Mean age was 52 years and 89 % were male. Median plasma apoE was 49.0 mg/L in PWH and 43.3 mg/L in controls, p < 0.001. HIV was associated with higher plasma apoE after adjusting for potential confounders, including triglycerides (odds ratio 2.14 [95 % CI: 1.39-3.29], p < 0.001). In PWH, higher plasma apoE was associated with a previous AIDS-defining condition in linear models before adjustment for triglycerides and integrase strand transfer inhibitor use in fully adjusted linear models. CONCLUSIONS: PWH had higher plasma apoE than controls even after adjusting for triglycerides. Further studies are needed to elucidate the clinical impact of high plasma apoE in PWH.
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Síndrome da Imunodeficiência Adquirida , Infecções por HIV , Humanos , Masculino , Pessoa de Meia-Idade , Feminino , Infecções por HIV/diagnóstico , Infecções por HIV/epidemiologia , Biomarcadores , Apolipoproteínas E/genética , Triglicerídeos , Fatores de RiscoRESUMO
BACKGROUND: We examined obstructive and nonobstructive plaque volumes in populations with subclinical and clinically manifested coronary artery disease (CAD) using quantitative computed tomography (QCT). METHODS: 855 participants with CAD (274 asymptomatic individuals, 254 acute chest pain patients without acute coronary syndrome (ACS), and 327 patients with ACS) underwent QCT of proximal coronary segments to assess participant-level plaque volumes of dense calcium, fibrous, fibrofatty, and necrotic core tissue. RESULTS: Nonobstructive (<50% stenosis) plaque volumes were greater than obstructive plaque volumes, irrespective of population (all p<0.0001): Asymptomatic individuals (mean (95% CI)): 218 [190-250] vs. 16 [12-22] mm3; acute chest pain patients without ACS: 300 [263-341] vs. 51 [41-62] mm3; patients with ACS: 370 [332-412] vs. 159 [139-182] mm3. After multivariable adjustment, nonobstructive fibrous and fibrofatty tissue volumes were greater in acute chest pain patients without ACS compared to asymptomatic individuals (fibrous tissue: 122 [107-139] vs. 175 [155-197] mm3, p<0.01; fibrofatty tissue: 44 [38-50] vs. 71 [63-80] mm3, p<0.01. Necrotic core tissue was greater in ACS patients (29 [26-33] mm3) compared to both asymptomatic individuals (15 [13-18] mm3, p<0.0001) and acute chest pain patients without ACS (21 [18-24] mm3, p<0.05). Nonobstructive dense calcium volumes did not differ between the three populations: 29 [24-36], 29 [23-35], and 41 [34-48] mm3, p>0.3 respectively. CONCLUSION: Nonobstructive CAD was the predominant contributor to total atherosclerotic plaque volume in both subclinical and clinically manifested CAD. Nonobstructive fibrous, fibrofatty and necrotic core tissue volumes increased with worsening clinical presentation, while nonobstructive dense calcium tissue volumes did not.
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Síndrome Coronariana Aguda , Doença da Artéria Coronariana , Placa Aterosclerótica , Humanos , Doença da Artéria Coronariana/diagnóstico por imagem , Doença da Artéria Coronariana/epidemiologia , Cálcio , Valor Preditivo dos Testes , Dor no Peito , Necrose , Angiografia Coronária/métodosRESUMO
Background: Fraction of exhaled nitric oxide with an expiratory flow of 50 mL/s (FENO50) is a biomarker of eosinophilic airway inflammation. Liver transplant recipients have an increased risk of pulmonary infections, but little is known about the burden of chronic pulmonary diseases in this group. We aimed to assess the prevalence of elevated FENO50 in liver transplant recipients and compare it to controls from the general population. Methods: FENO50 was measured in 271 liver transplant recipients from The Danish Comorbidity in Liver Transplant Recipients (DACOLT) study and 1,018 age- and sex-matched controls from The Copenhagen General Population Study (CGPS). Elevated FENO50 was defined as ≥25 or ≥50 parts per billion (ppb). The analyses were adjusted for known and suspected confounders. Results: The median age of the liver transplant recipients was 55 years (interquartile range (IQR) 46-64), and 58% were men. The liver transplant recipients had a higher median FENO50 than the controls [16 ppb (IQR 10-26) vs. 13 ppb (IQR 8-18.), p < 0.001]. Furthermore, the liver transplant recipients had a higher prevalence of elevated FENO50 (for FENO50 ≥25 ppb 27% vs. 11%, p < 0.001 and ≥50 ppb 4% vs. 2%, p = 0.02). The results were similar after adjusting for age, sex, smoking status, use of airway medication, and blood eosinophil counts [the adjusted odds ratio (OR) for FENO50 ≥25 ppb was 3.58 (95% CI: 2.50-5.15, p < 0.0001) and the adjusted OR for FENO50 ≥50 ppb was 3.14 (95% CI: 1.37-7.20, p = 0.007)]. Conclusion: The liver transplant recipients had elevated FENO50, implying increased eosinophilic airway inflammation. The clinical impact of this finding needs further investigation.
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Transplante de Fígado , Óxido Nítrico , Masculino , Humanos , Pessoa de Meia-Idade , Feminino , Estudos de Coortes , Transplante de Fígado/efeitos adversos , Eosinófilos , InflamaçãoRESUMO
AIMS: Dynamic myocardial computed tomography (CT) perfusion (DM-CTP) can, in combination with coronary CT angiography (CCTA), provide anatomical and functional evaluation of coronary artery disease (CAD). However, normal values of myocardial blood flow (MBF) are needed to identify impaired myocardial blood supply in patients with suspected CAD. We aimed to establish normal values for MBF measured using DM-CTP, to assess the effects of age and sex, and to assess regional distribution of MBF. METHODS AND RESULTS: A total of 82 healthy individuals (46 women) aged 45-78 years with normal coronary arteries by CCTA underwent either rest and adenosine stress DM-CTP (n = 30) or adenosine-induced stress DM-CTP only (n = 52). Global and segmental MBF were assessed. Global MBF at rest and during stress were 0.93 ± 0.42 and 3.58 ± 1.14 mL/min/g, respectively. MBF was not different between the sexes (P = 0.88 at rest and P = 0.61 during stress), and no correlation was observed between MBF and age (P = 0.08 at rest and P = 0.82 during stress). Among the 16 myocardial segments, significant intersegmental differences were found (P < 0.01), which was not related to age, sex, or coronary dominance. CONCLUSION: MBF assessed by DM-CTP in healthy individuals with normal coronary arteries displays significant intersegmental heterogeneity which does not seem to be affected by age, sex, or coronary dominance. Normal values of MBF may be helpful in the clinical evaluation of suspected myocardial ischaemia using DM-CTP.
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Angiografia por Tomografia Computadorizada , Angiografia Coronária , Circulação Coronária , Imagem de Perfusão do Miocárdio , Humanos , Feminino , Masculino , Pessoa de Meia-Idade , Idoso , Valores de Referência , Imagem de Perfusão do Miocárdio/métodos , Angiografia Coronária/métodos , Circulação Coronária/fisiologia , Angiografia por Tomografia Computadorizada/métodos , Doença da Artéria Coronariana/diagnóstico por imagem , Doença da Artéria Coronariana/fisiopatologia , Fatores Etários , Fatores Sexuais , Tomografia Computadorizada por Raios X/métodos , Velocidade do Fluxo Sanguíneo/fisiologiaRESUMO
BACKGROUND: It is increasingly clear that triglyceride-rich lipoproteins are proinflammatory and cause low-grade systemic inflammation. However, it is currently unknown whether elevated plasma triglycerides are causally related to the development of psoriasis, a skin disorder driven by chronic inflammation. OBJECTIVES: To determine if elevated plasma triglycerides are associated with increased risk of psoriasis in observational and Mendelian randomization analysis. METHODS: Consecutive individuals from the Copenhagen General Population Study were included. We used plasma triglycerides (n = 108 043) and a weighted triglyceride allele score (n = 92 579) on nine known triglyceride-altering genetic variants. Genetic results were replicated in 337 159 individuals from the UK Biobank. Psoriasis was defined using the International Classification of Diseases, version 10 (ICD-10) code for hospital contact in the main analyses, and prescription of topical antipsoriatics for mild psoriasis in the sensitivity analysis. RESULTS: During a follow-up of median (range) 9.3 (0.1-15.1) years from 2003 to 2015 through 2018, 855 (1%) individuals were diagnosed with psoriasis by ICD-10 in the observational analysis and 772 (1%) in the Mendelian randomization analysis. In the observational analysis, the multivariable adjusted hazard ratio for psoriasis by ICD-10 was 1.26 [95% confidence interval (CI) 1.15-1.39] per doubling in plasma triglycerides with a corresponding causal odds ratio of incident psoriasis of 2.10 (95% CI 1.30-3.38). Causality was confirmed from data from the UK Biobank. Results were similar but slightly attenuated when we used topical antipsoriatic prescriptions for mild psoriasis. CONCLUSIONS: Elevated plasma triglycerides are associated with an increased risk of psoriasis in observational and Mendelian randomization analysis.
Psoriasis is a common skin condition, characterized by inflammation in the body (the body's response to an unwanted agent). People with psoriasis often have higher lipid levels in their blood compared with people without psoriasis. Some studies have shown that triglyceride-rich lipoprotein (a certain type of lipid) is irritative to the body and can cause inflammation. However, it is unclear whether high levels of triglycerides in the blood can cause them to penetrate into the skin and trigger the onset of psoriasis. We aimed to test this question in 100,000 people from a Danish population without previously diagnosed psoriasis. Specifically, we measured plasma triglycerides at initial examination and at the same time assessed the same people for genetic variants that impact on the concentration of plasma triglycerides. Importantly, genetic variants are inherited by chance, meaning that we could look specifically at whether a change in triglycerides was the mechanism that causes psoriasis. Next, we observed these people for about 10â years and noted any new occurrence of psoriasis during follow-up. We found that the risk of developing psoriasis was higher both as a function of plasma triglyceride concentration and the genetic variants that increase plasma triglyceride concentration. Overall, our study findings suggest that high levels of triglycerides in the blood could be a causal risk factor for the development of psoriasis.
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Análise da Randomização Mendeliana , Psoríase , Triglicerídeos , Humanos , Psoríase/genética , Psoríase/sangue , Psoríase/epidemiologia , Feminino , Masculino , Triglicerídeos/sangue , Pessoa de Meia-Idade , Adulto , Idoso , Dinamarca/epidemiologia , Fatores de Risco , Predisposição Genética para Doença , Polimorfismo de Nucleotídeo Único , Hipertrigliceridemia/genética , Hipertrigliceridemia/sangue , Hipertrigliceridemia/epidemiologiaRESUMO
PURPOSE OF REVIEW: Atherosclerotic cardiovascular disease (ASCVD) is the leading cause of death despite the development of effective treatments. Recently, elevated remnant cholesterol and low-grade inflammation have emerged as factors explaining part of the residual ASCVD risk. Interestingly, the coexistence of both high remnant cholesterol and low-grade inflammation can further increase the risk of ASCVD. The aim of this review is to describe the role of elevated remnant cholesterol and low-grade inflammation, separately and combined, in ASCVD. RECENT FINDINGS: Results from recently published studies, including observational and genetic Mendelian randomization studies, support a causal relationship between elevated remnant cholesterol and low-grade inflammation on risk of ASCVD in both primary and secondary prevention settings. In addition, current evidence from observational studies suggests that the coexistence of elevated remnant cholesterol and low-grade inflammation further increases the risk of ASCVD. SUMMARY: Recent observational studies suggest that high remnant cholesterol combined with low-grade inflammation may confer a particular high risk for ASCVD. Attention on the dual threat from high remnant cholesterol and low-grade inflammation is necessary, and further research in this field is warranted. The effect of remnant cholesterol-lowering drugs and anti-inflammatory drugs on ASCVD risk alone and combined remains to be elucidated. VIDEO ABSTRACT: http://links.lww.com/COCN/A20.
Assuntos
Aterosclerose , Doenças Cardiovasculares , Humanos , Triglicerídeos , Doenças Cardiovasculares/etiologia , Lipoproteínas/genética , Colesterol , Aterosclerose/etiologia , Inflamação/complicações , Fatores de RiscoRESUMO
PURPOSE OF REVIEW: Lipoprotein(a) is an important causal risk factor for cardiovascular disease but currently no available medication effectively reduces lipoprotein(a). This review discusses recent findings regarding lipoprotein(a) as a causal risk factor and therapeutic target in cardiovascular disease, it reviews current clinical recommendations, and summarizes new lipoprotein(a) lowering drugs. RECENT FINDINGS: Epidemiological and genetic studies have established lipoprotein(a) as a causal risk factor for cardiovascular disease and mortality. Guidelines worldwide now recommend lipoprotein(a) to be measured once in a lifetime, to offer patients with high lipoprotein(a) lifestyle advise and initiate other cardiovascular medications. Clinical trials including antisense oligonucleotides, small interfering RNAs, and an oral lipoprotein(a) inhibitor have shown great effect on lowering lipoprotein(a) with reductions up to 106%, without any major adverse effects. Recent clinical phase 1 and 2 trials show encouraging results and ongoing phase 3 trials will hopefully result in the introduction of specific lipoprotein(a) lowering drugs to lower the risk of cardiovascular disease.