Low-Dose Aspirin for Prevention of Cardiovascular Disease in Patients with Chronic Kidney Disease

Background

Chronic kidney disease (CKD) is a major risk factor for the development of cardiovascular disease (CVD). Previous trials have investigated the effects of low-dose aspirin on CVD prevention in patients with diabetes; however, patients with CKD were not examined. The role of aspirin in diabetics is controversial, and the available literature is contradictory. Therefore, we studied whether low-dose aspirin would be beneficial for patients with CKD, a group that is at high risk for CVD.

Method

From a total of 25340 patients with CKD, 1884 recipients of low-dose aspirin (100 mg/day) were paired 1∶1 with non-recipients for analysis using propensity score matching. The primary endpoint was the development of atherosclerotic CVD, including coronary arterial disease, stroke, and peripheral arterial disease. Secondary endpoints included death from any cause, bleeding events, doubling of serum creatinine, and renal death.

Results

The incidence of a primary endpoint of any atherosclerotic CVD was significantly higher in the aspirin users than in the non-users (P<0.001). Secondary endpoints, including all-cause mortality and composite bleeding events, were not significantly different between the aspirin users and the non-users. However, the doubling of serum creatinine levels (P = 0.001) and renal death (P = 0.042) were significantly associated with the use of aspirin.

Conclusion

These results suggest that the use of low-dose aspirin in patients with CKD may have harmful consequences related to the development of CVD and renal progression.     

The prevalence of increased serum IgE and Aspergillus sensitization in patients with COPD and their association with symptoms and lung function

Background

Allergy and Aspergillus hypersensitivity (AH) were shown to be associated with severe symptoms or worse lung function in COPD patients. The prevalence of elevated total IgE (T-IgE) and its association with clinical symptoms and lung function in COPD have not been studied. The prevalence of AH and its correlation with clinical characteristics in a COPD cohort of larger sample size is also lacking.

Methods

273 patients with COPD were evaluated by respiratory symptoms, blood test, chest HRCT, lung function, serum detection of T-IgE and Aspergillus specific IgE. Patients with T-IgE ≥ 1000 KU/L were further investigated for allergic bronchopulmonary aspergillosis (ABPA).

Results

The prevalence of elevated T-IgE and AH in patients with COPD was 47.3% and 15.0%, respectively. Eight patients (2.9%) met the diagnostic criteria for ABPA. Compared with the normal T-IgE group, patients with elevated T-IgE had a longer history of dyspnea (p < 0.01), an earlier onset of dyspnea after chronic cough/expectoration (p < 0.01), and were more likely to wheeze (p < 0.01). They also showed worse lung functions and more severe GOLD staging (p < 0.01). Analysis of the clinical data in male patients with smoking as the risk factor showed the same results. To evaluate the clinical characteristics of COPD with AH, patients with elevated T-IgE were further divided into subgroups with and without AH. When compared with the normal T-IgE group, both the two subgroups showed longer history of dyspnea (p < 0.01), an earlier onset of dyspnea (p < 0.01) and a worse status of lung function (p < 0.05). Correlation analysis demonstrated that T-IgE was correlated positively with the time length of dyspnea (r = 0.401, p < 0.001), and the ratio of duration of dyspnea to that of chronic cough/expectoration (r = 0.59, p < 0.001), but negatively with FEV1/FVC% (r = −0.194, p = 0.001), and FEV1%predicted (r = −0.219, p < 0.001).

Conclusions

There was a high prevalence of elevated serum T-IgE and AH in patients with COPD. Serum T-IgE level was correlated with symptoms such as dyspnea and impairment of lung function. Allergens other than Aspergillus may have similar effects on disease expression or progression of COPD.     

Lifetime Smoking History and Cause-Specific Mortality in a Cohort Study with 43 Years of Follow-Up

BackgroundIn general, smoking increases the risk of mortality. However, it is less clear how the relative risk varies by cause of death. The exact impact of changes in smoking habits throughout life on different mortality risks is less studied.MethodsWe studied the impact of baseline and lifetime smoking habits, and duration of smoking on the risk of all-cause mortality, mortality of cardiovascular diseases (CVD), chronic obstructive pulmonary disease (COPD), any cancer and of the four most common types of cancer (lung, colorectal, prostate, and breast cancer) in a cohort study (Vlagtwedde-Vlaardingen 1965–1990, with a follow-up on mortality status until 2009, n = 8,645). We used Cox regression models adjusted for age, BMI, sex, and place of residence. Since previous studies suggested a potential effect modification of sex, we additionally stratified by sex and tested for interactions. In addition, to determine which cause of death carried the highest risk we performed competing-risk analyses on mortality due to CVD, cancer, COPD and other causes.ResultsCurrent smoking (light, moderate, and heavy cigarette smoking) and lifetime persistent smoking were associated with an increased risk of all-cause, CVD, COPD, any cancer, and lung cancer mortality. Higher numbers of pack years at baseline were associated with an increased risk of all-cause, CVD, COPD, any cancer, lung, colorectal, and prostate cancer mortality. Males who were lifetime persistent pipe/cigar smokers had a higher risk of lung cancer [HR (95% CI) = 7.72 (1.72–34.75)] as well as all-cause and any cancer mortality. A longer duration of smoking was associated with a higher risk of COPD, any and lung cancer [HR (95% CI) = 1.06 (1.00–1.12), 1.03 (1.00–1.06) and 1.10 (1.03–1.17) respectively], but not with other mortality causes. The competing risk analyses showed that ex- and current smokers had a higher risk of cancer, CVD, and COPD mortality compared to all other mortality causes. In addition, heavy smokers had a higher risk for COPD mortality compared to cancer, and CVD mortality.ConclusionOur study indicates that lifetime numbers of cigarettes smoked and the duration of smoking have different impacts for different causes of mortality. Moreover, our findings emphasize the importance of smoking-related competing risks when studying the smoking-related cancer mortality in a general population and that smoking cessation immediately effectively reduces the risk of all-cause and any cancer mortality.     

Chronic Obstructive Pulmonary Disease-Related Non-Small-Cell Lung Cancer Exhibits a Low Prevalence of EGFR and ALK Driver Mutations

Lung cancer and chronic obstructive pulmonary disease (COPD) are two major lung diseases. Epidermal growth factor receptor (EGFR) mutations, v‐Ki‐ras2 Kirsten rat sarcoma (KRAS) mutations and anaplastic lymphoma kinase (ALK) gene rearrangements represent driver mutations that are frequently assessed on initial evaluation of non-small-cell lung cancer (NSCLC). The present study focused on the expression of driver mutations in NSCLC patients presenting with COPD and further evaluated the association between NSCLC and COPD. Data from 501 consecutive patients with histologically proven recurrent or metastatic NSCLC were analyzed retrospectively. The patients underwent spirometry and genotyping of EGFR, ALK, and KRAS in tissue samples. Patient characteristics and expression of driver mutations were compared between the COPD and non-COPD groups.Among 350 patients with spirometric results, 106 (30.3%) were diagnosed with COPD, 108 (30.9%) had EGFR mutations, 31 (8.9%) had KRAS mutations, and 34 (9.7%) showed ALK rearrangements. COPD was independently associated with lower prevalences of EGFR mutations (95% confidence interval [CI], 0.254–0.931, p = 0.029) and ALK rearrangements (95% CI, 0.065–0.600, p = 0.004). The proportions of EGFR mutations and ALK rearrangements decreased as the severity of airflow obstruction increased (p = 0.001). In never smokers, the prevalence of EGFR mutations was significantly lower in the COPD group than in the non-COPD group (12.7% vs. 49.0%, p = 0.002). COPD-related NSCLC patients exhibited low prevalences of EGFR mutations and ALK rearrangements compared with the non-COPD group. Further studies are required regarding the molecular mechanisms underlying lung cancer associated with COPD.     

The Association between Continuity of Care and All-Cause Mortality in Patients with Newly Diagnosed Obstructive Pulmonary Disease: A Population-Based Retrospective Cohort Study, 2005-2012

BackgroundThe disease burden is increasing for chronic obstructive pulmonary disease (COPD) due to increasing of the growth rate of prevalence and mortality. But the empirical researches are a little for COPD that studied the association between continuity of care and death and about predictors effect on mortality.ObjectiveTo investigate the association between continuity of care (COC) and chronic obstructive pulmonary disease (COPD) mortality and to identify other mortality-related factors in COPD patients.MethodsWe conducted a longitudinal, population-based retrospective cohort study in adult patients with COPD from 2002 to 2012 using a nationwide health insurance claims database. The study sample included individuals aged 40 years and over who developed COPD in 2005 and survived until 2006. We performed a Cox proportional hazard regression analysis with COC analyzed as a time-dependent covariate.ResultsOf the 3,090 participants, 60.8% died before the end of study (N = 1,879). The median years of survival for individuals with high COC (COC index≥0.75) was 3.92, and that for patients with low COC (COC index<0.75) was 2.58 in a Kaplan Meier analysis. In a multivariate, time-dependent analysis, low COC was associated with a 22% increased risk of all-cause mortality (HR, 1.22; 95% CI, 1.09–1.36). Not receiving oxygen therapy at home was associated with a 23% increased risk of all-cause mortality (HR, 1.23; 95% CI, 1.01–1.49). Moreover, the risk of all-cause mortality for individuals who admitted one time increased 38% (HR, 1.38; 95% CI, 1.21–1.59), two times was 63% (HR, 1.63; 95% CI, 1.34–1.99) and 3+ times was 96% (HR, 1.96; 95% CI, 1.63–2.36) relative to the reference group (no admission).ConclusionsHigh COC was associated with a decreased risk of all-cause mortality. In addition, home oxygen therapy and number of hospital admissions may predict mortality in patients with COPD.     

Chronic Obstructive Pulmonary Disease Is Not Associated with KRAS Mutations in Non-Small Cell Lung Cancer

Mutations in epithelial growth factor receptor (EGFR), as well as in the EGFR downstream target KRAS are frequently observed in non-small cell lung cancer (NSCLC). Chronic obstructive pulmonary disease (COPD), an independent risk factor for developing NSCLC, is associated with an increased activation of EGFR. In this study we determined presence of EGFR and KRAS hotspot mutations in 325 consecutive NSCLC patients subjected to EGFR and KRAS mutation analysis in the diagnostic setting and for whom the pulmonary function has been determined at time of NSCLC diagnosis. Information about age at diagnosis, sex, smoking status, forced vital capacity (FVC) and forced expiratory volume in 1 sec (FEV₁) was collected. Chronic obstructive pulmonary disease(COPD) was defined according to 2013 GOLD criteria. Chi-Square, student t-test and multivariate logistic regression were used to analyze the data. A total of 325 NSCLC patients were included, 193 with COPD and 132 without COPD. COPD was not associated with presence of KRAS hotspot mutations, while EGFR mutations were significantly higher in non-COPD NSCLC patients. Both female gender (HR 2.61; 95% CI: 1.56–4.39; p<0.001) and smoking (HR 4.10; 95% CI: 1.14–14.79; p = 0.03) were associated with KRAS mutational status. In contrast, only smoking (HR 0.11; 95% CI: 0.04–0.32; p<0.001) was inversely associated with EGFR mutational status. Smoking related G>T and G>C transversions were significantly more frequent in females (86.2%) than in males (61.5%) (p = 0.008). The exon 19del mutation was more frequent in non-smokers (90%) compared to current or past smokers (36.8%). In conclusion, KRAS mutations are more common in females and smokers, but are not associated with COPD-status in NSCLC patients. EGFR mutations are more common in non-smoking NSCLC patients.     

Low-dose aspirin use and survival in breast cancer patients: A nationwide cohort study

BackgroundPreclinical evidence from breast cancer cell lines and animal models suggest that aspirin could have anti-cancer properties. In a large breast cancer patient cohort, we investigated whether post-diagnostic low-dose aspirin use was associated with a reduction in the risk of breast cancer-specific mortality.MethodsWe identified 15,140 newly diagnosed breast cancer patients within the Scottish Cancer Registry. Linkages to the Scottish Prescribing Information System provided data on dispensed medications and breast cancer-specific deaths were identified from National Records of Scotland Death Records. Time-dependent Cox regression models were used to calculate hazard ratios (HR) and 95% CIs for breast cancer-specific and all-cause mortality by post-diagnostic low-dose aspirin use. HRs were adjusted for a range of potential confounders including age at diagnosis, year of diagnosis, cancer stage, grade, cancer treatments received, comorbidities, socioeconomic status and use of statins. Secondary analysis investigated the association between pre-diagnostic low-dose aspirin use and breast cancer-specific and all-cause mortality.ResultsPost-diagnostic users of low-dose aspirin appeared to have increased breast cancer-specific mortality compared with non-users (HR 1.44, 95% CI 1.26, 1.65) but this association was entirely attenuated after adjustment for potential confounders (adjusted HR 0.92, 95% CI 0.75, 1.14). Findings were similar in analysis by increasing duration of use and in analysis of pre-diagnostic low-dose aspirin use.ConclusionIn this large nationwide study of breast cancer patients, we found little evidence of an association between post-diagnostic low-dose aspirin use and cancer-specific mortality.     

Association between Chronic Obstructive Pulmonary Disease and Lung Cancer: A Case-Control Study in Southern Chinese and a Meta-Analysis

Background

Lung cancer and chronic obstructive pulmonary disease (COPD) share a common risk factor in cigarette smoking and a large portion of patients with lung cancer suffer from COPD synchronously. We therefore hypothesized that COPD is an independent risk factor for lung cancer. Our aim was to investigate the intrinsic linkage of COPD (or emphysema, chronic bronchitis and asthma) and lung cancer.

Methods

The present hospital-based case-control study included 1,069 patients with newly diagnosed lung cancer and 1,132 age frequency matched cancer-free controls. The odds ratios (ORs) for the associations between each previous pulmonary disease and lung cancer were estimated with logistic regression models, adjusting for age, sex, family history of cancer, BMI and pack year smoking. In meta-analysis, the pooled effects of previous pulmonary diseases were analyzed with random effects models; and stratification analyses were conducted on smoking status and ethnicity.

Results

In the case-control study, previous COPD was associated with the odds for increased risk of lung cancer (OR = 1.29, 95% confidence interval [CI] = 1.00∼1.68); so were emphysema (OR = 1.55, 95%CI = 1.03∼2.32) and chronic bronchitis (OR = 1.22, 95%CI = 0.99∼1.67); while asthma was associated with odds for decreased risk of lung cancer (OR = 0.29, 95%CI = 0.16∼0.53). These associations were more pronounced in smokers (P<.05 for all strata), but not in non-smokers. In meta-analysis, 35 studies (22,010 cases and 44,438 controls) were identified. COPD was significantly associated with the odds for increased risk of lung cancer (pooled OR = 2.76; 95% CI = 1.85–4.11), so were emphysema (OR = 3.02; 95% CI = 2.41–3.79) and chronic bronchitis (OR = 1.88; 95% CI = 1.49–2.36); and these associations were more pronounced in smokers than in non-smokers (P<.001 respectively). No significant association was observed for asthma.

Conclusion

Previous COPD could increase the risk of lung cancer, especially in smokers.     

Systemic and Pulmonary Vascular Remodelling in Chronic Obstructive Pulmonary Disease

BackgroundChronic Obstructive Pulmonary Disease (COPD) is associated with subclinical systemic atherosclerosis and pulmonary vascular remodelling characterized by intimal hyperplasia and luminal narrowing. We aimed to determine differences in the intimal thickening of systemic and pulmonary arteries in COPD subjects and smokers. Secondary aims include comparisons with a non-smokers group; determining the clinical variables associated with systemic and pulmonary intimal thickening, and the correlations between systemic and pulmonary remodelling changes.MethodsAll consecutive subjects undergoing lung resection were included and divided into 3 groups: 1) COPD, 2) smokers, and 3) non-smokers. Sections of the 5th intercostal artery and muscular pulmonary arteries were measured by histo-morphometry. Four parameters of intimal thickening were evaluated: 1) percentage of intimal area (%IA), 2) percentage of luminal narrowing, 3) intimal thickness index, and 4) intima-to-media ratio.ResultsIn the adjusted analysis, the systemic arteries of COPD subjects showed greater intimal thickening (%IA) than those of smokers (15.6±1.5% vs. 14.2±1.6%, p = 0.038). In the pulmonary arteries, significant differences were observed for %IA between the 2 groups (37.3±2.2% vs. 29.3±2.3%, p = 0.016). Among clinical factors, metabolic syndrome, gender and COPD status were associated with the systemic intimal thickening, while only COPD status was associated with pulmonary intimal thickening. A correlation between the %IA of the systemic and pulmonary arteries was observed (Spearman’s rho = 0.46, p = 0.008).ConclusionsGreater intimal thickening in systemic and pulmonary arteries is observed in COPD patients than in smokers. There is a correlation between systemic and pulmonary vascular remodelling in the overall population.     

Impact of Preexisting Interstitial Lung Disease on Acute,Extensive Radiation Pneumonitis: Retrospective Analysis of Patients with Lung Cancer

IntroductionThis study investigated the clinical characteristics and predictive factors for developing acute extended radiation pneumonitis with a focus on the presence and radiological characteristics of preexisting interstitial lung disease.MethodsOf 1429 irradiations for lung cancer from May 2006 to August 2013, we reviewed 651 irradiations involving the lung field. The presence, compatibility with usual interstitial pneumonia, and occupying area of preexisting interstitial lung disease were retrospectively evaluated by pretreatment computed tomography. Cases of non-infectious, non-cardiogenic, acute respiratory failure with an extended bilateral shadow developing within 30 days after the last irradiation were defined as acute extended radiation pneumonitis.ResultsNine (1.4%) patients developed acute extended radiation pneumonitis a mean of 6.7 days after the last irradiation. Although preexisting interstitial lung disease was found in 13% of patients (84 patients), 78% of patients (7 patients) with acute extended radiation pneumonitis cases had preexisting interstitial lung disease, which resulted in incidences of acute extended radiation pneumonitis of 0.35 and 8.3% in patients without and with preexisting interstitial lung disease, respectively. Multivariate logistic analysis indicated that the presence of preexisting interstitial lung disease (odds ratio = 22.6; 95% confidence interval = 5.29–155; p < 0.001) and performance status (≥2; odds ratio = 4.22; 95% confidence interval = 1.06–20.8; p = 0.049) were significant predictive factors. Further analysis of the 84 patients with preexisting interstitial lung disease revealed that involvement of more than 10% of the lung field was the only independent predictive factor associated with the risk of acute extended radiation pneumonitis (odds ratio = 6.14; 95% confidence interval = 1.0–37.4); p = 0.038).ConclusionsPretreatment computed tomography evaluations of the presence of and area size occupied by preexisting interstitial lung disease should be assessed for safer irradiation of areas involving the lung field.     

The Effect of Statins on Blood Gene Expression in COPD

BackgroundCOPD is currently the fourth leading cause of death worldwide. Statins are lipid lowering agents with documented cardiovascular benefits. Observational studies have shown that statins may have a beneficial role in COPD. The impact of statins on blood gene expression from COPD patients is largely unknown.ObjectiveIdentify blood gene signature associated with statin use in COPD patients, and the pathways underpinning this signature that could explain any potential benefits in COPD.MethodsWhole blood gene expression was measured on 168 statin users and 451 non-users from the ECLIPSE study using the Affymetrix Human Gene 1.1 ST microarray chips. Factor Analysis for Robust Microarray Summarization (FARMS) was used to process the expression data. Differential gene expression analysis was undertaken using the Linear Models for Microarray data (Limma) package adjusting for propensity score and surrogate variables. Similarity of the expression signal with published gene expression profiles was performed in ProfileChaser.Results25 genes were differentially expressed between statin users and non-users at an FDR of 10%, including LDLR, CXCR2, SC4MOL, FAM108A1, IFI35, FRYL, ABCG1, MYLIP, and DHCR24. The 25 genes were significantly enriched in cholesterol homeostasis and metabolism pathways. The resulting gene signature showed correlation with Huntington’s disease, Parkinson’s disease and acute myeloid leukemia gene signatures.ConclusionThe blood gene signature of statins’ use in COPD patients was enriched in cholesterol homeostasis pathways. Further studies are needed to delineate the role of these pathways in lung biology.     

Associations of ABHD2 Genetic Variations with Risks for Chronic Obstructive Pulmonary Disease in a Chinese Han Population

The human α/β hydrolase domain-containing protein 2 gene (ABHD2) plays a critical role in pulmonary emphysema, a major subset of the clinical entity known as chronic obstructive pulmonary disease (COPD). Here, we evaluated genetic variation in the ABHD2 gene in a Chinese Han population of 286 COPD patients and 326 control subjects. The rs12442260 CT/CC genotype was associated with COPD (P < 0.001) under a dominant model. In the former-smoker group, the rs12442260 TT genotype was associated with a decreased risk of developing COPD after adjusting for age, gender and pack-years (P = 0.012). Rs12442260 was also associated with pre-FEV1 (the predicted bronchodilator forced expiratory volume in the first second) in controls (P = 0.027), but with FEV1/ forced vital capacity (FVC) ratios only in COPD patients (P = 0.012) under a dominant model. Results from the current study suggest that ABHD2 gene polymorphisms contribute to COPD susceptibility in the Chinese Han population.     

A Short-Term Effect of Low-Dose Aspirin on Major Hemorrhagic Risks in Primary Prevention: A Case-Crossover Design

Background

Very few studies have examined the risk of short-term adverse hemorrhage of low-dose aspirin use in primary prevention. This case-crossover study examined the transient effect of low-dose aspirin use on major hemorrhagic risks.

Methods

A representative database of 1,000,000 patients randomly sampled from the Taiwan''s National Health Insurance Research Database in 2000 was analyzed. The study cohort consisted of a total of 501,946 individuals, aged 30–95 years old, at risk of a major bleeding event in 2000. A case-crossover study was used to retrieve data on 10,905 incident patients with major hemorrhagic complications (3,781 cerebral and 7,124 gastrointestinal) and prescribed low-dose aspirin (≤300 mg/day) from 2000–2008. A 56-day time window (∼2 months) was used as the case period for which the odds ratio (OR) was estimated using the ratio of patients exposed during the 56-day case period only (1–56 days before the index date) compared to its corresponding 56-day control period only (57–112 days before the index date).

Results

Four hundred eighty-nine (4.5%) of the 10,905 hemorrhagic patients had used low-dose aspirin during the 56-day case only period; 294 (2.7%) of the same patients had used low-dose aspirin during control only period. Low-dose aspirin use increase the risk of developing a major hemorrhage 1.33-fold (95% CI = 1.13–1.55, P<0.0001). Significance was found prominent in 4,453 non-hypertensive and non-diabetic subjects (Adjusted odds ratio  = 1.88, 95% CI = 1.21–2.91).

Conclusion

Transient low-dose aspirin use increases risk for major hemorrhagic events in Han Chinese.     

Is Long-Term Low-Dose Aspirin Therapy Associated with Renal Dysfunction in Patients with Type 2 Diabetes? JPAD2 Cohort Study

Background

Low-dose aspirin is widely recommended for patients at high risk for cardiovascular disease (CVD); however, it remains uncertain whether long-term treatment adversely affects renal function in patients with diabetes.We investigated whether long-term low-dose aspirin affects renal dysfunction in patients with diabetes.

Methods

We conducted a randomized controlled trial (RCT), the Japanese Primary Prevention of Atherosclerosis with Aspirin for Diabetes (JPAD) trial, to evaluate low-dose aspirin as primary prevention for CVD in patients with type 2 diabetes. We followed the patients with negative urine dipstick albumin of the JPAD trial in a cohort study after the RCT period was completed. Patients were randomly allocated to receive aspirin (81 mg or 100 mg daily, aspirin group) or no aspirin (no aspirin group). After the RCT, the treating physician decided whether to administer aspirin. We evaluated the incidence of positive urine dipstick albumin and annual changes in estimated glomerular filtration rate (eGFR).

Results

Positive urine dipstick albumin developed in 297 patients in the aspirin group (n = 1,075) and 270 patients in the no aspirin group (n = 1,098) during follow-up (median, 8.5 years). Intention-to-treat analysis showed low-dose aspirin did not increase the incidence of positive urine dipstick albumin (hazard ratio [HR], 1.17; 95% confidence interval [CI], 0.995–1.38). On-treatment analysis yielded similar results (HR, 1.08; 95% CI, 0.92–1.28). Multivariable analysis showed the incidence of positive urine dipstick albumin was higher among the elderly and those with elevated serum creatinine, high hemoglobin A1c, or high blood pressure; however, low-dose aspirin did not increase the risk of positive urine dipstick albumin. There were no significant differences in annual changes in eGFR between the groups (aspirin, −0.8 ± 2.9; no aspirin, −0.9 ± 2.5 ml/min/1.73m²/year).

Conclusion

Long-term low-dose aspirin does not affect eGFR and positive urine dipstick albumin in patients with type 2 diabetes.     

Parathyroid Hormone as a Novel Biomarker for Chronic Obstructive Pulmonary Disease: Korean National Health and Nutrition Examination Survey

Objective

To understand and predict chronic obstructive pulmonary disease (COPD), a biomarker that reflects disease severity is needed.

Research Design and Methods

Data from 10269 adults aged over 40 years of age were retrieved from the Korea National Health and Nutrition Examination Survey (KNHANES), and 1302 patients met the criteria for COPD. The association between values of vitamin D and parathyroid hormone (PTH), and COPD severity including lung function and quality of life, were analyzed.

Results

In COPD patients, lung function was inversely related to PTH values (P = 0.02 for FVC [% predicted]; P < 0.001 for FEV₁ [% predicted]); however, the association of lung function with vitamin D levels was not statistically significant in a multivariable analysis. Value of PTH was independently associated with EQ5D-index (P = 0.04), but vitamin D level showed no significant relationship with EQ5D-index (P = 0.59) or EQ5D-VAS (P = 0.81).

Conclusions

Elevation of PTH, unlike vitamin D, is independently associated with COPD severity, and may be a better biomarker for COPD.     

Heterozygosity for E292V in ABCA3, lung function and COPD in 64,000 individuals

Background

Mutations in ATP-binding-cassette-member A3 (ABCA3) are related to severe chronic lung disease in neonates and children, but frequency of chronic lung disease due to ABCA3 mutations in the general population is unknown. We tested the hypothesis that individuals heterozygous for ABCA3 mutations have reduced lung function and increased risk of COPD in the general population.

Methods

We screened 760 individuals with extreme pulmonary phenotypes and identified three novel (H86Y, A320T, A1086D) and four previously described mutations (E292V, P766S, S1262G, R1474W) in the ABCA3 gene. We genotyped the entire Copenhagen City Heart study (n = 10,604) to assess the clinical importance of these mutations. To validate our findings we genotyped an additional 54,395 individuals from the Copenhagen General Population Study.

Results

In the Copenhagen City Heart Study individuals heterozygous for E292V had 5% reduced FEV₁ % predicted compared with noncarriers (t-test: p = 0.008), and an increased odds ratio for COPD of 1.9 (95% CI: 1.1-3.1). In contrast, the A1086D mutation was associated with increased FEV₁ % predicted (p = 0.03). None of the other ABCA3 mutations associated with lung function or COPD risk in the Copenhagen City Heart Study. In the larger Copenhagen General Population Study, and in the two studies combined, E292V heterozygotes did not have reduced lung function or increased risk of COPD (p = 0.11-0.98), while this was the case for the positive controls, surfactant protein-B 121ins2 heterozygotes and α₁-antitrypsin ZZ homozygotes.

Conclusion

Our results indicate that partially reduced ABCA3 activity due to E292V is not a major risk factor for reduced lung function and COPD in the general population. This is an important finding as 1.3% in the Danish population has partially reduced ABCA3 function due to E292V.     

Body size and composition and risk of site-specific cancers in the UK Biobank and large international consortia: A mendelian randomisation study

BackgroundEvidence for the impact of body size and composition on cancer risk is limited. This mendelian randomisation (MR) study investigates evidence supporting causal relationships of body mass index (BMI), fat mass index (FMI), fat-free mass index (FFMI), and height with cancer risk.Methods and findingsSingle nucleotide polymorphisms (SNPs) were used as instrumental variables for BMI (312 SNPs), FMI (577 SNPs), FFMI (577 SNPs), and height (293 SNPs). Associations of the genetic variants with 22 site-specific cancers and overall cancer were estimated in 367,561 individuals from the UK Biobank (UKBB) and with lung, breast, ovarian, uterine, and prostate cancer in large international consortia. In the UKBB, genetically predicted BMI was positively associated with overall cancer (odds ratio [OR] per 1 kg/m² increase 1.01, 95% confidence interval [CI] 1.00–1.02; p = 0.043); several digestive system cancers: stomach (OR 1.13, 95% CI 1.06–1.21; p < 0.001), esophagus (OR 1.10, 95% CI 1.03, 1.17; p = 0.003), liver (OR 1.13, 95% CI 1.03–1.25; p = 0.012), and pancreas (OR 1.06, 95% CI 1.01–1.12; p = 0.016); and lung cancer (OR 1.08, 95% CI 1.04–1.12; p < 0.001). For sex-specific cancers, genetically predicted elevated BMI was associated with an increased risk of uterine cancer (OR 1.10, 95% CI 1.05–1.15; p < 0.001) and with a lower risk of prostate cancer (OR 0.97, 95% CI 0.94–0.99; p = 0.009). When dividing cancers into digestive system versus non-digestive system, genetically predicted BMI was positively associated with digestive system cancers (OR 1.04, 95% CI 1.02–1.06; p < 0.001) but not with non-digestive system cancers (OR 1.01, 95% CI 0.99–1.02; p = 0.369). Genetically predicted FMI was positively associated with liver, pancreatic, and lung cancer and inversely associated with melanoma and prostate cancer. Genetically predicted FFMI was positively associated with non-Hodgkin lymphoma and melanoma. Genetically predicted height was associated with increased risk of overall cancer (OR per 1 standard deviation increase 1.09; 95% CI 1.05–1.12; p < 0.001) and multiple site-specific cancers. Similar results were observed in analyses using the weighted median and MR–Egger methods. Results based on consortium data confirmed the positive associations between BMI and lung and uterine cancer risk as well as the inverse association between BMI and prostate cancer, and, additionally, showed an inverse association between genetically predicted BMI and breast cancer. The main limitations are the assumption that genetic associations with cancer outcomes are mediated via the proposed risk factors and that estimates for some lower frequency cancer types are subject to low precision.ConclusionsOur results show that the evidence for BMI as a causal risk factor for cancer is mixed. We find that BMI has a consistent causal role in increasing risk of digestive system cancers and a role for sex-specific cancers with inconsistent directions of effect. In contrast, increased height appears to have a consistent risk-increasing effect on overall and site-specific cancers.

Mathew Vithayathil and colleagues study associations of body mass index and other measures with incidence of specific cancers.     

Dose–Risk and Duration–Risk Relationships between Aspirin and Colorectal Cancer: A Meta-Analysis of Published Cohort Studies

Background

In previous meta-analyses, aspirin use has been associated with reduced risk of colorectal cancer. However, uncertainty remains on the exact dose–risk and duration–risk relationships.

Methods

We identified studies by searching several English and Chinese electronic databases and reviewing relevant articles. The dose-response meta-analysis was performed by linear trend regression and restricted cubic spline regression. Subgroup analyses were conducted to explore possible heterogeneity among studies. Potential heterogeneity was calculated as Q statistic and I ² value. Publication bias was evaluated using funnel plots and quantified by the Begg’s and Egger’s test.

Results

Twelve studies were included in this meta-analysis. An inverse association between aspirin use and colorectal cancer was observed in both the overall group (RR = 0.74, 95% CI 0.64–0.83 for aspirin dose; RR = 0.80, 95% CI 0.75–0.85 for frequency of aspirin use; RR = 0.75, 95% CI 0.68–0.81 for years of aspirin use) and subgroups stratified by sex and cancer site. The dose-response meta-analysis showed that there was a 20% statistically significant decreased risk of colorectal cancer for 325 mg aspirin per day increment, 18% decreased risk for 7 times aspirin per week increment and 18% decreased risk for 10 years aspirin increment.

Conclusion

Long-term (>5 years), low-dose (75–325 mg per day) and regular aspirin use (2–7 times per week) can effectively reduce the risk of colorectal cancer.     

Dynamic hyperinflation is associated with a poor cardiovascular response to exercise in COPD patients

Background

Pulmonary hyperinflation has the potential for significant adverse effects on cardiovascular function in COPD. The aim of this study was to investigate the relationship between dynamic hyperinflation and cardiovascular response to maximal exercise in COPD patients.

Methods

We studied 48 patients (16F; age 68 yrs ± 8; BMI 26 ± 4) with COPD. All patients performed spirometry, plethysmography, lung diffusion capacity for carbon monoxide (TLco) measurement, and symptom-limited cardiopulmonary exercise test (CPET). The end-expiratory lung volume (EELV) was evaluated during the CPET. Cardiovascular response was assessed by change during exercise in oxygen pulse (ΔO₂Pulse) and double product, i.e. the product of systolic blood pressure and heart rate (DP reserve), and by the oxygen uptake efficiency slope (OUES), i.e. the relation between oxygen uptake and ventilation.

Results

Patients with a peak exercise EELV (%TLC) ≥ 75% had a significantly lower resting FEV₁/VC, FEF₅₀/FIF₅₀ ratio and IC/TLC ratio, when compared to patients with a peak exercise EELV (%TLC) < 75%. Dynamic hyperinflation was strictly associated to a poor cardiovascular response to exercise: EELV (%TLC) showed a negative correlation with ΔO₂Pulse (r = - 0.476, p = 0.001), OUES (r = - 0.452, p = 0.001) and DP reserve (r = - 0.425, p = 0.004). Furthermore, according to the ROC curve method, ΔO₂Pulse and DP reserve cut-off points which maximized sensitivity and specificity, with respect to a EELV (% TLC) value ≥ 75% as a threshold value, were ≤ 5.5 mL/bpm (0.640 sensitivity and 0.696 specificity) and ≤ 10,000 Hg · bpm (0.720 sensitivity and 0.783 specificity), respectively.

Conclusion

The present study shows that COPD patients with dynamic hyperinflation have a poor cardiovascular response to exercise. This finding supports the view that in COPD patients, dynamic hyperinflation may affect exercise performance not only by affecting ventilation, but also cardiac function.