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Association of metabolomic markers and response to nutritional support: A secondary analysis of the EFFORT trial using an untargeted metabolomics approach.
Struja, T, Wolski, W, Schapbach, R, Mueller, B, Laczko, E, Schuetz, P
Clinical nutrition (Edinburgh, Scotland). 2021;(9):5062-5070
Abstract
BACKGROUND & AIMS The EFFORT trial reported a substantial risk reduction for adverse events and mortality in medical in-patients receiving a nutritional support intervention. With the use of an untargeted metabolomics approach, we investigated the prognostic and therapeutic potential of metabolomic markers to understand, whether there are distinct metabolic patterns associated with malnutrition risk as assessed by the Nutritional Risk screening (NRS 2002) score, the risk of 30-day mortality and the response to nutritional support, respectively. METHODS Out of the 2088 samples we randomly selected 120 blood samples drawn on day 1 after hospital admission and before treatment initiation. Samples were stratified by NRS 2002, treatment allocation (intervention vs. control), and mortality at 30 days, but not on the type of medical illness. We performed untargeted analysis by liquid chromatography mass spectrometry (LC-MS/MS). RESULTS We measured 1389 metabolites in 120 patients of which 81 (67.5%) survived until day 30. After filtering, 371 metabolites remained, and 200 were matched to one or more Human Metabolome Data Base (HMDB) entries. Between group analysis showed a slight distinction between the treatment groups for patients with a NRS 3, but not for those with NRS 4 and ≥ 5. C-statistic between those who died and survived at day 30 ranged from 0.49 (95% confidence interval 0.35-0.68) for a combination of 5 metabolites/predictors to 0.66 (95% confidence interval 0.53-0.79) for a combination of 100 metabolites. Pathway analysis found significant enrichment in the pathways for nitrogen, vitamin B3 (nicotinate and nicotinamide), leukotriene, and arachidonic acid metabolisms in nutritional support responders compared to non-responders. CONCLUSION In our heterogenous population of medical inpatients with different illnesses and comorbidities, metabolomic markers showed little prognostic and therapeutic potential for better phenotyping malnutrition and response to nutritional therapy. Future studies should focus on more selected patient populations to understand whether a metabolomic approach can advance the nutritional care of patients.
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Hypertensive Retinopathy and the Risk of Stroke Among Hypertensive Adults in China.
Chen, X, Liu, L, Liu, M, Huang, X, Meng, Y, She, H, Zhao, L, Zhang, J, Zhang, Y, Gu, X, et al
Investigative ophthalmology & visual science. 2021;(9):28
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Abstract
PURPOSE This study aimed to investigate the association between hypertensive retinopathy and the risk of first stroke, examine possible effect modifiers in hypertensive patients, and test the appropriateness of the Keith-Wagener-Barker (KWB) classification for predicting stroke risk. METHODS In total, 9793 hypertensive participants (3727 males and 6066 females) without stroke history from the China Stroke Primary Prevention Trial were included in this study. The primary outcome was first stroke. RESULTS Over a median follow-up of 4.4 years, 592 participants experienced their first stroke (509 ischemic, 77 hemorrhagic, and six unclassifiable strokes). In total, 5590 participants were diagnosed with grade 1 retinopathy (57.08%), 1466 with grade 2 retinopathy (14.97%), 231 with grade 3 retinopathy (2.36%), and three with grade 4 retinopathy (0.03%). Grades 1 and 2 were merged and classified as mild retinopathy, and grades 3 and 4 were merged and classified as severe retinopathy. There was a significant positive association between hypertensive retinopathy and the risk of first stroke and first ischemic stroke, and no effect modifiers were found. The hazard ratios (HRs) for first stroke were as follows: mild versus no retinopathy, 1.26 (95% confidence interval [CI], 1.01-1.58, P = 0.040), and severe versus no retinopathy, 2.40 (95% CI, 1.49-3.84, P < 0.001). The HRs for ischemic stroke were as follows: severe versus no retinopathy, 2.35 (95% CI, 1.41-3.90, P = 0.001), and nonsignificantly increased HRs for mild versus no retinopathy, 1.26 (95% CI, 0.99-1.60, P = 0.057). CONCLUSIONS There was a significant positive association between hypertensive retinopathy and the risk of first stroke in patients with hypertension, indicating that hypertensive retinopathy may be a predictor of the risk of stroke. A simplified two-grade classification system based on the KWB classification is recommended for predicting stroke risk.
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The Association Between Asthma and Risk of Myasthenia Gravis: A Systematic Review and Meta-analysis.
Yingchoncharoen, P, Charoenngam, N, Ponvilawan, B, Thongpiya, J, Chaikijurajai, T, Ungprasert, P
Lung. 2021;(3):273-280
Abstract
PURPOSE This study aimed to investigate the association between asthma and risk of myasthenia gravis (MG) using the method of systematic review and meta-analysis. METHODS Potentially eligible studies were identified from Medline and EMBASE databases from inception to July 2020 using search strategy that comprised terms for "Asthma" and "Myasthenia Gravis". Eligible cohort study must consist of one cohort of individuals with asthma and another cohort of individuals without asthma. Then, the study must report relative risk (RR) with 95% confidence intervals (95% CIs) of incident MG between the groups. Eligible case-control studies must include cases with MG and controls without MG. Then, the study must explore their history of asthma. Odds ratio (OR) with 95% CIs of the association between asthma status and MG must be reported. Point estimates with standard errors were retrieved from each study and were combined together using the generic inverse variance method. RESULTS A total of 6,835 articles were identified. After two rounds of independent review by five investigators, two cohort studies and three case-control studies met the eligibility criteria and were included into the meta-analysis. Pooled analysis showed that asthma was significantly associated with risk of MG with the pooled risk ratio of 1.38 (95% CI 1.02-1.86). Funnel plot was symmetric, which was not suggestive of publication bias. CONCLUSION The current study found a significant association between asthma and increased risk of MG.
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Clinical risk predictors in atrial fibrillation patients following successful coronary stenting: ENTRUST-AF PCI sub-analysis.
Goette, A, Eckardt, L, Valgimigli, M, Lewalter, T, Laeis, P, Reimitz, PE, Smolnik, R, Zierhut, W, Tijssen, JG, Vranckx, P
Clinical research in cardiology : official journal of the German Cardiac Society. 2021;(6):831-840
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AIMS: This subgroup analysis of the ENTRUST-AF PCI trial (ClinicalTrials.gov Identifier: NCT02866175; Date of registration: August 2016) evaluated type of AF, and CHA2DS2-VASc score parameters as predictors for clinical outcome. METHODS Patients were randomly assigned after percutaneous coronary intervention (PCI) to either edoxaban (60 mg/30 mg once daily [OD]; n = 751) plus a P2Y12 inhibitor for 12 months or a vitamin K antagonist [VKA] (n = 755) plus a P2Y12 inhibitor and aspirin (100 mg OD, for 1-12 months). The primary outcome was a composite of major/clinically relevant non-major bleeding (CRNM) within 12 months. The composite efficacy endpoint consisted of cardiovascular death, stroke, systemic embolic events, myocardial infarction (MI), and definite stent thrombosis. RESULTS Major/CRNM bleeding event rates were 20.7%/year and 25.6%/year with edoxaban and warfarin, respectively (HR [95% CI]: 0.83 [0.654-1.047]). The event rates of composite outcome were 7.26%/year and 6.86%/year, respectively (HR [95% CI]): 1.06 [0.711-1.587]), and of overall net clinical benefit were 12.48%/year and 12.80%/year, respectively (HR [(95% CI]: 0.99 [(0.730; 1.343]). Increasing CHA2DS2-VASc score was associated with increased rates of all outcomes. CHA2DS2-VASc score ≥ 5 was a marker for stent thrombosis. Paroxysmal AF was associated with a higher occurrence of MI (4.87% versus 2.01%, p = 0.0024). CONCLUSION After PCI in AF patients, increasing CHA2DS2-VASc score was associated with increased bleeding rates and CHA2DS2-VASc score (≥ 5) predicted the occurrence of stent thrombosis. Paroxysmal AF was associated with MI. These findings may have important clinical implications in AF patients.
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Cross-sectional study of aortic valve calcification and cardiovascular risk factors in older Danish men.
Khurrami, L, Møller, JE, Lindholt, JS, Urbonaviciene, G, Steffensen, FH, Lambrechtsen, J, Karon, M, Frost, L, Busk, M, Egstrup, K, et al
Heart (British Cardiac Society). 2021;(19):1536-1543
Abstract
OBJECTIVE Aortic valve calcification (AVC) and coronary artery calcification (CAC) are predictors of cardiovascular disease (CVD), presumably sharing risk factors. Our objectives were to determine the prevalence and extent of AVC in a large population of men aged 60-74 years and to assess the association between AVC and cardiovascular risk factors including CAC and biomarkers. METHODS Participants from the DANish CArdioVAscular Screening and intervention trial (DANCAVAS) with AVC and CAC scores and without previous valve replacement were included in the study. Calcification scores were calculated on non-contrast CT scans. Cardiovascular risk factors were self-reported, measured or both, and further explored using descriptive and regression analysis for AVC association. RESULTS 14 073 men aged 60-74 years were included. The AVC scores ranged from 0 to 9067 AU, with a median AVC of 6 AU (IQR 0-82). In 8156 individuals (58.0%), the AVC score was >0 and 215 (1.5%) had an AVC score ≥1200. In the regression analysis, all cardiovascular risk factors were associated with AVC; however, after inclusion of CAC ≥400, only age (ratio of expected counts (REC) 1.07 (95% CI 1.06 to 1.09)), hypertension (REC 1.24 (95% CI 1.09 to 1.41)), obesity (REC 1.34 (95% CI 1.20 to 1.50)), known CVD (REC 1.16 (95% CI 1.03 to 1.31)) and serum phosphate (REC 2.25 (95% CI 1.66 to 3.10) remained significantly associated, while smoking, diabetes, hyperlipidaemia, estimated glomerular filtration rate and serum calcium were not. CONCLUSIONS AVC was prevalent in the general population of men aged 60-74 years and was significantly associated with all modifiable cardiovascular risk factors, but only selectively after adjustment for CAC ≥400 AU. TRIAL REGISTRATION NUMBER NCT03946410 and ISRCTN12157806.
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Factors associated with heart failure hospitalization in patients with high sodium excretion: subanalysis of the ESPRIT, evaluation of sodium intake for the prediction of cardiovascular events in Japanese high-risk patients, cohort study.
Sadanaga, T, Hirota, S, Mitamura, H
Heart and vessels. 2021;(1):85-91
Abstract
We have reported that high sodium excretion ≥ 4.0 g/day, assessed by repeated measurements of spot urine, is associated with composite cardiovascular (CV) events of heart failure (HF) hospitalization, acute coronary syndrome, cerebrovascular events, and documented CV deaths in Japanese high-risk patients with either stable and compensated congestive HF, high brain natriuretic peptide, coronary artery disease, cerebrovascular disease, chronic kidney disease, or atrial fibrillation. A total of 520 patients were enrolled. During the median follow-up period of 5.2 years, 105 (20%) experienced composite CV events, which were predominantly driven by 60 (12%) HF hospitalizations. The aim of the present study was to elucidate which subgroups of patients with high sodium excretion were associated with HF hospitalization. We divided the enrolled patients into three groups according to the amount of sodium excretion (< 3.0 g/day, 3.0-3.99 g/day (reference), and ≥ 4.0 g/day) based on a median of 14 measurements during follow-up. We assessed the hazard ratio for HF hospitalization according to age, bodyweight, and gender, using the Cox hazard model. In the total population, high sodium excretion ≥ 4.0 g/day was associated with HF hospitalization [hazard ratio (HR) 1.75, confidence interval (CI) 1.05-2.83] after adjustment for gender, age, and bodyweight, but was not associated with other CV events. In older patients (≥ 75 years old), high sodium excretion ≥ 4.0 g/day was associated with HF hospitalization after adjustment for gender and bodyweight (HR 3.25, CI 1.55-6.55), which was not observed in younger (< 75 years old) patients. In patients with lower bodyweight (< 60 kg), high sodium excretion ≥ 4.0 g/day was associated with HF hospitalization after adjustment for age and gender (HR 3.05, CI 1.34-6.61), which was not observed in heavier (≥ 60 kg) patients. High sodium excretion is associated with HF hospitalization in patients with older age and lower bodyweight in Japanese high-risk patients.
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Non-invasive stratification of hepatocellular carcinoma risk in non-alcoholic fatty liver using polygenic risk scores.
Bianco, C, Jamialahmadi, O, Pelusi, S, Baselli, G, Dongiovanni, P, Zanoni, I, Santoro, L, Maier, S, Liguori, A, Meroni, M, et al
Journal of hepatology. 2021;(4):775-782
Abstract
BACKGROUND & AIMS Hepatocellular carcinoma (HCC) risk stratification in individuals with dysmetabolism is a major unmet need. Genetic predisposition contributes to non-alcoholic fatty liver disease (NAFLD). We aimed to exploit robust polygenic risk scores (PRS) that can be evaluated in the clinic to gain insight into the causal relationship between NAFLD and HCC, and to improve HCC risk stratification. METHODS We examined at-risk individuals (NAFLD cohort, n = 2,566; 226 with HCC; and a replication cohort of 427 German patients with NAFLD) and the general population (UK Biobank [UKBB] cohort, n = 364,048; 202 with HCC). Variants in PNPLA3-TM6SF2-GCKR-MBOAT7 were combined in a hepatic fat PRS (PRS-HFC), and then adjusted for HSD17B13 (PRS-5). RESULTS In the NAFLD cohort, the adjusted impact of genetic risk variants on HCC was proportional to the predisposition to fatty liver (p = 0.002) with some heterogeneity in the effect. PRS predicted HCC more robustly than single variants (p <10-13). The association between PRS and HCC was mainly mediated through severe fibrosis, but was independent of fibrosis in clinically relevant subgroups, and was also observed in those without severe fibrosis (p <0.05). In the UKBB cohort, PRS predicted HCC independently of classical risk factors and cirrhosis (p <10-7). In the NAFLD cohort, we identified high PRS cut-offs (≥0.532/0.495 for PRS-HFC/PRS-5) that in the UKBB cohort detected HCC with ~90% specificity but limited sensitivity; PRS predicted HCC both in individuals with (p <10-5) and without cirrhosis (p <0.05). CONCLUSIONS Our results are consistent with a causal relationship between hepatic fat and HCC. PRS improved the accuracy of HCC detection and may help stratify HCC risk in individuals with dysmetabolism, including those without severe liver fibrosis. Further studies are needed to validate our findings. LAY SUMMARY By analyzing variations in genes that contribute to fatty liver disease, we developed two risk scores to help predict liver cancer in individuals with obesity-related metabolic complications. These risk scores can be easily tested in the clinic. We showed that the risk scores helped to identify the risk of liver cancer both in high-risk individuals and in the general population.
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Sex disparities and adverse cardiovascular and kidney outcomes in patients with chronic kidney disease: results from the KNOW-CKD.
Jung, CY, Heo, GY, Park, JT, Joo, YS, Kim, HW, Lim, H, Chang, TI, Kang, EW, Yoo, TH, Kang, SW, et al
Clinical research in cardiology : official journal of the German Cardiac Society. 2021;(7):1116-1127
Abstract
AIMS: Longitudinal studies of the association between sex and adverse clinical outcomes in patients with chronic kidney disease (CKD) are scarce. We assessed whether major outcomes may differ by sex among CKD patients. METHODS We analyzed a total of 1780 participants with non-dialysis CKD G1-5 from the KoreaN cohort study for Outcome in patients with Chronic Kidney Disease (KNOW-CKD). The primary outcome was a composite of non-fatal cardiovascular events or all-cause mortality. Secondary outcomes included fatal and non-fatal cardiovascular events, all-cause mortality, and a composite kidney outcome of ≥ 50% decline in estimated glomerular filtration rate from baseline or the onset of end-stage kidney disease. RESULTS There were 1088 (61%) men and 692 (39%) women in the study cohort. The proportion of smokers was significantly higher in men (24% vs. 3%). During 8430 person-years of follow-up, 201 primary outcome events occurred: 144 (13%) in men and 57 (8%) in women, with corresponding incidence rates of 2.9 and 1.7 per 100 person-years, respectively. In multivariable Cox models, men were associated with a 1.58-fold (95% CI 1.06-2.35) higher risk of composite outcome. Propensity score matching analysis revealed similar findings (HR 1.81; 95% CI 1.14-2.91). Risk of all-cause mortality was significantly higher in men of the matched cohort. However, there was no difference in the risk of CKD progression. In the subgroup with coronary artery calcium (CAC) measurements, men had a higher likelihood of CAC progression. CONCLUSIONS In Korean CKD patients, men were more likely to experience adverse cardiovascular events and death than women.
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Hiding unhealthy heart outcomes in a low-fat diet trial: the Women's Health Initiative Randomized Controlled Dietary Modification Trial finds that postmenopausal women with established coronary heart disease were at increased risk of an adverse outcome if they consumed a low-fat 'heart-healthy' diet.
Noakes, TD
Open heart. 2021;(2)
Abstract
The Women's Health Initiative Randomized Controlled Dietary Modification Trial (WHIRCDMT) was designed to test whether the US Department of Agriculture's 1977 Dietary Guidelines for Americans protects against coronary heart disease (CHD) and other chronic diseases. The only significant finding in the original 2006 WHIRCDMT publication was that postmenopausal women with CHD randomised to a low-fat 'heart-healthy' diet in 1993 were at 26% greater risk of developing additional CHD events compared with women with CHD eating the control diet. A 2017 WHIRCDMT publication includes data for an additional 5 years of follow-up. It finds that CHD risk in this subgroup of postmenopausal women had increased further to 47%-61%. The authors present three post-hoc rationalisations to explain why this finding is 'inadmissible': (1) only women in this subgroup were less likely to adhere to the prescribed dietary intervention; (2) their failure to follow the intervention diet increased their CHD risk; and (3) only these women were more likely to not have received cholesterol-lowering drugs. These rationalisations appear spurious. Rather these findings are better explained as a direct consequence of postmenopausal women with features of insulin resistance (IR) eating a low-fat high-carbohydrate diet for 13 years. All the worst clinical features of IR, including type 2 diabetes mellitus (T2DM) in some, can be 'reversed' by the prescription of a high-fat low-carbohydrate diet. The Women's Health Study has recently reported that T2DM (10.71-fold increased risk) and other markers of IR including metabolic syndrome (6.09-fold increased risk) were the most powerful predictors of future CHD development in women; blood low-density lipoprotein-cholesterol concentration was a poor predictor (1.38-fold increased risk). These studies challenge the prescription of the low-fat high-carbohydrate heart-healthy diet, at least in postmenopausal women with IR, especially T2DM. According to the medical principle of 'first do no harm', this practice is now shown to be not evidence-based, making it scientifically unjustifiable, perhaps unethical.
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Body composition parameters and functional status test in predicting future acute exacerbation risk among hospitalized patients with chronic obstructive pulmonary disease.
Karanikas, I, Karayiannis, D, Karachaliou, A, Papanikolaou, A, Chourdakis, M, Kakavas, S
Clinical nutrition (Edinburgh, Scotland). 2021;(11):5605-5614
Abstract
BACKGROUND & AIMS Chronic obstructive pulmonary disease (COPD) is a leading cause of morbidity and mortality worldwide. Nutritional and functional status derangement is a commonly seen in COPD patients, and this is associated with a higher disease severity and mortality. To assess body composition analysis - measured by segmental multi-frequency bioelectrical impedance analysis (BIA)- and functional status and investigate their relationship with the COPD acute exacerbation risk. METHODS Eighty COPD patients admitted to hospital for COPD acute exacerbation were prospectively followed-up for one year after discharge, focusing on a new incidence of COPD acute exacerbation. Following discharge, participants' body composition was assessed with the use of segmental multi-frequency BIA, whereas physical function by performing 5-repetitions and 30 s sit-to-stand (STS) tests. Unadjusted and multivariate logistic regression analyses were performed to evaluate the ability of the various measures to predict incidence of future COPD acute exacerbation in one-year period. RESULTS Seventy-six out of 80 participants completed the study and were analyzed. Fifty-one [24 male (47.1%)] out of 76 participants (67.1%), mean aged of 69.3 ± 8.9 years, developed at least one new COPD acute exacerbation during the one year follow-up. The probability of COPD acute exacerbation in one year was significantly related to BMI (OR = 0.75, 95% CI; 0.61-0.91, p = 0.004) and Fat Free Mass (OR = 0.88, 95% CI; 0.79-0.97, p = 0.012) after adjustment for sex, age and smoking index (pack × years). Both 5-repetitions and 30 s STS tests had a good predictive ability for the incidence of COPD acute exacerbation in one year (AUC = 0.80, 95% CI; 0.65-0.95, p = 0.009 and AUC = 0.83, 95% CI; 0.70-0.96, p = 0.004, respectively). CONCLUSION In an observational study among patients admitted with COPD acute exacerbation, body composition analysis parameters and functional status are related to acute exacerbation risk incidence.