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- 2019
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Tidskriftsartikel (refereegranskat)
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| 4. |
- Klionsky, Daniel J., et al.
(författare)
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Guidelines for the use and interpretation of assays for monitoring autophagy
- 2012
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Ingår i: Autophagy. - : Informa UK Limited. - 1554-8635 .- 1554-8627. ; 8:4, s. 445-544
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Forskningsöversikt (refereegranskat)abstract
- In 2008 we published the first set of guidelines for standardizing research in autophagy. Since then, research on this topic has continued to accelerate, and many new scientists have entered the field. Our knowledge base and relevant new technologies have also been expanding. Accordingly, it is important to update these guidelines for monitoring autophagy in different organisms. Various reviews have described the range of assays that have been used for this purpose. Nevertheless, there continues to be confusion regarding acceptable methods to measure autophagy, especially in multicellular eukaryotes. A key point that needs to be emphasized is that there is a difference between measurements that monitor the numbers or volume of autophagic elements (e.g., autophagosomes or autolysosomes) at any stage of the autophagic process vs. those that measure flux through the autophagy pathway (i.e., the complete process); thus, a block in macroautophagy that results in autophagosome accumulation needs to be differentiated from stimuli that result in increased autophagic activity, defined as increased autophagy induction coupled with increased delivery to, and degradation within, lysosomes (in most higher eukaryotes and some protists such as Dictyostelium) or the vacuole (in plants and fungi). In other words, it is especially important that investigators new to the field understand that the appearance of more autophagosomes does not necessarily equate with more autophagy. In fact, in many cases, autophagosomes accumulate because of a block in trafficking to lysosomes without a concomitant change in autophagosome biogenesis, whereas an increase in autolysosomes may reflect a reduction in degradative activity. Here, we present a set of guidelines for the selection and interpretation of methods for use by investigators who aim to examine macroautophagy and related processes, as well as for reviewers who need to provide realistic and reasonable critiques of papers that are focused on these processes. These guidelines are not meant to be a formulaic set of rules, because the appropriate assays depend in part on the question being asked and the system being used. In addition, we emphasize that no individual assay is guaranteed to be the most appropriate one in every situation, and we strongly recommend the use of multiple assays to monitor autophagy. In these guidelines, we consider these various methods of assessing autophagy and what information can, or cannot, be obtained from them. Finally, by discussing the merits and limits of particular autophagy assays, we hope to encourage technical innovation in the field.
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- Albrecht, Eva, et al.
(författare)
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Telomere length in circulating leukocytes is associated with lung function and disease
- 2014
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Ingår i: European Respiratory Journal. - : European Respiratory Society (ERS). - 0903-1936 .- 1399-3003. ; 43:4, s. 983-992
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Tidskriftsartikel (refereegranskat)abstract
- Several clinical studies suggest the involvement of premature ageing processes in chronic obstructive pulmonary disease (COPD). Using an epidemiological approach, we studied whether accelerated ageing indicated by telomere length, a marker of biological age, is associated with COPD and asthma, and whether intrinsic age-related processes contribute to the interindividual variability of lung function. Our meta-analysis of 14 studies included 934 COPD cases with 15 846 controls defined according to the Global Lungs Initiative (GLI) criteria (or 1189 COPD cases according to the Global Initiative for Chronic Obstructive Lung Disease (GOLD) criteria), 2834 asthma cases with 28 195 controls, and spirometric parameters (forced expiratory volume in is (FEV1), forced vital capacity (PVC) and FEV1/FVC) of 12 595 individuals. Associations with telomere length were tested by linear regression, adjusting for age, sex and smoking status. We observed negative associations between telomere length and asthma (beta= -0.0452, p= 0.024) as well as COPD (beta= -0.0982, p=0.001), with associations being stronger and more significant when using GLI criteria than those of GOLD. In both diseases, effects were stronger in females than males. The investigation of spirometric indices showed positive associations between telomere length and FEV1 (p=1.07 x 10(-7)), FVC (p=2.07 x 10(-5)), and FEV1/FVC (p =5.27 x 10(-3)). The effect was somewhat weaker in apparently healthy subjects than in COPD or asthma patients. Our results provide indirect evidence for the hypothesis that cellular senescence may contribute to the pathogenesis of COPD and asthma, and that lung function may reflect biological ageing primarily due to intrinsic processes, which are likely to be aggravated in lung diseases.
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- Vergaro, Giuseppe, et al.
(författare)
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Circulating levels and prognostic cut-offs of sST2, hs-cTnT, and NT-proBNP in women vs. men with chronic heart failure
- 2022
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Ingår i: ESC Heart Failure. - : John Wiley & Sons. - 2055-5822. ; 9:4, s. 2084-2095
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Tidskriftsartikel (refereegranskat)abstract
- Aims To define plasma concentrations, determinants, and optimal prognostic cut-offs of soluble suppression of tumorigenesis-2 (sST2), high-sensitivity cardiac troponin T (hs-cTnT), and N-terminal pro-B-type natriuretic peptide (NT-proBNP) in women and men with chronic heart failure (HF). Methods and results Individual data of patients from the Biomarkers In Heart Failure Outpatient Study (BIOS) Consortium with sST2, hs-cTnT, and NT-proBNP measured were analysed. The primary endpoint was a composite of 1 year cardiovascular death and HF hospitalization. The secondary endpoints were 5 year cardiovascular and all-cause death. The cohort included 4540 patients (age 67 +/- 12 years, left ventricular ejection fraction 33 +/- 13%, 1111 women, 25%). Women showed lower sST2 (24 vs. 27 ng/mL, P < 0.001) and hs-cTnT level (15 vs. 20 ng/L, P < 0.001), and similar concentrations of NT-proBNP (1540 vs. 1505 ng/L, P = 0.408). Although the three biomarkers were confirmed as independent predictors of outcome in both sexes, the optimal prognostic cut-off was lower in women for sST2 (28 vs. 31 ng/mL) and hs-cTnT (22 vs. 25 ng/L), while NT-proBNP cut-off was higher in women (2339 ng/L vs. 2145 ng/L). The use of sex-specific cut-offs improved risk prediction compared with the use of previously standardized prognostic cut-offs and allowed to reclassify the risk of many patients, to a greater extent in women than men, and for hs-cTnT than sST2 or NT-proBNP. Specifically, up to 18% men and up to 57% women were reclassified, by using the sex-specific cut-off of hs-cTnT for the endpoint of 5 year cardiovascular death. Conclusions In patients with chronic HF, concentrations of sST2 and hs-cTnT, but not of NT-proBNP, are lower in women. Lower sST2 and hs-cTnT and higher NT-proBNP cut-offs for risk stratification could be used in women.
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| 7. |
- Vergaro, Giuseppe, et al.
(författare)
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NT-proBNP for Risk Prediction in Heart Failure : Identification of Optimal Cutoffs Across Body Mass Index Categories
- 2021
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Ingår i: JACC. Heart failure. - : American College of Cardiology. - 2213-1779 .- 2213-1787. ; 9:9, s. 653-663
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Tidskriftsartikel (refereegranskat)abstract
- ObjectivesThe goal of this study was to assess the predictive power of N-terminal pro–B-type natriuretic peptide (NT-proBNP) and the decision cutoffs in heart failure (HF) across body mass index (BMI) categories.BackgroundConcentrations of NT-proBNP predict outcome in HF. Although the influence of BMI to reduce levels of NT-proBNP is known, the impact of obesity on prognostic value remains uncertain.MethodsIndividual data from the BIOS (Biomarkers In Heart Failure Outpatient Study) consortium were analyzed. Patients with stable HF were classified as underweight (BMI <18.5 kg/m2), normal weight (BMI 18.5-24.9 kg/m2), overweight (BMI 25-29.9 kg/m2), and mildly (BMI 30-34.9 kg/m2), moderately (BMI 35-39.9 kg/m2), or severely (BMI ≥40 kg/m2) obese. The prognostic role of NT-proBNP was tested for the endpoints of all-cause and cardiac death.ResultsThe study population included 12,763 patients (mean age 66 ± 12 years; 25% women; mean left ventricular ejection fraction 33% ± 13%). Most patients were overweight (n = 5,176), followed by normal weight (n = 4,299), mildly obese (n = 2,157), moderately obese (n = 612), severely obese (n = 314), and underweight (n = 205). NT-proBNP inversely correlated with BMI (β = –0.174 for 1 kg/m2; P < 0.001). Adding NT-proBNP to clinical models improved risk prediction across BMI categories, with the exception of severely obese patients. The best cutoffs of NT-proBNP for 5-year all-cause death prediction were lower as BMI increased (3,785 ng/L, 2,193 ng/L, 1,554 ng/L, 1,045 ng/L, 755 ng/L, and 879 ng/L, for underweight, normal weight, overweight, and mildly, moderately, and severely obese patients, respectively) and were higher in women than in men.ConclusionsNT-proBNP maintains its independent prognostic value up to 40 kg/m2 BMI, and lower optimal risk-prediction cutoffs are observed in overweight and obese patients.
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| 8. |
- Aimo, Alberto, et al.
(författare)
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High-sensitivity troponin T, NT-proBNP and glomerular filtration rate : A multimarker strategy for risk stratification in chronic heart failure
- 2019
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Ingår i: International Journal of Cardiology. - : Elsevier BV. - 0167-5273 .- 1874-1754. ; 277, s. 166-172
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Tidskriftsartikel (refereegranskat)abstract
- Background: In a recent individual patient data meta-analysis, high-sensitivity troponin T (hs-TnT) emerged as robust predictor of prognosis in stable chronic heart failure (HF). In the same population, we compared the relative predictive performances of hs-TnT, N-terminal fraction of pro-B-type natriuretic peptide (NT-proBNP), hs-C-reactive protein (hs-CRP), and estimated glomerular filtration rate (eGFR) for prognosis.Methods and results: 9289 patients (66 ± 12 years, 77% men, 85% LVEF <40%, 60% ischemic HF) were evaluated over a 2.4-year median follow-up. Median eGFR was 58 mL/min/1.73 m2 (interquartile interval 46–70; n = 9220), hs-TnT 16 ng/L (8–20; n = 9289), NT-proBNP 1067 ng/L (433–2470; n = 8845), and hs-CRP 3.3 mg/L (1.4–7.8; n = 7083). In a model including all 3 biomarkers, only hs-TnT and NT-proBNP were independent predictors of all-cause and cardiovascular mortality and cardiovascular hospitalization. hs-TnT was a stronger predictor than NT-proBNP: for example, the risk for all-cause death increased by 54% per doubling of hs-TnT vs. 24% per doubling of NT-proBNP. eGFR showed independent prognostic value from both hs-TnT and NT-proBNP. The best hs-TnT and NT-proBNP cut-offs for the prediction of all-cause death increased progressively with declining renal function (eGFR ≥ 90: hs-TnT 13 ng/L and NT-proBNP 825 ng/L; eGFR < 30: hs-TnT 40 ng/L and NT-proBNP 4608 ng/L). Patient categorization according to these cut-offs effectively stratified patient prognosis across all eGFR classes.Conclusions: hs-TnT conveys independent prognostic information from NT-proBNP, while hs-CRP does not. Concomitant assessment of eGFR may further refine risk stratification. Patient classification according to hs-TnT and NT-proBNP cut-offs specific for the eGFR classes holds prognostic significance.
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| 9. |
- Aimo, Alberto, et al.
(författare)
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Prognostic Value of High-Sensitivity Troponin T in Chronic Heart Failure : An Individual Patient Data Meta-Analysis
- 2018
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Ingår i: Circulation. - 0009-7322 .- 1524-4539. ; 137:3, s. 286-297
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Tidskriftsartikel (refereegranskat)abstract
- Background: Most patients with chronic heart failure have detectable troponin concentrations when evaluated by high-sensitivity assays. The prognostic relevance of this finding has not been clearly established so far. We aimed to assess high-sensitivity troponin assay for risk stratification in chronic heart failure through a meta-analysis approach.Methods: Medline, EMBASE, Cochrane Library, and Scopus were searched in April 2017 by 2 independent authors. The terms were “troponin” AND “heart failure” OR “cardiac failure” OR “cardiac dysfunction” OR “cardiac insufficiency” OR “left ventricular dysfunction.” Inclusion criteria were English language, clinical stability, use of a high-sensitivity troponin assay, follow-up studies, and availability of individual patient data after request to authors. Data retrieved from articles and provided by authors were used in agreement with the PRISMA statement. The end points were all-cause death, cardiovascular death, and hospitalization for cardiovascular cause.Results: Ten studies were included, reporting data on 11 cohorts and 9289 patients (age 66±12 years, 77% men, 60% ischemic heart failure, 85% with left ventricular ejection fraction <40%). High-sensitivity troponin T data were available for all patients, whereas only 209 patients also had high-sensitivity troponin I assayed. When added to a prognostic model including established risk markers (sex, age, ischemic versus nonischemic etiology, left ventricular ejection fraction, estimated glomerular filtration rate, and N-terminal fraction of pro-B-type natriuretic peptide), high-sensitivity troponin T remained independently associated with all-cause mortality (hazard ratio, 1.48; 95% confidence interval, 1.41–1.55), cardiovascular mortality (hazard ratio, 1.40; 95% confidence interval, 1.33–1.48), and cardiovascular hospitalization (hazard ratio, 1.42; 95% confidence interval, 1.36–1.49), over a median 2.4-year follow-up (all P<0.001). High-sensitivity troponin T significantly improved risk prediction when added to a prognostic model including the variables above. It also displayed an independent prognostic value for all outcomes in almost all population subgroups. The area under the curve–derived 18 ng/L cutoff yielded independent prognostic value for the 3 end points in both men and women, patients with either ischemic or nonischemic etiology, and across categories of renal dysfunction.Conclusions: In chronic heart failure, high-sensitivity troponin T is a strong and independent predictor of all-cause and cardiovascular mortality, and of hospitalization for cardiovascular causes, as well. This biomarker then represents an additional tool for prognostic stratification.
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| 10. |
- Aimo, Alberto, et al.
(författare)
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Revisiting the obesity paradox in heart failure : Per cent body fat as predictor of biomarkers and outcome
- 2019
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Ingår i: European Journal of Preventive Cardiology. - : Sage Publications. - 2047-4873 .- 2047-4881. ; 26:16, s. 1751-1759
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Tidskriftsartikel (refereegranskat)abstract
- Aims Obesity defined by body mass index (BMI) is characterized by better prognosis and lower plasma N-terminal pro-B-type natriuretic peptide (NT-proBNP) in heart failure. We assessed whether another anthropometric measure, per cent body fat (PBF), reveals different associations with outcome and heart failure biomarkers (NT-proBNP, high-sensitivity troponin T (hs-TnT), soluble suppression of tumorigenesis-2 (sST2)). Methods In an individual patient dataset, BMI was calculated as weight (kg)/height (m) (2) , and PBF through the Jackson-Pollock and Gallagher equations. Results Out of 6468 patients (median 68 years, 78% men, 76% ischaemic heart failure, 90% reduced ejection fraction), 24% died over 2.2 years (1.5-2.9), 17% from cardiovascular death. Median PBF was 26.9% (22.4-33.0%) with the Jackson-Pollock equation, and 28.0% (23.8-33.5%) with the Gallagher equation, with an extremely strong correlation (r = 0.996, p < 0.001). Patients in the first PBF tertile had the worst prognosis, while patients in the second and third tertile had similar survival. The risks of all-cause and cardiovascular death decreased by up to 36% and 27%, respectively, per each doubling of PBF. Furthermore, prognosis was better in the second or third PBF tertiles than in the first tertile regardless of model variables. Both BMI and PBF were inverse predictors of NT-proBNP, but not hs-TnT. In obese patients (BMI >= 30 kg/m(2), third PBF tertile), hs-TnT and sST2, but not NT-proBNP, independently predicted outcome. Conclusion In parallel with increasing BMI or PBF there is an improvement in patient prognosis and a decrease in NT-proBNP, but not hs-TnT or sST2. hs-TnT or sST2 are stronger predictors of outcome than NT-proBNP among obese patients.
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