| 1. |
- Nawaz, Sara, et al.
(author)
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Novel inflammatory biomarkers in postural orthostatic tachycardia syndrome
- 2023
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In: Europace. - 1532-2092 .- 1099-5129. ; , s. 345-345
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Conference paper (peer-reviewed)abstract
- IntroductionPostural Orthostatic Tachycardia Syndrome (POTS) is a disorder characterized by excessive orthostatic tachycardia and orthostatic intolerance. While traditional inflammatory biomarkers tend to be normal, a subclinical inflammatory process may be present in POTS.PurposeWe aimed to analyse novel inflammatory biomarkers in POTS patients: Growth Differentiation Factor 15 (GDF15), Neutrophil Gelatinase Associated Lipocalin (NGAL), Intercellular Adhesion Molecule 1 (ICAM-1), Tumour Necrosis Factor Receptor 1 (TNFR1) and Tumour Necrosis Factor Receptor 2 (TNFR2) and compared them to healthy controls. These inflammatory biomarkers have been shown to be independent predictors of major adverse cardiovascular events in other populations.MethodsAn age- and sex-matched case-control study included 65 patients verified to have POTS by positive head-up tilt-testing and cardiovascular autonomic tests, and 65 healthy controls (mean age: 31.1 vs 31.5 years, 84% females) with negative active standing tests and no history of syncope, orthostatic intolerance, or endocrine disease. High-sensitivity chemiluminescence sandwich immunoassay was used to measure plasma levels of inflammatory biomarkers in a blinded fashion. Descriptive statistics compared groups and a univariate ANOVA was employed. Biomarker values were log-transformed. A score incorporating all biomarkers was generated to see if the totality of biomarkers discriminated POTS patients from controls.ResultsBaseline characteristics are displayed in Table 1. Mean levels of GDF15 (p=0.01), NGAL (p=0.003), ICAM-1 (p=0.04) and TNFR1 (p=0.03) were significantly higher in POTS vs controls, whereas TNFR2 (p=0.04) was significantly lower in POTS (p=0.04). The product of four upregulated biomarkers divided by TNFR2 produced a receiver operator curve (ROC) with an area under the curve (AUC) of 0.703 (pConclusionPOTS patients had increased GDF15, NGAL, TNFR1 and ICAM-1 levels and reduced TNFR2 levels suggesting underlying, yet undefined, subclinical inflammatory processes involving neutrophil and endothelial activation.
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| 2. |
- Ricci, Fabrizio, et al.
(author)
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Increased levels of circulating endostatin are linked to orthostatic hypotension
- 2023
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In: European Heart Journal. - 1522-9645 .- 0195-668X. ; 44:Supplement_2
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Conference paper (peer-reviewed)abstract
- BackgroundOrthostatic hypotension (OH) occurs when blood pressure regulation fails. The underlying molecular mechanism of OH remain largely unexplored. Endostatin is a biologically active molecule cleaved by matrix metalloproteinases, elastases and cathepsins from collagen XVIII in the extracellular matrix and inhibits angiogenesis. Circulating levels of endostatin have been proposed to be involved in blood pressure (BP) regulation, by inducing nitric oxide release. To date, the relationship between endostatin and OH have not been examined.PurposeWe aimed to investigate circulating levels of endostatin in patients with verified OH by tilt test at a tertiary syncope unit compared with healthy age- and sex-matched controls from the same geographical region.MethodsWe performed an age- and sex-matched case-control study in 150 patients with OH verified by positive head-up tilt-testing and other cardiovascular autonomic tests at a tertiary syncope unit, and 150 healthy controls with negative active standing tests and no history of syncope, orthostatic intolerance, and endocrine disease. High-sensitivity chemiluminescence sandwich immunoassay was used to measure circulating levels of endostatin in a blinded fashion. Receiver operating characteristic curves were constructed to analyze the discriminative ability of endostatin in OH compared with healthy controls. Multivariate logistic regression was used to assess the association between endostatin, OH and hemodynamic variables adjusting for age and sex.ResultsStudy characteristics are displayed in the Table. Patients with OH had significantly higher absolute levels of circulating endostatin compared with healthy controls (59,024 ± 2513 vs. 44,090 ± 1978 pg/mL, p<0.001). Multivariate-adjusted logistic regression analysis controlling for age, sex, minimum systolic and minimum diastolic BP during tilt, identified endostatin as an independent determinant for OH (beta-coefficient 0.80, p=0.025). The obtained area under the curve was 0.70, P<0.001, Figure).ConclusionsOur findings indicate that patients with orthostatic hypotension have increased circulating levels of endostatin, independent of age, sex, and hemodynamic variables. Our results highlight the relevance of investigating the molecular pathways related to orthostatic hypotension. Further studies are warranted to assess the prognostic and therapeutic role of endostatin assessment in individuals with orthostatic hypotension.
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| 3. |
- Ricci, Fabrizio, et al.
(author)
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Orthostatic hypotension is associated with higher levels of circulating endostatin
- 2024
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In: European Heart Journal Open. - 2752-4191.
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Journal article (peer-reviewed)abstract
- AimsThe pathophysiology of orthostatic hypotension (OH), a common clinical condition, associated with adverse outcomes, is incompletely understood. We examined the relationship between OH and circulating endostatin, an endogenous angiogenesis inhibitor with antitumor effects proposed to be involved in blood pressure (BP) regulation.MethodsWe compared endostatin levels in 146 patients with OH and 150 controls. A commercial chemiluminescence sandwich immunoassay was used to measure circulating levels of endostatin. Linear and multivariate logistic regressions were conducted to test the association between endostatin and OH.ResultsEndostatin levels were significantly higher in OH patients (59,024 ± 2513 pg/mL) versus controls (44,090 ± 1978 pg/mL, p<0.001). A positive linear correlation existed between endostatin and the magnitude of systolic BP decline upon standing (p<0.001). Using multivariate analysis, endostatin was associated with OH (adjusted odds ratio per 10% increase of endostatin in the whole study population = 1.264, 95%CI 1.141-1.402), regardless of age, sex, prevalent cancer, and cardiovascular disease, as well as traditional cardiovascular risk factors.ConclusionCirculating endostatin is elevated in patients with orthostatic hypotension and may serve as a potential clinical marker of increased cardiovascular risk in patients with orthostatic hypotension. Our findings call for external validation. Further research is warranted to clarify the underlying pathophysiological mechanisms.
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| 4. |
- Ruge, Toralph, et al.
(author)
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A comparison between endostatin and conventional biomarkers on 30-day mortality and renal replacement therapy in unselected intensive care patients
- 2021
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In: Biomedicines. - : MDPI AG. - 2227-9059. ; 9:11
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Journal article (peer-reviewed)abstract
- Endostatin may predict mortality and kidney impairment in general populations as well as in critically ill patients. We decided to explore the possible role of endostatin as a predictor of 30-day mortality, acute kidney injury (AKI), and renal replacement therapy (RRT) in a cohort of unselected intensive care unit (ICU) patients. Endostatin and creatinine in plasma were analyzed and SAPS3 was determined in 278 patients on ICU arrival at admission to a Swedish medium-sized hospital. SAPS3 had the highest predictive value, 0.85 (95% C.I.: 0.8–0.90), for 30-day mortality. Endostatin, in combination with age, predicted 30-day mortality by 0.76 (95% C.I.: 0.70–0.82). Endostatin, together with age and creatinine, predicted AKI with 0.87 (95% C.I.: 0.83–0.91). Endostatin predicted AKI with [0.68 (0.62–0.74)]. Endostatin predicted RRT, either alone [0.82 (95% C.I.: 0.72–0.91)] or together with age [0.81 (95% C.I.: 0.71–0.91)]. The predicted risk for 30-day mortality, AKI, or RRT during the ICU stay, predicted by plasma endostatin, was not influenced by age. Compared to the complex severity score SAPS3, circulating endostatin, combined with age, offers an easily managed option to predict 30-day mortality. Additionally, circulating endostatin combined with creatinine was closely associated with AKI development.
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| 5. |
- Ruge, Toralph, et al.
(author)
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Is medical urgency of elderly patients with traumatic brain injury underestimated by emergency department triage?
- 2020
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In: Upsala Journal of Medical Sciences. - : Taylor & Francis. - 0300-9734 .- 2000-1967. ; 125:1, s. 58-63
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Journal article (peer-reviewed)abstract
- Background: Mortality is high among elderly patients with traumatic brain injury (TBI). Recent data suggest that early surgical intervention and aggressive rehabilitation may reduce mortality rates even in elderly patients. Our aim was therefore to study the Rapid Emergency Triage and Treatment System-Adult (RETTS-A) triage of patients with isolated TBI and examine the differences in acute management according to age. Methods: We included 306 adult patients with isolated severe TBI and an abbreviated injury scale (AIS) score >= 3. Using a cut-off of 60 years of age, differences in triage priority according to RETTS-A, time to first computed tomography (CT) scan, length of hospital stay (LOS), and 30-day survival were studied. Results: In patients with an AIS score of 3 and 4, we observed that elderly patients had a longer time from admission to first CT scan. In addition, we observed that elderly patients were less often triaged with the highest priority level, despite similar AIS scores. LOS was significantly higher in elderly patients (median 9 days compared with 3 days for younger patients, p < 0.001). Finally, age, triage priority, and AIS score were independent risk factors for mortality. Conclusion: Elderly patients with isolated TBI are managed differently than younger patients, which could be due to an under-triage of elderly patients by RETTS-A.
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| 6. |
- Sun, Jiangming, et al.
(author)
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ADAM-17 Activity and Its Relation to ACE2 : Implications for Severe COVID-19
- 2024
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In: International Journal of Molecular Sciences. - 1661-6596. ; 25:11
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Journal article (peer-reviewed)abstract
- There is a lack of studies aiming to assess cellular a disintegrin and metalloproteinase-17 (ADAM-17) activity in COVID-19 patients and the eventual associations with the shedding of membrane-bound angiotensin-converting enzyme 2 (mACE2). In addition, studies that investigate the relationship between ACE2 and ADAM-17 gene expressions in organs infected by SARS-CoV-2 are lacking. We used data from the Massachusetts general hospital COVID-19 study (306 COVID-19 patients and 78 symptomatic controls) to investigate the association between plasma levels of 33 different ADAM-17 substrates and COVID-19 severity and mortality. As a surrogate of cellular ADAM-17 activity, an ADAM-17 substrate score was calculated. The associations between soluble ACE2 (sACE2) and the ADAM-17 substrate score, renin, key inflammatory markers, and lung injury markers were investigated. Furthermore, we used data from the Genotype-Tissue Expression (GTEx) database to evaluate ADAM-17 and ACE2 gene expressions by age and sex in ages between 20–80 years. We found that increased ADAM-17 activity, as estimated by the ADAM-17 substrates score, was associated with COVID-19 severity (p = 0.001). ADAM-17 activity was also associated with increased mortality but did not reach statistical significance (p = 0.06). Soluble ACE2 showed the strongest positive correlation with the ADAM-17 substrate score, follow by renin, interleukin-6, and lung injury biomarkers. The ratio of ADAM-17 to ACE2 gene expression was highest in the lung. This study indicates that increased ADAM-17 activity is associated with severe COVID-19. Our findings also indicate that there may a bidirectional relationship between membrane-bound ACE2 shedding via increased ADAM-17 activity, dysregulated renin–angiotensin system (RAS) and immune signaling. Additionally, differences in ACE2 and ADAM-17 gene expressions between different tissues may be of importance in explaining why the lung is the organ most severely affected by COVID-19, but this requires further evaluation in prospective studies.
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| 7. |
- Wessman, Torgny, et al.
(author)
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Relationships Between Charlson Comorbidity Index Associated Biomarkers and Outcomes Among Participants in the Malmö Diet and Cancer Study
- 2024
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In: Biomarkers. - 1366-5804. ; 28:8, s. 722-730
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Journal article (peer-reviewed)abstract
- Introduction: The aim was to evaluate two biomarker scores trained to identify comorbidity burden in the prediction of specified chronic morbidities, and mortality in the general population. Methods: Cardiovascular biomarkers were measured in the cardiovascular cohort of the Malmö Diet and Cancer Study. A score of 19 biomarkers associated with Charlson Comorbidity Index (CCI) was created (BSMDC). Individuals with CCI diagnoses and other major comorbidities were excluded. Another score of 11 biomarkers associated with comorbidity burden from a previous study of acute dyspnea was also created (BSADYS). The scores were prospectively evaluated for prediction of mortality, and some chronic diseases, using Cox Proportional Hazards Modell.Results: Fully adjusted models showed that BSMDC was significantly associated per 1 SD increment of the score with incident COPD, 55%, and congestive heart failure, 32%; and with mortality, 33% cardiovascular, 91% respiratory, 30% cancer, and 45% with all-cause mortality. The BSADYS showed no association with these outcomes, after simultaneous inclusion of both biomarker scores to all the clinical covariates.Conclusion: BSMDC shows strong prediction of morbidity and mortality in individuals free from comorbidities at baseline, and the results suggest that healthy individuals with high level of BSMDC would benefit from intense preventive actions.
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| 8. |
- Wessman, Torgny, et al.
(author)
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The association between length of stay in the emergency department and short-term mortality
- 2022
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In: Internal and Emergency Medicine. - : Springer Science and Business Media LLC. - 1828-0447 .- 1970-9366. ; 17:1, s. 233-240
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Journal article (peer-reviewed)abstract
- The detrimental effects of increased length of stay at the emergency department (ED-LOS) for patient outcome have been sparsely studied in the Swedish setting. Our aim was to further explore the association between ED-LOS and short-term mortality in patients admitted to the EDs of two large University hospitals in Sweden. All adult patients (> 18 years) visiting the ED at the Karolinska University Hospital, Sweden, from 1/1/2010 to 1/1/2015 (n = 639,385) were retrospectively included. Logistic regression analysis was used to determine association between ED-LOS and 7- and 30-day mortality rates. All patients were triaged according to the RETTS-A into different levels of medical urgency and subsequently separated into five quintiles of ED-LOS. Mortality rate was highest in highest triage priority level (7-day mortality 5.24%, and 30-day mortality 9.44%), and decreased by lower triage priority group. For patients with triage priority levels 2–4, prolonged ED-LOS was associated with increased mortality, especially for lowest priority level, OR for priority level 4 and highest quintile of ED-LOS 30-day mortality 1.49 (CI 95% 1.20–1.85). For patients with highest triage priority level the opposite was at hand, with decreasing mortality risk with increasing quintile of ED-LOS for 7-day mortality, and lower mortality for the two highest quintile of ED-LOS for 30-day mortality. In patients not admitted to in-hospital care higher ED-LOS was associated with higher mortality. Our data suggest that increased ED-LOS could be associated with slightly increased short-term mortality in patients with lower clinical urgency and dismissed from the ED.
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| 9. |
- Wollmer, Martin, et al.
(author)
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Plasma calprotectin in the emergency department : a potential clinical biomarker for patients with infectious diseases
- 2021
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In: Scandinavian Journal of Clinical and Laboratory Investigation. - : Taylor & Francis. - 0036-5513 .- 1502-7686. ; 81:7, s. 593-597
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Journal article (peer-reviewed)abstract
- Increased levels of plasma calprotectin are reported in patients with infectious diseases. However, the clinical usefulness of calprotectin as a biomarker to identify patients with infectious diseases in the emergency department (ED) setting has not been investigated. To study the ability of calprotectin to discriminate patients with acute infectious diseases and dyspnea from patients with other causes of acute dyspnea in the ED setting. Patients aged ≥18 years seeking ED during daytime on weekdays between March 2013 and July 2018, with acute dyspnea, were included. Participants (n = 1287) were triaged according to Medical Emergency Triage and Treatment System-Adult score (METTS-A) or Rapid Emergency Triage and Treatment System (RETTS), and blood samples were collected. The association between calprotectin and other markers of infectious diseases, i.e. biomarkers (CRP, leucocytes) and body temperature, was studied. The predictive value of calprotectin for the outcome of acute infection was evaluated with receiver operating characteristic (ROC) analysis. Univariate cross-sectional regression showed significant associations between calprotectin and leucocytes, CRP and body temperature. Patients with severe infections including pneumonia (n = 119) had significantly higher concentrations of calprotectin compared to patients with heart failure (n = 162) or chronic obstructive pulmonary disease (n = 183). When tested for the outcome of acute infection (n = 109), the area under the ROC curve (AUROC) was for CRP 0.83 and for calprotectin 0.78. Plasma calprotectin identifies infectious diseases in ED patients with acute dyspnea, and the clinical usefulness of Calprotectin in the ED has to be further studied.
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| 10. |
- Wändell, Per, et al.
(author)
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A machine learning tool for identifying patients with newly diagnosed diabetes in primary care
- 2024
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In: Primary Care Diabetes. - 1751-9918 .- 1878-0210.
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Journal article (peer-reviewed)abstract
- BACKGROUND AND AIM: It is crucial to identify a diabetes diagnosis early. Create a predictive model utilizing machine learning (ML) to identify new cases of diabetes in primary health care (PHC).METHODS: A case-control study utilizing data on PHC visits for sex-, age, and PHC-matched controls. Stochastic gradient boosting was used to construct a model for predicting cases of diabetes based on diagnostic codes from PHC consultations during the year before index (diagnosis) date and number of consultations. Variable importance was estimated using the normalized relative influence (NRI) score. Risks of having diabetes were calculated using odds ratios of marginal effects (ORME). Four groups by age and sex were studied, age-groups 35-64 years and ≥ 65 years in men and women, respectively.RESULTS: The most important predictive factors were hypertension with NRI 21.4-29.7 %, and obesity 4.8-15.2 %. The NRI for other top ten diagnoses and administrative codes generally ranged 1.0-4.2 %.CONCLUSIONS: Our data confirm the known risk patterns for predicting a new diagnosis of diabetes, and the need to test blood glucose frequently. To assess the full potential of ML for risk prediction purposes in clinical practice, future studies could include clinical data on life-style patterns, laboratory tests and prescribed medication.
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| 11. |
- Wändell, Per, et al.
(author)
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The association between BMI and 90-day mortality in patients with and without diabetes seeking care at the emergency department.
- 2021
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In: Upsala Journal of Medical Sciences. - : Uppsala Medical Society. - 0300-9734 .- 2000-1967. ; 126
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Journal article (peer-reviewed)abstract
- Background: The impact of body mass index (BMI) on mortality varies with age and disease states. The aim of this research study was to analyse the associations between BMI categories and short- and long-term mortality in patients with or without diabetes seeking care at the emergency department (ED) with acute dyspnoea.Population and methods: Patients aged ≥18 years at ED during daytime on weekdays from March 2013 to July 2018 were included. Participants were triaged according to the Medical Emergency Triage and Treatment System-Adult score (METTS-A), and blood samples were collected. Totally, 1,710 patients were enrolled, with missing values in 113, leaving 1,597 patients, 291 with diabetes and 1,306 without diabetes. The association between BMI and short-term (90-day) and long-term (mean follow-up time 2.1 years) mortality was estimated by Cox regression with normal BMI (18.5-24.9) as referent category, with adjustment for age, sex, METTS-A scoring, glomerular filtration rate, smoking habits and cardiovascular comorbidity in a fully adjusted model. The Bonferroni correction was also used.Results: Regarding long-term mortality, patients with diabetes and BMI category ≥30 kg/m2 had a fully adjusted Hazard Ratio (HR) of 0.40 (95% confidence interval [CI]: 0.23-0.69), significant after the Bonferroni correction. Amongst patients without diabetes, those with underweight had an increased risk but only of borderline significance, whilst risks in those with overweight or obesity did not differ from reference.Regarding short-term mortality, risks did not differ from reference amongst patients with or without diabetes.Conclusions: We found divergent long-term mortality risks in patients with and without diabetes, with lower risk in obese patients (BMI ≥ 30 kg/m2) with diabetes, but no increased risk for patients without diabetes and overweight (BMI: 25-29.9 kg/m2) and obesity.
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| 12. |
- Wändell, Per, et al.
(author)
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The C-reactive protein Albumin ratio was not consistently associated with cardiovascular and all-cause mortality in two community-based cohorts of 70-year-olds.
- 2023
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In: Scandinavian Journal of Clinical and Laboratory Investigation. - 0036-5513 .- 1502-7686. ; , s. 1-5
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Journal article (peer-reviewed)abstract
- C-reactive protein (CRP)/Albumin ratio (CAR) seems to mirror disease severity and prognosis in several acute disorders particularly in elderly patients, which we aimed to study. As method we use a prospective study design; the Prospective Investigation of the Vasculature in Uppsala Seniors (PIVUS; n = 912, women 50%; mean age 70 years, baseline 2001 and 2004, median follow-up 15.0 years, end of follow-up 2019) and the Uppsala Longitudinal Study of Adult Men (ULSAM, n = 924 mean age 71 years, baseline 1991-1995, median follow-up 15.6 years, end of follow-up 2016). Serum samples were used for analyses of CRP and Albumin. Cox regression analyses were performed for cardiovascular and all-cause mortality in models adjusting for several factors (age; physical activity; Interleukin-6; cardiovascular (CVD) risk factors: smoking, BMI level, systolic blood pressure, LDL-cholesterol, and diabetes), with 95% confidence interval (CI). When adjusting for age and CVD risk factors, CAR was significantly associated with cardiovascular mortality for meta-analyzed results from PIVUS and ULSAM, HR 1.09 (95% 1.01-1.18), but neither in PIVUS (HR 1.14, 95% CI 0.99-1.31) nor in ULSAM (1.07, 95% CI 0.98-1.17). Additionally, CAR was significantly associated with all-cause mortality in ULSAM 1.31 (95% CI 1.12-1.54) but not in PIVUS HRs 1.01 (95% 0.089-1.15). The predictive value of CAR was similar to CRP alone in PIVUS and ULSAM and slightly better than albumin for the prediction of CVD-mortality in ULSAM. In conclusion, CAR was not consistently associated with cardiovascular and all-cause mortality in the two cohorts. The prognostic value of CAR for long-term CVD-mortality was similar to CRP.
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| 13. |
- Wändell, Per, et al.
(author)
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The predictive value of cardiovascular outcomes and mortality assessed by the C-reactive protein to albumin ratio in the UK Biobank
- 2024
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In: BMC Cardiovascular Disorders. - : BioMed Central (BMC). - 1471-2261. ; 24:1
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Journal article (peer-reviewed)abstract
- BACKGROUND: The C-reactive protein/albumin ratio (CAR) seems to mirror disease severity and prognosis in several acute disorders particularly in elderly patients, yet less is known about if CAR is superior to C-reactive protein (CRP) in the general population.METHODS: Prospective study design on the UK Biobank, where serum samples of CRP and Albumin were used. Cox regression analyses were conducted to assess all-cause and cardiovascular mortality, myocardial infarction, ischemic stroke, and heart failure over a follow-up period of approximately 12.5 years. The Cox model was adjusted for established cardiovascular disease (CVD) risk factors, including age, sex, smoking habits, physical activity level, BMI level, systolic blood pressure, LDL-cholesterol, statin treatment, diabetes, and previous CVD, with hazard ratios (HRs) and corresponding 95% confidence intervals (CIs). Analyses were also stratified by sex, CRP level (< 10 and ≥ 10 mg/ml) and age (< 60 and ≥ 60 years).RESULTS: In total, 411,506 individuals (186,043 men and 225,463 women) were included. In comparisons between HRs for all adverse outcomes, the results were similar or identical for CAR and CRP. For example, both CAR and CRP, adjusted HRs for all-cause mortality were 1.13 (95% CI 1.12-1.14). Regarding CVD mortality, the adjusted HR for CAR was 1.14 (95% CI 1.12-1.15), while for CRP, it was 1.13 (95% CI 1.11-1.15).CONCLUSIONS: Within this study CAR was not superior to CRP in predictive ability of mortality or CVD disorders.CLINICAL TRIAL REGISTRATION NUMBER: Not applicable (cohort study).
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