Search

Obstructive sleep apnea (OSA) as a worldwide prevalent condition carries risk for cardiovascular and metabolic diseases, ultimately increasing overall mortality rates. Non-alcoholic fatty liver disease (NAFLD) can be considered as the primary metabolic disease, but also as a coexisting OSA comorbidity. Although prevalence of NAFLD covers quarter of world population, it increases with OSA presence. It can be speculated that chronic intermittent hypoxia (CIH) and sympathetic nervous system overactivity are involved in NAFLD pathogenesis and progression from simple steatosis through steatohepatitis to fibrosis. CIH provides the environment for liver oxidative stress, inflammation and increases the expression of genes involved in cholesterol and fatty acids synthesis. Catecholamines increase b-oxidation in liver and release free fatty acids from adipose tissue in plasma which inhibit insulin effects. Obesity and insulin resistance as key players in NAFLD development and advancement, deepen vicious circle of oxidative stress, inflammation and dyslipidemia. If not treated, OSA in NAFLD patients has been associated with inflammation, hepatocytes' necrosis, and fibrosis. Continuous positive airway pressure (CPAP) represents gold standard for OSA therapy, allowing the unimpeded air passage through upper parts of respiratory system. However, it has been demonstrated that CPAP therapy have beneficial effects on cardiometabolic outcomes and slow liver degeneration.

Purpose: Obstructive sleep apnea (OSA) is characterised by increased systemic inflammation, and is often accompanied with type 2 diabetes mellitus (T2DM) and cardiovascular disease. The aim of this investigation was to evaluate gene expression of resistin, its receptor CAP1 and CD36 as the indicators of the inflammatory changes in PBMCs in relation to the severity of OSA, and the presence of type 2 diabetes mellitus (T2DM) in OSA., Methods: Severity of OSA was defined by the apnea/hypopnea index (AHI): AHI < 30: mild to moderate OSA (MM-OSA), AHI ≥ 30: severe OSA (S-OSA). Presence of T2DM was captured: OSA with T2DM (OSA + T2DM), OSA without T2DM (OSA-T2DM). PBMC resistin, CAP1, and CD36 mRNA were determined by real-time PCR., Results: Resistin mRNA was significantly upregulated in S-OSA (N = 54) compared to the MM-OSA (N = 52, P = 0.043); CAP1 and CD36 mRNA levels did not differ between the groups (P = 0.302; P = 0.166, respectively). Resistin mRNA was significantly upregulated in OSA + T2DM (N = 29) compared to the OSA-T2DM (N = 77, P = 0.029); CAP1 and CD36 mRNA levels did not differ between the groups (P = 0.662; P = 0.108, respectively). AHI and T2DM were independent predictors of resistin mRNA above the 75th percentile (OR = 3.717 [1.152-11.991]; OR = 3.261 [1.000-10.630], P = 0.042 respectively)., Conclusion: Resistin gene upregulation in S-OSA indicates its possible contribution to increased inflammation in S-OSA and makes it a possible marker of the disease severity. Resistin gene upregulation in OSA + T2DM suggests that a joint effect of these two comorbidities may have a major contribution to increased inflammation and complications that arise from this state., (© 2023. The Author(s), under exclusive licence to Springer Nature Switzerland AG.)

Background and Aims: Obstructive sleep apnea (OSA) is closely linked to obesity and related adverse metabolic changes, including dyslipidemia. However, it is not clear whether OSA is an independent contributing factor to dyslipidemia, or the observed association is a reflection of a concomitant presence of obesity. Additionally, dyslipidemia is usually evaluated through measurement of parameters of routine lipid status, while more precise evaluation of lipid homeostasis is rarely performed in OSA. In this study, we analyzed markers of cholesterol synthesis and absorption in patients with OSA with respect to the presence of obesity and the disease severity., Methods and Results: This study enrolled 116 OSA patients. Concentrations of non-cholesterol sterols (NCS), measured by LC-MS/MS, were used as markers of cholesterol synthesis and absorption. Apnea-hypopnea index (AHI) and oxygen saturation (SaO 2 ) were utilized as markers of OSA severity. Serum lipid status parameters were determined by routine enzymatic methods. Markers of cholesterol synthesis were increased (P = 0.005), whilst markers of cholesterol absorption decreased (P = 0.001) in obese OSA patients. Cholesterol synthesis/absorption ratio was elevated in obese subjects (P < 0.001). Concentration of cholesterol synthesis marker lathosterol was significantly higher in subjects with severe OSA (P = 0.014) and we observed a trend of decreased cholesterol absorption in these patients. AHI was revealed as an independent determinant of lathosterol concentration (P = 0.022)., Conclusions: Our results suggest that the presence of obesity and severe forms of OSA is characterized by elevated endogenous cholesterol synthesis. AHI was singled out as an independent determinant of the serum level of cholesterol synthesis marker lathosterol., Competing Interests: Declaration of competing interest None., (Copyright © 2022 The Italian Diabetes Society, the Italian Society for the Study of Atherosclerosis, the Italian Society of Human Nutrition and the Department of Clinical Medicine and Surgery, Federico II University. Published by Elsevier B.V. All rights reserved.)

Introduction: Thrombotic complications, such as pulmonary embolism, are common in COVID-19 patients. Point-of-care ultrasound is a highly recommended tool for orientation in critically ill patients with suspected or confirmed complications., Methods: An observational study was conducted on 32 consecutive patients with confirmed pulmonary embolism and COVID-19 infection treated in the Intensive Care Unit of the University Hospital Medical Center "Bežanijska kosa", Belgrade, Serbia, between April 2021 and March 2022. Predictors of the need for oxygen support were determined, while point-of-care echocardiographic parameters and various anamnestic, laboratory, and clinically significant parameters were correlated with the Pulmonary Embolism Severity Index (PESI) score., Results: More than two-thirds of patients in our study had PE symptoms present at hospital admission (68.8%). The majority of patients had segmental pulmonary embolism (48.4%), with high to very high PESI score values in 31.3% of patients. Pneumonia was present in 68.8% of the study population. The PESI score was negatively correlated with diastolic blood pressure and SaO2 at the time of PE diagnosis, LV ejection fraction, and PVAT. A positive correlation was found between the PESI score, maximum CRP, and D-dimer at the time of PTE diagnosis. A larger right ventricular diameter was associated with a greater need for oxygen support., Conclusion: Point-of-care echocardiography is a valuable tool for the risk assessment of COVID-19 patients with pulmonary embolism. Right ventricular size stood out as a significant marker of disease severity.

Null.

Introduction: Obstructive sleep apnea (OSA) is a serious condition linked with various metabolic disorders and associated with increased all-cause and cardiovascular mortality. Although the potential mechanisms of pathophysiological processes related to OSA are relatively well known, the data regarding the correlation between obstructive sleep apnea, dyslipidemia, and systemic inflammation are still inconclusive. Methods: The study was conducted as a retrospective cohort study including 328 patients with newly diagnosed obstructive sleep apnea during the period between April 2018, and May 2020, in University Clinical Hospital Center "Bezanijska kosa", Belgrade, Serbia. Polysomnography was performed in all patients according to the protocol. Numerous demographic, antropometric, laboratory, and clinical data were correlated to Apnea-Hypopnea Index (AHI) as a dependent variable, with a particular review on the relation between lipid abnormalities, inflammatory parameters, and obstructive sleep apnea severity. Multivariate logistic regression model was used to assess predictors of severe OSA (AHI ≥30 per hour). Results: A total of 328 patients were included in the study. The mean age of the patients was 54.0 ± 12.5 years and more than two-thirds were male (68.8%). The majority of the patients had an AHI of at least 30 events per hour. Patients with severe OSA were more frequently male, obese, hypertensive and hyperlipidemic, and had increased neck circumference (both male and female patients). One hundred and thirty-two patients had metabolic syndrome. Patients with severe OSA more frequently had metabolic syndrome and significantly higher levels of glucose, creatinine, uric acid, AST, ALT, CK, microalbumine/creatinine ratio, triglyceride, total cholesterol, HDL, total cholеsterol to HDL-C ratio, CRP, and ESR. In the multivariate linear regression model with AHI (≥30 per hour) as a dependent variable, of demographic and clinical data, triglycerides ≥1.7 mmol/L and CRP >5 mg/L were significantly associated with AHI≥30 per hour. Conclusion: The present study on 328 patients with newly diagnosed obstructive sleep apnea revealed significant relation of lipid abnormalities, inflammatory markers, and other clinically important data with obstructive sleep apnea severity. These results can lead to a better understanding of the underlying pathophysiological processes and open the door to a new world of potentially useful therapeutic modalities., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2022 Popadic, Brajkovic, Klasnja, Milic, Rajovic, Lisulov, Divac, Ivankovic, Manojlovic, Nikolic, Memon, Brankovic, Popovic, Sekulic, Macut, Markovic, Djurasevic, Stojkovic, Todorovic and Zdravkovic.)

Acute coronary syndrome (ACS) in patients with COVID-19 is triggered by various mechanisms and can significantly affect the patient’s further treatment and prognosis. The study aimed to investigate the characteristics, major complications, and predictors of mortality in COVID-19 patients with ACS. All consecutive patients hospitalized from 5 July 2020 to 5 May 2021 for ACS with confirmed SARS-Co-2 were prospectively enrolled and tracked for mortality until 5 June 2021. Data from the electronic records for age and diagnosis, matched non-COVID-19 and COVID-19 ACS group, were extracted and compared. Overall, 83 COVID-19 ACS patients, when compared to 166 non-COVID ACS patients, had significantly more prevalent comorbidities, unfavorable clinical characteristics on admission (acute heart failure 21.7% vs. 6.6%, p < 0.01) and higher rates of major complications, 33.7% vs. 16.8%, p < 0.01, and intrahospital 30-day mortality, 6.7% vs. 26.5%, p < 0.01. The strongest predictors of mortality were aortic regurgitation, HR 9.98, 95% CI 1.88; 52.98, p < 0.01, serum creatinine levels, HR 1.03, 95% CI 1.01; 1.04, p < 0.01, and respiratory failure therapy, HR 13.05, 95% CI 3.62; 47.01, p < 0.01. Concomitant ACS and COVID-19 is linked to underlying comorbidities, adverse presenting features, and poor outcomes. Urgent strategies are needed to improve the outcomes of these patients.

Introduction: Health care workers have had a challenging task since the COVID-19 outbreak. Prompt and effective predictors of clinical outcomes are crucial to recognize potentially critically ill patients and improve the management of COVID-19 patients. The aim of this study was to identify potential predictors of clinical outcomes in critically ill COVID-19 patients., Methods: The study was designed as a retrospective cohort study, which included 318 patients treated from June 2020 to January 2021 in the Intensive Care Unit (ICU) of the Clinical Hospital Center "Bezanijska Kosa" in Belgrade, Serbia. The verified diagnosis of COVID-19 disease, patients over 18 years of age, and the hospitalization in ICU were the criteria for inclusion in the study. The optimal cutoff value of D-dimer, CRP, IL-6, and PCT for predicting hospital mortality was determined using the ROC curve, while the Kaplan-Meier method and log-rank test were used to assess survival., Results: The study included 318 patients: 219 (68.9%) were male and 99 (31.1%) female. The median age of patients was 69 (60-77) years. During the treatment, 195 (61.3%) patients died, thereof 130 male (66.7%) and 65 female (33.3%). 123 (38.7%) patients were discharged from hospital treatment. The cutoff value of IL-6 for in-hospital death prediction was 74.98 pg/mL (Sn 69.7%, Sp 62.7%); cutoff value of CRP was 81 mg/L (Sn 60.7%, Sp 60%); cutoff value of procalcitonin was 0.56 ng/mL (Sn 81.1%, Sp 76%); and cutoff value of D-dimer was 760 ng/mL FEU (Sn 63.4%, Sp 57.1%). IL-6 ≥ 74.98 pg/mL, CRP ≥ 81 mg/L, PCT ≥ 0.56 ng/mL, and D-dimer ≥ 760 ng/mL were statistically significant predictors of in-hospital mortality., Conclusion: IL-6 ≥ 74.98 pg/mL, CRP values ≥ 81 mg/L, procalcitonin ≥ 0.56 ng/mL, and D-dimer ≥ 760 ng/mL could effectively predict in-hospital mortality in COVID-19 patients., Competing Interests: The authors declare that there is no conflict of interest regarding the publication of this paper., (Copyright © 2022 Marija Milenkovic et al.)

Objectives: Obstructive sleep apnea (OSA) is a common condition closely related to obesity, insulin resistance, dyslipidemia, and cardiovascular disease. The aim of this study was to explore the possible relationship between OSA and proprotein convertase subtilisin/kexin type 9 (PCSK9)., Methods: Full-night polysomnography was performed on 150 participants who were divided into three groups: controls, OSA patients on statin therapy, and OSA patients not on statin therapy. Biochemical markers, plasma low-density lipoprotein (LDL) and high-density lipoprotein (HDL) subclasses, and PCSK9 were determined., Results: PCSK9 was highest in OSA patients on statins compared to the control group and to OSA patients not on statins (p = 0.036 and p = 0.039, respectively), after adjustment for body mass index (BMI). LDL diameter was greater in OSA patients not on statins compared to OSA patients on statins (p = 0.032). PCSK9 was highest in the group of patients with all three risk factors (diagnosed OSA, statins, BMI ≥25 kg/m2) compared to groups with no, one, and two risk factors (p = 0.031, p = 0.001, and p = 0.029, respectively). Presence of OSA, statin therapy, and BMI ≥25 kg/m2 when combined were independently associated with higher levels of PCSK9 when adjusted for antihypertensive therapy, small dense LDL, and HDL 3c subclass (odds ratio = 2.849; interquartile range [1.026-7.912], p = 0.044)., Conclusion: Statin therapy was closely related to PCSK9. OSA along with obesity and statin use induces elevation of PCSK9., (© 2022 The Author(s). Published by S. Karger AG, Basel.)

Introduction: Risk stratification is an important aspect of COVID-19 management, especially in patients admitted to ICU as it can provide more useful consumption of health resources, as well as prioritize critical care services in situations of overwhelming number of patients., Materials and Methods: A multivariable predictive model for mortality was developed using data solely from a derivation cohort of 160 COVID-19 patients with moderate to severe ARDS admitted to ICU. The regression coefficients from the final multivariate model of the derivation study were used to assign points for the risk model, consisted of all significant variables from the multivariate analysis and age as a known risk factor for COVID-19 patient mortality. The newly developed AIDA score was arrived at by assigning 5 points for serum albumin and 1 point for IL-6, D dimer, and age. The score was further validated on a cohort of 304 patients admitted to ICU due to the severe form of COVID-19., Results: The study population included 160 COVID-19 patients admitted to ICU in the derivation and 304 in the validation cohort. The mean patient age was 66.7 years (range, 20-93 years), with 68.1% men and 31.9% women. Most patients (76.8%) had comorbidities with hypertension (67.7%), diabetes (31.7), and coronary artery disease (19.3) as the most frequent. A total of 316 patients (68.3%) were treated with mechanical ventilation. Ninety-six (60.0%) in the derivation cohort and 221 (72.7%) patients in the validation cohort had a lethal outcome. The population was divided into the following risk categories for mortality based on the risk model score: low risk (score 0-1) and at-risk (score > 1). In addition, patients were considered at high risk with a risk score > 2. By applying the risk model to the validation cohort ( n = 304), the positive predictive value was 78.8% (95% CI 75.5% to 81.8%); the negative predictive value was 46.6% (95% CI 37.3% to 56.2%); the sensitivity was 82.4% (95% CI 76.7% to 87.1%), and the specificity was 41.0% (95% CI 30.3% to 52.3%). The C statistic was 0.863 (95% CI 0.805-0.921) and 0.665 (95% CI 0.598-0.732) in the derivation and validation cohorts, respectively, indicating a high discriminative value of the proposed score., Conclusion: In the present study, AIDA score showed a valuable significance in estimating the mortality risk in patients with the severe form of COVID-19 disease at admission to ICU. Further external validation on a larger group of patients is needed to provide more insights into the utility of this score in everyday practice., Competing Interests: The authors declare that there is no conflict of interest regarding the publication of this paper., (Copyright © 2021 Marija Zdravkovic et al.)

Introduction: Telomeres are protective chromosomal ends. Short telomeres are a proven biomarker of biological aging. We aimed to find an association of telomere length and telomerase activity in circulating leukocytes and thromboaspirates of patients with acute myocardial infarction. Furthermore, association of the telomere-telomerase system with oxidative stress markers (as common risk factors for coronary artery disease (CAD)) was tested., Material and Methods: Patients were selected from the patients admitted to the intensive care unit with acute myocardial infarction with ST-segment elevation (STEMI), with the following inclusion criteria - STEMI patients between 18 and 80 years old of both genders and candidates for primary percutaneous coronary intervention, with infarction pain present for a maximum of 12 h. In all the patients leukocyte telomere length, telomerase activity and scores related to oxidative-stress status (Protective, Damage and OXY) were evaluated., Results: Patients were divided into different groups: with stable angina pectoris (AP) ( n = 22), acute myocardial infarction with: STEMI ( n = 93), non-obstructive coronary arteries (MINOCA) ( n = 7), blood vessel rupture ( n = 6) at three time points, and compared to the group of 84 healthy subjects. Telomerase activity was significantly higher in all CAD sub-groups compared to the control group (AP = 0.373 (0.355-0.386), STEMI = 0.375 (0.349-0.395), MINOCA = 0.391 (0.366-0.401), blood vessel rupture = 0.360 (0.352-0.385) vs. CG = 0.069 (0.061-0.081), p < 0.001), while telomeres were significantly shorter in STEMI, MINOCA and blood vessel rupture groups compared to the control group (STEMI = 1.179 (0.931-1.376), MINOCA = 1.026 (0.951-1.070), blood vessel rupture = 1.089 (0.842-1.173) vs. CG = 1.329 (1.096-1.624), p = 0.030]. Values of OXY score were significantly higher in STEMI and MINOCA patients compared to the control group and AP patients (5.83 (4.55-7.54) and 10.28 (9.19-10.72) vs. 4.94 (3.29-6.18) and 4.18 (2.58-4.86), p < 0.001). Longer telomeres and higher telomerase activity were found in thromboaspirates, compared to the peripheral blood leukocytes in the same patients (1.25 (1.01-1.84) vs. 1.18 (0.909-1.516), p = 0.036; and 0.366 (0.367-0.379) vs. 0.366 (0.367-0.379), p < 0.001, respectively). In addition, telomere length and telomerase activity had good diagnostic ability to separate STEMI patients from healthy persons., Conclusions: Leukocyte telomere length and telomerase activity can differentiate CAD patients from healthy persons, and relate CAD to oxidative stress., Competing Interests: The authors declare no conflict of interest., (Copyright: © 2021 Termedia & Banach.)

Introduction: Mortality among critically ill COVID-19 patients remains relatively high despite different potential therapeutic modalities being introduced recently. The treatment of critically ill patients is a challenging task, without identified credible predictors of mortality., Methods: We performed an analysis of 160 consecutive patients with confirmed COVID-19 infection admitted to the Respiratory Intensive Care Unit between June 23, 2020, and October 2, 2020, in University Hospital Center Bezanijska kosa, Belgrade, Serbia. Patients on invasive, noninvasive ventilation and high flow oxygen therapy with moderate to severe ARDS, according to the Berlin definition of ARDS, were selected for the study. Demographic data, past medical history, laboratory values, and CT severity score were analyzed to identify predictors of mortality. Univariate and multivariate logistic regression models were used to assess potential predictors of mortality in critically ill COVID-19 patients., Results: The mean patient age was 65.6 years (range, 29-92 years), predominantly men, 68.8%. 107 (66.9%) patients were on invasive mechanical ventilation, 31 (19.3%) on noninvasive, and 22 (13.8%) on high flow oxygen therapy machine. The median total number of ICU days was 10 (25 th to 75 th percentile: 6-18), while the median total number of hospital stay was 18 (25 th to 75 th percentile: 12-28). The mortality rate was 60% (96/160). Univariate logistic regression analysis confirmed the significance of age, CRP, and lymphocytes at admission to hospital, serum albumin, D-dimer, and IL-6 at admission to ICU, and CT score. Serum albumin, D-dimer, and IL-6 at admission to ICU were independently associated with mortality in the final multivariate analysis., Conclusion: In the present study of 160 consecutive critically ill COVID-19 patients with moderate to severe ARDS, IL-6, serum albumin, and D-dimer at admission to ICU, accompanied by chest CT severity score, were marked as independent predictors of mortality., Competing Interests: The authors declare that there is no conflict of interest regarding the publication of this paper., (Copyright © 2021 Viseslav Popadic et al.)

We investigated circulating levels of inflammatory biomarkers pentraxin-3 (PTX3), cyclophilin A (CypA), and heparin-binding epidermal growth factor-like growth factor (HB-EGF); oxidative stress; and antioxidant status markers in the patients with ST-segment elevation acute myocardial infarction (STEMI) to better understand a relationship between inflammation and oxidative stress. We examined the impact of oxidative stress on high values of inflammatory parameters. The study included 87 patients with STEMI and 193 controls. We observed a positive correlation between PTX3 and HB-EGF (ρ = 0.24, P = .027), CyPA, and sulfhydryl (SH) groups (ρ = 0.25, P = .026), and a negative correlation between PTX3 and SH groups (ρ = -0.35, P = .001) in patients with STEMI. To better understand the effect of the examined parameters on the occurrence of high concentrations of inflammatory parameters, we grouped them using principal component analysis. This analysis identified the 4 most contributing factors. Optimal cutoff values for discrimination of patients with STEMI from controls were calculated for PTX3 and HB-EGF. An independent predictor for PTX3 above the cutoff value was a "metabolic-oxidative stress factor" comprised of glucose and oxidative stress marker prooxidant-antioxidant balance (odds ratio = 4.449, P = .030). The results show that higher PTX3 values will occur in patients having STEMI with greater metabolic and oxidative stress status values.

Inflammatory biomarkers - pentraxin-3 (PTX3), cyclophilin A (CypA) and heparin-binding epidermal growth factor-like growth factor (HB-EGF) were examined in patients with ST-segment elevation myocardial infarction (STEMI) undergoing revascularization with primary percutaneous coronary intervention (pPCI) and stent implanting. Investigated parameters were compared between patients with and without obstructive coronary artery disease (CAD). In addition, their changes were tested in circulation before and immediately after pPCI. The study group consisted of 81 STEMI patients. Patients were classified in the STEMI-CAD group if they had significant obstructive CAD or in MINOCA group if they had no significant stenosis. In STEMI-CAD patients inflammatory parameters were determined prior to and after pPCI intervention. Immediately after pPCI, in STEMI-CAD patients levels of PTX3 were significantly lower (1.52 vs. 2.17 μg/L, p  < .001), while the levels of HB-EGF (14.61 vs. 12.03 pg/L, p  < .001) and CyPA (15.95 vs. 8.62 μg/L, p  < .001) were significantly higher compared to levels before pPCI. STEMI-CAD patients had lower PTX3 values 2.17 μg/L (1.55-5.10 μg/L) than MINOCA patients 5.06 μg/L (2.77-6.7 μg/L), p  = .046. Diagnostic accuracy of PTX3 for discrimination MINOCA from STEMI-CAD patients was low (area under receiver operating characteristic curve = 0.770). Evaluation of PTX3 values may be helpful in the understanding of MINOCA aetiology but they couldn't distinguish stenosis severity in STEMI patients. Inflammatory biomarkers significantly changed after pPCI but the possibility of clinical use of these biomarkers needs to be evaluated in a larger prospective study.

Background: The role of matrix metalloproteinase-9 (MMP-9) and tissue inhibitor of matrix metalloproteinase-1 (TIMP-1) in sepsis after major abdominal surgery and sepsis-associated organ dysfunction is unexplored., Materials and Methods: Fifty-three patients with sepsis after major abdominal surgery were compared to 50 operated and 50 nonoperated controls. MMP-9, TIMP-1, biomarkers of inflammation, kidney and liver injury, coagulation, and metabolic disorders were measured daily during 96 h following diagnosis of sepsis and once in controls. MMP-9/TIMP-1 ratios and disease severity scores were calculated. Use of vasopressors/inotropes, mechanical ventilation, and survival were recorded., Results: Septic patients had lower MMP-9 and MMP-9/TIMP-1 ratios but higher TIMP-1 levels compared to controls. AUC-ROC for diagnosis of sepsis was 0.940 and 0.854 for TIMP-1 and 0.924 and 0.788 for MMP-9/TIMP-1 ratio (sepsis versus nonoperated and sepsis versus operated controls, resp.). Lower MMP-9 and MMP-9/TIMP-1 ratio and higher TIMP-1 levels were associated with shorter survival. MMP-9, TIMP-1, and MMP-9/TIMP-1 ratio correlated with biomarkers of inflammation, kidney and liver injury, coagulation, metabolic disorders, and disease severity scores. Use of vasopressors/inotropes was associated with higher TIMP-1 levels., Conclusions: MMP-9, TIMP-1, and MMP-9/TIMP ratio were good diagnostic or prognostic biomarkers of sepsis after major abdominal surgery and were linked to sepsis-associated organ dysfunction.

Sepsis-associated acute kidney injury (SA-AKI) severely impacts morbidity and mortality in surgical patients with sepsis. Matrix metalloproteinase-9 (MMP-9) and tissue inhibitor of matrix metalloproteinase-1 (TIMP-1) have an important role in pathophysiology of sepsis but they have been unexplored in SA-AKI. We aimed to investigate the role of MMP-9 and TIMP-1 in septic surgical patients with SA-AKI and to evaluate them as diagnostic biomarkers of SA-AKI. This prospective observational study compared 53 major abdominal surgery patients with sepsis divided into SA-AKI (n = 37) and non-SA-AKI (n =16) group to 50 controls without sepsis matched by age, gender, comorbidities and type of surgery. Blood and urine samples from septic patients were collected on admission to ICU and 24, 48, 72 and 96 h later and once from the controls. The levels of MMP-9, TIMP-1, neutrophil gelatinase-associated lipocalin (NGAL), kidney injury molecule-1, urea and creatinine were measured. MMP-9/TIMP-1 ratio and disease severity scores, such as Sequential Organ Failure Assessment (SOFA), were calculated. Septic patients with SA-AKI had higher serum TIMP-1 levels and lower serum MMP-9 levels and lower MMP-9/TIMP ratio, compared to septic patients without SA-AKI and controls. The levels of these biomarkers did not change significantly over time. MMP-9, TIMP-1 and MMP-9/TIMP-1 ratio correlated with urea, creatinine, NGAL, and SOFA scores. Moreover, using the area under ROC curve, we showed that TIMP-1 and MMP-9/TIMP-1 ratio, but not MMP-9, were good diagnostic biomarkers of SA-AKI. We report for the first time the potential diagnostic value of TIMP-1 and MMP-9/TIMP-1 ratio in SA-AKI.

Introduction and Objectives: Uric acid and gamma-glutamyl transferase are prognostic indicators in chronic heart failure. Nevertheless, the mechanism underlying the association between uric acid, gamma-glutamyl transferase, and chronic heart failure progression and prognosis remains largely unknown., Methods: The association of uric acid and gamma-glutamyl transferase with flow-mediated dilation and echocardiographic indices of cardiac remodeling was addressed in 120 patients with chronic ischemic heart failure. To determine the independent contribution of uric acid and gamma-glutamyl transferase to the flow-mediated dilation and echocardiographic indices of remodeling, a series of multiple linear regression models, based on traditional and nontraditional risk factors impacting upon these parameters, were constructed., Results: Uric acid, but not gamma-glutamyl transferase, was an independent predictor of flow-mediated dilation. Uric acid was associated with all the echocardiographic indices of left ventricular dysfunction tested in 3 multiple-regression models. Uric acid correlated with left ventricular end-systolic diameter, left ventricular end-diastolic diameter, left ventricular end-systolic volume, and left ventricular end-diastolic volume (r = 0.337; r = 0.340; r = 0.321; r = 0.294; P = .001, respectively). Gamma-glutamyl transferase was an independent predictor of left ventricular end-systolic volume and left ventricular end-diastolic volume, after adjustment for all variables. Gamma-glutamyl transferase correlated with left ventricular end-systolic diameter, left ventricular end-diastolic diameter, left ventricular end-systolic volume, and left ventricular end-diastolic volume (r = 0.238, P = .009; r = 0.219, P = .016; r = 0.359, P < .001; r = 0.369, P = .001, respectively)., Conclusions: Serum uric acid and gamma-glutamyl transferase levels are associated with left ventricular remodeling in patients with chronic ischemic heart failure., (Copyright © 2013 Sociedad Española de Cardiología. Published by Elsevier Espana. All rights reserved.)

Objectives: Epidemiological evidence concerning the role of iron, a lipid peroxidation catalyst, in atherosclerosis and coronary artery disease (CAD) is inconsistent., Design and Methods: Exploratory factor analysis was used to examine the potential clustering of variables known to be associated with CAD using data from 188 patients with angiographically-approved disease. The resulting factors were then tested for their association with serum ferritin and soluble transferrin receptor (sTfR) as indicators of body iron status., Results: Factor analysis resulted in a reduction of a variable number from the original 15 to 5 composite clusters. These factors were interpreted as (1) "proatherogenic factor" with positive loadings of TC, LDL-C, apoB and TG; (2) "inflammatory factor" with positive loadings of hsCRP, fibrinogen and MDA; (3) "antiatherogenic factor" with positive loadings of HDL-C and apoA-I; (4) "obesity factor" with positive loadings of weight and waist; and (5) "antioxidative status factor" with positive loadings of SOD and age and negative loading of superoxide anion. "Inflammatory", "obesity" and "antiatherogenic" factors predicted high ferritin values and the "proatherogenic factor" predicted high sTfR values. We compared the ability of the "proatherogenic factor" with that of a multivariable logistic model that included the "proatherogenic factor" and sTfR values in predicting significant stenosis in patients. The area under the ROC curve was 0.692 vs. 0.821, respectively., Conclusions: "Inflammatory", "obesity", "antiatherogenic" and "proatherogenic" factors were associated with increased parameters of body iron status. The measurement of sTfR improves the prediction of CAD based on clustered cardiovascular risk factors., (Copyright © 2014 The Canadian Society of Clinical Chemists. Published by Elsevier Inc. All rights reserved.)

Background: A research on novel cardiovascular risk factors is mainly focused on patients with clinically verified coronary artery disease (CAD), while less is known about their presence in symptomatic patients, but without angiographically proven occlusion of coronary arteries. The aim of this study was to compare plasma low-density lipoprotein (LDL) and high-density lipoprotein (HDL) size and subclasses in stable angina patients with and without significant obstructive CAD., Methods: LDL and HDL subclasses were analysed in 100 stable angina patients with ≥50% of obstruction and 40 patients with less than 50% of luminal narrowing, as assessed by coronary angiography., Results: Patients with <50% of obstruction had reduced mean HDL size and higher proportion of small HDL particles (P < 0.05). HDL size and proportion of small HDL particles were significant and independent predictors of obstructive CAD (P < 0.05, respectively)., Conclusions: Stable angina patients with <50% of coronary obstruction have more favourable HDL subclasses distribution than patients with significant coronary stenosis.

Introduction: State of severe oxidative stress is encountered in sepsis. Paraoxonase 1 (PON1) protects against oxidative stress but also undergoes inactivation upon that condition. We investigated PON1 activity in surgical patients with sepsis in relation to oxidative stress status, inflammation, disease severity, and survival., Methods: Prospective observational study. Sixty-nine surgical patients with sepsis were compared to 69 age/sex matched healthy controls. PON1 paraoxonase and diazoxonase activities, selected biochemical, hematological and oxidative stress parameters were measured on admission to ICU and 24, 48, 72, and 96 hours later. Disease severity scores were calculated daily., Results: Septic patients had significantly lower PON1 activities compared to control group at all time points. PON1 activities had good capacity to differentiate septic patients from healthy controls. Low PON1 activities were associated with higher disease severity scores and higher risk of death. Correlation between PON1 activity and markers of inflammation failed to reach significance. Decrease in PON1 activity was correlated with an increase in reducing components in plasma., Conclusion: Our study demonstrated lower PON1 activity in surgical patients with sepsis compared to healthy controls. PON1 activity also reflected severity of the disease. Low PON1 activity was associated with higher mortality of surgical patients with sepsis.

Background: The aim of the study was to determine the clinical usefulness of N-terminal pro-B-type natriuretic peptide (NT-proBNP) and symmetric dimethylarginine (SDMA) for detection of renal and left ventricular (LV) diastolic dysfunction in chronic kidney disease (CKD) patients and renal transplant (RT) recipients., Methods: We included 98 CKD and 44 RT patients. We assessed LV function using pulsed-wave Doppler ultrasound. Diastolic dysfunction was defined when the E:A ratio was <1., Results: Independent predictors of NT-proBNP levels were age, creatinine, and albumin in CKD patients and age and urea in RT patients. Determinants of SDMA in CKD patients were glomerular filtration rate (GFR) and NT-proBNP and creatinine in RT patients. In RT patients with diastolic dysfunction, NT-proBNP and SDMA were significantly higher than in patients without diastolic dysfunction (F = 7.478, P < 0.011; F = 2.631, P < 0.017). After adjustment for GFR, the differences were not seen. In CKD patients adjusted NT-proBNP and SDMA values for GFR were not significantly higher in patients with diastolic dysfunction than in patients without diastolic dysfunction., Conclusions: NT-proBNP is useful for detection of LV diastolic dysfunction in RT recipients. When evaluating both NT-proBNP and SDMA it is necessary to consider GFR as a confounding factor., (© 2013 Wiley Periodicals, Inc.)

Objectives: The study was designed to evaluate associations between symmetric dimethylarginine (SDMA), inflammation, and superoxide anion (O2∙-) with endothelial function and to determine their potential for screening of endothelial dysfunction in patients with chronic kidney disease (CKD) and renal transplant (RT) recipients., Materials and Methods: We included 64 CKD and 52 RT patients. Patients were stratified according to brachial artery flow-mediated dilation (FMD)., Results: Logistic regression analysis showed that high SDMA and high sensitive C-reactive protein (hs-CRP) were associated with impaired FMD in CKD and RT patients, after adjustment for glomerular filtration rate. The ability of inflammation, SDMA, and O2∙- to detect impaired FMD was investigated by receiving operative characteristic analysis. Hs-CRP (area under the curves (AUC) = 0.754, P < 0.001), IL-6 (AUC = 0.699, P = 0.002), and SDMA (AUC = 0.689, P = 0.007) had the highest ability to detect impaired FMD. SDMA in combination with inflammatory parameters and/or O2∙- had better screening performance than SDMA alone., Conclusions: Our results indicate a strong predictable association between hs-CRP, SDMA, and endothelial dysfunction in CKD patients and RT recipients. The individual marker that showed the strongest discriminative ability for endothelial dysfunction is hs-CRP, but its usefulness as a discriminatory marker for efficient diagnosis of endothelial dysfunction should be examined in prospective studies.

Objective: Small, dense low-density lipoprotein-cholesterol (sdLDL-C) is a recently recognised marker of cardiovascular disease risk. On the other hand, the usefulness of sdLDL-apoB concentration determination in clinical practice offers grounds for further exploration. This study investigates the associations of sdLDL-C and sdLDL-apoB with serum lipid parameters and LDL size in healthy men and women., Methods: The concentrations of sdLDL-C and sdLDL-apoB were measured after heparin-magnesium precipitation of serum samples from ninety-five asymptomatic subjects (47 men, 30 premenopausal and 18 menopausal women). LDL size was determined by gradient gel electrophoresis and serum lipid and lipoprotein parameters were measured by routine laboratory methods., Results: Compared to premenopausal women, men had higher sdLDL-C (P<0.001) and sdLDL-apoB concentrations (P<0.001). No difference in the sdLDL-C concentration was found between men and menopausal women. Menopause status was associated with higher concentrations of both sdLDL-C (P<0.01) and sdLDL-apoB (P<0.05). Subjects with the LDL B phenotype had elevated sdLDL-C (P<0.01) and sdLDL-apoB concentrations (P<0.001). LDL size and triglycerides were independent determinants of both sdLDL-C and sdLDL-apoB concentrations., Conclusion: Gender and menopausal status have significant impact on sdLDL-C and sdLDL-apoB concentrations. The variability in sdLDL-C and sdLDL-apoB levels is considerably influenced by changes in LDL size and triglyceride concentration. Our results suggest that the characterisation of sdLDL particles by evaluating sdLDL-C could be complemented with sdLDL-apoB determination.

Elevated serum uric acid (UA) is associated with higher risk for cardiovascular disease (CVD). Smaller, denser low density lipoprotein (LDL) and high-density lipoprotein (HDL) particles are the potential risk factors for CVD, while the role and diagnostic value of inflammatory markers are firmly established. This current cross-sectional study investigates interrelationships between UA, high sensitivity C-reactive protein (hsCRP) and fibrinogen concentrations with LDL and HDL sizes in healthy middle-aged subjects. The outcomes-of-interest were smaller, denser LDL and HDL particles (LDL size or=318micromol/L) was a significant predictor of smaller, denser LDL and HDL particles (OR=3.09; P<0.01; n=19 and OR=4.40; P<0.001; n=23, respectively). The observed relationship with smaller HDL size persisted after adjustment for conventional cardiovascular risk factors. UA strongly correlated with both markers of inflammation. In addition, the higher hsCRP level correlated with smaller LDL size (P<0.05), while fibrinogen concentration was inversely related to HDL size (P<0.05). Multiple regression analysis revealed that HDL size and inflammatory markers remained independent determinants of UA concentration. In conclusion, higher serum UA and low-grade inflammation are closely linked to alterations in lipoprotein metabolism which may represent an early sign of atherosclerosis in asymptomatic subjects.

Objectives: High-density lipoprotein (HDL) associated paraoxonase 1 (PON1) is an essential component of HDLs' capability to protect low-density lipoproteins (LDL) from oxidative modification and thus to limit the atherosclerotic process. The aim of the current study was to investigate the association between oxidative stress status, indices of inflammation and PON1 status parameters., Design and Methods: We determined the relationship between the oxidative stress status, inflammatory markers and PON1 status parameters in 261 middle-aged subjects: 156 coronary heart disease (CHD) patients and 105 CHD-free subjects (as the control group). The PON1 status involved PON1 activity measurements towards two substrates: paraoxon (POase activity) and diazoxon (DZOase activity) and subsequent PON1(Q192R) activity phenotype determination., Results: A statistically significant greater malondialdehyde (MDA) concentration in the RR phenotype subjects compared to QQ subjects within the CHD group was apparent (P<0.05). Multiple linear regression analysis revealed an independent influence of plasmatic SOD activity (P<0.05) on POase values and MDA (P<0.01) and O(2)(-) (P<0.05) on DZOase values. Involvement of inflammatory markers (fibrinogen and hsCRP) in the regression model did not hinder the influence of SOD and MDA on POase and DZOase activities, respectively., Conclusions: Our CHD patients were in a state of oxidative stress, which was most evident in the RR phenotype group. The QQ phenotype group is associated with the lowest oxidative stress status level and also with a better capacity for anti-oxidative protection. Oxidative stress in CHD patients is maintained by systemic low-grade inflammation, which results in PON1 enzymatic activity exhaustion. Therefore, deeper investigation of an effective anti-oxidative and anti-inflammatory therapy should be necessary in order to increase anti-oxidative potency and improve PON1 status of CHD patients.

Objectives: The aim of our study was to determine the cost-effectiveness of coronary artery disease (CAD) diagnostic parameters in a clinical laboratory setting., Design and Methods: The effectiveness of apolipoproteins, lipoproteins and high sensitivity C-reactive protein (hs-CRP) supplementary to Framingham scoring data within a CAD risk assessment procedure was established in 221 CAD patients and 289 controls. The total costs of diagnostic procedures were calculated and incremental cost-effectiveness analysis was applied., Results: A diagnostic strategy employing Framingham calculation followed by apolipoprotein A-I (apoA-I) had the lowest cost per additional successfully diagnosed patient than the same strategy followed by hs-CRP in the low (2.63 vs. 24.47 euros) and intermediate-risk groups (2.96 vs. 122.85 euros). In the high-risk group the diagnostic strategy employing apoA-I saved 9.14 euros in comparison to the strategy employing hs-CRP., Conclusion: Cost-effectiveness analysis of different diagnostic markers results in improved identification of at-risk patients at a lower health cost for society.

Epidemiological studies have shown that a high serum uric acid concentration is a risk factor for coronary artery disease (CAD). However, the issue of whether it is an independent cardiovascular risk factor or simply a marker of co-existing conditions is a matter of controversy. In the present case-controlled study, we explored the association between serum uric acid and angiographically defined CAD in middle-aged subjects (356 CAD patients and 350 healthy individuals). Serum uric acid in CAD patients was significantly higher than that in healthy individuals (359 +/- 88.7 and 289 +/- 79.3 micromol/l, respectively, p < 0.01) and remained significantly higher after adjusting for confounding factors (F = 79.77, p < 0.01). The association between uric acid and CAD was not limited to the hyperuricemic range of values, but was also found in the high-normal range (p < 0.01). An unadjusted odds ratio (OR) of 5.0 was obtained in both genders (p < 0.01). Female patients with > 50% stenosis (clinically significant CAD), regardless of the number of diseased vessels, had higher uric acid concentrations than those with < 50% stenosis even after adjusting for confounders (F = 3.79, p = 0.01). In conclusion, we have demonstrated that high serum uric acid is independently associated with CAD and that uric acid determination could be useful as one of the markers of clinically significant CAD.

Objectives: In addition to many traditional risk factors for coronary artery disease (CAD) development, enhanced oxidative stress and inflammation are serious conditions that may also be classified as novel risk factors. In the present study, we assessed the relationship between several parameters of oxidative stress status [malonaldehyde (MDA), superoxide anion (O(2)(-)) and plasma and erythrocyte superoxide dismutase (SOD) activities] with high sensitivity C-reactive protein (hsCRP) and fibrinogen as inflammation markers., Design and Methods: Oxidative stress status parameters, inflammation markers and lipid status parameters were measured in 385 subjects [188 coronary heart disease (CHD) patients with angiographically diagnosed coronary artery disease (CAD), 141 patients with occlusion >50% in at least one major coronary artery (CAD+) and 47 patients with occlusion less than 50% (CAD-), and 197 CHD-free middle-aged subjects (the control group)]., Results: The plasma MDA concentration and the level of O(2)(-) in plasma were significantly higher in combination with significantly lower SOD activity in the CAD+ group vs. the control group. By using multiple stepwise regression analysis, fibrinogen and hsCRP showed independent correlation with MDA. Binary logistic regression analysis indicated that both MDA and O(2)(-) were significantly associated with CAD development and adjustment for inflammatory markers weakened this association in the case of MDA., Conclusions: The relationship between oxidative stress parameters and inflammatory species suggest their strong mutual involvement in atherosclerosis development that leads to CAD progression.

Prospective studies have demonstrated that markers of inflammation, such as high-sensitivity C-reactive protein (hsCRP) and fibrinogen, predict future cardiovascular disease risk. However, the association between the hsCRP and fibrinogen levels and the extent of coronary stenosis in patients with coronary artery disease (CAD) remains controversial. The aim of our case-control study was to assess the association of inflammatory markers with the occurrence and extent of CAD. Serum hsCRP and plasma fibrinogen levels were measured in 138 patients with angiographically assessed CAD and in 183 healthy subjects matched according to age and gender. According to the number of significantly stenosed (>or= 50%) vessels, the patients were classified in four groups: those without stenosis (0-vessel disease) and those with 1, 2 or 3-vessel disease. The hsCRP and fibrinogen levels were significantly higher in patients than in controls (p < 0.001). Although the hsCRP and fibrinogen levels tended to increase with the number of stenotic vessels, the differences were only significant for hsCRP (p < 0.01). Regression analysis indicated hsCRP as an independent predictor for the presence (OR = 3.573, p < 0.05) and extent of CAD (beta = 1.095, p < 0.05). In conclusion, the present study is the first report concerning the frequency distribution of hsCRP in Serbian healthy subjects and CAD patients. We have shown that elevated levels of hsCRP are associated with the presence and extent of CAD.

High plasma HDL-cholesterol (HDL-c) is a well-established protective factor in coronary artery disease (CAD). One of its potential protective mechanisms is the inhibition of the cytokine-induced upregulation of expression of cellular adhesion molecules (CAMs). High sCAM levels were found to be associated with low HDL-c in some studies performed mostly in hyperlipidemic subjects, but this association has not yet been investigated in CAD patients. In addition, conflicting results were obtained from in vitro studies that explored the proposed HDL effect on cytokine-induced CAM expression. The aim of the present case-control study was to investigate whether low HDL-c values are associated with CAM overexpression in normolipidemic CAD patients and healthy individuals, matched according to age and gender. Plasma HDL-c, sICAM-1, sVCAM-1, and sE-selectin were measured in 37 normolipidemic patients with angiographically verified coronary artery disease and in 52 healthy normolipidemic subjects. The sCAM values obtained in the subjects (patients or controls) with low HDL-c levels (< 1.03 mmol/L) were compared with the values in the subjects with high HDL-c (>or= 1.03 mmol/L). No significant difference was found between sICAM-1, sVCAM-1, and E-selectin values obtained in subjects with low and high HDL-c, either among the patients or the healthy controls. In conclusion, low HDL-c levels are not associated with CAM overexpression in normolipidemic CAD patients and healthy subjects.