Serum Levels of Adiponectin Are Strongly Associated with Lipoprotein Subclasses in Healthy Volunteers but Not in Patients with Metabolic Syndrome.

Metabolic syndrome (MS) is a widespread disease in developed countries, accompanied, among others, by decreased adiponectin serum levels and perturbed lipoprotein metabolism. The associations between the serum levels of adiponectin and lipoproteins have been extensively studied in the past under healthy conditions, yet it remains unexplored whether the observed associations also exist in patients with MS. Therefore, in the present study, we analyzed the serum levels of lipoprotein subclasses using nuclear magnetic resonance spectroscopy and examined their associations with the serum levels of adiponectin in patients with MS in comparison with healthy volunteers (HVs). In the HVs, the serum levels of adiponectin were significantly negatively correlated with the serum levels of large buoyant-, very-low-density lipoprotein, and intermediate-density lipoprotein, as well as small dense low-density lipoprotein (LDL) and significantly positively correlated with large buoyant high-density lipoprotein (HDL). In patients with MS, however, adiponectin was only significantly correlated with the serum levels of phospholipids in total HDL and large buoyant LDL. As revealed through logistic regression and orthogonal partial least-squares discriminant analyses, high adiponectin serum levels were associated with low levels of small dense LDL and high levels of large buoyant HDL in the HVs as well as high levels of large buoyant LDL and total HDL in patients with MS. We conclude that the presence of MS weakens or abolishes the strong associations between adiponectin and the lipoprotein parameters observed in HVs and disturbs the complex interplay between adiponectin and lipoprotein metabolism.

Advanced Oxidation Protein Products Are Strongly Associated with the Serum Levels and Lipid Contents of Lipoprotein Subclasses in Healthy Volunteers and Patients with Metabolic Syndrome.

The association between advanced oxidation protein products (AOPPs) and lipoprotein subclasses remains unexplored. Therefore, we performed comprehensive lipoprotein profiling of serum using NMR spectroscopy and examined the associations of lipoprotein subclasses with the serum levels of AOPPs in healthy volunteers (HVs) and patients with metabolic syndrome (MS). The serum levels of AOPPs were significantly positively correlated with the serum levels of very-low-density lipoprotein (VLDL), intermediate-density lipoprotein (IDL), and low-density lipoprotein (LDL); however, they were significantly negatively correlated with high-density lipoprotein (HDL). These lipoproteins (and their subclasses) differed markedly regarding the direction of correlations between their lipid contents and AOPPs. The strength of the correlations and the relative contributions of the subclasses to the correlations were different in the HVs and patients with MS. As revealed by orthogonal partial least squares discriminant analyses, the serum levels of IDL were strong determinants of AOPPs in the HVs, whereas the serum levels of VLDL and the lipid content of LDL were strong determinants in both groups. We conclude that IDL, VLDL, and LDL facilitate, whereas HDL diminishes the bioavailability of serum AOPPs. The presence of MS and the lipid contents of the subclasses affect the relationship between lipoproteins and AOPPs.

Association between Serum Free Fatty Acids and Clinical and Laboratory Parameters in Acute Heart Failure Patients.

Very little is known about the association between individual serum free fatty acids (FFAs) and clinical and laboratory parameters (indicators of heart failure severity) in acute heart failure (AHF) patients. Here, the baseline serum levels of FFAs, 16:0 (palmitic acid), 16:1 (palmitoleic acid), 18:0 (stearic acid), 18:1 (oleic acid), 18:2 (linoleic acid), 18:3 (alpha-linolenic acid or gamma-linolenic acid), 20:4 (arachidonic acid), 20:5 (eicosapentaenoic acid), and 22:6 (docosahexaenoic acid), were determined in 304 AHF patients (94.7% belonged to New York Heart Association functional class IV) using gas chromatography. Spearman correlation coefficients were used to examine the associations between the individual and total (the sum of all FFAs) FFAs and clinical and laboratory parameters. After applying a Bonferroni correction to correct for multiple testing, the total FFAs, as well as the individual FFAs (except FFAs 18:0, 20:5, and 22:6), were found to be significantly positively correlated with serum albumin. Only a few additional associations were found: FFA 16:0 was significantly negatively correlated with systolic pulmonary artery pressure, FFA 18:3 was significantly negatively correlated with C-reactive protein and body mass index, and FFA 20:4 was significantly negatively correlated with blood urea nitrogen. Based on our results, we conclude that in patients with severe AHF, individual and total serum FFAs are slightly associated with established laboratory and clinical parameters, which are indicators of heart failure severity.

Genetic deletion of MMP12 ameliorates cardiometabolic disease by improving insulin sensitivity, systemic inflammation, and atherosclerotic features in mice.

BACKGROUND: Matrix metalloproteinase 12 (MMP12) is a macrophage-secreted protein that is massively upregulated as a pro-inflammatory factor in metabolic and vascular tissues of mice and humans suffering from cardiometabolic diseases (CMDs). However, the molecular mechanisms explaining the contributions of MMP12 to CMDs are still unclear. METHODS: We investigated the impact of MMP12 deficiency on CMDs in a mouse model that mimics human disease by simultaneously developing adipose tissue inflammation, insulin resistance, and atherosclerosis. To this end, we generated and characterized low-density lipoprotein receptor (Ldlr)/Mmp12-double knockout (DKO) mice fed a high-fat sucrose- and cholesterol-enriched diet for 16-20 weeks. RESULTS: DKO mice showed lower cholesterol and plasma glucose concentrations and improved insulin sensitivity compared with LdlrKO mice. Untargeted proteomic analyses of epididymal white adipose tissue revealed that inflammation- and fibrosis-related pathways were downregulated in DKO mice. In addition, genetic deletion of MMP12 led to alterations in immune cell composition and a reduction in plasma monocyte chemoattractant protein-1 in peripheral blood which indicated decreased low-grade systemic inflammation. Aortic en face analyses and staining of aortic valve sections demonstrated reduced atherosclerotic plaque size and collagen content, which was paralleled by an improved relaxation pattern and endothelial function of the aortic rings and more elastic aortic sections in DKO compared to LdlrKO mice. Shotgun proteomics revealed upregulation of anti-inflammatory and atheroprotective markers in the aortas of DKO mice, further supporting our data. In humans, MMP12 serum concentrations were only weakly associated with clinical and laboratory indicators of CMDs. CONCLUSION: We conclude that the genetic deletion of MMP12 ameliorates obesity-induced low-grade inflammation, white adipose tissue dysfunction, biomechanical properties of the aorta, and the development of atherosclerosis. Therefore, therapeutic strategies targeting MMP12 may represent a promising approach to combat CMDs.

Low Valine Serum Levels Predict Increased 1-Year Mortality in Acute Heart Failure Patients.

Considering the relationship between disease severity and the extent of metabolic derangement in heart failure, we hypothesized that the serum levels of metabolites may have prognostic value for 1-year mortality in acute heart failure (AHF). The AHF study was a prospective, observational study enrolling consecutive patients hospitalized due to AHF. Metabolites were measured in serum collected at admission using NMR spectroscopy. Out of 315 AHF patients, 118 (37.5%) died within 1 year after hospitalization for AHF. The serum levels of 8 out of 49 identified metabolites were significantly different between patients who were alive and those who died within 1 year after hospitalization for AHF. Of these, only valine was significantly associated with 1-year mortality (hazard ratio 0.73 per 1 standard deviation increase, 95% confidence interval: 0.59-0.90, p = 0.003) in the multivariable Cox regression analyses. Kaplan-Maier analysis showed significantly higher survival rates in AHF patients with valine levels above the median (>279.2 µmol/L) compared to those with valine levels ≤ 279.2 µmol/L. In a receiver operating characteristics curve analysis, valine was able to discriminate between the two groups with an area under the curve of 0.65 (95% CI 0.59-0.72). We conclude that valine serum levels might be of prognostic value in AHF.

Associations between Endothelial Lipase and Apolipoprotein B-Containing Lipoproteins Differ in Healthy Volunteers and Metabolic Syndrome Patients.

The association between serum levels of endothelial lipase (EL) and the serum levels and composition of apolipoprotein B (apoB)-containing lipoproteins in healthy subjects and patients with metabolic syndrome (MS) remained unexplored. Therefore, in the present study, we determined the serum levels and lipid content of apoB-containing lipoproteins using nuclear magnetic resonance (NMR) spectroscopy and examined their association with EL serum levels in healthy volunteers (HVs) and MS patients. EL was significantly negatively correlated with the serum levels of cholesterol in large very low-density lipoprotein (VLDL) particles, as well as with total-cholesterol-, free-cholesterol-, triglyceride-, and phospholipid-contents of VLDL and intermediate-density lipoprotein particles in MS patients but not in HVs. In contrast, EL serum levels were significantly positively correlated with the serum levels of apoB, triglycerides, and phospholipids in large low-density lipoprotein particles in HVs but not in MS patients. EL serum levels as well as the serum levels and lipid content of the majority of apoB-containing lipoprotein subclasses were markedly different in MS patients compared with HVs. We conclude that EL serum levels are associated with the serum levels and lipid content of apoB-containing lipoproteins and that these associations are markedly affected by MS.

Associations between Endothelial Lipase, High-Density Lipoprotein, and Endothelial Function Differ in Healthy Volunteers and Metabolic Syndrome Patients.

Metabolic syndrome (MS) is characterized by endothelial- and high-density lipoprotein (HDL) dysfunction and increased endothelial lipase (EL) serum levels. We examined the associations between EL serum levels, HDL (serum levels, lipid content, and function), and endothelial function in healthy volunteers (HV) and MS patients. Flow-mediated dilation (FMD), nitroglycerin-mediated dilation (NMD), serum levels of HDL subclasses (measured by nuclear magnetic resonance (NMR) spectroscopy), and EL serum levels differed significantly between HV and MS patients. The serum levels of triglycerides in large HDL particles were significantly positively correlated with FMD and NMD in HV, but not in MS patients. Cholesterol (C) and phospholipid (PL) contents of large HDL particles, calculated as HDL1-C/HDL1-apoA-I and HDL1-PL/HDL1-apoA-I, respectively, were significantly negatively correlated with FMD in HV, but not in MS patients. Cholesterol efflux capacity and arylesterase activity of HDL, as well as EL, were correlated with neither FMD nor NMD. EL was significantly negatively correlated with HDL-PL/HDL-apoA-I in HV, but not in MS patients, and with serum levels of small dense HDL containing apolipoprotein A-II in MS patients, but not in HV. We conclude that MS modulates the association between HDL and endothelial function, as well as between EL and HDL. HDL cholesterol efflux capacity and arylesterase activity, as well as EL serum levels, are not associated with endothelial function in HV or MS patients.

Cholesterol Content of Very-Low-Density Lipoproteins Is Associated with 1-Year Mortality in Acute Heart Failure Patients.

Considering the relationship between the extent of metabolic derangement and the disease severity in heart failure, we hypothesized that the lipid content of very-low-density lipoprotein (VLDL) may have prognostic value for 1 year mortality in acute heart failure (AHF). Baseline serum levels of VLDL cholesterol (VLDL-C), VLDL triglycerides (VLDL-TG), VLDL phospholipids (VLDL-PL), and VLDL apolipoprotein B (VLDL-apoB) were measured using NMR spectroscopy. We calculated the ratios of the respective VLDL lipids and VLDL apoB (VLDL-C/VLDL-apoB, VLDL-TG/VLDL-apoB, and VLDL-PL/VLDL-apoB), as estimators of the cholesterol, triglyceride, and phospholipid content of VLDL particles and tested their association with mortality. Out of 315 AHF patients, 118 (37.5%) patients died within 1 year after hospitalization for AHF. Univariable Cox regression analyses revealed a significant inverse association of VLDL-C/VLDL-apoB (hazard ratio (HR) 0.43, 95% confidence interval (CI) 0.29−0.64, p < 0.001), VLDL-TG/VLDL-apoB (HR 0.79, 95% CI 0.71−0.88, p < 0.001), and VLDL-PL/VLDL-apoB (HR 0.37, 95% CI 0.25−0.56, p < 0.001) with 1 year mortality. Of the tested parameters, only VLDL-C/VLDL-apoB remained significant after adjustment for age and sex, as well as other clinical and laboratory parameters that showed a significant association with 1 year mortality in the univariable analyses. We conclude that cholesterol content of circulating VLDL (VLDL-C/VLDL-apoB) might be of prognostic value in AHF.

HDL-apoA-II Is Strongly Associated with 1-Year Mortality in Acute Heart Failure Patients.

The prognostic value of the subset of high-density lipoprotein (HDL) particles containing apolipoprotein (apo)A-II (HDL-apoA-II) in acute heart failure (AHF) remains unexplored. In this study, baseline serum levels of HDL-apoA-II (total and subfractions 1−4) were measured in 315 AHF patients using NMR spectroscopy. The mean patient age was 74.2 ± 10.5 years, 136 (43.2%) were female, 288 (91.4%) had a history of cardiomyopathy, 298 (94.6%) presented as New York Heart Association class 4, and 118 (37.5%) patients died within 1 year after hospitalization for AHF. Multivariable Cox regression analyses, adjusted for age and sex as well as other clinical and laboratory parameters associated with 1-year mortality in the univariable analyses, revealed a significant inverse association of HDL-apoA-II (hazard ratio (HR) 0.67 per 1 standard deviation (1 SD) increase, 95% confidence interval (CI) 0.47−0.94, p = 0.020), HDL2-apoA-II (HR 0.72 per 1 SD increase, 95% CI 0.54−0.95, p = 0.019), and HDL3-apoA-II (HR 0.59 per 1 SD increase, 95% CI 0.43−0.80, p < 0.001) with 1-year mortality. We conclude that low baseline HDL-apoA-II, HDL2-apoA-II, and HDL3-apoA-II serum levels are associated with increased 1-year mortality in AHF patients and may thus be of prognostic value in AHF.

NOMOGRAM CONTAINING SIMPLE ROUTINE CLINICAL AND BIOCHEMICAL PARAMETERS CAN PREDICT PATHOLOGIC VENTRICULAR REMODELING IN STEMI PATIENTS.

Heart failure is the leading cause of morbidity and mortality worldwide, with ischemic heart disease being one of the most important etiologic factors. Heart failure develops due to ventricular remodeling, which leads to increases in left ventricular end-systolic and end-diastolic volumes. In this prospective observational study, we included 101 patients with first episode of ST-segment elevation myocardial infarction in whom percutaneous coronary intervention was conducted within 12 h and Thrombolysis in Myocardial Infarction III flow was achieved. The aim was to determine which clinical and biochemical parameters can help predict pathologic ventricular remodeling 1 year after myocardial infarction. We created a nomogram based on routinely used blood tests and vital parameters which showed highest correlation with pathologic ventricular remodeling. The nomogram included NTproBNP value 12 h after reperfusion, aspartate transaminase value 12 h after reperfusion, systolic blood pressure value on admission, and culprit coronary artery. We performed ROC analysis which yielded great predictive value of the nomogram. The area under curve was 0.907 (95% CI 0.842-0.973). The nomogram value of -3.54 had 91.4% sensitivity and 74.0% specificity. We believe that this nomogram, once validated, could offer a widely available, low-cost option that would help identify patients at risk of developing pathologic left ventricular remodeling and achieve this at a very early stage of myocardial infarction (12 h after reperfusion has been achieved).

Does shifting to professional emergency department staffing affect the decision for chest radiography?

BACKGROUND: The study aims to determine whether shifting to professional emergency department (ED) teams leads to a higher rate of radiologic workup. METHODS: We retrospectively analyzed a total of 2,000 patients presenting to the ED of a tertiary teaching hospital in two time periods: group 1 (G1) comprised 1,000 consecutive patients enrolled from December 21, 2012 to January 5, 2013 (all patients were examined by an internal medicine specialist); group 2 (G2) comprised 1,000 consecutive patients enrolled from December 21, 2018 to January 3, 2019 (all patients were examined by an emergency physician). RESULTS: The chest X-ray (CXR) was performed in 40.6% of all patients. There was no difference in the frequency of CXR (38.9% in G1 vs. 42.3% in G2, P=0.152). More CXRs were performed in G2 patients older than 65 years, in female patients older than 65 years, in patients presenting during the evening and night shifts or off-hours, in patients with a history of malignancy, in patients with gastrointestinal bleeding, and in patients with bradycardia, but fewer in patients presenting with arrhythmia. No difference in the rates of pathological CXR was found (47.3% in G1 vs. 52.2% in G2, P=0.186). Compared with G2, higher sensitivity and specificity were obtained for the binary logistic regression model predicting pathological findings in G1. CONCLUSIONS: Shifting to professional ED teams does not increase radiologic workup. By implementing deliberate usage of ultrasound, some self-governing procedures, case-oriented investigations, and center-specific recommendations, unnecessary radiologic workup can be avoided. Professional ED teams could lead to a higher standard of emergency care.

Sepsis and septic shock - an observational study of the incidence, management, and mortality predictors in a medical intensive care unit.

AIM: To prospectively determine the number of patients with sepsis and septic shock in a medical intensive care unit (ICU) using the Sepsis-3 definition; to analyze patients' characteristics, clinical signs, diagnostic test results, treatment and outcomes; and to define independent risk factors for ICU mortality. METHODS: This prospective observational study enrolled all patients with the diagnosis of sepsis treated in the medical ICU of "Sestre Milosrdnice" University Hospital Center, Zagreb, between April 2017 and May 2018. RESULTS: Out of 116 patients with sepsis, 54.3% were female. The median age was 73.5 years (IQR 63-82). The leading source of infection was the genitourinary tract (56.9%), followed by the lower respiratory tract (22.4%). A total of 35.3% of the patients experienced septic shock. Total ICU mortality for sepsis was 37.9%: 63.4% in patients with septic shock and 24.0% in patients without shock. Independent risk factors for ICU mortality were reduced mobility level (odds ratio [OR] 11.16, 95% confidence interval [CI] 2.45-50.91), failure to early recognize sepsis in the emergency department (OR 6.59, 95% CI 1.09-39.75), higher Sequential Organ Failure Assessment score at admission (OR 2.37, 95% CI 1.59-3.52), and inappropriate antimicrobial treatment (OR 9.99, 95% CI 2.57-38.87). CONCLUSION: While reduced mobility level and SOFA score are predetermined characteristics, early recognition of sepsis and the choice of appropriate antimicrobial treatment could be subject to change. Raising awareness of sepsis among emergency department physicians could improve its early recognition and increase the number of timely obtained specimens for microbial cultures.

Acute poisonings in Croatia: differences in epidemiology, associated comorbidities and final outcomes - a single-centre 15-year follow-up.

PURPOSE: To determine the demographic and social characteristics of acutely intoxicated patients in the emergency department (ED), intention of drug/chemical intake, main toxic agents, outcomes and time trends for all variables. METHODS: This prospective, observational study included acutely intoxicated patients treated in the ED of the University Hospital Centre Sisters of Charity, Zagreb, Croatia, during the years 2001, 2010 and 2015. The diagnosis was derived from patient's self-report, clinical observations and laboratory test results (quantitative test for serum ethanol levels and qualitative tests for drugs in urine). RESULTS: A total of 1593 patients were enrolled in the study (331 in 2001, 618 in 2010, 644 in 2015), with a predominance of men (55.9%, 65.2%, 70.7%, respectively). The median age was 28 [18-89], 39 [18-92] and 40 years [18-95], respectively. There was a decline in the number of suicide attempts during the study (46.2%, 22.2%, 17.1% of patients, respectively) with a predominance of women (64.1-68.2%), and an escalation in the number of unintentional overdoses by substances of abuse (50.2%, 72.3%, 81.7% of patients, respectively) with a predominance of men (74.1-79.1%). Ethanol was the main toxic agent (40.2%, 69.4%, 75.8% of patients, respectively), used primarily as a substance of unintentional overdose. Anxiolytics were the most frequently implicated pharmaceuticals among all patients (46.5%, 32.0%, 18.5% of patients, respectively) and the main substance used in suicide attempts. The number of patients hospitalized in the Intensive Care Unit (ICU) decreased during the study from 20.2% of all patients in 2001 to 7.9% in 2010 and 6.8% in 2015. They accounted for 7.2%, 5.8% and 5.6% of all ICU-treated patients, respectively. In-hospital mortality (ED and ICU) caused by acute intoxications was low (0.9%, 0.8%, 0.8%, respectively). CONCLUSIONS: The escalation of overdoses by ethanol was a major medical and public concern in Zagreb. Anxiolytics were the main substance used in suicide attempts, with a low death rate due to their good safety profile.