Red cell distribution width and mortality in carotid atherosclerosis.

BACKGROUND: Red cell distribution width (RDW) is associated with morbidity and mortality in chronic cardiac disease. The aim of the present study was to investigate the role of RDW as a predictor of adverse outcome in patients with carotid atherosclerosis. MATERIALS AND METHODS: We prospectively studied 1065 of 1286 consecutive patients with neurological asymptomatic carotid artery stenosis as assessed by duplex Doppler sonography. The study end points were all-cause mortality and cardiovascular mortality respectively. RESULTS: During a median follow-up time of 6·2 years (interquartile range 5·9-6·6), corresponding to 5551 overall person-years, 275 patients (25·8%) died. Of them, 182 patients (66·2%) died due to cardiovascular causes. RDW was significantly associated with adverse outcome. In a continuous multivariate Cox regression analysis, the adjusted hazard ratio for each per cent increase in RDW was 1·39 (95% CI 1·27-1·53; P < 0·001) for all-cause and 1·43 (95% CI 1·28-1·60; P < 0·001) for cardiovascular mortality respectively. Kaplan-Meier estimates showed a gradual relationship between increasing quartiles of RDW and death (log rank P < 0·001). Adjusted hazard ratios for all-cause death ranged from 0·89 to 1·94 for the highest vs. the lowest quartile (P < 0·001 for trend) and for cardiovascular death from 1·08 to 2·34 for the highest vs. the lowest quartile (P < 0·001 for trend) respectively. CONCLUSIONS: Red cell distribution width was significantly and independently associated with all-cause and cardiovascular death in patients with asymptomatic carotid atherosclerosis.

An increase of interleukin-33 serum levels after coronary stent implantation is associated with coronary in-stent restenosis.

The study aim was to determine the predictive value of interleukin (IL)-33, a recently described member of the IL-1 family of cytokines, for the development of in-stent restenosis (ISR). IL-33 serum levels were measured in 387 consecutive patients undergoing percutaneous coronary intervention (PCI) of whom 193 had stable angina, 93 non-ST elevation myocardial infarction (NSTEMI), and 101 ST-elevation MI (STEMI), respectively. Blood was taken directly before and 24h after stent implantation. The presence of ISR was initially evaluated by clinical means after six to eight months. When presence of myocardial ischemia was suspected, coronary angiography was performed to confirm the suspected diagnosis of ISR. Clinical ISR was present in total in 34 patients (8.8%). IL-33 was detectable in 185 patients and was below detection limit in 202 patients. In patients with decreased IL-33 (n=95), unchanged or non-detectable levels (n=210) or increased levels of IL-33 after PCI (n=82), ISR-rate was 2.1%, 9.5% and 14.6%, respectively (p<0.05). Accordingly, patients with ISR showed a significant increase of IL-33 upon PCI (p<0.05). This association was independent from clinical presentation and risk factors as well as numbers and type of stents. In patients with both stable and unstable coronary artery disease, an increase of IL-33 serum levels after stent implantation is associated with a higher rate of in-stent restenosis.

SARS-CoV-2-related mortality and treatment delays for cancer patients in Austria : Findings of a multicentric nationwide study.

BACKGROUND: Cancer patients infected with severe acute respiratory syndrome coronavirus type 2 (SARS-CoV-2) have an increased risk of mortality. Here, we investigated predictive factors for coronavirus disease 2019 (COVID-19) associated mortality in patients with neoplastic diseases treated throughout Austria. METHODS: In this multicentric nationwide cohort study, data on patients with active or previous malignant diseases and SARS-CoV­2 infections diagnosed between 13 March 2020 and 06 April 2021 were collected. Collected data included the stage of the malignant disease and outcome parameters 30 days after the diagnosis of SARS-CoV­2 infection. RESULTS: The cohort consisted of 230 individuals of which 75 (32.6%) patients were diagnosed with hematologic malignancies and 155 (67.4%) with solid tumors. At a median follow-up of 31 days after COVID-19 diagnosis, 38 (16.5%) patients had died due to COVID-19. Compared to survivors, patients who died were older (62.4 vs. 71.4 years, p < 0.001) and had a higher ECOG performance status (0.7 vs. 2.43, p < 0.001). Furthermore, higher neutrophil counts (64.9% vs. 73.8%, p = 0.03), lower lymphocyte counts (21.4% vs. 14%, p = 0.006) and lower albumin levels (32.5 g/l vs. 21.6 g/l, p < 0.001) were observed to be independent risk factors for adverse outcomes. No association between mortality and systemic antineoplastic therapy was found (p > 0.05). In 60.6% of the patients, therapy was postponed due to quarantine requirements or hospital admission. CONCLUSION: Mortality of Austrian cancer patients infected with SARS-CoV­2 is comparable to that of other countries. Furthermore, risk factors associated with higher mortality were evident and similar to the general population. Treatment delays were frequently observed.

The prognostic impact of soluble apoptosis-stimulating fragment on mortality in patients with carotid atherosclerosis.

BACKGROUND AND PURPOSE: Markers of apoptosis are associated with cardiovascular disease. The soluble apoptosis-stimulating fragment (sFAS) was found to be a predictor for outcome in patients with heart failure, but its importance in patients with atherosclerotic disease has not been fully understood as yet. The aim of the present study was to investigate the impact of sFAS on all-cause and cardiovascular mortality in patients with atherosclerosis in the carotid arteries. METHODS: We studied 981 of 1286 consecutive patients with neurological asymptomatic carotid atherosclerosis as evaluated by duplex Doppler sonography. Patients were prospectively followed for long-term all-cause and cardiovascular mortality. RESULTS: During a median follow-up of 6.2 years (interquartile range, 5.9 to 6.6 years), a total of 250 deaths (25.5%), including 165 (66%) cardiovascular deaths, were recorded. The risk for all-cause and for cardiovascular mortality, respectively, increased significantly with sFAS concentrations (P<0.001). The hazard ratio for all-cause death was elevated by 2.3-fold (P<0.001) and for cardiovascular death by 2.4-fold (P<0.001) in patients within the highest quintile of sFAS compared with patients within the lowest quintile, respectively. Results remained significant after adjustment for potential confounders and established cardiovascular risk factors, including high-sensitivity C-reactive protein. Patients with high sFAS but low high-sensitivity C-reactive protein had a comparable survival rate with those with elevated high-sensitivity C-reactive protein only (P=0.50). CONCLUSIONS: Markers of apoptosis, as measured by sFAS, were found to be independent risk predictors for death in patients with atherosclerotic disease in the carotid arteries.

G-CSF Predicts Cardiovascular Events in Patients with Stable Coronary Artery Disease.

Granulocyte-colony-stimulating-factor (G-CSF) induces mobilization of progenitor cells but may also exert pro-inflammatory and pro-thrombotic effects. Treatment with recombinant G-CSF after acute myocardial infarction is currently under examination and has been associated with in-stent restenosis. However, it is not known whether plasma levels of endogenous G-CSF are also associated with an increased cardiovascular risk. Therefore we included 280 patients with angiographically proven stable coronary artery disease. G-CSF was measured by specific ELISA and patients were followed for a median of 30 months for the occurrence of major adverse cardiovascular events (MACE: death, myocardial infarction, re-hospitalization). Those with cardiac events during follow-up showed significant higher G-CSF levels (32.3 pg/mL IQR 21.4-40.5 pg/mL vs. 24.6 pg/mL IQR 16.4-34.9 pg/mL; p<0.05) at baseline. Patients with G-CSF plasma levels above the median had a 2-fold increased risk for MACE (p<0.05). This was independent from established cardiovascular risk factors. In addition, G-CSF above the median was a predictor of clinical in-stent restenosis after implantation of bare-metal stents (6.6% vs. 19.4%; p<0.05) but not of drug-eluting stents (7.7% vs. 7.6%; p = 0.98). This data suggests that endogenous plasma levels of G-CSF predict cardiovascular events independently from established cardiac risk factors and are associated with increased in-stent restenosis rates after implantation of bare metal stents.

Monocyte subset distribution in patients with stable atherosclerosis and elevated levels of lipoprotein(a).

BACKGROUND: Lipoprotein(a) (Lp(a)) is a proatherogenic plasma lipoprotein currently established as an independent risk factor for the development of atherosclerotic disease and as a predictor for acute thrombotic complications. In addition, Lp(a) is the major carrier of proinflammatory oxidized phospholipids (OxPL). Today, atherosclerosis is considered to be an inflammatory disease of the vessel wall in which monocytes and monocyte-derived macrophages are crucially involved. Circulating monocytes can be divided according to their surface expression pattern of CD14 and CD16 into at least 3 subsets with distinct inflammatory and atherogenic potential. OBJECTIVE: The aim of this study was to examine whether elevated levels of Lp(a) and OxPL on apolipoprotein B-100-containing lipoproteins (OxPL/apoB) are associated with changes in monocyte subset distribution. METHODS: We included 90 patients with stable coronary artery disease. Lp(a) and OxPL/apoB were measured, and monocyte subsets were identified as classical monocytes (CMs; CD14++CD16-), intermediate monocytes (IMs; CD14++CD16+), and nonclassical monocytes (NCMs; CD14+CD16++) by flow cytometry. RESULTS: In patients with elevated levels of Lp(a) (>50 mg/dL), monocyte subset distribution was skewed toward an increase in the proportion of IM (7.0 ± 3.8% vs 5.2 ± 3.0%; P = .026), whereas CM (82.6 ± 6.5% vs 82.0 ± 6.8%; P = .73) and NCM (10.5 ± 5.3 vs 12.8 ± 6.0; P = .10) were not significantly different. This association was independent of clinical risk factors, choice of statin treatment regime, and inflammatory markers. In addition, OxPL/apoB was higher in patients with elevated Lp(a) and correlated with IM but not CM and NCM. CONCLUSIONS: In conclusion, we provide a potential link between elevated levels of Lp(a) and a proatherogenic distribution of monocyte subtypes in patients with stable atherosclerotic disease.

Association of small dense LDL serum levels and circulating monocyte subsets in stable coronary artery disease.

OBJECTIVE: Atherosclerosis is considered to be an inflammatory disease in which monocytes and monocyte-derived macrophages play a key role. Circulating monocytes can be divided into three distinct subtypes, namely in classical monocytes (CM; CD14++CD16-), intermediate monocytes (IM; CD14++CD16+) and non-classical monocytes (NCM; CD14+CD16++). Low density lipoprotein particles are heterogeneous in size and density, with small, dense LDL (sdLDL) crucially implicated in atherogenesis. The aim of this study was to examine whether monocyte subsets are associated with sdLDL serum levels. METHODS: We included 90 patients with angiographically documented stable coronary artery disease and determined monocyte subtypes by flow cytometry. sdLDL was measured by an electrophoresis method on polyacrylamide gel. RESULTS: Patients with sdLDL levels in the highest tertile (sdLDL≥4mg/dL;T3) showed the highest levels of pro-inflammatory NCM (15.2±7% vs. 11.4±6% and 10.9±4%, respectively; p<0.01) when compared with patients in the middle (sdLDL=2-3mg/dL;T2) and lowest tertile (sdLDL=0-1mg/dL;T1). Furthermore, patients in the highest sdLDL tertile showed lower CM levels than patients in the middle and lowest tertile (79.2±8% vs. 83.9±7% and 82.7±5%; p<0.01 for T3 vs. T2+T1). Levels of IM were not related to sdLDL levels (5.6±4% vs. 4.6±3% vs. 6.4±3% for T3, T2 and T1, respectively). In contrast to monocyte subset distribution, levels of circulating pro- and anti-inflammatory markers were not associated with sdLDL levels. CONCLUSION: The atherogenic lipoprotein fraction sdLDL is associated with an increase of NCM and a decrease of CM. This could be a new link between lipid metabolism dysregulation, innate immunity and atherosclerosis.

Glycoprotein 130 polymorphism predicts soluble glycoprotein 130 levels.

OBJECTIVE: Interleukin-6 (IL-6) is a key cytokine in inflammatory diseases. It exerts its biological function via binding to a homodimer of its signal transducer glycoprotein 130 (gp130). Soluble gp130 (sgp130) is the natural inhibitor of IL-6 trans-signalling. The aim of this study was to test a possible influence of the gp130 genotype on sgp130 serum levels. MATERIAL AND METHODS: In two separate populations, subjects were genotyped for the gp130 polymorphism G148C. Sgp130, IL-6 and soluble interleukin-6 receptor (sIL-6R) levels were measured. The OSLO population consisted of 546 male subjects at high risk for CAD. The VIENNA population consisted of 299 male subjects with angiographically proven CAD. RESULTS: In the OSLO population, 124 (22.7%) subjects were hetero- or homozygote for the rare C allele. Individuals carrying the polymorphism had significantly higher levels of sgp130. In a multivariate linear regression model this association remained significant (adjusted p=0.001). In the VIENNA population, 48 (16.1%) subjects were hetero- or homozygote for the rare C allele. Consistent with the former study, sgp130 levels were significantly higher in carriers of the polymorphism compared to wildtype carriers (adjusted p=0.038). In the VIENNA population, sgp130 levels were significantly higher in diabetic patients. In the OSLO population, sgp130 was higher in patients with increased body mass index and in smokers (p<0.05). CONCLUSIONS: Sgp130 serum levels are significantly higher in subjects carrying the gp130 polymorphism G148C compared to wildtype carriers. This finding proposes a possible genetical influence on sgp130 levels which may alter individual coping mechanisms in inflammatory diseases.

Soluble ST2 and interleukin-33 levels in coronary artery disease: relation to disease activity and adverse outcome.

OBJECTIVES: ST2 is a receptor for interleukin (IL)-33. We investigated an association of soluble ST2 (sST2) and IL-33 serum levels with different clinical stages of coronary artery disease. We assessed the predictive value of sST2 and IL-33 in patients with stable angina, non-ST elevation myocardial infarction (NSTEMI) and ST elevation myocardial infarction (STEMI). METHODS: We included 373 patients of whom 178 had stable angina, 97 had NSTEMI, and 98 had STEMI. Patients were followed for a mean of 43 months. The control group consisted of 65 individuals without significant stenosis on coronary angiography. Serum levels of sST2 and IL-33 were measured by ELISAs. RESULTS: sST2 levels were significantly increased in patients with STEMI as compared to patients with NSTEMI and stable angina as well as with controls. IL-33 levels did not differ between the four groups. During follow-up, 37 (10%) patients died and the combined endpoint (all cause death, MI and rehospitalisation for cardiac causes) occurred in 66 (17.6%) patients. sST2 serum levels significantly predicted mortality in the total cohort. When patients were stratified according to their clinical presentation, the highest quintile of sST2 significantly predicted mortality in patients with STEMI, but not with NSTEMI or stable coronary artery disease. sST2 was a significant predictor for the combined endpoint in STEMI patients and in patients with stable angina. Serum levels of IL-33 were not associated with clinical outcome in the total cohort, but the highest quintile of IL-33 predicted mortality in patients with STEMI. CONCLUSIONS: Serum levels of sST2 are increased in patients with acute coronary syndromes as compared to levels in patients with stable coronary artery disease and in individuals without coronary artery disease. sST2 and IL-33 were associated with mortality in patients with STEMI but not in patients with NSTEMI or stable angina.

Small high-density lipoprotein is associated with monocyte subsets in stable coronary artery disease.

OBJECTIVE: High-density lipoprotein (HDL) particles are heterogeneous in structure and function and the role of HDL subfractions in atherogenesis is not well understood. It has been suggested that small HDL may be dysfunctional in patients with coronary artery disease (CAD). Monocytes are considered to play a key role in atherosclerotic diseases. Circulating monocytes can be divided into three subtypes according to their surface expression of CD14 and CD16. Our aim was to examine whether monocyte subsets are associated with HDL subfractions in patients with atherosclerosis. METHODS: We included 90 patients with angiographically stable CAD. Monocyte subsets were defined as classical monocytes (CD14++CD16-; CM), intermediate monocytes (CD14++CD16+; IM) and non-classical monocytes (CD14+CD16++; NCM). HDL subfractions were measured by electrophoresis on polyacrylamide gel. RESULTS: Serum levels of small HDL correlated with circulating pro-inflammatory NCM and showed an inverse relationship to circulating CM independently from other lipid parameters, risk factors, inflammatory parameters or statin treatment regime, respectively. IM were not associated with small HDL. In particular, patients with small HDL levels in the highest tertile showed dramatically increased levels of NCM (14.7 ± 7% vs. 10.7 ± 5% and 10.8 ± 5%; p = 0.006) and a decreased proportion of CM (79.3 ± 7% vs. 83.7 ± 6% and 83.9 ± 6%; p = 0.004) compared to patients in the two lower tertiles. In contrast, intermediate HDL, large HDL and total HDL were not associated with monocyte subset distribution. CONCLUSION: Small HDL levels are associated with pro-inflammatory NCM and inversely correlated with CM. This may suggest that small HDL could have dysfunctional anti-inflammatory properties in patients with established CAD.

Usefulness of hemoglobin level to predict long-term mortality in patients with asymptomatic carotid narrowing by ultrasonography.

Anemia is associated with the cardiovascular outcome in healthy subjects but its impact on outcome in patients with cardiovascular disease has not yet been fully understood. Therefore, we assessed the long-term influence of hemoglobin on all-cause and cardiovascular mortality in patients with atherosclerotic disease. We prospectively studied 1,065 of 1,286 consecutive patients with asymptomatic carotid narrowing. During a median follow-up of 6.2 years, corresponding to 5,551 overall person-years, 275 patients (25.8%) died. Continuous measures of hemoglobin displayed a significant inverse effect on all-cause mortality and cardiovascular mortality (adjusted hazard ratio [HR] for increase of 1 SD of hemoglobin 0.73, 95% confidence interval [CI] 0.64 to 0.83; p <0.001) and adjusted HR 0.76, 95% CI 0.64 to 0.89; p = 0.001, respectively). The cumulative 6-year survival rate was 61%, 79%, 80%, and 81% in the first, second, third, and fourth quartile of hemoglobin (log-rank p <0.001). Patients within the first quartile (<12.9 g/dl) had a significantly increased risk of all-cause mortality (adjusted HR 1.93, 95% CI 1.46 to 2.54, p <0.001) and cardiovascular mortality (adjusted HR 1.68, 95% CI 1.19 to 2.36, p = 0.003) compared to patients with greater levels. In conclusion, our study has demonstrated a significant association with hemoglobin levels and all-cause and cardiovascular mortality in patients with carotid narrowing. Nevertheless, additional research, in terms of randomized controlled trials, is needed to warrant these findings and to evaluate potential therapeutic interventions.