Tissue factor pathway-related biomarkers in liver cancer: activated factor VII-antithrombin complex and tissue factor mRNA levels are associated with mortality.

Background: Tissue factor (TF), the main initiator of the coagulation cascade, plays a role in cancer progression and prognosis. Activated factor VII-antithrombin complex (FVIIa-AT) is considered an indirect marker of TF exposure by reflecting TF-FVIIa interaction. Objectives: To assess the link between FVIIa-AT plasma levels, TF messenger RNA (mRNA) expression, and survival in cancer. Methods: TF pathway-related coagulation biomarkers were assessed in 136 patients with cancer (52 with hepatocellular carcinoma, 41 with cholangiocarcinoma, and 43 with colon cancer) undergoing surgical intervention with curative intent. TF mRNA expression analysis in neoplastic vs nonneoplastic liver tissues was evaluated in a subgroup of 91 patients with primary liver cancer. Results: FVIIa-AT levels were higher in patients with cancer than in 136 sex- and age-matched cancer-free controls. In patients with cancer, high levels of FVIIa-AT and total TF pathway inhibitor were associated with an increased mortality risk after adjustment for confounders, but only FVIIa-AT remained a predictor of mortality by including both FVIIa-AT and total TF pathway inhibitor in Cox regression (hazard ratio, 2.80; 95% CI, 1.23-6.39; the highest vs the lowest quartile). This association remained significant even after adjustment for extracellular vesicle-associated TF-dependent procoagulant activity. In the subgroup of patients with primary liver cancer, patients with high TF mRNA levels had an increased mortality risk compared with that for those with low TF mRNA levels (hazard ratio, 1.92; 95% CI, 1.03-3.57), and there was a consistent correlation among high FVIIa-AT levels, high TF mRNA levels, and increased risk of mortality. Conclusion: High FVIIa-AT levels may allow the identification of patients with cancer involving high TF expression and predict a higher mortality risk in liver cancer.

Proteomic analysis of urinary extracellular vesicles highlights specific signatures for patients with primary aldosteronism.

Background: Urinary extracellular vesicles (uEVs) can be released by different cell types facing the urogenital tract and are involved in cellular trafficking, differentiation and survival. UEVs can be easily detected in urine and provide pathophysiological information "in vivo" without the need of a biopsy. Based on these premises, we hypothesized that uEVs proteomic profile may serve as a valuable tool in the differential characterization between Essential Hypertension (EH) and primary aldosteronism (PA). Methods: Patients with essential hypertension (EH) and PA were enrolled in the study (EH= 12, PA=24: 11 Bilateral Primary Aldosteronism subtype (BPA) and 13 Aldosterone Producing Adenoma (APA)). Clinical and biochemical parameters were available for all the subjects. UEVs were isolated from urine by ultracentrifugation and analysed by Transmission Electron Microscopy (TEM) and nanotrack particle analysis (NTA). UEVs protein content was investigated through an untargeted MS-based approach. Statistical and network analysis was performed to identify potential candidates for the identification and classification of PA. Results: MS analysis provided more than 300 protein identifications. Exosomal markers CD9 and CD63 were detected in all samples. Several molecules characterizing EH vs PA patients as well as BPA and APA subtypes were identified after statistical elaboration and filtering of the results. In particular, some key proteins involved in water reabsorption mechanisms, such as AQP1 and AQP2, were among the best candidates for discriminating EH vs PA, as well as A1AG1 (AGP1). Conclusion: Through this proteomic approach, we identified uEVs molecular indicators that can improve PA characterization and help in the gain of insights of the pathophysiological features of this disease. In particular, PA was characterized by a reduction of AQP1 and AQP2 expression as compared with EH.

Hidden Comorbidities in Asthma: A Perspective for a Personalized Approach.

Bronchial asthma is the most frequent inflammatory non-communicable condition affecting the airways worldwide. It is commonly associated with concomitant conditions, which substantially contribute to its burden, whether they involve the lung or other districts. The present review aims at providing an overview of the recent acquisitions in terms of asthma concomitant systemic conditions, besides the commonly known respiratory comorbidities. The most recent research has highlighted a number of pathobiological interactions between asthma and other organs in the view of a shared immunological background underling different diseases. A bi-univocal relationship between asthma and common conditions, including cardiovascular, metabolic or neurodegenerative diseases, as well as rare disorders such as sickle cell disease, α1-Antitrypsin deficiency and immunologic conditions with hyper-eosinophilia, should be considered and explored, in terms of diagnostic work-up and long-term assessment of asthma patients. The relevance of that acquisition is of utmost importance in the management of asthma patients and paves the way to a new approach in the light of a personalized medicine perspective, besides targeted therapies.

CD14+-Monocytes Exposed to Apolipoprotein CIII Express Tissue Factor.

Apolipoprotein CIII (ApoCIII) represents a key regulator of plasma lipid metabolism and a recognized risk factor for atherosclerosis and cardiovascular diseases. Beyond the regulation of lipoprotein trafficking, ApoCIII is also involved in endothelial dysfunction and monocyte recruitment related to atherothrombosis. With tissue factor (TF) being the primary initiator of the blood coagulation cascade, we hypothesized that ApoCIII-treated monocytes could express it. Hence, human CD14+-monocytes and autologous neutrophils were incubated with ApoCIII and sera from human subjects containing previously measured ApoCIII amounts. By RT-qPCR and ELISA, CD14+-monocytes, but not neutrophils, were found to show increased mRNA expression and production of TNFα, IL-1ß and IL-6 as well as TF mRNA once exposed to ultra-purified ApoCIII. By flow cytometry, CD14+-monocytes were found to rapidly express TF on their cell surface membrane when incubated with either ApoCIII or sera with known concentrations of ApoCIII. Finally, preincubation with specific ApoCIII-neutralizing antibodies significantly reduced the ability of most sera with known concentrations of ApoCIII to upregulate TF protein, other than partially inhibiting cytokine release, in CD14+-monocytes. In sum, herein we demonstrate that ApoCIII activates CD14+-monocytes to express TF. The data identify a potential mechanism which links circulating apolipoproteins with inflammation and atherothrombosis-related processes underlying cardiovascular risk.

Modulation of factor VIII pharmacokinetics by genetic components in factor VIII receptors.

INTRODUCTION: Gene variation in receptors for circulating factor VIII (FVIII) is candidate to explain the large inter-patient variability of infused FVIII pharmacokinetics (PK) in haemophilia A (HA). AIM: To compare in an Italian HA cohort (n = 26) the influence on FVIII PK of genetic components in four von Willebrand factor (VWF)/FVIII receptors. METHODS: Genotypes of low-density lipoprotein receptor (LDLR), asialoglycoprotein receptor minor subunit (ASGR2), family 4 member M (CLEC4M), stabilin2 (STAB2) and ABO blood-group, and VWF:Ag levels were included as independent variables in linear regression analyses of two-compartment model (TCM) - standard half-life (SHL) FVIII PK parameters. RESULTS: In the initial FVIII distribution phase, the STAB2 rs4981022 AA, ASGR2 rs2289645 TT and LDLR rs688 TT genotypes may contribute to increase Cmax , and prolong or shorten AlphaHL. In the elimination phase, a shorter BetaHL was associated with the CLEC4M rs868875 GG (beta-coefficient .366, p = .025) and ASGR2 rs2289645 TC (beta-coefficient .456, p = .006) genotypes, which also showed shorter mean residence time (MRT) than TT genotypes (p = .021). The alpha and beta phase effects were independent of ABO and VWF:Ag levels at baseline. The association of the LDLR rs2228671 genotypes with clearance was independent of ABO (beta-coefficient -.363, p = .035) but not of other receptors or VWF:Ag, which may point out multiple and competing interactions. CONCLUSIONS: With the limitation of the small number of HA patients, these observations highlight multiple genetic components acting in distinct phases of FVIII PK and contributing to explain FVIII PK variability. This analysis provides candidates for genotype-based, individual tailoring of FVIII substitutive treatment.

High Plasma Levels of Activated Factor VII-Antithrombin Complex Point to Increased Tissue Factor Expression in Patients with SARS-CoV-2 Pneumonia: A Potential Link with COVID-19 Prothrombotic Diathesis.

Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) is the causal agent of coronavirus disease 2019 (COVID-19), in which coagulation abnormalities and endothelial dysfunction play a key pathogenic role. Tissue factor (TF) expression is triggered by endothelial dysfunction. Activated factor VII-antithrombin (FVIIa-AT) complex reflects indirectly FVIIa-TF interaction and has been proposed as a potential biomarker of prothrombotic diathesis. FVIIa-AT plasma concentration was measured in 40 patients (30 males and 10 females; 64.8 ± 12.3 years) admitted with SARS-CoV-2 pneumonia during the first pandemic wave in Italy. Two sex- and age-matched cohorts without COVID-19, with or without signs of systemic inflammation, were used to compare FVIIa-AT data. The FVIIa-AT plasma levels in COVID-19 patients were higher than those in non-COVID-19 subjects, either with or without inflammation, while no difference was observed among non-COVID-19 subjects. The association between COVID-19 and FVIIa-AT levels remained significant after adjustment for sex, age, C-reactive protein, renal function, fibrinogen, prothrombin time and activated partial thromboplastin time. Our results indicate that SARS-CoV-2 infection, at least during the first pandemic wave, was characterized by high FVIIa-AT levels, which may suggest an enhanced FVIIa-TF interaction in COVID-19, potentially consistent with SARS-CoV-2-induced endotheliopathy.

Combination of CLEC4M rs868875 G-Carriership and ABO O Genotypes May Predict Faster Decay of FVIII Infused in Hemophilia A Patients.

The C-type lectin CLEC4M binds and internalizes factor VIII (FVIII). Common CLEC4M variants have been associated with FVIII pharmacokinetic (PK) profiles in hemophilia A (HA) patients. The two-compartment PK analysis of plasma-derived (pd-) and full length recombinant FVIII concentrates was conducted in twenty-six patients (FVIII:C ≤ 2 IU/dL). F8, ABO blood-groups, and the CLEC4M rs868875A/G polymorphism were genotyped. CLEC4M genotype groups differed for the elimination rate constant K 1-0 (p < 0.001), half-life (K 1-0 HL), and the Beta rate constant. Patients treated with pd-FVIII also differed in the Alpha phase. In linear regression models, the contribution of the CLEC4M genotypes to FVIII PK parameters remained significant after correction for ABO, age, and VWF antigen levels at PK. Combined CLEC4M rs868875A/G and ABO genotypes displayed significant interaction (K 1-0, p = 0.014). Compared to other combined genotypes, the G-carriers/O genotypes showed half-reduced K 1-0 HL (p = 0.008), and faster FVIII clearance (mean 7.1 ± 2.2 mL/h/kg SE) than in the G-carriers/non-O (mean 2.4 ± 0.3 mL/h/kg SE), (p = 0.038). Comparison in HA patients recruited in several countries suggests that CLEC4M genotypes coherently influence infused FVIII half-life and clearance. Our analysis supports substantially faster FVIII decay associated with the rs868875 G-carrier/ABO O genotypes, which has potential implications for genetically tailored substitutive HA treatment.

The Asialoglycoprotein Receptor Minor Subunit Gene Contributes to Pharmacokinetics of Factor VIII Concentrates in Hemophilia A.

BACKGROUND: The asialoglycoprotein receptor (ASGPR) binds with high affinity factor VIII (FVIII) through its N-linked oligosaccharides. However, its contribution to the wide inter-individual variation of infused FVIII pharmacokinetics (PK) in hemophilia A (HA) is unknown. OBJECTIVE: To investigate the variability in FVIII PK outcomes in relation to genetic variation in the ASGR2, encoding the ASGPR2 subunit. METHODS: Thirty-two HA patients with FVIII:C ≤2 IU/dL underwent 66 single-dose FVIII PK studies. PK parameters were evaluated in relation to ASGR2 5' untranslated region (5'UTR) polymorphisms, which were investigated by recombinant and white blood cell reverse transcription-polymerase chain reaction approaches. RESULTS: The 5'UTR polymorphisms determine a frequent and conserved haplotype (HT1) in a regulatory region. The HT1 homozygotes may differ in the amounts of alternatively spliced mRNA transcripts and thus ASGPR2 isoforms. Compared with the other ASGR2 genotypes, the c.-95TT homozygotes (n = 9), showed threefold longer Alpha HL (3.60 hours, 95% confidence interval: 1.44-5.76, p = 0.006), and the c.-95TC heterozygotes (n = 17) showed 25% shorter mean residence time (MRT; 18.5 hours, 15.0-22.0, p = 0.038) and 32% shorter Beta HL (13.5 hours, 10.9-16.0, p = 0.016). These differences were confirmed in patients (n = 27) undergoing PK studies (n = 54) with full-length FVIII only. In different linear regression models, the contribution of the ASGR2 genotypes remained significant after adjustment by ABO genotypes and von Willebrand factor (VWF) antigen levels, and explained 14% (MRT), 15 to 18% (Beta HL), and 22% (Alpha HL) of parameter variability. CONCLUSION: Infused FVIII distribution was modulated by frequent ASGR2 genotypes, independently from and together with ABO and VWF antigen levels, which has potential implications for genetically tailored substitutive treatment in HA.

Novel protein-truncating variant in the APOB gene may protect from coronary artery disease and adverse cardiovascular events.

Background and aims: Genetic testing is still rarely used for the diagnosis of dyslipidemia, even though gene variants determining plasma lipids levels are not uncommon. Methods: Starting from a a pilot-analysis of targeted Next Generation Sequencing (NGS) of 5 genes related to familial hypercholesterolemia (LDLR, APOB, PCSK9, HMGCR, APOE) within a cardiovascular cohort in subjects with extreme plasma concentrations of low-density lipoprotein (LDL) cholesterol, we discovered and characterized a novel point mutation in the APOB gene, which was associated with very low levels of apolipoprotein B (ApoB) and LDL cholesterol. Results: APOB c.6943 G > T induces a premature stop codon at the level of exon 26 in the APOB gene and generates a protein which has the 51% of the mass of the wild type ApoB-100 (ApoB-51), with a truncation at the level of residue 2315. The premature stop codon occurs after the one needed for the synthesis of ApoB-48, allowing chylomicron production at intestinal level and thus avoiding potential nutritional impairments. The heterozygous carrier of APOB c.6943G > T, despite a very high-risk profile encompassing all the traditional risk factors except for dyslipidemia, had normal coronary arteries by angiography and did not report any major adverse cardiovascular event during a 20-years follow-up, thereby obtaining advantage from the gene variant as regards protection against atherosclerosis, apparently without any metabolic retaliation. Conclusions: Our data support the use of targeted NGS in well-characterized clinical settings, as well as they indicate that.a partial block of ApoB production may be well tolerated and improve cardiovascular outcomes.

Identification of a Novel Serological Marker in Seronegative Rheumatoid Arthritis Using the Peptide Library Approach.

Rheumatoid arthritis (RA) is a systemic autoimmune disease characterized by chronic inflammation mainly affecting the joints leading to cartilage and bone destruction. The definition of seropositive or seronegative RA is based on the presence or absence of rheumatoid factor (RF) and anti-citrullinated peptide antibodies (ACPAs). Other autoantibodies have been identified in the last decade such as antibodies directed against carbamylated antigens, peptidyl-arginine deiminase type 4 and v-Raf murine sarcoma viral oncogene homologue B. In order to identify relevant autoantigens, we screened a random peptide library (RPL) with pooled IgGs obtained from 50 patients with seronegative RA. Patients' sera were then used in an ELISA test to identify the most frequently recognized peptide among those obtained by screening the RPL. Sera from age- and sex-matched healthy subjects were used as controls. We identified a specific peptide (RA-peptide) recognized by RA patients' sera, but not by healthy subjects or by patients with other immune-mediated diseases. The majority of sera from seronegative and seropositive RA patients (73.8% and 63.6% respectively) contained IgG antibodies directed against the RA-peptide. Interestingly, this peptide shares homology with some self-antigens, such as Protein-tyrosine kinase 2 beta, B cell scaffold protein, Liprin-alfa1 and Cytotoxic T lymphocyte protein 4. Affinity purified anti-RA-peptide antibodies were able to cross react with these autoantigens. In conclusion, we identified a peptide that is recognized by seropositive and, most importantly, by seronegative RA patients' sera, but not by healthy subjects, conferring to this epitope a high degree of specificity. This peptide shares also homology with other autoantigens which can be recognized by autoantibodies present in seronegative RA sera. These newly identified autoantibodies, although present also in a percentage of seropositive RA patients, may be considered as novel serum biomarkers for seronegative RA, which lacks the presence of RF and/or ACPAs.

Detection of Urinary Exosomal HSD11B2 mRNA Expression: A Useful Novel Tool for the Diagnostic Approach of Dysfunctional 11ß-HSD2-Related Hypertension.

Objective: Apparent mineralocorticoid excess (AME) is an autosomal recessive disorder caused by the 11ß-hydroxysteroid dehydrogenase type 2 (11ß-HSD2) enzyme deficiency, traditionally assessed by measuring either the urinary cortisol metabolites ratio (tetrahydrocortisol+allotetrahydrocortisol/tetrahydrocortisone, THF+5αTHF/THE) or the urinary cortisol/cortisone (F/E) ratio. Exosomal mRNA is an emerging diagnostic tool due to its stability in body fluids and its biological regulatory function. It is unknown whether urinary exosomal HSD11B2 mRNA is related to steroid ratio or the HSD11B2 662 C>G genotype (corresponding to a 221 A>G substitution) in patients with AME and essential hypertension (EH). Aim of the Study: To detect and quantify HSD11B2 mRNA from urinary exosomes in samples from family members affected by AME and EH, and to evaluate the relationship between exosomal HSD11B2 mRNA, steroid ratio, 662C>G genotype, and hypertension. Methods: In this observational case-control study, urinary steroid ratios and biochemical parameters were measured. Urinary exosomes were extracted from urine and exosomal HSD11B2 mRNA was quantified by Droplet Digital PCR (ddPCR). B2M (ß-2 microglobulin) gene was selected as the reference housekeeping gene. Results: Among family members affected by AME, exosomal urinary HSD11B2 mRNA expression was strictly related to genotypes. The two homozygous mutant probands showed the highest HSD11B2 mRNA levels (median 169, range 118-220 copies/µl) that progressively decreased in 221 AG heterozygous with hypertension (108, range 92-124 copies/µl), 221 AG heterozygous normotensives (23.35, range 8-38.7 copies/µl), and wild-type 221 AA subjects (5.5, range 4.5-14 copies/µl). Heterozygous hypertensive subjects had more HSD11B2 mRNA than heterozygous normotensive subjects. The F/E urinary ratio correlated with HSD11B2 mRNA copy number (p < 0.05); HSD11B2 mRNA strongly decreased while THF+5αTHF/THE increased in the two probands after therapy. In the AME family, HSD11B2 copy number correlated with both F/E and THF+5αTHF/THE ratios, whereas in EH patients, a high F/E ratio reflected a reduced HSD11B2 mRNA expression. Conclusions: HSD11B2 mRNA is detectable and quantifiable in urinary exosomes; its expression varies according to the 662 C>G genotype with the highest levels in homozygous mutant subjects. The HSD11B2 mRNA overexpression in AME could be due to a compensatory mechanism of the enzyme impairment. Exosomal mRNA is a useful tool to investigate HSD11B2 dysregulation in hypertension.

Whole-genome sequencing analysis of semi-supercentenarians.

Extreme longevity is the paradigm of healthy aging as individuals who reached the extreme decades of human life avoided or largely postponed all major age-related diseases. In this study, we sequenced at high coverage (90X) the whole genome of 81 semi-supercentenarians and supercentenarians [105+/110+] (mean age: 106.6 ± 1.6) and of 36 healthy unrelated geographically matched controls (mean age 68.0 ± 5.9) recruited in Italy. The results showed that 105+/110+ are characterized by a peculiar genetic background associated with efficient DNA repair mechanisms, as evidenced by both germline data (common and rare variants) and somatic mutations patterns (lower mutation load if compared to younger healthy controls). Results were replicated in a second independent cohort of 333 Italian centenarians and 358 geographically matched controls. The genetics of 105+/110+ identified DNA repair and clonal haematopoiesis as crucial players for healthy aging and for the protection from cardiovascular events.

rs629301 CELSR2 polymorphism confers a ten-year equivalent risk of critical stenosis assessed by coronary angiography.

BACKGROUND AND AIMS: Novel genetic determinants associated with coronary artery disease (CAD) have been discovered by genome wide association studies. Variants encompassing the CELSR2- PSRC1-SORT1 gene cluster have been associated with CAD. This study is aimed to investigate the rs629301 polymorphism association with the extent of CAD evaluated by coronary angiography (CAG), and to evaluate its associations with an extensive panel of lipid and lipoprotein measurements in a large Italian cohort of 2429 patients. METHODS AND RESULTS: The patients were collected by four Intensive Care Units located in Palermo and Verona (Italy). Clinical Records were filed, blood samples were collected, lipids and apolipoproteins (apo) were measured in separate laboratories. CAD was defined by the presence of stenotic arteries (>50% lumen diameter) by CAG. The presence of CAD was associated with the rs629301 genotype. Patients with CAD were 78% and 73% (p = 0.007) of the T/T vs. T/G + G/G genotype carriers respectively. T/T genotype was also correlated with the number of stenotic arteries, with a 1.29 (1.04-1.61) risk to have a three-arteries disease. T/T genotype correlated with higher levels of LDL-, non-HDL cholesterol, apoB, apoE and apoCIII, and lower HDL-cholesterol. Logistic Regression confirmed that rs629301was associated with CAD independently from the common risk factors, with a risk similar to that conferred by ten years of age [odds ratios were 1.43 (1.04-1.96) and 1.39 (1.22-1.58) respectively]. CONCLUSIONS: rs629301 risk allele was independently associated with the extension and severity of CAD and positively with apoE and apoB containing lipoproteins.

Basophil Blood Cell Count Is Associated With Enhanced Factor II Plasma Coagulant Activity and Increased Risk of Mortality in Patients With Stable Coronary Artery Disease: Not Only Neutrophils as Prognostic Marker in Ischemic Heart Disease.

Background White blood cell count, which is inexpensive and widely available in clinical practice, has been proposed to provide prognostic information in coronary artery disease (CAD). Elevated levels of white blood cell subtypes may play different roles in atherothrombosis and predict cardiovascular outcomes. Methods and Results The association between white blood cell counts and mortality was evaluated in 823 subjects with angiographically demonstrated and clinically stable CAD in an observational-longitudinal study. The correlation among white blood cell counts and factor II plasma coagulant activity was analyzed in 750 subjects (554 CAD and 196 CAD-free) not taking anticoagulant drugs. Subjects with overt leukocytosis or leukopenia were excluded. In the longitudinal study after a median follow-up of 61 months, 160 (19.4%) subjects died, 107 (13.0%) of whom from cardiovascular causes. High levels of neutrophils, monocytes, eosinophils, and basophils were associated with an increased mortality rate. In multiadjusted Cox regression models, only neutrophils and basophils remained predictors of total and cardiovascular mortality. The associations remained significant after adjustment for traditional cardiovascular risk factors and by including D-dimer and the chemokine CXCL12 in the regression models. Neutrophils and basophils were also significant predictors of factor II plasma coagulant activity variability after adjustment for blood cell counts, age, sex, inflammatory markers, CAD diagnosis, and prothrombin G20210A polymorphism. Factor II plasma coagulant activity was similarly increased in subjects with high neutrophil and basophil counts and in carriers of the prothrombin 20210A allele. Conclusions Both high neutrophil and basophil blood counts may predict mortality in patients with clinically stable CAD and are associated with enhanced factor II plasma coagulant activity, thereby suggesting underlying prothrombotic mechanisms.

Serum Uric Acid Levels, but Not rs7442295 Polymorphism of SCL2A9 Gene, Predict Mortality in Clinically Stable Coronary Artery Disease.

Serum uric acid (SUA) has been associated with cardiovascular disease, but up to now whether SUA is an independent cardiovascular risk factor or merely a disease-related epiphenomenon remains still controversial. within the framework of the Verona Heart Study, we prospectively followed 703 subjects with angiographically demonstrated and clinically stable coronary artery disease between May 1996 and March 2007. At baseline, SUA levels were measured in all the patients. Genotype data of SCL2A9 rs7442295 polymorphism, which has been associated with SUA by genome-wide association studies, were available for 686 subjects (97.6%). After a median follow-up of 57 months, 116 patients (16.5%) had died, 83 (11.8%) because of cardiovascular causes. Patients with hyperuricemia, defined by SUA levels above the 75th percentile (≥0.41 mmol/L), had an increased total and cardiovascular mortality rate than those with SUA below this threshold level (23.3% vs 14.1%, P = 0.048 and 19.4% vs 9.2%, P = 0.001, respectively, by Kaplan-Meier with Log-Rank test). These associations were confirmed by Cox regression after adjustment for sex, age, other predictors of mortality, coronary revascularization, and drug therapies at discharge (hazard ratio for total mortality 1.87 [1.05-3.34], P = 0.033; hazard ratio for cardiovascular mortality 2.09 [1.03-4.25], P = 0.041). Although associated with SUA levels, rs7442295 polymorphism did not predict total or cardiovascular mortality. our data support that SUA may be a prognostic cardiovascular biomarker, predicting total and cardiovascular mortality in the setting of secondary prevention of coronary artery disease. On the other hand, SCL2A9 gene polymorphism, notwithstanding a clear influence on SUA levels, was not associated with mortality.

High Plasma Concentration of Apolipoprotein C-III Confers an Increased Risk of Cerebral Ischemic Events on Cardiovascular Patients Anticoagulated With Warfarin.

INTRODUCTION: Apolipoprotein C-III (Apo CIII) is a crucial regulator of triglyceride-rich lipoproteins (TRLs) and influences the risk of cardiovascular diseases. High levels of Apo CIII have been also associated with cerebrovascular events and earlier works showed procoagulant effects of Apo CIII. The main aim was to assess whether the plasma concentration of Apo CIII could confer an increased risk of cerebral ischemic events in anticoagulated patients at high-risk of cardioembolism. METHODS: We systematically checked medical records and quantified cerebral ischemic events in a selected cohort of 118 subjects [median age 68 with interquartile range (IQR) 59-75 years, 66.9% males, 52.5% with coronary artery disease (CAD)], taking anticoagulant therapy with warfarin because of atrial fibrillation (AF) and/or mechanical prosthetic heart valves. All the subjects, enrolled between May 1999 and December 2006, were prospectively followed until death or July 31, 2018. Assessments of complete plasma lipid and apolipoprotein profiles, including Apo A-I, B, CIII, and E, were available for all subjects at enrollment. RESULTS: After a median follow-up of 109 months (IQR, 58-187), 24 subjects (20.3%) had cerebral ischemic events: stroke (n = 15) and TIA (n = 9). Subjects with plasma concentration of Apo CIII above the median value (10.3 mg/dL) had an about three-fold increased risk of stroke/TIA than those with lower levels of Apo C-III [hazard ratio 3.08 (95%CI, 1.22-7.77)]. This result was confirmed in multiple Cox regression models adjusted for gender, age, CAD, AF, diabetes, hypertension, plasma lipids, and CHA2DS2-VASc score. By stratifying the sample on the basis of Apo CIII level and CHA2DS2-VASc score, an additive effect was observed with the highest risk in subjects with both high Apo C-III concentration and CHA2DS2-VASc score. CONCLUSION: High Apo CIII plasma levels may be associated with an increased risk of ischemic stroke/TIA in high-risk cardiovascular patients anticoagulated with warfarin.