Antiapolipoprotein A-1 Autoantibody Positivity Is Associated with Threatened Abortion.

BACKGROUND: Autoantibodies against apolipoprotein A-1 (anti-ApoA-1 IgG) were demonstrated to be associated with cardiovascular outcomes in several inflammatory diseases. As balanced inflammation is critical for uncomplicated pregnancy, we aimed to investigate the prevalence of anti-ApoA-1 IgG and anti-c-terminal ApoA-1 autoantibodies (Ac-terAA1 IgG) in a cohort of pregnant women and their potential relationship with threatened abortion (TA). METHODS: Between 2012 and 2014, 371 consecutive outpatient pregnant women were included in this study and followed until delivery. Anti-ApoA-1 and anti-Ac-terAA1 IgG were measured by ELISA technique on serum samples collected between the 24th and 26th week of pregnancy. Associations with TA were tested using linear regression analysis and C-statistics. RESULTS: Median age was 34 with a prevalence of the Caucasian ethnicity (90.5%). TA occurred in 10 women (2.7%). C-statistics indicated that anti-ApoA-1 and anti-Ac-terAA1 IgG levels upon study inclusion were predictive of TA (0.73, 95% confidence interval [CI] 0.69-0.78, p < 0.001 and 0.76, 95% CI 0.71-0.80, p < 0.001 and 0.76, 95% CI 0.71-0.80, p < 0.001 and 0.76, 95% CI 0.71-0.80, p < 0.001 and 0.76, 95% CI 0.71-0.80. CONCLUSION: Anti-ApoA-1 and anti-Ac-terAA1 IgG are independently associated with TA during pregnancy with an appealing NPV. The causal biological mechanisms underlying this association as well as the possible clinical relevance of these findings require further investigations.

Atherosclerosis in Rheumatoid Arthritis: Promoters and Opponents.

Substantial epidemiological data identified cardiovascular (CV) diseases as a main cause of mortality in patients with rheumatoid arthritis (RA). In light of this, RA patients may benefit from additional CV risk screening and more intensive prevention strategies. Nevertheless, current algorithms for CV risk stratification still remain tailored on general population and are burdened by a significant underestimation of CV risk in RA patients. Acute CV events in patients with RA are largely related to an accelerated atherosclerosis. As pathophysiological features of atherosclerosis overlap those occurring in the inflamed RA synovium, the understanding of those common pathways represents an urgent need and a leading challenge for CV prevention in patients with RA. Genetic background, metabolic status, gut microbiome, and systemic inflammation have been also suggested as additional key pro-atherosclerotic factors. The aim of this narrative review is to update the current knowledge about pathophysiology of atherogenesis in RA patients and potential anti-atherosclerotic effects of disease-modifying anti-rheumatic drugs.

Diabetes and Vascular Disease: Is It All About Glycemia?

BACKGROUND: Diabetes is increasing over time, mainly driven by obesity, aging, and urbanization. Classical macro- and microvascular complications represent the final result of a complex interplay involving atherosclerosis at all stages. METHODS: In this review, we aim at focusing on current updates in the pathophysiology of vascular disease in diabetes and discussing how new therapies might influence the management of these patients at high cardiovascular risk. Diabetes shows accelerated atherosclerosis with a larger inflammatory cell infiltrate, thus favoring the development of heart failure. 'Diabetic cardiomyopathy' perfectly describes a specific ischemia- and hypertension- independent entity due to diabetes-related metabolic alterations on myocardial function. Moreover, platelets from subjects with diabetes display a typical hyperreactivity explaining the stronger adhesion, activation, and aggregation. Additionally, diabetes provokes an exaggerated stimulation of the endothelium, with an increased release of reactive oxygen species and a reduced release of nitric oxide, both key elements of the endothelial dysfunction. Also, the coagulation cascade and leukocytes activate contributing to this pro-thrombotic environment. Neutrophils have been recently recognized to play a pivotal role by releasing neutrophil extracellular traps. Finally, microparticles from platelets, neutrophils or monocytes are detrimental effectors on the vessel wall and are involved both in vascular dysfunction and in thrombotic complications. CONCLUSION: In light of these findings, the therapeutic management of diabetes needs to be mostly focused on limiting the progression of complications by targeting precise pathophysiological mechanisms rather than the mere glycemic control, which failed to markedly reduce the risk for macrovascular complications and mortality.

Baseline serum levels of osteopontin predict clinical response to treatment with nivolumab in patients with non-small cell lung cancer.

Treatment with nivolumab improves survival and response rate in non-small cell lung cancer (NSCLC). Nevertheless, due to its high financial cost, identifying predictors of response to treatment has become an urgent need. Here, we focused on serum osteopontin (OPN), a pleiotropic protein overexpressed in lung cancer and involved in the immune response. A cohort of NSCLC patients (n = 72) treated with nivolumab was enrolled. Blood samples were collected at the time of first five nivolumab administrations. OPN and high-sensitivity C-reactive protein (hs-CRP) were assayed at each time point. The primary endpoint was to assess the predictive value of baseline serum levels of OPN towards overall survival (OS). Secondary endpoints included the potential association between OPN, hs-CRP and response to nivolumab. OPN and hs-CRP correlate with each other, with neutrophil count and biochemical markers of metastatic disease. At baseline, serum OPN increased with increasing Eastern Cooperative Oncology Group scale of Performance Status (ECOG PS). When Eastern Cooperative Oncology Group scale of Performance Status) (RECIST) criteria were considered, high baseline OPN levels were associated with a worse response to nivolumab. Cox hazard regression further confirmed baseline serum OPN as a predictor of mortality with the best predictive accuracy for serum levels above 37.7 ng/mL. Patients above the cut-off value had a higher mortality rate as compared to low serum OPN levels during follow up. Serum OPN may have a predictive role in NSCLC patients treated with nivolumab. Although larger confirmatory studies are needed, measuring serum OPN levels at baseline can be a clinically useful tool in a near future.

Serum PCSK9 levels at the second nivolumab cycle predict overall survival in elderly patients with NSCLC: a pilot study.

Monoclonal antibodies targeting PD-1 are used for treating NSCLC. To date, proprotein convertase subtilisin/kexin type 9 (PCSK9) has been poorly investigated in the oncologic field. Here, we aimed at evaluating whether serum PCSK9 might represent a predictive factor for OS in older patients with advanced NSCLC under nivolumab treatment. Among 78 patients with advanced, pre-treated NSCLC previously enrolled in a prospective study at Ospedale Policlinico San Martino in Genoa (Italy), 44 patients have been included in this sub-analysis due to the availability of serum samples for the measurement of PCSK9. Before each nivolumab administration, clinical information and blood samples were collected. Median age was 71, with a prevalence of the male sex. The most represented histological type of lung cancer was adenocarcinoma. The majority of patients were former smokers (72.1%). Median PCSK9 levels were 123.59 (86.32-169.89) ng/mL and 117.17 (80.46-147.79) ng/mL at cycle 1 and 2, respectively. Based on a receiver operating characteristic curve analysis, a PCSK9 value at cycle 2 of 95 ng/mL was found as the best cutoff point for OS. Kaplan-Meier analysis demonstrated that patients below the PCSK9 cutoff (< 95 ng/mL) experienced a better OS, as confirmed by Cox proportional hazard regression analysis. In this pilot study, circulating levels of PCSK9 < 95 ng/mL at the time of the second cycle of nivolumab treatment could independently predict a better OS in elderly patients with advanced, pre-treated NSCLC. However, further studies are warranted to validate these preliminary results.

Baseline hs-CRP predicts hypertension remission in metabolic syndrome.

BACKGROUND: Inflammation, overweight and other cardiovascular risk factors might negatively impact on hypertension remission in metabolic syndrome (MetS), independently of the pharmacological treatment. Here, the potential influence of systemic inflammation (assessed by serum high-sensitivity C-reactive protein [hs-CRP]) on hypertension remission will be investigated in a cohort of hypertensive patients with MetS. MATERIAL AND METHODS: Hypertensive patients with MetS (n = 100) were enrolled, treated under current behavior/dietary/pharmacological recommendations and followed up for 12 months. All patients received medications and nutritional advice based on Mediterranean-like dietary pattern in addition to psychological and physical activity counselling. At baseline (T0), 6 (T1) and 12 (T2) months of follow-up, clinical data, haematological and biochemical profiles and serum hs-CRP were measured. RESULTS: As compared to T0, at T2 patients displayed improvements in anthropometric and metabolic profiles. At T2, the hypertension remission rate was 13.0%. Serum hs-CRP did not change overtime in the overall cohort. Surprisingly, patients who experienced hypertension remission were less treated with antihypertensive drugs, but developed a weak improvement in anthropometric measures during follow-up. The hypertension remission group had lower baseline levels of hs-CRP as compared to non-remission. Low baseline hs-CRP (<2 µg/mL, cut-off value identified by ROC curve) predicted hypertension remission, independently of antihypertensive treatment implementation, baseline systolic blood pressure and waist circumference improvement. CONCLUSIONS: Remission of hypertension in MetS is independently associated with baseline low CRP levels, which might suggest a critical role for inflammation in sustaining high blood pressure levels.

Impact of different ectopic fat depots on cardiovascular and metabolic diseases.

A growing body of evidence is pointing out the pathophysiological role of fat accumulation in different organs. Ectopic fat depots within heart, liver, skeletal muscle, kidney, and pancreas as well as around blood vessels might be more associated to cardiometabolic risk than classical variables, such as body mass index. Among different mechanisms, lipid metabolism appears to be particularly influenced by ectopic fat depots. Indeed, intracellular accumulation of nonesterified fatty acids, and triglycerides promotes endoplasmic reticulum stress, mitochondrial uncoupling, oxidative stress, and altered membrane composition/function, finally promoting inflammatory response and cell death. The dysfunctional adipose tissue was shown to induce both local and systemic effects, with relevant clinical consequences. Epicardial fat and myocardial steatosis have been associated with the development of atrial fibrillation and ventricular dysfunction. Similarly perivascular adipose tissue appears to trigger atherosclerosis and hypertension. Nonalcoholic fatty liver disease has been recognized both as the hepatic manifestation of metabolic syndrome and as a cardiovascular (CV) risk factor. Importantly, the renal sinus fat emerged as a potential player in kidney dysfunction. Finally, both skeletal muscle and pancreatic fat depots have been indicated as potential endocrine modulators of insulin resistance. Considering the global rise in the prevalence of obesity, the understanding of mechanisms underlying ectopic fat accumulation represents an urgent need, with potential clinical implications for CV risk stratification. Here, we attempt to update the current knowledge of the different ectopic fat depots, focusing on underlying mechanisms and potential clinical implications.

Baseline neutrophil-to-lymphocyte ratio is associated with long-term T2D remission after metabolic surgery.

AIMS: Metabolic surgery is considered as a therapeutic option for obese patients with type 2 diabetes (T2D). In order to identify novel laboratory variables that could improve the selection of patients who might greatly benefit from a surgical approach, we focused on the neutrophil-to-lymphocyte ratio (NLR) as a predictor of long-term T2D remission following metabolic surgery. METHODS: Thirty-one obese patients with T2D included in this pilot study underwent Roux-en-Y gastric bypass or biliopancreatic diversion (BPD) at the Surgical Department of Genoa University, IRCCS Ospedale Policlinico San Martino in Genoa (Italy). Before surgery, serum samples were collected to evaluate blood count, glycemic profile, and circulating neutrophil degranulation products. RESULTS: The median age was 56 years, median body mass index (BMI) was 32.37 kg/m2, and median glycated hemoglobin was 8.4%. White blood cell count was in a range of normality, with a median NLR of 1.97. By a receiver operating characteristic curve analysis, NLR has been found to be significantly associated with T2D remission at 1, 3, and 5 years and the best cutoff of ≤ 1.97 has been identified by Youden index. When comparing study groups according to NLR cutoff, those with NLR ≤ 1.97 were older and underwent more often BPD. By a logistic regression analysis, NLR ≤ 1.97 has been found to predict T2D remission across 5 years, irrespective of baseline BMI. CONCLUSIONS: A baseline low NLR is associated with long-term T2D remission in obese patients undergoing metabolic surgery, suggesting that circulating inflammatory cells (i.e., neutrophils) might negatively impact on T2D remission.

Novel findings in neutrophil biology and their impact on cardiovascular disease.

Neutrophils are the most abundant circulating leucocytes in healthy humans. These cells are central players during acute inflammatory responses, although a growing body of evidence supports a crucial role in chronic inflammation and chemokines and cytokines related to it as well. Thus, both humoral and cellular components are involved in the development of plaque formation and atherosclerosis. Accordingly, CANTOS trial using an interleukin-1 beta antibody confirmed that inflammatory cytokines contribute to the occurrence of myocardial infarction and cardiac death independent of changes in lipids. Recent data revealed that neutrophils are a heterogeneous population with different subsets and functional characteristics (i.e. CD177+ cells, OLFM4+ neutrophils, proangiogenic neutrophils, neutrophils undergoing reverse migration, and aged neutrophils). Importantly, neutrophils are able to synthesize de novo proteins. Neutrophil extracellular trap generation and NETosis have been considered as very important weapons in sterile inflammation. Neutrophil-derived microvesicles represent another mechanism by which neutrophils amplify inflammatory processes, being found at high levels both at the site of injury and in the bloodstream. Finally, neutrophil aging can influence their functions also in relation with host age. These recent acquisitions in the field of neutrophil biology might pave the way for new therapeutic targets to prevent or even treat patients experiencing cardiovascular (CV) diseases. Here, we discuss novel findings in neutrophil biology, their impact on CV and cerebrovascular diseases, and the potential implementation of these notions into daily clinical practice.

Serum osteopontin negatively impacts on intima-media thickness in patients with systemic lupus erythematosus.

BACKGROUND: Ultrasound evaluation of carotid intima-media thickness (cIMT) has been extensively used for potentially improving cardiovascular (CV) risk stratification in several patients' categories. Subjects with systemic lupus erythematosus (SLE) have been investigated by both imaging and molecular biomarker approaches with contrasting results. Here, we focused on the role of osteopontin (OPN) as biomarker of subclinical atherosclerosis associated with SLE. MATERIALS AND METHODS: Eighty females (age 18-65 years) affected by SLE and eighty age-matched healthy female controls without a clinical history of CV disease underwent ultrasound evaluation of cIMT and blood sample assay of high-sensitivity C-reactive protein (hs-CRP) and OPN. RESULTS: Healthy controls and SLE patients significantly differed for CV risk factors (ie, waist circumference, hypertension and dyslipidaemia) and the inflammatory status. Noteworthy, an opposite association between cIMT and OPN was observed in the two study groups. Whereas OPN was positively associated with mean cIMT (r = 0.364; P = 0.001) in SLE patients, a negative correlation was found in healthy controls. Furthermore, in SLE patients increased circulating levels of OPN were associated with the use of hydroxychloroquine and the positivity for the anti-dsDNA autoantibodies. At linear regression analysis, only OPN remained independently associated with cIMT also after adjustment for age, smoking pack-year, Heart SCORE, disease length and steroid therapy length. CONCLUSIONS: These results indicate that serum OPN levels were strongly associated with subclinical atherosclerosis in patients with LES and it might be a useful CV biomarker that requires additional validation in larger trials.

Impact of Red Wine Consumption on Cardiovascular Health.

BACKGROUND: The devastating effects of heavy alcohol drinking have been long time recognized. In the last decades, potential benefits of modest red wine drinking were suggested. In European countries in which red wide intake is not negligible (such as France), the association between cholesterol and cardiovascular (CV) risk was less evident, suggesting the action of some protective molecules in red wine or other foods and drinks. METHODS: This narrative review is based on the material searched for and obtained via PubMed up to May 2016. The search terms we used were: "red wine, cardiovascular, alcohol" in combination with "polyphenols, heart failure, infarction". RESULTS: Epidemiological and mechanistic evidence of a J-shaped relationship between red wine intake and CV risk further supported the "French paradox". Specific components of red wine both in vitro and in animal models were discovered. Polyphenols and especially resveratrol largely contribute to CV prevention mainly through antioxidant properties. They exert beneficial effects on endothelial dysfunction and hypertension, dyslipidemia, metabolic diseases, thus reducing the risk of adverse CV events such as myocardial infarction ischemic stroke and heart failure. Of interest, recent studies pointed out the role of ethanol itself as a potential cardioprotective agent, but a clear epidemiological evidence is still missing. The aim of this narrative review is to update current knowledge on the intracellular mechanism underlying the cardioprotective effects of polyphenols and ethanol. Furthermore, we summarized the results of epidemiological studies, emphasizing their methodological criticisms and the need for randomized clinical trials able to clarify the potential role of red wine consumption in reducing CV risk. CONCLUSION: Caution in avowing underestimation of the global burden of alcohol-related diseases was particularly used.

Pre-surgery age-adjusted Charlson Comorbidity Index is associated with worse outcomes in acute cholecystitis.

BACKGROUND: Beneficial effects of cholecystectomy in acute cholecystitis (AC) might be weakened by complications. The age-adjusted Charlson Comorbidity Index (CCI) assesses disease relevance in the prediction of one-year mortality. AIMS: To evaluate whether age-adjusted CCI predicted complications (including surgical complications, intensive care unit [ICU] admission, and in-hospital death) among patients undergoing cholecystectomy for AC. Associations between age-adjusted CCI and the length of hospital stay have been also evaluated. METHODS: 271 patients were enrolled at Ospedale Policlinico San Martino (Genoa, Italy) between 2005 and 2013. Clinical data and blood samples were collected. RESULTS: Patients' median age was 67 years. They underwent more frequently video-laparoscopic cholecystectomy with a limited rate of conversion to open cholecystectomy. Surgical complications occurred in 23 patients (8.5%). 6 patients (2.2%) needed ICU admission, while death occurred in 4 patients (1.5%). According to the cut-off point identified by ROC curve, an age-adjusted CCI cut-off value of 5 was found predictive for in-hospital complications also when confounders were considered (OR 1.35, 95% CI 1.02-1.79, p = 0.035). No association between adjusted CCI and the length of hospital stay was found. CONCLUSIONS: In patients surgically treated for AC, age-adjusted CCI could represent an additional tool, along with available risk scores, to help surgeons in choosing the best therapeutic option.

Radiologic Cerebral Reperfusion at 24 h Predicts Good Clinical Outcome.

Cerebral reperfusion and arterial recanalization are radiological features of the effectiveness of thrombolysis in acute ischemic stroke (AIS) patients. Here, an investigation of the prognostic role of early recanalization/reperfusion on clinical outcome was performed. In AIS patients (n = 55), baseline computerized tomography (CT) was performed ≤ 8 h from symptom onset, whereas CT determination of reperfusion/recanalization was assessed at 24 h. Multiple linear and logistic regression models were used to correlate reperfusion/recanalization with radiological (i.e., hemorrhagic transformation, ischemic core, and penumbra volumes) and clinical outcomes (assessed as National Institutes of Health Stroke Scale [NIHSS] reduction ≥ 8 points or a NIHSS ≤ 1 at 24 h and as modified Rankin Scale [mRS] < 2 at 90 days). At 24 h, patients achieving radiological reperfusion were n = 24, while the non-reperfused were n = 31. Among non-reperfused, n = 15 patients were recanalized. Radiological reperfusion vs. recanalization was also confirmed by early increased levels of circulating inflammatory biomarkers (i.e., serum osteopontin). In multivariate analysis, ischemic lesion volume reduction was associated with both recanalization (ß = 0.265; p = 0.014) and reperfusion (ß = 0.461; p < 0.001), but only reperfusion was independently associated with final infarct volume (ß = - 0.333; p = 0.007). Only radiological reperfusion at 24 h predicted good clinical response at day 1 (adjusted OR 16.054 [1.423-181.158]; p = 0.025) and 90-day good functional outcome (adjusted OR 25.801 [1.483-448.840]; p = 0.026). At ROC curve analysis the AUC of reperfusion was 0.777 (p < 0.001) for the good clinical response at 24 h and 0.792 (p < 0.001) for 90-day clinical outcome. Twenty-four-hour radiological reperfusion assessed by CT is associated with good clinical response on day 1 and good functional outcome on day 90 in patients with ischemic stroke.

Epicardial adipose tissue and cardiovascular diseases.

Obesity is a heterogeneous disease with different degrees of cardiovascular (CV) and metabolic manifestations. Certain ectopic fat depots may contribute to obesity-related CV risk and may explain part of the risk differential observed in metabolically healthy obese and the so called "obesity paradox". The growing interest towards the potential impact of epicardial adipose tissue (EAT) in cardiovascular (CV) risk has led to deepen its biological function. Genetic, epigenetic and environmental factors may drive the shift towards a dysfunctional EAT characterized by a pro-inflammatory and pro-fibrotic phenotype. Due to the close anatomic proximity to coronary arteries, a thicker and dysfunctional EAT actively contribute to development and progression of coronary atherosclerosis. Beside classical paracrine transmission, EAT may directly release mediators into the vasa vasorum of the coronary arterial wall, a mechanism referred to as "vasocrine". Similarly, the pro-inflammatory and pro-fibrotic secretome characterizing dysfunctional EAT may impair cardiac structure and function, thus being implicated in the pathogenesis of diastolic heart failure and atrial fibrillation. The development of 3D imaging techniques have paved the way for clarifying the causative role of EAT in CV pathophysiology, the use of EAT volume/thickness in CV risk stratification and potential cardio-protective effects of EAT reduction. The aim of this narrative review is to update current knowledge on the pathophysiological functions of EAT, focusing on basic mechanisms and potential clinical implications.

C-Reactive Protein Levels at the Midpregnancy Can Predict Gestational Complications.

Although essential for a successful pregnancy, a growing body of evidence suggests that maternal inflammation, when dysregulated, may represent a risk factor for both maternal and neonatal outcomes. Here, we assessed the accuracy of maternal C-reactive protein (CRP) concentrations at the middle phase of pregnancy in the identification of maternal adverse outcomes (MAO) until delivery. A correlation between CRP and a complicated pregnancy including both maternal and neonatal adverse outcomes has been investigated, too. In this retrospective study, conducted at the Diabetology Unit of IRCCS Ospedale Policlinico San Martino, Genoa (Italy), 380 outpatient pregnant women have been enrolled at the prenatal visit before performing a 75 g oral glucose tolerance test at 24th-26th gestational week for gestational diabetes mellitus (GDM) screening. Demographic, medical, and reproductive history has been obtained by verbal interview. Data about pregnancy and delivery have been retrieved from medical records. The median value of maternal baseline serum CRP was 3.25 µg/mL. Women experiencing MAO were older, more frequently suffering from hypertension, and showed higher CRP concentrations, with a cutoff value >1.86 µg/mL found by a ROC curve analysis to be accurately predictive for MAO. By a logistic regression analysis, serum CRP levels >1.86 µg/mL have been found to predict MAO also considering maternal age, hypertension, and GDM. Maternal CRP levels have been positively associated with overall pregnancy adverse outcomes (maternal and neonatal), too. In conclusion, in pregnant women serum levels of CRP can early recognize subjects at higher risk for maternal and neonatal complications needing a more stringent follow-up.

Resistin exerts a beneficial role in atherosclerotic plaque inflammation by inhibiting neutrophil migration.

BACKGROUND: Neutrophil functions have been shown to be modulated by adipocytokines during atherogenesis. The immuno-regulatory role of resistin on neutrophil-mediated activities in atherosclerotic patients remains elusive. Here, we aimed at exploring the association between serum levels of resistin and neutrophil products either in the systemic circulation or within plaques in a cohort of patients with severe carotid plaque stenosis undergoing endarterectomy. In addition, we assessed the effects of resistin on neutrophil pro-atherosclerotic functions in vitro. METHODS: Inflammatory biomarkers, neutrophil products and resistin levels were assessed in patients' sera and carotid plaques by ELISA and immunohistochemistry analysis. In vitro, human primary neutrophils isolated from healthy donors were assessed on different substrate cultures for: degranulation (by ELISA), migration (by microchemotaxis Boyden chamber), F-actin polymerization (by fluorescent assay), integrin and chemokine receptor expression (by flow cytometry) and apoptosis (by both morphologic analysis and flow cytometry). RESULTS: Serum resistin was positively correlated with serum levels of neutrophil granule products, but inversely with intraplaque neutrophil and MMP-9 contents. In vitro, resistin was detected in supernatants of degranulating neutrophils and positively correlated with other granule products. Although resistin did not affect neutrophil degranulation, apoptosis and integrin or chemokine receptor expression, pre-incubation with human recombinant resistin abrogated CXCL8-induced neutrophil migration and F-actin polymerization by inhibiting ERK2 phosphorylation. CONCLUSION: Resistin can be released by degranulating neutrophils and blunts neutrophil plaque infiltration by modulating their migration towards known atherosclerotic mediators. These results suggest a potential immunoregulatory role of resistin in inhibiting neutrophil-mediated atherosclerotic activities.

Reduction in TIMP-2 serum levels predicts remission of inflammatory bowel diseases.

BACKGROUND: Growing evidence indicates tissue inhibitors of matrix metalloproteinases (TIMPs) as potential players in inflammatory bowel disease (IBD), but, no prospective data are available in IBD remission/relapse. MATERIAL & METHODS: In this prospective pilot study, a cohort of IBD patients (n = 32) was enrolled and treated with monoclonal anti-TNF-α antibodies. Patients were clinically followed up for a median period of 54 weeks. Serum circulating levels of C-reactive protein (CRP), TIMP-1 and -2, matrix metalloproteinase (MMP)-9 and -8, myeloperoxidase (MPO) and neutrophil elastase (NE) were assessed by ELISA at enrolment and at the end of the treatment. RESULTS: The percentage (%) TIMP-2 reduction from baseline to end of treatment was independently associated with IBD remission at the end of treatment and follow-up as well. ROC curve analysis further confirmed the good prognostic accuracy of % TIMP-2 reduction over the treatment period. Conversely, no other change in inflammatory molecule concentrations was able to predict short- or long-term IBD remission. CONCLUSIONS: This study indicates TIMP-2 reduction during IBD treatment with monoclonal anti-TNF-α antibodies as a potential prognostic parameter of short and long term remission. To understand if TIMP-2 is an innocent biomarker or an active pathophysiological factor in IBD remains to be clarified.

Serum PCSK9 levels predict the occurrence of acute coronary syndromes in patients with severe carotid artery stenosis.

BACKGROUND: The pharmacological inhibition of Proprotein Convertase Subtilisin/Kexin type 9 (PCSK9) has shown to dramatically impact on low-density lipoprotein-cholesterol (LDL-C) levels and associated cardiovascular (CV) diseases. However, the potential use of PCSK9 serum levels as a CV risk biomarker remains to be clarified. METHODS: 189 patients with severe carotid artery atherosclerosis undergoing carotid endarterectomy (CEA) and whose clinical records and serum sample aliquots for PCSK9 level measurement were available both directly before CEA and at 24-month follow-up were included in the present pilot study. The study endpoint was to determine whether PCSK9 serum levels prior to CEA would predict the occurrence of acute coronary syndromes (ACS) at 24-month follow-up. RESULTS: PCSK9 serum levels were significantly accurate in predicting ACS at 24-month follow-up, as assessed by ROC curve analysis (AUC: 0.719 [95% CI 0.649-0.781]). According to the cut-off point indicated by Youden's index, PCSK9 values >431.3 ng/mL were correlated with a higher risk of ACS occurrence (Log Rank test, p = 0.0003). At Cox regression analysis, the predictive ability of high serum PCSK9 was confirmed also after adjustment for age, gender, baseline statin treatment and active smoking, dyslipidemia, and chronic coronary artery disease (HR 17.04 [95% CI 3.34-86.81]; p = 0.001). CONCLUSIONS: High serum PCSK9 levels predict ACS occurrence at 24-month follow-up after CEA in patients with severe carotid artery stenosis. Larger clinical studies are needed to evaluate whether PCSK9 serum levels could be used towards predicting the risk of ACS in patients with advanced carotid atherosclerosis.

Serum adiponectin levels predict acute coronary syndrome (ACS) in patients with severe carotid stenosis.

As endocrine organ, adipose tissue may modulate inflammatory response by releasing a wide range of mediators, known as adipocytokines. Due to the complex balance between pro- and anti-inflammatory activity their pathophysiological and prognostic role in cardiovascular (CV) diseases still remains debated. Here, we consider the potential associations of circulating adipocytokines adiponectin, leptin and their ratio (LAR), with metabolic and inflammatory profiles in 217 patients with severe carotid stenosis. A prospective analysis investigating their predictive role toward acute coronary syndromes (ACS) was also drawn over a 12-month follow-up period. Serum leptin was positively associated with fasting insulinemia and HOMA-IR, but not with lipid profile and inflammation. Conversely, adiponectin was negatively associated with glucose, insulin, HOMA-IR, triglycerides and both systemic and intraplaque inflammatory markers whereas a positive association with high-density lipoprotein cholesterol (HDL-c) was observed. Accordingly, a significant association with metabolic profile was reported for LAR. According to the cut-off point identified by ROC curve, adiponectin values≤2.56µg/mL were correlated with a higher risk of ACS occurrence at 12months' follow-up (p-value for Log Rank test=0.0003). At Cox regression analysis the predictive ability of low serum adiponectin was confirmed also after adjustment for age, male gender and diabetes. In conclusion, adiponectin may be considered a biomarker of metabolic compensation, inversely associated with chronic low-grade inflammation. Circulating adiponectin is also associated with lower risk of adverse CV events in patients with severe carotid stenosis.