Reduced incidence of cardiovascular events in hyper-Lp(a) patients on lipoprotein apheresis. The G.I.L.A. (Gruppo Interdisciplinare Aferesi Lipoproteica) pilot study.

BACKGROUND: Lipoprotein apheresis (LA) is the elective therapy for homozygous and other forms of Familial Hypercholesterolemia, Familial Combined Hypercholesterolemia, resistant/intolerant to lipid lowering drugs, and hyper-lipoproteinemia(a). Lipoprotein(a) [Lp(a)] has been classified as the most prevalent genetic risk factor for coronary artery disease and aortic valve stenosis. AIM: Our multicenter retrospective study has the aim to analyze the incidence of adverse cardiovascular events (ACVE) before and during the LA treatment, in subjects with elevated level of Lp(a) (>60 mg/dL) [hyper-Lp(a)] and chronic ischemic heart disease. METHODS: We collected data of 23 patients (mean age 63 ± 9 years, male 77%; from hospital of Pisa 11/23, Pistoia 7/23, Verona 2/23, Padova 2/23 and Ferrara 1/23), with hyper-Lp(a), pre-apheresis LDL-cholesterol <100 mg/dL, cardiovascular disease, on maximally tolerated lipid lowering therapy and LA treatment (median 7 years, interquartile range 3-9 years). The LA treatment was performed by heparin-induced LDL precipitation apheresis (16/23), dextran-sulphate (4/23), cascade filtration (2/23) and immunoadsorption (1/23). The time lapse between first cardiovascular event and beginning of apheresis was 6 years (interquartile range 1-12 years). RESULTS: The recorded ACVE, before and after the LA treatment inception, were 40 and 10 respectively (p < 0.05), notably, the AVCE rates/year were 0.43 and 0.11 respectively (p < 0.05) with a 74% reduction of event occurrence. CONCLUSIONS: Our data confirm long-term efficacy and positive impact of LA on morbidity in patients with hyper-Lp(a) and chronic ischemic heart disease on maximally tolerated lipid lowering therapy.

Sudden hearing loss and Crohn disease: when Cogan syndrome must be suspected.

Cogan's syndrome is a rare systemic vasculitis of unknown origin. It is characterized by the presence of worsening audiovestibular and ocular symptoms that may manifest simultaneously or sequentially. No specific diagnostic laboratory tests or imaging studies exist. The diagnosis is clinical and should be established as early as possible so as to initiate prompt treatment with steroids and prevent rapid progression to deafness or blindness and potentially fatal systemic involvement. We report a case of association between Cogan's syndrome and ileal Crohn's disease which we believe deserves attention since, after an accurate review of the literature, we have found approximately 250 reports of patients with Cogan's syndrome, only 13 of whom with concurrent chronic inflammatory bowel disease; of these 13 cases, none experienced improvement after therapy. In the light of the good outcome obtained in our case, we proposed a valid treatment option with boluses of steroids, combined with early systemic immunosuppression and intra-tympanic steroid injections.

[Dyslipidemia: news in diagnosis and drug therapy]. / Dislipidemie: attualita' in diagnosi e terapia farmacologica.

Plasma lipid levels are to a large extent determined by genetic factors. In its more extreme forms this is manifested as familial hyperlipidemias, which are an important cause of premature coronary heart disease. It has been demonstrated that rigorous treatment of familial forms reduces the burden of ischemic heart disease. Statins are among the most studied drugs in cardiovascular prevention; a number of large-scale clinical trials have demonstrated that statins substantially reduce cardiovascular morbidity and mortality in both primary and secondary prevention. The currently available evidence suggests that the clinical benefit is largely independent of the type of statin, but depends on the extent of LDL-C lowering. When the most potent statins are insufficient, LDL-C apheresis should be used.

Functional lecithin: cholesterol acyltransferase is not required for efficient atheroprotection in humans.

BACKGROUND: Mutations in the LCAT gene cause lecithin:cholesterol acyltransferase (LCAT) deficiency, a very rare metabolic disorder with 2 hypoalphalipoproteinemia syndromes: classic familial LCAT deficiency (Online Mendelian Inheritance in Man No. 245900), characterized by complete lack of enzyme activity, and fish-eye disease (Online Mendelian Inheritance in Man No. 136120), with a partially defective enzyme. Theoretically, hypoalphalipoproteinemia cases with LCAT deficiency should be at increased cardiovascular risk because of high-density lipoprotein deficiency and defective reverse cholesterol transport. METHODS AND RESULTS: The extent of preclinical atherosclerosis was assessed in 40 carriers of LCAT gene mutations from 13 Italian families and 80 healthy controls by measuring carotid intima-media thickness (IMT). The average and maximum IMT values in the carriers were 0.07 and 0.21 mm smaller than in controls (P=0.0003 and P=0.0027), respectively. Moreover, the inheritance of a mutated LCAT genotype had a remarkable gene-dose-dependent effect in reducing carotid IMT (P=0.0003 for average IMT; P=0.001 for maximum IMT). Finally, no significant difference in carotid IMT was found between carriers of LCAT gene mutations that cause total or partial LCAT deficiency (ie, familial LCAT deficiency or fish-eye disease). CONCLUSIONS: Genetically determined low LCAT activity in Italian families is not associated with enhanced preclinical atherosclerosis despite low high-density lipoprotein cholesterol levels. This finding challenges the notion that LCAT is required for effective atheroprotection and suggests that elevating LCAT expression or activity is not a promising therapeutic strategy to reduce cardiovascular risk.

Inhibitory effects of fenofibrate on apoptosis and cell proliferation in human endothelial cells in high glucose.

Fenofibrate has beneficial effects on the progression and clinical emergence of atherosclerosis in normoglycemic and in diabetic patients. Given the involvement of endothelium in these processes, we speculated that fenofibrate may influence endothelial cell apoptosis and proliferation, regulators of endothelium integrity. Fenofibrate effects on apoptosis and proliferation were studied in human umbilical vein endothelial cells under normal (5.5 mmol/l, NG) and high (22 mmol/l, HG) glucose with or without fenofibrate (50 micromol/l). Apoptosis was evaluated by annexin V, by poly(ADP-ribose) polymerase protein cleavage, and cyclooxygenase-2 (COX-2), Bax/Bcl-2, and p53 protein levels; proliferation was assessed by determining cell cycle phase distribution and the amounts of the cell cycle regulators E2F1, cyclin D1, E1, and A and the levels of the hyper-phosphorylated form of the retinoblastoma protein (ppRb). HG resulted in increased (p<0.05) apoptosis rate associated with COX-2 protein overexpression, without modification of Bax/Bcl2 ratio and p53 levels. Fenofibrate decreased apoptosis and normalized increased COX-2 expression in HG (p<0.05). Both in HG and NG, fenofibrate dramatically reduced cell proliferation (p<0.05) through a G1/G0 block mediated by the reduction in ppRb and the decrease in E2F1, cyclin E1, A, and D1 protein expression, with a mechanism that, for cyclin E1, occurred at the posttranscriptional level. In conclusion, our data show that fenofibrate reduces apoptosis caused by HG but severely interferes with endothelial cell proliferation both in NG and HG. The resulting effect may influence endothelium integrity in vivo and may impact the outcome of acute complications of atherosclerosis in diabetes.

Metformin and aspirin treatment could lead to an improved survival rate for Type 2 diabetic patients with stage II and III colorectal adenocarcinoma relative to non-diabetic patients.

Metformin, the drug of choice in the treatment of type 2 diabetes mellitus (DM2), in addition to aspirin (ASA), the drug prescribed for cardioprotection of diabetic and non-diabetic patients, have an inhibitory effect on cancer cell survival. The present population-based study conducted in the province of Trieste (Italy), aimed to investigate the prevalence of DM2 in patients with colorectal adenocarcinoma (CRC) and survival for CRC in diabetic and nondiabetic patients. All permanent residents diagnosed with a CRC between 2004 and 2007 were ascertained through the regional health information system. CRC-specific and relative survival probabilities were computed for each group of patients defined by CRC stage, presence or absence of DM2 treated with metformin, and presence or absence of daily ASA therapy. A total of 515 CRC patients without DM2 and 156 with DM2 treated with metformin were enrolled in the study. At the time of CRC diagnosis, 71 (14%) nondiabetic and 39 (25%) diabetic patients were taking ASA daily. The five-year relative survival for stage III CRC was 101% [95% confidence interval (CI)=76-126] in the 18 patients with DM2 treated with metformin and ASA, 55% (95% CI=31-78) in the 23 without DM2 treated with ASA, 55% (95% CI=45-65) in the 150 without DM2 not taking ASA, and 29% (95% CI=13-45) in the 43 with DM2 treated with metformin, however not with ASA. The findings support the hypothesis of a possible inhibitory effect of metformin and ASA on CRC cells. Randomized controlled trials are required to verify this hypothesis.

Relationships between desacylated and acylated ghrelin and insulin sensitivity in the metabolic syndrome.

CONTEXT: Metabolic syndrome shows clustered metabolic abnormalities with major roles for insulin resistance and obesity. Ghrelin is a gastric hormone whose total plasma concentration (T-Ghr) is associated positively with insulin sensitivity and is reduced in obesity. Ghrelin circulates in acylated (A-Ghr) and desacylated (D-Ghr) forms, but their potential differential associations with insulin resistance and whether they are differentially altered in obesity remain undefined. OBJECTIVE: Our objective was to determine potential differential associations of ghrelin forms with insulin resistance [homeostasis model assessment of insulin resistance (HOMA-IR)] and the impact of obesity on their plasma concentrations in metabolic syndrome. DESIGN: This is a cross-sectional study. SETTING: The study was performed in a metabolic outpatient unit. PATIENTS: Patients with metabolic syndrome (National Cholesterol Education Program-Adult Treatment Panel III; n = 45, 23 males/22 females) were included in the study. MAIN OUTCOMES: The main study outcomes were metabolic syndrome criteria, HOMA-IR, and ghrelin forms. RESULTS: Plasma insulin and HOMA-IR were associated negatively with T-Ghr and D-Ghr but positively with A-Ghr and acylated to desacylated ghrelin (A/D-Ghr) ratio (n = 45; P < 0.05). Compared with nonobese [body mass index (BMI) < 27.5 kg/m(2); n = 12, six males/six females], obese metabolic syndrome patients (BMI > 27.5 kg/m(2); n = 33) had lower T-Ghr and D-Ghr but comparable A-Ghr and higher A/D-Ghr ratio (P < 0.05). BMI and waist circumference (WC) were positively related with HOMA-IR (n = 45; P < 0.05). However, opposite associations between A/D-Ghr ratio and HOMA-IR remained significant after adjustment for sex and BMI (or WC). Additional obese individuals without metabolic syndrome (n = 10: age-, sex-, BMI-, and WC-matched to obese metabolic syndrome patients) had lower T-Ghr but higher A-Ghr (P < 0.05) compared with age-, sex-matched healthy nonobese counterparts (n = 15). T-Ghr and A-Ghr were comparable in obese with or without metabolic syndrome. CONCLUSION: Obesity could alter circulating ghrelin profile, and relative A-Ghr excess could contribute to obesity-associated insulin resistance in metabolic syndrome.

Gender-Specific Association of Desacylated Ghrelin with Subclinical Atherosclerosis in the Metabolic Syndrome.

OBJECTIVE: Ghrelin, a gastric hormone with pleiotropic effects modulates vascular function and may influence atherosclerosis. Plasma ghrelin is reduced in the metabolic syndrome (MS), which is also characterized by early atherosclerosis. Ghrelin circulates in acylated (AG) and desacylated (DAG) forms. Their relative impact and that of gender on subclinical atherosclerosis in MS is unknown. AIM OF THE STUDY: To investigate potential associations of total, AG and DAG with carotid atherosclerosis and with gender in the MS. METHODS: Plasma total ghrelin, AG, DAG and carotid artery IMT (cIMT) were measured in 46 MS patients (NCEP-ATP III criteria, 22M/24F). RESULTS: Compared with males, females had higher (p <0.05) total and DAG. In the association analysis, age and plasma glucose were positively (p <0.05) correlated with cIMT in all MS patients. The positive (p <0.05) association between cIMT and age was also confirmed in males, while that between cIMT and glucose was significant in women. In contrast, neither total ghrelin nor AG and DAG were associated with cIMT in all MS patients nor in the male subgroup. In females, a negative (p <0.05) association between carotid artery IMT, DAG and glucose was detected, but not between cIMT, total ghrelin and AG. In multivariate modeling, DAG remained negatively (p <0.05) associated with cIMT after adjusting for plasma glucose and cardiovascular risk factors. CONCLUSIONS: These data indicate a negative independent association between DAG and cIMT in middle-aged women with the MS and suggest a gender-specific modulatory function of DAG in the development of atherosclerosis.

Lack of Fibronectin Extra Domain A Alternative Splicing Exacerbates Endothelial Dysfunction in Diabetes.

Glucose-induced changes of artery anatomy and function account for diabetic vascular complications, which heavily impact disease morbidity and mortality. Since fibronectin containing extra domain A (EDA + FN) is increased in diabetic vessels and participates to vascular remodeling, we wanted to elucidate whether and how EDA + FN is implicated in diabetes-induced endothelial dysfunction using isometric-tension recording in a murine model of diabetes. In thoracic aortas of EDA-/-, EDA+/+ (constitutively lacking and expressing EDA + FN respectively), and of wild-type mice (EDAwt/wt), streptozotocin (STZ)-induced diabetes impaired endothelial vasodilation to acetylcholine, irrespective of genotype. However STZ + EDA-/- mice exhibited increased endothelial dysfunction compared with STZ + EDA+/+ and with STZ + EDAwt/wt. Analysis of the underlying mechanisms revealed that STZ + EDA-/- mice show increased oxidative stress as demonstrated by enhanced aortic superoxide anion, nitrotyrosine levels and expression of NADPH oxidase NOX4 and TGF-ß1, the last two being reverted by treatment with the antioxidant n-acetylcysteine. In contrast, NOX1 expression and antioxidant potential were similar in aortas from the three genotypes. Interestingly, reduced eNOS expression in STZ + EDA+/+ vessels is counteracted by increased eNOS coupling and function. Although EDA + FN participates to vascular remodelling, these findings show that it plays a crucial role in limiting diabetic endothelial dysfunction by preventing vascular oxidative stress.

Dysregulation of the endothelial nitric oxide synthase-soluble guanylate cyclase pathway is normalized by insulin in the aorta of diabetic rat.

Antiatherogenic effects of nitric oxide (NO) are mediated by activation of soluble guanylate cyclase (sGC) and are impaired by diabetes in animals and humans. We investigated whether uncontrolled diabetes and insulin therapy effect expression and function of the main enzymes of the endothelial nitric oxide (eNOS)-sGC signaling pathway in vivo. Expression and function of eNOS, sGC and protein kinase G (PKG) were studied by Western blot analysis and vasorelaxation to NO-donor in thoracic aortas from control (CON) and streptozotocin (SZT)-induced diabetic rats during uncontrolled diabetes (DM) and insulin treatment (INS) for 8 weeks. Protein level of eNOS was increased (+300%, P < 0.05), while sGC (-50%) and PKG (-65%) proteins were reduced (P < 0.03) in aortas of DM. Insulin treatment normalized these defects resulting in eNOS, sGC and PKG aortic protein content comparable to control. In aortic rings, diethylamine NONOate (DEA-NONOate)-induced vasorelaxation was attenuated (P< or =0.05) in DM compared to control and returned to normal in INS. Thus, experimental diabetes decreases sGC and PKG expression and their NO-dependent activation in aorta despite overexpression of eNOS. These abnormalities are normalized by insulin treatment and improved metabolic control.

Pulmonary artery aneurysm and sarcoidosis.

Pulmonary artery aneurysm unassociated to congenital heart disease and pulmonary hypertension is exceedingly rare. Its pathogenesis and correct management remain unknown. Sarcoidosis is a systemic disease that can exceptionally involve large vessels, leading to stenosis and dilatation. Pulmonary artery aneurysm has never been described in association with sarcoidosis. Surgical approach should prevent aneurysm rupture, but it is not known when surgery should be preferred to strict medical follow-up. In this report we present a case of large pulmonary artery aneurysm associated to systemic sarcoidosis underlining problematic management of diseases 'forgotten' by evidence based medicine.

Omega-3 Polyunsaturated Fatty Acids: Structural and Functional Effects on the Vascular Wall.

Omega-3 polyunsaturated fatty acids (n-3 PUFA) consumption is associated with reduced cardiovascular disease risk. Increasing evidence demonstrating a beneficial effect of n-3 PUFA on arterial wall properties is progressively emerging. We reviewed the recent available evidence for the cardiovascular effects of n-3 PUFA focusing on structural and functional properties of the vascular wall. In experimental studies and clinical trials n-3 PUFA have shown the ability to improve arterial hemodynamics by reducing arterial stiffness, thus explaining some of its cardioprotective properties. Recent studies suggest beneficial effects of n-3 PUFA on endothelial activation, which are likely to improve vascular function. Several molecular, cellular, and physiological pathways influenced by n-3 PUFA can affect arterial wall properties and therefore interfere with the atherosclerotic process. Although the relative weight of different physiological and molecular mechanisms and the dose-response on arterial wall properties have yet to be determined, n-3 PUFA have the potential to beneficially impact arterial wall remodeling and cardiovascular outcomes by targeting arterial wall stiffening and endothelial dysfunction.

[Achieving optimal cholesterol levels in patients with chronic ischemic heart disease: from guidelines to the real world]. / Il raggiungimento dei target raccomandati di profilo lipidico in una popolazione con cardiopatia ischemica cronica: dalle linee guida al mondo reale.

BACKGROUND: It is known that less than half of patients with coronary heart disease reaches the target of LDL cholesterol (LDL-C) <100 mg/dl. According to the latest international guidelines, this target has been lowered to <70 mg/dl in very high-risk patients. METHODS: From November 1, 2009 to December 31, 2012, 4953 patients with coronary heart disease were enrolled in the Cardiovascular Registry of Trieste (Italy). We assessed clinical data, LDL-C levels, statin prescription and medium-term outcome in patients with coronary heart disease. RESULTS: At first clinical evaluation, LDL-C values were available for only 61.5% of patients. The target level of LDL-C <70 mg/dl was reached in 17% of cases and LDL-C <100 mg/dl in 53%. Patients with lower LDL-C levels were more frequently males, with higher cardiovascular risk profile, more comorbidity and more frequent polypharmacy. LDL-C levels influenced statin prescription: in patients with LDL-C ≥ 100 mg/dl, cardiologists started or modified the dosage of statin therapy twice more than in patients with LDL-C <100 mg/dl, even if only in less than 20% of cases. Patients with LDL-C <100 mg/dl in statin therapy had better prognosis, whereas patients with low LDL-C levels without statin therapy had the worst prognosis. Other prognostic factors in this population with LDL-C <100 mg/dl were age, presence of heart failure, comorbidities (evaluated with Charlson index) and polypharmacy. CONCLUSIONS: In our population of outpatients with coronary heart disease, the target of LDL-C <100 mg/dl was reached in 53% of cases. LDL-C levels influenced statin prescription and modification of dosages. The medium-term outcome is closely influenced by the achievement of target LDL-C levels and statin prescription.

Familial HDL deficiency due to ABCA1 gene mutations with or without other genetic lipoprotein disorders.

Mutations in ABCA1 have been shown to be the cause of Tangier disease (TD) and some forms of familial hypoalphalipoproteinemia (HA), two genetic disorders characterized by low plasma HDL levels. Here we report six subjects with low HDL, carrying seven ABCA1 mutations, six of which are previously unreported. Two mutations (R557X and H160FsX173) were predicted to generate short truncated proteins; two mutations (E284K and Y482C) were located in the first extracellular loop and two (R1901S and Q2196H) in the C-terminal cytoplasmic domain of ABCA1. Two subjects found to be compound heterozygotes for ABCA1 mutations did not have overt clinical manifestations of TD. Three subjects, all with premature coronary artery disease (pCAD), had a combination of genetic defects. Besides being heterozygotes for ABCA1 mutations, two of them were also carriers of the R3500Q substitution in apolipoprotein B and the third was a carrier of N291S substitution in lipoprotein lipase. By extending family studies we identified 17 heterozygotes for ABCA1 mutations. Plasma HDL-C and Apo A-I values in these subjects were 38.3 and 36.9% lower than in unaffected family members and similar to the values found in heterozygotes for Apo A-I gene mutations which prevent Apo A-I synthesis. This survey underlines the allelic heterogeneity of ABCA1 mutations and suggests that: (i) TD subjects, if asymptomatic, may be overlooked and (ii) there may be a selection bias in genotyping towards carriers of ABCA1 mutations who have pCAD possibly related to a combination of genetic and environmental cardiovascular risk factors.

Carbohydrate requirement and insulin concentration during moderate exercise in type 1 diabetic patients.

The lack in control of insulin release combined with an inadequate carbohydrate (CHO) ingestion accounts for the occurrence of frequent metabolic unbalances during exercise in type 1 diabetic patients. The aim of the study was to quantify, in these patients, the CHO requirement to prevent hypoglycemia during moderate exercise performed at different time intervals after morning subcutaneous insulin injection. Twelve type 1 diabetic patients and 12 well-matched healthy subjects cycled 4 times for 1 hour at a constant workload. The rate of glucose oxidation was calculated continuously by indirect calorimetry throughout the exercise, while blood parameters were assessed periodically and orally given CHO were checked. CHO needed by the patients to prevent hypoglycemia decreased as the time elapsed from insulin administration increased, amounting to 0.63 +/- 0.30, 0.44 +/- 0.32, 0.28 +/- 0.24, and 0.14 +/- 0.18 g/kg after 1, 2.5, 4, and 5.5 hours, respectively. Total glucose requirement during moderate exercise (sum of alimentary and extracellular source) was correlated (r = 0.739, P <.001) to plasma insulin concentration, but not with fitness level. Time elapsed from last insulin dose is not a factor influencing the risk of hypoglycemia during exercise when a proportional, appropriate amount of CHO is ingested.

Production of polyacrylamide gradient gel for lipoprotein electrophoretic separation.

BACKGROUND: Small LDL are associated with risk of coronary heart disease. Gradient gel electrophoresis for LDL separation is not a simple method and high-quality non-denaturing gradient gels are lacking. METHODS: In this paper, we describe a method for the preparation of a polyacrylamide gel system that consists of an upper linear gradient gel (1.8-10%) and a lower homogeneous gel (16%) for the determination of LDL size. RESULTS: The linear gradient is highly reproducible. Intra-inter gel coefficients of variation for LDL particle size are lower than 0.6%. CONCLUSION: Effective LDL size measurement from pre-stained serum samples is possible in a stable gel.

Myostatin expression is not altered by insulin deficiency and replacement in streptozotocin-diabetic rat skeletal muscles.

BACKGROUND AND AIMS: Insulin is a major post-prandial muscle-anabolic hormone. A substantial loss of skeletal muscle mass occurs in insulin-deprived diabetes and is reversed by insulin treatment. Myostatin is a negative regulator of muscle mass upregulated in several chronic catabolic conditions. Whether myostatin expression is altered in insulin-deprived diabetes is unknown. In spite of opposite effects on muscle mass the potential role of basal circulating insulin in the regulation of myostatin expression is also undetermined. METHODS: We measured (Northern Blot) myostatin transcript levels in muscle groups with different fiber composition in streptozotocin-diabetic male rats receiving one of the following treatments for eight weeks: (1) control (C); (2) diabetes without treatment (DM); (3) diabetes with once-daily slow-acting insulin treatment (INS). RESULTS: INS normalized plasma insulin and prevented weight reduction observed in DM. In fast-twitch gastrocnemius muscle myostatin transcript levels were unchanged (P>0.4) in both DM and INS compared to C. Myostatin transcripts were not measurable in any group in slow-twitch soleus muscle. CONCLUSIONS: Muscle-specific myostatin expression is not increased under catabolic conditions in insulin-deprived diabetes. Insulin treatment also does not change myostatin transcript levels. The data provide the first assessment of potential interplay between insulin and myostatin and they do not support a major role of circulating insulin in the in vivo regulation of myostatin gene expression. A role of myostatin in muscle catabolism in chronic insulin-deprived diabetes is also not indicated by the current results.

HELP LDL apheresis reduces plasma pentraxin 3 in familial hypercholesterolemia.

BACKGROUND: Pentraxin 3 (PTX3), a key component of the humoral arm of innate immunity, is secreted by vascular cells in response to injury, possibly aiming at tuning arterial activation associated with vascular damage. Severe hypercholesterolemia as in familial hypercholesterolemia (FH) promotes vascular inflammation and atherosclerosis; low-density lipoprotein (LDL) apheresis is currently the treatment of choice to reduce plasma lipids in FH. HELP LDL apheresis affects pro- and antiinflammatory biomarkers, however its effects on PTX3 levels are unknown. We assessed the impact of FH and of LDL removal by HELP apheresis on PTX3. METHODS: Plasma lipids, PTX3, and CRP were measured in 19 patients with FH undergoing chronic HELP LDL apheresis before and after treatment and in 20 control subjects. In the patients assessment of inflammation and oxidative stress markers included also plasma TNFα, fibrinogen and TBARS. RESULTS: At baseline, FH patients had higher (p = 0.0002) plasma PTX3 than matched control subjects. In FH PTX3 correlated positively (p≤0.05) with age, gender and CRP and negatively (p = 0.01) with HELP LDL apheresis vintage. The latter association was confirmed after correction for age, gender and CRP. HELP LDL apheresis acutely reduced (p≤0.04) plasma PTX3, CRP, fibrinogen, TBARS and lipids, but not TNFα. No association was observed between mean decrease in PTX3 and in LDL cholesterol. PTX3 paralleled lipids, oxidative stress and inflammation markers in time-course study. CONCLUSION: FH is associated with increased plasma PTX3, which is acutely reduced by HELP LDL apheresis independently of LDL cholesterol, as reflected by the lack of association between change in PTX3 and in LDL levels. These results, together with the finding of a negative relationship between PTX3 and duration of treatment suggest that HELP LDL apheresis may influence both acutely and chronically cardiovascular outcomes in FH by modulating PTX3.

Inflammation impairs eNOS activation by HDL in patients with acute coronary syndrome.

AIMS: The aim of the present study was to evaluate the high-density lipoprotein (HDL) structure and endothelial NO synthase (eNOS) activation capacity in ST-elevation myocardial infarction (STEMI) patients with different acute-phase inflammatory response (APR). METHODS AND RESULTS: Forty-five STEMI patients were stratified in quartiles according to the delta CRP level, calculated by subtracting the CRP value at admission from the CRP peak value (APR peak). The HDL structure and HDL capacity to stimulate NO production were evaluated at admission and at APR peak. STEMI patients with a low APR had a completely preserved HDL structure and HDL ability to activate eNOS and promote NO production, which did not change during STEMI. On the contrary, HDL from STEMI patients developing a significant APR had compromised ability to stimulate eNOS and promote NO production, and underwent a significant particle remodelling during STEMI. The defective capacity to stimulate NO production of HDL isolated from STEMI patients with high APR was explained, at least in part, by the reduced PON-1 and S1P content. The HDL ability to promote cell cholesterol efflux through different pathways was preserved in ACS patients independently of the inflammatory response. CONCLUSION: The present results extend previous studies reporting an impaired eNOS-activating capacity of HDL from ACS patients, showing that only a subset of patients undergoing STEMI, and in particular those developing an important inflammatory response, have circulating HDL defective in stimulating endothelial eNOS and NO production.

Nonalcoholic fatty liver and metabolic syndrome in Italy: results from a multicentric study of the Italian Arteriosclerosis society.

Nonalcoholic fatty liver disease (NAFLD) is associated with all the components of metabolic syndrome (MS) and might to be considered an additional component of MS itself. The Italian Society for the Study of Atherosclerosis (SISA) in 2005 started a research project aimed to study the NAFLD, using ultrasound (US), in nondiabetic MS subjects matching at least one of the ATP III criteria for HDL-C or triglycerides [TG]. Prevalence of US-NAFLD and its associated risk factors and prevalence of hypertransaminasemia and its possible determinants were evaluated. NAFLD prevalence was 0.78. Men with steatosis compared to men without steatosis were younger (P < 0.05) with higher TG (P < 0.03), homeostasis model assessment insulin resistance (HOMA-R) (P < 0.003), and visceral fat thickness (VFT) (P < 0.0001). Women with steatosis showed higher TG (P < 0.05), HOMA-R (P < 0.04), VFT (P < 0.0001), and lower age (P < 0.05). At multivariate analyses, VFT (P < 0.0001), HOMA-R (P < 0.02), and TG/HDL (P < 0.05) were associated with severity of NAFLD. Age (P < 0.05), LogTG (P < 0.005), and VFT (P < 0.01) were associated with higher ALT. The US prevalence of steatosis in this study (0.78) is the highest reported in patients with MS. Considering the exclusion of severe obese and diabetic patients and the recruitment criteria, this finding highlights the prominent role played by the alterations of lipid metabolism in the pathogenesis of NAFLD.