COMPARATIVE EFFECT OF APHERESIS vs ATORVASTATIN/APHERESIS ON MARKERS OF INFLAMMATION IN PATIENTS WITH FAMILIAL HYPERCHOLESTEROLEMIA

Objective: Patients with Familial Hypercholesterolemia (FH) have increased cardiovascular events. Clinical trials have demonstrated that lowering circulating lipid levels by LDL-apheresis has beneficial effects on prognosis. However, whether apheresis vascular effects in FH are related to modulation of pro- and anti-inflammatory cytokines, and whether the combination of apheresis with atorvastatin is able to enhance the putative anti-inflammatory effect of apheresis remains unknown. We examined, in a intra-patient study, the effect of atorvastatin/apheresis vs. apheresis alone on the releasing of circulating pro- and anti-inflammatory markers. Methods: 9 heterozygous patients (56+11 years) with FH (mean cholesterol 385+42 mg/dL) were treated with apheresis alone and afterwards with apheresis plus atorvastatin 40 mg/d. Lipid profiles, serum C-reactive protein, CK, GOT, GGT, the antiinflammatory markers IL-4 and IL-10 and the pro-inflammatory markers INFg and IL-6 were determined before and at 2, 4, 6 and 8 days after apheresis and atorvastatin/apheresis. Results: Treatment with atorvastatin/apheresis significantly reduced lipid profile more than LDL-apheresis alone at each scheduled time. When compared to apheresis alone, combined treatment statistically decreased cholesterol by more than 25-35% at all times and relatively increased IL-4 concentration. The levels of cholesterol in atorvastatin/apheresis patients were inversely correlated with those of IL-4 and IL-10 and positively correlated with IFNg. Conclusion: The combination of atorvastatin with LDL-apheresis decreased serum cholesterol levels more than apheresis alone. Apheresis had an anti-inflammatory effect and the effect of the drug reducing cholesterol levels affects the balance between proand anti-inflammatory cytokines in favor of anti-inflammation contribute

Lipoprotein(a) in familial hypercholesterolemia: Tips from family history.

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Myeloperoxidase modulation by LDL apheresis in Familial Hypercholesterolemia

<p>Abstract</p> <p>Background</p> <p>Myeloperoxidase (MPO) is a marker of plaque vulnerability and a mechanistic bridge between inflammation and cardiovascular disease, and thus is a suitable target for therapeutic strategy against cardiovascular disease.</p> <p>Methods</p> <p>Since hypercholesterolemia is associated with atherosclerosis and inflammation, we tested whether MPO serum levels were up-regulated in Familial Hypercholesterolemia (FH) and whether acute reduction of total cholesterol (TC) would also reduce MPO concentration. FH subjects undergoing LDL-apheresis (LDL-A) treatment are a paradigmatic clinical model where TC rapidly plunges from extremely high to extremely low levels after selective LDL removal, and then spontaneously rebounds to baseline conditions. This clinical setting allows multiple intra-patient observations at different plasma TC concentrations. We measured MPO levels in serum by ELISA tests, and in peripheral leukocytes by immunofluorescence, to learn whether they were affected by the changes in TC levels. Serum MPO was measured before and serially up to the 14^thday following LDL-A.</p> <p>Results</p> <p>In both serum and peripheral leukocytes, MPO concentrations were <it>i) </it>higher than in sex- and age-matched healthy controls (<it>p </it>< 0.01); <it>ii) </it>decreased with TC reduction; <it>iii) </it>parallel with TC time course; <it>iv) </it>correlated with plasma TC. At regression analysis, plasma TC was the only variable considered that influenced MPO serum levels (<it>β </it>0.022 ± 0.010, <it>p </it>< 0.0001).</p> <p>Conclusions</p> <p>In FH the MPO serum levels were modulated through changes in the TC concentrations carried out by LDL-A. Further study is needed to determine whether reduced MPO levels obtained by LDL-A could have any therapeutic impact.</p

Polidistrectual vascular involvement in Familial Hyperchilomicronemia

A 72-year-old man was referred to our clinic with a lipid profile, under combination therapy with a statin and ezetimibe, characterized by severe hypertriglyceridemia (7230 mg/dl), hypercholesterolemia (374 mg/dl), low HDL-cholesterol (17 mg/dl), and normal circulating Lp"a". The patient had undergone post-traumatic splenectomy and presented a history of systemic hypertension treated medically with well-controlled blood pressure. The patient had also presented in the past abdominal pain with subsequent diagnosis of chronic pancreatitis complicated by diabetes mellitus, well compensated when he came to our attention. Following a pathological exercise test, a coronary angiogram was performed which showed a significant stenosis of the right coronary artery, which was treated successfully with percutaneous coronary intervention. Clinical work-up revealed ectasia of the abdominal aorta (28 mm), non significant bilateral carotid artery disease, and peripheral artery disease of the femoral-popliteal axis symptomatic for intermittent claudication. A lipidogram was also performed and electrophoretic lipoprotein patterns did not vary 2 hours after heparin infusion, pointing to the existence of lipoprotein lipase deficit. Electrophoresis also showed a broadband of chylomicrons at baseline, at the beginning, and at the end of heparin infusion. Hyperchilomicronemia is a rare genetic disorder with an incidence of 1 per 1000000. Following diagnosis, our patient began plasma exchange therapy with subsequent improvement of his lipid profile. At the present time, he is regularly followed up at our clinic and non invasive imaging has excluded any significant progression of atherosclerosis after 2 years of therapy

Tangier Disease: a plasma proteome approach

Background. Tangier disease (TD) is a rare autosomal recessive disorder characterized by a deficiency or absence of high-density lipoprotein caused by mutations in the adenotriphosphatebinding cassette transporter-1 gene (ABCA1). These lead to a defect in cellular cholesterol removal causing the deposition of cholesterol esters throughout reticuloendothelial system. Methods. We enrolled a homozygous TD patient and the heterozygous father. Whole plasmatic extracts were processed and mass spectrometry analyses of peptide fragments were performed on MALDI TOF/TOF equipment. Trypsin digestion produces a constant set of peptide fragments distinctive of each starting protein (finger print). Peptide ions are automatically processed by MASCOT and GPS Explorer software, which provide us the identification of starting proteins. Peaks, indicative of different peptides, also subjected to mass/mass analysis by means of fragmentation in a collision chamber. Such second mass analysis provided aminoacid sequence of peptide and the identification of possible post-translational modifications. Results. The very high sensitivity of the method allowed us to identify plasma proteins less peresented (<1.2 pg/ml). Apolipoprotein A-I, haptoglobin, alpha-2 macroglobulin, fibrinogen beta chain and isoform 1 of alpha-1 antitrypsin (C.I. 95%) resulted to be downregulated, while serotransferrin and Ig kappa resulted upregulated in the homozygous TD patient respect to the heterozygous. The same pattern was also observed by routine assays. Conclusions. The downregulation of the acute phase proteins observed in this case was unexpected. Proteome analyses may help in identification of abnormal metabolic pathways eventually activated in TD

Routine laboratory tests to risk-stratify patients with chronic coronary artery disease

AbstractBackgroundSeveral biohumoral variables, taken individually, are predictors of prognosis in patients with chronic coronary artery disease (CAD). We hypothesized that taken together, laboratory tests provide prognostic information that is additive to a complete diagnostic work-up.MethodsWe prospectively examined 2370 consecutive patients with chronic CAD, as shown by a >50% coronary stenosis (in 95% of patients), previous coronary revascularization (in 31% of patients), and/or previous myocardial infarction (MI, in 54% of patients). We tested the ability of laboratory and clinical variables to predict future cardiac events (cardiac death and non-fatal MI).ResultsDuring follow-up (median, 46 months), 147 patients (6.2%) died from cardiac causes and 81 (3.4%) experienced a non-fatal MI. Using multivariate analysis, after adjustment for clinical variables (including left ventricular ejection fraction and angiographic extent of coronary stenoses), a high-density lipoprotein cholesterol (HDLc) concentration<35mg/dL (p<0.0001), a neutrophil-to-lymphocyte ratio >2.4 (p=0.0014), and an fT3 serum level<2.1pg/mL with normal thyrotropin (low-T3 syndrome) (p=0.0260) showed an independent and incremental prognostic value, and were associated with an increase in the rate of cardiac events of 86%, 57% and 41%, respectively. When these variables were added to clinical and instrumental variables, the prognostic power of the model increased significantly (global chi-square improvement: from 157.01 to 185.07, p<0.0001).ConclusionLow HDLc, high neutrophil-to-lymphocyte ratio and low-T3 syndrome, both individually and taken together, provide prognostic information that is independent of and incremental to the main clinical and instrumental findings

Insulin resistance is a major determinant of myocardial blood flow impairment in anginal patients

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Efficacy and safety of niacin/laropiprant therapy in familial hypercholesterolemic patients with coronary artery disease

Background: Cardiovascular disease is the principal cause of premature mortality and morbidity in Europe. Patients with familial hypercholesterolemia are at particularly increased risk and, despite lipid-lowering therapy, continue to experience cardiovascular events. Currently, for these patients a new treatment option is represented by extended-release niacin/laropiprant (ERN/LRPN). Material and Methods: We followed-up for 16 weeks a group of 23 familial hypercholesterolemic patients (mean age 61?7 years, 74% male) with chronic coronary artery disease and ERN/LRPN added on top of maximally tolerated lipid-lowering therapy. ERN/LRPN was administered at the dose of 1 gr/day for the first 4 weeks and then at 2 gr/day for the remaining period. Clinical examination and blood sampling (including lipid profile, renal and hepatic function) were performed at baseline, after 4 weeks, at the end of follow-up, and in the case of eventual clinical manifestations. Results: During follow-up, 14 patients discontinued therapy due to side effects (headache, asthenia, and gastrointestinal disorders in 4 patients, muscle aches and CK increase in 3 patients, eruptive skin rash in 2 patients, onset of diabetes mellitus in 2 patients, dizziness associated with inability to drive in 1 patient, acute hepatitis in 1 patient and palpitations in 1 patient) and 2 patients voluntarily interrupted the therapy. In the remaining 7 patients, an improvement in lipid profile was observed (total cholesterol -14%, HDL cholesterol +7%, LDL cholesterol -16%, Triglycerides -53%, Apolipoprotein A1 +8%, Apolipoprotein B -21%, Apolipoprotein E -31%) in the absence of substantial changes in other laboratory analyses (with the exception of a non-significant increase in uric acid). Intolerable skin flushing was not observed in any patient. In addition, among patients who did report flushing, a reduction in the incidence of the episodes was observed after the first month of therapy

Adiponectin and cardiometabolic risk factor: effect on myocardial blood flow in patients with dilated cardiomyopathy

Purpose: Adiponectin (ADN) is an insulin-sensitizing, anti-atherogenic and anti-inflammatory adipocytokine, with endothelial protective effects. In patients with dilated cardiomyopathy (DCM), absolute myocardial blood flow (MBF) is frequently impaired because of coronary microvascular/endothelial dysfunction. We aimed at evaluating whether the potential effects of ADN on MBF in DCM are modulated by cardiometabolic risk factors. Methods: Sixty-one consecutive patients (46 males, age 59?10 yrs) with LV dysfunction (LV ejection fraction 38?9%, range 19-54%) and angiographically normal coronary arteries were studied. Absolute MBF was measured by positron emission tomography, using 13N-Ammonia as flow tracer, both at rest and during dipyridamole infusion (0.56 mg/kg I.V. over 4 min). Abnormal MBF was defined for resting MBF<0.65 ml/min/g and dipyridamole MBF<1.36 ml/min/g. Plasma adiponectin was measured by a specific ELISA (Linco Research). Cardiometabolic risk factors including age, sex, insulin resistance, lipid profile and obesity were entered into a multivariate linear regression analysis to assess independent determinants of adiponectin and, in turn, their effect on myocardial and microvascular damage. Results: Abnormal MBF was present in 34/61 patients, in 13/31 (42%) with ADN higher than median value and in 21/30 (70%) with ADN levels lower than median value (p<0.05). Among cardiometabolic risk factors, only HDL-cholesterol and obesity were independent determinants of ADN [0.34 (0.13), -0.34 (0.14), &#946;-coefficient (SE), respectively, p<0.05] at multivariate analysis. After correction for HDL-cholesterol and obesity the positive association between ADN and MBF remained significant (p<0.05). Conclusion: ADN is a determinant of MBF in DCM patients and is related with low HDL-cholesterol and obesity

Low High-Density Lipoprotein Cholesterol and Abnormal Glucose Control in Idiopathic Left Ventricular Dysfunction

Aims: To investigate whether cardiovascular (CV) risk factors are associated with myocardial blood flow (MBF) abnormalities and play any prognostic role in patients with idiopathic left ventricular (LV) dysfunction. Methods: We studied 83 patients (61 males, age 60?10 years) with mild-to-severe LV dysfunction (mean ejection fraction 38%, range 19-53%), no history of diabetes and angiographically normal coronary arteries. We measured absolute MBF by positron emission tomography and 13N-ammonia at rest and after dipyridamole. The following CV risk factors were recorded: age, sex, family history of coronary artery disease or dilated cardiomyopathy, newly diagnosed type II diabetes (NIDD), insulin resistance (IR, defined as Homeostasis Model Assessment index >2), hypertension, hypercholesterolemia, low high density lipoprotein (HDL) cholesterol, smoking habit, and obesity. Cardiac death, transplantation, and progressive LV dysfunction were the censored events during followup. Results: Depressed MBF reserve (<2) was present in 48 patients (58%). Using multivariate logistic regression analysis, low HDL cholesterol (P = 0.039) and NIDD or IR (P = 0.012) were the only variables significantly associated with depressed MBF during stress after adjustment for risk factors, LV function and pharmacological treatment. Moreover, low HDL cholesterol (P = 0.039) and female sex (P = 0.021) were significantly associated with depressed MBF reserve. During follow-up (median, 6 years), cardiac events occurred in 18 patients (22%). At Cox regression analysis, depressed MBF reserve (P = 0.034) and LV dilatation (P = 0.047) were the only significant and independent predictors of event-free survival. Conclusion: In idiopathic LV dysfunction, low HDL cholesterol and NIDD/IR are associated with abnormal hyperemic MBF and flow reserve. Risk factors are not determinants of patient outcome, which is predicted by MBF reserve and LV dilatation