Lipoprotein-associated phospholipase A2 (Lp-PLA2): a review of its role and significance as a cardiovascular biomarker.

OBJECTIVE: To conduct a comprehensive, systematic review of studies assessing the significance of lipoprotein-associated phospholipase A2 in cardiovascular diseases (CVDs). MATERIAL AND METHODS: A review of the literature was performed using the search term "Lipoprotein-associated phospholipase A2 (Lp-PLA2)" and each of the following terms: "cardiovascular risk," "cardiovascular death," "atherosclerotic disease," "coronary events," "transient ischemic attack (TIA)," "stroke," and "heart failure." The searches were performed on Medline, Google Scholar and ClinicalTrials.gov. RESULTS: The majority of published studies showed a significant association between Lp-PLA2 levels and cardiovascular events after multivariate adjustment. The association was consistent across a wide variety of subjects of both sexes and different ethnic backgrounds. CONCLUSIONS: The role of Lp-PLA2 as a significant biomarker of vascular inflammation was confirmed, and Lp-PLA2 seems to be closely correlated to cardiovascular events. It may be an important therapeutic target and may have an important role in prevention, risk stratification and personalised medicine.

Lipoprotein-associated phospholipase A2 activity in patients with preserved left ventricular ejection fraction.

BACKGROUND: A significant proportion of heart failure (HF) patients have preserved ejection fraction (EF). Considering that inflammation and oxidative stress are involved in HF evolution, we investigated lipoprotein-associated phospholipase A2 (LpPLA2), an enzyme involved in these pathophysiologic processes in relation to EF. METHODS AND RESULTS: The study included 208 HF patients and 20 healthy controls. HF patients with preserved EF (HFpEF) represented 42.31% of all HF patients. LpPLA2 activity was significantly increased in HF patients when compared with controls and was higher in HFpEF than in HF with reduced EF patients (HFrEF). The incidence of left ventricular hypertrophy was higher in HFpEF than in HFrEF (EF < 50). CONCLUSION: Confirming its role as a marker of vascular inflammation, LpPLA2 seems to be a biomarker constantly correlated with HF, regardless of etiology. Elevated plasma values of LpPLA2 in HFpEF are consistent with the exacerbated inflammatory status.

[Update regarding the role of biomarkers in early diagnosis of non-small cell bronchopulmonary cancer]. / Actualitati privind rolul markerilor tumorali in detectia precoce a neoplasmului bronhopulmonar NSCC.

Early diagnosis of lung cancer by non-invasive methods has a low sensibility: 60% of peripheral cancers could be diagnosed by computed tomography, 60% of the central ones by sputum cytology. More specific for detecting central microinvasive lesions could be bronchoscopy with autofluorescence, but this is a method with a low number of patients to be performed on, because of the specific technique. For all these reasons there are some other methods to be tried in this respect--one of them is to find one or more molecules--tumoral markers--which have to be specific in establishing the risk of developing lung cancer, to make an early diagnosis of cancer and to predict the evolution under treatment. The detecting tumoral markers in sputum, blood, bronchoalveolar lavage was not so largely explored related to the final goal--the possibility of identifying and quantifying the most specific ones for the screening of lung cancer. The present paper has as purpose to make an review of tumoral markers--"classical" markers as: CEA, NSE, TPA, beta2 microglobulina, CA 125, CA 15-3--considered not such a high sensibility and specificity for lung cancer screening versus new molecules, studied intensively as: SCC-Ag, CYFRA 21-1, ferritin, sIL-2R, CCK-BB, glycosyltransferases. Those new molecules have a higher sensibility, but also could have a higher specificity for each type of lung cancer.

Low basal levels of circulating adiponectin in patients undergoing coronary stenting predict in-stent restenosis, independently of basal levels of inflammatory markers: lipoprotein associated phospholipase A2, and myeloperoxidase.

OBJECTIVE: The aim of this study was to find a pre-interventional marker with the capacity to predict in-stent restenosis (ISR). Considering the anti-atherosclerotic role of adiponectin (APO), an adipocytokine with anti-inflammatory, anti-proliferative, anti-oxidative and anti-thrombotic properties, low plasma levels of APO might be correlated with the risk of ISR. We investigated the correlations between the plasma levels of APO and two markers of inflammation: lipoprotein associated phospholipase A2 (Lp-PLA2) and myeloperoxidase (MPO). DESIGN AND METHODS: 80 patients with angiographically significant stenosis underwent percutaneous coronary intervention (PCI) with bare metal stent. Plasma APO concentration and plasma Lp-PLA2 and MPO activities were evaluated immediately before and after PCI, then followed-up at 24, 48, 72 h, and at 1, 3, 6 months, respectively. ISR was evaluated at 6 months after stenting by follow-up coronary angiograms, and it was defined as >50% stenosis of the target lesion. RESULTS: ISR was present in 33.75% of patients. Baseline APO plasma concentration, measured before PCI, was lower in ISR patients than those without ISR [3.97 (+/-1.05) vs 6.65 (+/-2.95) microg/mL respectively, p<0.001]. The patients with APO values less than 4.9 microg/mL at discharge were more susceptible to develop ISR (odd ratio, 4.27; 95% CI, 1.56-11.72, p<0.001). ISR rate was independent of inflammation markers Lp-PLA2 and MPO baseline values, measured before PCI. CONCLUSIONS: The persistence of a low APO plasma level at discharge and 6 months afterwards may be used as a clinically useful marker for ISR prediction in patients undergoing PCI.

Antioxidant defense capacity in scleroderma patients.

BACKGROUND: Oxidative stress is associated with scleroderma (systemic sclerosis) and is supposed to favor disease progression by complex effects on the vascular endothelium and on fibroblasts. METHODS: Plasma oxidative process marker, thiobarbituric acid-reactive substances, and several markers of antioxidant defense capacity (plasma total antioxidant activity, serum albumin, uric acid and glutathione, superoxide dismutase and catalase) were evaluated by spectrophotometric methods using blood samples collected from 23 scleroderma patients and 21 healthy controls. RESULTS: In scleroderma patients, thiobarbituric acid-reactive substances levels (mmol/L plasma) were significantly elevated (29.3+/-5.8) compared with healthy controls (16.6+/-3.1, p<0.001). Total antioxidant activity (mmol Trolox/L) was significantly lower in scleroderma patients than in controls (1.29+/-0.13 vs. 1.55+/-0.23, p<0.001), as well as the antioxidant gap (mmol Trolox/L) (0.57+/-0.18 vs. 0.92+/-0.22, p<0.001). Superoxide dismutase activity (IU/g hemoglobin) was markedly decreased in patients as compared with controls (395+/-184 vs. 659+/-211, p<0.001). CONCLUSIONS: Lower plasma total antioxidant activity and plasma antioxidant gap in scleroderma patients show that plasma antioxidant defense is deficient in scleroderma patients. As previous studies on this issue are controversial, the decreased erythrocyte superoxide dismutase activity found in the patients in this study needs further investigation.

Vascular endothelial growth factor, lipoporotein-associated phospholipase A2, sP-selectin and antiphospholipid antibodies, biological markers with prognostic value in pulmonary hypertension associated with chronic obstructive pulmonary disease and systemic lupus erithematosus.

OBJECTIVE: Pulmonary arterial hypertension (PH) is a progressive disease with a poor prognosis that ultimately leads to right ventricular failure and death. The pathogenesis of severe PH seems to be related to inflammatory responses and coagulation disturbances. Many diseases can develop PH in their course, thus aggravating their outcome. The objective was to investigate the values of vascular endothelial growth factor (VEGF), sP-selectin, lipoprotein-associated phospholipase A2 (PLA2-LDL), antiphospholipid antibodies (APLA) and their relation with PH, in systemic lupus erythematosus (SLE) and chronic obstructive pulmonary disease (COPD), two conditions in which the occurrence of PH is frequent. DESIGN: Prospective clinical study. SETTING: A University Department of Internal Medicine, a National Institute of Research. PATIENTS: 30 SLE patients (15 patients without PH (group I) and 15 patients with PH group II)), 30 patients with COPD (15 patients without PH (group III) and 15 patients with PH (group IV)) and 10 healthy controls, selected by clinical, immunological, echocardiographical criteria and pulmonary functional tests. MAIN OUTCOME MEASURES: VEGF, sP-selectin and PLA2-LDL level in plasma and presence of antiphospholipids antibodies (lupus anticoagulant, anticardiolipin and anti beta2 GPI) in plasma. - RESULTS: In patients with PH, the values of VEGF were significantly increased [group II (1023.1) and IV (904.3)] compared with group I (744.2), III (356.4), and controls (330.3). The values of sP-selectin in group II (9.7), and IV (10.4) were also increased compared with controls (6). APLA were present in all patients in group II (100%), and in 8 patients in group IV (53%), while in the other groups the frequency was low (33% group I and 13% group III). PLA2-LDL activity was higher in group II (429.1) and group IV (394.5) than in group I (317.8), group III (343.2) and controls (256.3). CONCLUSION: PH is a severe complication in COPD and SLE. The increased values of VEGF, PLA2-LDL and P-selectin in patients with long standing PH are related to severe endothelial dysfunction and may have prognostic values. APLA may have pathogenic value in SLE patients with PH. APLA are possibly implicated in the pathogenesis of PH in these diseases. VEGF, APLA and sP-selectin may constitute new therapeutic targets for PH.

Plasma markers of endothelial dysfunction in type 2 diabetics.

BACKGROUND: Type 2 diabetes, or non-insulin-dependent diabetes mellitus, represents an independent risk factor for cardiovascular diseases (CVD), being characterized by a continuous low-grade inflammation and endothelial activation state. Atherosclerotic lesions occur in diabetic patients at an earlier age with severe clinical manifestations and poor outcome. Our objective was to investigate the correlation between lipoprotein-associated phospholipase A2 (PLA2-LDL), myeloperoxidase (MPO), and paraoxonase (PON), enzymes implicated in the evolution of endothelial dysfunction associated with type 2 diabetes. METHODS: One hundred diabetic patients [50 without documented coronary artery disease (group 1) and 50 with CVD (group 2)] and 46 healthy controls were investigated for PLA2-LDL, MPO, and PON activities. RESULTS: PLA2-LDL activity was significantly higher in group 2 than in group 1 and among controls. PON activity was lower in group 1 than in controls, reaching the lowest level in group 2. MPO activity was higher in type 2 diabetics than among controls, with similar values in groups 1 and 2. CONCLUSIONS: The evaluation of PLA2-LDL, MPO, and PON activities may improve early diagnosis of CVD in asymptomatic patients with type 2 diabetes and can help to evaluate accelerated atherosclerosis and microvascular disease.

The significance of human platelet-activating factor-acetylhydrolase in patients with chronic stable angina.

BACKGROUND: Inflammatory reactions within coronary atherosclerotic plaques are increasingly thought to be crucial determinants of the clinical course in patients with coronary artery disease (CAD). Platelet-activating factor-acetylhydrolase (PAF-AH) is considered to reflect the ongoing inflammatory process in patients with CAD. Our objective was to determine the activity of PAF-AH in patients with stable angina and its correlations to lipoprotein levels and the inflammatory status of the patient. METHODS: Forty-five patients with documented CAD and stable angina and 20 controls were investigated for PAF-AH activity, lipoprotein levels, and peripheral neutrophil (PMN) activity. RESULTS: Patients were divided into two groups according to the values of PAF-AH activity (group 1: 250 IU/l). A correlation was observed between PAF-AH activity and LDL-C and HDL-C in controls and in all patients. The percentage of granulocytes generating intracellular O(2)(-) in unstimulated PMN was higher in group 2 patients than in group 1 patients and controls. The phagocytic activity of PMNs had an inverse correlation with PAF-AH in group 2. High intracellular O(2)(-) generation was coupled with low extracellular release of the anion and phagocytosis impairment in group 2. During the follow-up period, some of the patients in group 2 displayed a worsening of the clinical state and/or resting ECG changes. CONCLUSIONS: PAF-AH activity in patients with stable angina is correlated with hyperlipemia and a high PMN activation state, and it may be considered a potential predictor of vascular risk.

Patients with primary antiphospholipid syndrome and coronary microvascular dysfunction--a distinct clinical subset.

UNLABELLED: Morbidity of patients with cardiac syndrome X (CSX) is high. Impairment of microvascular endothelial function has been suggested to be a mechanism of the disease. The study was undertaken to assess some of the characteristics of patients with primary antiphospholipid syndrome (pAPS) and CSX. METHODS: We studied 36 patients with CSX, 14 patients having pAPS and 10 healthy controls. Patients evaluation included: clinical examination, 12-lead ECG, effort treadmill test (protocol Bruce modified), determination of plasma triglycerides, cholesterol, antiphospholipid antibodies (APLA). There were determined as markers of the inflammatory state: serum phospholipase (PL-A2) and peripheral neutrophils activity. RESULTS: Patients with pAPS presented normal values of serum cholesterol and triglycerides levels, normal PL-A2 activity, moderate superoxide anion generation. Patients without APLA presented hyperlipidemia, increased PL-A2 activity, increased superoxide anion generation. During the follow-up period we found a correlation between P1-A2 activity and ischemic episodes, but only in patients with CSX and pAPS there were registered cardiovascular events. CONCLUSION: Patients with SCX and pAPS represent a distinct clinical subset, being characterized by minimal inflammation, absence of usual risk factors for coronary heart disease, more severe prognosis related to recurrent thromboses and the need for early anticoagulant therapy.

Apoptotic rate in patients with myelodisplastic syndrome treated with modulatory compounds of pro-apoptotic cytokines.

Excessive apoptosis has a central role in ineffective hematopoiesis in myelodysplastic syndrome (MDS). The aim of the study was to quantify apoptosis and Bcl-2 expression in patients with MDS and to use these parameters in the evaluation of treatment efficacy with compounds modulating proapoptotic cytokines. Bone marrow (BM) samples from eight MDS patients were studied: four with refractory anemia and four with refractory anemia with ringed sideroblasts. Two patients with Hodgkin disease without BM determination were studied for control. Therapy consisted in administration of pentoxyphylline, dexamethasone and ciprofloxacin. Biochemical assay of apoptosis and Bcl-2 was performed using annexin V-biotin conjugate antibody and anti-human Bcl-2 antibody respectively, followed by streptavidine-peroxidase conjugate, and peroxidase substrate. Ultrastructural investigation of BM samples was performed with standard electron microscopy techniques. Most of BM hematopoietic cells in the MDS patients had ultrastructural features of various stages of apoptosis including chromatin condensation and margination, cytoplasm condensation and budding of nuclear and plasma membranes to produce apoptotic bodies. Bcl-2 expression showed an inverse correlation with the rate of the apoptotic process. Periodic evaluation of these two parameters has shown an increase of Bcl-2 expression and a decrease of apoptotic rate in patients who had responded to the treatment. Response to the treatment was appreciated in accordance with their transfusion needs. Treatment efficiency diminished in time. The rate of apoptosis was inversely correlated with the level of Bcl-2 expression. These results confirm the importance of the apoptotic process evaluation in monitoring MDS treatment.

Platelet-activating factor acetylhydrolase activity in patients with chronic stable angina (preliminary results).

Coronary atherosclerotic disease is related to endothelial inflammation and dysfunction, thrombosis and plaque instability. Different inflammatory markers are studied in stable angina and coronary acute syndromes, in order to stratify better the risk and to prevent the cardiovascular events. Platelet-activating factor (PAF) and platelet activating factor acetylhydrolase (PAF-AH) represent a complex with proinflammatory actions, possibly related to progression of atherosclerotic lesions. In our study, we investigated PAF-AH activity in 30 patients with stable angina, trying to demonstrate a relation of PAF-AH activity with the severity of the coronary disease.

The antiphospholipid antibodies.

Antiphospholipid antibodies (APLAs) are a group of autoantibodies directed against certain phospholipids, or their protein cofactors. Assay of APLAs is important because their interaction with anionic phospholipid-protein cofactors can generate a syndrome of hypercoagulability associated with a wide variety of thromboembolic events. This article presents the characteristics of some APLAs [anticardiolipin antibodies (aCLAs), lupus anticoagulant (LA) and anti-beta2-glycoprotein I antibodies (anti-beta2-GPIAs)], their action, and their interaction with blood and endothelial cells. The presence of APLAs has been reported in many diseases (autoimmune diseases, atherosclerosis, infections, malignancies), being related to pathogenic mechanisms and/or to a more severe evolution of the disease.

Significance of platelet-activating factor acetylhydrolase in patients with non-insulin-dependent (type 2) diabetes mellitus.

BACKGROUND: Non-insulin dependent diabetes mellitus (NIDDM) represents an independent risk factor for cardiovascular diseases (CVD), being characterized by a continuous low-grade inflammation and endothelial activation state. Plasma platelet - activating factor - acetylhydrolases (PAF-AHs) are a subgroup of Ca(2+)-independent phospholipase A(2) family (also known as lipoprotein-associated phospholipases A(2)) that hydrolyze and inactivate the lipid mediator platelet-activating factor (PAF) and/or oxidized phospholipids. This enzyme is considered to play an important role in inflammatory diseases and atherosclerosis. The present study aims to investigate the relations between the levels of PAF-AH activity and LDL-cholesterol / HDL-cholesterol (LDL-ch / HDL-ch) ratio in NIDDM patients as compared to controls. METHODS: serum PAF-AH activity was measured in 50 patients with dyslipidemia, in 50 NIDDM patients and in 50 controls (normal lipid and glucose levels). Total cholesterol, LDL-ch, HDL-ch, triglyceride and blood glucose were determined in all subjects. RESULTS: All NIDDM patients display hiperlipidemia, with increased LDL-ch and triglyceride levels. There is a significant correlation between LDL-ch levels (especially LDL-ch / HDL-ch ratio) and PAF-AH activity in dyslipidemic and NIDDM patients. CONCLUSION: Diabetic and dyslipidemic patients have an increased plasma PAF-AH activity correlated with their LDL-ch levels and mainly with LDL-ch / HDL-ch ratio. Plasma PAF-AH high levels appear to be important as a risk marker for endothelial dysfunction in patients with NIDDM.