Djordje Radak

Oxidized low-density lipoprotein as a biomarker of cardiovascular diseases

Abstract Atherosclerosis is a life-long illness that begins with risk factors, which in turn contribute to the development of subclinical disease, followed by the establishment of overt cardiovascular disease (CVD). Thrombotic-occlusive complications of atherosclerosis are among the most widespread and costly health problems. Oxidized low-density lipoprotein (OxLDL) plays an important role in atherogenesis by promoting an inflammatory environment and lipid deposition in the arterial wall. As cardiovascular events occur in individuals without common risk factors, there is a need for additional tools that may help in CVD risk assessment and management. The use of biomarkers has improved diagnostic, therapeutic and prognostic outcome in cardiovascular medicine. This review elaborates on the value of circulating OxLDL as a biomarker of CVD. Three enzyme-linked immunosorbent assays (4E6, DLH3 and E06) using murine monoclonal antibodies for determination of OxLDL blood levels have been developed. However, none of these assays are currently approved for routine clinical practice. We identified studies investigating OxLDL in CVD (measured by 4E6, DLH3 or E06 assay) by searching the PubMed database. Circulating OxLDL was found to be associated with all stages of atherosclerosis, from early atherogenesis to hypertension, coronary and peripheral arterial disease, acute coronary syndromes and ischemic cerebral infarction. The results of studies investigating the usefulness of OxLDL for CVD prediction were also summarized. Furthermore, OxLDL was found to be associated with pathologic conditions linked to CVD, including diabetes mellitus, obesity and metabolic syndrome (MetS). In addition, we have addressed the mechanisms by which OxLDL promotes atherogenesis, and the effects of antiatherogenic treatments on circulating OxLDL. Finally, we highlight the evidence suggesting that lipoprotein (a) [Lp(a)] is the preferential carrier of oxidized phospholipids (OxPL) in human plasma. A strong association between OxPL/apoB level (representing the content of OxPL on apolipoprotein B-100 particles, measured by E06 assay) and Lp(a) has been determined.

Link between oxidative stress and acute brain ischemia.

The pathogenesis of acute brain ischemia (ABI) is highly complex and involves multiple mechanisms including free radical generation. Imbalance between the cellular production of free radicals and the ability of cells to defend against them is referred to as oxidative stress. Oxidative stress is one of the mechanisms contributing to neuronal damage, potentially induced through the ABI. Through interactions with a large number of molecules, reactive oxygen species may irreversibly destroy or alter the function of the cellular lipids, proteins, and nucleic acids and initiate cell signaling pathways after cerebral ischemia. Future investigations should focus on the understanding of oxidative stress mechanisms and neuroprotection in order to discover new treatment targets.

Network topology reveals key cardiovascular disease genes.

The structure of protein-protein interaction (PPI) networks has already been successfully used as a source of new biological information. Even though cardiovascular diseases (CVDs) are a major global cause of death, many CVD genes still await discovery. We explore ways to utilize the structure of the human PPI network to find important genes for CVDs that should be targeted by drugs. The hope is to use the properties of such important genes to predict new ones, which would in turn improve a choice of therapy. We propose a methodology that examines the PPI network wiring around genes involved in CVDs. We use the methodology to identify a subset of CVD-related genes that are statistically significantly enriched in drug targets and “driver genes.” We seek such genes, since driver genes have been proposed to drive onset and progression of a disease. Our identified subset of CVD genes has a large overlap with the Core Diseasome, which has been postulated to be the key to disease formation and hence should be the primary object of therapeutic intervention. This indicates that our methodology identifies “key” genes responsible for CVDs. Thus, we use it to predict new CVD genes and we validate over 70% of our predictions in the literature. Finally, we show that our predicted genes are functionally similar to currently known CVD drug targets, which confirms a potential utility of our methodology towards improving therapy for CVDs.

Eversion carotid endarterectomy--our experience after 20 years of carotid surgery and 9897 carotid endarterectomy procedures.

BACKGROUND The aim of this article is to review our experience in surgical treatment of carotid atherosclerosis using eversion carotid endarterectomy (eCEA) in 9,897 patients performed in the last 20 years, with particular attention to diagnostic approach, surgical technique, medical therapy, and final outcome. METHODS From January 1991 to December 2010, 9,897 primary eCEAs were performed for high-grade carotid stenosis. Patients treated for restenosis after previous carotid surgery were excluded from the analysis. Follow-up included routine clinical evaluation and noninvasive surveillance, with duplex scanning, 1 and 6 months after surgery, and annually afterward. RESULTS The majority of the patients were symptomatic (stroke, 42.8%; transient ischemic attack, 55.1% [focal cerebral and retinal ischemia]), whereas only 2.1% of the patients were asymptomatic. For the final diagnosis, duplex scanning was performed in 83.4% of patients and angiography in only 16.3% (P < 0.001). Average carotid artery clamping time was 11.9 ± 3.2 minutes, and the majority of the patients were operated under general anesthesia (99.4%). Intraoperative shunting and local anesthesia were rarely performed; 0.6% of the patients were operated under local anesthesia, and in 0.5% of the patients, intraluminal shunt was used. Neurological and total morbidity showed a steady decline over time, with rate of neurological morbidity of 1.1% and total morbidity of 3.9% at the end of 2010. Neurological mortality and total mortality also showed a steady decline over time, with rate of neurological mortality of 0.3% and total mortality of 0.8% at the end of 2010. There was a low rate of both, nonsignificant restenosis (<50%), which was verified in 2.1% of the patients, and significant restenosis (>50%), which was observed in 4.3% of the patients. CONCLUSION Our data show that eCEA is a reliable surgical technique for the treatment of atherosclerotic carotid disease, with low morbidity and mortality. The specificity of our experience is the significant number of patients with preoperative stroke, but despite this fact, results are comparable with previously published series. It also highlights the importance of comprehensive surgical training in reducing complications.

Health-related quality of life among patients with peripheral arterial disease.

We evaluated health-related quality of life (HRQoL) among patients with peripheral arterial disease (PAD) and compared the results with those of the general population. We also evaluated the possible association between some demographic and clinical characteristics of patients with PAD and HRQoL. A cross-sectional study involved 102 consecutive patients with verified PAD referred to the Dedinje Vascular Surgery Clinic in Belgrade. The HRQoL was measured using Medical Outcome Survey Short Form 36 (SF-36). Patients with PAD had significantly lower mean SF-36 scores for physical functioning, role-physical, bodily pain, social functioning, role-emotional, and mental health in comparison with the general population. The HRQoL was significantly more impaired in patients with severe PAD. Patients with PAD had a reduced HRQoL compared with the general population. The impact of PAD on HRQoL was independent of other factors related to both the disease and the HRQoL.

Association of MMP-8 promoter gene polymorphisms with carotid atherosclerosis: Preliminary study

OBJECTIVE Matrix metalloproteinases (MMPs) are involved in the remodeling of the extracellular matrix in the arterial wall. Collagen I is associated with vascular smooth muscle cell (VSMC) migration and monocyte differentiation. MMP-8 is expressed in atherosclerotic plaque and preferentially cleaves collagen type I. The aim of this study was to investigate the associations of two MMP-8 promoter polymorphisms, rs11225395 (-799C/T) and rs1320632 (-381 A/G), with carotid plaque occurrence, and the influence of these polymorphisms on MMP-8 mRNA expression in plaque tissue. METHODS The study included a total of 766 participants: 277 controls and 489 patients with carotid atherosclerosis undergoing endarterectomy. The two investigated polymorphisms were genotyped by PCR-RFLP. The gene expression analysis was performed by real-time PCR. RESULTS In females only, a significantly higher frequency of the -381G allele was found in patients with carotid atherosclerosis compared to controls (OR, 1.7; 95% CI 1.1-2.9; p = 0.001). Significant up-regulation of MMP-8 gene expression was observed in patients carrying the -381G allele compared to those with the AA genotype (mean factor, 3.54; S.E. range, 0.643-19.551; p = 0.007). Carotid plaque tissue of the haplotype G(-381)T(-799) showed a significantly higher mRNA level compared with the reference A(-381)C(-799) haplotype (p = 0.003). CONCLUSION Our preliminary results indicate that MMP-8 -381A/G and -799C/T gene polymorphisms could be risk factors for carotid atherosclerosis. Further validation and functional studies are needed to establish the potential regulatory role of these polymorphisms and their impact on susceptibility to carotid atherosclerosis.

Factors Related To Venous Ulceration A Cross-Sectional Study

The aim of the study was to determine the factors related to venous ulceration. Patients with venous ulceration (278 patients) were compared with 1401 patients in other categories of clinical classification of venous disease (clinical, etiologic, anatomic, and pathophysiological [CEAP]). Demographic, anthropometric, and clinical data were collected. Univariate and multivariate logistic regression analyses were used. According to multivariate analyses, risk factors for venous ulceration were age, male sex, personal history of superficial and deep venous thrombosis, diabetes, high blood pressure, skeletal or joint disease in the legs and emphysema or chronic obstructive pulmonary disease, higher body mass index and physical inactivity, parental history of ankle ulcer as well as reflux in deep and perforator veins, deep obstruction, and combination of reflux and obstruction. It seems reasonable to pay special attention to patients in whom the postulated risk factors for venous ulceration are present.

Changes in hypothalamus-pituitary-adrenal axis following transient ischemic attack.

Acute brain ischemia caused by transient ischemic attack initiates a complex sequence of events in the central nervous system and hypothalamic–pituitary–adrenal (HPA) axis which may ultimately culminate in neuronal and cell damage. The brain is highly susceptible to ischemia and in response to stress shows changes in morphology and chemistry that are largely reversible. These responses are known to modify the function of the HPA axis, but their mechanisms are not yet clear. Duration and size of the HPA axis activation are regulated by corticotropin-releasing hormone, vasopressin (AVP), and glucocorticoids, including cortisol. Numerous studies suggest that activation of these hormones following brain ischemia can result in neurohormonal dysfunction that can exacerbate long-term prognosis following stroke. These studies represent evidence that changes in the HPA axis play an important role in brain ischemia.

Body mass index and primary chronic venous disease--a cross-sectional study.

OBJECTIVES This study aims to investigate whether overweight and obesity are related to the clinical (C) category of clinical, etiologic, anatomic and pathophysiologic (CEAP) classification of chronic venous disease (CVD). DESIGN A cross-sectional study. MATERIALS AND METHODS The study was conducted in Serbia, in the year 2011. Men and women aged >18 years, consecutively coming to venous specialists because of venous problems in the legs, were included in the study. Patients demographic, anthropometric and clinical data were collected. For the analysis, univariate and multivariate logistic regressions were used. RESULTS The study comprised 1116 subjects with primary CVD, 384 (34.4%) men and 732 (65.6%) women. Among them 464 (41.6%) were normal-weight patients (body mass index (BMI) < 25.0 kg m(-2)), 476 (42.7%) were overweight (BMI = 25.0-29.9 kg m(-2)) and 176 (15.8%) were obese (BMI ≥ 30.0 kg m(-2)). According to multivariate analysis, the CEAP C category of CVD was significantly more advanced in overweight and obese patients, the association being more pronounced in obese. Compared groups did not differ in the presence of venous reflux. In univariate analysis, venous obstruction was related to overweight and obesity but this association did not substantially affect the relationship between obesity and CEAP C categories of CVD. CONCLUSION The CEAP C categories of CVD were significantly related to overweight and obesity, and this association was independent of age, sex and some other postulated risk factors.

Anesthetics and cerebral protection in patients undergoing carotid endarterectomy.

EREBRAL ISCHEMIA/HYPOXIA may occur in a vari-ety of perioperative circumstances. The main pathophy-siologic aspects involved in cerebral ischemia/reperfusion arecaused by adenosine triphosphate (ATP) consumption, theexcitotoxic actions of glutamate, changes in ionic homeostasis,and formation of free radicals (Fig 1). Outcomes from suchevents range from subclinical neurocognitive deficits to cata-strophic neurologic morbidity or death.