Current Vascular Pharmacology - Volume 15, Issue 2, 2017

Sodium-glucose co-transporter 2 (SGLT2) inhibitors are a new class of antidiabetic drugs that inhibit glucose and sodium reabsorption at proximal tubules. These drugs may exhibit renoprotective properties, since they prevent the deterioration of the glomerular filtration rate and reduce the degree of albuminuria in patients with diabetes-associated kidney disease. In this review we consider the pathophysiologic mechanisms that have been recently implicated in the renoprotective properties of SGLT2 inhibitors. The beneficial effects of SGLT2 inhibitors on the conventional risk factors for kidney disease (such as blood pressure, hyperglycaemia, body weight and serum uric acid levels) may explain, at least in part, the observed renal-protecting properties of these compounds. However, it has been hypothesized that the most important mechanisms for this phenomenon include the reduction in the intraglomerular pressure, the changes in the local and systemic degree of activation of the renin-aldosterone-angiotensin system and a shift in renal fuel consumption towards more efficient energy substrates such as ketone bodies. The beneficial effects of SGLT2 inhibitors on various aspects of renal function make them an attractive choice in patients with (and possibly without) diabetes-associated renal impairment.

Background: Endovascular (EVAR) or open surgical (OSR) repair are current treatment options for abdominal aortic aneurysm (AAA). Objective: To produce a systematic review comparing the impact of these 2 treatment options on renal function during mid- and long term follow up. Methods: The MEDLINE, EMBASE and Cochrane databases and key references were searched. Results: Six studies were included from 2000 to 2016, (4 retrospective and 2 RCT studies) reporting on 2,102 patients (54%; 1096 EVAR, 46%; 1006 OSR). The mean age in EVAR group ranged from 69.4 to 73.8 years (91% males), and in OSR group from 68 to 73.6 years (91% males). The data were too heterogeneous to perform a meta-analysis. All studies used GFR (Glomerular Filtration Rate) or estimated GFR (eGFR) to record renal function. The commonest risk factors were the presence of hypertension (77.5%), hyperlipidaemia (48.3%), coronary artery disease (42%) and smoking (37.8%). During follow up, new events of renal impairment (increase >20% in GFR) in EVAR patients and in OSR patients were 58 (5.3%) and 52 (5.2%), respectively. The mean GFR was decreased during follow up period in both types of the procedure. Conclusion: There is lack of definitive evidence to prove the superiority of OSR over EVAR regarding renal function in the post-operative follow up period. It appears that renal impairment may occur after both interventions. Further prospective research is needed to clarify the issue.

Apoptosis may contribute to a significant proportion of neuron death following acute brain ischemia (ABI), but the underlying mechanisms are still not fully understood. Brain ischemia may lead to stroke, which is one of the main causes of long-term morbidity and mortality in both developed and developing countries. Therefore, stroke prevention and treatment is clinically important. There are two important separate areas of the brain during ABI: the ischemic core and the ischemic penumbra. The ischemic core of the brain experiences a sudden reduction of blood flow, just minutes after ischemic attack with irreversible injury and subsequent cell death. On the other hand, apoptosis within the ischemic penumbra may occur after several hours or days, while necrosis starts in the first hours after the onset of ABI in the ischemic core. ABI is characterized by key molecular events that initiate apoptosis in many cells, such as overproduction of free radicals, Ca2+ overload and excitotoxicity. These changes in cellular homeostasis may trigger either necrosis or apoptosis, which often depends on cell type, cell age, and location in the brain. Apoptosis results in DNA fragmentation, degradation of cytoskeletal and nuclear proteins, cross-linking of proteins, formation of apoptotic bodies, expression of ligands for phagocytic cell receptors and finally uptake by phagocytic cells. This review focuses on recent findings based on animal and human studies regarding the apoptotic mechanisms of neuronal death following ABI and the development of potential neuroprotective agents that reduce morbidity. The effects of statins on stroke prevention and treatment as well as on apoptotic mediators are also considered.

Background: Chronic kidney disease (CKD) is a worldwide public health problem and an independent risk factor for cardiovascular disease (CVD). Objective: We assessed cardiovascular risk in end-stage renal disease (ESRD) patients and evaluated the relationship between serum uric acid (SUA) and lipoprotein subfractions. Methods: The study group consisted of 66 patients on dialysis and a control group of 25 healthy volunteers. Concentration of high-density lipoproteins (HDL) and low-density lipoproteins (LDL) subfractions were analysed using a Lipoprint™. Lipid profiles and SUA were measured. Results: Statistically significant differences between control and study group both with increased and normal SUA level were observed for HDL subfractions (1-5 [p = 0.0014 – 0.0001] and 7 – 10 [p=0.016], large and small HDL subfractions [p<0.0001]), LDL-2 subfraction [p = 0.016] and IDL-B [p = 0.015]. A significant decrease by 66% in CVD prevalence was found in dialysis patients with increased level of SUA (> 428 μmol/l) (p = 0.034). Association between SUA and CVD prevalence was independent of large, intermediate and small HDL subfractions as well as of very low-density lipoprotein (VLDL), intermediate- density lipoproteins-C, -B, -A (IDL-C, IDL-B and IDL-A). Conclusion: Our study demonstrated that higher SUA level might be associated with lower prevalence of CVD among haemodialysis patients. An elevated SUA concentration in haemodialysis population may be a marker of better nutritional status and also represent the antioxidant properties SUA.

Background: Epicardial adipose tissue (EAT) is a visceral adipose tissue (AT) surrounding and infiltrating myocardium and coronary arteries. Increased EAT may represent a chronic inflammatory injury and a link with coronary artery disease (CAD). Metalloproteinases (MMPs) are involved in expansion of AT. Objective: To evaluate MMP-2 and -9 behaviour in EAT from CAD patients. Methods: In EAT and subcutaneous AT (SAT) from patients undergoing coronary artery bypass graft (CABG, n=26) or valve replacement (No CABG, n=18), MMP-2 and -9 activity and localization, inflammatory cells and vascular endothelial growth factor (VEGF) levels were determined. Results: In EAT from CABG, MMP-2 and -9 activity was increased compared with No CABG (p=0.041 and p=0.027, respectively) and compared with SAT (p=0.005 and p=0.048, respectively). In CABG patients EAT showed higher infiltration of macrophages and T lymphocytes than SAT (p=0.01 and p=0.002, respectively). In No CABG patients no sign of cellular retention was observed in EAT or SAT. Vascular density was higher in EAT from CABG than No CABG (p=0.015) and it was directly correlated with MMP-2 (p=0.006) and MMP-9 (p=0.02). VEGF levels in EAT were directly associated with MMP-2 (p=0.016). Conclusion: In EAT from CABG patients the increase of MMP-2 and -9 activity and the presence of inflammatory cells would be partially responsible for extracellular matrix (ECM) remodeling and major vascular density necessary for EAT expansion. Improved knowledge of EAT behaviour may allow to identify new therapeutic targets for the treatment of CAD.

Background: Chronic Kidney Disease (CKD) is an independent risk factor for cardiovascular disease (CVD). CKD is accompanied by high cardiovascular mortality due to many factors, but atherosclerosis is thought to be a major cause at every CKD stage. It has been suggested that measuring and estimating changes in high density lipoprotein (HDL) and low density lipoprotein (LDL) subfractions may be important for predicting CVD in CKD patients. Objective: The aim of this study was to determine and compare levels of HDL and LDL subfractions in patients with different CKD stages. Methods: The study included 115 patients with CKD (CKD stage 2-25 patients, CKD stage 3-25; CKD stage 4-25 and CKD 5 undergoing dialysis - 40 patients) and 25 volunteers without CKD (control group). The Lipoprint System (Quantimetrix®) was used to analyse HDL and LDL subfractions. Results: There were significant differences in the distribution of HDL1-HDL5 subfractions levels, which were significantly higher in patients with impaired renal function than in the control group (p≤0.013 for all comparisons). HDL7-HDL10 subfractions were significantly more prevalent in healthy volunteers compared with CKD patients (p≤0.001 for all comparisons). The analysis of LDL subfractions revealed significant differences only in IDL-B (p<0.05), IDL-A (p<0.05) and LDL2 (p<0.001) between patients with CKD stage 5 and controls. Conclusion: CKD influenced HDL and LDL subfractions. In CKD patients, large HDL subpopulations were more prevalent in contrast to small HDL subfractions in healthy subjects. Identification of patients with increased level of large HDL subfractions could be useful to identify CKD subjects at increased CV risk. Further studies with larger populations and with the application of a several methods of subfraction measurement are necessary to confirm these results.

Objectives: Recent research has shown that hypovitaminosis D may increase the risk of hypertension, vascular disease, diabetes mellitus, obesity and Metabolic Syndrome (MetS). Endothelial Dysfunction (ED) is one of the key components of MetS which is associated with an imbalance between vasoactive substances such as Nitric Oxide (NO) and Endothelins (ET). In this study, we assessed the association of 25(OH) D3 level with endothelial dysfunction and subclinical atherosclerosis in MetS patients. Design and Methods: 105 MetS patients and 48 controls were included. 25(OH) D3 levels were measured using Ultra-High Performance Liquid Chromatography (UHPLC). NOx (NO2 plus NO3) and Endothelin- 1(ET-1) concentrations were determined along with routine biochemical tests. Flow-Mediated Dilatation (FMD) and carotid Intima-Media Thickness (cIMT) were measured by ultrasonography. Results: In MetS patients, vitamin D and NOx levels were significantly lower (p<0.001), while ET-1 levels were higher than controls (p<0.005). MetS patients with ED exhibited significantly lower vitamin D levels than their counterparts free of ED. Vitamin D levels were correlated positively with FMD and NOx, and negatively with systolic blood pressure and body mass index. Subclinical atherosclerosis as assessed by the cIMT did not associate with low vitamin D levels. Conclusion: Vitamin D deficiency seen in MetS patients is more prominent in the presence of ED. Hypovitaminosis D may affect endothelial cells, and participate in the development of hypertension.

Background: The growing body of evidence suggests that atherosclerosis risk factors are important in cognitive decline. Objective: To analyse insulin sensitivity, insulin secretion capacity, plasma insulin, adiponectin and lipid levels in normoglycaemic, nonobese patients with Alzheimer’s disease (AD) (group A, n=62), mild cognitive impairment (MCI) (group B, n=41), and healthy controls (group C, n=25). Method: Insulin sensitivity was determined by euglycemic hyperinsulinaemic clamp (M value) and homeostasis model assessment (HOMA-IR), insulin secretion capacity by first-phase insulin response (FPIR), plasma insulin by RIA, adiponectin by ELISA, total cholesterol (TC), high-density lipoprotein cholesterol (HDL-C), low-density lipoprotein cholesterol (LDL-C) and triglycerides by enzymatic method. Results: Insulin sensitivity was the lowest in group A (M value: A: 6.2±2.5; B:7.7±2.7; C:8.2±1.5 mg/min/kg, p<0.001; HOMA-IR: A: 4.6±2.2; B: 3.3±1.7; C: 1.5±1.0, p<0.001) as well as FPIR (A:68.9±27.8; B:112.5±47.1; C:147.4±56.0 mU/l, p<0.001). Plasma insulin was higher in group A vs B vs C, while adiponectin was lower in group A vs B vs C. Simultaneously, total and LDL-C were higher and HDL-C levels were lower in groups A and B vs C, with no difference between groups A and B. Triglycerides did not differ between the groups. Binary logistic regression analysis identified only M value, FPIR and plasma insulin as independent predictors of AD and MCI. Conclusion: These results imply that in AD and MCI insulin resistance with increased plasma insulin and decreased FPIR may be associated with the development of AD and MCI, accompanied with milder influence of low adiponectin levels and atherogenic lipid profile.

Background: Addictive behaviours in adolescents such as alcohol consumption and smoking are rapidly increasing worldwide. Objective: No previous study has examined smoking status and alcohol consumption in adolescents of Northern Greece in relation to their food habits. Therefore, we assessed the smoking status and alcohol consumption, as well the food habits, of this population. Method: Adolescents (495 boys and 508 girls) aged 15±1 years old and 15±2 years old respectively, completed questionnaires regarding smoking, alcohol and food habits. Results: Tobacco use and alcohol consumption were reported by 9.2% and 48.1% of them, respectively. Of those that drank alcohol, 13.9% were also smokers. Older adolescents were more likely to consume foods high in fat and sugar, low in vitamins and minerals as well as foods, considered by them to be less healthy and prepared in a less healthy way. Moreover, smoker adolescents were less likely to choose foods considered to be healthy and prepared in a healthy way, whereas they were more likely to choose foods high in fat content. Conclusions: Both smoking and alcohol consumption may affect cardiovascular risk and the vasculature. Poor lifestyle (and risk of vascular events) can start at an early age.

Background and objective: Contrast-induced acute kidney injury (CI-AKI) is a serious complication of the administration of iodinated contrast media (CM) for diagnostic and interventional cardiovascular procedures and is associated with substantial morbidity and mortality. While the preventative measures can mitigate the risk of CI-AKI, there remains a need for novel and effective therapeutic approaches. The pathogenesis of CI-AKI is complex and not completely understood. CM-induced renal tubular cell apoptosis caused by the activation of endoplasmic reticulum (ER) stress is involved in CIAKI. We previously demonstrated that valsartan alleviated CM-induced human renal tubular cell apoptosis by inhibiting ER stress in vitro. However, the nephroprotective effect of valsartan on CI-AKI in vivo has not been investigated. Therefore, the aim of this study was to explore the protective effect of valsartan in a rat model of CI-AKI by measuring the amelioration of renal damage and the changes in ER stressrelated biomarkers. Method and Results: Our results showed that the radiocontrast agent meglumine diatrizoate caused significant renal insufficiency, renin-angiotensin system (RAS) activation, and renal tubular apoptosis by triggering ER stress through activation of glucose-regulated protein 78 (GRP78), activating transcription factor 4 (ATF4), caspase 12, CCAAT/enhancer-binding protein-homologous protein (CHOP) and c-Jun N-terminal protein kinase (JNK) (P<0.05; n=6 in each group). Pre-treatment with valsartan significantly alleviated renal dysfunction, pathological injury, and apoptosis along with the inhibition of ER stressrelated biomarkers (P<0.05; n=8 in each group). Conclusion: Valsartan could protect against meglumine diatrizoate-induced kidney injury in rats by inhibiting the ER stress-induced apoptosis, making it a promising strategy for preventing CI-AKI.