Current Vascular Pharmacology - Volume 17, Issue 4, 2019

In recent years, the Angiotensin-(1-7)/Mas receptor [Ang-(1-7)/Mas] sub-branch of the Renin-Angiotensin System (RAS) in the brain, and Angiotensin Type 2 Receptors (AT2R), have attracted scientific interest, as there is evidence that they constitute an essential pathway in cardiovascular regulation, in health and in disease. By acting centrally, the Ang-(1-7)/Mas axis - that has been termed ‘the axis of good’- can exert blood pressure-lowering effects, while also favourably altering baroreflex sensitivity and noradrenergic neurotransmission. Thus, research has focused on the possible neuro- and cardioprotective effects of this pathway in the setting of cardiovascular disease, ultimately aiming to evaluate the potential for development of novel therapeutic strategies based on its modulation. We summarize the available evidence from experimental studies in this context, aiming to assess current limits of scientific knowledge relevant to this newly-described ‘player’ in haemodynamic regulation, that may become a potential therapeutic target.

Aspirin plays a pivotal role in the management of patients with Coronary Artery Disease (CAD) with well-recognised benefits of reducing recurrent myocardial infarction and minimising the risk of stent thrombosis for those undergoing Percutaneous Coronary Intervention (PCI). Dual antiplatelet therapy is mandated for patients undergoing PCI and typically consists of aspirin and a P2Y12 receptor antagonist. Aspirin hypersensitivity poses a significant clinical dilemma, as the safety and efficacy of oral antiplatelet combinations that exclude aspirin have not been validated. Although, genuine hypersensitivity to aspirin is encountered infrequently, it can be challenging when managing patients with concomitant CAD given the paucity of safe and effective alternatives. Aspirin desensitization is a potential and safe option but may not always be practical. This review aims to highlight the challenges of aspirin hypersensitivity in patients undergoing PCI and propose a treatment algorithm to address this issue in clinical practice.

Over the last 3 decades, hypolipidaemic treatment has significantly reduced both Cardiovascular (CV) risk and events, with statins being the cornerstone of this achievement. Nevertheless, residual CV risk and unmet goals in hypolipidaemic treatment make novel options necessary. Recently marketed monoclonal antibodies against proprotein convertase subtilisin/kexin type 9 (PCSK9) have shown the way towards innovation, while other ways of PCSK9 inhibition like small interfering RNA (Inclisiran) are already being tested. Other effective and well tolerated drugs affect known paths of lipid synthesis and metabolism, such as bempedoic acid blocking acetyl-coenzyme A synthesis at a different level than statins, pemafibrate selectively acting on peroxisome proliferator-activated receptor (PPAR)- alpha receptors and oligonucleotides against apolipoprotein (a). Additionally, other novel hypolipidaemic drugs are in early phase clinical trials, such as the inhibitors of apolipoprotein C-III, which is located on triglyceride (TG)-rich lipoproteins, or the inhibitors of angiopoietin-like 3 (ANGPTL3), which plays a key role in lipid metabolism, aiming to beneficial effects on TG levels and glucose metabolism. Among others, gene therapy substituting the loss of essential enzymes is already used for Lipoprotein Lipase (LPL) deficiency in autosomal chylomicronaemia and is expected to eliminate the lack of Low- Density Lipoprotein (LDL) receptors in patients with homozygous familial hypercholesterolaemia. Experimental data of High-Density Lipoprotein (HDL) mimetics infusion therapy have shown a beneficial effect on atherosclerotic plaques. Thus, many novel hypolipidaemic drugs targeting different aspects of lipid metabolism are being investigated, although they need to be assessed in large trials to prove their CV benefit and safety.

Background: Real-world evidence from published observational studies of adherence to Novel Oral Anticoagulants (NOACs) medications and associated clinical outcome events in Atrial Fibrillation (AF) patients, was reviewed systematically. Methods: Observational studies assessing patient adherence to NOACs conducted on AF patients between September 2010 and June 2016 were identified by systematic searching keywords to locate eligible studies, in accordance with Cochrane guidelines. PubMed, Scopus and Google Scholar databases were searched to identify the studies. Meta-analysis was performed using a random effects model with DerSimonian-Laird weighting to obtain pooled effect sizes. Results: From 185 potentially relevant citations, 6 studies, comprising 1.6 million AF patients, were included. Among these, successful adherence to NOACs occurred in 75.6%. Adherence levels were higher in patients treated with dabigatran (72.7%) compared with those treated with apixaban (59.9%) or rivaroxaban (59.3%). However, adherence was still suboptimal (relative to an expected 80% adherence rate). Bleeding events in non-adherent patients were found to be 7.5%. Conclusion: Suboptimal adherence to NOACs among AF patients was highlighted as a significant risk factor that may affect clinical outcomes, with a higher percentage of non-adherent patients having bleeding events. There is an urgent need for research on the effects of specific interventions to improve patient adherence to NOACs and to assess the related outcome factors that may be associated with adherence.

Background: We hypothesized that perioperative HbA1c influenced the pattern and outcomes of Lower Extremity Amputation (LEA). Methods: A retrospective analysis was conducted for all patients who underwent LEA between 2000 and 2013. Patients were categorized into 5 groups according to their perioperative HbA1c values [Group 1 (<6.5%), Group 2 (6.5-7.4%), Group 3 (7.5-8.4%), Group 4 (8.5-9.4%) and Group 5 (≥9.5%)]. We identified 848 patients with LEA; perioperative HbA1c levels were available in 547 cases (Group 1: 18.8%, Group 2: 17.7%, Group 3: 15.0%, Group 4: 13.5% and Group 5: 34.9%). Major amputation was performed in 35%, 32%, 22%, 10.8% and 13.6%, respectively. Results: The overall mortality was 36.5%; of that one quarter occurred during the index hospitalization. Mortality was higher in Group 1 (57.4%) compared with Groups 2-5 (46.9%, 38.3%, 36.1% and 31.2%, respectively, p=0.001). Cox regression analysis showed that poor glycemic control (Group 4 and 5) had lower risk of mortality post-LEA [hazard ratio 0.57 (95% CI 0.35-0.93) and hazard ratio 0.46 (95% CI 0.31-0.69)]; this mortality risk persisted even after adjustment for age and sex but was statistically insignificant. The rate of LEA was greater among poor glycemic control patients; however, the mortality was higher among patients with tight control. Conclusion: The effects of HbA1c on the immediate and long-term LEA outcomes and its therapeutic implications need further investigation.

Background: There is a close relationship between lipid metabolism disorders and atherosclerosis. Guidelines focus on lowering Low-Density Lipoprotein Cholesterol (LDL-C) levels. However, it should be kept in mind that LDL and High-Density Lipoprotein (HDL) consist of subfractions which can affect the progression of atherosclerosis. Objective: We assessed the concentration of LDL and HDL subfractions in patients with Acute Coronary Syndromes (ACS). The influence of the presence of type 2 diabetes mellitus on LDL and HDL subfractions was also analyzed. Methods: The study group consisted of 127 patients (62 men, 65 women) with ACS. All patients had coronary angiography and coronary angioplasty and stenting when necessary. Medical history was collected during 12 months of follow-up. HDL and LDL subfraction distribution was measured using Lipoprint (Quantimetrix). Results: No differences in LDL nor HDL subfractions were observed between ST-Segment Elevation Myocardial Infarction (STEMI), Non-ST-Segment Elevation Myocardial Infarction (NSTEMI) and unstable angina (UA) patients. However, those with restenosis and the necessity of repeated revascularization had higher levels of intermediate-density lipoprotein C (IDL-C) (p=0.055) and LDL3 (p=0.048) as compared with the patients without, while the level of IDL A (IDLA) was lower than in the latter group (p=0.036). In diabetic patients, the percentage share of HDL10 and small-dense HDL was significantly higher while the share of HDL1 (small-dense) (p=0.028), HDL4 (intermediate density) (p=0.052) and HDL5 (intermediate density) (p=0.060) were lower than in patients without DM. Conclusion: Patients with multi-vessel CAD disease had higher levels of LDL3 subfraction and IDL-C and a lower proportion of IDLA.

Background: Intraplaque angiogenesis, the process of generating new blood vessels mediated by endothelial cells, contributes to plaque growth, intraplaque hemorrhage, and thromboembolic events. Platelet-derived Exosomes (PLT-EXOs) affect angiogenesis in multiple ways. The ability of miR-126, one of the best-characterized miRNAs that regulates angiogenesis, carried by PLT-EXOs to influence angiogenesis via the regulation of the proliferation and migration of endothelial cells is unknown. In this study, we aimed to investigate the effects of PLT-EXOs on angiogenesis by Human Umbilical Vein Endothelial Cells (HUVECs). Methods: We evaluated the levels of miR-126 and angiogenic factors in PLT-EXOs from Acute Coronary Syndrome (ACS) patients and healthy donors by real-time Polymerase Chain Reaction (PCR) and western blotting. We incubated HUVECs with PLT-EXOs and measured cell proliferation and migration with the Cell Counting Kit-8 assay and scratch assay, respectively. We also investigated the expression of miR-126 and angiogenic factors in HUVECs after exposure to PLT-EXOs by western blotting and real-time PCR. Results: PLT-EXOs from ACS patients contained higher levels of miR-126 and angiogenic factors, including Vascular Endothelial Growth Factor (VEGF), basic Fibroblast Growth Factor (bFGF), and Transforming Growth Factor Beta 1 (TGF-β1), than those from healthy donors (p<0.05). Moreover, the levels of exosomal miR-126 and angiogenic factors were increased after stimulation with thrombin (p<0.01). HUVEC proliferation and migration were promoted by treatment with activated PLT-EXOs (p<0.01); they were accompanied by the over-expression of miR-126 and angiogenic factors, including VEGF, bFGF, and TGF-β1 (p<0.01). Conclusion: Activated PLT-EXOs promoted the proliferation and migration of HUVECs, and the overexpression of miR-126 and angiogenic factors, thereby elucidating potential new therapeutic targets for intraplaque angiogenesis.

Background: Most of the available literature on ST-Elevated myocardial infarction (STEMI) in women was conducted in the developed world and data from Middle-East countries was limited. Aims: To examine the clinical presentation, patient management, quality of care, risk factors and inhospital outcomes of women with acute STEMI compared with men using data from a large STEMI registry from the Middle East. Methods: Data were derived from the third Gulf Registry of Acute Coronary Events (Gulf RACE-3Ps), a prospective, multinational study of adults with acute STEMI from 36 hospitals in 6 Middle-Eastern countries. The study included 2928 patients; 296 women (10.1%) and 2632 men (89.9%). Clinical presentations, management and in-hospital outcomes were compared between the 2 groups. Results: Women were 10 years older and more likely to have diabetes mellitus, hypertension, and hyperlipidemia compared with men who were more likely to be smokers (all p<0.001). Women had longer median symptom-onset to emergency department (ED) arrival times (230 vs. 170 min, p<0.001) and ED to diagnostic ECG (8 vs. 6 min., p<0.001). When primary percutaneous coronary intervention (PPCI) was performed, women had longer door-to-balloon time (DBT) (86 vs. 73 min., p=0.009). When thrombolytic therapy was not administered, women were less likely to receive PPCI (69.7 vs. 76.7%, p=0.036). The mean duration of hospital stay was longer in women (6.03 ± 22.51 vs. 3.41 ± 19.45 days, p=0.032) and the crude in-hospital mortality rate was higher in women (10.4 vs. 5.2%, p<0.001). However, after adjustments, multivariate analysis revealed a statistically non-significant trend of higher inhospital mortality among women than men (6.4 vs. 4.6%), (p=0.145). Conclusion: Our study demonstrates that women in our region have almost double the mortality from STEMI compared with men. Although this can partially be explained by older age and higher risk profiles in women, however, correction of identified gaps in quality of care should be attempted to reduce the high morbidity and mortality of STEMI in our women.

Background: Cardiac performance depends on optimum ventriculoarterial coupling which is impaired in patients with heart failure (HF). Galectin-3 is a mediator of myocardial fibrosis and remodeling, and is associated with clinical status in patients with chronic HF. We examined the association of arterial stiffness with galectin-3 levels in patients with HF of ischemic etiology. Methods: We consecutively enrolled 40 patients with stable ischemic HF and reduced ejection fraction. Central aortic stiffness was evaluated non-invasively by measuring carotid femoral pulse wave velocity (PWV). Among other factors, serum levels of galectin-3 and b-type natriuretic peptide (BNP) were measured. Results: The median galectin-3 levels in our study population were 12.9 (10.8-18.7) ng/ml and the mean PWV was 9.31±2.79 m/sec. There was significant association of galectin-3 levels with age (r=0.48, p=0.003), creatinine clearance (r=-0.66, p<0.001) and BNP levels (r=0.36, p=0.05). There was a significant association of galectin-3 levels with PWV (r=0.37, p=0.03) and patients with PWV above median also had significantly increased levels of galectin-3 compared with patients with lower values of PWV [16.1(11.8-25.2) vs. 12.1(10.5-14) ng/ml, p=0.03]. Conclusion: We found an association of arterial stiffness and PWV with galectin-3 levels in patients with chronic HF of ischemic etiology. These findings suggest a pathway driving arterial stiffening and myocardial remodelling in HF. This may provide insight into the mechanism determining prognosis and clinical status of patients with HF.

Background: Lifestyle remains a huge driving force of Cardiovascular Diseases (CVD) onset/ progression. Lifestyle-patterns are highly dependent on gender-related attitudes. Objective: To evaluate the gender-specific association of lifestyle-related factors (adherence to Mediterranean diet (MedDiet), Physical Activity (PA), smoking) with 10-year first and recurrent CVD events. Methods: Two prospective studies, the ATTICA (2002-2012, n=3,042 subjects free-of-CVD) and GREECS (2004-2014, n=2,172 subjects with Acute Coronary Syndrome (ACS)) were undertaken. Baseline adherence to MedDiet (MedDietScore <27/≥27, range 0-55), PA (sedentary/physically active) and smoking (current/never) was tested against 10-year first (ATTICA) and recurrent (GREECS) CVD events, in men and women. Results: The “superiority” of men over women regarding overall CVD events was revealed in both first (ATTICA, 19.7% men vs. 11.7% women, p<0.001) and recurrent CVD events, but less significantly (GREECS, 38.8% men vs. 32.9% women, p=0.016). Gender-stratified analysis revealed that: lower adherence to MedDiet in women (Odds Ratio (OR)=1.22, 95% Confidence Interval (95%CI) 1.03, 1.51) and PA (OR=1.35, 95%CI 1.01, 1.85) and smoking (OR=1.28, 95%CI 1.04, 1.82) in men, were independent predictors of 10-year first CVD event; whereas, adherence to MedDiet (OR=1.28, 95%CI 1.01, 1.59), PA (OR=1.25, 95%CI 1.01, 2.50) and smoking (OR=1.15, 95%CI 1.01, 1.30) in women, yet only adherence to MedDiet (OR=1.27, 95%CI 1.01, 1.35) and PA (OR=1.27, 95%CI 1.02, 1.59) in men, were independent predictors of 10-year CVD recurrent events. Conclusion: Differences between men and women, in the effect-size measures of lifestyle-related factors, underline different paths for men and women, probably contributing to better designing strategies for primary and secondary CVD prevention.

Background: We have found that anagliptin, a dipeptidyl peptidase-4 inhibitor (DPP-4) significantly ameliorates arterial stiffness in Type 2 Diabetes Mellitus (T2DM) patients compared with an equivalent hypoglycaemic agent, glimepiride. However, it remains unclear whether switching DPP-4 inhibitors to tofogliflozin, a selective inhibitor of Sodium-Glucose Cotransporter 2 (SGLT2) improves arterial stiffness in T2DM patients. Methods: Nineteen T2DM patients who had received DPP-4 inhibitors for at least 1 year were enrolled in this study. Clinical parameters and arterial stiffness evaluated by cardio-ankle vascular index (CAVI) were measured at baseline and after 6-months treatment with tofogliflozin. Results: At 6 months after switching to tofogliflozin, CAVI, waist circumference, body weight, body mass index, subcutaneous and visceral fat volume, white blood cell number, fasting plasma insulin, uric acid, aspartate transaminase (AST), γ-glutamyl transferase (GTP), and advanced glycation end products (AGEs) were significantly reduced, while red blood cell number, haemoglobin, and HbA1c values were increased. When stratified by median values of change in CAVI after switching to tofogliflozin (ΔCAVI), baseline serum levels of AGEs were significantly higher in the low ΔCAVI group (high responder) than in the high one (low responder). ΔAST and ΔGTP were positively correlated with ΔCAVI. Conclusion: The present study suggests that switching DPP-4 inhibitors to tofogliflozin ameliorates arterial stiffness in T2DM patients partly via improvement of liver function. Baseline serum levels of AGEs may identify patients who improve arterial stiffness more after treatment with tofogliflozin.