Current Vascular Pharmacology - Volume 19, Issue 6, 2021

Aging has been considered to be the most important non-modifiable risk factor for stroke and death. Changes in circulation factors in the systemic environment, cellular senescence and artery hypertension during human ageing have been investigated. Exosomes are nanosize membrane vesicles that can regulate target cell functions via delivering their carried bioactive molecules (e.g. protein, mRNA, and microRNAs). In the central nervous system, exosomes and exosomal microRNAs play a critical role in regulating neurovascular function and are implicated in stroke initiation and progression. MicroRNAs are small non-coding RNAs that have been reported to play critical roles in various biological processes. Recently, evidence has shown that microRNAs are packaged into exosomes and can be secreted into the systemic and tissue environment. Circulating microRNAs participate in cellular senescence and contribute to age-associated stroke. Here, we provide an overview of current knowledge on exosomes and their carried microRNAs in the regulation of cellular and organismal ageing processes, demonstrating the potential role of exosomes and their carried microRNAs in age-associated stroke.

Cardiovascular diseases (CVD) remain a major cause of death worldwide. Evidence suggests that the risk for CVD can increase at the fetal stages due to maternal metabolic diseases, such as gestational diabetes mellitus (GDM) and maternal supraphysiological hypercholesterolemia (MSPH). GDM is a hyperglycemic, inflammatory, and insulin-resistant state that increases plasma levels of free fatty acids and triglycerides, impairs endothelial vascular tone regulation, and due to the increased nutrient transport, exposes the fetus to the altered metabolic conditions of the mother. MSPH involves increased levels of cholesterol (mainly as low-density lipoprotein cholesterol) which also causes endothelial dysfunction and alters nutrient transport to the fetus. Despite that an association has already been established between MSPH and increased CVD risk, however, little is known about the cellular processes underlying this relationship. Our knowledge is further obscured when the simultaneous presentation of MSPH and GDM takes place. In this context, GDM and MSPH may substantially increase fetal CVD risk due to synergistic impairment of placental nutrient transport and endothelial dysfunction. More studies on the separate and/or cumulative role of both processes are warranted to suggest specific treatment options.

Background: There is a need to analyse the current approach to beta-blocker (BB) use in relation to exercise-based stress tests. Objective: We compared various guidelines regarding recommending abrupt vs. gradual discontinuation of BB prior to exercise tests. We also analyse the shortcomings of the currently recommended approach and suggest a new approach to avoid BB rebound. Methods: A narrative review is used to analyse this topic due to the lack of valid randomized clinical trials. Results: Omitting the BB therapy prior to exercise-based test has been recommended in guidelines for many years. Although reasonable, this approach has potential disadvantages since sudden BB withdrawal may induce a rebound phenomenon, which is also acknowledged in several guidelines. Conclusion: We observed inconsistency among relevant guidelines; there is no homogenous approach regarding BB use before exercise tests. Most guidelines recommend BB withdrawal for a couple of days before the test; they do not advise BB dose tapering. This approach is not standardised and raises the risk of BB rebound phenomenon before and during the test. Therefore, we suggest using half the prescribed BB dose at the usual time of administration (in the morning, prior to the exercise test).

Background: Patients with peripheral artery disease (PAD) fall under the category of a very high cardiovascular risk. Although consequent lipid-lowering therapy (LLT) is advised, only sparse data on attained target level in PAD exists. Objectives: We aimed to analyse contemporary guideline recommendations for LLT in symptomatic PAD patients. Methods: A monocentric, prospective, observational study involving 200 symptomatic PAD patients was conducted. Guideline target level attainment and LLT were analysed between 2017 and 2019. Results: Overall, 78.5% of the patients were on statin therapy, mainly of high intensity, with atorvastatin in 50% and rosuvastatin in 33% of the cases. The average statin dosage adjusted for simvastatin was 55 mg/d. Low density lipoprotein-cholesterol (LDL-C) was <1.8 mmol/L in 53% and <1.4 mmol/L in 34% of the cases. Mean LDL-C levels were at 1.85 ± 0.88 mmol/L. We observed no difference in the treatment and the target level attainment of patients with a stable PAD (intermittent claudication) or chronic critical PAD. However, patients with ≥ 1 vascular region affected (i.e., coronary and/or cerebrovascular) were treated more intensively and had lower LDL-C levels than patients with PAD alone. Conclusion: It appears that there are more awareness and improvement of previously documented undertreatment of LDL-C levels in symptomatic PAD patients. Although statin treatment is initiated in the majority of patients, our findings call for a continuously intensified LLT in symptomatic PAD patients.

Background: Pro-inflammatory mediators and oxidative stress are related to the severity of angina pectoris in patients with coronary heart disease. Objective: We evaluated the effects of pro-inflammatory mediators and oxidative stress on recurrent angina pectoris after coronary artery stenting in elderly patients. Methods: We determined the expression levels of malondialdehyde (MDA), acrolein (ACR), tumour necrosis factor-α (TNF-α), toll-like receptor 4 (TLR4), superoxide dismutase 3 (SOD3), paraoxonase-1 (PON-1), stromal cell-derived factor-1α (SDF-1α) and endothelial progenitor cells (EPCs) in elderly patients with recurrent angina pectoris after coronary artery stenting. Results: Levels of MDA, ACR, TNF-α and TLR4 were significantly increased (p<0.001), and levels of SOD3, PON-1, SDF-1α and EPCs were significantly decreased (p<0.001) in the elderly patients with recurrent angina pectoris after coronary artery stenting. MDA, ACR, TNF-α and TLR4 as markers of oxidative stress and pro-inflammatory mediators may have suppressed SOD3, PON-1, SDF-1α and EPCs as markers of anti-oxidative stress/anti-inflammatory responses. Oxidative stress and proinflammatory mediators were important factors involved in recurrent angina pectoris of elderly patients after coronary artery stenting. Conclusion: Oxidative stress and pro-inflammatory mediators could be considered as potential noninvasive prognostic, predictive, and therapeutic biomarkers for stable recurrent angina and recurrent unstable angina in elderly patients after coronary artery stenting.

Background: Thromboangiitis obliterans (TAO) is a chronic, non-atherosclerotic, progressive inflammatory vascular disease affecting the small- and medium-size arteries and veins of the extremities. Objective: To evaluate whether long-term anticoagulation with low-molecular-weight heparin (LMWH) and warfarin is beneficial for treating the inflammation and symptoms associated with TAO. Methods: Patients with TAO who underwent anticoagulation as the mainstay of treatment were included in this prospective study. Rest pain relief and healing of trophic lesions (as the primary and secondary endpoint) were investigated at Day 14 and after 6 months of follow-up. High sensitivity C-reactive protein (hsCRP), monocyte count, and ankle-brachial index (ABI) were recorded, and the difference was compared before and after 2-week anticoagulation. The Chi-square test was used to compare the difference between anticoagulant and aspirin groups (based on the literature). Results: From 2014 to 2019, 18 patients were included. Only 1 patient with wet gangrene received endo-therapy for a failing stent at the start of treatment. After ~14 days, 12 of 13 (92%) patients showed complete ulcer healing, and 17 of 18 (94%) patients showed complete relief from rest pain. Monocyte-counts and hsCRP levels decreased significantly (p<0.001) after a 2-week period of anticoagulation with LMWH. The mean follow-up was 2.6 years (range 0.5-5 years). At 6 months, all patients showed relief of rest pain and complete healing of trophic lesions. All endpoints were significantly improved compared with the aspirin group (p<0.01), and no rest pain or ulcer/gangrene recurred during follow-up. Conclusion: Anticoagulant therapy may alleviate the inflammation and symptoms of TAO.

Background: Platelet-activating-factor (PAF) is a lipid inflammatory mediator implicated in liver disease. Its main biosynthetic enzymes are cytidine diphosphate (CDP)-choline: 1-alkyl-2-acetyl-sn-glycerol-cholinephosphotransferase (PAF-CPT) and acetyl-coenzyme A: lyso-PAF-acetyltransferases (Lyso-PAF-AT). At the same time, PAF acetylhydrolase (PAF-AH) and lipoprotein-associated phospholipase A2 (Lp-PLA2) degrade PAF. Objective: To explore the relation of PAF metabolism with liver diseases and non-alcoholic fatty liver disease, as reflected by the fatty liver index (FLI). Methods: In 106 healthy volunteers, PAF concentration, the activity of its metabolic enzymes and gamma-glutamyl transferase (GGT) were measured in whole blood, leukocytes and serum, respectively and the FLI was calculated. Partial correlations and linear regression models were used. Results: In males, serum GGT activity was positively correlated with abdominal fat (as assessed by analysis of a manually defined region of interest in dual-energy X-ray absorptiometry), triacylglycerols, bound-PAF and Lp-PLA2, while the FLI was positively correlated with Lp-PLA2 activity. In females, serum GGT activity was negatively associated with high-density lipoprotein cholesterol (HDL-C) (age adjusted correlations, all p<0.05). Lp-PLA2 was a significant determinant of serum GGT activity in males after controlling for age, low- density lipoprotein cholesterol (LDL-C) and abdominal fat. The addition of bound-PAF in the model significantly increased the explained variance of serum GGT activity (total variance explanation 30%). Conclusion: Bound-PAF and Lp-PLA2 activity predicted serum GGT activity while Lp-PLA2 was also related to FLI. Our findings shed light on the metabolic pathways linking Lp-PLA2 to other atherosclerosis and/or oxidative markers, such as HDL-C, LDL-C, GGT and FLI and underline the important role of PAF.