Current Vascular Pharmacology - Volume 19, Issue 4, 2021

Coronary artery spasm (CAS) plays an important role in the pathogenesis of ischemic heart disease. The clinical manifestations of CAS include variant angina, myocardial infarction and sudden death. Although endothelial dysfunction and hyperreactivity of vascular smooth muscle cells have been associated with CAS, the underlying mechanisms remain unclear. Thus, there is a long way to go to truly understand the pathogenesis of CAS to formulate effective treatments. This article discusses the pathophysiological mechanisms as well as downstream molecular pathways of CAS, with a focus on potential therapeutic targets.

Background: Gentiana lutea (GL), commonly known as yellow gentian, bitter root, and bitterwort, belongs to family Gentianaceae. GL belongs to genus Gentiana, which is a rich natural source of iridoids, secoiridoids, xantones, flavonoids, triterpenoids, and carbohydrates. Medicinal plants from Gentiana species have anti-oxidant, anti-inflammatory, anti-mitogenic, anti-proliferative, and lipidlowering effects, as well as a cardioprotective, hypotensive, vasodilator and anti-platelet activities. Objective: We reviewed the recent literature related to the effects of Gentiana species, and their active components on vascular diseases. Methods: Data used for this review were obtained by searching the electronic database [PUBMED/ MEDLINE 1973 - February 2020]. The primary data search terms of interest were: Gentiana lutea, Gentienacea family, phytochemistry, vascular diseases, treatment of vascular diseases, antioxidant, anti-inflammatory, anti-atherogenic. Conclusion: Gentiana species and their constituents affect many different factors related to vascular disease development and progression. Therefore, Gentiana-based therapeutics represent potentially useful drugs for the management of vascular diseases.

Nicotinic acetylcholine receptors (nAChRs) comprise a large family of ligand-gated ion channels that have a broad distribution in neurons and non-neuronal cells throughout the body. Native nAChRs, activated by acetylcholine (ACh) endogenously, are involved in a variety of physiological and pathophysiological processes. They regulate processes necessary for network operations through neurotransmitter release, cell excitability and neuronal integration. Emerging evidence suggests that nAChRs are capable of regulating cardiovascular (CV) functions in a cell type-specific manner, through the nervous system and non-neuronal tissues. The aim of this review is to describe the most recent findings regarding the role of nAChRs inside and outside the nervous system in the regulation of CV activities.

Background: The increasing incidence of cardiovascular disease (CVD) threatens the Middle Eastern population. Several epidemiological studies have assessed CVD and its risk factors in terms of the primary prevention of CVD in the Middle East. Therefore, summarizing the information from these studies is essential. Aim: We conducted a systematic review to assess the prevalence of CVD and its major risk factors among Middle Eastern adults based on the literature published between January 1, 2012, and December 31, 2018, and carried out a meta-analysis. Methods: We searched electronic databases such as PubMed/Medline, ScienceDirect, Embase and Google Scholar to identify literature published from January 1, 2012, to December 31, 2018. All the original articles that investigated the prevalence of CVD and reported at least one of the following factors were included: hypertension, diabetes, dyslipidaemia, smoking and family history of CVD. To summarize CVD prevalence, we performed a random-effects meta-analysis. Results: A total of 41 potentially relevant articles were included, and 32 were included in the metaanalysis (n=191,979). The overall prevalence of CVD was 10.1% (95% confidence interval (CI): 7.1- 14.3%, p<0.001) in the Middle East. A high prevalence of CVD risk factors, such as dyslipidaemia (43.3%; 95% CI: 21.5-68%), hypertension (26.2%; 95% CI: 19.6-34%) and diabetes (16%; 95% CI: 9.9- 24.8%), was observed. The prevalence rates of other risk factors, such as smoking (12.4%; 95% CI: 7.7- 19.4%) and family history of CVD (18.7%; 95% CI: 15.4-22.5%), were also high. Conclusion: The prevalence of CVD is high (10.1%) in the Middle East. The burden of dyslipidaemia (43.3%) in this region is twice as high as that of hypertension (26.2%) and diabetes mellitus (16%). Multifaceted interventions are urgently needed for the primary prevention of CVD in this region.

Background: Statins are the mainstay of treatment for low-density lipoprotein cholesterol (LDL-C) lowering, however, some patients cannot tolerate statins because of adverse effects. Ezetimibe and proprotein convertase subtilisin/kexin type 9 inhibitors (PCSK9i) are alternative treatment options. The purpose of this meta-analysis was to compare LDL-C reduction with ezetimibe vs PCSK9i in patients not on statins. Methods: PubMed and EMBASE were searched until 14th March 2020 for randomized clinical trials (RCTs) assessing the efficacy of ezetimibe vs PCSK9i in patients not on statins. The primary outcome was a reduction in LDL-C levels. A subgroup analysis of statin intolerant patients was also performed. Results: We identified 8 RCTs that enrolled a total of 1602 patients comparing the two pharmacotherapies. PCSK9i lowered LDL-C levels significantly more than ezetimibe (mean difference (MD): -36.5; 95% confidence interval (CI) [-38.3, -34.7, p<0.00001, I²=4%]. In the statin intolerant subgroup, PCSK9i showed significantly greater reduction in LDL-C levels compared with ezetimibe (MD: -36.1; 95% CI [-39.2, -33.1, p<0.00001, I²=21%]. There were no significant differences in LDL-C reduction between different PCSK9i dosages (140 mg once every 2 weeks vs 420 mg once every 4 weeks) (MD: -1.87; 95% CI [-4.45, 0.71, p<0.16, I²=0]. Conclusion: Among patients who are statin intolerant or not receiving statins, PCSK9i use is associated with significantly lower LDL-C levels than after treatment with ezetimibe. PCSK9i might be useful in the prevention and treatment of atherosclerotic cardiovascular disease (ASCVD) in this subset of patients.

Background: Although cardiac resynchronisation therapy (CRT) is an important player in the treatment of patients with heart failure (HF), the proportion of CRT patients with no improvement in either echocardiographic or clinical parameters remains consistently high and accounts for about 30% despite meeting CRT implantation criteria. Furthermore, in patients suffering from HF, renal dysfunction accounts for as many as 30-60%. Accordingly, CRT may improve renal function inducing a systemic haemodynamic benefit leading to increased renal blood flow. Objectives: The aim of the present study was to evaluate the importance of renal function in response to resynchronisation therapy during a 12-month follow-up period. Materials and Methods: The study consisted of 46 HF patients qualified for implantation of cardiac resynchronisation therapy defibrillator (CRT-D). A CRT responder is defined as a person without chronic HF exacerbations during observation whose physical efficiency has improved owing to the New York Heart Association (NYHA) class improvement ≥1. Results: A statistically significant difference was noted between responders and non-responders regarding creatinine level at the 3^rd month (p=0.04) and, particularly, at the 12^th month (p=0.02) of follow-up (100±23 vs 139±78 μmol/l). Moreover, there was a remarkable difference between both study groups with regard to GFR CKD-EPI (glomerular filtration rate (GFR) assessed using the Chronic Kidney Disease Epidemiology Collaboration (CKD-EPI) formula) at the 6^th (p=0.03) and 12^th month (p=0.01) of follow-up. The reference values for initial creatinine concentrations (101 μmol/l) as well as GFR CKDEPI (63 ml/min/1.73m²) were empirically evaluated to predict favourable therapeutic CRT response. Conclusion: Predictive value of GFR CKD-EPI and creatinine concentration for a positive response to CRT was found relevant.

Background: Sex hormones influence lipoprotein metabolism; whether the hormonal fluctuation during normal menstrual cycle has impact on non-fasting lipids remains unclear. Objective: To examine the differences in postprandial triglyceride, apolipoprotein B (ApoB) and nonhigh density lipoprotein cholesterol (non-HDL-C) concentrations using a standardized fat tolerance test during the 2 menstrual cycle phases. Methods: We enrolled 25 healthy, menstruating women. Each of them underwent a fat tolerance test during the 2 phases of the menstrual cycle. Blood samples were collected at baseline and up to 6 h postprandially. Differences in serum triglycerides, ApoB and non-HDL-C between the 2 phases were assessed. The incremental area under the curve (iAUC) was calculated. Reproducibility of the measurements was tested using the intraclass correlation coefficient (ICC) and coefficient of variation (CV). Results: Serum triglyceride concentrations increased postprandially in both phases and the values were higher during the follicular compared with the luteal phase; however, the overall triglyceride response expressed as iAUC [median value (interquartile range)] did not differ between the follicular and the luteal phase [54.0 (-26.5, 107.0) and 48.0 (6.0, 114.5) mg x h/dl, respectively, p=0.64]. Serum ApoB concentrations did not increase postprandially and the overall ApoB response was not different between the 2 phases. Non-HDL-C concentrations changed postprandially, but the overall response was not different between the 2 phases of the menstrual cycle. Reproducibility of the measurements was moderate: ICC 0.689-0.848 for triglycerides, 0.721-0.771 for ApoB, 0.457-0.867 for non-HDL-C, and %CV >8 for all parameters. Conclusion: Serum triglyceride levels were higher during the follicular compared with the luteal phase after standardized meal consumption, but the overall postprandial triglyceride response did not differ between the 2 phases. Postprandial ApoB and non-HDL-C serum concentrations were not affected by the menstrual cycle.

Background: The association between Paget’s disease of bone (PDB) and increased cardiovascular (CV) risk has been suggested, but the literature is conflicting. Objective: Our study aimed to evaluate two markers of CV risk, namely, common carotid artery intimamedia thickness (cIMT) and the aortic pulse wave velocity (PWV) in patients with PDB. Methods: We enrolled 12 patients with PDB and 58 control subjects, matched for age. The diagnosis of PDB was based on clinical, radiological and biochemical parameters. Results: Patients with PDB showed higher PWV values than the controls, whereas cIMT was slightly but not significantly increased. Conclusion: These findings, although limited by the small study population, represent an original observation that deserves further study. The higher arterial stiffness in PDB could be related to the increased bone turnover or the high levels of oxidative stress that characterize this population.

Aims: This study aims to explore early intensive lipid-lowering therapy in patients with non- ST-segment elevation acute coronary syndrome (NSTE-ACS). Background: Lowering low-density lipoprotein cholesterol (LDL-C) levels can reduce cardiovascular morbidity and mortality in patients with atherosclerotic cardiovascular disease. Due to many reasons, the need for early intensive lipid-lowering therapy is far from being met in Chinese NSTE-ACS patients at high risk of recurrent ischaemic events. Objective: This study evaluates the feasibility, safety and efficacy of starting evolocumab in hospitals to lower LDL-C levels in Chinese patients with NSTE-ACS. Methods: In this prospective cohort study initiated by researchers, 334 consecutive patients with NSTEACS who had sub-standard LDL-C levels (LDL-C ≥2.3 mmol/L after regular oral statin treatment for at least 4 weeks; or LDL-C ≥3.2 mmol/L without regular oral statin treatment) were included. Patients who agreed to treatment with evolocumab (140 mg subcutaneously every 2 weeks, initiated in hospital and used for 12 weeks after discharge) were enrolled in the evolocumab group (n=96) and others in the control group (n=238). All enrolled patients received regular statin treatment (atorvastatin 20 mg/day or rosuvastatin 10 mg/day; doses unchanged throughout the study). The primary endpoint was the change in LDL-C levels from baseline to week 12. Results: Most patients (67.1%) had not received regular statin treatment before. In the evolocumab group, LDL-C levels decreased significantly at week 4 and remained stable at week 8 and 12 (all p<0.001). At week 12, the LDL-C percentage change from baseline in the evolocumab group was - 79.2±12.7% (from an average of 3.7 to 0.7 mmol/L), while in the control group, it was -37.4±15.4% (from an average of 3.3 to 2.0 mmol/L). The mean difference between these 2 groups was -41.8% (95% CI -45.0 to -38.5%; p<0.001). At week 12, the proportion of patients with LDL-C levels <1.8 mmol/L and 1.4 mmol/L in the evolocumab group was significantly higher than in the control group (96.8 vs 36.1%; 90.6 vs 7.1%; both p<0.001). The incidences of adverse events and cardiovascular events were similar in both the groups. Conclusion: In this prospective cohort study, we evaluated the early initiation of evolocumab in NSTEACS patients in China. Evolocumab combined with statins significantly lowered LDL-C levels and increased the probability of achieving recommended LDL-C levels, with satisfactory safety and good tolerance.

Background: High blood pressure (BP) is a leading risk factor for coronary artery disease and other major cardiovascular events. Objective: Blood pressure variability (BPV), ambulatory arterial stiffness index (AASI) and ankle- brachial index (ABI) have been proposed as indices that can improve risk stratification for an adverse cardiac outcome. However, their utility in the setting of acute coronary syndromes (ACS) is unclear. Methods: The ACS-BP study is a single-centre observational cohort study designed to investigate the prognostic role of haemodynamic load and arterial stiffness indices for cardio-renal outcomes in patients with acute myocardial infarction (AMI). All consecutive patients admitted with a diagnosis of acute AMI with or without ST segment elevation were screened for inclusion in the study. The management of AMI will follow current guidelines. Results and Discussion: Data from baseline clinical and laboratory parameters during their hospitalization were collected. The haemodynamic load of each patient was determined by clinical BP values as well as 24-h ambulatory BP monitoring. The AASI was calculated from the raw 24-h BP data and ABI was measured after the third day of hospitalization using a certified device. Patients were followed-up for 12 months in order to collect data for hard cardiovascular and renal endpoints. Conclusion: The study results should clarify the role of these non-invasive tools in secondary risk stratification of such patients.