Current Vascular Pharmacology - Volume 18, Issue 1, 2020

Cigarette smoking is one of the most important health concerns worldwide. Even though the rate of smoking is declining in developed countries, it is still experiencing growth in developing regions. Many studies have examined the relationship between smoking, as an established risk factor, and cardiovascular diseases. We provide an updated review of the underlying mechanisms of smokinginduced cardiovascular diseases, with a focus on the relationship between smoking and oxidative stress, particularly from the perspective of endothelial cell dysfunction. We review smoking-induced oxidative stress as a trigger for a generalized vascular inflammation associated with cytokine release, adhesion of inflammatory cells and, ultimately, disruption of endothelial integrity as a protective barrier layer. We also briefly discuss the harms related to the vaping of electronic cigarettes, which many erroneously consider as a safe alternative to smoking. We conclude that even though e-cigarette could be a helpful device during the transition period of cigarette quitting, it is by no means a safe substitute.

A considerable amount of data supports a 1.8-7.4-fold increased mortality associated with Cushing’s syndrome (CS). This is attributed to a high occurrence of several cardiovascular disease (CVD) risk factors in CS [e.g. adiposity, arterial hypertension (AHT), dyslipidaemia and type 2 diabetes mellitus (T2DM)]. Therefore, practically all patients with CS have the metabolic syndrome (MetS), which represents a high CVD risk. Characteristically, despite a relatively young average age, numerous patients with CS display a 'high' or 'very high' CVD risk (i.e. risk of a major CVD event >20% in the following 10 years). Although T2DM is listed as a condition with a high CVD risk, CS is not, despite the fact that a considerable proportion of the CS population will develop T2DM or impaired glucose tolerance. CS is also regarded as a risk factor for aortic dissection in current guidelines. This review considers the evidence supporting listing CS among high CVD risk conditions.

Inflammatory bowel diseases (IBD), largely represented by Crohn’s disease (CD) and ulcerative colitis (UC), alter gastrointestinal physiology and mucosal immunity through a complex inflammatory process. These diseases can lead to significant arterial endothelial dysfunction. There is also evidence linking IBD with a modification of cardiac structure and function. A growing body of research has associated IBD with an acceleration of arterial stiffness and atherosclerosis and an increased risk of cardiovascular (CV) morbidity and mortality. The focus of this review is two-fold. Firstly, the literature on IBD in relation to CV dysfunction was evaluated (mainly based on 25 relevant surveys carried out between 2005 and 2018). The vast majority of these studies support a significant association of IBD with a deterioration in CV function. Secondly, the literature available regarding the effect of IBD treatment on CV dysfunction was considered based on studies published between 2007 and 2018. This literature search suggests that IBD treatment may have the potential to ameliorate CV dysfunction resulting in CV benefits. This review will analyse the literature as well as consider emerging research perspectives regarding how IBD treatment could improve CV dysfunction.

Arterial stiffness (AS) is considered an independent predictor of cardiovascular disease (CVD) events. Among lipid lowering drugs, statins have a beneficial effect on AS, independent of their hypolipidaemic effect. Based on 3 meta-analyses and other studies, this effect is compound- and doserelated. Potent statins at high doses are more effective than less powerful statins. Ezetimibe (± statin) also seems to decrease AS in patients with dyslipidaemia. Fibrates have no effect on AS. Proprotein convertase subtilisin/kexin type 9 (PCSK9) inhibitors have data that beneficially affect all AS risk factors, suggesting a beneficial effect on artery compliance. However, there is no direct measurement of their effect on AS indices. In patients with dyslipidaemia, prescribing high dose statins (± ezetimibe) will not only decrease low-density lipoprotein cholesterol levels but also improve AS (in addition to other effects). This effect on AS may contribute to the observed reduction in vascular events.

Objective: To study the distribution of nitric oxide synthase (NOS) isoforms and protein levels in human haemorrhoids and rectal tissue. Methods: Protein expression of NOS1, NOS2 and NOS3 was compared between haemorrhoids (n=14) and normal rectal submucosa (n=6) using Western blot analysis. The localisation of all NOS isoforms to specific structures was determined by immunohistochemistry. Results: Western blot analysis showed median (interquartile range) protein levels of all NOS isoforms were 1.5-2.4 times higher in haemorrhoids than rectal tissue; 121.4 (55.2-165.5) vs 50.0 (25.5-73.7) for NOS1 (p=0.020), 32.2 (23.8-140.6) vs 14.8 (9.6-34.0) for NOS2 (p=0.109), and 80.1 (62.0-139.5) vs 54.3 (48.7 -61.7) for NOS3 (p=0.015). Immunohistochemistry revealed a different distribution and location of all NOS isoforms in vascular and non-vascular structure of haemorrhoids and rectal tissues. The number of haemorrhoid specimens showing positive immunoreactivity of NOS in the vascular endothelium was significantly higher than that in rectal tissue for NOS1 (11/14 (79%) vs 1/6 (17%); p=0.018) and NOS3 (8/14 (57%) vs 0/6 (0%); p=0.042), but not for NOS2 (6/14 (43%) vs 4/6 (67%); p=0.63). Conclusion: Haemorrhoids have significantly higher protein levels of NOS1 and NOS3 than rectal tissue. The vascular endothelium of haemorrhoids also has significantly higher positive immunoreactivity of NOS1 and NOS3 than rectal tissue suggesting that blood vessels in haemorrhoids are exposed to higher NO concentrations than those of rectal tissue. Since haemorrhoids exhibit marked vascular dilatation and present with bleeding or swelling, a reduction in NOS - by applying NOS inhibitors - may potentially improve the symptoms of haemorrhoids.

Background: Cardiovascular autonomic neuropathy (CAN) and distal symmetrical sensorimotor polyneuropathy (DSPN) are serious microvascular complications of diabetes mellitus (DM). Their simultaneous development remains disputable. The aim of the present study was to examine the correlation between CAN and the presence/severity of DSPN in DM. Methods: Subjects with type 1 (group A: n=51; mean age 40.4 years) and type 2 DM (group B: n=153; mean age 64.6 years) were studied. Evaluation of DSPN was based on neuropathy disability score. Assessment of CAN was based on the battery of 4 standardized cardiovascular autonomic function tests. Results: In group A, patients with moderate/severe DSPN exhibited a 12-fold higher likelihood of CAN in univariate analysis (p=0.035). However, significance was lost after adjustment for gender, age, DM duration, and haemoglobin A1c. In group A, likelihood for CAN did not correlate with the presence of mild DSPN in univariate and multivariate analysis. In group B, likelihood of CAN was similar in patients with mild and in those with moderate/severe DSPN compared with patients without DSPN in univariate and multivariate analysis. In between group comparison CAN was similarly distributed in the 2 groups (p for interaction=0.367), in patients with no, mild and moderate/severe DSPN. Conclusion: CAN does not always co-exist with degrees of DSPN, ranging from mild to moderate/ severe and is similarly distributed in T1DM and T2DM patients with mild and moderate/severe DSPN and in patients without DSPN.

Aim: To determine the prevalence, genetic characteristics, current management and outcomes of familial hypercholesterolaemia (FH) in the Gulf region. Methods: Adult (18-70 years) FH patients were recruited from 9 hospitals and centres across 5 Arabian Gulf countries. The study was divided into 4 phases and included patients from 3 different categories. In phase 1, suspected FH patients (category 1) were collected according to the lipid profile and clinical data obtained through hospital record systems. In phase 2, patients from category 2 (patients with a previous clinical diagnosis of FH) and category 1 were stratified into definitive, probable and possible FH according to the Dutch Lipid Clinic Network criteria. In phase 3, 500 patients with definitive and probable FH from categories 1 and 2 will undergo genetic testing for 4 common FH genes. In phase 4, these 500 patients with another 100 patients from category 3 (patients with previous genetic diagnosis of FH) will be followed for 1 year to evaluate clinical management and cardiovascular outcomes. The Gulf FH cohort was screened from a total of 34,366 patients attending out-patient clinics. Results: The final Gulf FH cohort consisted of 3,317 patients (mean age: 47±12 years, 54% females). The number of patients with definitive FH is 203. In this initial phase of the study, the prevalence of (probable and definite) FH is 1/232. Conclusion: The prevalence of FH in the adult population of the Arabian Gulf region is high. The Gulf FH registry, a first-of-a-kind multi-national study in the Middle East region, will help in improving underdiagnosis and undertreatment of FH in the region.

Background: The prevalence of traditional risk factors such as diabetes mellitus (DM) and obesity are increasing in patients with acute coronary syndrome (ACS). Furthermore, outcomes after ACS are worse in patients with DM. The high prevalence of DM and an early age at onset of ACS have been described in prior publications from the Gulf Coast Database. Aims: We aimed to define the effect of DM on total mortality following ACS presentation at 30-days and 1 year based on the Gulf COAST registry database. Methods: The Gulf COAST registry is a prospective, multinational, longitudinal, observational cohort study conducted among Gulf citizens admitted with a diagnosis of ACS. The outcomes among patients with DM following ACS were stratified into 2 groups based on their DM status. Cumulative survival stratified by groups and subgroup categories was assessed by the Kaplan-Meier method. Results: Of 3,576 ACS patients, 2,730 (76.3%) presented with non ST-segment elevation myocardial infarction (NSTEMI) and 846 (23.6%) with STEMI. Overall, 1906 patients (53.3%) had DM. A significantly higher in-hospital (4.8%), 30-day (6.7%) and 1-year (13.7%) mortality were observed in patients with DM compared with those without DM. The Kaplan-Meier survival curve showed significant differences in survival of ACS patients with or without DM, with a short period of time-to-event for DM patients with STEMI (30-days) and the longest (1-year) for NSTEMI patients without DM. Conclusion: DM patients presenting with ACS-STEMI have poor short-term outcomes while DMNSTEMI patients have poor long-term outcomes. This highlights the need for strategies to evaluate DM control and integration of care to control vascular risk among this high-risk population.

Background: Takayasu’s arteritis (TA) is a large-vessel vasculitis that predominantly affects the aorta, pulmonary artery, and its main branches. The cause of TA is still unclear. Objective: To identify the clinical characteristics of TA at onset in different patient groups. Methods: The clinical manifestations, laboratory, and angiographic findings of 53 patients with TA based on age at onset and sex were retrospectively analysed. Results: The ratio of the incidence of TA in males and females was 1:4. Chest pain, reduced glomerular filtration rate (GFR), and multivessel involvement were the most common symptoms at TA onset in male patients. 17% of patients had an onset age >40 years, and the percentage of TA patients >40 years old with chest pain was significantly higher [6 (66.7%) vs 13 (29.5%) and p=0.031] than that in TA patients <40 years old. However, their renal artery involvement [1 (11.1%) vs 21 (47.7%)), p=0.042], abdominal aorta lesion [0 (0.0%) vs 16 (38.1%), p=0.030], and multiple vessel involvement [2 (22.2%) vs. 32 (72.7%), p=0.004] were significantly less evident. Multivariate analysis showed that hypertension and thoracic aortic lesion were predisposing factors for TA diagnosis [odds ratio (OR)=3.918, 95% confidence interval (CI)=1.616-1566.185, p=0.026]. For patients with aortic insufficiency (OR=3.674, 95% CI=2.734-567.621, p=0.007) or aneurysm formation (OR=7.255, 95% CI=1.23-1628.614, p=0.044), ascending aortic lesion was an independent risk factor. Furthermore, patients >40 years with chest pain but no brachial pulse should be suspected to have TA. Conclusion: Hypertension and thoracic aortic lesion are predisposing factors for the diagnosis of TA. Male with TA was more prone to present with chest pain, multivessel involvement, and reduced GFR.

Background: Angiotensin II is a potent activator of the Rho-kinase (ROCK) pathway, through which it exerts some of its adverse vasoconstrictor effects. Clinical evidence on the effects of blocking the angiotensin II receptor 1 on ROCK activity in hypertensive patients is scarce. Objective: To demonstrate that ROCK activity in peripheral blood mononuclear cells (PMBCs) in patients with essential hypertension is reduced earlier than previously observed, along with blood pressure (BP) lowering on treatment with olmesartan. Methods: Prospective pilot open study; 17 hypertensive patients were treated with progressive olmesartan doses starting with 20 mg qd. BP was measured at 3, 6 and 9 weeks after treatment initiation. If treatment failed to normalize BP after 3 weeks, olmesartan dose was increased to 40 mg qd, and if still hypertensive after 6 weeks, 12.5 mg of hydrochlorothiazide qd was added. ROCK activity was measured at baseline and 9 weeks after treatment as myosin phosphatase target subunit 1 phosphorylation (MYPT1-p/T ratio) in PBMC. Results: Mean baseline BP was 162 ± 4.9/101 ± 2.4 mmHg. After 9 weeks of treatment, both systolic and diastolic BP were reduced by 41 and 22 mmHg, respectively (p<0.05). Mean pretreatment MYPT1- p/T ratio in PMBCs was significantly reduced by 80% after 9 weeks with olmesartan (p<0.01). Conclusion: Normotension achieved after 9 weeks in 82% of the patients treated with olmesartan was associated with a significant reduction of ROCK activity in PBMC.

Objective: To analyze characteristics, management and outcomes of patients with acute coronary syndromes (ACS) receiving chronic oral anticoagulant (OAC) therapy enrolled in the EPICOR (long-tErm follow-uP of antithrombotic management patterns In acute CORonary syndrome patients) prospective, international, observational study of antithrombotic management patterns in ACS survivors (NCT01171404). Methods: This post-hoc analysis evaluated the association between OAC use at baseline (OACb) and time from hospital admission to percutaneous coronary intervention (PCI) (tHA-PCI), pre-PCI thrombolysis in myocardial infarction (TIMI) 3 flow, stent type, length of hospitalization, and clinical endpoints; death, non-fatal MI, and non-fatal stroke, a composite of these ± bleeding, over 2 years’ followup. Results: Of 10,568 ACS patients, 345 (3.3%) were on OACb (non-ST-segment elevation ACS [NSTEACS], n=268; ST-segment elevation MI [STEMI], n=77). OACb patients were older with more comorbidities. In NSTE-ACS OACb patients, tHA-PCI was longer (median 57.4 vs. 27.8 h; p=.008), and TIMI 3 flow rarer (26.0 vs. 33.5%; p=0.035). OACb patients had longer mean hospital stay (NSTEACS: 8.9 vs. 7.6 days; p<0.001; STEMI: 9.5 vs. 7.8 days; p=0.015), and higher rates of the composite endpoint (NSTE-ACS: 16.8 vs. 8.8%; p<0.0001; STEMI: 23.4 vs. 5.9%; p<0.0001). Bleeding events were more common with OACb (NSTE-ACS: 6.0 vs. 3.3%; p=0.01; STEMI: 6.5 vs. 2.8%; p=0.04). Conclusion: At 2-years, OACb use was associated with an increased risk of cardiovascular and bleeding events in STEMI and NSTE-ACS. NSTE-ACS patients on OACb experienced prolonged time to intervention, lower rates of TIMI 3 flow and longer hospitalization.