Current Vascular Pharmacology - Volume 17, Issue 1, 2019

In Diabetes Mellitus (DM), hyperglycaemia and insulin resistance progressively lead to both microvascular and macrovascular complications. Whereas the incidence of microvascular complications is closely related to tight glycaemic control, this does not apply to macrovascular complications. Hyperglycaemia influences many interweaving molecular pathways that initially lead to increased oxidative stress, increased inflammation and endothelial dysfunction. The latter represents the initial in both types of vascular complications; it represents the “obligatory damage” in microvascular complications development and only “introductory damage” in macrovascular complications development. Other risk factors, such as arterial hypertension and dyslipidaemia, also play an important role in the progression of macrovascular complications. All these effects accumulate and lead to functional and structural arterial wall damage. In the end, all factors combined lead to the promotion of atherosclerosis and consequently major adverse cardiovascular events. If we accept the pivotal role of vascular wall impairment in the pathogenesis and progression of microvascular and macrovascular complications, treatment focused directly on the arterial wall should be one of the priorities in prevention of vascular complications in patients with DM. In this review, an innovative approach aimed at improving arterial wall dysfunction is described, which may show efficacy in clinical studies. In addition, the potential protective effects of current treatment approaches targeting the arterial wall are summarised.

Atherosclerosis and its cardiovascular complications are the main cause of death in diabetic patients. Patients with diabetes mellitus have a greater than 10-fold risk of cardiovascular disease in their lifetime. The carotid Intima-Media Thickness (cIMT), a surrogate marker for the presence and progression of atherosclerosis, predicts future cardiovascular events in asymptomatic subjects with Type 2 Diabetes Mellitus (T2DM). This review focuses on genetic variants that contribute to the pathobiology of subclinical atherosclerosis in the setting of T2DM. Specifically, we devoted our attention to wellstudied genes selected for their relevance for atherosclerosis. These include: The Renin-Angiotensin- Aldosterone System (RAAS), Apolipoprotein E (ApoE), Methylenetetrahydrofolate Reductase (MTHFR) and pro-inflammatory genes. The ever-growing availability of advanced genotyping technologies has made Genome-Wide Association Studies (GWAS) possible. Although several bioinformatics tools have been developed to manage and interpret the huge amounts of data produced, there has been limited success in the many attempts to uncover the biological meaning of the novel susceptibility loci for atherosclerosis.

Atherosclerosis and its clinical manifestations is a leading cause of disease burden worldwide. Currently, most of the individuals carrying a strong predisposition to complications of atherosclerosis because of monogenic dyslipidaemias remain undiagnosed and consequently are not given an opportunity for prevention. Therefore, one of the main public health challenges remains the identification of individuals with significantly increased risk for atherosclerosis due to monogenic predisposition. Next-Generation Sequencing (NGS) has revolutionized genetic testing in symptomatic patients. Although new genomic technologies are still developing, and evidence on the use of this methodology for screening purposes is still lacking, genome testing might provide a powerful tool for the identification of individuals at risk. This may pave the way for the implementation of personalized medicine in the field of atherosclerosis prevention. In this review, we discuss the potential of genetic screening for atherosclerosis prevention and present the potential target of 17 genes responsible for monogenic dyslipidaemias associated with atherosclerosis.

Coagulation factors can affect cellular processes that include inflammatory signaling by acting on endothelial protease activated receptors, vascular smooth muscle and inflammatory cells beyond the coagulation cascade. This is important in the pathogenesis of atherosclerosis. Accordingly, experimental data points to beneficial effects of coagulation protease inhibitors on the attenuation of atherosclerosis progression in animal models. However, available clinical data do not support the use of anticoagulants as an add-on treatment of atherosclerosis. New clinical studies are needed with a better selection of patients to clarify the role of novel direct anticoagulants in the management of atherosclerosis.

Background: Various antiplatelet drugs are used following Acute Coronary Syndromes (ACS). Of them, adenosine diphosphate receptor P2Y12 inhibitors clopidogrel, prasugrel and ticagrelor are currently used for post-ACS long-term treatment. Although they act on the same receptor, they differ in pharmacodynamics and pharmacokinetics. Several enzymes and transporters involved in the metabolism of P2Y12 inhibitors show genetic variability with functional impact. This includes Pglycoprotein, carboxylesterase 1 and, most notably, CYP2C19 that is important in clopidogrel activation. Common gain-of-function or loss-of-function alleles of CYP2C19 gene are associated with lower or higher platelet reactivity that may impact clinical outcomes of clopidogrel treatment. Prasugrel is considered to be less dependent on CYP2C19 variability as it is also metabolized by other CYP450 isoforms. Some studies, however, showed the relevance of CYP2C19 variants for platelet reactivity during prasugrel treatment as well. Ticagrelor is metabolized mainly by CYP3A4, which does not show functionally relevant genetic variability. Its concentrations may be modified by the variants of Pglycoprotein gene ABCB1. While no substantial difference between the clinical efficacy of prasugrel and ticagrelor has been documented, both of them have been shown to be superior to clopidogrel in post-ACS treatment. This can be partially explained by lower variability at each step of their metabolism. It is probable that factors influencing the pharmacokinetics of both drugs, including genetic factors, may predict the clinical efficacy of antiplatelet treatment in personalized medicine. Conclusion: We summarize the pharmacokinetics and pharmacogenetics of P2Y12 inhibitors with respect to their clinical effects in post-myocardial infarction treatment.

Cardiovascular disease and associated cerebral stroke are a global epidemic attributed to genetic and epigenetic factors, such as diet, life style and an increasingly sedentary existence due to technological advances in both the developing and developed world. There are approximately 5.9 million stroke-related deaths worldwide annually. Current epidemiological data indicate that nearly 16.9 million people worldwide suffer a new or recurrent stroke yearly. In 2014 alone, 2.4% of adults in the United States (US) were estimated to experience stroke, which is the leading cause of adult disability and the fifth leading cause of death in the US There are 2 main types of stroke: Hemorrhagic (HS) and ischemic stroke (IS), with IS occurring more frequently. HS is caused by intra-cerebral hemorrhage mainly due to high blood pressure, while IS is caused by either embolic or thrombotic stroke. Both result in motor impairments, numbness or abnormal sensations, cognitive deficits, and mood disorders (e.g. depression). This review focuses on the 1) pathophysiology of stroke (neuronal cell loss, defective blood brain barrier, microglia activation, and inflammation), 2) the role of the membrane protein caveolin- 1 (Cav-1) in normal brain physiology and stroke-induced changes, and, 3) we briefly discussed the potential therapeutic role of Cav-1 in recovery following stroke.

Dyslipidaemia occurs in pregnancy to secure foetal development. The mother shows a physiological increase in plasma total cholesterol and Triglycerides (TG) as pregnancy progresses (i.e. maternal physiological dyslipidaemia in pregnancy). However, in some women pregnancy-associated dyslipidaemia exceeds this physiological adaptation. The consequences of this condition on the developing fetus include endothelial dysfunction of the foetoplacental vasculature and development of foetal aortic atherosclerosis. Gestational Diabetes Mellitus (GDM) associates with abnormal function of the foetoplacental vasculature due to foetal hyperglycaemia and hyperinsulinaemia, and associates with development of cardiovascular disease in adulthood. Supraphysiological dyslipidaemia is also detected in GDM pregnancies. Although there are several studies showing the alteration in the maternal and neonatal lipid profile in GDM pregnancies, there are no studies addressing the effect of dyslipidaemia in the maternal and foetal vasculature. The literature reviewed suggests that dyslipidaemia in GDM pregnancy should be an additional factor contributing to worsen GDM-associated endothelial dysfunction by altering signalling pathways involving nitric oxide bioavailability and neonatal lipoproteins.

Stroke as a cause of long-term disability is a growing public health burden. Therefore, focusing on prevention is important. The most prominent aim of this strategy is to treat modifiable risk factors, such as arterial hypertension, the leading modifiable contributor to stroke. Thus, efforts to adequately reduce Blood Pressure (BP) among hypertensives are mandatory. In this respect, although safety and benefits of BP control related to long-term outcome have been largely demonstrated, there are open questions that remain to be addressed, such as optimal timing to initiate BP reduction and BP goals to be targeted. Moreover, evidence on antihypertensive treatment during the acute phase of stroke or BP management in specific categories (i.e. patients with carotid stenosis and post-acute stroke) remain controversial. This review provides a critical update on the current knowledge concerning BP management and stroke pathophysiology in patients who are either at risk for stroke or who experienced stroke.

Psoriasis (Pso) is a chronic inflammatory immune-mediated skin disease associated with several comorbidities. Despite the growing number of studies providing evidence for the link between Pso and Cardiovascular (CV) disorders, there are still many unsolved questions, dealing with the role of the skin disease as an independent risk factor for CV events, the influence of Pso severity and duration on CV damage, the presence of Psoriatic Arthritis (PsA) as a predictor of increased CV mortality and morbidity and the detection of reliable clinical, laboratory and/or instrumental parameters to stratify CV risk in psoriatic patients. Moreover, it remains to clarify if the early treatment of the dermatosis may lower CV risk. In this paper we will try to provide answers to these queries in the light of the updated data of the literature.

Background: Coronary Artery Calcifications (CACs) are associated with coronary atherosclerosis and Cardiovascular (CV) events. In “non-cardiovascular” settings, CACs can be easily detected on chest Multi-Detector Computed Tomography (MDCT). Their evaluation may help to better stratify CV risk in the general population, especially for primary prevention. Aims: We retrospectively evaluated the relationship between CAC distribution and CV risk, determined by Framingham Risk Score (FRS), in a cohort of patients who underwent chest MDCT performed for several clinical indications. Method: We retrospectively recruited 305 patients (194 men, 111 women; mean age 70.5 years) from 3 different Italian centres. Patients with coronary stent, pacemaker and/or CV devices were excluded from the study. Circumflex Artery (LCX), Left Main Coronary Artery (LMCA), left Anterior Descending artery (LAD) and right coronary artery (RCA) were analysed. Results: From a total population of 305 patients, 119 (39%) had low FRS (<10%), 115 (38%) had intermediate FRS (10-20%), and 71 (23%) had high FRS (>20%). The study identified 842 CACs located in decreasing order as follows: RCA (34.5%), LAD (32.3%), LCX (28%) and LMCA (13%). Statistical two-step analysis subdivided patients into two clusters according to FRS (risk threshold = 12.38%): cluster I (mean 9.34) and cluster II (mean 15.09). A significant association between CAC distribution and cluster II was demonstrated. CACs were mostly detected in patients with intermediate FRS. All patients (100%) with the highest CV risk showed intermediate RCA and LMCA involvement. Conclusion: Radiologists can note the distribution of CACs on a chest MDCT and should mandatorily record them in their reports. Depending on CAC presence and location, these findings may have important clinical implications, mostly in asymptomatic patients with intermediate FRS. This information may reclassify a patients' CV risk and improve clinical management.

Objectives: Accumulating evidence suggests a direct role of Uric Acid (UA) on Left Ventricular (LV) diastolic function in chronic kidney disease and Heart Failure (HF) patients. Recently, UA has been linked to LV Hypertrophy (LVH) and Diastolic Dysfunction (DD) in women with preserved Ejection Fraction (pEF) but not in corresponding men. We sought to assess if UA could predict indices of DD in hypertensive subjects with pEF independently of gender. Method: We consecutively recruited 382 apparently healthy hypertensive subjects (age: 61.7±10.7, women: 61.3%, median EF: 64%). In 318 patients in sinus rhythm, LV mass-indexed to body surface area-was calculated (LVMI). LVH was set as an LVMI >116g/m2 or 96 g/m2 in men and women, respectively. The ratio of early transmitral peak velocity (E) to the mitral annular early diastolic velocity (Em) was used as an approximation of mean left atrial pressure (E/Em). Results: UA [median (interquartile range): 5.4(2) mg/dl] independently predicted E/Em (adjusted coefficient: 1.01, p =0.026) while an interaction term between gender and UA was no significant (p=0.684). An ordinal score of DD was calculated taking into account increased E/Em, left atrium dilatation and LVH. Women with increased UA had 254% increased odds (adjusted OR=2.54, p=0.005) to be classified in the upper range of the DD score. Conclusion: In hypertensive subjects without HF, UA is independently associated with the presence of DD in both genders and correlates with its severity in women. Further prospective studies are warranted to evaluate the association of UA with adverse cardiovascular outcomes in high-risk populations such as HF with pEF.