Current Pharmaceutical Design - Volume 19, Issue 13, 2013

There is increasing evidence that an elevation of oxidative stress and associated oxidative damages are mediators of vascular injury in various cardiovascular pathologies, including hypertension. Accumulation of oxidative damage is thought to play an important role in aging and age-associated diseases such as hypertension and oxidative stress may function as a common trigger for activation of the senescence programme. In this regard, the role of telomeres in the onset, development and prognosis of hypertension has generated considerable interest. These structures may deteriorate in the onset and development of arterial hypertension in which their length may be a predictor of outcome. As telomere length by its nature is a marker of cell senescence, this parameter is of particular interest when studying the lifespan and fate of endothelial cells, cardiomyocytes and smooth muscle cells, especially so because telomere length seems to be regulated by various factors notably certain cardiovascular risk factors, such as smoking, sex and obesity that are associated with high levels of oxidative stress. This review focuses on the vascular effects of reactive oxygen species and the role of oxidative stress in hypertension- associated vascular damage. In addition it reviewes the considerable amount of data published recently on the role of telomeres to gain insights into the links between telomere length and hypertension, and assesses the usefulness of telomere length as a new marker of cardiovascular risk.

Age represents a significant risk factor for the onset and progression of cardiovascular disease, with the increase in life expectancy in developed countries going in parallel with increased incidence of such pathologies. Treatment strategies alternative or additive to pharmacological treatments are needed. The relationship between aging and progenitor cell-mediated repair is of great interest. Endothelial progenitor cells (EPC) mediate repair mechanisms for endothelial regeneration and maintenance, but they are subject to ageassociated changes affecting negatively their number and/or function. Aim of this review is to examine the impact of age on EPC-mediated vascular repair, with a focus on the metabolic pathways involved and on the therapeutic targets with potential for attenuating this effect.

For decades coronary macrovascular atherosclerosis has been considered the principal manifestation of coronary heart disease, with most of our effort dedicated to identifying and removal of coronary stenosis. However, growing body of literature indicates that coronary microcirculation also contributes substantially to the pathophysiology of cardiovascular disease. An understanding of mechanisms regulating microvascular function is of critical importance in understanding its role in disease, especially because these regulatory mechanisms vary substantially across species, vascular bed and due to comorbidities. Indeed, the most obvious consequence of coronary stenosis is that it may limit blood supply to the dependent myocardium to the point of causing ischaemia during exercise or even at rest. However, this flow limiting effect is not only due to the passive hydraulic effect of a narrowed conduit, but also to active responses in the coronary microcirculation triggered by the presence of an epicardial stenosis. To understand this problem it is important to review the inter-related mechanisms that regulate flow to the left ventricular wall and modulate transmural distribution of flow. These regulatory mechanisms operate hierarchically and are heterogeneously distributed along the coronary vascular tree. It is also important to discuss the effect of myocardial performance in modulating both blood flow demands and coronary resistance. Some of the interactions between coronary stenosis and microcirculation are transient, like those documented in acute coronary syndromes or during percutaneous interventions. However, microcirculatory remodeling may be triggered by a chronic coronary stenosis, leading to a sustained impairment of blood supply even after successful removal of the epicardial stenosis. A deeper understanding of these phenomena may explain paradoxical findings in patients undergoing coronary revascularization, particularly when functional tests are used in their assessment. These aspects are discussed in detail in this review.

The high-normal blood pressure (also known as prehypertension) is a clinical condition characterized by an increased cardiovascular risk as well as by the presence of target organ damage. This include an increased left ventricular mass, an endothelial dysfunction and an early renal functional and structural damage. Whether this is the case also for alterations of retinal vessels network, which are frequently detectable in established hypertension, is still largey undefined. The present paper, after discussing the main characteristics of the high-normal blood pressure state, will review the different approaches used throughout the years for assessing retinal microcirculatory network. Data collected by our group in subjects with high normal blood pressure will be also discussed, showing that arterial venular ratio values are reduced in this individuals with high-normal blood pressure and more so in established hypertension. These data indicate that retinal microvascular alterations 1) are of early appearance in the clinical course of hypertension and 2) are of frequent detection in the high-normal blood pressure state. The possible hemodynamic and non-hemodynamic mechanisms resposible for these structural alteations of the retinal microcirculation will be also discussed.

Endothelium plays a crucial role in modulating vascular function and structure, mainly by production of nitric oxide which protects the vasculature against the development of atherosclerosis and thrombosis. Traditional cardiovascular risk factors are characterized by endothelial dysfunction caused by an enhanced production of oxidative stress leading to destroy NO thus reducing its availability. A reduced endothelium-dependent relaxation is a predictor of cardiovascular events in high risk patients. Abdominal obesity is associated with microvascular endothelial dysfunction, through indirect mechanisms, such as insulin-resistance and the association with risk factors (including diabetes mellitus, hypertension and dyslipidemia), and directly, among others, by the production of adipokines and pro-inflammatory cytokines which in turn induce oxidative stress leading to a reduced NO availability. Several systems are amplified by the concomitant obesity and hypertension, thus generating a perpetual vicious circle which further contribute to the pathogenesis/progression of microvascular disease. Weight loss and modification of life-style ameliorate endothelial function in obese patients. It is conceivable that endothelial dysfunction might represent a complementary but crucial objective of a modern therapeutical approach leading to improve the prognosis in many patients, including obese patients, exposed to a high cardiovascular risk.

Ultrasound assessment of vascular biomarkers has been implemented for screening, prevention and improvement of cardiovascular risk stratification beyond classical risk factors including smoking, diabetes, hypercholesterolemia and hypertension. Thus, the presence of vascular damage at the sub-clinical, asymptomatic stages can identify a "vulnerable" patient, and aid in implementing cardiovascular prevention strategies. Increased intima-media thickness of the common carotid artery is a well-known marker of early atherosclerosis, which significantly correlates with the development of coronary or cerebro-vascular disease. More recently, guidelines for cardiovascular prevention in hypertension also introduced other vascular parameters evaluating both mechanical and functional arterial properties of peripheral arteries. Increased arterial stiffness, which can be detected by ultrasound at the common carotid, has been shown to predict future cardiovascular events and it is already considered a subclinical target organ of hypertensive patients. Even earlier vascular abnormalities such as endothelial dysfunction in the peripheral arteries, detected as reduced flow-mediated dilation of the brachial artery by ultrasound, have also been mentioned for their possible clinical use in the future. This manuscript reviews clinical evidence supporting the use of these different vascular markers for cardiovascular risk stratification, focusing on the need for an accurate, robust and reliable methodology for the assessment of vascular markers, which could improve their predictive value and increase their use in routine clinical practice.

Hypertension is universally considered the most detrimental among cardiovascular risk factors. Despite the overwhelming evidence of benefits deriving from lowering blood pressure, its control among the hypertensive population is still unsatisfactory. Resistant hypertension has a non negligible prevalence among hypertensive patients, and it is associated with a worse cardiovascular prognosis. There is need of new therapeutic approaches for reducing cardiovascular risk in this population. Sympathetic nervous system is known to play a major role in development and maintenance of essential hypertension, thus in the past decades several efforts have been made to counteract its overactivation. Novel non-pharmacological, promising approaches targeting sympathetic nervous system are now available, such as renal denervation and baroceptor-activating therapy. This review is aimed at describing essential clinical aspects of resistant hypertension, physiopatological basis of autonomic modulation as a target for hypertension treatment, and the available clinical evidence about efficacy and safety of device-based therapies for resistant hypertension. Present limitations and future perspectives were also considered.

Hypertension and insomnia are very common and often coexist. There is evidence to suggest that the increasing prevalence of arterial hypertension in the past decade might be related both to an increased prevalence of insomnia and to the decline of sleep duration due to modern lifestyle. The aim of this paper is to reconsider both the clinical evidence of the relationship between conditions of sleep loss and of perceived impairment in sleep quality with hypertension and the potential pathophysiological mechanisms underlying the biological plausibility of their relationship. Through a systematic search from MEDLINE, EMBASE, PsychINFO we selected articles, which reported experimental sleep deprivation designs, or studied sleep duration or insomnia and their relationship with blood pressure or hypertension in participants over 18 years. This analysis shows that experimental sleep deprivation, short sleep duration, and persistent insomnia are associated with increased blood pressure and increased risk of hypertension, even after controlling for other risk factors. Pathophysiological mechanisms underlying this association might be related to inappropriate arousal (“hyperarousal”) due to an overactivation of stress system functions. According this hypothesis, prolonged sleep loss or alterations of sleep quality might act as a neurobiological and physiologic stressor that impair brain functions and contribute to allostatic load, compromising stress resilience and somatic health.

Cardiometabolic risk comprises a cluster of traditional and emerging factors that are good indicators of a patient's overall risk for type 2 diabetes and cardiovascular disease. The insulin resistance, a key feature common to obesity and type 2 diabetes, is associated with impaired vascular response and contributes to increased cardiovascular risk. Abnormal vascular insulin signalling induces endothelial dysfunction, the initial step of atherosclerotic process, characterized by attenuated nitric oxide-mediated vasodilatation and atherogenic response. Insulin resistance and endothelial dysfunction are two pathological conditions that can co-exist, even if their cause-effect relationship is not yet clarified. Multiple signaling pathways shared by insulin resistance and endothelial dysfunction include hyperinsulinemia, glucotoxicity, lipotoxicity, and inflammation. These mechanisms selectively impair PI3K-dependent insulin in vascular endothelium harming endothelial balance and strengthening the evidence of the close association between metabolic and cardiovascular disease. The present review analyzes the close relationship between endothelial dysfunction and insulin resistance and explores the common mechanisms, with clinical considerations and pharmacological strategies.

Hyperuricemia is commonly associated with traditional risk factors such as dysglicemia, dyslipidemia, central obesity and abnormal blood pressure, i.e. the metabolic syndrome. Concordantly, recent studies have revived the controversy over the role of circulating uric acid, hyperuricemia, and gout as an independent prognostic factor for cardiovascular morbidity and mortality. In this regard, different studies also evaluated the possible role of xanthine inhibitors in inducing blood pressure reduction, increment in flow-mediated dilation, and improved cardiovascular prognosis in various patient settings. The vast majority of these studies have been conducted with either allopurinol or its active metabolite oxypurinol, i.e. two purine-like non-selective inhibitors of xanthine oxidase. More recently, the role of uric acid as a risk factor for cardiovascular disease and the possible protective role exerted by reduction of hyperuricemia to normal level have been evaluated by the use of febuxostat, a selective, non purine-like xanthine oxidase inhibitor. In this review, we will report current evidence on hyperuricemia in cardiovascular disease. The value of uric acid as a biomarker and as a potential therapeutic target for tailored old and novel “cardiometabolic” treatments will be also discussed.

Significant technical advances in small animal molecular imaging techniques and in imaging probes with high specificity for various molecular targets have been produced in the last ten years. Notwithstanding, the clinical applicability of molecular imaging proceeds slowly. In animal experiments, multimodality molecular imaging techniques based on hybrid scanners are increasing, providing more insight into path physiologic phenomena associated with cardiovascular disease. In parallel, we assisted in the development of a new generation of multi-imaging probes, such as PET/MRI probes, particularly effective in hybrid scanners. More recently, in order to gain in inherently low sensitivity of MRI, hyperpolarized magnetic resonance spectroscopy using hyperpolarized 13C was proposed. Preliminary results obtained in experimental animal studies seem to confirm the potentialities of hyperpolarized 13C magnetic resonance to monitor myocardial energetics. In this review the preclinical cardiovascular applications and the potential for clinical translation are discussed.

Macroeconomic variables primarily related to the health care system are the result of two key factors. On the one hand, the results obtained for preserving the health of individuals improving, also, the quality of life and, on the other hand, the costs to be supported in order to reach these results. There is evidence that a balance between these two parameters must be obtained in an era of limited economic resources and, therefore, measures, which can achieve these variables, are under study. Cost-effectiveness ratio is the most economic factor analyzed still lending to define the relationship between costs and disease. With regard to cardiovascular risk, budgets not always in line with established expectations are under exam. Quantitative measures related to cost-effectiveness ratio as the estimate-score system, which sets specific scores for the symptoms of the disease, are studied to improve the budget that regulates costs and results on public health including cardiovascular risk characterized by a high frequency of adverse events.

Glyconanoparticles are very useful tools for proteomic and glycomics research. They mainly contain glycosylated gold nanoparticles, glycosylated quantum dots, and magnetic glyconanoparticles. This review summarized the glyconanoparticle progress on biolabeling, in vitro or in vivo imaging, biosensing, targeted drug delivery, and other biomedical applications in recent years. The core of glyconanoparticle applications is to study the carbohydrate-mediated interactions, which opens the new field in glycobiology.

Mesenchymal stem cells (MSCs) were first isolated more than 50 years ago from the bone marrow. Currently MSCs may also be isolated from several alternative sources and they have been used in more than a hundred clinical trials worldwide to treat a wide variety of diseases. The MSCs mechanism of action is undefined and currently under investigation. For in vivo purposes MSCs must be produced in compliance with good manufacturing practices and this has stimulated research on MSCs characterization and safety. The objective of this review is to describe recent developments regarding MSCs properties, physiological effects, delivery, clinical applications and possible side effects.

DNA topoisomerases are an important family of enzymes that catalyze the induction of topological changes in the DNA molecule. Their ability to modulate the topology of the DNA makes DNA topoisomerases a key player in several vital cell processes such as replication, transcription, chromosome separation and segregation. Consequently, they already represent an important collection of macromolecular targets for some of the established anticancer drugs on the market as well as serve as templates in the development of novel anticancer drugs especially supported by recent structural advances in the field. The aim of this review is to provide an overview of the recent developments in the field of DNA poisons - a major class of human topoisomerase IIα inhibitors - of which several are already in clinical use. Due to frequently experienced occurrence of serious side effects of these molecules during therapy, especially cardiotoxicity issues, further drug design efforts were initiated already yielding novel promising compounds that have overcome this issue and already entered into clinical studies. Some of the presented and discussed chemical classes include intercalators, non-intercalators and redox-dependent poisons of human topoisomerase IIα. In particular, this review focuses on the currently available structure-based standpoint of molecular design and on the medicinal chemist's perspective of this field of anticancer drug design.

CYP2C19 is one of the principal enzymes involved in the metabolism of clopidogrel. The genes encoding CYP enzymes are polymorphic, with common alleles conferring reduced function. A loss-of-function allele, CYP2C19*2, is associated with an increased risk of major adverse cardiovascular events, particularly stent thrombosis, in patients with acute coronary syndromes who are receiving clopidogrel, especially among those undergoing percutaneous coronary intervention. Newer, more potent P2Y12 inhibitors like prasugrel and ticagrelor have been introduced recently in the daily clinical practice with better cardiovascular outcome in these patients. The purpose of this review article is to provide information regarding the clinical use of CYP2C19 genotyping in patients requiring antiplatelet therapy.