Current Vascular Pharmacology - Volume 12, Issue 1, 2014

From the first description of its anatomy by T. Willis to the novel therapeutic manipulations, it is unanimously recognized that the sympathetic nervous system (SNS) holds a crucial role in cardiovascular homeostasis. The introduction of sophisticated techniques, as microneurography and regional norepinephrine spillover provided the evidence for the role of sympathetic overactivity in various cardiovascular disease entities. Sympathetic activation is common in patients with essential hypertension and contributes to initiation, maintenance and progression of the disease and it contributes to the manifestation of its major complications. A considerable body of evidence relates SNS overactivity with high sodium intake in experimental animals and humans and the underlying mechanisms have nowadays been elucidated. SNS activity is more pronounced in patients with resistant hypertension and there are several conditions that lead to this phenomenon, as older age, kidney disease, obesity and metabolic syndrome, mental stress and sleep apnea. SNS overactivity holds also a key physiopathological role in heart failure, acute coronary syndromes and arrhythmias. Moreover, inhibition of sympathetic overactivity by various means, including central SNS suppressing drugs, peripheral alpha- and beta- adrenergic receptor blockers, or novel approaches as renal sympathetic denervation have been used successfully in the treatment of all these disorders.

The prevalence of resistant hypertension and existing limitations in antihypertensive drug therapy renders the interventional management of hypertension an attractive alternative. Carotid baroreceptors have been traditionally thought to be implicated only in short-term blood pressure regulation; however recent evidence suggests that the baroreceptors might play an important role even in the long-term blood pressure regulation. Electrical baroreflex stimulation appears safe and effective and might represent a useful adjunct to medical therapy in patients with resistant hypertension. This review endeavors to summarize the complex pathophysiology of blood pressure regulation, to describe the baroreflex circuit, its anatomy and physiology, to present previous data refuting a role for the baroreceptors in the long-term control of blood pressure and recent animal and human data suggesting an effective role of carotid baroreceptor activation in long-lasting blood pressure reduction. In this paper we attempt to critically evaluate existing information in this area and provide the scientific basis for carotid baroreceptor stimulation in the management of resistant hypertension.

Renal sympathetic innervation plays an important role in blood pressure regulation. Gradual activation of renal sympathetic efferent nerves enhances renin release, promotes sodium and water re-absorption, and reduces renal blood flow and glomerular filtration rate. On the other hand, activation of renal afferent sympathetic nerves induced by renal injury results in central sympathetic activation. This reciprocal relationship between the kidneys and the brain is involved in the pathogenesis of hypertension and other disease conditions characterized by sympathetic overactivity. Renal sympathetic nerve ablation has been recently introduced for the treatment of resistant hypertension. This review aims to provide the pathophysiological basis of renal nerve ablation for the attenuation of sympathetic overactivity.

Many difficult-to-treat clinical entities in the cardiovascular field are characterized by pronounced sympathetic overactivity, including resistant hypertension and heart failure, underlining the need to explore therapeutic options beyond pharmacotherapy. Autonomic modulation via carotid baroreceptor activation has already been evaluated in clinical trials for resistant hypertension, and relevant outcomes with regard to safety and efficacy of the technique are critically presented. The pathophysiological background of heart failure renders carotid baroreceptor stimulation a potential treatment candidate for the disease. Available data from animal models with heart failure point towards significant cardioprotective benefits of this innovative technique. Accordingly, the effects of baroreceptor activation treatment (BAT) on cardiac parameters of hypertensive patients are well-promising, setting the basis for upcoming clinical trials with baroreflex activation on patients with heart failure. However, as the potential therapeutic of BAT unfolds and new perspectives are highlighted, several concerns are raised that should be meticulously addressed before the wide application of this invasive procedure is set in the limelight.

The sympathetic nervous system is overactivated in resistant hypertension and several other disease conditions. A reciprocal association between the brain and the kidney has been described, in that sympathetic overactivity affects renal function while renal injury stimulates central sympathetic drive. Renal nerve ablation has been recently introduced as a potential alternative for the management of resistant hypertension, mainly due to current limitations in pharmacologic antihypertensive therapy. Data accumulated thus far point towards an efficacious and safe interventional method for the management of treatment resistance, with additional benefits on glucose metabolism and cardiac structure and function. Furthermore, beneficial effects have been observed in patients with chronic kidney disease, obstructive sleep apnea, polycystic ovary syndrome, and sympathetically driven tachyarrhythmias. However, as with every novel technique, several questions need to be answered and concerns need to be addressed before the wide application of this interventional approach.

Among current epidemics, chronic kidney disease (CKD) is accompanied with high morbidity and mortality rates inherently associated with the thriving comorbidities of hypertension and cardiovascular disease. In this mutually reinforcing triad, adequate control of high blood pressure emerges as extremely important for decreasing patients’ complication rates and prolonging life expectancy. However, hypertension control in this particular group of patients is often proven an arduous task, presenting high rates of resistance. Sympathetic nervous system (SNS) overactivity is implicated not only in the pathophysiological basis of difficult-to-treat hypertension, but also in the development and progression of renal disease, thus rendering SNS a prime therapeutic target in CKD. As renal nerve ablation (RNA) is finding its place among other invasive procedures in the cardiovascular arena, the potential therapeutic impact of this innovative treatment modality is gradually expanding from resistant hypertension to other high blood pressure-related clinical conditions like CKD. Encouraging results of clinical trials testing efficacy and safety of renal nerve ablation in resistant hypertensives provide the opportunity to apply the procedure in other subgroups of hypertensive patients. Available data regarding renal function of study participants suggest the safe implementation of RNA in patients with renal disease, but both unexplored benefits as well as potential hazards should be taken into account and critically evaluated. While renal denervation has been tested in selected cases of patients with renal disease, the results of large, multicenter trials evaluating the effects of this procedure on large cohorts of patients with CKD are eagerly anticipated.

Cumulative evidence nowadays supports the dominant role of sympathetic nervous system (SNS) activation in patients with hypertension, congestive heart failure, and renal dysfunction. During the last years innovative interventional treatments [renal sympathetic denervation (RSD) and baroreflex activation therapy (BAT)] have emerged and accompanied by sustained reductions of blood pressure (BP) levels. Moreover, these promising therapies are favorable not only on BP regulation but also on the SNS overdrive-related organ damage. The present review focuses on the association of SNS activation with renal and cardiac diseases and presents the cardiorenal effects of RSD and BAT in experimental and clinical settings.

The two novel approaches recently introduced for the treatment of resistant hypertension, i.e. carotid baroreceptor stimulation and renal denervation, share a number of similarities but are also characterized by important differences. The similarities include the evidence that both interventions have as common pathophysiological background the state of sympathetic overdrive characterizing essential hypertension. In addition both procedures 1) are invasive, 2) exert in the short-term period clearcut blood pressure lowering effects and 3) still face a number of open questions, particularly related to the long-term blood pressure lowering effects, impact on end-organ damage and on cardiovascular events. The differences include the fact that two procedures act on distinct targets that trigger sympathetic activation and consequently blood pressure increase. In addition, only in the case of carotid baroreceptor stimulation the blood pressure effects can be easily assessed immediately following the implantation. Finally, the economic costs, metabolic effects and impact on vagal modulation of heart rate are different between the two interventions. This paper will provide a comparison of the background, effects and outcome of renal denervation and carotid baroreceptor stimulation, stressing whenever possible the clinical implications of the main features of the two interventions.

In about 48% hypertensive patients in the United States, blood pressure remains higher than accepted treatment targets despite broad availability of effective pharmaceutical agents. Of these 48%, recent estimates define about 10-11% have treatment-resistant hypertension (TR-HTN). Compensatory changes in sympathetic nervous system function are an important component of HTN. Recent technical advances targeting the sympathetic activity of the carotid sinuses (Baroreflex Activation Therapy-BAT) and the renal sympathetic nerves (Renal Denervation Therapy-RDT) have renewed interest in invasive therapy for the treatment of drug-resistant hypertension. Encouraging results from the recent Rheos Pivotal and Symplicity HTN-2 trials on the safety and efficacy of BAT and RDT respectively, indicate that invasive approaches can safely reduce blood pressure in patients with resistant hypertension. The main goal of this article is to review the results of preclinical and clinical studies on the electric stimulation of the carotid sinus and the catheter-based renal denervation.

Vascular diseases, including atherosclerosis, angioplasty-induced restenosis, vessel graft arteriosclerosis and hypertension-related stenosis, remain the most prevalent cause of death in the developed world. The aetiology of vascular diseases is multifactorial with both genetic and environmental factors. Recently, some of the most promising research identifies the epigenetic modification of the genome to play a major role in the disease development, linking the environmental insults with gene regulation. In this process, modification of DNA by methylation, and histone modification by acetylation, methylation, phosphorylation and/or SUMOylation are reported. Importantly, recent studies demonstrated that histone deacetylase (HDAC) enzymes are crucial in endothelial integrity, smooth muscle proliferation and in the formation of arteriosclerosis in animal models. The study of HDACs has shown remarkable specificity of HDAC family members in vascular cell growth/death that influences the disease process. Interestingly, the effects of HDACs on arteriosclerosis development in animal models have been observed after HDAC inhibition using specific inhibitors. This provides a new approach for the treatment of vascular disease using the agents that influence the epigenetic process in vascular cells. This review updates the rapid advances in epigenetics of vascular diseases focusing on the role of HDAC family in atherosclerosis. It will also discuss the underlying mechanisms of histone acetylation in vascular cells and highlight the therapeutic potential of such agents.

Endothelial progenitor cells (EPCs) have recently been employed in cell-based therapy (CBT) to promote regeneration of ischemic organs, such as heart and limbs. Furthermore, EPCs may sustain tumour vascularisation and provide an additional target for anticancer therapies. CBT is limited by the paucity of cells harvested from peripheral blood and suffers from several pitfalls, including the low rate of engrafted EPCs, whereas classic antiangiogenic treatments manifest a number of side effects and may induce resistance into the patients. CBT will benefit of a better understanding of the signal transduction pathway(s) which drive(s) EPC proliferation, trafficking, and incorporation into injured tissues. At the same time, this information might outline alternative molecular targets to impair tumor neovascularisation and improve the therapeutic outcome of antiangiogenic strategies. An increase in intracellular Ca2+ concentration is the key signal in the regulation of cellular replication, migration, and differentiation. In particular, Ca2+ signalling may regulate cellcycle progression, due to the Ca2+-sensitivity of a number of cycline-dependent kinases, and gene expression, owing to the Ca2+-dependence of several transcription factors. Recent work has outlined the role of the so-called store-operated Ca2+ entry in driving EPC proliferation and migration. Unravelling the mechanisms guiding EPC engraftment into neovessels might supply the biological bases required to improve CBT and anticancer treatments. For example, genetic manipulation of the Ca2+ signalling machinery could provide a novel approach to increase the extent of limb regeneration or preventing tumour vascularisation by EPCs.

In recent years, the development of more effective drugs has provided a better prognosis and an increase in life expectancy for patients at all-stages of cancer. On the other hand, the price for the improving effectiveness of therapies against malignant tumors is the development of severe and potentially life-threatening drug reactions. Among these, cardiac toxic effects have recently gained particular attention. The term cardiotoxicity includes many possible pathological manifestations, but the most frequent is the reduction in cardiac function, potentially leading to heart failure and death. Importantly, the development of cardiac dysfunction may occur immediately after drug administration, or after years. The purpose of this review is to discuss the clinical features of cardiotoxicity, its molecular basis and novel possible strategies to reduce the likelihood of serious cardiac complications.

The role of vitamin D (VitD) has recently been expanded beyond bone homeostasis and regulation of calcium levels. VitD deficiency has been proposed as a new risk factor for cardiovascular disease, including stroke. Low 25(OH)VitD levels are very common among post-stroke patients, probably due to their limited mobility and decreased sunlight exposure along with a higher prevalence of malnutrition, and they have been associated with previous and incident cerebrovascular events. Contributing mechanisms have been linked to the association of VitD deficiency with the presence of hypertension, diabetes mellitus and atherosclerosis. Moreover, there is experimental evidence demonstrating that VitD exerts neuroprotective effects, such as stimulation of neurotrophic factors, quenching of oxidative hyperactivity and regulation of neuronal death, as well as antithrombotic properties. It is plausible that VitD supplementation could be a beneficial intervention for the prevention and/or treatment of cerebrovascular disease possibly by decreasing the aforementioned cerebrovascular risk factors and simultaneously by improving neurologic and cognitive functions, thereby reducing falls and fractures in post-stroke patients. However, study results are still conflicting and data from large, randomized clinical trials are needed to clarify these speculations.

Advanced cirrhosis is frequently associated with renal dysfunction. Hepatorenal syndrome (HRS) is characterized by the occurrence of kidney injury in cirrhotic patients in the absence of other identifiable causes. HRS is classified in 2 different types. Type 1 is characterized by acute renal failure and rapid functional deterioration of other organs, usually related to a precipitating event. Type 2 is characterized by slowly progressive renal failure and refractory ascites. Advanced liver disease induces the progression of hemodynamic alterations such as arterial vasodilation of splanchnic circulation and impairment of cardiac function. The resulting ineffective circulating blood volume promotes the activation of both the renin-angiotensin-aldosterone and sympathetic nervous system, by an increase of antidiuretic hormone activity, in an attempt to restore volemia. Despite fluid retention, ascites and dilutional hyponatremia, renal function is often initially preserved by renal production of vasodilators. However, further insults can lead to an imbalance between systemic vasoconstriction and local renal vasodilation, resulting in progressive renal failure. Over the last decade, clinical strategies to prevent HRS have been improved by a better understanding of the natural history of renal failure in cirrhosis, resulting in a reduction of HRS prevalence in cirrhotic patients. Vasoconstrictor drugs may improve renal function, but the effect on mortality has not yet been established. Vaptans, nonpeptide vasopressin receptor antagonists, may also reduce hyponatraemia and ascites, even if the clinical effects in HRS remain unknown. This review updates the pathophysiology, diagnosis and management of HRS.

Omentin is an adipokine preferentially produced by visceral adipose tissue with insulin-sensitizing effects. Its expression is reduced in obesity, insulin resistance and type 2 diabetes. Omentin is also positively related with adiponectin, high-density lipoprotein levels and negatively related with body mass index, waist circumference, insulin resistance, triglyceride and leptin levels. Lower plasma omentin levels contribute to the pathogenesis of insulin resistance, type 2 diabetes and cardiovascular diseases in obese or overweight patients. Omentin has anti-inflammatory, antiatherogenic, anti-cardiovascular disease and antidiabetic properties. With respect to vascular biology, omentin causes vasodilatation of blood vessels and attenuates C-reactive protein-induced angiogenesis. The ability of omentin to reduce insulin resistance in conjunction with its anti-inflammatory and anti-atherogenic properties makes it a promising therapeutic target. Thus, omentin may have beneficial effects on the metabolic syndrome and could potentially be used as a biologic marker and/or pharmacologic agent/target in this respect.

Coronary artery disease is the major cause of mortalilty in the West with coronary artery bypass surgery (CABG) being a means of restoring blood supply to ischaemic myocardium. The long saphenous vein is the most commonly used bypass conduit but its patency is inferior to the internal thoracic artery, the ‘gold standard’ graft. In conventional procedures the saphenous vein is harvested in such a manner that considerable vascular damage is inflicted. The structures mainly affected by this vascular trauma are the endothelium, autonomic nerves and vascular smooth muscle all containing cells with the potential to release nitric oxide (NO). While the majority of studies into the potential role of NO in vein graft performance have focussed on the involvement of endothelial nitric oxide synthase (eNOS) less information is available regarding the role of the inducible isoform of nitric oxide synthase (iNOS). While the effects of eNOS-derived NO are principally beneficial, iNOS is generally associated with pathological conditions. While potential pathophysiological roles of iNOS are discussed in this review we also outline many studies suggesting that this isoenzyme plays an important role in maintaing vein graft patency in patients undergoing CABG, particularly when the saphenous vein is harvested with minimal surgical trauma.

Cardiovascular risk factors are associated with coronary artery disease (CAD) and with cognitive dysfunction. However, the precise pathogenic mechanisms responsible for this association remain elusive. In the present study, CAD patients with cognitive impairment showed significantly higher platelet activation compared with CAD patients without cognitive impairment. In addition, we identified platelet activity to be a significant independent predictor for the severity of cognitive impairment in these patients. We discuss the link between platelet hyperactivity and dementia (including Alzheimer`s disease) based on the literature and our findings. We also discuss the potential mechanisms involved. This link may become a therapeutic option.

In recent decades we have seen a surge in the incidence of diabetes in industrialized nations; a threat which has now extended to the developing world. Type 2 diabetes is associated with significant microvascular and macrovascular disease, with considerable impact on morbidity and mortality. Recent evidence has cast uncertainty on the benefits of very tight glycaemic goals in these individuals. The natural history of disease follows an insidious course from disordered glucose metabolism in a pre-diabetic state, often with metabolic syndrome and obesity, before proceeding to diabetes mellitus. In the research setting, lifestyle, pharmacological and surgical intervention targeted against obesity and glycaemia has shown that metabolic disturbances can be halted and indeed regressed if introduced at an early stage of disease. In addition to traditional anti-diabetic medications such as the glinides, sulphonylureas and the glitazones, novel therapies manipulating the endocannabinoid system, neurotransmitters, intestinal absorption and gut hormones have shown dual benefit in weight loss and glycaemic control normalisation. Whilst these treatments will not and should not replace lifestyle change, they will act as invaluable adjuncts for weight loss and aid in normalising the metabolic profile of individuals at risk of diabetes. Utilizing novel therapies to prevent diabetes should be the focus of future research, with the aim of preventing the challenging microvascular and macrovascular complications, and ultimately cardiovascular death.

Background: In the era of Abdominal Aortic Aneurysm (AAA) screening, pharmacotherapies to attenuate AAA growth are sought. HMG Co-A reductase inhibitors (statins) have pleiotropic actions independent of their lipid lowering effects and have been suggested as potential treatment for small AAAs. We systematically review the clinical evidence for this effect. Methods: Medline, EMBASE and the Cochrane Central Register of Controlled Trials (1950-2011) were searched for studies reporting data on the role of statin therapy on AAA growth rate. No language restrictions were placed on the search. References of retrieved articles and pertinent journals were hand searched. Included studies were reviewed by 2 independent observers. The search retrieved 164 papers, 100 were irrelevant based on their title, 47 were reviews and 1 was a letter. 8 studies were excluded based on review of their abstract leaving 8 for inclusion in the study. Results: Eight observational clinical studies with a total of 4,466 patients were reviewed. Four studies demonstrated reduced AAA expansion in statin users while 4 studies failed to demonstrate this effect. The method of determining AAA growth rates varied significantly between the studies and the ability of many studies to control for misclassification bias was poor. Conclusions: The claim that statins attenuate AAA growth remains questionable. Further prospective studies with stringent identification and verification of statin usage and a standardised method of estimating AAA growth rates are required. Statin type and dose also merit consideration.

Chronic venous disease (CVeD) is a debilitating condition that affects millions of individuals worldwide. The condition can result in varicose veins, or advance to severe skin changes and venous ulceration. The fundamental basis for CVeD is inflammation within the venous circulation and that it is subjected to increased hydrostatic pressure resulting in increased ambulatory venous pressure. The inflammation involves leukocytes, in particular macrophages and monocytes, inflammatory modulators and chemokines, cytokine expression, growth factors, metalloproteinase (MMP) activity, and many regulatory pathways that perpetuate inflammation. Sulodexide (SDX) is a glycosaminoglycan with pro-fibrinolytic and anti-thrombotic properties. We have previously demonstrated that SDX inhibits the secretion of pro-zymogen MMP-9 from human leukocytes without displacing high molecular complexes of MMP-9. The anti-inflammatory properties of SDX on activated leukocytes have not been well established. We hypothesized that SDX will reduce the secretion of inflammatory mediators from lipopolysaccharide (LPS)-stimulated macrophages. Therefore, we evaluated the effects of SDX on LPS-stimulated macrophage secretion of various inflammatory and anti-inflammatory cytokines, chemokines, and colony stimulating factors. We used microplatebased multiplex immunoassays. LPS-stimulated macrophages in vitro caused a substantial increase of interleukins, tumor necrosis factor, interferon, chemokines and colony stimulating factors. The addition of SDX caused both a dose-dependent and dose-independent decrease in nearly all of the inflammatory cytokines, chemokines and colony stimulating factors. These findings suggest that SDX has a significant effect on the release of inflammatory mediators from macrophages, and may be useful in the treatment of early and advanced CVeD.