Current Vascular Pharmacology - Volume 11, Issue 4, 2013

Adverse reactions to bare metal stent implantation include stent thrombosis and restenosis. Although thrombosis in bare metal stents seems mainly to be affected by procedural factors, restenosis is a more complex procedure involving mechanisms of tissue repair after vessel injury occurring during implantation. This procedure includes early platelet and leukocyte invasion, followed by smooth muscle cell proliferation, as well as further inflammatory cell recruitment mediated by expression of chemokines and leukocyte activation at the site of the injury. In this report, we will focus on the role of inflammation in the development of in-stent restenosis in bare metal stents. In particular, we will describe the pathologic evidence implicating inflammatory cell involvement in the development of restenosis in animal and human models; we will analyze the molecular mechanisms linking inflammation with restenosis; and will review the association of pre-existing or procedure-induced systemic inflammation with adverse reactions at follow-up.

In-stent restenosis and stent thrombosis represent the main adverse reactions to coronary stents and individual susceptibility appears to play an important role in their onset. In particular, inflammatory status, classically assessed by C-reactive protein levels, predicts the risk of in-stent restenosis after bare-metal stent implantation but not after drug-eluting stent (DES) implantation. On the other hand, C-reactive protein seems to predict the risk of stent thrombosis after treatment with DES but not with bare-metal stent. If DES have considerably reduced, as compared to bare-metal stent, the rate of adverse reaction in the first year after implantation, concern is emerging about late events that seem to be related to delayed healing and allergic reactions to polymers, a process in which eosinophils play an important role by enhancing restenosis and thrombosis.

Since the introduction of coronary vessel scaffold by metallic stent, percutaneous coronary intervention has become widely performed all over the world. Although drug-eluting stent technology has further decrease the incidence of in-stent restenosis, there still remaining issues related to stent implantation. Vessel inflammation is one of the causes that may be related to stent restenosis as well as stent thrombosis. Therefore, systemic therapies targeting inflammation emerged as adjunctive pharmacological intervention to improve outcome. Statins, corticosteroids, antiplatelets, and immunosuppresive or anti-cancer drugs are reported to favorably impact outcome after bare-metal stent implantation. In type 2 diabetic patients, pioglitazone may be the most promising drug that can lower neointimal proliferation and, as a result, lower incidence of restenosis and target lesion revascularization. On the other hand, several new stent platforms that might decrease inflammatory response after drug-eluting stent implantation have been introduced. Because durable polymer used in the first generation drug-eluting stents are recognized to be responsible for unfavorable vessel response, biocompatible or bioabsorbable polymer has been introduce and already used clinically. Furthermore, polymer-free drug-eluting stent and bioresorbable scaffold are under investigation. Although vessel inflammation may be reduced by using these new drug-eluting stents or scaffold, long-term impact needs to be investigated further.

Hemostasis is an intrinsic property of the vascular system that prevents blood loss during accidental disruption of the vessel wall. Late mechanisms of hemostasis comprise vessel repair and wound healing. In contrast, the early mechanism of hemostasis comprises the quick formation of a blood cell plug, also known as thrombus, whose function is to seal the region of the vessel near the compromised surface or area. Despite the simplicity of the concept, the molecular mechanisms underlying early hemostasis are highly complex. The local rheological properties of the blood flow, the vascular region and the nature of the injury determine the mechanism of thrombogenesis. Components of the plasma, blood cells such as platelets and vascular endothelial cells are involved in thrombosis. This review focuses on platelet-vascular wall interactions during thrombosis and hemostasis and provides an overview of the main underlying molecular mechanisms.

Platelets play an important role in both normal hemostasis and pathological thrombus formation. The key role of platelets in thrombosis is highlighted by the clinical benefit of treatment with antiplatelet drugs. Aspirin, either alone or in combination with clopidogrel in high-risk patients, is the most widely used antiplatelet agent. However, there is an individual response to these agents that may reduce the cardiovascular protection in patients who achieve a lower antiplatelet effect. Recently, P2Y12 receptor antagonists more potent than clopidogrel (e.g., prasugrel and ticagrelor) have been approved for patients with acute coronary syndromes and those undergoing percutaneous coronary interventions; these drugs provide greater platelet inhibition than clopidogrel. However, the increased effectiveness of these treatments has underscored the importance of carefully balancing the risks of ischemia and bleeding to achieve the best clinical outcomes. The increased knowledge of the molecular mechanisms of platelet activation has prompted a search for novel pharmacological targets for the inhibition of platelet reactivity. This article reviews the molecular mechanisms of action and limitations of use of current and emerging antiplatelet agents for treatment of cardiovascular disease.

Thrombosis is the pathological face of the hemostatic process, and is still the major cause of death in the Western society. Many different components have been identified that contribute to the thrombotic occlusion of the vasculature and several therapeutic approaches have been developed to treat this severe clinical complication. In the last several years, a number of new agents have been under (pre)clinical investigation that are targeting von Willebrand factor (VWF), a protein that nicely exemplifies the thin line between the normal hemostatic process and an overly active system that gives rise to thrombotic events. Indeed, several epidemiological studies have found that increased plasma levels of VWF are associated with an increased risk for cardiovascular complications. VWF is a multimeric protein that is pertinent to the recruitment of platelets to the growing thrombus. VWF and platelets circulate together without interacting under normal conditions, and should combine into a thrombus selectively when necessary. This delicate process is highly regulated by various endothelial- and plasma proteins as well as by changes in shear stress. In the present review, an update is provided about our current knowledge on VWF as a risk factor, mediator and pharmacological target in association with thrombosis.

Urocortin comprises a group of endogenously produced peptide hormones that belong to the corticotropinreleasing factor (CRF) family with promising future as potential drugs for the treatment of heart disease. Members of the urocortin family are known to act as potent regulators of cardiac and vascular functions, through the activation of the CRF receptors that are highly expressed in heart and peripheral tissues. Urocortin exhibits potent vasodilatory effects in arteries from different species. These effects have been related to its capability to regulate the intracellular Ca2+ concentrations ([Ca2+]i) by different molecular mechanism. Beside, urocortin increases heart contractility and evokes positive inotropic and lusitropic effects by mechanisms involving different kinases signalling pathways. Urocortin peptides have also the ability to protect the heart from ischemia and reperfusion injuries by their improvement of post-ischemic cardiac performances, which include the recovery of heart contraction, the prevention from intracellular Ca2+ overload and the reduction of cardiac cell death. Furthermore, heart protection by urocortin involves the regulation of the transcription of specific genes acting to minimize mitochondrial damage, cell death, and oxidative stress. This review summarizes some of the recent findings related to the molecular mechanism underlying the role of urocortin in both vascular and cardiac function.

Despite the great progress in cardiovascular health and clinical care along with marked decline in morbidity and mortality, cardiovascular diseases remain the leading causes of death and disability in the developed world. New therapeutic approaches, targeting not only systematic but also causal dysfunction, are ultimately needed to provide a valuable alternative for treatment of complex cardiovascular diseases. In heart failure, there are currently a number of trials that have been either completed or are ongoing targeting the sarcoplasmic reticulum calcium ATPase pump (SERCA2a) gene transfer in the context of heart failure. Recently, a phase 2 trial was completed, demonstrating safety and suggested benefit of adeno-associated virus type 1/SERCA2a gene transfer in advanced heart failure, supporting larger confirmatory trials. The experimental and clinical data suggest that, when administrated through perfusion, virus vector carrying SERCA2a can also transduce vascular endothelial and smooth muscle cells (EC and SMC) thereby improving the clinical benefit of gene therapy. Indeed, recent advances in understanding the molecular basis of vascular dysfunction point towards a reduction of sarcoplasmic reticulum Ca2+ uptake and an impairment of Ca2+ cycling in vascular EC and SMC from patients and preclinical models with cardiac diseases or with cardiovascular risk factors such as diabetes, hypercholesterolemia, coronary artery diseases, as well as other conditions such as pulmonary hypertension. In recent years, several studies have established that SERCA2a gene-based therapy could be an efficient option to treat vascular dysfunction. This review focuses on the recent finding showing the beneficial effects of SERCA2a gene transfer in vascular EC and SMC.

The TRP family of cation-permeable channels owes its name to a Drosophila TRP mutant with impaired vision due to transient rather than sustained receptor potential. Mammalian TRP channels can be grouped into 6 subfamilies, including TRPC, TRPM, TRPV, TRPA, TRPP and TRPML and a number of TRP family members have been identified in the vasculature. TRP channels play an important functional role in the vasculature as mediators of cation influx across the plasma membrane, thus contributing to a large number of processes such as vascular smooth muscle contraction and vascular pressure or the responses to oxidative stress, mechanical stimuli, heat and hypoxia-induced vascular remodelling. TRP channelopaties are involved in the pathogenesis of different disorders including hypertension and cardiomyopathy. A number of identified natural compounds and synthetic agents have been reported to modulate TRP function, and are the base for therapeutical strategies.

Vascular smooth muscle cells (VSMCs) contraction can be evoked by the rise of cytosolic [Ca2+] owing to transmembrane Ca2+ influx or sarcoplasmic reticulum (SR) Ca2+ release. Although the classical ionotropic role of voltagedependent (L-type) Ca2+ channels (VGCCs) is known, we review here data suggesting a new metabotropic function of VGCCs in vascular smooth muscle cells. VGCCs can trigger Ca2+ release from the SR in the absence of extracellular Ca2+. During depolarization, VGCCs can activate G proteins and phospholipase C (PLC)/inositol 1,4,5-trisphosphate (InsP3) pathway leading to Ca2+ release and arterial contraction. This new metabotropic role of VGCCs, referred as calcium channel-induced Ca2+ release (CCICR), has a major role in tonic VSM contractility, as it links sustained membrane depolarization and Ca2+ channel activation with metabotropic Ca2+ release from the sarcoplasmic reticulum (SR) and tonic smooth muscle contraction. This new role of VGCCs could have a wide functional relevance for the pathogenesis of vasospasms mediated by membrane depolarization and vasoactive agents that can activate VGCCs. Precise understanding of CCICR could help to optimize pharmacological treatments for clinical conditions where Ca2+ channels antagonists are recommended.

Cardiac hypertrophy arises as a response of the heart to many different pathological stimuli that challenge its work. Regardless of the initial pathologic cause, cardiac hypertrophy shares some characteristics resulting from a genetic reprogramming of several proteins. Recent studies point to Ca2+ as a key signaling element in the initiation of this genetic reprogramming. In fact, besides its important role in excitation-contraction coupling, Ca2+ regulates cardiac growth by activation of Ca2+-dependent transcription factors. This mechanism has been termed excitation-transcription (ET) coupling. Some information about cardiac ET coupling is being gathered from the analysis of cardiac hypertrophy development, where two Ca2+ dependent enzymes are key actors: the Ca2+/calmodulin kinase II (CaMKII) and the phosphatase calcineurin, both activated by Ca2+/Calmodulin. In this review we focus on some neurohormonal signaling pathways involved in cardiac hypertrophy, which could be ascribed as activators of ET coupling, for instance, adrenergic stimulation and the renin-angiotensin-aldosterone system. β-adrenergic receptor (β-AR) produces cAMP, which directly, (through cAMP response element) or indirectly (through activating Epac) induces cardiac hypertrophy. α1 AR and angiotensin receptor type 1 are Gq protein coupled receptors, which when activated, stimulate phospholipase C producing inositol 1,4,5 triphosphate (IP3) and diacylglycerol (DAG). IP3 promotes elevation of [Ca2+] in the nucleus, activating CaMKII/MEF2 (myocyte enhancer factor 2) pathway and may indirectly induce Ca2+ entry through transient receptor potential channels (TRPC). Other TRPC channels are activated by DAG. Ca2+ entry activates calcineurin/NFAT hypertrophic signaling. By promoting L-type Ca2+ channel expression, aldosterone may also have an important role in the genetic reprogramming during hypertrophy.

There is occurring a progressive increase in peripheral arterial disease (PAD) in the United States and around the World. This is undoubtedly associated with deterioration in health status and an increase in cardiovascular risk factors. There are multiple old and new antithrombotic and anticoagulation medications that have been used for the treatment of PAD. Several are considered in this review. The purpose of antithrombotics in surgery is the prevention of thrombosis of surgical bypass grafts in order to help maintain their patency. Multiple different medication approaches can be made in association with surgery. Just as in the case of peripheral vascular surgery, thrombosis also plagues the long-term maintenance of patency following peripheral vascular interventions (PVIs). Platelets play a key role in the initiation and propagation of thrombus formation following these PVIs and the use of antithrombotic medication helps reduce the likelihood of intravascular thrombus formation and adverse ischemic events during and after the procedure. Currently used antithrombotic agents after percutaneous peripheral revascularization include aspirin, clopidogrel, cilostazol and warfarin. Available medications remain in a state of flux and new oral direct thrombin and Factor Xa inhibitors may also find a place as clinical evidence-based medicine accumulates.

The annual rate of ipsilateral stroke associated with asymptomatic carotid stenosis has fallen from 2-4% to <1% in the last 20 years due to improvements in medical therapy. The fundamental benefits of this are relevant to whether patients undergo revascularisation or not. We aimed to evaluate existing international guidelines for the management of carotid stenosis, identifying important similarities and differences. The websites of the American Heart Association, Society for Vascular Surgery, European Society for Cardiology, European Society for Vascular Surgery, British Cardiovascular Society and UK Vascular Society were searched for guidelines relating to primary prevention for asymptomatic atherosclerotic carotid disease in September 2011 and independently reviewed by 2 authors. The following guidelines were identified and compared: The Joint British Societies 2nd (JBS2) 2005 guideline, the 4th European Society for Cardiology (ESC) 2007 guideline, the joint American Heart Association/Society for Vascular Surgery (AHA/SVS) guideline 2011 and subsequent 2011 SVS update, the American Heart Association (AHA) prevention of stroke guideline 2010, the AHA secondary prevention for atherosclerotic coronary and vascular disease 2011 update, and the European Society for Vascular Surgery (ESVS) Section A carotid guideline. There was no UK guidance from its vascular society. Important differences were evident in methods of risk assessment, treatment targets for blood pressure and low density lipoprotein cholesterol, and the use of anti-platelet agents. These differences are highlighted in 2 case scenarios. There is now clear, evidence based guidance from British, European and US cardiovascular bodies regarding optimal targets for risk factor modification. These can be adopted as standard operating procedure for clinical practice and the medical arms of carotid interventional trials. In the future imaging biomarkers may help provide an understanding of the risk of an individual carotid lesion to help guide therapy.

Both conduit and resistance arterial vessels may show vascular morphological and functional alterations due to cigarette smoking. Pathological lesions involve the arterial wall or intravascular lumen with, primarily, narrowing and thrombo-embolic events as an effect of endothelial and blood cell changes related to smoking. Functional disorders are the result of a wide spectrum of biochemical, physiological and metabolic factors. While conduit vessel alterations have been widely investigated, little is known about the changes induced by smoking on the microcirculation. It would seem that the endothelium, platelet aggregation and adhesiveness, nervous system and metabolic changes play a role in damaging resistance arteries and, then, the microcirculation. The result of these effects changes the blood flow and perfusion particularly to the heart, brain and kidney. Alterations of the microcirculation can cause severe and widespread damage because, in addition to the complications of the atherosclerotic lesion which characterizes large arteries, there is a failure of body organs linked to the degree of microvascular damage. Moreover, it seems that 2 major compounds of cigarette smoke are capable of determining vascular damage; initially, nicotine acts preferably on large arteries and carbon monoxide on small arteries, although both compounds damage the vascular system.

Renal artery stenosis (RAS) is a cause of hypertension and ischemic nephropathy. The incidence of this disorder is probably less than 1% in patients with mild hypertension, but rises to as high as 10 to 40% in patients with acute, severe or refractory hypertension. Significant RAS can be caused by atheromatous plaques, or due to fibromuscular dysplasia (FMD). Atherosclerotic lesions are present in almost 7% of adults older than 65 years and up to 50% of patients presenting with diffuse atherosclerotic disease. In contrast to atherosclerosis, FMD most often affects women under the age of 50 and typically involves the distal main renal artery or the intrarenal branches. The optimal treatment for RAS is not yet established. Based on recent trials, we reviewed the literature on pharmacological and endovascular treatment of atherosclerotic RAS and ischemic nephropathy.