Current Vascular Pharmacology - Volume 6, Issue 4, 2008

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Endovascular (EVAR) abdominal aortic aneurysm (AAA) repair has been established as a successful procedure in the short term and may constitute a viable long-term alternative to open repair (OR). The procedure has been associated with lower operative and mid-term morbidity and mortality compared to OR, but long-term results remain largely controversial. EVAR has also been associated with a significant risk of implant and procedure-related complications, such as graft thrombosis and cardiovascular events, necessitating interventional and pharmaceutical management. Medical management of patients undergoing EVAR is required for several different reasons. Patients with an AAA have an increased risk of cardiovascular death, necessitating treatment to reduce the overall risk for cardiovascular events. Treatment is inline with the medical management of coronary artery disease including anti-platelet therapy and statins. Anti-platelet therapy is also mandatory to prevent complications such as graft-limb thrombosis and peripheral arterial disease (PAD), which is common in patients with an AAA. Especially in patients with PAD, aspirin, clopidogrel and statins remain the mainstay of medical management. Unfortunately, there is a lack of prospective randomised trials concerning the medical management of patients that have undergone abdominal aortic endo-grafting. We review the current literature on the medical treatment of patients undergoing EVAR, focusing on peri-operative management, anti-platelet agents and statins.

Abdominal aortic aneurysm (AAA) is a common and deadly problem. The aortic diameter increases in association with a complex remodeling process that includes changes in the structure and content of key proteins, elastin and collagen. As these changes occur, the tissue mechanical properties also change. The natural history of AAA is progressive enlargement to a point of mechanical tissue failure typically followed by death. Currently, the marker used to predict the risk of impending rupture is the largest transverse diameter. After reaching a diameter threshold of 5.5 cm the AAA needs to be surgically repaired. This criterion does not consider any patient-specific information or heterogeneity of the AAA that may, in some cases, lead to rupture before the AAA reaches the standard intervention threshold. Conversely, in many patients, continued observation beyond this threshold is safe. While no medical treatment is yet approved, doxycycline (Doxy) has been shown to greatly reduce AAA growth in animal models and has been shown to slow growth in 1 small clinical trial. While larger prospective randomized trials are needed, one unknown is what effect Doxy has on the structural integrity of the aortic wall. That is, does slowed AAA growth, by Doxy treatment, prevent rupture, or does the wall continue to weaken and the AAA instead ruptures at a smaller diameter? Using an established animal model of AAA, we begun to determine the changes in tissue mechanics compliance of the aorta as the AAA develops. Our current research is focused on verifying that these changes mimic the observed changes seen in the human population as reported by other researchers, so that we can confidently study how potential drug therapies may affect wall strength and compliance in the human population. The long-term objectives are to understand better factors related to progression of AAA and help verify that drug therapy with Doxy will decrease the chance of rupture by preventing wall weakening and maintaining function of the aorta.

C-reactive protein (CRP) is an acute-phase protein, which has been used in clinical practice as a non specific marker of inflammation. Many studies have shown that CRP is associated with atherosclerotic cardiovascular disease. It is currently unknown if CRP plays an active role as an etiologic factor in cardiovascular disease. The mechanisms by which CRP may contribute to the pathogenesis of cardiovascular disease are poorly understood. The effect of CRP on atherogenesis may include interactions with other factors of immunity and inflammation, such as the complement system, as well as a direct effect of CRP on the cells involved in atherosclerotic lesions. We review the literature concerning the mechanisms by which CRP may influence the development of cardiovascular disease and discuss the findings of clinical studies assessing the association between CRP and cardiovascular disease.

Prospective epidemiologic studies have shown that dyslipidemia and hyperglycemia are major risk factors for atherosclerotic cardiovascular diseases. Undesirable metabolic conditions are observed to coexist in patients with metabolic syndrome, which is an important risk factor for cardiovascular disease. To prevent cardiovascular disease, a pleiotropic agent is needed to improve the metabolic disorder in patients with metabolic syndrome. Bile acid binding resins increase the fecal excretion of bile acids. The decrease in bile acids returned to the liver leads to an up-regulation of hepatic low-density lipoprotein (LDL) receptor activity, which decreases LDL cholesterol (LDL-C) in the circulation and increases high-density lipoprotein cholesterol. On the other hand, bile acids can also regulate the transcription of genes involved in LDL-C synthesis and cholesterol homeostasis via nuclear hormone receptors. Consequently, these receptors may represent novel therapeutic targets for dyslipidemia and provide insight into the role of the bile acid pathway in other metabolic processes. This review focuses on the recent findings on bile acid binding resins and cardiovascular disease risk factors. Moreover, known and proposed mechanisms of how bile acid binding resins may improve glucose and energy metabolism are discussed; these effects may help to explain the mechanisms by which bile acid binding resins may reduce cardiovascular disease.

“Metabolic treatment” involves the use of drugs to improve cardiomyocyte function. Trimetazidine is the most investigated drugs in this group. The ESC 2006 guidelines on the management of patients with stable angina mention the efficacy of metabolic treatment in improving physical efficiency and decreasing the recurrence of pain. The available data suggest that combined therapy of trimetazidine and haemodynamic drugs is an effective antianginal treatment that reduces the risk of pain recurrence (in as many as 64% of patients). The most recent studies also suggest that trimetazidine might be effective in patients with acute coronary syndromes, ischemic cardiomyopathy and heart failure. However, while trimetazidine has shown beneficial effects on surrogate endpoints in several small trials its effect on cardiovascular events is uncertain. Further large randomized studies are needed before its effects on cardiovascular events can be evaluated.

Recent studies revealed an exceedingly high mortality with diastolic heart failure that was previously regarded as relatively benign compared to systolic heart failure. Prominent risk factors for diastolic heart failure are increasing age, hypertension and diabetes. These risk factors are associated with coronary microvascular rarefaction and resultant decreased coronary flow reserve, thereby rendering the myocardium vulnerable to ischemia. We discuss the importance of angiogenic gene programming in preserving the coronary microvasculature, preserving cardiac function and altering disease course. Further, we discuss the possible utility of therapies that activate hypoxia inducible factor-1 in preventing rarefaction of the coronary microvasculature and maintaining cardiac diastolic function.

Essential hypertension is an insulin resistant state. Early insulin signaling steps are impaired in essential hypertension and a large body of data suggests that there is a crosstalk at multiple levels between the signal transduction pathways that mediate insulin and angiotensin II actions. At the extracellular level the angiotensin converting enzyme (ACE) regulates the synthesis of angiotensin II and bradykinin that is a powerful vasodilator. At early intracellular level angiotensin II acts on JAK-2/IRS1-IRS2/PI3-kinase, JNK and ERK to phosphorylate serine residues of key elements of insulin signaling pathway therefore inhibiting signaling by the insulin receptor. On another level angiotensin II inhibits the insulin signaling inducing the regulatory protein SOCS 3. Angiotensin II acting through the AT1 receptor can inhibit insulininduced nitric oxide (NO) production by activating ERK 1/2 and JNK and enhances the activity of NADPH oxidase that leads to an increased reactive oxygen species generation. From the clinical standpoint, the inhibition of the renin angiotensin system improves insulin sensitivity and decreases the incidence of Type 2 Diabetes Mellitus (T2DM). This might represent an alternative approach to prevent type 2 diabetes in patients with hypertension and metabolic syndrome, (i.e. insulin resistant patients). This review will discuss: a) the molecular mechanisms of the crosstalk between the insulin and angiotensin II signaling systems b) the results of clinical studies employing drugs targeting the renin-angiotensin IIaldosterone systems and their role in glucose metabolism and diabetes prevention.

Platelets from patients affected by diabetes mellitus and metabolic syndrome show an impaired sensitivity to physiological antiaggregating agents and an enhanced activation state, mirrored by an increased expression of membrane activation markers; furthermore, they are more prone to form spontaneous microaggregates with ADP receptor involvement. These abnormalities are responsible for a pro-thrombotic condition, contributing to a high cardiovascular risk. This pattern of platelet abnormalities provides a strong rationale for aggressive antiplatelet therapy strongly recommended by guidelines both in diabetes mellitus and in metabolic syndrome, not only in the setting of acute coronary syndromes, but also for the long-term prevention of the cardiovascular events. Antiplatelet therapy in these pathological conditions, however, is still a matter of intense debate, especially because a high prevalence of “resistance” to these drugs (and to aspirin in particular) has been described in these patients. This may result in non-significant reductions in cardiovascular events. Different factors seem to be involved, including: i) genetic polymorphisms; ii) hyperglycemia and poor metabolic control; iii) reduced sensitivity to nitric oxide; iv) a pro-inflammatory and/or pro-thrombotic status, and, v) increased oxidative stress. This review will take into consideration: i) the results of the most relevant studies addressing the effects of the antiaggregating treatment in patients affected by diabetes mellitus and/or metabolic syndrome, and, ii) the biochemical mechanisms accounting for the impaired sensitivity to aspirin and thienopyridines in the above mentioned clinical conditions.

Background: In various cardiac diseases, thrombembolism constitutes a major risk, and in these patients clinically silent microembolic signals (MES) are detectable within the transcranial Doppler frequency spectrum (TCD) of the major brain arteries. MES are already an accepted surrogate parameter of the future risk of stroke in patients with carotid artery stenosis. The aim of this review is to summarize and evaluate the data about occurence and clinical impact of MES in patients with chronic cardiac diseases and to clarify whether cardiogenic MES can serve as a surrogate parameter of the heart's future thrombembolic risk as well. Methods: We performed a systematic MEDLINE search and reviewed the currently available literature about chronic cardiac diseases and atheroaortic plaques leading to MES apart from cardiosurgical procedures. Conclusion: The cardiac conditions producing MES are heterogenous and therefore the prevalence of MES is highly variable. The data in patients with acute or after myocardial infarction, endocarditis, patent foramen ovale, mitral valve prolapse, dilatative cardiomyopathy and intracardiac thrombus is promising but only small patient cohorts have been investigated by means of TCD in these categories. MES in atrial fibrillation, or derived from atheroaortic plaques, have been investigated more intensively, but again larger cohorts need to be explored to draw firm conclusions. In all cardiac diseases there is a lack of large prospective studies allowing to reliably correlating MES with clinical events. Compared to carotid artery disease, the current knowledge about the impact of cardiogenic MES on the patient's risk is sparse. This should encourage the clinical research in this promising field.

Cannabinoids (natural, endogenous and synthetic compounds) produce vasorelaxation in resistance and conduit arteries. Several putative mechanisms have been proposed to explain this effect of cannabinoids. The aim of the present review is to discuss the different mechanisms involved in the vasorelaxant effect of endogenous and synthetic cannabinoids in resistance and conduit arteries. Research on the vascular effects of cannabinoids suggests that the magnitude of the vasorelaxation and the mechanisms involved are not identical in all vascular beds with one or two mechanisms predominating. Either extracellular or intracellular mechanisms are involved. With regard to the former, the stimulation of cannabinoid CB1, CB2 or nonCB1/nonCB2 cannabinoid receptors and the stimulation of vanilloid receptors, transient potential vanilloid receptors, on perivascular nerve endings with the subsequent release of the vasodilator neurotransmitter calcitonin gene-related peptide have been described. With regard to the latter, the main mechanisms implicated include nitric oxide release, metabolism to vasoactive arachidonic metabolites or prostanoid analogues, or endothelium derived hyperpolarising factor release. The knowledge of these mechanisms is crucial to identify new therapeutic targets and to understand the consequences in different vascular beds.

Paroxysmal Nocturnal Hemoglobinuria (PNH) is a rare, acquired stem cell disorder, with its primary clinical manifestations being hemolytic anemia, marrow failure and thrombophilia. Chronic hemolysis, failures of the fibrinolytic system, increased leukocyte-derived tissue factor levels in plasma, procoagulant microparticles generated through complement-mediated damage of platelets and venous endothelium are related to the acquired hypercoagulable state. Visceral thrombosis (including hepatic veins and mesenteric veins), cerebrovascular events and pulmonary embolism predict a poor outcome. Thrombosis is also associated with significant morbidity during pregnancy. Depending on the sites of thrombosis, a score-based probability to predict outcome can be assigned. Abdominal vein thromboses account for the majority of morbidity and mortality related to thrombosis, and time-dependent trends suggest that mortality rates tend to decline, with the advent of evolution of therapeutic and diagnostic strategies. In contrast, mortality rates from cerebrovascular events display no significant decline. Prompt diagnosis requires both clinical suspicion and sophisticated imaging techniques, along with multidisciplinary therapeutic intervention. In the eculizumab era, a significant reduction of thrombotic events was observed during therapy, and long-term follow up is needed to establish any benefit in rates and pattern of this complication. However, up to now, only bone marrow transplantation permanently abolishes the coagulation defect.