Current Vascular Pharmacology - Volume 9, Issue 5, 2011

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Aim of the present Consensus Statement is to provide a comprehensive and up to-date document on the pathophysiology, atherogenicity and clinical significance of low density lipoproteins (LDL) subclasses. We sub-divided our Statement in 2 sections: section I discusses the pathophysiology, atherogenicity and measurement issues, while section II is focused on the effects of drugs and lifestlyle modifications. Suggestions for future research in the field are highlighted at the end of section II. Each section includes Conclusions.

One of the critical points in the pathogenesis of aortic aneurysms (AAs) is the disruption of the balance between vascular extracellular matrix (ECM) deposition and degradation. AAs are common features in some genetically determined diseases of the connective tissue, such as Marfan and Ehlers-Danlos. Acquired factors determining an enhanced inflammatory state of the arterial wall also play a key role. Previous studies have determined the role of tumor growth factor β (TGF-β); as a principal mediator of the pathogenesis of the alterations of the arterial wall homeostasis in AAs. The medical management of any AA is mainly focused on the use of pharmacological agents that reduce hemodynamic stress of the aortic wall, since hypertension is the major risk factor for the enlargement and rupture of the AAs. However, this is far from being a comprehensive pathophysiology-based therapeutic approach. Drugs potentially able to reduce the release of TGF-β may play a role in the pathogenesis of the AAs. They work by improving matrix repair, decreasing the proteolytic pattern and inhibition of angiotensin-converting enzyme (ACE) as well as preventing angiotensin II-induced angiotensin type-1 receptor (AT1R) activation. A new pathophysiology-based therapeutic approach, involving the mechanisms leading to the rupture of the AAs, could represent an additional tool in combination with the current established antihypertensive therapy.

A causal relationship between exposure to smoking and increase in blood pressure (BP) is not yet clearly demonstrated. Some observations suggest a transient increase while smoking a cigarette or when exposed to passive smoking. Late stable hypertension may also occur as a consequence of smoking. This could be attributed to the progression of atherogenesis triggered by smoking (e.g. endothelial dysfunction). Endothelial dysfunction is strongly associated with hypertension. Impaired nitric oxide (NO) availability attributable to oxidative stress production, which causes NO breakdown, has also been considered as another mechanism. Smoking and hypertension seem to have an additive effect as risk factors for cardiovascular disease.

Aldosterone, a steroid hormone with mineralocorticoid activity, is far more than merely a salt-and-water hormone. Aldosterone has a number of non-classical, mineralocorticoid receptor (MR)-mediated actions, including tissue remodeling, modulation of vascular tone and stimulating inflammation and fibrosis, which may fuel progression of end organ damage. Aldosterone breakthrough during blockade of the renin-angiotensin aldosterone system (RAAS) may explain why this treatment regimen only confers partial cardiovascular and renal protection. Of major interest, aldosterone is deleterious only if inappropriately high for its sodium status i.e. high aldosterone and high sodium. The mechanism of sodium dependence of aldosterone-induced renal and cardiovascular damage continues to fascinate. Aldosterone excess increases sodium and fluid retention and consequently increases blood pressure, which, in turn, mediates target organ damage. Moreover, blood pressure independent effects play a role with dissociation of low circulating and high tissue aldosterone levels during high sodium intake and possibly enhanced MR signaling. MR blockade is a valuable strategy, which has potency to halt the progressive end organ damage as observed during current treatments. In heart failure, MR blockade on top of RAAS blockade reduces hard clinical endpoints. Despite encouraging results on the intermediate endpoint proteinuria, long-term data on the efficacy and safety of MR blockade in preventing dialysis and/or cardiovascular endpoints in chronic kidney disease are still lacking. It is obligatory that future clinical studies on the effects of MR blockade on endorgan damage take into account the sodium status.

The antiphospholipid syndrome (APS) is an autoimmune disease in which recurrent vascular thrombosis, pregnancy morbidity or a combination of these events is associated with the persistent presence of circulating antiphospholipid antibodies (aPL). Evidence shows that the dominant antigenic targets for aPL in APS are phospholipid-binding plasma proteins such as β2glycoprotein I and prothrombin. The pathogenic role of aPL in thrombosis is widely accepted but the mechanisms by which these antibodies mediate disease are only partially understood. aPL may affect the normal procoagulant and anticoagulant reactions occurring on cell surface, and also may interact with certain cells, altering the expression and secretion of procoagulant substances. The intracellular signal transduction triggered by aPL has been a focus of intensive research and the p38 mitogen activated protein kinase (MAPK) pathway has been revealed as a major player in the aPL-mediated cell activation. In addition, some candidates as cell-receptor for phospholipid-binding plasma proteins have been identified. The recognition of the intracellular signaling triggered by aPL is a step forward in the design of new modalities of targeted therapies for thrombosis in APS including specific inhibitors of MAPK pathway or antagonists of the putative receptors. Furthermore, novel findings regarding the role of aPL in T-cells responses mark new advances in the understanding of the immunological reactions in APS and open new insights into possible therapeutic approaches to APS. In this article, we review the pathophysiological mechanisms of thrombosis and the specific new targeted therapies for the treatment in APS.

Pharmacologic therapy represents the mainstay of treatment for heart failure in children. However, medical therapy for this population is not widely standardized. This is mainly due to the heterogeneity of potential etiologies, the specific challenge of patients with univentricular physiology and the lack of evidence-based prospective randomized clinical trials in pediatric patients. In fact, most current strategies are based largely on extrapolated data from adult studies. Although the classic drugs for heart failure i.e. diuretics, angiotensin-converting enzyme inhibitors, β-blockers and cardiac glycosides, still play a major role in the treatment of pediatric heart failure, newer alternative therapies such as levosimendan and nesiritide are increasingly utilized with promising early results. A systematic literature search of PubMed and MEDLINE databases using relevant terms was performed. All clinical trials and relevant manuscripts about the current pharmacologic treatment of heart failure in the pediatric population were reviewed. New drugs such as levosimendan and nesiritide and the treatment of single-ventricle patients were also included.

The wet form of age related macular degeneration (AMD), known also as exudative or neovascular, is characterized by the formation of a pathological choroidal neovascular membrane (CNV) responsible for most cases of severe blindness. Vascular endothelial growth factor (VEGF) is a homodimeric glycoprotein acting as a growth factor selective for endothelial cells; it regulates angiogenesis and enhances vascular permeability and plays a leading role in this disorder. The consistent association between CNV and increased VEGF-A expression provides a strong reason for exploring the therapeutic potential of anti-VEGF agents in the treatment of neovascular AMD. The importance of VEGF for the development of AMD-related CNV has led to the development of a strategy able to block its pathologic effects. The rationale is that a blockade of VEGF actions could be effective in arresting choroidal angiogenesis and also reducing the vascular permeability, which is frequently the main cause of visual acuity deterioration. However, VEGF has also important functions in vascular physiology. The effects of anti-VEGF therapy may inhibit these functions. Herein we report the systemic adverse events secondary to intravitreal administration of these compounds, i.e. the main cardiovascular effects (thrombosis, hemorrhage, hypertension, proteinuria), as well as the less frequent cerebrovascular accidents, myocardial infarction, transient ischemic attacks, deep vein thrombosis, pulmonary embolism and thrombophlebitis.