Current Pharmaceutical Design - Volume 13, Issue 10, 2007

Atherosclerotic disease remains the number one killer of the aging population in Western Society and numbers of cardiovascular events are strongly increasing in developing countries. Worldwide, about 20 million deaths per year are caused by this inflammatory disease and the costs for health care and loss of productivity are impressive. Despite the advances in treatment of cardiovascular disease, the increasing incidence of type II diabetes in developed countries deserves careful consideration, since this will surely enhance morbidity and mortality rates due to cardiovascular disease. Improvement of our understanding of the mechanisms that lead to atherosclerotic disease has resulted in innovative modalities that may help diagnose, prevent and treat this life threatening disease. Pathological studies revealed that next to atherosclerotic plaque burden, also the plaque phenotype is a major determinant of acute coronary thrombotic occlusion. Plaque rupture or plaque erosion may lead to activation of coagulation cascades and induce a thrombotic occlusion of the lumen. Cross-sectional studies demonstrated that plaques that are associated with thrombotic occlusion often encompass large lipid cores with a thin fibrous cap and a large number of inflammatory cells that secrete matrix degrading proteases and destabilize the plaque. Stabilizing this so called vulnerable plaque is one of the major challenges in the research domain of cardiovascular diseases. Many pharmaceutical companies run research and development programs to image, detect and stabilize the plaques prone to induce an adverse coronary event. The stakes are high. However, there is an ongoing debate how to define the vulnerable plaque and whether the patient is a vulnerable entity himself and should be treated accordingly. In this issue of Current Pharmaceutical Design you will find research papers that cover the current status and remaining issues in this very active field of the research on the vulnerable atherosclerotic plaque. Atherosclerosis: An Inflammatory Disease: It is now well established that atherosclerosis is an inflammatory disease and that the body's immune system plays a central role in the initiation and progression of atherosclerotic lesion development [1]. The recent insights into how the immune system recognizes endogenous and exogenous ligands and how ligation of innate immune receptors results in a local inflammatory response have opened exciting new therapeutic avenues [2]. Local plaque inflammation is now considered as a major determinant of destabilisation of the advanced atherosclerotic lesion. Cross-sectional studies demonstrated that atherosclerotic plaques that are associated with thrombotic occlusion often encompass large lipid cores with a thin fibrous cap and a large number of inflammatory cells that secrete matrix degrading proteases and destabilize the plaque. Macrophages express proteases like MMP1, MMP9 and cathepsins that degrade the collagen and elastin structures of the arterial wall and thereby induce expansive remodelling and breakdown of the fibrous cap [3-6]. Subsequently, the plaque may rupture and the now uncovered atheromatous core induces a strong coagulatory response. Thrombotic occlusion of the coronary artery may be the fatal consequence of these events. Stabilizing the atheromatous inflammatory vulnerable plaque is one of the major challenges in cardiovascular research. Stabilising the Vulnerable Plaque: the Natural History of the Disease: Although plaque rupture is associated with the presence of a large lipid pool, macrophages and a thin fibrous cap, the predictive value of these histopathological determinants for the occurrence of rupture of the so-called “vulnerable plaque” is unknown. In fact, since prospective studies have not yet been performed, we do not really know the phenotype and natural development of the vulnerable plaque. For successful application of new imaging techniques to visualize the vulnerable plaque that will predict a clinical event, many questions merit careful attention among which are the following: (1) How specific are the established histological features that have been considered representative for “the vulnerable plaque”, i.e. a large lipid core and cap inflammation, for the development of plaque rupture? (2) Are the histopathological determinants of ruptured plaques locally or systemically observed phenomena? In other words, could sampling for the presence of arterial wall inflammation or lipid-core formation be extrapolated to the total coronary atherosclerotic circulation? (3) If a vulnerable plaque ruptures, what is the chance that this plaque rupture eventually leads to a clinical syndrome? More questions like this could be raised but these questions all share the same denominator that can be summarized as follows: “What is the natural history of human atherosclerotic disease?” There is no doubt that longitudinal studies including imaging may help answering this question [7]. Until then, scientific experimental evidence in non human experimental models will point to potential molecular targets that may stabilize the vulnerable plaque and patient.

Innate immunity is the first line of defence against invading micro-organisms. The family of Toll-like receptors (TLRs) recognizes pathogen-associated molecular patterns (PAMPs) that are carried by the invading micro-organisms. Infectious pathogens have been implicated to play an important role in atherosclerosis. Nowadays, evidence is accumulating that TLRs play an important role in the initiation and progression of atherosclerosis too. A lot is known about the exogenous ligands that are able to activate the TLRs, but it is also known that endogenous ligands have the capacity to activate TLRs when exogenous ligands are absent. Studies on knockout mice, epidemiological studies and even human polymorphism studies confirmed the important role of TLRs in development and progression of atherosclerotic disease. Studies with antagonists against TLR ligands and vaccination studies demonstrated that TLR signaling might be a potential target for intervention in the initiation and progression of atherosclerosis.

Rupture of vulnerable plaques is the main cause of acute coronary syndrome and myocardial infarction. Identification of vulnerable plaques is therefore essential to enable the development of treatment modalities to stabilize such plaques. Several diagnostic methods are currently tested to detect vulnerable plaques. Angiography has a low discriminatory power to identify the vulnerable plaque, but does provide information about the entire coronary tree and serves as guide for invasive imaging techniques and therapy. Angioscopy offers a direct visualization of the plaque surface and intra- luminal structures like thrombi and tears. However, angioscopy is difficult to perform, invasive and only the proximal part of the vessels can be investigated. IVUS (intravascular ultrasound) provides some insight into the composition of plaques. The detection of vulnerable plaques is mainly based on series of case reports with a lack of prospectivity and follow- up. Palpography, an IVUS derived technique, reveals information, which is not recognizable in IVUS. It can differentiate between deformable and non-deformable tissue, which enables the technique to detect vulnerable plaques with a positive predictive value. The clinical value of palpography is currently under investigation. Thermography assesses the temperature heterogeneity as an indicator of the metabolic state of the plaque. A coincidence of temperature rise and localization of vulnerable plaque was suggested. OCT (optical coherence tomography) can provide images with ultrahigh resolution utililizing the back-reflection of near-infrared light from optical interfaces in tissue. Drawbacks are the low penetration depth into tissue and the absorbance of light by blood. Raman spectroscopy can provide quantification about the molecular composition of the plaque. Long acquisition time, the low penetration depth and light absorbance by blood limit the performance of the technique. Another light emitting technique is NIR (near infrared spectroscopy), which identifies lipid loaded plaques and is tested currently in clinical trials. Non-invasive MRI (magnetic resonance imaging) and multislice spiral computed tomography (MSCT), with their excellent ability to identify lipid-rich tissue, have been utilized to characterize potentially vulnerable plaques foremost in non-moving structures like the carotid arteries. Due to the resolution of the techniques small plaque structure cannot be assessed. The role of non-invasive imaging in vulnerable plaque detection is currently under investigation. Several invasive and non-invasive techniques are currently under development to assess the vulnerable plaque. Most of the techniques show exiting features, but none have proven their value in an extensive in vivo validation and all have a lack of prospective data.

Acute coronary syndromes (ACS), i.e. unstable angina and myocardial infarction, are the leading causes of death in developed countries and developing countries alike. Lipid lowering intervention studies have demonstrated a 30% risk reduction in recurrent cardiovascular events and death, despite only modest improvement in angiographic stenosis. This discrepancy suggested that cholesterol lowering by statins may lead to stabilization of vulnerable plaques rather than reducing stenosis per se. The predominant effect of statins is to lower lipid levels by inhibiting cholesterol biosynthesis. Besides the lipid lowering effects, statins have also been shown to modulate the inflammatory status and improve endothelial function amongst others, commonly referred to as “pleiotropic effects”. In the present review we will discuss different determinants which lead to plaque vulnerability and subsequently we will expand on the plaque stabilizing or “pleiotropic” effects of statin treatment.

The need to identify and characterize vulnerable atherosclerotic lesions in humans has lead to the development of various animal models of plaque vulnerability. In this review, current concepts of the vulnerable plaque as it leads to an acute coronary event are described, such as plaque rupture, erosion, intraplaque hemorrhage and neovascularization. Recently developed animal models that have attempted to reproduce these concepts are described and evaluated based on their suitability in the study of vulnerable plaques. Although certain features of plaque vulnerability have been reported in animal models, a model encompassing all aspects of the vulnerable plaque is lacking.

Immune responses against oxidized forms of LDL play a critical role in activation and regulation of the inflammatory process that characterizes all stages of atherosclerosis. In humans oxidized LDL is targeted by both IgM and IgG autoantibodies. Immunization of hypercholesterolemic animals with oxidized LDL has been shown to inhibit atherosclerosis demonstrating that at least some of these immune responses have a protective effect. The identification of the structures in oxidized LDL that are responsible for activation of immunity has made it possible to develop novel therapeutic approaches for treatment of atherosclerosis based on active (vaccines) and passive (antibodies) immunization. Studies performed in atherosclerosis-prone mice demonstrate that both peptide-based vaccines and recombinant IgG targeting epitopes in oxidized LDL significantly reduce atherosclerosis. There is also evidence antibodies against oxidized LDL could also be used for imaging atherosclerosis.

LDL-lowering therapies, predominantly involving statins, have been shown to significantly reduce cardiovascular events in asymptomatic subjects as well as in subjects with clinically established atherosclerotic cardiovascular disease. However, despite statin therapy, significant number of cardiovascular events continue to occur indicating the need for additional targets for atherosclerosis management. A number of pre-clinical studies have suggested that several HDL based therapies have the potential to stabilize or regress atherosclerosis consistent with epidemiologic evidence of an inverse relationship between coronary heart disease and HDL cholesterol levels. One such therapeutic approach involves direct infusion of HDL or HDL like molecules for rapid remodeling and stabilization of atherosclerosis. Pre-clinical and proof of concept type preliminary clinical studies suggest the feasibility and potential efficacy of this emerging new therapeutic paradigm.

Atherosclerosis is currently viewed as an inflammatory disease in which the initiation and progression of the atherosclerotic plaque towards a rupture prone, unstable plaque is driven by leukocyte recruitment mediated by various inflammatory mediators. Recently, interest in chemotactic cytokines or chemokines with regard to atherosclerosis has been growing as chemokines mediate the influx of leukocytes that is typical of atherothrombosis. The activity of the majority of chemokines is overlapping and chemokines are not only produced by the various cellular constituents of the atherosclerotic plaque but also by activated platelets. Consequently, the direct influence of individual chemokines on plaque destabilisation and rupture is widespread and rather unclear. Experimental research has already established the role of a number of chemokines in advanced atherosclerosis. Nevertheless, given the complexity and size of the chemokine family, further screening of cardiovascular disease for chemokine level and genetic polymorphisms for chemokines will be warranted as the search for viable biomarkers of plaque destabilization as well as novel therapeutic targets for specific atheroregressive therapeutic compounds is ongoing. With regard to the latter, clinical trials with specific chemokine inhibitory strategies, like chemokine receptor antagonists, are already underway in other inflammatory disorders. Summarizing, chemokine inhibition likely constitutes an important therapeutic option next to already established drugs in the management of cardiovascular disease.

Nowdays the endothelium is considered a key determinant of vascular health. NO is the principal mediator of all endothelial protective effects, due to its antinflammatory, antiproliferative, immunomodulatory and vasorelaxant properties. On the contrary, a growing body of evidence suggests that endothelial dysfunction is associated with cardiovascular events. Emerging data suggest that acute coronary syndromes (ACS) may involve a complex interplay between endothelial dysfunction, inflammation and thrombosis. Despite the success in reducing the mortality from acute cardiovascular events, the incidence of cardiovascular disease and its complication continues to increase. New insights into mechanisms of endothelial dysfunction, such as a better understanding of the regulation of vascular sources of oxygen radicals, may lead to novel therapeutic strategies with the potential to improve prognosis. The key pharmacological agents that improve clinical outcome in high-risk patients are statins, ACE-inhibitors or angiotensin receptor antagonists. Compelling scientific evidence suggests that these medications are effective in improving endothelial function. The present review focuses on the potential importance of benefits on endothelium of these medicaments in the management of acute coronary syndromes.

Risk factors for atherosclerotic cardiovascular disease (CVD) are highly co-prevalent but poorly identified and treated. The Screening for Heart Attack Prevention and Education (SHAPE) Task Force from the Association for Eradication of Heart Attack (AEHA) has recently proposed a new strategy that recommends screening for sublinical atherosclerosis and implementing aggressive treatment of “vulnerable patients”. The Task Force has also envisioned future developments that may shift mass screening strategies to mass prophylactic therapy. The “Polypill” concept, introduced by Wald and Law suggests a combination of statin, low-dose antihypertensives, aspirin and folic acid, in a single pill, taken prophylactically by high risk population can cut CVD event rates by as much as 80%. In this communication, we review the challenges and promises of such a strategy. “Polypill” is but one of an astronomical number of possible multiconstituent pills (MCCP). Attractive as the MCCP concept is, it lacks evidence from randomized controlled trials, and begs numerous questions about the credibility of the concept, the design and synthesis of such complex pills, pharmacokinetics, pharmacodynamics, bioequivalence, “class” vs. unique properties, interactions, evidence of clinical efficacy and safety, regulatory approval, post-marketing surveillance, prescription vs. over-the- counter use, responsibility for initiating and monitoring therapy, patient education, counterfeiting and importation, reimbursement, advertisement, patent protection, commercial viability, etc. If these issues are favorably addressed, MCCP stand to dramatically change the manner in which CVD is prevented particularly in developing societies. Notwithstanding, assuming low commercial interests, realizing the promises of MCCP will demand serious attention from national public health policymakers. The clinical and regulatory implications of population-based secondary prevention (which rely on a different evidence base, and in which entirely different risk-benefit and cost-effectiveness considerations apply) remain issues for active debate.