Genetic instability and atherosclerosis: can somatic mutations account for the development of cardiovascular diseases?

Several observations suggest that cancer and atherosclerosis may entail fundamentally common biological mechanisms. The accumulation of lipids and the proliferation of smooth muscle cells (SMCs) are the main histological features of sclerotic plaque formation. The most prominent theory concerning the pathophysiological mechanisms of atherosclerotic plaque formation is the "inflammatory response to injury" hypothesis, which states that SMC proliferation is an inflammation-fibroproliferative reaction to different insults to the artery wall. However, recent evidence suggests that alterations at the DNA level may contribute significantly to the development of the disease. In accordance with these findings, the "monoclonal" hypothesis of atherosclerosis has been suggested. This hypothesis proposes that atherosclerosis begins as a mutation or viral infection, transforming a single, isolated smooth muscle cell into the progenitor of a proliferative clone, as seen in carcinogenesis. Studies of DNA damage in atherosclerotic tissues are lacking. Biological evidence for the hypothesis that cancer and atherosclerosis may share pathological mechanisms is discussed, emphasizing the need to perform studies investigating the involvement of somatic mutations in heart diseases.     

"Pro-resolution" and anti-inflammation, a role of RvE1 in anti-atherosclerosis and plaque stabilization

Inflammation governs atherosclerosis and is firmly regulated. Endogenous mechanisms to keep inflammation self-limiting are unclear. In the present article, we propose that RvE1 (resolution E1), an endogenous lipid mediator, inhibits inflammation through "pro-resolution" and counter-modulating immunity in atherosclerosis. The background comes from studies on the potent programming of resolution and immuno-inflammation of RvE1 and its precursor, eicosapentaenoic acid, in treating chronic inflammatory disease with unknown mechanisms. In light of the interaction between RvE1 and leukotrieneB4 (LTB4) and their potential impaired immunity regulation hematostasis, we hypothesize that RvE1 play an anti-atherosclerosis and plaque stabilization role through "pro-resolution" and anti-inflammation which may be realized by blocking LTB4/BLT1 (receptor of LTB4) pathway. Our hypothesis generates potentially clinical viewpoint to systematically look for pro- and anti-inflammation and "pro-resolution" process in atherosclerosis. Furthermore, we suggest that RvE1 might be particularly indicated for the treatment of atherosclerotic diseases and plaque stabilization which might ensure an effective management for patients with coronary artery disease.     

The pathogenesis of atherosclerosis in autoimmune rheumatic diseases: roles of inflammation and dyslipidemia

As patients with autoimmune rheumatic diseases live longer due to improved therapies and preventive measures, death and disability from atherosclerosis, particularly myocardial infarcts, are increasing. The relative risks for atherosclerosis vary from approximately 1.6 in ankylosing spondylitis and psoriatic arthritis to 3.0 in rheumatoid arthritis (RA), and 6.0 in systemic lupus erythematosus (SLE). Increased risks are found when analyzed by atherosclerotic events, causes of death, or surrogate measures of atherosclerosis, such as carotid artery plaque, intimal-media thickness, or coronary artery calcification. At all ages among adults, atherosclerosis is increased in patients with SLE or RA compared to healthy controls. For example, in women with SLE under the age of 40 years, approximately 13% have carotid plaque compared to 2% of controls; over age 59 the percentages are 71 and 45, respectively. For patients with RA, prevalence is 7% under the age of 40 in patients compared to zero in controls; over 59 years the prevalences are 80% and 44%, respectively. In this review we will discuss the mechanisms involved as well as an overview of the natural history in pathobiology.     

Autoreactive antibody repertoire is perturbed in atherosclerotic patients

In patients with clinical symptoms of coronary atherosclerosis, T cells are activated and directed to autologous proteins contained in the active plaques, suggesting that autoimmune responses may play a role in atherosclerosis progression. Organ-specific autoimmune diseases are sometimes accompanied by broad alterations of serum autoreactive antibody repertoires. We thus investigated antibody repertoires at a global level, using a technique of immunoblotting that allows for the quantitative screening of antibody reactivities in complex antibody mixtures toward a large panel of antigens derived from homologous tissue extracts, followed by multiparametric statistical analysis of the data. We analyzed the autoreactive IgG repertoire in 20 patients with documented coronary atherosclerosis and in 20 matched healthy controls. Total proteins from atherosclerotic carotid specimens and normal arterial tissues (target organs) and from kidney, liver, and stomach (non-target control organs) were used as panels of antigens. Patients had a significantly perturbed antibody repertoire and an enhanced autoreactivity of IgG to target and non-target organs, as compared with controls. Reactivity of purified IgG to plaque and normal artery proteins was greater in patients, but reactivity of IgG in the whole serum toward normal arterial tissue was lower than in controls; this suggests that, in patients, autoreactivity toward normal arteries is regulated by serum factors. Our data indicate that atherosclerotic patients develop a perturbed humoral immune response directed toward arterial proteins, which impacts on the overall autoreactive repertoire. These findings further substantiate that autoimmune processes take place in atherosclerosis and most likely influence disease progression.     

Coronary atherosclerosis and interventions: Pathological sequences and restenosis

The primary cause of cardiac morbidity and mortality in developed countries is ischemic (coronary) heart disease. The incidence of this disease is virtually all due to atherosclerosis, and ischemic heart disease is also the most prevalent disease in the industrialized world, causing over 40% of all deaths in the United States and Western Europe. In Japan, the incidence of ischemic heart disease due to coronary atherosclerosis is gradually increasing as well. Compared with the classical nomenclature of atherosclerosis; that is, fatty streak, fibrous plaque and complicated lesions, the term Stary's classification has been universally accepted because it reflects the more recently acquired knowledge about the morphological and biochemical details of the processes in coronary atherosclerosis, which have been obtained by new strategies such as angioscopy, intravascular ultrasound and molecular biological methods. The term Stary's classification has been applied for the coronary atherosclerosis of patients with acute coronary syndrome at the National Cardiovascular Center, for the analysis of predisposing atherosclerosis of these patients. The recent findings regarding acute coronary syndrome resulting from a rupture of coronary atherosclerotic plaques indicate that this syndrome is probably the most important mechanism underlying the sudden onset. It has been found that the risk of plaque rupture may depend more on plaque composition than on plaque size. Plaques rich in soft extracellular lipids and macrophages are possibly more vulnerable to plaque rupture. Two of the goals of the present review are to clarify how plaque disruption occurs and to elucidate the relationship between plaque disruption and coronary risk factors in elderly Japanese patients with acute coronary syndrome. Coronary stents have been shown to be efficacious in the treatment of acute and threatened closure complicating percutaneous transluminal coronary angioplasty (PTCA) and have produced encouraging initial results in the prevention of restenosis. In the autopsy study of restenosis after PTCA, it was observed that dense caps of collagen fibers in the adventitia in the vicinity of the disrupted internal elastic laminae were present in all of the remodeling lesions. It is suggested that remodeling, which resulted in adventitial scarring, is one of the major causative factors of restenosis after PTCA. The long-term success of stenting, however, remains limited by the occurrence of late in-stent restenosis, with an incidence of 20-42% depending on the stent design and the patient population studied. Another aim of the present review is to describe the pathological mechanism of restenosis after PTCA and/or stent replacement and, consequently, the vascular remodeling that occurs around adventitial tissue after PTCA and intimal hyperplasia that is chronically irritated by a foreign body granulomatous reaction after stenting. Finally, the results of the investigation of the effect of a tissue factor pathway inhibitor on the prevention of interventional restenosis is described.     

Less Travelled Roads in Clinical Immunology and Allergy: Drug Reactions and the Environmental Influence

The elevated cardiovascular morbidity in rheumatoid arthritis, systemic lupus erythematosus, and the antiphospholipid syndrome is well known, as well as the pulmonary involvement observed in these conditions and to a major extent in systemic sclerosis. These manifestations constitute a major challenge for clinicians involved in patient management. Moreover, several issues regarding the link between autoimmune rheumatic diseases and cardio pulmonary morbidity remain largely enigmatic. The mechanistic role of certain autoantibodies frequently observed in association with heart and lung diseases or the pathogenetic link between chronic inflammation and the pathways leading to atherosclerosis or pulmonary vascular changes are yet to be elucidated. As such, these questions as well as treatment strategies are of common interest to rheumatologists, immunologist, pulmonologists, and cardiologists and thus call for an interdisciplinary approach. This paradigm has been well established for rare conditions such as the Churg–Strauss syndrome. Nowadays, it seems that this approach should be expanded to encompass more common conditions such as coronary heart disease, pulmonary arterial hypertension or dilated cardiomyopathy. The present issue of Clinical Reviews in Allergy and Immunology addresses the new knowledge and concepts of autoimmune-related cardiopulmonary diseases. The issue derives from the 2010 International Autoimmunity Meeting held in Ljubljana, Slovenia and is thus timely and dedicated to the latest developments in this new multidisciplinary field.     

Inflammation: a pivotal link between autoimmune diseases and atherosclerosis

Premature coronary heart disease has emerged as a major cause of morbidity and mortality in systemic autoimmune diseases. Recent epidemiologic and pathogenesis studies have suggested a great deal in common between the pathogenesis of prototypic autoimmune disease such as rheumatoid arthritis (RA) and systemic lupus erythematosus (SLE) and that of atherosclerosis. Some of the most remarkable data in support of a link between autoimmunity and atherosclerosis comes from epidemiological studies of patients with autoimmune disorders (RA and SLE). Many epidemiologic observations have linked systemic inflammation with the cardiovascular events in autoimmune disease such as RA and SLE. Inflammation is increasingly being considered central to the pathogenesis of atherosclerosis and an important risk factor for vascular disease. Systemic inflammation may be regarded as accelerating the atherosclerotic process. Systemic levels of soluble inflammatory mediators such as C-reactive protein (CRP) have been associated with cardiovascular risk in the general population. CRP, or more specifically high sensitivity-hsCRP, is a marker of systemic inflammation that has been identified as a valid biomarker of cardiovascular risk. Furthermore, the immunomodulatory and anti-inflammatory actions of statins may affect their utility in the context of chronic inflammatory autoimmune disease. Thus, effective control or dampening of inflammation, with such agents, should be included in the therapeutic armamentarium of autoimmune diseases with the aim of protecting against cardiovascular disease.     

Accelerated atherosclerosis in systemic lupus erythematosus and other connective tissue diseases

Connective tissue diseases are associated with increased morbidity and mortality related to a higher rate of cardiovascular events and higher prevalence of subclinical atherosclerosis. Atherosclerosis is now considered a multifactorial process where autoimmunity and chronic inflammation play an important pathogenic role. In systemic autoimmune rheumatic diseases in general, and in systemic lupus erythematosus in particular, atherosclerosis cannot be explained by traditional cardiovascular risk factors alone. Cellular and humoral mechanisms, together with specific factors associated with the disease itself and/or its treatments, have been advocated to explain the acceleration of arterial wall organic damage in these patients. Endothelial dysfunction, carotid intima-media thickness and plaque evaluations provide accurate detection of atherosclerotic process at a preclinical stage, before appearance of clinical disease, allowing preventive measure introduction with the aim to modify the cardiovascular risk in subjects with systemic autoimmune rheumatic diseases.     

Inflammation markers in acute coronary syndrome

Inflammation is a component of atherosclerotic plaque, but it is also a possible pathogenetic factor of acute coronary event responsible for coronary instability. Inflammatory markers are considered as new risk factors for atherosclerosis. Among others (C-reactive protein (CRP) is the best known marker of inflammatory response which is most frequently found in patients with acute myocardial infarction preceded by a period of instability. High values of inflammatory markers indicate poor prognosis after acute myocardial infarction. Therapy may lower the inflammatory component and the risk of coronary disease. Specific response of inflammatory marker during diagnostic and percutaneous coronary interventions indicates more severe coronary disease.     

Coronary heart disease in 48 autopsy patients 30 years old and younger

We studied 48 autopsy patients younger than 30 years who had severe coronary atherosclerosis. Twenty-one patients (44%) died suddenly, 26 (54%) had a history of chest pain, and one had chronic congestive heart failure. Twenty-one patients (44%) had single-vessel disease, 19 (40%) had two-vessel disease, and only nine (16%) had three or four major coronary arteries severely narrowed (greater than 75% cross-sectional area luminal narrowing) by atherosclerotic plaques. Thrombi in coronary arteries were noted in 27 patients (56%) and the left anterior descending coronary artery was the most frequently involved. The severity of coronary atherosclerosis was much less in patients younger than 30 years, and the atherosclerotic plaque consisted largely of foam cells, fibrous tissue, and pultaceous debris, with minimal calcific deposits. Thus, it is this population that is most likely to be susceptible to regression of the atherosclerotic plaque.     

Atherogenesis as a reflection of immune inflammation in the vascular wall

Despite numerous basic and applied studies into the pathogenesis and treatment of atherosclerosis, there is no theory which could explain the development of the whole complex of changes united under the term "atherosclerosis". Examining the causes of atherosclerosis disclosed a pathogenetic association of the immunoregulatory signal CD40-CD40L with the occurrence of arterial atherosclerotic lesions. Studies of the immune mechanisms responsible for the pathogenesis of atherosclerosis (autoimmune complexes containing oxidative modification of LDL, T and B lymphocytes, inflammation mediators, hemoadhesive molecules, and immunoregulatory molecules showed the leading role of autoimmune mechanisms in atherosclerosis. The conceptual result of the studies is that the authors have elucidated the leading role of immune inflammation in the appearance and development of arterial atherosclerotic lesions. The development of a new concept of assessing the pathogenesis of atherosclerosis in the context of immune inflammation in the vascular wall opens new vistas for the treatment of this disease.     

Pathology of the cardiovascular system--new findings

Presented is a review of important new informations in the field of cardiovascular pathology. The particular items discussed are hypertension (new definition and classification), etiopathogenesis of atherosclerosis, ischemic heart disease (unstable plaque; acute coronary syndrome; advances in therapy), valvular diseases (changing spectrum; calcific aortic stenosis; mitral valve prolapse), cardiomyopathies (new definition; etiology), infective endocarditis (changing pattern), senile heart diseases, and endomyocardial biopsy.     

The mainstream hypothesis that LDL cholesterol drives atherosclerosis may have been falsified by non-invasive imaging of coronary artery plaque burden and progression

That LDL cholesterol drives atherosclerosis is a widely if not almost universally held belief, and this belief strongly influences the mainstream approach to coronary heart disease. However heart disease has a number of stages, and in terms of primary prevention, the initiation and progression of silent or sub-clinical atherosclerosis is clearly fundamental. However, studies that address the efficacy of interventions and practices aimed at the primary prevention of heart disease almost always use event-based endpoints such as fatal or non-fatal myocardial infarction or unstable angina. These endpoints do not directly relate to the primary prevention of silent atherosclerosis and to apply these results to asymptomatic individuals in this context involves an extrapolation.The advent of non-invasive imaging techniques which allow the determination of coronary artery plaque burden and progression of plaque has provided a unique opportunity to examine the relationship between both traditional and emerging risk factors and the extent of sub-clinical coronary artery disease and in particular allow the testing of the hypothesis that LDL cholesterol drives coronary atherosclerosis. Consistent with earlier autopsy studies, the use of electron beam tomography and contrast enhanced CT angiography techniques have created a large body of evidence which appears to falsify this hypothesis. The large number of null results for the association between serum LDL cholesterol levels and the prevalence or progression of both calcified and non-calcified plaque in the appropriate vascular bed and involving large numbers of men and women over a wide range of age, ethnic background, plaque burden and cholesterol levels cannot be easily dismissed. If the hypothesis is false, this has a significant impact on currently held views regarding risk factors and therapeutic interventions in the case of individuals who are asymptomatic, that is, issues associated with primary prevention. Also, if the hypothesis is false, then the use of changes in LDL as a surrogate marker for judging the importance of various risk factors for silent atherosclerosis and thus coronary artery disease can be called into question.     

Allograft heart accelerated atherosclerosis: evidence for cell-mediated immunity in pathogenesis

The problem of accelerated atherosclerosis in the allograft heart continues to adversely effect the long term survival of transplant patients. Most traditional risk factors influencing atherogenesis do not appear to play an important role in accelerated atherosclerosis. Additional causative factors proposed in recent years are not without controversy. An immune-mediated endothelial damage by cytotoxic B-cell antibodies as the initial injury in the induction of accelerated atherosclerosis has not been confirmed on morphologic grounds. This study is based on six cases (four autopsies and two explanted hearts) from transplant patients whose hearts were examined at different post-transplantation intervals (24 h to 14 mo). Our morphologic findings of a segmental coronary vasculitis involving primarily the outer two-thirds of the media and adventitia suggest that the early vascular manifestations may reflect tissue rejection similar to that seen in the myocardium. Furthermore, our findings from the medium size coronary arteries are suggestive of a cell-mediated immune injury probably directed against the smooth muscle cells of the media. Although the end result (occlusive coronary lesion) may reveal some morphologic similarities in both naturally occurring atherosclerosis and accelerated atherosclerosis, the pathogenetic mechanisms involved in these two conditions may differ.     

Chronic inflammation-enhanced atherosclerosis: can we consider it as a new clinical syndrome?

Incidence of cardiovascular disease in patients with chronic autoimmune disorder like rheumatoid arthritis is much higher than in general population. Cardiovascular events (e.g. myocardial infarction or stroke) are caused by premature accelerated development of atherosclerosis. Chronic inflammation-enhanced atherosclerosis syndrome is proposed as a separate syndrome occurring in patients suffering of chronic inflammation. It is suggested that atherosclerosis as an inflammatory disease and long-lasting extravascular inflammation have common mechanisms resulting in an increase in atherosclerosis and its sequellae, cardiovascular diseases.     

Down-Regulation of Endothelial Expression of Endothelial Cell Protein C Receptor and Thrombomodulin in Coronary Atherosclerosis

Coronary atherosclerosis with occlusive thrombosis is the major cause of acute myocardial infarction. Although plaque rupture is usually hypothesized to be the predisposing event in coronary thrombosis, the possibility cannot be excluded that local changes in the anticoagulant properties of the endothelium overlying the plaque contribute to this process. It is evident that thrombomodulin and the endothelial cell protein C receptor are critical players in the control of the thrombogenic process. This study examined whether thrombomodulin and the endothelial cell protein C receptor are down-regulated on endothelial cells overlying the atherosclerotic plaque in coronary arteries and thus could potentially favor local thrombus formation. Sections of archival left and right coronary arteries (n = 18 each) with severe atherosclerosis from the native heart of six patients who underwent heart transplantation were immunostained for CD31, CD34, endothelial cell protein C receptor, and thrombomodulin using a streptavidin-biotin-peroxidase method. Controls included left and right coronary arteries from autopsy cases with no atherosclerosis (n = 6), and also from cases with mild atherosclerosis (n = 5). The apparent density of all of these proteins was much higher in control than in atherosclerotic arteries. Our findings support the hypothesis that both endothelial cell protein C receptor and thrombomodulin are down-regulated in coronary arteries with atherosclerosis. These changes would be expected to result in reduced inhibition of thrombogenic and anti-inflammatory activity on the endothelium overlying atherosclerotic regions and thus could contribute to coronary thrombosis.     

Link between intracellular pathogens and cardiovascular diseases

Atherosclerosis is a multifactorial disease with an important inflammatory component. Inflammatory cells such as T-lymphocytes, macrophages and monocytes play a key role not only in its origin but also during plaque rupture. In addition, it has been suggested that infection could be the cause of atherosclerosis. Serologic studies involving polymerase chain reaction, immunocytochemistry and electron microscopy support the hypothesis of an association between Chlamydia pneumoniae and atherosclerosis. This intracellular pathogen is able to replicate in macrophages, vascular cells and smooth muscle cells. C. pneumoniae can then release inflammatory cytokines which contribute to instability of the plaque. C. pneumoniae may be recovered through cell culture from coronary atherosclerotic plaques and has a strong association with one allele, of the major histocompatibility system among patients with acute coronary syndromes. Other intracellular pathogens that have been implicated in atherosclerosis include cytomegalovirus, Mycoplasma pneumoniae and Helicobacter pylori. To test the hypothesis that C. pneumoniae plays a role in the instability of plaque, we conducted a prospective clinical trial, using the macrolide antibiotic roxithromycin in 202 patients. The preliminary results show a statistically significant reduction in the incidence of acute coronary events at 30 days.     

Everolimus,a promising medical therapy for coronary heart disease?

Coronary heart disease is mainly caused by atherosclerosis, which is a multifactotial and systemic disease. Lipid metabolism disorder and chronic inflammation are two well accepted mechanisms leading to atherosclerosis. The key initiating process in athrogenesis is lipid retention in subendothelium. Inflammatory activity plays an important role in the whole pathogenesis of atherosclerosis. Recent investigations have demonstrated that rapamycin reduces lipid retention by increasing adipose-tissue lipase activity and decreasing lipoprotein lipase activity. Rapamycin also reduce intracellular lipid accumulation in smooth muscle cells and macrophages. Since rapamycin is a definite immunosuppressive agent, and inflammatory process has been involved in atherosclerosis, the compound would have effect on the progression of atherosclerosis through reducing inflammatory activity. Moreover, rapamycin would protect plaque from rupture by selectively clearing macrophages without affecting vascular smooth muscle cells.     

Renin: at the heart of the mast cell

Summary:  Cardiac mast cells proliferate in cardiovascular diseases. In myocardial ischemia, mast cell mediators contribute to coronary vasoconstriction, arrhythmias, leukocyte recruitment, and tissue injury and repair. Arrhythmic dysfunction, coronary vasoconstriction, and contractile failure are also characteristic of cardiac anaphylaxis. In coronary atherosclerosis, mast cell mediators facilitate cholesterol accumulation and plaque destabilization. In cardiac failure, mast cell chymase causes myocyte apoptosis and fibroblast proliferation, leading to ventricular dysfunction. Chymase and tryptase also contribute to fibrosis in cardiomyopathies and myocarditis. In addition, mast cell tumor necrosis factor-α promotes myocardial remodeling. Cardiac remodeling and hypertrophy in end-stage hypertension are also induced by mast cell mediators and proteases. We recently discovered that cardiac mast cells contain and release renin, which initiates local angiotensin formation. Angiotensin causes coronary vasoconstriction, arrhythmias, fibrosis, apoptosis, and endothelin release, all demonstrated mechanisms of mast-cell-associated cardiac disease. The effects of angiotensin are further amplified by the release of norepinephrine from cardiac sympathetic nerves. Our discovery of renin in cardiac mast cells and its release in pathophysiological conditions uncovers an important new pathway in the development of mast-cell-associated heart diseases. Several steps in this novel pathway may constitute future therapeutic targets.