Introduction

Atherosclerosis is responsible for cardiovascular disease being the leading cause of death in developed countries (World Health Organization Statistical Information System, http:\\www.who.int\whosis ). Atherosclerotic lesions may be present throughout a person’s lifetime. The earliest lesions in atherosclerosis, the so-called fatty streak, may be found in children. Progression of the fatty streak leads to an advanced complicated lesion later in life. For an acute ischaemic condition to occur, plaque rupture or endothelial erosions must develop resulting in thrombus formation on the surface of an atherosclerotic plaque.

Atherosclerosis is a chronic inflammatory disease of the arterial intima . Premature and accelerated atherosclerosis, with enhanced cardiovascular morbidity and mortality, occurs in the course of systemic inflammatory diseases such as rheumatoid arthritis (RA), systemic lupus erythematosus (SLE) and vasculitis .

In the initial phase of the atherosclerotic process, lipoproteins are retained and modified in the vessel wall, resulting in an inflammatory response in the surrounding cells. As part of this initial vascular response, arterial endothelial cells (ECs) express leucocyte adhesion molecules. The expression of these molecules is enhanced in most patients with systemic vasculitis . Furthermore, autoantibodies such as anti-cardiolipin antibodies, anti-EC antibodies and antineutrophil cytoplasmic antibodies (ANCA) may further activate ECs as has been demonstrated in vitro . Chemokines guide recruitment of immune cells that enter the vessel wall at sites where leucocyte adhesion molecules are expressed. Importantly, elevated levels of many chemokines that are important for atherogenesis can be detected in patients with systemic vasculitis . Probably, the most important cell recruited during atherogenesis is the monocyte which differentiates into a macrophage after leaving the circulation. These macrophages take up lipids and form lipid-laden foam cells in the vascular intima. Next to monocytes, neutrophils penetrate the vascular wall in atherosclerosis . These cells are pro-atherogenic. Importantly, myeloperoxidase (MPO), an enzyme from neutrophils, has been implicated in the pathogenesis of atherosclerosis ( Fig. 1 ) . There is substantial evidence that oxidants generated by MPO have a key role in the modification of low- (LDL) and high-density lipoprotein (HDL) particles .

Role of myeloperoxidase (MPO) catalyzed pathways in the generation of atherogenic low density lipoprotein (LDL) and dysfunctional high density lipoprotein (HDL) particles. Within the human atherosclerotic plaque LDL is enriched with products of chlorination due to enzymatic activity of MPO. Also nitric-oxide-derived oxidants can be detected in the plaque. MPO-generated reactive nitrogen species facilitates lipid peroxidation and protein nitration and converts LDL into a high uptake form that is taken up by the macrophage scavenger receptor CD36. Also, MPO-catalyzed carbamylated LDL is taken up by scavenger receptor SRA-1. Furthermore, HDL isolated from plaques contains MPO and its oxidant products. The degree of modified HDL correlates with an impaired cholesterol efflux from macrophages. So, MPO also induces impaired functional activities of HDL. Reproduced with permission from Nicholls and Hazen (10).

The adaptive immune system is also involved in the pathophysiology of accelerated atherosclerosis . Uptake, processing and presentation of antigens by dendritic cells and other antigen-presenting cells in the intima and adventitia leads to activation of the adaptive immune response. Vascular dendritic cells not only have an important role in the development of systemic autoimmune diseases, but also play a part in the further progression in atherosclerosis. Antigens such as modified LDL (mLDL), heat shock proteins and beta2-glycoprotein 1 may preferentially stimulate Th1 cells which predominate during the atherosclerotic process . Of special importance are CD4 ⁺ CD28 ⁻ T cells. Monoclonal expansion of these T cells occurs in ruptured plaques in patients with myocardial infarction . This subset of T cells is also implicated in systemic autoimmune diseases such as systemic vasculitis . Abnormalities of Treg and the pro-inflammatory Th17 cells are important in systemic vasculitis , and have also been shown to have a role in atherogenesis . Finally, autoantibodies to β2-glycoprotein 1, mLDL and heat shock proteins may be important in acceleration of atherosclerosis in systemic vasculitis .

Diabetes, hypertension, dyslipidaemia, abdominal obesity (metabolic syndrome), impaired renal function, persistent proteinuria and increased production of C-reactive protein are more common in patients with systemic vasculitis than in healthy controls . The aim of this review is to discuss the association between prevalence and aetiology of cardiovascular diseases and systemic vasculitis.

Accelerated atherosclerosis in vasculitides

Vasculitides are diseases characterised by inflammation of blood vessels. Its clinical manifestations are dependent on the localisation and size of the involved vessels as well as on the nature of the inflammatory process. Vasculitis can be secondary to other conditions or constitute a primary, in most cases, autoimmune disorder . Secondary vasculitides may be associated with infectious diseases, connective tissue diseases and/or with certain drugs. Primary vasculitides are systemic diseases with variable clinical expression ( Table 1 ) and will be discussed.

In the ‘large-vessel vasculitides’, the vasculitic process is confined to the aorta and its major branches. The most common form, particularly in the white population, is giant cell arteritis (GCA). Histopathologically, invasion of the vessel wall with macrophages, lymphocytes and plasma cells is seen. In addition, giant cells are present in the lesions. Clinically, the disease frequently presents with headache, tenderness of the scalp, claudication of the jaw and/or tongue, loss of vision and polymyalgia rheumatica. Systemic symptoms, such as fatigue, malaise and fever with highly elevated erythrocyte sedimentation rate (ESR) are almost invariably present. The disease occurs generally at older age, above 50 years, almost exclusively in whites.

Takayasu arteritis (TA) is another form of large-vessel vasculitis. It affects the aorta and its brachiocephalic branches but may also affect the pulmonary arteries, other visceral arteries and arteries of the lower extremities. Lesions are characterised by granulomatous GCA with infiltrates of lymphocytes, plasma cells, eosinophils, histiocytes and Langerhans cells. As a result of active inflammation, segmental narrowing and dilatation with aneurysm formation may occur. At the time of active inflammation, systemic symptoms are present accompanied by an increased acute phase response. Later occurring symptoms are related to the localisation and extent of obstruction of the involved vessels and may include claudication of upper and lower extremities, cerebral symptoms, ischaemic bowel disease, renal vascular hypertension, aortic insufficiency and others. The disease occurs at younger age, particularly women between 15 and 45 years of age and is most frequent in Orientals, Africans and Latin-Americans.

GCA and TA generally require steroid therapy for more than 1 year, often accompanied by other immunosuppressives such as methotrexate (MTX), azathioprine, tocilizumab and/or anti-tumour necrosis factor (anti-TNF) therapy .

Epidemiologic reports of patients with GCA suggest that long-term mortality in this disease is not increased compared with the general population of the same age . The risk of a stroke, in the vertebrobasilar territory in particular, is increased. This complication, however, mainly occurs at the time of diagnosis before therapy is started . In addition, the occurrence of aortic aneurysmal disease and aortic dissection is also clearly increased in this disease. This latter complication, however, is in particular observed during long-term follow-up. Mortality due to ischaemic heart disease, however, is not increased . Endothelial dysfunction occurs in patients with active disease, but normalises during steroid therapy . Indeed, it has been suggested that corticosteroid therapy in these patients may be anti-atherogenic and not pro-atherogenic . Gonzalez-Juanatey et al. demonstrated that carotid-artery intima media thickness (IMT) was lower in patients with GCA than in age-matched controls . In addition, as expected in unselected elderly individuals, carotid plaques are commonly observed in both GCA patients and controls.

In TA, accelerated atherosclerosis has been clearly documented .

In autopsy reports in young TA patients, atherosclerotic changes are well documented . Seyahi et al. performed ultrasonography in 30 female patients with TA . Atherosclerotic plaques in the carotid artery were present in 27% of the patients and in only 2% of the age-matched, sex-matched controls. Plaques in the carotid arteries were only present in patients with documented arteritis involving the carotid artery. Compared to the TA patients without atherosclerotic plaques, patients with atherosclerotic plaques were consistently older and had higher levels of total cholesterol. Mean IMT of carotid arteries was also significantly increased compared with controls. Arterial stiffness is also more prominent in carotid arteries and aorta, areas predominantly affected by TA, rather than the peripheral femoral arteries which are only infrequently affected by the disease . Stroke in TA occurs in 10–20% of cases. Both haemodynamic compromise in large artery stenosis and thromboembolic mechanisms play a pathophysiological role in the development of this complication . Furthermore, symptomatic coronary artery disease occurs in 10–30% of TA patients .

Vasculitides involving predominantly medium-sized vessels are Kawasaki disease (KD) and polyarteritis nodosa (PAN). KD is a form of systemic vasculitis that mainly affects infants and children under 5 years of age. There is a clear ethnic bias towards oriental or Afro-Caribbean children. Principal symptoms include persistent fever, reddening of palms and soles, cervical lymphadenopathy, polymorphous exanthema and injection of conjunctiva, lips, tongue, oral and/or pharyngeal mucosa. About one-third of the patients suffer from cardiovascular complications, such as coronary artery dilatation, pericarditis and/or cardiac failure. Patients are treated with low-dose aspirin in combination with high-dose intravenous gamma globulin. In patients who do not respond to gamma globulin treatment, high-dose steroids and/or anti-TNF therapy are advised.

It is controversial whether KD is associated with accelerated atherosclerosis. Young adults with a history of KD may have abnormal brachial artery reactivity , although this could not be confirmed in several other studies . Furthermore, carotid IMT and arterial stiffness in adolescents with a history of KD is increased compared to sex- and age-matched healthy controls . From these studies, we previously concluded that patients with KD might be predisposed to accelerated atherosclerosis . More recently, however, autopsy examinations of KD patients did not reveal significant atherosclerotic lesions , whereas carotid IMT measurements were found to be distinctly different from those in young adults with familiar hypercholesterolaemia, suggesting that the remodelling process in KD is different from atherosclerosis .

Another form of medium-sized vessel vasculitis is classical PAN. According to the Chapel Hill definition , PAN is an ANCA-negative form of vasculitis confined to medium-sized arteries without involvement of smaller-sized vessels. Applying this definition, PAN is now an extremely rare disease. The disease is mainly associated with infections, such as hepatitis B virus, human immunodeficiency virus (HIV) and/or streptococcal infection. No case series have been reported with respect to the development of accelerated atherosclerosis in PAN as defined according to the Chapel Hill definitions.

Finally, within the spectrum of vasculitis ‘small-vessel vasculitides’ occur. Patients with small-vessel vasculitis can be classified according to the presence or absence of ANCA. Patients with small-vessel vasculitis without ANCA have immune complex vasculitis such as IgA vasculitis (Henoch Schönlein purpura), essential cryoglobulinaemic vasculitis, hypocomplementemic urticarial vasculitis or anti-glomerular basement membrane disease. These forms of vasculitis are characterised by attacks of purpura, urticaria, arthralgias/arthritis, gastrointestinal symptoms and/or glomerulonephritis. In these forms of vasculitis, it has not been studied whether accelerated atherosclerosis occurs.

Furthermore, small-vessel vasculitides may be associated with ANCA . In these vasculitides, patients are being classified as having either granulomatosis with polyangiitis (Wegener’s; GPA), eosinophilic granulomatosis with polyangiitis (Churg Strauss; EGPA) or microscopic polyangiitis (MPA). In GPA, granulomatous inflammation of the respiratory tract, systemic vasculitis and necrotising crescentic glomerulonephritis are found. Limited forms of the disease also occur. Clinically, the disease is characterised by symptoms of the upper respiratory tract, such as bloody nasal discharge, nasal ulceration, chronic sinusitis and/or otitis. Systemic symptoms, such as malaise, arthralgias and myalgias, are frequently present. Later on, manifestations of small-vessel vasculitis may occur in virtually every organ. In EGPA, patients have asthma, hypereosinophilia and systemic vasculitis. Initially, most patients suffer from nasal obstruction due to nasal polyposis, asthma, lung infiltrates and systemic symptoms. Finally, systemic vasculitis occurs in different organs. Mononeuritis multiplex often dominates the clinical picture in these patients.

In MPA, most patients present with systemic symptoms, such as fever, malaise, arthralgia, myalgia and skin vasculitis. Later on, a renal–pulmonary syndrome often occurs.

ANCA in GPA, EGPA and/or MPA are directed to MPO or proteinase 3 . Untreated, these diseases result in death within weeks to months. Since the introduction of cyclophosphamide and prednisolone as standard therapy, survival has improved dramatically from <20% at 1 year to at least 60% 5-year survival. With prolonged survival, patients may experience long-term sequelae as a result of their vasculitis or its treatment .

Patients with AAV clearly have increased mortality as a consequence of cardiovascular disease. Generally, early deaths in patients with AAV are due to the disease itself and/or infectious complications of immunosuppressive drugs . Late deaths, however, are either due to cardiovascular disease and/or malignancies . In patients with AAV the relative risk (RR) for coronary heart disease (CHD) is two- to fourfold that in control subjects . The differences in RR for CHD are especially noteworthy in younger patients with AAV. However, in older patients, the burden of CHD is much higher. In addition, patients with AAV suffer more often from a stroke (odds ratio: 3–4) .

Consistent with these findings, patients with AAV may demonstrate signs of accelerated subclinical atherosclerosis that can be detected by ultrasound (e.g., carotid plaques, intima–media thickening), increased aortic stiffness and/or impaired endothelial function.

Results obtained in AAV patients with respect to IMT measurements are, however, conflicting . Further, endothelial function tests also reveal contradictory results in different studies . Raza et al. assessed endothelial function by measuring flow-mediated brachial artery vasodilatation after reactive hyperaemia and found significantly impaired vasodilatation in AAV patients that normalised during therapy . Endothelial function as assessed by plethysmography after infusion of acetylcholine demonstrated an impaired or an increased response . Importantly, EC dysfunction may be expressed differently in resistance or microvascular vessels versus large vessels such as the brachial artery . Finally, abnormal ankle–brachial pressure indexes and/or increased arterial stiffness are reported in patients with AAV .

Findings in patients with AAV suggest that during active disease patients may experience acceleration of the atherosclerotic process. However, when inflammation is controlled, these patients may have atherosclerotic development as in healthy subjects since endothelial function and arterial stiffness now return to normal values. Because damage that has occurred in the blood vessel may persist, every disease reactivation may damage blood vessels further, resulting in acceleration of the atherosclerotic process as compared to healthy, age-matched controls .