Translational Mini-Review Series on Immunology of Vascular Disease: Accelerated atherosclerosis in vasculitis


  • J. W. Cohen Tervaert

    1. Department of Internal Medicine, Division of Clinical and Experimental Immunology, Maastricht University Medical Center, Maastricht, the Netherlands
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J. W. Cohen Tervaert, Division of Clinical & Experimental Immunology, Department of Internal Medicine, Clinical Immunology Laboratory, Maastricht UMC, PO Box 5800, 6202 AZ Maastricht, the Netherlands.


Premature atherosclerosis has been observed during the course of different systemic inflammatory diseases such as rheumatoid arthritis and sytemic lupus erythematosus. Remarkably, relatively few studies have been published on the occurrence of accelerated atherosclerosis in patients with vasculitis. In giant cell arteritis (GCA), mortality because of ischaemic heart disease is not increased. In addition, intima media thickness (IMT) is lower in patients with GCA than in age-matched controls. In contrast, IMT is increased significantly in Takayasu arteritis, another form of large vessel vasculitis occurring in younger patients. In Takayasu arteritis and in Kawasaki disease, a form of medium-sized vessel vasculitis, accelerated atherosclerosis has been well documented. In small vessel vasculitis because of anti-neutrophil cytoplasmic autoantibodies-associated vasculitis, cardiovascular diseases are a major cause of mortality. IMT measurements reveal conflicting results. During active disease these patients experience acceleration of the atherosclerotic process. However, when inflammation is controlled, these patients have atherosclerotic development as in healthy subjects. Several risk factors, such as diabetes and hypertension, are present more often in patients with vasculitis compared with healthy controls. In addition, steroids may be pro-atherogenic. Most importantly, many patients have impaired renal function, persistent proteinuria and increased levels of C-reactive protein, well-known risk factors for acceleration of atherosclerosis. Enhanced oxidation processes, persistently activated T cells and reduced numbers of regulatory T cells are among the many pathophysiological factors that play a role during acceleration of atherogenesis. Finally, autoantibodies that may be relevant for acceleration of atherosclerosis are found frequently in elevated titres in patients with vasculitis. Because patients have an increased risk for cardiovascular events, vasculitis should be treated with as much care as possible. In addition, treatment should be considered with angiotensin-converting-enzyme inhibitors and/or angiotensin receptor-1 blockers, statins and acetylsalicyl acid. Finally, classical risk factors for cardiovascular disease should be monitored and treated as much as possible.


Cardiovascular mortality because of atherosclerosis is the leading cause of death in developed countries [World Health Organization statistical information system,]. Atherosclerotic lesions may be present throughout a person's lifetime; the earliest lesions in atherosclerosis, the so-called fatty streak, may often already be found in children. Progression of the fatty streak to an advanced, complicated lesion occurs mainly later in life. Recently, it has become evident that atherosclerosis per se rarely causes myocardial infarction, stroke or other life-threatening complications. For an acute ischaemic condition to develop, plaque rupture or endothelial erosions must develop resulting in thrombus formation on the surface of the atherosclerotic plaque [1,2].

At present, atherosclerosis is considered to be a chronic inflammatory disease of the arterial intima [3]. This inflammation is the result of a complex interplay of innate and adaptive immune responses. The immune response in atherosclerosis is not always harmful, as protective immune responses are also elicited during the course of the disease [4]. A proinflammatory T helper 1 (Th1)-type cellular immune reaction prevails in the atherosclerotic lesion. Regulatory T cells (Tregs), however, suppress this proinflammatory response [4,5]. Also, humoral immune responses may be either harmful or protective, and it has been postulated that some antibodies may result in acceleration of the atherosclerotic process, whereas other antibodies inhibit atherosclerosis [6].

Premature atherosclerosis has been observed during the course of different systemic inflammatory diseases, such as rheumatoid arthritis and systemic lupus erythematosus [7–18]. In these diseases, an increased prevalence of atherosclerosis and, consequently, increased cardiovascular morbidity and mortality has been observed. Remarkably, relatively few studies have been published on the occurrence of accelerated atherosclerosis in patients with vasculitis, a typical chronic vascular inflammatory disease. The mechanism of vascular damage in vasculitis is the subject of a complementary review in this series [19]. In the present paper we discuss data on the prevalence and pathophysiology of atherosclerosis in vasculitis.

Occurrence of accelerated atherosclerosis in vasculitis

Vasculitides are diseases characterized by inflammation of blood vessels, the clinical manifestations of which are dependent upon the localization and size of the involved vessels as well as upon the nature of the inflammatory process. Vasculitis can be secondary to other conditions or, in most cases, constitute a primary autoimmune disorder. Underlying conditions in the secondary vasculitides are infectious diseases, connective tissue diseases and hypersensitivity disorders. Primary vasculitides are systemic diseases with variable clinical expression (Table 1) [20] and will be discussed.

Table 1.  Primary vasculitides.
  • Associated with anti-neutrophil cytoplasmic autoantibodies.

Large vessel vasculitisGiant cell (temporal) arteritis
Takayasu's arteritis
Medium-sized vessel vasculitisPolyarteritis nodosa
Kawasaki disease
Small vessel vasculitisWegener's granulomatosis
Churg–Strauss syndrome
Microscopic polyangiitis
Henoch–Schönlein purpura
Essential cryoglobulinaemic vasculitis
Cutaneous leucocytoclastic angiitis

In large vessel vasculitides the vasculitic process is confined to the aorta and its major branches. The most common form, particularly in the Caucasian 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 presents frequently with headache, tenderness of the scalp, claudication of the jaws and/or tongue, loss of vision and polymyalgia rheumatica. Systemic symptoms, such as fatigue, malaise and fever with highly elevated erythrocye sedimentation rate, are almost invariably present. The disease occurs generally at older age, above 50 years, almost exclusively in Caucasians.

Takayasu arteritis 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 characterized by granulomatous GCA with infiltrates of lymphocytes, plasma cells, eosinophils, histiocytes and Langhans 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 localization 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, etc. The disease occurs at younger age, particularly in women between 15 and 45 years, and is most frequent in Oriental, African and Latin American populations. GCA and Takayasu arteritis generally require steroid therapy for more than 1 year, often accompanied by other immunosuppressives such as methotrexate and/or azathioprine [21,22].

Epidemiological 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 [23,24]. However, the occurrence of aortic aneurysmal disease and aortic dissection is clearly increased in this disease, while mortality because of ischaemic heart disease, however, is not increased [25]. Endothelial dysfunction occurs in patients with active disease, but normalizes during steroid therapy [26]. Indeed, it has been suggested that corticosteroid therapy in these patients may be anti-atherogenic and not pro-atherogenic [27].

In a recent study, Gonzalez-Juanatey et al. demonstrated that carotid-artery intima media thickness (IMT) was lower in patients with GCA than in age-matched controls [28]. In addition, as expected in unselected elderly individuals, carotid plaques are observed commonly in both GCA patients and controls.

In Takayasu arteritis accelerated atherosclerosis has been documented clearly [29–31]. In autopsy reports in young patients with Takayasu arteritis, atherosclerotic changes have been well documented [32]. In a recent study, Seyahi et al. performed ultrasonography in 30 female patients with Takayasu arteritis [30]. Atherosclerotic plaques in the carotid artery were present in 27% of the patients and in only 2% of the age- and sex-matched controls. Plaques in the carotid arteries were present only in patients with documented arteritis involving the carotid artery. Compared with the Takayasu 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 increased significantly compared with controls. Arterial stiffness is also more prominent in carotid arteries and aorta, areas affected predominantly by Takayasu arteritis, rather than the peripheral femoral arteries which are affected only infrequently by the disease [33].

Vasculitides effecting medium-sized vessels are Kawasaki disease (KD) and polyarteritis nodosa (PAN). KD is a form of systemic vasculitis that affects mainly 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, polymorphous exanthema, injection of conjunctiva, lips, tongue, oral and/or pharyngeal mucosa and cervical lymphadenopathy. 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-tumour necrosis factor therapy is advised.

Noto et al. studied 20 adolescents with a history of KD (age 16·6 years) and compared IMT thickness with sex- and age-matched healthy controls. IMT and arterial stiffness were significantly higher in KD than in controls [34]. From this study, Noto et al. concluded that in patients with KD coronary arteries might be predisposed to accelerated atherosclerosis. These results were confirmed recently in a much larger study from Hong Kong [35]. Whether flow-mediated dilatation of the brachial artery in KD is impaired in comparison with healthy age-matched controls is controversial [36,37].

Another form of medium-sized vessel vasculitis is classical PAN. According to the Chapel Hill definition [20], PAN is a 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 associated mainly with infections such as hepatitis B 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 anti-neutrophil cytoplasmic autoantibodies (ANCA). Patients with small vessel vasculitis without ANCA have Henoch–Schönlein purpura, essential cryoglobulinaemic vasculitis or cutaneous leucocytoclastic angiitis that is confined to the skin. Henoch–Schönlein purpura occurs predominantly in children, but may also affect adults. Clinically, the disease is characterized by attacks of purpura, arthralgias/arthritis and gastrointestinal symptoms. Glomerulonephritis is found frequently, especially in older-aged patients. In skin, intestinal lesions and renal lesions, immunoglobulin A (IgA) deposits can be found along the vessel wall.

Essential cryoglobulinaemia is another form of immune complex-mediated small vessel vasculitis. Circulating cryoglobulins consist of polyclonal IgG and monoclonal (type II) or polyclonal (type III) IgM with rheumatoid factor activity. The disease is associated frequently with hepatitis C virus infection; however, in a substantial proportion of patients no hepatitis C virus can be found [38]. Clinically, patients have purpura, arthralgia/arthritis and glomerulonephritis. Other organs can also be affected.

Leucocytoclastic angiitis of the skin is nearly always a secondary form of vasculitis. In some patients, however, no underlying condition and a paucity of immune deposits are found.

Whether or not accelerated atherosclerosis occurs in Henoch–Schönlein purpura, cryoglobulin-associated vasculitis and cutaneous leucocytoclastic angiitis has not been studied.

Finally, small vessel vasculitides may be associated with ANCA [39]. In these vasculitides, patients are being classified as having either Wegener's granulomatosis, Churg–Strauss syndrome or microscopic polyangiitis. In Wegener's granulomatosis, granulomatous inflammation of the respiratory tract, systemic vasculitis and necrotizing crescentic glomerulonephritis is found. Limited forms of the disease also occur. Clinically, the disease is characterized 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 Churg–Strauss syndrome, patients have asthma, hypereosinophilia and systemic vasculitis. Initially, most patients suffer from nasal obstruction because of 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 microscopic polyangiitis most patients present with systemic symptoms such as fever, malaise, arthralgia, myalgia and skin vasculitis. Later, a renal–pulmonary syndrome often occurs.

The ANCA in Wegener's granulomatosis, Churg–Strauss syndrome and/or microscopic polyangiitis are directed to myeloperoxidase (MPO) or proteinase 3. Untreated, these diseases result in death within weeks to months. As the introduction of cyclophosphamide and prednisolone as standard therapy [21] survival has improved dramatically, from less than 20% at 1 year to at least 60% survival at 5 years. With prolonged survival, patients may experience long-term sequelae as a result of their vasculitis or its treatment.

Several studies have now shown that, during long-term follow-up, cardiovascular disease is a major cause of mortality in patients with ANCA-associated vasculitis [40–48]. Zaenker et al. reported that patients with Wegener's granulomatosis had a higher frequency of cardiovascular diseases compared with healthy controls [odds ratio (OR) 6·7][49]. In line with these findings, patients with ANCA-associated vasculitis more often had stroke and/or myocardial infarction (OR 3–4) [50].

Conflicting results are obtained in patients with ANCA-associated vasculitis with respect to IMT measurements. Zaenker et al.[49] and de Leeuw et al.[51] found increased IMT values in patients with ANCA-associated vasculitis compared with healthy controls, whereas no increase was observed in two other studies [52] (M. C. Slot and J. W. Cohen Tervaert, unpublished observation). Other markers for atherosclerosis have also been studied in patients with ANCA-associated vasculitis. Raza et al. assessed endothelial function by measuring flow-mediated brachial artery vasodilatation after reactive hyperaemia [53] and found significantly impaired vasodilatation in patients with active vasculitis that normalized during therapy. Endothelial function as assessed by plethysmography after infusion of acetylcholine demonstrated impaired responses [54]. However, contradictory results were found in two other studies [55,56] where increased vasodilator responses after acetylcholine infusion were observed. Because patients were measured during remission, it was speculated that a relative overproduction of endothelium-derived vasodilatory substances might have induced enhanced vasodilator responses to acetylcholine, as patients in this phase of the disease still have low-grade inflammation. Otherwise, endothelial cell dysfunction may be expressed differently in resistance or microvascular vessels versus large vessels such as the brachial artery [56]. Finally, abnormal ankle-brachial pressure indexes and/or increased arterial stiffness are reported in patients with ANCA-associated vasculitis [57,58]. The degree of stiffness was found to correlate with active inflammation, and during remission findings were comparable to healthy controls [57].

Findings in patients with ANCA-associated vasculitis 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, as 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 compared with healthy age-matched controls.

Pathophysiology of accelerated atherosclerosis in vasculitis

The prevalence of some cardiovascular risk factors is increased in patients with vasculitis compared with the background population. Notably, diabetes and hypertension are much more common in patients with vasculitis [30,50,56]. These findings are related probably to the therapeutic regimen that is used for vasculitis [21]. Glucocorticosteroids are pro-atherogenic by affecting plasma lipoproteins, promoting insulin resistance and sodium retention resulting in hypertension. Otherwise, co-trimoxazole and methotrexate may increase homocysteine levels. Furthermore, weight gain may increase the risk of cardiovascular events in vasculitis. It has been demonstrated recently that patients with Wegener's granulomatosis gained 7·3% weight during the first year after diagnosis and approximately 20% of the patients gained more than 10 kg in the first year of treatment [59]. However, compared with the background population the number of patients with obesity does not seem to be increased [30,50]. Finally, impaired renal function, persistent proteinuria and increased levels of C-reactive protein are also important risk factors for cardiovascular events in patients with vasculitis that are clearly more prevalent than in the background population.

All these risk factors may influence the initial phase of the atherosclerotic process in which lipoproteins are retained and modified in the vessel wall, resulting in rapid activation of an inflammatory response in the surrounding cells [60]. As part of the initial vascular response to modified low-density lipoprotein (LDL) particles in the intima, endothelial cells in the arteries express leucocyte adhesion molecules. The expression of these molecules is enhanced in patients with vasculitis [61]. Furthermore, autoantibodies that are often found in vasculitis, such as ANCA, anti-endothelial cell antibodies and anti-cardiolipin antibodies, may further activate endothelial cells, as has been demonstrated in vitro[61,62].

Chemokines guide the recruitment of immune cells that enter the vessel wall at sites where leucocyte adhesion molecules are expressed. Importantly, elevated levels of one of the most important chemokines for atherogenesis, i.e. CCL2/MCP1, are found in patients with vasculitis, and the detection of this chemokine is a possible marker of disease activity [63–68]. Other chemokines, such as CCL5 (regulated upon activation normal T cell expressed and secreted), also play an important role in the pathophysiology of atherogenesis and are increased in the circulation of some patients with active vasculitis.

Probably the most important cell recruited during atherogenesis is the monocyte that differentiates into a macrophage, which takes up lipids and forms lipid-laden foam cells in the vascular intima. Macrophages recognize oxidized LDL via scavenger receptors. Apart from scavenger receptors, other pattern recognition receptors such as Toll-like receptors (TLR) also play an important role in the pathophysiology of atherosclerosis [69]. Endothelial and macrophage expression of TLR-1, TLR-2 and TLR-4 have been found to be increased in atherosclerotic lesions [4]. TLR-2 plays an important role in the pathogenesis of bacteria-enhanced atherogenesis. Because patients with vasculitis often suffer from recurrent bacterial infections, bacterial stimulation of macrophages via TLR-2 may play a role in the acceleration of atherosclerosis in vasculitis [70]. Persistent cytomegalovirus infection occurs often during therapy for vasculitis, and this may also activate TLR-2 [71].

Next to monocytes, neutrophils penetrate the vascular wall in atherosclerosis [72]. Although the pathophysiological significance of these cells during atherogenesis has not yet been well documented, it is suggested that these cells are pro-atherogenic [73]. Neutrophils play a major role in the development of many forms of vasculitis [74,75]. In particular, MPO, an important enzyme from myeloid granules, has been implicated in the pathogenesis of atherosclerosis [76,77]. Substantial evidence supports the notion that oxidants generated by MPO play a key role in the modification of LDL particles in the vascular wall. Although there is a suggestion that MPO may be produced by atherosclerotic macrophages, there is also evidence that MPO may be derived from neutrophils in the vascular wall in atherosclerosis [72]. It has been demonstrated that the measurement of MPO levels may be useful in risk stratification of patients with atherosclerosis [78,79]. In addition, MPO polymorphism studies have demonstrated an increased risk for cardiovascular events in patients with chest pain [80]. MPO also plays an important role in the pathogenesis of systemic vasculitis [81], and elevated levels of circulating MPO have been demonstrated during active disease [82]. Whether or not MPO polymorphisms influence the risk of developing vasculitis has, however, not been demonstrated clearly [83,84].

Apart from the innate immune system, adaptive immune responses are also involved in the pathophysiology of atherosclerosis. For this, uptake, processing and presentation of antigens by dendritic cells (DCs) and other antigen-presenting cells in the intima and adventitia are needed. DCs are usually present in normal arteries, especially localized in segments with low shear stress, predilection sites for atherosclerosis [4]. In situ maturation of DCs in the vascular wall is an early event in the pathogenesis of large vessel vasculitis [85]. It can be postulated that these vascular DCs not only initiate vasculitis but also play a role in the further progression of atherosclerosis. Antigens that are presented to the adaptive immune system are antigens from infectious microorganisms and of modified endogenous structures. These latter antigens are thought to be major targets for the immune response in atherosclerosis [4]. Autoantigens that have been best characterized are modified LDL, heat shock proteins and antigens that play a role in apoptosis, e.g. β2-glycoprotein I (β2GP-I). These autoantigens may preferentially stimulate proinflammatory Th1 cells that predominate during the atherosclerotic process. T cell activation is dependent upon the binding of the peptide/major histocompatibility complex complex to the T cell receptor and surface co-stimulatory molecules. Increased levels of co-stimulatory molecules have been demonstrated on circulating T cells in vasculitis (e.g. [86]). In addition, co-stimulatory receptors that confer inhibitory signals, such as cytotoxic T lymphocyte antigen-4, have been implicated in the pathogenesis of vasculitis [87]. As a consequence, T cells from patients with vasculitis may be ‘ready to attack’ when an autoantigen is presented.

One important proinflammatory T cell that has been involved in the pathogenesis of atherosclerosis is the so-called CD4+CD28- T cell [88]. Monoclonal expansion of these T cells occurs in ruptured plaques from patients with myocardial infarction. Interestingly, this subgroup of T cells are also implicated in the pathogenesis of vasculitis [89]. An increased number of these cells are found in granulomatous lesions and in the circulation of patients with Wegener's granulomatosis.

Apart from proinflammatory T cells such as Th1, CD4+CD28- and/or Th17, Tregs also play a role in atherogenesis [5]. First, atherosclerotic plaques contain relatively few Tregs. Secondly, depletion of Tregs in experimental models increases plaque formation. Thirdly, administration or stimulation of Tregs inhibit plaque development in experimental models. Several studies have been performed on Tregs in vasculitis. In patients with Wegener's granulomatosis in remission an expanded proportion of regulatory T cells that are functionally defective was found [90]. In addition, in patients with active Churg–Strauss syndrome, regulatory T cells producing interleukin-10 are detected rarely compared with patients with chronic eosinophilic pneumonia and/or asthma [91]. Finally, in patients with hepatitis C-associated mixed cryoglobulinaemia significantly lower numbers of Tregs are found compared with patients with hepatitis C without cryoglobulin-associated vasculitis. Interestingly, Treg levels increased when a complete remission of cryoglobulin-associated vasculitis was induced, whereas Treg levels in non-responders did not change [92]. Therefore, defective T cell regulation may be present in patients with vasculitis which may result in acceleration of the atherosclerotic process. In addition to T cells, autoantibodies may also play a role in the acceleration of atherosclerosis. Autoantibodies to modified LDL are common in humans and increased levels of IgG antibodies to modified LDL have been suggested to be pro-atherogenic, whereas IgM antibodies to modified LDL may be anti-atherogenic [6]. Increased levels of IgG antibodies to modified LDL have been demonstrated in patients with vasculitis when compared with healthy controls [93,94]. In these studies, it was found that particularly IgG antibodies to LDL, modified via the MPO pathway, are increased [94]. A second category of autoantibodies that have been implicated in atherosclerosis are antibodies directed to heat shock proteins. In experimental models, infusion of antibodies to heat shock protein-65 result in the development of atherosclerosis. In addition, in patients with cardiovascular disease, antibody levels to heat shock protein 60/65 are increased, predicting further development of the disease [95]. Anti-HSP65 antibody titres are also elevated in patients with systemic vasculitis [96,97]. Finally, antibodies to β2GP-I may induce acceleration of atherosclerosis. β2GP-I is the target auto-antigen in the anti-phospholipid syndrome. In experimental models, it has been demonstrated that immunization with β2GP-I and adoptive transfer of β2GP-I reactive lymphocytes enhances atherogenesis [98,99]. Autoantibodies to β2GP-I can be detected in a substantial proportion of patients with vasculitis. Whether these antibodies are related to accelerated atherosclerosis in these patients is, however, not yet clear [100,101].


Accelerated atherosclerosis has been described in various forms of vasculitis. Whether acceleration of the process takes place only during active disease or pro-atherogenic conditions persist during remission of the disease is not yet clear. Among the many pathophysiological factors that play an important role in the acceleration of atherosclerosis in vasculitis are enhanced oxidation processes, persistently activated T cells and reduced numbers of Tregs. Finally, autoantibodies that may be relevant for acceleration of the atherosclerotic process are found frequently in elevated titres in patients with vasculitis. These findings suggest that patients with vasculitis are at risk for cardiovascular events such as myocardial infarction and stroke and, hence, should be treated with angiotensin-converting-enzyme inhibitors and/or angiotensin receptor-I blockers, statins and acetylsalicyl acid. In addition, classical risk factors for cardiovascular disease should be monitored and treated as much as possible in these patients.