Introduction and Epidemiology
Atherosclerosis during lupus is an important issue because of its major impact in terms of morbi-mortality and prognosis.
The last years are by the understanding of new pathophysiological mechanisms of atherosclerosis in connective which led to new therapeutic concepts. However, several questions remain unanswered about the particular mechanisms responsible for the accelerated atherosclerosis, with a precise profile of the most exposed patients, to the most appropriate ways to evaluate this cardiovascular risk and finally about the potential specific therapeutic intervention to reduce efficiently this cardiovascular risk in this patient population.
Long considered as the first cause of cardiovascular of mortality systemic lupus erythematosus, pericarditis, myocarditis and conduction disorders specific to the disease have been replaced gradually atherothrombotic ischemic attacks.
Urowitz and coll were the first there are 30 years to recognize Lupus as major cause of mortality by myocardial infarction and/or others ischemic cardiovascular diseases . Currently, it is established that cardiovascular mortality constitutes the first cause of death in Systemic Lupus Erythematosus. Lupus patient between 35 and 44 years are the most touched, with a relative risk of myocardial infarction of 50 in relation to healthy people of the same age.
In a Canadian cohort relative risk of myocardial infarction in Systemic Lupus Erythematosus was evaluated at 10, the coronary artery disease (« CAD ») to 17 and that of cerebrovascular accident (« CVA ») to 7,9. An other study showed a relative risk (« RR ») of hospitalization for myocardial infarction of 2,2 in lupus patient between 18 and 44 years.
In lupus, was observed subclinical atherosclerosis with high prevalence of carotid plaque and coronary calcification of scanner. Case-control studies have found an prevalence of carotid plaque of atheromatous higher in « SLE » groups (Odds Ratio to 2,4) after adjustement for age, gender, ethniciy and conventional of cardiovascular risk factor.
Pathogenesis and Physiopathology
A prevalence higher of conventional cardiovascular risk
The literature data show a prevalence of conventional cardiovascular risk higher in lupus patient than in general population of the same age and the same gender. So, was noted a higher prevalence of hypertension during « SLE » with a particular lipid profile characterised by an increase of the VLDL, normal or elevated LDL, low HDL and abnormal metabolism of chylomicrons. This profile was associated with qualitatives abnormalities of lipoproteine LDL with high binding affinity to proteoglycans, an increase in the pro-atherogenic lipoprotein A and a decrease in paraoxonase which plays an important role in LDL oxidation.
The prevalence of the metabolic syndrom is also higher in « SLE » than in the general population.
Pathophysiological explanation for a possible common mechanism involving inflammation and premature artherosclerosis have been proposed to explain the increase frequency.
Significantly greater concentrations more important of homocystein, a well-known factor of endothelial dysfunction, have been also reported during SLE.
These findings argue for an important role of factors precipitated in the genesis of atheromatous during the lupus. However, this role doesn’t fully explain this excess risk as showed by a cohort of 296 lupus patient followed for 8,6 years in which the increase of incidence of the atheromatous cardiovascular events was only partially explained by classic cardiovascular risk factor.
Finally, chronic inflammatory diseases such as SLE are providers of disability and sometimes extreme sedentarity lifestyle, this creating a vicious circle by increasing cardiovascular risk in particular the risk of coronary heart disease to which the lack of physical activity has proved to be an independent cardiovascular risk factor.
A study makes on 242 women with SLE followed from 2004 to 2007 showed a narrow link between low physical activity and increased subclinical atherosclerosis independent of other conventional cardiovascular risk factors.
A care in the sense in optimizing Physical activity and reducing weight gain should be considered in these patients.
A likely role of the treatments: corticosteroids and NSAIDs
Corticosteroid are known as causing cardiovascular side effects with the endothelial dysfunction,hypertension, and lipid and carbohydrate metabolic disorders.
On the other hand, the therapeutic effect of corticosteroids in relation to their anti-inflammatory and immunosuppressive properties are suggesting a positive effect of reducing atherosclerosis through the treatment of underlying disease.
It is not currently established that low doses of corticosteroids commonly used in SLE have the same cardiovascular iatrogenic profile that high doses.
In practice, the question of pro-atherogenic or anti-atherogenic role of corticosteroids has not yet decided in the particular case of connective and chronic inflammatory rheumatism. So, Davis and coll have shown an increased of the risk of vascular morbidity-mortality related cumulative doses of corticosteroids especially in patients with positive rheumatoid factor. However, in SLE, a benefice of corticosteroids on atherosclerosis was suggested as illustrated the work of Roman and coll.
In the light of these data, the current recommendations of learned societies (EULAR, SNFMI) recommend a careful indication of corticosteroid therapy and limited to the lowest effective dose.
Specific physiopathological factors
During many years, artheroclerosis was perceived as a phenomenon primarily « mechanics » of lipid accumulation in the vascular wall.
Recently, it was demonstrated that chronic inflammation is an central element in this process of atherosclerosis in all its steps. In thsi context, monocytes, macrophages, T lymphocytes and cytokines play an important role in athrogenesis.
PCR, whose synthesis is dependent of interleukin 6 (IL6), is currently considered as an important marker of cardiovascular risk and autoimmunity is strongly incriminated in atherosclerosis mechanisms in the general population.
During the lupus, these inflammatory phenomenon, disturbances observed in the cytokine environment, adhesion molecules and humoral immunity contribute to key stages of atherosclerosis including endothelial dysfunction and the formation and growth of the plate. in SLE, there is an increase in the synthesis of inflammatory mediators and an overactivation of Toll-like receptors that promote endothelial dysfunction, and the influx of macrophages and their differentiation into foam cells. there is also an increase in oxidized LDL (Ox-LDL) and lower HDL cholesterol which gives way to the pro-inflammatory HDL. antiphospholipid antibodies also play an important role through cross-reactivity between the Ox-LDL and cardiolipins and high affinity glycoprotein I for oxidized LDL.
Role of adaptive immunity and innate immunity
Endothelial dysfunction is an early event and key in the process of atherogenesis is largely associated with chronic increase in blood levels of inflammatory mediators, key players in the adaptive and innate immunity.
Systemic inflammation of the connective tissue is accompanied by an increase of the main mediators of inflammation including Tumor Necrosis Factor-α (TNF),interleukin 1 (IL1), CRP and CD40. These mediators promote an early and essential step in the process of atherosclerosis namely endothelial dysfunction and the overexpression of monocyte adhesion molecules (ICAM and VCAM). these mediators play also other important and ubiquitous role in atherogenesis through complement activation, endothelial secretion of monocyte chemotactic protein, macrophage capatation LDL,the stimulation of the monocyte production of the tissue factor and the production of growth factors and monocytic differentiation into macrophages and foam cell (M-CSF,GM-CSF,G-CSF). a case-control study of 109 patients with lupus and 78 controls, high concentrations of adhesion molecules (ICAM, VCAM) and TNF-α were associated with more severe atherosclerosis.
Interleukin 12 (IL12) and interferon ᵧ also play an important role in atherogenesis. IL-12 is abundantly present in atherosclerotic lesions.
It is produced by macrophages, smooth muscle cells and endothélioales cells.Its secretion is stimulated by the oxidized LDL.
Inhibition of IL12 in animal models results in a significant reduction of the atherosclerotic process. interferon ᵧ inhibits the growth of endothelial cells and smooth muscle cells and inhibits collagen synthesis contributing embrittlement of the atheromatous plaque. It has also led to increased secretion of TNF-α and IL1.
The first step of innate immunity is the recognition of antigens by receptors called « Pattern Receptors » (PRR). Recognized antigens are then called « Pathogen Associated Molecular Pattern » (PAMPs). Toll-like Receptors (TLRs) represent a variety of PRR and play a crucial role in atherosclerosis. The variety of the incriminated TLRs would be determinative of the risk and severity of atherogenesis process.
Role of lipid abnormalities
In lupus mice with atherosclerosis, treatment with simvastatin has beneficial effects on atherosclerosis, the title of autoantibodies and kidney damage. In this animal model, the anti-LDL antibodies are highly correlated with glomerular and osteopenia.
Oxidized LDL (Ox-LDL) is the lipid form the most likely to be taken up by macrophages. Its presence causes a major immune response by stimulation of monocytes and T cells and production of anti-Ox-LDL autoantibodies whose highest rate was associated with more severe and extensive atherosclerosis.The formation of active-Ox LDL chemotactic factors and growth factors (MCP, M-CSF), which allow the recruitment of monocytes and their differentiation into macrophages and foam cells. The elevation of Ox-LDL is strongly associated with coronary heart disease as well as in the general population in SLE patients. The normal HDL plays an important athero-protective role.It frees up the LDL macrophages and vascular wall and prevent its oxidation. It thus lowers the Ox-LDL and thus inhibits the recruitment of inflammatory mediators.
Role of antiphospholipid antibodies: A cross-reactivity of autoantibodies against cardiolipins and Ox-LDL was mentioned as one of atherothrombotic mechanisms[69,70]. The high affinity beta2 glycoprotein I (GPI) for Ox-LDL contributes to the formation of the complex strongly present GPI-LDL in SLE and antiphospholipid syndrome (APS). It has the property of being easily captured by the macrophages which facilitates the transformation into foam cells. GPI has been widely found in the atheroma plaque from carotid endarterectomy of parts at the sub endothelium, internal elastic lamina with a strong concomitant presence of CD4 T lymphocytes.
Care of cardiovascular risk in lupus
The care of cardiovascular risk of patient with lupus starts with a good assessment of that risk, strict management of traditional cardiovascular risk factors, and finally a specific and lasting effective treatment of inflammatory disease.
The imperative need to establish a codified preventive and curative approach and unique to this category of patients can be felt more than ever.
Identify efficient Tools for a proper evaluation of cardiovascular risk
There is a very strong correlation between coronary atherosclerosis and ultrasound measurement of carotid intima-media thickness.
In a general population, the intima-media thickness(IMT) and the carotid plaque are independent prognostic markers of the risk cardiovascular events.There are also highly correlated to traditional cardiovascular factor as diabet,hypercholesterolemia and hypertension.
Advanced age, sex, and the presence of conventional cardiovascular risk factors have been implicated in accelerated atherosclerosis. Thus, the Framingham score is correlated in some significant ways to study the presence of coronary artery calcification in RA.
The prevalence of symptomatic coronary artery disease in SLE is 8% to 16% while that of subclinical coronary artery disease was 38% in adults and 16% in children. This difference could be detected thanks to noninvasive ultrasonographic methods to detect atherosclerosis in 28-40% of lupus patients and therefore constitute in this sense an objective and efficient tool to prejudge the vascular risk of patients.
Older age, the long duration of evolution of the disease, the cumulative dose of corticosteroids,the presence of nephropathy but also hypertension,smoking and presence of metabolic syndrome have been identified as risk factors for developing cardiovascular disease in SLE patients. Thus the Framingham score did not appear perfectly suitable for cardiovascular risk assessment in SLE.
CRP, the fibrinogen, the rate of IL6 and CD40 / CD40L molecules and anti-Ox LDL antibodies have been described as potential markers of cardiovascular risk. However, lupus with secondary antiphospholipid antibodies syndrome seems to be the situation or atherosclerosis was most pronounced. Indeed, high concentrations of adhesion molecules and TNF have been correlated with a more significant coronary atherosclerosis in patients with lupus. Moreover, the finding that verifies increasingly now is that the effect on the cardiovascular risk exerted by the lupus would be equivalent to that exerted by a classic cardiovascular risk factors such as diabetes. In lupus, a specific algorithm considering the duration of disease, the treatments used, the existence or not of an SAPL and / or severe visceral manifestations is necessary.
Ensure an optimum contol of inflammatory disease: The close relationship between chronic inflammation and accelerated atherosclerosis lets predict that the stabilization of the underlying disease through effective background therapy can slow the process of atherogenesis and a fortiori the risk of cardiovascular events. This figure is still subject of some controversy although several recent studies have validated this hypothesis.
In some studies, methotrexate treatment caused a significant decrease in markers of inflammation and associated with a significant decrease in mortality in RA patients (RP between 0.3 and 0.4).Similiaires of studies have shown a protective role of anti-TNF-α. These data, however, remain controversialas in other studies in which a case-control study of 3501 patients with RA, immunosuppression has not been identified as a factor influencing the cardiovascular morbidity and mortality.
Similarly the use of anti-TNF has been correlated in some work to a higher prevalence of atherosclerotic plaque, a finding that may be explained by a score of activity and scalability of the greatest disease in patients receiving this type of treatment. Thus, Anker et al showed excess cardiovascular mortality in patients receiving high doses of anti-TNF, but this finding was later explained by the existence of a pre-existing severe heart failure in the population of patients presented this high mortality. in practice, despite the discrepancy results that would be related in large part to methodological limitations of some studies, the beneficial effects of adequate basic treatment appear to outweigh the negative effects through the control of inflammation, improvement in clinical condition of patients and therefore their physical activity and finally the potential savings they allow in relation to the use of corticosteroids and NSAIDs For the latter molecules, including corticosteroids, reiterate the need to use the minimum dose required to control the disease and for the shortest time possible.
Energetically manage classic risk factors: the management of conventional cardiovascular risk factors should go hand in hand with the specific treatment of inflammatory disease by considering patients as high risk patients. Specific target about this category of patients on modifiable risk factors should be defined. Chronic inflammatory rheumatic diseases such as lupus are also major providers of functional disability with consequent inactivity that often perpetuates at a distance flare-ups knowing that the lack of physical activity was found to be an independent risk factor for disease coronary artery. A care in this direction is important in optimizing rehabilitation and physical activity of patients and reducing overweight.
Better know the role of pharmacologic treatments
Statins: Statins reduce the risk of cardiovascular morbidity and mortality, and have anti-inflammatory and immunomodulatory properties. Ricker and coll. showed a significant decrease in CRP with reduction of cardiovascular risk in patients on pravastatin or atorvastatin.In SLE, Petri and coll. have not demonstrated benefit of statins on the risk of coronary heart disease in SLE patients with proper lipid profile. However, the Anglo-Saxons advocate to target a LDL of less than 1 g / l with a preferential use of statins as well as in rheumatoid arthritis.
Antiplatelet agents: Regarding antiplatelet agents, a cohort study conducted in 2002 had suggested a benefit with aspirin in terms of survival in patients with SLE. However, it is not established that it must be administered systematically in every lupus patient.its use should for the moment be integrated into the framework of classical indications considering the RA and SLE as full risk factor.in SLE, it has been recommended to give aspirin each time the disease is associated with other cardiovascular risk factor, an antiphospholipid syndrome or a history of cardiovascular disease.
The angiotensin converting enzyme: Regarding the angiotensin converting enzyme (ACE) inhibitors, their cardiovascular benefit has particularly in diabetic patients can not be extrapolated for SLE patients. However, considering SLE patients as FDR in itself, IEC then become molecules of choice when there is an associated hypertension or renal impairment.
Hydroxychloroquine: hydroxychloroquine, currently as an important treatment in SLE also has a beneficial effect by increasing HDL cholesterol.
Immunosuppressors: used in severe forms of lupus, there is currently no assessment of their use on the prevalence of cardiovascular complications of lupus, we have some experimental data that suggests anti atherogenic effects of mycophenolate mofetil (MMF ).
Cardiovascular complications are the leading cause of death in lupus patients, that cardiovascular risk is related to the high prevalence of traditional risk factors, potential iatrogenic effects of corticosteroids and nonsteroidal anti-inflammatory and specific pathophysiological factors. Identifying codified approaches and efficient diagnostic tools are needed for the evaluation and management of cardiovascular risk in SLE patients. The lasting stabilization of the inflammatory disease, strict management of classic risk factors (control of metabolic parameters, tobacco cessation and the fight against physical inactivity) are two essential components in the management of cardiovascular risk in these patients.
Dr Mustapha MECILI, Dr Emmanuel ANDRES and Dr Khalifé KHALIFE
The Department of Cardiology, CHR Metz-Thionville, Metz, France.
The Department of Internal Medicine, Diabetes and Metabolic Diseases of CHRU Strasbourg, France.