The role of endothelial damage and dyslipidemia in the development of cardiovascular pathology in psoriatic arthritis

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Introduction. Psoriatic arthritis (PsA) is a chronic inflammatory disease from the group of seronegative peripheral spondyloarthritis. Currently, the frequency of occurrence of PsA among people suffering from psoriasis ranges from 13.5 to 47.5% [1]. Currently, PsA, which is based on chronic immune inflammation, is characterized as a disease with a high risk of cardiovascular complications [1]. The aim of this study is to determine the main links in the pathogenesis of endothelial damage and dyslipidemia and their role in the development of cardiovascular complications in patients of this group.
Materials and methods. An analysis of the Russian and foreign literature on the problems of chronic immune inflammation in PsA, damage to the vascular wall (in particular, the intima of the arteries), and cardiovascular complications in this disease was carried out. The criteria for inclusion in the study were the content of materials in the literature on the above topics for the period 2010-2020. Literary sources published earlier than 2010 were not included in the study.
Results. The Russian and foreign literature presents the results of clinical studies that reliably reveal a higher incidence of morbidity and mortality from cardiovascular events in patients with PsA in comparison with those without this disease [2]. Damage and subsequent dysfunction of the endothelium as a response to chronic immune inflammation is a systemic manifestation of atherosclerosis, the complications of which lead to premature mortality in patients with PsA [2]. According to some authors, PsA reduces life expectancy by an average of 3-4 years, while the most common causes of mortality are myocardial infarction and stroke. Among women suffering from this disease, the mortality rate exceeds the population by 59%, among men - by 65% ​​[3]. It is believed that cardiovascular complications are in direct proportion to the severity of PsA and can be explained by an increase in blood flow through the vasculature of the dermis, as well as by the immune nature of inflammation [3]. This is consistent with the European Society of Cardiology Guidelines, according to which patients with severe PsA have a higher risk of cardiovascular events [4].
The urgency of the problem. According to E.I. Markelova. et al. (2016), in the structure of the causes of death in PsA, cardiovascular complications are in the first place (23.6%) and outpace cancer, diseases of the respiratory system and gastrointestinal tract [5]. These data are confirmed by the results of a large study by Lihi E. (2014), according to which diseases of the circulatory system (32%) were in the first place among the causes of death in PsA. The authors of the study conclude that there is an increased mortality among patients with PsA among the population, the prognostic factors for which are the high activity of the disease, which is expressed in the value of ESR, CRP and the rate of X-ray destruction [6]. With normal ESR values, mortality in patients was 3.2%, while with ESR more than 15 mm / h - 17%. Bone destruction increased the mortality rate of patients by 25.7%. At the same time, a higher mortality rate was observed in patients treated with basic anti-inflammatory drugs, incl. genetically engineered biological preparations (14.4%) compared with untreated individuals (10.5%) [6]. Another study (Degtyarev OV et al., 2015) also revealed the highest mortality of patients with psoriatic arthritis from cardiovascular events, where 33% of deaths were myocardial infarction and stroke [7]. Gladman D.D. (2019) et al. in their observation of the structure of cardiovascular pathology, myocardial infarction (28%), stroke (4%) and heart failure (4%), as well as a higher mortality rate from diseases of the circulatory system in PsA patients compared to the population level [8]. Thus, psoriatic arthritis is significantly associated with an increased risk of cardiovascular mortality.
Risk factors for cardiovascular complications in PsA. Among the risk factors for PsA, the burdened heredity for CVD, arterial hypertension, dyslipidemia and metabolic syndrome are especially distinguished [9]. According to M.N. Favarato. (2014), arterial hypertension occurs in 87.55% of patients with PsA [9]. According to I.Z. Gaidukova. (2015), this pathology is found in 53% of cases, hypercholesterolemia - in 55% of cases, an increase in triglyceride levels - in 14.4% of cases [10]. Francesco C. (2020) considers PsA to be an independent risk factor for hypertension and cardiovascular mortality [11]. It is important to note that the cause of lipid changes can be drugs for the treatment of PsA, for example, cyclosporine and TNF-a inhibitors can lead to an increase in triglyceride levels [12]. A special role in the pathogenesis of cardiovascular complications is played by the fact that most patients do not receive rational antihypertensive treatment. Some blockers of adrenergic receptors and angiotensin receptors, lipid-lowering agents, angiotensin-converting enzyme inhibitors, antiarrhythmic agents and calcium antagonists can worsen the course and provoke an exacerbation of PsA [12].
Lipid disorders. Special attention is paid to the study of cholesterol metabolism in PsA. The pathology of the lipid spectrum today allows us to consider psoriatic disease as a manifestation of "cholesterol" diathesis [13]. According to M.V. Akhlupkina (2011), the synthesis of cholesterol and LDL with their subsequent release into the systemic circulation is naturally caused by the overproduction of cytokines and dysregulation of cellular immunity accompanying PsA [13]. Dyslipidemia in PsA is characterized by an increase in proatherogenic lipid fractions - the study of the lipid spectrum in PsA patients revealed an increase in the level of lipoproteins, mainly low and very low density, correlating with the duration of the disease - with early and preclinical PsA, the increase in LDL and VLDL was more pronounced [14]. Thus, it can be assumed that changes in the lipid profile depend not only on the severity, but also on the duration of the disease. An increase in serum total cholesterol levels, according to some authors, in PsA varies widely - from 20 to 80%, and the most common types of hyperlipidemia are hyperlipoproteinemia IIA, IIB and IV types, as well as an increase in the level of apoproteins (which, presumably, indirectly indicates a severe course of the disease) [15]. According to Kirby B. (2020), hypercholesterolemia in PsA patients occurs 2.5 times more often than in the general population (18 and 8%, respectively), and often precedes the clinical manifestation of arthritis [16]. Some data also indicate the detection of significant violations of the lipid profile (an increase in the level of free fatty acids, triglycerides, total cholesterol) already at an early (subclinical) stage of PsA [17]. So, Acebes C. et al. (2015) conducted a study of 200 patients with PsA who did not have complaints and symptoms of cardiovascular diseases and found an increase in the concentration of low density lipoproteins, which did not correlate with the level of C-reactive protein, gender, age of arthritis or the index of prevalence and severity of psoriasis (PASI) [17]. In another study (Badaiki W. et al., 2019), an increased level of apolipoprotein-b, lipoprotein-a and triglycerides is detected already at the time of PsA debut [18]. Thus, the increased cardiovascular risk in PsA is mainly associated with the systemic nature of immune inflammation, and lipid disorders can be considered a marker of endothelial damage and subclinical atherosclerosis. The results of these studies allow us to consider dys- and hyperlipidemia as an indirect sign of endothelial damage and atherosclerosis already at the preclinical stage of PsA, which does not always reflect the activity of arthritis. These disorders develop early and for a long time, long before the clinical manifestation of vascular atherosclerosis, go unnoticed, and by the time lipid disorders are detected, many patients already have manifestations of coronary artery disease, including myocardial infarction. Other factors of cardiovascular complications also contribute to the manifest violation of lipid metabolism: impaired peroxidation processes and glycation of plasma lipoprotein receptors, disorders in the coagulation system and endothelial dysfunction. The result is a significantly increased total risk of CVD [19]. In order to study the features of the course of PsA in patients with dyslipidemia, Boehncke W.H. (2010) examined 72 patients. The authors found that in 76% of patients with type 2-A dyslipidemia (hypercholesterolemia), a distal variant of the articular syndrome was observed, in 82% with type 2-B dyslipidemia - polyarthritic and spondyloarthritic variants, in 69% with type 4 dyslipidemia - oligoarthritic and polyarthritic variants [twenty]. It can be assumed that a certain type of dyslipidemia may also be associated with the clinical form of PsA articular syndrome.
Endothelial damage and endothelial dysfunction. The relationship of endothelial dysfunction with the peculiarities of the pathogenesis of psoriatic arthritis and the classic factors of cardiovascular risk is the leading factor in the pathogenesis of cardiovascular pathology in this disease. In the presence of cardiovascular risk factors in persons over forty years of age, additional factors for PsA patients are young age, long duration and high activity of arthritis [21]. The pathogenesis of cardiovascular complications in PsA originates in damage to the vascular wall. The immune response induces overproduction of proinflammatory mediators, where serum inflammatory mediators are of greatest interest - proinflammatory cytokines, matrix metalloproteinases, immune complexes, and C-reactive protein, the level of which is determined in clinical practice to assess the overall activity of the inflammatory process in PsA [21]. In the systemic circulation, cells are activated endothelium, currently recognized as the largest human endocrine organ. On the surface of the activated endothelium, mediators are formed with procoagulant and proatherogenic properties, causing lipid deposition on the vascular wall, and, subsequently, hypercoagulation and the formation of atherosclerotic plaques [22]. We can conclude that in PsA patients, control of the degree of arthritis activity through rational therapy leads to the normalization of hemostasis and a decrease in the severity of endothelial dysfunction.
Echocardiographic changes in psoriatic arthritis. Changes in the vascular wall in PsA caused by damage to the endothelium are studied in detail using ultrasound. According to modern data, the combination of PsA and arterial hypertension is a qualitatively new condition associated with endothelial damage [23]. Subclinical involvement of the cardiovascular system in systemic inflammation in the form of arterial hypertension reflects not only changes in the lipid profile, but also a thickening of the intima-media complex (IMC) of the arteries. Carotid arteries are the most convenient for ultrasound examination. The data of some works show that the early development of atherosclerosis is characteristic of patients with PsA - the value of the intima-media complex (IMC) in this pathology significantly increases [23]. Mease also reports a significant increase in IMF in PsA. P. (2020), noting that ultrasound can detect it already at the preclinical stage [24]. According to the results of the study by Mueller R. B. (2013), the mean IMI in the group of patients with PsA was significantly higher (0.76 mm) than in the control group (0.64 mm) [25]. It is noteworthy that the authors of the studies did not reveal a significant dependence of the IMC thickness on the level of LDL, VLDL, CRP, as well as arterial hypertension; however, IMC changes correlated with the severity of arthritis, the presence of spondylitis and did not depend on the anti-inflammatory therapy being performed. This is consistent with the data of the study by Fitzgerald K. (2012), where in the group of patients with PsA there were significantly higher IMR values ​​(0.7 mm) than in the control group (0.6 mm), the IMR value also correlated with the duration diseases [26]. We can assume that angiogenesis is one of the key factors in vascular wall damage in psoriatic arthritis. The detected changes in the intima-media complex of the carotid arteries without clinical signs of coronary artery disease are quite indicative of the involvement of angiogenesis in systemic inflammation.
Violations of autonomic regulation of the heart in patients with PsA. Chronic systemic inflammation has a negative effect on autonomic regulation of cardiac activity by reducing heart rate variability (HRV) [27]. The latter can probably be regarded as an independent factor of poor prognosis and cardiovascular events in PsA [27]. According to the clinical study of A.P. Rebrova. (2011, Saratov), ​​the deterioration of HRV indicators was found in all patients with PsA (the study involved only persons without signs of cardiovascular diseases and corresponding complaints). Changes in autonomic regulation are mainly manifested in the form of a decrease in HRV and excessive activation of its sympathetic link, which undoubtedly indicates a negative effect of systemic inflammation on the autonomic regulation of the heart and reflects the tension of adaptation mechanisms of the cardiovascular system within the framework of systemic inflammation [27].
The most common cardiovascular disorders in PsA. According to various authors, the most common cardiovascular disorders in PsA include: hypertension, ischemic heart disease with / without rhythm disturbances, wall thickening / dilatation of the gastric chambers, acquired valvular defects, myocardial dystrophy, non-rheumatic myocarditis [28]. Arterial hypertension (AH) is one of the independent risk factors for the development of vascular catastrophes; it occurs more often in psoriatic arthritis than in the general population [28]. A natural consequence of the increased cardiovascular risk, manifested by a higher frequency of coronary artery bypass grafting than in the population, is a high incidence of myocardial infarction, amounting to 4.38 per 1000 patient / years [29]. The analysis of the prevalence of cardiovascular diseases among patients with PsA was carried out in Atzeni F. et al. (2013). According to the results of the study, hyperlipidemia, clinical manifestations of atherosclerosis and, finally, the incidence of myocardial infarction were significantly higher in PsA than in the control group. A high level of cardiovascular mortality was also revealed [29]. According to Tracy Y. Z. et al. (2012), the relative risk of developing myocardial infarction is quite high even in young patients. The number of cases of myocardial infarction in patients with PsA was 5.13 per 1000 patient / years versus 3.58 in the control group [30]. The authors especially note morehigh incidence of stenosis of the left coronary artery in patients with PsA [30].
Organic changes in the cardiovascular system in psoriatic arthritis. The most significant stigma in PsA according to ECHO-KG is aortitis [31]. According to I.Z. Gaidukova. (2011), dilatation of the aorta and focal seals on its posterior wall, found in 36% of patients, are presumably associated with psoriatic spondylitis. Echocardiographic changes were detected in 21 patients (5.7%), aortic insufficiency occurred 6 times more often than mitral, combined mitral-aortic defect was found twice as often as isolated [31]. Atzeni F. et al. (2010) in their study of the structure of cardiovascular disorders in 30 patients with PsA who did not have cardiac complaints, obtained the following results: in 27% of patients, diastolic dysfunction was found, in 17% - systolic dysfunction of the left ventricular myocardium, aortic and mitral failure was identified in 37% and 16.7% of patients, respectively [32]. These data allow us to assume the presence of preclinical and subclinical cardiovascular disorders in patients without corresponding complaints, which complicates the timely diagnosis of complications. A large Russian study by I.Z. Gaidukova (2011), was aimed at identifying the relationship between endothelial damage and cardiovascular complications in 120 patients with PsA without clinical manifestations of cardiovascular pathology. According to the results of the study, arterial hypertension was detected in 55.29% of patients, dyslipidemia - in 63% of patients with PsA (28% in the comparison group), in 34.38% of patients the presence of atherosclerotic plaques was revealed. Among patients with traditional risk factors, the clinical manifestation of IHD developed in patients with a longer duration and activity of the disease. We can assume that PsA activity is directly related to an increase in vascular stiffness [33]. In a similar study by Wollina U. et al. (2010) 153 patients with PsA took part. Arterial hypertension was detected in 53% of patients (30.9% in the control group), hypercholesterolemia - 55% and 16.4%, triglyceridemia - 14.4% and 7.2%, respectively. Only 44.4% of PsA patients took antihypertensive drugs (81.8% in the comparison group). The authors also assessed the risk of death from CVD on the SCORE scale: low risk was found in 62% of patients, moderate - in 17.5%, high - in 16.1%, and in 4.7% of patients - very high. In the comparison group, the same assessment was 83.33%, 11.1%, 5.6% and 0 people, respectively [34]. Thus, arterial hypertension in PsA patients is found 22.1% more often, while taking antihypertensive drugs, on the contrary, is 37.4% less, which once again emphasizes the role of rational combination therapy in the prevention of cardiovascular complications in these patients.
Evaluation of cardiovascular risk in patients with PsA An increase in cardiovascular mortality in PsA at the population level was demonstrated by the results of a 4-year European study, which included 446 patients with spondyloarthritis, incl. PsA [35]. The authors assessed the risk of cardiovascular accidents according to SCORE, recorded the occurrence of cardiovascular events after 1 and 4 years. According to the results of the study, the occurrence of coronary artery disease and atrial fibrillation in patients with PsA was registered more often than in the control group; the risk of death from CVD on the SCORE scale was 1%. In the first year and by the end of the study, angina clinic developed in 8.3% and 51.2% of patients, arterial hypertension - in 12.5% ​​and 49%, myocardial infarction developed in 1.6% and 5.8%, atrial fibrillation - in 1.6% and 7.0% of patients, respectively. During the study, 3 patients died from myocardial infarction [82]. According to Peters M.J. (2010), the level of cardiovascular risk of CVC was average and above average in most patients with PsA (55%) [36]. It can be concluded that there is a correlation between CWR and thickening of the IMC of the carotid arteries, the level of total cholesterol and LDL cholesterol in PsA patients. The study of this problem seems to be a promising direction in the prevention of cardiovascular mortality in patients of this group.
Conclusion. In patients with psoriatic arthritis, endothelial dysfunction is established, which correlates with the degree of activity of this disease. High disease activity, early age of onset of PsA, an increase in C-reactive protein, and X-ray destruction of joints are added to the classic cardiovascular risk factors in patients with PsA. A decrease in arthritis activity is associated with a decrease in the severity of damage to the vascular wall. Thus, analyzing numerous scientific data, it can be concluded that the initial risks of cardiovascular events in patients with PsA exceed those in those without this disease. Early detection of cardiovascular risk factors, search for reliable and modern diagnostic methods (duplex scanning of the carotid arteries, determination of circulating endothelial cells, etc.) and criteria for assessing endothelial damage, subclinical atherosclerosis and cardiovascular risk, taking into account the pathogenesis of PsA, is dictated by the need to start early measures aimed at preventing / reducing mortality from cardiovascular complications in this disease.

About the authors

Zarema R. Khismatullina

Bashkir State Medical University

Email: hzr07@mail.ru
ORCID iD: 0000-0001-8674-2803
SPIN-code: 6602-4060

MD, Dr. Sci. (Med.), Professor

Russian Federation, Lenina str., 3, 450008, Ufa, Republic of Bashkortostan

Ksenia M. Koreshkova

Bashkir State Medical University

Author for correspondence.
Email: saitik16@yandex.ru
ORCID iD: 0000-0001-6039-8311
SPIN-code: 4427-1594

assistant lecturer

Russian Federation, Lenina str., 3, 450008, Ufa, Republic of Bashkortostan

References

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