Systemic Lupus Erythematosus and Cardiovascular Diseases: A Systematic Review

Systemic lupus erythematosus (SLE) is an autoimmune condition characterized by multi-organ involvement. The clinical presentation often varies from mild to moderate to severe. The cardiovascular system may also be affected, often portending a poor prognosis for patients. Although the relationship between SLE and cardiovascular disorders has been extensively explored through case reports and literature reviews, few systematic reviews explicitly focusing on this association have been conducted. In light of this, this systematic review aims to analyze the extent of the association between SLE and cardiovascular diseases (CVDs), by exploring the risk of developing CVDs, including myocardial infarction (MI), atherosclerosis, myocarditis, pericarditis and arrhythmias, in SLE patients vs. non-SLE patients. We followed the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) guidelines to perform the systematic review. A detailed search was done covering the period from March 2003 to March 2023 using three databases: PubMed, Google Scholar, and Cochrane. The PubMed search identified 597 articles, while Google Scholar and Cochrane searches yielded 559 and three articles, respectively. Of the 1159 articles retrieved, we chose eight for final consideration, after excluding papers that did not discuss the role of SLE in CVDs, papers published earlier than 2003, and papers with incomplete data. The eight studies chosen included two narrative reviews, two systematic reviews, and four observational studies. In this systematic review, SLE was proven to have a strong relationship with diverse CVDs, including rare ones scarcely discussed in the literature, such as vasculitis and aortic dissection. All eight of the final papers indicated a connection between SLE and CVDs, based on the systematic analysis of these articles, which revealed that most recent research supports a higher risk of peripheral arterial occlusive disease (PAOD), MI, pericarditis, myocarditis, and other cardiovascular disorders in individuals with SLE. These associations may have certain gray areas, as patient characteristics and comorbidities often affect the extent of illness and long-term prognosis. Larger-scale studies are required to probe this relationship further and research the etiopathogenesis involved in order to improve patient outcomes. The effects of SLE on the heart are, however, unequivocal.


Introduction And Background
The classical autoimmune disease, systemic lupus erythematosus (SLE), is associated with a significant global disease burden. However, epidemiological estimates differ considerably between various ethnic, racial, and age groups [1]. The condition is more prevalent in younger women, with a female-to-male prevalence ratio of approximately 10:1 [2]. Survival rates in SLE have significantly improved, yet deaths due to cardiovascular disease (CVD) in lupus have not [3]. CVD accounts for approximately one-third of deaths in SLE and, in some cohorts, is the leading cause of mortality in lupus [4]. This illness is characterized by numerous clinical manifestations, antibodies, and the involvement of one or more organ systems [5]. These antibodies produced in SLE are directed to a host of self-molecules found in the nucleus, cytoplasm, and cell surfaces [6]. These include antinuclear antibodies (ANAs) (present in more than 95% of patients), antidouble stranded DNA (ds-DNA), and anti-Smith (ant-Sm antibodies). endocrine, genetic, and immunological, resulting in the development of autoantibodies that cause tissue damage through diverse mechanisms [7]. This pathological mechanism is explained as an interruption of tolerance in genetically predisposed people and exposure to environmental factors, causing the activation of autoimmunity [7]. Cardiac involvement in patients with SLE can negatively impact all components of the cardiovascular system and heart, including the pericardium, conducting system, myocardium, valves, and coronary arteries, and is associated with increased morbidity and mortality [8].
Cardiovascular manifestations in SLE result from numerous pathophysiological mechanisms that work in tandem, and increase morbidity and mortality in SLE patients [2]. The malfunction of endothelial cell activation, which results in the development of lectin-like oxidized low-density lipoprotein receptor 1 (LOX-1), causes endothelial cell dysfunction [2]. By causing the release of tissue necrotic factor-alpha (TNF-a), interleukin 6 (IL-6), and interleukin 12 (IL-12), which are essential for attracting monocytes to adhere to endothelial cells, LOX-1, a pro-inflammatory receptor, raises the risk of CVDs in SLE [9]. Another mechanism of cardiac disease in SLE is the disruption of innate immunity [2]. This immune dysregulation is associated with a distinct subset of lupus pro-inflammatory neutrophils known as low-density granulocytes (LDG), which are found in increased numbers in SLE and promote in vitro endothelial cell damage [10]. These LDGs trigger the formation of neutrophil extracellular traps (NETs), which facilitate unstable coronary plaque and thrombus formation [11]. A third mechanism of cardiac disease in SLE is the disruption of adaptive innate immunity [2]. This occurs through the excessive activation of T lymphocytes, including CD4+ T cells, promoting vascular injury and thrombus formation by IFN-1 signaling [12]. This systematic review aims to examine and consolidate the relevant information on the connection between SLE and CVDs.

Review Methods
The Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) criteria were used to perform a systematic literature search [13].

Eligibility Criteria
We employed specific inclusion criteria to select the studies relevant to our systematic review. Studies evaluating the role of SLE in the etiopathogenesis of various cardiovascular diseases were selected as the primary target of our research. We decided to gather studies published from 2003 to 2023, including free full texts, systematic reviews, traditional reviews, case reports, literature reviews, and observational studies. Studies on animals, those with incomplete data, those with free full-texts unavailable, and articles that did not meet our research goals were excluded.

Selection Strategy
Two authors conducted a thorough screening (M.A.N. and A.B.), each blinded to the other's ratings, employing identical search plans in all databases, and wherever they disagreed about the articles' fulfillment of the inclusion or exclusion criteria, a third author (I.M.S.) intervened. Initially, articles were reviewed using titles and abstracts, and afterward, the entire articles were read.

Database and Search Strategy
To conduct this systematic review, we selected studies from PubMed, Google Scholar, and Cochrane Database, covering the period from March 2003 to March 2023, to elicit only the most relevant articles for our systematic review assessing the role of SLE in the etiopathogenesis of CVDs. Keywords used in all search engines were as follows: 'SLE' or Systemic Lupus Erythematosus' AND 'cardiovascular diseases' or 'cardiac diseases' or 'heart diseases' or 'cardiac manifestations'. We combined the keywords in every combination to generate the maximum number of articles for screening.

Analysis of Study Quality
Out of the eight articles selected for this study, two were narrative reviews, two were systematic reviews, and four were observational studies. The quality assessment tools used for this systematic review included the Newcastle Ottawa Scale (NOS) [14] for cohort and case-control studies; Assessment of Multiple Systematic Reviews 2 (PRISMA 2020 Checklist) for systematic reviews and meta-analyses [13]; and Scale for the Assessment of Narrative Review Articles (SANRA) for narrative reviews [15]. Each assessment tool had its own criteria and different systems of scoring. Two reviewers, independently using commonly used tools for each type of study, assessed each selected study for risk of bias. We accepted a score of at least 70% for each assessment tool to ensure that only high-quality papers were used. Table 1 gives further insight into the quality assessment tools and the accepted articles.

Type of Study
Total Score Accepted Score (>70) Accepted Studies

Results
The comprehensive and exhaustive database searches of PubMed, Google Scholar, and Cochrane elicited 1159 potentially related titles based on the study inclusion criteria for this systematic review. The removal of duplicates left 1062 articles, after which all remaining records were screened using the title and abstract. A secondary review was then carried out by reading full-text articles and using detailed inclusion and exclusion criteria to eliminate irrelevant articles not possessing the required data for this systematic review. This holistic evaluation yielded 15 articles related to our research question, which were further subjected to the screening tools (PRISMA, SANRA, and Newcastle Ottawa Scale). After a quality appraisal, we eliminated seven studies, and the remaining eight articles were included in our systematic review. These articles comprised two systematic reviews, four observational studies, and two narrative reviews. We created a PRISMA flowchart for study identification and filtering of the articles as shown in Figure 1 [13]. Table 2 summarizes the features of the articles included in the review.
Pericarditis is the most common cardiac manifestation of SLE [24]. However, it is uncommon for acute pericarditis to be the leading symptom at the time of diagnosis of SLE, and it occurs in just 1% of patients [25]. A case report by Bezwada et al. discussed myopericarditis with pericardial effusion as the initial presentation of SLE [26]. Furthermore, Gupta et al. published a case report on constrictive pericarditis as the initial manifestation of SLE [27]. In this case, echocardiography showed a thickened pericardium with effusion and motion abnormalities consistent with constrictive pericarditis. At the same time, a CT scan of the chest revealed pericardial effusion, pericardial thickening, and normal lung parenchyma with mild bilateral pleural effusion. Narang et al. published a case series discussing three patients who developed acute pericarditis without prior history of SLE but were later diagnosed with SLE [25]. On investigation, two of these cases had the classical electrocardiography finding of diffuse ST-segment elevation with PR interval depression. At the same time, one demonstrated low voltage without signs of PR and ST-segment changes and electrical alternans. Non-steroidal anti-inflammatory drugs (NSAIDs) are the primary choice in managing pericarditis; however, SLE treatment includes disease-modifying anti-rheumatologic drugs (DMARDs), glucocorticoids, and even immunomodulators as SLE is an organ-threatening condition [25].
A systematic review and meta-analysis by Bello  Cardiac tamponade is, however, a rare entity, estimated to occur in fewer than 1% of patients with SLE [28]. Emorinken et al. discussed a case of cardiac tamponade as an unusual first presentation of SLE. Findings, in this case, included the chest radiograph showing an increased cardiac silhouette, an expected result in cardiac tamponade [29]. Investigations showed a massive proximate pericardial effusion measuring 2.7 cm in the parasternal long-axis view and 2.4 cm in the subcoastal view [29]. Additionally, ANAs with a titer of 1:1280 (<1:80), anti-Sm, anti-SSA, and anti-dsDNA antibodies were all positive [29]. Chourabi et al. have reported that when cardiac tamponade is diagnosed with SLE, it often presents as the initial finding in patients with a previously undiagnosed disease [30]. Goswami et al. conducted a case series involving 409 patients with SLE. They reported that pleuritis, the size of the effusion, and the presence of anti-nucleosome antibodies were essential predictors of tamponade in the 24 patients who developed tamponade [31].
Zhang et al. conducted a retrospective case-control study on 125 lupus myocarditis (LM) cases [21]. The cases included 25 patients with SLE who developed LM, while the controls comprised 100 of those who had SLE but did not develop LM. In seven cases (28%), LM was the first presentation of SLE and presented at earlier stages, which was in direct contrast with the controls (20.88 ± 35.73 vs. 44.08 ± 61.56 months, p=0.008) [21]. Furthermore, 23 of the LM cases (92%) showed reduced left ventricular ejection fraction (<50%), and all patients had wall motion abnormalities [21]. Studies have shown that LM is not a common manifestation of SLE, presenting in about 9% of SLE patients [32].
A case series of eight cases of neonatal lupus by Teixeria et al. discussed the presence of positive autoantibodies anti-Ro/SSA (90% of the cases), anti-La/SSB, and anti-U1 RNP4 in mothers of affected infants [33]. All mothers were diagnosed with SLE/antiphospholipid syndrome, and seven out of the eight cases developed cardiac manifestations of neonatal lupus, with five having complete heart block and the other two having second-degree heart block and bradycardia, respectively [33]. Neonatal lupus as a disease entity occurs due to passively-acquired autoimmunity, in which tissue injury in the fetus results from the transplacental transfer of maternal IgG autoantibodies to SSA/Ro and SSB/La intracellular proteins [34]. These maternal antibodies cross the placenta to fetal tissue as early as the 11th week of gestation [35]. Skin, liver, and blood cells are regenerative; hence, the effect of these antibodies is short-lived. However, cardiac cells are not regenerative, and therefore, permanent reversal of third-degree heart block has never been seen in the literature [34]. CHB carries significant mortality (20-30%, primarily fetal/ neonatal) and morbidity (67% require permanent pacing before adulthood) [36].
Studies have shown that SLE patients are at increased risk of accelerated atherosclerosis, a notable cause of morbidity and mortality in these patients. A cohort study by Chuang et al. sought to holistically define the association between SLE and peripheral arterial occlusive disease (PAOD); 10,144 SLE patients and 10,144 controls were enrolled in the study [18]. In the SLE group, compared to the non-SLE cohort, the incidence of PAOD was shown to be 9.39 times higher (95% CI: 7.70-11.15) [18]. Additionally, SLE was found to be a separate risk factor for PAOD. This is because patients with SLE aged under 34 years had the highest adjusted risk of PAOD (HR: 47.6, 95% CI: 26.8-84.4) [18]. The risk of PAOD peaked in the first year of follow-up and then gradually dropped. As a result, SLE is a distinct risk factor for the emergence of cardiovascular disease [37].
Using the non-invasive ultrasonic biopsy score, Abu-Shakra et al. conducted a case-control study in 2008 to identify intimal and medial alterations in the common carotid and common femoral arteries of 51 patients with SLE and their matched controls [38]. These alterations are highly prognostic of the onset of clinical CVD [39]. A score of 0 means that all four blood vessels are normal, and a score of 40 means that all blood vessels have symptomatic plaques. This score goes from 0 to 40. Patients with SLE had an overall ultrasonic biopsy score 1.8 times greater than the controls [38]. Atherosclerotic plaques were much more common in patients with SLE, with an odds ratio of 3.17, and 28% of SLE patients had at least one of the four arteries affected by an atherosclerotic plaque, compared to 10% of control patients [38]. Only 37% of the SLE patients had standard scores in all vessels, as opposed to 67% of the controls [38]. In a case-control study, 65 patients with SLE (mean age: 40.3 ± 11.6 years) and 69 control subjects (mean age: 42.7 ± 12.6 years) without a history of coronary artery disease were screened for the presence of coronary artery calcification using electronbeam CT [40]. The findings of this investigation revealed that lupus patients (20 of 65 patients) had coronary artery calcification more frequently than control participants (6 of 69 subjects) (p=0.002) [40]. The mean calcification score was 68.9 ± 244.2 in patients vs. 8.8 ± 41.8 in controls (p=0.001). The study found that the age of onset is also lower in SLE and that the prevalence of coronary artery atherosclerosis is noticeably higher [40].
A recent case report by Al-Jehani et al. reported Libman-Sacks Endocarditis (LSE) in a previously undiagnosed patient [41]. Immunology tests, however, led to the diagnosis of SLE. An even rarer case, Coxiella burnetii endocarditis in a patient with SLE, was reported by Alqallaf et al. [42]. SLE's most common specific valvular involvement is LSE, with frequent involvement of the left-sided cardiac valves [43]. A crosssectional study by Moyssakis et al. evaluated the prevalence of LSE in 342 consecutive SLE patients (297 females and 45 males) using Doppler echocardiography. LSE was diagnosed in 38 cases (24 mitral, 13 aortic, and one tricuspid valve) [44]. This study concluded that Libman-Sacks verrucous lesions were reported in one out of 10 patients suffering from SLE, and the lesions were associated with disease duration, activity, and antiphospholipid antibodies. These cases highlight the importance of endocarditis as a presenting cardiac manifestation in SLE.
Less common cardiovascular manifestations of SLE include vasculitis and aortic dissection. Leone [46]. Spontaneous coronary artery dissection (SCAD) is another uncommon cardiac SLE manifestation, with few case reports in the literature so far. A case report by Chaaban and Kshatriya described a case of SCAD in a 37-year-old female with hypertension, and a history of smoking, both risk factors for the disease [47]. Ullah et al. systematically reviewed 10 articles about SCAD associated with rheumatologic conditions and found that many cases were related to systemic lupus. Furthermore, most patients presented with non-ST elevation myocardial infarction involving the left main coronary artery [48]. SCAD is an underdiagnosed disease that requires a high index of suspicion.

Conclusions
This systematic review studied the link between SLE and CVDs while considering the wide range of associations between these phenomena. In addition, the possible causal pathways were also explored. Our study shows a greater prevalence of a diverse range of cardiovascular diseases in SLE, which leads to increased morbidity and mortality. Furthermore, SLE is an independent risk factor for PAOD and MI. More research on the connections and associations between SLE and CVDs, including the survival rates of patients with CVDs as a sequelae of SLE. is required to improve short-, medium-, and long-term patient outcomes. This is because, even though survival rates in SLE have improved over the years, deaths due to CVDs in SLE have not shown a similar trend. Protocols should be developed to ensure that clinicians maintain a high index of suspicion when encountering patients presenting with CVDs such as PAOD, MI, pericarditis, myocarditis, or conduction defects so that they are investigated in a timely manner.

Conflicts of interest:
In compliance with the ICMJE uniform disclosure form, all authors declare the following: Payment/services info: All authors have declared that no financial support was received from any organization for the submitted work. Financial relationships: All authors have declared that they have no financial relationships at present or within the previous three years with any organizations that might have an interest in the submitted work. Other relationships: All authors have declared that there are no other relationships or activities that could appear to have influenced the submitted work.