Can Pioglitazone Safeguard Patients of Lichen Planus Against Homocysteine Induced Accelerated Cardiovascular Aging and Reduced Myocardial Performance: A Systematic Review

Lichen planus (L.P.) is a long-standing mucocutaneous inflammatory condition. A less familiar but essential illness association is increased arterial stiffness, endothelial dysfunction, and advanced atherosclerosis. Enhanced cardiac reconditioning and reduced performance of the heart have been suggested. Thiazolidinediones were commenced to manage hyperglycemia in diabetes mellitus. Recently, the class attained popularity after its action on vascular physiology was discovered. With this review, we attempted to explore whether an antidiabetic drug, pioglitazone (PIO), a peroxisome proliferator‑activated receptor γ (PPAR gamma) agonist, can defend patients of lichen planus against increased arterial stiffness and cardiac changes. We methodically screened numerous databases using focused words and phrases for relevant articles. After a comprehensive exploration, we applied the inclusion and exclusion criteria and performed a quality appraisal. Items retained were exhaustively studied. High homocysteine (HHcy) levels in lichen planus play a significant role in modifying the arteries and leading to their dysfunction. Not only does homocysteine affect the precursor cells, but it also increases the free radical damage. Arterial damage and upraised resistance encountered by the heart reduce its performance. After an exhaustive analysis, in our opinion, pioglitazone works in various miscellaneous ways to mitigate the homocysteine mediated changes. Early inclusion of the drug in managing patients with lichen planus seems promising in minimizing the harmful effects of high homocysteine. Evaluating the risk-benefit ratio, we believe that a trial of pioglitazone could be given to patients without underlying cardiac conditions.


Introduction And Background
Lichen ruber planus, or simply lichen planus (L.P.), was first put forward by Dr. Erasmus Wilson in 1869. It is a chronic cell-mediated, autoimmune, inflammatory disease that has an incidence of 0.4-1.9% worldwide. L.P. is the primary representative of lichenoid conditions and is depicted by small papules, often associated with overwhelming itching [1]. The "5P's Disease," as we traditionally remember, affects not only the skin, hair, nails, but also the mucous membranes of the genital tract, gastrointestinal tract, and the eyes [2]. Though the disease's exact etiology is unknown, one of the proposed molecular pathogenesis theories suggests triggering factors that lead to intrinsic or foreign antigens' presentation [1]. Basal keratinocytes are presented as exotic antigens to activated CD8+T cells due to the underlying inflammation. The upregulation of cytokines and intercellular adhesion molecule-1 (I-CAM-1) correlated with the T-helper one cells has also been suggested in this pathogenesis [3]. Studies have shown raised levels of homocysteine and fibrinogen levels in these patients.
Vascular aging is a process that affects all three layers of an artery. At the intima, endothelial dysfunction occurs due to inflammation and reduced vasodilation due to reduced nitric oxide production. The media shows less elastin and an increased amount of collagen, contributing to increased arterial stiffness. Loss of innervation and increased fat deposition at the adventitia further contributes to inflammation [4]. Changes in arterial stiffness and alterations in the mechanical properties are measured by noninvasive markers like pulse pressure (PP), pulse waveform velocity (PWV), and augmentation index (AI) [5,6]. Pulse waves generated during each cardiac contraction travel from the heart until they encounter either resistance or a branch point, where they are then reflected. These reflected waves appear late when the arteries are elastic. However, as the stiffness increases, these waves appear early and with more incredible wave-pulse velocity. A part of the reflection is also sent to the aorta, which results in limited wave energy to the peripheral arteries, thus preventing damage to the microcirculation [7]. Pulse wave velocity is measured as PWV = Length (meters)/ΔTime (seconds). Length is the distance between the two points of the recording, and ΔTime is the time difference between the appearance of a pulse wave at these two points relative to the peak of the R wave on the electrocardiogram. The value of PWV increases with arterial stiffness. The Moens-Korteweg equation defines factors that affect the amount of PWV, PWV =√(EH/2ρR), E is Young's modulus of the arterial wall, H is the thickness of the wall, R is the radius of the artery at the end of the diastole, and ρ is the density of blood [8]. This tells us that reduced arterial elasticity, diameter, and increased thickness, increase PWV, and damage the microcirculation leading to an increased cardiac workload [7]. Increased arterial aging is thus known to mediate cardiac remodeling and reduce cardiac functions. Two persistent inflammatory diseases of the skin that are frequently credited with an increased risk of thrombosis and cardiovascular disease are L.P. and Psoriasis [9]. Certain studies have shown a significant increase in blood homocysteine levels is associated with the severity of oral lichen planus (O.L.P) [10]. Others illustrate an association with the duration of the disease and not the severity. High homocysteine (HHcy) can lead to the earlier onset of atherosclerotic cardiovascular disease.
Pioglitazone is therapeutically used in patients with diabetes and obesity. However, investigators have not explored pioglitazone as a vasculoprotective drug in Lichen Planus. Also, cardiovascular aging in lichen planus is relatively a topic less looked at and needs more attention. Our review article focuses on homocysteine as the modifiable culprit and its mediated effects on vascular aging and cardiac dysfunction in patients of lichen planus. We further investigate our concern, whether pioglitazone can be used as a potential drug, in the future, in patients with lichen planus to curtail arterial aging and mediated myocardial dysfunction.

Review Methods
We obeyed the Preferred Reporting Items for Systematic reviews and Meta-Analysis (PRISMA) guidelines for conducting our systematic review. As shown below in Figure 1, we systematically searched multiple electronic databases, such as PubMed, PubMed Central, Web of Science, Google Scholar, Scopus, and Medline for data collection. We explored the database by using terms of medical subject heading (MeSH) and keywords: "lichen planus," "homocysteine," arterial stiffness," "vascular aging," "myocardial performance index," "left ventricle, "and "pioglitazone," separately and in combination to find relevant studies. We performed a nonautomated search on the reference lists of included studies and systematic reviews. We found a total of 2955 articles from the electronic database and one from the university library. PRISMA-Preferred Reporting Items for Systematic reviews and Meta-Analysis, PMC-PubMed Central, AXISappraisal tool for cross-sectional studies, AMSTAR-a measurement tool to assess systematic reviews, SYRCLE-systematic review center for laboratory animal experimentation, SANRA-scale for the assessment of narrative review articles, L.P.-lichen planus, CVS-cardiovascular system, PIO-pioglitazone

Inclusion Criteria
There was no language restriction. We included studies in English, Spanish, German, randomized control trials (RCT), clinical trials, cross-sectional, case-control, cohort studies, systematic reviews, traditional reviews, opinions, animal studies, letters to the editor editorials. We identified and included studies published in the last 27 years. We had studies conducted in humans of age 10 years onwards.

Exclusion Criteria
Grey literature, books, documents, case series, case reports, overlapping studies, duplicate studies, and studies before 1993.

Results
A total of 2956 studies were obtained by scrutinizing the databases. Records were analyzed based on the title and appropriate abstract and were filtered, applying inclusion-exclusion criteria. We studied a total of 197 reviews that were then filtered. We removed duplicate studies. After setting a 70% benchmark, we assessed 81 studies for quality, and only 41 qualified after applying the quality assessment tools. We used the following means: Clinical trials = Cochrane Risk Bias Assessment tool, Observational studies= Newcastle Ottawa, AXIS, A systematic review, and meta-analysis = AMSTAR, Animal trials = SYRCLE, Literature review articles = SANRA Our review includes 367 patients of lichen planus from six different studies, five case-control, and one crosssectional study depicting the increased prevalence of high homocysteine (HHcy) levels and arterial stiffness. The review includes 621 patients from different studies who benefitted and improved arterial stiffness and elasticity after taking pioglitazone. A total of 17,011 patients from four randomized control trials and a meta-analysis showed reduced inflammation and decreased cardiovascular death. Overall, we found that Pioglitazone pretreatment or early treatment seems promising in mitigating high homocysteine actions.

Increased Homocysteine, the Modifiable Culprit: Pathophysiology
Homocysteine, an amino acid part of the methionine pathway, requires both vitamin B12 and folic acid as coenzymes to convert into methionine. A remarkable nutritive inadequacy of folic acid and Vitamin B12 in patients of oral lichen planus (O.L.P.) is seen. As a result, homocysteine levels rise. High homocysteine levels have also been related to disease severity [10]. An analytical study in 2015 revealed abnormally HHcy levels in patients with oral-cutaneous lichen planus and psoriasis [9]. Moreover, certain studies explain the role of the MTHFR 677 gene polymorphism in L.P. [11,12]. The results of Rashed et al. disclosed that folate deficiency and hyperhomocysteinemia were associated with the TT mutant genotype. However, these results were insignificant (P>0.05) [13]. Castro et al. also reported HHcy levels and lower folate levels in homozygoteTT mutants of the MTHFR 677 gene [11]. These results contrast with Kujundzic et al., who said no association between MTHFR genotype and O.L.P. [14]. This inconsistency could be due to the population's alteration as both cutaneous and oral lichen planus patients were studied in the former. In contrast, only patients with oral lichen planus were studied in the latter. The two pathways of increased Homocysteine in L.P., as explained above, are shown below in Figure 2.

MTHFR-methyl tetra hydro folate reductase
The possible mechanism behind heightened arterial stiffness due to inflated levels of homocysteine has not been fully comprehended. The central hypothesis suggests increased remodeling of the vascular wall due to magnified oxidative stress [15]. The induced endothelial dysfunction, in turn, encourages the proliferation of vascular smooth muscle cells and deposition of glycosaminoglycans in the matrix, which further impairs vasodilatation [16]. The endothelial cells' growth and integrity may be jeopardized due to reduced methylation potential due to high Homocysteine and S-adenosylhomocysteine levels [17]. During its autooxidation to thiolactone and inhibition of glutathione peroxidase expression, the generation of free radicals has also been suggested (Figures 3, 4) [18]. As shown below, Figure 3 briefly discusses the pathophysiology of high homocysteine-mediated changes in the cardiovascular system.

FIGURE 4: Protective Role of Pioglitazone on Homocysteine Mediated Changes
(Left to right: The leftmost column represents the hypoxia-mediated neovascularization in a normal artery. The column in the middle represents the changes mediated by increased homocysteine, and the right column depicts the protective actions of pioglitazone by inhibiting high homocysteine mediated changes. Neovascularization begins with hypoxia and inducible factors. EPC then adheres to the endothelium and migrates towards the hypoxic areas. Migration is stimulated by VEGF, IL8, mainly. Homocysteine mediated ill effects are listed in the middle column, and PIO, overcomes them.) PKC-protein kinase C, NADPH-nicotinamide adenine dinucleotide phosphate, VSMC-vascular smooth muscle cell, EPC-endothelial precursor cells, TNFa-tumor necrosis factor-alpha, GAGsglycosaminoglycans, PIO-pioglitazone, VEGF-vascular endothelial growth factor, IL8-interleukin 8, TGF Beta-tumor growth factor-beta, FGF-fibroblast-derived growth factor, IGF-insulin-like growth factor, p67phox, p47phox, RAC1 are components of NADPH oxidase, NO-nitric oxide One of the main mechanisms we would like to emphasize is reducing the number of endothelial precursor cells (EPC) and impairing their functional activities such as adhesion, multiplication, migration, and vasculogenesis capacity. As shown in Figure 3, the mechanism of these effects has been proposed to inhibit protein kinase C (PKC). The manifestation levels of nicotinamide adenine dinucleotide phosphate (NADPH) oxidase subunits, p47phox, NADPH oxidase 2, p67phox, p22phox, RAC-1 (Ras-related C3 botulinum toxin substrate 1) are upregulated by Hcy [19,20]. This results in increased free radicals hydrogen peroxide (H2O2), hydroxyl ions (OH-), peroxynitrite (ONOO-), which damage the endothelium. Furthermore, Hcy induces apoptosis of EPC. Vascular endothelial growth factor (VEGF) and Interleukin 8 (IL8) is suppressed with Hcy [19]. Koller et al. demonstrated that nitric oxide (NO) pathway dysfunction causes reduced dilation of arterioles [20,15]. Augmented production of superoxides has been shown to lessen nitric oxide availability, which modifies the mitochondrial function regulation in the heart. These pathomechanisms also illustrate how HHcy enhances glucose and lactate uptake and curtails free fatty acid uptake by the heart. The concurrently boosted thromboxane A2 (TXA2) activity in the platelets and blood vessels was also narrated. These variations are due to the heightened synthesis of free radicals. They lead to an increase in tumor necrosis factor-alpha (TNFα), NFκbeta (nuclear factor kappa light chain enhancer of B cells), and cause vessels' remodeling ( Figures 3, 4) [20]. Eleftheriadou et al. in 2013 demonstrated that acute methionineinduced hyperhomocysteinemia reduces aortic distensibility and worsens the myocardial performance of the left ventricle (Tei index) in healthy individuals [21].

Vascular Remodeling Induced Arterial Stiffness, Effects on the Left Ventricle, and Myocardial Performance Index in Lichen Planus
Vascular stiffness measured in the cardio-ankle vascular index (CAVI) is believed to be a better approach to evaluate arterial stiffness than the conventional method of pulse wave velocity because CAVI is independent of blood pressure [22]. Studies often use carotid-femoral pulse wave velocity (cfPWV), carotid radial PWV, augmentation index (AI), carotid intima-media thickness (CIMT), aortic strain (AS) and distensibility (AD), aortic stiffness index (ASI) to evaluate arterial aging. In 2018, research ascertained that HHcy concentrations were linearly correlated with cfPWV and intensified arterial stiffness [23]. The cf PWV was considerably higher in the high homocysteine group than in the standard. No substantial discrepancy in carotid-radial PWV between the two groups was recognized [15]. A survey by Lim et al. in 2002 concluded that Hcy induced cardiovascular morbidity was slightly reinforced in women compared to men [24]. Sheng et al. in 2015 suggested that homocysteine levels were associated with cfPWV and carotid-ankle pulse wave velocity (caPWV) in men but not in women. This difference may be attributed to the gender difference and faster conversion to Hcy to cystathionine in men [25]. Arterial stiffness has to be described with inflammation, as it may not provide any information alone [26]. Two cross-sectional studies, one in 2018 and the other in 2009, suggested a 14% increase in average arterial stiffness for persistent inflammatory diseases and a positive correlation between cfPWV and years of duration (but not with disease severity), respectively [27,28].
Studies have suggested that high Hcy levels could directly affect the left ventricle and its functions, as illustrated in Figure 3. A survey of 2013 suggests plasma homocysteine levels positively correlate with left ventricular hypertrophy, reduced isovolumetric relaxation time, and diastolic dysfunction [29]. HHcy levels also appear to be involved in left ventricular dilation; however, the resulting hypertrophy is inadequate to reimburse the enhanced wall stress [30]. This may lead to a reduced ejection fraction. Two studies suggested a substantial inverse association of HHcy with LVEF in patients with hypertension, but not in patients with normal blood pressure [31,32]. Rossi et al. also independently confirmed the inverse relationship between LV systolic function and HHcy [31]. High blood pressure enhances the effect of homocysteine levels on arterial stiffness, which is explained by high blood pressure-induced susceptibility of the endothelium to the deleterious impacts of homocysteine.  HHcy-high homocysteine, LVM-left ventricle mass, LVH-left ventricular hypertrophy, LVEF-left ventricle ejection fraction, CHD-coronary heart disease, CAD-coronary artery disease, B.P-blood pressure Further, the impact of HHcy may partly be mediated through arterial stiffness. Stiffening of the large vessels, such as that of the aorta, boosts the speed of the pressure wave. The pressure wave that has been reflected reaches the heart faster, at the end of systole rather than the diastole. The systolic blood pressure (SBP) and the cardiac afterload, as a result, increase. This may result in left ventricle remodeling [33]. The left ventricle's wall thickness and mass-volume ratio are negatively associated with the distensibility of the arteries. Arterial stiffness may be associated with LV twisting, reduced myocardial systolic function, and performance index [34]. It produces impedance matching, which reduces wave reflection, exposing the microcirculation to excessive pulsatile stress, resulting in organ damage.
Our meta-analysis describes the homocysteine-mediated cardiovascular changes in a total of 192 patients of lichen planus from four different case-control studies, as mentioned in Table 2. Baykal et al., in 2020, established an intermediate positive association between length of the disorder and increased arterial stiffness. Impaired systolic and diastolic activities were deduced in patients with lichen planus [35]. Risk is increased in the existence of resistant and chronic disease and with erosive lichen planus. Changes in both the systolic and diastolic functions may be attributed to HHcy's direct effect on the left ventricle and secondary effects due to increased arterial stiffness. Nasiri et al. suggested that patients with L.P. had a significantly greater mean CIMT. A positive relation was also explained between L.P. and HHcy and creactive protein (CRP) levels [36]. Koseoglu et al. demonstrated that AS, and AD, were considerably lower, and aortic stiffness index ASI was reasonably elevated in the L.P. group. The myocardial performance index (Tei index) was enormous in this group. They negatively associated L.P.'s duration with the changes and positively associated it with the Tei index and ASIβ [37]. Saleh et al. concluded that L.P. induced greater markers of cardiovascular and metabolic risk factors, probably due to prolonged inflammation. Hence, high Hcy levels and other cytokines may play a role in cardiovascular remodeling and increased morbidity [38]. Below-mentioned, Table 2 depicts the studies included in the discussion concerning the effects of increased arterial stiffness mediated left ventricular changes. Table 3 summarizes the studies discussing the effects of increased homocysteine levels on arterial stiffness in lichen planus and other inflammatory conditions.

Protective Role of Pioglitazone: Mechanism of Action
Pioglitazone (PIO), which was introduced as an antidiabetic drug, has now been shown to effectively mitigate the Hcy induced arterial stiffness, improve endothelial function, and decrease cardiovascular morbidity. Arterial stiffness is associated with an increase in cardiac high sensitive Troponin T and increased risk of a first cardiovascular event [38][39][40]. Zhu et al. in 2018 confirmed that PIO inhibits Hcy-Induced PKC inactivation, as shown in Figure 4, point 1 [19]. Western Blot analysis of EPC treated with PIO demonstrated that it significantly inhibited the phosphorylation of PKC. Flow cytometry studies showed decreased PKC mediated reactive oxygen species intracellularly. The results revealed that the drug attenuates Hcy induced EPC dysfunctions, such as reduced migration and adhesiveness. It also promotes antioxidant properties. PIO also restricts the upregulation of NADPH subunits, Nox2, and p67phox. Further, it has been shown to have pleiotropic effects involving anti-apoptosis and anti-senescence [19]. One of the studies confirmed its effect on VEGF and IL8. As shown in Figure 4, point 3, VEGF AND IL-8, which are otherwise reduced by homocysteine, are normalized by PIO.
PIO's effect is mediated by two intranuclear receptors, the retinoid X receptor, and the PPAR-gamma. A study by Xu et al. in 2017 used GW9662 (5 μM) as a distinctive PPAR-γ blocker to deduce whether PIO exercised its effect on EPCs against Hcy by activating the PPAR-γ receptor [41]. The production of cytokines by EPCs was normalized under the effect of PIO. These results revealed that GW9662 did not prevent PIO from intervening and blocking the Hcy-induced reduction in VEGF and IL-8 production. This suggests that PIO's defensive mechanism occurs via a PPAR-γ-independent pathway [41]. Li et al. illustrated that PIO also blocked Hcy-induced p38 mitogen-activated protein kinase phosphorylation. It inhibited the homocysteine elicited vascular smooth muscle cell migration independent of the PPAR-gamma receptor pathway, as depicted in Figure 4, point 4 [42]. A randomized control trial (RCT) depicted that PIO significantly decreased pulse wave velocity. Besides, it significantly improved aortic elasticity and reduced inflammation [43]. In 2006, another RCT demonstrated a reduction in pro-inflammatory cytokine levels (tumor necrosis factoralpha, the IL-6, and IL-1 beta) with PIO. Reduced vascular cell adhesion molecule 1 (V-CAM-1) and intercellular adhesion molecule 1 (I-CAM-1) with PIO indicated an improvement in endothelial function.
Decreased arterial stiffness was concluded as "AI" was reduced, and PWV decreased by 16.3%. However, significant changes were seen in blood pressure [44]. Another RCT in 2006 with 462 patients concluded after a one and a half year treatment period that pioglitazone delayed the advancement of CIMT [45]. The drug improves endothelial vasomotion, inhibits procoagulant processes, and has powerful antiproliferative and antioxidant effects [46]. Methylation of enzymes generally silences them. PIO reduces inducible nitric oxide synthase (iNOS) DNA methylation by downregulating the process and thus increases the activity of iNOS [47]. This has been represented in Figure 4, point 5. Overall, PIO modestly lowers blood pressure, reduces microalbuminuria, arterial stiffness, and reduces carotid wall thickening. It reduces the effects on the heart and decreases cardiac remodeling. Figure 4 depicting the mechanism of action of PIO against HHcy mediated arterial stiffness.
A meta-analysis involving 16,390 patients [48] and the PROactive (PROspective pioglitAzone Clinical Trial In Macrovascular Events) trial of PIO concluded a reduction in cardiovascular mortality and non-fatal myocardial infarction. Although hospitalization rates due to heart failure inflated significantly, the death rates for heart failure did not change [49]. The insulin resistance intervention after stroke (IRIS) trial that analyzed the effect of pioglitazone on future cardiovascular events also had comparable results. Some critics assert that the results showed a significant decline in cardiovascular consequences. Others debated the design and statistical analyses, and they evaluated the deductions to be flawed [49]. One discovery that everybody acknowledges is that PIO increases hospitalization incidence but not the mortality for congestive heart failure. Its impact on the heart remains inconclusive, and it is contraindicated in patients with New York Health Association Functional Classification (NYHA) class III or IV. Warnings exist for its use in any patient with heart failure [50]. Research has also shown an increased risk of fractures and weight gain as its most common side effects in high-risk patients. As shown below, Table 4 includes studies describing the protective role of pioglitazone by blocking homocysteine mediated arterial changes.  EPC-endothelial precursor cells, PKC-protein kinase C, VEGF-vascular endothelial growth factor, NADPH oxidase-nicotinamide adenine dinucleotide phosphate, PPAR-gamma-peroxisome proliferator-activated receptors, MAPK-mitogen-activated protein kinase, DM-diabetes mellitus, RCT-randomized control trial, iNOS-inducible nitric oxide synthase, ICAM 1-intercellular adhesion molecule 1, VCAM 1-vascular cell adhesion protein 1, PWV-pulse wave velocity, AI-augmentation index, CAD-coronary artery disease, PIO-pioglitazone, RA-rheumatoid arthritis Limitations PIO seems to have promising effects in alleviating the Hcy induced arterial changes and cardiac remodeling; however, its safety profile on the heart remains uncertain. Many authors seem to have conflicting remarks about the adverse effects of the drug. Moreover, we found no RCTs or case-control studies where patients with L.P. were treated with PIO. PIO has been used previously in patients with Lichen Planus. However, its effectiveness in the other subtypes is less known. Our systematic review will hopefully pave the way for more exploration of this topic. The box ( Figure 5), as shown below, shows questions that remain unanswered and need further investigation.

Conclusions
We aimed to assess if pioglitazone is the new generation drug against homocysteine induced changes in L.P and whether it can be used in routine management. We deduced that nutritional deficiency, genetic polymorphism, and disease severity of L.P increase homocysteine. High Hcy leads to intima-media damage and apoptosis of EPCs thus reducing neovascularization. It also decreases nitric oxide-mediated vasodilation. It further increases free radicals, VSMC proliferation, and GAG deposition. HHcy lowers the mitochondrial quantity in the heart; increases afterload leading to LV hypertrophy, dilation, & diastolic dysfunction. Thus, reducing myocardial performance overall. Impedance matching damages microcirculation.
PIO, an anti-apoptotic, enhances neovascularization, vasodilation and reverts all the above mechanisms induced by HHCY, in ways independent of its PPAR-gamma receptor pathway. Cardiac changes and incidence of fatal cardiac events are also reduced. Surveys claim it to be used for specific subtypes of lichen planus. Assessing the risk-benefit ratio, we should give PIO a fair trial in managing patients with lichen planus with no history of cardiac disease. Given early, it might prevent cardiovascular and inflammationrelated morbidity. Our research on this topic is crucial as these underlying processes, which are otherwise preventable, are often overlooked and intensify patient morbidity. Questions like when should the drug be initiated and in whom and whether it is safe, or is there a better drug to treat L.P. and mitigate the ill effects HHcy concurrently, remain unanswered. Our survey will hopefully pave the way for more exploration.

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.