Endothelial dysfunction is the first step in the development of atherosclerosis. It is well known that association between cardiovascular disease (CVD) and CVD risk factors and endothelial dysfunction has been provided. Meanwhile the risk of CV events has increased in patients with chronic severe inflammation including inflammatory bowel disease (IBD) such as Crohn’s disease and ulcerative colitis, rheumatoid arthritis (RA), systemic lupus erythematosus (SLE), and systemic sclerosis (SSc) [1]. Whereas previous reports provided that accelerated atheromatosis and arterial stiffening in patients with primary systemic vasculitides (PSV) such as Takayasu arteritis, Kawasaki disease, and Bechet’s disease have been shown [2]. In this article, the author will review current knowledge and trends of arterial stiffness in chronic severe inflammation along with Takayasu arteritis in detail. 

Endothelial Dysfunction in Atherosclerosis

Endothelial dysfunction is the first step in the development of atherosclerosis. It is well known that association between cardiovascular disease (CVD) and CVD risk factors and endothelial dysfunction has been provided. Meanwhile the risk of CV events have increased in patients with chronic severe inflammation including IBD, RA, SLE, and SSc [1]. It has been proposed that flow-mediated vasodilation (FMD) and nitroglycerin-mediated vasodilation (NMD) in the brachial artery are potential procedures for assessing vascular endothelial and vascular smooth muscle cell (VSMC) function in atherosclerosis status [3]. The previous reports on the diseases of migraine, COVID-19, cardiovascular disease (CVD), chronic kidney disease (CKD), dyslipidemia, aging liver, NAFLD, hypertension, and obesity using FMD and NMD tests have been provided [4-23].

Functional and Structural Arterial Stiffness in Chronic Severe Inflammation

It is known that increased arterial stiffness is a well-recognized CV risk factor independent of blood pressure [1]. Zanoli et al. described immune mediated mechanisms that the excessive inflammation can lead to atherosclerosis and arterial stiffness [1]. Although cardiometabolic diseases and risk factors have been associated with arterial stiffness, however, it is known that blood pressure and age are 2 main determinants of arterial stiffness [24]. It is known that vascular inflammation involves many cell types, multiple mediators such as cytokines, chemokines, and ROS. Meanwhile, many receptors and complex pro-inflammatory signaling pathways including NF-κB, mitogen-activated protein kinases, canonical wingless-related integration site (WNT)/β-catenin and STAT3 have been shown. The previous report indicated the association between increased arterial dysfunction and the severity of inflammatory in chronic inflammatory diseases such as RA and IBD [25]. It is suggested that chronic severe inflammation including SLE, SSc, RA, and IBD leads to functional arterial stiffness such as decreased smooth muscle cell (SMC) relaxation and structural arterial stiffness such as increased SMC migration and intima proliferation [1]. It has been shown that decreased SMC relaxation leads to functional arterial stiffness status whereas increased SMC migration and intima proliferation, extracellular matrix stiffness, uncoiled stiff collagen, and elastin degradation can result in structural arterial stiffness state [26]. They described that inflammation mediated immune mechanism can lead to atherosclerosis and arterial stiffness. While it has been noted that PWV reflecting arterial stiffness is increased by adverse structural and functional alterations including an impaired endothelial-dependent dilation, medial hypertrophy, and elevated smooth muscle tone in the vessel wall [27]. In addition to endothelial dysfunction, it is putative that functional arterial stiffness such as decreased SMC relaxation and structural arterial stiffness such as increased SMC migration and intima proliferation mediated by immune mechanism have been suggested in chronic severe inflammatory such as RA, SLE, SSc, and IBD.

Association between atherosclerosis surrogate makers and chronic severe inflammatory diseases

The association between the risk of CV events and chronic severe inflammation including SSc, RA, SLE, and IBD has been also observed [1]. Evidence provided that endothelial dysfunction, accelerated atheromatosis (atherosclerosis), and accelerated arterial stiffness have been reported in patients with chronic severe inflammatory diseases [1]. Several reports provided the studies of atherosclerosis surrogate markers including FMD, IMT, and PWV demonstrating the reduced FMD, increased carotid IMT, and increased arterial stiffness in patients with chronic severe inflammatory disease [28-30]. Wang et al. [28] have reported the decreased FMD in patients with SLE using a meta-analysis, whereas increased carotid IMT in patient with RA has been shown [29]. Though IBD patients seem to have a lower prevalence of traditional CV risk factors, increased risk of coronary heart disease (CHD) and cerebrovascular disease have been observed suggesting chronic inflammation and consequent arterial stiffness as a causal factor [31]. Increased PWV studies have been reported in patients with SLE, BD, and SSc [30-32]. It is known that chronic severe inflammation status leads to functional and structural arterial stiffening. Furthermore, disease duration is related inversely to FMD value in patients with SLE, positively to carotid IMT value in patients with RA, and positively to PWV in patients with SLE and IBD [28-31]. Additionally, it is known that chronic autoimmune thyroiditis, so called Hashimoto’s Thyroiditis (HT) is characterized by positive antithyroid antibodies [33]. Some studies in Hashimoto’s Thyroiditis patients with euthyroidism showed the decreased FMD and the increased carotid IMT, suggesting the relationship between thyroid autoimmunity and inflammation [34, 35]. Evidence provided that endothelial dysfunction, accelerated atheromatosis and arterial stiffness have been reported in patients with chronic severe inflammatory diseases. Based on evidence, it is putative that the decreased FMD, increased IMT, and raised PWV were shown in patients with chronic severe inflammatory diseases such as RA, SLE, SSc, and IBD suggesting that association between surrogate markers and the duration of inflammation may be observed.

Arterial Stiffness in Primary Systemic Vasculitides

Meanwhile, primary systemic vasculitides (PSV) including small, medium, and large vessel PSV, due to the response to local vessel wall inflammation, the progression of both atherosclerosis and arteriosclerosis status have been indicated [1]. It is known that the mechanisms of vascular wall inflammation included endothelial dysfunction, autoantibody-mediated or -associated vascular damage, immune complex formation and complement activation [36]. Evidence showed accelerated atheromatosis (atherosclerosis) and arterial stiffening in patients with PSV including large vessel such as TA, middle vessel such as Kawasaki Disease (KD), and variable size such as Bechet’s disease [2]. Regarding middle vessel PSV, KD, the previous study indicated that the fever duration, cTnI, NT-proBNP, and ESR were correlated with coronary artery diameter [37]. With respect to comparison between KD and multisystem inflammatory syndrome in children (MIS-C), it is putative that the different pathogenesis between KD and MIS-C that IL-17 drives but not MIS-C hyperinflammation has been provided [8]. With respect to the large vessel PSV, TA, the author previously described a few case reports of Takayasu arteritis (TA) and a review article of TA focusing on common carotid artery (CCA) features such as macaroni sign on gray-scale ultrasonography (US) and peak systolic velocity (PSV) on CCA by pulsed and color Doppler US [38-40]. US findings in the 32-year-old female provided that inflammation of TA itself due to duration and severity of inflammation caused arteriosclerosis resulting in deterioration of the disease to the latte phase as previously mentioned [38, 40]. The author also showed the association between inflammatory activity and peak systolic velocity on CCA using followed up by Doppler US suggesting that peak systolic velocity may reflect inflammatory activity and process in TA itself [39, 40]. The recent report indicated that carotid wall vasculization on contrast enhanced US is related to high sensitivity and specificity for inflammatory activity in TA patients [41]. Similar to previous reports [39, 40], the study showed that baPWV is an independent indicator of activity in TA suggesting that this result may correlate with systemic inflammation [42]. The previous study demonstrated that inflammation in Takayasu arteritis may cause systemic atherosclerosis and arteriosclerosis. Evidence showed accelerated atheromatosis and arterial stiffening in patients with PSV such as Takayasu arteritis, Kawasaki disease, and Behcet’s disease. It is putative that inflammatory activity in TA may be assessed using followed up by Doppler US, CEUS, and baPWV.

In addition to endothelial dysfunction, it is presumed that functional arterial stiffness such as decreased SMC relaxation and structural arterial stiffness such as increased SMC migration and intima proliferation mediated by immune mechanism have been suggested in chronic severe inflammatory such as RA, SLE, SSc, and IBD. Evidence provided that endothelial dysfunction, accelerated atheromatosis and arterial stiffness have been reported in patients with chronic severe inflammatory diseases. Based on evidence, it is putative that the decreased FMD, increased IMT, and raised PWV were shown in patients with chronic severe inflammatory diseases demonstrating that the association of surrogate markers such as FMD, IMT, and PWV with the duration of inflammation has been suggested. The previous study demonstrated that inflammation in Takayasu arteritis may cause systemic atherosclerosis and arteriosclerosis. Evidence showed accelerated atheromatosis and arterial stiffening in patients with PSV such as Takayasu arteritis, Kawasaki disease, and Behcet’s disease. It is plausible that inflammatory activity in Takayasu arteritis can be estimated using followed up by Doppler US, CEUS, and baPWV suggesting that these findings may be attributed to therapeutic strategy and determination of therapy effect.

Based on evidence, the associations between surrogate markers and the duration of inflammation have been suggested in patients with chronic severe inflammatory diseases. It is plausible that evidence showed accelerated atheromatosis and arterial stiffening in patients with primary systemic vasculitides such as Takayasu arteritis, Kawasaki disease, and Behcet’s disease. The study demonstrated that inflammation in Takayasu arteritis may cause systemic atherosclerosis and arteriosclerosis. Inflammatory activity in Takayasu arteritis may be estimated using followed up by Doppler ultrasonography, contrast-enhanced ultrasonography, and brachial-ankle pulse wave velocity suggesting that these findings may at least in part contribute to therapeutic strategy and determination of therapy effect.

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