Hypertension and aging are 2 major determinants of arterial stiffness and is also independent risk factor for COVID-19 mortality [1]. It is known that COVID-19 can cause early vascular aging and arterial stiffness. Meanwhile, dyslipidemia, diabetes, and obesity are regarded as risk factors for endothelial dysfunction and for worse outcomes in COVID-19 [2]. The author previously reported that interrelationship among lipid profile, arterial stiffness, and VSMC function was shown [3] and also described the arterial stiffness in chronic severe inflammation along with Takayasu arteritis [4]. The previous report demonstrated the persistent arterial stiffness, endothelial dysfunction, and high oxidative stress leading to cardiac performances in patients with COVID-19 even at 12 months after infection [5]. In this article, the author will review the current knowledge and trends of arterial stiffness in COVID-19 along with persistent inflammatory process in detail.

It is known that SARS-CoV-2 infection depends on ACE2 and TMPRSS2 as host cell factors [6]. The position paper recommended that the endothelial biomarkers and function such as flow-mediated vasodilation (FMD) should be assessed for their usefulness of the risk stratification in patients with COVID-19 [7]. The author has previously suggested that COVID-19 may be a systemic endothelial disease or a multi-organ disease including endothliitis, hypercoagulability, and cytokine storm especially in severe stage [8-10]. With respect to the SARS-CoV-2 Omicron variant, the author emphasized the importance of estimation of the endothelial function evaluated by FMD test because this strain exhibited more efficient transduction of ACE2-expressing target cells, leading to endothelial dysfunction [11]. The author also suggested the assessment of endothelial function for risk stratification, follow-up of convalescence, and prediction of autoimmune disease in patients with multisystem inflammatory syndrome in children (MIS-C) [12]. 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 [13]. The previous reports on the diseases of COVID-19, migraine, cardiovascular disease (CVD), chronic kidney disease (CKD), dyslipidemia, aging liver, NAFLD, hypertension, obesity, and chronic severe inflammation using FMD and NMD examinations have been provided [3,4 8-12, 14-27]. With regard to other endothelial biomarkers and FMD examinations in COVID-19, several reports have been provided [28-33].

It is thought that arterial stiffness reflecting underlying arteriosclerosis was an indicator of the aortic wall alterations [34]. It is known that blood pressure and age as chronic low grade inflammatory statuses are 2 main determinants of arterial stiffness [35] and is also independent risk factor for COVID-19 mortality [1]. It is known that COVID-19 can cause early vascular aging and arterial stiffness. Meanwhile, dyslipidemia, diabetes mellitus, and obesity are regarded as risk factors for endothelial dysfunction and for worse outcomes in COVID-19 [2]. The author previously described that interrelationship among lipid profile, arterial stiffness, and VSMC function was shown and lipid profiles may be respectively associated with structure and function changes of VSMC rather than endothelial dysfunction [3]. Regarding inflammation status, it has induced inflammatory cytokines (TNF-α and IL-1), oxidative stress such as ROS, and macrophage and neutrophils [36]. Many pro- or anti-inflammatory immune cells and cytokines are included in the inflammatory response mediated largely by ROS and mechanisms of hypertension [36]. It has been shown that decreased smooth muscle cell (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 [36, 37]. It is presumed that functional and structural arterial stiffness have been suggested in chronic severe inflammatory including inflammatory bowel disease (IBD) such as Crohn’s disease and ulcerative colitis, rheumatoid arthritis (RA), systemic lupus erythematosus (SLE), and systemic sclerosis (SSc) as previously described [4]. Similar to FMD study, the position statements recommended that arterial stiffness should be monitored in studies of COVID-19 outcome and therapy effects [7]. Previous reports suggested that the patients with COVID-19 appeared to be associated with an increased PWV reflecting arterial stiffness [38-40]. Rodilla et al. indicated that arterial stiffness estimated by admission pulse pressure>60 mm Hg and systolic BP<120 mm Hg contributes independently to all-cause mortality in patients with COVID-19 [1]. Regarding patients with multisystem inflammatory syndrome in children (MIS-C), they showed endothelial dysfunction and arterial stiffness demonstrating an association between endothelial dysfunction and left ventricular dysfunction [41]. Whereas the report indicated that the COVID-19-related cytokine storm has been presumed to the consequence of aging [42]. Covid-19 effects on ARTErial Stiffness and vascular AgeiNg (CARTESIAN) study is the first international multicenter study including carotid-femoral PWV, central BP, carotid ultrasound, and brachial FMD 6 and 12 months after COVID-19 infection to provide the interrelationship between COVID-19, severity, and early vascular ageing [43]. Based on the evidence, it is putative that in addition to the disorders of hypertension, age, cardiometabolic diseases, and chronic severe inflammation, the association of COVID-19 with arterial stiffness have been suggested.

It is suggested that acute inflammation leads to endothelial dysfunction in infection and/or vaccination studies [36]. In the salmonella typhi vaccination study, in vaccinated healthy individuals, the inverse correlation between FMD value and ADMA level was observed demonstrating that ADMA may be a link between endothelial dysfunction and inflammation [44]. Meanwhile, previous study provided that systemic inflammation decreased NO bioavailability leading to increase of vascular stiffness even in healthy subjects [45]. With respect to the chronic hepatitis C virus (HCV) infection, based on the evidence, the chronic HCV infection disease can contribute to not only liver damage but also systemic atherosclerosis condition as previously mentioned [20]. With regard to mRNA COVID-19 vaccination, the previous study by Terentes-Printzios et al. provided that the BNT162b2 mRNA COVID-19 vaccine induces a moderate and transient short-term endothelial dysfunction assessed by FMD and subsequently reverses in 48 h suggesting that these results may have implications for CV safety [46]. Meanwhile, arterial stiffness assessed by carotid-femoral PWV is not changed by vaccination [46]. It is plausible that the mRNA COVID-19 vaccination induces endothelial dysfunction and subsequently reverses suggesting that these findings may indicate the CV safety. In addition, arterial stiffness assessed by carotid-femoral PWV is not changed by vaccination indicating that decreased SMC relaxation as functional arterial stiffness and increased SMC migration and intima proliferation as structural arterial stiffness may not be affected.

It is known that following acute COVID-19 infection, a patient with physical and neuropsychiatric manifestations lasting longer than 12 weeks is considered as Long COVID, chronic COVID syndrome or post-acute sequelae of COVID-19 [47]. Jud et al. suggested that COVID-19 may affect arterial stiffness, capillary morphology, endothelial microparticles (EMP), parameters of arginine, kynurenine and homocysteine metabolism, and inflammation subsequently leading to COVID-19-related endothelial dysfunction and inflammatory vasculopathy in patients 6 months after SARS-CoV-2 infection [39]. Meanwhile, ADMA and CD31+/CD42b- EMP have been related to capillary changes in patient with systemic sclerosis [48]. Jud et al. indicated that post- COVID-19 patients displayed highly capillary ramifications, bushy capillaries and capillary loss suggesting that SARS-CoV-2 affected persistently microvasculature [39]. Natalello et al. studied microvasculature using nailfold capillaroscopy (NVC) to investigate the morphological alterations of microcirculation at the level of the capillaries of the nailfold bed and revealed that COVID-19 patients present microvascular abnormalities at NVC [49]. Gao et al. have reported a decreased FMD showing an inverse correlation between FMD value and TNF-α level for 327 days after recovery suggesting that the early onset of atherosclerosis along with long-term cardiovascular outcomes are warranted in COVID-19 survivors late after recovery [50]. Regarding the importance of inflammation for endothelial dysfunction, it is known that TNF-α level reduced the endothelium-dependent relaxation through altered NO production and/or induced ROS status [50]. They speculated that impaired FMD is caused by chronic low-grade inflammatory state due to the elevated TNF-α and hsCRP even 1 year after diagnosis [50]. It is known that the upstream cytokine IL-1β affects IL-6 levels subsequent leading to CRP [36]. Meanwhile, the previous report indicated that at least, partially, a relationship between arterial stiffness and TNFα has been recognized [36]. The report by Willems et al. provided that the endothelin-1 (ET-1) values reflecting microvascular dysfunction were significantly elevated in acute COVID-19 as compared to controls, and higher 3 months post-COVID-19 suggesting persistent endothelial activation [51]. Evidence showed the persistent endothelial cell activation, coagulation activation and inflammation at 3 months after COVID-19, raising that the new hypothesis of IL-1 family cytokines such as IL-18, induced arterial inflammation [51]. Regarding IL-18, it is expressed in human failing myocardium and carotid atherosclerotic plaques [36]. Fan et al. described that hypercoagulability, endotheliopathy, and inflammation approximating one year after recovery have been identified in some patients [52]. Lambadiari et al. showed increased PWV, central PP and SBP among COVID-19 patients indicating the increased arterial stiffness [53]. They emphasized that oxidative stress such as malondialdehyde (MDA) shows the main factor attributing to vascular dysfunction in COVID-19 patients exhibiting 10-fold higher compared to hypertensives and normal controls. In contrast to hypertensives, they suggested that the activation of the renin-angiotensin-aldosterone system as probable mechanisms may be more significant for the similar vascular and cardiac dysfunction observed in patients with COVID-19 [53]. Meanwhile, the increased plasma ACE2 level was associated with increased risk of major cardiovascular events in a global study [54]. It also predicts mortality in aortic stenosis and is associated with severe myocardial fibrosis [55]. Plasma ACE2 activity is raised in patient after COVID-19 infection and remains elevated to a median of 114 days post-infection [56]. Phetsouphanh et al. described that ACE2 activity was significantly higher in Long COVID (LC) and asymptomatic matched control (MC) compared to the human coronavirus (HCoV) group at months 3 and 4 after SARS-CoV-2 infection and decreased at 8 months in both groups [57]. At 12 months after COVID-19 infection, the results demonstrated the persistent arterial stiffness, endothelial dysfunction, and high oxidative stress leading to cardiac performances in patients with COVID-19 [5, 53]. Regarding young healthy adult report, Szeghy et al. described that six-month recovery from COVID-19 infection may be necessary to improve the arterial stiffness markers, thereby suggesting the possibly contributing to increased CV health [58]. With regard to reactive hyperaemia index (RHI) using post-occlusive reactive hyperaemia peripheral arterial tonometry (RH-PAT) assessing peripheral endothelial function, the previous study suggested that post- COVID syndrome (PCS) patients with sustained moderate to severe fatigue and exertion intolerance for more than six months after COVID-19 showed the decreased RHI value and alteration of endothelial biomarker such as ET-1 [59]. Regarding immunological dysfunction, Phetsouphanh et al. demonstrated that combinations (two, three, and four analytes) of the inflammatory mediators including IFN-β, PTX3, IFN-γ, IFN-λ2/3 and IL-6 have been associated with Long COVID with 78.5-81.6% accuracy. Results provided a persistent inflammatory response following mild-to-moderate acute COVID-19 infection suggesting the possibilities including sustained antigen, autoimmunity driven by antigenic cross-reactivity or a reflection of damage repair [54]. Based on the evidence, the persistent microvascular dysfunction has been demonstrated by microvascular changes (capillary changes and NVC features) along with ET-1 level after COVID-19 infection. It is putative that plasma ACE2 activity remains elevated after COVID-19 infection suggesting that relationship between COVID-19 and CV risks and events may be present. It is plausible that the sustained arterial stiffness, endothelial dysfunction, and high oxidative stress lead to cardiac manifestations after COVID-19 infection. The author suggests that the increased PWV change reflecting functional and/or structural arterial stiffness may be observed dependently on the severity and duration of inflammatory process in COVID-19 patients with sustained clinical manifestations and inflammatory biomarkers such as TNF-α levels.

It is plausible that the mRNA COVID-19 vaccination induces endothelial dysfunction and subsequently reverses suggesting that these findings may demonstrate the CV safety. Additionally, it is putative that functional and structural arterial stiffness may not be affected. The previous study indicated that arterial stiffness estimated by admission pulse pressure contributes independently to all-cause mortality in patients with COVID-19. Based on the evidence, the severe inflammation in COVID-19 may affect microvascular dysfunction demonstrated by microvascular changes such as capillary changes and NVC features along with ET-1 level and contribute to sustained inflammation after COVID-19 infection. It may be plausible that the sustained endothelial dysfunction, arterial stiffness, and high oxidative stress lead to cardiac manifestations after COVID-19 infection. Due to sustained inflammation and endothelial dysfunction, the author suggests that the increased PWV may be associated with the severity and duration of inflammation in COVID-19 patients with persistent clinical manifestations and inflammatory biomarkers such as TNF-α.

The severe inflammation in COVID-19 may affect microvascular dysfunction and contribute to persistent inflammation after COVID-19 infection. It is plausible that the sustained endothelial dysfunction, arterial stiffness, and high oxidative stress lead to cardiac manifestations after COVID-19 infection. The author indicates that in addition to impaired FMD, the increased PWV may be associated with the severity and duration of inflammatory process in COVID-19 patients with persistent clinical manifestations and inflammatory biomarkers, thereby suggesting that the early onset of atherosclerosis in non-CVD patients and CV outcomes in preexisting CVD patients after COVID-19 are warranted.

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