SYSTEMATIC REVIEW published: 24 September 2021 doi: 10.3389/fcvm.2021.719523 Valve Abnormalities, Risk Factors for Heart Valve Disease and Valve Replacement Surgery in Spondyloarthritis. A Systematic Review of the Literature Hye-Sang Park 1 , Ana Laiz 2,3 , Jesus Sanchez-Vega 4,5 , Petra Díaz del Campo 6 , Maria Auxiliadora Martín-Martínez 6 , Mercedes Guerra-Rodríguez 6 and Hector Corominas 1,2,3* 1 Rheumatology Department, Hospital Dos de Maig, Barcelona, Spain, 2 Rheumatology and Autoimmune Diseases Department, Hospital Universitari de la Santa Creu i Sant Pau, Barcelona, Spain, 3 Department of Medicine, Universitat Autònoma de Barcelona (UAB), Barcelona, Spain, 4 Cardiology Department, Hospital Universitari Bellvitge, Hospitalet de Llobregat, Spain, 5 Department of Medicine, Universitat de Barcelona (UB), Barcelona, Spain, 6 Research Unit, Spanish Society of Rheumatology, Madrid, Spain Objective: Evaluate the evidence on the abnormalities of the aortic root and heart Edited by: Natalia Lopez-Andres, valves, risk and prognostic factors for heart valve disease and valve replacement surgery NavarraBiomed, Spain in spondyloarthritis. Reviewed by: Methods: A systematic literature review was performed using Medline, EMBASE and Jiancheng Han, Capital Medical University, China Cochrane databases until July 2021. Prevalence, incidence, risk and prognostic factors Delia Reina, for heart valve disease; dimension, morphology, and pathological abnormalities of the Hospital of Sant Joan Despí Moisès Broggi, Spain valves were analyzed. Patient characteristics (younger age, history of cardiac disease or *Correspondence: longer disease duration) and period of realization were considered for the analysis. The Hector Corominas SIGN Approach was used for rating the quality of the evidence of the studies. hcorominas@santpau.cat Results: In total, 37 out of 555 studies were included. Overall, the level of evidence Specialty section: was low. The incidence of aortic insufficiency was 2.5–3.9‰. Hazard Ratio for aortic This article was submitted to insufficiency was 1.8–2.0. Relative risk for aortic valve replacement surgery in ankylosing Heart Valve Disease, a section of the journal spondylitis patients was 1.22–1.46. Odds ratio for aortic insufficiency was 1.07 for Frontiers in Cardiovascular Medicine age and 1.05 for disease duration. Mitral valve abnormalities described were mitral Received: 02 June 2021 valve prolapse, calcification, and thickening. Aortic valve abnormalities described were Accepted: 17 August 2021 calcification, thickening and an echocardiographic “subaortic bump.” Abnormalities of Published: 24 September 2021 the aorta described were thickening of the wall and aortic root dilatation. The most Citation: Park H-S, Laiz A, Sanchez-Vega J, common microscopic findings were scarring of the adventitia, lymphocytic infiltration, Díaz del Campo P, and intimal proliferation. Martín-Martínez MA, Guerra-Rodríguez M and Conclusions: A higher prevalence and risk of aortic valve disease is observed in patients Corominas H (2021) Valve with ankylosing spondylitis. Studies were heterogeneous and analysis was not adjusted Abnormalities, Risk Factors for Heart Valve Disease and Valve Replacement by potential confounders. Most studies did not define accurate outcomes and may have Surgery in Spondyloarthritis. A detected small effects as being statistically significant. Systematic Review of the Literature. Front. Cardiovasc. Med. 8:719523. Keywords: systematic (literature) review, HVD (heart valve disease), spondyloarthritis, echocardiography, cardiac doi: 10.3389/fcvm.2021.719523 image, epidemiology, psoriatic arthritis, valve (lesions, repair, replacement) Frontiers in Cardiovascular Medicine | www.frontiersin.org 1 September 2021 | Volume 8 | Article 719523 Park et al. Heart Valve Disease in Spondyloarthritis INTRODUCTION (1). Two experimental studies observed that enthesis tissue resident T cells were also present in the aortic root and Spondyloarthropathies are a complex group of rheumatic valve (15, 16) while being absent from the myocardium (15). diseases characterized by inflammation, erosion and new bone Overexpression of interleukin-23 in vivo resulted in a dense formations at peripheral and axial sites. The primary site infiltrate of T cells, macrophages and neutrophils in the of inflammation in spondyloarthropathies is thought to be attachment site of the aortic valve leading to the aortic wall the enthesis. as well as in the enthesis (15, 16). It can be hypothesized that Another distinctive trait of spondyloarthritis is its overlap inflammation of the valve attachment site may produce tissue with other autoimmune organ diseases such as psoriasis, uveitis degeneration that leads to aortic valve insufficiency. and inflammatory bowel disease. Textbooks and classical review This is the first systematic review of the literature to articles also consider the heart as another organ frequently evaluate heart valve disease and valve replacement surgery in involved in spondyloarthritis and associated diseases (1, 2). spondyloarthritis. The aim of this systematic review of the Cardiac conduction disorders and valvular heart diseases are literature is to evaluate the existing evidence on the abnormalities described as a specific cardiac manifestation of spondyloarthritis. of the aortic root and heart valves, as well as the risks and These statements are based on studies by Bergfeldt and prognostic factors for heart valve disease and valve replacement other contemporary investigators. Bergfeldt was not the surgery in spondyloarthritis. The objective of this study is to first investigator to describe cardiac manifestations in reappraise the presumption that heart valve disease is distinctive spondyloarthritis, but his work originated the concept of in patients with spondyloarthritis. “HLA-B27 associated cardiac disease”. These studies were cross-sectional or case series describing HLA-B27 positivity or sacroiliitis in a group of patients with atrioventricular blocks, MATERIALS AND METHODS pacemakers and/or aortic regurgitations. Other frequently A systematic review was conducted to identify all studies cited studies (3–8) were non adjusted case-control studies published up to December, 2020. This review was guided by involving small sample sizes that compared the proportion of the preferred reporting items for systematic review and meta- patients with valve disease in spondyloarthritis with control analysis (PRISMA) statement (Supplementary Material 1) (17). subjects. While the results may be interesting, the design and methods of the studies preclude the drawing of any associations between spondyloarthritis with atrioventricular blocks or Search Strategy A systematic search strategy was performed using the databases aortic regurgitations. Furthermore, several recent studies have of Pubmed (Medline), EMBASE (Elsevier), and the Cochrane found no significant association between spondyloarthritis Library (Wiley) by a librarian (MG). The search strategy and heart valve diseases (9, 10). Therefore, we find that the included MeSH terms and free text using different combinations evidence of heart valve disease in spondyloarthritis should be (Supplementary Material 2). The search was limited to studies systematically reappraised. published until July 2021 in English, French, Korean, and Cardiac complications have been a research topic of growing Spanish. Additional references were manually retrieved by interest over the last two decades. The frequent motto of research reviewing the references of the included studies. An update of into the cardiac complications associated with rheumatic diseases the systematic research was performed before the submission of is that chronic systemic inflammation may produce fibrosis in the manuscript. the myocardium and related structures (11). As publication in cardiac complications increased, a wide spectrum of cardiac complications has been described for systemic autoimmune Inclusion Criteria diseases including heart valve diseases and conduction disorders Studies were included if they had the characteristics (12, 13). Concurrently, cardiac complications spectrum in described below: spondyloarthritis has also widened to ventricular dysfunction, Population: Patients with a diagnosis of SpA and fulfilling myocarditis, pericarditis, heart failure or ischaemic heart disease classification criteria of ASAS, ESSG, Amor, modified New (14). But are some cardiac complications more relevant in York, ARA, Moll and Wright, or CASPAR criteria. Als, patients different rheumatic diseases? older than 18 years presenting grade II bilateral sacroiliitis or Just as Bergfeldt and other authors marked a milestone in grade III or superior if unilateral sacroiliitis by X-Ray; and/or the investigation of spondyloarthritis, we similarly suspect that HLAB27 positivity; that also fulfilled two or more clinical there may be a distinctive association between spondyloarthritis characteristics (peripheral arthritis, enthesitis, dactylitis, uveitis, with heart valve disease. The aortic valve attachment site and inflammatory back pain, psoriasis, inflammatory bowel disease, peripheral entheses are known to have histological similarities history of urethritis, or infective diarrhea) were included. Intervention: valve insufficiency, regurgitation, dilatation, valvular bump, stenosis, annuloplasty, or valve replacement Abbreviations: AS, Ankylosing Spondylitis; ReA, Reactive arthritis; PsA, Psoriatic confirmed by cardiac imaging [transthoracic echocardiogram Arthritis; uSpA, undifferentiated spondyloarthritis; SpA, spondyloarthritis; TTE, Transthoracic echocardiography; TOE, Transesophageal echocardiography; ASE, (TTE), transesophageal echocardiogram (TOE), or cardiac American Society of Echocardiography; EACVI, European Association of magnetic resonance (CMR)], post-mortem and/or surgical Cardiovascular Imaging. pathology or ICD codes. Frontiers in Cardiovascular Medicine | www.frontiersin.org 2 September 2021 | Volume 8 | Article 719523 Park et al. Heart Valve Disease in Spondyloarthritis Outcomes: Frequency measured by prevalence, prevalence SIGN grading system which implies high risk of confounding ratio, incidence proportion and rate; Risk and prognostic factors and non-causality. Seven studies were qualified as level 2+ measured by hazard ratio (HR), odds ratio (OR), risk ratio (RR), with low risk for confounding and moderate probability for and risk difference (RD). causality. Other eight studies were descriptive studies qualified Study design: Meta-analysis, systematic review of the literature, as level 3. Details for each of the 35 studies are shown case-control, cohort, cross sectional studies, and case series with in Table 1. more than five patients. Exclusion Criteria Frequency, Risk, and Prognostic Factors Studies carried out in patients younger than 18 years, adolescents for Heart Valve Disease and pregnant women; studies not suited to the PICO framework Prevalence in terms of the patient sample, intervention, comparison The prevalence of valve insufficiency and stenosis were group(s), outcome(s) or study design; studies carried out in described in patients with ankylosing spondylitis (AS), psoriatic animals or populations based in ethnic minorities; and abstracts, arthritis (PsA), Reiter’s Syndrome (ReS) and undifferentiated posters, narrative reviews, letters, editorials, and any type of spondyloarthritis (uSpA). The majority of studies retrieved were unpublished study. small scaled with the exception of some nationwide health databases. Also, some studies were carried out in specific groups: Article Selection patients without known cardiac disease, patients aged under A total of 555 citations were peer reviewed by two 60, or with more than 10 years of disease duration. Period rheumatologists (H.S.P and A.L) under the assessment of of execution and imaging technique were considered for the a senior methodologist (P.D and M.A.M). The reviewers synthesis of the data. independently performed two-stage screening (title/abstract and In the general AS population the reported prevalence of full-text screening), data extraction and risk of bias assessment. aortic insufficiency was 3.3–18% (19, 23, 28, 31, 32, 43, 44, 46). Some studies were not available mainly because of antiquity The prevalence of aortic stenosis was 0–4% (31, 43), of mitral (Supplementary Material 3). They were previously consulted insufficiency was 2–74% (31, 43), of mitral stenosis was 0–2% in two different national university library sources and the (19, 32), of tricuspid insufficiency was 0–94% (31, 43), and of documentary collection of the Spanish Society of Rheumatology. pulmonary insufficiency was 0–43% (31, 43). Only one study The original authors were also contacted if possible. EndNote X8 reported prevalence in relation to the degree of severity (31) software was used to manage the literature references. which was 4.8% for moderate aortic insufficiency, 0.53% for severe aortic insufficiency, 1% for moderate mitral insufficiency, Data Extraction and Data Analysis 3% for moderate tricuspid insufficiency, and 2% for moderate For data extraction, standardized forms from the Critical pulmonary insufficiency. Appraisal Tools 3.0. Platform (http://www.lecturacritica.com/ Three studies based on health insurance databases reported en/) was used. Risk of bias and quality of the evidence was rated a prevalence of 1.1–3.9% which is lower than those based on according to the Scottish Intercollegiate Guidelines Network small samples (4, 21, 34) probably due to the difference in the Approach (SIGN; http://www.sign.ac.uk/). Due to the small scale diagnostic method and severity of valve disease. One health of the majority of the studies and heterogeneity in the design, a insurance database reported the prevalence of aortic and mitral qualitative synthesis was carried out rather than a meta-analysis. valve disease by age intervals but did not distinguish insufficiency Some aspects were considered as critical to integrate the from stenosis (48). The prevalence of aortic valve disease was information. Specific characteristics of the population, such as 2.6% between 65 and 69 years, 6.7% between 70 and 74 years, younger age, history of cardiac disease or disease duration were 10.9% between 75 and 79 years and 17.1% in age 80 or older (48). contrasted for the results. A cardiologist specialized in cardiac The prevalence of mitral valve disease was 3.8% between 65 and imaging (J.S.V) was consulted for the interpretation of the data. 69 years, 9.8% between 70 and 74 years, 14.1% between 75 and 79 Valve and aorta involvement was accepted only if confirmed years and 19.2% in age 80 or older. by accurate techniques. Period of execution was also taken Four studies described the prevalence of valve disease in into account considering the evolution of imaging techniques groups of young AS patients aged under 60 (4, 7, 18, 23, 28). They throughout time. observed aortic insufficiency in 3.3–16%, mitral insufficiency in 0–32%, pulmonary insufficiency in 3% and tricuspid insufficiency RESULTS in 2–77.6%. Aortic insufficiency was mild in 9.1%, moderate in 6.8–9% (7, 18). Mitral insufficiency was mild in 20.5% and Of the original 555 studies, we selected 118 studies for further moderate in 9–11.4% (7, 18). Mitral valve stenosis was observed reading based on title and abstract screening. After excluding 83 in 1.5% (18). studies following full text reading, we included 37 studies in the Eight studies described the prevalence of valve disease in AS analysis, as presented in the PRISMA flow-chart (Figure 1). patients without known cardiac disease or symptoms (3, 8, 10, The reasons to exclude the remaining studies after reading 20, 35, 36, 38, 45). They observed aortic insufficiency in 0–34.5% the full text are provided in the Supplementary Material 4. and mitral insufficiency in 0–49%. Moderate aortic insufficiency Nineteen studies had a level of evidence 2- according to the was observed in 2.3–10.3%. Frontiers in Cardiovascular Medicine | www.frontiersin.org 3 September 2021 | Volume 8 | Article 719523 Park et al. Heart Valve Disease in Spondyloarthritis FIGURE 1 | PRISMA flow chart. In two studies based on AS patient groups with more than As for PsA the reported prevalence was wide ranged. A 10 years of disease duration, aortic insufficiency was observed study based on a nationwide population registry detected 0.4% in 8.3–10% (24, 37) of which moderate in 3% (24). Mitral prevalence of aortic insufficiency. In a study of small samples insufficiency was observed in 29% of which 2% was moderate and the prevalence of mild aortic insufficiency was 10%, mild mitral 1% severe (24). insufficiency was 16% and mild tricuspid insufficiency was Frontiers in Cardiovascular Medicine | www.frontiersin.org 4 September 2021 | Volume 8 | Article 719523 Park et al. Heart Valve Disease in Spondyloarthritis TABLE 1 | Characteristics of the studies included in the systematic literature review. References Study type Population Sample size Diagnosis Outcomes Quality (SIGN) Almasi et al. (18) Case control AS 67 vs. 40 TTE - Prevalence of mitral, aortic, 2- (excluding cardiac Criteria of ASE tricuspid and pulmonar valve disease, cardiovascular insufficiency or stenosis risk factors and other comorbidities) Alves et al. (19) Cross sectional AS 40 TTE - Prevalence of Aortic 3 Criteria of ASE & insufficiency ESC guidelines - Prevalence of mitral valve prolapse Arnason et al. (20) Case control AS (excluding unstable 29 vs. 13 TTE - Prevalence of aortic 2- angina or infarction <6 TOE Criteria of insufficiency months) expert cardiologist - Morphologic findings of the valves and the aorta - Dimension of the aorta Bengtsson et al. (21) Cohort AS uSpA 6,448 ICD - Incidence of AoI and valve 2+ PsA 5,190 replacement surgery 16,063 - HR for AoI Biesbroek et al. (22) Cross sectional AS (excluding if known 16 TTE - Morphologic findings of the 3 cardiac disease) CMR aorta Criteria aortic root - Dimension of the aorta dilatation if >4.1 cm Brewerton et al. (23) Case control AS 30 vs. 30 TTE - Prevalence of valve disease 2- if age under 65 years No - Morphologic findings of the (excluding criteria available valves and the aorta cardiorespiratory disease) Brunner et al. (24) Cross sectional AS 100 TTE - Prevalence of 3 if more than 15 years of Criteria of valvular aortic insufficiency disease duration disease according (excluding Pso, PsA to “The or ReA) Echo Manual” Bulkley and Roberts Case series AS 8 Necropsy - Pathology 3 (25) Cantero Hinojosa Case control AS 30 vs. 30 TTE - Morphologic findings of the 2- et al. (26) (excluding cardiovascular Criteria of valves disease) ASE guidelines - Dimension of the aorta Crowley et al. (3) Case control AS 59 vs. 44 TTE - Prevalence of valve disease 2- (excluding cardiac disease Criteria of or hypertension) ASE guidelines de Almeida et al. (27) Case control SpA 35 vs. 34 TTE - Prevalence of aortic 2- (excluding valve disease) Criteria of insufficiency ASE guidelines - Morphologic findings of the valves and the aorta - Dimension of the aorta Eddarami et al. (28) Cross sectional AS 94 TTE - Prevalence of aortic 3 insufficiency - Morphologic findings of the valves and the aorta - Dimension of the aorta Gonzalez Juanatey Case control PsA 50 vs. 50 TTE - Risk difference of valve 2+ et al. (9) (excluding cardiovascular Criteria of disease diseases and ASE guidelines - Dimension of the aorta cardiovascular risk factors) Gunes et al. (10) Case control AS 35 vs. 25 TTE - Morphologic findings of the 2- (excluding ischemic Criteria of valves and the aorta cardiac disease, ASE guidelines - Dimension of the aorta cardiovascular risk factors and other comorbidities) (Continued) Frontiers in Cardiovascular Medicine | www.frontiersin.org 5 September 2021 | Volume 8 | Article 719523 Park et al. Heart Valve Disease in Spondyloarthritis TABLE 1 | Continued References Study type Population Sample size Diagnosis Outcomes Quality (SIGN) Hannu et al. (29) Cohort ReA 18 TTE - Prevalence of valve disease 2- (excluding AS, PsA) Criteria of - Morphologic findings of ASE guidelines the aorta Kawasuji et al. (30) Case series AS 3 Necropsy - Pathology 3 - Surgical findings Klingberg et al. (31) Cohort AS 187 TTE - Measures of association with 2+ (excluding Pso, IBD, Criteria of clinical variables, OR pregnancy or dementia) ASE guidelines Klopf et al. (32) Case control AS 11 vs. 17 TTE - Morphologic findings of 2- Criteria the valves not available LaBresh et al. (33) Case control SpA 36 vs. 29 TTE - Morphologic findings of the 2- Criteria valves and the aorta not available - Dimension of the aorta Ljung et al. (34) Cohort AS 346 ICD - Prevalence of valve disease 2+ - Measures of association with clinical variables, OR Midtbø et al. (35) Case control AS 139 vs. 126 TTE - Prevalence of aortic and mitral 2+ (excluding cardiovascular Criteria according valve insufficiency disease) to EACVI and ASE guidelines Midtbø et al. (36) Case control AS 106 vs. 106 TTE - Prevalence of aortic and mitral 2+ (excluding cardiovascular Criteria according valve insufficiency disease) to EACI & - Aortic root diameter ASE guidelines O’Neill et al. (37) Case control AS 24 vs. 24 TTE Criteria not - Prevalence of valve disease 2- if more than 10 years of available - Morphologic findings of the disease duration valves and the aorta Park et al. (38) Case control AS 70 vs. 25 TTE - Morphologic findings of the 2- (excluding cardiac TOE valves disease) Criteria of - Dimension of the aorta and ASE guidelines the valves Paulus et al. (39) Case series ReA 3 Necropsy Surgery - Pathology 3 - Surgical findings Pines et al. (40) Case control PsA 25 vs. 32 TTE - Prevalence of valve disease 2- Criteria of - Morphologic findings of expert cardiologist the valves Qaiyumi et al. (41) Case series AS, ReA 7 Necropsy - Pathology 3 Roldan et al. (7) Case control - AS 44 vs. 30 TTE - Measures of association, risk 2- if age under 60 years TOE difference (excluding rheumatic Criteria of clinically - Morphologic findings of the fever, other SpA or iv significant valves and the aorta drug abuse) alteration - Dimension of the aorta and numerically the valves defined by investigators Siao et al. (42) Cohort AS 3,780 ICD - HR for valve disease 2+ - HR for valve replacement surgery Soroush et al. (43) Case control AS 50 vs. 40 TTE - Prevalence 2- Criteria - Measure of association, not available risk difference Sukenik et al. (44) Case control AS 40 vs. 40 TTE - Prevalence of valve disease 2- (excluding rheumatic fever Criteria or syphilis) not available (Continued) Frontiers in Cardiovascular Medicine | www.frontiersin.org 6 September 2021 | Volume 8 | Article 719523 Park et al. Heart Valve Disease in Spondyloarthritis TABLE 1 | Continued References Study type Population Sample size Diagnosis Outcomes Quality (SIGN) Sun et al. (45) Case control AS 20 vs. 20 TTE - Prevalence of valve disease 2- (excluding cardiac diseas) Criteria not available Szabo et al. (4) Cross sectional AS during 1996–2006 8,616 ICD - Prevalence 3 - Measures of association: standardized prevalence ratio and risk of valvular heart disease by sex and age Thomas et al. (46) Case control AS 23 TTE - Prevalence of valve disease 2- Criteria of - Morphologic findings of expert cardiologist the aorta Tucker et al. (47) Case control AS 35 vs. 20 TTE - Morphologic findings of the 2- (Excluding known aortic Criteria of valves and the aorta valve disease) ASE guidelines - Dimension of the aorta Ward (48) Cohort AS 19,254,030 ICD - Prevalence of Aortic 2+ (42,327 insufficiency and mitral vs. 19,211,703) insufficiency - Incidence valve replacement surgery - RR valve replacement surgery Yildirir et al. (8) Case control AS 88 vs. 31 TTE - Prevalence of valve disease 2- (excluding cardiac Criteria of - Measures of association, risk disease, cardiovascular ASE guidelines difference risk factors and other - Morphologic findings of the rheumatic diseases) valves and the aorta - Dimension of the aorta 10% (9). In another study no valve disease was observed at Risk of Heart Valve Disease in Patients With SpA all (40). When compared to a control population without AS, age and sex In a small study of ReA population mild aortic insufficiency adjusted HR for aortic insufficiency was significantly increased was seen in 5.6% and mild mitral insufficiency in 5.6% (29). in AS (HR 1.9, 95% IC 1.3–2.9), uSpA (HR 2.0, 95% IC 1.2–3.5), One study carried out in a mixed population of and PsA (HR 1.8, IC 1.4–2.4) (21). Similar results was observed spondyloarthritis (AS, PsA, ReA) reported a prevalence of in a nationwide population registry in patients with AS with a aortic insufficiency of 11.4%, which was mild in 8.5% and HR of 1.67 (95% CI 1.38–2.02, p < 0.001) when adjusted by moderate in 2.9%. Mild mitral insufficiency was reported in confounders (28). 8.6% (27). Standardized prevalence ratio for aortic valvular heart disease Risk or Prognostic Factors of SpA for Heart Valve was 1.59 (95% IC 1.31–1.91) and for non-aortic valvular heart Disease Manifestation disease was 1.58 (95% IC 1.43–1.74%) (4). Three studies presented data about association of clinical SpA Prevalence difference when compared to control groups features with valve disease presentation (7, 31, 34). Age and showed contrasting results. Two studies carried out in an AS disease duration showed association in all three studies. The OR group younger than 60 years without known cardiac disease for the duration of symptoms was 1.05 (31, 34) and the OR for showed significantly higher prevalence for aortic insufficiency age was 1.07 (34). Also male sex (OR 2.57), NSAID treatment (7, 8) and mitral insufficiency (8) in AS groups. (OR 0.37) (34), mSASSS (OR 1.02), history of anterior uveitis However, six other studies based on PsA and AS groups (OR 2.72) showed statistically significant association (19). No without cardiac disease showed no significant difference in valve statistically important association was found for: disease activity, disease compared to control groups (9, 18, 35, 36, 38, 43). severity, diabetes mellitus or smoking habits (31). Incidence Frequency and Risk for Valve Surgery Two studies reported on the incidence of aortic insufficiency for Prevalence and Incidence for Valve Surgery AS, PsA and uSpA based on a nationwide population registry The prevalence of valve replacement surgery in AS was reported (21, 48). The incidence proportion of aortic insufficiency was as 0.6–2.5% (21, 44). The prevalence of aortic valve surgery in PsA 3.8‰ for AS, 2.5‰ for undifferentiated SpA and 3.9‰ for PsA by a nationwide population registry was 0.4% (21). (21). The incidence rate (1,000 person-years at risk) of aortic The incidence of aortic valve replacement or repairing in AS insufficiency was 0.7 (0.4–0.9) for AS, 0.5 (0.2–0.7) for uSpA, and patients was 1.25 per 1,000 person-years in age between 65 and 0.7 (0.5–0.8) for PsA (21). 69, 1.83 per 1,000 person-years in age between 70 and 74, 2.61 Frontiers in Cardiovascular Medicine | www.frontiersin.org 7 September 2021 | Volume 8 | Article 719523 Park et al. Heart Valve Disease in Spondyloarthritis per 1,000 person-years in age between 75 and 79 and 2.79 per consists in a thickening of the aortomitral junction from the 1,000 person-year in age 80 or older (48). The incidence of mitral aortic cusps to the anterior mitral leaflet. valve surgery was 0.54 per 1,000 person-years in age between 65 Calcification of the aortic valve was seen in 8.57% of SpA and 69, 0.73 per 1,000 person-years in age between 70 and 74, patients without known cardiac disease (27). 0.72 per 1,000 person-years in age between 75 and 79 and 0.55 per Thickening of the aortic valve in the AS and SpA population 1,000 person-year in age 80 or older (48). The incidence increased without known cardiac disease was 10–20% by TTE (27, 33) and substantially over time in patients with AS but this increment also 41–77% by TOE (7, 38). Two studies showed higher prevalence occurred in the controls so the risk remained constant over time. of thickening in AS patients when compared to control groups (7, 38). The mean aortic valve thickness was 0.18–0.32 cm (7, 38). Risk for Valve Surgery Subaortic bump was studied by five studies. The range of RR of aortic valve repairing or replacement surgery in AS patients prevalence was broad. Two studies reported a prevalence of compared to the control population was significantly increased at 25–77% when measured with TOE (7, 20). Other three studies all ages (48). In a nationwide population registry the HR for valve described a lower prevalence of 4–31% measured by TTE (26, replacement surgery after developing valvular heart disease was 33, 47). When compared to a control group, subaortic bump was higher in AS patients compared to those without AS with a HR of more prevalent in AS patients (7, 20). 5.09 (95% CI 1.55–16.68, p = 0.007) (28). At ages between age 65–69 RR was 1.34 (95% CI 1.10–1.63), Pathology between age 70–74 was 1.22 (95% CI 1.05–1.43), between 75 Macroscopic findings were thickening of aortic valve cusps and 59 was 1.25 (95% CI 1.10–1.43) and 1.46 (95% CI 1.32– (25, 30, 39, 41). The most common microscopic findings were 1.63) in age 80 or older (48). RR of mitral valve surgery in AS scarring of the adventitia, lymphocytic infiltration and intimal patients compared to the control population was not statistically proliferation of valve cusps (25, 30, 39). significant in any age group (48). None of the studies retrieved described SpA disease associated risk or prognostic factors for Morphology, Dimension, and Pathology of valve repairment surgery. the Aorta Morphology Morphologic abnormalities of the aorta observed were Morphology and Pathology of the Aortic thickening of the aortic wall and aortic root dilatation. The and Mitral Valves thickening of the aortic wall was evaluated in two studies (7, 37). Morphology The thickening of the posterior aortic wall had a prevalence of A total of 12 studies reported morphologic abnormalities by 4.17% by TTE (37) and 61.4% by TOE (7), but only the latter cardiac imaging in mitral and aortic valves. Type of imaging provided the definition of thickening as >2.2 mm. Aortic root technique and period of realization were considered to synthesize dilatation prevalence was between 1.11 and 26.1% by TTE, 25% the information. by TOE and 0% by CMR (7, 8, 10, 22, 23, 28, 29, 46). Mitral valve abnormalities described were mitral valve Some reported lower prevalence between 2.99 and 4.5% (8, prolapse (8, 19, 32, 37, 40), mitral valve calcification (23, 27) and 10, 23, 29) and others reported higher prevalence between 12.5 thickening of the mitral valve (7, 8, 27, 28). Mitral valve prolapse and 26.1% (7, 22, 46). This wideness of range in prevalence was had a prevalence between 4.17 and 56%. In studies published in not explained by differences in population, year of publication, the 80’s the prevalence ranged from 10 to 36.4% in AS (19, 32) and cardiac imaging test or criteria used to diagnose dilatation. 56% in PsA (40). The other two studies published after the 90;s Disease duration showed correlation with aortic root dilatation showed much lower prevalence of 4.17–5.7% but were carried out (8) but disease severity and spine deformity showed no significant in AS without known cardiac disease (8, 37). When compared difference of aortic root dilatation (46). to a control group the differences in prevalence were irrelevant (8, 37). Dimension Mitral valve calcification was observed in two studies based Fourteen studies reported measurement data on aortic root on AS and SpA population without known valve disease with a diameter, ascending aorta diameter and aortic wall thickness. prevalence of 6.67–8.57%. Mean aortic root diameter in AS patients was 3.2–3.4 cm (8, Thickening of the mitral valve was observed in two studies 20, 36) and in PsA patients was 3 cm (9). Other studies described carried out on patients without known valve disease with a dimension at different sites of the aortic root: at the annulus prevalence of 2.22–22.86% (8, 27, 28) and on patients younger 1.6–3.1 cm (7, 26, 33, 38, 47), at the sinotubular junction 2.4–3.3 than 60 years (7) with a prevalence of 34%. The latter study (7, 12) and at the sinuses of Valsalva 3.4–3.7 cm (8, 26, 31). Some was carried out by TOE which is the most suitable imaging measured in mid cusp and above the cusp without specifying modality for mitral valve anatomy. Mitral valve thickening was the exact place of measurement even though most followed more prevalent in AS patients when compared to a control group American Society of Echocardiography guidelines. In mid cusp (7). The mean mitral valve thickening was 0.12–0.36 cm (7, 38). the diameter was 1.9–3.3 cm (26, 33, 47) and above the cusp Aortic valve abnormalities described were calcification, 2.0–3.4 cm (26, 33, 47). thickening and an echocardiographic “subaortic bump.” It is Case control studies also reported diameter in control groups a distinctive finding most described in spondyloarthritis that (7, 9, 20, 26, 33, 36, 38, 47). Only two studies concluded that the Frontiers in Cardiovascular Medicine | www.frontiersin.org 8 September 2021 | Volume 8 | Article 719523 Park et al. Heart Valve Disease in Spondyloarthritis difference was statistically significant with a mean difference of Results may be spurious or may not have detected association. 0.2 cm (7, 8). The diameter was similar for AS patients regarding Another important point to consider is the absence of clinically positivity for HLA-B27, presence of inflammatory activity or relevant outcome definition of valve disease and abnormality. severe sacroiliitis (26). One study found a trend for increasing The grade of severity, mechanism of valve disease and relevant age and larger aortic root dimension but no significant relation abnormalities considering age-related degeneration are very for the duration of disease symptoms (47). important information that most of the studies omitted. Some Ascending aorta diameters were reported in 5 studies. Mean studies found statistically significant differences in clinically diameters ranged from 2.4 to 4.7cm (10, 22, 27, 28, 38) in AS irrelevant results. Some other potentially interesting results are patients. Similar diameters were reported in ReA 2.7 cm and in difficult to interpret due to imprecise description of the results. PsA 2.9 cm (27). The evidence is weak due to the low quality of the majority of Aortic wall thickness at the anterior wall ranged from 0.24 to the studies. 0.25 cm (7, 20) and at the posterior wall from 0.27 to 0.38 cm This is the first systematic review of the literature (7, 20). regarding heart valve disease and aortic abnormalities in spondyloarthritis. A cardiac imaging specialist was consulted Pathology for strict interpretation of clinically relevant information. Some Macroscopic findings of the aorta were dilatation of the aortic limitations are to be considered. Meta-analysis was not possible root and ascending aorta (25, 30, 39, 41). Most common due to the heterogeneity in the design and clinical measures microscopic findings were scarring of the adventitia, lymphocytic employed. The incomplete retrieval of the bibliography may infiltration and intimal proliferation (25, 30). affect some of the results but the majority of the missing studies were old and probably of lower evidence quality. DISCUSSION CONCLUSIONS Prevalence and incidence of valve heart disease had a wide range of variability due to the small number of samples, heterogeneity The conclusion of our study is that further studies with larger in sample and outcome definitions. Some studies found a sample sizes, multivariate analysis, and a better definition of higher prevalence of valve disease when compared to control outcomes are needed. Data to assess valve and aortic diseases populations with low grade of evidence (7, 8) while others did in spondyloarthritis is weak and may be spurious because of not (9, 18, 35, 36, 38, 43). Key aspects in valve degeneration are possible confounders. age, mechanism of valve disease and grade of severity but very few studies provided these information (49, 50). Non-adjusted studies based on nationwide health databases DATA AVAILABILITY STATEMENT showed higher HR for aortic insufficiency and slightly higher The original contributions presented in the study are included RR for valve replacement surgery compared to the general in the article/Supplementary Material, further inquiries can be population (7, 8, 21, 48). According to some studies, age and directed to the corresponding author/s. disease duration showed association with valve disease with weak evidence for causality (7, 31, 34). These may be potential confounders but this possibility was not analyzed. AUTHOR CONTRIBUTIONS Morphologic abnormalities of the mitral and aortic valves were: calcification, thickening, subaortic bump and mitral valve MG-R performed the systematic literature search. HSP and AL prolapse (7, 20, 26, 33, 47). Subaortic bump, mitral and were involved in data screening, extraction, analysis, and drafted aortic valve thickening were more frequent in SpA patients the manuscript. PD, HC, and MM-M contributed substantially to when compared to control groups (7, 33, 38). Morphologic the study conceptions, design, and critical revision of the article. abnormalities of the aorta were aortic root dilatation and JS-V was consulted for interpretation of the extracted data as a thickening of the posterior aortic wall. The prevalence of these referent cardiac imaging expert. All authors read and approved findings was wide ranging. No difference was observed when the final manuscript. sorted by population, year of publication or type of cardiac imaging used. ACKNOWLEDGMENTS The diameter of the aortic root and ascending aorta were similar to control groups (7, 9, 20, 26, 33, 36, 38, 47). No We thank David Bridgewater and David Moore for the English significant difference was found when comparing mean aortic editing of the article. root diameter regarding different AS disease characteristics. Several critical points are raised for the interpretation of the SUPPLEMENTARY MATERIAL results. Very few studies were adjusted by potential confounders. Nationwide databases adjusted by sex and age but lacked clinical The Supplementary Material for this article can be found information to analyze potential confounders. Smaller studies online at: https://www.frontiersin.org/articles/10.3389/fcvm. lacked power or did not use adjusted models for design. 2021.719523/full#supplementary-material Frontiers in Cardiovascular Medicine | www.frontiersin.org 9 September 2021 | Volume 8 | Article 719523 Park et al. Heart Valve Disease in Spondyloarthritis REFERENCES 21. Bengtsson K, Forsblad-d’Elia H, Lie E, Klingberg E, Dehlin M, Exarchou S, et al. Risk of cardiac rhythm disturbances and aortic regurgitation in 1. Gensler LS. Axial spondyloarthritis: the heart of the matter. Clin Rheumatol. different spondyloarthritis subtypes in comparison with general population: (2015) 34:995–8. doi: 10.1007/s10067-015-2959-1 a register-based study from Sweden. Ann Rheum Dis. (2018) 77:541– 2. Hochberg MC. Rheumatology. Edinburgh: Mosby (2003). p. 947. 8. doi: 10.1136/annrheumdis-2017-212189 3. Crowley JJ, Donnelly SM, Tobin M, FitzGerald O, Bresnihan B, Maurer 22. Biesbroek PS, Heslinga SC, Konings TC, van der Horst-Bruinsma IE, Hofman BJ, et al. Doppler echocardiographic evidence of left ventricular diastolic M, van de Ven PM, et al. Insights into cardiac involvement in ankylosing dysfunction in ankylosing spondylitis. Am J Cardiol. (1993) 71:1337– spondylitis from cardiovascular magnetic resonance. Heart. (2017) 103:745– 40. doi: 10.1016/0002-9149(93)90551-M 52. doi: 10.1136/heartjnl-2016-310667 4. Szabo SM, Levy AR, Rao SR, Kirbach SE, Lacaille D, Cifaldi M, et al. 23. Brewerton DA, Gibson DG, Goddard DH, Jones TJ, Moore RB, Increased risk of cardiovascular and cerebrovascular diseases in individuals Pease CT, et al. The myocardium in ankylosing spondylitis. A with ankylosing spondylitis: a population-based study. Arthritis Rheum. clinical, echocardiographic, and histopathological study. Lancet. (1987) (2011) 63:3294–304. doi: 10.1002/art.30581 1:995–8. doi: 10.1016/S0140-6736(87)92268-9 5. Bergfeldt L. HLA-B27-associated cardiac disease. Ann Intern Med. (1997) 24. Brunner F, Kunz A, Weber U, Kissling R. Ankylosing spondylitis and heart 15:621–9. doi: 10.7326/0003-4819-127-8_Part_1-199710150-00007 abnormalities: do cardiac conduction disorders, valve regurgitation and 6. Bergfeldt L, Insulander P, Lindblom D, Möller E, Edhag O. An important diastolic dysfunction occur more often in male patients with diagnosed genetic risk factor for lone aortic regurgitation and severe conduction system ankylosing spondylitis for over 15 years than in the normal population? Clin abnormalities. Am J Med. (1988) 82:12–8. doi: 10.1016/0002-9343(88)90497-4 Rheumatol. (2006) 25:24–9. doi: 10.1007/s10067-005-1117-6 7. Roldan CA, Chavez J, Wiest PW, Qualls CR, Crawford MH. Aortic root 25. Bulkley BH, Roberts WC. Ankylosing spondylitis and aortic disease and valve disease associated with ankylosing spondylitis. J Am Coll regurgitation. Description of the characteristic cardiovascular Cardiol. (1998) 32:1397–404. doi: 10.1016/S0735-1097(98)00393-3 lesion from study of eight necropsy patients. Circulation. (1973) 8. Yildirir A, Aksoyek S, Calguneri M. Echocardiographic evidence of cardiac 48:1014–27. doi: 10.1161/01.CIR.48.5.1014 involvement in ankylosing spondylitis. Clin Rheumatol. (2002) 21:129– 26. Cantero Hinojosa J, Salvatierra Ossorio J, Raya Alvarez E, Miras Parra 34. doi: 10.1007/s10067-002-8271-x F, Salvatierra Ríos D. An echocardiographic study of the aortic root in 9. Gonzalez-Juanatey C, Amigo-Diaz E, Miranda-Filloy JA, Testa A, Revuelta J, ankylosing spondylitis. An Med Interna. (1997) 14:565–8. Garcia-Porrua C, et al. Lack of echocardiographic and Doppler abnormalities 27. de Almeida FA, Albanesi Filho FM, de Albuquerque EM, Magalhaes EC, de in psoriatic arthritis patients without clinically evident cardiovascular disease Menezes ME. Echocardiography in the evaluation of cardiac involvement in or classic atherosclerosis risk factors. Semin Arthritis Rheum. (2006) 35:333– seronegative spondylo-arthropathies. Medicina. (1995) 22:231–6. 9. doi: 10.1016/j.semarthrit.2005.12.002 28. Eddarami J, Azzouzi H, Ichchou L. Heart involvement in a moroccan 10. Gunes Y, Tuncer M, Guntekin U, Sahin M, Yazmalar L. Effects population with spondyloarthritis: a cross-sectional study. J Saudi H Assoc. of ankylosing spondylitis on the heart. Acta Cardiol. (2009) (2021) 3:191–6. doi: 10.37616/2212-5043.1258 64:385–92. doi: 10.2143/AC.64.3.2038026 29. Hannu T, Nieminen MS, Swan H, Leirisalo-Repo M. Cardiac findings of 11. Nurmohamed MT, Heslinga M, Kitas GD. Cardiovascular reactive arthritis: an observational echocardiographic study. Rheumatol Int. comorbidity in rheumatic diseases. Nat Rev Rheumatol. (2015) (2002) 21:169–72. doi: 10.1007/s00296-001-0154-y 11:693–704. doi: 10.1038/nrrheum.2015.112 30. Kawasuji M, Hetzer R, Oelert H, Stauch G, Borst HG. Aortic valve 12. Miner JJ, Kim AH. Cardiac manifestations of systemic lupus erythematosus. replacement and ascending aorta replacement in ankylosing spondylitis: Rheum Dis Clin North Am. (2014) 40:51–60. doi: 10.1016/j.rdc.2013.10.003 report of three surgical cases and review of the literature. Thorac Cardiovasc 13. Corrao S, Messina S, Pistone G, Calvo L, Scaglione R, Licata G, Surg. (1982) 30:310–4. doi: 10.1055/s-2007-1022414 et al. Heart involvement in rheumatoid arthritis: systematic review and 31. Klingberg E, Sveälv BG, Täng MS, Bech-Hanssen O, Forsblad-d’Elia H, meta-analysis. Int J Cardiol. (2013) 167:2031–8. doi: 10.1016/j.ijcard.2012. Bergfeldt L. Aortic regurgitation is common in ankylosing spondylitis: time 05.057 for routine echocardiography evaluation? Am J Med. (2015) 128:1244– 14. Liew JW, Ramiro S, Gensler LS. Cardiovascular morbidity and mortality in 50.e1. doi: 10.1016/j.amjmed.2015.04.032 ankylosing spondylitis and psoriatic arthritis. Best Pract Res Clin Rheumatol. 32. Klopf D, Maisch B, Raab B, Auer I, Sprotte G, Kochsiek K. Cardiac (2018) 32:369–89. doi: 10.1016/j.berh.2019.01.002 involvement in chronic polyarthritis and ankylosing spondylitis - an 15. Sherlock JP, Joyce-Shaikh B, Turner SP, Chao CC, Sathe M, Grein J, et al. IL- echocardiographic and immunological study. Eur H J. (1987) 8:95– 23 induces spondyloarthropathy by acting on ROR-γt+ CD3+CD4–CD8– 100. doi: 10.1093/eurheartj/8.suppl_J.95 entheseal resident T cells. Nat Med. (2012) 18:1069–76. doi: 10.1038/nm.2817 33. LaBresh KA, Lally EV, Sharma SC, Ho G Jr. Two-dimensional 16. Reinhardt A, Yevsa T, Worbs T, Lienenklaus S, Sandrock I, Oberdörfer L, et al. echocardiographic detection of preclinical aortic root abnormalities Interleukin-23–dependent γ/δ T cells produce interleukin-17 and accumulate in rheumatoid variant diseases. Am J Med. (1985) 78:908– in the enthesis, aortic valve, and ciliary body in mice. Arthritis Rheumatol. 12. doi: 10.1016/0002-9343(85)90211-6 (2016) 68:2476–86. doi: 10.1002/art.39732 34. Ljung L, Sundström B, Smeds J, Ketonen M, Forsblad-d’Elia H. Patterns 17. Liberati A, Altman DG, Tetzlaff J, Mulrow C, GÃtzsche PC, Ioannidis JPA, of comorbidity and disease characteristics among patients with ankylosing et al. The PRISMA statement for reporting systematic reviews and meta- spondylitis—a cross-sectional study. Clin Rheumatol. (2018) 37:647– analyses of studies that evaluate healthcare interventions: explanation and 53. doi: 10.1007/s10067-017-3894-0 elaboration. BMJ. (2009) 339:b2700. doi: 10.1136/bmj.b2700 35. Midtbø H, Gerdts E, Berg IJ, Rollefstad S, Jonsson R, Semb AG. Ankylosing 18. Almasi S, Farahani B, Samiei N, Rezaei Y, Mahmoodi H, Qorbani spondylitis is associated with increased prevalence of left ventricular M, et al. Echocardiographic and electrocardiographic findings in hypertrophy. J Rheumatol. (2018) 45:1249–55. doi: 10.3899/jrheum.171124 patients with ankylosing spondylitis without cardiovascular risk 36. Midtbø H, Semb AG, Matre K, Rollefstad S, Berg IJ, Gerdts E. Left ventricular factors. J Teh Uni H Center. (2020) 15:43–9. doi: 10.18502/jthc.v15 systolic myocardial function in ankylosing spondylitis. Arthr Care Res. (2019) i2.4182 71:1276–83. doi: 10.1002/acr.23765 19. Alves MG, Espirito-Santo J, Queiroz MV, Madeira H, Macieira-Coelho E. 37. O’Neill TW, King G, Graham IM, Molony J, Bresnihan B. Echocardiographic Cardiac alterations in ankylosing spondylitis. Angiology. (1988) 39:567– abnormalities in ankylosing spondylitis. Ann Rheum Dis. (1992) 51:652– 71. doi: 10.1177/000331978803900702 4. doi: 10.1136/ard.51.5.652 20. Arnason JA, Patel AK, Rahko PS, Sundstrom WR. Transthoracic and 38. Park SH, Sohn IS, Joe BH, Hwang HJ, Park CB, Jin ES, et al. transesophageal echocardiographic evaluation of the aortic root and Early cardiac valvular changes in ankylosing spondylitis: a subvalvular structures in ankylosing spondylitis. J Rheumatol. (1996) transesophageal echocardiography study. J Cardiovasc Ultrasound. (2012) 23:120–3. 20:30–6. doi: 10.4250/jcu.2012.20.1.30 Frontiers in Cardiovascular Medicine | www.frontiersin.org 10 September 2021 | Volume 8 | Article 719523 Park et al. Heart Valve Disease in Spondyloarthritis 39. Paulus HE, Pearson CM, Pitts W Jr. Aortic insufficiency in five patients with 48. Ward MM. Lifetime risks of valvular heart disease and pacemaker Reiter’s syndrome. A detailed clinical and pathologic study. Am J Med. (1972) use in patients with ankylosing spondylitis. J Am Heart Assoc. (2018) 53:464–72. doi: 10.1016/0002-9343(72)90142-8 7:e010016. doi: 10.1161/JAHA.118.010016 40. Pines A, Ehrenfeld M, Fisman EZ, Kaplinsky N, Samra Y, Ronnen 49. Iung B, Vahanian A. Epidemiology of valvular heart disease in adults. Nat Rev M, et al. Mitral valve prolapse in psoriatic arthritis. Arch Intern Cardiol. (2011) 8:162–72. doi: 10.1038/nrcardio.2010.202 Med. (1986) 146:1371–3. doi: 10.1001/archinte.1986.003601901 50. Coffey S, Cairns BJ, Iung B. The modern epidemiology of heart valve disease. 49021 Heart. (2016) 102:75–85. doi: 10.1136/heartjnl-2014-307020 41. Qaiyumi S, Hassan ZU, Toone E. Seronegative spondyloarthropathies in lone aortic insufficiency. Arch Intern Med. (1985) 145:822– Conflict of Interest: AL has received speaker fees/honoraria from Abbvie, Lilly, 4. doi: 10.1001/archinte.1985.00360050066010 Novartis, Pfizer, and UCB. HC has received speaker fees/honoraria from BMS, 42. Siao WZ, Liu CH, Wang YH, Wei JC, Jong GP. Increased risk of valvular Gebro, MSD, Lilly, Novartis, Pfizer, Roche, Sanofi, and UCB and has participated heart disease in patients with ankylosing spondylitis: a nationwide population- in consulting for Abbvie, Amgen, Biogen, Celgene, Gilead, Kern, Pfizer, and Sanofi. based longitudinal cohort study. Ther Adv Musculoskel Dis. (2021) 13:1– 10. doi: 10.1177/1759720X211021676 The remaining authors declare that the research was conducted in the absence of 43. Soroush M, Mominzadeh M, Ghelich Y, Soroosh S, Pasha MA. Investigation any commercial or financial relationships that could be construed as a potential of cardiac complications and their incidence in patients with ankylosing conflict of interest. spondylitis. Med Arch. (2016) 70:35–8. doi: 10.5455/medarh.2016.70.35-38 44. Sukenik S, Pras A, Buskila D, Katz A, Snir Y, Horowitz J. Cardiovascular Publisher’s Note: All claims expressed in this article are solely those of the authors manifestations of ankylosing spondylitis. Clin Rheumatol. (1987) 6:588– and do not necessarily represent those of their affiliated organizations, or those of 92. doi: 10.1007/BF02330598 the publisher, the editors and the reviewers. Any product that may be evaluated in 45. Sun JP, Khan MA, Farhat AZ, Bahler RC. Alterations in cardiac diastolic this article, or claim that may be made by its manufacturer, is not guaranteed or function in patients with ankylosing spondylitis. Int J Cardiol. (1992) 37:65– 72. doi: 10.1016/0167-5273(92)90133-N endorsed by the publisher. 46. Thomas D, Hill W, Geddes R, Sheppard M, Arnold J, Fritzsche J, et al. Early detection of aortic dilatation in ankylosing Copyright © 2021 Park, Laiz, Sanchez-Vega, Díaz del Campo, Martín-Martínez, spondylitis using echocardiography. Aust N Z J Med. (1982) Guerra-Rodríguez and Corominas. This is an open-access article distributed under 12:10–3. doi: 10.1111/j.1445-5994.1982.tb02416.x the terms of the Creative Commons Attribution License (CC BY). The use, 47. Tucker CR, Fowles RE, Calin A, Popp RL. Aortitis in ankylosing distribution or reproduction in other forums is permitted, provided the original spondylitis: early detection of aortic root abnormalities with author(s) and the copyright owner(s) are credited and that the original publication two dimensional echocardiography. Am J Cardiol. (1982) in this journal is cited, in accordance with accepted academic practice. No use, 49:680–6. doi: 10.1016/0002-9149(82)91946-4 distribution or reproduction is permitted which does not comply with these terms. Frontiers in Cardiovascular Medicine | www.frontiersin.org 11 September 2021 | Volume 8 | Article 719523