Introduction
Valvular heart disease remains an important cause of cardiovascular morbidity and mortality. Degenerative and functional disease predominates in aging populations in high-income countries, whereas rheumatic heart disease (RHD) remains a major cause of valve dysfunction in many low- and middle-income regions [1]. Mitral valve function depends on the coordinated action of the leaflets, annulus, chordae, and cardiac chambers, as well as interactions between endothelial signaling, extracellular-matrix turnover, inflammation, and mechanical stress [2].
In RHD, cross-reactive immune responses following group A streptococcal infection initiate valvulitis. Repeated injury leads to leaflet fibrosis, commissural fusion, and chordal thickening and shortening [3]. Early regurgitation may progress to mitral stenosis (MS) or mixed disease, consistent with the spectrum described by the World Heart Federation criteria [4].
This clinicopathological sequence is well established, although the contribution of individual molecular pathways remains uncertain. Systemic lupus erythematosus (SLE) and antiphospholipid syndrome (APS) more commonly involve leaflet thickening, Libman–Sacks vegetations, and mitral regurgitation (MR) [5–7]. Antiphospholipid antibodies (aPL) are associated with valvular abnormalities and thromboembolic complications, which may occur despite modest valve dysfunction [5].
Endothelial activation and immunothrombosis are plausible contributors, but their role in human valvular lesion formation is not fully established. In rheumatoid arthritis (RA), population studies indicate an increased incidence of MR, and cardiac magnetic resonance (CMR) studies show subclinical myocardial abnormalities [8, 9]. Neither a consistent primary leaflet phenotype nor a causal link between these myocardial findings and MR has been demonstrated.
Previous studies have addressed cardiac involvement in systemic sclerosis [10], heart failure in autoimmune rheumatic diseases [11], and cardiac dysfunction in mixed connective tissue disease [12]. These contributions provide broader cardiovascular context but do not directly compare mitral valve phenotypes and their underlying mechanisms across RHD, SLE/APS, and RA.
This review examines these conditions because the evidence for their association with mitral valve disease differs substantially. We distinguish established rheumatic remodeling from incompletely validated immunothrombotic mechanisms in SLE/APS and hypotheses linking RA to MR. Clinical and imaging findings are assessed separately from evidence of causality.
The aim is to clarify how these distinctions inform imaging, thromboembolic risk assessment, and management, while identifying where disease-specific interpretations or treatments lack sufficient support.
Review methodology
Information sources and search strategy
This structured narrative review was prepared with reference to the Scale for the Assessment of Narrative Review Articles (SANRA) [13]. The literature search addressed the epidemiology, mechanisms, clinical phenotypes, imaging, and management of mitral valve disease in RHD, SLE, APS, and RA.
PubMed/MEDLINE, Scopus, and Web of Science Core Collection were searched for publications from 1 January 2015 to 10 October 2026. Earlier landmark publications were considered when they provided foundational clinical, pathological, or mechanistic evidence not adequately superseded by more recent studies. Medical Subject Headings (MeSH), where applicable, and free-text terms were considered in PubMed/MEDLINE.
Search expressions were adapted to the indexing systems and technical requirements of Scopus and Web of Science.
The search combined two conceptual blocks: disease-related terms and mitral valve-related terms. Terms within each block were linked using OR, and the two blocks were combined using AND. The core expression was: (“rheumatic heart disease” OR “rheumatic fever” OR “systemic lupus erythematosus” OR “antiphospholipid syndrome” OR “rheumatoid arthritis”) AND (“mitral valve” OR “mitral regurgitation” OR “mitral stenosis” OR “Libman-Sacks endocarditis” OR “nonbacterial thrombotic endocarditis” OR “valvulopathy”).
Additional terms covering endothelial activation, immune-mediated fibrosis, valvular endothelial and interstitial cells, complement activation, neutrophil extracellular traps, immunothrombosis, echocardiography, cardiac magnetic resonance, computed tomography, and valve intervention were considered to identify relevant mechanistic, diagnostic, and therapeutic studies.
In Web of Science, four disease-specific searches combined each principal disease term with “mitral valve” in the Topic field using AND. These searches identified 341 records for RHD, 49 for SLE, 57 for APS, and 18 for RA, yielding 465 records before deduplication.
Reference lists of relevant original studies, systematic reviews, meta-analyses, guidelines, and key narrative reviews were also examined to identify additional publications. The search supported an integrative narrative synthesis rather than a formal systematic review.
Eligibility criteria and study selection
Eligible publications were English-language, peer-reviewed clinical and mechanistic studies, systematic reviews, meta-analyses, consensus documents, and guidelines addressing mitral valve involvement in RHD, SLE, APS, or RA. Experimental studies were included when directly relevant to the proposed mechanisms, and narrative reviews, case reports, and small series were considered when they provided relevant background or described uncommon valve phenotypes. Publications unrelated to the review objectives, duplicates without additional findings, non-English-language reports, conference abstracts with insufficient methodological detail, editorials, and non-peer-reviewed sources were excluded.
The searches identified 2,579 records: 1,610 from PubMed/MEDLINE, 504 from Scopus, and 465 from Web of Science. Preliminary deduplication using digital object identifiers and normalized titles removed 650 duplicates, leaving 1,929 records for eligibility assessment.
Initial automated screening of titles and available abstracts identified potentially relevant records for further evaluation. Subsequent selection was based on relevance to mitral valve disease, methodological characteristics, and the directness of the supporting evidence. Together with additional publications identified from reference lists, 44 scientific and clinical publications were retained for the narrative synthesis.
The SANRA methodological reference [13] brought the bibliography to 45 references.
Evidence synthesis, hierarchy, and interpretation
Evidence was synthesized narratively because study designs, populations, definitions of valve involvement, imaging protocols, and clinical outcomes varied substantially. No meta-analysis was performed. The strength of mechanistic evidence was assessed qualitatively according to its directness, consistency, disease specificity, methodological quality, and clinical relevance.
Contemporary guidelines, systematic reviews, meta-analyses, and large longitudinal cohorts were given greatest weight when interpreting epidemiology, clinical phenotypes, and management. Mechanistic assessment prioritized disease-specific human imaging, pathological, and valve-tissue studies. Retrospective and cross-sectional studies supported associations and phenotype characterization, whereas experimental studies provided evidence of biological plausibility without establishing human valve-specific causality.
Case reports and small series illustrated uncommon presentations but were not used to establish prevalence, causality, treatment efficacy, or the overall evidence category.
Clinical phenotypes, mechanistic causality, and therapeutic effects were assessed separately. A documented valve lesion or epidemiological association was not considered proof of its proposed mechanism, and findings from circulating cells, experimental models, or non-mitral tissue were not automatically extrapolated to human mitral valve injury. Classification depended on the quality and directness of evidence supporting each claim, rather than the number of studies reporting related findings.
Mechanistic pathways were classified as established, supported but incompletely validated, or hypothesis-generating. Established pathways required convergent disease-specific human clinical, imaging, pathological, or tissue evidence supporting the clinicopathological sequence; individual molecular intermediates were not considered established without direct valve-specific validation. Supported but incompletely validated pathways had consistent observational, serological, imaging, or mechanistic support but lacked complete disease- or valve-specific causal validation.
Hypothesis-generating pathways relied mainly on epidemiological associations, indirect imaging findings, or systemic and experimental evidence without direct prospective demonstration of the proposed causal relationship. These categories describe mechanistic certainty within a qualitative narrative framework and do not constitute a formal GRADE assessment or risk-of-bias evaluation.
Interpretation also accounted for differences between disease groups. RHD evidence included population screening, longitudinal observations, human valve-tissue studies, and intervention data. SLE/APS evidence came mainly from selected clinical and echocardiographic cohorts, serological associations, and studies of systemic immunothrombosis, with limited direct validation in human valve tissue.
RA evidence was predominantly indirect, comprising associations with incident MR and CMR findings of myocardial abnormalities. Differences in patient selection, imaging ascertainment, and outcomes limited direct comparisons of prevalence, effect sizes, and mechanisms across diseases.
Epidemiology and disease-specific mitral valve phenotypes
Rheumatic heart disease
An updated meta-analysis of 58 echocardiographic screening studies involving 215,552 children and adolescents aged 5–20 years reported a pooled prevalence of borderline or definite RHD of 24 per 1000 [14]. This estimate reflects screened populations in endemic regions and should not be extrapolated to all ages or settings. The WHF staging framework also recognizes latent disease that may not present as clinically apparent MS or MR [4].
The burden extends into adulthood, as illustrated by studies of mitral valve surgery and long-term outcomes in patients with rheumatic disease [15–18].
Systemic lupus erythematosus and antiphospholipid syndrome
Estimates of valve involvement in SLE/APS depend on patient selection, echocardiographic ascertainment, and aPL status. In the CSTAR cohort, valve disease was identified in 27.4% of 508 patients with SLE undergoing clinically indicated echocardiography, while mitral involvement occurred in 11.2%. Mitral abnormalities were more frequent in aPL-positive than aPL-negative patients (20.1% vs.
7.3%) [7], consistent with the association between aPL and valve lesions reported in a meta-analysis [6]. In the longitudinal APS cohort of Pons et al., 72 of 144 imaged patients had valve disease, predominantly mitral thickening and MR. However, only 47.3% of the full cohort underwent echocardiography, limiting interpretation of disease prevalence [5].
In another cohort of 383 patients with APS or persistent aPL positivity, aPL-associated valve disease was identified in 11.5%; anti-β2-glycoprotein I IgG positivity and arterial thrombosis were associated with greater odds of involvement [19].
Rheumatoid arthritis and epidemiologic interpretation
In UK Biobank, 6673 participants with RA and 486,072 controls without baseline valve disease were followed for a median of approximately 13.7 years. RA was associated with incident MR (adjusted hazard ratio 1.54), but not with incident MS [8]. Detailed valve imaging was unavailable, so the association could not distinguish primary leaflet disease from degenerative, ventricular, or atrial functional mechanisms.
These findings therefore do not establish primary rheumatoid valvulitis.
Differences in population selection, imaging ascertainment, and outcome definitions limit direct comparisons of disease frequency across RHD, SLE/APS, and RA. Table 1 summarizes the principal clinical and imaging studies and their limitations.
Disease-specific mechanisms and evidence-graded mitral valve framework
The framework distinguishes established clinicopathological remodeling in RHD from incompletely validated immunothrombotic mechanisms in SLE/APS and hypotheses linking myocardial or chamber remodeling to MR in RA. These categories describe the certainty of the proposed mechanisms rather than the presence or severity of valve disease.
Valvular endothelium and interstitial cells
Valvular endothelial cells (VECs) form a surface barrier, while valvular interstitial cells (VICs) maintain the extracellular matrix. Inflammatory or mechanical injury can increase endothelial permeability, leukocyte recruitment, and profibrotic VIC activation [2]. Persistent injury may reduce leaflet compliance and promote fibrosis or calcification, although findings from degenerative or aortic valve disease cannot be directly extrapolated to autoimmune mitral disease.
Proteomic analysis of human rheumatic mitral and aortic valves identified prothymosin alpha as a disease-associated protein; complementary experiments linked it to CD8 + T-cell activation, type I collagen recognition, and altered VIC signaling [20]. These findings support immune–stromal interactions in rheumatic valve tissue, but their contribution to progressive fibrosis remains incompletely defined.
Rheumatic heart disease
Post-streptococcal molecular mimicry can trigger cross-reactive immune responses and valvular inflammation in RHD [3]. Studies of inflammation-associated lymphatic remodeling [21] and M1 macrophage involvement in VLA4/VCAM-1 signaling [22] provide additional mechanistic evidence, but their predominantly experimental findings do not establish validated therapeutic targets in human disease.
The established clinicopathological sequence involves progressive leaflet and chordal thickening, commissural fusion, subvalvular fibrosis, and variable calcification. Earlier disease may be predominantly regurgitant, whereas chronic remodeling can produce MS or mixed dysfunction [3]. Fixed anatomical abnormalities may continue to determine hemodynamic impairment even when inflammatory activity has diminished.
SLE and APS
SLE/APS-associated valvulopathy typically comprises leaflet thickening, sterile vegetations, and MR [5–7, 19]. Experimental studies show that aPL, particularly anti-β2-glycoprotein I antibodies, can induce endothelial inflammatory and procoagulant responses, including tissue factor expression [23, 24]. Interactions between β2-glycoprotein I, extracellular DNA, and neutrophil extracellular traps (NETs) provide another potential link between autoimmunity and thrombosis [25].
Complement activation may further promote endothelial activation, leukocyte recruitment, platelet activation, and procoagulant signaling [26]. These findings support systemic immunothrombotic mechanisms in APS but do not establish their direct contribution to human Libman–Sacks lesion formation.
Histopathological studies of nonbacterial thrombotic endocarditis (NBTE) describe platelet-rich vegetations with little inflammation, although much of this evidence comes from malignancy-associated rather than autoimmune disease [27]. Endothelial injury and thrombo-inflammatory deposition therefore provide a plausible explanation for SLE/APS-associated valve lesions, but direct validation in human valve tissue remains incomplete.
Rheumatoid arthritis
Population data associate RA with incident MR but not MS [8]. This association does not identify the anatomical substrate, and the available epidemiological and CMR studies do not establish a reproducible RA-specific inflammatory leaflet phenotype [8, 9].
CMR findings of subclinical myocardial tissue abnormalities and altered mechanics in RA suggest a possible substrate for ventricular remodeling, papillary muscle displacement, annular distortion, and secondary MR [9]. However, these findings have not been prospectively linked to incident or quantitatively assessed MR. The epidemiological association and myocardial imaging abnormalities must therefore be treated as separate observations, with secondary remodeling remaining a hypothesis rather than an established RA-specific mechanism.
Figure 1 summarizes these distinctions in mechanistic certainty.
Fig. 1Evidence-graded framework of disease-associated mechanisms and mitral valve phenotypes. In RHD, immune-mediated valvular injury progresses to structural remodeling and MS, MR, or mixed disease.
This clinicopathological sequence is established, although individual molecular intermediates have differing levels of support. In SLE/APS, endothelial activation and immunothrombotic mechanisms may contribute to leaflet thickening, sterile vegetations, and embolic complications, but direct valve-specific causal validation remains incomplete. In RA, the association with MR and the myocardial abnormalities detected by CMR do not establish a causal relationship; secondary myocardial or chamber remodeling is therefore presented as a hypothesis.
Solid arrows denote established relationships, dashed arrows supported but incompletely validated relationships, and dotted arrows hypothesis-generating relationships. The framework summarizes mechanistic certainty qualitatively and does not imply quantitative comparability across diseases. aPL antiphospholipid antibodies; APS antiphospholipid syndrome; C3 complement component 3; C5 complement component 5; CMR cardiac magnetic resonance; MR mitral regurgitation; MS mitral stenosis; NETs neutrophil extracellular traps; RA, rheumatoid arthritis; RHD rheumatic heart disease; SLE systemic lupus erythematosus; TF tissue factor; VIC valvular interstitial cell
Clinical decision implications of the evidence-graded framework
The framework supports clinical interpretation without replacing guideline thresholds for valve intervention. In RHD, characteristic commissural, leaflet, and subvalvular abnormalities direct assessment toward hemodynamic severity, chamber consequences, and suitability for percutaneous mitral commissurotomy (PMC) or surgery. Prevention of recurrent rheumatic injury remains distinct from treatment of established structural damage [3, 4, 28–31].
In SLE/APS, valve morphology and embolic potential require consideration alongside MR severity. TEE may clarify suspected vegetations or a valvular source of embolism [5–7, 19, 32]. Isolated leaflet thickening does not itself establish an indication for therapeutic anticoagulation; diagnosed NBTE warrants separate assessment, including consideration of anticoagulation after evaluation of bleeding risk [33].
Treatment also depends on systemic disease activity, thrombotic history, and aPL profile [34–36]. Infective endocarditis must be excluded before lesions are attributed to autoimmune NBTE or immunosuppression is intensified [33].
In RA, MR should be assessed for conventional degenerative, ischemic, ventricular, or atrial functional mechanisms, with CMR used selectively to clarify myocardial or chamber abnormalities [8, 9, 28]. The available evidence does not support intensifying RA-directed immunomodulatory treatment solely to reverse MR. Table 2 summarizes the diagnostic and therapeutic implications.
Table 1Selected Clinical and Imaging Studies Relevant to Mitral Valve DiseaseDisease/StudyStudy designStudy population/sample sizeAssessment/imagingMain findingKey limitationRHD — Mutarelli et al., 2025 [14]Systematic review and meta-analysis58 studies; 215,552 children and adolescentsEchocardiographic screeningPooled prevalence of echocardiographically detected RHD: 24/1000 (95% CI 20–30)Predominantly pediatric endemic populationsSLE — Chen et al., 2025 [7]Observational CSTAR cohort508 patients with SLE undergoing echocardiographyEchocardiographyAny heart valve involvement: 27.4%; mitral involvement: 11.2%Clinically selected patients undergoing echocardiographyAPS — Pons et al., 2023 [5]Longitudinal single-center cohort144 patients with APS undergoing echocardiographyTransthoracic echocardiographyHeart valve involvement in 72/144 imaged patients (50%)Only 47.3% of full cohort underwent echocardiographyAPS/aPL — Pan et al., 2023 [19]Observational cohortn = 383EchocardiographyaPL-associated valve disease in 11.5%Observational design; associations do not establish causalityRA — Wang et al., 2025 [8]Prospective population-based cohortRA n = 6,673; controls n = 486,072No dedicated valve imaging phenotyping reportedRA was associated with incident MR: adjusted HR 1.54 (95% CI 1.32–1.81)No detailed valve morphology or classification of MR mechanismRA — Tarjanyi et al., 2025 [9]Mixed case-control study48 patients with RA; 34 age- and sex-matched controlsCMRSubclinical abnormalities of myocardial tissue characteristics and mechanics in RAMyocardial findings provide indirect evidence; no demonstrated causal link to MRRHD — Bouchahda et al., 2024 [20]Multimodality imaging study41 patients with rheumatic MSThree-dimensional echocardiography, CMR, and CTCMR yielded larger MVA measurements than three-dimensional echocardiography; CT calcium score did not correlate with MS severitySmall cohort; limited generalizabilitySLE — Yamamoto et al., 2023 [21]Retrospective surgical cohort26 patients with SLE undergoing cardiovascular surgery; 17 underwent valve surgeryRetrospective assessment of surgical outcomesNo in-hospital deaths or bleeding/embolic complications in the overall surgical cohortSmall, heterogeneous surgical cohort; outcomes not restricted to mitral valve surgeryAPS — Eviatar et al., 2023 [22]Retrospective surgical cohort26 patients with APS undergoing valve surgeryRetrospective assessment of early and late surgical outcomesSevere complications in 14/26 patients (53.8%) across early and late follow-upSmall, selected cohort; heterogeneous procedures and follow-upaPL antiphospholipid antibodies; APS antiphospholipid syndrome; CMR cardiac magnetic resonance; CI confidence interval, CT computed tomography; HR hazard ratio; MR mitral regurgitation; MS mitral stenosis; MVA mitral valve area; RA rheumatoid arthritis; RHD rheumatic heart disease; SLE systemic lupus erythematosus.This table summarizes selected key clinical and imaging studies relevant to mitral valve involvement in RHD, SLE, APS, and RA and is not intended to represent an exhaustive systematic evidence summary. Study designs, sample sizes, imaging protocols, patient selection criteria, and outcome definitions differ substantially across studies; therefore, reported prevalence estimates, effect sizes, and clinical outcomes should not be directly compared between disease groups. The main findings should be interpreted in the context of the study-specific limitations presented in the table.
Evidence derived from observational studies supports clinical associations but does not necessarily establish causality, while indirect myocardial imaging findings should not be considered proof of a disease-specific valvular mechanism. Sample sizes refer to the populations or procedures specified in the individual studies and may not represent the total number of participants enrolled.
Table 2Clinical decision implications of the evidence-graded frameworkDiseaseDominant evidence-supported substrateDiagnostic implicationTherapeutic implicationRheumatic heart disease (RHD)Established progression from immune-mediated valvular injury to commissural, leaflet, chordal, and subvalvular remodeling [3, 4]. Human tissue and experimental studies provide additional mechanistic evidence with differing levels of validation [23–25].Assess hemodynamic severity, commissural fusion, leaflet mobility, calcification, subvalvular disease, and chamber consequences to determine suitability for PMC or surgery [4, 31–33].Secondary antibiotic prophylaxis prevents recurrent rheumatic injury but does not reverse established structural damage. Valve intervention depends on severity and anatomy, with PMC in suitable patients and surgery when indicated and percutaneous treatment is unsuitable [31, 34, 40].Systemic lupus erythematosus/antiphospholipid syndrome (SLE/APS)Leaflet thickening, sterile vegetations, and MR are documented clinical phenotypes [5–7, 19].
Endothelial and immunothrombotic mechanisms have systemic and experimental support, but direct validation in human autoimmune valve lesions remains incomplete [26–30].Assess valve morphology and embolic potential alongside MR severity. Consider TEE when Libman–Sacks/NBTE or a valvular embolic source is suspected [5–7, 19, 35]. Exclude infective endocarditis before attributing lesions to autoimmune NBTE [36].Treat systemic disease according to its activity and established indications [37, 38].
Isolated leaflet thickening does not itself justify therapeutic anticoagulation; in diagnosed NBTE, anticoagulation should be considered after assessment of bleeding risk [36]. Thrombotic history and aPL profile guide APS treatment [38, 39]. Consider valve intervention for conventional structural indications or selected cases of recurrent embolization despite appropriate therapy [31, 36, 39].Rheumatoid arthritis (RA)Association with incident MR without an established RA-specific primary leaflet phenotype.
Myocardial or chamber remodeling is a plausible but unproven explanation [8, 9].Evaluate degenerative, ischemic, ventricular functional, and atrial functional causes of MR. Use CMR selectively to clarify myocardial or chamber abnormalities [8, 9, 31].Treat MR according to its demonstrated mechanism and established cardiovascular indications. Available evidence does not support intensifying RA-directed immunomodulatory therapy specifically to reverse MR [8, 9, 31].This framework supports clinical interpretation and does not replace guideline-defined thresholds for valve severity or intervention.
Established clinical phenotypes are distinguished from proposed mechanisms with incomplete valve-specific validation. aPL antiphospholipid antibodies; APS antiphospholipid syndrome; CMR cardiac magnetic resonance; MR mitral regurgitation; NBTE nonbacterial thrombotic endocarditis; PMC percutaneous mitral commissurotomy; RA rheumatoid arthritis; RHD rheumatic heart disease; SLE systemic lupus erythematosus; TEE transesophageal echocardiography
Mitral stenosis in rheumatic heart disease and selected systemic autoimmune rheumatic diseases
Rheumatic mitral stenosis and hemodynamic assessment
MS is a characteristic late manifestation of RHD, resulting from commissural fusion, leaflet restriction, chordal shortening, and subvalvular fibrosis [3]. Its hemodynamic consequences depend on valve area, heart rate, cardiac output, rhythm, and left atrial compliance. Obstruction increases left atrial and pulmonary pressures, while tachycardia may worsen symptoms by shortening diastolic filling time.
The 2025 ESC/EACTS guidelines define clinically severe rheumatic MS by a mitral valve area ≤ 1.5 cm²; intervention decisions also require assessment of symptoms, gradients, pulmonary pressures, rhythm, and valve anatomy [28].
Echocardiographic phenotyping and commissurotomy
Transthoracic echocardiography (TTE) is the primary diagnostic modality. Two-dimensional planimetry is the reference echocardiographic method for anatomical valve area, whereas transmitral gradients depend on flow [28]. Assessment should include commissural fusion, leaflet mobility and thickness, calcification, subvalvular disease, associated MR, and chamber consequences.
The Wilkins score supports procedural assessment but does not replace detailed evaluation of commissural anatomy; three-dimensional echocardiography may clarify uncertain morphology [29, 30]. Transesophageal echocardiography (TEE) should be performed before percutaneous mitral commissurotomy (PMC) to exclude left atrial thrombus and is also important after embolic events [28].
PMC is a first-line intervention in appropriately selected patients with clinically severe rheumatic MS and suitable anatomy [28, 37]. Severe or bi-commissural calcification, left atrial thrombus, more than mild MR, absent commissural fusion, or concomitant disease requiring surgery argue against PMC [28, 29]. Mild-to-moderate calcification does not necessarily preclude the procedure when commissural fusion is present and severe subvalvular disease is absent.
Selection therefore requires assessment of the distribution of structural abnormalities rather than reliance on a score alone [28, 29].
Mitral stenosis in SLE and APS
MS attributable to SLE or APS is uncommon compared with leaflet thickening and MR [5–7, 19]. Its presence should prompt consideration of coexisting RHD, degenerative calcification, or changes related to previous valve intervention. An APS case described progressive leaflet thickening and fusion after mitral repair, followed by MS and recurrent MR within two years [38].
This isolated observation does not establish a reproducible autoimmune stenotic mechanism. PMC should therefore not be assumed appropriate without demonstrated commissural fusion and otherwise suitable anatomy [28, 29].
Mitral regurgitation in rheumatic and selected systemic autoimmune rheumatic diseases
Rheumatic mitral regurgitation
MR may predominate in early or active RHD. Excessive leaflet tip motion associated with chordal elongation and inflammatory leaflet or subvalvular changes is recognized in the WHF criteria [4, 30]. Chronic remodeling produces leaflet restriction, commissural or chordal fusion, and chordal shortening, often resulting in combined regurgitation and stenosis.
Echocardiography should define the mechanism and severity of MR, including leaflet and chordal morphology, annular dimensions, chamber remodeling, pulmonary pressures, and associated MS [30].
SLE and APS: Libman-Sacks valvulopathy
Leaflet thickening and MR are common manifestations of SLE/APS-associated valve disease, particularly in aPL-positive patients [5–7, 19]. Libman–Sacks vegetations may impair coaptation and provide a source of systemic or cerebral embolism, even when MR is modest [5–7, 32]. TEE is useful when TTE is inconclusive or an embolic event raises suspicion of a valvular source [32].
A valve mass should not be considered sterile solely because the patient has SLE or APS. Assessment must integrate imaging, blood cultures, clinical evidence of infection, disease activity, aPL status, and embolic events within the diagnostic approach to suspected endocarditis [33]. Valve-specific embolic risk models and surveillance intervals remain insufficiently validated; follow-up therefore depends on lesion morphology, clinical history, and serial imaging [33, 36].
Rheumatoid arthritis
RA is associated with incident MR, but the available studies do not establish a characteristic primary leaflet lesion or a disease-specific mechanism [8, 9]. CMR-detected myocardial abnormalities provide a possible explanation for secondary MR, although a direct prospective relationship has not been demonstrated [9]. Degenerative, ischemic, ventricular functional, and atrial functional causes should therefore be assessed before MR is attributed to RA-related inflammation.
Across these conditions, assessment should distinguish primary leaflet or subvalvular disease from secondary MR caused by ventricular or atrial remodeling. Rheumatic and Libman–Sacks-associated MR generally involve structural valve lesions, whereas the mechanism in patients with RA requires individual characterization. Table 3 summarizes the principal phenotypes and the evidence supporting their proposed mechanisms.
Table 3Mitral valve phenotypes and mechanistic evidence in rheumatic heart disease and selected systemic autoimmune rheumatic diseasesDiseaseProposed mechanismPrimary evidence baseMechanistic evidence statusMitral morphologyValve phenotypeThromboembolic relevanceClinical clueRheumatic heart disease (RHD)Post-streptococcal immune-mediated valvulitis followed by fibrotic remodeling [3]. Human tissue and experimental studies provide additional evidence on cellular pathways [23–25].Guidelines, population-based echocardiographic studies, longitudinal clinical observations, human pathological/valve-tissue studies, and intervention studies [3, 4, 23–25, 31–33, 40]Established clinicopathological sequence [3, 4]; individual molecular pathways have differing levels of validation [23–25].Commissural fusion; leaflet/chordal thickening and shortening; subvalvular fibrosis [4, 33]MS, MR, or mixed MS/MR [4, 31, 40]Primarily related to AF and left atrial thrombus in advanced MS [31]Commissural fusion + subvalvular disease; anatomy determines PMC suitability [31, 32]Systemic lupus erythematosus (SLE)aPL-associated endothelial activation and immunothrombosis may contribute to clinically documented valve lesions [6, 7, 26–29].Systematic review/meta-analysis, clinical and echocardiographic cohorts, serological associations; mechanistic evidence predominantly indirect or non-valve-specific [6, 7, 26–29]Clinical valve involvement is documented; proposed molecular mechanisms remain incompletely validated in human valve tissue [6, 7, 26–29].Leaflet thickening with or without sterile Libman–Sacks vegetations [6, 7].Predominantly MR; clinically relevant MS uncommon [6, 7]May be disproportionate to MR severity [6, 7]Sterile vegetations/leaflet thickening; exclude infective endocarditis [6, 7, 35]Antiphospholipid syndrome (APS)Endothelial activation and immunothrombotic pathways may contribute to valve lesions; direct valve-specific causality remains incompletely validated [19, 26–30].Longitudinal/retrospective clinical cohorts and serological associations; systemic and experimental immunothrombotic studies; limited direct human valve-tissue evidence [5, 19, 26–30]Valve involvement and thrombotic associations are clinically supported; the proposed valve-specific mechanisms remain incompletely validated [5, 19, 26–30].Leaflet thickening with or without sterile vegetations [5, 19].Predominantly MR; stenotic or mixed lesions uncommon [5, 19, 41]Valve lesions may contribute to embolism; systemic APS-related thrombosis must also be considered [5, 19].Integrate aPL profile, embolic history, and valve morphology [5, 19]Rheumatoid arthritis (RA)Myocardial or chamber remodeling is a possible, unproven explanation for the association with MR [8, 9].Prospective population cohort and CMR study of myocardial abnormalities; neither establishes a valve-specific causal mechanism [8, 9].Hypothesis-generating mechanism; the association with MR is supported, but a causal link to myocardial or chamber remodeling is unproven [8, 9].No characteristic RA-specific leaflet phenotype established by the cited studies [8, 9].Association with incident MR; no significant association with MS in the cited cohort [8].RA-specific valvular embolic risk not established by the cited studies [8, 9].Assess degenerative, ischemic, ventricular functional, and atrial functional MR [8, 9]Mechanistic evidence status refers to the proposed causal pathway, not to the presence or severity of the clinical phenotype. Categories follow the qualitative framework described in the Methods and do not constitute a formal GRADE assessment.
Established clinicopathological relationships do not imply that every molecular intermediate has been validated. Differences in study populations and methods preclude direct quantitative comparisons across diseases. AF atrial fibrillation; aPL antiphospholipid antibodies; APS antiphospholipid syndrome; CMRcardiac magnetic resonance; MR mitral regurgitation; MS mitral stenosis; PMC percutaneous mitral commissurotomy; RA rheumatoid arthritis; RHD rheumatic heart disease; SLE systemic lupus erythematosus
Multimodality imaging and diagnostic integration
Echocardiography as the diagnostic foundation
Echocardiography is the first-line modality for assessing valve morphology, hemodynamic severity, chamber response, pulmonary pressures, and potential embolic sources [4, 28, 30]. Additional imaging should address a specific unresolved question. TEE is particularly useful for detecting left atrial thrombus, clarifying the mechanism of MR, and evaluating suspected Libman–Sacks/NBTE lesions [28, 32].
Three-dimensional echocardiography provides complementary visualization of commissures and leaflet geometry [29, 30].
CT and CMR in rheumatic mitral disease
CT and CMR complement echocardiography in RHD [39–41]. CT defines the distribution of valvular, commissural, and annular calcification and helps assess procedural anatomy. CMR quantifies ventricular volumes and function and can clarify MR severity when echocardiographic assessment is inconclusive [40, 41].
However, measurements obtained with different modalities are not necessarily interchangeable. In a study of 41 patients with rheumatic MS, CMR yielded larger mitral valve area measurements than three-dimensional echocardiography, while CT calcium scores did not correlate with stenosis severity [42].
Imaging in SLE/APS and RA
In SLE/APS, imaging should assess both valve dysfunction and potential embolic sources, since clinically important lesions may coexist with mild MR. Suspected Libman–Sacks/NBTE lesions require echocardiographic assessment and clinical evaluation to exclude infective endocarditis [32, 33]. CT or CMR may be useful when echocardiography is inconclusive or when additional structural or myocardial assessment is needed [32, 40, 41].
In RA, CMR can characterize myocardial and chamber abnormalities that may help explain secondary MR, but these findings do not establish RA as its cause or demonstrate primary leaflet inflammation [9]. Imaging should therefore define the observed valve and myocardial abnormalities without assuming a disease-specific mechanism. Further studies are needed to determine whether additional imaging improves prediction of embolism, structural progression, or the need for intervention in these populations.
Integrated management of mitral valve disease
General principles
Management should address systemic disease activity, valve dysfunction, and hemodynamic or thromboembolic complications. Control of inflammation does not necessarily reverse established structural damage, while valve intervention does not eliminate the underlying rheumatic, autoimmune, or thrombotic disorder [28, 31, 34–36]. Table 1 summarizes how these distinctions inform treatment.
Rheumatic heart disease
Long-term antibiotic prophylaxis reduces recurrent rheumatic fever, with intramuscular benzathine benzylpenicillin generally more effective than oral prophylaxis [31]. It remains important even when established valve damage requires intervention, but should not be expected to reverse commissural fusion or subvalvular fibrosis.
Intervention depends on symptoms, hemodynamic severity, and anatomy. PMC is appropriate in selected patients with clinically severe rheumatic MS and suitable valve morphology; surgery is considered when intervention is indicated but PMC is contraindicated or unlikely to provide a durable result [28, 29, 37]. Decisions in rheumatic MR also depend on ventricular consequences, reparability, and procedural risk [28, 30].
SLE and APS
Immunomodulatory treatment in SLE should follow overall disease activity and organ involvement. EULAR recommendations support hydroxychloroquine unless contraindicated, with glucocorticoids, conventional immunosuppressants, and biologic therapies selected according to clinical circumstances [34]. Evidence that these treatments reliably reverse established Libman–Sacks valvulopathy is lacking; leaflet thickening or a stable vegetation alone should therefore not automatically prompt treatment escalation.
In APS, antithrombotic treatment depends primarily on thrombotic history and the aPL risk profile. Vitamin K antagonists are recommended after arterial thrombosis and for long-term treatment after unprovoked venous thrombosis. Rivaroxaban should not be used in triple-positive APS, and direct oral anticoagulants are not recommended in definite APS with arterial events [35].
Isolated leaflet thickening or stable valve dysfunction does not itself establish an indication for therapeutic anticoagulation. In diagnosed NBTE, however, anticoagulation should be considered after assessment of bleeding risk, including in patients without previous embolism [33].
Treatment evidence specific to Libman–Sacks/NBTE lesions comes mainly from observational studies, small series, and expert consensus [36]. The choice and duration of anticoagulation, potential benefit of immunomodulation, and imaging surveillance should therefore be individualized according to the underlying disorder and clinical course [33–36]. Infective endocarditis must be excluded before lesions are attributed to autoimmune NBTE or immunosuppression is intensified [33].
Surgery may be considered for conventional structural indications or selected cases of recurrent embolization despite appropriate medical therapy [28, 36].
Surgical evidence in SLE and APS is limited to small, selected cohorts, whose complication rates cannot be directly compared because populations and procedures differ [43, 44]. Repair versus replacement and prosthesis selection require consideration of anatomy, expected durability, anticoagulation requirements, thrombotic and bleeding risks, renal function, and pregnancy plans.
Rheumatoid arthritis and longitudinal care
In patients with RA, MR should be evaluated for degenerative, ischemic, ventricular functional, and atrial functional mechanisms rather than attributed to primary rheumatoid valvulitis [8, 9]. Treatment and surveillance should follow the demonstrated mechanism, symptoms, chamber remodeling, and established indications for intervention [28]. RA activity warrants treatment for rheumatological indications, but the cited CMR findings do not establish that antirheumatic therapy reverses MR [9].
Critical appraisal, knowledge gaps, and future directions
Longitudinal disease trajectories and human mechanistic validation
Much of the evidence on autoimmune mitral valve involvement comes from cross-sectional studies and retrospective cohorts, limiting conclusions about progression and causality. Priorities in RHD include identifying predictors of structural progression and long-term procedural durability [28, 45]. In SLE/APS, serial imaging is needed to establish which leaflet abnormalities or Libman–Sacks lesions remain stable and which precede worsening MR, embolism, or rare stenotic remodeling [5–7, 19].
Mechanistic studies also differ in their directness. Human rheumatic valve-tissue findings [20] and predominantly experimental lymphatic and macrophage studies [21, 22] cannot be assigned equivalent causal weight. In APS, systemic evidence supports endothelial activation and immunothrombosis [23–26], but their contribution to human Libman–Sacks lesions remains uncertain.
Histopathological findings from predominantly malignancy-associated NBTE require caution when extrapolated to autoimmune disease [27]. Studies combining human valve tissue with single-cell, spatial, and proteomic analyses could help distinguish active injury from established fibrosis.
Differences in patient selection, lesion definitions, imaging methods, and outcomes further limit comparisons across RHD, SLE/APS, and RA. Prospective studies should use standardized definitions and imaging protocols while accounting for disease-specific characteristics.
Imaging and therapeutic priorities
Imaging studies need reproducible definitions of leaflet thickening, vegetation morphology and mobility, interval progression, and embolic outcomes [5–7, 32]. Measurements from different modalities also require validation before they are used interchangeably, as illustrated by discrepancies between echocardiographic and CMR-derived valve area in rheumatic MS [42]. In RA, studies combining quantitative MR assessment with CMR tissue characterization and ventricular and atrial geometry are needed to determine whether myocardial abnormalities precede or contribute to regurgitation [8, 9].
Such studies should distinguish conventional degenerative and functional mechanisms from any proposed RA-specific process.
Key therapeutic questions include whether immunomodulation modifies Libman–Sacks lesions, how to optimize antithrombotic treatment for valve-associated embolic disease, and when surgery is beneficial, including the long-term outcomes of repair versus replacement [34–36, 43, 44]. Prospective studies should relate treatment exposure to serial valve morphology, hemodynamics, systemic disease activity, and thrombotic risk, using outcomes such as embolism, structural progression, intervention, and survival. This would provide a stronger basis for surveillance and treatment than the presence of valve abnormalities alone.
Limitations of the review
This narrative review used a structured literature search that was undertaken across multiple bibliographic databases, but did not follow a formal systematic review protocol. Differences in study populations, lesion definitions, imaging methods, and outcomes prevented quantitative synthesis and limited comparisons across diseases. The strength and directness of evidence differ considerably across RHD, SLE/APS, and RA.
Direct human valve-specific evidence was uneven, requiring some mechanistic interpretations to draw on systemic or experimental findings. The proposed evidence categories represent a qualitative, unvalidated classification and should guide interpretation and research priorities rather.
Conclusions
Similar mitral valve lesions can arise in different disease settings, but the evidence supporting their mechanisms varies. In RHD, the progression from immune-mediated injury to fibrotic valve remodeling is well established. SLE/APS is associated with leaflet thickening, Libman–Sacks vegetations, and MR, with embolic complications that may exceed the apparent hemodynamic burden.
The contribution of specific immunothrombotic pathways to these lesions remains incompletely validated. In RA, the association with MR does not establish primary autoimmune valvulopathy or a causal link to myocardial remodeling.
Clinical assessment should identify the anatomical mechanism and consequences of valve dysfunction. This supports anatomy- and severity-based management in RHD, combined valvular and thromboembolic assessment in SLE/APS, and evaluation of conventional MR mechanisms in RA. Treatment of systemic disease should be distinguished from treatment of established valve damage and its complications.
The proposed framework supports these decisions within existing guidelines; it does not justify disease-specific treatment escalation without supporting evidence. Prospective studies linking serial imaging, human tissue findings, treatment exposure, and clinical outcomes are needed to validate the proposed mechanisms and improve management.