Abstract
Degenerative aortic stenosis (AS) is the most common valvular heart disease in developed countries, particularly in individuals over 65 years of age. While the indication for aortic valve replacement in the presence of symptoms is well established, the optimal management of patients with severe asymptomatic AS remains controversial. This review integrates the epidemiology and pathophysiology of AS, the contribution of echocardiography and other diagnostic modalities (computed tomography, cardiac magnetic resonance, biomarkers), and summarizes contemporary evidence comparing early intervention versus clinical surveillance. Advanced parameters such as global longitudinal strain, mechanical dispersion, myocardial work, Global work index, as well as structural and functional cardiac damage staging systems, are highlighted. Collectively, randomized controlled trials from RECOVERY, AVATAR, EVOLVED, and EARLY transcatheter aortic valve replacement trials, complemented by registries such as CURRENT AS and observational analyses suggest that early intervention strategy reduces the risk of heart failure-related hospitalizations and cerebrovascular events in asymptomatic severe AS, while the impact on all-cause mortality remains less consistent across studies. Identifying the optimal time window for intervention before irreversible myocardial damage occurs, and refining patient selection using advanced imaging modalities, remain key priorities for both clinical practice and research. Current evidence indicates that, although watchful waiting continues to be appropriate in carefully selected patients, early intervention is gaining stronger support, particularly in those with adverse prognostic markers or in settings where close surveillance is not feasible.
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Keywords
Introduction
Degenerative aortic stenosis (AS) is the most common valvular disease in high income countries, especially in patients over 65 years of age, with an incidence ranging from 2% to 9%.1,2 Aortic valve sclerosis is the main precursor of AS and occurs in approximately one-third of the population over 65 years old. The prevalence of aortic sclerosis increases with age, affecting an estimated 25% of individuals over 65 and nearly 50% of those over 85. Among this group, 1.8% to 1.9% progress annually to clinically significant AS. 3 Longitudinal studies have demonstrated that lipid infiltration of the aortic valve, together with active oxidative processes, induces valvular inflammation and, over time, alterations in tissue biology that promote progressive fibro calcification.4–8
The management of patients with severe asymptomatic AS remains controversial, particularly regarding the optimal timing for intervention, whether by surgical aortic valve replacement (SAVR) or transcatheter aortic valve replacement (TAVR). Predicting symptoms onset in older patients, whose functional capacity may be limited by comorbidities, presents a clinical challenge in attributing symptoms exclusively to AS. 9 Up to 40% of patients with severe AS report no symptoms at diagnosis, and exercise testing can unmask latent symptoms in nearly one-third, underscoring the limitations of relying solely on spontaneous symptom reporting. 9
The classification of patients with severe AS as “asymptomatic” remains challenging and may not accurately reflect the true absence of functional limitation. Many patients unconsciously reduce their physical activity, mask exertional symptoms and lead to underrecognition of disease severity. Objective assessment, including exercise testing, has therefore emerged as an important tool to confirm asymptomatic status and refine risk stratification.9,10
According to the 2020 American (ACC/AHA) and the 2025 European Society of Cardiology (ESC) guidelines, severe AS is defined by a peak aortic jet velocity (Vmax) ≥ 4.0 m/s, a mean transvalvular gradient ≥40 mm Hg, or an aortic valve area (AVA) ≤ 1.0 cm2. In asymptomatic patients, intervention is recommended when left ventricular ejection fraction (LVEF) falls below 50% without another cause, or when exercise testing unmasks symptoms. For patients at low procedural risk, early intervention is considered reasonable (Class IIa) if adverse prognostic features are present, including very high or rapidly progressing Vmax (≥0.3 m/s per year), severe valve calcification (Agatston score >2000 AU in men or >1200 AU in women), markedly elevated natriuretic peptides (>3× age- and sex-adjusted normal), LVEF <55% attributable to AS, or a sustained fall in systolic blood pressure >20 mm Hg during exercise testing. In the absence of these factors, careful active surveillance remains appropriate, although limited resources or long waiting times may also favor an early intervention strategy.1,2,11
The 2025 European guidelines introduce a paradigm shift in the management of asymptomatic severe AS. While earlier recommendations emphasized expectant management with close surveillance, a more proactive strategy is now supported. Aortic valve replacement (AVR) is recommended (Class IIa) in asymptomatic patients at low procedural risk who present with adverse prognostic features, marking a transition from a watchful waiting approach to earlier intervention in carefully selected cases. 9
This review is based on a structured search of PubMed/MEDLINE and Embase, prioritizing randomized trials, meta-analyses, and key observational studies on early intervention in asymptomatic severe AS, along with relevant contemporary data.
Natural History
In 1968, Ross and Braunwald published in Circulation a landmark review on the natural history of surgically untreated AS, describing it as a progressive disease with a long latent period characterized by gradual obstruction due to valve thickening and calcification, leading to chronic left ventricular (LV) pressure overload and, in advanced stages, the onset of symptoms. 12 It is now well recognized that AS is not a passive degenerative process but the consequence of a complex interplay of genetic, lipid, inflammatory, neovascular, fibrotic, and calcific mechanisms that collectively contribute to progressive valvular thickening and stiffening. Mechanical stress and conventional cardiovascular risk factors promote endothelial injury, subendothelial accumulation and oxidation of LDL and Lp(a), and a chronic inflammatory response that activates valve interstitial cells, inducing myofibroblastic and osteoblast-like phenotypes, extracellular matrix remodeling, and matrix–vesicle–mediated microcalcification, which together drive progressive fibrocalcific remodeling of the aortic valve throughout disease progression.13,14
The classic clinical presentation includes the triad of angina, dyspnea from heart failure, and syncope. These 3 major symptoms may be accompanied by other clinical manifestations such as fatigue, reduced exercise tolerance, and lower-limb edema. The appearance of any of these symptoms marks a prognostic turning point: without intervention, patients with heart failure survive on average 2 years, those with syncope around 3 years, and those with angina up to 4 or more years. 3
Approximately two-thirds of patients with severe AS managed conservatively will develop symptoms within 5 years of diagnosis, and nearly 75% will have died or undergone surgery within that period. The natural progression is characterized by an average increase in Vmax of 0.3 m/s/year and a decrease in AVA of 0.1 cm2/year. Factors such as smoking, dyslipidemia, male sex, diabetes mellitus, hypertension, chronic kidney disease, baseline aortic valve calcification, and coronary artery disease predict accelerated progression. 15
The risk of sudden death in severe asymptomatic AS has been estimated at ∼1% per year; after symptom onset, the risk rises to ∼3% within 3 to 6 months, and up to 6.5% may die before surgery. In ∼70% of sudden deaths in asymptomatic patients, no classic symptoms are identified beforehand; hemodynamic severity is directly associated with greater risk.15,16
The prognosis of unoperated patients with severe AS is poor. A study published in The Annals of Thoracic Surgery (2006) showed markedly reduced overall survival, with rates at 1, 5, and 10 years of 62%, 32%, and 18%, respectively. Outcomes were especially adverse in older patients and in those with LV dysfunction, heart failure, or chronic kidney disease. 17 These findings underscore the need for careful assessment and close follow-up, even in the absence of symptoms, to accurately identify those who might benefit from intervention.
Additionally, the combination of a high aortic valve calcium score and marked frailty has been associated with increased mortality, highlighting the importance of jointly assessing calcific burden and functional status to estimate prognosis and guide decision-making. 18
Indications and Management of Patients With AS
Current American and European guidelines endorse, as a Class I recommendation with Level of Evidence A, intervention in patients with severe AS and symptoms.1–3,11 However, this symptom-based approach may fail to timely identify patients with early myocardial damage who remain asymptomatic (Table 1).
Comparison of Clinical Criteria Between ESC and AHA/ACC Guidelines for AVR.
ESC, European Society of Cardiology; AHA, American Heart Association; ACC, American College of Cardiology; AVR, aortic valve replacement; AS, aortic stenosis; LVEF, left ventricular ejection fraction.
Low surgical risk based on STS-PROM (http://riskcalc.sts.org/stswebriskcalc/#/calculate) and EuroSCORE II (http://www.euroscore.org/calc.html) < 4%. 9
Pathophysiology of AS and Ventricular Remodeling
As the aortic valve orifice narrows, LV pressure rises. In response to this chronic overload, the LV enters a compensatory phase aimed at normalizing wall stress, according to Laplace's law, and maintaining systolic function.3,4 However, even in early stages, histopathological changes such as myocyte apoptosis and focal necrosis can be detected, and with disease progression there is progressive infiltration by myofibroblasts and development of diffuse interstitial fibrosis, predominantly subendocardial, while collagen deposition within the mid-myocardial layer becomes irreversible over time. This maladaptive remodeling process reduces myocardial elasticity and performance, leading to loss of the initially adaptive benefit of hypertrophy, symptom onset, progressive LV systolic dysfunction, and a decline in LVEF.3,4
Contemporary clinical studies have demonstrated a strong association between both diffuse and focal fibrosis, reductions in global longitudinal strain (GLS), and poorer survival, even when aortic valve intervention is performed before overt LVEF impairment.3,19–21 Myocardial fibrosis has emerged as a key determinant of disease progression and adverse outcomes in AS, providing prognostic information that is independent of conventional parameters such as LVEF and AS severity. 21 Two distinct patterns can be identified using cardiac magnetic resonance imaging: (i) focal replacement fibrosis detected by late gadolinium enhancement (LGE), which reflects irreversible myocyte injury; and (ii) diffuse interstitial fibrosis, assessed and quantified using T1 mapping and extracellular volume (ECV) fraction, which can be detected early in the disease process, may show partial reversibility after valve intervention and is associated with LV remodeling and decompensation. Both patterns carry independent prognostic significance: the presence of LGE has been associated with higher risk of mortality and adverse outcomes, including after AVR, 21 while diffuse interstitial fibrosis (ECV/T1 mapping) provides significant prognostic value across AS severities, including moderate and asymptomatic severe cohorts, 21 and may help refine the timing of intervention beyond hemodynamic severity alone.21–24
Role of Echocardiography in Severe Asymptomatic AS
Echocardiography is the gold standard for comprehensive assessment of AS. A guideline-directed multiparametric approach is required for confirming the diagnosis, grading hemodynamic severity, and assessing LV remodeling and function.
Peak aortic jet velocity (Vmax)
A strong independent predictor of adverse outcomes; Vmax ≥4.0 m/s defines severe AS, and values ≥5.0 m/s (AHA/ACC) or >5.0 m/s (ESC) denote very severe stenosis and higher risk of rapid progression and sudden death.1,9,16
Mean transvalvular gradient (ΔPmean)
A ΔPmean ≥40 mm Hg is a cornerstone criterion of severe AS. ΔPmean ≥60 mm Hg is a criterion for very severe AS.
9
And a mean transvalvular gradient ≥50 mm Hg is indicative of advanced, very severe stenosis and worse outcomes.7,16,25
AVA and indexed AVA
AVA ≤0.75 cm2 or indexed AVA ≤0.6 cm2/m2 accompanied by a Vmax ≥4.5 m/s or a mean transvalvular gradient ≥50 mm Hg is indicative of advanced, very severe AS and, which is associated with worse clinical outcomes.7,16,25
Dimensionless index
The dimensionless index (DI) has been consistently associated with prognosis in AS, with lower values predicting higher mortality. Rusinaru et al
26
reported that the risk of all-cause mortality and AVR increased by approximately 25% for every 0.05 decrease in DI; patients with very low DI (<0.20) had particularly high rates of adverse events compared with those with severe AS but higher DI values. Furthermore, the combination of DI, AVA, and Vmax was shown to constitute a more sensitive set of factors associated with adverse cardiac events than AVA alone or AVA combined with Vmax26–28
Flow status: stroke volume index
Stroke volume index (SVi) <35 ml/m2 defines low flow, even with normal LVEF, and is associated with poorer outcomes.
20
Markers of LV remodeling and hemodynamic impact
LV remodeling in severe asymptomatic AS is best characterized by LV hypertrophy, defined by an increased LV mass index using established sex-specific thresholds.29,30 A higher LV mass index is independently associated with worse outcomes even in the absence of symptoms. 31 In parallel, left atrial (LA) enlargement, assessed by indexed LA volume, reflects chronically elevated LV filling pressures and provides incremental prognostic information in asymptomatic AS. 30 Importantly, among asymptomatic patients with severe AS, preserved LVEF, and LV hypertrophy, AVR has been associated with lower long-term mortality compared with conservative management, supporting LV hypertrophy as a marker of early ventricular injury that may help identify patients who benefit from earlier intervention. 29
LVEF and Mortality in Severe Asymptomatic or Minimally Symptomatic AS
In the presence of LV hypertrophy and/or concentric remodeling, frequently observed in AS, mixed aortic valve disease, or paradoxical low-flow low-gradient AS, LVEF tends to overestimate true LV systolic function. Consequently, even modest reductions in LVEF may already reflect significant myocardial dysfunction. Current guidelines recommend intervention in asymptomatic patients with severe AS and an LVEF <50% (Class I), a rare finding (<1% of asymptomatic cases) and typically indicative of advanced, often symptomatic stages.
9
However, observational data suggest that higher LVEF thresholds may be clinically relevant: in a cohort of 1678 patients with severe AS and preserved LVEF, an LVEF <55% was associated with lower 60-month survival compared with LVEF ≥55%.
32
In a Japanese registry of 3815 patients, those with LVEF <60% managed conservatively had higher all-cause and cardiovascular mortality, sudden death, valve-related events, and heart failure hospitalizations than those with LVEF ≥60%, a risk that was significantly attenuated by early intervention.
33
Similarly, an international multicentre registry showed that Vmax ≥5.0 m/s or LVEF <60% were associated with higher all-cause and cardiovascular mortality, even after AVR31,33,34 In a large international registry of 1493 patients with bicuspid aortic valve disease, LVEF <60% was independently associated with substantially increased mortality risk, supporting current recommendations to raise guideline cutoff values from 50% to 60% in patients with AS.
35
Taken together, these findings indicate that LVEF values below conventionally “normal” thresholds (<55% and <60% in selected high-risk settings) are associated with excess mortality, supporting consideration of earlier intervention in selected patients32,34
Global longitudinal strain
GLS is a sensitive marker of early subendocardial dysfunction in AS and may become abnormal before any decline in LVEF, helping to identify patients who are already transitioning toward myocardial damage. 36 Impaired baseline GLS (<16%) has been shown to correlate with worse functional capacity, a higher incidence of atrial fibrillation, the presence of revascularized coronary artery disease, increased LV mass index, and more severe AS.37,38 In asymptomatic patients with severe AS, an individual participant data meta-analysis demonstrated that impaired GLS is common (affecting nearly one third of patients) and is associated with a 2.5-fold higher risk of death, with GLS <14.7% emerging as the best prognostic threshold for mortality risk stratification. 36 In addition, GLS can be complemented by LV mechanical dispersion (MD) and in patients with severe AS, preserved LVEF and no/mild symptoms, MD ≥68 ms is independently associated with higher mortality, and the combination of MD ≥68 ms plus impaired GLS (≤15%) identifies a particularly high-risk subgroup compared with having none or only one abnormal parameter.37–39 Overall, GLS is especially useful in clinical scenarios in which treatment timing is challenging, such as asymptomatic severe AS or discordant echocardiographic severity metrics.
Emerging Echocardiographic Parameters
Valvulo-arterial impedance index (Zva)
Zva is a marker of global LV hemodynamic load that integrates both valvular and arterial components of afterload. In asymptomatic severe AS, higher Zva values have been associated with worse clinical outcomes. 40 In the landmark study by Hachicha et al, a Zva ≥4.5 mm Hg·ml−1·m2 was associated with a 2.7 to 3.7-fold higher risk of overall and cardiovascular mortality, while intermediate values between 3.5 and 4.5 mm Hg·ml−1·m2 conferred a 2.3 to 3.1-fold increase. Patients with Zva >3.5 had significantly poorer survival when treated medically, whereas those with lower Zva ≤3.5 or undergoing AVR achieved outcomes like or better than general population. 39 Mantha et al confirmed the prognostic value of Zva, suggesting that values >3.5 to 5.0 mm Hg·ml−1·m2 reflect excessive LV afterload and predict adverse events, LV dysfunction, and higher mortality in asymptomatic severe AS. 27 These findings highlight Zva as a practical, integrative index for refining risk stratification and optimizing timing of intervention in patients with severe AS.
Overall, echocardiography enables anatomical and hemodynamic classification of AS and the identification of ventricular dysfunction signs that may justify earlier intervention even without overt symptoms.
Role of Exercise Testing, Stress Echocardiography, and Cardiopulmonary Exercise Testing
These modalities play a central role in the evaluation of asymptomatic severe AS. The development of exertional dyspnea, angina, syncope, or an abnormal blood pressure response (failure to rise or a sustained fall >20 mm Hg) identifies high-risk patients who should be managed as patients with symptomatic AS, consistent with a Class I indications for intervention in the 2025 ESC guidelines. 9 Quantitative exercise Doppler echocardiography provides incremental prognostic value beyond clinical findings: a baseline AVA ≤0.75 cm2 and an exercise-induced increase in mean transvalvular gradient ≥18 to 20 mm Hg are independently associated with adverse outcomes.40–43 Thus, exercise testing is recommended for risk stratification in asymptomatic severe AS, while stress exercise echocardiography provides additional prognostic information by quantifying hemodynamic response to exertion.2,43,44 Cardiopulmonary exercise testing, alone or combined with stress echocardiography, is useful to differentiate cardiac from pulmonary limitation or deconditioning in patients with nonspecific symptoms and can detect impaired cardiac reserve to improve risk stratification. 45 Altogether, these functional assessments complement resting echocardiography by integrating exercise capacity, hemodynamic load, and ventricular response, and their abnormal findings are increasingly incorporated into guideline-directed decision-making to support earlier intervention in selected asymptomatic patients.
Complementary Diagnostic Modalities
Computed Tomography
Quantification of aortic valve calcium is a key diagnostic and prognostic tool, with established thresholds (≥1200 Agatston units in women and ≥2000 in men) confirming severe AS. Computed tomography offers an alternative anatomical measure of severity that is truly flow independent, reliable, inexpensive, and reproducible. 46 It is particularly valuable in clinical scenarios with discordant hemodynamic criteria, such as low-flow, low-gradient AS with reduced LVEF (mean transvalvular gradient <40mm Hg, AVA ≤ 1cm2, LVEF<50%), low-flow, low-gradient AS with preserved LVEF (mean transvalvular gradient <40mm Hg, AVA ≤ 1cm2, SVi ≤ 35 ml/m2, LVEF≥50%) and normal-flow, low-gradient AS (mean transvalvular gradient <40 mm Hg, AVA ≤1.0 cm2, SVi >35 mL/m2, LVEF ≥50%).9,18,46
Blood Biomarkers
BNP/NT-proBNP are cardiac biomarkers that are released in response to increased ventricular and atrial wall stress. 47 AS leads to progressive hemodynamic changes and LV hypertrophy, and natriuretic peptides levels correlate with Vmax, AVA, and mean transvalvular gradients. Elevated circulating levels are associated with and abnormal blood pressure response to exercise, symptom onset, increased mortality, and the need for intervention.3,4,19 Among asymptomatic patients with moderate or severe AS, higher natriuretic peptide levels have been associated with the development of symptoms and AVR requirement, while in patients undergoing surgical or transcatheter AVR, elevated NT-proBNP were independently associated with an increased risk of mortality and heart failure rehospitalization and provides important prognostic value when incorporated into multimarker risk scores.48,49 However, BNP and NT-proBNP have limited specificity as markers of AS severity and AS-related myocardial wall stress, since multiple clinical factors can lead to misinterpretation, either overestimating level (eg, renal dysfunction, advanced age, female sex, atrial fibrillation, inflammation, hyperthyroidism, among others) or underestimating levels (notably obesity); therefore, natriuretic peptides should interpreted in clinical context and alongside imaging- based AS severity assessment. 47
Mechanical Dispersion and Myocardial Work: Role in Risk Stratification
Mechanical Dispersion
Standard deviation of the time-to-peak longitudinal strain in 16 LV segments (measured from QRS onset). Higher MD reflects mechanical desynchrony related to fibrosis, conduction abnormalities, and pressure overload. In 364 patients with severe AS, LVEF ≥50%, and minimal or no symptoms, MD ≥68 ms independently predicted higher mortality with an adjusted Hazard Ratio (HR) 1.41; 95% CI [1.01-1.96]. The combination of elevated MD and impaired GLS (≥ −15%) doubled mortality risk compared with the absence of these criteria, improving reclassification and discrimination over GLS alone
Myocardial Work and Global Work Index
Integrates GLS with estimated afterload (brachial systolic blood pressure + mean transvalvular gradient) to build pressure–strain loops and derive Global Work index (GWI), constructive work, wasted work, and efficiency. In the AVATAR subanalysis 50 ; 86 asymptomatic severe AS patients, LVEF >50%, AVA <1 cm2, mean transvalvular gradient >40 mm Hg), GWI ≤2000 mm Hg% was linked to higher mortality (26% vs 2%) and combined death/HF hospitalization (42% vs 5%, P < .001). In multivariate analysis, GWI and GLS were independent predictors; GWI showed superior discrimination (AUC 0.87 vs 0.70 for mortality; P = .034). Prognostic value persisted in both operated and conservatively managed patients. Consistent findings have been reported by Fortuni et al. 51
MD provides insight into synchrony and damage extent; myocardial work (MW)/GWI adjusts LV performance to hemodynamic load, particularly relevant in AS. Combining MD, MW, and GLS can detect subclinical dysfunction invisible to LVEF, identify high-risk patients in asymptomatic phases, and optimize surgical timing before irreversible deterioration
Relevant Associated Conditions
AS and transthyretin amyloidosis (ATTR): The coexistence of AS and ATTR is more frequent than previously thought in elderly severe AS patients, particularly men and TAVR candidates. Typical profile: male, mean age 79, advanced dyspnea (NYHA III-IV ∼60%), carpal tunnel history (∼30%), low-flow/low-gradient pattern (∼86%), marked hypertrophy (septum ∼18 mm).53,54 Pathophysiologically, oxidative stress, chronic inflammation, and extracellular remodeling contribute to both valve calcification and amyloidogenesis. This association correlates with greater hypertrophy, more symptoms, and worse prognosis (mortality ∼44% at 33 months). Recognizing this entity is crucial as it may influence treatment strategy, follow-up, and expectations of intervention response. Systematic detection via bone scintigraphy with specific tracers and cardiac magnetic resonance (CMR) with LGE can improve risk stratification and guide personalized management. 54
AS and Lipoprotein(a)
Lipoprotein(a) (Lp[a]) is not only independently associated with valve calcification and AS development but is also considered a causal factor, as supported by genetic and Mendelian randomization studies. 55 In ASTRONOMER, 26 each 10 mg/dL rise in Lp[a] increased accelerated progression risk by ∼10%; higher oxidized phospholipids carried by Lp[a] also correlated with progression. Measuring Lp[a] can identify individuals for closer follow-up and early interventions.56,57
Cardiac Damage Staging
The staging classification of cardiac damage in AS was first proposed by Généreux et al in 2017, in a pivotal analysis of 1661 patients with severe AS enrolled in the PARTNER 2 trials. 58 This framework complements valvular severity assessment by linking AS to the extent of extravalvular cardiac damage, categorizing patients into 5 stages of cardiac injury (stages 0–4) according to progressive involvement of cardiac structures: none (Stage 0), LV damage with LV hypertrophy (LV mass index >95 g/m2 women and 115 g/m2 men) (Stage 1), LA and/or mitral valve damage with LA volume >34 ml/m2, AF, or ≥ moderate MR (Stage 2), pulmonary artery vasculature or tricuspid valve dysfunction (PASP ≥60 mm Hg) or ≥ moderate TR (Stage 3), and RV damage with TAPSE <16 m or moderate to severe RV dysfunction) (Stage 4).58–61 This model reflects the cumulative impact of chronic pressure overload and myocardial maladaptation, integrating both structural and functional consequences of disease progression.
Each stage incorporates well-validated echocardiographic markers of remodeling and dysfunction, including LV hypertrophy, diastolic or systolic dysfunction, LA enlargement, pulmonary hypertension, and RV dysfunction. In the original cohort, the prevalence of stages was 2.8%, 12.8%, 50.8%, 24.9%, and 8.7%, respectively, and one-year mortality increased stepwise from 4.4% to 24.5% (P < .001), with a 46% higher risk of death for each incremental stage (HR 1.46). 58 This staging system conceptualized AS as a progressive myocardial disease rather than an isolated valvular disorder, providing incremental prognostic value beyond traditional surgical risk and frailty scores (Net Reclassification Index ≈ 0.15), thereby shifting the clinical paradigm from valve-centered severity assessment toward a more comprehensive evaluation of myocardial disease burden. 58
Since its introduction, this framework has been validated in multiple independent cohorts. In asymptomatic severe AS, Tastet et al reported a similar distribution (Stages 0-4: 10%, 44%, 35%, 11%) with a graded increase in mortality and adverse cardiac events, even in patients without symptoms. 60 A substantial proportion of these asymptomatic patients already exhibit advanced stages of cardiac damage, reinforcing the concept that absence of symptoms does not equate to absence of disease progression. 62
Although the original staging system proposed by Généreux et al remains the most widely used framework, subsequent studies have introduced variations in the definition of cardiac damage, particularly with the incorporation of advanced imaging parameters such as myocardial strain and cardiac magnetic resonance. Despite this heterogeneity, the overall concept of progressive extravalvular cardiac involvement and its strong prognostic significance has been consistently validated across different populations.
In symptomatic AS populations undergoing TAVR, Vollema et al and Abdelfattah et al confirmed the independent prognostic significance of each stage, with adjusted hazard ratios between 1.3 and 1.5 per stage increase and markedly higher postprocedural mortality in Stages ≥ 3.63,64 Most recently, Takeji et al extended this concept to moderate and severe AS, both symptomatic and asymptomatic, demonstrating a continuous gradient in long term (5-year) mortality across stages (from 8% in Stages 0-1% to 37% in Stage 4), independent of symptom status and hemodynamic severity. 61
This evidence confirms that the extent-of-cardiac-damage staging system has evolved from a descriptive anatomic concept to a robust, prognostically validated framework that integrates structural and functional consequences of AS. Is incorporation into clinical decision-making could refine the timing of intervention, especially among asymptomatic or moderate AS patients, by identifying those with early extra-valvular injury at higher risk for adverse outcomes.
Clinically, cardiac damage progresses in a sequential pattern from LV involvement to LA/mitral changes, pulmonary vascular and tricuspid disease, and ultimately RV dysfunction.58,60,62,63 Mortality rises sharply beyond Stage 2, supporting the concept that intervention before or at the onset of this stage may prevent irreversible remodeling, even in the absence of symptoms.58,60 AS should be regarded as a progressive myocardial disease continuum rather than a purely valvular condition. In this context, integrating cardiac damage staging into routine evaluation may help identify a therapeutic window for earlier intervention, particularly in patients classified as asymptomatic by conventional criteria (Table 2).
Evidence from Randomized Trials, Registries, and Observational Studies in Asymptomatic AS.
AS, aortic stenosis; AVR, aortic valve replacement; EF, ejection fraction; LVEF, left ventricular ejection fraction; SAVR, surgical aortic valve replacement; CV, Cardiovascular; CMR, cardiac magnetic resonance; TAVR, transcatheter aortic valve replacement
A simplified schematic representation of the cardiac damage staging framework is provided in the central illustration.
Systematic Review and Meta-Analysis (Généreux et al, JACC 2025)
Pooling RECOVERY, AVATAR, EARLY TAVR, and EVOLVED in a study-level meta-analysis using a random-effects model, the early valve intervention strategy (SAVR/TAVR) was associated with significant reductions in morbidity outcomes compared with clinical surveillance, including HF hospitalization, with no heterogeneity (HR 0.28; 95% CI [0.17-0.47]; P < .01; I2 = 0%), unplanned CV hospitalization (including HF-related admissions) (HR 0.40; 95% CI [0.30-0.53]; P < .01; I2≈4%), and stroke (HR 0.62; 95% CI [0.40-0.97]; P = .03; I2 = 0%). In contrast, early intervention did not significantly reduce all-cause mortality (HR 0.68; 95% CI [0.40-1.17]; P = .17; I2≈61%) or CV mortality (HR 0.67; 95% CI [0.35-1.29]; P = .23; I2≈50%), showing a moderate heterogeneity for mortality endpoints and minimal heterogeneity for hospitalization and stroke outcomes.
71
In the subgroup analyses by intervention modality, suggested a possible survival benefit in the SAVR (RECOVERY and AVATAR), whereas EARLY TAVR did not. EVOLVED was not included in SAVR/TAVR subgrouping because both modalities were permitted. Overall, these findings suggest that early intervention primarily reduces clinical events and healthcare utilization (HF- and CV-related admissions and stroke
Meta-Analysis (Jacquemyn et al, 2025; International Journal of Cardiology)
This recent time-to-event meta-analysis from 4 randomized controlled trials (RCTs) comparing early AVR versus conservative management in asymptomatic severe AS (RECOVERY, AVATAR, EARLY TAVR, and EVOLVED; n = 1427) found that an early AVR strategy was associated with significantly lower all-cause mortality (HR 0.72; 95% CI [0.53-0.97]; P = .031), cardiovascular mortality (HR 0.56; 95% CI [0.36-0.89]; P = .014), and heart failure–related hospitalization (HR 0.31; 95% CI [0.18-0.53]; P < .001) compared with conservative management, with no evidence of effect modification by intervention modality (SAVR vs TAVR). 72 Crossover to AVR was frequent in the conservative arm (median time to conversion, 13.4 months), reaching 42.8% at 1 year, 82.3% at 3 years, and 94.9% at 5 years. These results contrast with a prior study-level pooled analysis of the same trials, which demonstrated significant reductions in unplanned CV/HF hospitalization and stroke but no statistically significant mortality benefit, underscoring how analytic strategy can influence inference. Jacquemyn et al reconstructed individual patient–level time-to-event data from digitized Kaplan–Meier curves and analyzed outcomes using a Cox frailty approach, which may yield narrower confidence intervals and greater sensitivity to detect survival differences than pooling trial-reported HRs. However, this reconstructed approach could not pool stroke outcomes because only one trial provided suitable Kaplan–Meier curves for that endpoint, and it incorporated populations with heterogeneous risk profiles (younger, lower-risk SAVR cohorts vs older, more comorbid TAVR cohorts), which may partly explain discrepancies across meta-analyses. 72
Systematic Review and Meta-Analysis (de Pontes et al, The American Journal of Cardiology 2025)
This complementary 2025 systematic review and random-effects meta-analysis evaluated early AVR versus conservative management in asymptomatic severe AS with preserved LVEF, including 7 studies (4 RCTs + 3 observational; n = 2531) with a median follow-up of 49.3 months. 73 Using a random-effects model, early AVR was associated with lower all-cause mortality (HR 0.51; 95% CI [0.31-0.83]) and cardiac mortality (RR 0.51; 95% CI [0.30-0.89]) in the overall pooled analysis, while showing no significant differences for several nonfatal endpoints. However, in the prespecified RCT-only subanalysis (n = 1427), early AVR was associated with lower stroke (RR 0.62; 95% CI [0.40-0.95]) and hospitalization for CV causes (RR 0.41; 95% CI [0.27-0.63]), without a significant mortality difference, underscoring how conclusions may differ depending on whether observational data are included versus restricting synthesis to randomized evidence. 73
Discussion
The classification of patients with severe AS as asymptomatic remains inherently challenging. This designation may be misleading in clinical practice. Reliance on patient- reported symptoms alone may result in misclassification, as many individuals adapt their level of physical activity and fail to recognize early functional limitation. This issue is particularly relevant when interpreting contemporary randomized trials, in which objective strategies such as exercise testing were incorporated to confirm asymptomatic status.10,16,67 Differences in symptom assessment and patient selection may therefore contribute to the heterogeneity observed across studies evaluating early intervention versus clinical surveillance. 74
From a clinical perspective, this highlights that “asymptomatic” severe AS should be viewed as a dynamic and potentially transitional state rather than a truly benign condition. Incorporating objective functional assessment into routine evaluation may improve risk stratification and help identify patients who could benefit from earlier intervention. 9
The optimal timing of intervention in asymptomatic severe AS remains a subject of ongoing debate, requiring clinicians to balance the risks of premature intervention against the possibility of progressive and potentially irreversible myocardial damage with conservative management. Recent randomized evidence has strengthened the rationale for earlier intervention in selected patients; however, the magnitude and consistency of benefit—particularly regarding mortality has not been uniform across trials. RECOVERY showed a marked reduction in cardiovascular and all-cause mortality with early surgery in very severe asymptomatic AS, whereas AVATAR, although underpowered, demonstrated a significant reduction in a composite endpoint including all-cause death and suggested a favorable mortality signal with early SAVR.16,50
In contrast, among the more contemporary trials, EARLY TAVR showed a significant reduction regarding the primary composite endpoint of death, stroke, or unplanned cardiovascular hospitalization, driven mainly by fewer hospitalizations, but did not demonstrate a clear, isolated mortality benefit. 70 EVOLVED, which selectively enrolled patients with mid-wall fibrosis on CMR, did not significantly demonstrate a reduction of the primary composite endpoint of all-cause death or unplanned AS-related hospitalization, nor did it show a clear mortality reduction with early AVR. 69 This underscores heterogeneity by trial design, patient profile, and intervention modality.
This heterogeneity is also evident across meta-analysis. Conventional study-level meta-analysis pooling of trial-reported estimates has most consistently demonstrated reductions in heart failure–related and unplanned cardiovascular hospitalizations and stroke, while showing less consistent effects on all-cause and cardiovascular mortality. 71 Conversely, a recently published meta-analysis reconstructing individual patient data (IPD) from the 4 available RCTs in asymptomatic severe AS (RECOVERY, AVATAR, EARLY TAVR, EVOLVED) reported significant reductions in all-cause mortality, cardiovascular mortality and heart failure hospitalizations favoring early AVR. 72 In addition, a separate 2025 systematic review that included both randomized and observational evidence (4 RCTs plus 3 observational studies) reported lower mortality with early AVR in the overall pooled analysis, but in its prespecified RCT-only analysis, the most consistent benefits were reductions in stroke and CV hospitalizations, without a significant mortality difference. 73
Together, these findings highlight how analytic approach (IPD reconstruction vs study-level pooling), crossover rates, event counts, follow-up duration, endpoint availability (eg, limited stroke data for reconstruction), and population heterogeneity across SAVR and TAVR cohorts (younger, lower-risk surgical populations vs older, more comorbid transcatheter populations) can substantially influence interpretation of treatment effects.
The role of TAVR in asymptomatic severe AS has been explored in recent RCTs, although several important questions remain. The EARLY TAVR trial demonstrated that early transcatheter intervention significantly reduced the composite endpoint of death, stroke, or unplanned cardiovascular hospitalization compared with clinical surveillance, primarily driven by a reduction in unplanned hospitalizations, without a clear mortality benefit. 70 Notably, early TAVR was also associated with improved quality of life and more favorable cardiac remodeling. 70 In contrast, the EVOLVED trial, which enrolled higher-risk patients with myocardial fibrosis, did not show a significant reduction in death or AS-related hospitalization with early intervention, although its findings are limited by small sample size and the predominance of surgical treatment. 69
Taken together, these data suggest that early TAVR may improve clinical outcomes primarily by reducing morbidity rather than mortality, although the generalizability of these findings remains uncertain. Beyond short-term outcomes, the role of TAVR in asymptomatic patients must be considered within a broader lifetime management strategy. 75 In younger or lower-risk individuals, key concerns include long-term valve durability, the feasibility of future coronary access, and the management of transcatheter valve failure. While valve-in-valve TAVR and redo-TAVR have emerged as feasible options with acceptable short-term outcomes, surgical explantation of transcatheter valves remains complex and associated with substantial risk. 75
Therefore, although TAVR represents an attractive minimally invasive option and is increasingly used across a broader age spectrum, current evidence is insufficient to support its routine use in all asymptomatic patients. Ongoing trials and long-term follow-up studies will be critical to better define patient selection and optimize lifetime management strategies in this population.
Clinically, operating too soon exposes patients to procedural risks and prosthesis-related limitations; while waiting for symptoms may lead to progression, irreversible myocardial damage, fibrosis and adverse remodeling, features associated with worse outcomes. According to the 2025 ESC/EACTS guidelines on valvular heart disease, intervention should be considered in asymptomatic patients (confirmed by a normal exercise test, if feasible) with severe, high-gradient AS and LVEF ≥50% as an alternative to close active surveillance when procedural risk is low (Class IIa). 9 Also, AVR should also be preferred when close clinical surveillance is not feasible.
For asymptomatic patients with severe AS and LVEF ≥50%, the presence of one or more high-risk parameters may further support consideration of early aortic valve intervention,
9
including:
Very severe AS: Vmax ≥5.0 m/s or mean transvalvular gradient ≥60 mm Hg. Severe valve calcification: (Agatston score >2000 AU in men or >1200 AU in women). Rapid hemodynamic progression (Vmax increase ≥0.3 m/s per year) Markedly elevated natriuretic peptides: BNP or NT-proBNP >3 times the upper limit of normal, attributable to AS. Reduced LVEF <55% attributable to AS. Abnormal exercise response on treadmill testing, such as a sustained fall in systolic blood pressure >20 mm Hg, is a guideline-recognized high-risk feature and helps to objectively unmask symptoms.
In asymptomatic patients with severe AS who do not meet any of the criteria for early intervention, a strategy of close and proactive clinical and echocardiographic surveillance is recommended to assess disease progression and detect early structural damage before symptoms onset.
Key features that may signal transition from compensated hypertrophy to early myocardial injury include:
Recognition of these findings may help personalize decision-making regarding the optimal window for aortic valve intervention in these patients.
Conclusions
In conclusion, contemporary evidence supports a paradigm shift toward earlier intervention in selected asymptomatic patients with severe AS, guided by multimodal assessment of myocardial structural and functional consequences rather than hemodynamic severity alone. However, the identification of optimal intervention thresholds remains an active area of clinical investigation, requiring careful integration of hemodynamic markers, advanced imaging, and individual risk profiles. Further refinement of risk stratification tools and of the precise threshold beyond which myocardial damage becomes irreversible is still needed.
Decision-making in asymptomatic severe AS integrating clinical, imaging, and cardiac damage staging parameters. The decision between early intervention and surveillance should be based on an integrated assessment rather than a single parameter. Advanced cardiac damage (Stage ≥2) is associated with worse outcomes but should be interpreted within the overall clinical context. BNP: B-type natriuretic peptide; GLS: global longitudinal strain; LVEF: left ventricular ejection fraction; LC: left ventricle; RV: right ventricle; LVEF: left ventricular ejection fraction.
Cardiac damage staging adapted from Généreux et al (2017). 58
Footnotes
Funding
The authors received no financial support for the research, authorship, and/or publication of this article.
Declaration of Conflicting Interests
The author declared the following potential conflicts of interest with respect to the research, authorship, and/or publication of this article: P Pibarot has received institutional funding from Edwards Lifesciences, Medtronic, Pi-Cardia, Cardiac Success, Boston Sc., Novartis for echocardiography core laboratory analyses and research studies in the field of valvular heart disease, for which he received no personal compensation.