Скриншот аортального клапана как независимый клинический знак системных заболеваний, диастической дисфункции и риска смерти: большое эхокардиографическое коортовое исследование.

Introduction

Aortic valve sclerosis (AVS) is the most common valvular abnormality in older adults and represents the first step in the continuum of calcific aortic valve disease. Traditionally regarded as a benign finding, accumulating evidence indicates that AVS is an active, progressive condition associated with aging and systemic comorbidities, particularly metabolic disorders [ 1 ]. These promote chronic inflammation and endothelial dysfunction which contribute to leaflet fibrosis, thickening, and ultimately calcification [ 2 , 3 ]. Importantly, AVS has been associated with adverse outcomes, including cardiovascular death and all-cause mortality [ 4 – 6 ]. AVS manifests along a continuum from early leaflet thickening to advanced calcification. Although CT allows quantitative assessment of calcium burden and AVC severity in relation to clinical characteristics [ 7 ], AVS assessed by echocardiography is more complex [ 8 , 9 ] and has rarely been evaluated beyond a simple presence-or-absence designation. Moreover, while a few prior studies have compared AVS with cardiac findings on echocardiography [ 10 – 12 ], the extent to which AVS severity relates to changes in cardiac structure and function remains uncertain. Considering AVS assessed by echocardiography as a continuum may clarify how progressive thickening and calcification relate to systemic metabolic and inflammatory processes and their potential effects on cardiac structure, function, and overall prognosis.

In this study, we leveraged a large, contemporary echocardiographic database to examine AVS across its full spectrum of severity. Our aims were to characterize associations between progressive AVS severity and systemic comorbidities, to evaluate its relationship with structural and hemodynamic changes of the heart, and to determine the independent prognostic significance of valvular calcification for clinical outcomes and survival.

Methods

Study Design, Participants, and Data Collection

All consecutive subjects that underwent echocardiography examinations recorded in the echocardiography database of a university-affiliated laboratory during a 12-year period (2011–2022) were retrieved for analysis. Individuals aged ≥18 years were included in the current cohort. For patients with multiple examinations, the index study was analyzed. Medical diagnoses of the individuals (ICD-9 codes) were retrieved from the electronic medical records. Echocardiographic data including original measurements of dimensions and calculations of volumes were performed according to standard recommendations of the American Society of Echocardiography and the European Association of Cardiovascular Imaging using 2D and/or linear, m-mode-guided measurements [ 13 ]. Individuals with more than mild aortic stenosis, defined as a mean transvalvular pressure gradient ≥20 mm Hg, an aortic valve area ≤1.5 cm 2 , a peak aortic jet velocity ≥3.0 m/s, or a qualitative echocardiographic assessment indicating more than mild aortic stenosis, were excluded. AVS severity was classified according to the reported echocardiographic appearance: valves were considered normal if no leaflet thickening or calcification was present; thickened if leaflet thickening was present without calcification; calcified if any calcification was present regardless of leaflet thickness; and severely calcified if the valve leaflets were heavily calcified. These classifications were based on standardized clinical reports recorded by the reporting clinician at the time of the index examination as part of the routine echocardiographic protocol at our center. Assessments utilized evaluation in standard transthoracic windows including parasternal and apical views. Relative wall thickness was calculated as (2 × PWd)/LVEDD, where PWd is the left ventricular (LV) posterior wall thickness in diastole and LVEDD is the LV end-diastolic dimension. LV ejection fraction (EF) was measured at rest and was assessed either by the Simpson biplane method or estimated qualitatively by the reporting cardiologist. Mitral e’ velocity and the E/e’ ratio were measured at the lateral mitral annulus, to estimate ventricular relaxation and filling pressures. Data on mortality were retrieved from the National Census Bureau to determine vital status. Survival was calculated from the date of the index echocardiogram, and administrative censoring was applied to all patients alive as of June 30, 2023. All hospitalizations in the cardiac intensive care and cardiology department were retrieved for analysis of cardiovascular hospitalizations. The Institutional Ethical Committee for human studies of the university-affiliated hospital approved the study protocol. Informed consent was waived by the Ethical Committee as the study was observational and data were analyzed retrospectively. A total of 42,959 individuals met the inclusion criteria and were included in the final analysis ( Fig. 1 ).

Study flowchart. Flow diagram illustrating the selection of the study cohort from the initial population-based sample.

Statistical Analysis

Baseline clinical characteristics were compared using analysis of variance for continuous variables and chi-square tests for categorical variables. Survival was analyzed from the date of the echocardiographic examination performed. Follow-up time was calculated using Kaplan-Meier estimate of potential follow-up. Kaplan-Meier curves with the log-rank test were used to compare survival. Multivariable Cox proportional hazard regression analysis was used to evaluate independent variables associated with survival and event-free survival from the composite endpoint of death and cardiovascular hospitalizations. Multivariable Cox regression analysis incorporated age, sex, heart failure, hypertension, diabetes, ischemic heart disease, atrial fibrillation, and chronic renal failure. An additional model included E/e’ ratio. Proportionality assumptions of the Cox regression models were evaluated by log-log survival curves and with the use of Schoenfeld residuals. Transformations were applied where appropriate to meet model assumptions. Variables were assessed for confounding, interaction, and potential collinearity. A p value of <0.05 was considered statistically significant. SPSS version 17.0 for Windows (SPSS Inc., Chicago, IL, USA) was used for the statistical analysis.

Results

Baseline Characteristics and Systemic Disease Burden

A total of 42,959 individuals were included in the cohort analysis. Patients were grouped according to echocardiographic assessment of AVS severity. Normal valve morphology was observed in 29,724 (69%), thickened valves in 6,980 (16%), calcified valves in 5,534 (13%), and severely calcified valves in 721 (2%) ( Fig. 2 ). Baseline characteristics ( Table 1 ) demonstrated a graded, stepwise increase in patient age, clinical comorbidity burden, and prevalent heart failure across the four AVS severity groups. Patients with advanced AVS were significantly older, highlighting the degenerative nature of the condition and its association with aging. The prevalence of major cardiovascular and systemic risk factors showed a pronounced, graded escalation with increasing AVS severity. The prevalence of hypertension, diabetes mellitus, atherosclerotic cardiovascular disease, heart failure, atrial fibrillation, and renal failure demonstrated notable, graded increases across the severity spectrum. A corresponding stepwise increase in the mean number of comorbidities per individual was also observed. These findings suggest that AVS serves as a clinical marker of underlying systemic disease burden. The prevalence of heart failure showed a steep, stepwise increase from the normal group to the most severe calcification group ( Table 1 ). This highlights that AVS is a powerful marker of escalating baseline systemic risk and prevalent heart failure.

Distribution of aortic valve sclerosis (AVS) severity in the study cohort pie chart illustrating the relative proportions of individuals with normal valve morphology, thickened valves, calcified valves, and severely calcified valves among 42,959 participants.

Table 1. Baseline clinical characteristics stratified by AVS severity ​ Normal ( N = 29,724) Thickened ( N = 6,980) Calcified ( N = 5,534) Severely calcified ( N = 721) Total ( N = 42,959)
p value Age, years 55±20 66±14 74±11 79±10 60±19 <0.001 Age >70 years 7,289 (25) 2,932 (42) 3,694 (67) 583 (81) 14,498 (34) <0.001 Gender (male) 16,974 (57) 3,847 (55) 3,057 (55) 412 (57) 24,290 (57) 0.004 Death 3,908 (13) 1,832 (26) 2,145 (39) 311 (43) 8,196 (19) <0.001 Number of comorbidities 2.1±2.2 3.0±2.2 4.2±2.2 4.4±2.1 2.6±2.3 <0.001 Heart failure 4,124 (14) 1,623 (23) 1,927 (35) 266 (37) 7,940 (18) <0.001 HF type  HFPEF 1,901 (6) 733 (11) 989 (18) 134 (19) 3,757 (9) <0.001  HFMREF 658 (2) 290 (4) 334 (6) 46 (6) 1,328 (3)  HFREF 1,397 (5) 561 (8) 582 (11) 81 (11) 2,621 (6) Hypertension 12,337 (42) 4,055 (58) 4,202 (76) 561 (78) 21,155 (49) <0.001 Diabetes mellitus 7,344 (25) 2,318 (33) 2,535 (46) 312 (43) 12,509 (29) <0.001 Obesity 4,393 (15) 1,035 (15) 993 (18) 121 (17) 6,542 (15) <0.001 Hyperlipidemia 10,722 (36) 3,299 (47) 3,169 (57) 406 (56) 17,596 (41) <0.001 Ischemic heart disease 7,421 (25) 2,511 (36) 2,586 (47) 331 (46) 12,849 (30) <0.001 Prior myocardial infarction 5,073 (17) 1,317 (19) 1,317 (24) 173 (24) 7,880 (18) <0.001 CABG 811 (3) 295 (4) 296 (5) 37 (5) 1,439 (3) <0.001 Atrial fibrillation 3,569 (12) 1,440 (21) 1,674 (30) 242 (34) 6,925 (16) <0.001 Chronic renal failure 4,341 (15) 1,538 (22) 1,810 (33) 266 (37) 7,955 (19) <0.001 Hemodialysis 622 (2) 292 (4) 394 (7) 56 (8) 1,364 (3) <0.001 CVA 3,760 (13) 1,292 (19) 1,355 (24) 210 (29) 6,617 (15) <0.001 Body mass index, kg/m 2 27±7 27±6 28±6 27±5 27±7 <0.001 Values are presented as mean ± standard deviation or n (%). Groups were defined as: normal (no leaflet thickening or calcification), thickened (leaflet thickening without calcification), calcified (any calcification regardless of leaflet thickness), and severely calcified (heavily calcified valve leaflets). p values reflect overall group comparisons using ANOVA for continuous variables and χ 2 tests for categorical variables. HFpEF, heart failure with preserved ejection fraction; HFmrEF, heart failure with mildly reduced ejection fraction; HFrEF, heart failure with reduced ejection fraction; CABG, coronary artery bypass grafting; CVA, cerebrovascular accident.

Baseline clinical characteristics stratified by AVS severity

Values are presented as mean ± standard deviation or n (%). Groups were defined as: normal (no leaflet thickening or calcification), thickened (leaflet thickening without calcification), calcified (any calcification regardless of leaflet thickness), and severely calcified (heavily calcified valve leaflets). p values reflect overall group comparisons using ANOVA for continuous variables and χ 2 tests for categorical variables.

HFpEF, heart failure with preserved ejection fraction; HFmrEF, heart failure with mildly reduced ejection fraction; HFrEF, heart failure with reduced ejection fraction; CABG, coronary artery bypass grafting; CVA, cerebrovascular accident.

Aorto-Ventricular Coupling and Diastolic Disease

The graded increase in AVS severity was associated with corresponding changes in cardiovascular structure and function ( Table 2 ). Increasing AVS severity was associated with larger vascular dimensions and more pronounced LV geometric changes. Specifically, the degree of AVS was directly associated with a stepwise increase in the proximal ascending aorta index. Correspondingly, a graded increase was observed in LV geometric parameters, including the LV interventricular septal thickness, LV mass index, and relative wall thickness, indicating concentric geometry of the ventricle. These structural changes were accompanied by a graded deterioration in diastolic function. The index of myocardial relaxation, mitral valve e’, showed a progressive decrease, while the E/e’ ratio showed a corresponding increase, suggesting progressive diastolic dysfunction with elevated LV filling pressures. The downstream consequences of this pressure overload were reflected by a parallel increase in the LA volume index (LAVI) and the tricuspid regurgitation peak gradient, a surrogate for pulmonary artery systolic pressure, reflecting post-capillary pulmonary venous hypertension due to elevated LV filling pressures. Interestingly, LV EF remained preserved on average across all AVS groups. Consistent with the hemodynamic findings on echocardiography, HF prevalence increased proportionally with AVS severity, driven primarily by the heart failure with preserved ejection fraction (HFpEF) phenotype, which nearly doubled the increase observed for HFrEF (19% versus 11%, respectively; Table 1 ).

Table 2. Baseline echocardiographic characteristics stratified by AVS severity ​ Normal ( N = 29,724) Thickened ( N = 6,980) Calcified ( N = 5,534) Severely calcified ( N = 721) Total ( N = 42,959)
p value LV EF, % 57±11 57±12 56±13 56±13 57±11 <0.001 LVEDD, mm 47±7 49±7 49±7 47±9 48±7 <0.001 LV ESD, mm 31±7 32±8 32±9 32±9 31±7 <0.001 LV IVSd, mm 9.3±2.9 9.8±2.9 10.3±2.8 11.1±4.7 9.6±2.9 <0.001 LV PWd, mm 8.8±2.6 9.0±2.5 9.4±2.7 9.8±2.7 9.0±2.6 <0.001 Relative wall thickness 0.38±0.26 0.39±0.44 0.40±0.17 0.44±0.17 0.39±0.29 <0.001 LV mass index, gr/mm 2 94±40 106±83 112±57 114±43 99±53 <0.001 LA volume index, mL/m 2 23±11 29±14 33±15 35±15 26±13 <0.001 MV E/A 1.2±0.6 1.1±0.7 1.1±0.7 1.2±0.9 1.2±0.6 <0.001 e’ lateral, m/s 11.2±5.2 9.2±4.5 8.3±4.9 8.4±6.7 10.3±5.2 <0.001 MV E/e’ (lateral) 7.6±3.9 9.1±4.5 10.7±5.5 11.6±5.4 8.3±4.4 <0.001 TR peak gradient, mm Hg 25±10 29±11 32±12 32±12 27±11 <0.001 Severe MR 480 (2) 246 (4) 233 (4) 44 (6) 1,003 (2) <0.001 AV mean gradient, mm Hg 6.2±4.1 5.9±3.1 8.4±4.2 11.2±5.4 6.9±4.3 <0.001 Proximal Ascending Aorta Index, mm/m 2 16.9±2.8 18.1±2.9 18.8±3.1 19.1±3.1 17.4±3.0 <0.001 Values are presented as mean ± standard deviation. EF, ejection fraction; EDD, end-diastolic diameter; ESD, end-systolic diameter; IVSd, interventricular septal thickness at diastole; PWd, posterior wall thickness at diastole; LV, left ventricle; LA, left atrium; MV, mitral valve; MR, mitral regurgitation; TR, tricuspid regurgitation.

Baseline echocardiographic characteristics stratified by AVS severity

Values are presented as mean ± standard deviation.

EF, ejection fraction; EDD, end-diastolic diameter; ESD, end-systolic diameter; IVSd, interventricular septal thickness at diastole; PWd, posterior wall thickness at diastole; LV, left ventricle; LA, left atrium; MV, mitral valve; MR, mitral regurgitation; TR, tricuspid regurgitation.

AVS and Adverse Clinical Outcomes

Median follow-up time was 1,312 days (95% CI: 1,292–1,331). Kaplan-Meier survival analysis demonstrated that increasing AVS severity was associated with a steep and progressive decline in cumulative survival (Log-rank p < 0.001; Fig. 3 ). To assess the independent contribution of AVS severity to mortality beyond baseline comorbidities, we performed multivariable Cox proportional hazards analysis. In the unadjusted model ( Table 3 , model 1), AVS severity (reference: normal group) was strongly associated with increased risk of all-cause mortality. In the adjusted model including demographics and major cardiovascular risk factors (model 2), the risk remained highly significant, with mortality progressively increasing across AVS severity categories. In the fully adjusted model (model 3), which additionally controlled for the E/e’ ratio, the mortality hazard demonstrated a clear incremental increase across the spectrum ( p < 0.001). Patients with severe calcification exhibited the highest independent risk, with a 1.61-fold increased hazard of death (HR: 1.61; 95% CI: 1.38–1.87; Table 3 ). Similar, significant graded associations were observed for the composite endpoint of death and cardiovascular hospitalization ( Table 4 ).

Kaplan-Meier survival curves by aortic valve sclerosis (AVS) severity. Kaplan-Meier curves illustrating cumulative survival stratified by AVS severity (normal, thickened, calcified, severely calcified). Survival declined progressively with increasing severity, with patients in the severely calcified group demonstrating the shortest median survival (1,643 days). Overall comparison across groups was highly significant (log-rank χ 2 = 1,946.7, p < 0.001).

Table 3. Cox proportional hazards models for mortality according to AVS severity Variable Model 1: unadjusted HR (95% CI)
p value Model 2: adjusted HR (95% CI)
p value Model 3: adjusted + diastolic HR (95% CI)
p value AVS severity ​ <0.001 ​ <0.001 ​ <0.001  Normal 1.0 (reference) ​ 1.0 (reference) ​ 1.0 (reference) ​  Thickening 1.72 (1.63–1.82) <0.001 1.09 (1.03–1.15) 0.003 1.20 (1.12–1.28) <0.001  Calcification 2.81 (2.67–2.96) <0.001 1.22 (1.15–1.29) <0.001 1.30 (1.22–1.40) <0.001  Severe calcification 3.89 (3.47–4.37) <0.001 1.41 (1.25–1.58) <0.001 1.61 (1.38–1.87) <0.001 Other covariates Age, years – ​ 1.04 (1.03–1.04) <0.001 1.04 (1.03–1.04) <0.001 Sex (male) – ​ 1.04 (1.00–1.09) 0.08 1.12 (1.06–1.19) <0.001 Heart failure – ​ 1.55 (1.47–1.64) <0.001 1.53 (1.43–1.64) <0.001 Hypertension – ​ 0.83 (0.79–0.88) <0.001 0.78 (0.73–0.83) <0.001 Diabetes mellitus – ​ 1.30 (1.24–1.36) <0.001 1.31 (1.24–1.39) <0.001 Ischemic heart disease – ​ 0.85 (0.81–0.90) <0.001 0.83 (0.78–0.88) <0.001 Atrial fibrillation – ​ 1.12 (1.07–1.18) <0.001 1.10 (1.03–1.18) 0.005 Chronic renal failure – ​ 2.31 (2.19–2.43) <0.001 2.36 (2.22–2.52) <0.001 Ln MV E/e’ – ​ – ​ 1.17 (1.10–1.25) <0.001 Hazard ratios (HRs) with 95% confidence intervals (CIs) are shown for three models: model 1: unadjusted, model 2: adjusted for age, sex, and clinical comorbidities, and model 3: further adjusted for diastolic function (Ln MV E/e’). Normal valve morphology served as the reference category.

Cox proportional hazards models for mortality according to AVS severity

Hazard ratios (HRs) with 95% confidence intervals (CIs) are shown for three models: model 1: unadjusted, model 2: adjusted for age, sex, and clinical comorbidities, and model 3: further adjusted for diastolic function (Ln MV E/e’). Normal valve morphology served as the reference category.

Table 4. Cox proportional hazards models for the combined endpoint of death and cardiovascular hospitalization according to AVS severity ​ Model 1: unadjusted HR (95% CI) Model 2: adjusted HR (95% CI) Model 3: adjusted + diastolic HR (95% CI) AVS severity <0.001 <0.001 <0.001  Normal 1.0 (reference) 1.0 (reference) 1.0 (reference)  Thickening 1.67 (1.59–1.75), <0.001 1.12 (1.07–1.18), <0.001 1.20 (1.13–1.27), <0.001  Calcification 2.52 (2.40–2.64), <0.001 1.21 (1.15–1.27), <0.001 1.26 (1.19–1.34), <0.001  Severe calcification 3.13 (2.81–3.49), <0.001 1.33 (1.19–1.48), <0.001 1.48 (1.29–1.69), <0.001 Hazard ratios (HRs) with 95% confidence intervals (CIs) are shown for three Cox proportional hazards models examining the combined endpoint of death and cardiovascular hospitalization. Model 1 is unadjusted; model 2 is adjusted for age, sex, and clinical comorbidities; model 3 is further adjusted for diastolic function (Ln MV E/e’). Normal valve morphology served as the reference category.

Cox proportional hazards models for the combined endpoint of death and cardiovascular hospitalization according to AVS severity

Hazard ratios (HRs) with 95% confidence intervals (CIs) are shown for three Cox proportional hazards models examining the combined endpoint of death and cardiovascular hospitalization. Model 1 is unadjusted; model 2 is adjusted for age, sex, and clinical comorbidities; model 3 is further adjusted for diastolic function (Ln MV E/e’). Normal valve morphology served as the reference category.

Subgroup Analyses

Sex-stratified analysis (online suppl. Tables 1 and 2; for all online suppl. material, see https://doi.org/10.1159/000552614 ) demonstrated that both men and women shared a similar clinical profile as AVS severity progressed. In both sexes, increased calcification was consistently associated with a higher comorbidity burden, concentric LV geometry, and a higher prevalence of HFpEF. Both sexes showed a consistent, stepwise increase in mortality risk as valve severity worsened, which was comparable across both groups. Multivariable Cox interaction testing confirmed that the prognostic impact of AVS on all-cause mortality was consistent across both sexes (interaction p = 0.922).

We also stratified by age (65-year threshold) (online suppl. Tables 3 and 4). While older participants had a higher baseline burden of comorbidities, HF, and diastolic dysfunction, both groups showed a consistent, stepwise increase in these parameters as valve severity worsened. A significant interaction was observed between AVS severity and age. While mortality risk increased incrementally in both cohorts ( Fig. 4 and Table 5 ), early thickening was a significant independent predictor of death in younger patients, whereas in the older cohort, this risk became significant only at more advanced stages of calcification.

Kaplan-Meier survival curves by age and AVS severity. Impact of AVS severity on all-cause mortality stratified by age is shown for the four AVS categories: normal (blue), thickened (green), calcified (purple), and severely calcified (red). a Subjects aged 65 years and under ( N = 23,715). b Subjects aged over 65 years ( N = 19,244). Both cohorts demonstrate a significant, dose-dependent decline in survival as AVS severity increases (Log-rank p < 0.001). Notably, in the older cohort, survival disadvantage is primarily evident with calcified and severely calcified valves, whereas in the younger cohort, even milder thickening is associated with reduced survival. AVS, aortic valve sclerosis.

Table 5. Age-stratified multivariable Cox regression models for all-cause mortality stratified by AVS severity ​ Age ≤65 ( N = 23,715), HR (95% CI) Age >65 ( N = 19,244), HR (95% CI) AVS severity ​ <0.001 ​ <0.001 Normal 1.0 (reference) ​ 1.0 (reference) ​ Thickening 1.57 (1.40–1.77) <0.001 1.02 (0.94–1.11) 0.64 Calcification 1.54 (1.30–1.82) <0.001 1.18 (1.09–1.28) <0.001 Severe calcification 1.99 (1.20–3.29) 0.007 1.48 (1.27–1.74) <0.001 Adjustment: the models are adjusted for age, sex, heart failure, hypertension, diabetes mellitus, ischemic heart disease, atrial fibrillation, renal failure, and Ln MV E/e’ ratio. Interaction analysis: a formal interaction test between age (categorized as ≤65 vs. >65 years) and AVS severity was statistically significant (interaction p < 0.001). AVS, aortic valve sclerosis; CI, confidence interval; HR, hazard ratio.

Age-stratified multivariable Cox regression models for all-cause mortality stratified by AVS severity

Adjustment: the models are adjusted for age, sex, heart failure, hypertension, diabetes mellitus, ischemic heart disease, atrial fibrillation, renal failure, and Ln MV E/e’ ratio.

Interaction analysis: a formal interaction test between age (categorized as ≤65 vs. >65 years) and AVS severity was statistically significant (interaction p < 0.001).

AVS, aortic valve sclerosis; CI, confidence interval; HR, hazard ratio.

Discussion

In this large, population-based cohort, we demonstrate that AVS severity is a graded marker of systemic and structural cardiovascular disease and is associated with escalating clinical risk. Increasing AVS severity was significantly linked to a higher baseline burden of systemic comorbidities and was accompanied by pronounced concentric geometry of the LV, a structural change associated with echocardiographic evidence of diastolic dysfunction, and an increased prevalence of HF, specifically HFpEF. Critically, even after accounting for these strong correlates, AVS severity conferred a substantial, dose-dependent independent risk of all-cause mortality, which progressively increased across the spectrum of calcification. This finding was similarly robust for the composite endpoint of death and cardiovascular hospitalization, confirming the independent prognostic value of severe AVS.

AVS as a Marker of Systemic Disease

The graded increase in comorbidities across AVS severity groups in our cohort underscores that AVS is not a benign, isolated valvular finding, but rather a marker of systemic disease burden. Patients with more advanced AVS consistently demonstrated higher prevalence of hypertension, diabetes, renal dysfunction, atrial fibrillation, and atherosclerotic cardiovascular disease, with the mean number of comorbidities nearly doubling across the spectrum. This stepwise escalation highlights the close interplay between AVS and systemic metabolic and inflammatory disorders. These observations align with prior studies, showing that AVS shares risk factors and pathogenic pathways with atherosclerosis, including chronic inflammation, oxidative stress, and metabolic dysregulation [ 7 , 14 – 17 ]. Our findings extend this concept by demonstrating that the severity of AVS tracks proportionally with the burden of systemic disease, suggesting that AVS may serve as a clinical marker of widespread vascular and metabolic dysfunction. Recognizing AVS in this context confirms it is not just a localized degenerative process but an important systemic manifestation of cardiovascular risk, with implications for both prognosis and management.

AVS, Cardiovascular Remodeling, and Diastolic Dysfunction

Beyond its systemic associations, AVS severity was consistently associated with cardiac structural and functional remodeling. We observed an increase in the proximal aortic diameter with AVS severity. Aortic enlargement is associated with increased stiffness and reduced compliance, changes that are also influenced by aging and systemic comorbidities [ 18 , 19 ]. Several prior studies, including some utilizing CT-based AVS assessments, have described an association between AVS and indices of LV diastolic dysfunction [ 10 – 12 ]. Our study expands these findings to a much larger, general population all of whom underwent echocardiography. Notably, these abnormalities occurred in the setting of preserved EF, underscoring a phenotype dominated by impaired relaxation and elevated filling pressures. Clinically, this translated into a rising prevalence of heart failure across AVS categories, driven predominantly by HFpEF rather than HFrEF. Similarly, a previous study reported that greater AV calcium burden on CT was associated with a higher risk of developing heart failure [ 12 ]. This is supported by a recent study demonstrating that AVS, including mild AS, is highly prevalent among patients with HFpEF and is significantly associated with diastolic dysfunction [ 20 ]. Such observations situate AVS within a broader aorto-ventricular remodeling continuum, in which systemic metabolic and inflammatory stressors contribute to both valvular calcification and myocardial fibrosis. The association of AVS severity with diastolic indices highlights its potential role as a marker of HFpEF risk, reinforcing the view that AVS should be considered not only a valvular finding but part of a broader systemic and myocardial remodeling process. However, it is important to note that the prognostic implications of worsening AVS were independent of changes in diastolic function.

Mechanistic Interpretation

Aging and the systemic stressors identified in our cohort create a pro-inflammatory and metabolically adverse milieu that fosters endothelial dysfunction, oxidative stress, and lipid infiltration [ 3 ]. These upstream disturbances activate valvular interstitial cells, driving fibrotic and osteogenic signaling that culminates in leaflet thickening and calcification [ 21 ]. In parallel, the myocardium is exposed to the same systemic stressors but responds primarily with fibrotic remodeling, impaired relaxation, and elevated filling pressures [ 22 ], consistent with the HFpEF phenotype observed in our cohort. Local mechanical influences may coexist with these systemic drivers. Direct valvular afterload and reduced aortic compliance could contribute to remodeling, though their relative impact is difficult to delineate. The associations we observed are consistent with the hypothesis that systemic metabolic and inflammatory disturbances could underlie the relationship between AVS severity and related valvular and myocardial changes. Taken together, AVS severity reflects a systemic disease process with tissue-specific manifestations: fibrosis and calcification in the valve and predominantly fibrosis in the myocardium. This integrated view situates AVS within a continuum of systemic cardiovascular remodeling, including valvular pathology, vascular changes, and myocardial dysfunction.

Prognostic and Clinical Implications

The prognostic analyses in our cohort indicate that AVS severity is associated with progressively worse outcomes. Survival declined across AVS categories, and these associations remained evident even after adjustment for age, sex, comorbidities, and diastolic indices. The prognostic impact of AVS was consistent across both sexes but was significantly modified by age. Early valve thickening served as a marker of risk only in younger patients, potentially reflecting a state of accelerated biological aging. In the elderly, this incremental prognostic value was likely attenuated by competing age-related higher mortality.

Prior studies provide strong evidence that AVS is associated with an increased risk of atherosclerotic cardiovascular disease, progression to severe aortic stenosis [ 23 ], cardiovascular mortality, and all-cause mortality [ 4 – 6 ]. The dose-dependent nature of the relationship suggests that AVS severity reflects a continuum of risk rather than a binary finding. Patients with severe calcification demonstrated the highest independent risk, associated with a greater than 60% increased hazard of all-cause mortality and similarly elevated risk for the composite of death and cardiovascular hospitalization. While these results cannot establish causality, they highlight that AVS severity may provide incremental prognostic information beyond traditional risk factors and echocardiographic measures of diastolic function.

These findings support the view that AVS severity is not a benign echocardiographic observation but a marker of systemic disease burden, myocardial remodeling, and adverse outcomes. Recognizing AVS in this graded context suggests that the clinical relevance of aortic valve disease begins well before the onset of hemodynamic obstruction. This identifies an early stage of the disease spectrum that may encourage a more comprehensive evaluation of comorbidities and diastolic function, allowing clinicians to better identify and optimize management of the underlying metabolic and inflammatory milieu within the systemic disease continuum.

Limitations

Several limitations of this study should be acknowledged. First, the retrospective design introduces the possibility of residual confounding and limits causal inference. Although we adjusted for major comorbidities and diastolic indices, unmeasured factors may have contributed to the observed associations. Second, AVS severity was assessed visually, which, while practical in routine echocardiography, is inherently subjective and may lack the precision of quantitative measures such as CT calcium scoring. A direct comparison between echocardiographic grading and CT-based quantification was not performed in this study. Further studies are needed to determine if the latter offers incremental prognostic value over the visual assessment used here. Furthermore, as this study relied on original clinical reports, inter-observer variability was not prospectively evaluated. Third, the analysis was based on a single time-point assessment, precluding evaluation of AVS progression and its temporal relationship to myocardial remodeling and outcomes. Fourth, direct measures of vascular compliance, central pressures, or biomarker profiling were not available, limiting mechanistic insight into local versus systemic contributors. Finally, as this was a single-center study, generalizability to other populations may be constrained.

Conclusion

In this large cohort, AVS severity emerged as a graded marker of systemic comorbidities, myocardial remodeling, and adverse outcomes. Severity functioned as a continuum, with progressive associations to HFpEF and independent risk of mortality and cardiovascular hospitalization. AVS severity is a clinically relevant indicator of systemic and myocardial disease burden, with prognostic significance beyond traditional risk factors.

Statement of Ethics

The research was conducted according to internationally accepted ethical standards for research practice and reporting. The Institutional Committee for Human Studies of Hadassah Medical Center approved the study protocol, approval No. 0043–22. The need for written informed consent was waived by the Institutional Committee for Human Studies of Hadassah Medical Center.

Conflict of Interest Statement

The authors declare no conflicts of interest.

Funding Sources

The authors received no specific funding for this work.

Author Contributions

Conceptualization, methodology, supervision, and formal analysis: I.G. and D.L.; writing – original draft preparation: I.G.; writing – review and editing: D.L., A.V., D.R.Z., E.O., O.A., and I.G. All authors have read and agreed to the published version of the manuscript.

Funding Statement

The authors received no specific funding for this work.

Data Availability Statement

The data of this study are available but due to restrictions are not publicly available but are available from the corresponding author upon reasonable request, with the agreement of the Ethical Committee.

References

Associated Data

Supplementary Materials

Data Availability Statement

The data of this study are available but due to restrictions are not publicly available but are available from the corresponding author upon reasonable request, with the agreement of the Ethical Committee.