Low aortic valve calcium score as an imaging red flag for concomitant transthyretin cardiac amyloidosis in severe aortic stenosis: A CAUSATIVE study subanalysis

Background Transthyretin amyloid cardiomyopathy (ATTR-CM) frequently coexists with severe aortic stenosis (AS). In this setting, non-contrast cardiac computed tomography (CCT) may reveal a relatively low aortic valve calcium (AVC) burden despite hemodynamically severe AS, potentially reflecting a mixed calcific and non-calcific (including amyloid) valvular substrate. Purpose To evaluate whether low AVC identifies a higher probability of concomitant ATTR-CM and should be considered an imaging red flag in older patients with severe AS. Methods This subanalysis of the prospective, multicenter CAUSATIVE study1 included consecutive patients aged ≥65 years with symptomatic severe degenerative AS (aortic valve area <1.0 cm²), indication for aortic valve replacement, and ≥1 clinical/echocardiographic red flag for amyloidosis. All patients underwent standardized CCT AVC quantification and a systematic diagnostic work-up for ATTR-CM. Patients were stratified by sex-specific tertiles of indexed AVC (Agatston units, AU). Multivariable logistic regression tested the association between indexed AVC and ATTR-CM, with the odds ratio calculated for a 1000-unit change in indexed Agatston units, adjusting for age, sex, estimated glomerular filtration rate (eGFR), and low-flow low-gradient (LFLG) AS phenotype. Results Among 504 patients, 104 (20.6%) were diagnosed with ATTR-CM. ATTR-CM prevalence decreased across increasing AVC tertiles both in men (38.5%, 33%, and 15.2%; p-trend = 0.001) and women (18.8%, 9.2%, and 4.3%; p-trend = 0.009). In multivariable analysis, indexed AVC was independently and inversely associated with ATTR-CM (odds ratio 0.49 per 1000 AU/m²; 95% CI 0.32–0.73; p=0.001). Adjusted predicted probability curves demonstrated a marked increase in ATTR-CM probability at lower indexed AVC values, particularly in men (Figure 1). Using guideline-referenced CT-AVC likelihood strata, ATTR-CM prevalence was highest in the “unlikely severe” stratum (37.3%; NNT 2.68) and lowest in the “very likely severe” stratum (14.0%; NNT 7.12) (Table 1). Conclusion In older patients with severe AS undergoing aortic valve replacement evaluation, a low aortic valve calcium score is independently associated with concomitant ATTR-CM and should be considered an imaging red flag prompting dedicated amyloidosis assessment. Reliance on calcium score thresholds alone may underestimate the likelihood of severe AS in patients with dual pathology.