Prognostic value of quantitative SPECT/CT metrics in transthyretin amyloid cardiomyopathy

Background 99mTc-labeled cardiac single-photon emission tomography with computed tomography (SPECT/CT) enables noninvasive diagnosis of transthyretin amyloid cardiomyopathy (ATTR-CM). The Mayo 3D Score, calculated as the ratio of mean left ventricular myocardial radiotracer uptake to right atrial blood-pool uptake using SPECT/CT volumes, demonstrated excellent diagnostic performance in pathology-based validation studies. However, its prognostic value remains uncertain. We examined its association with all-cause mortality. Methods At a single, tertiary referral center, we retrospectively identified consecutive ATTR-CM patients who underwent 3-hour 99mTc-pyrophosphate SPECT/CT (6/2017-1/2025), with available Mayo 3D Score. The Mayo 3D Score was categorized into tertiles based on its distribution. The primary outcome was all-cause mortality; time-to-event was calculated from the index SPECT/CT study to death or last follow-up. Survival was assessed using Kaplan–Meier methods and compared using the log-rank test. Cox proportional hazards models were used to evaluate the Mayo 3D Score as a continuous variable, both unadjusted and adjusted for age, sex, and Charlson Comorbidity Index (CCI). Mortality was additionally evaluated across 3 calendar-year strata to assess temporal stability. To account for comorbidity burden, survival analyses were stratified by CCI tertiles. Results 704 patients with ATTR-CM were included (median age 78 years, 93% male). Mayo 3D Score tertiles were defined as low (<1.40, n=261), intermediate (1.40-1.69, n=216), and high (≥1.70, n=227). Higher Mayo 3D Score tertiles were associated with male sex, lower CCI, lower ejection fraction, greater wall thickness, higher cardiac biomarkers, and advanced disease stage (all p < 0.01, Figure 1). Mayo stage differed significantly across tertiles (p=0.006), whereas NAC stage did not (p=0.82). Overall mortality was stable across time periods (log-rank p=0.72). All-cause mortality did not differ significantly across Mayo 3D Score tertiles (log-rank p=0.11, Figure 2A), but differed significantly across Mayo stage, NAC stage, and CCI (log-rank p<0.001 for all, Figure 2B,C). When analyzed as a continuous variable, the Mayo 3D Score was not associated with mortality in unadjusted Cox analysis (HR 0.84, 95% CI 0.62–1.15; p=0.28) or after adjustment for age, sex, and CCI (HR 1.16, 95% CI 0.84–1.60; p=0.37). In sensitivity analyses stratified by CCI tertiles, mortality remained similar across Mayo 3D Score tertiles (log-rank p>0.2). Conclusions In this large ATTR-CM cohort, the quantitative SPECT/CT Mayo 3D Score was not associated with all-cause mortality, even after accounting for comorbidity burden. In contrast, established clinical staging systems remained strong predictors of survival. These findings support interpretation of quantitative SPECT/CT metrics primarily as diagnostic biomarkers, rather than surrogates of prognosis, in ATTR-CM.