Among 9,170 consecutive patients undergoing [99mTc]Tc-DPD bone scintigraphy, Perugini grade 1 scans — historically treated as equivocal for transthyretin amyloid cardiomyopathy (ATTR-CM) — mapped overwhelmingly to a non-infiltrative cardiometabolic phenotype defined by hypertension, elevated BMI, chronic ischemic heart disease, anemia, and reduced eGFR, rather than the septal thickening and elevated extracellular volume seen in confirmed grade ≥2 ATTR-CM. Despite low infiltration markers, grade 1 carried a 30% higher adjusted risk of heart failure hospitalization or death versus grade 0 (HR 1.30, 95% CI 1.07–1.59). Critically, a cardiometabolic subgroup within grade 1 — hypertension plus high BMI plus low hematocrit — matched or exceeded the mortality risk of confirmed amyloid cases (median HR 2.46 vs. 1.76).
This finding challenges the reflexive assumption that an equivocal amyloid scan warrants primarily an amyloid workup cascade. The field has long lacked a clear management pathway for grade 1, creating diagnostic paralysis. By reframing grade 1 as a cardiorenal-metabolic signal rather than a low-sensitivity amyloid positive, clinicians could redirect resources toward treating modifiable comorbidities driving the actual excess mortality. The imaging-phenotype association framework — essentially a phenome-wide scan across 1,243 variables — is a methodologically elegant approach increasingly applied in cardiovascular imaging. Limitations include single-center retrospective design and modest grade 1 sample size (n=175). As a preprint not yet peer-reviewed, these conclusions warrant independent replication before reshaping clinical protocols. Still, the paradigm shift from "rule out amyloid" to "treat the cardiometabolic substrate" is compelling and overdue.
