Deep Clinical Phenotyping of Perugini Grade 1 on Bone Scintigraphy: An Imaging-Phenotype Association Study

Purpose A planar Perugini grade 1 scan is equivocal for transthyretin amyloid cardiomyopathy (ATTR-CM), has no dedicated management pathway and is biologically heterogeneous, spanning early or low-burden ATTR, AL amyloidosis and non-amyloid blood-pool activity. Rather than investigating grade 1 as a step toward amyloid confirmation, we characterized the clinical phenotype it marks and tested whether that phenotype, rather than amyloid, drives its prognosis. Methods We studied 9,170 consecutive patients who underwent [99mTc]Tc-DPD bone scintigraphy between 2010 and 2020, graded on planar imaging by blinded expert consensus. Using an imaging-phenotype association (IPA) framework analogous to genome-wide association analysis, we related Perugini grade to 1,243 clinical, laboratory, echocardiographic, cardiac magnetic resonance and ICD-10 comorbidity variables from electronic health records, adjusting for age, sex and cancer history. The outcome was a composite of heart failure hospitalization or death. Results Grade 1 occurred in 175 (1.9%) and grade ?2 in 142 (1.6%) patients. Grade ?2 reproduced the canonical infiltrative ATTR phenotype, with greater septal thickness, higher extracellular volume, neuropathy and atrial fibrillation, validating the framework. Grade 1 instead marked a non-infiltrative cardiometabolic phenotype dominated by hypertension, chronic ischemic heart disease, high BMI, anemia, reduced eGFR and atrial enlargement, with low extracellular volume and septal thickness arguing against meaningful infiltration. Grade 1 carried worse outcomes than grade 0 (adjusted HR 1.30, 95% CI 1.07 to 1.59). Within grade 1, a cardiometabolic phenotype defined by hypertension, high BMI and low hematocrit, with or without chronic ischemic heart disease, identified patients whose risk matched or exceeded that of grade ?2 (median HR 2.46 versus HR 1.76), indicating that grade 1 prognosis is driven substantially by comorbid cardiometabolic disease rather than amyloid burden. Conclusions Perugini grade 1 is neither uniform early amyloid nor a benign artifact but a mixed-etiology, predominantly non-infiltrative cardiometabolic phenotype that carries clinically meaningful risk. A simple cardiometabolic phenotype stratifies this risk, supporting reinterpretation of grade 1 and a management focus on cardiorenal comorbidity alongside selective amyloid workup. The IPA framework provides a scalable approach to characterizing cardiovascular imaging biomarkers.