Deep Clinical Phenotyping of Planar Perugini Grade 1 on Bone Scintigraphy: An Imaging-Phenotype Association Study
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Aims
Planar Perugini grade 1 is equivocal for transthyretin amyloid cardiomyopathy (ATTR-CM), has no dedicated management pathway and is heterogeneous, spanning low-burden amyloid and non-amyloid blood-pool activity. Rather than treating it as a step toward amyloid confirmation, we characterized the clinical phenotype grade 1 marks and tested whether that phenotype accounts for its prognosis.
Methods and Results
We studied 9,170 consecutive patients undergoing [ 99m Tc]Tc-DPD bone scintigraphy. Grade was assigned by blinded expert consensus on planar images, per the original Perugini definition. Using an imaging-phenotype association (IPA) framework, we linked grade to 1,243 clinical, laboratory, echocardiographic, CMR and ICD-10 parameters. The endpoint was a composite of heart failure or death. Grade 1 occurred in 175 (1.9%) and grade ≥2 in 142 (1.6%) patients. Grade ≥2 reproduced the 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. Low extracellular volume and septal thickness argued against infiltration. Grade 1 carried worse outcomes than grade 0 (adjHR 1.30, 95% CI 1.07-1.59). Within grade 1, a phenotype of hypertension, high BMI and low hematocrit reached or exceeded grade ≥2 risk (HR 2.46 vs 1.76).
Conclusion
Planar grade 1 is neither uniform early amyloid nor a benign artifact but a mixed-etiology, predominantly non-infiltrative cardiometabolic phenotype carrying clinically meaningful risk. This supports reinterpreting grade 1 and prioritizing cardiorenal comorbidity alongside selective amyloid workup.
