PET Tracer for Imaging Cardiac Amyloidosis - Title. PET Tracer for Imaging Cardiac Amyloidosis Abstract. Amyloidosis are disorders of protein conformation and metabolism wherein insoluble fibrils are deposited in different critical organs of the body, causing dysfunction, and eventual death. The unifying feature among these proteins is their propensity to misfold into β-pleated sheets, form nonbranching fibrils, resist proteolysis, and induce mechanical disruption and oxidative stress in affected organs, such as heart, liver, kidney, and gastrointestinal tract. The two most common types of cardiac amyloidosis (CA) prevalent in the United States are AL and ATTR. Clinically when a subject with amyloid is identified on any biopsy, the type of amyloid is confirmed through immunohistochemistry, electron microscopy, and laser microdissection with mass spectrometry–based proteomic analysis. The latter technique is the gold standard; however, it is not widely available. While fat pad biopsies have notoriously low sensitivity, fundamentally biopsies are invasive and associated with risk of complication, especially target organ biopsies, such as endomyocardial biopsies. Additionally, endomyocardial biopsies are primarily available only at large academic centers with advanced HF programs contributing to geographic disparities in diagnosis. In terms of noninvasive diagnostic resources, Tc-99m-PYP, (current standard of care, the bone scan agent) enables evaluation of ATTR (detects only microcalcifications) and shows low sensitivity to allow analysis at earlier stages (clinically detects only grade 2 and 3). We recently identified a high affinity PET tracer (Fluselenamyl, FSA) for noninvasive detection of β-amyloid and recently finished proof-of-concept studies in AD subjects. Of note, FSA uniquely detects both higher order (cored plaques) and lower order misfolded protein (diffuse plaques). Although compositions of amyloid plaques within the brain and CA are different, they do share β-sheet conformation homology which mediates the disease pathology. For the pilot proof-of-concept PET imaging, a Tc-99m-PYP confirmed subjects were scanned on supine position in Siemens Vision (PET/CT) following intravenous injection of the radiotracer. 18F-FSA shows striking uptake and retention in the left ventricle of ATTR mutant/variant consistent with substantial presence of amyloid fibrosis, while clearance from its WT counterpart suggesting significant response to the treatment with Tafamidis, the TTR stabilizer. These data offer us opportunity to further investigate its potential for imaging ATTR and AL CA. Overall, aims of this clinical translational RO1imaging proposal are: 1) Perform proof of concept studies using 18F-Fluselenamyl (FSA) to assess its sensitivity for imaging ATTR cardiac amyloidosis in vivo, Conduct comparative analysis in patients with ATTR and positive 99mTc-PYP-SPECT imaging (Grade 2 or Grade 3; 10 Patients) and control HFpEF subjects without amyloid (n=10). 2) Evaluate potential of 18F-FSA imaging for detection of a TTR-CM in patients with negative 99mTc-PYP imaging (grade 0 or grade 1, 10 patients). 3) Perform comparative analysis of performance 18F-Fluselenamyl & 99mTc-PYP SPECT to investigate their sensitivity and specificity for mapping cardiac amyloidosis accurately with disease staging pre- and 6- and 12 months post-therapy (Tafamidis; subjects, n=10). 4) Evaluate potential of 18F-Fluselenamyl to noninvasively image light chain amyloidosis (AL) with cardiac involvement and assess its sensitivity to differentiate AL (subjects, n=10) and ATTR CA (Aim 1) in vivo. Successful execution of these aims could enable translation of this versatile diagnostic tool for imaging ATTR subjects at high resolution, allow differentiation of ATTR and AL CA, and potentially offer a companion diagnostic for evaluating therapeutic efficacy.
