Increasing Amyloidosis Awareness and Diagnosis Through Programmatic Imaging, Blood/Urine Testing and Pathology

Transthyretin cardiac amyloidosis (ATTR-CA) is an infiltrative cardiomyopathy caused by extracellular deposition of insoluble transthyretin amyloid fibrils in the myocardium. Unstable changes in the wild type and variant (familial) stimulate misfold aggregation and ultimately form amyloid fibrils and deposit in various tissues including the heart. Generally, cardiac amyloidosis is a cause of heart failure with preserved ejection fraction. The heart involvement with amyloidosis may represent part of a systemic disease with multiorgan involvement as is seen with light chain amyloidosis (AL). A distinct form of cardiac amyloidosis is the deposition of misfold transthyretin that results from aggregation of the native protein or from inherited mutations in the transthyreyin (TTR) gene, in particular in old patients and, with the increase of the aged population, the incidence of ATTR-CA is increasing although its real presence and correct diagnosis lacks standardized strategies, in particular due to diseases in the differential diagnosis with similar phenotypes. The Wild type ATTR-CA also known as senile systemic amyloidosis caused by age related misfolding of the TTR is the most frequent form of age-related cardiac amyloidosis. Hereditary ATTR-CA due to gene mutations can also lead to cardiac amyloidosis but in Brazil the most frequent mutation Val30Met usually has a clinical phenotype predominantly neurological contrary to the USA, where the mutation Val122Ile is more frequent with a cardiomyopathy phenotype. Lack of recognition of cardiac amyloidosis due to the presence of nonspecific symptoms and associated comorbidities commonly leads to delayed diagnosis and disease progression. Echocardiography is the first line technique for patients presenting with heart failure but there is still a gap on the clinical utility of the multiparametric parameters or their combination in patients where conventional echocardiogram raises the suspicion of cardiac amyloidosis. The study will be one of the first in its kind to prospectively delineate the presence of cardiac amyloidosis in a patient population where this hypothesis has not been properly evaluated.

Study Design:In this cohort study, patients undergoing evaluation for amyloidosis will be provided with diagnostic tools to confirm the diagnosis; in cases where verified, subtype methodologies for amyloidosis subtype characterization will be employed. If there is a suspicion of amyloidosis complementary imaging, etiologic evaluation with TTR sequencing, paraprotein evaluation (serum and urine serum protein electrophoresis and immunofixation, serum-free light), and pyrophosphate scintigraphy will be performed. If the origin of amyloid protein cannot be determined, further evaluation with biopsy of the amyloid deposition and mass spectrometry will be undertaken. Initially, fatpad biopsy and minor salivary glands will be performed. If unrevealing, the affected organ will be biopsied for amyloid tissue characterization.