Amyloidosis is a heterogeneous group of protein misfolding disorders characterized by the deposition of amyloid fibrils in tissues, which causes progressive organ dysfunction. Among the various forms, cardiac involvement by transthyretin (ATTR) and immunoglobulin light chain (AL) amyloidosis is particularly significant, as it is the main determinant of prognosis and treatment. In clinical practice, tissue biopsy remains crucial for diagnosing amyloidosis. Amyloid histological typing can be performed using antibody-based methods such as immunohistochemistry and immunoelectron microscopy. Mass spectrometry-based bottom-up proteomics has emerged as a powerful alternative, offering precise identification and quantification of amyloidogenic proteins. Despite being regarded as an effective technique for amyloid typing, the application of proteomics remains limited to specialized centers due to its technical complexity and lack of standardization in clinical workflows. This paper describes the current use of proteomics in patients with cardiac amyloidosis, based on the experience of referral centers in the USA and Europe, to provide guidance on improving the technique’s reliability and to identify standard practices, challenges, and gaps in the clinical application of amyloidosis typing.
