Issue 17, 2024

Molecular basis for non-invasive diagnostics of cardiac amyloids using bone tracers

Abstract

Amyloid diseases including Alzheimer's, Parkinson's and over 30 others are incurable life-threatening disorders caused by abnormal protein deposition as fibrils in various organs. Cardiac amyloidosis is particularly challenging to diagnose and treat. Identification of the fibril-forming protein, which in the heart is usually amyloid transthyretin (ATTR) or amyloid immunoglobulin light chain (AL), is paramount to treatment. A transformative non-invasive diagnostic modality is imaging using technetium-labeled pyrophosphate or diphosphonate bone tracers, 99mTc-PYP/DPD/HMDP. For unknown reasons, these tracers show preferential uptake by ATTR deposits. The tracer-binding moiety is unknown and potentially involves amyloid fibrils and/or amyloid-associated calcific deposits. We propose that, like in the bone, the tracers chelate to surface-bound Ca2+ in amyloid. In high-affinity protein sites, Ca2+ is coordinated by pairs of acidic residues. To identify such residues on amyloids, we harnessed atomic structures of patient-derived cardiac amyloids determined using cryogenic electron microscopy since 2019. These structures help explain why most but not all ATTR deposits uptake 99mTc-PYP/DPD/HMDP radiotracers, while in AL the opposite is true. Moreover, fibril structures help explain greater microcalcification observed in ATTR vs. AL deposits. These findings may aid the diagnostics and therapeutic targeting of cardiac amyloidosis and are relevant to other amyloids.

Graphical abstract: Molecular basis for non-invasive diagnostics of cardiac amyloids using bone tracers

Article information

Article type
Minireview
Submitted
17 Jun 2024
Accepted
19 Jul 2024
First published
22 Jul 2024
This article is Open Access
Creative Commons BY-NC license

Biomater. Sci., 2024,12, 4275-4282

Molecular basis for non-invasive diagnostics of cardiac amyloids using bone tracers

E. Lewkowicz, S. Jayaraman and O. Gursky, Biomater. Sci., 2024, 12, 4275 DOI: 10.1039/D4BM00816B

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