Molecular basis of amyloid deposition in myocardium: not only ATTR and AL. Case report

Abstract

Alterations in the proteostasis network and accumulation of misfolded protein aggregates — is one of the new pathogenesis concepts of chronic heart failure. We hypothesis in addition to well-known transthyretin (ATTR) and AL-amyloidosis some patients may represent amyloid lesion in myocardium came from undescribed amyloidogenic precursors due to misfolding of myocardial structural proteins.Here, we report on the case of patient with hypertrophic and restrictive phenotype of cardiomyopathy, biventricular heart failure, considered for heart transplant, and excluded known types of amyloidosis. Genetic testing revealed extended deletion in the gene of giant protein titin (TTN).We present with the use of bioinformatic analysis and molecular modeling how this mutation could lead to unfolding of corresponding protein and open its amyloidogenic motifs for intermolecular interactions, therefore, provide amyloidogenic ability. This data enables in more detail to decipher the pathogenesis of chronic heart failure on the background of cardiomyopathy, planning further studies for development of personalized risk profiling in different types of amyloidosis and elaborate more personalized treatment approach for such patients in the future.

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“…Moreover, current therapeutics have a lot of side effects, including cardiotoxicity, which negatively affects patient lifestyle [4]. Amyloidosis may be caused not only by transthyretin (ATTR) or immunoglobulin light-chain (AL) fibrils [5] but also potentially a deletion in the gene of giant protein titin (TTN) [6], which drastically hinders the therapy against amyloidosis.…”