Peter P. Rainer, Peihong Dong, Matteo Sorge, Justyna Fert-Bober, Ronald J. Holewinski, Yuchuan Wang, Catherine A. Foss, Steven S. An, Alessandra Baracca, Giancarlo Solaini, Charles G. Glabe, Martin G. Pomper, Jennifer E. Van Eyk, Gordon F. Tomaselli, Nazareno Paolocci, Giulio Agnetti

Rationale: Disrupted proteostasis is one major pathological trait that heart failure (HF) shares with other organ proteinopathies, such as Alzheimer's and Parkinson's diseases. Yet, differently from the latter, whether and how cardiac preamyloid oligomers (PAOs) develop in acquired forms of HF is unclear. Objective: We previously reported a rise in mono-phosphorylated, aggregate-prone desmin in canine and human HF. We now tested if mono-phosphorylated desmin acts as the seed nucleating PAOs formation and determined if positron emission tomography (PET) is able to detect myocardial PAOs in non-genetic HF. Methods and Results: Here, we first show that toxic cardiac PAOs accumulate in the myocardium of mice subjected to transverse aortic constriction (TAC), and that PAOs co-migrate with the cytoskeletal protein desmin in this well-established model of acquired HF. We confirm this evidence in cardiac extracts from human ischemic and non-ischemic HF. We also demonstrate that Ser-31 phosphorylated (pSer31) desmin aggregates extensively in cultured cardiomyocytes. Lastly, we were able to detect the in vivo accumulation of cardiac PAOs using positron emission tomography (PET) for the first time in acquired HF. Conclusions: pSer31 is a likely candidate seed for the nucleation process leading to cardiac PAOs deposition. Desmin post-translational processing and misfolding constitute a new, attractive avenue for the diagnosis and treatment of the cardiac accumulation of toxic PAOs that can now be measured by PET in acquired HF.