Ulrike Resch (Vienna / AT; Cologne / DE; Duesseldorf / DE), Luisa Schmidt (Cologne / DE), Philipp Antczak (Vienna / AT; Cologne / DE), Stefan Müller (Cologne / DE), Jan-Wilm Lackmann (Cologne / DE), Artur Lichtenberg (Duesseldorf / DE), Hug Aubin (Duesseldorf / DE), Marcus Krüger (Cologne / DE), Elivra Weber (Duesseldorf / DE)
BACKGROUND:
Heart failure remains a major cause of morbidity and mortality worldwide and its prevalence steadily increases. Despite improved pharmacologic and surgical treatment options knowledge of molecular mechanisms underlying the progressive pathologic changes in the heart still needs to be improved. Ischemic and dilated cardiomyopathy (ICM/DCM) are two major types of cardiomyopathies which often exhibit similar clinical symptoms despite essentially different etiologies. To characterize disease-differentiating ventricular proteome signatures and molecular patterns, we performed in-depth, label-free quantitative proteome profiling of left and right ventricles (LV/RV) biopsies from 68 ICM patients (51 male, 17 female, 60.2±6.0 years, BMI 26.2±4.3) and 68 DCM patients (45 male, 23 female, 52.7±11.7 years, BMI 26.0±5.1) admitted to heart transplantation.
METHODS:
A spectral library and an optimized 30SPD dia-PASEF acquisition on a Evosep-timsTOF Pro2 system was utilized.
RESULTS:
We successfully established a feasible and robust proteomic workflow in sample and data analysis time and identified 3000 to 5000 across all samples. LMMA-bioinformatic analysis revealed a significantly different proteome in LV and RV tissue, which is furthermore differentiating ICM form DCM. Our protein-network analysis suggests a substantial proteotoxic, oxidative-reductive stress in ICM´s ventricles which translates into distinguished defects in fatty acid mobilization and mitochondrial function, specifically complex I, resulting into a vicious, energy-depleting cycle. This perpetuates into malfunctioning cytoskeletal and extracellular matrix assembly, myocardial scarring and tissue remodeling. Furthermore, our large dataset allowed to uncover ventricular proteins specific to physiological covariates such as sex, BMI and comorbidities like diabetes.
CONCLUSIONS:
Comparative ventricular proteome profiling of ante-mortem human heart tissue in such a large patient cohort has not been described so far. More than 300 significant proteins discriminating ICM and DCM provide new molecular links for basic research and precision medicine-based intervention strategies.