Myocardial recovery with mechanical circulatory support is linked to alternative splicing and subcellular localization of CAMK2D

Cardiac reverse remodeling occurs in a small subset of heart failure patients treated with guideline-directed therapies. This phenomenon, which is defined by reduced ventricular dilatation and improved systolic function, is most common in patients receiving left ventricular assist device (LVAD) therapy. Identifying therapeutic targets for initiating reverse remodeling is an area of great clinical interest, as these patients experience improved outcomes and quality of life. Targets may be discovered among the unique molecular changes associated with partial myocardial functional recovery induced by LVAD; however, the mechanisms underlying this favorable response are incompletely understood. To identify molecular signatures of recovery, we studied paired pre- and post-LVAD myocardial samples from heart failure patients who received LVAD as a bridge-to-transplant (10 responders, 9 non-responders) and non-failing controls. We performed bulk RNA-sequencing, tandem-mass-tag (TMT) quantitative proteomics, and TMT quantitative phospho-proteomics with follow-up mechanistic and functional investigations in primary rodent cardiomyocytes and human engineered heart tissues (EHTs).