Junctophilin-2 abundance is unaltered in human heart failure samples with disrupted T-tubules and contractility.

T-tubules are structural components of the cardiomyocyte plasma membrane that are imperative for efficient excitation-contraction coupling and cardiac contraction. Junctophilin-2 (JPH2) has been postulated in multiple preclinical models to play a key role in T-tubule structure development, maintenance, and organisation by anchoring the sarcoplasmic reticulum to the sarcolemma and maintaining the spatial distance between excitation contraction coupling proteins. Animal studies have shown that JPH2 downregulation leads to T-tubule dysfunction and impaired cardiac contractility, and upregulation of JPH2 has been shown to rescue heart failure in animals, holding therapeutic promise. However, human-level data on JPH2's role in heart failure remain sparse, particularly regarding its protein abundance and functional relevance in human disease, which is imperative for validating therapeutic target selection. In this study, we examined JPH2 protein levels in 152 human samples, including healthy hearts, hearts with cardiovascular risk factors, and failing hearts of various etiologies. We found that JPH2 abundance remains unchanged in human heart failure, despite significant disruption in T-tubule structure and cardiac dysfunction in these patients. Our findings suggest that JPH2 abundance alone is insufficient to preserve T-tubule integrity in failing human hearts and challenge the role of JPH2 in human disease. This work underscores the critical need for human tissue-based models in cardiovascular research, highlighting their potential in bridging preclinical findings to clinical applications.