Relationship between Multi-Scale Cardiomyocyte Organization and Function in Trabeculae of the Failing Human Heart

Abstract

Invaginations of the plasma membrane within cardiomyocytes form the transverse tubule network (t-tubules), and at “dyadic junctions” these come into close association with regions of the sarcoplasmic reticulum (SR). In addition to many of the key excitation-contraction (EC) coupling proteins, junctions contain junctophilin-2 (JPH2), which is implicated in both the formation and maintenance of junctions. In human heart failure there is a loss of cardiac function which is generally associated with impairment of EC coupling processes, as well as changes to t-tubule structure and protein distribution. The aim of this study was to investigate the link between structural re-organization of cardiomyocytes and the loss of contractile function in trabeculae from failing human hearts.We obtained trabeculae from explanted human hearts in end-stage heart failure and performed force measurements followed by immuno-labelling to determine correlations between protein distribution and functional performance in the failing human heart. Cardiac trabeculae were processed along with samples taken from the free wall to investigate the variability of structure and protein distribution, including t-tubules, JPH2 and ryanodine receptors (the SR calcium release channel) using confocal imaging. Findings from these experiments revealed that there is a high degree of variability of trabecular structure and function, both within and between hearts. Trabeculae exhibiting poor contractile function often had low cardiomyocyte content and remaining myocytes showed disorganization of t-tubules and EC coupling proteins.These findings demonstrate a clear link between trabecula structure and function in the diseased human heart and support the idea that cardiomyocyte organization at cell and tissue levels is correlated with cardiac function. Furthermore, while trabeculae are useful for studying cardiac function, trabecula and cardiomyocyte structure must be considered when interpreting functional results.