Plasticity of Surface Structures and 2-Adrenergic Receptor Localization in Failing Ventricular Cardiomyocytes During Recovery from Heart Failure Lyon et al: Nanoscale Reverse Remodeling in Heart Failure

Background—Cardiomyocyte surface morphology and T-tubular structure are significantly disrupted in chronic heart failure with important functional sequelae, including redistribution of sarcolemmal beta2adrenergic receptors ( 2AR) and localized secondary messenger signaling. Plasticity of these changes in the reverse remodeled failing ventricle is unknown. We used AAV9.SERCA2a gene therapy to rescue failing rat hearts, and measured z-groove index, Ttubule density and compartmentalized 2AR-mediated cAMP signals using a combined nanoscale scanning ion conductance microscopy-Förster resonance energy transfer technique. Methods and Results—Cardiomyocyte surface morphology, quantified by z-groove index and T-tubule density, was normalized in reverse remodeled hearts following SERCA2a gene therapy. Recovery of sarcolemmal microstructure correlated with functional 2AR redistribution back into the z-groove and T-tubular network, whereas minimal cAMP responses were initiated following local 2AR stimulation of crest membrane, as observed in failing cardiomyocytes. Improvement of 2AR localization was associated with recovery of AR-stimulated contractile responses in rescued cardiomyocytes. Retubulation was associated with reduced spatial heterogeneity of electrically-stimulated calcium transients, and recovery of myocardial BIN-1 and TCAP protein expression, but not junctophilin-2. Conclusions—In summary, abnormalities of sarcolemmal structure in heart failure show plasticity with reappearance of z-grooves and T-tubules in reverse remodeled hearts. Recovery of surface topology is necessary for normalization of 2AR location and signaling responses.