Increased Density Of Serca Pumps At The Periphery Of Cardiac Purkinje Cells After Myocardial Infarction

BACKGROUND. The trigger of ventricular tachyarrhythmias after myocardial infarction (MI) has been attributed to increased incidence of electrogenic Ca2+ waves in cardiac Purkinje cells (Pcells). A change in Ca2+ release channel (CRC) gating properties and overload of intracellular Ca2+ store are 2 potential causes of this increase. We analysed through a model of intracellular Ca2+ dynamics the spontaneous Ca2+ transients of Pcells after MI. Regional protein expression was assessed for potential remodelling associated with ischemia.METHODS. Pcells were dispersed enzymatically from dog, pig, sheep, and human Purkinje fibers dissected from normal hearts and from hearts with MI. Spontaneous local Ca2+ transients were studied by high resolution confocal fluorescence microscopy techniques. Specific antibodies were used to map proteins involved in Ca2+ release/uptake functions (ERCs, SERCAs).RESULTS. In Pcells of MI heart, the density and firing rate of Ca2+-release sites were increased by 20% [Normal: 3.0 ± 0.3 sites /25µm (14 scans; 12 cells) vs MI: 3.6 ± 0.2 sites /25µm (9 cells); Pu003c0.05] and 120% [Normal:0.77 ± 0.10 sparks/s (42 sites, 12 cells) vs MI: 1.74 ± 0.23 sparks /s (40 sites, 9 cells); Pu003c0.05), respectively. A model fit of Ca2+-waves in MI Pcells revealed 50% increase in amplitude, 25% faster decay, and 35% elevation of Ca2+-uptake rate. No change was observed in CRC expression. However SERCAs redistribution to the cell periphery was detected in all animal MI models and in human heart with large MI. Peripheral protein expression and gene expression of SERCA2 showed 4.5 and 2.3 times increases post MI, respectively. Interestingly, no change was observed in regulatory protein phospholamban.CONCLUSION. An unknown factor associated with myocardial ischemia mediates a dramatic increase in SERCA expression at the Pcell periphery, i.e. wherein the CRCs IP3R and RyR3 are specifically located. We propose a mechanistic model of intracellular Ca2+ cycling demonstrating that augmentation of peripheral SERCA activity is sufficient to promote pro-arrhythmic spontaneous Ca2+ release in Pcells of post-MI human heart.