Ca²⁺/calmodulin-dependent protein kinase II-dependent remodeling of Ca²⁺ current in pressure overload heart failure

Ca²⁺/calmodulin-dependent protein kinase II (CaMKII) activity is increased in heart failure (HF), a syndrome characterized by markedly increased risk of arrhythmia. Activation of CaMKII increases peak L-type Ca²⁺ current (I_Ca) and slows I_Ca inactivation. Whether these events are linked mechanistically is unknown. I_Ca was recorded in acutely dissociated subepicardial and subendocardial murine left ventricular (LV) myocytes using the whole cell patch clamp method. Pressure overload heart failure was induced by surgical constriction of the thoracic aorta. I _Ca density was significantly larger in subepicardial myocytes than in subendocardial/ myocytes. Similar patterns were observed in the cell surface expression of α1c, the channel pore-forming subunit. In failing LV, I _Ca density was increased proportionately in both cell types, and the time course of I_Ca inactivation was slowed. This typical pattern of changes suggested a role of CaMKII. Consistent with this,measurements of CaMKII activity revealed a2-3-fold increase (p < 0.05) in failing LV. To test for a causal link, we measured frequency-dependent I_Ca facilitation. In HF myocytes, this CaMKII-dependent process could not be induced, suggesting already maximal activation. Internal application of active CaMKII in failing myocytes did not elicit changes in I_Ca. Finally, CaMKII inhibition by internal diffusion of a specific peptide inhibitor reduced I_Ca density and inactivation time course to similar levels in control and HF myocytes. I _Ca density manifests a significant transmural gradient, and this gradient is preserved in heart failure. Activation of CaMKII, a known pro-arrhythmic molecule, is a major contributor to I_Ca remodeling in load-induced heart failure.