Antisense Strategies for Treatment of Heart Failure

In the mammalian heart, intracellular Ca²⁺ movements are tightly regulated at various levels within the cell (1 ). The sarcoplasmic reticulum (SR) plays an important role in orchestrating the movement of calcium during each contraction and relaxation. Excitation leads to the opening of voltage-gated L-type Ca²⁺ channels, allowing the entry of a small amount of Ca²⁺ into the cell. Through a coupling mechanism between the L-type Ca²⁺ channel and the SR release channels (ryanodine receptors), a larger amount of Ca²⁺ is released, activating the myofilaments leading to contraction. During relaxation, Ca²⁺ is reaccumulated back into the SR by the SR Ca²⁺ adenosine triphosphatase (ATPase) pump (SERCA2a) and extruded extracellularly by the sarcolemmal Na⁺ /Ca²⁺ exchanger. The contribution of each of these mechanisms for lowering cytosolic Ca²⁺ varies with species. In humans, approx 70% of the Ca²⁺ is removed by SERCA2a and approx 30% by the Na⁺ /Ca²⁺ exchanger (1 ). The Ca²⁺ pumping activity of SERCA2a is influenced by phospholamban. In the unphosphorylated state, phospholamban inhibits the Ca²⁺ -ATPase, whereas phosphorylation of phospholamban by cyclic adenosine monophosphate (cAMP)-dependent protein kinase and by Ca²⁺ -calmodulin-dependent protein kinase reverses this inhibition (2 ). Ca²⁺ transients recorded from failing human myocardial cells or trabeculae reveal a significantly prolonged Ca²⁺ transient with an elevated end-diastolic intracellular Ca²⁺ (3 ,4 ).