Alterations in Early Action Potential Repolarization Causes Localized Failure of Sarcoplasmic Reticulum Ca ²⁺ Release

Abstract

Abstract-Depressed contractility of failing myocytes involves a decreased rate of rise of the Ca 2ϩ transient. Synchronization of Ca 2ϩ release from the junctional sarcoplasmic reticulum (SR) is responsible for the rapid rise of the normal Ca 2ϩ transient. This study examined the idea that spatially and temporally dyssynchronous SR Ca 2ϩ release slows the rise of the cytosolic Ca 2ϩ transient in failing feline myocytes. Left ventricular hypertrophy (LVH) with and without heart failure (HF) was induced in felines by constricting the ascending aorta. Ca 2ϩ transients were measured in ventricular myocytes using confocal line scan imaging. Ca 2ϩ transients were induced by field stimulation, square wave voltage steps, or action potential (AP) voltage clamp. SR Ca 2ϩ release was significantly less well spatially and temporally synchronized in field-stimulated HF versus control or LVH myocytes. Surprisingly, depolarization of HF cells to potentials where Ca 2ϩ currents (I Ca ) were maximal resynchronized SR Ca 2ϩ release. Correspondingly, decreases in the amplitude of I Ca desynchronized SR Ca 2ϩ release in control, LVH, and HF myocytes to the same extent. HF myocytes had significant loss of phase 1 AP repolarization and smaller I Ca density, which should both reduce Ca 2ϩ influx. When normal myocytes were voltage clamped with HF AP profiles SR Ca 2ϩ release was desynchronized. SR Ca 2ϩ release becomes dyssynchronized in failing feline ventricular myocytes because of reductions in Ca 2ϩ influx induced in part by alterations in early repolarization of the AP. Therefore, therapies that restore normal early repolarization should improve the contractility of the failing heart. (Circ Res. 2005;96:543-550.) Key Words: heart failure Ⅲ excitation contraction coupling Ⅲ sarcoplasmic reticulum Ⅲ calcium transients H emodynamic overload induces cardiac hypertrophy and alterations in the contractile properties of the resident cardiac myocytes, both of which can help the heart maintain cardiac output. However, when the hemodynamic stress is persistent, the heart usually makes a transition from compensated hypertrophy to a progressively deteriorating functional state termed congestive heart failure (CHF). This transition is known to be associated with alterations in the magnitude, duration, and kinetics of the systolic Ca 2ϩ transient. Multiple cellular and molecular changes are thought to underlie the abnormal Ca 2ϩ transient of the hypertrophied/ failing myocyte. [1][2][3][4][5][6][7] The reduced size and prolonged duration of the Ca 2ϩ transient involves reduced sarcoplasmic reticulum (SR) Ca 2ϩ stores 1,7-9 resulting from a slowed rate of SR Ca 2ϩ uptake. This reduced SR function is thought to be caused by reductions in the density of the SR Ca 2ϩ ATPase (SERCA) 10 -12 and by reduced phosphorylation of the SERCA inhibitory protein phospholamban (PLB). [13][14][15] There is also some evidence for an increased rate of Ca 2ϩ "leak" from the SR through "hyperphosphorylated" Ca 2ϩ release channels (ryanodine receptors, RYR). 16,17 R...

Altered Cardiac Myocyte Ca Regulation In Heart Failure

“…In addition, the detailed effects on Ca handling for each K current class differ somewhat. The reduction in I to can reduce the early AP repolarization (notch) and decrease the amount of I Ca during the early part of the AP because of a decreased electrochemical driving force (19,48). This can reduce the amount of SR Ca release, or at least reduce the synchronization of SR Ca release, which is important for synchronizing contraction.…”

“…Note that increases in transverse tubules would be required to prevent a reduction in surface-to-volume ratio in the much larger HF myocyte. Moreover, what looked like a spatial drop-out in ECC efficacy in feline HF myocytes (i.e., possibly missing transverse tubules) was shown to be attributed to the altered AP waveform with much less transient outward current (I to ) in HF (19). That is, without the early repolarization driven by I to , the early AP plateau is more positive and decreases the driving force for I Ca and thus limits junctional activation (48).…”

Transient outward potassium current and Ca2+ homeostasis in the heart: beyond the action potential

“…They observed that when early repolarization is slowed, I Ca,L shows a decreased peak and slower kinetics, in spite of similar or greater total Ca 2+ influx compared to that with fast early repolarization. Slowdeveloping I Ca,L results in asynchronous SR Ca 2+ release, which is less efficient to rapidly increase [Ca 2+ ] i at systole (50,51). This alteration may become more accentuated, with progression to heart failure, when intrinsic reduction of I Ca,L amplitude may occur (51).…”

“…Slowdeveloping I Ca,L results in asynchronous SR Ca 2+ release, which is less efficient to rapidly increase [Ca 2+ ] i at systole (50,51). This alteration may become more accentuated, with progression to heart failure, when intrinsic reduction of I Ca,L amplitude may occur (51). One of the expected consequences would be slower and weaker contraction activation.…”

Excitation-contraction coupling and mitochondrial energetics

“…A major deficit in failing myocytes is the reduced Ca 2+ content of the SR, which is related to decreased expression and activity of the SR Ca 2+ -ATPase [84,92,146,153] and an increased Ca 2+ leak of the RyR2 due to hyperphosphorylation [84,94,112,122]. These defects, potentially aggravated by L-type Ca 2+ channel dysfunction [41,71,81,86,113,131,146,184] or t-tubular derangement [32,86,115,145,184] [17,81,113,115,146,184]. Decreased SR Ca 2+ -ATPase activity is partly compensated by increased expression and activity of the NCX [16,65,93,146,178,190] The underlying mechanisms for elevated [Na + ] i are incompletely understood, but may involve a decrease in Na + /K + -ATPase activity [58,156,169,172,175,206], enhanced Na + /H + -exchanger (NHE) activity [2,6,40,142], or an increase in a tetrodotoxin-sensitive persistent (late) I Na …”