Abstract 11797: Fixing Ca2+ Leakage From Cardiac Ryanodine Receptor by Low-dose of β Blocker Safely Enhances Inotropic Response to Milrinone in Acute Heart Failure
Background: Aberrant Ca2+ release through cardiac ryanodine receptor(RyR2) is a major cause of heart failure and lethal arrhythmia. Recently we reported that low-dose landiolol, an ultra-short-acting β1-blocker, in combination with milrinone effectively improved cardiac function and eliminated mechanical alternans in patients with acute heart failure. Here, the aim of the present study is to clarify the mechanism by which landiolol corrected intracellular abnormal Ca2+ handling.
Methods and Results: Cardiomyocytes were isolated from the LVs of canine HF model by 4-week’s rapid pacing (n=6). First, we investigated the effect of the various concentrations of landiolol on cell shortening. Landiolol (10 nM) did not have any appreciable effect on cell shortening in normal and failing cardiomyocytes. Then, we investigated the effect of milrinone (10 µM) plus landiolol (10 nM) on peak intracellular Ca2+ transient (CaT), cell shortening (CS), Ca2+ spark frequency (CaSF), sarcoplasmic reticulum Ca2+ content ([Ca2+]SR) by confocal microscopy, and phosphorylation levels of ryanodine receptor (RyR2) and phospholamban (PLB) by Wesrern blot. In failing cardiomyocytes, compared with normal cardiomyocytes (=100%), CaSF(+60%) was significantly increased, and both peak CaT(-80%) and CS(-80%) were markedly decreased. Addition of milrinone slightly increased peak CaT and CS, while CaSF significantly increased with an increase in [Ca2+]SR. Co-addition of landiolol to milrinone significantly decreased the CaSF witrather an increase in [Ca2+]SR, and both peak CaT and CS were much improved. Landiolol (10 nM) suppressed the hyperphosphorylation of RyR2 (Ser2808) in failing cardiomyocytes. In contrast, landiolol (10 nM) had no effect on the phosphorilation level of PLB (Ser16 and Thr17). Landiolol (10 nM) significantly inhibited the alternans of Ca2+ transient and cell shortening under the same pacing rate (0.5Hz) in failing cardiomyocytes (P < 0.01).
Conclusion: Low-dose β1 blocker to milrinone inhibited Ca2+ leakage through the failing RyR2 by selectively suppressing the hyperphosphorilation of RyR2. The suppression of milrinone-induced Ca2+ leakage may lead to effective improvement of cardiac function and suppression of arrhythmogenesis.
- © 2012 by American Heart Association, Inc.