Chaudhary Khuram W, Rossman Eric I, Piacentino Valentino, Kenessey Agnes, Weber Chris, Gaughan John P, Ojamaa Kaie, Klein Irwin, Bers Donald M, Houser Steven R, Margulies Kenneth B
Cardiovascular Research Center, Temple University, Philadelphia, Pennsylvania 19140, USA.
J Am Coll Cardiol. 2004 Aug 18;44(4):837-45. doi: 10.1016/j.jacc.2004.05.049.
The objective of the present study was to determine whether improved contractility after left ventricular assist device (LVAD) support reflects altered myocyte calcium cycling and changes in calcium-handling proteins.
Previous reports demonstrate that LVAD support induces sustained unloading of the heart with regression of pathologic hypertrophy and improvements in contractile performance.
In the human myocardium of subjects with heart failure (HF), with non-failing hearts (NF), and with LVAD-supported failing hearts (HF-LVAD), intracellular calcium (Ca(2+)) transients were measured in isolated myocytes at 0.5 Hz, and frequency-dependent force generation was measured in multicellular preparations (trabeculae). Abundance of sarcoplasmic reticulum Ca(2+) adenosine triphosphatase (SERCA), Na(+)/Ca(2+) exchanger (NCX), and phospholamban was assessed by Western analysis.
Compared with NF myocytes, HF myocytes exhibited a slowed terminal decay of the Ca(2+) transient (DT(terminal), 376 +/- 18 ms vs. 270 +/- 21 ms, HF vs. NF, p < 0.0008), and HF-LVAD myocytes exhibited a DT(terminal) that was much shorter than that observed in HF myocytes (278 +/- 10 ms, HF vs. HF-LVAD, p < 0.0001). Trabeculae from HF showed a negative force-frequency relationship, compared with a positive relationship in NF, whereas a neutral relationship was observed in HF-LVAD. Although decreased SERCA abundance in HF was not altered by LVAD support, improvements in Ca(2+) transients and frequency-dependent contractile function were associated with a significant decrease in NCX abundance and activity from HF to HF-LVAD.
Improvement in rate-dependent contractility in LVAD-supported failing human hearts is associated with a faster decay of the myocyte calcium transient. These improvements reflect decreases in NCX abundance and transport capacity without significant changes in SERCA after LVAD support. Our results suggest that reverse remodeling may involve selective, rather than global, normalization of the pathologic patterns associated with the failing heart.
本研究的目的是确定左心室辅助装置（LVAD）支持后收缩力的改善是否反映了心肌细胞钙循环的改变以及钙处理蛋白的变化。
先前的报告表明，LVAD支持可导致心脏持续卸载，病理性肥大消退，收缩性能改善。
在心力衰竭（HF）患者、非衰竭心脏（NF）患者以及LVAD支持的衰竭心脏（HF-LVAD）患者的人心肌中，以0.5 Hz的频率在分离的心肌细胞中测量细胞内钙（[Ca(2+)]i）瞬变，并在多细胞制剂（小梁）中测量频率依赖性力的产生。通过蛋白质免疫印迹分析评估肌浆网Ca(2+) 三磷酸腺苷酶（SERCA）、钠/钙交换体（NCX）和受磷蛋白的丰度。
与NF心肌细胞相比，HF心肌细胞的Ca(2+) 瞬变的终末衰减减慢（终末衰减时间[DT(terminal)]，HF为376±18毫秒，NF为270±21毫秒，p<0.0008），HF-LVAD心肌细胞的DT(terminal) 比HF心肌细胞短得多（278±10毫秒，HF与HF-LVAD相比，p<0.0001）。HF的小梁显示出负性力-频率关系，而NF为正性关系，而HF-LVAD则观察到中性关系。尽管HF中SERCA丰度的降低未因LVAD支持而改变，但[Ca(2+)]i瞬变的改善和频率依赖性收缩功能与从HF到HF-LVAD时NCX丰度和活性的显著降低有关。
LVAD支持的衰竭人心脏中速率依赖性收缩力的改善与心肌细胞钙瞬变的更快衰减有关。这些改善反映了LVAD支持后NCX丰度和转运能力的降低，而SERCA没有显著变化。我们的结果表明，逆向重塑可能涉及与衰竭心脏相关的病理模式的选择性而非全局性正常化。
