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Heart failure - a challenge to our current concepts of excitation-contraction coupling.

机译:心力衰竭-对我们目前的激励-收缩耦合概念提出的挑战。

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Development of novel therapeutic strategies for congestive heart failure (CHF) seems to be hampered by insufficient knowledge of the molecular machinery of excitation-contraction (EC) coupling in both normal and failing hearts. Cardiac hypertrophy and failure represent a multitude of cardiac phenotypes, and available invasive and non-invasive techniques, briefly reviewed here, allow proper quantification of myocardial function in experimental models even in rats and mice. Both reduced fractional shortening and reduced velocity of contraction characterize myocardial failure. Only when myocardial function is depressed in vivo can meaningful studies be done in vitro of contractility and EC coupling. Also, we point out potential limitations with the whole cell patch clamp technique. Two main factors stand out as explanations for myocardial failure. First, a basic feature of CHF seems to be a reduced Ca(2+) load of the sarcoplasmic reticulum (SR) mainly due to a low phosphorylation level of phospholamban. Second, there seems to be a defect of the trigger mechanism of Ca(2+) release from the SR. We argue that this defect only becomes manifest in the presence of reduced Ca(2+) reuptake capacity of the SR and that it may not be solely attributable to reduced gain of the Ca(2+)-induced Ca(2+) release (CICR). We list several possible explanations for this defect that represent important avenues for future research.
机译:对于充血性心力衰竭(CHF)的新型治疗策略的开发似乎由于对正常和衰竭心脏中的兴奋收缩(EC)耦合的分子机制的了解不足而受到阻碍。心脏肥大和衰竭代表​​多种心脏表型,在此简要介绍的可用侵入性和非侵入性技术可对实验模型中的心肌功能进行正确定量,即使在大鼠和小鼠中也是如此。分数缩短缩短和收缩速度降低均表征了心肌衰竭。只有在体内心肌功能受到抑制时,体外收缩性和EC耦合才能进行有意义的研究。此外,我们指出了整个细胞膜片钳技术的潜在局限性。有两个主要因素可以作为对心肌衰竭的解释。首先,CHF的基本特征似乎是减少了肌浆网(SR)的Ca(2+)负荷,这主要是由于phosphorlamban的磷酸化水平较低。其次,似乎存在Ca(2+)从SR释放的触发机制的缺陷。我们认为,该缺陷仅在减少SR的Ca(2+)重摄取能力的存在下变得明显,并且它可能不完全是由于Ca(2+)诱导的Ca(2+)释放的减少而引起的( CICR)。我们列出了对该缺陷的几种可能的解释,这些解释代表了未来研究的重要途径。

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