Liao R, Helm P A, Hajjar R J, Saha C, Gwathmey J K
Cardiovascular Disease Laboratory, Harvard Medical School, Boston, Massachusetts, USA.
Yale J Biol Med. 1994 Sep-Dec;67(5-6):247-64.
Multiple abnormalities have been reported in the setting of human heart failure. It is unclear whether detected changes reflect adaptive alterations in myocardium subjected to increased and sustained hemodynamic overload or are pathogenic to the disease process. As a result of the observation that the primary defect in heart failure is decreased pump function, investigators have concentrated their efforts on determining systolic [Ca2+]i as a logical corollary and a causative mechanism for contractile dysfunction. A simple cause and effect relationship has therefore been proposed with regard to contractile dysfunction and [Ca2+]i. Yet some investigators have found no difference in peak systolic [Ca2+]i between failing and non-failing human myocardium, whereas others have found peak [Ca2+]i to be significantly reduced in failing hearts. Resting calcium concentrations have been reported either to be elevated in failing human myocardium or not different from non-failing human myocardium. Investigators should now appreciate that the force-calcium relationship is not a simple relationship. One must take into account the prolonged time course and slowed mobilization of [Ca2+]i as opposed to simply peak [Ca2+]i. When put in perspective of mechanisms and determinants of the Ca(2+)-force relationship, we begin to realize that failing human myocardium has the "potential" to generate normal levels of force. Only when stressed by [Ca2+]i overload and/or frequency perturbation does myocardium from patients with end-stage heart disease demonstrate contractile failure. Although [Ca2+]i availability and mobilization are likely to play a role in the systolic as well as diastolic dysfunction reported in human heart failure, it is likely that other mechanisms are involved as well (e.g., myocardial energetics). Myocardial energetics is directly related to [Ca2+]i and mobilization in failing human myocardium, because metabolites, e.g., ADP, inhibit pumps, such as sarcoplasmic reticulum Ca2+ ATPase activity. We therefore conclude that there is a role for intracellular calcium mobilization and myocardial energetics for systolic and diastolic dysfunction seen in human heart failure.
在人类心力衰竭的情况下，已报告了多种异常情况。目前尚不清楚检测到的变化是反映了心肌在增加且持续的血流动力学过载情况下的适应性改变，还是对疾病进程具有致病性。由于观察到心力衰竭的主要缺陷是泵功能下降，研究人员将精力集中在确定收缩期[Ca2+]i上，将其作为收缩功能障碍的合理推论和致病机制。因此，关于收缩功能障碍和[Ca2+]i之间提出了一种简单的因果关系。然而，一些研究人员发现，衰竭和非衰竭的人类心肌之间收缩期峰值[Ca2+]i没有差异，而另一些研究人员则发现衰竭心脏中的峰值[Ca2+]i显著降低。据报道，静息钙浓度在衰竭的人类心肌中升高，或者与非衰竭的人类心肌没有差异。研究人员现在应该认识到，力-钙关系并非简单关系。必须考虑到[Ca2+]i的时间进程延长和动员减慢，而不仅仅是峰值[Ca2+]i。从Ca(2+)-力关系的机制和决定因素的角度来看，我们开始意识到衰竭的人类心肌具有产生正常力水平的“潜力”。只有在受到[Ca2+]i过载和/或频率扰动的压力时，终末期心脏病患者的心肌才会表现出收缩功能衰竭。尽管[Ca2+]i的可用性和动员可能在人类心力衰竭中报告的收缩期和舒张期功能障碍中起作用，但也可能涉及其他机制（例如心肌能量学）。心肌能量学与衰竭的人类心肌中的[Ca2+]i和动员直接相关，因为代谢产物（例如ADP）会抑制泵，如肌浆网Ca2+ ATPase活性。因此，我们得出结论，细胞内钙动员和心肌能量学在人类心力衰竭中所见的收缩期和舒张期功能障碍中起作用。
