2-Deoxy adenosine triphosphate improves contraction in human end-stage heart failure
2-Deoxy adenosine triphosphate improves contraction in human end-stage heart failure
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DOI：
10.1016/j.yjmcc.2014.12.002
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发表时间：
2015-02-01
影响因子：
5
通讯作者：
Regnier, Michael
中科院分区：
文献类型：
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作者：
Moussavi-Harami, Farid;Razumova, Maria V.;Regnier, Michael
我们正在开发一种通过增加心肌2脱氧atp （dATP）来治疗心力衰竭的新方法。我们在啮齿类动物模型中的研究表明，在体外用dATP替代三磷酸腺苷（ATP）作为能量底物或在体内提高dATP可增加心肌收缩，心肌天然dATP池的少量增加足以改善心功能。在这里，我们首次报道了dATP对成人心肌收缩的影响。我们测量了化学脱膜的多细胞心室壁制剂的收缩特性，并从终末期心力衰竭患者身上分离出肌原纤维。与ATP相比，在饱和和生理Ca2+浓度下，dATP的等长力都增加了。这导致Ca2+对力的敏感性（pCa(50)）增加0.06个pCa单位。脱膜壁肌的力再发率（k(tr)）和离体肌原纤维的收缩激活率（k(ACT)）也有所增加，表明与ATP相比，衰竭心肌的过桥结合和循环增加。这些数据表明，dATP可以增加衰竭心肌的dP/dT和收缩压。重要的是，即使力量发展的幅度和速度增加，肌原纤维松弛到50%和90%的时间没有增加。这些数据，以及我们之前在啮齿动物模型中的研究，显示了提高心肌dATP以增强收缩和恢复心泵功能的前景。这些数据也支持对这种治疗心力衰竭的新方法进行进一步的临床前评估。(C) 2014 Elsevier Ltd.版权所有。
We are developing a novel treatment for heart failure by increasing myocardial 2 deoxy-ATP (dATP). Our studies in rodent models have shown that substitution of dATP for adenosine triphosphate (ATP) as the energy substrate in vitro or elevation of dATP in vivo increases myocardial contraction and that small increases in the native dATP pool of heart muscle are sufficient to improve cardiac function. Here we report, for the first time, the effect of dATP on human adult cardiac muscle contraction. We measured the contractile properties of chemically-demembranated multicellular ventricular wall preparations and isolated myofibrils from human subjects with end-stage heart failure. Isometric force was increased at both saturating and physiologic Ca2+ concentrations with dATP compared to ATP. This resulted in an increase in the Ca2+ sensitivity of force (pCa(50)) by 0.06 pCa units. The rate of force redevelopment (k(tr)) in demembranated wall muscle was also increased, as was the rate of contractile activation (k(ACT)) in isolated myofibrils, indicating increased cross-bridge binding and cycling compared with ATP in failing human myocardium. These data suggest that dATP could increase dP/dT and end systolic pressure in failing human myocardium. Importantly, even though the magnitude and rate of force development were increased, there was no increase in the time to 50% and 90% myofibril relaxation. These data, along with our previous studies in rodent models, show the promise of elevating myocardial dATP to enhance contraction and restore cardiac pump function. These data also support further pre-clinical evaluation of this new approach for treating heart failure. (C) 2014 Elsevier Ltd. All rights reserved.