Cardiac Myosin Activation for the Treatment of Systolic Heart Failure.
Cardiac Myosin Activation for the Treatment of Systolic Heart Failure.
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DOI：
10.1097/fjc.0000000000000929
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发表时间：
2021-01-01
影响因子：
3
通讯作者：
Buckley LF
中科院分区：
文献类型：
--
作者：
Bernier TD;Buckley LF
左心室收缩功能障碍是射血分数降低的心力衰竭的标志性病理。用β-肾上腺素能受体激动剂、磷酸二酯酶-3抑制剂或左西孟旦增加左心室收缩力未能改善临床结局，在某些情况下，增加了心源性猝死的风险。β-肾上腺素能受体激动剂和磷酸二酯酶-3抑制剂在晚期心力衰竭中仍具有重要作用。因此，对于改善左心室收缩功能的安全且有效的疗法仍然存在未满足的需求。两种新型心肌细胞生长因子，omecamtiv mecarbil和danicamtiv，靶向心肌肌球蛋白，以增加左心室收缩性能。Omecamtiv Mecarbil和Danicamtiv均不影响心肌细胞钙处理，这是与心脏降钙素和钙增敏剂相关的危及生命的心律失常的潜在机制。2期临床试验表明，这些心肌肌球蛋白激活剂延长左心室收缩期射血时间，促进左心室和心房逆向重构。在较高的血浆浓度下，这些药物可能与心肌缺血和舒张功能受损有关。正在进行的III期临床试验将评估Omecamtiv Mecarbil的临床疗效和安全性。这些药物对血液动力学和肾脏的影响最小，因此有必要对指南指导的神经激素阻滞剂难治性晚期心力衰竭患者进行额外研究。
Left ventricular systolic dysfunction is the hallmark pathology in heart failure with reduced ejection fraction. Increasing left ventricular contractility with beta-adrenergic receptor agonists, phosphodiesterase-3 inhibitors, or levosimendan has failed to improve clinical outcomes and, in some situations, increased the risk of sudden cardiac death. Beta-adrenergic receptor agonists and phosphodiesterase-3 inhibitors retain an important role in advanced heart failure. Thus, there remains an unmet need for safe and effective therapies to improve left ventricular systolic function. Two novel cardiac myotropes, omecamtiv mecarbil and danicamtiv, target cardiac myosin to increase left ventricular systolic performance. Neither omecamtiv mecarbil nor danicamtiv affects cardiomyocyte calcium handling, the proposed mechanism underlying the life-threatening arrhythmias associated with cardiac calcitropes and calcium sensitizers. Phase 2 clinical trials have demonstrated that these cardiac myosin activators prolong left ventricular systolic ejection time and promote left ventricular and atrial reverse remodeling. At higher plasma concentrations, these agents may be associated with myocardial ischemia and impaired diastolic function. An ongoing phase 3 clinical trial will estimate the clinical efficacy and safety of omecamtiv mecarbil. Additional study of these agents, which have minimal hemodynamic and renal effects, is warranted in patients with advanced heart failure refractory to guideline-directed neurohormonal blockers.