Is Protein Kinase C Inhibition the Tip of the Iceberg in New Therapeutics for Acutely Decompensated Heart Failure?
Is Protein Kinase C Inhibition the Tip of the Iceberg in New Therapeutics for Acutely Decompensated Heart Failure?
复制标题
蛋白激酶 C 抑制只是急性失代偿性心力衰竭新疗法的冰山一角吗？
DOI：
10.1016/j.jacbts.2017.11.005
复制
发表时间：
2017
期刊：
影响因子：
--
通讯作者：
Sam,Flora
中科院分区：
文献类型：
--
作者：
Pimental,DavidR;Sam,Flora
心力衰竭（HFrEF）或收缩性心力衰竭（如通常所知）是收缩力受损的疾病。神经激素系统的长期抑制是HFrEF长期治疗的关键，其允许逆转重塑，并且是目前治疗的主流，从而改善发病率和死亡率。然而，改善HFrEF收缩功能的靶向治疗不太成功，对于急性失代偿性心力衰竭（ADHF），正性肌力药物始终低于预期，尽管这些患者的短期血流动力学反应有所改善（1）。事实上，长期使用正性肌力药会增加死亡率（2）。然而，ADHF的管理仍然严重影响患者结局、健康提供者和整个卫生保健系统，因此，自米力农被发现以来，美国食品和药物管理局（FDA）在25年以上的时间里没有批准过正性肌力药。（Primacor）于1987年获得批准，其仿制药米力农于2002年获得批准。正性肌力药物增加HFrEF的收缩力和泵功能，通过直接增加肌球蛋白活性（3）或细胞内钙通量（4），从而提高肌丝蛋白的收缩力，从而提高ADHF和HFrEF的心输出量。然而，长时间使用正性肌力药物会影响结局，有些药物会导致心律失常，其机制被认为是由于心肌耗氧量增加（5）或通过刺激B-1肾上腺素能受体产生变时效应（6）。左西孟旦是一种钙增敏剂，可增加心脏对钙的敏感性，但可增加心脏收缩力，而不会增加细胞内钙。在2个独立的试验中，（7，8），左西孟旦与安慰剂相比，尽管临床和症状改善，但仍是预防性的。强心苷抑制钠-钾-ATP酶（Na+/K+-ATP酶），导致钠蓄积，进而增加细胞钙。这会激活钠钙交换器，导致正性肌力作用;然而，强心苷的治疗窗口非常窄（9）。肌球蛋白激活剂Omecamtiv Mecarbil可改善短期心脏功能（ATOMIC-AHF）（10），但对死亡率的长期影响尚未研究。
(HFrEF) or systolic heart failure (as it was commonly known) is a disease of impaired contractility. Long-term inhibition of the neurohormonal system is pivotal to the chronic treatment of HFrEF, which allows for reverse remodeling and is currently the mainstay of treatment, resulting in improved morbidity and mortality. However, targeted therapy to improve contractile function in HFrEF has been less successful, and for acutely decompensated heart failure(ADHF), positive inotropic drugs have consistently fallen short of expectations despite showing improved short-term hemodynamic responses in these patients (1). In fact, prolonged use of positive inotropes increases mortality (2). However, management of ADHF continues to weigh heavily on patient outcomes, health providers, and the health care system as a whole, and as such, there has been no approval of a positive inotrope by the US Food and Drug Administration (FDA) in more than 25 years, since milrinone (Primacor) was approved in 1987 and its generic, milrinone, in 2002.Positive inotropic drugs increase contractility and pump function in HFrEF, either by increasing myosin activity directly (3) or intracellular calcium flux (4), resulting in improved contractile force of the myofilament proteins and, as such, improved cardiac output in ADHF and HFrEF. However, prolonged use of positive inotropic agents worsens outcomes, and some are proarrhythymic, the mechanism of which is thought to be due to increased myocardial oxygen consumption (5) or chronotropic effects through stimulation of b-1 adrenergic receptors (6). Levosimendan, a calcium sensitizer, increases the sensitivity of the heart to calcium but increases cardiac contractility without a rise in intracellular calcium. In 2 separate trials,(7, 8), levosimendan compared to placebo was proarrhythmic despite clinical and symptomatic improvement. Cardiac glycosides inhibit sodium-potassium-ATPase (Na+/K+-ATPase), resulting in sodium accumulation which, in turn, increases cellular calcium. This activates the sodiumcalcium exchanger resulting in a positive inotropic action; however, cardiac glycosides have a very narrow therapeutic window (9). The myosin activator omecamtiv mecarbil improves short-term cardiac performance (ATOMIC-AHF)(10) but long-term effects on mortality remain unstudied.