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首页> 外文期刊>Cureus. >Omecamtiv Mecarbil: A Novel Mechanistic and Therapeutic Approach to Chronic Heart Failure Management
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Omecamtiv Mecarbil: A Novel Mechanistic and Therapeutic Approach to Chronic Heart Failure Management

机译：Omecamtiv Mecarbil：一种新型的慢性心力衰竭管理的机制和治疗方法

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Heart failure (HF) is a major public health problem in the United States as well as worldwide. Chronic heart failure is a syndrome of reduced cardiac output resulting from impaired ventricular function, impaired filling, or a combination of both. Associated symptoms include dyspnea, fatigue, and decreased exercise tolerance. HF has a marked effect on morbidity and mortality, given limited therapeutic choices. The first line of therapeutic agents indicated in heart failure are beta-blockers. Other drugs and therapeutic modalities employed in HF treatment include angiotensin-receptor blockers (ARBs), sacubitril (neprilysin inhibitor) combination with the ARB, valsartan, small doses of aldosterone receptor antagonists (ARAs) in the setting of angiotensin-converting enzyme (ACE) inhibitors, and beta-blockers. Additionally, the sodium-glucose transporter-2 inhibitor, dapagliflozin in the setting of ACE inhibitors, ARBs, or sacubitril-valsartan plus beta-blocker have been employed. Other therapeutic modalities have included loop diuretics, digoxin, the hydralazine-isosorbide dinitrate combination, ivabradine, the inotropes, dobutamine, milrinone, and dopamine. Decreased cardiac contractility is central to the systolic HF. Therapeutic agents employed to increase cardiac contractility in HF are limited because of their mechanistic-related adverse effect profiles. Omecamtiv mecarbil (OM) is a first of its class cardiac myosin activator that increases the cardiac contractility by specifically binding to the catalytic S1 domain of cardiac myosin, to be employed in heart failure treatment. This agent has demonstrated benefit in reducing heart rate, peripheral vascular resistance, mean left arterial pressure, and left ventricular end-diastolic pressure in the animal models. Additionally, OM is known to improve systolic wall thickening, stroke volume (SV), and cardiac output (CO). OM increases systolic ejection time (SET), cardiac myocyte fractional shortening without significant increase of LV dP/dtmax, myocardial oxygen consumption, and myocyte intracellular calcium. The benefits of OM have been demonstrated through key trials, as (i) The Acute Treatment with Omecamtiv mecarbil to Increase Contractility in Acute Heart Failure (ATOMIC-AHF), and (ii) The Chronic Oral Study of Myosin Activation to Increase Contractility in Heart Failure (COSMIC-HF). The Global Approach to Lowering Adverse Cardiac Outcomes Through Improving Contractility in Heart Failure (GALACTIC-HF) trial is ongoing and can help provide further clinical data.?OM provides a novel mechanism and therapeutic approach to managing patients with HF. Preclinical and clinical data suggest that OM capability can improve cardiac function, decrease ventricular wall stress, reverse ventricular remodeling, and promote sympathetic withdrawal.
机译：心力衰竭（HF）是美国的主要公共卫生问题以及全世界。慢性心力衰竭是由于心室功能受损，填充物受损或两者组合而导致的心输出减少的综合征。相关症状包括呼吸困难，疲劳和减少运动耐受性。鉴于治疗选择有限，HF对发病率和死亡率有显着影响。心力衰竭中表明的第一线治疗剂是β-受体阻滞剂。 HF处理中使用的其他药物和治疗方式包括血管紧张素受体阻滞剂（ARB），囊氨腈（Neprilysin抑制剂）组合在血管紧张素转换酶（ACE）的设置中，缬沙坦，小剂量的醛固酮受体拮抗剂（ARAS）抑制剂和β受体阻滞剂。另外，已经采用了钠 - 葡萄糖转运蛋白-2抑制剂Dapagliflozin，在αCE抑制剂，ARBS或Sacubitril-Valsartan Plusβ-阻滞剂中已经采用。其他治疗方式包括环利尿剂，高辛，氢氮嗪 - 异山梨醇二硝酸二硝基组合，Ivabradine，inotropes，多巴酚丁胺，MilRinone和多巴胺。心脏收缩性降低是收缩性HF的核心。由于其机械相关的不良反应谱，用于在HF中增加心脏收缩性的治疗剂受到限制。 OmecaMTIV Mecarbil（OM）是其第一个Carciac Myosin活化剂，通过特异性结合心脏肌球蛋白的催化S1结构域来增加心脏收缩性，以便在心力衰竭治疗中使用。该试剂对降低心率，外周血血管抗性，平均左动动脉压和动物模型的左心室末端舒张压的益处。另外，已知OM改善收缩壁增厚，行程体积（SV）和心输出（CO）。 OM增加收缩式喷射时间（设定），心肌细胞分数缩短，无需显着增加LV DP / DTmax，心肌氧消耗和肌细胞细胞内钙。通过关键试验证明了OM的好处，如（i）欧姆姆蒂夫麦克巴尔的急性治疗，以增加急性心力衰竭（原子-AHF）的收缩性，（ii）慢性口服肌肌素激活，增加心脏收缩性失败（COSMIC-HF）。通过改善心力衰竭（Galactic-HF）试验的收缩性降低不良心脏结果的全局方法正在进行，并且可以帮助提供进一步的临床数据.?OM提供了一种新的机制和治疗方法来管理HF患者。临床前和临床数据表明，OM能力可以改善心脏功能，降低心室壁应力，逆向心室重塑，促进交感神经戒断。

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