Mathew L, Katz S D
Columbia Presbyterian Medical Center, Department of Medicine, Columbia University College of Physicians and Surgeons, New York, New York, USA.
Drugs Aging. 1998 Mar;12(3):191-204. doi: 10.2165/00002512-199812030-00003.
Congestive heart failure (CHF) is a common cardiovascular disorder that is characterised, in part, by a decreased cardiac output reserve. Accordingly, there is ongoing interest in the role of positive inotropic agents (e.g. adrenergic agonists and phosphodiesterase type III inhibitors, which mediate their cardiovascular effects via a cyclic adenosine monophosphate-dependent mechanism) in the treatment of CHF. However, enthusiasm for positive inotropic therapy in CHF has been dampened by the results of clinical trials, which have shown that these drugs are associated with an increased risk of mortality. Calcium sensitising agents are a heterogeneous group of positive inotropic agents that mediate their cardiovascular actions (at least in part) by increasing the sensitivity of the contractile elements to calcium. Increased sensitivity to calcium may be related to changes in calcium binding to troponin C, or to direct effects on the actin-myosin complex. In addition, the inhibition of phosphodiesterase type III may contribute to the positive inotropic action of calcium sensitising agents. Five agents with calcium sensitising properties (pimobendan, levosimendan, MCI-154, EMD-53998 and CGP-48506) have been studied as possible therapies for CHF. All of these agents have demonstrated a positive inotropic action in isolated cardiac tissue and in animal models of CHF. In clinical trials, pimobendan, the most extensively studied of these drugs, was well tolerated and was associated with improved exercise tolerance during the first 6 months of therapy; however, it was also associated with a nonsignificant trend towards increased mortality. Because many of the calcium sensitising agents also inhibit phosphodiesterase type III activity, the long term safety of these agents is uncertain. Large-scale survival trials are required to determine the long term safety and efficacy of these agents before their role in the treatment of CHF can be defined.
充血性心力衰竭（CHF）是一种常见的心血管疾病，其部分特征是心输出量储备降低。因此，人们一直关注正性肌力药物（如肾上腺素能激动剂和III型磷酸二酯酶抑制剂，它们通过环磷酸腺苷依赖性机制介导其心血管作用）在CHF治疗中的作用。然而，CHF正性肌力治疗的热情因临床试验结果而受挫，这些试验表明这些药物与死亡率增加风险相关。钙增敏剂是一类异质性的正性肌力药物，它们（至少部分地）通过增加收缩元件对钙的敏感性来介导其心血管作用。对钙敏感性增加可能与钙与肌钙蛋白C结合的变化有关，或与对肌动蛋白-肌球蛋白复合物的直接作用有关。此外，III型磷酸二酯酶的抑制可能有助于钙增敏剂的正性肌力作用。五种具有钙增敏特性的药物（匹莫苯丹、左西孟旦、MCI-154、EMD-53998和CGP-48506）已作为CHF的可能治疗方法进行了研究。所有这些药物在离体心脏组织和CHF动物模型中均表现出正性肌力作用。在临床试验中，这些药物中研究最广泛的匹莫苯丹耐受性良好，且在治疗的前6个月与运动耐量改善相关；然而，它也与死亡率增加的非显著趋势趋势趋势有关。由于许多钙增敏剂也抑制III型磷酸二酯酶活性，这些药物的长期安全性尚不确定。在确定它们在CHF治疗中的作用之前，需要进行大规模生存试验以确定这些药物的长期安全性和疗效。
