Zaza Antonio, Rocchetti Marcella
Department of Biotechnology and Biosciences, University of Milano Bicocca Milan, Italy.
Eur Cardiol. 2025 Jun 30;20:e20. doi: 10.15420/ecr.2024.52. eCollection 2025.
Long-term use of modulators of myocardial function has been scaled down because of the partially detrimental effects of currently available agents. Nonetheless, inotropy and lusitropy remain unmet needs in the treatment of chronic heart failure (HF). This underlies the interest in SERCA2a stimulation, a novel approach. This short review describes the identification of SERCA2a stimulating activity in istaroxime, an inotropic compound characterised by its minimal proarrhythmic effects despite its multiple targets, and the development of its derivatives into a novel class of ino-lusitropic agents. The benefits achieved with istaroxime derivatives (versus istaroxime) consist of their selectivity for SERCA2a stimulation and pharmacokinetics suitable for chronic oral administration. Considering the role of SERCA2a depression in HF and the accompanying electrical instability, selective restoration of SERCA2a function provides an appealing approach to HF therapy. Beneficial effects of SERCA2a stimulation by istaroxime have also been recently described in non-cardiac tissues, thus suggesting even broader and unexpected indications for this new class of agents.
由于目前可用药物存在部分有害作用，心肌功能调节剂的长期使用已有所减少。尽管如此，在慢性心力衰竭（HF）的治疗中，心肌收缩力和舒张性能仍未得到满足。这引发了人们对刺激肌浆网钙ATP酶2a（SERCA2a）这一新型方法的兴趣。这篇简短综述描述了在伊司他肟中发现的刺激SERCA2a的活性，伊司他肟是一种正性肌力化合物，尽管有多个靶点，但具有最小的促心律失常作用，还描述了其衍生物发展成为一类新型的正性肌力-舒张性能改善药物的过程。伊司他肟衍生物（与伊司他肟相比）的优势在于它们对SERCA2a刺激具有选择性，并且具有适合长期口服给药的药代动力学特性。考虑到SERCA2a功能降低在HF中的作用以及伴随的电不稳定，选择性恢复SERCA2a功能为HF治疗提供了一种有吸引力的方法。最近还报道了伊司他肟刺激SERCA2a在非心脏组织中的有益作用，因此表明这类新型药物有更广泛和意想不到的适应症。
