Empagliflozin directly improves diastolic function in human heart failure
Empagliflozin directly improves diastolic function in human heart failure
复制标题
DOI：
10.1002/ejhf.1328
复制
发表时间：
2018-12-01
影响因子：
18.2
通讯作者：
Sossalla, Samuel
中科院分区：
文献类型：
--
作者：
Pabel, Steffen;Wagner, Stefan;Sossalla, Samuel
恩格列净是一种临床使用的口服降糖药物，可抑制钠依赖性葡萄糖协同转运蛋白2，最近已对其心血管安全性进行了评价。令人惊讶的是，与安慰剂相比，恩格列净降低了心力衰竭（HF）的死亡率和住院率。然而，其潜在机制仍不清楚。因此，我们的研究的目的是调查是否恩格列净可能会导致直接的多效性作用对myocardial.Methods和结果为了评估可能的直接心肌效应恩格列净，我们进行了收缩性实验，在toto-isolated人收缩末期HF心室小梁。恩格列净显著降低舒张张力，而收缩力没有改变。这些结果在糖尿病和非糖尿病小鼠的小鼠心肌中得到证实，表明糖尿病条件的独立影响。在人HF心肌细胞中，恩格列净不影响钙瞬变幅度或舒张期钙水平。通过研究舒张期HF（射血分数保留的HF，HFpEF）患者和大鼠的心肌纤维，进一步阐明了舒张功能改善的机制。恩格列净通过增强肌丝调节蛋白的磷酸化水平，有益地降低肌丝被动刚度。静脉注射恩格列净在麻醉HFpEF大鼠显着改善心脏舒张功能测得的超声心动图，而收缩收缩力不受influenced.Conclusion恩格列净通过改善舒张刚度，从而舒张功能对心肌造成直接多效性效应。这些影响与糖尿病状况无关。由于舒张功能障碍和HF的药物治疗是一个未满足的需求，我们的结果为新的转化研究提供了依据，也可能有助于理解EMPA-REG OUTCOME试验。
Aims Empagliflozin, a clinically used oral antidiabetic drug that inhibits the sodium-dependent glucose co-transporter 2, has recently been evaluated for its cardiovascular safety. Surprisingly, empagliflozin reduced mortality and hospitalization for heart failure (HF) compared to placebo. However, the underlying mechanisms remain unclear. Therefore, our study aims to investigate whether empagliflozin may cause direct pleiotropic effects on the myocardium.Methods and results In order to assess possible direct myocardial effects of empagliflozin, we performed contractility experiments with in toto-isolated human systolic end-stage HF ventricular trabeculae. Empagliflozin significantly reduced diastolic tension, whereas systolic force was not changed. These results were confirmed in murine myocardium from diabetic and non-diabetic mice, suggesting independent effects from diabetic conditions. In human HF cardiomyocytes, empagliflozin did not influence calcium transient amplitude or diastolic calcium level. The mechanisms underlying the improved diastolic function were further elucidated by studying myocardial fibres from patients and rats with diastolic HF (HF with preserved ejection fraction, HFpEF). Empagliflozin beneficially reduced myofilament passive stiffness by enhancing phosphorylation levels of myofilament regulatory proteins. Intravenous injection of empagliflozin in anaesthetized HFpEF rats significantly improved diastolic function measured by echocardiography, while systolic contractility was unaffected.Conclusion Empagliflozin causes direct pleiotropic effects on the myocardium by improving diastolic stiffness and hence diastolic function. These effects were independent of diabetic conditions. Since pharmacological therapy of diastolic dysfunction and HF is an unmet need, our results provide a rationale for new translational studies and might also contribute to the understanding of the EMPA-REG OUTCOME trial.