BACKGROUND AND AIMS Sodium-glucose linked cotransporter-2 (SGLT2) inhibitors reduce the likelihood of hospitalization for heart failure and cardiovascular death in both diabetic and non-diabetic individuals with reduced ejection fraction heart failure. Because SGLT2 inhibitors lead to volume contraction with reductions in both preload and afterload, these load-dependent factors are thought to be major contributors to the cardioprotective effects of the drug class. Beyond these effects, we hypothesized that SGLT2 inhibitors may also improve intrinsic cardiac function, independent of loading conditions. METHODS Pressure-volume (P-V) relationship analysis was used to elucidate changes in intrinsic cardiac function, independent of alterations in loading conditions in animals with experimental myocardial infarction, a well-established model of HFrEF. Ten-week old, non-diabetic Fischer F344 rats underwent ligation of the left anterior descending (LAD) coronary artery to induce myocardial infarction (MI) of the left ventricle (LV). Following confirmation of infarct size with echocardiography 1-week post MI, animals were randomized to receive vehicle, or the SGLT2 inhibitor, empagliflozin. Cardiac function was assessed by conductance catheterization just prior to termination 6 weeks later. RESULTS The circumferential extent of MI in animals that were subsequently randomized to vehicle or empagliflozin groups was similar. Empagliflozin did not affect fractional shortening (FS) as assessed by echocardiography. In contrast, load-insensitive measures of cardiac function were substantially improved with empagliflozin. Load-independent measures of cardiac contractility, preload recruitable stroke work (PRSW) and end-systolic pressure volume relationship (ESPVR) were higher in rats that had received empagliflozin. Consistent with enhanced cardiac performance in the heart failure setting, systolic blood pressure (SBP) was higher in rats that had received empagliflozin despite its diuretic effects. A trend to improved diastolic function, as evidenced by reduction in left ventricular end-diastolic pressure (LVEDP) was also seen with empagliflozin. MI animals treated with vehicle demonstrated myocyte hypertrophy, interstitial fibrosis and evidence for changes in key calcium handling proteins (all p < 0.05) that were not affected by empagliflozin therapy. CONCLUSION Empagliflozin therapy improves cardiac function independent of loading conditions. These findings suggest that its salutary effects are, at least in part, due to actions beyond a direct effect of reduced preload and afterload.

中文翻译：

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依帕列净的负荷独立作用有助于改善实验性心力衰竭的心功能，并降低射血分数。

背景和目的钠-葡萄糖连接的cotransporter-2（SGLT2）抑制剂可降低射血分数心力衰竭的糖尿病和非糖尿病患者因心力衰竭和心血管死亡而住院的可能性。由于SGLT2抑制剂会导致体积收缩，同时降低前负荷和后负荷，因此这些负荷依赖性因素被认为是该药类心脏保护作用的主要贡献者。除这些作用外，我们假设SGLT2抑制剂也可能改善内在的心脏功能，而与负荷情况无关。方法采用压力-体积（PV）关系分析来阐明内在心脏功能的变化，而与实验性心肌梗死（一种完善的HFrEF模型）的负荷条件的变化无关。十周龄的非糖尿病Fischer F344大鼠结扎左前降支（LAD）冠状动脉，以诱发左心室（LV）的心肌梗塞（MI）。在MI后1周通过超声心动图确认梗死面积后，将动物随机接受赋形剂或SGLT2抑制剂依帕列净。刚终止6周后，通过电导导管插入术评估心脏功能。结果随后随机分为媒介物或依帕列净组的动物的MI的周向范围相似。如超声心动图评估，依帕格列净不影响分数缩短（FS）。相比之下，依帕格列净可显着改善对负荷不敏感的心脏功能指标。与负荷无关的心脏收缩力测量，接受恩帕格列净的大鼠的预负荷可招募中风功（PRSW）和收缩末期压力容积关系（ESPVR）较高。与心力衰竭患者的心脏功能增强相一致，尽管接受利尿剂利尿剂的大鼠收缩压（SBP）较高。依帕列净还可以观察到舒张功能改善的趋势，左室舒张末期压力（LVEDP）降低也证明了这一点。用媒介物治疗的MI动物表现出心肌细胞肥大，间质纤维化和关键钙处理蛋白变化的证据（所有p <0.05），不受Empagliflozin治疗的影响。结论Empagliflozin治疗可改善心脏功能，而与负荷状况无关。这些发现表明，它的有益作用是，