Load-independent effects of empagliflozin contribute to improved cardiac function in experimental heart failure with reduced ejection fraction
Load-independent effects of empagliflozin contribute to improved cardiac function in experimental heart failure with reduced ejection fraction
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DOI：
10.1186/s12933-020-0994-y
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发表时间：
2020-02-08
影响因子：
9.3
通讯作者：
Gilbert, Richard E.
中科院分区：
文献类型：
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作者：
Connelly, Kim A.;Zhang, Yanling;Gilbert, Richard E.
背景和目的钠-葡萄糖相关协同转运蛋白2（SGLT 2）抑制剂可降低射血分数降低的糖尿病和非糖尿病心力衰竭患者因心力衰竭住院治疗和心血管死亡的可能性。由于SGLT 2抑制剂导致容量收缩，前负荷和后负荷均减少，因此这些负荷依赖性因素被认为是该类药物心脏保护作用的主要贡献者。除了这些作用之外，我们假设SGLT 2抑制剂还可以改善内在心脏功能，与负荷条件无关。方法采用压力-容积（P-V）关系分析方法，观察心肌梗死（HFrEF）后心脏固有功能的变化，并与负荷条件的改变无关。对10周龄的非糖尿病Fischer F344大鼠进行左前降支（LAD）冠状动脉结扎以诱导左心室（LV）的心肌梗死（MI）。在MI后1周通过超声心动图确认梗死面积后，将动物随机接受溶剂或SGLT 2抑制剂恩格列净。在6周后处死前通过电导导管插入术评估心脏功能。结果随后随机分配至溶剂组或恩格列净组的动物中MI的周向范围相似。根据超声心动图评估，恩格列净不影响缩短分数（FS）。相比之下，恩格列净显著改善了心脏功能的负荷不敏感指标。在接受恩格列净的大鼠中，心肌收缩力、前负荷复搏功（PRSW）和收缩末期压容积关系（ESPVR）的负荷非依赖性指标较高。尽管恩格列净具有利尿作用，但接受恩格列净的大鼠收缩压（SBP）较高，这与心力衰竭情况下心脏功能增强一致。在恩格列净组中也观察到舒张功能改善的趋势，如左心室舒张末期压（LVEDP）降低所证明。用媒介物处理的MI动物表现出肌细胞肥大、间质纤维化和关键钙处理蛋白变化的证据（所有p < 0.05），其不受恩格列净治疗的影响。结论恩格列净治疗改善心功能不依赖于负荷条件。这些研究结果表明，其有益的影响，至少部分是由于行动以外的直接影响，减少前负荷和后负荷。
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.