BACKGROUND Heart failure with preserved ejection fraction (HFpEF) is often manifested as impaired cardiovascular reserve. We sought to determine if conducted vasodilation, which coordinates microvascular resistance longitudinally to match tissue metabolic demand, becomes compromised in HFpEF. We hypothesized that the metabolic vasodilator adenosine facilitates and that inhibition of ADK (adenosine kinase) augments conducted vasodilation for a more efficient myocardial perfusion and improved left ventricle (LV) diastolic function in HFpEF. METHODS AND RESULTS We assessed conducted vasodilation in obese ZSF1 rats that develop LV diastolic dysfunction and is used to model human HFpEF. Additionally, conducted vasodilation was measured in arterioles isolated from the right atrial appendages of patients with HFpEF. We found a markedly reduced conducted vasodilation both in obese ZSF1 rats and in patients with HFpEF. Impaired conducted vasodilation was accompanied by increased vascular ADK expression. Isolated rat and human arterioles incubated with adenosine (10 nmol/L) or ADK inhibitor ABT-702 (0.1 µmol/L) both displayed augmented conducted vasodilation. Treatment of obese ZSF1 rats with ABT-702 (1.5 mg/kg, IP for 8 weeks) prevented LV diastolic dysfunction, and in a crossover design augmented conducted vasodilation and improved LV diastolic function. ABT-702 treated obese ZSF1 rats exhibited reduced expression of myocardial carbonic anhydrase 9 and collagen, surrogate markers of myocardial hypoxia. CONCLUSIONS Upregulation of vascular ADK mitigates adenosine-facilitated conducted vasodilation in obese ZSF1 rats and in patients with HFpEF. We propose that pharmacological inhibition of ADK could be beneficial for therapeutic augmentation of conducted vasodilation, thereby improving tissue perfusion and LV diastolic function in HFpEF.

中文翻译：

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腺苷激酶抑制作用增强了血管舒张功能，并通过保留射血分数防止了心力衰竭时左心室舒张功能障碍。

背景技术保留射血分数（HFpEF）的心力衰竭通常表现为心血管储备受损。我们试图确定进行的血管舒张（在纵向上协调微血管阻力以匹配组织的新陈代谢需求）是否在HFpEF中受损。我们假设代谢性血管舒张剂腺苷促进并且对ADK（腺苷激酶）的抑制作用增强了血管舒张作用，从而在HFpEF中更有效地进行了心肌灌注并改善了左心室（LV）舒张功能。方法和结果我们评估了肥胖的ZSF1大鼠的血管扩张作用，该大鼠发生LV舒张功能障碍，并用于模拟人HFpEF。另外，在从HFpEF患者的右心耳分离出的小动脉中测量了进行的血管舒张。我们发现肥胖的ZSF1大鼠和HFpEF患者的血管舒张功能均明显降低。进行性血管舒张受损伴有血管ADK表达增加。与腺苷（10 nmol / L）或ADK抑制剂ABT-702（0.1 µmol / L）孵育的大鼠和人小动脉均显示出增强的血管舒张作用。用ABT-702（1.5 mg / kg，IP持续8周）治疗肥胖的ZSF1大鼠可预防LV舒张功能障碍，并在交叉设计中增加了进行的血管舒张功能并改善了LV舒张功能。ABT-702治疗的肥胖ZSF1大鼠的心肌碳酸酐酶9和胶原蛋白（心肌缺氧的替代标志物）表达降低。结论在肥胖的ZSF1大鼠和HFpEF患者中，血管ADK的上调可减轻腺苷促进的血管舒张。