Adenosine Kinase Inhibition Augments Conducted Vasodilation and Prevents Left Ventricle Diastolic Dysfunction in Heart Failure With Preserved Ejection Fraction
Adenosine Kinase Inhibition Augments Conducted Vasodilation and Prevents Left Ventricle Diastolic Dysfunction in Heart Failure With Preserved Ejection Fraction
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DOI：
10.1161/circheartfailure.118.005762
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发表时间：
2019-08-01
影响因子：
9.7
通讯作者：
Bagi, Zsolt
中科院分区：
文献类型：
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作者：
Davila, Alec;Tian, Yanna;Bagi, Zsolt
背景：心力衰竭伴射血分数保留（HFpEF）常表现为心血管储备受损。我们试图确定传导血管舒张是否在HFpEF中受到损害，血管舒张是纵向协调微血管阻力以匹配组织代谢需求的。我们假设代谢性血管舒张剂腺苷促进了血管舒张，抑制ADK（腺苷激酶）增强了传导血管舒张，从而使HFpEF的心肌灌注更有效，并改善了左心室（LV）的舒张功能。方法和结果：我们评估了左室舒张功能障碍的肥胖ZSF1大鼠的血管舒张功能，并用于模拟人HFpEF。此外，对HFpEF患者右心房附件分离的小动脉进行血管舒张测量。我们发现肥胖的ZSF1大鼠和HFpEF患者的血管舒张明显减少。血管舒张功能受损，血管ADK表达增加。与腺苷（10 nmol/L）或ADK抑制剂ABT-702 （0.1 μ mol/L）孵育的离体大鼠和人小动脉均显示增强的传导血管舒张。ABT-702治疗肥胖ZSF1大鼠（1.5 mg/kg，连续8周）可预防左室舒张功能障碍，并在交叉设计中增强了传导血管舒张功能，改善了左室舒张功能。ABT-702处理的肥胖ZSF1大鼠心肌碳酸酐酶9和胶原蛋白表达降低，这是心肌缺氧的替代标志物。结论：血管ADK的上调减轻了肥胖ZSF1大鼠和HFpEF患者中腺苷介导的血管舒张。我们认为药物抑制ADK可能有利于治疗性地增强传导血管舒张，从而改善HFpEF的组织灌注和左室舒张功能。
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 mu mol/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.