Davila, Alec Christopher; Biomedical Sciences (Augusta University, 2019-05)
      Background. Heart failure with preserved ejection fraction (HFpEF) is often manifested as impaired cardiac and microvascular reserve, for which no current effective therapies are available. We sought to determine if conducted vasodilation, which coordinates microvascular resistance longitudinally becomes compromised in HFpEF. We tested the hypothesis that inhibition of adenosine kinase (ADK), the major adenosine-metabolizing enzyme and novel therapeutic target, augments conducted vasodilation; therefore, improving tissue perfusion and left ventricle (LV) diastolic function. Methods and Results. Conducted vasodilation was assessed ex vivo in coronary arterioles isolated from right atrial appendages of patients with or without HFpEF diagnosis and in skeletal muscle arteries of the rodent model of HFpEF, ZSF1 rats. Obese ZSF1 rats displayed LV diastolic dysfunction over a 20-week lifespan as indicated by reduced E/A ratio and increased deceleration time of mitral flow velocity observed on echocardiogram. Conducted vasodilation in both HFpEF patients and obese ZSF1 rats were significantly reduced, which was associated with increased vascular expression of ADK. Isolated arterioles incubated with ADK inhibitor, ABT-702 (0.1 μM) displayed an improved conducted vasodilation. In vivo treatment of obese ZSF1 rats with ABT-702 (1.5 mg/kg, i.p. for 8-week) prevented LV diastolic dysfunction, and in a crossover design, ADK inhibition improved conducted vasodilation and LV diastolic function. Furthermore, ABT-702 treatment reduced surrogate markers of myocardial hypoxia (carbonic anhydrase 9 expression and fibrosis) in obese ZSF1 rats. Moreover, mice with endothelium-specific deletion of ADK exhibited augmented vasodilation and were protected against the development of transverse aortic constriction-induced LV dysfunction. Conclusion. Collectively, upregulation of microvascular ADK impairs conducted vasodilation in HFpEF. Pharmacological inhibition of ADK improves microvascular vasodilator function and provides beneficial effects on myocardial perfusion and LV diastolic function in HFpEF.