Abstract 16127: Adenosine-kinase Inhibition Improves Conducted Coronary Arteriole Dilation in HFpEF Patients
With alarmingly growing incidence (1% increase/year among heart failure patients) and mortality rate (5.2% annual death) heart failure with preserved ejection fraction (HFpEF) commonly develops due to coronary microvascular dysfunction (CMD). The nature of mechanism linking CMD with HFpEF remains elusive. We hypothesized that vascular endothelial adenosine-kinase (ADK) limits adenosine availability and thereby impairs conducted coronary arteriole dilation in HFpEF. Coronary arterioles (CA, ~100 μm in diameter) from right atrial appendages were obtained from patients with HFpEF (N=10) or age-matched controls (N=10) without the clinical HFpEF diagnosis. Conduced CA dilation was examined, ex vivo, by focal application of endothelium-dependent agonist, bradykinin and subsequent measurements of diameter at local and remote sites (500 and 1000 μm away from the focal stimulation) with videomicroscopy. We found that the magnitude of conducted, but not the local, CA dilation was significantly reduced in HFpEF patients. Incubation of the arteries with adenosine or with a specific ADK inhibitor, ABT-702 augmented conducted CA dilation in HFpEF patients, who exhibited an increased ADK protein expression in CA, as assessed by immunohistochemistry and Western blotting. In addition, mice with endothelium-specific deletion of ADK exhibited an augmented conducted vasodilation, which was accompanied by increased propagation of endothelial [Ca2+] upon focal agonist stimulation. ADK inhibition by ABT-702 or genetic ADK deletion in cultured human CA endothelial cells also increased endothelial [Ca2+]. Collectively, our data demonstrate for the first time that the impaired conducted CA dilation is augmented after inhibition of ADK in HFpEF, likely via increasing endothelial ADO availability and facilitating Ca2+-dependent endothelial hyperpolarization spread.
Author Disclosures: A. Davila: None. H. Dou: None. Y. Huo: None. V. Patel: None. N. Weintraub: None. Z. Bagi: None.
- © 2016 by American Heart Association, Inc.