Contributor: Seyedeh Maryam Hosseini, MD
Heart failure with preserved ejection fraction is characterized by impaired cardiovascular reserve and coronary microvascular dysfunction. Tissue hypoxia activates endogenous adenosine secretion leading to vasodilation of the myocardial microvasculature. By increasing tissue perfusion in working myocardium, adenosine responds to increased metabolic demand. Davila et al. demonstrate that this adenosine vasodilation mechanism is impaired in HFpEF due to up-regulation of the adenosine kinase (ADK) enzyme gene. ADK changes adenosine to its inactive form. Increasing endogenous adenosine by inhibiting the ADK enzyme pharmacologically may have therapeutic potential to improve coronary vasodilation, myocardial perfusion and LV diastolic dysfunction in HFpEF.
Obese ZSF1 rats used to model human HFpEF, and isolated arterioles from right atrial appendages of HFpEF patients were used in this study. In both of these groups, microvasculature vasodilation was impaired (measured via video microscopic assessment). In addition to impaired vasodilation, both of these groups had increased ADK gene expression when compared to a lean control group of healthy rats. Treatment of both groups with ADK enzyme inhibition (ABT-702, 1.5mg/kg) restored vasodilation and improved LV diastolic function (namely E/A ratio and mitral DT). Treatment of HFpEF model rats with ABT-702 (chemical used to inhibit ADK) decreased tissue hypoxia markers, myocardial cabonic anhydranse 9 and collagen.
In short, adenosine, a potent endogenous vasodilator normally released in response to myocardial hypoxia, is converted by adenosine kinase (ADK) to an inactive adenosine in HFpEF. This may worsen tissue-level hypoxia and contribute to diastolic dysfunction.
No study is perfect. A significant limitation in this study is sample size, especially in the subgroup of ABT-702 with only 4 animals studied. Also, this study provides no direct causative links between impaired vasodilation and diastolic dysfunction, and other mechanisms of diastolic dysfunction independent of vasodilation cannot be excluded. In addition, it is important to note that vasodilation measurement in the obese ZSF1 rat group was done on skeletal muscle arterioles due to technical considerations and therefore the observed impairment and improvement of LV function pre and post ABT-702 treatment could potentially also be attributed to yet to be studied systemic effects.