Circulating Ectonucleotidases Signal Impaired Myocardial Perfusion at Rest and Stress

Abstract

Background Ectonucleotidases maintain vascular homeostasis by metabolizing extracellular nucleotides, modulating inflammation and thrombosis, and potentially, myocardial flow through adenosine generation. Evidence implicates dysfunction or deficiency of ectonucleotidases CD39 or CD73 in human disease; the utility of measuring levels of circulating ectonucleotidases as plasma biomarkers of coronary artery dysfunction or disease has not been previously reported. Methods and Results A total of 529 individuals undergoing clinically indicated positron emission tomography stress testing between 2015 and 2019 were enrolled in this single-center retrospective analysis. Baseline demographics, clinical data, nuclear stress test, and coronary artery calcium score variables were collected, as well as a blood sample. CD39 and CD73 levels were assessed as binary (detectable, undetectable) or continuous variables using ELISAs. Plasma CD39 was detectable in 24% of White and 8% of Black study participants (P=0.02). Of the clinical history variables examined, ectonucleotidase levels were most strongly associated with underlying liver disease and not other traditional coronary artery disease risk factors. Intriguingly, detection of circulating ectonucleotidase was inversely associated with stress myocardial blood flow (2.3±0.8 mL/min per g versus 2.7 mL/min per g±1.1 for detectable versus undetectable CD39 levels, P<0.001) and global myocardial flow reserve (Pearson correlation between myocardial flow reserve and log(CD73) -0.19, P<0.001). A subanalysis showed these differences held true independent of liver disease. Conclusions Vasodilatory adenosine is the expected product of local ectonucleotidase activity, yet these data support an inverse relationship between plasma ectonucleotidases, stress myocardial blood flow (CD39), and myocardial flow reserve (CD73). These findings support the conclusion that plasma levels of ectonucleotidases, which may be shed from the endothelial surface, contribute to reduced stress myocardial blood flow and myocardial flow reserve.

Keywords: adenosine; coronary artery calcium; ectonucleotidase; myocardial flow reserve; positron emission tomography.

Figure 1. Catabolic activity of CD39 and CD73 produces anti‐inflammatory adenosine.

CD39 catabolizes ATP and ADP, generating inorganic phosphate and AMP, the latter of which is then catabolized by CD73 to form adenosine. Adenosine is known to have vasorelaxant and antithrombotic properties. PET indicates positron emission tomography; and P_i, inorganic phosphate.

Figure 2. Decade of age and the presence of detectable plasma CD39.

*P<0.001 based on Fisher exact test.

Figure 3. Decade of age and plasma log(CD73).

Box plots represent median and 25th and 75th percentiles. Circles represent data points that are >1.5 and <3 times below or above the box limits. Stars represent points that are >3 times below the lower or above the upper box limits. P=0.08 based on ANOVA; n per age category: 20 to 29 (n=6), 30 to 39: (n=15), 40 to 49 (n=55), 50 to 59: (n=113), 60 to 69: (n=147), 70 to 79 (n=114), 80 to 89 (n=13).

Figure 4. Summary of the key study findings.

Study findings support an inverse relationship between plasma ectonucleotidases, stress myocardial blood flow (CD39), and myocardial flow reserve (CD73). CAC indicates coronary artery calcium; and PET, positron emission tomography.