Arterial CO2 as a potent coronary vasodilator: A preclinical PET/MR validation study with implications for cardiac stress testing

Myocardial blood flow (MBF) is the critical determinant of cardiac function. However, its response to increases in partial pressure of arterial CO2 (PaCO2), particularly with respect to adenosine, is not well characterized because of challenges in blood gas control and limited availability of validated approaches to ascertain MBF in vivo. Methods: By prospectively and independently controlling PaCO2 and combining it with 13N-ammonia PET measurements, we investigated whether a physiologically tolerable hypercapnic stimulus (;25 mm Hg increase in PaCO2) can increase MBF to that observed with adenosine in 3 groups of canines: without coronary stenosis, subjected to non-flow-limiting coronary stenosis, and after preadministration of caffeine. The extent of effect on MBF due to hypercapnia was compared with adenosine. Results: In the absence of stenosis, mean MBF under hypercapnia was 2.1 6 0.9 mL/min/g and adenosine was 2.2 6 1.1 mL/min/g; these were significantly higher than at rest (0.9 6 0.5 mL/min/g, P , 0.05) and were not different from each other (P 5 0.30). Under left-anterior descending coronary stenosis, MBF increased in response to hypercapnia and adenosine (P , 0.05, all territories), but the effect was significantly lower than in the left-anterior descending coronary territory (with hypercapnia and adenosine; both P , 0.05). Mean perfusion defect volumes measured with adenosine and hypercapnia were significantly correlated (R 5 0.85) and were not different (P 5 0.12). After preadministration of caffeine, a known inhibitor of adenosine, resting MBF decreased; and hypercapnia increased MBF but not adenosine (P , 0.05). Conclusion: Arterial blood CO2 tension when increased by 25 mm Hg can induce MBF to the same level as a standard dose of adenosine. Prospectively targeted arterial CO2 has the capability to evolve as an alternative to current pharmacologic vasodilators used for cardiac stress testing.