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 due to challenges in blood gas control and limited availability of validated approaches to ascertain MBF in vivo. By prospectively and independently controlling PaCO2 and combining it with (13)N-ammonia Positron Emission Tomography (PET) measurements, we investigated whether a physiologically tolerable hypercapnic stimulus (~25-mmHg increase in PaCO2) can increase MBF to that observed with adenosine in three groups of canines: (i) without coronary stenosis; (ii) subjected to non-flow limiting coronary stenosis; and (iii) following pre-administration of caffeine. The extent of effect on MBF due to hypercapnia was compared to adenosine. Methods and Results: In the absence of stenosis, mean MBF under hypercapnia was 2.1±0.9 ml/min/g and adenosine was 2.2±1.1 ml/min/g were significantly higher than at rest (0.9±0.5 ml/min/g, P<0.05); and were not different from each other (P = 0.30). Under left-anterior descending coronary (LAD) stenosis, MBF increased in response to hypercapnia and adenosine (p<0.05, all territories) but the effect was significantly lower than in the LAD territory (with hypercapnia and adenosine; both p<0.05). Mean perfusion defect volumes measured with adenosine and hypercapnia were significantly correlated (R=0.85) and were not different (P = 0.12). Following pre- administration 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 mmHg can induce MBF to the same level as standard dose of adenosine. Prospectively targeted arterial CO2 has the capability to evolve as an alternative to current pharmacological vasodilators used for cardiac stress testing.