Arterial CO₂ as a Potent Coronary Vasodilator: A Preclinical PET/MR Validation Study with Implications for Cardiac Stress Testing

Abstract

Myocardial blood flow (MBF) is the critical determinant of cardiac function. However, its response to increases in partial pressure of arterial CO 2 (PaCO 2 ), 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 PaCO 2 and combining it with 13 N-ammonia PET measurements, we investigated whether a physiologically tolerable hypercapnic stimulus (;25 mm Hg increase in PaCO 2 ) 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 CO 2 tension when increased by 25 mm Hg can induce MBF to the same level as a standard dose of adenosine. Prospectively targeted arterial CO 2 has the capability to evolve as an alternative to current pharmacologic vasodilators used for cardiac stress testing.

Effects of Hypercapnia on Myocardial Blood Flow in Healthy Human Subjects

“…Studies in canines demonstrated the dynamic response of MBF over a range of 30-60 mm Hg. More recently, Yang et al showed no significant difference between the responses to hypercapnia and adenosine infusion in canines without coronary stenosis, with MBF doubling over that at baseline (8).…”

The Effect of Carbonated Natural Mineral Water on Oxidative Stress in Experimental Myocardial Ischemia

“…The effect of carbon dioxide seems to be similar with those exert by carbon monoxide and nitric oxide, inducing vasodilatation associated with smooth cells proliferation reduction, and having an inhibitor effect on platelets aggregation [14,15]. In vivo animal studies with coronary vessels vasoconstriction follow by stenosis (induced by caffeine), vasodilatation effect activity of carbon dioxide was demonstrated with significantly improved coronary blood flow (PET studies of the heart) [16]. The oxidative stress contribution to ischemia has been intensively studied, with a special attention given to quantitative assessment of oxidative stress parameters and their relationship with the ischemia progression and consequences.…”

Accurate needle-free assessment of myocardial oxygenation for ischemic heart disease in canines using magnetic resonance imaging

“…All animals were studied according to the NIH "Guide for the Care and Use of Laboratory Animals" following approval of Institutional Animal Care and Use Committee. In a subset of the animals, a left lateral thoracotomy was performed as previously described by our group (22). A Doppler probe was attached distal to the first branch of the left anterior descending coronary artery (LAD) to enable measurement of coronary blood flow velocity (CBFV).…”

“…The proposed method builds on previous studies from our laboratory and elsewhere, which show that tolerable levels of hypercapnia leads to more than 2-fold increase in myocardial blood flow and similar modulation in oxygenation in extent to that observed with adenosine (commonly used coronary vasodilator) in both in dogs and in humans (22) (28). Although our findings in this study are limited to canines, given that all cardiac stress testing paradigms have been first successfully demonstrated in dogs, and 25-mmgHg increase in PaCO2 is tolerable in humans, we anticipate that the proposed approach would translate well in humans.…”

“…Previous studies have shown that arterial CO2 tension when increased by 25 mmHg from baseline levels can accentuate myocardial blood flow by more than 2-fold, a hallmark of potent coronary vasodilators (22); and that such changes can be identified with 2D myocardial BOLD-CMR. However, studies to determine whether repeat exposure of the heart to a predefined CO2 stimulus can be used to improve the detection of healthy and hypoperfused myocardium with or without coronary stenosis have not been reported.…”