Adenosine stress CMR perfusion imaging of the temporal evolution of perfusion defects in a porcine model of progressive obstructive coronary artery occlusion

Abstract

Adenosine stress CMR perfusion imaging can quantify absolute perfusion and myocardial perfusion reserve (MPR) in coronary artery disease (CAD) with higher spatial resolution than positron emission tomography, the only clinically available technique for quantitative myocardial perfusion imaging. While porcine models of CAD are excellent for studying perfusion abnormalities in chronic CAD, to date there are a limited number of studies that use quantitative perfusion for evaluation. Therefore, we developed an adenosine stress CMR protocol to evaluate the temporal evolution of perfusion defects in a porcine model of progressive obstructive CAD. 10 Yucatan minipigs underwent placement of an ameroid occluder around the left circumflex artery (LCX) to induce a progressive chronic coronary obstruction. Four animals underwent a hemodynamic dose range experiment to determine the adenosine dose inducing maximal hyperemia. Each animal had a CMR examination, including stress/rest spiral quantitative perfusion imaging at baseline and 1, 3, and 6 weeks. Late gadolinium enhancement images determined the presence of myocardial infarction, if any existed. Pixelwise quantitative perfusion maps were generated using Fermi deconvolution. The results were statistically analyzed with a repeated mixed measures model to block for physiological variation between the animals. Five animals developed myocardial infarction by 3 weeks, while three developed ischemia without an infarction. The perfusion defects were located in the inferolateral myocardium in the perfusion territory of the LCX. Stress perfusion values were higher in remote segments than both the infarcted and ischemic segments (p < 0.01). MPR values were significantly greater in the remote segments than infarcted and ischemic segments (p < 0.01). While the MPR decreased in all segments, the MPR recovered by the sixth week in the remote regions. We developed a model of progressive CAD and evaluated the temporal evolution of the development of quantitative perfusion defects. This model will serve as a platform for understanding the development of perfusion abnormalities in chronic occlusive CAD.

Myocardial blood flow is the dominant factor influencing cardiac magnetic resonance adenosine stress T2

“…It is interesting to note that in humans adenosine stress increases HR, 29,48–50 but pre‐clinically some studies report a decrease 8,51 similar to ours (Supporting Figure 2D,E), while others describe an increase 5,50,52 . This difference is not species specific, but instead may be caused by the anesthesia: studies using injectable anesthetics describe increased HR, while studies using inhaled anesthesia report a decrease in HR.…”

“…While it is surprising that MBF decreased at the highest dose of adenosine, other groups have observed a similar reversal 8 . Mechanistically, this may be due to saturation or delayed activation of specific adenosine receptor subtypes within the myocardium, shifting the predominant downstream effector; indeed, the vasodilatory action of the A 2A and A 2B adenosine receptors is opposed by activation of the A 1 and A 3 receptor subtypes 55 .…”

“…Previous pig studies by various groups used adenosine for stress imaging at doses ranging from 0.14 to 0.50 mg/kg/min, 5,7,8,52,54 all to differing hyperemic effects, making dose considerations and hyperemic expectations difficult to predict. Our study has clarified this; both the 3× and 4× doses of adenosine induce maximal hyperemia in Yorkshire pigs, with peak MBF at the 3× dose (Figure 3), and peak MBV at the 4× dose (Figure 5).…”

“…One method for probing myocardial tissue is stress imaging, which reveals the change in various hemodynamic factors between rest and hyperemic stress, a state induced via vasodilators such as adenosine, regadenoson, or dipyridamole 1–4 . Stress imaging can detect pre‐symptomatic stenoses, 5–8 and has been recognized as a successful predictor of major adverse cardiovascular events 9,10 . Currently, it is performed using several different imaging techniques, including first pass perfusion cardiac magnetic resonance (CMR), 11 positron emission tomography/single‐photon emission computed tomography imaging, 12,13 computed tomography (CT) perfusion angiography, 14,15 and myocardial contrast echocardiography, 16 but unfortunately, these imaging techniques require radiation exposure and/or injection of a contrast agent or tracer.…”

Ferumoxytol‐enhanced magnetic resonance T1 reactivity for depiction of myocardial hypoperfusion

“…We then performed native and FE adenosine stress testing (Figure 1). A left ventricular short-axis stack of T1 maps (base, mid, apex) was acquired at rest and at peak pharmacologic stress (adenosine, 300 μg/kg/min, 4-min infusion) 26 using the 5(3)3(3)3 MOLLI sequence 4 with a balanced steady-state free precession (bSSFP) readout and ECG triggering in all swine (n = 13) (FOV = 240 x 300 mm, TR = 2.6 ms, TE = 1.1 ms, TI = 100-180 ms, slice thickness = 8 mm, pixel bandwidth = 1085 Hz, flip angle = 35 ; Appendix S1). Because SASHA was borne out of efforts to reduce systematic T1 measurement errors related to off-resonance, flip angle, T2 dependence, heart rate (HR) fluctuations and magnetization transfer, we also, in eight swine, performed ECG-triggered rest and stress native T1 mapping using the SASHA 5 (Siemens WIP 1041B) sequence (n = 8) (FOV = 240 x 300 mm, TR = 2.8 ms, TE = 1.2 ms, fixed TS = 600 ms, 27 slice thickness = 8 mm, pixel bandwidth = 1085 Hz, flip angle = 70 ).…”