Assessment of collateral artery function and growth in a pig model of stepwise coronary occlusion
Daphne de Groot, Sebastian Grundmann, Leo Timmers, Gerard Pasterkamp, Imo E. Hoefer
American Journal of Physiology. Heart and Circulatory Physiology
Therapeutic stimulation of collateral artery growth is a promising approach for treatment of cardiovascular diseases. Unfortunately, translation into clinical practice yet remains cumbersome. Cardiovascular physiology and anatomy are major determinants of vascular growth processes. Hence, large-animal models are needed to improve clinical translatability of preclinical research. Furthermore, acute complete occlusions are mostly applied in experimental research, whereas stepwise occlusions are
... re often observed in human disease. We developed a model of coronary collateral artery growth in which 1) the artery is occluded in a step wise approach, and 2) effects of local treatment can be measured individually for each supplying coronary vessel. A hemodynamically relevant stenosis was created by implantation of a tapered stent at day 0 (d0) in the left circumflex artery (LCX), followed by complete arterial occlusion at day 14 (d14). Fluorescent microspheres were injected for demarcation of perfusion territories at each time point. Three and four weeks after induction of stenosis, collateral conductance measurements were performed for each coronary artery separately using differently labeled fluorescent microspheres. Postmortem angiography after acute LCX occlusion confirmed the presence of preexistent coronary anastomoses in the pig. The tapered stent created a hemodynamically significant stenosis immediately postplacement (fractional flow reserve, 0.70 Ϯ 0.03). Between day 21 and 28, collateral conductance significantly increased in both the left anterior descending (LAD) and the right coronary artery (RCA)supplied, collateral-dependent territories (LAD d21, 0.77 Ϯ 0.14; LAD d28, 1.35 Ϯ 0.12; RCA d21, 0.88 Ϯ 0.29; RCA d28, 1.70 Ϯ 0.16 ml · min Ϫ1 ·g Ϫ1 · 100 mmHg Ϫ1 ), indicating collateral artery growth. We here describe a new translational minimally invasive model of coronary collateral artery growth in pigs, according to a defined protocol of LCX-stenosis and subsequent occlusion, allowing preclinical evaluation of arteriogenic therapies. preclinical model; arteriogenesis; collateral conductance THERAPEUTIC ANGIOGENESIS AND arteriogenesis, i.e., stimulation of capillary and collateral growth, has been envisioned as an alternative treatment modality for cardiovascular diseases for several years, but has not yet found its way into daily clinical practice (13). Many chemical and biological entities have been proposed as putative agents in experimental studies, while clinical effects yet remain small. Several reasons for this divergence have been identified, such as anatomy, physiology, occlusion rates, delivery issues, and comorbidities, which frequently differ between patients and preclinical models.