from the LGA, splenic artery, both the LGA and splenic artery, or the celiac trunk.
9.7 Therapeutic Potential of Left Gastric Artery
The swine that underwent GACE with 125 μg of morrhuate sodium demon-strated a significant decrease in serum ghrelin levels after 4 weeks. The animal that received the highest dose (2,000μg) during GACE died on post-procedure day #1 from a ruptured gastric ulcer. There was no significant weight loss seen in the experimental animals during the study period.
Histopathologic analysis of the gastric mucosa showed a decrease in tissue ghrelin after GACE, overall preserved tissue architecture, and microulcers at the gastro-esophageal junction in all animals. These microulcers were assumed to be secondary to non-target embolization of the distal esophageal branches of the LGA.
Even though this early study was unable to demonstrate the modulation of body weight after GACE of the LGA, it was the first to prove that serum ghrelin levels could be modulated via this minimally invasive technique.
As a follow-up to their earlier work, Arepally et al. (2008) randomly distributed ten healthy, growing swine into two groups to evaluate the ability of GACE of the LGA to suppress serum ghrelin levels and modulate weight. The animals underwent percutaneous angiography of the celiac axis and SMA through the right femoral artery to identify the LGA and other potential accessory gastric arteries. Super-selective angiography of these vessels was performed to identify all fundal vessels.
Five swine underwent sham embolization with normal saline, while the other five underwent GACE using 125μg of morrhuate sodium as the embolic agent.
Of note, all animals that underwent GACE required embolization of arteries in addition to the LGA in order to achieve angiographic stasis of flow to the fundus.
The swine were fed an ad libitum diet after the procedure. Body weight and serum ghrelin levels were again measured prior to the procedure and at 1 week intervals after the procedure for 4 weeks in total. No histopathologic correlation was performed in this study.
The control animals in this study had a pre-procedural serum ghrelin level of 1,078 pg/dL, which was not significantly different than the average post-procedural levels over 4 weeks (1,104 pg/dL). Conversely, animals that had undergone GACE demonstrated a significant decrease in the average serum ghrelin levels over 4 weeks (pre-procedure: 1,006.3 pg/dL; post-procedure average: 684.3 pg/dL).
Serum ghrelin levels decreased each week after GACE for the first 3 weeks of the study period, but rose closer to pre-procedural levels at the fourth week (876.6 pg/
dL). This finding is interesting because angiography performed 4 weeks after GACE (prior to animal sacrifice) showed that the previously embolized fundal vessels had re-obtained patency.
Thus, the increase in serum ghrelin levels at 4 weeks was thought to be secondary to either revascularization of fundal vessels, collateral flow to the gastric fundus, or possibly the compensatory production of ghrelin by other sites in the body. Regardless, the authors were able to demonstrate that animals gained weight at a slower pace after GACE (a 7.8 % increase in body weight over 4 weeks) than control animals (a 15 % increase in body weight over 4 weeks). Furthermore, even though intra-procedural angiography demonstrated the areas of non-target embolization in either branches of the hepatic, splenic, or esophageal arteries, there were no clinical sequelae in the treated animals, despite the well-recognized risks of
increased post-procedural pain and tissue necrosis in cases of non-target emboli-zation in humans.
These findings provided more evidence that minimally invasive, trans-arterial embolization of the LGA can suppress serum ghrelin levels and modulate weight with potentially fewer complications than other, more invasive surgical techniques.
Bawudun et al. (2012) sought to assess whether the embolic agent used to embolize the LGA affected changes seen in serum ghrelin levels, body weight, and body fat composition. In this study, healthy canines underwent percutaneous angiography of the celiac trunk with super-selective angiography of the LGA. The animals were randomly divided into a control group that underwent a simulated embolization with normal saline, an experimental group that underwent LGA embolization using a liquid sclerosing agent (bleomycin A5 hydrochloride (BAH) emulsed with lipiodol ultrafluid), and an additional experimental group that underwent mechanical embolization with 500–700 μm polyvinyl alcohol (PVA) particles. The canines were fed a fixed diet based after the procedure.
Body weight and serum ghrelin levels were measured prior to the procedure and at 1 week intervals after the procedure for 8 weeks in total. Body fat area was assessed by computed tomography (CT) prior to the procedure and 8 weeks after the procedure. Weekly barium meals during the study period, in addition to histopath-ologic analysis after animal sacrifice, were used to assess for gastric mucosal changes in response to LGA embolization.
The average serum ghrelin levels in both experimental groups decreased signi-ficantly over the study period in comparison to control animals. The average drop in serum ghrelin was 15.8 % with the sclerosing agent and 30.2 % after mechanical embolization, while non-embolized animals demonstrated a 13.6 % increase in serum ghrelin levels. Although, it should be noted that the most significant decrease in serum ghrelin was again demonstrated within the first 3 weeks after embolization of the LGA with a slow rise back toward pre-procedural levels in later weeks.
In this study, CT angiography performed at 8 weeks showed the LGA to be persistently occluded, suggesting that the cause for this increase in ghrelin is either collateral flow from other arteries or a compensatory increase in production from other sites in the body. Both experimental groups showed an equal decrease in the amount of both subcutaneous and overall fat area by CT, which was significantly greater than that seen in the control group. Additionally, both treatment groups demonstrated a significant amount of weight loss after LGA embolization in comparison to the control group. The weight loss seen was most pronounced within the first 3 weeks after LGA embolization with a slow rise in weights seen during later time points in the study period for both groups.
Notably, the authors were able to correlate the serum ghrelin levels with body weight. There were no clinically significant adverse events during the study period, even though non-target embolization occurred in three animals in the BAH-lipiodol group. Histopathologic analysis demonstrated no evidence of gastric mucosal ulceration or significant changes in the overall architecture of the gastric mucosa in either group. These findings demonstrated that both liquid and mechanical
embolization can safely suppress ghrelin levels, induce weight loss, and lower body fat content.
Liquid sclerosing agents show promise in suppressing ghrelin and modifying weight gain, in part, secondary to their ability to deeply penetrate into the smallest of vessels. However, these materials are known to be highly toxic and can result in clinically significant tissue necrosis. Therefore, Paxton et al. (2013) sought to evaluate the efficacy of bariatric LGA embolization using clinically available microspheres (40μm), a mechanical embolization agent. These extremely small spheres can pass deeper into tissues than the much larger PVA particles (range from 300 to 1,000μm) and provide long-term occlusion to the fundal vessels. These characteristics could hopefully induce a more permanent weight loss.
In this study, ten growing swine underwent percutaneous angiography of the celiac axis and SMA to delineate the gastric vascular supply. Super-selective angiography was used to identify all fundal vessels. The fundal vessels included the LGA, small branches of the splenic artery (likely SGAs), and an accessory LGA arising from the left hepatic artery. Five animals underwent embolization of the fundal vessels with normal saline. The experimental animals’ vessels were embolized with 4–6 mL of 40μm microspheres mixed with equal parts of nonionic contrast. After the procedure, the swine were fed a fixed diet. Body weight and serum ghrelin levels were measured prior to the procedure and at 1-week intervals after the procedure for 8 weeks in total. The gastric mucosa was evaluated by endoscopy, rather than by histopathology, in order to replicate the clinical conditions.
The pre-procedure serum ghrelin levels in the control and experimental groups were 1,591.6 pg/dL and 1,605.7 pg/dL, respectively, which were not significantly different. The post-procedure average serum ghrelin levels in the control and experimental groups were 1,920.5 pg/dL and 1,067.8 pg/dL, respectively. The decrease in serum ghrelin levels for the experimental group was significantly greater than that seen in the control group. Additionally, the experimental animals gained less weight over the study period (3.8 kg) than the control animals (9.4 kg).
Endoscopy performed at 3 weeks after LGA embolization demonstrated ulcers in 40 % (2/5) treated animals, but both were located along the lesser curvature rather than at the gastric fundus. All the treated animals demonstrated mild gastritis at endoscopy. These results show that LGA embolization to treat obesity is feasible with commercially available products and results in significant changes in serum ghrelin and modulation of subject weight.