THE ROLE OF PIEZO2 MECHANOSENSITIVE ION CHANNEL IN ENTEROCHROMAFFIN (EC) CELL MECHANOSENSITIVITY

Background: Diagnosis of gastroparesis (GP) is based on the combination of upper gastrointestinal symptoms in the setting of delayed gastric emptying without evidence of mechanical obstruction.Key mechanisms identified in GP are related to the impaired gastric motility attributed to abnormal neuronal function and depletion of the interstitial cells of Cajal (ICC).This data was based on underlying pathophysiological findings taking place in the gastric body and antrum.More recently the focus on GP pathophysiology mechanisms has shifted to the pylorus.The aim of this study was to investigate the prevalence of ICC-opathy and fibrosis affecting the antrum and pylorus in drug refractory GP patients.Methods: Surgical full thickness pyloric and antral biopsies were obtained during the placement of a gastric electrical stimulation (GES) system and the performance of a pyloroplasty (PP) in 27 patients (20 diabetic (DM) and 7 idiopathic (ID); age: 43.2 (20-78) years; 23 female) who had failed all available medical therapies.Gastric emptying (GE) scintigraphy was performed using the standardized 4-hour protocol, with GP defined as > 60% isotope retention test meal retention at 2hours and > 10% at 4 hour.Tissues were stained with H&E, trichrome for fibrosis and C-Kit for ICC presence.ICC counts were calculated as the mean of ICC counts per 20 high power field (HPF).Depletion of ICC was defined as less than 10 cells /HPF in the antral and pyloric smooth muscle based on prior control data from our group.Fibrosis in the smooth muscle was graded from trichrome staining.Results: Overall 27 patients with a mean duration of 5.5 (1-17) years of GP symptoms underwent GES + PP surgery and gastric tissue samples were obtained from the antrum.19 of these patients (3 ID) also contributed pyloric biopsies for analysis.Fourteen (74%) GP patients (12 DM) showed depletion of pyloric ICC, while 11 patients (40%) had ICC loss in the antrum (6 DM). 8 (42%) patients (6 DM) had <10 ICC in both the antrum and pylorus.In addition, pyloric smooth muscle fibrosis was present in 14 (74 %) (13 DM) GP patients, and 10 (37%) (7DM) patients had antral smooth muscle fibrosis.Overall 7 (37%) patients (6 DM) had smooth muscle fibrosis present in both regions: pylorus and antrum, which 3(16%) (2 DM) had a combination of depletion of ICC as well as fibrosis in both biopsy locations.Conclusions: 1) Pyloric loss of ICC accompanied by smooth muscle fibrosis was identified in 74% of severely symptomatic GP patients, manly of diabetic etiology exceeding the 40% of GP patients with the same changes in antral smooth muscle.2) This data extends our knowledge of the pathophysiology of GP and elucidates the dominant role of the pylorus, setting the stage for evidence based treatment strategies.