Accumulation of continuous life stress (chronic stress) often causes gastric symptoms. Although central oxytocin has antistress effects, the role of central oxytocin in stress-induced gastric dysmotility remains unknown. Solid gastric emptying was measured in rats receiving acute restraint stress, 5 consecutive days of repeated restraint stress (chronic homotypic stress), and 7 consecutive days of varying types of stress (chronic heterotypic stress). Oxytocin and oxytocin receptor antagonist were administered intracerebroventricularly (icv). Expression of corticotropin-releasing factor (CRF) mRNA and oxytocin mRNA in the paraventricular nucleus (PVN) of the hypothalamus was evaluated by real-time RT-PCR. The changes of oxytocinergic neurons in the PVN were evaluated by immunohistochemistry. Acute stress delayed gastric emptying, and the delayed gastric emptying was completely restored after 5 consecutive days of chronic homotypic stress. In contrast, delayed gastric emptying persisted following chronic heterotypic stress. The restored gastric emptying following chronic homotypic stress was antagonized by icv injection of an oxytocin antagonist. Icv injection of oxytocin restored delayed gastric emptying induced by chronic heterotypic stress. CRF mRNA expression, which was significantly increased in response to acute stress and chronic heterotypic stress, returned to the basal levels following chronic homotypic stress. In contrast, oxytocin mRNA expression was significantly increased following chronic homotypic stress. The number of oxytocin-immunoreactive cells was increased following chronic homotypic stress at the magnocellular part of the PVN. Icv injection of oxytocin reduced CRF mRNA expression induced by acute stress and chronic heterotypic stress. It is suggested that the adaptation mechanism to chronic stress may involve the upregulation of oxytocin expression in the hypothalamus, which in turn attenuates CRF expression.

IMPORTANCE The left atrial appendage is a key site of thrombus formation in atrial fibrillation (AF) and can be occluded or removed at the time of cardiac surgery. There is limited evidence regarding the effectiveness of surgical left atrial appendage occlusion (S-LAAO) for reducing the risk of thromboembolism. OBJECTIVE To evaluate the association of S-LAAO vs no receipt of S-LAAO with risk of thromboembolism among older patients undergoing cardiac surgery. DESIGN, SETTING, AND PARTICIPANTS Retrospective cohort study of a nationally representative Medicare-linked cohort from the Society of Thoracic Surgeons Adult Cardiac Surgery Database (2011–2012). Patients ≥65 years old with AF undergoing cardiac surgery (coronary artery bypass grafting [CABG], mitral valve surgery ± CABG, aortic valve surgery ± CABG) with and without concomitant S-LAAO were followed until December 31, 2014. EXPOSURE S-LAAO vs. no S-LAAO. MAIN OUTCOME MEASURES Primary outcome was readmission for thromboembolism (stroke, transient ischemic attack, or systemic embolism) at up to 3 years follow-up, as defined by Medicare claims data. Secondary endpoints included hemorrhagic stroke, all-cause mortality, and a composite endpoint (thromboembolism, hemorrhagic stroke, all-cause mortality). RESULTS Among 10,524 patients undergoing surgery (median age of 76 years; 39% female; median CHA2DS2-VASc score of 4), 3,892 (37%) underwent S-LAAO. Overall, at a mean follow-up of 2.6 years, thromboembolism occurred in 5.4%, hemorrhagic stroke in 0.9%, death in 21.5%, and the composite endpoint in 25.7%. S-LAAO, compared with no S-LAAO, was associated with lower unadjusted rates of thromboembolism (4.2% vs. 6.2%), all-cause mortality (17.3% vs. 23.9%), and the composite endpoint (20.5% vs. 28.7%), but no significance difference in rates of hemorrhagic stroke (0.9% vs. 0.9%). After inverse probability-weighted adjustment, S-LAAO was associated with a significantly lower rate of thromboembolism (subdistribution hazard ratio [HR] 0.67, confidence interval [CI] 0.56–0.81, p<0.0001), death (HR 0.88, CI 0.79–0.97, p=0.001), and the composite endpoint (HR 0.83, CI 0.76–0.91, p<0.001), but not hemorrhagic stroke (subdistribution HR 0.84, 0.53–1.32, p=0.44). S-LAAO, compared with no S-LAAO, was associated with a lower risk of thromboembolism among those discharged without anticoagulation (unadjusted rate 4.2% vs. 6.0%, adjusted subdistribution HR 0.26, CI 0.17–0.40, p<0.001), but not among those discharged with anticoagulation (unadjusted rate 4.1% vs. 6.3%, adjusted subdistribution HR 0.88, CI 0.56–1.39, p=0.59). CONCLUSIONS AND RELEVANCE Among older patients with AF undergoing concomitant cardiac surgery, S-LAAO compared with no S-LAAO, was associated with a lower risk of readmission for thromboembolism over the three years. These findings are supportive of S-LAAO, but randomized trials are necessary to provide definitive evidence.

In our daily life, individuals encounter with various types of stress. Accumulation of daily life stress (chronic stress) often causes gastrointestinal symptoms and functional gastrointestinal diseases. Although some can adapt toward chronic stress, the adaptation mechanism against chronic stress remains unknown. Although acute stress delays gastric emptying and alters upper gastrointestinal motility, effects of chronic stress on gastric motility still remain unclear. We investigated the effects of acute (single stress) and chronic (repeated stress for 5 consecutive days) stress on solid gastric emptying and interdigestive gastroduodenal contractions in rats. It is well established that acute restraint stress inhibits solid gastric emptying via central corticotropin-releasing factor (CRF). To investigate whether the sensitivity to CRF is altered following chronic stress, CRF was administered intracisternally. Ghrelin is involved in regulating gastric emptying and upper gastrointestinal motility in rodents. The changes in plasma active ghrelin levels and mRNA expression in the stomach were studied following chronic stress. To evaluate the effects of chronic stress on the hypothalamus-pituitary-adrenal (HPA) axis, plasma corticosterone levels were also measured. Delayed gastric emptying observed in acute stress was completely restored following chronic stress. Acute stress abolished gastric phase III-like contractions, without affecting duodenal phase III-like contractions in the interdigestive state. Impaired gastric phase III-like contractions were also restored following chronic stress. Plasma ghrelin levels and ghrelin mRNA expression were increased significantly after chronic stress. Intracisternal injection of CRF delayed gastric emptying and impaired gastric motility in rats who received chronic stress. Plasma corticosterone concentrations were no more elevated following chronic stress. The restored gastric emptying following chronic stress was antagonized by the administration of ghrelin receptor antagonists. The adaptation mechanism may involve upregulation of ghrelin expression and attenuation of the HPA axis. In contrast, the sensitivity to central CRF remained unaltered following chronic stress in rats.