Medical Therapy After CABG: the Known Knowns, the Known Unknowns, and the Unknown Unknowns.

PURPOSE: Medical therapies play a central role in secondary prevention after surgical revascularization. While coronary artery bypass grafting is the most definitive treatment for ischemic heart disease, progression of atherosclerotic disease in native coronary arteries and bypass grafts result in recurrent adverse ischemic events. The aim of this review is to summarize the recent evidence regarding current therapies in secondary prevention of adverse cardiovascular outcomes after CABG and review the existing recommendations as they pertain to the CABG subpopulations. RECENT FINDINGS: There are many pharmacologic interventions recommended for secondary prevention in patients after coronary artery bypass grafting. Most of these recommendations are based on secondary outcomes from trials which include but did not focus on surgical patients as a cohort. Even those designed with CABG in mind lack the technical and demographic scope to provide universal recommendations for all CABG patients. CONCLUSION: Recommendations for medical therapy after surgical revascularization are chiefly based on large-scale randomized controlled trials and meta-analyses. Much of what is known about medical management after surgical revascularization results from trials comparing surgical to non-surgical approaches and important characteristics of the operative patients are omitted. These omissions create a group of patients who are relatively heterogenous making solid recommendations elusive. While advances in pharmacologic therapies are clearly adding to the armamentarium of options for secondary prevention, knowing what patients benefit most from each therapeutic option remains challenging and a personalized approach is still required.

Impact of autonomic regulation on burnout and performance in thoracic surgery residents.

Objective: This study sought to determine the feasibility of collecting physiologic data in thoracic surgery residents and whether it would correlate with burnout and burnout with performance. Methods: This was a prospective study of thoracic surgery residents over a 5-month period. Participants were evaluated with a wearable biometric device (heart rate variability and sleep) and the Maslach Burnout Inventory. Resident performance was quantified using Accreditation Council for Graduate Medical Education Milestones (scale, 1-5) normalized to program-designated targets (3 for postgraduate year 6 or lower residents and 4 for postgraduate year 7 residents). Results: The cohort consisted of 71% female participants (5/7) with 86% of residents having 1 or more children. High levels of emotional exhaustion (median, 30 [interquartile range, 20-36], where >26 is high) and high levels of depersonalization (median, 16 [interquartile range, 14-22], where >12 is high) were common, but personal accomplishment was also uniformly high (median, 43 [interquartile range, 41-46], where >38 is high). There was a significant correlation between heart rate variability and emotional exhaustion (r(12) = 0.65, P = .01) but not depersonalization (P = .28) or personal accomplishment (P = .24). Depersonalization and personal accomplishment did not correlate with resident performance (P = .12 and P = .75, respectively); however, increased emotional exhaustion showed a significant correlation with higher resident performance during periods when burnout was reported (r(6) = 0.76, P = .047). Conclusions: Dynamic measurement of resting heart rate variability may offer an objective measure of burnout in thoracic surgery residents. Thoracic surgery residents who report high levels of burnout in this cohort maintained the ability to meet program-designated milestones at or above the level expected of their postgraduate year.

Alterations in pancreatic islet cell function in response to small bowel resection.

After 50% proximal small bowel resection (SBR) in mice, we have demonstrated hepatic steatosis, impaired glucose metabolism without insulin resistance, and increased pancreatic islet area. We sought to determine the consequences of SBR on pancreatic ß-cell morphology, proliferation, and expression of a key regulatory hormone, glucagon-like peptide-1 (GLP-1). C57BL/6 mice underwent 50% SBR or sham operation. At 10 wk, pancreatic insulin content and secretion was measured by ELISA. Immunohistochemistry was performed to determine structural alterations in pancreatic α-and ß-cells. Western blot analysis was used to measure GLP-1R expression, and immunoassay was used to measure plasma insulin and GLP-1. Experiments were repeated by administering a GLP-1 agonist (exendin-4) to a cohort of mice following SBR. After SBR, there was pancreatic islet hypertrophy and impaired glucose tolerance. The proportion of α and ß cells was not grossly altered. Whole pancreas and pancreatic islet insulin content was not significantly different; however, SBR mice demonstrated decreased insulin secretion in both static incubation and islet perfusion experiments. The expression of pancreatic GLP-1R was decreased approximately twofold after SBR, compared with sham and serum GLP-1, was decreased. These metabolic derangements were mitigated after administration of the GLP-1 agonist. Following massive SBR, there is significant hypertrophy of pancreatic islet cells with morphologically intact α- and ß-cells. Significantly reduced pancreatic insulin release in both static and dynamic conditions demonstrate a perturbed second phase of insulin secretion. GLP-1 is a key mediator of this amplification pathway. Decreased expression of serum GLP-1 and pancreatic GLP-1R in face of no change in insulin content presents a novel pathway for enteropancreatic glucose regulation following SBR.NEW & NOTEWORTHY Metabolic changes occur following intestinal resection; however, the effects on pancreatic function are unknown. Prior studies have demonstrated that glucagon-like protein-1 (GLP-1) signaling is a crucial player in the improved insulin sensitivity after bariatric surgery. In this study, we explore the effect of massive small bowel resection on gut hormone physiology and provide novel insights into the enteropancreatic axis.

Intestinal epithelial cell-specific Raptor is essential for high fat diet-induced weight gain in mice.

Mammalian target of rapamycin complex 1 (mTORC1) is a major regulator of cell growth and proliferation through fuel sensing. Systemic inhibition of mTOR as well as manipulation of its downstream products prevent diet-induced obesity. The purpose of this study was to determine the consequences of intestine-targeted mTORC1 inhibition. To attenuate intestinal mTORC1 activity, Villin-CreER mice were crossed with Raptorflox/flox mice, creating an intestinal-specific Raptor null line (i-Raptor -/-). Mice were fed a high fat diet (HFD) and compositional changes as well as food intake levels were assessed. Over a five-week time course, i-Raptor -/- mice consistently gained less body weight on a HFD compared to wildtype (WT) mice secondary to significantly reduced food intake. Importantly, the i-Raptor -/- mice did not appear to be malnourished, demonstrated by their preservation of lean body mass. i-Raptor -/- mice also maintained a normal metabolic profile without significant changes in triglyceride or fasting glucose levels. Further investigation revealed that GDF-15 mRNA expression was significantly enhanced in i-Raptor -/- enterocytes when refed with HFD after overnight starvation. In summary, our study establishes that loss of intestinal specific-mTORC1 is protective of the development of diet-induced obesity by reducing food intake without altering the metabolic profile.

A Novel Approach to Calculating Small Intestine Length Based on Magnetic Resonance Enterography.

BACKGROUND: Bowel length is an important factor in the management of patients with intestinal failure and short bowel syndrome. However, it is difficult to accurately measure the length of the small intestine. Our aim was to demonstrate the feasibility of a dedicated software algorithm for calculating small intestine length based on magnetic resonance enterography (MRE) images. STUDY DESIGN: A custom algorithm for image thresholding, wall identification, segmentation, and path extraction was designed and implemented. Algorithm output included the Euclidean distance from the pylorus to the terminal ileum and coordinates of points along that route. For validation, 10 C57BL/6 mice underwent bowel preparation before MRE. After sacrifice, the entire small bowel was removed and the ex vivo small intestine length was measured in a standardized manner. Calculated and ex vivo length measurements were compared. RESULTS: Mean absolute difference and mean percentage difference between the 2 modalities were 1.8 ± 3.8 cm (p = 0.24) and 9.4% ± 6.0%, respectively. CONCLUSIONS: This study demonstrates the feasibility of a dedicated, computer-vision-based algorithm that can reliably and accurately calculate the length of the small intestine using MRE images. A validated, noninvasive approach to measuring small intestine length that can be implemented using available clinical imaging can have a dramatic clinical impact on management in patients with short bowel syndrome, Crohn's disease, and other intestinal disorders.

Independence of gut bacterial content and neonatal necrotizing enterocolitis severity.

INTRODUCTION: Necrotizing enterocolitis (NEC) is a common and devastating gastrointestinal disease of premature infants. NEC severity varies widely. Recent data have demonstrated a strong link between gut microbial dysbiosis and development of NEC. We tested the hypothesis that alterations in the gut microbiome at the time of diagnosis predict the severity of NEC. METHODS: We used prospectively collected fecal samples from very low birth weight infants who developed NEC, stratifying by NEC severity. Fecal bacterial DNA was sequenced using 16S rRNA pyrosequencing. A generalized Wald-type test based on the Dirichlet multinomial distribution was used to test for differences in microbial communities. RESULTS: Of 489 infants at risk, 30 NEC cases had 410 fecal samples collected in the 28days prior to the onset of NEC available for analysis. There were no differences in the pre-NEC gut microbial community between infants treated medically vs. surgically, or those with NEC totalis. Furthermore, neither treatment of NEC significantly changed the gut microbiome post-NEC among the survivors. CONCLUSION: We found no evidence that the gut microbiome, prior to the onset of disease, differentiates the clinical course of NEC. These data suggest that factors other than the gut microbiome may dictate disease severity. LEVEL OF EVIDENCE: Level 4.

Toll-like receptor 4 is critical for the development of resection-associated hepatic steatosis.

BACKGROUND: A significant number of children with short bowel syndrome experience intestinal failure-associated liver disease. We recently demonstrated accelerated hepatic steatosis after 50% small bowel resection (SBR) in mice. Since SBR is associated with alterations in the gut microbiome, the purpose of this study was to determine whether TLR4 signaling is critical to the development of resection-associated hepatic steatosis. METHODS: Male C57BL6 (control) and TLR4-knockout (KO) mice underwent 50% proximal SBR. Liver sections were analyzed to obtain the percent lipid content, and Ileal sections were assessed for morphological adaptation. Intestinal TLR4 mRNA expression was measured at 7days and 10weeks. RESULTS: Compared to controls, TLR4 KO mice demonstrated similar weight gain and morphological adaptation after SBR. Hepatic steatosis was decreased 32-fold in the absence of TLR4. Intestinal TLR4 mRNA expression was significantly elevated 7days after SBR. We also found that TLR4 expression in the intestine was 20-fold higher in whole bowel sections compared with isolated enterocytes. CONCLUSIONS: TLR4 signaling is critical for the development of resection-associated steatosis, but not involved in intestinal adaptation after massive SBR. Further studies are needed to delineate the mechanism for TLR4 signaling in the genesis of resection-associated liver injury. LEVEL OF EVIDENCE: Animal study, not clinical.

Liver steatosis induced by small bowel resection is prevented by oral vancomycin.

BACKGROUND: Intestinal failure-associated liver disease causes significant mortality in patients with short bowel syndrome. Steatosis, a major component of intestinal failure-associated liver disease has been shown to persist even after weaning from parenteral nutrition. We sought to determine whether steatosis occurs in our murine model of short bowel syndrome and whether steatosis was affected by manipulation of the intestinal microbiome. METHODS: Male C57BL6 mice underwent 50% small bowel resection and orogastric gavage with vancomycin or vehicle for 10 weeks. DNA was extracted from stool samples then sequenced using 16s rRNA. Liver lipid content was analyzed. Bile acids were measured in liver and stool. RESULTS: Compared with unoperated mice, small bowel resection resulted in significant changes in the fecal microbiome and was associated with a >25-fold increase in steatosis. Oral vancomycin profoundly altered the gut microbiome and was associated with a 15-fold reduction in hepatic lipid content after resection. There was a 17-fold reduction in fecal secondary bile acids after vancomycin treatment. CONCLUSION: Massive small bowel resection in mice is associated with development of steatosis and prevented by oral vancomycin. These findings implicate a critical role for gut bacteria in intestinal failure-associated liver disease pathogenesis and illuminate a novel, operative model for future investigation into this important morbidity.