Cardiovascular Comorbidities and Inflammatory Bowel Disease: Causes and Consequences.

Patients with inflammatory bowel disease (IBD) have an increased risk of cardiovascular disease (CVD) such as myocardial infarction and stroke. CVD in patients with IBD might occur in those with younger age and active disease, which are not traditional risk factors of CVD. Atherosclerotic CVD (ASCVD) and IBD are both proinflammatory conditions, and the underlying chronic inflammation might drive ASCVD risk. Decreasing inflammation might reduce this risk; however, data are limited. IBD medications can increase or decrease ASCVD risk. There are no specific guidelines or modalities to assess ASCVD in IBD. Early detection and risk stratification strategies have been established in other chronic inflammatory disorders. This article discusses causes of CVD in IBD and strategies to modify the consequences.

Coronary artery calcium scoring for cardiovascular risk assessment in patients with inflammatory bowel disease.

BACKGROUND: Inflammatory bowel disease (IBD) is associated with higher incidence of atherosclerotic cardiovascular disease (ASCVD). Data investigating the role of coronary artery calcium (CAC) scoring in identifying subclinical atherosclerotic disease in IBD patients is scarce. METHODS: Using data obtained from the CLARIFY registry, a prospective study of no-charge coronary artery calcium (CAC) testing at University Hospitals, we reviewed patients with ulcerative colitis (UC) or Crohn's disease (CD) who underwent CAC scoring from 2014 to 2020. We investigated the concordance between CAC risk and 10-year estimated ASCVD risk by AHA/ACC pooled cohort equation using pre-established thresholds for statin prescription (CAC≥100, 10-year ASCVD risk ≥7.5%). We additionally investigated the association between CAC, preventive therapy initiation and Major Adverse Cardiovascular Events (MACE). RESULTS: A total of 369 patients with IBD were included (174 UC, 195 CD), with median age of 60 years. The median CAC score was 14.9 with no significant difference between UC and CD (P = .76). Overall, 151 (41%) had CAC of 0, 108 (29%) had CAC 1-99, 61 (17%) had CAC 100 to 399, and 49 (13%) had CAC ≥400 with no difference in CAC distribution between CD and UC (P = .17). There was no difference in median CAC between IBD or age/sex-matched controls (P = .34). Approximately half of the patients (52%) with IBD had 10-year estimated ASCVD risk of 7.5% or higher. Among patients with ASCVD risk <7.5% (n = 163), 29 (18%) had CAC≥100 and among patients with ASCVD risk ≥7.5% (n = 178), 102 (57%) had CAC <100. There was no difference between CAC<100 vs CAC≥100 with respect to CRP, use of immunosuppressive or amino-salicylate therapy, IBD severity or complications. CAC score (AUROC 0.67 [0.56-0.78]), but not PCE ASCVD risk (AUROC 0.60 [0.48-0.73]), was predictive of MACE. The best cut-off for CAC score was 76 (sensitivity = 60%, specificity = 69%), and was associated with 4-fold increase in MACE (Hazard Ratio 4.0 [2.0-8.1], P < .001). CONCLUSION: Subclinical atherosclerosis, as evaluated by CAC scoring, is prevalent in patients with IBD, and is associated with cardiovascular events. Further studies are needed to understand underlying biological processes of increased atherosclerotic disease risk among adults with IBD.

Rates of Intestinal Resection and Colectomy in Inflammatory Bowel Disease Patients After Initiation of Biologics: A Cohort Study.

BACKGROUND & AIMS: 50% to 80% Crohn's disease (CD) and 10% to 30% ulcerative colitis (UC) patients require surgery over their lifetime. Biologic therapies may alter this natural history, but data on the effect of biologics on surgery rates in this patient population are mixed. We sought to investigate the influence of biologics on surgery prevalence in CD and UC. METHODS: We used a commercial database (Explorys Inc, Cleveland, OH), which includes electronic health record data from 26 major integrated US healthcare systems. We identified all patients who were diagnosed with CD or UC that were treated with any biologics between 2015 and 2020. The primary outcome was to examine the association between biologics therapy and the prevalence of bowel resection. Also, we identified the factors associated with surgery in IBD patients on biologics. RESULTS: Of 32,904,480 patients in the database, we identified 140,540 patients with CD and 115,260 patients with UC, of whom 25,840 (18%) and 9,050 (7.8%) patients received biologics, respectively. The prevalence of intestinal resection was significantly lower in biologics-treated CD patients (9.3%) compared to those who did not receive biologics (12.1%) (p < .001). Similarly, biologic-treated UC patients were significantly less likely to undergo colectomy (7.3%) compared to UC patients who did not receive biologic therapy (11.0%) (p < .001). Tobacco use, Clostridium difficile infection, and perianal disease were associated with intestinal resection in CD. Colon neoplasm and Clostridium difficile infection were associated with colectomy in UC. CONCLUSIONS: In this study of a large healthcare administrative database, inflammatory bowel disease (IBD) patients treated with biologics were significantly less likely to undergo bowel resection when compared to those who never received biologics. This data suggests that biologics may impact surgical rates in IBD.

Significant Facility-Level Variation in Utilization of and Adherence with Secondary Prevention Therapies Among Patients with Premature Atherosclerotic Cardiovascular Disease: Insights from the VITAL (Veterans wIth premaTure AtheroscLerosis) Registry7.

PURPOSE: We investigated facility-level variation in the use and adherence with antiplatelets and statins among patients with premature and extremely premature ASCVD. METHODS: Using the 2014-2015 nationwide Veterans wIth premaTure AtheroscLerosis (VITAL) registry, we assessed patients with premature (age at first ASCVD event: males < 55 years, females < 65 years) and extremely premature ASCVD (< 40 years). We examined frequency and facility-level variation in any statin, high-intensity statin (HIS), antiplatelet use (aspirin, clopidogrel, ticagrelor, prasugrel, and ticlopidine), and statin adherence (proportion of days covered ≥ 0.8) across 130 nationwide VA healthcare facilities. Facility-level variation was computed using median rate ratios (MRR), a measure of likelihood that two random facilities differ in use of statins or antiplatelets and statin adherence. RESULTS: Our analysis included 135,703 and 7716 patients with premature and extremely premature ASCVD, respectively. Across all facilities, the median (IQR) prescription rate of any statin therapy, HIS therapy, and antiplatelets among patients with premature ASCVD was 0.73 (0.70-0.75), 0.36 (0.32-0.41), and 0.77 (0.73-0.81), respectively. MRR (95% CI) for any statin use, HIS use, and antiplatelet use were 1.53 (1.44-1.60), 1.58 (1.49-1.66), and 1.49 (1.42-1.56), respectively, showing 53, 58, and 49% facility-level variation. The median (IQR) facility-level rate of statin adherence was 0.58 (0.55-0.62) and MRR for statin adherence was 1.13 (1.10-1.15), showing 13% facility-level variation. Similar median facility-level rates and variation were observed among patients with extremely premature ASCVD. CONCLUSIONS: There is suboptimal use and significant facility-level variation in the use of statin and antiplatelet therapy among patients with premature and extremely premature ASCVD. Interventions are needed to optimize care and minimize variation among young ASCVD patients.

Premature Atherosclerotic Cardiovascular Disease Risk Among Patients with Inflammatory Bowel Disease.

BACKGROUND: Recent literature has shown an association between atherosclerotic cardiovascular disease and inflammatory bowel disease, potentially mediated through chronic inflammatory pathways. However, there is a paucity of data demonstrating this relationship among young patients with premature atherosclerotic cardiovascular disease. METHODS: Using data from the nationwide Veterans wIth premaTure AtheroscLerosis (VITAL) registry, we assessed the association between extremely premature and premature atherosclerotic cardiovascular disease (age at diagnosis: ≤40 years and ≤55 years, respectively) and inflammatory bowel disease. Patients were compared with age-matched controls without atherosclerotic cardiovascular disease. Multivariable regression models adjusted for traditional risk factors. RESULTS: We identified 147,600 patients and 9485 patients with premature and extremely premature atherosclerotic cardiovascular disease, respectively. Compared with controls, there was a higher prevalence of overall inflammatory bowel disease among premature (0.96% vs 0.84%; odds ratio [OR] 1.14; 95% confidence interval [CI], 1.08-1.21) and extremely premature (1.36% vs 0.75%; OR 1.82; 95% CI, 1.52-2.17) patients. After adjustment, these associations attenuated in both premature and extremely premature groups (OR 1.07; 95% CI, 1.00-1.14 and OR 1.61; 95% CI, 1.34-1.94, respectively). CONCLUSION: Inflammatory bowel disease is associated with higher odds of extremely premature atherosclerotic cardiovascular disease, especially for those age ≤40 years. With increasing age, this risk is attenuated by traditional cardiometabolic factors such as obesity, hypertension, diabetes, smoking, and dyslipidemia. Prospective studies are needed to assess the role of early intervention to decrease cardiovascular risk among young patients with inflammatory bowel disease.

Inflammatory Bowel Disease Does Not Impact Mortality but Increases Length of Hospitalization in Patients with Acute Myocardial Infarction.

BACKGROUND AND AIM: Inflammatory bowel diseases (IBD) have been associated with increased risk of cardiovascular events. We aimed to investigate the outcomes of myocardial infarction (MI) in patients with IBD. METHODS: We performed a cross-sectional study utilizing data from the Nationwide Inpatient Sample from the years 1998 to 2010. ICD-9-CM codes were used to identify patients with Crohn's disease (CD) (555.X), ulcerative colitis (UC) (556.X), and acute MI (410.X). Outcomes in patients with MI with and without IBD were compared. Univariate analysis was performed. Multivariate logistic regression was used to determine the effect of UC and CD on in-hospital MI mortality after adjusting for confounders. RESULTS: A total of 2,629,161 MI, 3,607 UC and 3784 CD patients were analyzed. UC (odds ratio [OR], 1.12; 95% CI 0.98-1.29) and CD (OR 0.99; 95% CI 0.86-1.15) did not affect in-hospital mortality in patients with MI. There was no difference between in-hospital mortality in patients with MI with or without UC (7.75% vs. 7.05%; p = 0.25) or in patients with MI with or without CD (6.50% vs. 6.59%; p = 0.87). The length of stay (LOS) was higher in IBD patients and total charges were statistically higher in patients with UC as compared to non-IBD patients ($65,182 vs. $53,542; p < 0.001). CONCLUSIONS: This study shows that IBD does not impact in-hospital mortality from MI. However, patients with MI with IBD have longer LOS. Patients with UC have higher total hospitalization charges than patients with MI without IBD. Further prospective studies are needed to assess the outcomes of MI in IBD patients.

Cardiovascular Risk Assessment and Impact of Medications on Cardiovascular Disease in Inflammatory Bowel Disease.

There is increased risk of cardiovascular disease in patients with chronic inflammatory disorders such as rheumatoid arthritis, psoriatic arthritis, and systemic lupus erythematosus. Studies have shown association between cardiovascular disease (eg, myocardial infarction, heart failure, stroke) and inflammatory bowel disease. Medications such as infliximab and adalimumab (monoclonal antibodies to tumor necrosis factor α) may help decrease the inflammatory burden and cardiovascular risk; however, there have been reports of hypertriglyceridemia and worsening of moderate to severe heart failure with these medications. Janus kinase inhibitors, such as tofacitinib, have been associated with hyperlipidemia and thromboembolism. We aim to discuss clinical and imaging modalities to assess cardiovascular risk in inflammatory bowel disease patients and review the role of various medications with respect to cardiovascular disease in this population.

Fecal Microbiota Transplantation for Recurrent Clostridium difficile Infection in Patients With Multiple Comorbidities: Long-Term Safety and Efficacy Results From a Tertiary Care Community Hospital.

BACKGROUND: Cure rates of Clostridium difficile infection (CDI) with fecal microbiota transplant (FMT) have been promising. However, there is debate regarding success of FMT in patients with comorbidities. METHODS: Electronic chart review was done to collect data on patients who underwent FMT from January 2015 to August 2017. Charts were analyzed in November 2018 with a median follow-up of 25.4 months (interquartile range 20 - 31 months). RESULTS: Twenty patients underwent FMT. The primary success rate at our institution was 90% and overall success rate was 100%. Six patients (43%) had FMT failure (two early and four late). CONCLUSIONS: This case series is a description of our center's initial experience with FMT for treatment of recurrent CDI. Our high success rate reiterates the efficacy and safety of FMT in this population including patients with comorbidities.

Atherosclerotic cardiovascular disease in inflammatory bowel disease: The role of chronic inflammation.

Inflammatory bowel disease (IBD) causes systemic vascular inflammation. The increased risk of venous as well as arterial thromboembolic phenomena in IBD is well established. More recently, a relationship between IBD and atherosclerotic cardiovascular disease (ASCVD) has been postulated. Systemic inflammatory diseases, such as rheumatoid arthritis and systemic lupus erythematosus, have well characterized cardiac pathologies and treatments that focus on prevention of disease associated ASCVD. The impact of chronic inflammation on ASCVD in IBD remains poorly characterized. This manuscript aims to review and summarize the current literature pertaining to IBD and ASCVD with respect to its pathophysiology and impact of medications in order to encourage further research that can improve understanding and help develop clinical recommendations for prevention and management of ASCVD in patients with IBD.

Risk of Myocardial Infarction in Inflammatory Bowel Disease: A Population-based National Study.

BACKGROUND & OBJECTIVE: Chronic inflammation is linked to increased cardiovascular risk. Inflammatory bowel disease (IBD) is characterized by chronic inflammation of the gastrointestinal tract and elevated pro-inflammatory markers. The association between IBD and myocardial infarction (MI) is not well understood. We sought to elucidate this risk using a large database. METHODS: We reviewed data from a large commercial database (Explorys, IBM Watson) that aggregates electronic medical records from 26 nationwide health care systems. Using systemized nomenclature of medicine-clinical terms, we identified adult patients (20 to 65 years) with a diagnosis of IBD-ulcerative colitis (UC) or Crohn's disease (CD)-who had active records between August 2013 and August 2018. We then examined the risk of MI in patients with or without IBD. RESULTS: Out of 29,090,220 patients, 131,680 (0.45%) had UC, and 158,750 (0.55%) had CD. Prevalence of MI was higher in patients with UC and CD versus non-IBD patients (UC 6.7% vs CD 8.8% vs non-IBD 3.3%, odds ratio [OR] for UC 2.09 [2.04 -2.13], and CD 2.79 [2.74-2.85]. The odds of MI in IBD patients overall were highest in younger patients and decreased with age (age 30-34 years: OR 12.05 [11.16-13.01], age 65+ years: OR 2.08 [2.04-2.11]). After adjusting for age, race, sex, and traditional cardiovascular risk factor, IBD conferred greater odds of MI (adjusted odds ratio [aOR] 1.25 [1.24-1.27]). CONCLUSION: In this large cohort, IBD is associated with significantly increased MI compared with non-IBD patients. The relative risk of MI was highest in younger patients and decreased with age. These findings emphasize the need for aggressive risk factor reduction in IBD.

Beta-catenin cleavage enhances transcriptional activation.

Nuclear activation of Wnt/ß-catenin signaling is required for cell proliferation in inflammation and cancer. Studies from our group indicate that ß-catenin activation in colitis and colorectal cancer (CRC) correlates with increased nuclear levels of ß-catenin phosphorylated at serine 552 (pß-Cat552). Biochemical analysis of nuclear extracts from cancer biopsies revealed the existence of low molecular weight (LMW) pß-Cat552, increased to the exclusion of full size (FS) forms of ß-catenin. LMW ß-catenin lacks both termini, leaving residues in the armadillo repeat intact. Further experiments showed that TCF4 predominantly binds LMW pß-Cat552 in the nucleus of inflamed and cancerous cells. Nuclear chromatin bound localization of LMW pß-Cat552 was blocked in cells by inhibition of proteasomal chymotrypsin-like activity but not by other protease inhibitors. K48 polyubiquitinated FS and LMW ß-catenin were increased by treatment with bortezomib. Overexpressed in vitro double truncated ß-catenin increased transcriptional activity, cell proliferation and growth of tumor xenografts compared to FS ß-catenin. Serine 552-> alanin substitution abrogated K48 polyubiquitination,  ß-catenin nuclear translocation and tumor xenograft growth. These data suggest that a novel proteasome-dependent posttranslational modification of ß-catenin enhances transcriptional activation. Discovery of this pathway may be helpful in the development of diagnostic and therapeutic tools in colitis and cancer.

Epithelial TNF Receptor Signaling Promotes Mucosal Repair in Inflammatory Bowel Disease.

TNF plays an integral role in inflammatory bowel disease (IBD), as evidenced by the dramatic therapeutic responses in Crohn's disease (CD) patients induced by chimeric anti-TNF mAbs. However, treatment of CD patients with etanercept, a decoy receptor that binds soluble TNF, fails to improve disease. To explore this discrepancy, we investigated the role of TNF signaling in Wnt/ß-catenin-mediated intestinal stem cell and progenitor cell expansion in CD patients, human cells, and preclinical mouse models. We hypothesized that TNF exerts beneficial effects on intestinal epithelial cell (IEC) responses to injury. In CD patients, intestinal stem cell and progenitor cell Wnt/ß-catenin signaling correlates with inflammation status. TNF-deficient (Tnf-/-) mice exhibited increased apoptosis, less IEC proliferation, and less Wnt signaling when stimulated with anti-CD3 mAb. Bone marrow (BM) chimera mice revealed that mucosal repair depended on TNF production by BM-derived cells and TNFR expression by radioresistant IECs. Wild-type→Tnfr1/2-/- BM chimera mice with chronic dextran sodium sulfate colitis exhibited delayed ulcer healing, more mucosal inflammation, and impaired Wnt/ß-catenin signaling, consistent with the hypothesis that epithelial TNFR signaling participates in mucosal healing. The direct effect of TNF on stem cells was demonstrated by studies of TNF-induced Wnt/ß-catenin target gene expression in murine enteroids and colonoid cultures and TNF-induced ß-catenin activation in nontransformed human NCM460 cells (TOPFlash) and mice (TOP-GAL). Together, these data support the hypothesis that TNF plays a beneficial role in enhancing Wnt/ß-catenin signaling during ulcer healing in IBD. These novel findings will inform clinicians and therapeutic chemists alike as they strive to develop novel therapies for IBD patients.

Clinical outcomes in patients with a diagnosis of "indefinite for dysplasia" in Barrett's esophagus: a multicenter cohort study.

BACKGROUND AND STUDY AIM: Data are limited on the natural history of patients with Barrett's esophagus with a diagnosis of "indefinite for dysplasia" (IND). The aims of this study were to: (i) determine rates of progression to high grade dysplasia (HGD) or esophageal adenocarcinoma, and compare these with rates for low grade dysplasia (LGD); and (ii) determine the proportion of patients whose histological IND diagnosis changed on follow-up endoscopy. PATIENTS AND METHODS: Demographic, endoscopic, and histologic information of patients with diagnoses of IND and LGD and at least 12 months of follow-up were extracted from the database of a multicenter Barrett's esophagus study. Rates and times for progression to HGD and esophageal adenocarcinoma and regression to nondysplastic epithelium were calculated. Proportions of diagnoses upgraded to HGD/esophageal adenocarcinoma or downgraded to nondysplastic epithelium at first follow-up endoscopy were evaluated. RESULTS: Amongst 2264 patients, 83 with a diagnosis of IND (mean age 60 years, 95 % men, 95 % white; mean follow-up 5.6 years) and 79 with diagnosis of LGD were identified. In the IND group, annual incidences of esophageal adenocarcinoma and HGD were 0.21 % and 0.64 %, respectively, representing a combined incidence of 0.8 %. Mean time to progression was 4.72 years. Within the IND group 55 % patients showed regression to nondysplastic epithelium at first follow-up endoscopy and the overall regression rate was 80 %. Corresponding rates in LGD patients were similar. CONCLUSIONS: Lesions diagnosed as IND and LGD show similar biological behavior and can be treated as a single category with respect to surveillance and follow-up.

Endoscopic evaluation of surgically altered bowel in patients with inflammatory bowel diseases.

Patients with inflammatory bowel diseases often undergo surgical procedures for medically refractory disease or colitis associated dysplasia. Endoscopic evaluation of the surgically altered bowel is often needed to assess for disease recurrence, its severity, and for therapy. It is important to obtain and review the operative report and abdominal imaging before performing the endoscopy. Diagnostic and therapeutic endoscopy can be safely performed in most patients with inflammatory bowel disease with altered bowel anatomy under conscious sedation without fluoroscopy. Carefully planned stricture therapy with balloon dilation or needle knife stricturotomy can be performed for simple, short, and fibrotic strictures. A multidisciplinary approach involving a team of endoscopist, endoscopy nurse, colorectal surgeon, gastrointestinal pathologist, and gastrointestinal radiologist is important for a safe and effective endoscopy. We attempt to review the aspects that need consideration before the endoscopy, the technique of endoscopy, and briefly the therapies that can be performed during endoscopy of the bowel through an ileostomy, a colostomy, in the diverted large bowel or ileal pouch, and small bowel after stricturoplasty and bowel bypass surgery in patients with inflammatory bowel diseases.

Community gastroenterologists can learn diminutive colon polyp histology characterization with narrow band imaging by a computer-based teaching module.

BACKGROUND AND AIM: The aim of the present study was to evaluate the impact of a computer-based teaching module on the performance of community gastroenterologists for characterization of diminutive polyps (≤5 mm) using narrow band imaging video clips. METHODS: Eighty videos were distributed in pre- and post-test DVD along with a 20-min audiovisual teaching presentation detailing endoscopic features differentiating adenomas from hyperplastic polyps using narrow band imaging. Each participant first reviewed pretest video clips and entered their responses for polyp histology and their confidence in diagnosis: high: ≥90% or low: <90%. Following this, they reviewed the teaching module and assessed the post-test videos. Performance characteristics were calculated for pre- and post-test videos by comparing predicted histology with actual histology. Fisher's exact test was used for analysis and the kappa statistic was calculated for interobserver agreement. RESULTS: Fifteen gastroenterologists in community practice completed the study. Sensitivity, specificity, accuracy and negative predictive value in characterization of polyp histology improved significantly post-test compared to pretest. In post-test, accuracy was 92% for high-confidence diagnoses and the proportion of these increased with training from 46% (pretest) to 64% (post-test); P < 0.001. Interobserver agreement for diagnosis improved from fair (kappa = 0.23) in pretest to moderate (kappa = 0.56) in post-test. CONCLUSIONS: A teaching module using video clips can be used to teach community gastroenterologists polyp histology characterization by narrow band imaging. Whether this translates into real-time high accuracy in polyp detection needs to be further evaluated.