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A Comprehensive Analysis of the Impact of Acute Myocardial Infarction in Patients With Celiac Disease

Open AccessPublished:May 15, 2022DOI:https://doi.org/10.1016/j.gastha.2022.04.018

      Background and Aims

      We aimed to study the impact of acute myocardial infarction (AMI) in patients with celiac disease (CD).

      Methods

      We used the National Inpatient Sample 2011–2018 to identify patients aged 18 years and older with a history of CD who presented with AMI using International Classification of Disease Nineth and Tenth Revision codes. Primary outcome of interest was mortality differences in AMI patients with and without CD. Secondary outcomes were in-hospital length of stay, hospital costs, and coronary revascularization.

      Results

      A total of 2,287,840 weighted patients were included in this study with a principal diagnosis of AMI. Among this population, 183,027 weighted patients had a history of CD (0.08%), and 2,286,010 weighted patients had AMI without a history of CD (99.92%). Most AMI patients with and without CD were older (69.57 ± 13.21 vs 67.08 ± 13.87 years, respectively) and white (92.55% vs 75.39%, respectively). Patients with AMI and CD were more likely to be female than patients without CD (53.76% vs 38.47%; P < .05). In our study, we found that the difference in hospital charges (adjusted mean difference $2644.7) was lower among AMI and CD; however, length of stay was higher among patients with CD (adjusted mean difference 0.36 day) although they were not statistically significant (P > .05). Both cohorts had higher number of Medicare recipients and lower number of patients who self-pay. Our study also found that smoking was more prevalent among patients with CD, 12.14%, vs patients without CD, 2.51%. Moreover, patients with CD who developed AMI had a lower adjusted odds of mortality than those without CD (adjusted odds ratio [aOR] 0.41; P < .05). Patients with CD and AMI also had lower odds of coronary revascularization (aOR 0.80; P < .05). In addition, we found that adults with CD had a lower odds of developing AMI (aOR 0.78; P < .05).

      Conclusion

      CD is a chronic disease leading to chronic inflammation and various nutrition-related problems which can lead to increased morbid conditions. However, we found lower odds of AMI among patients with CD, as well as lower mortality and comorbidities related to AMI, thus contradicting previous assumptions.

      Keywords

      Abbreviations used in this paper:

      aMD (adjusted mean difference), AMI (acute myocardial infarction), aOR (adjusted odds ratio), CD (celiac disease), GFD (gluten-free diet), HLD (hyperlipidemia), ICD-9 (International Classification of Diseases, Nineth Revision), ICD-10 (International Classification of Diseases, Tenth Revision), LOS (length of stay), NIS (National Inpatient Sample), T2DM (type 2 diabetes mellitus)

      Introduction

      Celiac disease (CD) is an intestinal immune-mediated disease triggered by the ingestion of gluten in genetically susceptible individuals. Previously thought to be a disease of childhood, the prevalence of CD is now estimated to affect 1% of the world's population with increasing prevalence in adults.
      • Rubio-Tapia A.
      • Murray J.A.
      Celiac disease.
      While intestinal manifestations are common, CD has been associated with a wide range of extraintestinal manifestations including acute myocardial infarction (AMI). Studies have found CD to be associated with significant increases in cardiovascular disease (CVD), such as cardiomyopathies and premature atherosclerosis, compared with the general population.
      • Wang I.
      • Hopper I.
      Celiac disease and drug absorption: implications for cardiovascular therapeutics.
      Although previous reports have established that chronic inflammation and autoimmune diseases are associated with accelerated atherosclerosis, few studies have assessed the outcomes between CD and non-CD with AMI.
      • Zhao Q.
      Inflammation, autoimmunity, and atherosclerosis.
      With approximately 2.3 million Americans at risk of cardiac complications,
      • Gajulapalli R.D.
      • Pattanshetty D.J.
      Risk of coronary artery disease in celiac disease population.
      we aim to assess the impact of AMI in patients with CD.

      Methods

      Data source

      Our study is a retrospective cohort study using the combined 2011–2018 National Inpatient Sample (NIS), an initiative provided by the Healthcare Cost and Utilization Project.
      HCUP Databases
      Healthcare Cost and Utilization Project (HCUP).
      The NIS is one of the largest all-payer databases available in the United States and is maintained by the Agency for Healthcare Research and Quality. It comprises records of over 7 million unweighted and over 35 million weighted hospital encounters each year.
      HCUP Databases
      Healthcare Cost and Utilization Project (HCUP).
      The data provided in the database are initially unweighted, then using an algorithm provided by Healthcare Cost and Utilization Project, it is converted to weighted data, which allows for estimates on a national level.
      HCUP Databases
      Healthcare Cost and Utilization Project (HCUP).
      Institutional review board approval was not required for this study as the NIS includes patient information that has been deidentified and made publicly available.

      Study population

      The NIS includes a 20% random sample of all inpatient hospitalizations from over 45 states and contains 1 primary diagnosis and up to 39 secondary diagnoses using International Classification of Diseases, Tenth Revision, (ICD-10), as well as 29 secondary diagnoses with the International Classification of Diseases, Nineth Revision, Clinical Modification (ICD-9-CM) codes. ICD codes were used to identify hospitalizations with a principal diagnosis of AMI (ICD-9: 410.xx; ICD-10 code: I21.xx) and a secondary diagnosis of CD (ICD-9 code: 579.0; ICD-10 code: K90.0) (Table 1). All patients included in this study were 18 years of age or older. The primary outcome of interest was mortality differences in admissions. Secondary outcomes were in-hospital length of stay (LOS), hospital costs, and differences in outcomes based on coronary revascularization.
      Table 1List of ICD-9 and ICD-10 Codes Used in the Study
      ICD-9ICD-10
      410.xxAcute myocardial infarctionI21.xxAcute myocardial infarction
      - 410.0- I21
      - 410.1- I21.0
      - 410.2- I21.1
      - 410.3- I21.2
      - 410.4- I21.3
      - 410.5- I21.4
      - 410.6- I21.9
      - 410.7
      - 410.8
      - 410.9
      579.0Celiac diseaseK90.0Celiac disease

      Statistical analysis

      The Pearson chi-square test and Student’s t-test were utilized for assessing baseline categorical and continuous variables, respectively. After adjusting for characteristics and comorbidities to account for confounding variables such as insurance status, age, gender, race, hospital bed size, Charlson comorbidity index, day of admission, hospital region/teaching status, and median income quartile based on zip code, a 2-step hierarchical multivariate regression model was used to calculate odds ratios of events associated with AMI in CD patients, such as coronary revascularization, developing AMI, and mortality. Furthermore, a multivariate regression model was used to find the difference in LOS and hospital charges (adjusted for inflation over time) in patients presenting with AMI and CD compared to non-CD patients. Stata Version 17 by StataCorp LLC (College Station, TX) was utilized for all statistical analyses.

      Results

      A total of 2,287,840 weighted patients were included in this study with a principal diagnosis of AMI. Among this population, 183,027 weighted patients had a history of CD (0.08%), and 2,286,010 weighted patients had AMI without a history of CD (99.92%) (Table 2). Most AMI patients with and without CD were older (69.57 ± 13.21 vs 67.08 ± 13.87 years, respectively) and white (92.55% vs 75.39%, respectively). However, patients with AMI and CD were more likely to be female than patients without CD (53.76% vs 38.47%; P < .05).
      Table 2Baseline Characteristics of Patients With Acute Myocardial Infarction With and Without Celiac Disease from 2011 to 2018
      VariablesCeliac (N = 183,027)No celiac (N = 2,286,010)P value
      Age (y)69.57 (±13.21)67.08 (±13.87)<.05
      Gender, %<.05
       Male46.2461.53
       Female53.7638.47
       Charlson comorbidity index2.56 (±1.59)2.70 (±1.76).101
      Race, %<.05
       White92.5575.39
       Other7.4524.61
      Comorbidities, %
       CAD76.8879.85.172
       HLD57.8064.31<.05
       HTN55.4955.06.871
       T2DM29.1938.10<.05
       CHF28.9031.37.3336
       Anemia32.0822.09<.05
       End-stage renal disease3.183.72.591
       Obesity12.1416.11<.05
       Acute renal failure12.7216.36.067
       Smoking12.142.51<.05
      CAD, coronary artery disease; CHF, congestive heart failure; HTN, hypertension.
      The most prevalent comorbidities in the CD cohort were coronary artery disease, hyperlipidemia (HLD), hypertension, type 2 diabetes mellitus (T2DM), congestive heart failure, and anemia (Table 2). Moreover, prevalence of conditions normally associated with risk of AMI such as coronary artery disease, HLD, T2DM, congestive heart failure, and obesity was lower in the CD cohort than in the non-CD cohort (Table 2). Patients with CD and AMI also had lower odds of coronary revascularization (adjusted odds ratio [aOR] 0.80; P < .05) (Table 3). In addition, we found that adults with CD had lower odds of developing AMI (aOR 0.78; P < .05) (Table 3). Furthermore, patients with CD who developed AMI had lower adjusted odds of mortality than those without CD (aOR 0.41; P < .05) (Table 3).
      Table 3Outcomes of AMI Hospitalizations With CD vs Without CD
      OutcomesAMI + CDAMI + no CDP value
      Significant P values ≤ .05 at 95% confidence interval indicates statistical significance.
      Adjusted odds ratio95% CI (LL-UL)Adjusted P value
      Weighted logistic regressions were performed adjusting for confounders including baseline characteristics such as age at admission, sex, race, hospital characteristics including bed size, location/teaching status, region, type of admission, median household income, payer status, and pre-existing comorbidities.
      All-cause in-hospital mortality2.31%4.98%<.050.410.19–0.87<.05
      Coronary revascularization50.29%55.69%<.050.800.65–0.99<.05
      Insurance status
      Medicare67.05%57.33%<.05
      Self-pay1.45%5.85%<.05
      Total hospital charges (mean)
      Adjusted for inflation over time.
      $85,911.3090,950.00.355
      Length of stay (d) (mean ± SD)4.74 ± 5.074.54 ± 5.31.445
      CI, confidence interval; LL, lower level; UL, upper level.
      a Significant P values ≤ .05 at 95% confidence interval indicates statistical significance.
      b Weighted logistic regressions were performed adjusting for confounders including baseline characteristics such as age at admission, sex, race, hospital characteristics including bed size, location/teaching status, region, type of admission, median household income, payer status, and pre-existing comorbidities.
      c Adjusted for inflation over time.
      In our study, we found that the difference in hospital charges (adjusted mean difference [aMD] $2644.7) was lower among patients with AMI and CD; however, LOS was higher among patients with CD (aMD 0.36 day) although they were not statistically significant (P > .05) (Table 3). Both cohorts had higher number of Medicare recipients and lower number of patients who self-pay (Table 3). Our study also found that smoking was more prevalent among patients with CD, 12.14%, vs patients without CD, 2.51%.

      Discussion

      CD, previously known as celiac sprue, is a chronic, systemic immune-mediated enteropathy triggered by ingestion of gluten in genetically susceptible individuals.
      • Green P.H.
      • Cellier C.
      Celiac disease.
      Once considered a disease of childhood, CD is estimated to affect 1% of the population worldwide with increasing prevalence in adults.
      • Rubio-Tapia A.
      • Murray J.A.
      Celiac disease.
      The disease is associated with human leukocyte antigen, specifically DQ2 and DQ8 haplotypes, a group of genes located on chromosome 6 that are responsible for regulating the immune system.
      • Fasano A.
      • Catassi C.
      Clinical practice. Celiac disease.
      CD is unique in that its clinical presentation is variable and can include intestinal and/or extraintestinal manifestations. Common gastrointestinal symptoms include abdominal pain from malabsorption due to villous atrophy of the intestinal wall by intraepithelial lymphocytes.
      • Hüe S.
      • Mention J.J.
      • Monteiro R.C.
      • et al.
      A direct role for NKG2D/MICA interaction in villous atrophy during celiac disease.
      An emerging extraintestinal manifestation of CD of particular significance is the presumed increased risk of CVDs such as AMI. The increased risk of CVD is attributed to a combination of chronic inflammation, nutrient deficiencies, and an adaptive immune response.
      • Leffler D.A.
      • Green P.H.
      • Fasano A.
      Extraintestinal manifestations of coeliac disease.
      Previous reports have established that the presence of chronic inflammation and autoimmune disease is associated with accelerated atherosclerosis due to endothelial dysfunction.
      • Zhao Q.
      Inflammation, autoimmunity, and atherosclerosis.
      The resultant injury to the endothelium results in compensatory changes leading to procoagulant properties and recruitment of macrophages and T-lymphocytes. This mechanism is similar to that of acute coronary syndrome, a predisposing risk factor for AMI, whereby chronic inflammation leads to loss of the protective function of the endothelium.
      • Green P.H.
      • Cellier C.
      Celiac disease.
      This in turn leads to an increased propensity for stenosis and infarction of the coronary artery.
      • Green P.H.
      • Cellier C.
      Celiac disease.
      Despite these associations, our study revealed lower odds of developing an AMI in patients with CD. There is evidence that suggests that a gluten-free diet (GFD) may be protective against this increased CVD risk.
      • Wei L.
      • Spiers E.
      • Reynolds N.
      • et al.
      The association between coeliac disease and cardiovascular disease.
      A study carried out by Wei et al demonstrated an increase in CVD events only in patients with CD who had not been given a GFD.
      • Wei L.
      • Spiers E.
      • Reynolds N.
      • et al.
      The association between coeliac disease and cardiovascular disease.
      Another study by Whorwell et al found a reduction in the incidence and mortality of ischemic heart disease in patients with CD.
      • Whorwell P.J.
      • Alderson M.R.
      • Foster K.J.
      • et al.
      Death from ischaemic heart-disease and malignancy in adult patients with coeliac disease.
      Their proposed mechanism suggests an apparent protective effect of CD due to malabsorption of dietary lipids.
      • Whorwell P.J.
      • Alderson M.R.
      • Foster K.J.
      • et al.
      Death from ischaemic heart-disease and malignancy in adult patients with coeliac disease.
      Our data across 8 years strengthen this hypothesis by demonstrating a significant decrease in mortality among patients with CD who have concomitant AMI (Table 2). Our data also showed a significant decrease in the prevalence of comorbidities such as T2DM and HLD among patients with CD consistent with previous studies.
      • West J.
      • Logan R.F.
      • Card T.R.
      • et al.
      Risk of vascular disease in adults with diagnosed coeliac disease: a population-based study.
      These comorbidities are all prominent risk factors in the development of AMI.
      • El-Menyar A.
      • Zubaid M.
      • Shehab A.
      • et al.
      Prevalence and impact of cardiovascular risk factors among patients presenting with acute coronary syndrome in the middle East.
      Dietary management through a GFD is the only therapy for CD that has been shown to help manage symptoms and promote small-intestinal healing.
      • Gujral N.
      • Freeman H.J.
      • Thomson A.B.
      Celiac disease: prevalence, diagnosis, pathogenesis and treatment.
      In addition, GFD has been shown to have an impact on the BMI of patients with underweight patients gaining weight and obese/overweight patients losing weight.
      • Cheng J.
      • Brar P.S.
      • Lee A.R.
      • et al.
      Body mass index in celiac disease: beneficial effect of a gluten-free diet.
      The link between BMI and a GFD is important as there is an increased risk of mortality associated with increasing BMI.
      • Adams K.F.
      • Schatzkin A.
      • Harris T.B.
      • et al.
      Overweight, obesity, and mortality in a large prospective cohort of persons 50 to 71 years old.
      Our data demonstrated a lower prevalence of obese patients among those with CD and AMI.
      The results from our current study suggest that patients with CD and AMI had, on average, a longer length of hospital stay and a lower aMD in total hospital charges than patients with AMI alone although it was not statistically significant. Borrelli et al showed a downward trend in hospitalizations as well as LOS for patients with CD over a 19-year period from 1995 to 2014.
      • Eric P.
      • Borrelli E.P.
      Trends in hospitalizations for celiac disease in the United States.
      Similarly, our data showed a downward trend in patients with CD with and without AMI (Figure). There is evidence that shows a correlation between LOS and mean hospital charges whereby a decrease in LOS would result in an expected decrease in hospital costs.
      • Nicasio A.M.
      • Eagye K.J.
      • Kuti E.L.
      • et al.
      Length of stay and hospital costs associated with a pharmacodynamic-based clinical pathway for empiric antibiotic choice for ventilator-associated pneumonia.
      Figure thumbnail gr1
      FigureMortality in patients with acute myocardial infarction (AMI) with celiac disease (CD) vs without CD.
      The assessment of whether patients receive coronary revascularization, by percutaneous coronary intervention or coronary artery bypass grafting, takes into account many clinical factors such as age, comorbidities, prior myocardial infarction, and resting electrocardiography abnormalities.
      • Alonso Martín J.J.
      • Curcio Ruigómez A.
      • Cristóbal Varela C.
      • et al.
      Indicaciones de revascularización: aspectos clínicos.
      Our data demonstrated that patients with AMI and CD had lower odds of receiving revascularization. One study showed that after adjusting for comorbidities and demographic factors, morbidly obese patients had higher rates of coronary artery bypass grafting surgery than those not morbidly obese when presenting with an AMI.
      • Dhoot J.
      • Tariq S.
      • Erande A.
      • et al.
      Effect of morbid obesity on in-hospital mortality and coronary revascularization outcomes after acute myocardial infarction in the United States.
      The patients in our AMI-with-CD cohort not only were less likely to be obese but also exhibited fewer comorbidities, such as diabetes and HLD, which is consistent with previous data that show higher comorbid risk factors in obese patients.
      • Das S.R.
      • Alexander K.P.
      • Chen A.Y.
      • et al.
      Impact of body weight and extreme obesity on the presentation, treatment, and in-hospital outcomes of 50,149 patients with ST-Segment elevation myocardial infarction results from the NCDR (National Cardiovascular Data Registry).
      Cigarette smoking has been proven to have a negative impact on cardiovascular outcomes. It has been linked to increased risk of myocardial infarctions, stroke, and mortality. Our study showed that patients with CD were found to have higher rates of smoking. Although only approximately 12% of the CD patient sample size were cigarette smokers, further studies need to be done to assess this potential confounding variable. A meta-analysis performed in Britain reviewed the association of smoking to CD and found that patients who were smokers were less likely to have CD.
      • Wijarnpreecha K.
      • Lou S.
      • Panjawatanan P.
      • et al.
      Cigarette smoking and risk of celiac disease: a Systematic review and meta-analysis.
      However, no concrete studies exist that assess the outcomes of smoking and having CD and associated outcomes.
      Although our study contained a large sample size, certain limitations about this study must be addressed. Limitations include the administrative nature of the data set, inability to longitudinally trace patient encounters, and possibility of overcalculation or undercalculation of the disease as it is limited to ICD codes and/or multiple inpatient admissions of the same patient. ICD codes require proper documentation, which may not always be the case. In addition, this study contains data that encompass both ICD-9 and ICD-10 codes, and it is known that ICD-9 codes may not be as specific for CD as ICD-10 codes. Furthermore, it is not possible to specify the cause of death. Moreover, NIS does not provide data on severity of the disease process, and it can be difficult to establish a timeline regarding the disease process or to determine whether the patient’s CD is controlled and if they are on a GFD. The data set does not provide pertinent lab values or imaging that can help stratify the disease process and better guide researchers. However, the NIS is one of the largest publicly available databases that highlights outcomes associated with certain diseases, which are CD and AMI in our case.

      Conclusion

      Our study identified a significant association of AMI in patients with CD. Overall, patients who presented with a history of CD during 2011-2018 had lower odds of developing AMI, indicating a possible protective effect. These patients also had lower rates of comorbidities commonly associated with CVD, lower odds of mortality, and received coronary revascularization. These patients also had a longer LOS, less hospital charges, and decreased mortality compared to patients with AMI and without CD. In addition, we observed a decreasing trend in incidence of AMI in patients with CD and associated mortality from 2011 to 2018. We suspect that the underlying etiology may be due to immune-mediated intestinal damage and resultant malabsorption which may play a protective role in patients with CD.

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