Mahidol University, Bangkok, Thailand; Cleveland Clinic, Cleveland, Ohio, USA
aFaculty of Medicine Siriraj Hospital, Mahidol University, Bangkok, Thailand (Wasit Wongtrakul); bDepartment of Medicine, Faculty of Medicine Siriraj Hospital, Mahidol University, Bangkok, Thailand (Nipith Charoenngnam); cDepartment of Rheumatic and Immunologic Diseases, Cleveland Clinic, Cleveland, Ohio, USA (Patompong Ungprasert)
Background Ischemic colitis is a relatively common gastrointestinal disease caused by hypoperfusion of the colon. Recently, studies have suggested an association between heart failure (HF) and ischemic colitis, even though the magnitude of the reported association varied considerably across the studies. This systematic review and meta-analysis were performed to comprehensively explore whether patients with HF are at a higher risk of ischemic colitis compared with individuals without HF by combining the results of all available observational studies.
Methods Systematic literature review was performed using EMBASE, MEDLINE and Google Scholar database up to May 2020. Eligible studies could be any observational ones that evaluated whether patients with HF have a higher risk of ischemic colitis than individuals without HF. Point estimates and standard errors from each eligible study were combined together using the generic inverse variance method of DerSimonian and Laird.
Results The systematic review identified 7 case-control studies and 1 cross-sectional study. The pooled analysis found that patients with HF had a significantly higher risk of ischemic colitis with the pooled odds ratio of 3.42 (95% confidence interval 1.49-7.82; I2 96%). Funnel plot was relatively symmetric and was not suggestive of presence of publication bias.
Conclusion A significantly increased risk of ischemic colitis among patients with HF was demonstrated in this systematic review and meta-analysis.
Keywords Heart failure, ischemic colitis, epidemiology, meta-analysis, systematic review
Heart failure (HF) is a syndrome caused by cardiac abnormalities and neurohormonal changes, leading to elevated intracardiac pressures or reduced cardiac output [1]. The estimated incidence rate is approximately 300-400 new cases per 100,000 person-years, causing substantial healthcare and economic burden [2-5]. Symptoms and signs of HF include dyspnea, orthopnea, fatigue, peripheral edema, raised jugular venous pressure, cardiomegaly, and a third heart sound [6]. Common etiologies of HF are myocardial infarction, hypertension, valvular heart disease and cardiomyopathy [6].
With an incidence ranging from 4.5-45 new cases per 100,000 person-years [7,8], ischemic colitis is a relatively common gastrointestinal disease caused by hypoperfusion to the colon, leading to inflammation and hemorrhage of intestinal mucosa [9]. Classical clinical presentation of ischemic colitis is hematochezia and lower abdominal pain in patients aged older than 60 years [10]. Any conditions that can impair colonic perfusion, such as arterial emboli, thrombosis, trauma, hypotension and shock can predispose patients to ischemic colitis [10].
Recently, studies have suggested a relationship between HF and ischemic colitis, even though the magnitude of the reported association varied considerably [8,11-17]. Therefore, this systematic review and meta-analysis was performed to comprehensively explore whether patients with HF are at a higher risk of ischemic colitis compared with individuals without HF by combining the results of all available observational studies.
Two authors (W.W. and N.C.) independently conducted systematic literature review with no language limitation in EMBASE and MEDLINE database from inception to May 2020 to identify all published articles that explored the association between HF and ischemic colitis. The search strategy that includes the terms for “heart failure” and “ischemic colitis” is available as Supplementary Data 1. To maximize the comprehensiveness of the identification of eligible studies, the literature review was also performed in Google Scholar and bibliography of the included studies initially retrieved from EMBASE and MEDLINE. This study was performed according to the Preferred Reporting Items for Systematic Reviews and Meta-Analyses statement (Supplementary Data 2).
Eligible studies could be any observational ones that evaluated whether patients with HF have a higher risk of ischemic colitis than individuals without HF. Eligible cohort studies had to provide relative risks, incidence rate ratios, hazard risk ratios, or standardized incidence ratios with associated 95% confidence interval (CI) comparing the incidence of ischemic colitis between the 2 cohorts. Eligible case-control studies had to report odds ratios (OR) with 95%CI comparing the prevalence of HF between cases and controls. Eligible cross-sectional studies had to report OR with 95%CI of the association.
Standardized data collection form was used to extract the following details: last name of the first author; country of study; study design; year of publication; number of participants; recruitment of participants; identification and ascertainment of the diagnosis of HF and ischemic colitis; mean age of participants; percentage of male participants; confounders adjusted in multivariate analysis; and adjusted effect estimates with corresponding 95%CI. Two authors (W.W. and N.C.) assessed the quality of each cohort study according to Newcastle-Ottawa quality assessment scale [18].
Review Manager 5.3 software from the Cochrane Collaboration (London, United Kingdom) was used for all statistical analyses. To pool point estimates of all eligible studies together, the generic inverse variance method of DerSimonian and Laird was utilized in which the weight of each study for the pooled analysis was in reversal to its standard error [19]. Random-effect model, rather than fixed-effect model, was utilized as the eligible studies had different background populations and protocols. Cochran’s Q test was utilized to determine statistical heterogeneity, further complemented by I2 statistic which quantified the proportion of the total variation across studies incurring from heterogeneity rather than coincidence. A value of I2 of 0-25% represented insignificant heterogeneity; 26-50% low heterogeneity; 51-75% moderate heterogeneity; and >75% high heterogeneity [20]. Visualization of funnel plot was used to evaluate for the presence of publication bias.
A total of 1,336 articles (1,246 from EMBASE and 90 from MEDLINE) were identified. Duplication of 78 articles were removed, leaving 1,258 articles for title and abstract review. After the first round of title and abstract review, 1,210 articles were excluded as they obviously did not meet the eligibility criteria based on study design and type of article. As a result, 48 articles underwent further full-text review in which 42 articles were excluded because they did not investigate the association of interest, leaving 6 eligible studies for the meta-analysis. Review of bibliography of those eligible studies yielded 1 additional eligible study. Also, 1 additional eligible study was retrieved from Google Scholar. Finally, 7 case-control studies and 1 cross-sectional study were considered eligible and were included into the meta-analysis. Literature review and study selection process are summarized in Fig. 1. Description of study design, characteristics of participants and Newcastle-Ottawa assessment scales of the included studies are presented in Table 1.
Figure 1 Literature review and study selection process
Table 1 Main characteristics of the studies included in the meta-analysis
As shown in Fig. 2, the pooled analysis found that patients with HF had a statistically significantly higher risk of developing ischemic colitis than individuals without HF with the pooled OR of 3.42 (95%CI 1.49-7.82). The statistical heterogeneity was high with an I2 of 96%. The funnel plot of this meta-analysis was relatively symmetric and did not suggest the presence of publication bias (Fig. 3).
Figure 2 Forest plot of meta-analysis of the association between heart failure (HF) and ischemic colitis (IC)
CI, confidence interval; SE, standard error
Figure 3 Funnel plot of meta-analysis of the association between heart failure and ischemic colitis
OR, odds ratio; SE, standard error
This study is the first systematic review and meta-analysis to explore the risk of ischemic colitis among patients with HF. The pooled analysis found an approximately 3.4-fold increased risk of ischemic colitis. Concerning the potential mechanisms of this association, it is possible that ischemic colitis is a direct injury from reduced peripheral blood flow from low cardiac output in HF, as hypoperfusion to the colon is the principal pathogenesis of ischemic colitis [9]. In the state of reduced cardiac output in HF, blood flow is preserved for vital organs such as brain and heart by increased sympathetic activation and splanchnic vasoconstriction, resulting in reduced peripheral blood flow to tissue in gastrointestinal systems including the colon [21,22]. The circulation to the gastrointestinal tract could be further jeopardized by acute exacerbation of HF by any precipitating factors, such as excessive salt intake, arrhythmias [23] or infection [24], causing acute insufficiency of blood supply in the colon.
Another possible explanation is embolic phenomenon. It is well known that HF increases the risk of atrial fibrillation [25]. Increased intracardiac filling pressure, dysregulation of intracellular calcium of cardiac myocytes, and neurohormonal activation in HF contribute to atrial remodeling, fibrosis and development of atrial fibrillation [26]. Atrial fibrillation is a primary risk factor for systemic emboli [27]. Cardiac emboli to branches of inferior mesenteric artery can block blood supply to colon and cause ischemic colitis.
The increased risk may run through the shared atherosclerotic risk factors between the 2 conditions. The most common etiology of HF is coronary artery disease [28], a result of the narrowing of coronary artery by atherosclerotic plaque [29]. Therefore, risk factors of HF are similar to other atherosclerotic diseases, which include atherosclerotic occlusion of non-coronary vessels such as inferior mesenteric branches responsible for ischemic colitis [30].
This meta-analysis carries some limitations that should be recognized. First, the 5 studies [8,12,14,15,17] included in this meta-analysis relied on registry data and diagnostic codes to diagnose HF and ischemic colitis, potentially jeopardizing the diagnostic accuracy and completeness of case identification. Second, only 2 [14,16] of the 8 included studies adjusted their effect estimates for atherosclerotic risk factors (hypertension, dyslipidemia, diabetes mellitus, obesity, and smoking). Consequently, this association might be a result of those confounders rather than a true association. Also, only 2 studies [14,16] had a perfect Newcastle-Ottawa score while the rest had only fair quality with the score ranging from 4-8 points, which may have jeopardized the validity of the pooled effect estimates. Additionally, due to the limited geographical distribution of the studies (3 studies from the United States, 4 studies from Europe, 1 study from Asia, and none from Africa and South America), the results may not be generalizable to every population. Last, even though funnel plot of this study is symmetric, the interpretation of this plot is limited by the relatively small number of eligible studies. Therefore, publication bias in favor of studies that report positive association may have been present.
In conclusion, a significantly increased risk of ischemic colitis among patients with HF was observed in this systematic review and meta-analysis.
What is already known:
Known risk factors of ischemic colitis include conditions that can impair colonic perfusion, such as arterial emboli, thrombosis, and hypotension
What the new findings are:
The pooled analysis found that patients with heart failure had a significantly higher risk of developing ischemic colitis than individuals without heart failure
Based on the pooled analysis of the 8 included studies, the risk was increased by approximately 3.4-fold
Possible mechanisms were reduced colonic blood flow from low cardiac output and increased risk of embolic phenomenon
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