Cardiovascular manifestations of inflammatory bowel diseases and the underlying pathogenic mechanisms

Abstract

Inflammatory bowel disease (IBD), consisting of ulcerative colitis and Crohn’s disease, mainly affects the gastrointestinal tract but is also known to have extraintestinal manifestations because of long-standing systemic inflammation. Several national cohort studies have found that IBD is an independent risk factor for the development of cardiovascular disorders. However, the molecular mechanisms by which IBD impairs the cardiovascular system are not fully understood. Although the gut-heart axis is attracting more attention in recent years, our knowledge of the organ-to-organ communication between the gut and the heart remains limited. In patients with IBD, upregulated inflammatory factors, altered microRNAs and lipid profiles, as well as dysbiotic gut microbiota, may induce adverse cardiac remodeling. In addition, patients with IBD have a three- to four times higher risk of developing thrombosis than people without IBD, and it is believed that the increased risk of thrombosis is largely due to increased procoagulant factors, platelet count/activity, and fibrinogen concentration, in addition to decreased anticoagulant factors. The predisposing factors for atherosclerosis are present in IBD and the possible mechanisms may involve oxidative stress system, overexpression of matrix metalloproteinases, and changes in vascular smooth muscle phenotype. This review focuses mainly on 1) the prevalence of cardiovascular diseases associated with IBD, 2) the potential pathogenic mechanisms of cardiovascular diseases in patients with IBD, and 3) adverse effects of IBD drugs on the cardiovascular system. Also, we introduce here a new paradigm for the gut-heart axis that includes exosomal microRNA and the gut microbiota as a cause for cardiac remodeling and fibrosis.

INTRODUCTION

Systemic inflammation has been long regarded as a critical contributor to the onset and progression of cardiovascular diseases. Chronic inflammatory disorders, such as rheumatoid arthritis (RA), systemic lupus erythematosus, and psoriasis are associated with higher risks of atherosclerosis and arterial thromboembolic disease, including myocardial infarction (MI) and stroke (1–3). Inflammatory bowel diseases (IBD), including Crohn’s disease (CD) and ulcerative colitis (UC), are characterized by chronic inflammation of the gastrointestinal (GI) tract. According to the Centers for Disease Control and Prevention of the United States, an estimated 1.3% of US adults were diagnosed with IBD in 2015, and the prevalence is increasing. Although primarily a GI disorder, IBD affects other organs as well. Extraintestinal manifestations (EIMs) are common in both CD and UC, occurring in 25–40% of patients with IBD (4). As observed in other chronic inflammatory diseases, patients with IBD present a higher risk of developing cardiovascular diseases (CVD) (Fig. 1) (5–12). However, the gut-heart axis is a new field of research and the molecular mechanisms by which IBD induces CVD are poorly understood. There are several recent reviews of the pathogenesis of intestinal inflammation in IBD (13–16), therefore, the aim of this review is to introduce the concept of IBD-related heart and vascular diseases and particularly the potential causative mechanisms, including inflammatory cytokines such as tumor necrosis factor-α (TNF-α), interleukin (IL)-1β, and IL-6, microRNAs (miRNAs), soluble suppression of tumorigenesis-2 (sST2), angiotensin (ANG) II, matrix metalloproteinases (MMPs), and lipopolysaccharide (LPS) (17–19). New concepts involving gut-derived microRNAs and brain-derived neurotrophic factor (BDNF) are considered. We will discuss the adverse effects of common IBD medications on the cardiovascular system and conclude with a brief description of major knowledge gaps and potential future studies.

Figure 1.

Overview of cardiovascular diseases in patients with inflammatory bowel disease (IBD). Increased proinflammatory cytokines such as tumor necrosis factor-α (TNFα), interleukin (IL)-6, and IL-1β dysregulate circulating microRNAs (miRNAs) including miR-155 and contribute to dysbiosis. Together, these factors induce molecular remodeling in the heart and vasculature, resulting in cardiovascular diseases. BDNF, brain-derived neurotrophic factor; VTE, venous thromboembolism.

INCREASED RISKS OF CVD IN IBD

Heart Diseases in Patients with IBD

Heart failure.

Patients with IBD have higher risks for heart failure (HF), pericarditis, myocarditis, and arrhythmias. A Danish nationwide cohort study found that IBD is associated with an increased risk of hospitalization for HF (8) and a worse prognosis after MI in those with IBD, in particular, in relation with flares of GI inflammation (20). A population-based cohort study from Mayo Clinic in Minnesota found that the relative risk of acute MI was significantly increased in patients with CD or UC (discussed under Vascular Diseases in Patients with IBD) (14). They reported that an increased relative risk of HF was noted among patients with UC, but not CD (11).

Pericarditis.

Pericarditis is an extraintestinal complication of IBD (21). A large population-based study by Bernstein et al. (22) revealed that patients with both CD (0.19% vs. 0.06% control) and UC (0.23% vs. 0.07% control) had a significantly greater likelihood of having pericarditis than population controls, with a similar increased risk for women and men. Although several case studies reported pericarditis in patients with IBD (23, 24), the actual prevalence of the condition is quite low.

Myocarditis.

Myocarditis had a total risk of 4.6 per 100,000 years in patients with IBD based on a 16-year Danish nationwide cohort study of 15,572 patients with IBD, which is significantly higher than the general population. The incidence rate ratio for myocarditis was 8.3 for CD and 2.6 for UC when compared with the general population (25, 26). As for pediatric patients with IBD, 0.9% of the patients were found to have myocarditis with the occurrence increasing with age, according to a Finnish registry study (27). The overall incidence of myocarditis was 1.95/100,000 person-years. There are multiple case reports on patients with IBD with myocarditis (28–30). Mesalamine, a therapy for UC, may also induce myocarditis (31–33).

Arrhythmia.

Arrhythmia is also a frequent manifestation of cardiac involvement in patients with IBD (34). Nationwide cohort studies in Denmark and South Korea found that IBD significantly increased the risk of atrial fibrillation (AF), particularly during active flare-ups, which represents the most common sustained cardiac arrhythmia among patients with IBD (35, 36). Pattanshetty et al. (37) found that the prevalence of AF in patients with IBD from Ohio was higher across all age groups compared with the general population and that the patients with IBD with AF were much younger compared with the controls. Yorulmaz et al. (38) reported that prolonged QT dispersion was significantly more frequent in patients with stricturing and penetrating CD when compared with control subjects. Pediatric patients with IBD in remission also have significantly longer P-wave dispersion, QT dispersion, and corrected QT interval dispersion compared with age- and sex-matched controls, suggesting that pediatric patients with IBD may carry potential risks for serious atrial and ventricular arrhythmias over time even during remission (39).

Vascular Diseases in Patients with IBD

Coronary heart disease.

A 2011 study of Haapamaki et al. (40), comprising 2,831 patients with IBD from Finland, found that coronary heart disease occurred significantly more frequently in patients with IBD than controls (P = 0.004). Biondi et al. (6) noted that patients with IBD presented a 6.45-fold higher risk of carotid atherosclerotic plaque. The aforementioned Danish nationwide cohort study also found that the disease activity in IBD is associated with increased risks of MI, stroke, and cardiovascular death (7). A systematic review and meta-analysis suggested that IBD is associated with a modest increase in the risk of cardiovascular morbidity, including cerebrovascular accidents and ischemic heart disease (IHD), particularly in women (9), and this was confirmed by subsequent meta-analyses (10, 41). Another retrospective cohort study revealed that although IHD prevalence was higher in patients with IBD (n = 19,163), most diagnoses predated the diagnosis of IBD (12), indicating that IHD may occur before or after the diagnosis of IBD. This idea was supported by studies showing that extraintestinal manifestations such as MI may occur in up to 24% of patients with IBD before the onset of intestinal symptoms (42). Recently, a large study with 29,090,220 patients from 26 nations found that the prevalence of MI was significantly higher in patients with UC or CD versus patients with non-IBD, and that younger patients have the highest relative risk (43). A Korean nationwide study in 2019 concluded that the risk of MI is higher in patients with CD, particularly patients aged <40 yr, than in the general population, but only female patients with UC had an increased risk of MI (44). More recently, a retrospective cohort study of 1,435 patients with IBD from 12 IBD centers and 1,588 non-IBD controls was conducted in China and the risk of IHD was found to be significantly higher in patients with IBD than in non-IBD controls, and it peaked between the ages of 18 and 35 yr (45).

Although most observations support an association of IBD with coronary heart disease, Osterman et al. (46) reported that patients with UC had a significantly increased risk of first-time acute MI compared with patients from general practice in unadjusted, but not adjusted, analysis; patients with CD did not have an increased risk of MI in either unadjusted or adjusted analyses. Using a nationwide inpatient database, Barnes et al. (47) found that hospitalizations for acute MI were decreased among patients with IBD. Taken together, we believe there is a higher risk of coronary heart disease in patients with IBD, especially in women, and there is conflicting, but no consistent, increased risk of coronary disease in one form of IBD over the other.

Venous thromboembolism.

Deep vein thrombosis, pulmonary embolism, cerebral venous sinus thrombosis, as well as retinal, hepatic, portal, and mesenteric vein thromboses, carry substantial morbidity and mortality with even higher mortality rates in patients with IBD (48, 49). The prevalence of venous thromboembolism (VTE) in patients with IBD ranges from 1 to 7%, which is at least three times higher than the general population (10). A prospective study that included 13,756 patients with IBD and 71,672 matched controls from the United Kingdom found that patients with IBD had a higher risk of VTE than did controls (P < 0.0001; absolute risk 2.6 per 1,000 per person-years); and the increase in risk was much more prominent (P < 0.0001; 9.0 per 1,000 person-years) at the time of an IBD flare (50). Using the US Nationwide Inpatient Sample between 2000 and 2018, Faye et al. (51) found that the VTE cases in hospitalized individuals with IBD significantly increased from 192 to 295 cases per 10,000 hospitalizations (P < 0.001); the difference remained significant when stratified by UC and CD as well as by deep vein thrombosis and pulmonary embolism. A Japanese cohort study found that the VTE incidence rate in IBD was 1.03% (102.5 per 100,000 IBD person-years) in Japan (52). Similarly, the incidence of VTE was 0.9% in the hospitalized cohort (115 per 100,000 IBD person-years) in an East Asian study and the incidence was comparable between UC and CD (53). A multicenter study followed 8,549 Chinese patients with IBD for 12,373 person-years showed that the incidence rate of VTE was 371.8 per 100,000 person-years (54). In comparison, three population-wide estimates of VTE rates in South Korea, Taiwan, and Hong Kong reported annual incidences of 13.8, 15.9, and 19.9 per 100,000 person-years, respectively, in the general Asian population (55).

Arterial thromboembolism.

It is important to evaluate the risks of arterial thromboembolism (ATE) because they are associated with higher morbidity and mortality and occur after a longer duration of disease (56, 57). Although it is less pronounced than VTE, the risk of ATE, including ischemic stroke, focal white matter ischemia, cardiac ischemia, peripheral vascular disease, and mesenteric ischemia, is increased in IBD (49, 56). A study included 17,487 patients with IBD and 69,948 controls showed that patients with IBD had a markedly increased risk of acute mesenteric ischemia. Subgroup analysis revealed that women > 40 yr of age with IBD were at increased risk of MI, whereas those <40 yr exhibited a twofold higher risk for stroke (58). Another study found that while the risk for IHD was significantly increased for all IBD in both males and females, only CD was associated with increased risk for cerebrovascular disease (57). For undifferentiated ATE only females and those aged 0 to 39 yr and 40 to 59 yr had significantly increased risks. Lin et al. analyzed a total of 11,067 patients with IBD and 43,765 controls for the risk of peripheral arterial disease (PAD) by using Cox proportional hazards regression models and found that the risk of developing PAD was 1.29-fold in patients with IBD compared with the control cohort, after age, sex, and comorbidities were adjusted. They also found that those patients with IBD who required two or more hospitalizations per year were nearly 27.5-fold more likely to have PAD compared with the controls (59).

POTENTIAL PATHOGENIC MECHANISMS OF CVD IN IBD

Pathophysiological Mechanisms Leading to IBD

It is known that the etiology of IBD is multifactorial and its pathophysiology involves complex genetic, environmental, epithelial, microbial, and immune factors (60). Here, we only briefly summarize the major risk factors contributing to IBD and a detailed description of IBD pathophysiology is beyond the scope of this review on cardiovascular manifestations.

Host genetics.

Multiple studies suggested a heritable risk for IBD. Genome-wide association studies and other analyses have identified more than 240 risk variants that affect intracellular pathways recognizing microbial products such as NOD2; the autophagy pathway facilitating the recycling of intracellular organelles and removal of intracellular microorganisms; genes regulating epithelial barrier function such as ECM1; and pathways modulating innate and adaptive immunity (13, 60).

Environmental factors.

Despite the exact mechanism is still unknown, accumulating evidence suggests that environmental risk factors play a role in developing both CD and UC. Early-life exposures, lifestyle and hygiene, vaccinations, exposure to drugs, surgeries, psychological factors, dietary intake and nutrients, and gastrointestinal pathogens may increase the risk of developing IBD (61).

Mucosal immunity.

The mucosal immune system represents the largest component of the immune system, and it is a consensus that immunological abnormalities play an important role in IBD pathogenesis (60). Dysregulation of the innate immune system as well as the adaptive immune system is attributed to many characteristics of chronic inflammatory processes in IBD reveals. Studies have found that B cells, effector T cells, regulatory T cells, and memory T cells are critical in maintaining gut mucosal homeostasis and health and may contribute to IBD development.

Gut microbiota.

Intestinal microbiota is considered the major driver of IBD because both commensal and pathogenic microorganisms determine the consequence of an infection (13). Although it is difficult to demonstrate a definitive cause-effect relationship between intestinal microbiota and IBD, it is believed that microbial factors play important roles in the pathophysiology of IBD through impacting the immune systems and affecting host metabolism.

Potential Mechanisms of Cardiac Remodeling

Inflammatory cytokines may mediate cardiac impairment in IBD.

The cytokine responses characterizing IBD are the crucial pathophysiological elements governing the initiation, evolution, and, ultimately, the resolution of the inflammation (62). Particularly, the imbalance between proinflammatory and anti-inflammatory cytokines in IBD often causes disease perpetuation and tissue damage. Well-known proinflammatory cytokines, including TNF-α, IL-1β, and IL-6 that are all increased in IBD, have been linked to diminished cardiac function (Fig. 2).

Figure 2.

Potential mechanisms of heart diseases in patients with inflammatory bowel diseases (IBDs). 1) Increased soluble suppression of tumorigenesis-2 (ST2) (sST2) in inflammatory bowel disease (IBD) blocks interleukin (IL)-33/ST2 signaling, stopping the protection effect of IL-33. 2) Inflammatory cytokines, such as tumor necrosis factor-α (TNFα) and IL-6, and angiotensin II (ANG II) activate cardiac fibroblasts, leading to proliferation/migration of fibroblasts, matrix degradation, extracellular matrix (ECM) deposition, recruitment of inflammatory cells, and generation of myofibroblasts. GM-CSF, granulocyte-macrophage colony-stimulating factor; MMP, matrix metalloproteinase.

TNF-α-mediated adverse cardiac remodeling may involve cardiomyocytes, macrophages, (myo)fibroblasts, and the extracellular matrix (ECM). In cardiomyocytes, TNF-α exerts negative inotropic actions by perturbing calcium homeostasis (63) and may trigger an apoptotic response by activating intrinsic cell death pathways (64). In macrophages, TNF-α could stimulate the synthesis of other proinflammatory cytokines with proapoptotic, negative inotropic, and matrix-degrading properties, and may upregulate the expression of inducible nitric oxide synthase (iNOS) (65). In fibroblasts, TNF-α may disrupt the balance between MMPs and their inhibitors, leading to abnormal ECM degradation (66, 67). In the microvasculature, TNF-α increases permeability through modulation of endothelial cyclooxygenase-2 (68) and induces expression of endothelial adhesion molecules, such as intercellular adhesion molecule 1 and vascular cell adhesion molecule 1, thus enhancing adhesive interactions between circulating leukocytes and the endothelial lining (69). Neutrophils or proinflammatory monocytes may be trapped in the cardiac microcirculation, thus contributing to tissue injury and cardiac dysfunction. A multicenter longitudinal study found that anti-TNF-α therapy effectively reduced inflammation and reduced cardiovascular risk in patients with IBD (70). Anti-TNF-α therapy also seems to prevent cardiovascular events in most patients with RA. In patients with RA with advanced heart damage, however, anti-TNF-α agents would interfere with the beneficial preconditioning effects of TNF-α, introducing a “rheumatological dilemma” in clinical practice (71).

Experimental evidence suggests an important role for IL-1 signaling in the pathogenesis of cardiac dysfunction and adverse remodeling associated with HF (72). IL-1β could induce cardiovascular remodeling by activating nuclear factor κ B (NF-κB) and inducing MMPs (73, 74). Graff and Gozal found that intravenous injection of serial doses of recombinant IL-1β induced monophasic increases in ventilation, heart rate, and blood pressure in adults (75). Mice with genetic disruption of IL-1 signaling due to loss of IL1R1, the signaling receptor for IL-1, had attenuated adverse remodeling after MI, exhibiting suppressed inflammatory responses (76). IL-1 Trap, a dimeric fusion protein consisting of the ligand-binding domains of the extracellular portions of the IL-1 receptor components linked to the Fc portion of human immunoglobulin G₁, also ameliorated cardiac remodeling and reduced cardiomyocyte apoptosis after experimental acute MI in mice (77). However, some studies suggested that endogenous activation of subinflammatory levels of IL-1β may also play an adaptive role following pressure overload mediating growth factor-induced compensatory hypertrophy (78).

IL-6 induces the transcription factor STAT-3 via trans-signaling and activation of IL-6/STAT3 signaling pathway in IBD is well documented. Inhibition of IL-6/JAK/STAT3 pathway is proven effective treatments of IBD (79, 80). The role of IL-6/STAT3 signaling in cardiovascular system has also been extensively investigated (81, 82). Cardiomyocyte-specific overexpression of STAT3 in mice led to spontaneous concentric cardiac hypertrophy, demonstrating an important role for STAT3 in cardiomyocyte growth (83). IL-6-induced hypertrophic growth of cardiomyocytes was abolished by a negative regulator of gp130/JAK/STAT3 signaling, SOCS3, suggesting that IL-6-mediated activation of STAT3 promotes cardiac hypertrophy (84). However, there is evidence that p42/p44-MAPK and PI3K are sufficient for IL-6/gp130 to induce hypertrophy as well as survival in cardiomyocytes without JAK/STAT activation (85). Of note, IL-6 can activate NF-κB (86), albeit IL-6 is also a proven target of NF-κB (87, 88), forming a positive feedback loop.

Interferon-γ (IFN-γ) released by activated T-lymphocytes is also a major cytokine in patients with IBD and IFN-γ induces production of C-reactive protein (CRP) in human monocyte-derived macrophages and dendritic cells. Of note, macrophages are critically involved in plaque formation. IFN-γ and macrophages also play important roles in the development of oxidative stress for antimicrobial and antitumoral defense within the cell-mediated immune response (89). In fact, IFN-γ is considered the most important trigger for reactive oxygen species (ROS) formation and release whereas oxidative stress is a key player in the atherogenesis and progression of cardiovascular disease. In addition, IFN-γ can stimulate indoleamine-2,3-dioxygenase, an enzyme degrading tryptophan to kynurenine. Recent studies demonstrated that IFN-γ also exerts potent vessel-directed pathologic breakdown of the vascular barrier through disruption of the adherens junction protein VE-cadherin (90). It is well known that IFN-γ activates the JAK-STAT pathways and transcriptional activation in the cardiovascular system (91). Furthermore, IFN-γ can modulate large-conductance, calcium-activated potassium channels through PKG and PKA-related pathways in human cardiac fibroblasts (92).

Granulocyte-macrophage colony-stimulating factor (GM-CSF) is well recognized as a proliferative agent for hematopoietic cells and exerts a priming function on neutrophils (93). In GM-CSF-induced bone marrow differentiation, myeloperoxidase (MPO) activity and oncogene expression are upregulated (94). GM-CSF functions as a potent chemoattractant in vitro and can recruit neutrophils from the microvasculature and induce extravascular migration in vivo, suggesting that GM-CSF may contribute significantly to recruitment during intestinal inflammation. In patients with CD, serum levels of CM-CSF antibody are significantly higher when compared with patients with UC or control subjects and high GM-CSF antibody titers have been considered as a risk marker for aggressive CD behavior and complications including surgery (95). Paradoxically, recombinant CSFs have emerged as a potential tool for the treatment of IBD, showing some promise in the treatment of patients with active CD with recombinant human GM-CSF (96). In the heart, Blyszczuk et al. (97) found that GM-CSF promotes inflammatory dendritic cell formation but does not contribute to disease progression in experimental autoimmune myocarditis, a model of postinflammatory dilated cardiomyopathy. Conversely, during the early phase of MI, GM-CSF was found to facilitate infarct expansion in association with increased monocyte recruitment and inappropriate collagen synthesis in the infarcted region (98). Further study by Anzai et al. (99) identified GM-CSF as both a key contributor to the pathogenesis of MI and a potential therapeutic target. Thus, the role of GM-CSF seems to be controversial in both IBD and heart disease.

Angiotensin II induces cardiac fibrosis.

Higher levels of angiotensin (ANG) I and II were detected in the colonic mucosal biopsies of patients with CD compared with healthy controls, and ANG II levels have been shown to correlate with the degree of macroscopic inflammation as well (100–102). The renin-angiotensin-aldosterone system, of which ANG II seems to be the predominant effector, promotes several physiological and pathological functions, including the development of cardiac fibrosis (Fig. 2). The ANG II type 1 receptor (AT1R) mediates several effects of ANG II in (myo)fibroblasts, including cell proliferation, migration, and induction of ECM protein synthesis. After cardiac injury, the levels of ANG II are quickly elevated, inducing proliferation of cardiac fibroblasts and stimulating the expression of collagen (103, 104). In addition, ANG II activation of AT1R induces the expression TGF-β1, which in turn induces both hypertrophy and fibrosis in the heart (105).

ST2/IL-33 signaling influences cardiac remodeling.

The cardiovascular mechanisms associated with maladaptive remodeling are complex and not yet fully understood. The mechano-sensitive signaling pathways are the main systems that have been investigated. These systems are closely associated with cardiac fibrosis since they are involved from the beginning to the late stages of remodeling responses. The first biomechanical system induced during cardiac stretching is ST2/IL-33 and is composed of three mediators belonging to the IL-1 family: two isoforms of ST2, i.e., soluble ST2 (sST2) and transmembrane ST2L, with opposing biological activities, and the third component of this system, IL-33 that drives activity after binding to the ST2 moieties (106). The ST2/IL-33 system is cardioprotective during heart stretch responses when IL-33 is released into the extracellular space where it associates with ST2L, promoting cell survival, and blocking profibrotic intracellular signaling. When sST2 is released into the extracellular space, however, the ST2/IL-33 system becomes harmful to the heart: sST2 acts as a decoy receptor of IL-33 to silence ST2L/IL33 signaling and can sequester most IL-33, stopping its cardioprotection through ST2L (107).

Although research is currently ongoing to identify sources and molecular mechanisms involved in sST2 production, there is evidence that total ST2 proteins, as well as IL-33 levels, were highly expressed in patients with active UC (108). sST2 was the predominant form expressed in IBD and its expression strongly correlates with ST2 levels in the serum. Furthermore, ST2 levels are correlated with disease severity and serum inflammatory cytokines and serum ST2 levels may differentiate active from inactive UC (109). More recently, Boga et al. (110) found that serum ST2 levels were significantly increased not only in active UC versus inactive UC but also in active CD compared with inactive CD. Proinflammatory pathways in UC and CD driven by cytokines produced during the inflammatory processes might be responsible for increased sST2 levels in patients with active IBD. In support of this, Kumar et al. (111) observed that fibroblasts exposed to the proinflammatory cytokines IL-1 and TNF-α expressed sST2 rather than ST2L. Abnormal sST2 levels in the cardiac extracellular space have become a major event in the principal cardiovascular disorders involving biomechanical stretch responses (112, 113).

Dysregulated microRNAs may impair heart function in IBD.

MicroRNAs (miRNAs) are small RNA molecules containing 18–25 nucleotides. Because miRNAs normally assist in fine tuning the complexity of gene expression, the alterations in their expression often play crucial roles in the development of many human diseases. It has been shown that miRNAs have a significant role in regulating the pathogenesis of myocardial remodeling by modulating cardiac hypertrophy, cardiomyocytes injury, cardiac fibrosis, angiogenesis, and inflammatory response through multiple mechanisms.

Using a rat model of chronic colitis induced by dextran sodium sulfate (DSS), our group found that chronic colitis significantly altered the miRNA profile in the adult rat and this was accompanied by a decreased ejection fraction, increased left ventricular mass, elevated B-type natriuretic protein in the plasma, and decreased brain-derived neurotrophic factor (BDNF) in the myocardium (114). Among the 56 dysregulated cardiac miRNAs, miR-155 was confirmed to suppress BDNF, a neurotrophin mediating wide-ranging effects on the cardiovascular system. We also found that recombinant IL-1β increased miR-155 in cardiac myoblast (H9c2) cells and in the rat heart in vivo, suggesting that chronic colitis impairs heart function through an IL-1β/miR-155/BDNF signaling axis. A pathogenic function of miR-155 in the heart was also supported by a previous study showing that intraperitoneal injection of LPS increased cardiac miR-155 and adversely induced heart dysfunction in mice and that pharmacological inhibition of miR-155 using antagomiR improved heart function (115). To determine if any circulating miRNAs contribute to cardiac remodeling in patients with IBD, we isolated plasma exosomes from patients with UC and control subjects and profiled miRNAs using next-generation sequencing. We identified 20 differentially expressed miRNAs, including miR-29b that was markedly upregulated in patients with UC (116). Furthermore, we demonstrated that exosomal miR-29b of gut origin suppressed cardiac BDNF just as miR-155 did, suggesting that exosomes derived from the inflamed intestine mediate the gut-heart cross talk and play a role in IBD-induced cardiac impairment.

Dysbiotic gut microbiota contributes to heart dysfunction.

It is believed that dysbiotic gut microbiome plays a role in HF and the “gut hypothesis,” which postulates that bowel wall edema and an impaired intestinal barrier during HF causes microbiome translocation into the host circulation, endotoxemia, and consequently a heightened systemic inflammatory state, has prevailed over the years (117). In the gut of patients with IBD, salutary bacteria, such as Bifidobacterium adolescentis and Faecalibacterium prausnitzii, become depleted, whereas virulent bacteria, such as Proteobacteria, proliferate (118). Using fecal microbiota from wild-type C57BL/6J mice, we performed fecal microbiota transplantation (FMT) on both normal C57BL/6J and IL-10 knockout mice with constitutive gut inflammation. Echocardiography revealed a significant decrease in left ventricle ejection fraction in the IL-10^−/− mice compared with that in the C57BL/6J mice, and the decrease was significantly abrogated by FMT (119). Our findings suggest that healthy donor FMT will mitigate colitis-induced cardiac impairment, highlighting the importance of healthy gut microbiota to heart function. Further studies are warranted to validate the findings and elucidate the underlying mechanisms.

Potential Pathogenesis of Arrhythmia in IBD

Atrial electromechanical delay (EMD) has been considered as an early marker of AF. Efe et al. found that patients with active CD or UC had significantly prolonged left and right intra-atrial EMDs and interatrial EMD compared with patients on remission and healthy controls. The left and right intra-atrial EMDs and interatrial EMD were also higher in patients with IBD on remission compared with healthy controls, suggesting that chronic inflammation elsewhere may cause chronic structural and electrophysiological changes in the atrial tissue resulting in slow conduction (120). These findings were confirmed by Nar et al. (121) in patients with UC.

The acute phase reactant CRP and the cytokine IL-6 have been implicated in AF development (122). Increased circulating CRP may stay in atrial tissue and thereby induce myocarditis (37), as well as electrical changes in the atrium (120, 123), whereas IL-6 is strongly correlated with increased left atrium size (123) by activating MMP2 (124). In addition, P wave dispersion, which is accepted as a risk factor for the development of AF, was found to be high in patients with UC or CD (125). Furthermore, patients with UC were found to have significantly lower autonomic functions, especially parasympathetic function, which might trigger arrhythmia (126). It should be noted that patients with IBD treated with ciprofloxacin or azathioprine may develop arrhythmia (127, 128).

Vaze et al. (129) reported that circulating miR-106b, 26a-5p, 484, 20a-5p are associated with prevalent AF. Both miR-106b and miR-20a can regulate autophagy induced by leucine deprivation in C2C12 cells via targeting ULK1, suggesting that these miRNAs may affect myocardial remodeling by inhibiting autophagy in cardiomyocytes, which in turn leads to the development of AF (130). It is noteworthy that miR106b levels were significantly increased in the intestinal epithelia of patients with active CD compared with controls (131). miR-26a, an anti-inflammatory miRNA that suppresses IL-6 production in myeloid cells, was also increased in patients with both CD and UC (132). These findings suggest that dysregulated miR-106b and miR-26a may contribute to AF in patients with IBD.

Potential Mechanisms of Vascular Diseases in IBD

Altered lipid profile contributes to coronary artery disease.

Dyslipidemia is an established risk factor for coronary heart disease. A large cohort study found that low total cholesterol and high triglyceride levels are more frequent in patients with IBD (in particular, CD) compared with healthy controls (133). Multiple studies confirmed that lipid profile and lipid-related metabolites were significantly altered in patients with IBD, more specifically in CD (134–136). Epidemiologic studies provided evidence of a strong association between triglycerides and the development of coronary heart disease (137). It is also well documented that innate immune cells, including macrophages and dendritic cells, can sense certain lipid species, such as saturated fatty acids and oxidized low-density lipoprotein, and produce proinflammatory cytokines and chemokines detrimental to the heart (138, 139).

Reactive oxygen species induce endothelial dysfunction.

The activated immune cells that reach the mucosa in IBD stimulate the production of large quantities of ROS that are potentially harmful, such as superoxide and nitric oxide (NO), and the release of MPO producing hypochlorous acid that has strong oxidizing activity. Furthermore, endothelial dysfunction in IBD has been reported (140, 141). Endothelium-derived factors, such as NO and endothelin-1, may play a role in the development of arterial stiffness (142, 143) (Fig. 3). Inflammatory reactions lead to release of free radicals from leukocytes and activated macrophages (144).

Figure 3.

Pathogenic mechanisms of vascular diseases in inflammatory bowel diseases (IBDs). 1) Coagulant factors V, VII, VIII, X, VWF, and fibrinogen, as well as platelet count and activity, are increased while anticoagulation-related protein S and antithrombin are decreased in IBD. This leads to increased risks of venous thromboembolism. 2) Increased reactive oxygen species (ROS) and lipopolysaccharide (LPS) cause endothelial dysfunction, leading to vascular hyperplasia and foam cell formation. Matrix metalloproteinases (MMPs) and vascular calcification also contribute to arterial stiffness. GM-CSF, Granulocyte-macrophage colony-stimulating factor; HOCl, hypochlorous acid; MPO, myeloperoxidase; NO, nitric oxide; VWF, von Willebrand factor.

The most abundant free radical in human tissues is the superoxide anion, which is primarily produced in an enzymatic reaction catalyzed by xanthine oxidase (XO) in the GI tract (145, 146). Superoxide anion is then converted to H₂O₂. In neutrophils, H₂O₂ is utilized by MPO to produce the hypochlorite ion. In patients with IBD, circulating XO binds to vascular endothelial cells and produces site-specific oxidative injury of the artery. Although superoxide anion is a highly reactive, highly unstable, and very short-lived form of ROS that only acts near the place of its origin, H₂O₂ can freely diffuse across cell membranes and oxidize molecules located further, e.g., membrane lipids in arteries (146, 147).

Clinical studies reported the presence of high levels of nitrite/nitrate in the plasma, urine, and the lumen of the colon of patients with IBD, suggesting a deleterious role of NO (148, 149). It is known that proinflammatory cytokines are involved in the upregulation of iNOS expression in IBD, which generates high levels of NO (150). Excessive NO could be detrimental by creating reactive nitric oxygen species, such as peroxynitrite anion and nitroxyl anion. Gunnett et al. (151) reported that iNOS induces vascular dysfunction by activation of soluble guanylate cyclase and limiting availability of tetrahydrobiopterin. A study by Nagareddy et al. (152) found that induction of iNOS in cardiovascular tissues contributed to the depressed pressor responses to vasoactive agents and potentially endothelial dysfunction. It is widely accepted, however, that eNOS-produced NO reduces arterial stiffness. More research needs to be done to determine if and how NO generated from iNOS contributes to arterial stiffness in IBD.

The injured intestinal mucosal barrier in IBD allows microbial LPS and other endotoxins into circulation. LPS can induce the expression of proinflammatory cytokines, which in turn cause endothelial dysfunction and macrophage foam cell formation, and eventually lead to atherosclerosis (153). LPS has many detrimental effects, including oxidation of low-density lipoproteins toxic to endothelial cells and activation of macrophages that enhance atherosclerosis (154). Endothelial dysfunction may also be associated with hyperplasia of vascular smooth muscle cells and increased synthesis of collagen, resulting in structural arterial stiffening (155).

MMPs contribute to arterial stiffening.

MMPs are zinc-dependent endopeptidases that cleave several ECM proteins and as such modulate outcome of various physiological and pathological processes including MI, atherosclerosis, and congestive HF. Several MMPs are overexpressed in IBD (156–158). Specifically, MMP9 upregulation in animal models of colitis and human IBD is unequivocal and plasma MMP9 has been considered a marker of disease activity in IBD (159, 160). Collagen and elastin are two important components of the ECM in the vessel wall. Because of their collagenolytic and elastinolytic activities, MMPs degrade the ECM and hence create uncoiled, less effective collagen and broken and frayed elastin molecules, stiffening vessel walls (161). In addition to structural ECM components, MMP substrates also include a multitude of ligand and receptor substrates such as cytokines, chemokines, growth factors, and adhesion molecules that alter cellular migration, adhesion, and activation. MMPs, therefore, exert a strong influence on cardiac remodeling through multiple mechanisms. Under inflammatory conditions, MMPs are activated in different cell types, including macrophages, (myo)fibroblasts, endothelial cells, and smooth muscle cells (162, 163).

Calcification of vascular smooth muscle cells.

A recent study showed that more than one-third of patients with IBD in Greece had moderate to severe abdominal aortic calcium deposition, a marker of early atherosclerosis (164). Vascular calcification is multifactorial, and phosphate plays a key role in the process. Smooth muscle cells take up extracellular phosphate through a neutral sodium-phosphate cotransporter and this phosphate uptake leads to serial cellular changes, which ultimately result in bioapatite formation (165–167). TNF-α has been shown to induce alkaline phosphatase expression and calcification in vascular smooth muscle cells (168, 169). IL-1β and IL-6 also induced osteogenic activity in vascular cells (170). Thus, increased expression of these proinflammatory cytokines is likely causative to vascular smooth muscle calcification in patients with IBD (Fig. 3).

Pathogenesis of hypercoagulability as a cause of VTE and ATE in IBD is multifactorial.

Accumulating evidence suggests that it is not one particular mechanism that leads to hypercoagulability in IBD but rather a complex interplay of systems (171). On the molecular level, the upregulation of the inflammatory and coagulation systems create an enhanced thrombotic state that involves the coagulation cascade, natural coagulation inhibitors, fibrinolytic system, endothelium, immune system, and platelets (172). More specifically, this increased risk of VTE has been attributed to higher levels of inflammatory cytokines, acute phase reactants, procoagulants, and lower levels of anticoagulants (173). It has been shown that coagulation factors V, VII, VIII, X, XI, XII, von Willebrand factor, and fibrinogen, as well as production of fibrin and thrombin formation are all elevated during an IBD flare (174). Patients with IBD also have increased platelet counts (thrombocytosis) and increased platelet activity during active disease states (175). In addition, studies have suggested that patients with IBD have lower levels of protein S and antithrombin during active disease states, which are important drivers of anticoagulation (Fig. 3) (176). Alterations in coagulation and platelet function and susceptibility to thrombosis have also been demonstrated in animal models of IBD. Animal studies have shown that inflammatory cytokines, including TNF-α, IL-1β, and IL-6, played important roles as mediators of the platelet abnormalities and augmented thrombus development (177).

Homocysteine plays a role in VTE in IBD.

Hyperhomocysteinemia is likely another risk factor for VTE in patients with IBD. Homocysteine is a nonprotein-forming sulfur amino acid derived from S-adenosylmethionine and it can be remethylated to methionine and transsulfurated to cystathionine (178). Homocysteine can function as a procoagulation factor because it causes alterations in the vessel wall, increasing tissue factor and factor V expression, decreasing thrombomodulin and t-plasminogen activator expression, and attenuating protein C activation (179). Both plasma and mucosal homocysteine levels were significantly higher in patients with IBD compared with healthy controls and correlated with disease activity (180). Elevated plasma homocysteine levels may promote the development of arterial and venous thrombosis.

Involvement of the Central and Peripheral Nervous System in IBD-Associated CVD

It is well known that IBD causes EIM in the central and peripheral nervous system, which could contribute to pathogenesis of CVD. The incidence of neurological disorders in patients with IBD ranges between 0.25% and 47.5% (181). Accumulating evidence suggests that the central nervous system interacts dynamically via the vagus nerve with the intestinal immune system to modulate inflammation through humoral and neural pathways, using a mechanism also referred to as the intestinal cholinergic anti-inflammatory pathway. Lindgren et al. (182) reported vagal dysfunction in patients with UC. Patients with UC in clinical remission were also found to have significantly lower parasympathetic function when compared with those with CD and healthy controls (126). Coruzzi et al. (183) found that all indexes related to cardiac vagal control were significantly lower in patients with quiescent UC versus controls or patients with CD. Patients with CD usually have normal peripheral motor nerve function, but almost half of the patients show signs of autonomic neuropathy, suggesting autonomic nerve dysfunction as a feature of CD (184). It is well known that elevated TNF-α in IBD activates neurons in sensory circumventricular organs including the subfornical organ (SFO) (185). The SFO projects to the hypothalamic paraventricular nucleus, which has projections to the preganglionic sympathetic neurons in the intermediolateral cell column of the spinal cord to increase sympathetic nerve activity. Increased sympathetic nerve activity is detrimental to the heart and would enhance the progression of the disease.

It has been recognized that the heart consists of neuronal and nonneuronal cholinergic system (186). There is evidence that acetylcholine of both neuronal and nonneuronal origin acts in the heart through muscarinic and nicotinic receptors (187). The action of acetylcholine in the heart is terminated rapidly by cholinesterases (ChE), acetylcholinesterase, and butyrylcholinesterase. Recently, a larger case-control study by Shao et al. (188) found a negative association between serum ChE levels and the Crohn’s disease activity index (CDAI) score of patients with CD and the simple clinical colitis activity index score of patients with UC. Patients with both CD and UC presented substantially lower serum ChE levels when compared with healthy controls. In addition, patients with CD displayed significantly lower serum ChE levels than patients with UC.

Alterations in the sympathetic system and parasympathetic nervous system, also known as the cholinergic system, have been clearly documented in patients with CVD and IBD (189). However, the interplay between the sympathetic and parasympathetic system is complex and poorly understood. Recent studies suggest that the increased cholinergic tone in the heart by cholinesterase inhibitors has a positive effect on some cardiovascular disorders such as heart failure, suggesting that the cholinesterase inhibitors could be beneficial in managing certain cardiovascular disorders including IBD-induced CVD (190).

Role of Obesity, Diabetes, and Metabolic Complications in CVD Development of IBD

The production of proinflammatory cytokines by obesity through adipose tissue can have a dramatic impact on the initiation, clinical course, and management of IBD. Because of overlapping alterations in immune and inflammatory pathways, concomitant diabetes may be an important comorbidity in patients with IBD. Studies have shown that diabetes is a predictor of surgery in patients with CD (191) and a risk factor for postoperative surgical site infections in patients with fulminant UC (192). Metabolic syndrome is also a comorbid condition of IBD (193). In fact, metabolic syndrome and IBD share some pathophysiological characteristics, such as inflammation, insufficient immune response, and dysregulation of adipose tissue. Both metabolic syndrome and IBD are defined by chronic inflammation due to shared immune pathways. It is reasonable to anticipate that obesity, diabetes, and metabolic complications increase the chance of CVD in patients with IBD. However, there is very limited data available regarding the cardiovascular disease outcomes associated with patients with IBD with concomitant obesity, diabetes, and metabolic complications.

ADVERSE EFFECTS OF CURRENT IBD DRUGS ON THE CARDIOVASCULAR SYSTEM

Higher risk of cardiovascular diseases, particularly thrombotic events, in patients with IBD has garnered attention from patients and gastroenterologists alike. Recent consensus meetings directed toward thromboembolism in IBD have provided recommendations to improve the quality of care of patients and to prevent potentially life-threatening complications of thrombosis (194, 195). Although it is imperative that caregivers continue to promote prevention of CVD in patients with IBD, it is important to understand that medicines used in IBD may have salutary or detrimental effects on the cardiovascular system. Thus, in this review, we will briefly discuss the benefits and side effects of therapeutic drugs currently used in patients with IBD. The effects of IBD medications on the cardiovascular system, as well as the impact of CVD medications on the GI tract, are summarized in Table 1.

Table 1.

Effects of IBD drugs on the cardiovascular system and CVD drugs on the GI tract

Medication	CV Effects	GI Effects
IBD medications
5-Aminosalicylates	Myopericarditis (196)	Induction and maintenance of remission in IBD (197, 198)
	Arrythmia (199)
Corticosteroid	HF (200) Hypertension Hyperlipidemia	Induction of IBD remission
Azathioprine	Arrythmia (201)	Induction and maintenance of remission
Anti-TNF	HF (202) Decreased ATE (203)	Induction and maintenance of remission (204)
Anti-integrins (Vedolizumab)	Cerebral hemorrhage (205)	Induction and maintenance of remission
Anti-IL12/IL23 (Ustekinumab)	Dyslipidemia (206)	Induction and maintenance of remission
Tofacitinib	VTE (199) Induce herpes zoster (207)	Induction and maintenance of remission (208–210)
CVD medications
ACEI/ARB	Lower BP and treat HF	Improve disease outcomes in patients with IBD (211)
Aspirin	Anti-platelet and prevention for patients with high risk of CVD	Risk of GI bleeding Possibly increase the risk of developing CD (212)
Heparin	Reduce risk of VTE	Alleviate IBD inflammation (213)
Ridogrel	Anti-platelet	Reduce mucosal thromboxane B2 (214)
Statins	Lower cholesterol	Decrease risk of new onset IBD (215) Relieve inflammation in CD patients (216)

ACEI, angiotensin-converting enzyme inhibitors; ARB, angiotensin receptor blocker; BP, blood pressure; CD, Crohn’s disease; CV, cardiovascular; CVD, cardiovascular diseases; GI, gastrointestinal; HF, heart failure; IBD, inflammatory bowel disease; IL, interleukin; TNF, tumor necrosis factor; VTE, venous thromboembolism.

Direct Effect of IBD Drugs on the Cardiovascular System

TNF-α inhibitors.

Anti-TNF agents are effective in treating patients with IBD and they are the most commonly used biologics for IBD in the United Kingdom (204). A nationwide French cohort study suggested that anti-TNF treatment is associated with a decreased risk of acute arterial events in patients with IBD (203). However, some guidelines suggested that anti-TNF agents should be used with caution in patients with heart failure (71, 217). The in vivo evidence on the deleterious effects of TNF-α in the failing myocardium, and early clinical studies suggesting attenuated dysfunction in small groups of patients receiving TNF-α antagonists (218) fueled large clinical trials to investigate the effectiveness of TNF-α blockade with soluble TNFR (etanercept) in patients with heart failure with reduced ejection fraction (HFrEF). Unfortunately, the results were disappointing and the trials were halted prematurely because of the lack of clinical benefit (219). Combined trial data also showed no effect of etanercept on the primary end point of death or heart failure hospitalization in patients with HfrEF (220). A phase II anti-TNF-α trial examined the effects of infliximab, a chimeric monoclonal anti-TNF-α antibody, in patients with HfrEF, and found that TNF-α antagonism using infliximab had adverse effects, increasing all-cause mortality and heart failure hospitalizations in comparison with conventional treatment (221).

JAK-STAT inhibitors.

Tofacitinib is a first-generation pan JAK inhibitor primarily targeting JAK1 and JAK3 and the first oral small molecule approved for use in UC in the United States in 2012 (222). All tofacitinib studies demonstrated clinical improvement, which confirm its effectiveness for induction and maintenance in UC (208). Safety analyses concluded that tofacitinib treatment in patients with UC was associated with dose-dependent risk of herpes zoster, but the safety profile of tofacitinib in the UC clinical development program was manageable (207). In three phase 3, randomized, double-blind, placebo-controlled trials of tofacitinib therapy in adult patients with UC, adverse cardiovascular events occurred in 5 of 1,120 patients who received tofacitinib and in none who received placebo; tofacitinib was also associated with increased lipid levels compared with placebo. One patient in the 10-mg tofacitinib group in the induction 1 trial died from aortic dissection (209, 210). Of note, nearly all the involved patients had multiple risk factors that may have contributed to the development of these complications.

5-Aminosalicylic acid derivatives.

5-Aminosalicylic acid (5-ASA) derivatives work by blocking the activity of cyclooxygenase and lipoxygenase, thereby reducing the production of both limbs of arachidonic acid metabolism. Mesalazine, or mesalamine, is currently the core treatment of mild-to-moderate UC (223). It is also a less effective option for patients with CD preferring to avoid steroids (197, 198). Studies reported that pericarditis occurs as a complication of drug therapy by 5-ASA derivatives such as sulfasalazine, mesalamine, and balsalazide (196, 224). A mechanistic investigation revealed that mesalazine induced a dose- and time-dependent increase in mitochondrial ROS production, succinate dehydrogenase inhibition, mitochondrial enlargement, and cytochrome C release in rat heart mitochondria, suggesting that cardiotoxic effects of mesalazine are most likely associated with mitochondrial dysfunction and ROS formation (225).

Impact of IBD Drugs on Liver and Kidneys

TNF-α inhibitors.

TNF-α inhibitors are generally safe with a pretty low risk of causing severe drug-induced liver injury (DILI) (226). Alanine transaminase (ALT) levels are commonly elevated in patients with IBD treated with anti-TNF but, even in case of moderate or severe ALT increases, resolution seems to be the usual outcome (227). Liver injury is self-limiting in most patients and drug withdrawal is usually unnecessary. There are no standard guidelines for the management of anti-TNF-related liver injury. Patients with elevated ALT can continue the anti-TNF treatment because severe liver injury is rare and alternative medical options are limited in case of severe active IBD.

Drug-induced nephrotoxicity is rare in patients with IBD and there is paucity of data available (226). A possible mechanism underlying the development of renal complications during anti-TNF treatment could be interaction of anti-TNF antibodies with TNF in glomerular visceral epithelial cells. It has also been suggested that infliximab/TNF binding on the lymphocyte plasma membranes may induce apoptosis (228).

JAK-STAT inhibitors.

Currently, most safety data of JAK inhibitors are from patients with rheumatoid arthritis. Studies revealed elevated ALT or aspartate aminotransferase (AST) in patients exposed to tofacitinib, baricitinib, or upadacitinib compared with placebo, with most cases of elevated ALT/AST being asymptomatic and transient (229, 230). Elevated serum creatinine level is the most common adverse effect of tofacitinib (231). More studies, particularly long-term studies, are required to further illustrate the safety of JAK-STAT inhibitors.

5-ASA derivatives.

It has been reported that the incidence of elevated liver enzymes was in the range of 0–4% in patients treated with either low- or high dose of mesalazine (232). Drug-induced liver injury is the likely diagnosis if ALT and AST are commonly elevated to the range of 500–1,000 U/L. In multiple randomized controlled trials, however, no patient had to be withdrawn from the studies albeit case reports have indicated that mesalazine may cause a granulomatous hepatitis on biopsy (233, 234). Although sulfasalazine has been associated with cholestatic disease, granulomatous hepatitis, and acute liver failure, the incidence of DILI caused by sulfasalazine is low. A study including 4.7 million sulfasalazine prescriptions found only 3.1 cases of hepatitis per million prescriptions among patients with IBD (235). Mechanistically, transcriptomic studies in mice showed that sulfasalazine is involved in liver injury through multiple pathways, including redox processes, cytochrome p450 pathway, glutathione metabolism, epidermal growth factor receptor pathway, and the cytochrome p450 2C55 pathway (236, 237).

In 1990, the UK Medicines Safety Committee issued an alert on nephrotoxic reactions to mesalamine. Clinical trials suggested an annual risk of 0.26%, and questionnaire data estimated 1 case per 4,000 patient-years (238). Renal toxicity was reported in patients treated with the combined form of sulfasalazine (5-ASA bound to sulfapyridine) or the coated form of 5-ASA (mesalazine, olsalazine) (239). A few cases of renal toxicity have been reported with sulfasalazine in the form of an idiosyncratic. Mesalazine, on the other hand, has been reported to be responsible for a significant number of patients developing nephritis during its administration (240). Renal impairment may occur in up to 1 in 100 patients treated with 5-ASA, but clinically significant damage would occur in only 1 in 500 patients (241). Thus, measurements of serum creatinine before and during treatment have been advocated.

Management of CVD in patients with IBD is a significant challenge. Fortunately, traditional treatment for CVD, such as aspirin, statins, and propranolol are thought to be generally safe and useful. The use of angiotensin receptor blockers and angiotensin-converting enzyme inhibitors was also associated with improved disease outcomes in patients with IBD (242).

LIMITATIONS AND FUTURE STUDIES

Mounting evidence suggests that IBD is associated with increased risk for CVD especially in young adults and women, including heart failure, arrhythmias, and thrombosis. However, mechanistic studies are limited, and we just begin to understand how the heart communicates with the gut in normal and disease states. The potential mechanisms for increased risks of cardiovascular events in patients with IBD may involve elevated levels of inflammatory cytokines, ROS, MMPs, homocysteine and angiotensin, endothelial dysfunction, dyslipidemia, hypercoagulability, dysregulated miRNAs, dysbiotic gut microbiota, and drug toxicity. Multiple knowledge gaps remain and need to be addressed. More preclinical studies in animal models are warranted, which will help better understand the molecular mechanisms behind the development of CVD, particularly progressive remodeling of the cardiovascular system in response to long-term inflammation and thrombosis. Such research will also aid the development of new drugs targeting the gut-heart cross talk and VTE/ATE. Future studies on the role of dysbiosis in gut-heart cross talk will not only help understand how microbiota imbalance influences the cardiovascular system in IBD, but also identify specific microbial strains(s) responsible for the pathogenesis of CVD. Future research should pay more attention to how changes in gut microbial metabolites impact the cardiovascular system in patients with IBD. Molecular mechanisms by which MMPs of gut origin induce cardiac remodeling and fibrosis should be explored.

Perspectives and Significance

Studies have identified highly expressed inflammatory factors, altered microRNAs and lipid profiles, and gut microbiota imbalance as risk factors of cardiac impairment. In addition, increased procoagulant factors, platelet count/activity, and fibrinogen concentration as well as decreased anticoagulant factors are thought to play important roles in the development of VTE. Furthermore, atherosclerosis is likely a consequence of oxidative stress, overexpression of matrix metalloproteinases, and changes in vascular smooth muscle phenotype. These studies provided valuable insights into the molecular mechanisms by which IBD predisposes patients to CVD. We must acknowledge, however, that IBD is a complex gastrointestinal tract disorder affecting many if not all organs in the body. There is also heterogeneity in the inflammatory burden among the IBD population, making it challenging to evaluate risk factors and identify pathogenic mechanisms for CVD in such patients. Further preclinical studies with animal models and clinical studies on patients are needed to decipher how the cardiovascular system as well as other organs respond to the disease signals emanating from the inflamed intestine and to unravel the complex mechanisms of CVD development. An important goal would be to identify patients with IBD with long standing or severe disease who are at most risk for the development of CVD. Research into mechanisms should uncover blood-borne biomarkers that might be useful for surveillance. Clinical epidemiologic studies might then indicate which patients with IBD should be treated with drugs discovered by this mechanistic research in both preclinical models and in patients with disease. It is hoped that research in IBD CVD will also inform research in other severe inflammatory diseases, such as rheumatoid arthritis, where the risk of developing CVD is also great or even greater. The clinical management of IBD has been forced to increasingly adopt a multidisciplinary team approach including gastroenterology, cardiology, and hematology. Clinicians are now aware of the detrimental effects of chronic inflammation on the cardiovascular system, and VTE prophylaxis is strongly considered for hospitalized patients with IBD and sometimes even extended postdischarge.

GRANTS

This work was supported in part by the National Institutes of Health Grant R01 HL152683 (to Q. Li).

DISCLOSURES

No conflicts of interest, financial or otherwise, are declared by the authors.

AUTHOR CONTRIBUTIONS

Q.L. conceived and designed research; Y.X. prepared figures; Y.X. and Q.L. drafted manuscript; D.W.P., X.L., and Q.L. edited and revised manuscript; Y.X., D.W.P., X.L., and Q.L. approved final version of manuscript.