Several mechanisms have been proposed to possibly explain the pathophysiology of cardiac manifestations in CD. Firstly, the immune system is implicated as a major contributor, involving inflammation and oxidative stress [16]. Wang et al. similarly suggest an inflammatory pathway. They propose that a cumulative role of molecular mechanisms, inflammatory pathways, endothelial dysfunction, and genetic susceptibility factors is associated with cardiac manifestations in CD [17].

Additionally, inflammation plays a crucial role in the pathogenesis of both CD and cardiac disease. In CD patients, the ingestion of gluten activates the immune system, leading to the production of pro-inflammatory cytokines such as tumor necrosis factor-alpha (TNF-α), interleukin-1 (IL-1), and IL-6. These cytokines contribute to the development of intestinal inflammation, villous atrophy, and crypt hyperplasia observed in CD [17]. Furthermore, these cytokines and activated immune cells may influence the contractility and electrical stability of myocytes, resulting in fibroblast activation and cellular fibrosis [16]. Lebwohl et al. and Karadas et al. provide additional support for the role of chronic inflammation in cardiac manifestations [18, 19] (Fig. 2).

Forest plot: Forest plot for the hazard ratios/ odds ratios. A brief description of diagram including effect size, confidence interval, and statistical significance

Endothelial dysfunction serves as an early indicator of atherosclerosis, leading to vessel narrowing and development of a pro-inflammatory–prothrombotic state. Studies have shown that individuals with CD exhibit signs of endothelial dysfunction, including impaired flow-mediated dilation and elevated levels of endothelial activation markers such as von Willebrand factor and soluble intercellular adhesion molecule-1. These findings suggest that endothelial dysfunction in CD patients may influence the development of cardiac disease. Additionally, genetic risk factors, such as HLA (human leukocyte antigen) haplotypes, may establish a connection between cardiac conditions and CD [17]. However, Huang et al. suggest that there is no increased risk of coronary heart disease associated with genetic variants related to CD [20].

Furthermore, another significant mechanism involves autoimmunity, a process characterized by antigen mimicry that triggers an autoimmune response targeting self-antigens in various tissues, including the myocardium and small intestine [21,22,23,24,25,26]. Elnour et al. proposed a mechanism wherein severe nutritional deficiencies arise due to chronic malabsorption [12, 19, 22, 25, 26], potentially leading to cardiomyopathy over time. Disturbances in intestinal permeability among individuals with CD may facilitate the absorption of luminal antigens or infectious pathogens, ultimately causing damage to the heart through immune-mediated processes. Additionally, an immune response directed at an antigen present in both the heart and the small intestine may result in direct cardiac injury [12, 26,27,28]. Autoimmune diseases often exhibit a hereditary predisposition, with CD being prevalent in approximately 20% of adults [12].

Several patients who have secondary carnitine deficiency due to CD-related malabsorption even without systemic symptoms of carnitine deficiency were found to have DCM; however, it remains still inconclusive whether carnitine deficiency causes cardiomyopathy or merely an incidental finding seen in chronic malabsorption [21].

In comparison with the controls, individuals with CD exhibited higher systolic blood pressures and lower diastolic blood pressures. This phenomenon may be attributed to a hyperdynamic circulation resulting from iron deficiency anemia in patients experiencing chronic malabsorption [22].

In this systematic review, we have analyzed and synthesized the available literature to explore the association between Celiac disease and cardiac manifestations, including myocardial infarction, atrial fibrillation, cardiomyopathy, pericardial effusion [27, 29], and other related conditions.

One significant finding is the heightened risk of myocardial infarction in CD patients. A retrospective cross-sectional study conducted in Sweden, which compared 1075 individuals with biopsy-confirmed CD to a matched sample from the general population, identified a higher odds ratio (OR) of myocardial infarction in CD patients compared to controls [17]. Similarly, Conroy et al. reported an increased hazard ratio for ischemic heart disease and myocardial infarction in individuals with CD [30].

Another notable cardiac condition associated with CD is atrial fibrillation (AF). Research by West et al. demonstrated a slightly elevated risk of AF in CD patients, although not statistically significant [31]. In contrast, a larger study of 28,637 CD patients showed a significantly increased risk of AF [16]. These findings collectively suggest a potential link between CD and AF, though the precise mechanisms remain unclear.

Frustaci and colleagues conducted a case–control study, revealing a significantly higher prevalence of biopsy-confirmed CD in 187 patients and suggested “4.4% incidence of CD in patients with lymphocytic myocarditis” [32]. Conversely, Elfstrom and their team examined the link between CD and myocarditis or pericarditis in a Swedish national registry comprising 9,363 children and 4,969 adults with CD [33]. They found no significant association between CD and myocarditis in childhood (HR 0.2, 95% CI 0.0–1.5) or adulthood (HR 2.1, 95% CI 0.4–11.7). They also did not find a substantial connection between CD and pericarditis in childhood (HR 0.4, 95% CI 0.1–1.9) or adulthood (HR 1.5, 95% CI 0.5–4.0). These differing outcomes may be due to the rarity of myopericarditis in both study populations, underscoring the necessity for further investigation on this topic.

Furthermore, within the spectrum of CD-related myocarditis, Myrmel et al. highlighted the presence of myocarditis as an extra-intestinal manifestation of CD, a finding consistent with some prior studies demonstrating a link between CD and myocarditis. “Prevalence rates in these studies ranged from 1.8 to 5.7%.” Reliable evidence from case reports increases the strength of the association [23, 29, 33,34,35].

The association of cardiomyopathy in individuals with CD remains a topic of considerable uncertainty, requiring a comprehensive examination of the existing evidence. Wang et al. contributed valuable insights to our understanding of this association. Curione’s cohort study, which encompassed 52 patients diagnosed with idiopathic DCM, revealed that 5.8% of these patients had biopsy-confirmed CD [17]. These findings mark the consideration of CD as a potential comorbidity in patients with DCM. Noori et al.'s study results support Curione's study by suggesting that children with DCM may have a heightened likelihood of also having CD. Notably, their study detected tissue transglutaminase IgA -positive values in approximately 18% of the patients with DCM, reinforcing the potential connection between these two conditions [15, 21].

However, results from Elfstrom’s Swedish national registry did not find a statistically significant association between cardiomyopathy or CD [33]. Similar results from Emilsson, who conducted a comprehensive investigation involving 29,000 CD patients and 144,429 healthy controls, matched regarding age, sex, and place of residence to evaluate the risk of idiopathic DCM. Interestingly, their results did not show a statistically significant increase in the risk of DCM in patients with CD compared to that of control group. This finding underscores the variability in results across different studies and the need for cautious interpretation. These results seem to contrast with those of Curione et al. [15, 36].

Prati's study added another layer of insight, reporting that 1.9% of patients who were candidates for heart transplantation had positive tissue transglutaminase IgA, whereas only 0.37% in the control group tested positive. This aligns with similar results obtained by Curione, which resonate with the findings of our review (18.42% in the patients and 5.26% in the controls). These variations in seropositivity rates highlight the complexity of CD seropositivity as a potential marker in the context of DCM and emphasize the need for further investigation [15, 21, 37].

Additionally, Rashidinia's research uncovered a higher prevalence of celiac disease seropositivity among DCM patients when compared to the reported prevalence in the general population of Iran. This regional variation in celiac disease seropositivity further underscores the multifaceted nature of this relationship and the potential influence of geographical factors on its manifestation [24].

Furthermore, it is essential to acknowledge the collective findings of Elnour, Bohra, Mehra, Saada, and McGrath which suggest an increased risk of DCM associated with CD. These studies contribute to the growing body of evidence regarding the potential connection between CD and DCM [12, 25, 26, 29, 34].

However, all the varied results highlight the importance of considering the characteristics of the study population when interpreting results. The apparent discrepancy in the findings of these studies prompts us to consider several factors. First, the differing methodologies and study populations may contribute to these discrepancies. Curione et al.'s study focused on a specific cohort of patients with idiopathic DCM, while the Elfstrom’s Swedish national registry study included a broader population of individuals with CD. This highlights the importance of considering the characteristics of the study population when interpreting results.

Second, it is worth noting that the prevalence of CD varies across populations and regions. This variability might influence the observed associations. Moreover, the infrequency of DCM itself may affect the identification of connection. Moreover, the diagnosis of cardiomyopathy and CD may vary in accuracy and criteria between studies ranging from serology alone to biopsy findings, potentially affecting the observed associations.

Managing cardiac manifestations in celiac disease requires a comprehensive approach. While strict adherence to a gluten-free diet remains fundamental to mitigating associated risks, it is vital to acknowledge the complexity of this relationship as demonstrated by Schmucker et al. (2020), who reported a slight increase in the risk of developing type 2 diabetes with higher gluten consumption, a significant risk factor for cardiac morbidity [38]. However, the overall association between gluten intake and health outcomes remains unclear, based on a review of available evidence with low certainty. This evidence does not strongly support a clear link between gluten consumption and type 2 diabetes risk or cardiac events, or mortality. An included randomized controlled trial found no significant impact of gluten intake on cardiovascular risk factors, including blood pressure, LDL cholesterol, or BMI, although the certainty of these findings is also low. Unfortunately, these studies did not report data on adverse events or other outcomes.

Lebwohl et al. demonstrated that strict adherence to a gluten-free diet is associated with the reversal of histological features of CD and a decrease in immune activation linked to cardiac risk [18]. It has also been shown that a gluten-free diet can lead to the resolution of pleural and pericardial effusions. Additionally, some cases have exhibited improved cardiac function through a gluten-free diet, notably in the reduction in ventricular arrhythmias and improvements in ventricular volumes and ejection fraction [21, 22, 25, 26, 29].

Conversely, Rashidinia et al. found no improvement in cardiac features with a gluten-free diet (GFD) and hypothesized that seropositivity might be influenced by other unrecognized factors shared between CD and cardiomyopathy [24]. However, research on the impact of a gluten-free diet on cardiac health remains ongoing, with variable outcomes reported.

A crucial aspect of managing CD involves addressing chronic inflammation, which appears to correlate with the severity of ventricular arrhythmias in affected patients [4]. Nutritional therapy, including a gluten-free diet and supplementation with nutrients such as iron, calcium, and vitamins, remains the cornerstone of CD management [27, 35]. However, data on cardiac outcomes in CD patients are diverse and sometimes inconclusive demanding further evidence [34].

Hence, a stringent gluten-free diet results in complete or partial recovery in many cases and complete refractoriness in some. In essence, the management of cardiac manifestations in CD necessitates a comprehensive approach that combines dietary interventions, addressing inflammation, and managing associated comorbidities to optimize cardiac health in affected individuals.

It is important to acknowledge certain limitations in this review. The scope of this study was confined to free full-text articles written in the last 10 years, from 2013 to 2023 and written in the English language. This selection protocol aimed to collect comprehensive and up-to-date reviews of literature. However, it may have inadvertently excluded valuable insights from older, non-English, or paid publications. Though efforts were made to ensure the accuracy of the data presented, there may be potential bias in data from the sources selected in the study. Despite these limitations, this review strives to provide valuable insights into the topic of cardiac manifestations in CD, an association of CD with DCM within the limited constraints.