Coronary artery ectasia (CAE) is reported in 1.5–5% of patients who have undergone coronary angiography (Brunetti et al., 2014). CAE is defined as dilatation of an arterial segment diameter at least 1.5 times that of an adjacent natural artery and involves at least one-third of the relevant artery (Ozturk et al., 2015) (Figure 1). The terms CAE and coronary artery aneurysm (CAA) are frequently used interchangeably, however, they carry distinct phenotypes and definitions. CAE is characterized by dilatation of an arterial segment with at least one-third of the involved artery, whose diameter is at least 1.5 times of a proximal natural artery. Conversely, CAA is a focal-appearing dilatation. In this article, CAE refers to the diffused coronary dilatation with or without stenosis. Although CAE is a specialized form of traditional atherosclerotic coronary artery disease (CAD), it differs from CAD in many ways, as depicted in Table 1. In addition, coronary CT angiography is today an alternative diagnostic strategy (Figure 2). In contrast to its stenotic counterpart (i.e., CAD), CAE has been studied relatively infrequently. CAE encompasses clinical presentations and implications similar to those of CAD, including stable angina and acute coronary syndrome (ACS) that result from either coronary thrombus formation or impaired coronary blood flow due to dilated coronary arteries (Mavrogeni 2010). The key mechanism underlying CAE, however, has not been fully identified. In light of previous reports, it has been suggested that there may be more than one mechanism involved (Table 2). We herein evaluated lipid metabolism and immune-inflammatory responses that have been studied extensively in the pathogenesis of CAE.

In a report of familial hypercholesterolemia (FH), investigators described for the first time the association between plasma lipoproteins and coronary artery aneurysm. A 23-year-old male patient with homozygous familial hypercholesterolemia was confirmed with coronary artery dilatation by coronary angiography, and the patient presented with systemic xanthomatosis and severe hyper-low-density lipoproteinemia (Mabuchi et al., 1986; Genda et al., 1987). Another study revealed that repeated plasma exchange reduced serum low-density lipoprotein cholesterol (LDL-C) levels in heterozygous FH, resulting in angiographic improvements in CAE (Thompson et al., 1980). In a study of 197 asymptomatic hypercholesterolemic (FH) subjects, Sudhir et al. examined the prevalence of CAE and its association with coronary artery risk factors, and their results showed that the incidence of CAE was significantly higher in the FH population than in the control group and that it was associated with lower high-density lipoprotein cholesterol (HDL-C) levels (p = 0.003) and higher LDL-C/HDL-C ratios (p = 0.003) (Sudhir et al., 1995). Based on these studies, higher LDL-C levels, lower HDL-C levels, and a higher LDL/HDL ratio are now considered to reflect value in the prediction of the onset and development of CAE.

Collagen and elastin fibers in the dilated coronary segment were previously shown to be significantly degraded, with the inner and outer elastic layers destroyed, but there was no evidence of dilation found in the intact and uninjured sites of the media. This suggested that enzymatic degradation of the media may constitute a key point in the pathogenesis of CAE (Daoud et al., 1963; Markis et al., 1976; Swanton et al., 1978). At the molecular level, LDL-C is bound to elastin, collagen, and proteoglycan through oxidative modification that enhances its affinity for matrix components (Galis et al., 1995). The oxidized LDL-C is subsequently engulfed by macrophages and smooth muscle cells to develop the foam cells that enhance the active breakdown of the extracellular matrix by their production of matrix-degrading enzymes—including MMP-2, MMP-9, and MMP-12. These actions then ultimately lead to coronary artery dilation (Gertz et al., 2015) (Antoniadis et al., 2008).

Based on conventional lipid components, recent studies revealed that two phospholipid species in CAE, sphingomyelin (SM) and phosphatidylcholine (PC), were significantly downregulated compared with healthy controls (Boles et al., 2017). PC exerts the important action of carrying fatty acids and portrays an intermediate role in lipid metabolism; thus, PC expression profiles provide critical information on lipid regulation and disease effects (Wymann and Schneiter 2008). SM participates in the formation of coronary artery dilation by inducing atherosclerotic lipoproteins to infiltrate the arterial wall, stimulating lipoprotein aggregation and macrophage foam-cell formation (Stegemann et al., 2011).

CAE can be observed in herbide spray exposure, hereditary collagenosis, connective tissue diseases, autoimmune disease, etc. This demonstrates that inflammation is primary etiology of CAE, which is close linked to inflammatory response. From the pathogenesis of Kawasaki disease, inflammatory response induced CAE without the involvement of lipid metabolism disorder, which is a prerequisite for the development of CAE. Aberrant lipid metabolism will aggravate inflammatory response. Instead of CAE, Simple lipid metabolic disorders frequently result in coronary atherosclerosis. It is speculated that aberrant lipid metabolism may trigger CAE through inflammatory response or other mechanisms, which is neither a required or sufficient condition for CAE (Zhu et al., 2021).

The argument that CAE originates from a chronic inflammatory state has attracted wide attention in recent years, and chronic inflammatory mediators such as cytokines, proteolytic enzymes, growth factors, cell adhesion molecules, and systemic inflammatory mediators are known to be involved in its pathogenesis.

Genetic variation is reported to be a risk factor in coronary artery disease, and 50 genetic variants that are associated with coronary artery disease have been identified to the present time. However, the genetic mutations associated with coronary artery dilation have received inadequate investigation. Noori et al. identified a familial aggregation of KCNH1 (H member 1 of the potassium voltage-gated channel subfamily) mutations in a rare case of myocardial infarction and coronary dilatation following by diarrhea. KCNH1 is a voltage-gated potassium channel that is primarily expressed in the central nervous system (CNS), and the principal symptom of its mutation is epilepsy; however, the aforementioned patient and his family members did not manifest any associated neurologic signs. This is thus the first-ever report of a genetic mutation associated with CAE (Noori et al., 2019).

Genetic predisposition appears to exert an indirect effect on the development of dilation and is chiefly associated with ACE genotyping or FH. Authors of a retrospective review of 112 patients with CAE or CAD that was only confirmed by coronary angiography detected the ACE ID genotype in both groups and suggested that the DD genotype was a risk factor for CAE (Uyarel et al., 2005). Moreover, novel gene polymorphisms have in recent years been reported to be associated with an elevated incidence of CAE. For example, Yalcin et al. postulated that the c.894G>T polymorphism was a risk factor for CAE (Arif Yalcin et al., 2014). c.894G>T is a nucleotide polymorphism in the eNOS gene associated with eNOS activity, and these authors showed that the presence of the 894T allele increased the risk of CAE 2.8-fold (95% CI = 1.15–6.73; p = 0.027). As their T allele frequency was 65% in CAE patients and 38.6% in the control group, they posited that the eNOS gene c.894G> T polymorphism was a risk factor for CAE.

While CAE remains a significant clinical pathology associated with morbidity and mortality (Luo et al., 2017), its exact pathogenesis is not well established. In the pathogenesis of atherosclerosis, the imbalance in lipid metabolism induces inflammatory reactions (Ait-Oufella et al., 2006), and lipid metabolism-related factors also regulate inflammation (Nickel et al., 2009). Abnormal modification and localization of lipoproteins likewise regulate inflammatory reactions (Yu et al., 2015), inflammatory reactions then exacerbate the lipid metabolism imbalance, and inflammation and lipid metabolism disorders subsequently jointly promote the development of atherosclerosis (Andersen et al., 2016). Given that CAE is associated with atherosclerosis in 50% of cases and that disorders in lipid metabolism and abnormal immune and inflammatory reactions in CAE patients are widely reported (Endoh et al., 2004), we speculate that there must be a closer and more prominent relationship between abnormal lipid metabolism and the immune inflammation observed in CAE. Although it is currently not possible to elucidate the exact mechanism(s) subserving CAE due to the multiple contributions by different pathways and the different cell types and molecules involved, discerning the key points within these internal physiologic systems will facilitate the treatment of CAE patients in the future. In addition, novel and powerful lipid-lowering drugs are emerging. However, whether these drugs can inhibit the inflammatory immune responses of patients with CAE and also delay and reverse the process of coronary artery expansion requires further examination.