The literature search for this review was primarily conducted using internationally recognized academic databases, including PubMed, Web of Science, Embase, and Scopus. The search timeframe spanned from the inception of each database to 2025. The combinations of search keywords included “connexin 43”, “gap junction”, “hemichannel”, “arrhythmia”, etc. Additionally, Medical Subject Headings (MeSH) were used for expanded retrieval to ensure comprehensive coverage of relevant research fields.

Inclusion criteria: (1) Published in English; (2) Research content focusing on the molecular structure of Cx43, the functions of gap junctions/hemichannels, and their mechanisms of action in cardiovascular diseases (including Chagas disease); (3) Types of literature, including original research (basic experiments, clinical observations), systematic reviews, and meta-analyses; (4) with complete experimental design or data support.

Exclusion criteria: (1) Duplicated publications; (2) Unpublished materials such as abstracts and conference papers; (3) Research content not directly related to the mechanisms of Cx43 in heart diseases; (4) Literature with obvious methodological flaws or questionable conclusions.

Cx43 is the principal gap junction protein in mammalian cardiomyocytes, encoded by the connexin alpha 1 gene and composed of 382 amino acids (1).

Gap junctions are intercellular junctional structures composed of clusters of transmembrane channels, whose core function is to mediate the direct cytoplasmic exchange of ions and small-molecule metabolites between adjacent cells (2). The formation of these structures relies on the precise docking and juxtaposition of hemichannels (connexons) expressed by neighboring cells (3). Each hemichannel, functioning as the functional unit of a connexon, pairs with the corresponding hemichannel in an adjacent cell under physiological conditions, collectively forming a channel structure that spans the intercellular space (4). Notably, under specific circumstances such as pathological states or paracrine signaling regulation, individual hemichannels that traverse the entire depth of the plasma membrane can also function as transmembrane channels in non-contacting cells, mediating the transmembrane transport of ions and small-molecule metabolites even in the absence of intercellular contact (5).

Connexins are tetraspan transmembrane domain proteins, characterized by four highly conserved transmembrane domains (M1-M4), intracellular N-terminal and C-terminal regions (NT and CT) (6), which are interconnected by two extracellular loops (E1 and E2) and one cytoplasmic loop (CL) (2). The four transmembrane domains, along with extracellular and intracellular domains, oligomerize into hexameric connexons, which further assemble to form intercellular gap junction channels (2) (Figure 1).

Cx43 is widely distributed in the cardiovascular system, predominantly expressed in atrial and ventricular myocytes and the subendocardial conduction system, with high expression in the intercalated discs of ventricular myocytes to support rapid cardiac impulse conduction (7). Cx43 distribution in cardiomyocytes is tissue-specific, primarily localized at the end-to-end connections of intercalated discs (8). This distribution is crucial for maintaining electrical and mechanical coupling between cardiomyocytes (9). Studies indicate that in addition to forming classical gap junctions in intercalated discs, Cx43 can be localized to the inner and outer mitochondrial membranes via a mitochondrial targeting sequence (MTS) in its amino terminus (10). It forms complexes with voltage-dependent anion channels (VDAC) to regulate mitochondrial permeability transition pore (mPTP) opening and mediate mitochondrial dynamics and oxidative stress responses (11). Abnormal mitochondrial Cx43 is closely associated with heart failure, acute myocardial infarction, ischemia-reperfusion injury, arrhythmias, diabetic cardiomyopathy, and hypertensive heart disease (12).

Cx43 can form classical gap junctions (GJs) between adjacent cardiomyocytes or exist independently as hemichannels (HCs) on the plasma membrane (13). These two forms exhibit distinct physiological and pathological functions and contribute differentially to cardiac disease mechanisms (13).

Growing evidence indicates that Cx43 gap junctions (GJs) play a critical role in arrhythmogenesis by contributing to electrical uncoupling and structural remodeling (13). Cx43 GJs ensure the rapid and coordinated propagation of electrical impulses between cardiomyocytes (14). However, reduced expression, aberrant phosphorylation, or mislocalization of Cx43 impairs gap junctional conduction, resulting in slowed impulse propagation and increased electrical heterogeneity—key substrates for reentrant arrhythmias (14).

In pulmonary hypertension-associated arrhythmias, downregulation and disorganization of Cx43 have been shown to significantly increase arrhythmic susceptibility (15). In diabetic cardiomyopathy, Cx43 expression is reduced and its distribution altered, predisposing the heart to ventricular arrhythmias (15). During early cardiac hypertrophy, transient upregulation of Cx43 may serve to preserve electrical stability, but this is followed by a decline in expression and redistribution, characterized by decreased localization at the intercalated disks and increased lateral membrane presence—changes associated with elevated arrhythmia risk (16). Similarly, ischemic conditions induce Cx43 downregulation and lateralization from intercalated disks to transverse sarcolemmal regions, collectively contributing to arrhythmic events (16).

In rabbit models of myocardial infarction, Cx43 expression is markedly reduced in both infarcted and peri-infarct regions, with a positive correlation between the extent of downregulation and the incidence of arrhythmias (16), underscoring Cx43's essential role in maintaining cardiac conduction.

Furthermore, the functional state of Cx43 is closely regulated by its phosphorylation status (17). Under pathological conditions such as myocardial ischemia, oxidative stress, or hyperglycemia, excessive activation of protein kinase C (PKC) leads to abnormal phosphorylation at the serine 368 (S368) site of Cx43, which has been implicated in arrhythmogenesis (16).

Notably, studies on coronary artery disease–related arrhythmias have shown that pharmacological Cx43 enhancers can improve intercellular electrical conduction and reduce the occurrence of arrhythmias, thereby improving patient outcomes (17). Collectively, these findings suggest that targeted modulation of Cx43 expression, distribution, and phosphorylation may offer novel therapeutic strategies for the prevention and management of cardiac arrhythmias (17).

The pathological opening of Cx43 hemichannels (HCs) has been implicated in multiple mechanisms contributing to the initiation and maintenance of cardiac arrhythmias (14).

Firstly, under pathological stimuli, abnormal HC opening facilitates excessive release of intracellular ATP (15). In disease conditions, extracellular ATP accumulation can activate purinergic receptors such as P2X7, leading to intracellular calcium overload and sodium influx. These ionic disturbances promote delayed afterdepolarizations (DADs) and triggered activity, which are recognized as key initiating events in arrhythmogenesis (15).

Secondly, calcium influx through open hemichannels disrupts intracellular calcium homeostasis, directly altering the electrophysiological properties of cardiomyocytes (15). Calcium overload not only enhances sarcoplasmic reticulum (SR) calcium leak but also activates calcium-dependent enzymes such as calpains and phospholipases, leading to compromised membrane stability and abnormal action potential generation, thereby increasing arrhythmia susceptibility (16).

In addition, the release of glutamate and reactive oxygen species (ROS) via Cx43 HCs exacerbates local oxidative stress and excitotoxicity, further destabilizing membrane potential and promoting ectopic pacemaker activity and reentry-based arrhythmias (16). These microenvironmental alterations can also exert paracrine effects on neighboring cells, expanding the arrhythmogenic substrate (16).

Notably, Cx43 hemichannels participate in a self-amplifying “ROS–hemichannel positive feedback loop” that plays a critical role in arrhythmogenesis (Figure 2). Under oxidative stress, elevated ROS levels oxidize Cx43 HCs, promoting their pathological opening and resulting in further ATP and Ca²⁺ release. This, in turn, activates NADPH oxidase in adjacent cells, leading to enhanced ROS production and a vicious cycle of oxidative damage and hemichannel activation (17). This feedback loop promotes arrhythmias through three parallel mechanisms: (1) ROS-induced Cx43 internalization and degradation, causing slowed conduction and electrical heterogeneity; (2) Ca²⁺ overload–mediated DADs via hemichannel activity; and (3) ATP-induced inflammatory signaling. Importantly, this loop exhibits a spatial amplification effect, whereby hemichannel activation in a single cell may induce responses in 5–8 neighboring cells (16).

Furthermore, Cx43 HC opening is often accompanied by a decline in gap junction function (14). Excessive HC activation can promote Cx43 internalization and degradation, reducing the number of functional gap junctions and weakening electrical coupling, thereby facilitating conduction block and reentry (15).

Although these findings highlight the pivotal role of Cx43 hemichannels in arrhythmia pathogenesis, current anti-arrhythmic therapies do not target hemichannel activity (16). Future research should aim to elucidate the spatiotemporal characteristics of Cx43 HC activation and downstream signaling cascades, and to develop selective HC inhibitors that preserve gap junction function, offering new prospects for precise and effective arrhythmia management (17).

Atrial fibrillation (AF), the most common rapid atrial arrhythmia, is characterized by significantly reduced Cx43 expression in atrial myocardium (15). In angiotensin II-induced murine AF models, decreased Cx43 protein levels coincide with S368 dephosphorylation and lateral redistribution from intercalated discs (18). Yang et al. demonstrated that Cx43 overexpression reduces obstructive sleep apnea (OSA)-associated AF via the CaMKⅡγ/HIF-1 signaling axis (19).

The core mechanism of AF aligns with the “AF begets AF” theory, wherein AF drives atrial electrical and structural remodeling. Cx43 plays a central role in these remodeling processes (2). Interactions between Cx43 and multiple proteins/ion channels contribute to AF-related electrical remodeling (2). Oxidative stress, a key driver of AF progression, induces Cx43 phosphorylation and degradation via elevated reactive oxygen species (ROS), exacerbating electrical remodeling and AF susceptibility (2). Weakened interactions between Cx43 and calcium channels further impair calcium handling, aggravating AF pathology (2).

AF-induced structural remodeling involves chronic pathological changes, including extracellular matrix remodeling, myocardial fibrosis, and cellular phenotypic switching (19). Cx43-regulated fibrotic processes are central to this remodeling, marked by increased collagen volume fraction, elevated myofibroblast density, mitochondrial fragmentation, and intercalated disc disruption (20).

Chagas disease, caused by infection with the protozoan parasite Trypanosoma cruzi, is a neglected tropical disease with distinct clinical phases: acute, indeterminate, and chronic (21). Approximately 30% of chronically infected individuals progress to chronic Chagas cardiomyopathy (CCC), characterized by life-threatening cardiac manifestations including conduction abnormalities, ventricular arrhythmias, cardiomegaly, and heart failure (22).

Mounting evidence indicates that dysregulation of Cx43—manifested by altered expression, aberrant localization, and structural remodeling of gap junctions—constitutes a pivotal mechanism underlying Chagas disease-associated myocardial injury (23). These Cx43 abnormalities are closely associated with impaired electrical coupling and contractile dysfunction in the infected heart (24).

Chronic Cx43 deficiency contributes to myocardial interstitial fibrosis, likely by promoting fibroblast activation and excessive collagen deposition (25). Moreover, impaired gap junction communication diminishes synchronous contraction, increases mechanical stress, and promotes ventricular remodeling, ultimately leading to heart failure (26).

Abnormalities in Cx43 represent the core mechanism underlying arrhythmias in patients with chronic Chagas disease (31). These abnormalities disrupt the synchrony of myocardial electrical conduction, triggering reentrant arrhythmias and other rhythm disturbances, which constitute one of the leading causes of mortality in affected individuals (30).

In terms of therapeutic exploration, de Oliveira et al. (31) demonstrated that the TGF-β inhibitor GW788388 improves cardiac conduction by suppressing fibrosis and restoring the proper localization of Cx43. Additionally, Cx43 openers and blockers have shown potential in regulating electrophysiological function in experimental models; however, their clinical translation requires further validation (31).

Stable coronary artery disease (SCAD) is characterized pathologically by fixed coronary artery stenosis (stenosis degree >50%) (42). The stability of its clinical symptoms depends on the effective establishment of collateral circulation. Recent studies have revealed that connexin 43 plays a protective role in collateral circulation formation in SCAD through both channel-dependent and non-channel-dependent mechanisms (43).

In collateral circulation formation in stable angina, Cx43 plays a central role through endothelial cell—smooth muscle cell coordinated regulation. In endothelial cells, ischemic stress induces upregulation of Cx43 expression via the hypoxia-inducible factor 1α (HIF-1α) pathway (42). On the one hand, gap junction channels transmit vascular endothelial growth factor (VEGF-A) to adjacent cells, promoting vascular sprouting; on the other hand, Cx43 hemichannels are activated, releasing ATP to activate P2Y2 receptors in surrounding cells and initiating the ERK1/2 phosphorylation cascade (43). In smooth muscle cells, the carboxyl terminus of Cx43 directly binds to integrin β1, enhancing α—smooth muscle actin (α—SMA) expression and extracellular matrix deposition, thereby expanding the diameter of the neovascular lumen. At the same time, Cx43—mediated Ca²⁺ waves coordinate smooth muscle cell contraction, optimizing blood flow distribution to promote vascular maturation (44). This dual—cell regulatory network together constitutes the molecular basis of Cx43 in collateral circulation formation (40) (Figure 5).