Changes in ion channel function play an important role in the electrophysiological changes that occur during arrhythmias. The dysfunction of various cardiac ion channels, such as Na⁺, K⁺, and Ca²⁺ channels, increases the susceptibility to arrhythmia after MI (16, 17). K⁺ starts to change during the early stages of acute myocardial ischemia. Long-term ischemia leads to an increase in extracellular K⁺ concentration, which is the substrate and trigger for cardiac conduction velocity (CV) changes and arrhythmia (18). An increase in extracellular K⁺ concentration changes the resting membrane potential of cardiomyocytes, reduce the activity of voltage-gated Na⁺ channels, leads to a decrease in cell excitability and CV, and promotes unidirectional blockage and reentry (19, 20). CV and APD are important factors in the occurrence of arrhythmias, and changes in CV play important roles in the generation and maintenance of arrhythmias. Voltage-optical mapping studies of isolated hearts have shown that the induction of ventricular fibrillation (VF) at high activation frequencies is associated with decreased CV (21). It has also been suggested that arrhythmias may result from local CV heterogeneity (22). Many factors affect the CV, including coupling with non-muscle cells (23, 24), extracellular gaps, gap links, and extracellular ion concentrations (25–27). Among these, the upstroke velocity of the action potential is the key factor that affects CV, and the upstroke velocity mainly depends on the recovery of the Na⁺ channel. Therefore, the CV is closely related to Na⁺ channels (28).

The major subtype of voltage-gated Na⁺ channels, Na_v1.5, encoded by the SCN5A gene, is mainly expressed in the intercalated discs of the heart. It is the key channel for maintaining a normal CV and determining the excitability and conductivity of the heart. It also interacts with cAMP-dependent protein kinase A (PKA) and calmodulin-dependent kinase II (CaMKII). It can bind to various proteins such as CaMKII and membrane-associated guanylate kinase (MAGUK) to form macromolecular compounds that regulate gene transcription, protein synthesis, trafficking, membrane incorporation, channel function, and ultimately degradation (29, 30). Na_v1.5 remodeling is a key basis for the occurrence of VA reentry into the border zone of MI. Recent studies have shown that the autoimmune response against Na_v1.5 can cause conduction defects (31) and complete inactivation of Na_v1.5 due to a molecular dynamics disorder, can cause long QT syndrome type 3 (LQT3). Non-equilibrium gating leading to decreased availability of the Na_v1.5 closed conformation can cause Brugada syndrome (BrS). Moreover, Na_v1.5, dysfunction can lead to VA in pathophysiological conditions of heart disease, such as heart failure, dilated cardiomyopathy, and diabetic heart disease (32–34). Previous studies have determined that SCN5A mutations can induce a decrease in the amount and function of Na_v1.5, using genetic, electrophysiological, and molecular methods, leading to a series of VA such as LQT3, BrS, torsades de pointes, and idiopathic ventricular fibrillation. This process can be affected by time, temperature, environmental factors, and genetic factors (35, 36).

The heart beats rhythmically to drive the blood through the body. Cardiac action potentials are generated by the simultaneous opening and closing of many transmembrane ion channels. Dynamic changes in Ca²⁺ concentration play a key role in this process (37). RyR2 is the main Ca²⁺ release channel during systole and sarcoendoplasmic reticulum Ca²⁺-ATPase (SERCA) is the main Ca²⁺ uptake channel during systole in the SR, which is involved in excitation-contraction coupling. The amount of Ca²⁺ released by the SR through RyR2 largely determines the Ca²⁺ transient state (38). Ca²⁺ flows into the cell and is released from the SR via RyR2 to trigger the contractile myocardium, after which Ca²⁺ is mostly taken up or loaded into the SR via SERCA to trigger the diastolic myocardium. Genetic and acquired defects in RyR2 or SERCA have been suggested to be associated with a range of heart diseases, including life-threatening arrhythmias and heart failure (39) (40). These defects typically manifest as an impaired ability of RyR2 to remain closed during the diastolic phase of the cardiac cycle, resulting in enhanced diastolic Ca²⁺ release (DCR, manifested as Ca²⁺ sparks and Ca²⁺ waves) (41). The diastolic release of Ca²⁺ from the SR leads to prolonged APD and increased arrhythmic risk (10). Increasing the RyR2 activity in the ventricle and alleviating its inhibitory effect on RyR2-mediated Ca²⁺ release have been reported to independently cause catecholaminergic polymorphic VT (42). Furthermore, Xie et al. discovered that type 2a SERCA (SERCA2a) knockdown mice had a reduced arrhythmic risk of ischemic cardiomyopathy due to decreased SR diastolic Ca²⁺ leak (40). Therefore, intracellular Ca²⁺ homeostasis imbalance is a key factor in ischemic arrhythmia (43).

CaMKII is a multifunctional serine/threonine protein kinase widely expressed in vivo. Its activity is mainly modified and regulated by changes in intracellular Ca²⁺ content, and regulates intracellular Ca²⁺ dynamics, contractility, metabolism, and gene expression by phosphorylating various downstream targets (44). CaMKII has been identified as an important modulator of excitation-contraction and excitation-transcription coupling, a key determinant of the response to pathological cardiac remodeling, and is activated upon MI. CaMKII exerts proarrhythmic signaling through a large number of ion channels and SR-related proteins. CaMKII is known to activate L-type calcium channels, various K⁺ channels, Na_v1.5 and Na_v1.8 (45, 46). Stimulation of these channels results in early and delayed depolarization and spatially dispersed increases in repolarization, which promote arrhythmias, such as atrial fibrillation, ventricular tachycardia, and VF. CaMKII can also phosphorylate RyR2 and promote Ca²⁺ release from the SR into the cytoplasm (47). This SR Ca²⁺ leakage can activate proarrhythmic Ca²⁺-sensitive conductance. Overexpression of CaMKII has also been shown to induce structural and electrical remodeling of the heart, leading to impaired contractility and an increased risk of SCD. Conversely, inhibition of CaMKII helps maintain intracellular Ca²⁺ homeostasis after pressure overload and ischemic stress to prevent adverse electrical remodeling after MI (48, 49). Previous studies have demonstrated that CaMKII co-immunoprecipitates with Na_v1.5, and experiments have shown a stable physical interaction between phosphorylated CaMKIIδC and L1 of Na_v1.5. Phosphorylation of CaMKII enhances the inhibition of the late depolarization current of Na_v1.5, leading to the prolongation of the action potential, further disrupting Ca²⁺ homeostasis, and providing additional substrates for arrhythmia formation (50).

Inflammation is thought to trigger arrhythmia following MI. In an analysis of 478,524 individuals from the UK Biobank cohort, C-reactive protein (CRP) levels were found to be significantly and positively associated with the risk of developing atrial fibrillation. The heart rate for atrial fibrillation events increased significantly with increasing neutrophil count, monocyte count, and neutrophil-to-lymphocyte ratio (NLR), whereas the levels of systemic infection markers had an even stronger relationship with VA risk than the levels of systemic infection markers with atrial fibrillation risk. Restricted cubic spline analysis of the fully adjusted model showed that the risk of developing VA increased monotonically with increasing CRP levels and neutrophil counts; a similar association was observed between monocyte count, NLR, and VA occurrence (51). It adds precipitants and substrates to the VA in both the early acute injury phase and the subsequent chronic repair phase.

Repair of the infarcted heart depends on the timely suppression of the inflammatory response and the resolution of inflammatory infiltration after infarction. Damage-associated molecular pattern proteins released by necrotic cells after early MI trigger local and systemic inflammatory responses. Various inflammatory factors directly induce arrhythmias and recruit large numbers of neutrophils and monocytes. Under the action of inflammatory factors, recruited white blood cells change the function of ion channels and cause membrane potential changes (52). Simultaneously, many white blood cells infiltrate and exchange ions, nucleotides, metabolites, and electrical signals with the cardiomyocytes via connexins. The quantitative change and redistribution of connexins leads to gap junction remodeling, which is an important factor in inducing arrhythmia (53). Macrophages couple with cardiomyocytes through gap junctions containing connexin 43(Cx43), undergo synchronous depolarization, and participate in normal and abnormal cardiac conduction. Moreover, computer simulations have shown that an increased number of such junctions reduces the action potential upshoot and overshoot, leading to earlier repolarization and a shorter refractory period (54).

In addition, fever, increased heart rate, and increased oxygen consumption caused by a systemic inflammatory response can further promote arrhythmia and expansion of the lesion area. Subsequently, white blood cells remove dead cells and matrix debris through phagocytosis, thereby providing an environment for subsequent repair of the infarct area. An appropriate early inflammatory response can reduce the infarct area, promote scar formation, maintain the stability of the environment in the peri-infarct area, and contribute to recovery of the ischemic myocardium. Excessive and prolonged inflammatory responses can lead to apoptosis of myocardial cells, hypertrophy, and fibrosis of myocardial tissue in the non-infarcted area, leading to adverse remodeling of ischemia-related tissues and myocardial electrophysiological dysfunction. Monocyte and macrophage subsets secrete cytokines and growth factors that coordinate the repair, recruitment, and activation of mesenchymal cells, such as cardiac fibroblasts and vascular endothelial cells (55). Activated mesenchymal cells secrete a large number of extracellular matrix proteins (56), promote the formation of myocardial fibrosis scars, and thus provide a matrix for reentry, which is closely related to arrhythmia (57).

The heart adaptively responds to pathological injury, leading to cardiac remodeling characterized by cardiomyocyte hypertrophy and fibrosis. This remodeling includes chronic remodeling under volume/pressure load and acute repair under ischemia-hypoxia injury. During MI, phagocytosis of necrotic cells and tissues activates anti-inflammatory pathways that inhibit cytokine and chemokine signaling (58). Activation of the renin-angiotensin-aldosterone system and release of transforming growth factor-β induce the transformation of fibroblasts into myofibroblasts, causing ventricular fibrosis, similar to the macrophages mentioned above. When the number of myofibrocytes is considerable, nonmyocardial cells in the heart become obstacles to the propagation of action potentials. The differentiation state of fibroblasts has been previously shown to be associated with a change in the expression profile of ion channels, and the transition from fibroblasts to myofibroblasts can increase Na_v1.5; furthermore, they display rapid inward voltage-gated sodium currents that exhibit biophysical properties similar to the sodium currents found in cardiomyocytes (59). in vitro-cultured fibroblasts can electrically couple with cardiomyocytes to participate in excitation conduction through Cx43, and these intercellular connections allow myofibroblasts to influence the electrical activity of cardiomyocytes (60). Previous studies have generated mice that specifically express the optogenetic cation channel ChR2(H134R) in cardiac fibroblasts. After MI, fibroblasts are highly expressed in the injured area and close to cardiomyocytes in scar tissue, and light stimulation of the scar tissue can cause excitation of the whole heart and induce arrhythmia. Cx43 and other gap junction proteins, which are thought to mediate the coupling between cardiomyocytes and fibroblasts, are not required. Gap junctions and ephaptic coupling mediate the coupling between cardiomyocytes and fibroblasts in a cooperative but functionally redundant manner; however, this fibroblast-muscle coupling is not as strong as myofibroblast-myocyte coupling (61). These results suggest that electrical coupling between myofibroblasts and cardiomyocytes can destroy the original electrophysiological activity of the myocardium, induce electrophysiological abnormalities such as ectopic automaticity, posterior depolarization, and reentry, and promote the occurrence and development of arrhythmia.

In addition to directly affecting the electrical activity by coupling with cardiomyocytes, fibroblasts, which are the main cells producing extracellular matrix, are activated in large numbers after MI, promoting the deposition of extracellular matrix proteins (62). Various extracellular matrix proteins bind to cytokines, growth factors, and cell surface receptors to regulate the cell phenotype, thereby indirectly affecting arrhythmia. Structural remodeling of atrial fibrillation has been reported to involve the accumulation of cross-linked collagen in atrial fibroblasts. In a previous report, calcitonin receptor-knockout mice exhibited atrial fibrosis and increased susceptibility to atrial fibrillation due to collagen accumulation (63). A large amount of collagen and extracellular matrix can mechanically separate cardiomyocytes, destroy the continuity of myocardial bundles, interfere with the gap junction of cardiomyocytes, destroy the electrical coupling between cardiomyocytes, and cause discontinuous or “zigzag” conduction, leading to slow CV, unidirectional conduction block, and prolongation of the conduction path between cardiomyocytes, thus inducing arrhythmia. Myocardial fibrosis is an essential substrate for arrhythmias (64).

After MI, three distinct structural regions emerge in the left ventricle: the infarct, transition boundary, and remote zones (65). Magnetic resonance imaging shows that a large peri-infarct transition border zone is the single factor in the inducibility of monomorphic VT, providing mechanistic support for the association between peri-infarct size and mortality. Tissue inhomogeneity in the infarct border may provide a substrate for underlying reentrant arrhythmias, leading to SCD (66). In a study of 686 patients with apparent idiopathic nonsustained VA, left ventricular scars with annular patterns were associated with malignant arrhythmic events on cardiac magnetic resonance imaging. All patients with annular scars showed VA with a right bundle branch block, and multifocal VA was observed in 46% of patients. The prevalence of multifocal VA is much higher in patients with annular scars than in those with non-annular scars, suggesting that the influence of a specific infarct shape on VA should not be ignored (67). In addition, other studies have shown that the effect of fibrotic areas <20% and >80% on arrhythmia is relatively benign and that the arrhythmogenic effect is usually maximal at 30%–50% of the fibrotic area (64). Thus, inhibiting the progression of fibrosis without affecting MI healing may reduce the risk of arrhythmias.

In most pathological conditions, arrhythmia is often accompanied by inflammation and structural and electrical remodeling, with crosstalk. Upon initial ischemic injury, monocytes and macrophages are recruited and polarized to a proinflammatory phenotype, secreting inflammatory factors (such as IL-6, IL-1, and TNF-α), triggering a cytokine cascade. Inflammation rapidly induces the effect of cytokines on the expression of ion channels, which directly prolongs the QTc interval, and changes in these ion channels are negatively correlated with changes in CRP and IL-1 in patients. Although these changes are transient, they may significantly increase the risk of developing life-threatening VA in these patients (68). In addition, cardiac fibroblasts respond to IL-1 by acquiring a proinflammatory and matrix-degrading phenotype, delaying myofibroblast transformation and preventing premature acquisition of a matrix-synthetic phenotype until the infarct clears dead cells and matrix debris (69). In addition, some members of the chemokine family may also affect non-hematopoietic cells, such as cardiomyocytes, fibroblasts, and vascular cells, which mediate the transformation of fibroblasts into myofibroblasts or the recruitment of monocytes and neutrophils with fibroblast characteristics to promote the development of fibrosis (70, 71), which increases the axial resistance of the sarcoplasm. This enhances the coupling between fibroblasts and cardiomyocytes, both of which reduce the CV and increase the CV dispersion. As the activation of pro-inflammatory signals leads to cardiomyocyte death, mitochondrial membrane permeability transition pores open, perturb the intracellular Ca²⁺ balance, and increase ROS, triggering arrhythmic events. When intracellular Ca²⁺ increases in cardiomyocytes, CaMKII phosphorylation increases and activates IκB kinase, nuclear factor kappa B (NF-κB) is deinhibited, macrophage infiltration in the ischemic area increases, fibrosis scars become larger, and cardiac function is weakened (72). In the absence of endogenous CaMKII inhibitor 1 (CaMK2n1), the increased activation of CaMKIIδ-p38/JNK-NLRP3 inflammasome pathway leads to aggravated cardiomyocyte inflammation, aggravated ventricular remodeling and malignant VA (73). Single-cell sequencing of the infarcted and non-infarcted regions of ischemic cardiomyopathy revealed a large amount of leukocyte infiltration in the fibrotic myocardium, especially of proinflammatory CD⁴⁺ T cells (74). The presence of these inflammatory cells suggests that myofibroblast apoptosis occurs during the transition from the proliferative to mature phase of healing in the infarcted area, which may be regulated by inflammation (75). The increase in fibrosis can cause partial uncoupling of muscle fibers, a zigzag path of wave conduction, and slow or blocked conduction, which eventually leads to the occurrence of arrhythmia (76). Therefore, ischemic arrhythmia results from the crosstalk between the ion channel-fibrosis-inflammatory response and other factors.

When the body undergoes hypoxia-ischemia, the mitochondrial metabolism changes from oxidative phosphorylation to glycolysis, which reduces oxygen consumption and ensures ATP output (81). This metabolic transition leads to an increase in lactic acid, a decrease in intracellular pH, and an increase in the concentration of H⁺ in both the intercellular space and within the cell (82). H⁺ is exchanged with Na⁺ through the Na⁺/H⁺ exchanger, resulting in an increase in intracellular Na⁺ concentration. Simultaneously, owing to the decrease in Na⁺/ K ⁺ -ATPase activity, the extracellular transport of Na⁺ is reduced, leading to its accumulation in cells. In addition, the influx of Na⁺ ions into cells through nonselective cation channels activated by membrane stretching also leads to an increase in intracellular Na⁺ concentration. This increase in Na⁺ further activates the sodium-calcium exchanger (NCX) to operate in a “reverse mode,” eventually leading to intracellular Ca²⁺ overload (83) and causing early afterdepolarization or delayed afterdepolarization. When multiple depolarization events reach the threshold for sodium channel activation, a series of tachyarrhythmias can be induced. If this is extremely insufficient to induce an action potential, it may exacerbate regional differences in repolarization, leading to alternating or unidirectional conduction blocks and reentry (84). When Ca²⁺ overload occurs, a large amount of Ca²⁺ enters mitochondria through the mitochondrial Ca²⁺ uniporter (MCU) complex (85). Ultimately, this results in mitochondrial Ca²⁺ overload.

When mitochondrial calcium levels increase, the activity of the electron transport chain is stimulated, leading to a higher ROS release. Overproduction of mitochondrial-derived ROS may lead to the oxidation of RyR2 and further leakage of endoplasmic reticulum Ca²⁺, forming a vicious cycle (86). ROS also increases CaMKII phosphorylation. In ischemic heart disease, ROS production is increased in the infarct border region, which overactivates CaMKII phosphorylation and reduces INa density, thereby slowing the recovery rate after Na_v1.5 inactivation. In addition, the delay in repolarization and prolongation of the effective refractory period lead to a decrease in cardiac CV and even a conduction block (87). Mitochondria are the central hub for immune system activation, and their dysfunction leads to many inflammatory diseases. On the one hand, it relies on ROS to trigger an inflammatory response. Impaired mitochondrial function leads to activation of the tricarboxylic acid cycle and an increase in nitric oxide synthase, which eventually causes an increase in ROS. However, this does not depend on ROS for triggering inflammatory responses.

Mitochondrial Ca²⁺ binds to oxidized cardiolipin and triggers the release of the membrane gap protein cytochrome c into the cytoplasm. At the same time, the increase in Ca²⁺ and ROS levels can further open the mitochondrial permeability transition pore, leading to the immediate collapse of the mitochondrial membrane potential, release of cytochrome c, and activation of caspase protease, resulting in cardiomyocyte apoptosis (88). In the process, myocardial cells produce inflammatory factors such as TNF-α, IL-1β, and IL-6, leading to inflammatory response or dysfunction when myocardial injury occurs (89).

In recent years, studies have shown that, apart from the above effects through metabolism, inflammation, and oxidative stress, mitochondria are directly related to cell membrane Na_v1.5 in structure and function, and this association is different in various mitochondrial subsets. Subsarcolemmal mitochondria are more closely related to Na_v1.5 than to interfibrillar mitochondria and perinuclear subdomain mitochondria. This link may be established through the NCX, and its functional crosstalk includes sodium currents, Ca²⁺ dynamics, transcriptomics, and oxidative stress. Interestingly, the transcriptomics results showed that the negative correlation between SCN5A and SCL8B1 may be a compensatory result, indicating that the functions of the mitochondria and sodium channels are complementary. However, the mechanism by which Na⁺ channel expression or activity affects mitochondrial function or integrity requires further studied (90).