Abstract
Background: Autonomic innervation of the heart plays a pivotal role not only in regulating the heart rate but also in modulating the cardiac cell microenvironment via cell-cell interactions and influencing the heart’s repair capabilities. Currently, the primary clinical approach for treating myocardial infarction (MI) is percutaneous coronary intervention. However, the myocardial salvage rate remains low for patients with advanced disease. MI is recognized as an autonomic nervous system disorder, marked by sympathetic hyperactivity and the loss of parasympathetic nerves. Following MI, ventricular sympathetic nerve sprouting occurs, leading to an increase in ventricular sympathetic innervation and, consequently, an increased risk of ventricular arrhythmia, which is the primary cause of sudden cardiac death in patients with a history of MI. The vagus nerve positively regulates cardiomyocyte proliferation and regeneration, enhancing ventricular remodeling and cardiac function post-MI. This process is highly significant in the treatment and rehabilitation of MI. Cardiac autonomic nerves are influenced by factors such as inflammation, immunity, intercellular communication, metabolism, genetics, epigenetics, and cytokine secretion related to cardiac mesenchymal nerves. In recent years, significant advancements have been made regarding treatment for MI, specifically in the fields of autonomic nervous system therapies, stem cell and extracellular vesicle treatments, traditional Chinese medicine acupuncture and moxibustion, and peripheral electrophysiological stimulation and bioengineering materials. Summary: The balance of dominance between the sympathetic and parasympathetic nervous systems in the heart affects tissue regeneration and cardiac remodeling after MI. The secretion of neurons regulates the microenvironment of cardiac repair. The neural therapy of MI involves multiple fields such as traditional Chinese medicine, biomaterials, stem cell therapy, and drug research and development and has broad development prospects. Key Messages: The regulation exerted by the cardiac autonomic nervous system on the heart significantly influences the prognosis of MI. This involves nervous system modulation of inflammation and heart rate and complex interactions between neurons and cardiomyocytes, immune cells, fibroblasts, adipocytes, stem cells, and other cellular components. Genetic and epigenetic modifications, as well as shifts in energy metabolism, also play crucial roles.
Introduction
In the treatment of myocardial infarction (MI), time is of the utmost importance. The duration between the onset of symptoms and revascularization is critical as shorter intervals lead to less irreversible damage to the myocardium. Hence, the timing of reperfusion plays a pivotal role in determining the outcome of MI. However, in reality, only 2% patients with ST-segment elevation MI (STEMI) seek medical attention after 24–36 h, and merely 1% do so after 36–48 h [1]. This results in a significant increase in the MI-associated mortality and disability rates. The cardiac autonomic nerve axis, which regulates the heart’s rhythm, metabolic functions, and immune balance, is composed of the spinal cord stellate ganglion (SG), peripheral sympathetic nerve, and vagus nerve [2]. The administration of external spinal cord stimulation or SG stimulation has the potential to influence both sympathetic afferent activity and parasympathetic function. By modulating the balance between sympathetic and parasympathetic tone, these interventions can further regulate the stability of heart rhythm, alter the microenvironment of cardiac tissue, and ultimately impact cardiac regenerative capabilities [3].
MI induces pathological alterations within the autonomic nervous system, leading to structural remodeling of both cardiac sympathetic nerves and the heart. These changes are primarily marked by sympathetic activation and parasympathetic dysfunction, specifically manifesting as a reduction in vagal tone [4]. Sensory and parasympathetic nerves were essentially undetectable in the infarcted and peri-infarcted tissues of the myocardium. Conversely, an increase in sympathetic nerve density was noted in certain parts of the infarcted area between 4 and 14 days after MI. Moreover, abnormal sprouting and clustering of sympathetic nerves were observed in regions abundant in macrophages (MCs) and myofibroblasts [5]. The prominent perspective is that sympathetic hyperinnervation, characterized by an unusual surge in sympathetic nerve fiber density within the heart injury zone, serves as the primary culprit for VA occurrence after MI. Various studies have further substantiated that the sympathetic nerve density within the infarcted heart region is notably diminished compared to the unaffected, distal heart tissue. Intriguingly, despite this reduction in nerve density, the myocardium within the infarction zone remains responsive to both physiological sympathetic nervous system (SNS) stimuli and isoproterenol administration. This observed phenomenon could potentially be attributed to the preserved or even augmented β-adrenergic responsiveness in this cardiac region. Consequently, this enhancement leads to β-adrenergic receptor hypersensitivity and heightened susceptibility to arrhythmia, both of which are directly linked to the localized denervation deficit [6]. Vagus nerve stimulation (VNS) significantly impacts the hindrance of ventricular remodeling and cardiac dysfunction; however, its outcomes are influenced by numerous factors, including the type and location of stimulation, duration of VNS, and surrounding environment [7]. The vagal activity index possesses predictive and guiding significance for post-MI depression and PTSD [8]. Following MI, damage to both sympathetic and parasympathetic nerves results in a dangerously unstable electrical state of the heart. This instability not only exacerbates heart failure (HF) but also significantly increases the risk of fatal ventricular arrhythmia (VA), cardiac fibrosis, and ventricular remodeling [9]. Exploring the remodeling mechanism of the nervous system following MI and elucidating the role of the autonomic nervous system in cardiac regulation hold immense significance for the effective treatment and postoperative care of MI patients.
Cardiomyocytes (CMs), neural cells, and various interstitial cells collectively form the myocardial tissue, engaging in a dynamic interplay that facilitates myocardial tissue regeneration following MI. Prior investigations have established that nerve regeneration within the necrotic heart tissue is influenced by components of the extracellular matrix [10], notably neuronal guidance proteins (NGPs). These signaling proteins including semaphorins, netrins, slits, ephrins, and repetitive guidance molecules direct axon growth or growth inhibition. NGP receptors are present in multiple cell types such as CMs, endothelial cells (ECs), vascular smooth muscle cells (VSMCs), MCs, fibroblasts (FBs), neutrophils (polymorphonuclear neutrophils), red blood cells, and platelets. The ligand-receptor interactions involving these NGPs play a pivotal role in MI [11]. The intricate interactions between neurons, immune cells, FBs, and ECs shape the inflammatory response, tissue repair, and fibrosis in the heart following an MI. Notably, CMs and other mesenchymal cells also influence neuronal and synaptic development [12]. Additionally, the release of inflammatory factors, immune cell regulation, cellular metabolism, and rhythmic changes contribute to the modulation of cardiac autonomic nerve function.
Research efforts in recent decades have increasingly focused on targeting cardiac autonomic nerve regulation as a means to enhance MI prognosis. This includes the utilization of cardiac organoids, advancements in stem cell therapy and extracellular vesicles, drug development and clinical trials, and innovations in bioengineering materials. Neuromodulation therapy holds promise as a novel approach for treating cardiovascular diseases (CVDs). This review aimed to provide a comprehensive overview of the regulatory effects exerted by the SNS and parasympathetic nervous system (PNS) on the heart, exploring their roles and mechanisms in MI. Furthermore, it aims to enhance our understanding of the factors influencing cardiac autonomic nerve function and their subsequent impact on the heart following MI.
Regulation and Nourishment of the Nervous System for the Heart
Distribution of Sympathetic and Parasympathetic Nerves to the Heart
The sympathetic outflow from the human preganglionic heart mainly derives from the first to either the fourth or fifth thoracic spinal cord segments. Within the mediolateral cell column, nerve fibers from preganglionic sympathetic neurons (SN) – which facilitate cardiac sympathetic autonomic innervation – exit the spinal cord via the anterior root. These fibers then merge into the spinal nerve, traverse the anterior branch, and reach the paravertebral ganglion of the sympathetic chain through the white rami communicantes. At this point, they establish synapses with postganglionic neurons. Notably, preganglionic neurons have the capacity to form synapses with numerous postganglionic neurons, whereas postganglionic SN extend from cardiac nerve fibers to reach the heart. Interestingly, in approximately 80% individuals, the inferior cervical ganglion amalgamates with the first thoracic ganglion, giving rise to the cervicothoracic ganglion or SG. This structure is believed to supply the postganglionic cardiac nerve. MI can trigger bilateral SG remodeling via sympathetic nerve sprouting. Tyrosine hydroxylase (TH) serves as a distinctive marker for sympathetic nerves [13]. Immunohistochemical staining showed that the positive rate of TH in the left SG (LSG, 26.61% ± 11.54%) surpasses that in the right SG (15.94% ± 3.62%) [14]. It is worth noting that the postganglionic nerve traveling from the cervical and thoracic sympathetic chain to the heart emerges as an independent cardiac nerve from the paravertebral ganglion, bypassing the gray rami communicantes connecting to the spinal nerve, and innervates the sympathetic ganglion via the paravertebral nerve [15].
Cardiac sympathetic nerves enter the heart via the vascular poles. The arterial pole courses along the common carotid artery, subclavian artery, and brachiocephalic artery, ultimately reaching the aorta and pulmonary trunk. Meanwhile, the venous pole traces the path of the superior vena cava. Postganglionic sympathetic nerves and preganglionic parasympathetic nerves – offshoots of the vagus nerve and recurrent laryngeal nerve – converge on the heart’s surface, forming a plexus. The superficial (ventral) cardiac plexus lies adjacent to the left aortic arch and left pulmonary artery, as well as near the right ascending aorta and brachiocephalic trunk. However, the deep (dorsal) cardiac plexus is situated between the aortic arch and the tracheal bifurcation. Once these mixed autonomic nerves penetrate the pericardial sac, they extend toward the cardiac ganglia, interconnecting via local circuit neurons. This gives rise to ganglia or the epicardial plexus at the poles of the cardiac arteries and veins. Embedded within the epicardial fat, these plexuses constitute the cardiac intrinsic nervous system. Positioned at the heart’s base, the cardiac intrinsic nervous system serve as the ultimate regulators of cardiac function within the cardiac perineurium [2].
(Postganglionic) sympathetic nerve fibers directly innervate the myocardium or make their first synapse on the intracardiac ganglion situated within the myocardial wall and epicardial fat. Both parasympathetic (preganglionic) fibers establish synapses on intracardiac ganglia. These ganglia comprise diverse neuronal populations, including afferent neurons, efferent neurons, and local circuit neurons. The majority of ganglia are situated on various sides close to the atrium. Ventricular ganglia are primarily distributed in the epicardial fat adjacent to the aortic root and near the primary branches of coronary arteries. Estimates suggest the presence of 14,000–43,000 neurons in the epicardial plexus. The heart has approximately 700–1,500 ganglia, collectively forming nine ganglionic plexuses, known as the cardiac plexus – effectively, the “big and small brain” of the heart [2]. These plexuses comprise mixed cardiac nerves, specifically nerves originating from various cardiac sympathetic nerves as well as parasympathetic nerves [16]. The cardiac ganglia, which are highly interconnected and integrated, possess intrinsic activities that are regulated by sympathetic or parasympathetic (vagus) inputs. Consequently, the cardiac ganglion serves not merely as a relay station, rather as a local integration center for modulated input.
The activation of the SNS serves as a compensatory mechanism for the heart when cardiac function is compromised, aiming to maintain adequate cardiac output. Nevertheless, an excessively strong sympathetic reflex can result in unfavorable responses, such as VAs and cardiac remodeling. During MI, the nerve density diminishes, and the heart undergoes adaptive hyper-sympathetic excitation, persisting until the central parasympathetic influence is suppressed. Concurrently, the reactive upregulation of nerve growth factor (NGF) expression leads to elevated NGF levels in the LSG and serum. This surge in NGF prompts sympathetic nerve sprouting in both infarcted and non-infarcted regions, resulting in increased sympathetic nerve density. This nerve sprouting, in turn, impairs the expression and functionality of transient outward and inward rectifier current pathways in CMs via the phosphorylation of extracellular signal-regulated kinase and CREB, ultimately increasing the risk of atrial fibrillation [17]. As time progresses, the NGF level will steadily decline, ultimately leading to a reduction in cardiac sympathetic nerve density. This decrease, in turn, triggers HF, which emerges as another significant contributor to the high mortality rate following MI [18]. Sympathetic hyperinnervation predominantly emerged in the junctional zone 3 days following MI and subsequently persisted for a minimum duration of 3 months [19].
Sympathetic reinnervation of the LSG post-MI serves as the primary driver for the amplification of the cardiac sympathetic afferent reflex [20]. Suppressing LSG neuronal activity bolsters its electrophysiological stability, exerting a protective influence on the heart. Nerve sprouting signals elevate NGF levels in both the LSG and serum, leading to augmented cardiac nerve density in both infarct and non-infarct zones. Subsequently, the NFG production tapers off, presumably as an adaptive mechanism to counteract prolonged sympathetic hyperactivity, resulting in a decline in sympathetic nerve density. NGF exhibits tissue specificity and can modulate microcapillary components and the vascular microenvironment [21]. Sympathetic nerve terminals discharge neurotransmitters such as norepinephrine (NE), neuropeptide Y, and galanin. Notably, neuropeptide Y release can be stimulated by ghrelin, which in turn attenuates sympathetic nerve activity (SNA) in brown adipose tissue [22]. Fatal VA, a prevalent post-MI complication accounting for 50% of sudden cardiac deaths among MI survivors, is primarily attributed to heightened sympathetic nerve density [23]. Following MI, cardiac sympathetic nerves undergo cholinergic transdifferentiation, releasing both NE and acetylcholine (ACh). The latter’s release diminishes action potential duration (APD) dispersion, exerting an antiarrhythmic effect [24]. Chondroitin sulfate proteoglycan present in cardiac scars promotes sympathetic nerve regeneration within the scar, mitigating post-MI arrhythmia. This process is contingent on the chondroitin sulfate proteoglycan sulfation reaction (4S or 6S) [25]. Stimulating left sympathetic activation induces left ventricular (LV) nerve sprouting, leading to cardiac sympathetic hyperinnervation and nerve remodeling, thereby elevating the risk of post-MI VA [26]. Cardiac sympathetic denervation offers an effective treatment for ischemia-related arrhythmias and ischemic cardiomyopathy by elevating the ventricular fibrillation threshold (VFT) [27] (Fig. 1).
The vagus nerve regulates both local and systemic inflammatory responses via the cholinergic anti-inflammatory pathway (CAP), which is triggered by the α7-nicotinic acetylcholine receptor (α7-nAChR). This pathway’s activation in the heart prevents the loss of phosphorylated connexin 43 and exerts an anti-VA effect [28]. Acetylcholine, released from the vagus nerve, interacts with the nAChR on MCs, guiding reparative inflammation and promoting regeneration of the injured myocardium. Following MI, the vagus nerve on the cardiac surface is absent. However, stimulating vagus nerve activation can activate the IL-10/STAT3 signaling pathway, promoting M2 MC polarization and enhancing cardiac regeneration and repair [29]. Additionally, CAP activates the STAT3 signaling pathway in ECs and inhibits NF-κB activation, thereby protecting vascular function [30]. Parasympathetic nerves are typically labeled with choline acetyltransferase [13]. The deletion of α7-nAChR can lead to interstitial fibrosis in vascular ECs (EndMT), promoting cardiac fibrosis and dysfunction [31]. CAP can be activated through various methods, including cerebellar fast nuclear stimulation [32], auricular VNS [33], median nerve stimulation [34], pulsed ultrasound [35], and drugs such as the cholinesterase inhibitor bromopyridostigmine [36] and the α7-nAChR agonist (pha568487) [37]. Furthermore, periodic repolarization dynamics and deceleration capacity are novel ECG-based markers associated with sympathetic and vagal cardiac autonomic nervous system activity. The combination of periodic repolarization dynamics and deceleration capacity can predict the risk level after MI [38].
Nourishing Effect of Nerves on the Heart
The interaction between cardiac autonomic nerves and cells primarily relies on cell-to-cell communication. The neurons’ protective and reparative functions toward other cardiac cells hinge on the secretion and transmission of diverse factors. This neuronal function is characterized as the nourishing effect of nerves on tissues. While few studies have explicitly applied this concept, numerous investigations still affirm the role of neurons in maintaining tissue function. Notably, neurons’ secretory capabilities facilitate the repair of both tissues and nerves. Neuron-derived extracellular vesicles (NDEVs) are detectable in the bloodstream. Exercise stimulates NDEV secretion and enhances the vesicular content of neuroprotective factors, thereby augmenting NDEV’s neuroprotective efficacy [39]. As a medium for communication between neurons and other cells, NDEVs are rich in microRNAs (miRNAs), specifically including mir-132-5p, mir-218-5p, and mir-690, which serve as targets to enhance synaptic transmission and neuronal activity [40]. Mir-132-5p [41] is regarded as a cutting-edge marker for MI, while mir-218-5p [42] exhibits a cardioprotective function in myocardial ischemia-reperfusion injury by mitigating oxidative stress and inflammation via the MEF2c/NF-κB pathway.
Neuron-derived neurotrophic factor (NDNF, alternatively termed c4orf31) is a secreted protein that fosters neuronal growth, migration, extracellular matrix formation, and apoptosis inhibition. Given its role in promoting angiogenesis, NDNF, which is expressed and secreted by both neurons and ECs, is viewed as a promising therapeutic target for ischemic heart disease treatment [43]. Treatment with NDNF protein can revitalize human mesenchymal stem cells [44] and adipose-derived stem cells [45] in older individuals, enhancing the stem cells’ capacity to facilitate the repair of damaged tissues. NDNF can be activated by chronic ischemia, which reduces myocardial apoptosis and hypertrophy through the promotion of Akt phosphorylation, and subsequently enhances capillary formation following MI [46]. Neurogenic VEGF exerts neurotrophic effects and can enhance the development of the cortex and hippocampus [47]. VEGF, a crucial signaling molecule regulating vascular growth, also signifies cardiac angiogenesis [48]. Although the majority of studies currently suggest that sympathetic nerve remodeling is a detrimental factor in MI, sympathetic reinnervation is also regarded as an essential prerequisite for cardiac regeneration [49]. Therefore, it is imperative that sympathetic nerve sprouting simultaneously provides nourishment for the regeneration of cardiac tissue. Blood vessels and nerves are intertwined, and for cardiac repair, engineered biological implants must also incorporate functional blood vessels and nerves to achieve innervation [50]. However, to date, there is a significant dearth of pertinent research exploring the impact of EV, NDNF, and VEGF originating from distinct neurons (such as sympathetic and parasympathetic nerves) on cardiac function. Additionally, there is a scarcity of investigations into the effects and underlying mechanisms of NDEV in relation to MI. We believe that this constitutes a notable research gap that is worthy of further exploration.
Other Effects of Neural Innervation on the Heart
The main changes in the autonomic nervous system of the heart after an MI are an imbalance in the regulation of the sympathetic and vagus nervous systems, characterized by early sympathetic overactivation and decreased vagus nerve activity, while late sympathetic innervation gradually weakens, promoting decreased cardiac function. Meanwhile, abnormal neural innervation is accompanied by changes in the surrounding neural environment, including inflammation and immune regulation. The vagus nerve is activated by inflammation and exerts anti-inflammatory and reparative effects through the CAP pathway. After an MI, a large number of inflammatory factors are produced in the heart and peripheral blood. Inflammatory factors can trigger the vagus nerve and transmit signals to the solitary tract nucleus of the medulla oblongata through afferent neurons. Subsequently, the higher nervous system processes the signals and releases anti-inflammatory factors from the dorsal nucleus of the vagus nerve through efferent nerves [51]. In addition, the innervation of the heart also plays a role in cardiac fibrosis, myocardial blood supply and support, hemodynamics, and atherosclerosis.
The excessive activation of the SNS in the heart is associated with cardiac fibrosis. As we mentioned earlier, there is mutual influence between the cardiac nervous system and immune system, and this cross-talk relationship between the two is called “neuroimmune cross-talk”. The increase in SNS activity triggers an inflammatory cascade signal, leading to myocardial cell death and myocardial interstitial fibrosis. The PNS can inhibit cardiac inflammation through the CAP pathway [52]. The postganglionic neurons of the sympathetic nervous chain transmit signals from the species nervous system to peripheral targets of the autonomic nervous system, thereby participating in the regulation of target organ function of the autonomic nervous system [53]. The activity of the cardiac autonomic nervous system affects myocardial blood supply and oxygen consumption. The results of a 6-month single blind randomized controlled clinical trial showed that increasing vagus nerve activity and/or reducing SNA through breathing exercises can reduce heart rate and myocardial oxygen consumption, maintain autonomic nervous system balance, reduce cardiac burden, and alleviate anxiety in patients with coronary heart disease [54]. The balance between sympathetic and parasympathetic nervous systems affects the body’s blood pressure. The SNS mediates vasoconstriction, while acetylcholine induces vasodilation and thickening of the aortic wall, involving regulation of the tumor necrosis factor-α (TNF-α)/phosphatidylinositol 3-kinase (PI3K)/serine/threonine kinase 1 (AKT1) signaling pathway and inflammatory signaling pathway [55]. Cardiac nerves are also involved in the formation and stability of atherosclerosis. During the formation of atherosclerotic plaques, white blood cells infiltrate the connective tissue layer outside the artery. Inflammation mediates the formation of a broader axon network of cardiac nerves in the outer membrane stage of the plaque lesion. This neural immune cardiovascular interface (NICI) reaches the dorsal root ganglion through afferent nerves and further transmits information to the brain. The sympathetic efferent neurons project from the medulla oblongata and hypothalamus to the outer membrane through the medial lateral neurons of the spinal cord, the celiac ganglion, and the sympathetic chain ganglion. Thus, the NICI establishes a structural arterial brain circuit, and intervention in the arterial brain circuit promotes the disintegration of the outer membrane NICI, enhances plaque stability, and slows down disease progression [56]. The autonomic nervous system participates in the regulation of energy metabolism in the myocardium. The energy supply of the myocardium is mainly based on lipid metabolism, and excessive lipid accumulation in myocardial cells can cause myocardial cell dysfunction, macroscopically damaging the structure and function of the heart [57]. The autonomic nervous system of the heart is related to the TCA cycle and the pathway of hydroxy fatty acid metabolism [58]. The vagus nerve of the heart can optimize the levels of α/β-MHC and α-actin positive sarcomeres in myocardial cells, while reducing F-actin assembly in myocardial cells, improving glucose uptake, and reducing lipid deposition in muscle cells [59].
Factors and Mechanisms Influencing the Cardiac Autonomic Nervous System
Factors
Sleep
In healthy young individuals, there is a notable decrease in cardiovascular output as they transition from wakefulness to various stages of sleep during the night and day. Additionally, the cardiac autonomic innervation undergoes a shift, moving from sympathetic to parasympathetic (vagus) innervation. This rhythmic pattern of the heart is significantly correlated with beneficial effects on cardiovascular health [60]. Vagus nerve activity is dominant during sleep. However, MI may cause the loss of the vagus nerve’s physiological activation capacity during slumber, allowing the sympathetic nerve to remain dominant, consequently increasing the likelihood of sudden nocturnal death [61]. The prevalence of sleep disorders varies widely, ranging between 1.6% and 56%. Lack of sleep elevates the chance of developing CVD and fosters tissue oxidative stress as well as the infiltration of inflammatory factors [62]. In 1993, Somers et al. [63] discovered that rapid eye movement (REM) sleep is linked to sympathetic activation, suggesting that hemodynamic and SNS alterations during REM sleep could potentially contribute to the development of CVD. In healthy males, non-rapid eye movement (NREM) sleep correlates with the influence of the cardiac vagal nerve, whereas REM sleep is linked to cardiac sympathetic nerve activity. However, sleep apnea affects the interplay between cardiac autonomic regulation and delta sleep EEG. Consequently, patients diagnosed with sleep apnea syndrome exhibit higher SNA than the general population, thereby heightening their cardiovascular risk [64]. The autonomic control of the cardiovascular system during human sleep is influenced by both sleep stage and sleep cycle. Specifically, NREM sleep and the final cycle exhibit the highest vagal activity and the lowest sympathetic activity. Additionally, baroreflex sensitivity is elevated during sleep compared to wakefulness, further increasing during REM sleep, and is dependent on respiratory rate during NREM sleep [65]. A cross-sectional study has confirmed that sleep status has an impact on plasma epinephrine and NE concentrations and SNA in patients with MI [66]. Furthermore, sleep fragments have the potential to augment sympathetic hyperactivity, elevate the sprouting of cardiac sympathetic nerve endings, and boost the concentration of cardiac NE. Consequently, this process can hinder the expression of vps35, disrupting ATP7a-associated copper transportation and causing copper overload within the CMs. This overload, in turn, triggers cellular copper poisoning and apoptosis, ultimately contributing to the advancement of myocardial injury [67]. In summary, maintaining healthy sleep conditions and proper autonomic regulation while sleeping can effectively decrease cardiovascular stress and the associated risks. MI may trigger sympathetic hyperexcitability during slumber, elevating the danger of unexpected fatality from the ailment. Additionally, factors such as inadequate sleep, fragmented sleep, or sleep apnea have the potential to induce cardiac autonomic innervation disorder, thereby increasing the susceptibility to MI (Fig. 2).
Factors influencing the cardiac autonomic nervous system (created in BioRender, Yin, X. (2025), https://BioRender.com/v13i784).
Factors influencing the cardiac autonomic nervous system (created in BioRender, Yin, X. (2025), https://BioRender.com/v13i784).
Stress, Anxiety, and Depression
The level of vagus nerve control in depressed patients is lower than that in the control group, and a decrease in heart rate variability is considered an early indicator of depression [68]. Depression is closely related to autonomic nervous system imbalance [69]. Smoking causes damage to the vagus nerve, thereby increasing the risk of depression [70]. Both stress and pressure can induce neuroinflammation, which is a key pathogenesis factor of depression. The vagus nerve fibers transmit peripheral inflammatory signals to the brain, and then the higher centers project the information to brain regions such as the hypothalamus, amygdala, hippocampus, and frontal lobe. As a noninvasive treatment, VNS therapy has shown good efficacy in patients with severe depression [71]. It is worth noting that the right and left cervical vagus nerves of humans contain 25,489 ± 2,781 and 23,286 ± 3,164 fibers, respectively, including two-thirds of unmyelinated fibers and one-third of myelinated fibers. The proportion of sensory fibers is about three quarters, with special visceral and parasympathetic nerve fibers accounting for 13.2 ± 1.8% and 13.3 ± 3.0% and sympathetic fibers accounting for 13.0 ± 5.9% and 14.3 ± 4.0%, respectively. The superior branches of the heart include the PNS, vagal sensory, and sympathetic fibers. Therefore, there is a potential risk of activating the sympathetic nerve fibers of the superior cardiac branch when electrically stimulating the cervical vagus nerve [72]. The vagus nerve is considered a bidirectional communication pathway between the gut and brain in traditional Chinese medicine (TCM), which can transmit stress-induced changes in the gut microbiome to affect human hippocampal plasticity and behavior. This process mainly involves the reactive regulation of the vagus nerve to inflammatory stimuli and its impact on the dopamine neurotransmission pathway [73].
Obesity
Obesity can activate inflammatory signaling pathways and induce chronic inflammatory states in the body, thereby increasing SNS excitability and further causing myocardial damage [74]. The breakdown and browning of white adipocytes, as well as the thermogenesis of brown adipose tissue, are associated with SNS excitation and cardiac inflammation [75]. Correspondingly, the SNS can innervate the adipose tissue and reduce fat mass through lipolysis and thermogenesis [15]. The hypothalamic leptin signal is involved in SNS overactivation and inflammatory response, which explains obesity-related hypertension or hypertension, and leptin is an adipokine mainly secreted by the adipose tissue [76]. These pieces of evidence suggest that excessive accumulation of adipose tissue and abnormal lipolysis are the main culprits causing SNS overexcitation. Another study has confirmed that adiponectin secreted by adipose tissue can inhibit the expression of chemokine ligands and receptors, reduce levels of inflammatory cytokines, inhibit cardiac sympathetic remodeling, and alleviate MI [4]. The deficiency of G protein subunits Gqα and G11α (Gq/11α) in the dorsomedial hypothalamus leads to a decrease in sympathetic nervous activity, heart rate, and adaptation to low temperature environments in mice, as well as obesity related to reduced energy expenditure [77]. Obesity is a major risk factor for coronary heart disease, and the excessive excitation of the SNS can promote heart damage, increasing the risk of developing coronary heart disease, cardiac fibrosis, arrhythmia, and ventricular remodeling. The SNS also participates in the formation of atherosclerosis, which forces us to connect these pieces of information and consider the regulatory network between cardiac adipose tissue, myocardium, blood vessels, and nerves. Their complex crosstalk may open up new perspectives on MI cognition.
Mechanisms
Intercellular Interactions
The heart primarily consists of 11 distinct cell types, namely, atrial CMs, ventricular CMs, FBs, ECs, pericytes, smooth muscle cells, immune cells (derived from bone marrow and lymph), adipocytes, mesothelial cells, and neuronal cells. Notably, the neuronal cells comprise six subsets. Gaining insights into the traits of each cell type and their interactions aids in recognizing anatomical specificities, molecular attributes, intercellular networks, and spatial relationships [78]. Periostin-expressing cardiac FBs [79] and specific Schwann cell [80] subsets are intricately linked to postnatal CM maturation and innervation, playing a pivotal role in sympathetic tract tremor. The perineurium, composed of FBs, endothelial-like cells, and epithelial cells (also termed perineurial or mesenchymal cells), has a crucial neuroprotective and regenerative function. Leptin receptors located on the surface of these mesenchymal cells are modulated by leptin secreted from adipocytes. These receptors trigger the secretion of IL-33 and dispatch immunoregulatory signals to adipose tissue immune cells, thereby participating in inflammation regulation [15]. The intricate interactions between neurons and immune cells orchestrate the complex immune microenvironment within tissues, involving the secretion, transmission, and uptake of neurotrophic factors (NFs) and NDEVs [81].
Neurons, CMs, and FBs constitute a tightly interconnected triad within the heart. These cells engage in mutual interactions that modulate the pathophysiology of cardiac ailments and are pivotal in the innervation as well as pathological remodeling subsequent to MI. SN innervate the myocardium with a variable topological density, and this process of innervation is delicately controlled by NGF secreted by CMs. Neurons and CMs collaborate to form nerve-heart junctions. CMs serve as the primary source of cardiac NGF, responsible for regulating neuronal synapse formation and the innervation of CMs. The nerve-heart junction serves as a central hub, ensuring efficient signal transduction [45]. Cardiac FBs abundantly express NGF, which promotes the differentiation and proliferation of cardiac sympathetic nerves. Through the paracrine effect of FBs, NGF ensures the activity and function of sympathetic nerve synapses. Additionally, activated neurons establish contact with CMs, forming a prominent marker, tau-1, at the site of contact. This process regulates the electrophysiological characteristics of CMs [82]. Zhao and Ding believed that NGF solely influenced the differentiation of FBs, without affecting their proliferation, cell cycle, or migration [83]. Leptin receptor-positive cells in the sympathetic nerve tissue were also immunostained to detect FBs and perineurial markers, namely, PDGFR-α and ITG-β4 [15]. During myocardial injury, CD68-positive MCs synthesize and secrete NGF, a crucial factor for sympathetic nerve sprouting in peri-infarct tissues [23]. MC depletion has the potential to ease sympathetic hyperinnervation that occurs post-MI. Elevated catecholamine levels, secreted by sympathetic nerve terminals, can modulate cardiac sympathetic remodeling by interacting with β1-adrenergic receptors located on the MCs. This process, in turn, may trigger VA following MI [84]. The vagus nerve activates MC α7-nAChR by releasing acetylcholine, inducing M2 MC polarization, and promoting myocardial repair [85]. The LSG is encapsulated within the adipose tissue located in the thoracic cavity. Adiponectin, an adipokine secreted by adipocytes, possesses the capability to hinder the excessive activation of the cardiac ganglion plexus triggered by rapid atrial pacing. Additionally, it can prevent atrial fibrillation and suppress sympathetic neuronal activity, thereby averting cardiac remodeling and the onset of MI-induced VAs [4]. Sympathetic nerves play a crucial role in the regulation of adipose tissue, further stimulating adipocyte metabolism and energy expenditure via the activation of anti-inflammatory signal transduction in MCs [86].
Genes and Epigenetics
P2X ion channels, specifically P2X7R, exhibited significant upregulation 3 days post-MI. This upregulation facilitated the activation of NF-κB, inflammatory cell infiltration, and the expression of inflammatory factors, ultimately leading to sympathetic nerve remodeling [87]. High VEGF-B expression can facilitate angiogenesis, presenting a promising approach for the treatment of MI. Nevertheless, elevated VEGF-B levels also enhance the expression of factors like NR4A2, ATF6, and Manf that are linked to nerve growth and differentiation. This, in turn, can trigger nerve growth in the adult heart, leading to abnormal nerve distribution and subsequently increasing the risk of VA [88].
N6-methyladenosine (m6A) is the most prevalent post-translational modification in eukaryotic mRNA. The editing of m6A, modulated by methyltransferase-like enzyme 3 (METTL3), plays a crucial role in cardiac sympathetic hyperfunction. More precisely, the METTL3-mediated m6A modification regulates the translocation of TRAF6 to microglial mitochondria and activates the TRAF6/ECSIT pathway. This process ultimately fuels sympathetic hyperactivity, resulting in VAs following MI [89]. The vagus nerve mediates the activation of several cardiac pathways, including Janus kinase, extracellular signal-regulated kinase, signal transducer and activator of transcription [90], and akt/glycogen synthase kinase-3β [91], ultimately providing cardioprotection after MI. While the activation of these pathways may not rely on the CAP pathway, the precise excitation mechanism remains poorly understood.
When the body experiences chronic stress, sympathetic nerve fibers release an excessive amount of NE. In response, bone marrow niche cells activate β3-adrenergic receptors, leading to a reduction in CXCL12 levels. This, in turn, triggers the proliferation of hematopoietic stem cells (HSCs) in the bone marrow, resulting in elevated levels of neutrophils and inflammatory MCs in the body. Consequently, this process increases the risk of MI [92]. Certain noncoding RNAs also play a role in sympathetic remodeling. Jing et al. [93] discovered that miRNA let-7a has the ability to target and suppress the expression of NGF in MCs. This action subsequently lowers the validation level in hearts affected by MI, diminishes SNA, and ultimately eases cardiac remodeling in the aftermath of MI [93]. One week following MI, there is an elevation in the level of ubiquitin (UB) within the infarcted region, and it is believed that sympathetic hyperinnervation may correlate with heightened ubiquitination levels in the heart [94]. UB C-terminal hydrolase L1 (UCHL1) is a multifunctional protein abundant in neurons and serves as a deubiquitinating enzyme. The deletion of this enzyme is linked to axonal degeneration, progressive sensorimotor ataxia, and premature death in mice. Furthermore, it is hypothesized to contribute to the pathogenesis of neurodegenerative diseases and facilitate recovery after neuronal injury [95]. MI can enhance the expression of UCHL1 in myocardial tissue, leading to an increase in myocardial UB conjugates. Additionally, the upregulation of UCHL1 is intimately connected to the homeostasis of cardiac autophagic flux and protein regulation, thereby influencing cardiac remodeling and dysfunction subsequent to MI [96]. Identified through immunoprecipitation mass spectrometry, glucose-regulated protein 78 kDa (GRP78) interacts with UCHL1. This interaction promotes the degradation of GRP78 via deubiquitination and subsequently inhibits cardiac fibrosis post-MI [97]. However, further clarification is still needed regarding the relationship between UCHL1, cardiac neuronal injury, and the growth regulation of various nerve types.
Energy Metabolism
The activation of sympathetic nerves is influenced by both the level of energy metabolism within itself and the surrounding environment. ATP plays a role in sympathetic excitation [98]. Eliminating the Akt-releasing membrane channel protein PANX1 (pannexin 1) elevates glycolytic metabolism and ATP generation in CMs, while simultaneously suppressing neutrophil recruitment to these cells [99]. In the central nervous system, PANX1 serves as a medium for intercellular communication between neurons and astrocytes, thereby facilitating the development of spatial memory synapses [100]. The opening of PANX1 pores in peripheral nerves stimulates the activation of the NLRP3 inflammasome and the neuro-vasculature, hence initiating the neuroinflammatory cascade [101]. Opening the PANX1 channel and releasing ATP in CMs during hypoxia can stimulate sympathetic nerve fibers, ultimately leading to the exacerbation of myocardial injury [102]. Taken together, energy metabolism, immunity, and the autonomic nervous system are intricately linked. The diminished recruitment of ATP and immune cells aids in the suppression of sympathetic nerves, fostering a conducive environment for repair following MI. Consequently, a decrease in the glucose metabolic rate of neurons leads to the inhibition of sympathetic nerve excitability. Ghrelin, an intestinal hormone, not only stimulates growth hormone release, food intake, and fat deposition but also regulates autonomic and sympathetic remodeling. Furthermore, ghrelin elevates the VFT and enhances APD dispersion and APD alternation, offering sustained electrophysiological protection [103]. The exogenous administration of ghrelin showed significant inhibitory effects on MI-induced tachycardia, while also elevating plasma NE concentration [104]. Mechanistically, ghrelin is involved in the modulation of glucose homeostasis through its inhibitory effects on insulin secretion and its role in regulating glycogenolysis. This action can lead to a decrease in heat production and energy expenditure, a reduction in SNA, and potentially an improvement in the prognosis of MI [105]. Mao et al. [106] discovered that both exogenous and endogenous ghrelin have the ability to suppress cardiac sympathetic nerve activity. However, when the cervical vagal trunk is treated with brominated grade A atropine or capsaicin, it hampers the beneficial effects of ghrelin. Based on these findings, it can be hypothesized that ghrelin exerts its regulatory influence via the vagal afferent nerve [106]. Treatment with the oral ghrelin analog salrelin simultaneously reduced plasma epinephrine and dopamine levels, while also shifting the balance of autonomic activity towards parasympathetic activity [107]. Intracerebroventricular injection of ghrelin (5 μg/kg) produced optimal outcomes in terms of sympathetic inhibition [108]. However, further clarification and discussion are still warranted regarding the direct impact of metabolism on the peripheral autonomic nervous system, as well as the indirect influence of the central nervous system on the autonomic nerves. Evidently, the innervation of autonomic nerves by energy metabolism exhibits multifaceted and intricate characteristics.
Role of the Cardiac Autonomic Nervous System in MI
Cardiac Nerves and Cardiac Remodeling
Cardiac remodeling following MI involves several levels, including myocardial structure, vascular structure, and the cardiac autonomic nervous system. This process is accompanied by interactions between myocardial, vascular, and nerve components. The balance between cardiac sympathetic and vagal nervous systems plays a crucial role as a trigger and substrate for atrial and VAs. Any disruption in this balance can contribute to adverse ventricular remodeling, ultimately affecting the heart’s structure and function. Both ventricular remodeling and neuroinflammation are factors that can lead to HF after MI. Neuroinflammation can be further categorized into central and peripheral neuroinflammation. In response to stimuli like stress and hypoxia, microglia in the paraventricular nucleus (PVN) of the hypothalamus and locus coeruleus become activated. This activation promotes an inflammatory response in the central nervous system and activates the SNS, which can exacerbate myocardial fibrosis, apoptosis, and ventricular remodeling. Supplementation of vagal activity has been found to mitigate these responses [109]. MI can also disrupt redox homeostasis in the vagal node, resulting in damage to the sympathetic vagal afferent neurons and decreased reflex efferent parasympathetic nerve function. This, in turn, leads to pathological remodeling of the heart. It is worth noting that the vagus nerve remodeling process is modulated by estradiol, indicating a gender-related aspect to this pathological remodeling [110]. The vagus nerve interacts with CMs to attenuate CM apoptosis and mitigate cardiac tissue remodeling induced by MI [111]. VNS can utilize low-level stimulation of the left cervical vagus nerve (LL-VNS). Administering LL-VNS treatment for 3 weeks following an early MI can significantly enhance VA and LV function by suppressing cardiac neuronal sprouting and the inflammatory response [112]. Low-level VNS (targeting the inferior vena cava and inferior atrial ganglion plexus) has the potential to inhibit atrioventricular node conduction, reduce ventricular rate, and enhance SG nerve remodeling [113].
Cardiac Nervous System and Blood Vessels
The nervous system and vasculature exhibit structural interdependence and functional interconnectedness. Specifically, the heart’s nervous system plays a crucial role in regulating vascular regeneration. Activation of α7-nAChR has been found to enhance angiogenesis in isoproterenol-induced rat models of MI [114]. Furthermore, VNS mitigates the inflammatory response in coronary arteries by decreasing the proportion of CD68-positive MCs and reducing the release of inflammatory factors such as TNF-α and IL-1β. VNS also triggers the activation of the Akt stromal cell-derived factor-1α (SDF-1α) pathway in VSMCs, leading to improvements in the VSMC metabolic mode and repair of the infarcted myocardium [115]. In addition, vascular ECs respond to VNS stimulation by secreting SDF-1α, which subsequently promotes cardiac angiogenesis and augments cardiac vascular density [116]. Secretoneurin, a neuropeptide originating from secretogranin II (SGII), was first discovered in the dorsal horn of the spinal cord. This neuropeptide has the capability to store and release capsaicin [117]. It is specifically expressed within perivascular nerve fibers. Hypoxia triggers the expression of secreted nerve phosphatase, which subsequently activates Akt and extracellular signal-regulated kinase in ECs. Through the stimulation of VEGF binding to receptors on the surface of ECs, secretoneurin initiates coronary angiogenesis, enhances LV function, suppresses remodeling, and minimizes scar formation. Furthermore, in coronary VSMCs, secreted nerve phosphatase can also activate VEGF receptor-1 and FB growth factor receptor-3 [118].
Immunity and Inflammation
The inflammatory response is intimately linked to sympathetic reinnervation. MI is accompanied by a pronounced inflammatory reaction that activates MCs, leading to inflammatory and immune regulatory effects. Notably, MC chemoattractant protein MCP-1 (CCL2) experiences significant upregulation in the early post-MI phase, resulting in increased myocardial myeloid cell infiltration and subsequent deterioration of LV function [119]. In the inflammatory stage, M1 MCs are predominant and stimulate the expression of IL-1β, IL-6, and TNF-α in damaged and necrotic regions. However, as inflammation gradually subsides after 4–7 days, MCs shift toward the M2 subtype [120]. Notch signaling plays a crucial role in immune system development, influencing MC activation and function [121]. Studies have shown that Notch signaling becomes activated following MI, mediating an increase in M1 MCs and NGF expression [122]. Inflammatory cells synthesize and secrete NGF post-MI, promoting sympathetic nerve sprouting, leading to ventricular hyperinnervation [5]. Furthermore, neuronal remodeling in the LSG is influenced by the levels of inflammatory cytokines IL-1 [123] and IL-6. Chronic IL-6 overexpression mediates LSG neural remodeling via the G-protein signal transduction pathway, elevating the risk of VA after MI [124]. In summary, inflammation and associated cytokines stimulate the growth and regeneration of sympathetic nerves. The vagus nerve exerts a protective effect on heart tissue by releasing acetylcholine, regulating the inflammatory response and oxidative stress – a mechanism known as the CAP. This pathway has been validated in infectious diseases and ischemic cardiovascular and cerebrovascular conditions. Stimulating the vagus nerve (through surgery, electrical stimulation, drugs, or other methods) can augment the number of anti-inflammatory immune cells during the repair of ischemic or infarcted hearts, reducing oxidative stress and the production of inflammatory cytokines such as IL-1β, IL-6, TNF-α, and IL-10 [125]. Additionally, the CAP pathway activates the AMPK signaling pathway in cardiac MCs, thereby enhancing cardiac electrophysiological function, decreasing myocardial collagen expression and inflammatory cytokines, and preserving the ultrastructural integrity of the ischemic heart [126].
Application of Nervous System Regulation in the Treatment of MI
Biological Materials
In recent years, bioengineering materials have achieved noteworthy advancements in the medical field. Specifically, in the context of autonomic nerve therapy for MI, the seamless integration and application of electricity, magnetism, stem cells, and materials have proven effective in augmenting parasympathetic activity and restoring autonomic nerve balance through VNS. This approach offers substantial therapeutic benefits for MI patients. Electrical stimulation stands out as a direct and efficient method for vagus nerve activation. However, the majority of research has thus far centered on invasive electrical stimulation device implantation. Recently, a nanosheet conductive and adhesive hydrogel has been developed by combining two-dimensional titanium carbide (Ti3C2Tx) MXene with natural biocompatible polymers. This innovative material can be applied as a coating on heart tissue, stably adhering to the beating epicardium, resulting in significant improvements in cardiac function and the alleviation of pathological heart remodeling [127]. A closed-loop, self-powered LL-VNS system featuring a hybrid nanogenerator (h-ng) represents a novel implantable intelligent device. This device boasts flexibility, lightness, simplicity, and remarkably; it operates without electronic circuits, components, or batteries. The implantable h-ng achieved a maximum output of 14.8 V and 17.8 μA (peak to peak). Furthermore, in an in vivo study validating its effectiveness, LL-VNS therapy demonstrated an enhancement in myocardial fibrosis and atrial connexin levels. This improvement was mediated by the anti-inflammatory effects triggered by the NF-κB and AP-1 pathways [128]. Magnetic stimulation offers remote nerve regulation, overcoming the challenges posed by electrode implantation-related infections and nerve damage. However, achieving precise stimulation on a single vagus nerve remains challenging due to the magnetic field’s poor focusing ability. To address this, we propose a magnetic vagus nerve stimulation system. This system combines injectable chitosan/β-glycerophosphate hydrogel loaded with superparamagnetic iron oxide (SPIO) nanoparticles and a mild magnetic pulse sequence. This approach facilitates precise magnetic stimulation of a single vagus nerve while ensuring safety through minimally invasive implantation.
Under the influence of a mild magnetic field (∼100 mT), SPIO nanoparticles within the hydrogel demonstrate notable effects. Specifically, in rats injected with magnetic chitosan/β-glycerophosphate hydrogel in situ, we observed a reduction in heart rate and alterations in vagus nerve potential. Furthermore, 4 weeks of magnetic vagus nerve stimulation (20 Hz, 3 times daily, 5 min per session) significantly enhanced cardiac function, reduced infarct size, and suppressed inflammatory cell infiltration and inflammatory factor expression in rats with MI. These findings highlight the considerable potential of this approach in the clinical treatment of MI [129]. NGF has the capability to enhance the proliferation of human umbilical cord mesenchymal stem cells (hUCMSCs) and stimulate the tyrosine kinase A and phosphoinositide 3-kinase (PI3K) – serine/threonine protein kinase (Akt) signaling pathways within these cells, ultimately leading to cardioprotective effects. A heart patch, consisting of hUCMSCs embedded within a fibrin matrix and loaded with NGF-containing lactic glycolic acid (PLGA) nanoparticles, can ensure the sustained release of NGF. This innovative approach not only preserves the activity of hUCMSCs but also promotes cardiac vascular regeneration [130].
The application of biomaterials has made rapid progress in recent years, but there is still a lack of clinical research and clinical application-related fields of MI. IK-5001 is an injectable device, which contains 1% sodium alginate and 0.3% calcium gluconate solution. In a clinical study in 2014, a new injectable bioabsorbable stent constructed by using IK-5001 can selectively crosslink at the infarct site to form hydrogel, which not only plays a cardiac protective role but also improves microcirculation after MI [131]. This clinical trial conducted the first human safety study of IK-5001, confirming the feasibility and good tolerability of intracoronary injection of 2 mL IK-5001 within 7 days after STEMI in humans. It can be seen that although the transition of biomaterials from the laboratory to clinic is a long path, pre-existing research efforts have the potential to provide us with good context and research ideas for continued progress. Compared with traditional drugs, thrombolysis, and PCI treatment, the application of biomaterials can effectively improve ventricular remodeling and HF; moreover, owing to their good targeting, they can directly treat the infarcted site with drugs, enhancing the therapeutic effect.
Acupuncture and TCM
Acupuncture and moxibustion, a traditional Chinese medical (TCM) practice, involves the stimulation of specific skin acupoints to achieve therapeutic goals. Despite its rich historical background and extensive practical experience in treating various conditions, including MI, its widespread adoption and application have been hindered by the absence of a comprehensive theoretical foundation in anatomy and physiology. Furthermore, the requirement for practitioners to possess a profound understanding of Chinese medicinal heritage and advanced acupuncture techniques poses additional challenges [132]. Neiguan (PC6), a prominently utilized acupoint in the treatment of cardiovascular ailments, is situated within the pericardial meridian. Its efficacy in mitigating the symptoms of such diseases has been established through evidence. The application of acupuncture at Neiguan (PC6) demonstrates potential in decreasing the occurrence of spontaneous ventricular premature beats and cardiac fibrosis subsequent to MI. Additionally, it exhibits the ability to suppress inflammatory reactions, modulate the immune system, and hinder sympathetic excitation [133]. The findings of a multicenter, double-blind, parallel-controlled, randomized controlled trial have established that acupuncture, as an adjuvant therapy for STEMI patients following PCI, exhibits significant efficacy and favorable safety profile [134]. Electroacupuncture (EA) treatment is an evolution of traditional acupuncture. Through the precise application of current stimulation to specific acupoints or regions, EA not only alleviates the fear associated with acupuncture but also effectively stimulates the desired acupoints. The entire treatment procedure is both safe and hygienic. Acupuncture or EA stimulation of Neiguan (PC6) and Zusanli (ST36) has been confirmed in multiple clinical studies and trials to have benefits in reducing angina symptoms [135], atrioventricular remodeling [136], and adjuvant therapy after MI and PCI [134]. Clinical trials and clinical studies have more objectively provided adaptation criteria for acupuncture and moxibustion treatment, and many clinical guidelines around the world have included acupuncture and moxibustion treatment in the recommended treatment methods [137]. Research has consistently demonstrated that peripheral nerve electrical stimulation at targeted acupoints can trigger sympathomimetic effects, preserve cardiac self-compensation, facilitate cardiac autonomic regulation, and ultimately maintain optimal cardiac function [138]. EA can also decrease the level of NE following MI, enhance the density of growth-associated protein 43 and Th-positive nerve fibers, modulate sympathetic and parasympathetic remodeling, further diminish the size of MI, and enhance cardiac function [139]. The paraventricular nucleus (PVN) to intermediate nucleus pathway represents one of the key routes for EA to confer cardioprotection. When myocardial ischemia-reperfusion injury was treated with EA, there was an observed increase in the discharge frequency of pyramidal cells within the PVN, a reduction in energy, decreased expression of c-fos, and ultimately a mitigation of myocardial damage [140]. EA inhibited glutamatergic neuronal discharges in both the fastigial nucleus [141] and lateral hypothalamus [142] of the cerebellum. This, in turn, suppressed cardiac sympathetic nerves and mitigated cardiac injury. Furthermore, EA not only directly impacted autonomic nerve discharge but also influenced MC polarization post-MI. Specifically, EA administered at Neiguan (PC6) notably diminished sympathetic nerve remodeling, lowered tnf-α, IL-1β, and IL-6 levels in myocardial tissue, enhanced M2 MC polarization, and ameliorated myocardial fibrosis [143]. From the perspective of long-term prevention, traditional acupuncture or transcutaneous electrical stimulation of acupoints can not only effectively alleviate angina symptoms, regulate the autonomic nervous system, protect heart health, and prevent the occurrence of MI but also have higher safety and clinical compliance than traditional clinical treatments (drug therapy or PCI treatment), with fewer side effects [144]. From a therapeutic perspective, time is crucial for managing MI, and clinically, <3% patients are able to complete coronary blood flow recovery within prime time. Acupuncture, moxibustion, and EA stimulation are simple and fast, with relatively mild trauma and high acceptability. The cholinergic neuron reflex can regulate inflammatory responses within seconds and reduce myocardial damage [145]. Although anticoagulants and antiplatelet drugs have been used clinically to reduce reperfusion injury so far, their effectiveness is minimal. Vaginal nerve electrical stimulation has higher safety in reducing reperfusion injury and can be used as an adjuvant therapy to effectively reduce reperfusion-related arrhythmias, infarct size, and inflammatory biomarkers [146]. In terms of rehabilitation, randomized clinical trials have confirmed that VNS can effectively improve inflammation without interfering with cardiac regulation [147], making it a good rehabilitation treatment method. Both acupuncture and EA exhibit pronounced effects on autonomic nerve and immune regulation, making them valuable adjunctive therapies for MI.
Extracts from certain TCMs and natural plants exhibit remarkable efficacy in enhancing sympathetic nerve remodeling and cardiac function following MI, while also boasting excellent safety profiles. These extracts constitute valuable adjuvant therapies for MI and possess significant transformative potential. Notably, resveratrol stands out due to its ability to effectively suppress inflammation and oxidative stress post-MI. By inhibiting the expression of NGF in and around the infarcted region, resveratrol mitigates sympathetic remodeling and reduces the incidence of VA induction [148]. Resinous toxin injection into the LSG or epicardium was utilized to ablate SN by specifically targeting the transient receptor potential vanilloid 1/TH (TRPV1) [149]. Pinocembrin, a flavonoid compound primarily extracted from licorice, holds significant potential in enhancing the expression of ion channel proteins Cav1.2 and Kv4.3 in CMs. Its application is effective in improving the shortening of APD in these cells, while also reducing the occurrence and duration of ventricular fibrillation. Furthermore, pinocembrin demonstrates notable efficacy in decreasing NGF expression, enhancing autonomic nerve remodeling, and minimizing infarct size and myocardial fibrosis [150]. The mechanism of action by which these TCMs or natural plant extracts regulate the cardiac autonomic nervous system remains to be further explored, and clarification of the drugs’ pharmacokinetics is needed. TCM treatment has a long history of development in China for thousands of years. It is not only an empirical medicine but also has its unique theoretical basis, making it a good choice for MI adjuvant therapy. Compared to modern Western medicine treatment, TCM lacks considerable clinical data and more convenient usage methods. More certified preparation methods can be explored for TCM prescriptions. More clinical trials are still needed for TCM therapy, and the effective ingredients of TCM need to be discovered and purified to prepare tablets with higher purity and efficacy.
Cardiac Organoids
Induced pluripotent stem cells (iPSCs) have the potential to become renewable sources for pancreatic islets, dopaminergic neurons, retinal cells, and CMs, thus offering a novel perspective in regenerative medicine for the treatment of various diseases [151]. 3D-cultured cardiac organoids, derived from iPSCs, have gained widespread application in the field of MI. Through in vitro organoid culturing, researchers can obtain human-like hearts composed of CMs, FBs, and ECs. These cells self-organize to form cardiac organoids (HOs) that closely mimic the in vivo heart environment, enabling intuitive monitoring of functional changes [152]. Subjects exposed to a hypoxia-induced ischemic injury model may exhibit characteristics of the MI phenotype, including CM death, biomarker secretion, functional defects, calcium ion imbalance, and cardiac rhythm changes. Additionally, the availability of an animal model without MI offers a novel alternative for further investigation [153]. UB carboxyl-terminal esterase L1 (UCHL1) is a neuron-specific protein that plays a crucial role in Parkinson’s disease and stroke. It functions by deubiquitinating and stabilizing key pathological proteins, such as α-synuclein. When UCHL1 was knocked down in human iPSCs using CRISPR/Cas9 gene editing technology, the derived CMs exhibited increased susceptibility to hypoxia/reoxygenation-induced injury compared to wild-type CMs. Additionally, UCHL1 can bind to and stabilize HIF-1α after MI, revealing a novel protective effect of UCHL1 in MI by enhancing HIF-1α signal transduction [154]. Currently, the application of Ho primarily centers on drug trials and genetic testing, while research on cardiac autonomic nerves remains limited. However, significant advancements have been achieved in the development and application of brain organoids in neurodevelopment [155]. By simulating or constructing the cardiac autonomic nervous system in vitro, and directly observing the alterations in Ho’s MI model triggered by various nerve fibers, the innervation system of the heart can be intuitively exhibited. Compared with the heart, cardiac organoids lack vascular perfusion, and when the diameter of the organoid exceeds 1–2 mm, there will be a certain degree of necrosis inside the tissue. By regulating the Wnt signaling pathway, a similar vascular network has emerged in cardiac organoids [156]. The vascular group of cardiac organs improves their contractility and determines the communication ability between ECs, pericytes, FBs, and CMs [157]. However, there is currently no method to achieve neural networking of cardiac organoids. We believe that when this goal is achieved, the mechanism of crosstalk between nerves and the heart will become more apparent in humans. The in vitro organoid culture of human cells can visually observe changes in organoid structure and function and detect drug safety and sensitivity in vitro. However, whether structural changes in organoids can predict clinical outcomes in patients still requires further clinical research to confirm [158].
Stem Cell Therapy and Extracellular Vesicle Therapy
Stem cells utilized for tissue repair and regeneration encompass embryonic stem cells, HSCs, bone marrow mesenchymal stem cells (BMSCs), and adipose-derived stem cells. These cells have progressed into clinical trials for the treatment of ischemic heart disease. Additionally, extracellular vesicles secreted by stem cells, which comprise proteins, nucleic acids, and lipids, have gained widespread application in tissue regeneration. Specifically, BMSCs and their extracellular vesicles exhibit a therapeutic effect on CMs during MI, effectively mitigating CM apoptosis and oxidative stress [159]. The sympathetic nerve itself plays a crucial role in influencing the metabolism and proliferation of stem cells. When the SNS becomes hyperactive, it triggers a metabolic shift in stem cells, moving from oxidative phosphorylation to anaerobic glycolysis. This transition occurs through the interaction of ADRA 1b with serine threonine kinase and p38 mitogen-activated protein kinase signaling pathways. Additionally, this hyperactivity also serves to hinder the proliferation and migration capabilities of stem cells [160]. The senescence of HSCs relies significantly on the innervation of the bone marrow by the SNS. Furthermore, the absence of SNS nerve signaling or adrenoceptor β3 in the bone marrow microenvironment may result in premature aging of HSCs [161]. Stress-induced SNS excitement releases NE, leading to depletion of melanocyte stem cells [162]. Therefore, whether it is stress, trauma, or the excessive excitement of SNS caused by the activation of the SNS system mentioned earlier, it has an inhibitory effect on the function of most stem cells. Therefore, whether it is inhibiting SNS or striving to increase the number and function of stem cells, theoretically, it can play a role in the treatment of diseases. BMSC therapy can target the CAP, inhibiting inflammation and injury [163]. Cholinergic control is beneficial for the survival and function of bone cells [164]. On the other hand, it should be noted that SNS is still essential for the survival of stem cells. The dopamine released by SNS controls the expression of lymphocyte-specific protein tyrosine kinase (Lck), thereby regulating the MAPK-mediated signaling pathway triggered by stem cell factors in hematopoietic stem cells and progenitor cells, which is key to bone marrow transplantation and rapid hematopoietic stem cell and progenitor cell expansion [165]. Other EVs, such as heart-derived EVs, circulate to the rostral ventrolateral medulla of the PNS and promote oxidative stress and SNS excitation through Nrf2 downregulation mediated by EV-enriched miRNAs [166]. In terms of clinical application, the clinical study of implanting font cell patches into the surface of the left ventricle through a small incision in the left chest to treat dilated cardiomyopathy has confirmed its safety and feasibility, and the use of stem cell cardiac patches has improved the symptoms, exercise ability, and cardiac function of postoperative patients [167]. Human embryonic stem cells can differentiate into lineage-specific stem cells. Researchers used human embryonic stem cells to produce highly purified clinical grade cardiovascular progenitor cells, which were embedded in fibrin patches to treat patients with ischemic LV dysfunction. After 18 months of follow-up, no tumors or arrhythmias were found, and all patients’ cardiac function improved [168]. Stem cells combined with biomaterial patch therapy is a major development direction in stem cell therapy, which can compensate for the disadvantage of heart non-regeneration and directly repair heart damage while minimizing trauma. The integration of VNS nanomaterials and stem cell therapy seems to open up a new chapter in the treatment of MI. However, allogeneic stem cell transplantation still needs to consider issues related to immune rejection. Furthermore, obtaining autologous stem cell transplantation can cause additional trauma to patients. Extracellular vesicle transplantation can reduce immunogenicity to a greater extent, but maintaining its activity and efficacy for a longer period of time poses certain challenges.
Others
The kidneys participate in SNS response through hypoperfusion and loop diuretics, inhibiting the renin angiotensin aldosterone system to promote NE uptake, thereby inhibiting cardiac remodeling. Mineralocorticoid receptor antagonist eplerenone can improve cardiac sympathetic nervous activity and prevent LV remodeling in first-time STEMI patients. The results of a single-center, prospective, randomized evaluation study showed that spironolactone can inhibit cardiac sympathetic nerve activity and LV remodeling in patients after the first STEMI reperfusion [169]. Clinical studies have confirmed that empagliflozin (a sodium/glucose cotransporter 2, SGLT2) inhibitor can effectively improve myocardial nerve activity and reduce fatal VAs after AMI [170]. SGLT2 inhibitors promote osmotic diuresis and urinary sodium excretion, reduce circulating blood volume, alleviate cardiac workload, and improve LV function, while reducing reflex sympathetic neuropathy, resulting in insignificant changes in heart rate. The use of statins can inhibit cardiac sympathetic nervous activity in patients with first-onset STEMI [171]. Exploring the regulatory effects of common clinical drugs in CVD management on the autonomic nervous system of the heart is beneficial for guiding medication in clinical MI patients. Optogenetic stimulation can specifically silence or enhance the activity of a group of neurons. Its principle is to synergistically promote the genetic expression of photosensitive proteins in target cells, activate them through appropriate wavelength illumination, and then induce hyperpolarized currents to activate the target cells. By regulating the activity of the cardiac autonomic nervous system through optogenetic stimulation, specific stimulation of the vagus nerve of the heart can induce reparative inflammatory responses, promote cardiac regeneration and repair, and thus improve the prognosis of MI [29].
Low-level VNS can increase the VFT and prolong the effective refractory period of the ventricle [172]. The superior cervical ganglion (SCG) is involved in the neural innervation of the heart, providing a superior cardiac nerve that connects with postganglionic sympathetic nerve fibers originating from other sympathetic ganglia in the cardiac plexus. It should be noted that SCG is located near the carotid body (CB). During the acute phase of MI, the neurons in the area adjacent to SCG and CB increase, and both NFs and NF receptors in SCG are upregulated after MI. CB may mediate neuronal remodeling within SCG, promoting pathological neural innervation after MI [13]. Local neck cooling is a treatment method that is easy to implement during transportation, reducing myocardial damage in a vagus nerve dependent manner, while providing cardiac protection to the heart without altering core temperature [173].
Orexin receptor 2 (OX2R) is mainly expressed in neurons of the dorsal root ganglion (DRG). Extracardiac administration of OX2R agonists can weaken the cardiac sympathetic afferent reflex, thereby exerting a cardioprotective effect [174]. Ding hydrochloric acid treatment significantly reduced the nerve fiber density of growth-associated protein 43 and TH, reduced VA attacks, promoted M2 MC polarization, reduced inflammatory response, inhibited sympathetic nerve remodeling, and improved cardiac function after MI [175]. Resiniferatoxin improves cardiac dysfunction, ventricular electrophysiological characteristics, and sympathetic remodeling in MI rats by inhibiting excessive cardiac sympathetic drive [176]. Renal denervation can reduce the occurrence of ventricular tachycardia in AMI rats, decrease sympathetic nerve discharge in the kidneys, and inhibit local SNA and growth factor (NGF) protein expression in the heart after AMI. Renal denervation can also reduce the expression of NE, glutamate (Glu), and cerebrospinal fluid NE in the hypothalamus after AMI and increase the expression of gamma aminobutyric acid in the hypothalamus [177].
Discussion
The regulation exerted by the cardiac autonomic nervous system on the heart significantly influences the prognosis of MI. This involves nervous system modulation of inflammation and heart rate and complex interactions between neurons and CMs, immune cells, FBs, adipocytes, stem cells, and other cellular components. Genetic and epigenetic modifications, as well as shifts in energy metabolism, also play crucial roles. While sympathetic denervation often indicates a poorer prognosis, the nourishing effect of sympathetic nerves on tissue is vital for tissue regeneration. However, cholinergic innervation, primarily influenced by the vagus nerve, positively affects the anti-inflammatory environment and immune regulation of tissues. It plays a pivotal role in inhibiting cardiac pathological remodeling and VAs. The delicate balance between parasympathetic and sympathetic innervation is essential for maintaining tissue environmental homeostasis. This balance creates favorable conditions for tissue regeneration after MI, including inhibiting inflammation, promoting vascular regeneration, and reducing adverse cardiac remodeling. Advancements in various fields such as the development of biomaterials, promotion of acupuncture and moxibustion in TCM, emergence of cardiac organoid research, clinical application of stem cells and exosomes, and the development of diverse drugs have brought renewed hope for neuromodulation in MI. These advancements offer promising prospects for improving MI prognosis and adjuvant therapies. However, further research is needed to fully understand the recognition mechanisms and actions of different peripheral NFs.
Neuronal stimulation attempts to manage and treat MI by reconstructing physiological homeostasis, but the clinical translation of cardiac autonomic nervous system still faces many practical challenges. The development of biomaterials is rapid, but in the process of commercialization and clinical translation, high attention needs to be paid for their safety and tissue exclusion. MVNS is an injectable material with a 9-nm iron oxide core and more than 20-nm glycoside coating SPIO nanoparticles and temperature-sensitive hydrogel, which can be applied to the right vagus nerve for its stimulation. At present, STEMI remains a major life-threatening disease worldwide, and despite reperfusion therapy and optimal medical management, STEMI patients still face extremely high mortality rates and recurrent cardiovascular events. Therefore, it is necessary to explore new mechanisms, treatments, and rehabilitation methods for diseases. Vagal nerve stimulation has an excellent effect on reducing STEMI reperfusion injury. However, there is still a lack of long-term and extensive preclinical trials to confirm its safety and effectiveness. In addition, the risk and difficulty of performing vagus nerve dissection in clinical practice are high, and the trauma is significant. To truly move toward clinical application, it is still necessary to improve its application methods, such as in vitro patches. For gene therapy, the safety of naked mRNA intramyocardial injection has been validated in clinical studies, but its effectiveness still needs to be confirmed by a large number of clinical sample outcomes [178].
Acupuncture, moxibustion, and TCM treatment have a large number of clinical experience bases. The development of EA treatment and traditional Chinese patent medicines and simple preparations makes up for the high difficulty in popularizing its technology. The relationship between TCM acupoints and neural networks still needs further exploration to clarify their mechanisms in regulating the autonomic nervous system of the heart, which is beneficial to find more treatment strategies. The efficacy of stem cells in MI has been confirmed in many clinical studies, including autologous stem cell transplantation [179] and allogeneic stem cell transplantation [168]. Among them, autologous stem cell transplantation mainly relies on BMSCss, but obtaining stem cells can cause additional trauma to patients. Peripheral blood stem cells can obtain autologous stem cells with minimal trauma. Although coronary artery infusion successfully improves heart function, worsening vascular restenosis is a serious problem [180]. However, although SNS excitation can trigger stem cell dormancy or inhibition, the specific regulatory role of stem cells on cardiac autonomic nervous system is still unclear, which may be one of the important factors in the risk of vascular stenosis after stem cell therapy. Extracellular vesicles can avoid immunogenicity as much as possible, but their safety and stability are challenges in the clinical translation process. Regulation of the cardiac autonomic nervous system is not a simple neural regulation, rather a huge network regulation formed between myocardial nerve immune FBs and other stromal cells. We emphasize that while discussing the function of nerves on myocardial cells, we should also pay attention to the changes and functional participation of other cells. A comprehensive view of the microenvironmental changes after cardiac ischemia and infarction can help with a more comprehensive understanding of MI and its related issues.
Conflict of Interest Statement
There is no conflict interest.
Funding Sources
This study was funded by Jilin Provincial Natural Science Foundation (mechanism of iron homeostasis imbalance mediated by TfR1 and DMT1 activation in microglia and postoperative cognitive dysfunction caused by neuroinflammatory response, project number: YDZJ202101ZYTS122).
Author Contributions
Xiaorui Yin ([email protected]): acquisition of data, drafting the manuscript, software and drawing, and writing – reviewing and editing. Dan Cai ([email protected]): reviewing. Zhimin Song ([email protected]): supervision and financial support. Chunli Song ([email protected]): conceptualization and financial support.