The coronary arteries originate from the root of the aorta and are divided into two primary branches: The left main coronary artery (LMCA) and the right coronary artery (RCA) (52) (Fig. 1). The LMCA further branches into the left anterior descending (LAD) artery and the left circumflex (LCx) artery, while the RCA travels along the right atrioventricular groove (53). Coronary dominance refers to the origin of the posterior descending artery (PDA), which supplies the posterior inferior wall of the left ventricle (LV). There are three types of dominance: Right dominance (70%), where the RCA gives rise to the PDA; left dominance (10%), where the PDA is supplied by the LCx; and co-dominance (20%), where both the RCA and LCx contribute to the PDA (52). The RCA supplies the right atrium, right ventricle, sinoatrial node, atrioventricular node and parts of the posterior wall of the LV. By contrast, the LMCA delivers blood to the anterior wall and left side of the heart through the LAD and the posterior-lateral wall of the LV and left atrium (LA) via the LCx (52).

In coronary circulation, each vessel category uniquely supports myocardial perfusion (Fig. 1). Epicardial arteries, with diameters >400 µm, primarily function as conduits for blood flow to the myocardium, contributing only ~5% to the total vascular resistance (54,55). Pre-arterioles, ranging from 100-400 µm, are crucial for metabolic control and regulating the coronary blood flow, accounting for 20% of the vascular resistance. These vessels participate in the autoregulation of coronary flow, adjusting blood supply according to myocardial oxygen demand (56). Arterioles, with diameters between 40-100 µm, are the primary regulators of coronary blood flow, making up 60% of the vascular resistance (57). These small vessels are integral in local blood distribution and metabolic processes and are also a target of therapeutic interventions in conditions such as angina and myocardial ischemia (58). Capillaries, <10 µm in diameter, are vital for nutrient and gas exchange, contributing ~15% to vascular resistance (59). While they contribute to resistance, their fundamental function is facilitating the exchange of oxygen, nutrients and waste products at the cellular level (60). The capillary network's extensive surface area is essential for the diffusion of oxygen and nutrients to the heart muscle.

The myocardium, with its high metabolic demands, consumes ~5% of cardiac output, or 50-120 ml/100 g of myocardial tissue, with an oxygen extraction ratio of 60-70% (61,62). This high extraction ratio reflects the limited capacity of the myocardium to increase oxygen uptake under stress, highlighting the importance of efficient coronary blood flow (CBF) to meet elevated oxygen demands. As myocardial oxygen demand rises during physical activity or stress, CBF must adjust to ensure sufficient oxygen delivery to the heart (63,64). CBF is primarily diastolic, with 75% of the flow through the LMCA and 50% through the RCA occurring during diastole (65,66). During systole, left ventricular blood flow decreases due to the compression of coronary vessels by increased chamber pressure, while right ventricular flow is less affected by systolic pressure (67,68). To meet the increasing oxygen demand, CBF is tightly regulated by several mechanisms working in concert. Metabolic regulation plays a crucial role: carbon dioxide, adenosine, lactate and potassium ions are released by myocardial cells in response to elevated oxygen demand (69-74). In parallel, smooth muscle cells (SMCs) in the coronary arteries show a myogenic response to variations in blood pressure, modulating vascular tone to ensure consistent perfusion, even in the presence of fluctuations in systemic blood pressure (75,76). Additionally, the ANS further modulates CBF through its sympathetic and parasympathetic branches. Sympathetic activation, primarily through β-receptors, raises heart rate and myocardial contractility, increasing myocardial oxygen demand and triggers coronary vasodilation to meet these needs. Conversely, parasympathetic activity (via muscarinic receptors) promotes vasodilation by stimulating the release of nitric oxide (NO), especially during restful periods when myocardial oxygen demand is lower (77-79). The combined actions of metabolic signals, smooth muscle regulation and autonomic modulation ensure that the coronary circulation adjusts dynamically to meet the myocardial oxygen requirements, both at rest and during stress.

CMD is increasingly identified as a critical factor in the development of IHD, often manifesting clinically as angina in patients without significant coronary artery blockages on angiography (49,106). CMD results from the inability of the coronary microvasculature to properly regulate blood flow, leading to an imbalance between myocardial oxygen supply and demand, causing myocardial ischemia (107). Structural alterations in the microvasculature, including microvascular remodeling, capillary rarefaction and microvascular obstruction, contribute to CMD (108). These changes are frequently accompanied by an increase in left ventricular mass and vascular stiffness, further impairing myocardial perfusion (109). This can contribute to both chronic ischemia and heart failure, making it a key target for both diagnosis and therapy in IHD (110).

A key factor in the progression of CMD is endothelial dysfunction (107). The vascular endothelium normally regulates smooth muscle function by releasing vasodilators such as NO, which facilitates coronary vasodilation during periods of heightened oxygen demand (111). In CMD, the reduced ability of the endothelium to release these vasodilators, combined with increased endothelin-1 and other vasoconstrictors, leads to impaired vasodilation and reduced coronary reserve, exacerbating the supply-demand mismatch and contributing to myocardial ischemia (112-116). This endothelial dysfunction also contributes to vascular stiffness, further impairing coronary blood flow.

In addition to endothelial dysfunction, coronary vasospasm markedly contributes to CMD and IHD (117). These spasms, which can occur independently or alongside atherosclerotic lesions, cause temporary constrictions of both large and small coronary arteries, leading to transient reductions in blood flow (118,119). This can result in ischemic symptoms such as chest pain, especially during stress or after exposure to triggers such as cold or certain medications (120-123). Coronary vasospasm exacerbates CMD by further hindering the coronary vessels' ability to properly dilate in response to increased myocardial oxygen demand.

The management of IHD requires a multidisciplinary approach that integrates pharmacological, surgical and lifestyle interventions to alleviate symptoms, reduce risks and prevent disease progression (124). The primary objective is to address the underlying pathophysiological mechanisms while optimizing patient outcomes.

When pharmacological treatments are insufficient, surgical interventions become necessary. Percutaneous coronary intervention (PCI), commonly known as angioplasty, is used to dilate narrowed coronary arteries and is often combined with stent placement to keep the arteries open (132). CABG improves myocardial perfusion by grafting healthy vessels to bypass obstructed coronary arteries (133). For patients with severe, medication-resistant angina, coronary endarterectomy may be performed to excise atherosclerotic plaques from the coronary vessels (134).

While PCI is beneficial for restoring blood flow, it can also lead to reperfusion injury, where oxygen-rich blood reintroduced into ischemic tissues triggers oxidative stress and inflammation, leading to tissue damage (135,136). Additionally, refractory angina pectoris, which is characterized by persistent myocardial ischemia despite optimal medical treatment and procedures such as angioplasty or CABG, underscores the limitations of current treatments when microvascular dysfunction is present.

Restenosis, or the recurrence of arterial narrowing, is another challenge that arises after angioplasty, occurring in 30-50% of patients within 6 months to a year due to continued atherosclerosis progression or incomplete plaque removal (137). Although CABG can provide long-term relief by bypassing obstructed coronary arteries, graft failure and progression of disease in native coronary vessels often occur over time (138). Furthermore, in patients with mixed CAD and CMD, grafts may not bypass microvascular dysfunction, limiting their effectiveness (139).

However, while these procedures effectively address macrovascular disease, they may not fully resolve CMD. Despite these interventions, microvascular dysfunction can persist, leading to inadequate coronary perfusion and ongoing ischemia (139). This results in persistent angina and heart failure symptoms. In CMD, microvascular rarefaction and abnormal vasomotion remain unaddressed, as traditional treatments such as angioplasty and CABG primarily target macrovascular disease (140,141). Since CMD typically does not involve significant stenosis in large coronary arteries, it may not be detected by traditional diagnostic techniques such as coronary angiography, further complicating treatment (142). Consequently, treatments focusing solely on macrovascular disease may fail to address the underlying causes of ischemia, leading to suboptimal outcomes.

Additionally, therapies targeting neurovascular coupling and sympathetic inhibition are being explored to specifically address microvascular dysfunction (143). By modulating neurotransmitter levels at cardiac nerve terminals, these newer pharmacological approaches may help restore normal vascular tone and improve microvascular reactivity in patients with CMD (144). These emerging interventions may provide valuable adjuncts to PCI and CABG, particularly in patients with mixed CAD and CMD, where traditional treatments often fail to resolve the underlying microvascular pathology (145,146).

The ANS is essential in in regulating cardiac function, with both extrinsic and intrinsic components working together to control heart rate, contractility and coronary blood flow (147). The extrinsic component consists of neural fibers that connect the heart to the CNS, enabling the integration of systemic physiological responses. The intrinsic component includes autonomic nerve fibers within the heart, primarily those that traverse the pericardial sac, which release key neurotransmitters such as norepinephrine (NE) and acetylcholine (ACh) to modulate cardiac activity (148)

The SNS plays a vital role in modulating cardiac function and coronary blood flow (149). Originating from the thoracolumbar region of the spinal cord (T1-L2), sympathetic preganglionic neurons synapse in the cervicothoracic ganglia (commonly the C8-T1 stellate ganglion) and send postganglionic fibers that innervate the heart through the coronary arteries (150). These postganglionic sympathetic fibers release NE, which activates various adrenergic receptors present on cardiac myocytes and vascular SMCs.

β1 adrenergic receptors are primarily responsible for increasing heart rate and contractility, thereby elevating myocardial oxygen demand, a key factor in IHD. α1 receptors, located at the coronary vasculature, mediate vasoconstriction, which can worsen myocardial ischemia by restricting coronary blood flow. By contrast, α2 receptors play a protective role by regulating calcium handling in cardiomyocytes, helping to mitigate the effects of excessive sympathetic stimulation during IHD (151). The SNS, through norepinephrine and epinephrine release, increases heart rate and myocardial contractility via β1-adrenergic receptors, which increases myocardial oxygen demand (152). Additionally, SNS activation through α1-adrenergic receptors causes vasoconstriction, restricting coronary blood flow, particularly under conditions of heightened myocardial oxygen demand.

The right-sided sympathetic fibers predominantly influence chronotropism (heart rate), primarily by modulating the sinus node, while the left-sided fibers primarily affect the atrioventricular node, contributing to the regulation of cardiac rhythm (153). The asymmetry in SNS innervation may have implications for arrhythmias in IHD, particularly in atrial arrhythmias.

In IHD, a hallmark feature is sympathetic hyperactivity, which results in elevated myocardial oxygen demand, ischemic events and arrhythmias. Chronic SNS activation exacerbates ischemia, promotes vasoconstriction and contributes to the progression of heart failure.

The PNS regulates cardiac function through vagal innervation, with pre-ganglionic neurons originating from the medulla oblongata, specifically within the dorsal vagal motor nucleus and the nucleus ambiguus (150). These nuclei are essential for regulating nodal and ventricular tissue, respectively (154). The axons of these neurons travel along the vagus nerve and synapse within the intrinsic ganglionic plexuses, which are situated on the posterior atrial surface and the superior regions of the ventricles, embedded in the epicardial fat pads. Postganglionic parasympathetic neurons primarily release ACh, which interacts with muscarinic (M) receptors, particularly M2 receptors, to modulate heart rate and myocardial relaxation (155). ACh staining studies have demonstrated widespread cardiac cholinergic innervation throughout all chambers of the heart (156).

M2 receptors, classified as Gi-coupled G protein-coupled receptors, mediate their effects by reducing cyclic adenosine monophosphate (cAMP) levels. This cAMP reduction leads to negative chronotropy by inhibiting calcium influx via L-type calcium channels, slowing the pacemaker activity in the sinus node (90). This results in a slower heart rate (157). Additionally, M2 receptor activation promotes negative inotropy (reduced contractility) through hyperpolarization of pacemaker cells, primarily mediated by ACh-sensitive potassium channels (91).

In addition to ACh, the parasympathetic system also releases NO. It enhances ACh release from presynaptic neurons, further increasing parasympathetic tone. Additionally, NO inhibits the release of NE from sympathetic nerve terminals, reducing sympathetic drive to the heart, thus contributing to cardioprotection during stress and ischemia (92).

The ICANS is a sophisticated neural network embedded within the heart tissue that autonomously regulates heart rate and myocardial contractility, independent of central nervous system input (158). It consists of parasympathetic postganglionic neurons, preganglionic endings, interneurons, afferent neurons and efferent neurons (159). These components collectively form the intrinsic cardiac ganglia, which are organized into ganglionated plexi (GP) located on the atrial and ventricular surfaces within epicardial fat pads (160). The GP within the ICANS contain various types of neurons, including unipolar, bipolar and multipolar neurons, each contributing to the modulation of cardiac autonomic tone (161). These neurons are morphologically classified into spherical and straight ganglia, with spherical ganglia containing a higher density of neurons, potentially enhancing autonomic integration (158,162). These ganglia act as integration centers, coordinating sympathetic and parasympathetic signals and facilitating autonomous cardiac regulation (158). These elements collectively establish the intrinsic cardiac ganglia or ICNS, which includes sensitive neurons, regulatory interneurons and neurons that release a range of neuropeptides, such as norepinephrine (159,163). In IHD, ischemic injury can lead to pathological alterations in the ICANS, which disrupt the heart's electrophysiological stability. These disruptions, altering the balance between sympathetic and parasympathetic inputs, can impair signal transmission, increasing the susceptibility to arrhythmias, particularly ventricular arrhythmias, by altering the heart's response to acute stress (164,165).

The disruption of the nervous system in IHD was first documented by Hopkins et al (166), who observed structural abnormalities, including inclusions, vacuoles and degenerative changes, in the posterior atrial ganglia of patients with right coronary artery disease. Subsequent studies in guinea pigs following MI revealed altered neuronal excitability, impaired synaptic function and neurochemical changes in the affected neurons (167). These observations support the idea that ischemic injury induces pathological remodeling of the ICANS. Vaseghi et al (168) further advanced this understanding by showing that, despite ACh levels remaining stable in the border zones and remote myocardium post-MI, there were significant changes in parasympathetic neuronal firing frequencies. Neurons normally activated by VNS exhibited reduced firing rates, while neurons typically suppressed by vagal tone showed increased firing rates. These changes suggest that although the parasympathetic network remains anatomically intact post-MI, its functional integrity is compromised. Research indicates that parasympathetic dysfunction, often assessed through abnormal baroreflex sensitivity and HRV, is frequently observed in patients with cardiomyopathy and stroke, who may experience increased arrhythmia and heart failure risks due to disrupted neural signaling (169-173). In IHD, there is a critical imbalance between SNS overactivity and PNS dysfunction, impairing the ability of the body to effectively modulate the heightened sympathetic response (174).

Normally, the PNS counteracts SNS-induced vasoconstriction by promoting vasodilation (175). However, in IHD, endothelial dysfunction due to atherosclerosis impairs the vasodilatory effects of ACh. Under normal conditions, ACh interacts with muscarinic receptors on endothelial cells, triggering NO release, which contributes to smooth muscle relaxation and vasodilation (176). In IHD, reduced para-sympathetic activity fails to adequately counterbalance the SNS-driven increase in oxygen demand, exacerbating ischemic conditions (177), leading to enhanced vasoconstriction of the coronary arteries and reduced dilation capacity (178) This sympathetic dominance increases vascular resistance, which in turn raises myocardial workload and worsens the ischemic condition (179). Chronic SNS activation exacerbates myocardial oxygen demand and workload, aggravating ischemia and accelerating heart failure progression (180,181). This exacerbates the oxygen supply-demand mismatch during IHD and contributes to myocardial ischemia (182).

The SNS overactivity is critical for exacerbating ischemia and chronic inflammation in IHD (182,183). Upon binding to β-adrenergic receptors, particularly β2 receptors present on immune cells such as macrophages and T cells, NE or epinephrine stimulates adenylyl cyclase, resulting in an elevation of intracellular cAMP levels. Subsequently, the heightened cAMP concentrations activate protein kinase A, typically suppressing the secretion of pro-inflammatory cytokines, including TNF-α and IL-1β. However, chronic β2-AR activation can lead to receptor desensitization, reducing its anti-inflammatory effects over time. This desensitization is particularly relevant in chronic inflammatory diseases such as IHD, where prolonged receptor activation occurs (184). Additionally, NE binding to α1-adrenergic receptors on immune cells activates the phospholipase C pathway, which increases intracellular calcium levels and activates protein kinase C. This cascade amplifies pro-inflammatory responses by triggering the release of additional cytokines such as TNF-α, IL-6 and IL-1β (185,186). Moreover, α1-adrenergic activation promotes the upregulation of matrix metalloproteinases (MMPs) in macrophages, enzymes responsible for the degradation of extracellular matrix. MMPs weaken the fibrous cap covering atherosclerotic plaques, making them more susceptible to rupture and increasing the risk of thrombosis (187,188). In healthy conditions, ACh released from parasympathetic nerve terminals suppresses immune cell activation and cytokine production, thereby decreasing systemic inflammation and stabilizing plaques (189-191). The anti-inflammatory actions of ACh are predominantly mediated through M2 and nicotinic receptors, including the α7 nicotinic acetylcholine receptor on macrophages, which is integral to the cholinergic anti-inflammatory pathway. However, in IHD, parasympathetic dysfunction impairs this protective mechanism, exacerbating inflammation and increasing plaque instability (192,193).

In summary, the imbalance between SNS overactivity and PNS dysfunction in IHD exacerbates ischemic conditions and arrhythmia risks. Restoring parasympathetic tone may offer potential therapeutic benefits by counteracting sympathetic overactivity, improving autonomic balance and lowering the risk of cardiac events in patients with IHD.

SCS involves the surgical implantation of a pulse generator, typically placed in the abdomen, chest, or buttocks. This device, which functions similarly to cardiac pacemakers, delivers low-intensity electrical impulses that modulate neural activity near the spinal cord (195). Originally developed for chronic pain management (196), SCS has gained traction as a viable therapeutic option for cardiovascular conditions, including IHD. This application is based on its dual impact on pain sensation and autonomic heart regulation (197,198). In Europe, refractory angina, a persistent, severe type of chest pain associated with IHD, is a recognized indication for SCS therapy (195). SCS therapy has demonstrated efficacy in reducing the frequency and intensity of angina, enhancing exercise capacity and improving the overall quality of life, especially in patients for whom surgical interventions are not viable options (199-201). Evidence from randomized trials and comprehensive registry data has substantiated the clinical efficacy of SCS, demonstrating significant symptom relief in patients with refractory angina compared to those receiving no stimulation or conventional therapy alone (Table I) (199-211).

Clinical evidence supports the significant role of SCS in improving myocardial perfusion and autonomic function, critical in the management of IHD. SCS has been found to effectively enhance myocardial blood flow distribution and reducing myocardial oxygen consumption. This adjustment effectively addresses the critical imbalance between oxygen supply and demand commonly observed in ischemic regions (203). Even short-term application of SCS has been shown to bolster myocardial ischemia tolerance and enhance myocardial perfusion reserve (MPR), essential for managing refractory angina (211). Positron emission tomography studies have demonstrated this improvement at the microvascular level (212).

The underlying mechanisms for these benefits include a marked reduction in SNS activity and the normalization of intrinsic cardiac sympathetic tone (213). SCS also reduces neural synchrony between the dorsal horn (DH) and intermediolateral column (IML) of the spinal cord, stabilizing cardiac function during ischemia by mitigating excessive sympathetic excitation and arrhythmias (214). SCS mitigates the hyperactivity of the IML, which is responsible for sympathetic outflow to the heart (215). By decreasing the synchrony between the DH and IML neurons, SCS helps to lower excessive sympathetic excitation (215). During myocardial ischemia, ischemia-sensitive cardiac afferent neurons convey excitatory signals to the dorsal horn of the spinal cord, which triggers the spinal neural network (215). This activation results in heightened activity in the IML preganglionic sympathetic neurons, which then transmit excitatory signals to post-ganglionic neurons in the stellate and middle cervical ganglia (215,216). The subsequent increase in sympathetic activity directed to the heart can exacerbate myocardial injury, contributing to malignant ventricular tachyarrhythmias and raising the risk of sudden cardiac mortality (217). In cases of chronic MI, significant neural remodeling at various points along the cardiac neuraxis alters the pattern of sympathetic innervation, thereby amplifying the arrhythmogenic potential of the heart (218). Additionally, SCS has been shown to influence the ability of cardiac sensory neurons to transmit ischemic signals from the myocardium to spinal cord neurons, thus modulating the spinal sympathetic efferent pathways to the heart (215,219). Research also indicates that SCS is associated with improved HRV, a key marker of autonomic balance (220). Particularly in patients with IHD, SCS has demonstrated notable improvements in left ventricular ejection fraction and overall cardiac output, crucial metrics of heart function (221). Overall, SCS offers substantial therapeutic potential in CAD, particularly in enhancing myocardial perfusion and autonomic regulation. However, the precise mechanism by which SCS alleviates refractory angina remains unclear (212,222) and further large-scale studies with long-term follow-up are necessary to explore its full therapeutic potential and underlying mechanisms.

Initially developed for treating conditions such as epilepsy and depression (223,224), VNS is now increasingly recognized for its utility in managing IHD through targeting the brain-heart axis (225). Electrodes from this device are positioned around the vagus nerve in the neck (226), where controlled electrical impulses modulate vagal nerve activity, a critical component of the ANS that regulates essential functions including heart rate (34).

VNS is available in two modalities: open-loop and closed-loop systems (227). The open-loop system delivers constant electrical pulses and is traditionally used in the management of epilepsy (228). By contrast, the closed-loop system is designed to adjust the intensity of stimulation in response to real-time physiological feedback, such as fluctuations in heart rate, thus tailoring the therapy to individual patient needs (229). This adaptive feature of closed-loop VNS is especially advantageous in the treatment of IHD, as it dynamically responds to variations in cardiac demand (230). Closed-loop VNS represents an advanced form of therapy for cardiovascular diseases, offering real-time adjustments to stimulation parameters based on physiological feedback (230). This approach tailors treatment by fine-tuning stimulation intensity and timing to the changing needs of the patient, improving autonomic regulation and heart function (194). By integrating real-time monitoring of key health indicators such as HRV, breathing patterns and neural activity, closed-loop systems optimize therapeutic benefits while minimizing adverse effects (194).

Preclinical studies in animals have shown that VNS can enhance myocardial blood supply during ischemia, attenuate reperfusion injury and improve ventricular remodeling (Table II) (231-237). Clinical trials have also explored its potential (Table II) (238-240). One notable study investigated non-invasive low-level tragus stimulation in patients with STEMI, evaluating its effect on myocardial ischemia and reperfusion injury (240). The results demonstrated that VNS effectively reduced sympathetic tone, improved HRV and alleviated cardiac stress. In patients with IHD, vagal activation was also shown to improve cardiac blood supply and enhance left ventricular contractility (239).

Additionally, VNS can activate the cholinergic anti-inflammatory pathway (33,241). VNS stimulates enhances the release of acetylcholine activation of α7 nicotinic acetylcholine receptors on macrophages. This activation is essential for mediating the anti-inflammatory effects of VNS, which helps to inhibit the production of pro-inflammatory cytokines, such as TNF-α and IL-6 (242,243). This reduction in inflammatory markers is critical for preventing chronic inflammation that contributes to atherosclerosis and plaque instability. VNS has been shown to mitigate the accumulation of reactive oxygen species (ROS) and enhance mitochondrial energy metabolism during myocardial ischemia-reperfusion events. This protective effect is mediated through modulation of muscarinic receptors, specifically via the M2AChR/OGDHL/ROS axis, which plays a crucial role in reducing pyroptosis (244,245). Research also indicates that VNS promotes angiogenesis and improves coronary blood flow and cardiac function in hearts affected by ischemia. This is achieved by activating VEGF-A/B, which are essential for maintaining cardiac function and are intimately linked with coronary microvasculature and myocardial energy metabolism (246).

In addition to VNS and SCS, DBS is an invasive neuromodulation technique that implants electrodes into specific brain areas to deliver continuous electrical impulses (247). Initially developed for treating movement disorders such as Parkinson's disease and essential tremor (248), DBS has expanded into potential applications for managing IHD (249). DBS specifically targets brain areas involved in autonomic regulation, such as the subthalamic nucleus and the pedunculopontine nucleus (250). Stimulation of these areas has been shown to increase parasympathetic activity, contributing to improved HRV and overall cardiac function, which are particularly concerning for patients with IHD (254). Functional mapping along the rostrocaudal axis of the posterior insular cortex has identified distinct regions responsible for sympathoinhibitory and sympathoexcitatory control, aligning with past findings (252). This autonomic control extends beyond the insular cortex to involve the amygdala, hippocampus, hypothalamus, bed nucleus of the stria terminalis, ventrolateral medulla, parabrachial region and periaqueductal gray. Higher cortical regions, including the orbitofrontal cortex and dorsal cingulate cortex, receive and process afferent information from peripheral organs and modulate autonomic output to fine-tune cardiovascular functions (253). The capacity of DBS to alter these signaling pathways is crucial for balancing autonomic function, enhancing parasympathetic activity and alleviating sympathetic overactivation (249,254). DBS has been proved to decrease hemorrhagic and cardiovascular-related events in patients with Parkinson's disease with cardiovascular disease, including IHD (255). While research on DBS for IHD remains in its early stages, preliminary results show promise.

Techniques such as VNS and SCS require advanced equipment and skilled personnel, which may not be available in all healthcare settings. The considerable expenses associated with their surgical implantation and maintenance pose significant barriers to their widespread adoption, especially in cost-sensitive healthcare environments. For instance, although high-frequency SCS may reduce long-term healthcare costs, the initial outlay is substantial, with average device cost of ~$42,937 (256). These factors limit the broader application of these therapies, particularly in resource-limited areas (257). High costs make invasive VNS accessible mostly in well-resourced settings (258,259). Economic evaluations such as the incremental cost-effectiveness ratio help determine if the benefits of new technologies, measured in quality-adjusted life years, justify their costs (260,261). Such economic assessments are crucial for determining the feasibility of integrating neuromodulation techniques into standard CAD care. A thorough cost-benefit analysis is required to validate the choice of neuromodulation over established CAD management strategies, ensuring they provide value in improving patient outcomes.

Techniques such as DBS and SCS are invasive, necessitating surgical procedures that come with inherent risks including infection, bleeding and long-term complications. DBS, for example, may lead to intracranial hemorrhage, implant site infections and hardware issues such as electrode migration or skin erosion (262-264). SCS carries risks such as epidural hematomas, dural punctures and infections (265-267). The invasive nature of these interventions might deter patients, particularly when non-invasive alternatives exist. Surveys indicate patient concerns regarding the invasiveness, cost and potential side effects of DBS, which may discourage their use despite potential benefits (268,269). The clinical application of these procedures necessitates a meticulous assessment of the associated risks vs. the potential therapeutic gains. The short-term benefits of neural modulation are well-documented; however, the long-term effects remain less clear. Extended use could result in adverse outcomes, necessitating ongoing monitoring and research to evaluate safety and effectiveness. The ability to modify neural activity raises concerns about informed consent, potential neurological changes and the long-term implications of neuromodulation (270,271). For instance, tDCS is found to induce neurostructural changes in targeted brain areas; the long-term implications and potential unintended effects of these alterations require further study (272). DBS has demonstrated sustained efficacy in treating resistant depression over several years but may cause neuropsychiatric side effects, such as mood swings and cognitive impairments (273). A comprehensive understanding of these long-term side effects is essential for ensuring the ongoing safety and effectiveness of these therapies. Magnetic stimulation is a non-invasive technique that uses magnetic fields to generate electrical currents within targeted brain regions, thereby modulating cortical excitability (274). This method markedly influences the ANS, presenting substantial therapeutic potential for cardiovascular diseases (41). Neuro-cardiac-guided TMS, which tailors stimulation sites based on individual physiological responses, has been effective in regulating heart rate and promoting autonomic balance (275,276). The incorporation of TMS into cardiac rehabilitation programs offers a comprehensive approach by addressing both the physiological and psychological factors that affect the progression and management of IDH. Acupuncture, particularly through auricular vagus nerve stimulation (aVNS), has come to be recognized as a promising minimally invasive therapy for modulating the nervous system to alleviate symptoms and enhance cardiac function in IHD. As a non-invasive therapy, aVNS offers a patient-friendly alternative to more invasive procedures. Its ease of application makes it suitable for outpatient settings, providing an accessible treatment option for patients with IHD (277).

The sustainability and practicality of VNS systems depend on improving device longevity and user-friendliness. Current research focuses on extending battery life, enhancing durability and refining user interfaces to ensure effective, consistent treatment. For example, advances in wirelessly powered and batteryless VNS devices have the potential to eliminate frequent battery replacements, reducing the need for reoperations and improving long-term usability (278,289). These systems also aim to reduce device size while maintaining efficiency, making them more practical for patients (278,289). Additionally, user-friendly designs, such as portable and discreet transcutaneous VNS devices, allow patients to incorporate therapy into their daily routines with minimal disruption (258). These innovations are crucial for making VNS a more practical and effective long-term solution for managing CAD. The development of closed-loop VNS systems, which modify stimulation parameters in response to real-time physiological feedback, marks a significant advancement. However, challenges remain, particularly with motion artifacts during patient movement that can compromise the accuracy of physiological data (280). Research is focused on refining signal processing techniques for an improved differentiation between relevant physiological signals and noise, improving the reliability of these systems (194,281).

Neural modulation therapies often yield variable outcomes due to individual differences in anatomy and physiology, challenging the standardization of treatment protocols. Factors such as brain structure, baseline neuronal state, age, genetics and neurotransmitter levels markedly influence the effectiveness of these techniques (282-284). Cognitive strategies and functional connectivity patterns also contribute to individual differences (282,285). The movement towards personalized medicine in cardiovascular care is increasingly being driven by the integration of genetic, biochemical and physiological data into treatment strategies (286). In personalized medicine, advancements such as improved anatomical understanding of the vagus nerve have refined VNS precision (287). By identifying specific fiber types responsible for distinct physiological responses, it is now possible to selectively stimulate beneficial fibers while avoiding those that might cause adverse effects (288). Notable innovations include respiratory-gated auricular vagal afferent nerve stimulation, which synchronizes VNS with the respiratory cycle, delivering stimulation bursts during exhalation to enhance efficacy in conditions such as hypertension and depression (289,290). Another innovation, myoelectric-triggered auricular VNS, activates stimulation based on muscle movements, such as orofacial activity during rehabilitation exercises (291). This closed-loop design ensures precise timing, enhancing neuroplasticity and functional recovery in motor rehabilitation (292,293). Machine learning (ML) is revolutionizing CAD management by enhancing diagnostic accuracy, enabling early detection and improving risk stratification (294-296). Looking ahead, the fusion of neurotechnology and ML will drive innovations in CAD management (296), with future research focusing on refining VNS protocols (297,298), exploring neural-immune interactions in cardiovascular contexts (299) and conducting large-scale clinical trials. This integrated approach promises to markedly improve patient outcomes and longevity.