The central nervous system (CNS) plays a fundamental role in regulating cardiovascular function. It maintains a close relationship with the heart and blood vessel via a complex network of neurons. Though the sympathetic and parasympathetic branches of the autonomic nervous system, the CNS control a number of physiological parameters, including blood pressure, heart rate, and blood flow distribution. Studies have shown that various areas of the CNS, including the hypothalamus and brainstem, are capable of detecting hemodynamic changes and integrate cardiovascular responses via neural signaling pathways. Moreover, the CNS regulates cardiovascular function by influencing the endocrine system, including the regulation of hormone release, i.e., epinephrine and norepinephrine (8). This crosstalk between the neuroendocrine system governs not only short-term cardiovascular responses but also contributes to long-term adaptive adjustments, for example, the control of cardiovascular adaptation during physical activity, stress, and pathological states.

The peripheral nervous system (PNS) relays signals between the CNS and cardiovascular system via sympathetic and parasympathetic nerves. Sympathetic innervation is prominent in cardiac tissues, including myocardium, conduction systems, and heart valves, and exhibits a significant relationship with cardiac function changes.

The intima-media layer of the blood vessel lacks direct innervation, but the PNS connects with the tunica adventitia, contributing to coronary microvascular regulation. Sensory nerves detect physiological factors like blood pressure and oxygen saturation and convey this to the CNS for regulatory response.

Sympathetic nervous system activation induces increased heart rate, enhanced myocardial contractility, and vasoconstriction, ultimately leading to elevated blood pressure. Norepinephrine exerts its effects by binding to β-adrenergic receptors in cardiac tissue and α-adrenergic receptors in vascular tissue. Accumulating evidence has demonstrated that sympathetic overactivation is closely associated with the pathogenesis of several cardiovascular diseases, including heart failure and hypertension. Following myocardial injury, the cardiac sympathetic nervous system undergoes abnormal regeneration, a process referred to as sympathetic remodeling, which includes both denervation and hyperregeneration (7).

Pathogenic factors such as inflammation and myocardial ischemia alter the spatial distribution and density of cardiac sympathetic nerve fibers within the myocardium. This process involves both functional and structural remodeling; functionally, stimuli such as increased cardiac filling pressures and myocardial ischemia can trigger a cardiac-specific sympathoexcitatory reflex, leading to a selective increase in local sympathetic activity (9). Anatomical mapping studies have demonstrated that these changes manifest as a heterogeneous nerve pattern, characterized by denervation in the ischemic core and sympathetic hyperinnervation (or “hyper-sprouting”) in the peri-infarct and remote territories (10, 11).

Evidence has increasingly highlighted the role of sympathetic nervous system activation in modulating inflammatory processes within the coronary vasculature. Mohanta et al. (2022) demonstrated that in ApoE^-/^- mice, the adventitia of arteries is directly innervated by sympathetic and nociceptive (injurious receptor) axon endings. These neural elements interact with immune cells to form neuroimmune cardiovascular interfaces (NICIs), which play a regulatory role in atherosclerosis progression (6).

Previous studies have shown that increased plaques are positively correlated with extensive neuroinflammation in the PNS (4). Given the dependence of sympathetic nerves on norepinephrine-mediated signaling, it has been tentatively shown that lowering norepinephrine levels or surgically severing the nerve conduction pathways innervating the ependymal membrane decreases the influx of leukocytes into the atherosclerotic plaques due to endothelial cell activation and stress-induced leukocyte influx, and decreases plaque volume (12). In summary, the nervous system can intervene in the inflammatory response and thus participate in the treatment of coronary microvascular disease by regulating immune cells. The neuroanatomical basis and regulatory effects of the sympathetic nervous system on cardiovascular and immune responses are summarized in Figure 1 , which illustrates norepinephrine-mediated signaling, sympathetic remodeling, and immune-endothelial interaction in coronary microvascular disease.

Operating primarily through the vagus nerve, the parasympathetic nervous system utilizes acetylcholine as its principal neurotransmitter. Stimulation of these nerves normally results in reduction in heart rate, lowered myocardial contractility, and vasodilation, hence reducing blood pressure. Additionally, findings indicate that increased parasympathetic activity may counteract sympathetic excitatory effects and contribute to cardiovascular homeostasis. However, parasympathetic dysfunction is usually accompanied by arrhythmias and increased cardiovascular incidents in heart disease patients.

Over the past decade, significant advances have been made in our understanding of the cardiovascular-brain circuit (CBC)—a dynamic and reciprocal communication system integrating the nervous, cardiovascular, and immune systems. Rather than being limited to classical neural conduction, cardiovascular neuromodulation is now recognized to involve a complex neuro-immune-cardiovascular network, comprising two primary subsystems: the arterial-brain circuit (ABC) and the heart-brain circuit (HBC), which exhibit significant cross-talk in maintaining cardiovascular homeostasis (13, 14). These circuits integrate mechanical, inflammatory, and electrophysiological signals from the vasculature and heart, transmitting them to brain regions that coordinate neurohumoral responses (15).

The arterial-brain circuit (ABC) originates from specialized sensory neurons located in the outer arterial wall, which detect atherosclerotic plaque burden and local/systemic inflammation. These nociceptive afferent signals travel via thoracic spinal nerves (T6–T13) to the central nervous system, where they are processed in the spinal cord and subsequently relayed to higher-order brain centers, including the parabrachial nucleus and amygdala in the brainstem (6). The efferent limb consists of sympathetic fibers originating from the medulla oblongata and hypothalamus, descending through the intermediolateral column of the spinal cord, projecting to the coeliac and sympathetic ganglia, and finally innervating the arterial adventitia.

This entire circuit has been visually confirmed in mice using viral tracing techniques, which demonstrated that afferent nociceptive signals from atherosclerotic lesions relay through the T6–T13 spinal segments, project to brainstem regions such as the parabrachial nucleus and amygdala, and that sympathetic efferents return via specific ganglia to modulate the arterial immune environment (6). In this feedback loop, the sensory nervous system functions as the detector, and the sympathetic system acts as the effector, establishing a dynamic neurovascular communication interface.

The ABC exerts direct immune-regulatory functions, influencing both the formation and stability of atherosclerotic plaques. Sympathetic feedback through this circuit can regulate myeloid cell recruitment, cytokine production, and local vascular inflammation. Disruption of this circuitry—through sympathectomy or chemical denervation—has been shown to reduce atherosclerotic burden and promote plaque stability (6). Studies also revealed that neural remodeling, initiated by plaque-induced sensory input, can enhance sympathetic and parasympathetic sprouting in the arterial wall, creating a feedforward loop of inflammation and neurovascular remodeling (6). Experimental interruption of the ABC via ventral ganglionectomy led to a reduction in arterial tertiary lymphoid organ (AL0) number, size, and cellular composition, correlating with smaller, more stable plaques and attenuated vascular inflammation.

The HBC operates primarily through the vagus nerve and sympathetic nervous system, facilitating bidirectional communication between the heart and brain. Mechanical and electrophysiological signals from the heart, such as heart rate and pressure changes, are detected by baroreceptors and cardiac sensory neurons, which transmit information via vagal and sympathetic afferents to brain regions including the hypothalamus and brainstem nuclei (16, 17). The hypothalamus, serving as a central integrator, processes these inputs and coordinates downstream signals through vagal efferents and sympathetic fibers to peripheral tissues (13).

The HBC plays a pivotal role in modulating systemic and localized immune responses. Both sympathetic and vagal pathways establish neuroimmune circuits that regulate inflammatory processes via afferent and efferent signaling. Activation of vagal efferents leads to anti-inflammatory effects, primarily through α7 nicotinic acetylcholine receptors, while sympathetic overactivity promotes myeloid cell recruitment to vascular lesions and enhances systemic inflammation (18).

In patients with CMVD, abnormalities in cardiovascular regulation are closely linked to cognitive impairment and emotional dysregulation. Microvascular damage compromises cardiac perfusion, leading to clinical symptoms such as angina pectoris and heart failure, but also impacts brain function through the heart-brain axis. Within this framework, cardiac-origin signals transmitted via vagal and sympathetic nerves influence brain regions governing mood, behavior, and cognition (14).

Neutrophils are the first effector cells activated during the acute inflammatory response, serving as primary responders to tissue injury or infection and exacerbating inflammation through pro-inflammatory mediator release. Under conditions of sustained inflammatory conditions, their continuous accumulation and secretion of pro-inflammatory granule proteins like MPO, defensins, and CRISP3 contribute to tissue damage and chronic inflammation (24). Specific mechanisms include MPO’s role in facilitating LDL nitration and lipid peroxidation, promoting foam cell formation via macrophage ox-LDL uptake, and neutrophil-derived protease-associated lipid transfer proteins enhancing MMP-9’s matrix-degrading capacity by preventing its inactivation. Neutrophils also interact with endothelial cells, secreting tissue factor and chemokines that recruit more neutrophils and intensify inflammation (25). Evidence points to a significant association between neutrophils and the development and instability of atherosclerotic plaques (26). Clinical research shows that in individuals with coronary artery disease, neutrophil counts are directly connected with the severity of coronary lesions (27).

During persistent inflammation, monocytes differentiate into transitional effector cells that play a critical role in sustaining the immune response. Primarily derived from the bone marrow, monocytes circulate between the bloodstream and peripheral tissues. Their migration to vascular lesion sites is guided by chemokine signals like CCR2–CCL2 and CCR5–CCL5. Studies using animal models have demonstrated that elimination of these chemotactic signals can slow down atherosclerosis (28). Acute inflammation enables monocytes to mature into macrophages early, which enhances local phagocytosis and immunologic defense. Nevertheless, during immune over-activation, monocyte function can be impaired, advancing cardiovascular disease development (29).

Macrophages play a central role in chronic inflammation, ensuring tissue repair and immune homeostasis. In atherosclerotic lesions, macrophages originate from two main sources: resident vascular macrophages and monocytes that differentiate from circulation (30). Macrophage activation and polarization phenotypes, with M1 and M2 subtypes being more prevalent, are determined by the local microenvironment of the plaque and cytokine signals. Exposure to lipopolysaccharide (LPS) and interferon-gamma (IFN-γ) activates M1 macrophages, sometimes referred to as classically activated macrophages, resulting in the release of pro-inflammatory cytokines such interleukin-6(IL-6), interleukin-12(IL-12), and tumor necrosis factor-alpha (TNF-α). The cells contain a wide variety of pattern recognition receptors (PRRs) and begin inflammatory cascades on recognizing oxidized low-density lipoprotein (ox-LDL) and related substances (31, 32). In contrast, M2 macrophages, often referred to as alternatively activated macrophages, chiefly release anti-inflammatory cytokines (such as IL-10, TGF-β) and take part in immunoregulation and tissue remodeling (33).

Natural killer (NK) cells, a subset of lymphocytes, express receptors that are highly sensitive to cellular stress and pathological alteration. They exert potent cytotoxic effects by releasing perforin, granzymes, and/or cytokines such as IFN-γ. Chemokines such as MCP-1, and fractalkine, and cytokines, including IL-15, and IFN-γ, induce NK cell activation, cytotoxicity, and migration to atherosclerotic plaques. Upon activation, NK cells produce addition IFN-γ, which contributes to immune responses that promote atherosclerosis (34).

Adaptive immunity offers antigen-specific defense mechanisms and long-term immunological memory. In atherosclerosis, early activation of innate cells like monocytes and macrophages subsequently triggers adaptive immune responses, where T and B cells play pivotal roles.

One of the primary immune cell types drawn into atherosclerotic plaques are activated T cells, which also play a significant role in the development of the disease. Studies have shown that ApoE^-/- mice lacking both T and B cells develop less severe atherosclerotic lesions, whereas adoptive transfer of LDL-specific CD4^+ T cells into immunodeficient ApoE^-/- mice aggravates lesion development (35). Key T cell subsets in atherosclerosis, such as Th1, Th17, and T follicular helper (Tfh) cells, secrete distinct cytokines and exert divergent biological functions, forming a complex regulatory network governing plaque formation and progression.

Th1 cells are activated by antigens like ox-LDL and native LDL, releasing cytokines that promote inflammation (e.g., IFN-γ, TNF-α) that promote atherogenesis and vascular inflammation. IFN-γ is a major pro-atherogenic cytokine that exacerbates endothelial dysfunction, enhances monocyte recruitment, promotes macrophage activation, and facilitates foam cell formation (36).

Th17 cells and their signature cytokine IL-17A have been increasingly implicated in the pathogenesis of atherosclerosis, yet their precise role remains controversial. On the one hand, compelling evidence suggests that IL-17A promotes atherogenesis by inducing vascular endothelial cells to produce various chemokines, including CCL2, CXCL1, and CXCL5, which enhance leukocyte recruitment and amplify local inflammation. For instance, Lin et al. (2022) demonstrated that IL-17A-expressing Th17 subsets in the aorta induced endothelial chemokine production, directly linking Th17 activity to inflammatory cell infiltration and lesion development (37). Similarly, Robert et al. (2022) reviewed how IL-17A stimulates endothelial and smooth muscle cells to express adhesion molecules and pro-inflammatory mediators, further contributing to vascular dysfunction (38). However, this pro-atherogenic narrative is not universally supported. Some studies report that IL-17A may also exert protective effects, such as promoting fibrous cap formation and plaque stability under specific conditions (39). Moreover, Xu et al. (2020) emphasized the plasticity of Th17 cells, whose inflammatory or regulatory functions are shaped by their cytokine milieu, particularly by anti-inflammatory mediators like TGF-β and IL-10 (40). Supporting this nuance, Taleb et al. (2015) highlights in their comprehensive review that IL-17’s function in atherosclerosis is highly context-dependent, varying by genetic background, disease stage, and experimental conditions (41). While some murine models show IL-17A promotes lesion development, others suggest neutral or even protective roles, reflecting a complex interplay of immune regulation and environmental cues. This discrepancy likely stems from several factors. First, the effects of Th17/IL-17 signaling are modulated by the surrounding immune environment; for example, IL-10 can skew Th17 responses toward a less pathogenic phenotype. Second, murine models differ significantly in genetic and inflammatory profiles, which may not accurately reflect human pathology. Third, IL-17 may exert temporally distinct effects: pro-inflammatory in early lesion development and potentially reparative or stabilizing in later stages.

Regulatory T cells (Tregs) are well-established immunomodulators with anti-atherosclerotic properties. Tregs secrete IL-10 to suppress inflammatory processes and maintain immune tolerance. Reduced Treg activity or IL-10 production has been associated with increased local inflammation and enhanced atherosclerotic burden (42).

B cells contribute to both innate and adaptive immunity by secreting cytokines and antibodies, in addition to their roles in adaptive responses. They promote the progression of atherosclerosis through antibody-mediated responses targeting ox-LDL and by activating T cells (43). In contrast, B1 cells, a subset of B lymphocytes, secrete natural IgM antibodies. By preventing the production of foam cells, this activity prevents atherosclerosis (44). Figure 2 summarizes the contributions of macrophage polarization and T/B lymphocyte-derived cytokines to endothelial inflammation and immune cell recruitment in coronary microvascular disease.

On the one hand, sympathetic nerves are directly involved in the stress response, through innervation of adrenal medullary chromaffin cells, releasing catecholamine transmitters such as epinephrine, norepinephrine, and dopamine into the blood circulation, thus realizing the regulation of organismic and systemic immune functions; on the other hand, sympathetic nerves innervate almost all organs and tissues, releasing transmitters such as norepinephrine and neuropeptide Y through the endings to realize the target organs and regional immune regulation (45–47). Sympathetic release of norepinephrine able to attach toα- or β-adrenergic receptors on a variety of immune cells, affecting their migration, differentiation, and cytokine synthesis (48–50). Due to differences in transmitter concentrations, receptor expression levels, and inflammatory response processes, sympathetic regulation of immune function exhibits bidirectional regulation (51). For example, lower concentrations of norepinephrine (NE) have a stronger affinity for a-receptors and reduce intracellular Cyclic Adenosine Monophosphate (cAMP) levels, whereas higher concentrations of NE bind more strongly to β-receptors and cause an increase in intracellular cAMP levels (52); activation of B receptors on CD4+ T cells promotes their differentiation and synthesis of cytokines (53). However, macrophage’s production and release of TNF-α are inhibited when their B receptors are activated (54); Moreover, localized inflammatory lesions in the target organ can, to a certain extent, directly affect the normal morphology and functional activities of the sympathetic nerves, and thus the interaction between sympathetic nerves and the target-organ immunity is a dynamically regulated process (55).

In addition to its role in regulating visceral smooth muscle contraction, glandular secretion, and blood flow, the vagus nerve mediates an immunomodulatory mechanism known as the “inflammatory reflex”, primarily operating through the vagovagal circuit (56). Its anti-inflammatory capacity is primarily executed via the cholinergic anti-inflammatory pathway (CAIP) and various non-canonical regulatory pathways.

In the canonical pathway, pathological stimuli such as bacterial endotoxins trigger peripheral immune cells—primarily macrophages—to release large quantities of pro-inflammatory cytokines. Afferent vagal fibers detect these signals and transmit them to the central nervous system, which in turn stimulates efferent vagal pathways to secrete acetylcholine (ACh). Acetylcholine interacts with α7 nicotinic acetylcholine receptors (α7nAChR) present on immune cells, leading to the downregulation of pro-inflammatory cytokines, including TNF-α and IL-6 (57, 58). According to findings by Yang et al. (2022), α7nAChR is essential for the anti-inflammatory action exerted by the vagus nerve in response to lipopolysaccharide-induced cytokine storms. The diminished anti-inflammatory response to famotidine in mice lacking α7nAChR highlights the importance of this receptor and the vagal pathway in conventional inflammatory modulation (59).

Beyond the classical CAIP, the vagus nerve also modulates inflammation via non-canonical pathways, which do not rely on the spleen or α7nAChR-mediated signaling. According to de Araujo and de Lartigue (2020), maintaining intestinal immune stability is significantly governed by the hepatic branch of the vagus nerve (60). Experimental data indicate that selective hepatic vagotomy exacerbates colitis in mice (61), suggesting that this regulatory circuit may influence immune responses through the modulation of regulatory T cell (Treg) differentiation.

Recent investigations have brought attention to the involvement of intestinal microbiota in modulating the vagus nerve–mediated inflammatory reflex. Commensal microbes can communicate with the vagus nerve through microbial metabolites or mimic signaling, thereby impacting the central–peripheral neuroimmune axis and systemic inflammation (60). In addition, agents such as famotidine—an inhibitor of H2 histamine receptors—have been found to engage the vagus nerve–associated inflammatory circuit and suppress cytokine storms elicited by lipopolysaccharide (59), supporting the prospective treatment value of vagus-targeted interventions in inflammatory disorders.

Among the cytokines regulated by the vagus nerve, TNF-α serves as a critical factor in orchestrating the inflammatory cascade. Its expression is significantly influenced by vagal signaling via the CAIP. Specifically, vagal stimulation promotes ACh release, which binds to α7nAChR on immune cells and inhibits NF-κB, a principal transcription factor essential for driving TNF-α and other cytokine gene transcription (62, 63). In animal models with vagotomy, TNF-α levels were markedly elevated, underscoring the importance of intact vagal integrity in inflammatory control. In contrast, stimulation of the vagus nerve (VNS) in LPS-challenged murine models significantly reduced TNF-α concentrations, further substantiating the anti-inflammatory role of this neural pathway (58).

High mobility group box 1 (HMGB1), a non-canonical mediator secreted during infection or tissue trauma, is also subject to vagal regulation in the resolution stages of inflammation. Vagal stimulation significantly reduces HMGB1 release, and this could be mediated, at least in part, via α7nAChR signaling. Furthermore, the vagus nerve has been implicated in the downregulation of other pro-inflammatory cytokines (63, 64), indicating its broad regulatory role within the inflammatory network. Taken together, these findings underscore the pleiotropic immunomodulatory effects of vagal signaling in systemic inflammation.

As a promising modality in the field of bioelectronic medicine, VNS presents a novel therapeutic avenue. Nevertheless, the underlying mechanisms, as well as its long-term safety and efficacy, warrant further exploration in future studies.

C-fiber sensory neurons, also known as peptidergic neurons, situated in the trigeminal or dorsal root ganglia, are not only capable of receiving external injurious mechanical, temperature, and chemical stimuli, but are also activated by relevant factors involved in infectious and inflammatory responses (65–67). These sensory nerve fiber endings exhibit widespread presence in the mucous membranes of the skin, lungs, and gastrointestinal tract and exist in close proximity to local lymphoid tissues and immune cells. When the mucosal barrier is damaged, class C nerve fiber endings release peptide transmitters such as SP (Substance P) and CGRP (Calcitonin Gene Related Peptide), which act on the corresponding receptors on the adjacent immune cells to regulate the local immune microenvironment (66, 68–72). In addition to their direct modulation of local immune responses, these sensory nerve fibers also demonstrated the capacity to dampen systemic inflammatory responses during situations of endotoxemia (73–76). The observation suggests that the neural pathways involved with immune regulation can recruit a number of circuits, among them peripheral reflex mechanisms and central processing.

Microglia and T cells are the major populations of immune cells present within the CNS, whose overall roles are to maintain neural homeostasis and modulate neurological function. In addition to their immune surveillance and host defense role, microglia are involved in neuroprotective, synaptic reorganization, and tissue repair functions. Upon pathogen detection or tissue damage, microglia are rapidly activated by pattern recognition receptors and release a vast variety of cytokines to coordinate local immune response. For instance, pro-inflammatory mediators interleukin-1 beta (IL-1β) and TNF-α induce the recruitment of accessory immune cells, eosinophils, and neutrophils to infection- or injury-susceptible areas for antimicrobial defense (77).

Apart from their immunological functions, microglia also release neurotrophic factors including brain-derived neurotrophic factor (BDNF) and IL-4 that are jointly indispensable for neuronal survival and regeneration. IL-4, for instance, has been reported to increase neuronal growth and survival, and is of extreme importance to cognitive activities like learning and memory (77, 78). IL-4 and IFN-γ are both significant regulators of neuronal transmission. IL-4 deficiency causes extreme impairments of mouse learning behavior, whereas exogenously given IL-4 has the potential to reverse these impairments, demonstrating the critical role played by cytokines in cognitive function (77). Microglial modulation is also involved in following neuroregeneration injury by the release of neurotrophic factors while at the same time suppressing excessive inflammatory activities (79). In neurodegenerative disorders like Alzheimer’s disease, microglial activation might become polarized to a pro-inflammatory phenotype to further increase neuronal injury in a pattern closely correlated with β-amyloid accumulation (78).

Aside from their contribution to microglial activation, T cells—and crucial players within the adaptive immune system—are themselves important determinants of central nervous system (CNS) physiology. Activated CD4⁺ T cells secrete a variety of cytokines that impact both immune as well as neural function. For example, IL-2 secreted by CD4⁺ T cells, aside from stimulating other immune cells to proliferate, increases microglial activation, thus playing a pivotal role within localized immunity (77). IFN-γ, a cytokine secreted by CD4⁺ T cells, increases microglial antimicrobial effects, hence allowing for the elimination of microorganisms as well as potentially for triggering localized inflammatory responses (80, 81). Interestingly, IL-4, a cytokine secreted by Th2-polarized CD4⁺ T cells, has been shown to promote neuronal survival as well as regeneration, reducing cerebral injury caused by ischemia as well as trauma (82, 83). Conversely, IL-10, a secreted anti-inflammatory cytokine by some T cells, is crucial for its neuroprotective action. IL-10 reduces neuroinflammation by suppressing microglial release of pro-inflammatory mediators including TNF-α as well as IL-1β, thus ensuring resolution of inflammation after injury as well as neuronal survival (84, 85).

CD8⁺ T lymphocytes perform a vital function for the elimination of tumor cells and infected cells through the discharge of cytotoxins such as TNF-α and perforin. However, their activation under certain situations may unintentionally destroy normal neural tissues (77). In addition, cytokine-driven communication between neurons and immune cells plays an important role in cognitive function as well as synaptic plasticity. For example, IL-4 facilitates synaptogenesis and learning ability (86), whereas IL-6, which is mainly pro-inflammatory, can compromise neuronal function and plasticity by promoting chronic inflammatory signaling (87). Such context-dependent functions of cytokines are inherent to T cell activation and function in diverse physiological and pathological states. These interactions converge into a multi-circuit neuroimmune regulatory framework that influences immune polarization, cytokine expression, and inflammation. Figure 3 presents a comprehensive model summarizing these coordinated pathways.

Atherosclerotic plaques, an important risk factor for cardiovascular disease, consist of a progressive increase in cholesterol, fibrous tissue, and immune cells. When atherosclerotic plaques form, aggregates of immune cells also form in the outer connective tissue. These aggregates have similarities to lymph nodes and contribute to the modulation of immune activity. At the same time the connective tissue around the coronary arteries is rich in nerve fibers, and this outer tissue is used by the nervous system as a major conduit to all organs throughout the body. Upon reaching the brain, signals originating from the plaque influence the autonomic nervous system through vagal pathways, ultimately extending to the spleen. Specific immune cells are activated and enter the circulation, leading to plaque progression. Clinical epidemiological research has indicated that mental stress is a significant contributor to the risk of atherosclerosis and that increased mental stress can drive vascular inflammation and atherosclerotic plaque progression by activating cell adhesion factors on endothelial cells to enhance leukocyte recruitment to tissues (88). Meanwhile, long-term mental stress can also lead to elevated serum cholesterol levels and induce hyperlipidemia. Accordingly, mitigating psychological stress and enhancing mental well-being represent emerging therapeutic strategies in the prevention of stress-related cardiovascular disease.

In addition to mental stress, there is growing evidence that the relationship between injurious feelings and the immune system can further contribute to accelerating the inflammatory process through the mechanisms described above. Improvement of the mental state of individuals with cardiovascular diseases is an evermore integral element of care and is, in turn, closely linked with favorable clinical endpoints. Modulation of neurotransmitters, such as norepinephrine, as well as targeting multifunctional molecules such as Netrin-1, have been proven to be an innovative strategy in the therapy of cardiovascular diseases. In the framework of the development of atherosclerosis, neuroimmune cardiovascular interfaces (NICI)—created from interactions among nerve fibers, immune cells, and vascular endothelium—are shown to play a part in the generation of active plaque structures, such as the ABC complex, in the course of the atherogenic process. It is remarkable that peripheral nervous system axons in areas of atherosclerosis release epinephrine and other neurochemical signals into the vascular epithelium, which may trigger local recruitment and accumulation of immune cells, hence modulating lesion growth. Thus, a local model of stimulation of immune cells by abnormal electrical activity projected from the CNS and activation of β2-adrenoceptors may underlie the neuroimmune axis that regulates atherosclerosis. The targeted regulatory role of genetic techniques also provides some direction for neuroimmunologic approaches to prevent and delay atherosclerotic plaque formation and progression.

An increasing body of experimental evidence highlights the central role played by the neuroimmune system in the etiology of cardiovascular disorders. Of particular interest, it has been shown to play roles in the causation and perpetuation of pulmonary arterial hypertension (PAH), mainly through coordinated modulation of immune function and autonomic nervous system activity. Transcriptomic analyses of PAH models reveal upregulation of key inflammatory mediators, including TNF-α and TGF-β, in addition to the NF-κB signaling pathway being activated. These molecular changes contribute to pulmonary vascular remodeling and disease progression. Concurrently, excessive activation of the sympathetic nervous system (SNS) has been shown to exacerbate disease severity, whereas pharmacological or genetic suppression of SNS activity can alleviate pulmonary artery pressure and improve cardiac function (89).

Additionally, recent studies have identified a dynamic interplay between the heart and neuroimmune circuits in the context of hypertension, particularly through a functional “heart–brain–spleen axis” that modulates cardiac remodeling. In the framework of hypertension, pressure overloading of the heart stimulates the activation of the sympathetic nervous system, which, in turn, activates dorsal vagal complex and splenic innervation, driving placental growth factor secretion (PlGF). PlGF subsequently stimulates the proliferation of NRP1-expressing cardiac macrophages, thereby facilitating adaptive cardiac remodeling. Disruption of this neuroimmune axis, either through neural inhibition or blockade of the PlGF–NRP1 signaling cascade, impairs the heart’s compensatory remodeling capacity and increases susceptibility to heart failure (90). Clinically, circulating PlGF levels have been positively correlated with the degree of myocardial hypertrophy, further supporting the functional relevance of neuroimmune mechanisms in hypertension-induced cardiac pathology.

Recent advances have led to a surge in research have started to concentrate on the role of neuro-immune interactions in coronary microvascular disease, especially the regulatory mechanisms in microvascular endothelial dysfunction, vascular remodeling and microvascular inflammatory responses. For example, increased sympathetic nerve activity and immune responses may activate vascular endothelial cells, smooth muscle cells, and inflammatory responses, exacerbating microvascular damage and affecting microvascular function. Exploring the molecular mechanisms of neuro-immune interactions will enable a deeper comprehension of the pathogenesis of coronary microvascular disease and provide potential targets for clinical diagnostic and therapeutic programs and novel drug development.

The role of inflammation as a fundamental process in the initiation, progression, and destabilization of atherosclerotic plaques is now unequivocally established. Key pathological mechanisms include the activation of the NLRP3 (NOD-, LRR- and pyrin domain-containing protein 3) inflammasome within myeloid cells, which promotes the release of pro-inflammatory cytokines such as interleukin-1β. This understanding has propelled the investigation of targeted anti-inflammatory agents as a therapeutic strategy to mitigate residual cardiovascular risk beyond conventional lipid-lowering and antiplatelet therapies. Colchicine, a drug with a long history of clinical use, exerts broad anti-inflammatory effects primarily through disruption of microtubule dynamics. This interference impairs neutrophil chemotaxis, mobilization, and recruitment, while also indirectly inhibiting the oligomerization of the NLRP3 inflammasome (111). Recently, two landmark randomized controlled trials (RCTs), LoDoCo2 and COLCOT, have established that low-dose colchicine (0.5 mg daily), as an adjunct to standard secondary prevention therapy, significantly reduces the risk of major adverse cardiovascular events (MACE) in patients with stable coronary disease and recent myocardial infarction (112, 113). The success of these trials lends robust support to the concept of inflammation as a residual risk in atherosclerotic cardiovascular disease (ASCVD) and has directly spurred its investigation in the context of CMVD. Several trials are currently underway, most notably the COLHEART-PRESERVED (NCT06217120) study, which specifically enrolls patients with heart failure with preserved ejection fraction (HFpEF) and concomitant CMVD. This trial aims to directly assess whether colchicine can improve the primary endpoint of coronary flow reserve (CFR), thereby providing direct physiological evidence for the reversal of CMVD through anti-inflammatory therapy (114).

Several randomized controlled trials evaluating conventional anti-anginal vasodilators have reported neutral outcomes, highlighting the limitations of applying therapies designed for epicardial disease to the microvasculature. For example, the NIRVANA (NCT01665508) trial, which investigated the third-generation beta-blocker nebivolol in women with CMD, did not demonstrate a significant improvement in the co-primary endpoints of angina frequency and quality of life as measured by the Seattle Angina Questionnaire (115). Similarly, the EDIT-CMD (NCT04777045) trial reported that the non-dihydropyridine calcium channel blocker diltiazem failed to improve its primary endpoint of coronary flow velocity reserve (116). However, a pre-specified secondary analysis did note a reduction in the prevalence of acetylcholine-provoked epicardial spasm, suggesting a potential niche for this agent in patients with a vasospastic component.

Investigations into other pharmacological pathways have also been met with challenges. The PRIZE (NCT04097314) trial tested the hypothesis that selective antagonism of the endothelin-A receptor with zibotentan could improve microvascular function (117). The rationale was based on the vasoconstrictive effects of endothelin-1. Despite this targeted approach, the trial was negative, as zibotentan did not improve the primary endpoint of treadmill exercise duration compared to placebo. The collective results of these trials underscore the complexity of CMD and suggest that a single pharmacological approach may be insufficient for this heterogeneous patient population.

In contrast to the outcomes with small-molecule drugs, novel biologic and regenerative therapies are emerging as a potential avenue. The ESCaPE-CMD (NCT03508609) trial was designed to evaluate the safety and potential bioactivity of a novel regenerative therapy, intracoronary administration of autologous CD34+ cells (CLBS16) (118). The proposed mechanism of action involves the promotion of microvascular repair and neovascularization. The study successfully met its primary safety endpoint. Regarding efficacy, the trial demonstrated a statistically significant improvement in coronary flow reserve (CFR)—an objective physiological marker—at the 6-month follow-up in the treatment group compared to the sham-controlled group. These findings provide a promising, albeit preliminary, signal supporting the therapeutic potential of this intervention.

Early research efforts have alluded to the potential benefits of targeting specific patient subgroups. For instance, the pilot study NCT00570089 investigated the late sodium current inhibitor ranolazine, not in a broad NOCAD population, but specifically in women with documented myocardial ischemia in the absence of obstructive disease (119). While limited by its small sample size, the study reported trends toward improvement in angina symptoms and quality of life, suggesting that mechanism-specific drugs may hold value for select patient profiles.

The core tenets of precision medicine are most explicitly manifested in modern, mechanism-driven clinical trial designs, which tailor interventions based on underlying pathophysiological processes. The ongoing EXAMINE-CAD (NCT05294887) trial serves as a prime example of this advanced approach. The study protocol mandates initial invasive coronary function testing to phenotype patients and stratify them into endotypes, such as those with predominantly microvascular dysfunction versus those with a significant vasospastic component (120). Following stratification, the trial employs a randomized, crossover design to directly compare the therapeutic efficacy of two agents with distinct mechanisms of action: the beta-1 selective blocker bisoprolol and the non-dihydropyridine calcium channel blocker diltiazem.

The fundamental objective of trials like EXAMINE-CAD is to move beyond the question of if a drug works in a broad population, to in which specific patient phenotype a drug provides optimal benefit. The outcomes of such mechanism-based studies are highly anticipated, as they hold the potential to provide high-level evidence to inform the development of personalized treatment algorithms. By tailoring pharmacotherapy to the dominant underlying pathophysiology, this approach aims to improve clinical outcomes for the large and challenging population of patients with symptomatic NOCAD. The design, key characteristics, and primary outcomes of the clinical trials discussed in this review are summarized in Table 2 .

The PROMIS-HFpEF study, a landmark prospective, multinational, multicenter observational investigation, provided pivotal clinical evidence elucidating the systemic nature of CMVD (121). In this study, coronary flow reserve (CFR) was noninvasively assessed in rigorously characterized patients with heart failure with preserved ejection fraction (HFpEF) using transthoracic Doppler echocardiography under adenosine-induced hyperemia. Concurrently, systemic endothelial function was evaluated via peripheral arterial tonometry.

The study revealed a remarkably high prevalence of CMVD—defined as CFR < 2.5—in up to 75% of HFpEF patients. More importantly, it demonstrated, for the first time, a significant and independent association between impaired CFR and markers of systemic endothelial injury, including elevated urinary albumin-to-creatinine ratio (UACR) and reduced reactive hyperemia index (RHI). These findings challenge the conventional view of CMVD as a cardiac-isolated phenomenon and instead suggest that CMVD may represent a localized cardiac manifestation of broader systemic inflammatory and endothelial dysregulation. This paradigm shift provides a robust theoretical basis for investigating CMVD pathogenesis from neuroimmune and systemic perspectives.

Following the recognition of CMVD as a systemic disorder, dissecting its functional heterogeneity at the individual level necessitates clinical validation using invasive “gold standard” techniques. Two pivotal randomized controlled trials—CorCTCA (NCT03477890) and iCorMicA (NCT04674449)—have been specifically designed to address this objective. Both studies enrolled patients with angina and no obstructive coronary artery disease (INOCA), implementing a comprehensive invasive functional assessment protocol. This protocol includes guidewire-based measurements of coronary flow reserve (CFR) and index of microcirculatory resistance (IMR), as well as acetylcholine (ACh) provocation testing to evaluate endothelium-dependent and vasospastic dysfunction (122, 123).

The completed CorCTCA trial demonstrated considerable success at the diagnostic level, clearly stratifying patients into distinct pathophysiological endotypes—namely microvascular, vasospastic, or mixed forms of dysfunction. However, a paradoxical insight emerged from the 12-month follow-up: enhanced diagnostic precision did not translate into significant symptomatic improvement in angina. This “negative” therapeutic outcome constitutes perhaps the most thought-provoking aspect of the study, as it exposes a critical gap between diagnostic capability and effective treatment strategies in current clinical practice.

Notably, the use of acetylcholine, a key neurotransmitter, directly connects invasive diagnostics with neurovascular regulatory function, further underscoring the neuroimmune dimensions of CMVD pathophysiology. Against this backdrop, the ongoing iCorMicA trial carries heightened expectations. It aims to determine whether personalized, stratified therapeutic approaches—guided by precise endotype-based diagnosis—can effectively bridge the current “diagnosis-treatment gap” and deliver meaningful clinical benefit to patients.

Although invasive testing remains the current “gold standard” for assessing CMVD, its inherent limitations—including procedural invasiveness, high cost, and poor reproducibility—have constrained its widespread implementation in clinical practice. As a result, the development of reliable noninvasive diagnostic tools has become an inevitable trend in the field. The Imaging CMD Study (NCT05634031) exemplifies this direction, aiming to establish and validate a PET-based noninvasive diagnostic protocol centered on myocardial perfusion imaging, with direct comparisons to invasive physiological assessments (124). However, the broader significance of this study extends well beyond its immediate diagnostic objective. It represents a critical step toward the future of integrated, multimodal molecular imaging in the assessment of CMVD. The true potential of PET imaging lies in its versatility—not only enabling the visualization of myocardial blood flow, but also allowing for the interrogation of underlying molecular and cellular processes through the use of targeted radiotracers. Looking ahead, a PET-based diagnostic platform may allow for simultaneous, quantitative, and spatially resolved assessment of myocardial microvascular function, local inflammation, and autonomic innervation in a single imaging session. This could be achieved by combining ^13N-ammonia (for perfusion), ^18F-FDG (for inflammation), and ^11C-HED (for sympathetic innervation). Such an approach would enable, for the first time in vivo, a direct visualization of the dynamic interplay among perfusion abnormalities, inflammatory activity, and neurovascular dysregulation in CMVD—marking a paradigm shift from indirect inference to direct observation in cardiovascular research. The core design and characteristics of these key trials are summarized in Table 3 .

In summary, this series of logically progressive clinical trials has collectively established a novel framework for the diagnosis and investigation of CMVD, while providing critical insights for future exploration of neuroimmune mechanisms. First, forthcoming clinical studies must move beyond the outdated notion of CMVD as a homogeneous disease entity and instead utilize validated invasive or emerging non-invasive phenotyping tools to enable precise patient stratification and enrollment. Such approach will facilitate the assessment of therapeutic efficacy within populations defined by shared pathophysiological profiles. Second, endpoint measures in trials targeting neuroimmune pathways must be correspondingly refined. These should incorporate a composite of symptom improvement, objective functional indices—such as coronary flow reserve (CFR) and index of microvascular resistance (IMR)—and molecular imaging biomarkers capable of directly reflecting target engagement (e.g., PET-quantified myocardial inflammation or alterations in cardiac neural density). By integrating these advanced diagnostic strategies, the field of CMVD is now poised at a historical turning point—shifting from largely descriptive association studies to a new era of mechanism-driven, precision diagnosis-based clinical trials. Ultimately, this will address the central scientific question: can modulation of the neuroimmune axis reverse CMVD pathophysiology and improve patient outcomes?