Autonomic Imbalance in Cardiovascular Disease: Molecular Mechanisms and Emerging Therapeutics

Abstract

Autonomic imbalance is a key driver of cardiovascular disease progression, arising from disrupted interactions between sympathetic and parasympathetic signaling. This review explores the molecular mechanisms underpinning autonomic dysfunction, emphasizing the roles of β-adrenergic receptor (βAR) signaling, cyclic AMP (cAMP) compartmentation, and cholinergic regulation. Dysregulated cAMP nanodomain signaling, βAR desensitization, impaired vagal tone, and maladaptive autonomic nerve remodeling collectively promote structural, electrophysiological, and functional deterioration. Advances in high-resolution imaging and molecular mapping have revealed previously unrecognized pathways governing second-messenger compartmentation and neuromodulatory feedback loops. These insights are driving the development of next-generation therapeutics designed to selectively restore autonomic balance. Promising strategies include isoform-specific phosphodiesterase (PDE) inhibitors, vagus nerve stimulation (VNS), and axonal modulation therapy (AMT), which target norepinephrine (NE) and acetylcholine (ACh) pathways while preserving physiological responsiveness. Integrating pharmacological, neuromodulatory, and molecular approaches represents an evolving frontier for cardiovascular therapeutics. Future strategies will benefit from precision mapping of autonomic circuits, patient-specific profiling, and optimization of therapeutic timing. By linking fundamental molecular signaling with translational advances, this review highlights opportunities to improve treatment precision and efficacy for autonomic dysfunction in cardiovascular disease.

Graphical Abstract:

1. Introduction

The autonomic nervous system (ANS) is an integrative network that regulates involuntary processes, including heart rate, blood pressure, and metabolism, to maintain cardiovascular homeostasis. Comprising sympathetic and parasympathetic branches, the ANS balances cardiac output and recovery. Sympathetic activation drives catecholamine release, predominantly norepinephrine (NE), to regulate contractility and vascular tone, whereas parasympathetic activation, mediated by acetylcholine (ACh), promotes recovery and stabilizes electrophysiological function.

Preganglionic sympathetic neurons originate in the thoracic and lumbar spinal cord and project to paravertebral ganglia, such as the stellate ganglion, which relay postganglionic fibers to the heart (1).NE released from these terminals activates adrenergic receptors (ARs), including β-ARs, initiating G-protein-coupled receptor (GPCR) signaling cascades that regulate calcium (Ca) handling, excitability, and contractility. Parasympathetic fibers, arising from the nucleus ambiguus and dorsal motor nucleus, reach the heart via the vagus nerve and release ACh, which binds muscarinic acetylcholine receptors (mAChRs) to counterbalance sympathetic drive and stabilize cardiac rhythm. Although NE and ACh dominate autonomic control, co-transmitters such as neuropeptide Y (NPY), galanin, nitric oxide (NO), and ATP further fine-tune autonomic tone (2).

This review focuses on molecular pathways underlying autonomic regulation in cardiovascular health and disease, focusing on β-AR signaling, cAMP compartmentation, and muscarinic modulation. We highlight how disruptions in these pathways contribute to maladaptive remodeling, impaired electrophysiology, and arrhythmogenesis. Finally, we discuss emerging therapeutic strategies, including neuromodulation, precision pharmacology, and molecular interventions, aimed at restoring autonomic balance and improving cardiovascular outcomes.

2. Sympathetic Function, Dysregulation, and Emerging Therapeutics

2.1. Sympathetic Signaling in the Healthy Heart

Cardiac sympathetic regulation is primarily mediated by βARs, which respond to NE from sympathetic neurons and circulating epinephrine. The heart predominantly expresses β1-ARs (~80% in ventricles, ~70% in atria), which couple to Gs proteins to activate adenylyl cyclase (AC), elevate cAMP, and activate protein kinase A (PKA), enhancing inotropy, chronotropy, and lusitropy via phosphorylation of L-type Ca channels, phospholamban (PLB), and troponin (Figure 1) (3, 4).β2-ARs, although less abundant, are enriched within T-tubules and generate spatially confined cAMP responses that fine-tune local ion channel and Ca handling (5, 6). This compartmentation maintains signal specificity and prevent excessive cross-talk during sympathetic stress. The β1:β2-AR ratio varies by cardiac region, with higher β1-AR density in the ventricles compared to the atria, supporting specialized adrenergic responses (3).

Figure 1: Sympathetic and parasympathetic regulation of cardiac cAMP signaling.

The The sympathetic nervous system (SNS) activates β-adrenergic receptors (βARs), stimulating Gs proteins to activate adenylyl cyclase (AC), increasing cAMP production and protein kinase A (PKA) activation. This enhances Ca²⁺ handling and cardiomyocyte excitability. Signal termination occurs through phosphodiesterases (PDEs), G protein-coupled receptor kinase 2 (GRK2)-mediated receptor phosphorylation, and β-arrestin recruitment. The parasympathetic nervous system (PNS) counterbalances SNS effects via muscarinic acetylcholine receptors (mAChRs), which couple to Gi proteins to inhibit AC, reduce cAMP levels, and activate G-protein-gated inward rectifier K⁺ channels (GIRK). Acetylcholinesterase (AChE) rapidly degrades acetylcholine (ACh), terminating vagal signaling. Figure created with BioRender.com.

2.1.1. Compartmentalization of cAMP signaling

Subcellular βAR signaling specificity is shaped by localized cAMP degradation via phosphodiesterases (PDEs). PDE3, predominantly found near SERCA2a and PLB, regulates Ca reuptake and relaxation, while PDE4 isoforms cluster around βAR complexes, L-type Ca channels, and ryanodine receptors (RyRs), to limit excessive PKA-driven spontaneous Ca release (7–11). In addition to plasma membrane signaling, recent studies reveal a distinct pool of β1-ARs within the sarcoplasmic reticulum (SR), that form discrete cAMP pools to enhance SERCA2a activity via PKA-mediated PLB phosphorylation (12, 13). These intracellular β1-ARs are insulated from cytosolic cAMP diffusion, which may explain differences in efficacy between membrane-permeant versus hydrophilic β-blockers (12).

2.1.2. Heterogeneity of βAR signaling

βAR signaling is heterogeneous across the myocardium, shaped by apico-basal gradients, transmural differences, and regional innervation, influencing adrenergic tone and arrhythmia susceptibility even in healthy hearts (14–17). PDE isoform expression is similarly heterogenous. For example, PDE3A is enriched in ventricles, whereas PDE4D predominates in human atria, influencing local cAMP gradients and responses (18, 19).

Sex and age further modify sympathetic signaling. Males typically exhibit higher βAR density, sympathetic tone, Na⁺/Ca exchanger (NCX) activity, and arrhythmia susceptibility (20). In contrast, female hearts express higher Cav1.2, RyR, and PDE levels, supporting tighter cAMP compartmentation and distinct βAR responses (21–23). These distinctions may underlie the observed reduced responsiveness to β-blockers in female HF patients, with some trials reporting delayed ventricular improvement and lower survival benefit compared to men (24). Age-related remodeling further dampens βAR responsiveness, reducing βAR density and β1-mediated inotropy (25). This blunts the effectiveness of β-agonists in elderly HF patients, as evidenced by reduced hemodynamic response and delayed functional improvement (26). Concurrently, age-related redistribution of cAMP-PDE compartments may also disrupt local signal control (27), though the functional implications remain underexplored. These findings suggest that βAR-targeted therapies may require age- and sex-specific tailoring. Emerging approaches that restore downstream signaling precision or bypass receptor-level defects may offer greater efficacy in older or female patients. Importantly, βAR pathways are also critical during postnatal cardiac maturation, coordinating Ca handling, metabolism, and contractile development (28), suggesting that age-related shifts in signaling heterogeneity may have both developmental and degenerative relevance.

2.2. Sympathetic Remodeling in Heart Disease

Sympathetic remodeling is a defining feature of cardiovascular disease, including myocardial infarction (MI), heart failure (HF), and diabetic cardiomyopathy, and is supported by extensive clinical and preclinical evidence (29–31). Beyond changes in nerve density, remodeling involves altered neurotransmitter dynamics (32), β-AR signaling (3), and cyclic nucleotide compartmentation (8), which together create spatial gradients in adrenergic tone that destabilize electrophysiology and increase arrhythmia risk.

2.2.1. Structural Remodeling and Sympathetic Overdrive

Sympathetic nerve remodeling is among the most well-characterized forms of autonomic dysregulation in cardiovascular disease. Following MI, this remodeling includes persistent denervation within infarcted tissue and hyperinnervation of peri-infarct and remote myocardium (33, 34).= Denervation is driven by chondroitin sulfate proteoglycan (CSPG) accumulation, which inhibits axonal regrowth via neuronal protein tyrosine phosphatase sigma (PTPσ) activation (35), producing β-AR supersensitivity, and heightened responsiveness to circulating catecholamines. These effects have been observed in both rodent and rabbit models of MI, in which border zones also undergo structural and electrophysiological remodeling (33, 36).

Conversely, viable myocardium adjacent to scars becomes hyperinnervated, causing local NE surges and steep adrenergic gradients that destabilize electrophysiological function (33, 34). Similar denervation–hyperinnervation patterns have been observed in hypertensive HF, where subendocardial nerve loss of the left ventricle, increased arrhythmic susceptibility (37). Molecular adaptations accompany these structural changes. Reduced NE transporter (NET) expression slows NE clearance in denervated zones, prolonging β-AR activation and amplifying pro-arrhythmic Ca signaling (32). Notably, cyclic nucleotide signaling has been implicated in nerve remodeling. In rat MI, the PDE3A inhibitor, cilostazol suppressed sympathetic hyperinnervation in scar regions, via elevated adenosine-mediated A1 receptor activation (38), highlighting a cAMP–adenosine cross-talk mechanism controlling reinnervation.

2.2.2. Receptor Desensitization and Compartmental Disruption

Downstream of sympathetic remodeling, chronic βAR stimulation in HF and diabetic cardiomyopathy induces receptor desensitization and downregulation (39). This desensitization is mediated by G protein–coupled receptor kinase 2 (GRK2)- phosphorylation and β-arrestin recruitment, which blunts Gs–cAMP–PKA signaling and shifts activity toward pro-fibrotic and apoptotic β-arrestin pathways (40). β1-ARs are particularly vulnerable to downregulation, while β2-ARs tend to be preserved but become uncoupled from Gs, instead activating maladaptive signaling cascades (3). Importantly, these changes alter cAMP dynamics. In failing human hearts, β2-driven cAMP signaling becomes diffuse due to PDE uncoupling, causing cAMP spillover and destabilizing Ca cycling (41, 42).

Beyond receptor desensitization, disrupted downstream microdomain regulation also contributes to dysfunction. In diabetic cardiomyopathy, PDE4D upregulation at SERCA2a microdomains blunts local PKA activity and PLB phosphorylation, impairing Ca reuptake and contractility (43). Similarly, in a murine HFpEF model, SERCA2a-specific cAMP signaling was selectively blunted despite preserved global cAMP levels, implicating localized PDE remodeling rather than βAR loss (44). Computational models support these findings, demonstrating that altered localization of βAR, AC, and PDE HF reshapes cAMP gradients and heightens arrhythmia susceptibility (45). Together, these studies position microdomain integrity, not just receptor density, as a critical determinant of βAR signal fidelity and a promising therapeutic target.

2.3. Precision Therapies Targeting Sympathetic Signaling

Conventional treatments focused on balancing the overactive sympathetic nervous system, such as β-blockers, and neuromodulation, provide systemic benefits but lack molecular precision (reviewed in (46)). Here, we highlight two emerging strategies aimed at restoring spatial organization of sympathetic signaling: isoform-specific PDE modulation and PTPσ inhibition to normalized cAMP microdomains and promote functional reinnervation, respectively.

2.3.1. Isoform-Specific PDE Modulation

PDEs control the spatial resolution of βAR-cAMP-PKA signaling by confining cAMP within nanodomains (7, 8). While early clinical efforts with non-selective PDE inhibitors, showed short-term hemodynamic benefits in HF, they increased mortality, up to 17% higher, due to global cAMP elevation and arrhythmogenesis (47). Newer strategies therefore aim to target specific PDE isoforms and compartments, particularly PDE3 and PDE4, which regulate cAMP near βARs, RyRs, and Ca-handling proteins. The architecture of cAMP signaling is now known to involve specialized nanodomains, though many remain unmapped. Recent biosensor studies in healthy hearts identified novel compartments regulated by distinct PDE isoforms (48). One such domain, regulated by PDE3A2 at the nuclear envelope, suppresses hypertrophic gene transcription via local cAMP degradation. Inhibiting PDE3A2 at this site triggered hypertrophy in both rat and human cardiomyocytes, offering a mechanistic explanation for adverse outcomes with PDE3 inhibitors in HF (48).

Building on these insights, gene therapy approaches modestly overexpressing PDEs have shown benefit. In preclinical HF models, modest AAV9-mediated PDE4B overexpression (≈15–50%) preserved systolic function and reduced fibrosis (49). In contrast, excessive overexpression (≈50-fold) caused severe systolic dysfunction, including a ~50% reduction in fractional shortening, cardiac dilation, hypertrophy, and premature death (49), underscoring the need for dosing precision. Similarly, targeted delivery of PDE4B3 or PDE2A3, restored restored RyR2-localized cAMP gradients and reduced Ca²⁺ leak in pressure-overload and CPVT models (50). Notably, this strategy retained efficacy, even when βAR signaling was diminished, suggesting potential to improve downstream cAMP signaling fidelity in aged hearts with βAR downregulation, though age-specific validation remains necessary. Notably, PDE inhibition may also be beneficial in some disease contexts. In a pre-clinical model of diabetic cardiomyopathy, cardiomyocyte-targeted PDE4D inhibition restored SERCA2a-PLB axis cAMP signaling to control like levels, and rescued Ca handling and contractile function (43). These dual roles, where both overexpression and inhibition of PDEs can yield therapeutic benefit depending on spatial context, highlight the importance of mapping and modulating nanodomain-specific cAMP signaling.

Sex differences also shape PDE activity and therapeutic response. Female hearts display higher PDE4D expression and apical PDE activity (51), suggesting more robust local cAMP degradation. As such, females may benefit more from isoform-specific PDE modulation, while males may be more susceptible to pro-arrhythmic effects of global cAMP elevation. Supporting this, whole-heart optical mapping revealed that global PDE inhibition prevented repolarization heterogeneity in female hearts (51), potentially lowering their susceptibility to reentry. Nonetheless, most studies have not addressed sex or region-specific effects, emphasizing the need for tailored PDE-targeted therapies.

2.3.2. Protein tyrosine phosphatase receptor sigma (PTPRs) inhibition

Post-MI sympathetic denervation creates regions of βAR supersensitivity, disrupting spatial cAMP patterns, and promoting arrhythmogenesis (32, 33, 35). In preclinical MI models, inhibiting PTPσ, which mediates CSPG-driven axonal inhibition within the infarct scar, restores innervation and improves electrophysiological stability. In PTPσ knockout mice, sympathetic innervation, NE content and premature ventricular contraction (PVC) frequency were normalized to control levels post-MI (33). Similarly, the PTPσ inhibitor ISP, administered three days post-MI, restored NE content and nerve density to the scar and reduced arrhythmia inducibility, demonstrating strong translational promise (33). Follow-up studies using the small-molecule PTPσ inhibitors (HJ-01, HJ-02), promoted axon outgrowth in vitro (52) and also modulated post-MI inflammation, shifting macrophage profiles from pro-inflammatory to reparative phenotypes, limiting fibrosis, and preserving ventricular structure in a mouse model (53). Importantly, the benefits of PTPσ inhibition occur within a defined regenerative window. while untreated MI hearts eventually recover innervation after ~40 days post-MI (54), early PTPσ inhibition accelerates reinnervation and reduces arrhythmogenic risk during the vulnerable post-infarct period.

3. Parasympathetic Signaling in Cardiovascular Function and Therapeutic Treatments

3.1. Parasympathetic Signaling Pathways: In Health

In contrast to βAR-mediated sympathetic signaling, parasympathetic control is primarily mediated by M2 muscarinic receptors (M2Rs), the dominant cardiac subtype (Figure 1). M2Rs inhibit AC5/6 via Giα, supressing cAMP-PKA signaling, and activate GIRK channels, to hyperpolarize membranes and shorten APD, slowing heart rate and atrioventricular conduction (55, 56). Expression is highest in the atria and sinoatrial node, where dense vagal innervation provides precise autonomic control. Although ventricular M2R density and GIRK activity are lower, parasympathetic input can still influence ventricular cAMP microdomains via baroreflex pathways and β2AR crosstalk (56–59). ACh signaling is rapidly terminated by acetylcholinesterase (AChE), enabling tight beat-to-beat modulation.

3.1.1. Biphasic cAMP responses to muscarinic activation

While M2R activation classically supresses β-AR–driven cAMP, ACh withdrawal paradoxically triggers a rebound increase in contractility and heart rate (~60% ↑ ICaL), dependent on cAMP-PKA and partially mediated by PDE3 inhibition (60–63). A proposed pathway involves ACh-stimulated NO–cGMP signaling, which inhibits PDE3 and activates PDE2, altering cAMP degradation (60, 64, 65). In ventricles, this rebound mechanism, requires Gαs activation and Gβγ-stimulation of AC2/4. Computational modeling suggests that this may reflect cAMP redistribution between extra-caveolar and caveolar domains (63, 64). These findings challenge the view of muscarinic signaling as purely inhibitory and suggest a context-dependent capacity for localized cAMP stimulation.

3.1.2. Role of IKACh in cAMP-independent parasympathetic regulation

Parasympathetic signaling also regualtes cardiac excitability via GIRK1/4 channels, which generate the ACh induced inward rectifying K+ current (IKACh). This pathway slows heart rate and shortens atrial repolarization independently of cAMP. IKACh expression is spatially heterogeneous, with higher GIRK4 levels in the right atrium (RA) than in the left, leading to enhanced adenosine-induced RA APD shortening in human hearts (66). Similar gradients are observed in mice, where IKACh current density is highest in the SAN, followed by the RA (67). During metabolic stress, heightened RA GIRK activity may amplify inter-atrial repolarization differences and promote AF, supporting GIRK blockade as a therapeutic strategy. Gq signaling further modulates IKACh via protein kinase C (PKC), with isoform specific effects. For instance PKCε activation increases IKACh nearly fivefold in mouse hearts (68), potentially driving constitutive activity and arrhythmia in disease. While effects are most pronounced in atria, evidence suggests vagal input may also subtly influence ventricular inotropy (58, 59).

3.1.3. Parasympathetic signaling: age, and sex influences

Parasympathetic regulation, like its sympathetic counterpart, varies with development, aging, and sex. Early postnatal innervation is predominantly sympathetic, with parasympathetic tone increasing during adolescence (55, 69). Aging reduces vagal tone via reduced nerve density and impaired cholinergic transmission, shifting balance toward maladaptive Gs-coupled sympathetic signaling and elevated cAMP (55) (69). Heart rate variability declines ~60% by age sixty, reflecting reduced parasympathetic input and compensatory intrinsic pacemaker slowing (69). Sex differences further shape parasympathetic tone. Females typically exhibit higher vagal dominance, reduced arrhythmia and ischemic risk (70), attributed in part to estrogen-enhanced cholinergic activity and vagal responsiveness (71). Estrogen activates phosphoinositide-3 kinase (PI3K)-Akt signaling, which exerts cytoprotective effects in cardiomyocytes and attenuates reperfusion injury (72, 73). However, protective effects diminish after menopause (70), paralleling increased disease susceptibility.

3.2. Parasympathetic withdrawal and cholinergic deficit in cardiovascular disease

Parasympathetic withdrawal is a hallmark of cardiovascular disease, contributing to autonomic imbalance, structural remodeling, and increased arrhythmic risk. Disruption occurs at multiple levels, including impaired ACh release, altered MR signaling, and downstream remodeling of ion channel and second-messenger remodeling.

3.2.1. Cholinergic neurotransmission deficits

Loss of vagal tone in HF primarily reflects reduced ACh release rather than receptor desensitization. In canine HF, ganglionic stimulation fails to prolong sinus cycle length, while postganglionic activation preserves M2R responses, implicating disrupted presynaptic transmission (74). Supporting this, VAChT-deficient mice, with impaired vesicular ACh release, develop sympathovagal imbalance, ventricular hypertrophy, reduced ejection fraction, and elevated cardiac NE content (75, 76). At the cellular level, chronic cholinergic insufficiency increased peak Ca transients, mitochondrial oxidative stress, and GRK5 upregulation, which may desensitize βAR signaling and exacerbate remodeling (75). Loss of parasympathetic input likely also removes Gi-mediated inhibition of AC, amplifying βAR-driven cAMP–PKA activity and creating a feed-forward loop of sympathetic overactivity, disrupted Ca handling, and elevated arrhythmia risk. Therapeutically, enhancing cholinergic tone is protective. In VAChT-deficient mice, AChE inhibition restored synaptic ACh, normalized NE levels, and attenuated sympathetic overactivation (75). Similarly, reduced AChE expression in HF may represent a compensatory attempt to preserve vagal control (77). Conversely, following acute MI, sympathetic nerves can co-release ACh and NE, creating spatially heterogenous APD dispersion and impaired chronotropy, highlighting the complex, context-dependent role of ACh signaling (78).

3.2.2. Compensatory and maladaptive muscarinic signaling

In failing hearts, compensatory adaptations to parasympathetic withdrawal include increased M2R density, reduced AChE activity, and enhanced Giα signaling, leading to stronger AC inhibition and reduced cAMP production (77, 79). While, these changes may initially offset cholinergic loss, they become maladaptive under pathological stress. In a TAC-induced HF, elevated ACh has been shown to drive tonic M2R activation and enhanced ventricular IKACh upregulation, initially supporting repolarization, and limiting QT prolongation, but eventually suppressing local cAMP-PKA signaling, worsening Ca handling and contractile dysfunction (80). In contrast, atrial IKACh dysregulation directly promotes arrhythmogenesis. In AF, IKACh becomes constitutively active and uncoupled from M2R, causing excessive APD shortening and facilitating AF initiation and maintenance (81, 82). Thus, while ventricular IKACh activation may initially be protective, its chronic activation, or atrial dysregulation, facilitates pro-arrhythmic remodeling.

3.3. Therapeutic advancements to target parasympathetic withdrawal

Restoring parasympathetic tone is a promising therapeutic strategy to counteract autonomic imbalance, reduce sympathetic overdrive, and improve cardiac. Current approaches focus on neuromodulation and pharmacological enhancement of cholinergic signaling to rebalance βAR–cAMP pathways and reduce arrhythmogenic remodeling.

3.3.1. Neuromodulation therapies

Neuromodulation enhances vagal activity to suppress sympathetic dominance and improve autonomic balance. Vagus nerve stimulation (VNS) has shown cardioprotective effects in preclinical and clinical settings. In a porcine MI model, chronic VNS improved ejection fraction and reduced ventricular arrhythmias by stabilizing activation and repolarization at the border zone. However, it failed reverse the MI-induced increase in tyrosine hydroxylase, VAChT, or NPY neurons (83). A more selective approach, axonal modulation therapy (AMT), uses kilohertz-frequency alternating currents (KHFAC) to inhibit sympathetic efferent conduction. In preclinical MI models, AMT reduced reflex-mediated NE and NPY release, thereby attenuating sympathetic overdrive, improved myocardial relaxation, and decreased arrhythmogenic substrates, while preserving parasympathetic function (83, 84).

Clinical outcomes with VNS remain mixed. The ANTHEM-HF trial showed VNS improved left ventricular ejection fraction, HRV, and quality of life in HF patients. Long term follow-up showed enhanced baroreflex function and improved intrinsic heart rate recovery, with minimal adverse effects (85, 86). In contrast, the INOVATE-HF trial failed to meet primary endpoints, with only ~30% of patients responding to VNS (87, 88). These discrepancies reflect how stimulation parameters, neural targets, and titration protocols critically influence efficacy (83). Adverse effects of VNS center around implantation and the stimulation protocol, where patients can experience tachycardia followed by bradycardia with increasing stimulation intensity that can be ameliorated via adjustment of stimulation intensity (83, 89). To address these concerns, some experimental protocols aim to reach the neural fulcrum, a stimulation threshold balance point where afferent and efferent parasympathetic activity yields a null response (83).

There are also concerns that VNS might disrupt baroreflex sensitivity as an off-target effect, with some studies showing improvement and others not seeing any effect to baroreflex modulation (90). Even short-term transcutaneous VNS showed regional variability, where baroreflex sensitivity improved with right-sided stimulation but not left-sided in HF patients (91). However, in rodents VNS preserved reflex sensitivity while suppressing sympathetic activity (92). The variability in these results is again attributed to differences in dosing, neural targets, and stimulation titration.

3.3.2. Pharmacological approaches to restore parasympathetic tone

Pharmacological enhancement of cholinergic signaling offers another pathway to correct βAR–cAMP dysregulation. While no FDA-approved therapies specifically target parasympathetic withdrawal in the context of heart disease, acetylcholinesterase (AChE) inhibitors used in Alzheimer’s disease (AD) are being repurposed for cardiovascular applications due to overlapping risk factors such as aging, diabetes, and hypertension (61).

Large-scale clinical analyses suggest significant cardiac benefits. In AD patients, cholinesterase inhibitor use halved the incidence of new-onset HF (6% vs. 13%) and lowered cardiovascular mortality compared to non-users (93). Pyridostigmine, a reversible AChE inhibitor, approved for myasthenia gravis, has demonstrated improved HRV, accelerated heart rate recovery, reduced ventricular ectopy, and enhanced autonomic balance in HF patients (94–97). Preclinically, pyridostigmine restored parasympathetic tone, lowers cardiac NE levels, and improves autonomic balance in VAChT-deficient mice (75).

Importantly, efficacy of cholinergic therapies may be sex- and hormone-dependent. In a VAChT-overexpressing mice, ovariectomy caused cardiac dilation and failure, which was rescued by estrogen replacement, restoring fractional shortening and ejection fraction (71). These findings highlight the need to personalize parasympathetic-targeted therapies based on sex and hormonal status.

4. Conclusions and Future Directions

Autonomic imbalance, characterized by parasympathetic withdrawal and sympathetic overactivation, is a major driver of cardiovascular disease progression. Advances in understanding β-AR signaling, cholinergic control, and neurotransmitter regulation have revealed molecular pathways linking autonomic dysfunction to adverse remodeling, impaired contractility, and arrhythmogenesis.

Therapeutic strategies are rapidly evolving. Neuromodulation approaches, such as VNS and axonal modulation therapy, aim to enhance parasympathetic tone and reduce sympathetic drive, while pharmacological interventions, including cholinesterase inhibitors, MR modulators, and isoform-specific PDE inhibitors, focus on restoring cAMP–PKA balance. Together, these approaches highlight opportunities for combining bioelectronic medicine, precision pharmacology, and molecular therapies. Table 1 provides an integrated summary of emerging and established therapies across mechanistic targets and clinical applications.

Table 1:

Therapeutic Strategies Targeting Autonomic Imbalance

Category	Therapeutic Approach	Mechanism	Applications	Clinical Status
Pharmacological/ Molecular	PDE inhibitors	Regulates cAMP dynamics by targeting isoform-specific PDEs (e.g., PDE2, PDE3, PDE4).	HF (48–50, 98), Diabetic cardiomyopathy (43)	Preclinical and clinical studies in many cardiovascular diseases, including HF(48–50, 98), as reviewed in (99)
	Cholinesterase inhibitors	Enhance parasympathetic tone by increasing ACh availability	HF(61)	Experimental and clinical trials for heart diseases (93–96)
	CSPG-PTPσ inhibitors	Disrupts inhibitory PTPσ signaling to enhance nerve regeneration and autonomic reinnervation.	Acute and post-MI models (32, 33, 35, 52–54)	Preclinical studies in cardiac (32, 33, 35, 52–54)
Bioelectronic	Vagal nerve stimulation (VNS)	Enhances parasympathetic tone, reduces sympathetic overdrive.	MI (83, 84), HF(100), Arrhythmias (83)	Mixed outcomes in HF clinical trials (85, 86, 88, 89, 91)
	Axonal modulation therapy (AMT)	Blocks sympathetic efferent signals via kilohertz frequency alternating currents (KHFAC).	MI (83, 84)	Preclinical studies demonstrating efficacy in heart disease (83, 84).

Importantly, autonomic dysfunction shares key molecular features with neurodegenerative diseases like Alzheimer’s and Parkinson’s, including disrupted cAMP dynamics, impaired cholinergic signaling, and PTPσ-mediated nerve remodeling. These overlapping pathways across the heart–brain axis suggest that restoring autonomic tone may benefit both cardiovascular and neurological outcomes.

Future work should prioritize patient stratification, therapeutic timing, and sex- and age-specific differences to optimize efficacy and limit off-target effects. Emerging tools such as high-resolution imaging, multi-omics profiling, and advanced neuromodulation platforms will enable a deeper understanding of autonomic circuits and guide the development of personalized interventions. Leveraging these insights, next-generation therapies offer a path toward restoring autonomic homeostasis and improving outcomes in cardiovascular disease and beyond.