Inflammasome is a multiprotein oligomer present in immune cells comprising Nucleotide-binding oligomerization domain (NOD)-like receptors (NLR), Pyrin domain (PYD), and caspase activation and recruitment domain (CARD). NLRP3 inflammasome constitutes a focal point of research in cardiovascular diseases (14). Notably, extensive investigation have been conducted on NLRP3 inflammasome. NLRP3, identified as a nod-like receptor protein, functions as an intracellular pattern recognition receptor primarily linked to the inflammasome pathway. It possesses the ability to detect both pathogen-associated molecular patterns (PAMP) and damage-associated molecular patterns (DAMP) (15, 16). The primary defensive response during infections or tissue damage entails the discharge of cellular contents into the myocardial interstitium and the initiation of intracellular stress pathways. These pathways encompass Reactive oxygen species (ROS) production, oxidative stress, autophagy, and innate immunity triggering. Collectively, these processes contribute to the triggering of NLRP3 inflammasome (17–19). Mitochondrial fission plays a crucial role in enhancing ROS generation and releasing mitochondrial DNA into the cytoplasm, thereby facilitating the activation of NLRP3 inflammasome (17–19). NLRP3 inflammasome acts as a nexus, fostering inflammatory responses and functioning as an effector to initiate the cascade of inflammatory reactions (Figure 1). A critical step in this biological cascade is Caspase-1 activation, an enzyme precursor cleaved into an active form during NLRP3 inflammasome oligomerization (20). Caspase-1 is subsequently responsible for the maturation of pro-Interleukin-1β (pro-IL-1β) and pro-IL-18 into their active form. Gasdermin D (GSDMD)-NT pores formation triggers the processing and secretion of IL-1β and −18. Caspase-1 facilitates pore formation by cleaving various substrates associated with crucial metabolic pathways, actively facilitating the release of IL-1β and IL-18 (21).This culminates in a cascade of inflammatory reactions and the inflammatory infiltration of the myocardium, recognized as pyroptosis (22).

MI constitutes as a cardiovascular emergency precipitated by arterial thrombosis, resulting in a drastic reduction in myocardial blood flow (23, 24). The pathological features of MI delineate that, signaling pathways involving endothelial cell proliferation, apoptosis, and autophagy, as well as those of fibroblasts, orchestrate myocardial cell injury and the progression of MI. Notably, the NLRP3/Caspase-1-mediated pyroptosis pathway has emerged as a pivotal contributor (25). Research findings (26, 27) highlight that activation of the NLRP3 inflammasome fosters the release of IL-1β and IL-18 from myocardial and arterial endothelial cells, ultimately causing coronary artery impairment and exacerbation of MI. Furthermore, NLRP3 inflammasome activation prompts the release of IL-1β from fibroblasts, thereby instigating fibrotic alterations and promoting the enlargement of infarcted myocardial scars (28). It has been reported that oxidized LDL (oxLDL) within infarcted cardiomyocytes catalyzes cholesterol crystallization and induces the transcription of NLRP3 inflammasome and pro-IL-1β. Subsequent NLRP3 inflammasome activation triggers inflammatory cascade via the Nuclear factor kappa-B (NF-κB) pathway, leading to endothelial cell dysfunction and fostering atherosclerosis (29). Additionally, in accordance with Sandanger et al. (30), upregulation of NLRP3 inflammasome expression alongside pro-inflammatory cytokines IL-1 and IL-18 was documented in MI mice. This affirms, that inflammasome activation in fibroblasts exacerbates myocardial fibrosis and apoptosis, thereby aggravating MI. In summary, NLRP3 emerges as a critical risk factor for MI.

The initiation of NLRP3 inflammasome resulted in purinergic receptor P2X7 (P2X7R) activation through Adenosine triphosphate (ATP) and diverse toxins. This activation sets off processes like efflux of potassium, the generation of ROS, and mitochondrial DNA release. This cascade results in myocardial damage, myocardial cell necrosis, and the exacerbation of congestive heart failure (CHF) (31). Research indicates that NLRP3 inflammasome activation facilitates IL-1β and −18 extensive release, both of which have the potential to impair myocardial contractility (32). Concurrently, they interfere with the regulation of cytoplasmic calcium by altering the synthesis of proteins, inducing diastolic dysfunction, and subsequently impairing cardiac pumping function, thereby worsening heart failure or potentially inducing heart failure (33, 34). Xin-Li formula (XLF) is a traditional Chinese medicine formulation showing promise in treating heart failure. A study conducted on rats with heart failure induced by combined hyperlipidemia and MI revealed that XLF possesses anti-inflammatory properties. These effects are attributed to its ability to inhibit mammalian target of rapamycin (mTOR) phosphorylation, increasing the population of Foxp3+ T-regulatory cells (Tregs), and inhibiting NLRP3 activation in THP-1 macrophages. This leads to the inhibition of the inflammatory response mediated by NLRP3 inflammasomes, offering potential benefits for patients with heart failure (35). Moreover, Canakinumab is a therapeutic monoclonal antibody targeting IL-1β (36), holds promise in reducing tissue or cell inflammation by blocking IL-1β activity, and potentially inhibiting the inflammatory pathway triggered by the NLRP3 inflammasome. A sub-analysis conducted within the CANTOS trial demonstrated a reduction in the rates of heart failure hospitalization with the administration of canakinumab administration. The MRC-ILA-Heart study (37), which included 182 patients experiencing small acute myocardial infarction (AMI), revealed that NLRP3 inflammasome activation and the heightened IL-1 activity during the acute phase of myocardial infarction correlated with escalating heart failure risk. Canakinumab, conversely, demonstrated the ability to block NLRP3 inflammasome and IL-1β activations, highlighting IL-1-targeted therapy potential in preventing the recurrence of atherosclerotic thrombotic events and heart failure happening (38). In summary, NLRP3 inflammasome activation is implicated in the generation and exacerbation of chronic heart failure (CHF). Intervening within NLRP3 inflammasome pathway may hold promise for improving the prognosis of CHF.

ANS regulation governing cardiac function can be categorized into two systems. Firstly, the central nervous system comprises sympathetic and parasympathetic nerves extending from the brain and spinal cord to the heart. Secondly, the intrinsic cardiac nervous system, constituted by multiple ganglion plexuses (GP) distributed in the epicardial fat pad and within the Marshall ligament, encompassing both sympathetic and parasympathetic nerves. A crucial factor within cardiovascular disease progression is the imbalance in the functions of cardiac sympathetic and parasympathetic nerves. Pathophysiologically, ANS activation, including Sympathetic nervous system (SNS) and renin-angiotensin-aldosterone system (RAAS), serves as determinant within progression and recurrence of cardiovascular diseases (39). Both animal and clinical studies provide substantial evidence indicating that autonomic imbalance in cardiovascular diseases advances from vagal dominance in the early stages to sympathetic dominance in the later stages (40–42). The initial surge in sympathetic activity aims to maintain cardiac output. however, prolonged SNS can lead to increased adrenaline secretion, precipitating changes such as cardiac structural remodeling, deterioration of cardiac function, myocardial cell apoptosis, myocardial tissue fibrosis, and cardiac electrical remodeling. These alterations may manifest as symptoms such as chest tightness, shortness of breath, restricted exercise capacity, or difficulty lying down. Often, these factors can overlap or be causally linked, resulting in a substantial decrease in ejection fraction and severe clinical symptoms and consequences. The unfavorable clinical prognosis observed in patients with cardiovascular diseases is associated with the activation of the SNS, diminished parasympathetic nervous system activity, and reduced heart rate variability (43).

SNS excessive activation is a crucial factor in initiating inflammation and damage to heart. It's stated that the non-selective β-adrenergic receptor agonist isoproterenol (ISO) triggers various pro-inflammatory cytokine expressions within myocardial cells, including tumor necrosis factor (TNF)-α, IL-6, −1β, and −18, as a result of chronic β-adrenergic stimulation (44, 45). These pro-inflammatory cytokines are recognized contributors to myocardial injury and contribute to long-term pathological remodeling, such as myocardial fibrosis. A study on IL-18 in β-adrenergic injury-induced cardiac inflammation and fibrosis validated the findings of the previously mentioned research (46).. This study found that when the heart is excessively stimulated by stress hormones (acute β-adrenergic overstimulation), it triggers certain inflammatory response in heart cell, resulting in harmful changes in the heart structure. This process involves reactive oxygen and receptors called β1-adrenergic receptors. It sets off a chain reaction of cytokines and the infiltration of immune cells (macrophages), ultimately causing negative changes in the heart (Figure 2). SNS has receptors called α1-adrenergic receptors (α1-AR). In a significant experiment, using a substance called phenylephrine (PE) that activates these α1-adrenergic receptors in mice resulted in heart dysfunction and inflammation (47). Notably, PE injection markedly increased the expression levels of caspase-1, NLRP3, and IL-18 in the heart. In summary, The overstimulation of SNS can trigger the activation of NLRP3, setting off a series of inflammatory responses and ultimately leading to pyroptosis in myocardial cells.

Conversely, additional studies indicated that interrupting β-adrenergic receptor (β-AR) signaling can effectively inhibit IL-1β, NLRP3, and IL-18 activations, subsequently preventing their mediation of cardiac fibrosis (13). Consequently, within cardiovascular disease progression, NLRP3 inflammasome activation induced by excessive sympathetic activation is intricately linked to the progression of cardiovascular diseases. Strategies for inhibiting the overactivation of SNS and promoting VNS to maintain ANS balance present new avenues for therapeutic intervention in cardiac disease treating.

Medications, especially cancer drugs, have been known to potentially cause harmful effects on the heart (48). Prolonged administration of drugs may result in myocardial injury and compromised cardiac function, potentially resulting in cardiovascular diseases progression and, in severe cases, progressing to end-stage heart failure. Recent research (49) suggests that VNS therapy may possess cardioprotective properties. It achieves this by alleviating cardiac dysfunction mediated by the NLRP3 inflammasome, enhancing myocardial energy metabolism, reducing inflammatory infiltration, and safeguarding cardiac function in the aftermath of drug-induced injury.

Thermal injury pathogenesis is intricate, involving the confluence of factors such as systemic alterations in cytokine expression, free radical damage, and inadequate tissue perfusion. Thermal injury has the potential to initiate a systemic inflammatory response (SIRS), which may be instigated by the cascade reaction mediated by NLRP3 activation, leading to substantial release of IL-1β (58). Moreover, severe thermal injury has the potential to induce cardiac stress by causing a surge in plasma catecholamines. This leads to stress reactions and heightened sympathetic nerve tension due to increased metabolism, ultimately resulting in myocardial cell damage through the mitochondrial pathway (59). The mitochondrial pathway is a prominent mechanism for myocardial cell death (60). It promotes inflammatory cells infiltration into myocardial tissue by inducing oxidative stress, loss of growth factors, hypoxia, and triggering NLRP3 activation and DNA damage.

In a murine model of thermal injury, Xiaojiong Lu and colleagues delved into the deleterious effects of thermal injury on myocardial tissue and examined VNS impact on myocardial damage. The study underscored the pivotal role of VNS in safeguarding mitochondrial function and suppressing inflammation in myocardial tissue (61). Research findings unveiled notable pathological alterations in mouse myocardial tissue at 6 h and 24 h post-burn injury. At the molecular level, there were observable signs of mitochondrial swelling and dysfunction, coupled by an escalation in ROS linked to oxidative stress and an elevation in NLRP3 inflammasome expression. These observations highlight that thermal injury can lead to significant inflammatory infiltration and damage to the heart, suggesting the potential for post-burn cardiac dysfunction and heart failure (62). Importantly, mice subjected to VNS showed noticeable improvement in myocardial pathology. Critically, VNS effectively reduced thermal injury-induced swelling of myocardial mitochondria and NLRP3 inflammasome expression. Collectively, VNS demonstrates the ability to alleviate myocardial damage caused by thermal injury, potentially by reducing inflammatory infiltration in myocardial tissue induced by NLRP3 inflammasomes. Additionally, the study proposed that VNS might offer protection against cardiac injury through M3-AchR, though further investigation is required.

VNS improves cardiac function by connecting electrodes to the vagus nerve trunk in the neck and a pulse generator (63). In recent years, some studies have advanced VNS devices to enhance therapeutic effectiveness. Sun Yu and colleagues developed a closed-loop self-powered LL-VNS system using triboelectric nanogenerator technology (64). Their results indicated that, even with stimulation intensity much lower than traditional VNS, the system still produced significant therapeutic effects. Moreover, this system significantly reduced inflammatory infiltration of myocardial cells, thus preventing additional damage to the heart cells.

In recent research, Yao Lu and colleagues introduced a magnetic vagus nerve stimulation (mVNS) device. They replaced the traditional vagus nerve electrode with an injectable magnetic hydrogel containing superparamagnetic iron oxide (SPIO) nanoparticles, aiming for more precise and effective vagus nerve stimulation (65). Furthermore, they applied mVNS in an SD rat model and investigated its mechanism of action in myocardial ischemia-reperfusion injury (I/R). The research results revealed that mVNS treatment significantly alleviated myocardial I/R injury and the release of inflammatory cytokines, while inhibiting the expression of OGDHL (a protein associated with increased mitochondrial ROS levels) (66). This reduction in OGDHL expression contributed to less myocardial necrosis caused by myocardial I/R injury. Hence, mVNS could serve as a novel therapeutic approach to inhibit myocardial necrosis, significantly influencing the I/R injury process and improving the prognosis of ischemia-reperfusion myocardium. Additionally, the researchers used the M2AChR antagonist Otenzepad to explore the anti-necrotic mechanism of mVNS. The results showed that Otenzepad attenuated mVNS's function within limiting myocardial infarct size and inhibiting NLRP3 inflammasome activation. Consequently, mVNS may effectively inhibit myocardial necrosis by modulating the M2AChR/OGDHL/ROS axis, protecting the heart, and improving the prognosis of myocardial I/R injury. However, more investigation seems to be necessary to fully delve into the precise mechanism by which acetylcholine receptor activation reduces OGDHL expression.