Clinical researches have shown that frontal lobe strokes often cause arrhythmias like atrial fibrillation (AF), tachycardia, and ventricular arrhythmias (37, 38). Using functional magnetic resonance imaging to explore the relationship between heart rate and cortical activity found that increased heart rate or increased heart rate variability in healthy volunteers is associated with diminished MPFC activity (36, 39). Transcranial direct current stimulation of the MPFC induced post-exercise hypotension in subjects (40). These conditions suggest that the MPFC is involved in the regulation of the ANS (41). Animal experiments indicate that the vMPFC regulate acute restraint—induced tachycardia in rats. The infralimbic cortex promoted CoCl₂-induced tachycardia, while the prelimbic cortex have the opposite effect (42). Additionally, electrically stimulating the rat MPFC significantly increased blood pressure (43). In humans, studies on patients with vMPFC lesions in different locations have showed that the left vMPFC is linked to PN activation, and the right vMPFC to SN inhibition (44). This lateralized regulation of the ANS may clarify why right MPFC damage activates the SN.

The insular is often regarded as a key area for AIS—induced cardiac damage. Many clinical studies indicated that insular cortex involvement in ischemia often results in cardiac problems liked bundle branch block, arrhythmias, QT-interval prolongation, myocardial injury, and cardiac dysfunction (45–50). A study of 384 infarcts in the middle cerebral artery region found that patients with insula damage showed elevated levels of NE and neutrophils (51). Further comparison of right and left insula damage revealed that patients with right insula damage exhibited reduced heart rate variability (51, 52). Also, right insular damage and arrhythmia due to SN activation became an adverse factor affecting 1-year prognosis (46). Many studies have shown right insular damage was more likely to cause cardiac lesions, especially arrhythmias (13, 53–58), while left damage would lead to elevated troponin and BNP (59). These results implied right insular damage activated the SNS. A plausible explanation was that after right insula infarction, reduced PN tension and pressure reflex sensitivity allowed the SN to dominate autonomic nervous(AN) regulation (60). In a study by Oppenheimer SM and colleagues on patients undergoing epilepsy surgery, it had found that stimulation of the left insular cortex resulted in a slowing of the heart rate, while stimulation of the right insular cortex had the opposite effect (61). This indicated that the left insular was associated with the regulation of the PN system, and the right insular with the SNS. Animal of middle cerebral artery occlusion (MCAO) models also have confirmed that right insular damage led to increased plasma NE and QT-interval prolongation (62, 63). These experimental results support the existence of a lateralized effect of insula damage on cardiac regulation, which may be due to the dominant role of the right insula in controlling the PN downstream conduction pathway to the sinus node (64). Moreover, the insular cannot directly project to sympathetic preganglionic neurons; its regulation of the SNS likely requires integration through hypothalamic nuclei. For example, the glutamatergic relay in the dorsomedial hypothalamus (DMH) has been proven to be a pathway for its regulation of the SNS (34). Some studies have shown that the DMH exhibits asymmetry in the regulation of cardiac AN function, with the right DMH primarily responsible for regulating cardiac rhythm (65, 66). When the right insular is damaged, it may trigger dysregulation of the SNS via the DMH pathway, leading to arrhythmias. However, research on the mechanisms linking insular lesion location and hemispheric laterality to AN dysregulation and cardiac damage remains very limited. Further in-depth studies will help to better understand this area.

Limbic systems such as ACC, amygdala and hypothalamus can modulate cardiac activity through direct or indirect or periaqueductal gray (PAG) relay projections to the medulla oblongata and lateral horn of the spinal cord (29). In addition, the nucleus tractus solitarius (NTS), ventral lateral medulla (VLM), nucleus ambiguus (NA) and parabrachial nucleus (PBN) in the brainstem are also involved in their network connections (60). The ACC is interconnected with the insula cortex. The ACC mainly modulates the SN and PN systems via its ventral and dorsal regions (67, 68), with the left side predominantly engaging in parasympathetic regulation (69).

During stress, excess NE heightens amygdala—induced excitatory regulation of the SNS, strengthening SN activity (70). The amygdala, with its extensive neural connections to the hypothalamus and brainstem, modulates sympathetic preganglionic neuron activity via these pathways, impacting sympathetic output. Thus, the amygdala is crucial for regulating SNS and neuroendocrine responses to stress (71, 72). The hypothalamus plays a central role in maintaining the stability of the body's internal environment by regulating the ANS, and its anterior and posterior regions are representative of the PN and SN (73). And the paraventricular nucleus (PVN) of the hypothalamus can project directly or indirectly to the preganglionic neurons of the SN and play a role in the regulation of cardiac activity by afferent sensory signals from the heart via the NTS (74). The PAG, NTS, VLM, NA and PBN in the brainstem are key structures and relay stations in the ANS that connects the forebrain, limbic system and spinal cord (60, 75–77). These structures are involved in cardiovascular regulation, and their damage can cause severe SN activation (78–80). Numerous studies have shown that lesions to these structures lead to activation of the SNS, which can lead to a range of cardiac problems, especially arrhythmias (77, 81–88).

In summary, ischemic damage to central regions regulating the SN and PN networks may be excessive activation of SN, disrupting cardiac physiology and causing damage. Such patients should be closely monitored in clinical settings. Although a large number of studies have reported the relationship between the lateralization of brain injury sites and cardiac damage, how this lateralization regulates the activation of the SNS still lacks in-depth discussion and needs to be explored and elucidated by more studies.

In Takotsubo syndrome, AIS, and ISO-induced myocardial infarction animal models, a significant inflammatory response was observed in the heart, as evidenced by infiltration of inflammatory cells and upregulation of inflammatory factor levels (117–120). A large number of clinical, animal and cellular experiments demonstrated that post-stroke cardiac injury was closely related to inflammation, and that the main mechanism involved the up-regulation of pro-inflammatory factors and mediators, as well as the infiltration of inflammatory cells such as monocytes, macrophages, and lymphocytes (6, 19, 121–123). Researchers have long noted that stress-generated catecholamines may lead to cardiac damage and observed significant myocardial inflammation (124), and a positive correlation between leukocyte levels and NE levels (125). With the development of magnetic resonance imaging (MRI) techniques, significant macrophage infiltration of the myocardium has been observed in patients with Takotsubo syndrome (121). Animal experiments often use a model of ISO-induced cardiac damage. ISO is a β-AR agonist and has a chemical structure similar to that of biogenic amines and is often used as a synthetic model to study catecholamine toxicity. Several studies have found that elevated catecholamine levels, left ventricular inflammatory infiltration and myocardial fibrosis were observed in both ISO-induced and chronic stress-induced rat Takotsubo models (126). These results suggest that elevated catecholamines after AIS may be an important factor contributing to cardiac inflammation.

Several studies have reported several mechanisms to mimic catecholamine-induced cardiac inflammation with ISO: mainly Nod-like receptor protein 3 (NLRP3), TLR4/NF-κB pathway, JAK2/STAT3 pathway, and HMGB1-TLR4 signaling. SN excitability activates the NLRP3 vesicles in the heart and generates IL-1β to induce myocardial injury (127), and recent studies have also demonstrated that cardiac insufficiency occurring after MCAO in mice is associated with sustained pro-inflammatory changes in monocytes/macrophages driven by IL-1β (122). In the ISO-induced male mouse model of stress cardiomyopathy, ISO triggers NLRP3 inflammasome activation via NOX4-dependent mitochondrial ROS generation, up-regulates downstream inflammatory cytokines including IL-6 and TNF-α, and promotes recruitment of CD68⁺ CD11b⁺ macrophages into the myocardium (128). ISO also stimulates NLRP3 inflammasome via NOX4-dependent mitochondrial ROS and activates downstream inflammatory signals (e.g., IL6 and TNFα) while inducing infiltration of CD68 and CD11b-expressing macrophages into the myocardium of mice (129). In addition, MD2 is also activated by β1-AR-ROS signaling and induces macrophage polarization to generate inflammation via the β2-AR-cAMP-PKA-ROS axis (130). HK1 has also been found to activate NLRP3 in the myocardium of ISO-treated mice (131). This suggests that HK1, MD2 may also be a pathway that induces cardiac inflammation.

TLR4 has been shown to be extensively involved in stroke, myocardial infarction and inflammation, where its binding to the bridging molecules MyD88 or MAPK activates NF-κB and triggers the up-regulation of IL-1β, IL-18 and TNF-α expression (132–134). On the one hand, ISO can upregulate Gal-3 expression and induce myocardial inflammation and fibrosis via the TLR4/ MyD88/NF-κB pathway, and the use of the Gal-3 blocker MCP ameliorates this adverse outcome (135). On the other hand, myocardial inflammation and apoptosis can also be induced through the AMPK/NF-κB pathway (136).

The JAK2/STAT3 signaling pathway is also involved in ISO-induced myocardial inflammation and hypertrophy. Upon activation, it drives macrophages to polarize into a pro-inflammatory phenotype and induces the release of pro-inflammatory factors, and JAK2 inhibitors ameliorate myocardial inflammation (137). High mobility group protein 1 (HMGB1) is also found to be upregulated in expression in ISO-treated rat hearts and trigger inflammation through the HMGB1-TLR4 pathway (138). Several other signaling pathways, such as Mst1/Hippo, VEGF-B/AMPK/eNOS, AMPK/eNOS/AKT, and Nrf2/HO-1, have recently been found to be involved in the regulation of cardiac inflammation after ISO treatment (139–142).

The metabolism of NE has an important role in oxidative stress, such as ROS production (143). NE is eliminated mainly through presynaptic and extraneuronal reuptake as well as metabolism. First, oxidative deamination by monoamine oxidase (MAO) converts NE to dihydroxyphenylethanol. Then, it is converted to methoxyhydroxyphenylglycol (MHPG) catalyzed by catechol-O-methyltransferase (COMT). It is finally converted to 3-methoxy-4-hydroxymandelic acid (VMA) and 3-methoxynorepinephrine (NMN) in the liver and excreted via urine (144–146). Catecholamine-induced oxidative stress injury has been demonstrated in the heart (147). It can lead to increased lipid peroxidation, and several antioxidants can attenuate the damage caused by lipid peroxidation (148–150). For example, after ISO injection, the levels of antioxidant enzymes SOD and glutathione peroxidase (GSH-Px) in the myocardium of rats decreased significantly, while the contents of oxidative stress markers MDA and NO increased significantly. Inhibiting oxidative stress can effectively alleviate heart damage (120, 142). Cardiomyocytes treated with E produced hydroxyl radicals (⋅OH) and peroxynitrite (ONOO⁻) (151). The expression of antioxidants such as SOD, GSH-Px and catalase was also found to be decreased in H9c2 cardiomyocytes exposed to NE, while the expression of 4-hydroxynonenal was upregulated (152). These results suggest that catecholamine-induced oxidative stress is also an important cause of cardiac injury. In addition, when liver function is impaired, the activities of MAO and COMT decrease, and the ability to generate and clear catecholamine metabolites (such as VMA) declines, which may lead to the accumulation of these metabolites in the body (153–155). Similarly, when the kidneys are damaged, especially when the glomerular filtration rate (GFR) decreases, it can also lead to a reduction in the excretion of catecholamine metabolites, further intensifying the accumulation of these metabolites in the body (156). Therefore, when renal or hepatic dysfunction is present, the impaired clearance of these metabolites may act as a “second hit” to cardiac injury. However, current research on the association between the toxic byproducts of catecholamine metabolism and cardiac injury after stroke remains insufficient. Clarifying these relationships may be of significant importance for elucidating the mechanisms underlying neurogenic cardiac injury after stroke.

The conditions that trigger oxidative stress include multiple complex factors such as mitochondrial damage, inflammation, apoptosis and oxidative damage to proteins, lipids and DNA (11). Among these factors, ROS production is the main driver of oxidative stress. The source of catecholamine-induced ROS is multifactorial in nature and consists of the following two main aspects: (1) Stimulation of the AR: for example, in cardiac myocytes NADPH oxidase is activated by α1-AR stimulation, which leads to the generation of superoxide anion radicals (O₂−•) (157). (2) Enzymatic and non-enzymatic degradation of catecholamines: the MAO pathway induces oxidative deamination of NE to produce hydrogen peroxide (H₂O₂) which is further catalyzed to “⋅OH”; and degradation of NE by non-enzymatic pathways produces “aminochromes” toxic compounds (11, 158). This catecholamine-mediated oxidative stress causes aberrant cell signaling, intracellular Ca²⁺ overload, mitochondrial damage, inflammatory responses, and disruption of the extracellular matrix and lysosomes, which in turn triggers apoptosis in cardiomyocytes (159–163). Also, these adverse outcomes directly or indirectly enhance oxidative stress, ultimately causing arrhythmias, cardiac hypertrophy, myocardial fibrosis, cardiac insufficiency, and HF. These results suggest that catecholamine-induced oxidative stress may be central to cardiac injury.

Recent study indicates that renal denervation decreases catecholamine secretion in hypertensive HF rat models, lowering ROS and MDA levels and reducing myocardial hypertrophy and fibrosis. This may be related to the inhibition of BACH1 by the TGF-β1/SMADs/SP1 signaling pathway and the alleviation of mitochondrial oxidative stress by PACS-2 (164). However, there is currently a lack of more research to explain how renal denervation directly inhibits specific molecular pathways within the heart. This may be related to the fact that renal denervation reduces sympathetic nerve activity and catecholamine levels throughout the body, and it is precisely these systemic changes that ultimately affect the signal transduction pathways of the heart. In both ISO—treated mice and cardiomyocytes, p-JAK2, p-STAT3, MDA, NOX2, and NOX4 show increased expression, yet inhibitors can reverse this trend (137). Thus, JAK2/STAT3 signaling plays a dual role in ISO-induced oxidative stress and inflammation. In addition, the Mst1/Hippo, RAGE/NF-κB, ROS/NF-κB, TLR4/MyD88/MAPKS/NF-κB, and SIRT1/FOXO3a/MnSOD signaling pathways are also found to be involved in ISO-induced oxidative stress injury in the heart (139, 165–168). Activation of these signaling pathways may in part explain the mechanisms of catecholamine-induced cardiac inflammation and oxidative stress. However, these processes remain complex and can influence each other, and more mechanistic studies are needed.

Ca²⁺ is a key regulatory ion in cardiac excitation-contraction coupling. Excessive release of catecholamines sustains activation of the β-AR, leading to a significant increase in myocardial excitability and contractility. β-AR overactivation may trigger intracellular Ca²⁺ overload, which leads to a series of cardiomyocyte injuries. Meanwhile, Ca²⁺ overload activates Ca²⁺-dependent ATPase, leading to mitochondrial dysfunction and increased oxidative stress, which in turn triggers cardiomyocyte injury (169).

A significant increase in the level of Ca²⁺ in myocardial cells is observed in the ISO-induced myocardial ischemia model (170). Further studies have shown that ISO promotes Ca²⁺ transients and increases Ca²⁺ load in the myocardial sarcoplasmic reticulum (SR) via β-AR (171). In addition, ISO can cause Ca²⁺ overload via L-type calcium channels (LCC) (172). In cardiomyocytes, NE activates β1-AR, which in turn promotes Ca²⁺ endocytosis via LCC and triggers Ca²⁺ release from the SR via the ryanodine receptors (RyR2) pathway (173). Continuous accumulation of Ca²⁺ may continuously activate calcium ion-dependent ATPase, thereby damaging mitochondrial oxidative phosphorylation function. This impairment would further exacerbate the disturbance of intracellular Ca²⁺ homeostasis, disrupt normal energy metabolism, promote ROS accumulation, and ultimately lead to myocardial excitation-contraction dysfunction (169, 174). Intracellular Ca²⁺ overload is closely associated with the development of arrhythmias and may also directly induce cardiomyocyte apoptosis (175). This may be due to the opening of the mitochondrial permeability transition pore after impaired mitochondrial function, which triggers apoptosis (176).

Furthermore, oxidative stress can also cause impaired mitochondrial function, resulting in insufficient ATP production, ATP-dependent Na⁺-Ca²⁺ exchange disorders, and promoting Ca²⁺ accumulation (177). When 5-AR is activated, calmodulin-dependent protein kinase II (CaMKII) regulates calcium channels and RyR2 via PKA-dependent phosphorylation, thereby driving Ca²⁺ accumulation (146). Recently study found that 4-hydroxyketone, produced by NE metabolized by mitochondrial MAO-A, promotes Ca²⁺ accumulation through the voltage—dependent anion channel 1/inositol-1,4,5-trisphosphate receptor 1 (IP3R) pathway (178). ROS generated by NE metabolism cause intracellular Ca²⁺ overload either by modulating calcium—handling proteins or inducing membrane lipid peroxidation (143). The resulting mitochondrial Ca²⁺ accumulation disrupts the mitochondrial membrane potential and damages the respiratory chain, further boosting ROS production (11). This vicious cycle may exacerbate cardiomyocyte injury.

In numerous animal experiments, catecholamine-induced cardiomyocyte mitochondrial dysfunction has been observed. The ROS generated during catecholamine metabolism, such as O²−• and H₂O₂, can directly attack the lipids, proteins, and DNA of mitochondria. Consequently, the structure and function of mitochondria become impaired, and their normal oxidative phosphorylation process is affected (179, 180). Another product of the metabolic process, dopaldehyde and 3,4-dihydroxyphenylacetaldehyde, can also interfere with the normal physiological function of mitochondria, or even destroy the structure of mitochondria, leading to mitochondrial dysfunction (179). Moreover, catecholamine-induced mitochondrial Ca²⁺ overload inhibits mitochondrial respiration and ATP synthesis, and increases mitochondrial permeability (11). Ca²⁺ overload can cause mitochondrial dynamism abnormalities, which may be related to the acetylation of ATPase family AAA domain—containing protein 3A (181). ISO can reduce the expression of antioxidant enzymes such as SOD and CAT in mitochondria, thereby increasing mitochondrial oxidative stress levels (182).

Cardiomyocyte mitochondrial swelling and myofilament vacuolization were observed in rats after ISO treatment (183). Further analysis revealed that the respiratory control index reflecting oxidative phosphorylation (184), the cardiac phosphocreatine/ATP ratio, and ATP content were all reduced, while MDA and eNOS expression increased (185, 186). This indicates that ISO induced energy production impairment in the myocardium. Some studies have shown that after ISO intervention, mitochondrial dysfunction in the heart is associated with reduced expression of certain enzymes, including mitochondrial respiratory enzymes [such as NADH dehydrogenase, succinate dehydrogenase (SDH), and cytochrome c oxidase (CcO)] (187), aldehyde dehydrogenase 2 (ALDH2), and the mitochondrial enzyme β-hydroxyacyl-CoA dehydrogenase (HADH) (188).

Mitochondrial respiratory enzymes are crucial for normal mitochondrial physiological functions (189). NADH dehydrogenase, the first enzyme complex in the mitochondrial electron transport chain, mainly transfers electrons from NADH to coenzyme Q (CoQ) while pumping protons from the mitochondrial matrix into the intermembrane space to form a proton gradient for ATP synthesis. SDH, complex II of the respiratory chain, passes electrons from FADH2 to CoQ, linking the tricarboxylic acid cycle to the electron transport chain. As the terminal oxidase in the chain, CcO receives electrons from cytochrome C(Cyt-C) and transfers them to oxygen, completing the final step of electron transport and driving ATP synthesis. The reduction of NADH, SDH and CcO activities jointly weakens the oxidative phosphorylation efficiency of mitochondria, reduces ATP production, thereby leading to insufficient energy supply to cardiomyocytes and further affecting the contractile and diastolic functions of the myocardium (190). In addition, energy metabolism disorders can cause mitochondrial dysfunction, leading to an increase in ROS production and subsequently damaging the mitochondrial membrane and DNA. This kind of damage will further disrupt mitochondrial function and promote the release of Cyt-C, activate the caspase cascade reaction, and ultimately induce apoptosis of cardiomyocytes (190, 191).

ALDH2 is involved in metabolizing reactive aldehydes produced during oxidative stress and exerts cardioprotective effects by inhibiting oxidative stress and inflammationALDH2 (192). ALDH2-knockout mice show aggravated cardiac ischemia-reperfusion injury (193). HADH, which participates in fatty acid β-oxidation, causes abnormal energy production when reduced, as it impedes fatty acid oxidation (194). The study has found that SFRP4 is involved in ISO-induced cardiomyocyte mitochondrial damage, and using an SFRP4 inhibitor can alleviate mitochondrial dysfunction in the myocardium and HL-1 cells (195). In summary, cardiomyocytes have a high energy demand, and mitochondrial dysfunction may play a significant role in the development of neurogenic cardiomyopathy after AIS. Impaired mitochondrial function leads to disordered energy metabolism and reduced ATP production in cardiomyocytes. This exacerbates the imbalance of calcium ion homeostasis, ultimately causing cardiomyocyte apoptosis and necrosis and worsening myocardial injury (182, 183).

At physiological concentrations, the toxicity of catecholamines to cardiomyocytes is generally insignificant. However, excessive catecholamines may induce cardiomyocyte apoptosis. It should be noted that the longer the exposure time of cardiomyocytes to catecholamines, the more pronounced the potential damaging effects may become. In a large number of animal and cell experiments, it has been observed that NE and ISO can induce cardiomyocyte apoptosis (16, 152, 196). They achieve this by modulating the expression of Bcl-2 family proteins, for instance, enhancing Bax expression and suppressing Bcl-2 and Bcl-XL expression (197). In addition, NE and ISO can upregulate Cyt-C expression. By activating caspases (including caspase-2, caspase-3, caspase-6, and caspase-9) and death receptors [such as Fas and TNF receptor 1-associated death domain (TRADD)], and enhancing the activity of apoptotic protease activating factor-1 (Apaf-1), NE and ISO mediate cardiomyocyte apoptosis (197–200).

The Bcl-2 family plays a crucial regulatory role in apoptosis, involved in both mitochondrial and some extrinsic apoptotic pathways. It consists of two main subtypes: anti-apoptotic proteins like Bcl-2, Bcl-XL, and Bcl-w, and pro-apoptotic proteins, which include BAK, BAX, BOK, and BH3-only proteins (201). In rat H9C2 cardiomyocytes treated with NE, Hoechst fluorescence staining showed increased apoptosis, with upregulated BAX and downregulated Bcl-2 expression (202). n ISO-induced HF models, rats exhibited increased Bax, Cyt-C, Caspase-3, and Caspase-9 expression, alongside decreased Bcl-2 and Bcl-XL expression in the myocardium (203). BAX forms a heterodimer with Bcl-2, reducing its activity. This increases mitochondrial membrane permeability, releasing Cyt-C into the cytosol. Cyt-C binds to Apaf-1 to form an apoptosome, triggering the Caspase cascade, leading to cell destruction and apoptosis (201, 204). Conversely, Bcl-2 protects cells by inhibiting Cyt-C release (205). Overall, NE and ISO induce cardiomyocyte apoptosis via the mitochondrial apoptosis pathway mediated by the Bcl-2 family.

Following ISO treatment, rats exhibited remarkable myocardial injury, with upregulated cardiac expression of Fas and caspase-3/8/9, and TNF-α genes (120, 206, 207). Mice with TNF receptor 1 (TNFR1) knockout showed resistance to ISO-induced cardiac injury, marked by downregulated expression of IL-1 β, iNOS, NF-κB, and AP-1 (208). This implies the death receptor family participates in ISO-mediated cardiomyocyte apoptosis. After TNF α binds to TNFR1, its intracellular death domain recruits TRADD. This facilitates the assembly of signaling molecules like receptor-interacting protein kinase 1, Fas-associated death domain protein, and caspase-8, forming complex I. This process activates downstream genes (e.g., the caspase cascade) and promotes complex II formation, inducing apoptosis (199).

ISO also activates the TLR4/NF-κB and JAK2/STAT3 signaling pathways, triggering inflammatory responses that interact with apoptosis (135, 137). Additionally, other upstream signals participate in ISO-induced cardiomyocyte apoptosis. For example, TLR4/NOX4, p38 MAPK, and Jak1/Stat signaling are activated (209–211), affecting Cyt-C release, activating caspases, and mediating apoptosis via the mitochondrial apoptosis pathway. The β-AR-AC-cAMP-PKA pathway can activate transcription factors like CREB, promoting pro-apoptotic gene expression, and also induces cardiomyocyte apoptosis through the mitochondrial apoptosis pathway (212). ER stress and CaMKII-mPTP can cause Ca²⁺ overload and promote apoptosis in the same way (213, 214).

Many studies have confirmed that sustained activation of the SNS is closely related to cardiac hypertrophy (CH) (18, 215, 216), and that renal denervation of the SN can improve CH (164). This may be closely related to the increased secretion of catecholamines caused by SN hyperactivity (202, 217). Continuous pressure load can induce CH. This is an adaptive manifestation, but long-term pressure loads can lead to the generation of HF. CH is characterized by an increase in the heart weight—to—body weight ratio (HW/BW). Hematoxylin-eosin staining shows an increase in the cross-sectional area of cardiomyocytes, often accompanied by increased expression of CH-related genes such as BNP, β-MHC, and ANP (218). In animal HF models induced by NE and ISO, significant CH has been observed (219, 220). This may be related to the activation of signaling pathways such as MAPK, NF-κ B, Ca2+, JAK2/STAT3, G protein-coupled receptor kinases (GRKs), and Protein Kinase A (PKA).

When NE binds to cardiac α1-ARs, it activates p38 MAPK and ERK1/2, upregulating genes related to CH. NF-κB signaling activation induces myocardial inflammation and promotes CH (221). In a mouse CH model induced by NE, significant increases in the phosphorylation levels of p38, MAPK, ERK1/2, AKT, and NF-κB proteins occur in myocardial tissue, with notable upregulation of CH-related genes like ANP, BNP, and β-MHC. Moreover, pharmacological inhibition of the p38 MAPK/ERK1/2 and AKT/NF-κB pathways significantly attenuates CH in mice (218).

Ca²⁺ regulates CH through the calcineurin-NFAT and CaMKII-MEF2 pathways. When NFAT in the cell membrane is activated by calcineurin and translocated to the nucleus. It then interacts with nuclear transcription factors like GATA-4 and MEF2, upregulating the transcription of CH-related genes (222, 223). Interestingly, Ca²⁺ can activate the CaMKIIδB/CREB pathway, increasing mitochondrial Ca2+ uniporter(MCU) expression to alleviate CH (224). But recent studies show that MCU3 overexpression promotes Ca²⁺ uptake and induces CH (225). Thus, MCU upregulation may be a compensatory mechanism where different MCU subunits interact to regulate Ca²⁺ homeostasis. Calcineurin can also activate the pathway involving dynamic-related protein-1, upregulating mitochondrial E3 ubiquitin ligase 1 expression. This promotes mitochondrial fission and dysfunction, leading to CH (226, 227).

Some studies have indicated that JAK2/STAT3 signaling activation upregulates genes tied to CH. Activated STAT3 increases expression of ANP, BNP, and β-MHC, triggering CH. It also modulates AMPKα/mTOR signaling, influencing cardiomyocyte metabolism and autophagy, and thus CH regulation (202, 228). GRKs mainly impact cardiomyocyte signal transduction by regulating G protein-coupled receptor activity. Key GRKs like GRK2 and GRK5 play important roles. GRK2 influences cardiomyocyte survival and hypertrophy by regulating PI3K/AKT signaling (229). GRK5 enhances NFAT transcriptional activity, upregulating CH-related gene expression (230). SN-induced catecholamine release, binding to β-AR, activates adenylate cyclase and raises Cyclic adenosine monophosphate(cAMP) levels. As a second messenger, cAMP can activate PKA (231). PKA, via phosphorylated transcription factors like CREB and NFAT, regulates transcription of CH-related genes. PKA regulates the transcription of CH-related genes through phosphorylated transcription factors such as cAMP response element-binding protein (CREB) and NFAT (231).

Recent studies have found that ISO upregulates the expression of cardiac epidermal growth factor (Ereg) and nerve growth factor receptor (Ngfr). Knocking down Ereg downregulates the expression of Natriuretic Peptide Precursor B (Nppb) and Fibronectin 1 (Fn1), reduces cardiomyocyte size, and lowers fibronectin expression (232). Ngfr may promote the proliferation of cardiac fibroblasts and the synthesis of collagen by activating downstream signals such as p38 MAPK, leading to myocardial fibrosis and exacerbating the degree of CH (233). Neuraminidase 1 has also been found to interact with GATA4 to enhance Nppb expression, thereby promoting ISO-induced CH (234). It has been discovered that the activation of HDAC8/MMP12 stimulates Nppb expression and increases extracellular matrix degradation, thereby worsening CH (235). Additionally, SarcoEndoplasmic Reticulum Ca2+-ATPase (SERCA2a) is regarded as an important marker of pathological hypertrophy (236, 237). In a mouse HF model continuously stimulated by ISO for two weeks, the expression of SERCA2a in the heart was significantly reduced (238); The same down-regulation was also observed in neonatal rat cardiomyocytes when NE was applied for 24 h (239). Conversely, transfection of ascending aortic tract HF rats with adenovirus carrying the SERCA2a gene could significantly increase survival rates and restore the phosphocreatine/ATP ratio (240). Phospholamban (PLB), an endogenous inhibitor of SERCA2a, has an elevated expression that reduces the affinity of the calcium pump for Ca²⁺ and impays cardiac diastolic function (241). In ISO-induced exhaustion mice, the level of PLB significantly increased (242), while myocardial contractility was significantly enhanced after PLB knockout (243, 244).

Cardiac fibrosis (CF) is the excessive deposition of cardiac extracellular matrix (ECM) and fibrosis, causing structural and functional changes in the heart. It often occurs after myocardial injury or chronic inflammation (245). Many studies have indicated that NE and ISO can both induce CF (128, 246). For instance, in the cardiomyocytes and fibroblasts of rats treated with ISO, the expressions of basic fibroblast growth factor 2 (FGF2), collagen I and smooth muscle α-actin (α-SMA) significantly increased and promoted CF (247). However, CF development is extremely complex, involving various molecular mechanisms and signaling pathways, such as fibroblast activation and transformation, regulation by transforming growth factor β (TGF-β), inflammatory responses, and immune cell infiltration (248, 249).

In a healthy heart, fibroblasts are quiescent, primarily maintaining ECM homoeostasis by synthesizing and secreting small amounts of ECM components like collagen and fibronectin. When the heart is injured, fibroblasts are activated by factors such as TGF-β, Platelet-derived growth factor, and angiotensin II. This activation triggers downstream pathways, including the Smad and MAPK pathways, prompting fibroblast activation and their differentiation into myofibroblasts (MFB) (248). MFB enhance cellular contractility, exerting tension on myocardial tissue and affecting heart structure and function. They also overproduce and secrete ECM components, leading to excessive ECM deposition in the myocardial interstitial and gradual replacement of myocardial tissue with fibrosis (249). Other signal pathways, such as the Wnt/β-catenin and Notch pathways, are also involved in fibroblast activation and transformation (250, 251).

The SNS and the renin-angiotensin-aldosterone system (RAAS) form a tight “positive feedback” loop in heart diseases. The excitement of SNS can trigger the activation of RAAS, and the activation of RAAS in turn further intensifies SNS activities (244, 252). Central Angiotensin II enhances the excitability of preganglionic sympathetic neurons through the Angiotensin II Type 1 Receptor and increases the release of peripheral NE. The application of angiotensin-converting enzyme inhibitors (ACEI)/angiotensin II receptor blockers (ARB) can block this effect and reduce central sympathetic output (253). Meanwhile, the NE released by the renal sympathetic efferent fibers directly acts on the β1 receptor of parapylebular cells, stimulating the massive secretion of renin through the Gsα/cAMP/PKA signaling cascade, thereby initiating and amplifying the RAAS effect (254). RAAS activation is a key driving force for myocardial fibrosis. Angiotensin II and aldosterone induce the activation of myocardial fibroblasts, promote the synthesis of collagen and ECM (255, 256), and accelerate ECM remodeling by regulating the imbalance of matrix metalloproteinases (MMPs) and their inhibitors (TIMPs) (257, 258). In addition, the inflammatory response mediated by RAAS and the burst of reactive oxygen species (ROS) further aggravate CF and dysfunction. The above-mentioned mechanism reveals that the interactive dialogue between SNS and RAAS plays an important role in the process of CF (259, 260).

The persistent excessive activation of β-AR can cause cardiac pathological remodeling characterized by CF. For example, β-AR activation stimulates IL-18 secretion, promoting inflammation, and induces galectin-3 expression in macrophages, driving fibroblast to MFB transformation and causing CF (261, 262). Galectin-3 can mediate myocardial inflammation and promote CF through the TLR4/MyD88/NF- κB pathway (135). Blocking β-AR signaling will inhibit inflammasomes and improve CF (263). Studies have found that the activation of the β-AR-camp-PKA pathway triggers CF, which may be caused by promoting the expression of ROS, cardiomyocyte connective tissue growth factor, vascular endothelial growth factor, and TGF-β1 to trigger fibroblast proliferation (130, 264). Activating the NE-AR-PKC pathway upregulates BNIP3l expression, promoting cardiac fibroblast proliferation and ECM expression (265). Transient receptor potential (TRP) channels have also been found to regulate the proliferation, migration and differentiation of cardiac fibroblasts, as well as the synthesis and secretion of ECM (266). For instance, TGF- β1 activates TRPM7 channels to promote cardiac fibroblast proliferation, and TRPM7-mediated Ca²⁺ signaling enhances the fibrotic effects of TGF-β1 (267). Activation of TRPV4 can promote the proliferation and migration of fibroblasts (268). Recent studies have shown that methyltransferase-like 3, Insulin-like Growth Factor Binding Protein 3, and Set7 Methyltransferase are also involved in CF. Silencing METTL3 can down-regulate the expression of IGFBP3 and alleviate ISO-induced CF (269). Silencing Set7 also shows inhibition of CF (270).