A novel approach to the prevention and management of cardiovascular diseases: targeting brain–heart axis

Abstract

Epidemiological studies indicate that cardiovascular diseases are the leading cause of death and disability worldwide, imposing a significant socioeconomic burden. Despite continuous medical advancements and new preventive measures offering new prospects for the treatment of cardiovascular diseases, the incidence and mortality rates remain high, presenting a challenging outlook for prevention and treatment. Exploring new strategies for preventing and treating cardiovascular diseases has become particularly urgent. The recent research has shown a close relationship between heart health and brain health. The autonomic neural central network in the brain regulates heart function through efferent activities. Cardiac dysfunction leads to afferent remodeling of the heart, adversely affecting central neural circuits and impairing higher brain functions, hence giving rise to the “brain–heart axis” concept. In the recent years, the concept of the brain–heart axis has been further refined into the brain–heart axis and heart–brain axis. The brain–heart axis has become a new target for preventing and treating cardiovascular diseases. Establishing a comprehensive theoretical and mechanistic framework of the brain–heart axis is essential for enhancing our systematic understanding of the pathophysiological mechanisms of cardiovascular diseases and finding new therapeutic approaches. We will explore brain–heart interactions, including ischemic stroke-induced, stress-induced, and neurodegenerative cardiac damage, and discuss the potential mechanisms behind these interactions. In addition, we will summarize research on targeted brain function activity detection and cardiovascular disease prevention, aiming to provide references for future in-depth research and precision treatment in targeting brain regions for cardiovascular disease prevention.

Cardiovascular diseases (CVDs) are the leading cause of death and disability worldwide, imposing a huge socioeconomic burden. Epidemiology shows that by 2021, approximately 20.5 million people died from CVDs globally, accounting for nearly one-third of the total global deaths [1]. In recent years, along with the incessant progress of medical science, a series of innovative pharmaceuticals, interventional techniques and treatment modalities have been incorporated into the clinical therapeutics of CVDs. Such include novel antiplatelet agents, innovative regimens for cholesterol management, stem cell therapies, and catheter-based cardiac interventional operations. Notwithstanding the fact that these advancements have furnished novel prospects for the treatment of CVDs, the morbidity and mortality rates of CVDs persistently remain at a high level, and the landscape of prevention and treatment remains austere. Consequently, it has become especially exigent to explore novel strategies for the prevention and treatment of CVDs.

In 2019, the World Stroke Organization further proposed the concept of the “Brain–heart axis”, that is, a two-way communication network between the brain and the heart. We believe that the brain–heart connection is bidirectional. The brain–heart axis focuses on the impact of neurological changes on cardiac function. The autonomic nerve central network of the brain regulates cardiac function through its outgoing activities. The heart–brain axis primarily centers on neurological disorders induced by cardiac injury and alterations. Cardiac dysfunction triggers the remodeling of cardiac afferent nerves. This, in turn, exerts a detrimental impact on central neural circuits and compromises higher central functions [2–4]. Thus, in the prevention and treatment of cardiovascular diseases, our focus is more on the brain–heart axis. Studies have revealed that cardiac injury has emerged as the second major cause of acute death following ischemic stroke and also constitutes a significant determinant of long-term survival [5, 6]. Meanwhile, at present, over 1.5 million fatalities across the globe are correlated with neurocardiogenic syndromes, encompassing post-stroke cardiovascular complications, sudden unexpected death in epilepsy (SUDEP), takotsubo syndrome (TTS), and sudden neurogenic cardiac arrest.

Hence, it is of paramount significance to achieve a profound comprehension of the interplay between the cardiovascular system and the nervous system [2]. Establishing a comprehensive theoretical and mechanistic framework of the brain–heart axis is vital for enhancing our systemic understanding of the pathophysiological mechanisms of CVDs and finding new therapeutic methods. In this paper, we comprehensively review the mechanism through which the brain–heart axis modulates the prognosis of cardiovascular diseases. In addition, we explore the feasibility and potential limitations of targeting the brain–heart axis for the treatment and enhancement of the prognosis of CVDs. The purpose is to offer a reference for future, more profound research and precision treatment.

Brain–heart axis

The concept of the brain–heart axis

The brain–heart axis and the heart–brain axis together constitute the brain–heart interaction network. The brain–heart axis refers to the top-down regulatory pathway whereby the brain modulates cardiovascular function. For instance, neurological disorders such as stroke, epilepsy, and Parkinson’s disease can precipitate cardiac injuries, including arrhythmias and Takotsubo cardiomyopathy. Conversely, the heart–brain axis describes the bottom-up influence of the cardiovascular system on central nervous system function. Cardiac pathologies such as heart failure and arrhythmias may lead to neurological impairments, including cognitive decline and mood disorders.

The brain–heart axis is a complex physiological connection existing between the heart and the brain, involving intricate networks such as the autonomic nervous system (ANS), hormones, and cytokines. There is evidence suggesting that the brain–heart axis plays a role in common diseases such as hypertension, congestive heart failure, atrial fibrillation, and metabolic syndrome. This concept encompasses the interactions between the heart and the brain, including the impact of brain injury on the cardiovascular and vice versa. The mechanisms involved in the brain–heart axis include the complex.

Anatomy of the brain–brain–heart axis

The nervous system consists of the central nervous system (CNS) and the peripheral nervous system (PNS), with neurons being the most important participating cells in the nervous system. In the brain–heart axis, the efferent pathway from the brain to the heart begins in the medial prefrontal cortex and insular cortex, ultimately reaching the myocardial cells and coronary artery endothelial cells. In this process, the brain–heart axis successively passes through the cerebral cortex, thalamus, hypothalamus, cerebellum, and brainstem, with the brainstem itself composed of the midbrain, pons, and medulla oblongata (Fig. 1). The cortex is responsible for higher functions, and within the cortical regions, the prefrontal cortex, insula, somatosensory cortex, and limbic system are particularly important in the brain–heart axis. As part of the limbic system, the amygdala and hippocampus regulate emotions, memory, and context through functional connections with the prefrontal cortex. The paraventricular nucleus of the hypothalamus (PVN) is a major effector of the hormonal stress response, which can activate the hypothalamic–pituitary–adrenal axis by secreting adrenocorticotropic hormone. In the medulla oblongata, the rostral ventrolateral medulla (RVLM) is the final common efferent pathway for acute increases in blood pressure and blood flow, stemming from positive inotropic and chronotropic responses of the heart, as well as peripheral arterial and venous constriction. In contrast, the dorsal vagal nucleus (DVN) can receive inputs from the nucleus of the solitary tract (NST) and promote the sending of parasympathetic signals to the heart (Fig. 1).

Fig.1.

The brain–heart axis consists of key autonomic nervous networks and conduction systems. In the coronal plane of the brain, the autonomic nervous networks of the brain–heart axis are illustrated. The efferent routes start from the medial prefrontal cortex and insular cortex and conclude at the myocardial cells and artery epithelial cells. The afferent routes begin with input from chemoreceptors and baroreceptors and eventually reach the insular cortex. DVN dorsal vagal nucleus, NTS nucleus tractus solitarius, PVN paraventricular nucleus, RVLM rostral ventrolateral medulla

At the same time, the afferent pathway from the heart to the brain begins with chemoreceptors and baroreceptors and peaks in the insular cortex. The chemical and pressure signals from the chemoreceptors and baroreceptors reach the thalamus, which is the brain's relay center for sensory signals to the cortex. The thalamus transmits peripheral physiological response signals to the insular cortex, serving as a key integrator for hemodynamic regulation [7].

The brain–heart axis regulates cardiovascular function

The harm of brain damage to heart function

Based on the above content, it is known that the brain can influence heart function through various pathways, including the sympathetic and parasympathetic nervous systems, the RAAS, the HPA axis, immune inflammation, and others. In recent years, a significant amount of research has shown that brain injuries can induce various CVDs, including stroke-related heart dysfunction and stress-related heart disorders. Most of these mechanisms can be encompassed by the aforementioned pathways. We characterize brain injury illnesses as follows: brain injuries with definite etiology, such as stroke; neurological disorders linked to stress; post-traumatic sequelae, such as post-traumatic stress disorder (PTSD); and degenerative diseases with unexplained causation. The following sections will provide a detailed introduction to the CVDs that may result from brain injuries (Fig. 2).

Fig.2.

Common brain injuries and the CVDs they cause. The diagram shows that brain injuries caused by stroke, stress, PTSD, etc., result in arrhythmias, heart failure, coronary artery damage, Takotsubo syndrome, and hypertension. PTSD: post-traumatic stress disorder

Acute ischemic stroke-related cardiac insufficiency

Acute ischemic stroke (AIS) is one of the most severe cerebrovascular diseases. Although neurological damage remains the primary cause of death from stroke, cardiovascular complications are also a significant cause of post-stroke mortality [8]. In 1947, BYER and colleagues first reported that cerebrovascular disease can lead to myocardial injury and arrhythmias. Since then, stroke-related cardiac dysfunction has drawn widespread attention [9]. Recent studies indicate that the incidence of cardiovascular events post-stroke is approximately 20%, making it the second leading cause of death among stroke patients, with most events occurring within three days of the stroke [6]. About 4% of patients with cerebral hemorrhage experience a series of cardiac complications within two days, including acute myocardial infarction, ventricular fibrillation, acute heart failure, and cardiac death. Among these, acute heart failure is the most common severe in-hospital cardiac event [10, 11].

Post-stroke cardiovascular events, also known as “stroke heart syndrome” (SHS), mainly include the following five types: ischemic and nonischemic acute myocardial injury, accompanied by elevated cardiac biomarkers, usually asymptomatic; acute myocardial infarction post-stroke; left ventricular dysfunction, heart failure, and stress-induced cardiomyopathy post-stroke; electrocardiographic changes and arrhythmias; and post-stroke neurogenic sudden cardiac death [4].

The damage of cardiovascular system caused by nervous system disorder after stroke

The impairment of central nervous regulation of cardiac autonomic function caused by stroke is considered one of the reasons for cardiovascular system damage [4]. As one of the earliest recognized neurocardiological manifestations, sudden cardiac death post-stroke may be related to the excessive activation of the sympathetic nervous system [12]. Research has shown that the dorsal anterior insular cortex controls the cardiac parasympathetic nervous system, and ischemia in this area can lead to autonomic dysfunction, causing overactivation of sympathetic activity and inducing myocardial injury [13]. A catecholamine storm can result in contraction-band necrosis (CBN) and mitochondrial dysfunction. A study reported that CBN was observed in approximately 26% of nonbrain-death patients, the proportion increased to 89% in patients with SAH, and to 52% in patients with ischemic stroke [14]. Previous studies have indicated that although women have a lower risk of stroke than men, the brain–heart interaction has a greater impact on women due to the higher physiological and pathological activity levels in their nervous systems [14]. Additionally, stress-induced cardiomyopathy, which occurs after an acute cerebrovascular event, is independently associated with stroke mortality and increases the in-hospital mortality rate by more than threefold [15]. The incidence of stress-induced cardiomyopathy is approximately 0.5% to 1.2%, so it is clinically necessary to enhance screening for stress-induced cardiomyopathy or “neurogenic stunned myocardium” in stroke patients [16].

Impairment of cardiovascular system by ischemia after stroke

In clinical cases, initial cardiac troponin (cTn) level testing within 4.5 h of stroke symptom onset can improve the diagnostic efficiency of acute myocardial infarction (AMI), with a sensitivity of 90.9% and specificity of 74.8%. For patients with AIS, a higher cTn level corresponds to a mortality rate of 14.7%, which is six times higher than that of patients with normal levels. Basic research also indicates that 24 h after middle cerebral artery occlusion (MCAO), mice show a fourfold increase in cTn levels, correlating with increased mortality.

A recent meta-analysis estimated an incidence rate of 1.7% per year, encompassing 58 studies with a total of 130,000 patients. Among patients without known heart disease, 2.6% to 3.0% experience AMI within one year after their first AIS. Acute myocardial infarction patients hospitalized post-AIS face a doubled risk of death at discharge and within one year.

A cohort study involving 21,931 ischemic stroke patients revealed an eightfold increase in atrial fibrillation (AF) incidence post-stroke compared to propensity-matched individuals without stroke [17]. Detection rates of AF post-stroke largely depend on the duration of electrocardiographic monitoring. Studies suggest that extending monitoring time could uncover new-onset AF in up to 1/4 of stroke patients [18–20].

Additionally, a thrombolysis study on acute ischemic stroke patients found that 31% also had left ventricular dysfunction, with only 32% diagnosed before the stroke [21]. Among cerebral hemorrhage patients, about 7.2% had left ventricular dysfunction [22]. Post-stroke, AF incidence in this cohort was approximately 1/4 of the follow-up population [20]. Thus, it can be inferred that ischemia following acute ischemic stroke leads to significant changes in cardiac macrovasculature.

Stress-related cardiac insufficiency

Stress, also known as pressure, is a natural adaptive response of organisms to internal and external environmental stimuli. The core lies in the individual's brain's perception of stressors, which then activates physiological responses within the body to cope with potential threats. Since the concept of "stress" was widely accepted in the medical field, subsequent research has proven a close connection between stress and CVDs. Psychological stress can also induce heart failure. As early as the 1810s, doctors observed that mental stress in angina patients could exacerbate the course of the disease. Modern research has further revealed the association between stress and the increased incidence of CVDs as well as adverse outcomes [23]. The following sections will specifically discuss the impact of stress (including acute stress and chronic stress) on cardiovascular events.

Stress increases the incidence of CVDs

In the stress response, the HPA axis and the ANS play crucial roles. During acute stress, the amygdala facilitates the inactivation of the PNS and activates the sympathetic-adrenal-medullary (SAM) system and the HPA axis, rapidly releasing cortisol, catecholamines, and other substances, which collaboratively increase heart rate, blood pressure, systemic vascular resistance, and cardiac output [23, 24]. Interestingly, after these stressors are removed, these physiological responses quickly normalize through negative feedback regulation, but can still transiently cause temporary left ventricular systolic dysfunction and myocardial ischemia [25, 26].

In the case of chronic stress, the sustained activation of the HPA axis and excessive secretion of hormones like cortisol lead to cortisol resistance and inflammation, resulting in abnormal glucose and lipid metabolism, endothelial dysfunction, blood pressure fluctuations, plaque formation or rupture, and coronary artery thrombosis [27]. Additionally, the continuous activation of the sympathetic nervous system (SNS) and persistent inhibition of the PNS lead to increased cardiovascular tension, platelet activation and aggregation, and coagulation, further exacerbating endothelial dysfunction and inflammation, thereby increasing the risk of CVDs [28].

Clinical studies have found that stress increases the incidence of CVDs by 15% to 50% [29, 30], with a recurrence risk of up to 35% within ten years. Similar to stroke risk, women are more susceptible to stress-induced cardiovascular events [31]. The prevalence of coexisting psychological disorders and CVDs due to prolonged or excessive stress ranges from 13 to 40% [32]. Both acute and chronic stress events increase the risk of adverse cardiovascular events and mortality [23]. Stress-related physiological dysregulation increases all-cause mortality and cardiovascular disease mortality by 22% and 31%, respectively [33]. The following sections will specifically describe the impact of stress on common cardiovascular events.

Hypertension

Stress induces glial cells and neurons to produce pro-inflammatory cytokines, which trigger hypertension through vascular inflammation and activation of the RAAS [34]. This occurs because the brain's sympathetic efferent nerve transmission is influenced by the hypothalamic PVN, the RVLM, and pathways from the insular cortex to the NST and peripheral tissues [35]. Continuous stimulation of the sympathetic nervous system affects the heart, peripheral vascular system, and kidneys, leading to increases in blood pressure, cardiac output, vascular resistance, stiffness, and fluid retention [36]. This, in turn, creates a vicious cycle of hypertension progression.

Congestive heart failure

During the stress response, there is a sustained effect of neuroendocrine hormones, accompanied by dysregulation of inflammatory factors such as TNF-α, IL-1, IL-6, IL-8, IL-10, myeloperoxidase (MPO), inducible nitric oxide synthase (iNOS), and CRP [37], leading to congestive heart failure. Throughout the course of congestive heart failure, persistent sympathetic nerve activity and RAAS activity have been demonstrated to be implicated in chronic preservation and decline of ejection fraction leading to cardiogenic shock [38, 39]. Hypothalamic nuclei such as the PVN and medullary nuclei such as the RVLM and caudal ventrolateral medulla (CVLM) are the most active brain nuclei during congestive heart failure [40].

Coronary artery injury

Changes in emotions, particularly stress, can contribute to heart malfunction. Provocative events, such as public speaking, might create asymptomatic wall motion irregularities under low heart rate settings [41]. In individuals with established epicardial coronary artery disease (CAD), mental stress-induced myocardial ischemia (MSIMI) has been demonstrated to occur at a lower rate-pressure product level compared to exercise-induced ischemia [42]. A research demonstrated the association between emotional stress and the probability of cardiac events. During the World Cup in Germany, the incidence of acute coronary syndrome or arrhythmias increased by 3.3% in men and 1.8% in women compared to ordinary periods [43]. This behavior is ascribed to both acute and chronic stress impacting the immune system, notably through immunological inflammation [44, 45].

Takotsubo syndrome (TTS)

The most frequent condition in brain–heart axis is TTS, also known as stress-induced cardiomyopathy. Patients with mental or physical stress triggers might abruptly develop congestive heart failure, marked by ballooning of the left ventricular apex. TTS is an acute cardiac condition distinguished by transitory and typically reversible left ventricular systolic failure [25]. It is a rather rare disorder, with an incidence rate of 0.6% to 2.5% and a prevalence of 2%. Among all hospitalized patients throughout the year, TTS accounts for 0.018% to 0.02%. Stress is the most prevalent cause, with physical stressors accounting for 39% to 55% and mental stressors accounting for 17% to 33% [46]. In TTS patients, women outweigh males, with 90% of female patients being postmenopausal [47]. Although the frequency is higher in women, males have higher complication rates and death [48]. In individuals with stress-induced cardiomyopathy, catecholamine levels exceed those reported in myocardial infarction (MI) [49]. Excessive catecholamine stimulation affects the calcium homeostasis of myocardial cells, resulting to hypercontraction of sarcomeres, increased oxidative and metabolic stress, and decreased coronary microcirculation. Over time, increased catecholamine release induces severe histological alterations in cardiac cells, including inflammatory cell infiltration, higher extracellular matrix protein levels, and contraction band necrosis, known as myolysis [50].

Stress-induced vascular dysfunction is typically a critical element in the development of cardiovascular illnesses. The vascular adventitia is regulated by the ANS, with the nerve fiber ends in touch with adventitial mast cells. The adventitia and the smooth muscle cells of the media act together to control vasodilation and vasoconstriction. Under stress, the ANS releases neurotransmitters such as norepinephrine, leading to vasoconstriction and increased arterial pressure [51]. Additionally, sympathetic nerve fibers emit molecules including substance P and calcitonin gene-related peptide, which trigger mast cell degranulation and the production of vasoactive compounds such as histamine and leukotrienes. This induces vasodilation and increased permeability, promoting stress reactions including sweating. Moreover, stress-induced degranulation of adventitial mast cells leads to the instability of atherosclerotic plaques, intraplaque bleeding, and myocardial infarction [52].

Post-traumatic stress disorder-related cardiac insufficiency

PTSD is an anxiety condition produced by exposure to traumatic situations such as battle, natural disasters, sexual assault, and more. It is characterized by symptoms including re-experiencing the traumatic experience (e.g., intrusive thoughts, nightmares), cognitive or behavioral avoidance of reminders of the incident, and physiological hyperarousal. The brain–heart axis, which links the frontal and limbic parts of the brain to the brainstem and peripheral systems via the autonomic nervous system, is linked with aberrant amygdala, prefrontal cortex, and hippocampus functioning, as well as abnormal neuroendocrine aspects [53, 54]. These parallels with the neurological impairments in PTSD imply that the brain–heart axis might be a potential paradigm for explaining the elevated CVDs risk in PTSD.

PTSD is a neuropsychiatric illness associated to an increased risk of cardiovascular problems. Many physiological mechanisms are implicated in these disease states, including ANS dysfunction (e.g., increased heart rate, elevated blood pressure), neurohumoral system dysfunction (e.g., renin–angiotensin system, adrenal axis, cortisol), systemic inflammation, metabolic dysfunction, and maladaptive health behaviors (e.g., smoking, poor diet). Longitudinal studies have shown that individuals with PTSD or elevated PTSD symptoms have a higher incidence of various cardiovascular events and conditions, including myocardial infarction, coronary heart disease, stroke, and heart failure, suggesting that PTSD may be a modifiable risk factor for CVDs [55–58]. A review has summarized five prospective cohort studies, involving a total of 401,712 participants, estimating the relationship between PTSD and cardiovascular events and/or mortality. The effect sizes ranged from a risk ratio of 1.46 to 3.28 for CVDs and/or cardiac death, indicating the detrimental impact of PTSD on CVDs [59]. While PTSD is usually considered a risk factor for CVDs, most studies are cross-sectional and do not provide direct evidence of a causative connection [60]. Similarly, CVDs incidents can also elicit PTSD, thereby raising later CVDs risk. Therefore, more extensive study is needed in the future to completely understand the link between PTSD and CVDs.

The potential mechanisms by which the brain regulates cardiovascular diseases

In recent years, people have conducted detailed explorations of the interactions between the mechanisms of the brain and the heart, explaining the impact of brain injuries on the heart and the effects of heart failure on the brain [61]. At the molecular level, the advancement of the brain–heart axis reveals complex crosstalk mediated by the sympathetic and parasympathetic nervous systems, the renin–angiotensin–aldosterone system (RAAS), the hypothalamic–pituitary–adrenal (HPA) axis, microRNAs, and cytokines. Afferent pathways amplify pro-inflammatory signals to the periphery through the hypothalamus and brainstem, promoting neurogenic inflammation. At the organ level, cardiac dysfunction may be caused by various types of nerve damage. The study of the brain–heart axis also involves the mechanisms of cardiac dysfunction after stroke, including the activation of the HPA axis, regulation of the sympathetic and parasympathetic nervous systems, catecholamine surge, gut microbiota dysbiosis, immune response and inflammatory reactions, and the release of microvesicles and microRNA. In addition, the brain–heart axis is also related to atrial fibrillation. Atrial fibrillation is not only a pathogenic factor for cardiogenic stroke but also a manifestation of atrial substrate abnormalities, which can lead to the development of stroke unrelated to atrial fibrillation.

In the brain–heart axis, the main mechanisms through which the brain affects the heart include the ANS and the HPA axis [62], the renin–angiotensin–aldosterone system, immune and inflammatory responses [63], metabolic disorders, and other factors [64]. These also include the major risk factors involved in the onset of acute ischemic stroke (AIS) (age, sex, race, hypertension, smoking, diet, lack of physical activity) [65] and factors related to changes in the nervous system (gender, stress, etc.). Leading to ANS dysregulation and high inflammation, thereby inducing cardiac dysfunction in patients [66].

Autonomic nervous system dysfunction

The neural communication within the brain–heart axis involves both the sympathetic and parasympathetic branches of the ANS. The sympathetic pathway comprises a series of neural connections originating from the intermediolateral cell column located in the lateral horn of the thoracic and upper lumbar spinal cord segments. Preganglionic fibers from this region descend to the paravertebral ganglia, also known as the sympathetic chain, where some synapse with postganglionic neurons. These postganglionic fibers then travel along blood vessels—including the coronary arteries—toward the cardiac plexus. Ultimately, sympathetic fibers reach the sinoatrial node, atrioventricular node, ventricular myocardium, and coronary arteries, where norepinephrine released from sympathetic nerve endings activates adrenergic receptors, predominantly β-adrenergic receptors. The “fight or flight” response of the catecholaminergic storm following HPA axis and ANS activation is mediated at the molecular level by the activation of the forkhead box O (FOXO) gene [67, 68]. Norepinephrine stimulates receptors; this, in turn, activates the cyclic adenosine monophosphate-protein kinase A (cAMP-PKA) signaling pathway, leading to the release of calcium from the sarcoplasmic reticulum (Fig. 3.A). During this phase, the outflow of K⁺ is considerably limited, helping to preserve the excitability and contractility of cardiomyocytes for cell contraction. This chain of responses suppresses the Iₖₛ repolarizing K⁺ current, avoiding the excessive lengthening of the action potential (QT interval). At the same time, norepinephrine activates β2-adrenergic receptors, which through the protein kinase B (Akt)-FOXO pathway, reduce ubiquitin-mediated protein degradation, thereby regulating the protein homeostasis balance and maintenance of myocardial mass in cardiomyocytes.

Fig.3.

The four mechanisms of the brain–heart axis can be illustrated as follows: A The impact of ANS dysregulation on cardiac function, resulting in changes in myocardial contractility. B The mechanisms by which endocrine system dysfunction affects the cardiovascular system. The two classical pathways, HPA and RAAS, are shown. C Brain injury leading to localized and systemic inflammation. D Brain injury causing gastrointestinal dysfunction, dysbiosis of the gut microbiota, and bacterial translocation into the bloodstream, leading to distal inflammatory immune responses and further brain damage. AC adenylate cyclase, Ach acetylcholine, ACTH Adrenocorticotropic Hormone, AIS acute ischemic stroke, Akt protein kinase B, β1-R beta1-adrenergic receptor, β2-R beta2-adrenergic receptor, cAMP cyclic adenosine monophosphate, CRH corticotropin releasing hormone, FOXO forkhead box O, HPA hypothalamic-pituitary axis, ICAM intercellular adhesion molecule, IK-Ach acetylcholine-sensitive K⁺channel, IL-1β interleukin-1β, IL-6 interleukin-6, M2-R M2 muscarinic receptors, PKA protein kinase A, RAAS renin–angiotensin–aldosterone system, TNF-α tumor necrosis factor, VCAM vascular cell adhesion molecule

The vagus nerve, the tenth cranial nerve, is a key component of the parasympathetic system. It originates from two nuclei in the medulla oblongata: the dorsal vagal nucleus and the nucleus ambiguus. After exiting the medulla, the vagus nerve descends via the preganglionic vagus efferent fibers and bifurcates at the level of the carotid arteries into left and right branches. These branches traverse the thoracic cavity and reach the cardiac plexus, from which multiple vagal fibers extend to innervate the sinoatrial node, atrioventricular node, atria, and to a lesser extent, the ventricles—specifically the bundle of His and Purkinje fibers [69]. These nuclei are connected to the epicardial ganglia, communicating through postganglionic fibers that release acetylcholine and vasoactive intestinal peptide. Acetylcholine slows down depolarization by binding to M2 muscarinic receptors (M2-R), reducing intracellular cyclic adenosine monophosphate levels. Meanwhile, at the same time, the M2 receptor is coupled to G protein, activates the acetylcholine-sensitive K⁺channel (IK-ACh) through the β/γ subunit of G protein, increases the outflow of potassium ions, hyperpolarizes the cardiomyocyte membrane, increases the absolute value of the resting potential, and decreases the excitability of cardiomyocytes(Fig. 3A). Activation of those pathways lead to prolonged atrioventricular conduction time and decreased ventricular contractility. The ANS transmits damage signals between the brain and body through neuroimmune communication circuits. Inhibiting sympathetic excitation can suppress harmful neurogenic immune activation and catecholamine-induced cardiac toxicity [70].

When cardiovascular pathology precedes neurological changes, sensory receptors located in the heart and blood vessels transmit afferent signals via vagal C fibers to central nuclei such as the NTS. This ascending pathway modulates heartbeat perception and emotional tagging. Meanwhile, afferent sympathetic pathways ascend to the thalamus and insular cortex, contributing to phenomena such as referred pain in angina pectoris and amplification of central inflammation.

Endocrine system dysfunction hypothalamic–pituitary–adrenal axis

The catecholamine surge hypothesis is one of the main mechanisms of brain–heart interaction, linking cardiac dysfunction with physical or emotional stressors. The HPA axis is the major regulator of the body's hormones that integrate emotions, stress, physical activity status, and metabolism [71]. The HPA axis is a vital component of the neuroendocrine system, comprising complex interactions among the hypothalamus, pituitary gland, and adrenal glands. The paraventricular nucleus of the hypothalamus is the primary control center of the HPA, secreting corticotropin-releasing hormone, vasopressin, and other corticotropin-releasing factors, which stimulate the pituitary gland to release Adrenocorticotropic Hormone (ACTH), especially under stress conditions. ACTH stimulates the adrenal glands to release the steroid hormone cortisol (Fig. 3B). Elevated serum cortisol levels can exacerbate stroke severity and insular damage. More critically, prolonged elevation of cortisol may have neurotoxic effects and increase post-stroke mortality rates. Furthermore, adrenocorticotropic hormone activates the adrenal glands to release cortisol. Subsequently, catecholamines bind to β1-adrenergic receptors (β1-R), altering intracellular calcium ion levels, inducing oxidative stress, reducing adenosine triphosphate synthesis, leading to osmotic swelling, and causing myocardial cell death [72].

Renin–angiotensin–aldosterone system

The RAAS plays a crucial role in maintaining circulatory homeostasis. Angiotensin II stimulates the adrenal cortex to release aldosterone, leading to increased renal reabsorption of sodium and water, thus affecting blood pressure levels [73]. Although the role of aldosterone has traditionally been considered limited to the kidneys, multiple studies indicate that central activation of the RAAS contributes to the development of hypertension and heart failure [74]. Indeed, in salt-sensitive rats, the injection of aldosterone into the lateral ventricles promotes the development of hypertension, while the administration of mineralocorticoid receptor antagonists, such as spironolactone, in the lateral ventricles prevents this phenotype [75]. Beyond its impact on blood pressure, the RAAS also regulates metabolic signaling and heart rhythm. In TG (mRen2) 27 transgenic rats, which exhibit increased tissue RAAS activity, renin inhibition improved systemic insulin sensitivity, insulin metabolic signaling, and glucose transport [76]. Additionally, aldosterone regulates peripheral insulin resistance, further supporting its involvement in CVDs [77]. Moreover, RAAS activation modulates membrane ion channels and sarcoplasmic reticulum ion channels, with its activation having pro-arrhythmic effects [78]. Studies in patients with depression have shown that hyperaldosteronism is common among them, suggesting that elevated aldosterone levels may be a mediating factor linking depression with adverse vascular events [79]. These findings imply that the role of RAAS in the brain might be more significant than previously thought, and a better understanding of this pathway may help elucidate how chronic stress and depression trigger CVDs.

Natriuretic hormones

Natriuretic peptides (NPs) are a family of small peptides that function both as cardiovascular hormones and neuromodulators. The primary members include atrial natriuretic peptide (ANP), brain natriuretic peptide (BNP), and C-type natriuretic peptide (CNP). Their actions span multiple organ systems, including the heart, vasculature, kidneys, and brain. ANP and BNP are predominantly secreted by atrial cardiomyocytes, while CNP is mainly produced by vascular endothelial cells. NPs play a critical role in blood pressure regulation, vasodilation, and bronchodilation. They exhibit anti-inflammatory and metabolic effects, reduce preload, afterload, and volume overload, and inhibit the amplification cascades of the RAAS and SNS. This dual blockade forms a “blood pressure-lowering and anti-remodeling” safeguard. Notably, NP receptors are widely expressed in the CNS, where NPs act as neurotransmitters and neuromodulators involved in higher-order brain functions [80]. They are increasingly recognized not only as “sensors of cardiac load” but also as “regulators of brain homeostasis,” offering multi-target protection in areas such as neuroinflammation, cognition, emotion, and blood–brain barrier integrity.

Neuropeptide Y

Neuropeptides are signaling molecules composed of 3 to over 40 amino acids. They function both as fast-acting neurotransmitters or neuromodulators and as hormone-like messengers that diffuse through the bloodstream or cerebrospinal fluid to distant organs. Distributed in a network-like fashion across the brain and cardiovascular system, neuropeptides form a key molecular layer of the bidirectional heart–brain axis [81, 82]. Among them, neuropeptide Y (NPY) plays a central role in regulating heart rate, blood pressure, and emotional intensity via the amygdala–insula–nucleus tractus solitarius circuit. NPY modulates autonomic function by inhibiting the release of NE and acetylcholine, which drive sympathetic and parasympathetic activity, respectively. Under stress, sympathetic neurons co-release NPY and NE, leading to coronary vasoconstriction and increased heart rate, which may culminate in myocardial ischemia. NPY also suppresses parasympathetic preganglionic neurons, disrupting the circadian rhythm of blood pressure. In addition, NPY can independently induce vasoconstriction, elevate blood pressure, and trigger ventricular tachycardia. Although NPY’s inhibition of NE release may occasionally attenuate vasoconstriction, its direct vasoconstrictive effects dominate under pathophysiological conditions such as heart failure, hypertension, and acute stress [83, 84].

The immune system activates—inflammation

Due to the complex interplay between cerebrovascular and cardiovascular conditions, it is imperative to determine whether cardiac dysfunction is caused by brain injury and to understand its underlying mechanisms. Studies have shown that acute brain injury induces a sterile, systemic inflammatory response [85], exacerbating poor outcomes and increasing the risk of complications such as vasospasm, delayed cerebral ischemia (DCI), and pulmonary edema [86, 87]. These findings suggest that cardiac dysfunction may be caused by systemic dysfunction or inflammatory responses. On one hand, brain injuries, such as stroke, affect acute cardiac function, where neuronal damage in specific areas, including the insular cortex, directly impacts heart rate and ventricular pressure [88]. During this process, inflammatory cells are simultaneously activated [89], including the infiltration of circulating monocytes and macrophages into the peri-infarct zone within days after the injury. Microglia in the nervous system exhibit an M1 phenotype, promoting inflammatory responses through the release of pro-inflammatory cytokines or chemokines, including interleukins (IL-6, IL-1β), tumor necrosis factor (TNF-α), integrins, vascular cell adhesion molecule (VCAM), intercellular adhesion molecule (ICAM), and chemokines. These pro-inflammatory molecules mediate the recruitment of immune cells and the induction of systemic inflammation. Additionally, CD74-positive cells (including monocytes, macrophages, and dendritic cells) play a critical role in regulating the immune response after stroke (Fig. 3C). Studies have reported a significant increase in the number of CD74-positive cells in the peripheral circulation of patients with ischemic stroke. Chronically activated macrophages, through the action of TNF-α and IL-1β on endothelial nuclear factor-κB, disrupt the integrity of the blood–brain barrier and the permeability of distal organ barriers, interfering with the neurovascular unit [90]. While, acute myocardial infarction triggers a robust inflammatory response, leading to the release of pro-inflammatory cytokines such as IL-1β, IL-6, and TNF. These cytokines are capable of crossing the blood–brain barrier and activating microglial cells within the brain, thereby initiating neuroinflammation—a process potentially linked to cognitive impairment and depressive symptoms [91].

A series of research evidence suggests that neurogenic pro-inflammatory actions play a significant role in cardiovascular risk. In neurological disorders such as epilepsy and stroke, neuronal activity can be influenced by cytokines [92, 93]. In CVDs, cytokines play a role in the comorbid presentation of hypertension, chronic heart failure, metabolic syndrome, and stroke [34, 38, 94]. Furthermore, clinical data indicate that patients diagnosed with CVDs exhibit higher levels of pro-inflammatory factors in their blood, such as interleukins (IL-1α, IL-6), TNF-α, and C-reactive protein (CRP) [95, 96]. In Alzheimer's disease (AD), the accumulation of lipid droplets (LDs) is common1. Neurons transfer these LDs to microglia, leading to neuroinflammation1. Furthermore, Chronic inflammation is a hallmark of various cardiovascular and neurological disorders, including atherosclerosis, hypertension, and heart failure. Persistent inflammatory activity can compromise cerebral vasculature, resulting in cognitive decline and an elevated risk of dementia [97, 98]. In animal models of hypertension and heart failure, the injection of pro-inflammatory and anti-inflammatory factors into the central nervous system significantly affects sympathetic outflow, arterial pressure, and cardiac remodeling [99]. Animal models show a correlation between hypertension and levels of pro-inflammatory factors. Both pro-inflammatory and anti-inflammatory factors interact with components of the brain's renin–angiotensin system (RAS) to regulate blood pressure [100].

Studies have reported an interaction between sympathetic nervous activity and inflammatory responses in the progression of hemorrhagic and ischemic strokes [101–103]. Pro-inflammatory cytokines from damaged cells can increase sympathetic output and catecholamine levels in the blood by stimulating the posterior hypothalamus. Catecholaminergic stress coincides with the entry of immune cells into the heart, inducing cardiac injury in patients with subarachnoid hemorrhage (SAH). Additionally, the release of catecholamines and dysfunction of the parasympathetic nervous system can exacerbate myocardial dysfunction, leading to myocardial cell death. In the heart, β1-adrenergic stimulation triggers oxidative stress and calcium overload, which easily leads to myocardial cell damage. Therefore, inflammation is not only a factor in the development and progression of CVDs but also a crucial link in brain–heart interaction.

Digestive system metabolic disorders

In recent years, gut microbiota has become a hot topic in the research of various systemic diseases. Experimental studies have revealed the close links between gut microorganisms and cardiac dysfunction (the gut–heart axis, GHA), as well as the central nervous system (the gut–brain axis, GBA) [64, 104]. The gut–blood barrier is the body’s primary defense against toxins and pathogenic microorganisms, regulating the absorption of water and nutrients [105]. However, in certain diseases, including metabolic diseases, gastrointestinal diseases, CVDs, and cerebrovascular diseases, the integrity of the gut–blood barrier is compromised, leading to increased permeability and allowing microbial-derived molecules to enter [106] (Fig. 3D). The GBA is mediated by neural and humoral pathways and a wide array of signaling molecules, including cytokines, chemokines, hormones, and peptides, playing a crucial role in regulating immune responses and lymphocyte populations [107, 108]. The gut–brain axis can influence normal brain function and induce pathological cascades in neurological events [109], particularly in stroke. Dysbiosis of the gut microbiota induced by acute brain injury can activate neuroinflammation and immune responses in the brain, subsequently impairing neurological function [110]. Increased gut permeability has been observed after brain injury, promoting bacterial translocation to lymph nodes and various organs, including the liver, spleen, and lungs, and activating immune responses, which correlate with the severity and poor prognosis [111]. Additionally, studies have found that gut microbiota dysbiosis and elevated bacterial counts are associated with systemic inflammation in ischemic stroke patients, while bacterial metabolites mediate the balance between gut microbiota and pro-inflammatory immune responses [112, 113].

A clinical study reported that dysbiosis of the gut microbiota, characterized by increased levels of opportunistic bacteria and reduced levels of beneficial bacteria, can be observed in patients with large artery atherosclerotic ischemic stroke or transient ischemic attack (TIA). The elevated levels of Proteobacteria in the gut are positively correlated with the severity of the stroke [114]. Furthermore, commensal gut bacteria have a protective effect against brain damage caused by ischemic stroke, and their depletion or imbalance can lead to increased post-stroke mortality and affect post-stroke outcomes. It has been reported that gut dysbiosis induced by ileus alters the hemostatic function of T lymphocytes, involving the migration of T lymphocytes from the gut to the brain and the activation of pro-inflammatory responses, which further worsen post-stroke brain damage and lead to poor clinical outcomes [115]. Previous studies using a transient focal cerebral ischemia mouse model reported that gut T lymphocytes are transported to the meninges, where they induce neuroinflammation and the release of IL-17, further promoting the infiltration of immune cells into the damaged brain and enhancing the secretion of pro-inflammatory cytokines [116]. Dysbiosis is associated with post-stroke systemic inflammation, partially mediated by the microbial-immune crosstalk regulated by bacterial metabolites [117]. The vagus nerve innervates the gut–brain axis, maintaining gut barrier integrity and symbiosis through vagal signaling [118]. Preclinical models have shown that vagus nerve stimulation inhibits circulating TNF-α and IL-1β, reducing neuroinflammation [119]. Modulating the neuro-gut pathways may help reshape the post-stroke immune landscape. Multi-targeted therapies combining prebiotics, probiotics, dietary nutrients, and neurostimulation techniques hold promise for suppressing inflammation in distal organs by modulating host-microbiota crosstalk.

Acquiring insights on the brain–heart axis: surveillance and risk evaluation

Brain damage is an essential component in the incidence of cardiovascular events and strongly determines the course of the illness. Electrocardiographic abnormalities, myocardial damage, and arrhythmias commonly occur in acute stroke patients, even in the absence of intrinsic heart disease, showing a close contact between the brain and the heart [120]. Therefore, knowing the link between the two and effectively recording signals from this network is vital. Clinically, there are equivalent ways to monitor the pathophysiological changes emanating from the brain–heart axis. The next part will discuss the study on auxiliary technological approaches used to evaluate the brain–heart axis.

Hemodynamics

In the intricate network of the brain–heart axis, the neurological system continuously governs the cardiovascular system. When a section of this enormous working machine fails, it appears in other places. Among these clinical symptoms, alterations in hemodynamics are frequently the first and most obvious. Yujie Bai and colleagues observed a link between neuro-metabolism and ventricular dyssynchrony in patients with heart failure with reduced ejection fraction (HFrEF), as well as a correlation between neuro-metabolism and major arrhythmic events (MAEs) [121].

As is generally known, the ANS controls cardiac function through the brain–heart axis. In heart failure, numerous mediated signals along the brain–heart axis interact with the neuro-metabolic system, impacting the course of HF. This study comprised 197 HFrEF patients who received gated single-photon emission computed tomography (SPECT) cardiac perfusion imaging and 18F-fluorodeoxyglucose positron emission tomography/computed tomography (PET/CT) of the brain. The Cox model and mediation analysis were used to examine the association between brain metabolism and MAEs, and to construct and compare the central autonomic neural networks of individuals with and without MAEs. During a median follow-up of 3.1 years, 35 (17.8%) patients suffered MAEs. Compared to patients without MAEs, HFrEF patients experiencing MAEs (age 58, left ventricular ejection fraction 20.0%) showed decreased glucose metabolism in the insula, hippocampus, amygdala, cingulate gyrus, and caudate nucleus, which were independent predictors of MAEs (all P < 0.05). Brain hypometabolism was connected with ventricular dyssynchrony, which is a key risk factor for MAEs. Furthermore, individuals experiencing MAEs revealed reduced connectivity in the central autonomic neural network compared to those without MAEs (P < 0.05). The study illustrates the link between the neuro-metabolic-ventricular dyssynchrony axis through variations in cardiac ejection fraction. This novel brain–heart axis could increase our understanding of distinct pathogenic pathways in HFrEF.

In a consensus publication on TTS, Christian Templin and colleagues tried to employ functional magnetic resonance imaging (fMRI) to track the association between TTS and alterations in brain functional connectivity [25]. The study suggested that areas of the brain responsible for autonomic integration and/or limbic system processing could be implicated in the development of TTS. They examined the resting-state fMRI functional connectivity of TTS patients with healthy controls to discover alterations in brain areas related with autonomic function and limbic system modulation. The research comprised 15 TTS patients and 39 healthy controls. Resting-state functional connectivity was examined using fMRI, and networks relating to the sympathetic and parasympathetic nervous systems, as well as the default mode network, were established. Notably, compared to healthy controls, TTS patients demonstrated lower resting-state functional connectivity in networks relevant to the parasympathetic and sympathetic nervous systems. Key brain regions implicated included the amygdala, hippocampus, insula, and parts of the cingulate, parietal, temporal, and cerebellar regions. Additionally, the default mode network and limbic system areas in whole-brain analysis also exhibited lower functional connectivity. This study was the first to indicate decreased connectivity in central brain areas associated to autonomic function and limbic system modulation in TTS patients. These findings show that autonomic-limbic integration may play a crucial role in the pathogenesis of TTS, adding to a better knowledge of the condition. This paper gives fresh neurobiological insights into the link between TTS and alterations in brain functional connectivity using fMRI and bears promise as a possible path for future clinical evaluation of TTS.

Biological marker

The changes in the cardiovascular system caused by neurological illnesses are classified as the brain–heart axis, which can lead to major modifications in cardiac function, indicated in the biochemical detection of cardiac biomarkers [122, 123]. Cardiac problems post-stroke are the second biggest cause of mortality globally, influencing the care and prognosis of stroke patients. Cardiac biomarkers such as cTn, brain natriuretic peptide (BNP), N-terminal pro-brain natriuretic peptide (NT-proBNP) and Adipsin are commonly reported in stroke patients. Therefore, clinically, emphasis should be paid to the signs of heart damage and dysfunction reflected by these biomarkers to guide optimal therapy. A clinical review study indicated that cTnI concentrations are considerably higher in individuals with cerebral hemorrhage. BNP levels are high in individuals with cerebral infarction, whereas NT-proBNP concentrations are considerably raised in both acute ischemic stroke and cerebral hemorrhage patients, indicating cardiac damage and dysfunction post-stroke. The rise in cardiac biomarkers post-acute ischemic stroke and cerebral hemorrhage implies cardiac damage and dysfunction following stroke [124]. Furthermore, the latest research indicates that the serum Adipsin level can effectively predict the risk level of CVDs and the mortality rate after the event [125, 126]. These biochemical tests of biomarkers can assist in establishing supplementary diagnoses and act as indications of myocardial damage in stroke patients, identifying individuals at high risk for cardiac events. Clinicians, while focused on the treatment of cerebrovascular illnesses, should also evaluate cardiac biomarkers to give more early and precise therapy.

Electroencephalogram (EEG)

One proposed route by which the ANS regulates cardiac function is by monitoring variations in ANS activity, which has proven an efficient technique of anticipating changes in cardiac function. Utilizing the temporal resolution given by EEG data and various computer models of the brain–heart axis to noninvasively evaluate brain–heart function changes.

Research has presented a novel analytical model framework for assessing the interactions between brain and cardiac activity at the source brain level. This system depends on low-resolution electromagnetic tomography (LORETA) source localization using scalp electrophysiological recordings. It estimates BHI by analyzing the functional connections between cortical sources and circulatory dynamics [127]. The experimental results corroborated prior findings about the activation of brain areas regulating cardiac dynamics (e.g., insula, amygdala, hippocampus, and anterior/mid-cingulate cortex). Notably, the study indicated that during the cold pressor test, bidirectional activity of functional brain–heart communication increased compared to the resting state, notably targeting neural oscillations in the delta, beta, and gamma bands. The results established a functional link between certain brain areas and cardiovascular dynamics utilizing noninvasive recordings during intense sympathetic-parasympathetic activity. This strategy has potential for exploring brain–heart interactions in changeable ecological environments while retaining temporal precision.

However, the study method still has drawbacks, including the relatively poor spatial resolution of the sLORETA approach and the potential confounding factors such as physiological variables (e.g., respiration or blood pressure) that were not included. The study presented a noninvasive way to investigate the functional link between the activity of specific brain areas and cardiovascular dynamics under intense sympathetic-vagal stimulation. With the enhancement and follow-up of related technologies, tracking aberrant activities in the cortical regions can effectively reveal the etiology of linked cardiac dysfunctions.

Molecular imaging—neuroimaging technology

The so-called multimodal imaging, which integrates and combines numerous imaging methods, gives significant anatomical, functional, and molecular information [128]. Recently, research has applied multimodal molecular imaging tools to explore the influence of cerebral ischemia damage on cardiac function, examining the morphology and tissue inflammation of the brain and heart. Current study has established the importance of multimodal imaging in detecting alterations in the brain–heart axis following ischemic stroke. More persuasively, the approaches utilized in mouse models are consistent with those used in human patients [129]. Nele Hermanns and her team employed two mice models (transient MCAO and localized administration of vasoconstrictor ET-1) to imitate different degrees of stroke [130]. They applied positron emission tomography (PET) imaging targeting the mitochondrial translocator protein (TSPO) for inflammatory imaging, along with multi-organ magnetic resonance (MR) imaging and in vitro validation (immunostaining and flow cytometry). They observed that MCAO-induced stroke led to localized neuroinflammation, visible by PET imaging seven days post-stroke. MCAO also induced a modest decrease in left ventricular ejection fraction (LVEF), correlated with elevated cardiac TSPO PET signals but unrelated to leukocyte infiltration. The magnitude of the stroke linked with the degree of heart dysfunction. Early neuroinflammation was directly associated to cardiac dysfunction, notably in brain areas like the insular cortex. Inhibiting microglial activity lowered TSPO signals and was related with maintained heart function post-stroke. Early post-MCAO ischemic core and penumbra extent, as well as edema measured by T2-weighted MRI, were associated to moderate and prolonged reductions in systolic performance. This discovery can signal potential future concerns of heart malfunction. The study reveals that early localized neuroinflammation post-stroke influences future heart dysfunction. Additionally, systemic TSPO PET can monitor neuroinflammation, offering insights into inter-organ communication within the brain–heart axis and potentially directing treatment efforts to safeguard cardiac function post-stroke.

This research gives fresh insights into the molecular processes of cardiac dysfunction post-stroke and illustrates the potential of multimodal molecular imaging approaches in exploring brain–heart axis connections.

Feasible methods for treating cardiovascular diseases based on the brain–heart axis

The latest progress and basis of brain–heart axis-targeted therapy for cardiovascular diseases

In addition to the conventional symptomatic therapies for cardiovascular illnesses, we are researching new in-depth therapeutic techniques. Based on brain–heart axis studies, it is obvious that alterations in certain brain areas can contribute to various cardiovascular disorders. Given these discoveries, targeting brain areas for the treatment of cardiovascular disorders has become a practical method. This strategy entails generating tailored treatment regimens for disorders associated to the brain–heart axis, attaining "dual brain–heart treatment." The next part will offer a thorough assessment of the studies on targeting specific brain areas to treat cardiovascular disorders.

Intervention of primary motor cortex (M1)– raphe nucleus pathway in the treatment of myocardial infarction

The M1, which occupies a specific section of the cerebral cortex, plays a critical function in the brain and has strong relationships with other brain areas [131, 197] (Fig. 4). Research has discovered that glutamatergic neurons in the M1of mice can control heart activity via the relay brain area MnR [133] (Table 1). This discovery offers new approaches for treating myocardial infarction. For example, for patients with post-infarction sympathetic nervous overactivation that can induce malignant arrhythmias and lead to death, developing intervention methods targeting the M1-MnR pathway, such as specific drugs or neuroregulation techniques, could inhibit the excessive activation of sympathetic nerves, potentially improving cardiac function and reducing the risk of arrhythmias and other complications.

Fig.4.

In the brain–heart axis, the primary brain regions that regulate cardiovascular diseases are of significant importance. These regions can be visualized in a schematic diagram of the brain. M1 cerebral cortex, NTS nucleus of the solitary tract, OVLT organum vasculosum laminae terminalis, PVN paraventricular nucleus, RVLM rostral ventrolateral medulla, SFO Subfornical organ

Table 1.

Brain regions in the brain–heart axis targeted for the treatment of cardiovascular diseases

Brain regions	Cardiovascular-related potential function	Cardiovascular disease	Treatment
Primary Motor Cortex (M1)	Movement execution, higher cognitive processes [131], pain modulation [132]	Myocardial infarction [133]	Transcranial direct current stimulation (tDCS) [134], ginkgo biloba extract [135, 136], acupuncture [137] and electroacupuncture [138]
Hypothalamic Paraventricular Nucleus (PVN)	Stress	Heart failure [139], hypertension [140, 141], hypertrophy of the heart muscle [142]; myocardial ischemia–reperfusion injury [143]	Chemotherapy(glutamic acid [144], AMPK activator [145]), nuclear factor-κB (NF-κB) blockers, electroacupuncture [143]
Amygdala	Memory [146, 147], depression	Atherosclerosis [148, 149];hypertension [150]	psychotherapy [151, 152] and neurotherapy [153], electroconvulsive therapy [154], deep brain stimulation [155], chemotherapy(ketamine [156])
Hippocampus	Memory, emotion, stress, cognition [157]	Atherosclerosis [158, 159]	Electroconvulsive therapy [154], nerve stimulation [160]
Insula cortex	Emotion [161–163], anxiety [164], depression [165]	Arrhythmia [166]; cardiac injury [167]	Chemotherapy(adenylate cyclase 1 inhibitor [168], (R)-ketamine [169], repetitive transcranial magnetic stimulation (rTMS) [165] and deep transcranial magnetic stimulation (dTMS) [170]
Subfornical organ(SFO) and organum vasculosum of the lamina terminalis(OVLT)	Fluid balance	Hypertension [171, 172]	Sodium restricted diet [173, 174]
Rostral ventrolateral medulla(RVLM)	Stress [175], glycolipid metabolism	Hypertension [175–177]	Chemotherapy (Candesartan [175], Ang II receptor blocker [175], pioglitazone [178]), electroacupuncture [179]
Thalamus	modulate attention, memory [180], stress	Hypertension, arrhythmia	Acupuncture [181], deep brain stimulation [182, 183]
Pineal gland	–	Cardiac disease	Melatonin [184]
Solitary nucleus(NST)	Feeling [185]; pain [186]	Hypertension [176, 187], arrhythmia	Electroacupuncture [188], transcutaneous auricular vagus nerve stimulation (taVNS) [189, 190]
Prefrontal cortex	Emotion [191];memory [192]; cognition [193];pain [194, 195]	Hypertension	Transcranial focused ultrasound (tFUS) [196]

AMPK Adenosine 5’-monophosphate -activated protein kinase, dTMS deep transcranial magnetic stimulation, OVLT organum vasculosum laminae terminalis, M1 cerebral cortex/primary motor cortex, NF-κB nuclear factor-κB, NTS nucleus of the solitary tract, PVN paraventricular nucleus, RVLM rostral ventrolateral medulla, rTMS repetitive transcranial magnetic stimulation, SFO Subfornical organ, taVNS transcutaneous auricular vagus nerve stimulation, tDCS transcranial direct current stimulation, tFUS Transcranial focused ultrasound

Hypothalamic paraventricular nucleus regulates cardiac function

The PVN, positioned on each side of the top section of the third ventricle of the hypothalamus, plays a critical role in autonomic and neuroendocrine functions (Fig. 4, Table 1). Importantly, inflammatory mediators can create a high inflammatory state in the PVN, including pre-sympathetic neurons projecting to the rostral ventrolateral medulla, which play a crucial role in sympathetic excitation in chronic heart failure [139, 198]. By stimulating the PVN or modifying its neural activity, it is possible to enhance the balance between sympathetic and parasympathetic nerves, hence lowering cardiac stress and enhancing cardiac performance. Research has demonstrated that activating the PVN can control autonomic balance, lower peripheral vascular resistance, cure hypertension [140], and alleviate myocardial hypertrophy [142], therefore postponing the onset of heart failure. Although there are presently no large-scale clinical applications, related basic research provides a theoretical framework for creating PVN-targeted treatments for heart failure in the future.

The amygdala controls atherosclerosis through the neuroimmune cardiovascular interface

The amygdala is a critical component in the brain, part of the forebrain, positioned medially in the temporal lobe, near to the hippocampus (Fig. 4). It is a crucial component of the limbic system and is strongly involved with emotion processing, memory, and decision-making (Table 1). Research has proven that the activity of the amygdala is intimately connected to the risk of cardiovascular illnesses [148], notably stress-related cardiovascular problems produced by psychological worry [199] and emotional disturbances [200]. Excessive activation of the amygdala can increase the advancement of AS [148]. Recent investigations have indicated that the amygdala controls the modulation of plaques by the ANS through the cardiovascular interface [149]. Therefore, for individuals at risk of cardiovascular illnesses or those currently suffering from them, psychological or pharmaceutical therapies targeting the activity of the amygdala could help lower the risk of cardiovascular events. Methods such as cognitive behavioral therapy, relaxation training, or creating medications targeting the amygdala's neurotransmitter systems might help control the function of the amygdala and so lessen the harmful effects of stress on the circulatory system (Table 1).

Subfornical organ (SFO) and organum vasculosum of the lamina terminalis (OVLT) can be used in the treatment of hypertension

The SFO and the OVLT are two structures of the brain intimately associated to blood pressure control. Neurons in the SFO and OVLT can sense levels of circulating angiotensin II and aldosterone, as well as plasma osmolality, to send information about blood volume and blood pressure [201](Fig. 4). They have neuronal connections to the PVN, and current research reveals that the SFO and OVLT are upstream nuclei of the PVN, playing key roles in blood pressure control [171, 172]. In the treatment of hypertension, further identifying intervention targets and methods for these two brain regions, such as developing drugs that can modulate the activity of SFO and OVLT neurons or their related receptors, may provide new avenues for hypertension treatment, achieving more precise blood pressure control.

Nucleus tractus solitarius (NTS) stimulation regulates heart rhythm

The NTS is the initial relay station for visceral afferent information, particularly the caudal NTS, which receives input through the vagus and glossopharyngeal nerves from baroreceptors, cardiac receptors, chemoreceptors, and pulmonary receptors (Figs. 1, 4). Research has demonstrated that activating preproglucagon neurons in the NTS can boost the inhibitory actions of the vagus nerve on the heart, hence lowering heart rate and alleviating myocardial ischemia–reperfusion damage [202]. Clinically, for certain individuals with arrhythmias, especially those with tachyarrhythmias caused by excessive sympathetic nerve activity, neuroregulation procedures to activate the NTS might be undertaken to modify autonomic balance, attaining the objective of curing arrhythmias (Table 1).

Neuromodulatory techniques

Neuromodulation encompasses a spectrum of technologies that employ electrical, magnetic, ultrasonic, optical, or chemical modalities to reversibly modulate the activity of the central or peripheral nervous system. These approaches serve dual purposes: enabling the investigation of brain function and providing therapeutic options for pharmacoresistant neurological and psychiatric disorders. Depending on whether surgical access is required, neuromodulation can be broadly classified into non‑invasive and invasive modalities. Non‑invasive techniques include repetitive transcranial magnetic stimulation (rTMS), transcranial direct current stimulation (tDCS), transcranial alternating current stimulation (tACS), and transcranial focused ultrasound stimulation (tFUS/tUS) [196]. Invasive approaches, such as deep brain stimulation (DBS) and vagus nerve stimulation (VNS) [189, 190], require electrode implantation. Historically, these modalities have been applied primarily in the management of treatment‑resistant psychiatric disorders, Alzheimer’s disease, Parkinson’s disease, and related conditions. Recent advances in understanding the brain–heart axis have expanded the scope of neuromodulation to cardiovascular medicine. An increasing body of research now explores its potential to restore autonomic balance, attenuate maladaptive neurocardiac reflexes, and improve outcomes in conditions such as heart failure, arrhythmias, and hypertension. Depending on the disease phenotype and targeted neural circuitry, modalities such as tDCS [134], rTMS [165], and deep TMS (dTMS) [170] have demonstrated promising therapeutic effects. Despite these advances, several challenges remain. Certain techniques require craniotomy or electrode implantation, carrying risks of infection, immune reactions, and other complications. Optimal stimulation targets and parameters remain under debate, and there is no universally accepted set of biomarkers to predict treatment response. Even within the same disease entity and using identical stimulation protocols, inter‑individual variability in outcomes is substantial, underscoring the need for personalized parameter optimization [203]. Consequently, robust mechanistic studies and translational research are essential to strengthen the theoretical foundation and enhance the clinical persuasiveness of neuromodulation in both neurological and cardiovascular domains.

Cognitive behavioral therapy

Appropriate lifestyle habits can prevent cardiovascular and cerebrovascular diseases. Cardiovascular and cerebrovascular diseases share many common risk factors, such as high-stress environments, high cholesterol, high blood sugar, smoking, and obesity. These factors not only damage the blood vessels of the heart but also harm the cerebral blood vessels, increasing the risk of cardiovascular and cerebrovascular diseases. For example, hypertension can lead to thickening and hardening of the vessel walls, affecting the blood supply to both the heart and brain. Adopting good lifestyle habits is key to preventing and controlling CVDs. Regular exercise, a healthy diet, quitting smoking, and limiting alcohol intake are common and effective medical recommendations. A reasonable and healthy lifestyle can improve cardiovascular function and reduce the risk of disease [204, 205].

Furthermore, cognitive behavioral therapy is also of great reference value. From the previously stated information, we can clearly comprehend the function of mental illness in cardiovascular health. For patients with psychological disorders, corresponding psychological therapies are necessary means to reduce the risk of CVDs. Alleviating symptoms of depression and anxiety can, in turn, relieve stress in cardiovascular patients, reducing the risk of disease onset, hospitalization rates, and mortality [206]. For example, neuromodulation techniques such as TMS and DBS hold potential in regulating brain–heart functions. These techniques can influence cardiac function by modulating neural activity in the brain, offering new insights into the treatment of brain–heart axis-related diseases.

However, cognitive behavioral therapy presents several notable limitations. As a long-term therapeutic approach, it lacks sufficient efficacy in managing acute or severe psychiatric conditions. Moreover, cognitive behavioral therapy relies heavily on the patient’s active engagement and self-directed effort, which may significantly compromise its effectiveness in individuals with low motivation, impaired cognitive functioning, or limited self-awareness. Its emphasis on goal-oriented and structured protocols may also render it less suitable for patients requiring highly individualized interventions. Therefore, when formulating cognitive behavioral therapy -based treatment plans, clinicians must adopt a more personalized approach tailored to the specific needs and capacities of each patient.

Pharmacological approaches targeting neural and cardiac signal transduction

Psychotropic medication

In avoiding cardiovascular events in people with signs of mental illness, anti-anxiety and antidepressant drugs have a key role. Currently feasible first-line therapies give a certain amount of cardiovascular safety, reducing anxiety and depression symptoms while concurrently improving vascular inflammation, endothelial function, and arteriosclerosis, and decreasing the progression of AS. These drugs assist lower heart stress and the risk of adverse cardiac events [207].

Cardiovascular medication

Under the impact of the brain–heart axis, the cardiovascular system, as the final effector system, unavoidably demands the use of cardiovascular medicines, which are now the most effective therapies. More significantly, cardiovascular drugs have the ability to ameliorate patients' psychological stress situations. Reports have revealed that aspirin and statins are related with decreased odds of acquiring depression and anxiety symptoms [208]. The method may be by decreasing inflammation to reduce depressed symptoms. Other cardiovascular medicines, such as beta-blockers and angiotensin-converting enzyme inhibitors(ACEI), can produce anti-anxiety effects via regulating the ANS or the RAAS [209].

Traditional Chinese medicine has unique advantages in treating cardiovascular diseases through the brain–heart axis

During the authoring of this article, we observed that the treatment options for the brain–heart axis are remarkably comparable to the notion of “dual brain–heart treatment.” However, our approach varies from “dual brain–heart treatment” in that we do not simply focus on cardiovascular and cerebrovascular illnesses, but also on complicated neurological disorders, primary or secondary encephalopathies, etc. Additionally, within the general framework of “dual brain–heart treatment,” our focus is on specific brain regions, precisely controlling these areas to enhance the "dual brain–heart treatment" method. Upon grasping this perspective, we readily related the treatment of the brain–heart axis with the advantages of traditional Chinese medicine. Traditional Chinese medicine (TCM) provides the benefits of multi-targeted, low-adverse responses in the brain–heart axis network. For example, puerarin in kudzu root has been found to decrease neuroinflammation [210], protect nerve cells [211], and cure brain degenerative illnesses [212]. At the same time, kudzu root has been utilized in traditional Chinese medicine to treat cardiovascular illnesses with good efficacy. Furthermore, Salvia miltiorrhiza (Danshen) has long been utilized to promote blood circulation [213], and with deeper investigation, its usefulness in treating brain illnesses has also been proved [214]. Proprietary Chinese medications such as Guanxin Danshen dripping tablets can concurrently tackle cardiovascular problems and accompanying psychological concerns [215]. These traditional Chinese medications present new opportunities for the co-treatment of cardiovascular illnesses and mental health issues.

The challenges associated with pharmacological interventions targeting the brain–heart axis in the treatment of CVDs are readily apparent. While various classes of drugs demonstrate unequivocal efficacy within their respective domains, there remains a lack of effective agents capable of exerting simultaneous therapeutic effects across both neurological and cardiovascular systems. Cardiovascular medications are proficient in controlling downstream symptoms, yet they offer minimal benefit in addressing upstream cerebral injury. Conversely, psychotropic agents may mitigate the consequences of brain damage but fail to improve cardiovascular outcomes. The use of multiple drugs in combination often leads to psychological resistance and poor patient adherence. Moreover, the adverse effects associated with these medications cannot be overlooked. Given the intricate neurovascular architecture of the brain–heart axis and the complexity of its signaling pathways, minimizing unnecessary side effects is of paramount importance. Achieving integrated brain–heart therapy will require concerted efforts to develop a new generation of effective, targeted pharmacological agents.

Conclusion and prospect

The brain–heart axis is a system that realizes the interaction between the brain and the heart through complex neural and humoral regulatory mechanisms. This system is not only related to the basic physiological functions of the brain and heart, but also profoundly affects the regulation and balance of multiple organs and systems throughout the body. When patients have recurrent, unexplained cardiovascular diseases, we might consider turning our attention to the brain–heart axis, as it may provide us with new insights. The brain–heart axis network suggests that when brain injury, nervous system disorders, and mental illnesses occur, appropriate cardiovascular prevention should be implemented on the basis of brain rehabilitation treatment. Conversely, when encountering cardiovascular diseases, it is essential not to focus solely on the disease itself. In addition to symptomatic treatment of the condition, attention should also be given to potential brain disorders.

We believe that targeting the brain–heart axis offers substantial advantages:

• 1. Precision Treatment: By implementing targeted interventions on specific brain regions, we can more accurately regulate the cardiovascular system's functions, minimizing impacts on other healthy tissues and organs, thus improving treatment efficacy and reducing side effects. For example, DBS on key brain areas such as the hypothalamus can balance sympathetic and parasympathetic nervous systems, thereby enhancing heart function.

• 2. Addressing Root Causes: Targeting brain regions not only alleviates the symptoms of cardiovascular diseases but also treats the underlying causes, correcting the brain's abnormal regulation of the cardiovascular system. This approach holds the promise of fundamentally curing or slowing the progression of cardiovascular diseases. For instance, cardiovascular diseases induced by chronic stress can be improved by modulating the brain's stress response center to reduce the release of stress hormones, thereby enhancing cardiovascular function.

• 3. Personalized Treatment Plans: The same cardiovascular disease manifestation in different patients may result from different brain region abnormalities. Through detailed patient evaluations, such as neuroimaging and neurophysiological assessments, we can develop personalized targeted brain region treatment plans, improving the specificity and effectiveness of the treatments.

However, strategies targeting the brain–heart axis for cardiovascular disease management remain constrained by several methodological and translational gaps. Most notably, the absence of large-scale randomized controlled trials (RCTs) undermines the robustness of current evidence. Existing studies are predominantly cross-sectional or single-arm pre-post designs with limited sample sizes, rendering them insufficient to account for confounding variables such as age, sex, pharmacotherapy, and genetic predisposition. Lifestyle interventions—such as meditation and stress management—have been repeatedly associated with cardiovascular benefits, yet their methodological shortcomings, including lack of rigorous controls, high attrition rates, and short intervention durations, restrict conclusions to correlational inferences. To substantiate causal efficacy, future research must adopt multicenter, double-blind, sham-controlled RCTs to evaluate brain–heart interventions (e.g., transcutaneous vagus nerve stimulation, cognitive behavioral therapy) against hard clinical endpoints such as myocardial infarction, heart failure hospitalization, and all-cause mortality. Causal inference is further complicated by the bidirectional nature of brain–heart and heart–brain signaling, with current observational designs and unidirectional Mendelian randomization offering only weak evidence that cannot exclude reverse causality or pleiotropic bias [216]. Moreover, neurocardiac responsiveness exhibits substantial inter-individual variability, with heart rate variability changes differing by up to 5–tenfold across subjects under identical vagal stimulation or stress paradigms. Sex and genotype significantly influence central autonomic output, yet inadequate stratification in existing cohorts leads to diluted effect sizes [217]. Mechanistic understanding also remains superficial, with key uncertainties surrounding signal transduction pathways and cellular targets. A deeper theoretical foundation is urgently needed to support the clinical translation of brain–heart axis interventions.

Looking ahead, the brain–heart axis holds considerable promise for future development. Fundamentally, it encompasses complex interactions among the nervous, endocrine, and immune systems, yet the precise molecular mechanisms, signaling pathways, and regulatory networks governing these inter-system dynamics remain incompletely understood and warrant further investigation. The identification of more robust and specific biomarkers for brain–heart axis activity is also an unmet need. In parallel, the advent of advanced diagnostic technologies calls for refinement of neuroimaging criteria to improve diagnostic accuracy and reproducibility. As the concept of brain–heart co-management gains clinical traction, there is an urgent need to establish integrated care models that reflect this paradigm. Such models should foster interdisciplinary collaboration among neurology, cardiology, endocrinology, and geriatrics, thereby enhancing diagnostic precision, therapeutic efficacy, and long-term patient outcomes.

In summary, a better understanding of the commonalities between the central nervous system and cardiovascular diseases will significantly enhance patient management and outcomes. Cardiovascular symptoms resulting from brain injuries are clinically prevalent and impact patient prognosis, morbidity, and mortality. Researching clinical indicators for the early diagnosis of adverse brain–heart diseases will help improve clinical management and reduce mortality. Investigating new therapies for cardiac protection following brain injuries is highly warranted, as they could be applied within a broader time window to a large proportion of patients with brain lesions. We look forward to the construction of multidisciplinary teams and comprehensive approaches in the near future, making targeting brain regions of the brain–heart axis a feasible strategy for treating cardiovascular diseases. This would allow populations susceptible to cardiovascular and cerebrovascular diseases to benefit from this strategy.

Abbreviations

AC

Adenylate cyclase

Ach

Acetylcholine

ACEI

Angiotensin-converting enzyme inhibitors

ACTH

Adrenocorticotropic Hormone

AD

Alzheimer's disease

AF

Atrial fibrillation

AIS

Acute ischemic stroke

AMI

Acute myocardial infarction

Akt

Protein kinase B

AMPK

Adenosine 5’-monophosphate -activated protein kinase

ANP

Atrial natriuretic peptide

ANS

Autonomic nervous system

AS

Atherosclerosis

β1-R

Beta1-adrenergic receptor

β2-R

Beta2-adrenergic receptor

BBB

Blood–brain barrier

BNP

Brain natriuretic peptide

CAD

Coronary artery disease

cAMP

Cyclic adenosine monophosphate

CBN

Contraction-band necrosis

CNP

C-type natriuretic peptide

CNS

Central nervous system

CRH

Corticotropin releasing hormone

CRP

C-reactive protein

CT

Computed tomography

cTn

Cardiac troponin

CVDs

Cardiovascular diseases

CVLM

Caudal ventrolateral medulla

Danshen

Salvia miltiorrhiza

DBS

Deep brain stimulation

DIC

Delayed cerebral ischemia

dTMS

Deep transcranial magnetic stimulation

DVN

Dorsal vagal nucleus

EEG

Electroencephalogram

fMRI

Functional magnetic resonance imaging

FOXO

Forkhead box O

GBA

The gut–brain axis

GHA

The gut–heart axis

HF

Heart failure

HFrEF

Heart failure with reduced ejection fraction

HPA

Hypothalamic-pituitary axis

ICAM

Intercellular adhesion molecule

IK-Ach

Acetylcholine-sensitive K⁺channel

IL-1β

Interleukin-1β

IL-6

Interleukin-6

IL-10

Interleukin-10

IL-17

Interleukin-17

iNOS

Inducible nitric oxide synthase

LDs

Lipid droplets

LORETA

Low-resolution electromagnetic tomography

LVEF

Left ventricular ejection fraction

M2-R

M2 muscarinic receptors

M1

Cerebral cortex/primary motor cortex

MAEs

Major arrhythmic events

MCAO

Middle cerebral artery occlusion

MI

Myocardial infarction

MPO

Myeloperoxidase

MR

Magnetic resonance

MSIMI

Mental stress-induced myocardial ischemia

NF-κB

Nuclear factor-κB

NPs

Natriuretic peptides

NPY

Neuropeptide Y

NT-proBNP

N-terminal pro-brain natriuretic peptide

NTS

Nucleus of the solitary tract

OVLT

Organum vasculosum laminae terminalis

PET

Positron emission tomography

PKA

Protein kinase A

PTSD

Post-traumatic stress disorder

PNS

Peripheral nervous system

PVN

Paraventricular nucleus

RAAS

Renin–angiotensin–aldosterone system

RAS

Renin–angiotensin system

rTMS

Repetitive transcranial magnetic stimulation

RVLM

Rostral ventrolateral medulla

SAH

Subarachnoid hemorrhage

SAM

Sympathetic-adrenal-medullary

SFO

Subfornical organ

SHS

Stroke heart syndrome

SNS

Sympathetic nervous system

SPECT

Single-photon emission computed tomography

SUDEP

Sudden unexpected death in epilepsy

tDCS

Transcranial direct current stimulation

taVNS

Transcutaneous auricular vagus nerve stimulation

TCM

Traditional Chinese medicine

TIA

Transient ischemic attack

tFUS

Transcranial focused ultrasound

TMS

Transcranial magnetic stimulation

TNF-α

Tumor necrosis factor

TSPO

Translocator protein

TTS

Takotsubo syndrome

VCAM

Vascular cell adhesion molecule

Author contributions

Zheng Rong: Writing—original draft. ChenChen Meng: Writing -review & editing. Xinyi Li: Writing—review & editing. Xinyi Li: Investigation. Yangyang Gu: Investigation. Wei Mao: review & editing, Supervision, Project administration, Funding acquisition. Yulan Li: Conceptualization. All authors reviewed the manuscript.

Funding

This work was supported by the National Natural Science Foundation of China [grant numbers 82174150, 2021].

Data availability

No datasets were generated or analysed during the current study.

Declarations

Ethics approval

Not applicable.

Informed consent

Not applicable.

Competing interests

The authors declare no competing interests.