Along this line, the adrenergic nervous system’s adverse remodeling has been well characterized in different cardiovascular disorders [i.e., myocardial infarction (MI), HF] (Cao et al., 2000a; Zhou et al., 2004; Ajijola et al., 2012; Ajijola et al., 2015). Moreover, myocardial dysfunction gradually leads to an electrical excitability impairment, with neuromodulator dysregulation and cardiac nerve fibers impoverishment (Cao et al., 2000a; Gardner et al., 2015; Tapa et al., 2020). Furthermore, the ischemic process in the cardiac tissue increases oxidative stress, along with adenosine and other cardiolesive mediators (such as inflammatory cytokines), resulting in the activation of myocardial afferent neurons (Malliani et al., 1973; Dibner-Dunlap et al., 1993; Minisi and Thames, 1993; Huang et al., 1996). Interestingly, the sympathoexcitation reflex may partially attenuate the detrimental ischemic remodeling of the working myocardium (Minisi and Thames, 1991; Schwartz et al., 1992; Ardell et al., 2019). Histologic modifications in stellate ganglia neurons were found both in humans with ischemic cardiomyopathy, as well as in porcine models of chronic ischemia, resulting in inflammation enhancement, glial cell stimulation, and an increase in reactive oxygen species (ROS) production (Ajijola et al., 2012; Ajijola et al., 2015). Clinically, sympathetic hyperactivation in heart failure is treated pharmacologically through beta-adrenergic receptor (β-AR) antagonists and renin-angiotensin-aldosterone system (RAAS) inhibitors (Airaksinen et al., 1999; Floras, 2009; Triposkiadis et al., 2009; Fukuda et al., 2015). Additionally, neuromodulatory strategies to reduce sympathetic hyper-tone, (e.g., cardiac adrenergic denervation, thoracic epidural anesthesia, renal denervation, and stellate ganglion blockade) have been used in heart disease patients (Triposkiadis et al., 2009; Bourke et al., 2010; Fukuda et al., 2015; Shivkumar et al., 2016). Research studies also suggest the application of kilohertz frequency alternating current to the adrenergic chain, which attenuates sympathetic firing to the cardiac tissue, and reversibly blocks adrenergic conduction (Buckley et al., 2017). Similarly, in a post-MI experimental model, Chui et al. demonstrated that reversibly blocking adrenergic stimulation is associated with a decreased risk of ventricular tachycardia/ventricular fibrillation (Chui et al., 2017). Given the growing interest in neuromodulatory applications as a therapeutic solution for cardiovascular diseases, and the increased risk to develop neurodegenerative pathologies, such as AD, in patients with cardiovascular diseases, these innovative strategies and the associated molecular mechanisms deserve a deeper investigation.

The intrinsic cardiac nervous system (ICNS) is characterized by clusters of ganglia known as ganglionated plexi, localized in epicardial fat pads (Armour, 2008; Ardell et al., 2016). These ganglionated plexi are composed of a wide population of neurons, including cholinergic neurons and those that receive parasympathetic afferents, neurons that receive afferent signals directly from cardiomyocytes, and local interneurons (Armour, 2008; Ardell et al., 2016). Moreover, the ICNS interacts with upstream neural stations to control the electromechanical activity of the heart, beat by beat (Cardinal et al., 2009). However, maladaptive nervous system remodeling, found in myocardial infarction, heart failure, and other cardiac conditions, may affect the homeostasis of the ICNS dynamic neural system (Hardwick et al., 2008; Beaumont et al., 2015; Rajendran et al., 2016). Notably, Rajendran and others, described the processing dysfunction of afferent and efferent ICNS neuronal inputs in a cardiac post-ischemic porcine model (Rajendran et al., 2016). Interestingly, an analogous impairment also affects the intrathoracic and primary sensory ganglia in humans and animal models (Zucker et al., 2012; Wang et al., 2014; Ardell et al., 2016; Ajijola et al., 2017; Yoshie et al., 2020).

The cardiac plexus is situated at the base of the heart and is composed of a combination of cardiac nerves and small parasympathetic ganglia. Among these ganglia, the most important is the Wrisberg ganglion, located between the tracheal bifurcation and the pulmonary artery division. In addition, other small intrinsic parasympathetic ganglia are in the cardiac atrial wall. From the cardiac plexus, some nerve fibers run along the right coronary artery, left coronary artery, and their branches, reaching the heart. Other fibers penetrate the sinoatrial and atrioventricular node, or project to the thicker vascular walls in the atrial and ventricular myocardium. Stimulation of the vagus motor nucleus reduces both heart rate and myocardial contraction with a similar effect upon pressure. The vagus nerve is the 10th and longest cranial nerve, which provides an indispensable brain-body connection that modulates essential aspects of autonomic physiology like heart rate, breathing, blood pressure, gut motility, reflexes, and vital behavior (Prescott and Liberles, 2022). Vagal afferents provide the predominant sensory innervation to the heart, aorta, and other large caliber vessels, through the aortic depressor nerve. This nerve emerges from the vagal trunk and reaches the aortic arch and the right subclavian artery, close to its bifurcation with the common carotid artery, where the two leading vagal sensory neurons are located (Prescott and Liberles, 2022). These two nerve centers are involved in the neuronal innervation of the vasculature, monitoring blood flow along the whole circulatory system. Interestingly, sensory neurons are greatly affected by the freshly oxygenated blood pumped from the left ventricle, thus stabilizing blood pressure gradients and oxygenation rates along the vasculature. Vagal sensory neurons are categorized based on cellular features, such as biogeography, conduction velocity, developmental origin, and/or electrophysiological activity. Besides molecular functions, the physiological characteristics of vagal neurons are influenced by their terminal structures and strategic location along the body. Specifically, different chemosensory neurons react to the same neuromodulators, but are placed close to various upstream sensory cells, thus transmitting different sensory inputs to the brain tissue. Vagal mechanosensory neurons represent first-order sensory neural stations that directly detect internal organ cues (Reimann et al., 2008; Krasteva et al., 2011; Moreno-Domínguez et al., 2020). Conversely, different vagal afferents termed second-order neurons, sense signals from upstream sentinel cells, including enteroendocrine cells, glomus cells, immune cells, and taste cells (Bessac and Jordt, 2008; Han et al., 2018). In sum, the vagus nerve significantly impacts daily physiological functions. Therefore, approaches to modulate its activity may represent an intriguing and innovative opportunity for therapeutic solutions.

Notably, vagotomy (subdiaphragmatic) and vagus nerve electrical stimulation (VNS) seem to represent a potential therapeutic strategy in different clinical conditions, albeit some clinical concerns still remain to be addressed. Understanding vagal sensory activity may open new therapeutic horizons, turning on or off specific afferent endings, thus modulating the function of the autonomic nervous system. Of note, cardiac neurons of the PNS are located in the dorsal motor nucleus of the vagus (DMV) nerve, and the nucleus ambiguous in the medulla oblongata. Cholinergic preganglionic neurons project through the vagus and glossopharyngeal nerves, synapsing with postganglionic cells that in turn synapse onto the heart. Therefore, unlike sympathetic neurons, cardiac parasympathetic fibers are anatomically independent of the spinal cord (Airaksinen et al., 1999; Panneton et al., 2014; Petko and Tadi, 2022; Tindle and Tadi, 2022). The cholinergic system (Herring and Paterson, 2009) performs its function through the vagus nerve and its intrathoracic projections, releasing acetylcholine, nitric oxide, and vasoactive intestinal peptide as neurotransmitters by postganglionic fibers (Prescott and Liberles, 2022). Specifically, acetylcholine operates on inhibitory G protein-coupled muscarinic (Fu et al., 1993) M2 receptors, located on atrioventricular and sinoatrial cells and atrial cardiomyocytes, exerting distinct responses: a chronotropic negative effect (decrease of heart rate) due to the activation of potassium channels that produces sinus node cells hyperpolarization and a dromotropic negative effect (reduction of the impulses coming from the atrioventricular node) (Dhein et al., 2001).

New scientific insights (Chow et al., 2001) demonstrated a parasympathetic distribution both in ventricles and atria compartments with a greater fiber density in the endocardium compared to the epicardium (Crick et al., 1994; Crick et al., 1999). The right ventricle shows higher nerve density than the left one, although the subendocardium of the left ventricle denotes more fiber density than the right ventricle endocardium layer. As emerged by scintigraphy studies with metaiodobenzyl guanidine iodine 123 (MIBG-I (Haïssaguerre et al., 1998), different distribution patterns of sympathetic and parasympathetic nerves may modify cardiac performance under both physiologic and pathologic conditions (Rengo et al., 2016). Myocardial scintigraphy is a diagnostic analysis involved in the identification of myocardial perfusion dysfunction in cardiac stress conditions, often performed to detect ischemic heart disease. MIBG is a norepinephrine analog and one of the most used tracers for single-photon emission tomography (SPECT) and positron emission tomography (PET). MIBG allows for the visualization of presynaptic sympathetic nerve function due to its high affinity for presynaptic norepinephrine uptake-1 (NET) (Asghar et al., 2017), and is therefore a marker for cardiac adrenergic innervation. Studies have also analyzed cardiac fibers’ density with immunohistochemical approaches both in murine models and in human autopsy samples (Vracko et al., 1991; Wink et al., 2020). Kawano et al. investigated the distribution of autonomic nerves in autopsied hearts of humans without cardiovascular disease, using immunolabelling techniques for a cholinergic modulator (acetylcholinesterase, AChE) and an adrenergic marker (tyrosine hydroxylase, TH) (Kawano et al., 2003; Kawashima, 2005). The authors showed a greater prevalence of AChE-positive fibers and TH-positive axons density in the atrial chamber than in the ventricle, and lower innervation at the apex, compared to the ventricular base. Furthermore, more cholinergic positive fibers have been found in the subendocardial thickness than in the myocardium subepicardial layer. Overall, it is evident that the different distribution of adrenergic and cholinergic fibers modulates cardiac activity both in physiological and in pathological conditions.

Conversely, extracardiac signals of the sympathetic and parasympathetic nervous system interplay with a complex network of intrinsic cardiac neurons involved in the epicardial neural plexus formation (Armour, 2004). Notably, through its organization into ganglionated subplexuses on the surface of atria and ventricles (close to both the sinoatrial and atrioventricular nodes) (Pauza et al., 2000), the epicardial neural plexus constitutes a further layer of cardiac modulation of autonomic function (Wickramasinghe and Patel, 2013).

Of note, besides the autonomic reflexes, ANS homeostasis is modulated by a sophisticated and well-organized cardiovascular neurohormonal axis. Notably, stress-sensitive baroreceptors (mechanoreceptors) are located in both high-pressure arterial (aortic arch and carotid sinus) and low-pressure venous networks (systemic veins and atria/pulmonary arterial interface). Central and peripheral chemoreceptors, present in the brainstem, carotid sinus, and aortic arch respectively, detect the modifications in arterial oxygen and carbon dioxide concentration. Lastly, polymodal receptors located in the walls of the cardiac chambers, respond to both mechanical and chemical inputs and stimulate sympathetic nervous system outputs in the setting of receptor activity desensitization (Triposkiadis et al., 2009). In addition, ANS function is regulated via bidirectional feedback from the renin-angiotensin-aldosterone system. Notably, renal hypoperfusion, liable for cardiac output decreases, induces renin secretion and angiotensin- II (AT- II) production, leading to the enhancement of SNS tone centrally (Goldsmith, 2004; Li et al., 2006a) and abolishing, in parallel, baroreflex-modulated suppression of SNS activity (Murakami et al., 1997; Paton et al., 2013). Conversely, SNS output enhancement induces renin release (Goldsmith, 2004).

The cardiac autonomic system (Coote and Chauhan, 2016) also undergoes a molecular control regulated by particular neuromodulators, such as NGF and semaphorin 3a (Sema3a) (Ieda et al., 2007), a modulator of the “chemical repulsive factor” group (Tang et al., 2004). These two molecules operate together to support a regular innervation pattern from the epicardial to the endocardial compartment (Jiang et al., 2007). Indeed, an alteration of this model is related to dysfunction of cardiac signaling and may cause fatal arrhythmias (Chen et al., 2007).

Different reports (Kimura et al., 2012) have shown that sympathetic fibers release NGF, which promotes their survival and differentiation; in physiological conditions, this marker has been identified in different compartments, especially in those deeply innervated. It has also been detected in biofluids, where its concentration is influenced by norepinephrine’s synthesis, effects, and receptorial pathways. In addition, NGF levels may vary in different circadian phases. As several studies (Govoni et al., 2011) have highlighted, activation of various receptors can modulate NGF expression. For example, norepinephrine binding to beta-adrenoreceptors in cardiac stellate ganglia mediates upregulation of NGF synthesis (Hoard et al., 2008), while alpha sympathetic receptor activation decreases NGF release. Therefore, the rate of stimulus, its impulse, and the different context in which it occurs (in physiological and pathological conditions) may modify the neurotrophic output (Kreusser et al., 2008).

Other studies have demonstrated a sophisticated crosstalk between endothelin-1 (ET-1) (Ieda et al., 2004) and NGF: endothelin has been shown to enhance NGF levels in cultured cardiomyocytes (Cosgaya and Aranda, 1995). Therefore, endothelin-1 is also a pivotal molecule to ensure autonomic cardiac innervation homeostasis and an attractive molecular target in cardiac injuries.

Atrial fibrillation (AF) (Miyasaka et al., 2006) is the most common cardiac electrical disorder, with its prevalence increasing in recent decades, as shown in epidemiological data from the Framingham Heart study (Benjamin et al., 1994; Kornej et al., 2022). Cardiovascular aging contributes to the development of arrhythmia; thus, its prevalence is age-related: 70% of AF patients are over 65 years old. Recently, an increase in this condition has been documented in the occidental population, due to both increased aging and multifactorial genesis. The increasing prevalence of atrial fibrillation has been associated with relevant social, economic, and healthcare policy implications. AF shows a rapid and chaotic electrical atrial activity (400–600 bpm) leading to inadequate mechanical cardiac performance.

The diagnosis occurs with electrocardiography analysis detecting the loss of “P” waves on the isoelectric line and the irregularity of R- R cycles. A specific classification of AF (Benjamin et al., 1994; Gallagher and Camm, 1998; Kornej et al., 2022), based on duration and interruption of the sustained arrhythmia, identifies several patterns.

- paroxysmal atrial fibrillation (under 7 days within spontaneous arrest, usually in the first 48 h) (Yalcin et al., 2015);

The electrical dysfunction is characterized by a “storming electrical impulse” with alteration of cardiac rhythm (Wyse et al., 2002; Cappato et al., 2005; Gould et al., 2006; Miyasaka et al., 2006; de Chillou et al., 2008; Roy et al., 2008) and performances; AF physiopathology is multifactorial: alcohol abuse, hyperthyroidism, mechanical and phlogistic stimulation may accelerate the arrhythmogenic process upon critical atrial morphology. Alterations in conduction speed and reduction of the refractory period are favoured by arrhythmogenic substrates (Nguyen et al., 2009) to promote a microcircuits outflow that may preferably clash, burn, merge and lapse upon fibrotic and hypertrophic tissue, due to histopathologic remodeling. Specifically, as demonstrated, the ANS contributes to both the onset and progression of this disease (Coumel et al., 1978). Of note, the structural basis for this theory derived from the discovery of sizeable autonomic innervation fibers density and ganglionated Plexi (GP) associated with the pulmonary veins (PV) and within the atrial tissue, from which AF triggers often originate (Haïssaguerre et al., 1998). However, to better understand the etiology of AF a lot of studies sought to better characterize cellular substrates of AF. Specifically, the high density of β-adrenergic receptors and M2-type muscarinic receptors (cholinergic) in atrial and PV myocytes suggested these cells may directly communicate with the ICNS (Löffelholz and Pappano, 1985; Alexander et al., 2008). Yet, due to numerous factors (e.g., age and host environment), cardiomyocytes may respond differently to the same neural stimulus (Boknik et al., 2009). Part of this heterogeneity at the cellular level may be due to atrial remodeling that culminates in atrial fibrosis and alterations in cell signaling, such as calcium handling (Díaz et al., 2004; Hove-Madsen et al., 2004). Additionally, a sub-population of specialized cells, with their own pacemaker activity, was identified in the human atrium, pulmonary vein-left atrial (PV-LA) junction, and PV tissue (Cheung, 1981; Masani, 1986). These nodal-like cells interact with neurons from the ICNS and exhibit histological features of cardiac pacemaker similar to sinus node cells (Masani, 1986; Airaksinen et al., 1999). Accordingly, local innervation-induced modifications in the atrial myocardium’s electrophysiological environment may act as a stimulus for the further progression of sustained AF.

More recent electrophysiological reports (Wickramasinghe and Patel, 2013) and therapeutic results (de Chillou et al., 2008; Wickramasinghe and Patel, 2013; Chen et al., 2014) obtained with electrical ablation (Cappato et al., 2005) have suggested, as a new hypothesis, that a focal genesis, the “vagal or sympathetic trigger”, plays a key role in AF.

The persistence of AF induces cellular and subcellular modifications (such as intracellular Ca²⁺ accumulation, sarcolemma reduction, and glycogen accumulation), responsible for atrial physiological and structural abnormalities.

The atrial innervation is modulated by a sophisticated crosstalk between the two limbs of the cardiac autonomic nervous system (Jamali et al., 2017), whose imbalance causes the hyperfiring of cholinergic fibers, that support the vagotonic AF, and adrenergic axons that sustain the sympathetic AF (Li et al., 2013). Some authors have demonstrated in animal models that simultaneous choline-adrenergic activation easily induces AF. The arrhythmogenesis phenomenon can be driven by strong adrenergic waves, produced by stress conditions such as exercise and emotional changes. Patients suffering from “vagal trigger” AF are mostly healthy individuals with no evidence of cardiac disease. Conversely, patients with “sympatotonic” AF are usually elderly with different comorbidities and structural heart frailty.

Indeed, many clinical and preclinical reports have demonstrated cholinergic and sympathetic events to be triggers of AF. Evidence in canine models (Swissa et al., 2005; Tan et al., 2008) showed how simultaneous vagal and adrenergic stimulation (Ng et al., 2001) represents the main stimulus to ectopic focus activation. Other authors have demonstrated that silencing of paroxysmal AF (Yalcin et al., 2015) is triggered by rapid atrial spread, through bilateral cardiac ganglia (Xie et al., 2011) and cardiac vagal limbs ablation, producing total sympathovagal excitement abolition.

Neural modifications (Saygili et al., 2012), prompted by rapid atrial spread, also suggest atrial adrenergic fibers rejuvenation (Kimura et al., 2007). Sympathetic hyperinnervation, driven by norepinephrine spillover through the β–adrenergic stimulation (Suita et al., 2015), promotes the increase in protein kinase A (PKA) activity, modulated by ryanodine receptors (RyR2) hyperphosphorylation on atrial cardiomyocytes. The calcium released by atrial RyR2 induces fibrosis and apoptosis of myocytes and promotes the morphological transformation of atria, which in turn sustains the AF propensity.

MI is a common cardiovascular disease; its incidence runs in parallel with age and lifestyle, showing a spike in patients over 75 years old. Many risk factors are related to MI: smoking, hypercaloric diet, dyslipidemia, sedentary life, alcohol abuse, high blood pressure, and others. MI mostly occurs as a consequence of coronary artery disease and coronary stenosis and results in hypo-perfusion of the heart and cardiac oxygen deficiencies in specific cardiac areas, identified as ischemic territory. The main MI symptoms are chest pain or discomfort, which may radiate to the shoulder, arm, back, neck, or jaw, shortness of breath, nausea, faint, cold sweat, or fatigue, with women more exposed than men to develop atypical signs. These macroscopic abnormalities (Davis et al., 1988) also translate into molecular disorders driven by NGF. Indeed, NGF levels extensively increase after MI (whereas its expression decreases during heart failure and ventricular injury), triggering the sprouting of neurites and neuronal modifications (Davis et al., 1988; Hassankhani et al., 1995; Cao et al., 2000a; Zhou et al., 2004; Oh et al., 2006; Lorgis et al., 2009). MI is characterized by a continuous and sustained catecholaminergic tone, to contrast the decreased irroration of the ischemic area. This effect determines beta-adrenoreceptors overstimulation by NE spillover (Hasking et al., 1986) with an upregulation of NGF, which promotes fiber remodeling and cardiac hyperinnervation (Li and Li, 2015), which is eventually responsible for the development of cardiac arrhythmia. A sinusoidal trend in NGF expression has been demonstrated during MI by different scientific reports (Zhou et al., 2004). As observed in murine models, the first hours after MI with beta adrenoreceptors activation are characterized by NGF overproduction, while after the development of the consequential cardiac cell death, a decline in NGF levels is gradually established, inducing heart swelling due to alpha-adrenoreceptors stimulation (Kimura et al., 2010). Myocardial infarction is characterized by an increase in sympathetic output with a progressive reduction of parasympathetic activity centrally, which could represent a potential therapeutic target to improve cardiac function (Airaksinen et al., 1999; Olshansky et al., 2008; Ardell et al., 2016; Shivkumar et al., 2016). Specifically, cholinergic nervous system remodeling with slight oscillations in acetylcholine expression was observed in the apex, anterior wall, and lateral wall of the LV in healthy pigs compared to the MI experimental group (Vaseghi et al., 2017), accompanied by significant impairment in basal function and input of the cholinergic nervous system within the ICNS (Vaseghi et al., 2017). Moreover, morphological remodeling in the nodose ganglia was documented in the MI model, specifically characterized by a significant upregulation in calcitonin gene-related peptide (CGRP) and TH-positive neuronal cells, in parallel with a gradual decline in neuronal nitric oxide synthase levels accompanied by relevant neuron size increase (Ardell et al., 2016; Salavatian et al., 2017). These results indicate that intra and extracardiac cholinergic maladaptive remodeling develops in the myocardial ischemic injury context, with intact cholinergic nervous pathways but decreased cholinergic input (Vaseghi et al., 2017). These intact parasympathetic pathways may represent a novel therapeutic target for the treatment of chronic cardiovascular disorders, through VNS.

Impaired sensory information is one of the main drivers of acute autonomic responses to ischemic injuries and the progression of cardiac disorder. Wang et al. described an attenuation of HF in cardiac post-ischemic experimental models through selective chemical ablation of cardiac transient receptor potential cation channel subfamily V member 1 (TRPV1) receptors using epicardial resiniferatoxin (Wang et al., 2014). Thus, tailored neuromodulation may potentially affect sensory transduction in a reversible and on-demand manner (Wang et al., 2014; Ardell et al., 2016; Salavatian et al., 2017). Temporary occlusion of the left anterior descending (LAD) coronary artery results in nodose hyperactivity. However, direct (cervical vagal, VNS) and remote (thoracic the spinal cord, SCS) neuromodulation alleviates nodose response to transient myocardial ischemia events induced by repeated LAD ligations (Salavatian et al., 2017). Together, this evidence suggests that preventive neuromodulation affects myocytes metabolism, thus improving their resistance to stress stimuli (McGuirt et al., 1997; Southerland et al., 2007; Wang et al., 2014; Salavatian et al., 2016). Many experimental models have shown a strong infiltration of macrophages in the ischemic area. Immune cells contribute to increasing NGF production, activating its receptors TrkA and p75 (Ben-Zvi et al., 2007; Carter et al., 2010), which are also expressed in endothelial cell bodies. The increased release of NGF triggers a further hyperinnervation modulated by TrkA binding, whereas p75 (Lee et al., 1994; Habecker et al., 2008) activation induces the release of TNF alpha, a potent inflammatory modulator, which induces cardiomyocytes apoptosis. As emerged from different clinical data, the risks to develop severe arrhythmias (ventricular tachyarrhythmia, ventricular fibrillation) is higher for 30 days after MI and NGF sympathetic hyper-sprouting is the main promoter of arrhythmias and ventricular dysfunction (Hu et al., 2014a; Pius-Sadowska and Machaliński, 2021). During the inflammatory response, myocardial cells secrete phlogistic hypertrophic factors (Matsui et al., 1996), such as cardiotrophin-1 (CT-1), ciliar neurotrophic factor (CNTF), and leukemia inhibitory factor (LIF) (Sun and Zigmond, 1996), which are capable of both abolishing NE release and inducing cholinergic marker (choline acetyltransferase -ChAT and vesicular acetylcholine transporter- VaChT) synthesis in cardiac stellate ganglia (Zhou et al., 2005), via the interleukine-6 (IL-6) glycoprotein 130 (gp130) pathway. This process promotes a phenotype transdifferentiation. Indeed, immunolabelling showed cholinergic staining of adrenergic stellate neurons, with coexpression of TH and ACh immunopositive fibers (Olivas et al., 2016). Moreover, adrenergic fiber depletion occurs. All the reported changes are connected to NE overproduction, which suppresses TH synthesis (through proteasomal degradation) (Shi and Habecker, 2012) and attenuates norepinephrine reuptake. As a result, a decrease in NE cardiac expression is observed, accompanied by a reduction in MIBG reuptake (Dae et al., 1991). Experimental studies on mice (Rana et al., 2009) have shown that ChAT (key enzyme for acetylcholine synthesis) gene silencing (mice ChAT/- knockout) in adrenergic neurons reduced myocardial infarction. Specifically, Olivas and others found that the deletion of ChAT from sympathetic neurons abolished the post-MI increase in cardiac ACh content, culminating in ACh levels significantly lower than WT post-MI hearts. Conversely, NE levels did not change. This suggests that the increased ACh observed in the left ventricle after MI was due to the production of ACh by sympathetic nerves. Notably, the transient increase in cardiac ACh amount coincided with increased expression of the genes required for ACh production in the stellate ganglion and the appearance of ChAT and VAChT protein in TH + cardiac sympathetic neurons. In summary, these data indicate that cardiac sympathetic nerves produce ACh in addition to NE after MI (Olivas et al., 2016).

The shift from adrenergic to parasympathetic phenotype is also sustained by glycoprotein 130 receptors that allow the “cholinergic dress acquisition” of adrenergic neurons. Supporting a transitory cholinergic trans-differentiation in adrenergic cardiac neurons, after gp130 receptor deletion, parasympathetic genes were not expressed post- MI. Thus, transient sympathetic co-secretion of norepinephrine and acetylcholine may favor a strong reaction mediated by inflammatory cytokines (Nian et al., 2004), inducing cardiac remodeling and lethal arrhythmias which may cause sudden cardiac death (Cao et al., 2000a; Chen et al., 2001). Although functional implications of the sympathovagal signal (Cao et al., 2000a; Chen et al., 2001; Olshansky et al., 2008; De Ferrari et al., 2011) remain uncertain, multiple reports (Emanueli et al., 2014) suggest that concurring actions of NE and ACh from sympathetic fibers may underlie heart impairment and arrhythmia propensity. NGF and inflammatory cytokines are identified as new important therapeutic targets on which we may act to prevent the dramatic cardiac remodeling processes post-MI and ventricular injuries. As demonstrated, the use of agonists or antagonists of the NGF receptor (TrkA) (Kuruvilla et al., 2004) or the NGF gene transport may improve angiogenesis and cardiomyocytes survival, thus promoting the cardiac response after a few weeks post-myocardial infarction (Meloni et al., 2010).

Neuronal remodeling reaches its final phase with the development of heart failure (Jessup and Brozena, 2003), a complex clinical syndrome also characterized by a complete impairment of the autonomic nervous system. HF incidence is clearly age-related: 0.8% of individuals between 50 and 59 years old and up to 9.2% of subjects between 80 and 89 years old suffer HF, with occurrence doubling for each decade beginning from 40 years of age. The increased risk for males in younger ages is inverted in advanced decades, with females presenting a higher risk after menopause. Age represents the main risk factor for heart failure development (Di Bari et al., 2004), which is mostly associated with acute and chronic MI, hypertension, and valvular disorders (in particular, degenerative aortic stenosis and mitral regurgitation). As emerged in many reports (Vasan et al., 1995), HF is characterized by morpho-structural changes, with cardiomyocytes apoptosis and interstitial fibrosis, associated with left ventricle concentric hypertrophy (Wilde et al., 2008), aortic stiffness, and increased susceptibility to myocardial ischemia. Different comorbidities and simultaneous disorders, such as diabetes mellitus (Faerman et al., 1977), atrial fibrillation, lung injuries connected to Chronic Obstructive Pulmonary Disease (COPD), and kidney function worsening, can promote HF syndrome.

The pathophysiological basis of HF is constituted by a blood pressure decrease, which triggers a “reaction flow”; the cardiac output lowering is detected by carotid sinus receptors (Wang et al., 1990) that send impulses to the vasomotor bulbar center; this process determines a “switch” and promotes a strong “adrenergic firing” on the myocardial tissue. Sympatho-excitation in heart failure is also associated with reduced sensitivity of sympathetic-inhibitory reflexes, such as the arterial baroreflex and the cardiopulmonary reflex, to an increase in activity of peripheral chemoreceptors at a high plasma concentration of angiotensin II and to the reduction in the synthesis of nitric oxide (Lataro et al., 2017). The above-mentioned mechanisms exert a compensatory effect to ensure suitable cardiac contractile strength for a while, but sympathetic (Zhang and Anderson, 2014) hyperactivity rapidly contributes to disease progression and reduction of adrenergic stimulation (Eisenhofer et al., 1996). Thus, from asymptomatic ventricular dysfunction, the process evolves to HF, with cardiac output decline and lung hypertension. Adrenergic and RAAS system hyperstimulation acts as a compensatory mechanism to assure cardiac perfusion, but with disease progression, increases cardiac workload and induces peripheral vasoconstriction. Thereby kidney and skeletal musculature ischemia are promoted, resulting in decreased exercise tolerance and renal dysfunction.

The extensive activity of the endocrine system and adrenergic circuits promotes a bulky augmentation of phlogistic cytokines (IL-6; LIF; CT-1) (Ure and Campenot, 1994), secreted by stressed myocardial cells, resulting in myocytes apoptosis and metabolic cellular disorders, reactive oxygen species production and cardiac derangement. Naturally, in this contest the autonomic dysregulation also causes “peripherical and molecular turbulences”: adrenergic hyperfiring triggers a strong spillover of circulating catecholamines (especially norepinephrine) (Chidsey et al., 1965; Chidsey et al., 1963; Cohn et al., 1984; D'Elia et al., 2014), that exert their functions through beta-adrenoreceptors binding and try to contrast the lowering of blood pressure. In this phase, a robust hyperinnervation with NGF overproduction (Hassankhani et al., 1995) has been demonstrated to be mediated by beta-adrenoreceptors in different rodent experimental models with left anterior descending coronary artery ligation (D'Elia et al., 2014). A paradoxical phenomenon manifests during this process: hyperexcitement of sympathetic circuits tries to support the cardiac activity but, progressively, the inhibition of TH synthesis induces a decrease in norepinephrine cardiac levels with stimulation of alpha2-adrenoreceptor (alpha2-ARs), which also leads to reduction of NGF expression. Although the reduction of cardiac NE levels was assessed in an overt HF setting, the progressive accumulation of catecholamines in the synaptic space promotes the alpha2-ARs stimulation, that through the inhibitory presynaptic feedback loop tries to limit NE additional release. However, since the alpha2-ARs is coupled to Gi, the activation of this receptor contributes to a decline in NGF expression (Starke et al., 1975; Jie et al., 1987; Kubo et al., 1989; Grossman et al., 1991; Parker et al., 1995; Bylund, 2005; Govoni et al., 2011).

The entire process develops in a severe disruption of cardiac sympathetic fibers (Lorentz et al., 2013). Accordingly, autopsied human heart samples from patients with congestive heart failure (CHF) have revealed a dramatic loss of adrenergic TH-reactive fibers (Kaye et al., 2000; Qin et al., 2002).

From myocardial infarction to heart failure development, neurons in the adrenergic ganglia show an overlap between cholinergic and adrenergic markers and gradually promote the synthesis of parasympathetic modulators (Kanazawa et al., 2010), mediated by “cardiokines” (IL-6; LIF; CT- 1) secreted from “worn cardiomyocytes”. The mechanisms responsible for this switch still remain unclear, although it probably constitutes a protective mechanism instigated in the heart in order to avoid lethal consequences, such as arrhythmias, induced by chronic sustained adrenergic activity, and to help preserve innervations in the denervated areas.

AD is a complex neurodegenerative disorder and the main form of dementia, characterized by a progressive accumulation of cerebral parenchymal β-Amyloid (Aβ) plaques and intraneuronal tau neurofibrillary tangles, associated with widespread brain inflammatory processes. The disease induces a gradual cognitive decline with progressive memory dysfunction (Kanazawa et al., 2010; Castellani et al., 2010; Small et al., 1997-29). Although the main symptoms of AD predominantly concern the CNS, numerous extracerebral and systemic effects have been recently identified, which may also affect the cardiovascular tissue. In this regard, several studies have described interesting associations between Alzheimer’s disease and cardiac disorders, such as AF (Ihara and Washida, 2018), HF (Cermakova et al., 2015; Cohen and Mather, 2007; Hoth et al., 2008), and coronary artery disease (CAD) (Roger, 2013; Tublin et al., 2019). It was recently observed that AD patients exhibit Aβ deposits, besides cerebral areas, also in the cardiac tissue. Cardiac amyloid deposition was also found in patients affected by idiopathic dilated cardiomyopathy (iDCM) (Li et al., 2006b; Gianni et al., 2010; Troncone et al., 2016). However, nothing is currently known about the timeline of Aβ accumulation in the heart of AD patients and evidence is lacking in regard to the levels and concentrations of Aβ aggregates in the AD heart compared to the brain. It is however conceivable that similar pathological mechanisms, such as a failure of proper clearance of amyloid (including Aβ), may be responsible for both.

Age is the main risk factor for both AD and HF (Kivipelto et al., 2005; Viña and Lloret, 2010; Hölscher, 2011), and these disorders exhibit many other common risk factors, including metabolic and cardiovascular disorders, diet, lifestyle, or the higher risk in females after menopause. Importantly, many recent clinical studies demonstrated an interesting interaction between cerebral hypoperfusion and cognitive dysfunction in HF patients, strengthening the links between cardiovascular conditions, vascular dementia, and AD (Mansur et al., 2018; Ventoulis et al., 2021; Li et al., 2022). Notably, during HF, blood pressure progressively drops, resulting in brain hypoperfusion with a remarkable oxygen loss, increase in oxidative stress and neuronal metabolic impairment (Moreira et al., 2005; Pirchl and Humpel, 2009; Cermakova et al., 2015). Interestingly, clinical investigations demonstrated a positive correlation between cognitive deterioration and HF severity (Cohen and Mather, 2007-; Hoth et al., 2008). Neuroimaging studies corroborated these findings, describing significant brain morphological changes in HF patients (Vogels et al., 2007; Cermakova et al., 2015). Specifically, Kumar et al. observed severe demyelination in HF patients, associated with a dramatic cerebral atrophy that induces neuronal maladaptive remodeling with consequential impairment of axonal circuit functionality (Vogels et al., 2007; Kumar et al., 2011; Cermakova et al., 2015). Yet, the neuronal deterioration found in HF might be connected to a more complex etiopathology. Indeed, we and other groups propose that HF itself may also be a result of cardiac Aβ accumulation triggered by AD pathology, which would instigate an accumulation of multiple amyloid proteins in an understudied potential vicious cycle between brain and heart deterioration (Troncone et al., 2016; Wang et al., 2017; Sanna et al., 2019). However, more studies are needed to demonstrate this hypothesis.

Li and others have identified interesting missense mutations in PSEN1 (Asp333Gly) and PSEN2 (Ser130Leu) genes observed in AD patients affected by HF (Li et al., 2006b). In line with this, the Del Monte group has described the same AD-related gene variations in iDCM patients that exhibited cardiac inclusions consistent with amyloid accumulations (Gianni et al., 2010). All these findings provide evidence of the strong existing correlation between Alzheimer’s disease and heart failure conditions that likely may share common, yet poorly investigated, pathophysiological mechanisms. For instance, it is well known in the AD field that Aβ oligomers promote significant neurotoxicity, and among other toxic effects, they affect calcium currents, thus impairing neuronal homeostasis, synaptic health, and neurotransmission. Interestingly, similar detrimental effects on calcium handling were detected in cardiomyocytes’ challenged with Aβ oligomers, thus suggesting similar mechanism triggered by Aβ in the neuronal and cardiovascular environment (Gianni et al., 2010; Jang et al., 2022).

Besides synaptic, neuroimmune, and vascular dysfunction, AD is accompanied by a significant impairment in neurotrophic signalling, with a progressive loss of the two main neuromodulators, NGF and BDNF (Allen et al., 2011). Specifically, both these neurotrophins are severely affected during the neurodegenerative process in the early stages of the disorder. Indeed, several studies have described detrimental effects mediated by Aβ on the expression of neurotrophins, resulting in cognitive decline (Garzon et al., 2002; Arancio and Chao, 2007). Notably, a gradual failure of NGF signaling, with progressive TrkA (NGF receptor) downregulation was shown in the cholinergic basal forebrain nuclei (ChBF) (Davies and Maloney, 1976; Counts and Mufson, 2005), accompanied by a severe Aβ-induced BDNF decline in the cortex and hippocampus (Arancio and Chao, 2007). These progressive alterations in the neurotrophic pathway are associated with a gradual cognitive impairment both in elderly patients and in aging murine models (Tessarollo and Hempstead, 1998; Donovan et al., 2000; Sarter and Bruno, 2004; Jansen et al., 2007; Scharfman and Chao, 2013; Anastasia et al., 2014). Therefore, it is reasonable to hypothesize that restoring the neurotrophic pathway via viral vectors that produce NGF and BDNF, or through neurotrophins receptor agonists, may counteract neuronal deterioration and attenuate synaptic degeneration, thus improving cognitive decline, as proposed by some clinical studies (Graham et al., 2017; Castle et al., 2020; Ruiz-González et al., 2021; Eyjolfsdottir et al., 2022). Curiously, recent studies have also evidenced a significant dysregulation of the BDNF signaling pathway during aging (Miranda et al., 2019; Molinari et al., 2020). Elia and colleagues have described severe impairment in the cardiac autonomic nervous system exhibited by aged rats, associated with a significant deterioration of both adrenergic and cholinergic nerve fibers, together with a relevant downregulation in cardiac BDNF protein levels (Elia et al., 2021). This autonomic deregulation may be, at least in part, responsible for the risk of developing cardiovascular disease in the aging/Alzheimer’s heart. Accordingly, we speculate that a progressive degeneration of the neurotrophic pathway in AD may trigger a gradual decline in circulating NTFs levels, also resulting in a derangement of the cardiac nervous system, culminating in lethal heart disorders (such as AF, MI, HF). Therefore, neurotrophic factors may represent innovative and promising therapeutic frontiers to improve cerebral and cardiac prognosis and ameliorate the quality of life for both AD and HF patients.

In line with our hypothesis of a link between heart and brain dysfunction, recent clinical investigations, as well as studies in animal models, have highlighted the beneficial effects promoted by different cardioprotective drugs (i.e., Beta-blockers, Angiotensin Converting Enzyme (ACE) inhibitors, sartans, and Aldosterone receptor antagonists) in Alzheimer’s disease and cognitive dementia. The cardioprotective drugs, in addition to providing preventive effects (Carey and Fossati, 2022), also appear to prevent the neuronal accumulation of Aβ aggregates and result in a significant improvement in memory impairment in some clinical studies as well as in multiple animal models (Chen et al., 2020; Lee et al., 2020; Drews et al., 2021; Ouk et al., 2021; Wang et al., 2021; Beaman et al., 2022; Deng et al., 2022; Mehdipour et al., 2022). This evidence points to the possibility that combination therapies containing these compounds may have efficacy for the treatment and prevention of both cardiac diseases and dementia in older adults.

Angiotensin Converting Enzyme inhibitors reduce the activity of the ACE, which is responsible for the conversion of Angiotensin- I (AT- I) -produced as a result of different reactions between a liver compound (i.e., Angiotensinogen) and a kidney hormone (i.e., renin)- in the peptidic marker AT- II. Therefore, ACE inhibitors stop the inflammatory consequences and decrease norepinephrine, inducing remodeling of the cardiac fibers network and restoring cardiac performance. Moreover, RAAS dysfunction induces hyperproduction of the cortical adrenal mineral corticoid hormone “aldosterone”, whose function is to retain sodium in organic fluids, increasing the systolic ventricular tension and thereby causing hypertension. ACE inhibitors represent an important pharmacological treatment for cardiac output hypertension. Similarly, angiotensin receptor antagonists (ATRs), also called sartans, play a crucial role in the management of hypertension and HF (Cleland et al., 2005). These drugs counteract the adverse effects of AT- II, by blocking its presynaptic and/or postsynaptic receptors (Schlicker and Feuerstein, 2017) and restore RAAS signaling. Many scientific reports have explored the efficacy of ACE inhibitors, and their possible synergistic effect with sartans, both in human and animal models.

Renin inhibitor agents, such as aliskiren, represent another important resource in HF treatment: acting on the RAAS system, this drug prevents the conversion of angiotensinogen to angiotensin I.

The autonomic nervous system remodeling is one of the common factors involved in the etiopathological mechanisms of cardiovascular disorders, including cardiac arrhythmias, MI, and HF. Despite the advances in the medical and surgical fields, the progression of cardiac illnesses is still growing, together with the mortality rate (Florea and Cohn, 2014; McMurray et al., 2014; Shivkumar et al., 2016). Notably, the established pharmacological treatments for cardiac disorders act partially through neurohormonal inhibition, via β-ARs antagonism and/or RAAS blocking, thus modulating ANS activity, mitigating the aberrant cardiac electric events and restoring cardiac physiological homeostasis (Triposkiadis et al., 2009). As a matter of fact, the beneficial effect of the β-blocker therapy observed in HF patients is significantly proportionate to the degree of heart rate (HR) decrease (Fox et al., 2007). Specifically, cardiac prognosis improvement was obtained with treatments aimed at achieving low resting HR in heart failure, as demonstrated in the SHIFT (Systolic Heart Failure Treatment with the If Inhibitor Ivabradine) clinical trial, based on ivabradine therapy (Swedberg et al., 2010). Yet, numerous concerns remain regarding the neurohormonal modulation of the ANS tone through pharmacological approaches, including poor pharmacological specificity to discriminate the ANS branches (SNS and PNS) and considerable drug intolerance with recurring side effects. For instance, in a randomized controlled study conducted on select HF subjects (Lang et al., 1997; Cohn et al., 2003), the possible risks of moxonidine treatment emerged. This specific antihypertensive central medication decreased NE plasma levels, but did not show a selective block of sympathetic activity, thus increasing the morbidity and mortality risk in HF patients (Bristow, 2003). An extended knowledge of the dynamic connections between the nervous system and cardiac tissue has resulted in the development of novel therapeutic solutions based on the neuromodulatory stimulation of the ANS, including renal denervation and vagal nerve stimulation, which appear to exhibit significant beneficial effects in multiple cardiac disorders (Figure 2).

Adrenergic renal afferent and efferent fibers participate in the maintenance of cardiovascular homeostasis, counteracting stress stimuli that occur in cardiac injuries. Specifically, the renal sympathetic network is involved in the modulation of blood pressure, heart rate, and cardiac output (Esler, 2010). In chronic cardiac disorders (such as HF), the carotid chemoreceptors and baroreceptors transmit signals, such as those associated with decrease in blood pressure, cardiac output, and oxygen expenditure increase, to the brain, thus leading to RAAS activation, AT- II increase and in the central stimulation of sympathetic hyper tone (Murakami et al., 1997; Goldsmith, 2004; Li et al., 2006a; Paton et al., 2013). This culminates in renin over-release from renal glomeruli, resulting in a severe impairment of sodium and water handling (Ljungqvist and Wågermark, 1970; Goldsmith, 2004). Moreover, progressive renal hypoperfusion directly contributes to the SNS output centrally (Sobotka et al., 2011). This induces secretion of NE from adrenergic fibers, resulting in the upregulation of catecholamines circulating levels, which culminates in a dysregulation of the cardiac β-signaling pathway, thus fueling cardiac maladaptive remodeling and neurohormonal axis impairment (Böhm et al., 1988; Böhm et al., 1990). Interestingly, a long body of evidence demonstrates a tight correlation between cardiac and renal catecholamines spillover and morbidity/mortality rates (Hasking et al., 1986; Petersson et al., 2005). Therefore, multiple investigators proposed renal denervation as a therapeutic solution with positive prognostic effects to improve the quality of life in patients affected by heart disorders.