Studies on the Cardiac Nervous System - Dissertation Example

?Literature Review Brief Overview of Studies on the Cardiac Nervous System The heart was initially thought as an insensate organ (Fu & Longhurst, 2009). Studies on the anatomy of human intrinsic cardiac nervous system have been conducted for almost 85 years. In the 1950s, intrinsic cardiac ganglia were found primarily over the posterior surfaces of the atria and atrio-ventricular groove (Armour, Murphy, Yuan, MacDonald, & Hopkins, 1997). From then until now, the studies have evolved into defining their roles in heart function, the activities of the cardiac innervations at different conditions, the molecular mechanisms of their function, the diseases they are implicated in, and the effects of these discoveries in the management of cardiac diseases. As will be detailed below, histochemistry has played a major role in the study of cardiac nervous system. However, it is recognized that the only way to ascertain whether the inactivity or overdrive of a particular cardiac nerve plays a role in disease development and/or progression, for example blood pressure elevation, is through long-term prospective studies, which necessitates observation of hypertensive patients without any pharmacologic treatment (Grassi, 2010). Aside from the ethical issues of such studies, their feasibility demands extensive financial investment. Morphology of the cardiac nervous system As in any organ, the heart’s control comes from the central nervous system, the brain and the spinal cord. This part of the literature review looks at the cardiac innervation, starting from the central nervous system up to its final tributaries in the heart. 1. Sympathetic impulse from the central nervous system It has been shown that sodium sensors of the lamina terminalis at the anterior wall of the third ventricle is important in responding to changes in brain [Na+], which is sensitive to changes in intravascular fluid and partly to heart activity. From the lamina terminalis, the impulse then goes to the paraventricular nucleus of the hypothalamus (May, et al., 2009). In turn, the cardiovascular nuclei within the medulla oblongata receive innervations from hypothalamus, and other brain areas such as the insula, medial prefrontal cortex, and cuneiform nucleus, all of which regulating cardiovascular responses to emotion and stress, such as exercise and increase in temperature (Assadi & Motabar, 2011). Through descendant pathways, the supra-spinal and vasomotor centers of the medulla then send activator impulses to the preganglionic sympathetic neurons, which can be found within the lateral horn in the inter-medio-lateral nuclei of the thoracolumbar segment of the spinal cord. Their respective fibers exit the cord via the ventral root, and connect with postganglionic neurons from paravertebral sympathetic chain (Popa, et al., 2010). The superior, middle and inferior cardiac nerves from the neurons in the superior cervical ganglia and cervico-thoracic (stellate) ganglia, which communicates with cervical nerves C7-C8 and thoracic nerves T1-T2, follow the brachiocephalic trunk, common carotid arteries and subclavian arteries, and project from the base of the heart into the muscle, specifically in the ventricular sub-epicardium. Meanwhile, the other thoracic cardiac nerves travel through the posterior mediastinum to reach the heart (Shen et al., 2012). The cardiac superior nerves from the superior ganglion in front of C2 and C3 vertebrae go down toward the heart through the primitive carotid anterior to the large muscles of the neck. The small middle cervical ganglion, if present, is located at level of C6, near the thyroid artery. Its cardiac branch emerges after synapsing with the inferior cervical ganglion. On the right, it descends behind the primitive carotid to make up the dorsal part of the cardiac plexus, while receiving impulses from the principal pneumogastric and the recurrent nerves. On the other side, the nerves pass in between the left primitive carotid and the subclavian to converge at the deep part of the cardiac plexus. Finally, the inferior cervical ganglion can be found in between the base of the transverse process of the last cervical vertebrae and the first rib, medial to the costocervical artery. The inferior cardiac nerve is located behind the subclavian artery and anterior to the trachea, where it converges with the recurrent nerve and a medium cervical nerve tributary. Characteristically, the sympathetic nerves can be found traveling along arteries and nerves, particularly in the outer wall of blood vessels. They release the neurotransmitter norepinephrine upon stimulation (Assadi & Motabar, 2011). 2. Parasympathetic nervous system On the other hand, the synapse between preganglionic fibers and postganglionic parasympathetic neurons are located proximal to the myocardium. In addition, unlike sympathetic impulses, there are no parasympathetic nerves innervating the peripheral vessels (Popa, et al., 2010). The parasympathetic nerves are carried through the vagus nerves before dividing into superior, middle and inferior branches (Shen et al., 2012). The vagus nerve is a mixed nerve performing mostly sensory (80%), motor and secretory functions. It runs from the brainstem, through the base of the skull, passing in the neck with the carotid artery and jugular vein. It travels toward its insertions inside the carotid sheath, lateral to the carotid artery (Assadi & Motabar, 2011). It gets impulses from the dorsal motor nucleus partly, to control cardiac inotropism, and nucleus ambiguous mainly to control the rate of the heart (Rysevaite et al., 2011). On the other hand, the solitary nucleus receives sensory input from the heart to the brain. The left and right vagus nerves then converge between the superior vena cava and the aorta before heading to the sinus and atrio-ventricular nodes (Shen et al., 2012). Unlike the sympathetic innervation which synapses within chain ganglia to innervate the heart, the presympathetic fibers synapse at ganglia located directly on the heart. Short postsynaptic fibers thus innervate the organ, specifically the sino-atrial and atrio-ventricular nodes in the heart. Atrial muscle and ventricular myocardium are also innervated by vagal efferents (Assadi & Motabar, 2011). The diagram of autonomic pathways can be seen from Figure 1. 3. The sensory pathways The heart has two distinct separate sensory pathways, with one traveling with vagal preganglionic motor nerves and the other found adjacent to sympathetic efferents (Fu & Longhurst, 2009). As seen in Figure 2, Fu and Longhurst (2009) have determined the location of cardiac sympathetic afferents on the anterior and posterior ventricles. The cardiac plexi also synapse with the cervical plexus, brachial plexus and intercostal nerves (Assadi & Motabar, 2012). This explains why cardiac pathologies such as myocardial infarction and angina can present with chest pain radiating to the neck and shoulders. 4. Intracardiac Pathways of the Mediastinal Nerves Extrinsic cardiac nerves access the heart through the hilum, located at the base of the heart. The nerves that enter at the atrial part, around the ascending aorta and pulmonary trunk, extend into the ventricles, while those that pass through at the venous part of the hilum, around the pulmonary veins and vena cavae, innervate both the atria and ventricles. Specifically, within the venous part of hilum, most nerves concentrate at the 1) left atrial nerve fold, 2) between the entry of the right superior pulmonary vein (RSPV) and the superior vena cava (SVC), and 3) between the entry of the RSPV and left superior pulmonary vein (LSPV) (Pauza, Skripka, Pauziene, and Stropus, 2000). These nerves and bundles then extend epicardially to the atria and ventricles through left dorsal, dorsal right atrial, right ventral and ventral left atrial routes. Some are also located at the roots of pulmonary veins. These ganglia are interlinked by interganglionic nerves (Rysevaite et al., 2011). In particular, the right cardiac nerves project toward the atria and sinus node, and those on the left go toward the atrial-ventricular node and the left ventricle (Govoni, et al., 2011). 5. Intrinsic cardiac nervous system Extending from these nerves are the seven ganglionated nerve subplexuses of the heart. It must be noted that intracardiac nerves do not penetrate directly into the myocardium, but extend into the epicardium. The courses from the hilum are associated with protuberances and/or grooves of the heart wall, specifically by coronary interatrial and interventricular routes. In the end, the human epicardiac neural plexus (ENP) is composed of seven ganglionated subplexuses. Two pathways arise from the arterial part of the hilum, and extend to the left side via the left ventral coronary sulcus as well as to the right side via the right ventral coronary sulcus. On the other hand, those from the venous part of the hilum pass through five different pathways: 1) anterior interatrial sulcus and 2) sulcus located dorsally between the roots of SVC and RSPV proceeding to the right atrium; through the left atrial nerve fold toward the lateral left atrial surface; and via the 4) ventral and 5) dorsal surface of the left atrium to innervate the left atrium and the dorsal wall of the left ventricle. These pathways are interconnected complexly through thin, commisural nerves (Pauza, Skripka, Pauziene, and Stropus, 2000). In general, three-fourths of the epicardiac ganglia are located on the dorsal surface of the heart, and more than half are localized in the atria, particularly the left atrium. Still, ganglia at the ventral surface can also be found in the atrial regions of the heart (Pauza, Skripka, Pauziene, and Stropus, 2000). a. Coronary subplexi As stated above, their preganglionated nerves (preGNs) enter the hilum through the area beween the aorta and pulmonary trunk. Upon reaching the coronary arteries, they separate to follow the course of these vessels. Their epicardiac ganglia are then distributed at the ventral coronary sulcus on the surfaces of the ventricles. In particular the postganglionated nerves (postGNs) of the right coronary (RC) subplexus occupy the right ventral coronary sulcus, ventral and lateral surfaces of the right ventricle, as well as the right half of the conus arteriosus. On the other hand, those of the left coronary (LC) subplexus supply the inferior surface of the left auricle, ventral, lateral and dorsal surfaces of the left ventricle and coronary sulcus (Pauza, Skripka, Pauziene, and Stropus, 2000). b. Ventral Right (VRA) and Left (VLA) Atrial Subplexi The preGNs enter through the superior interatrial sulcus to occupy the ventral superior right atrium (VSRA), ventral inferior right atrium (VIRA), inferior surface of the right auricle (ISTA), and the ventral root of superior vena cava (RSVC). The postGNs then extend toward the ventral atrial regions. The VLA, on the other hand, occupies only the ventral left atrium surface, and its postGNs extend to the ventral inferior left atrium (VILA), where they merge with the postGNs of the VRA subplexus (Pauza, Skripka, Pauziene, and Stropus, 2000). c. Dorsal Right Atrial (DRA) Subplexus Its preGNs entry point is located between the SVC and RSPV, and its ganglionated field is at the sinus venarum. The greatest density of ganglia can be found in the dorsal superior right atrium (DSRA), RSVC, and above the interatrial septum. The postGNs are then located at the dorsal and lateral right atrium, which includes the sino-atrial node and superior surface of the right auricle (Pauza, Skripka, Pauziene, and Stropus, 2000). d. Left (LD) and Middle (MD) Dorsal Subplexi The preGNs enter through the front of the left superior pulmonary vein (LSPV) or the left atrial nerve fold, on its way to the left auricle and lateral left atrial surface. It innervates the dorsal left coronary sulcus (DLCS) and middle left atrium (MLA). PostGNs coursing along the left dorsal coronary sulcus spread onto the dorsal surface of the left ventricle. It also contributes to the innervation of the crux cordis (Pauza, Skripka, Pauziene, and Stropus, 2000). Meanwhile, the entry points of preGNs of MD subplexus are distributed between the left and right pulmonary veins, and sometimes from the left or below the inferior vena cava. They then innervate predominantly the dorsal left atrium and scarcely the crux cordis. The postGNs passing through the coronary sulcus then pass through the coronary sulcus to reach the dorsal surface of the ventricles. Those from crux cordis are distributed to the right auricle (Pauza, Skripka, Pauziene, and Stropus, 2000). Immunohistochemistry of intrinsic cardiac nerves Since the acetylcholine (ACh) has been discovered as the molecule responsible for impulse transmission between nerves, the enzymes of the cholinergic pathway, including the synthesizers, transferases and degraders, have thus been used to detect innervation of different organs. The ACh-degrading acetylcholinesterase (AChE) is the first histochemical staining successfully developed for the nervous system. In this method, acetylthiocholine was used to react with AChE in order to form insoluble copper-thiocholine. However, initial methods of AChE staining were initially unreliable because the formed precipitates were not able to localize the AChE activity. Many improvements in the reaction with metal ions were developed since then (Anglade and Godinot, 2010). Other enzymes were also tapped for the staining. The ACh-synthesizing choline acetyltransferase (ChAT) has been looked into for a possible role in immunohistochemistry, particularly using ChAT antibodies as staining probes. However, the use of these antibodies was initially hampered due to its limited capability of staining peripheral nerves. However, the discovery of the peripheral type ChAT isoform, and the formation of anti-peripheral ChAT antibodies facilitated the functionality of immunohistochemistry using ChAT molecules. Later on, ACh has been used in immunostaining via its reaction with tyrosine hydroxylase (TH), and the subsequent ionic fixation of its by-products (Anglade and Godinot, 2010). In the histochemical study of the human heart’s nervous system by Pauza, Skripka, Pauziene, and Stropus (2000) and as adapted by other studies on cardiac innervation, the whole mount preparation of hearts were immunostained using staining for AChE Briefly, hyaluronidase-treated hearts were incubated in acetylthiocholine iodine mixture. A contact microscope LUMAM K-1 (LOMO, Leningrad) was used to examine the heart in situ. Tungsten light was also used to see the ENP. Nerve cells were further visualized using bright-filed microscopes. Later studies such as that of Rysevaite et al. (2011) included ChAT and TH in their immunostaining protocol. Physiology The heart is a vital organ that pumps without respite to allow oxygen- and substrate-carrying blood to reach all tissues of the body. The autonomic afferent fibers innervating the heart share the same pathway with gastrointestinal, genitourinary, baroreceptors and chemoreceptors. They transmit signals to the medulla by cranial nerves X and IX (Assadi & Motabar, 2012). The heart’s movement is primarily controlled by the parasympathetic nervous system (PNS) (McKee and Moravec, 2010). PNS also controls the heart rate (Popa, et al., 2010). Aside from PNS, sympathetic innervation is also necessary in maintaining the homeostatic regulation of the heart (Govoni, et al., 2011). Even a temporary absence will cause all the other organs to cease their function. Thus, it must adapt to sub-optimal conditions in order to perform. The stimulation of vagal efferents results to a reduction in heart rate and reduction of blood pressure, while sympathetic afferent stimulation increases heart rate and blood pressure. In addition, the latter is the sole pathway responsible for the sensation of angina (Fu & Longhurst, 2009). In response to injurious conditions such as chronic high blood pressure or coronary artery occlusion, the heart activates different pathways meant to compensate for the decrease in function caused by the adverse changes (McKee and Moravec, 2010). A. Neurotrophins Any myocardial injury results to damaged cardiac nerve fibers, which undergo Wallerian degeneration. Immediately after axonal damage, the proximal and distal nerve ends retract, the axoplasm leaks out, and the membranes collapse. The macrophages that travelled to the site of injury lyse and phagocytose myelin. The neurotrophic factor-producing Schwann cells then proliferate. This facilitates neurilemma cell proliferation and axonal regeneration. The up-regulation of nerve growth factors (NGFs) in non-neuronal cells surrounding the damaged nerves allows regeneration of functional synapses. This is because, as demonstrated using in vitro and in vivo animal studies, norepinephrine inhibits NGF production, although other studies have contradictory findings. Thus, the damage of sympathetic nerves that releases the neurotransmitter results to the induction of NGF expression. Within hours, several neuronal sprouts grow from injured axons to wherever there is environment suitable for further growth. However, these new nerves alter the physiology of the heart. Other neurotrophins implicated in nerve regeneration process in the heart include brain-derived neurotrophic factor (BDNF), insulin-like growth factor (IGF) I/II and interleukin-1 (IL-1) (Govoni, et al., 2011). B. Neuro-hormonal pathways: sympathetic nervous system (SNS) SNS is one of the pathways activated by the heart in times of decreased cardiac function. It affects many physiologic parameters, such as body temperature, vascular resistance, cardiac output, and heart rate. When cardiac sympathetic nerves are activated, they release norepinephrine locally, stimulating the sensitive nearby areas. The neurotransmitter binds with beta-adrenergic receptors on cardiac muscles and on vascular smooth muscle cells, causing increased heart contraction (McKee and Moravec, 2010). The heart and kidneys are coordinated with regards to blood volume control. The mammalian cardiac sympathetic nerve activity’s relation with that of the kidneys has been described using sheep. During induced blood pressure elevation by increasing sodium concentration in the brain, increased cardiac sympathetic nerve activity (CSNA) and decreased renal sympathetic nerve activity (RSNA) result to urinary sodium loss. There must thus be a later inhibitory synapse to the renal nerves, but not in those innervating the heart. The resting burst of CSNA is also noted to be significantly lower than that of RSNA (May, et al., 2009). C. Receptor-mediated control However, these hormones will not elicit effect if the receptors to which they bind with are absent. For example, certain polymorphisms of ?-1A-adrenoreceptor gene are associated with hypertensive patients, with metabolic syndrome and consistent adrenergic overdrive. A study by Greenfield et al. (2009) has shown that patients with melanocortin-4 receptor deficiency have lesser adrenergic function and subsequent blood pressure values. Phosducin, on the other hand, regulates G-protein, modulating adrenergic stress responses, including hypertension (Grassi, 2010). Clinical significance 1. Central obesity, metabolic syndrome and sleep apnea It is important to note that adrenergic activity is more pronounced among individuals having abdominal obesity with concomitant hyper-insulinemia and greater insulin resistance. Similarly, adrenergic activation is seen in the presence of metabolic syndrome. Such sympathetic overdrive is evident in normal blood pressure levels. Furthermore, the obstructive sleep apnea obese individuals suffer potentiates sympatho-excitatory effects (Grassi, 2010). 2. Hypertension Essential hypertension is described as. It is attributed to SNS, since central sympathetic outflow, sympathetic nerve traffic and plasma norepinephrine are found to be already elevated in young subjects even with very mild blood pressure increase. The levels also seem to continuously increase as the disease progresses. In addition, fluctuations in plasma norepinephrine values have a pattern similar to that of the heart rate. This suggests the relatively greater influence of the SNS on sinus node as compared to that of the vagal tone (Grassi, 2010). Adrenergic neural factors, as well as vasopressin and aldosterone, also contribute to end-organ damage, particularly cardiac hypertrophy and vascular alterations, seen among hypertensive individuals. Specifically, it causes pro-atherogenic vascular effects, and decreases arterial compliance. These effects are potentiated by the development of left ventricular diastolic dysfunction (Grassi, 2010). 3. Acute cardiovascular conditions Coronary artery blood flow disruption causing myocardial ischemia is clinically recognized as angina or retrosternal pain. The sudden reduction of blood perfusion results to a rapid shift to oxygen-independent glycolysis, producing lactic acid. The stimulation of sympathetic afferent fibers by chemical mediators such as serotonin, histamine, thromboxane A2, activated platelets, lactic acid, bradykinin, and reactive oxygen species, is responsible for the perception of angina and subsequent activation of fight or flight response, leading to tachycardia, hypertension and/or arrhythmias (Fu & Longhurst, 2009). Plasma norepinephrine levels are found to be elevated immediately after a coronary artery disease, subsequent myocardial ischemia or thrombotic cerebrovascular event, such as stroke (Grassi, 2010). Abnormal patterns of innervation have been seen in infarcted human hearts. Particularly, excessive sympathetic nerve sprouting of an electrically remodeled myocardium causes ventricular tachycardia, ventricular fibrillation and sudden cardiac death. The effectiveness of anti-adrenergic ?-blockers in preventing ventricular tachyarrhythmia and associated heart problems points to the role of increased sympathetic nerve magnitude and/or activity in the development of cardiac pathology. The NGF production resulting from sympathetic nerve damage also stimulate the activity of immune inflammatory cells such as lymphocytes, mast cells, eosinophils, as well as epithelial cells, keratinocytes, melanocytes, smooth muscle cells, and endocrinal cells, suggesting that NGF promotes tissue healing after injury. In fact, NGF has been demonstrated to promote angiogenesis (Govoni et al., 2011). 4. Atrial arrhythmias Simultaneous sympathetic and vagal nerve discharges as well as intrinsic cardiac nerve activity likely result to paroxysmal atrial tachycardia and pacing-induced sustained atrial fibrillation. In fact, modulation of the autonomic nervous system, particularly the continuous low-level stimulation of left cervical vagus nerve and subsequent decreased stellate ganglion activity, has been seen to prevent atrial tachyarrhythmias (Shen et al., 2012). 5. Chronic heart failure Heart failure is the endpoint gradually reached by most unmanaged cardiovascular diseases. The constant presence of insulting conditions results to chronic activation of neuro-hormonal pathways. SNS, for example, pushes myocardial cells to oxidative stress in order to produce increased energy that sustains the increased heart contraction. In chronic heart diseases, SNS will go as far as taking over the control of the heart. The PNS, therefore, is relegated to the backseat. If the stress is unrelieved, the reactive oxygen species induce necrosis and apoptosis. Without these cells, the heart will eventually weaken and fail. The hyper-activation of the SNS and under-activation of PNS thus cause the progression of chronic heart failure (McKee and Moravec, 2010). Interestingly, despite the increase in cardiac release of norepinephrine due to sympathetic overdrive, there is still a decreased cardiac norepinephrine stores in congestive heart failure. The oxidative damage, particularly to myocardial ?-receptors, also results to decreased norepinephrine uptake by the cardiac sympathetic nerve terminals, due to a decreased norepinephrine transporter density in sympathetic nerve endings. This contributes to the increased myocardial interstitial norepinephrine, reduced myocardial adrenoreceptors and myocyte apoptosis. This process has been found to be chamber-specific (Liang, 2007). Many thus advocate the use of biofeedback in order to modulate SNS activation and to promote PNS function. This technique utilizes stress management exercises that can supposedly train a person to control the autonomic nervous system. According to a review by McKee and Moravec (2010), studies have demonstrated the clinical significance of biofeedback in improving the quality of life of patients with heart failure. Meditation, for example, has been shown to reduce circulating norepinephrine. A randomized clinical trial with 33 participants also showed improved perceived stress, emotional distress and exercise tolerance after biofeedback-assisted stress management. Pharmacologically, many treatment options are available. Oral antagonists of RAAS and SNS can be given in patients with abnormally low ejection fraction. However, increasing dosages do not seem to necessarily improve life expectancy. Other management approaches include anticytokine therapy, cardioverter defibrillators, cardiac resynchronization devices, and epicardial constraining devices (Hauptman and Mann, 2011). 6. Spinal cord injury Interestingly, it has been noted that cardiovascular diseases are the leading causes of morbidity and mortality among individuals who sustained spinal cord injury (SCI), which disrupts the descendent pathways from the central nervous system to spinal sympathetic neurons, particularly the inter-medio-lateral nuclei at T1-L2 cord segments. Immediately after the SCI, norepinephrine release from suprarenal glands resulting to massive sympathetic stimulation and reflex parasympathetic activity occur for about 3 to 4 minutes. As such, severe hypertension and reflex bradycardia or tachyarrhythmia are experienced. A massive decrease of plasma norepinephrine then occurs. Cutaneous vasodilation, venodilation, decreased venous return, arterial hypotension, reduced cardiac output, bradyarrhythmia, atrioventricular nodal block, deep vein thrombosis, and bradycardia result. Since impulses from vasomotor centers are also disrupted, regulated vasoconstriction fails, and venous pooling occurs. Blood stasis paves the way for deep vein thrombosis. Due to the lack of blood reaching the brain, the SCI victim experiences dizziness, light-headedness, headache, fatigability, nausea, syncope, sweating, and pallor. The vascular bed, skeletal muscles and RAAS all contribute to compensate for arterial hypotension. In the chronic phase of the injury, dysreflexia, coronary heart disease and systemic atherosclerosis are experienced (Popa, et al., 2010). 7. Loss of consciousness Neurally mediated syncope refers to a reflex response resulting to vasodilation, bradycardia and subsequent systemic hypotension and cerebral hypoperfusion. Vasovagal reaction, carotid sinus syncope, situational syncope, and glossopharyngeal neuralgia are some of the types of neutrally mediated syncope. It involves sensory inputs from vagal afferents, as well as pain and central pathways, affecting the nucleus tractus solitarius, which initiates sympatho-inhibition and vagal efferent activation (Assadi & Motabar, 2011). For example, the carotid sinus reflex arc is made up of an afferent limb arising from mechanoreceptors located at the internal carotid artery that transmits impulses through cranial nerve IX to medulla, terminating in the nucleus tractus solitarius. The efferent limb innervation, through the vagus nerve, starts with the efferent limb innervating the sino-atrial and atri-ventricular nodes. In carotid sinus syncope, blood pressure elevation increases the baroreceptor firing rate, activating vagal efferents, which acts to decrease the heart rate and lower the blood pressure (Assadi & Motabar, 2011). References Anglade, P. & Larabi-Godinot, Y. (2010). Historical landmarks in the histochemistry of the cholinergic synapse: perspectives for future researches. Biomedical Research, 31(1), pp. 1-12. Armour, J. A., Murphy, D. A., Yuan, B., MacDonald, S., & Hopkins, D. A. (1997). Gross and Microscopic Anatomy of the Human Intrinsic Cardiac Nervous System. The Anatomical Record, 247, 289-298. Assadi, R. & Motabar, A. (2011). Heart Nerve Anatomy. Retrieved from: emedicine.medscape.com/article/1923077-ov erv iew #show all Fu, L. & Longhurst, J. C. (2009). Regulation of cardiac afferent excitability in ischemia. In B. J. Canning & D. Spina (Eds.), Sensory Nerves, Handbook of Experimental Pharmacology. Berlin: Springer-Verlag. Govoni, S., Pascale, A., Amadio, M., Calvillo, L., D’Elia, E., Cereda, C., Fantucci, P.,…Vanoli, E. (2011). NGF and heart: Is there a role in heart disease? Pharmacological Research, 63, 266-277. Grassi, G. (2010). Sympathetic Neural Activity in Hypertension and Related Diseases. American Journal of Hypertension, 23(10), 1052-1060. Hauptman, P. J. & Mann, D. L. (2011). The vagus nerve and autonomic imbalance in heart failure: past, present, and future. Heart Fail Rev, 16, 97-99 Liang, C. (2007). Cardiac sympathetic nerve terminal function in congestive heart failure. Acta Pharmacol Sin, 28(7), 921-927. May, C. N., Frithiof, R., Hood, S. G., McAllen, R. M., McKinley, M. J., & Ramchandra, R. (2009). Specific control of sympathetic nerve activity to the mammalian heart and kidney. Exp Physiol, 95(1), 34-40. McKee, M. G. & Moravec, C. S. (2010). Biofeedback in the treatment of heart failure. Cleveland Clinic Journal of Medicine, 77(suppl. 3), S56-S59 Pauza, D. G., Skripka, V., Pauziene, N., & Stropus, R. (2000). Morphology, Distribution, and Variability of the Epicardiac Neural Ganglionated Subplexuses in the Human Heart. The Anatomical Record, 259, 353-382. Popa, C., et al. 2010. Vascular dysfunctions following spinal cord injury. Journal of Medicine and Life, 3(3), 275-285. Shen, M. J., Choi, E., Tan, A. Y., Lin, S. F., Fishbein, M. C., Chen, L. S., & Chen, P. (2012). Neural mechanisms of atrial arrhythmias. Nature, 9, 30-39. Read More