Cardiovascular Manifestations of Autonomic Disorders

Sympathetic, Parasympathetic, and Intrinsic Neuronal Control

The anatomy and physiology of the cardiovascular autonomic nervous system is a complex interplay of sympathetic, parasympathetic, and intrinsic neurons in addition to a number of well-established reflexes ( Fig. 102.1 ). In addition to direct afferent and efferent connections between the brain and central nervous system and the heart and vascular system that control all aspects of cardiac physiologic function, visceral integration and reflexes maintain and optimize blood pressure. The sympathetic and parasympathetic systems are often thought of as opposing forces; however the intricate feedback between these systems, the intrinsic cardiac nervous system, and numerous reflex arcs allows for highly refined regulation of cardiac electrical and mechanical function.

Cardiac autonomic nerves can anatomically be broken down into central, intrathoracic, and intrinsic cardiac components. ^, The cardiac intrinsic components are located in the epicardial fat pads and cardiac ganglia. These ganglionated plexi include afferent, efferent, and interconnecting neurons. The ganglia (located in the region of the posterior left atrium, aortopulmonary window, anterior/posterior right atrium, and junction of the inferior vena cava and inferior right atrium) give input to the sinus and atrioventricular nodes ( Fig. 102.2 ). The left and right cardiac nerves are a combination of sympathetic and parasympathetic nerves entering and leaving the heart.

From the heart, afferent sensory neurons provide real-time information on cardiac status via parasympathetic (vagal trunk/nodose ganglia) and sympathetic (dorsal root ganglia) tracts to the higher centers. Efferent motor neurons travel from the central system to the epicardial cardiac structures. Sympathetic efferents travel from the intermediolateral spinal cord to the superior, middle, and cervicothoracic (stellate) ganglia. The pre-ganglionic neurons secrete acetylcholine that binds to nicotinic receptors. The post-ganglionic nerves then project from the stellate ganglia (C8-T1) plus T2-T4 to the epicardium of the atria and ventricles where the postganglionic neurons release norepinephrine, which binds to alpha- and beta-adrenergic receptors. Parasympathetic efferents originate in the nucleus ambiguous and medulla oblongata and travel through the vagus nerve to the cardiac ganglia. Approximately 80% of fibers in the vagus nerve are thought to be afferent, however. Parasympathetic pre-ganglionic neurons release acetylcholine to activate nicotinic and muscarinic cholinergic receptors. Post-ganglionic neurons secrete acetylcholine to activate muscarinic receptors in the myocardium and vasculature.

The sympathetic and parasympathetic nervous systems are generally thought of as parallel and separate systems, though there is some crossover between sympathetic and parasympathetic systems as well as afferent and efferent pathways. Identification of neuron types is often only possible by assessment of specific neurotransmitters (which is beyond the scope of this chapter). The antagonization that does occur happens at both pre- and postsynaptic levels. Norepinephrine and acetylcholine impair the release of the other and afferent signals are processed at multiple levels of the system. Further, the cotransmitter neuropeptide Y released from sympathetic nerves can also inhibit acetylcholine. Cardiac electrophysiologic effects of sympathetic and parasympathetic systems are summarized in Table 102.1 .

Baroreflex

Autonomic innervation of arteries, veins, and capillaries control vascular tone and diameter. Afferent neurons respond to chemical and mechanical stimuli in regions such as the aortic arch and carotid sinus to regulate blood flow, blood pressure, and heart rate via baroreflexes with the ultimate goal of protecting cerebral perfusion. Baroreceptors existing in the walls of major blood vessels (mechanoreceptors in the aortic arch, carotid sinus, origin of the right subclavian artery in addition to low pressure sensors in the atria and pulmonary artery) are activated by stretch related to blood pressure/volume and activate the brain stem predominantly via the vagus nerve. These mechanoreceptors are stretch-dependent, leading to an increased frequency of discharge in the glossopharyngeal nerve and the aortic nerve, which coalesce with the vagus nerve. The low-pressure cardiopulmonary baroreceptors respond to volume, and when volume increases there is a vasodilatory response and drop in blood pressure in addition to a decrease in vasopressin, which leads to an increase in salt and water excretion.

Critical adjustment for postural changes is predominantly controlled through baroreflexes ( Fig. 102.3 ). As vascular pressures change, the relative sympathetic to parasympathetic activity is modified to allow for increased vascular tone, cardiac contractility, and heart rate. Abruptly elevated blood pressure leads to increased stretch of baroreceptors and increased firing, causing decreased sympathetic and increased parasympathetic activity. This change in activity leads to reduced arteriolar resistance and decreased venous tone, as well as decreased heart rate and cardiac contractility.

With standing, less pressure is sensed by the baroreceptors, which leads to vasoconstriction and increased heart rate to prevent drop in blood pressure and associated symptoms. At rest, the baroreflex allows the parasympathetic input to predominate and inhibits sympathetic output. This critical reflex is not consistently present for patients with orthostatic hypotension and vasovagal syncope discussed later. One must recall that the “intrinsic heart rate” of the sinus node is approximately 100 beats per minute (bpm), and what we consider normal resting heart rate (50 to 70 bpm) is the result of elevated parasympathetic input relative to sympathetic. Therefore, heart rate can be raised with decreased parasympathetic stimulation.

Chemoreflex

Chemoreceptors respond to hypoxia and hypercapnia. When activated they lead to vasoconstriction and hyperventilation. There are peripheral (carotid body) and central (brainstem) chemoreceptors. In obstructive sleep apnea, for example, chemoreflexes respond to the recurrent apnea/hypoxia with a sympathetic vasoconstriction and a bradycardic response, which is adaptive initially but ultimately can have pathologic consequences.

Diving Reflex

The diving reflex is a powerful reflex in response to diving under water in mammals to allow for prolonged submersion. There is a simultaneous increase in parasympathetic and sympathetic drive. Crucial organ oxygenation is protected including a dramatic bradycardia to decrease myocardial oxygen demand.

Autonomic Dysfunction in the Setting of a Structurally Normal Heart

Autonomic dysregulation can lead to neurally mediated syncope from orthostatic hypotension/vasovagal syncope or carotid sinus syndrome. These are disorders of autonomic reflexes. Other disorders such as postural tachycardia syndrome (POTS) and inappropriate sinus tachycardia (IST) are thought to be in part due to elevated sympathetic activity. These syndromes, which are more common in young women, can have significant overlap. Though not life-threatening, these disorders can significantly impair quality of life.

Vasovagal syncope occurs after upright posture or after painful stimuli or emotional stress. Prodromal symptoms of diaphoresis, a “warm sensation” and nausea, often occur. Vasovagal syncope is reported to occur in over 40% of women and 30% of men by the age of 60 due to lack of effective reflex response to posture and venous pooling or in response to external stimuli. Decreased cardiac output and a potential paradoxical vasodilation with hypotension and possible bradycardia can lead to syncope. Treatment for vasovagal syncope, when episodes are frequent, include lifestyle modification, hydration, lower extremity compression stockings, beta blockers, and fludrocortisone/midodrine. While most vasovagal syncope involves a combination of hypotension and bradycardia (mixed), in some cases patients may have a primary “cardio-inhibitory” response with pronounced bradycardia that responds to pacemaker implantation.

POTS patients have symptoms (lightheadedness, palpitations, etc.) with standing that are associated with a rise in heart rate of ≥30 bpm without an associated drop in systolic blood pressure. POTS is much more prevalent in women (∼75%) in the age range of 15 to 25 years, but overall prevalence is low at around 0.2%. A full understanding of mechanism is not clear but has been postulated to involve components of autonomic denervation, hypovolemia, possible autoimmunity, hypervigilance, and deconditioning. In fact, a structured exercise program starting with recumbent exercises can be used as a treatment prior to considering pharmacologic therapies such as beta blockers. IST is a resting heart rate over 100 bpm, or over 90 bpm on average Holter monitor recordings, without reversible cause and associated with symptoms. IST occurs in less than 1.5% of the population. Similar to POTS, the cause is not completely understood. Medical therapy with beta blockers or Ivabradine (an I f current blocker) can be utilized to decrease heart rate in some cases.

Neural pathology can secondarily occur in a number of disorders including but not limited to diabetes, Parkinson disease, and multisystem atrophy. Neurologic injury including spinal cord disorders, severe head injury, subarachnoid hemorrhage, and stroke can manifest with distinct cardiac electrophysiologic abnormalities including brady- and tachyarrhythmias. ^, In some instances the resulting autonomic dysfunction is transient and can resolve with resolution of the primary pathology, such as in subarachnoid hemorrhage. In more chronic disease states, such as Parkinson or multisystem atrophy, the autonomic manifestations can be chronic and progressive.

Autonomic Dysfunction in the Setting of Intrinsic Cardiac Disease

Autonomic dysfunction can occur due to, and further exacerbate, primary cardiac pathology including myocardial infarction as well as ischemic and nonischemic cardiomyopathy and associated heart failure. These disorders can directly damage cardiac nerves. Subsequent increase in sympathetic (including increased cardiac norepinephrine spillover and increased activation of the renin-angiotensin-aldosterone system in the kidneys) and decrease in parasympathetic output may occur to maintain homeostasis; however, the persistent afferent pathologic signaling can lead to a cycle of worsening cardiac dysfunction and proarrhythmia.

Persistently elevated sympathetic stimulation in heart failure can cause tachycardia, increased afterload, and ventricular remodeling. Subsequent changes can lead to downregulation of beta-1 receptors at the plasma membrane. Cardiac injury can lead to sympathetic nerve death, which is followed by heterogenous nerve sprouting at scar border zones and supersensitivity of denervated regions within the myocardium. The altered myocardium becomes prone to ventricular arrhythmias in the acute and chronic phases of disease. Interestingly, changes are not limited to the heart itself, with evidence that cardiac injury can lead to changes within the stellate ganglia. When parasympathetic dysfunction is present, manifestations include abnormal heart rate response with tachycardia and decreased heart rate variability, which is a marker for increased mortality.

Atrial Fibrillation

Mechanisms of atrial fibrillation (AF) are complex and incompletely understood. Pulmonary vein triggers are well established as the primary target of electrophysiologic intervention and increased ectopy can be triggered by sympathetic stimulation. However, numerous other factors including atrial stretch, fibrosis, altered calcium handling, and autonomic pathology are thought to be involved to varying degrees.

The posterior left atrium is highly innervated by ganglionated plexi with parasympathetic nerves predominating. The data for the relative contribution of vagal stimulation and the ganglionated plexi to the initiation and maintenance of AF is mixed. Vagal nerve stimulation can induce AF, and there are data that injection of botulinum toxin into the fat pads where ganglionated plexi reside can decrease AF episodes. Although relative contributions of the sympathetic and parasympathetic nervous system still need to be fully elucidated, the role of the autonomic nervous system in general is clear, exemplified by the fact that in orthotopic heart transplant patients (complete cardiac denervation), AF is rare, except for patients with active graft rejection.