The new england journal of medicine

Review Article

Dan L. Longo, M.D., Editor Baroreflex Dysfunction

Horacio Kaufmann, M.D., Lucy Norcliffe‑Kaufmann, Ph.D., and Jose‑Alberto Palma, M.D., Ph.D.​​

he autonomic nervous system innervates all body organs, in- From the Department of Neurology, Dys‑ cluding the cardiovascular system. Smooth muscle in arteries, arterioles, autonomia Center, New York University School of Medicine, New York. Address and veins and pericytes in capillaries receive autonomic innervation, which reprint requests to Dr. Kaufmann at the T Dysautonomia Center, NYU Langone modulates vascular smooth-muscle tone and vessel diameter. Afferent sensory neurons with receptors monitoring local changes in the chemical and mechanical Health, 530 First Ave., Suite 9Q, New York, NY 10016, or at ­horacio​.­kaufmann@​ environment provide the information that allows the autonomic nervous system to ­nyulangone​.­org. regulate blood flow within every organ and redirect cardiac output to vascular N Engl J Med 2020;382:163-78. beds as needed. The autonomic nervous system provides moment-to-moment control DOI: 10.1056/NEJMra1509723 1 of blood pressure and heart rate through baroreflexes. These negative-feedback Copyright © 2020 Massachusetts Medical Society. neural loops regulate specific groups of both sympathetic neurons sending nerve impulses to the vasculature, the heart, and the kidney and parasympathetic neurons sending nerve impulses to the sinus node of the heart. We describe the main features of baroreflexes and the clinical phenotypes of baroreflex impairment.

Baroreflexes Baroreflexes enable the circulatory system to adapt to varying conditions in daily life while maintaining blood pressure, heart rate, and blood volume within a narrow physiologic range. Baroreceptors embedded in the walls of major arteries and veins and the heart elicit distinct reflexes.2 They continuously signal to the nucleus of the solitary tract, located in the brain stem, through the vagus and glossopharyngeal nerves and are activated by stretch when blood pressure, blood volume, or both rise (Fig. 1). To counter the rise, baroreceptors evoke reflex inhibition of efferent sympathetic signals to splanchnic, skeletal-muscle, and renal blood vessels, causing vasodilatation. A concomitant increase in parasympathetic-nerve traffic to the sino- atrial node slows the heart rate. Conversely, when a change to a standing position is made, baroreceptors are unloaded, allowing vasoconstriction and tachycardia to buffer the fall in blood pressure that would otherwise occur. Not infrequently, there is initial orthostatic hypotension caused by a transient mismatch between cardiac output and peripheral vascular resistance, which quickly rebounds. Arterial baroreceptors in the carotid sinuses and aortic arch sense pressure changes, and cardiopulmonary baroreceptors in thoracic veins and the heart sense changes in blood volume. Both arterial and cardiopulmonary baroreceptors inhibit efferent sympathetic neurons, leading to vasodilatation, but only arterial barore- ceptors influence the heart rate. Arterial baroreceptors preferentially target the splanchnic circulation, and cardiopulmonary baroreceptors inhibit sympathetic renal outflow, reducing renin release and proximal tubular sodium reabsorption. Baroreceptor activation also suppresses vasopressin release and sodium appetite, increasing urine output (Fig. 1). Mechanosensing by arterial baroreceptors is medi- ated by the mechanically activated excitatory ion channels PIEZO1 and PIEZO2.3

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AFFERENTS CENTRAL EFFERENTS

High-pressure Paraventricular baroreceptors nucleus Supraoptic (arterial) nucleus Carotid

AVP

Aortic

Low-pressure baroreceptors (cardiopulmonary) Rostral ventrolateral Glossopharyngeal medulla Nucleus NTS ambiguus Pulmonary Parasympathetic Atrial neurons Vagus SAN

Ventricular CVLM ACh Sympathetic NE ganglia ACh IML NE

Dorsal-root Renin ganglia NE

NE

Preganglionic Postganglionic Sympathetic neurons

Figure 1. Neuroanatomy of Baroreflexes. Afferent baroreflex mechanosensing neurons with axonal receptors in thoracic arteries (aortic arch and carotid sinuses) and the heart have their cell bodies in the nodose and petrosal ganglia (yellow ovals) of the glossopharyngeal and vagal nerves (nerves IX and X, respectively) and synapse with neurons in the brain‑stem medulla oblongata at the nucleus of the solitary tract (NTS). From the NTS, there are three baroreflex pathways. The first is an inhibitory pathway that restrains sympathetic outflow to the vasculature. Through interneurons in the caudal ventrolateral medulla (CVLM), neurons in the NTS inhibit sympathetic (premotor) pacemaker neurons in the rostral ventrolateral medulla. The neurons in the rostral ventrolateral medulla are the source of sympathetic activity to the vasculature and are organized in groups that preferentially or exclusively control the movement of sympathetic efferent nerves to specific vascular beds. Axons of barosensitive neurons in the rostral ventrolateral medulla descend through the spinal cord and activate the two‑neuron (preganglionic and postganglionic) sympathetic efferent pathway to skeletal muscle and mesenteric and renal vessels. The second path‑ way activates vagal efferents to slow the heart rate through a direct projection to preganglionic parasympathetic neurons in the nucleus ambiguus of the medulla, which activate postganglionic parasympathetic neurons to the sinoatrial node. The third pathway connects the NTS with the supraoptic nucleus) and the paraventricular nucleus in the hypothalamus, controlling arginine vasopressin (AVP) release from the pituitary. Also shown are renal afferents and muscle ergoreceptors (thinly myelinated group III and IV afferents), which reach the cord through the dorsal‑root ganglia and have important modulatory effects on the baroreflex. ACh denotes acetylcholine, IML inter‑ mediolateral cell column, NE norepinephrine, and SAN sinoatrial node.

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Baroreflexes during the Cardiac Cycle, or high thoracic spinal cord lesions, autonomic Respiratory Entrainment, and Other Inputs dysreflexia results in a similar phenomenon when At rest, afferent baroreceptor discharge on the stimuli from the viscera or skin trigger abnor- nucleus of the solitary tract maintains a tonic mal spinal sympathetic activation.8,9 So-called level of peripheral sympathetic inhibition and functional autonomic disorders are encountered cardiovagal activation. In synchronicity with the most frequently in the clinic and are not associ- pulse wave, afferent baroreceptor discharge in- ated with any detectable nerve disease. The esti- creases with each systole and decreases during mated prevalence in the United States of most of diastole, causing reciprocal changes in sympa- the disorders affecting baroreflexes is shown in thetic and vagal efferent activity. Vagal efferent Table 1. neurons also entrain with respiratory neurons and are inhibited during inspiration, giving rise Efferent Baroreflex Failure to respiratory sinus arrhythmia. When the baro- reflex pathways are damaged, these physiologic Diseases affecting baroreflex sympathetic effer- rhythms are lost or blunted. ent neurons impair the release of norepinephrine The nucleus of the solitary tract also receives at the neurovascular junction. Insufficient vaso- and integrates information from other sources, constriction on standing or exertion leads to ortho- including peripheral and central chemorecep- static hypotension and symptoms of organ hypo- tors, renal mechanoreceptors and chemoreceptors perfusion, including lightheadedness or dizziness, through renal afferent nerves, muscle ergorecep- visual blurring, and syncope. Dyspnea, subtle tors (muscle afferents that are stimulated by mus- cognitive slowing, and fatigue are common and cle work) (Fig. 1), and respiratory neurons, as well disappear in the supine position. Clinically, this as cortical and hypothalamic neurons. Increased disorder is defined by a sustained fall in blood input from chemoreceptors heightens sympathetic pressure of at least 20/10 mm Hg within 3 min- outflow in congestive heart failure, pulmonary utes after assumption of an upright posture,18 hypertension, and chronic obstructive pulmonary but in some cases, the fall in blood pressure is disease,4-6 and altered renal afferent activity may delayed, occurring after prolonged standing.19 underlie sympathetic-nerve excitation in arterial Supine hypertension (blood pressure, >140/90 hypertension. mm Hg) develops in 50% of patients with effer- ent baroreflex failure, probably as a result of the Baroreflex Impairment activation of residual sympathetic fibers and de- Diseases affecting baroreflex neurons cause un- nervation supersensitivity.20 Loss of the normal stable blood pressure with acute symptoms of nocturnal profile of blood-pressure dipping im- hypoperfusion or hyperperfusion. Lesions of af- pairs extracellular fluid-volume regulation. It is ferent, central, or efferent baroreflex neurons thought that abnormally elevated blood pressure result in distinct but overlapping cardiovascular throughout the night causes renal excretion of phenotypes. Clinicians use the term autonomic sodium and water (i.e., pressure natriuresis), failure when referring to diseased efferent baro- resulting in overnight loss of extracellular fluid reflex neurons, because other autonomic fibers volume, with worsening orthostatic hypotension are also frequently affected, impairing bladder, in the morning. However, lowering overnight gastrointestinal, and sexual function. Baroreflex blood pressure may not consistently reduce natri- failure commonly refers to compromised afferent uresis.21 Lack of sympathetic activation of renal neurons, which affect cranial nerves IX and X but tubular epithelia impairs sodium reabsorption22 cause no additional autonomic deficits. Paroxys- and may contribute to pressure natriuresis.23 Long- mal sympathetic hyperactivity, which occurs in term supine hypertension is associated with patients with severe acquired brain injury, causes target-organ damage. hypertension, diaphoresis, and tachycardia. Dif- fuse damage to white-matter tracts, including Preganglionic versus Postganglionic descending fibers from the right insula, and to Efferent Baroreflex Failure other cortical areas that normally inhibit sympa- Impaired release of norepinephrine may be the thetic activity, as well as maladaptive spinal cord result of disorders affecting peripheral postgan- plasticity, may explain these episodes.7 In cervical glionic sympathetic neurons or the preganglionic

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Table 1. Estimated Prevalence in the United States of Disorders Affecting Baroreflex Function.

Disorder Prevalence or Incidence Disorders without detectable nerve disease Neurally mediated (reflex) syncope Vasovagal syncope or situational syncope (i.e., syncope on 130 million people (40% of the popula‑ micturition or defecation) tion) have had ≥1 episode10 Carotid sinus syndrome and glossopharyngeal neuralgia 5–10% of patients with unexplained syncope11 Postural tachycardia syndrome 500,00012 Takotsubo cardiomyopathy 10,000 new cases/yr13 Disorders with pathological substrate Metabolic disorders Diabetes mellitus 20–30% of patients with type 1 or type 2 diabetes (about 25 million people)14 Porphyria <1000 people Neurodegenerative disorders Synucleinopathy Parkinson’s disease 800,000 people15 Dementia with Lewy bodies 600,000 people16 Multiple-system atrophy 15,000 people Pure autonomic failure <10,000 people Amyloid neuropathy Hereditary transthyretin amyloidosis <5000 people Acquired (AL [light-chain], AA, or wild-type transthyretin) amyloidosis 25,000 people Acquired disorders Paroxysmal sympathetic hyperactivity caused by acute brain injury 150,000 people7 Spinal cord injury (T6 or above) 100,000 people9 Acquired afferent baroreflex failure <10,000 people Chemotherapy-induced and toxic autonomic neuropathies* 50,000 people Autonomic neuropathies due to infectious diseases† 10,000 people17 Immune-mediated and paraneoplastic autonomic disorders‡ <5000 people Rare genetic autonomic disorders (familial dysautonomia, dopamine– <1000 people β-hydroxylase deficiency, mutations in CYB561, and others)

* Causes include antineoplastic agents, organic solvents, acrylamide, and heavy metals, as well as marine toxins (e.g., ciguatera and toxins from Irukandji jellyfish). † The infectious diseases include human immunodeficiency virus infection, Chagas’ disease, leprosy, and tetanus. ‡ Disorders in this category include the Guillain–Barré syndrome, limbic encephalitis, autonomic autoimmune ganglion‑ opathy, paraneoplastic autonomic neuropathy, and acute autonomic and sensory neuronopathy.

and premotor neurons in the spinal cord and onic lesions, the pressor response to adrenergic brain stem that activate them (Fig. 1). Although agents is exaggerated because of adrenergic dener- the lesions are different, the severity of ortho- vation supersensitivity, which is probably caused static hypotension is similar. The supine plasma by an increased number of receptors.24 Converse- norepinephrine levels tend to be low in patients ly, in preganglionic or premotor lesions, sympa- with postganglionic lesions but normal in pa- thetic postganglionic neurons are spared but tients with preganglionic or premotor sympa- are disconnected from central influences. In thetic lesions (Fig. 2). In patients with postgangli- preganglionic but not postganglionic lesions,

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A Efferent Failure 1200 150 5

4 900 100 3 P<0.001 600 2 50 300 Epinephrine (pg/ml) Vasopressin (pg/ml) 1 Norepinephrine (pg/ml)

0 0 0 Supine Upright Supine Upright Supine Upright

B Afferent Failure 1200 150 10 P<0.001 P<0.001 8 900 100 6 600 4 50 300 Epinephrine (pg/ml) Vasopressin (pg/ml) 2 Norepinephrine (pg/ml)

0 0 0 Supine Upright Emotional Supine Upright Supine Upright Crisis Arousal or Crisis

C Vasovagal Syncope 1200 150 20

P<0.01 P<0.001 900 15 100

600 10 P<0.01 P<0.05 50 300 5 Epinephrine (pg/ml) Vasopressin (pg/ml) Norepinephrine (pg/ml)

0 0 0 Supine Upright Syncope Supine Syncope Supine Syncope

Figure 2. Neurohormonal Responses in Patients with Baroreflex Dysfunction. Shown are plasma levels of norepinephrine, epinephrine, and vasopressin in 51 patients with efferent baroreflex failure (Panel A), 29 patients with afferent baroreflex failure (Panel B), and 63 patients with vasovagal syncope (Panel C). Also shown are plasma levels of norepinephrine and vasopressin at the time of emotional arousal or autonomic crisis in patients with congenital afferent baroreflex failure (Panel B) and nor‑ epinephrine, epinephrine, and vasopressin at the time of syncope in patients with vasovagal syncope (Panel C). T bars denote standard errors. norepinephrine-reuptake inhibitors significant- mon cause is synucleinopathies (Table 1), includ- ly increase norepinephrine levels at the neuro- ing pure autonomic failure, Parkinson’s disease, vascular junction and raise blood pressure.25 dementia with Lewy bodies, and multiple-system atrophy, which are caused by intracellular accu- Causes mulation of misfolded α-synuclein in nerve tis- Baroreflex efferent neurons are most often dam- sue. Similarly, in light-chain and transthyretin aged by diabetes mellitus. The second most com- amyloidosis, overproduced, misfolded amyloid

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deposits are found in sympathetic neurons, but sary, Holter monitoring to rule out cardiac ar- the deposits are extracellular.26 Autoimmune rhythmias. mechanisms can also target sympathetic axons A simple, bedside diagnostic test to distin- or block cholinergic transmission in autonomic guish neurogenic from non-neurogenic causes ganglia.27 Rare genetic mutations can impair of orthostatic hypertension is the ratio of the norepinephrine synthesis or release, and toxic increase in heart rate (in beats per minute) to neuropathies can affect autonomic fibers of the the decrease in systolic blood pressure (in milli- baroreflex (Table 1). meters of mercury). Since the heart-rate response The two most common synucleinopathies, to hypotension is pronounced in patients with Parkinson’s disease and Lewy body dementia, non-neurogenic orthostatic hypotension but is have a predominantly postganglionic phenotype. blunted in those with efferent baroreflex failure, Multiple-system atrophy is rare but much more a ratio below 0.5 indicates baroreflex failure and aggressive, and it has a preganglionic phenotype, provides a sensitive and specific cutoff value with postganglionic sympathetic neurons largely during passive tilt and active standing.33 spared but compromised connections between Laboratory autonomic testing in patients with the nucleus of the solitary tract and the hypo- efferent baroreflex failure shows a reduced or thalamic nuclei regulating vasopressin release missing blood-pressure overshoot after the Val- (Fig. 1).28-30 salva maneuver and, frequently, reduced respira- Baroreflex dysfunction can be the initial pre- tory sinus arrhythmia. Measurement of plasma sentation of all synucleinopathies and may allow norepinephrine levels, in both the supine and for early diagnosis, before the appearance of standing positions, can help localize the site of typical motor or cognitive deficits.28 Prospective the lesion and confirm the diagnosis. Prolonged studies show that for patients with isolated ef- tilt may be necessary in cases of delayed ortho- ferent baroreflex failure (i.e., pure autonomic static hypotension. Once neurogenic orthostatic failure), the cumulative risk of a future diagnosis hypotension has been established, a careful neu- of Parkinson’s disease, Lewy body dementia, or rologic examination to identify motor, sensory, multiple-system atrophy is 10% per year.28 More- or cognitive abnormalities could help to deter- over, prospective, population-based studies of mine the underlying cause (e.g., synucleinopathy healthy persons have shown that a decrease in or diabetes). heart-rate variability or peak exercise heart rate carries an increased risk of a later diagnosis of Afferent Baroreflex Failure Parkinson’s disease.31,32 It is suspected that these persons already had a synucleinopathy, solely af- Sympathetic activation is blunted in efferent fecting autonomic neurons at the time. Indeed, baroreflex failure but is unrestrained and over- patients with incidental Lewy body disease at active in afferent baroreflex failure. Without autopsy, with no signs of Parkinson’s disease mechanosensing afferent inputs, neurons in the when they were alive, have abnormal synuclein nucleus of the solitary tract do not inhibit the deposits in the heart. premotor sympathetic neurons in the rostral ventrolateral medulla (an area of basal and re- Diagnosis flex control of sympathetic activity), barosensi- In clinical practice, particularly in the case of tive sympathetic neurons are unrestrained, and elderly patients, orthostatic hypotension due to the release of norepinephrine causes vasocon- neurologic (i.e., neurogenic) causes needs to be striction, tachycardia, and increased blood pres- distinguished from common non-neurogenic sure. Headaches, flushing, and agitation are causes (i.e., dehydration, hemorrhage, anemia, common, and blood pressure is unstable through- and medications). Diagnosis requires a careful out the day.34 Orthostatic hypotension is part of history taking and physical examination (show- the syndrome, but it is not always present. It is ing a sustained fall in blood pressure of at least likely that central command and receptors out- 20/10 mm Hg with assumption of an upright side the baroreflex system, including the ves- posture after being in the supine position) and tibular otoliths, activate sympathetic neurons a 12-lead electrocardiogram or, when neces- in the standing position.35

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Acquired Afferent Baroreflex Failure blocked by atropine, indicating that it is not Acquired afferent baroreflex failure is a compli- mediated by activation of vagal efferents.38 Slow- cation of damage to the glossopharyngeal and ing of the heart rate in patients with familial vagal fibers due to radiotherapy to the neck, dysautonomia when they are in the standing radical neck surgery for cancer, or rare tumors position may be the result of decreased right that affect the nucleus of the solitary tract. The atrial filling, as observed in denervated heart disorder occurs after carotid endarterectomy or preparations. Increasing right atrial pressure angioplasty involving damage to or stretch of the increases the heart rate in the denervated heart, baroreceptors.34 Symptoms may appear several and increasing right atrial filling in patients with years after surgery and sometimes herald tumor familial dysautonomia by placing them in the recurrence. The clinical severity of the disorder head-down position also raises their heart rate, depends on the extent of the afferent lesion, perhaps revealing the intrinsic responses of a which is variable. Afferent baroreflex failure is deafferented heart.38 also well recognized in patients with the Guillain– Barré syndrome, who have wild swings in blood Cardiovascular Autonomic pressure with a relatively invariant heart rate. A Disorders without Detectable lack of reciprocal heart-rate changes during Nerve Disease changes in blood pressure is diagnostic. The same blunted heart-rate changes occur in labora- The vast majority of patients seen in autonomic tory animals with sinoaortic denervation and in clinics (Table 1) have no detectable nerve dis- mice lacking mechanosensing PIEZOs.3 ease. They report discrete episodes with symp- toms and acute cardiovascular changes, but apart Congenital Afferent Baroreflex Failure from these episodes, blood-pressure regulation Familial dysautonomia (the Riley–Day syndrome) appears to be normal. is a hereditary sensory and autonomic neuropa- thy due to a founder mutation that causes a Vasovagal Syncope splicing defect in ELP1 in children with Jewish Vasovagal syncope is triggered by a reflex that ancestors. Reduced levels of ELP1 (elongator causes sympathetic inhibition and parasympa- complex protein 1) prevent the growth and sur- thetic activation. The acute fall in blood pressure vival of afferent neurons, including those involved and heart rate causes transient loss (or near loss) in baroreflexes.36,37 From birth, patients also have of consciousness due to global cerebral hypoper- other features of glossopharyngeal and vagal fusion. Vasovagal syncope is very common in the dysfunction, including swallowing abnormalities general population, with the highest prevalence and blunted hypoxic ventilatory drive. At times among teenagers, athletes, and the elderly. With of stress, sympathetic activation is unopposed a sufficient degree of orthostatic stress, vasova- (i.e., baroreflexes are unrestrained and there are gal syncope can be induced in more than 75% of no parasympathetic responses), causing persis- healthy people. It is not a predictor of adverse tent hypertension, tachycardia, and flushing.38 cardiovascular outcomes.10 Although falling to Fear, intense emotions, or illness can trigger the the ground serves the physiological purpose of spillover of dopamine from sympathetic termi- removing gravitational stress and immediately nals, causing nausea, retching, and vomiting.39 restoring cardiac output and perfusion to the During these episodes (referred to as autonomic brain, it can result in head trauma and bone crises), patients can have inappropriate vasopres- fractures. Consciousness is regained rapidly, and sin release and hyponatremia for unknown rea- there are no neurologic sequelae.40 sons (Fig. 2). The vasovagal reaction can be triggered by As in acquired afferent baroreflex failure, direct emotional, sensory, or hemodynamic stimuli recordings show that sympathetic efferent activ- (e.g., the sight of blood, colonoscopy, acute pain, ity is no longer coupled to the cardiac cycle.36 prolonged standing in a warm environment, or Complete failure of the baroreceptor afferents dehydration), but triggers may not be immedi- results in orthostatic hypotension with a para- ately apparent. In some older men, the same doxical slowing of the heart rate that is not reflex response occurs when turning the neck

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generates pressure in the carotid area (i.e., carotid Figure 3 (facing page). Blood Pressure and Heart Rate sinus syndrome). Susceptibility increases after in Patients with Baroreflex Dysfunction. the use of diuretics or vasodilators, including Panel A shows continuous blood-pressure and heart-rate alcohol, marijuana, and alpha-blockers. The vaso- recordings in a 70-year-old man with efferent baroreflex vagal reaction can occasionally be triggered failure. In efferent baroreflex failure, blood pressure is while a person is sitting or lying down (e.g., dur- in the hypertensive range when the patient is supine, and it falls immediately when the patient is upright, ing medical procedures). with minimal tachycardia. Blood pressure returns to In the prodromal phase, which usually lasts baseline as soon as the patient returns to the supine for 30 seconds or longer, sympathetic efferent position. Emotional arousal has no notable effect on activation and epinephrine release cause skin heart rate or blood pressure. In Panel B, continuous vasoconstriction, with facial pallor, diaphoresis, blood-pressure and heart-rate recordings show afferent baroreflex failure in a 28-year-old woman. In this condi‑ and piloerection, and nausea and gastric discom- tion, blood pressure is unstable in all positions, and fort are common. These signs and symptoms of when the patient is upright, the heart rate slows. This autonomic activation are an important anamnes- patient has a pacemaker programmed to provide elec‑ tic clue because they are present in vasovagal trical stimulation only when the heart rate falls to 60 syncope but not in efferent baroreflex failure. At beats per minute or less (inset, showing pacemaker rhythm on electrocardiography). Blood pressure re‑ the time of syncope, sympathetic efferent activ- turns to baseline values on the patient’s return to the ity ceases and norepinephrine levels fail to in- supine position. Blood pressure and heart rate increase crease, but there is marked epinephrine release with emotional arousal and are markedly exaggerated from the adrenal medulla, which is not under owing to unrestrained sympathetic outflow. In Panel C, baroreflex control (Fig. 2). Hypotension causes the recordings show functional baroreflex dysfunction (vasovagal syncope) in a 22-year-old woman. In cases hypoperfusion of the brain (including the retina) of vasovagal syncope, the initial heart-rate and blood- and sensations of lightheadedness, visual dim- pressure responses to an upright tilt are normal, fol‑ ming, and muffled sounds. Hyperventilation, lowed by a sudden onset of bradycardia and hypoten‑ which begins in the prodromal phase, leads to sion, which are rapidly reversible on the patient’s return hypocapnia, which constricts cerebral vessels to the supine position. The recording shows a typical cardioinhibitory response. Although vasodilatation is a and exacerbates the decrease in cerebral blood constant feature, the slowing of the heart ranges from 41 f low. Vasopressin is released (Fig. 2), and high a few milliseconds (vasodepressor) to prolonged sinus levels of circulating vasopressin contribute to arrest (cardioinhibitory). Blood pressure and heart rate facial pallor and the sensation of nausea. Plasma remain unchanged during emotional arousal. renin levels may also increase, probably through the renal pressor receptors. Although direct vagal measurements in hu- The prevalence of this syndrome is high among mans are not possible, muscarinic blockade with young white women, the demographic group with atropine prevents bradycardia during vasovagal the lowest orthostatic tolerance. Some subtle syncope, supporting its vagal origin. Sympathetic abnormalities in the baroreflexes have been re- withdrawal further adds to the lengthening of ported, but data on their natural history are the heartbeat intervals, which is variable, rang- limited. Although no proposed mechanism ap- ing from milliseconds to more than 30 seconds plies to all affected patients, hyperventilation,44 of sinus arrest42 (Fig. 3), sometimes prompting physical deconditioning or cardiac atrophy,45 the use of pacemakers. Atropine prevents brady- abnormal intravascular volume control, and de- cardia but not syncope, underscoring the crucial fects in the cardiac norepinephrine transporter46 role of vasodilatation. Parasympathetic activa- may all play a role. The syndrome frequently tion may contribute to the vasodilatation through coexists with joint hypermobility syndrome endothelial nitric oxide release.43 (Ehlers–Danlos syndrome, type III).47 Some patients have a stresslike neurohor- Postural Tachycardia Syndrome monal response when upright, with high levels Postural tachycardia syndrome is characterized of epinephrine and norepinephrine in plasma by marked tachycardia in the standing position, (hyperadrenergic postural tachycardia syndrome). with no fall in blood pressure but with symp- Underscoring the heterogeneous nature of the toms of sympathetic activation (palpitations, disorder, mild distal small-fiber neuropathies chest pain, shortness of breath, and anxiety).18 have also been reported (neuropathic postural

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A Efferent Failure 100 100 90 90 80 80 70 70 Heart Rate (beats/min) 60 60 50 50 23:00 25:00 27:00 29:00 31:00 33:00 35:00 37:00 39:00 2:00 3:00 4:00 5:00 6:00 7:00 8:00 9:00 10:00 160 160 140 140 120 120 100 100 80 80 60 60 40 40 20 Upright Emotional arousal Blood Pressure (mm Hg) 20 23:00 25:00 27:00 29:00 31:00 33:00 35:00 37:00 39:00 2:00 3:00 4:00 5:00 6:00 7:00 8:00 9:00 10:00 Time (min:sec)

B Afferent Failure

90 160 80 140 120 70 100 60 80 Heart Rate (beats/min) 60 50 14:00 16:00 18:00 20:00 22:00 24:00 26:00 28:00 30:00 32:00 31:00 32:00 33:00 34:00 35:00 36:00 37:00 38:00 39:00 40:00

250 250

200 200

150 150

100 100

50 50 Supine Upright Emotional arousal Blood Pressure (mm Hg)

14:00 16:00 18:00 20:00 22:00 24:00 26:00 28:00 30:00 32:00 31:00 32:00 33:00 34:00 35:00 36:00 37:00 38:00 39:00 40:00 Time (min:sec)

C Vasovagal Syncope 140 140 120 120 100 100 80 80 Heart Rate (beats/min) 60 60 15:00 20:00 25:00 30:00 35:00 40:00 45:00 0:30 1:00 1:30 2:00 2:30 3:00 3:30

140 140 120 120 100 100 80 80 60 60 40 40 Upright Emotional arousal Blood Pressure (mm Hg) 30 30 15:00 20:00 25:00 30:00 35:00 40:00 45:00 0:30 1:00 1:30 2:00 2:30 3:00 3:30 Time (min:sec)

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tachycardia syndrome). No correlation exists be- Figure 4 (facing page). Main Sites of Action tween the intensity of symptoms and the heart of Pharmacologic Treatments for Afferent rate, and reducing tachycardia often does not and Efferent Baroreflex Failure. alleviate symptoms.48 Psychological stress may Pharmacologic treatments for neurogenic orthostatic contribute to the hyperadrenergic phenotype. hypotension act mainly at the level of the sympathetic Increased anxiety and heightened somatic vigi- postganglionic neurons. Pyridostigmine, midodrine, 49 and droxidopa enhance sympathetic vasoconstriction lance are not uncommon. through different mechanisms. By inhibiting the enzyme The postural tachycardia syndrome is diag- acetylcholinesterase (AChE), pyridostigmine augments nosed when symptoms occur within 10 minutes cholinergic neurotransmission at the sympathetic and after the patient has assumed an upright posi- parasympathetic ganglia. Midodrine is converted to an tion, with an unexplained, sustained rise in the α1-adrenergic receptor agonist, causing vasoconstriction. Droxidopa is a synthetic precursor that is converted to heart rate of 30 beats per minute (40 beats per norepinephrine (NE), the main postganglionic sympa‑ 18 minute in children). The diagnosis is precluded thetic neurotransmitter, causing vasoconstriction. Yohim‑ by other findings that explain the tachycardia bine, a blocker of central and peripheral α2-adrenergic (e.g., fever, anemia, hyperthyroidism, or the use receptors, can enhance vasoconstriction in patients of diuretics, vasodilators, stimulant or sympa- with preganglionic efferent baroreflex lesions. Octreo‑ tide, a synthetic somatostatin analogue that activates thomimetic agents, norepinephrine-reuptake somatostatin receptors (SSTRs) and causes intense inhibitors, or β-adrenergic agonists). A related ­vasoconstriction of splanchnic blood vessels, has been disorder is inappropriate sinus tachycardia, caus- used for postprandial hypotension. Fludrocortisone ing a resting heart rate above 100 beats per (not shown), a mineralocorticoid agonist, increases minute, with symptoms and palpitations that ­sodium and water reabsorption in renal tubules, thus expanding extracellular fluid volume. Pharmacologic are thought to be due to faster pacing at the treatments for afferent baroreflex failure combine cen‑ sinus node, β-adrenergic hypersensitivity, de- trally acting agents, including benzodiazepines, which creased parasympathetic activity, or a combina- activate γ-aminobutyric acid (GABA) receptors at mul‑ tion of these factors.12 tiple levels within the brain and spinal cord, and α2- adrenergic agonists such as clonidine, dexmedetomi‑ dine, and methyldopa, which act at different regions Other Disorders with of the brain and spinal cord. Calcium-channel blockers Heightened Sympathetic and α-adrenergic and β-adrenergic blockers can be Activity used to dampen paroxysmal hypertension owing to their vasodilatory and bradycardic effects. Carbidopa, Takotsubo cardiomyopathy is caused by abnor- a reversible, competitive inhibitor of aromatic l-amino acid decarboxylase (AAAD), reduces production of do‑ mally increased sympathetic activity. Patients with pamine and NE and appears to be useful for lessening this disorder are usually postmenopausal women, blood-pressure variability. NET denotes norepinephrine with neurologic or psychiatric disorders in more transporter. than 50% of patients but without clinically sig- nificant obstructive coronary artery disease.50 Symptoms mimic an acute coronary syndrome, Although most patients survive and regain ven- with acute chest pain, dyspnea, and sometimes tricular function, evidence of excessive sympa- syncope. Takotsubo cardiomyopathy can be trig- thetic and blunted parasympathetic responses gered by physical or emotional stimuli, includ- persists, and episodes may recur.51 ing acute pain and severe emotional distress. Anecdotally reported causes include pheochro- Treatment of Baroreflex mocytoma and afferent baroreflex failure. Echo- Dysfunction cardiography shows ballooning of the left ven- tricle, resembling a Japanese octopus trap Baroreflex dysfunction should be explained to (takotsubo) with a narrow neck and round bottom. the patient, and information should be provided In the acute phase, catecholamine levels are high about trigger avoidance, salt and water loading, and heart-rate variability is reduced, suggesting physical training when fitness is low, the use of a state of baroreflex imbalance. Rates of in- countermaneuvers at the onset of premonitory hospital shock and death among patients with symptoms, and the avoidance of falls. In chron- takotsubo cardiomyopathy are similar to the rates ic baroreflex disorders, patients can withstand among those with acute coronary syndromes.50 very low blood pressures because of an expanded

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Activation Inhibition GABAA receptor Breakdown Benzodiazepines or reuptake

Brain β-Adrenergic blockers

NE

Clonidine β-Adrenergic Heart Dexmedetomidine receptor Methyldopa

Calcium α2-Adrenergic receptor N-type Calcium-channel Benzodiazepines Brain stem calcium channel blockers Yohimbine

GABAA receptor Clonidine Neurovascular junction Dexmedetomidine Blood vessel Methyldopa N-type calcium channel Calcium α2-Adrenergic receptor

Yohimbine

Calcium-channel Sympathetic blockers ganglion SSTR Spinal cord

Sympathetic postganglionic neuron α1-Adrenergic receptor Sympathetic ganglion Sympathetic terminal Octreotide Pyridostigmine α-Adrenergic α -Adrenergic blockers 2 Yohimbine receptor AChE

NE Dopamine NET L-dopa Midodrine ACh AAAD Norepinephrine NE AAAD reuptake inhibitors Carbidopa Nicotinic ACh Non-neuronal receptor tissues Droxidopa AAAD

autoregulatory range. Symptoms usually appear Milder symptoms may go unrecognized, and in when the mean blood pressure, when measured some cases of chronic efferent baroreflex fail- at the level of the heart, falls below 75 mm Hg.52 ure, loss of consciousness can occur with little

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Side Effects Severe hyponatremia Severe Abdominal bloating, gas bloating, Abdominal Supine hypertension, headache hypertension, Supine hyperglycemia hypertension term complica ‑ long - term hypertension; failure renal and heart include tions hospitalizationof risks increased and death sudden and reason any for ­ during sleep frequency, increased salivation, brady ‑ salivation, increased frequency, cardia supine hypertension and may cause may and hypertension supine retention urinary like symptoms influenza - like Hypertension, Piloerection, insomnia, reduced appetite reduced insomnia, Piloerection, cramps, Nausea, abdominal Headache; can worsen supine worsen can Headache; Hypokalemia and ankle edema, supine edema, ankle and Hypokalemia Increased gastrointestinal motility, urinarymotility, gastrointestinal Increased Piloerection, pruritus of scalp; can worsencan scalp; of pruritus Piloerection, 2B 2B 2B 2B 1B 2B 2B 2B 1A 1A Level of Evidence

amino acid decarboxylase acid - amino l adrenergic antagonist; more antagonist; - adrenergic agonist; prevents water excretion, water prevents agonist; 2 adrenergic receptor agonist; receptor - adrenergic 2 1 Mechanism of Action and Comments pronounced pressor response in patients with high with patients in response pressor ­ pronounced studies long - term no levels; norepinephrine plasma der of small intestines; reduces intestinal carbohydrate intestinal reduces intestines; small of der effec ‑ vasodilatation; insulin - mediated and absorption minimal hypotension; postprandial reducing in tive studies long - term no absorption; systemic inhibitors (e.g., carbidopa or benserazide); efficacy hasefficacy benserazide); or carbidopa (e.g., inhibitors slowed absorption mo; 12 to up for evaluated been meal high - calorie or high - fat ­ after reduces nocturia, and increases blood pressure in the in pressure blood increases and nocturia, reduces studies small only morning; of norepinephrine at neurovascular junction; more pro ‑ more junction; neurovascular at norepinephrine of plasmahigh with patients in response pressor nounced studies long - term no levels; norepinephrine oxide nitric binding by partly hypotension, ­ orthostatic studies small only vessels; splanchnic of pronounced pressor response in patients with low with patients in response pressor pronounced and those pg/ml) (<200 levels norepinephrine plasma aromatic take not do who stimulating neurotransmission, cholinergic glionic small; is effect pressor norepinephrine; of ­ release studies long - term no rate; heart ­ lowers causes vasoconstriction and increase in peripheral in increase and vasoconstriction causes in ‑ without pressure blood raises resistance, ­ vascular barrier blood–brain cross not does rate; heart creasing and water retention; increases blood pressure after pressure blood increases retention; water and treatment of days 3–5 Competitive inhibitor of alpha glucosidases in brush bor ‑ brush in glucosidases alpha of inhibitor Competitive Central and peripheral α peripheral and Central Prodrug converted to α to converted Prodrug bioavailability prolongs inhibitor; Norepinephrine - reuptake reduces and pressure, blood raises cells, red Increases vasoconstrictor potent analogue; somatostatin Synthetic decarboxylase; more dopa - decarboxylase; by norepinephrine to Converted gan ‑ enhances inhibition; acetylcholinesterase Reversible Synthetic vasopressin V Synthetic Activates mineralocorticoid receptors, resulting in sodium in resulting receptors, mineralocorticoid Activates

Dose 5.4 mg, 2–3 times/day 2–3 mg, 5.4 50–100 mg before meals before mg 50–100 level of the active metabolite active the of level half - dose; a after hr 1–2 peaks hr 3–4 is life about peaks level norepinephrine monoexponen ‑ dose; a after hr 3 of half - life a with decline, tial plasma dose; a after hr 1–2 peaks with patients in hr 5.2 is half - life in hr 21.6 and metabolism active metabolism slow with those dose; a after hr 2 peaks ­ level injection) neous hr 2 almost of half - life injection); 2–3 hr 2–3 hr 3–4 of half - life life of 1–2 hr 1–2 of half - life nighttime; with higher doses higher with 2.5–15 mg, 2–3 times/day; plasma times/day; 2–3 mg, 2.5–15 plasma times/day; 2–3 mg, 100–600 level plasma times/day; 2 mg, 10–18 plasma times/day; 2–3 mg, 30–60 (subcuta ‑ times/wk 2–3 units/kg, 50 (subcutaneoustimes/day 2–3 μg, 100 0.05 mg, administered intranasally at intranasally administered mg, 0.05 0.05–0.2 mg, once/day; little benefit little once/day; mg, 0.05–0.2 62 59

25 60 63 57 58 61 erythropoietin prandial hypotension prandial Pharmacologic Treatment of Baroreflex Dysfunction.* Baroreflex of Treatment Pharmacologic 2. Table Acarbose Recombinant Octreotide Pyridostigmine Desmopressin Drug For orthostatic and post - and orthostatic For Midodrine Fludrocortisone Atomoxetine Yohimbine Droxidopa

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Side Effects Side effects vary effects Side next morning; dry cough, rhinorrhea cough, dry morning; next rebound hypertension can occur can hypertension rebound withdrawal on occur can hypertension rebound withdrawal on occur can hypertension rebound withdrawal on static hypotension and cause reboundcause and hypotension static hypertension worsen orthostatic hypotension the hypotension worsen orthostatic morning next worsen orthostatic hypotension the hypotension worsen orthostatic morning next the hypotension worsen orthostatic morning next next morning; gastroparesis, insomnia gastroparesis, morning; next the hypotension worsen orthostatic morning next long retention; urinary depression, addiction depression, term: static hypotension and cause reboundcause and hypotension static hypertension Mild increase in gastrointestinal motility gastrointestinal in increase Mild Can worsen orthostatic hypotension the hypotension orthostatic worsen Can Short term: gastroparesis and ileus; and gastroparesis term: Short ileus; and gastroparesis term: Short ileus; and gastroparesis term: Short Short term: can worsen or unmask ortho ‑ unmask or worsen can term: Short Increases nocturnal natriuresis and can and natriuresis nocturnal Increases Increases nocturnal natriuresis and can and natriuresis nocturnal Increases can and natriuresis nocturnal Increases Can worsen orthostatic hypotension the hypotension orthostatic worsen Can can and natriuresis nocturnal Increases respiratory of risk increased term: Short Short term: can worsen or unmask ortho ‑ unmask or worsen can term: Short 4 2B 3B 3B 3B 1B 3B 3B 2B 2B 2B 2B 2B 3B Level of Evidence

Adrenergic agonist - Adrenergic Nitric oxide donor oxide Nitric 2 α Phosphodiesterase inhibitor Phosphodiesterase adrenergic receptors α - adrenergic of Blockade adrenergic receptors β - adrenergic of Blockade Mechanism of Action and Comments Type 1 angiotensin receptor antagonist receptor angiotensin 1 Type Only small studies, with inconsistent results inconsistent with studies, small Only GABA agonist; used to abort hypertensive episodes hypertensive abort to used agonist; GABA episodes episodes episodes blocks synthesis of dopamine and norepinephrine; and dopamine of synthesis blocks hyperten ‑ of episodes catecholamine - induced reduces retching or sion vidually assessed; medication should be administered be should medication assessed; vidually bedtime at only 1 blocker; enhances vascular nitric oxide production oxide nitric vascular enhances blocker; β - 1 Adrenergic agonist; used to abort hypertensive abort to used agonist; - Adrenergic hypertensive abort to used agonist; - Adrenergic hypertensive abort to used agonist; - Adrenergic 2 2 2 α α α Reversible competitive inhibition of dopa - decarboxylase; of inhibition competitive Reversible benefit ratio should be indi ‑ be should ratio risk - benefit blocker; Calcium - channel

Dose Dose varies Dose 5–20 mg/day 5–20 250 mg (oral) mg 250 100–400 mg/day 100–400 0.05–0.2 mg (oral) mg 0.05–0.2 100–200 mg, 3 times/day 3 mg, 100–200 0.2–0.4 μg/kg/hr, IV infusion IV μg/kg/hr, 0.2–0.4 0.1 mg/hr (patch) at bedtime at (patch) mg/hr 0.1 life of 12–16 hr 12–16 of half - life hr; 3–5 in life of half - life dose; a after min 60 hr 4 after 0.5–2 hr in patients with rap ‑ with patients in hr 0.5–2 after hr 6 to 3 after and metabolism id metabolism slow with those in active metabolite peaks in 3–4 hr 3–4 in peaks metabolite active tablet); plasma level peaks in peaks level plasma tablet); hr 7 of half - life hr; 2.5–5 dose; a after min 30–90 peaks 30–56 hr half - life 0.1 mg at bedtime; plasma level peakslevel plasma bedtime; at mg 0.1 25 mg at bedtime; plasma level peakslevel plasma bedtime; at mg 25 5 mg at bedtime; plasma level peaks level plasma bedtime; at mg 5 of level plasma bedtime; at mg 50 30 mg at bedtime (controlled - releasebedtime at mg 30 level plasma needed; as mg 2.5–10 39 34 and caffeine and ­ hypertension Clonidine Dexmedetomidine Methyldopa Carbidopa Drug Indomethacin, ibuprofen, Indomethacin, (nocturnal) supine For Sildenafil Nitroglycerin Nebivolol Losartan Nifedipine failure baroreflex afferent For Diazepam Clonidine Metoprolol Prazosin GABA denotes γ - aminobutyric acid, and IV intravenous. * 

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awareness, particularly in patients with cogni- options include centrally acting α2-adrenergic tive deficits.53 Treatment is aimed at preventing agonists (e.g., clonidine and dexmedetomidine) severe hypotension that might result in syncope. and the peripherally acting decarboxylase inhibi- Discontinuing or reducing the dose of aggravat- tor carbidopa, which blocks the synthesis of dopa- ing drugs (see Table S1 in the Supplementary mine and reduces downstream norepinephrine Appendix, available with the full text of this ar- production, blunting catecholamine-induced hyper- ticle at NEJM.org) and sleeping with the head of tensive episodes (Fig. 4 and Table 2).39 the bed elevated, to lower blood pressure and In vasovagal syncope, low blood pressure and reduce overnight diuresis, are effective.54 Abdom- bradycardia can linger, and when the patient at- inal binders target the splanchnic circulation tempts to stand, loss of consciousness can recur. and increase blood pressure.55 Rapidly drinking Reassuring the patient about the benign nature 500 ml of water raises blood pressure as a result of the condition is important. In recurrent cases of an osmopressor sympathetic reflex and tem- triggered by prolonged standing, midodrine68 can porarily alleviates symptoms of orthostatic hypo- be effective but beta-blockers are not.12 Contro- tension.56 versy surrounds the use of cardiac pacemakers, Pharmacologic treatment of neurogenic ortho- which may reduce the rate of recurrent cardio- static hypotension combines intravascular vol- inhibitory carotid sinus syndrome.69 Post hoc ume expansion and vasoconstrictor drugs (Fig. 4 analysis of long-term studies showed that dual- and Table 2). Because orthostatic hypotension chamber pacing may be effective in patients 40 and supine hypertension typically coexist, the years of age or older who have prolonged, spon- pharmacologic treatment of one usually exacer- taneous heart pauses, suggesting a bradyarrhyth- bates the other. Fludrocortisone induces an mic cause.70 For patients with the postural tachy- expansion of extracellular fluid volume, raising cardia syndrome, no therapies have been blood pressure. After approximately 2 weeks, uniformly successful. Recommendations include plasma volume returns to normal (mineralo- discontinuing all drugs that cause tachycardia. corticoid escape), but the pressor effect persists. A regular, progressive exercise training program Long-term use of fludrocortisone in high doses is probably the most effective approach, and ad- increases the risks of heart failure, renal fibro- dressing neuropsychological components can be sis,64 sudden unexpected death during sleep,65 helpful.49,71 and hospitalization for any reason.66 Pressor A large observational study showed improved agents, such as the α-adrenergic agonist mido- survival among patients with takotsubo cardio- drine and the norepinephrine precursor droxi- myopathy who were treated with angiotensin- dopa, are short-acting and relatively safe. The converting–enzyme inhibitors or angiotensin- pressor response to droxidopa depends on the receptor blockers but not with beta-blockers, for extent of postganglionic sympathetic neuronal up to 1 year after an acute takotsubo event. These loss and denervation supersensitivity to adrener- observational findings underscore the need for gic agents.24 Norepinephrine-reuptake inhibitors, controlled trials.13 such as atomoxetine, have a pressor effect when the peripheral sympathetic neurons are intact, in Conclusions preganglionic or premotor sympathetic lesions such as multiple-system atrophy.25 Patients with Baroreflex dysfunction is a treatable condition severe supine hypertension may need additional with multiple causes. It is most prevalent in func- treatment with antihypertensive agents (Table 2), tional disorders, which cause temporary states but such agents may worsen orthostatic hypo- of autonomic imbalance and in which emotional tension the morning after administration.20 components often play a role. Neurodegenerative, In patients with afferent baroreflex failure, metabolic, autoimmune, traumatic, or toxic mech- benzodiazepines can dampen the hyperadrener- anisms can damage the neurons of the baro­ gic states. However, because neurons in the glos- reflex. Recent developments in research on trans- sopharyngeal nerve also provide sensory input thyretin amyloidosis show the potential for halting from peripheral chemoreceptors, respiratory drive the progression of and reversing autonomic is often compromised, and benzodiazepines in- neuropathy by silencing protein production.72,73 crease the risk of respiratory depression.67 Other Similar strategies may work in the synucleinopa-

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