Handbook of Clinical Neurology, Vol.

167 (3rd series)

Geriatric Neurology
S.T. DeKosky and S. Asthana, Editors
https://doi.org/10.1016/B978-0-12-804766-8.00008-X
Copyright © 2019 Elsevier B.V. All rights reserved

Chapter 8

Autonomic dysfunction: Diagnosis and management

MARTINA RAFANELLI1, KATHLEEN WALSH2, MOHAMED H. HAMDAN2, AND LAURA BUYAN-DENT3*
1
Division of Geriatric Cardiology and Medicine, University of Florence, Florence, Italy
2
Division of Cardiovascular Medicine, University of Wisconsin School of Medicine and Public Health, Madison, WI, United States
3
Department of Neurology, University of Wisconsin School of Medicine and Public Health, Madison, WI, United States

Abstract
The autonomic nervous system is designed to maintain physiologic homeostasis. Its widespread connec-
tions make it vulnerable to disruption by many disease processes including primary etiologies such as Par-
kinson’s disease, multiple system atrophy, dementia with Lewy bodies, and pure autonomic failure and
secondary etiologies such as diabetes mellitus, amyloidosis, and immune-mediated illnesses. The result
is numerous symptoms involving the cardiovascular, gastrointestinal, and urogenital systems. Patients
with autonomic dysfunction (AUD) often have peripheral and/or cardiac denervation leading to impair-
ment of the baroreflex, which is known to play a major role in determining hemodynamic outcome during
orthostatic stress and low cardiac output states. Heart rate and plasma norepinephrine responses to ortho-
static stress are helpful in diagnosing impairment of the baroreflex in patients with orthostatic hypotension
(OH) and suspected AUD. Similarly, cardiac sympathetic denervation diagnosed with MIBG scintigraphy
or 18F-DA PET scanning has also been shown to be helpful in distinguishing preganglionic from postgan-
glionic involvement and in diagnosing early stages of neurodegenerative diseases. In this chapter, we
review the causes of AUD, the pathophysiology and resulting cardiovascular manifestations with empha-
sis on the diagnosis and treatment of OH.

INTRODUCTION In this chapter, we review the causes of autonomic

The autonomic nervous system (ANS) is designed to
maintain physiologic homeostasis. It consists of the
sympathetic and parasympathetic nervous systems,
both of which have central and peripheral nervous sys-
tem components. Its widespread connections make it
vulnerable to disruption by many disease processes such
as neurodegenerative disorders resulting in numerous
symptoms involving the cardiovascular, gastrointestinal,
and urogenital systems. The degree to which dysau-
tonomia contributes to a patient’s overall disability can
be quite variable. Constipation, urinary urgency and
incontinence, heat intolerance, and orthostatic hypo-
tension (OH) are frequent problems that contribute
significantly to morbidity and mortality, especially in
the elderly.
dysfunction (AUD), the pathophysiology and resulting
cardiovascular manifestations with emphasis on the
diagnosis and treatment of OH.
CAUSES OF AUTONOMIC DYSFUNCTION
Primary etiologies
PARKINSON’S DISEASE
Parkinson’s disease (PD) is a neurodegenerative disease
largely known for its motor symptoms of resting tremor,
bradykinesia, rigidity, shuffling gait, and postural insta-
bility (see Chapter 14). The average age of onset is
60 years, but can range from younger to older age. The
incidence is between 8 and 18 per 100,000 person–years
(de Lau and Breteler, 2006). It was first formally

*Correspondence to: Laura Buyan-Dent, M.D., Ph.D., Associate Professor of Neurology, 7th Floor, MFCB, 1685 Highland Avenue,
Madison, WI 53705-2281, United States. Tel: + 1-608-263-9800, Fax: +1-608-263-0412, E-mail: dent@neurology.wisc.edu
124 M. RAFANELLI ET AL.
described in 1817 by Dr. James Parkinson, but descrip-
tions of “PD-like” conditions date back to ancient times.
The cause of PD remains unknown with recent research
suggesting a genetic predisposition that is triggered by a
variety of environmental factors (Lesage and Brice,
2009; Kalia and Lang, 2015). Pathologic hallmarks of
the disease include loss of dopamine producing neurons
in the substantia nigra resulting in disruption of the path-
ways of the basal ganglia many of which are involved
with motor control, thereby causing the motor manifes-
tations of the disease. In addition, Lewy bodies, which
consist of the misfolded protein a-synuclein, can be
found throughout the central nervous system and ANS
(Hughes et al., 1993; Braak et al., 2003).
About 40% of patients will develop clinically signif-
icant OH as a result of cardiovascular autonomic insuf-
ficiency or failure (Goldstein, 2003; Merola et al.,
2017). The severity is quite variable ranging from post-
prandial lightheadedness to syncope upon standing. The
combination of lightheadedness or syncope and gait
disturbance tremendously increases the risk of falls
leading to increased disability, morbidity, and mortality.
A complicating factor in dealing with OH in PD is that
the dopaminergic medications, used to control some of
the motor symptoms, such as dopamine agonists (prami-
pexole, ropinirole, rotigitine) and levodopa can worsen
OH. Levodopa is converted to dopamine, which in low
doses acts as a selective vasodilator due to stimulation
of the DA-1 receptors in the renal, mesenteric, cerebral,
and coronary beds. Peripheral metabolism of levodopa is
blocked by carbidopa, which can help alleviate some of
these hemodynamic effects. Therefore, patients with PD
and OH struggle with balancing treatment of motor
symptoms with dopaminergic medications and treatment
of OH with the resulting complications (Asahina et al.,
2013; Kalia and Lang, 2015).
MULTIPLE SYSTEM ATROPHY
Multiple system atrophy (MSA) is one of the atypical
parkinsonian conditions, formerly referred to as
Parkinson-Plus syndrome. MSA can be divided into
three subtypes or variants: parkinsonian (formerly
striato-nigral degeneration), cerebellar (formerly olivo-
ponto-cerebellar atrophy), and autonomic (formerly
Shy–Drager). MSA is a sporadic, fatal neurodegenera-
tive disease, although familial forms have been reported.
Estimated prevalence is 3.4–5 cases per 100,000 people.
The age at onset ranges from 53 to 65 years. The mean
survival is 6–10 years (Peeraully, 2014; Palma et al.,
2018). The pathologic hallmark is oligodendroglial
cytoplasmic inclusions (Papp–Lantos Bodies) that con-
sist of misfolded a-synuclein aggregates. Lewy bodies
may be present, but to a lesser degree than in patients
with idiopathic PD (Ramirez and Vonsattel, 2014).
Patients with MSA will demonstrate a varying
combination of akinetic-rigid parkinsonian-like motor
symptoms, cerebellar dysfunction, and severe dysauto-
nomia. The motor symptoms are largely levodopa
unresponsive or only transiently responsive. The dysau-
tonomia is due to loss of function of central autonomic
centers. Loss of sympathetic activity occurs preganglio-
nically because of degeneration of sympathetic pregan-
glionic neurons in the intermediolateral cell column of
the thoracolumbar spinal cord. Patients often have OH
early in the disease process with the resulting symptoms
(Peeraully, 2014; Palma et al., 2018).
DEMENTIA WITH LEWY BODIES
Dementia with Lewy bodies (DLB) is the second most
common neurodegenerative dementia after Alzheimer’s
disease in patients older than 65 years, with a slight
male predominance. Pathologically, it is classified as a
synucleinopathy as a result of abnormal deposition of
a-synuclein (Ramirez and Vonsattel, 2014). Clinically,
fluctuations in cognition with marked changes in atten-
tion and alertness, parkinsonism, and visual hallucina-
tions are frequent signs of the disease. Progressive
significant cognitive decline and parkinsonian motor
symptoms are often present early in the disease process.
Usually the cognitive symptoms and extrapyramidal par-
kinsonian symptoms appear within approximately 1 year
of each other. Dysautonomia is not required for diagno-
sis, but is a frequent supporting finding. OH, constipa-
tion, and urinary incontinence are the most common
autonomic symptoms (Walker et al., 2015; McKeith
et al., 2017).
PURE AUTONOMIC FAILURE
Pure autonomic failure (PAF) is another synucleinopathy
characterized by dysautonomia without motor, sensory,
or cognitive abnormalities. It is a sporadic, adult-onset,
slowly progressive disorder. Unlike other synucleinopa-
thies, AUD in PAF only affects the peripheral ANS
(Kaufmann et al., 2001; Orimo et al., 2002). A deficit
in norepinephrine (NE) synthesis and release occurs.
People with PAF have a variety of autonomic related
symptoms, with OH being a prominent one. Lighthead-
edness, faintness, neck pain in a coat hanger distribution
(poor perfusion of neck muscles) may bring patients to
medical attention. Symptoms are worse in the morning,
after meals, during hot weather, and after hot baths or
showers, and are relieved by lying down (Garland
et al., 2013).
In patients with PAF, norepinephrine levels are
decreased when supine and fail to increase upon stand-
ing. Measurements of plasma catecholamines and their
metabolites suggest decreased synthesis of catechol-
amines in sympathetic nerves. Baroreflex failure can
 AUTONOMIC DYSFUNCTION: DIAGNOSIS AND MANAGEMENT
be seen with lack of blood pressure (BP) overshoot dur-
ing the Valsalva maneuver. Many patients with PAF will
experience supine hypertension possibly due to abnor-
mal baroreflex buffering and/or denervation hypersensi-
tivity of adrenergic receptors. In patients who have
experienced significant OH for 5 years, without develop-
ment of neurologic signs of parkinsonism or cerebellar
dysfunction, a diagnosis of MSA is unlikely (Garland
et al., 2013; Kaufmann et al., 2017; Singer et al., 2017).
A summary of primary causes of AUD including clin-
ical presentation and cardiovascular manifestations is
provided in Table 8.1.
Secondary etiologies
In most conditions causing or contributing to peripheral
neuropathy, the autonomic nerve fibers are affected
along with the sensory and motor fibers. The degree of
clinical symptoms is highly variable and can encompass
dysfunction of the cardiovascular, urogenital, and gastro-
intestinal components of the ANS. There are many
causes of peripheral neuropathy including metabolic
dysfunction, infections, toxin exposure, drug effects,
rheumatologic disease, paraneoplastic conditions, and
genetic diseases. Conditions in which cardiovascular
dysautonomia is prominent is the main focus of this
section.
DIABETES MELLITUS
Diabetes mellitus (DM) is a common cause of peripheral
neuropathy and the most common cause of autonomic
neuropathy in the developed world. DM causes a sym-
metric, length-dependent neuropathy affecting all types
of nerve fiber. This commonly results in symmetric
stocking and glove distribution paresthesias, numbness,
and pain. In addition, there is often length-dependent loss
of thermoregulatory functions and loss of sudomotor
responses, resulting in temperature insensitivity and loss
of sweating (Vinik et al., 2003). Many diabetics will
develop cardiovascular autonomic neuropathy character-
ized by increased resting heart rate (HR), if the parasym-
pathetic system is involved. Some will develop a fixed
HR with inadequate response to physiologic demands
when both the sympathetic and parasympathetic cardiac
innervations are affected (Spallone et al., 2011; Agashe
and Petak, 2018). OH can result from sympathetic vaso-
motor denervation leading to inadequate vasoconstric-
tion in peripheral and splanchnic beds with changes of
body position (Vinik et al., 2003).
GUILLIAN–BARR
e SYNDROME
Acute inflammatory demyelinating polyradiculoneuro-
pathy (AIDP) also known as Guillian–Barr
e syndrome,
is an immune-mediated illness in which the nervous
125
system is disrupted at the level of the nerve root and
proximal nerve fibers. It is believed to be a T-cell-driven
autoimmune response directed at peripheral nerve mye-
lin. If severe enough, axonal loss occurs. As the name
implies, multiple nerve roots are affected and the
number and degree of impairment correlate with disease
severity. Often there is an ascending paralysis with or
without paresthesias. In more severe cases, especially
with the development of respiratory failure, dysautono-
mia occurs. Most common manifestations are tachycar-
dia, labile blood pressures, cardiac arrhythmias, and
vasomotor and sudomotor dysfunction (Dimachkie and
Barohn, 2013; Zaeem et al., 2019). Treatment is with
intravenous immunoglobulins and/or plasma exchange
(Hughes et al., 2003; Wijdicks and Klein, 2017).
AUTOIMMUNE AUTONOMIC NEUROPATHY AND
GANGLIONOPATHY
Autoimmune autonomic neuropathy and ganglion-
opathy (AAG) is an autoimmune disorder resulting in
disruption of the peripheral parasympathetic and sym-
pathetic systems. This is also known as pure acute
dysautonomia, acute panautonomic neuropathy, or acute
pandysautonomia. It usually presents with profound
autonomic failure over several weeks, often with OH
and gastrointestinal symptoms. A prior history of a viral
infection is sometimes reported. Although there is pro-
found failure of the peripheral ANS, there is no evidence
of sensorimotor peripheral neuropathy. Antibodies to
ganglionic nicotinic acetylcholine receptors can be
detected in the serum, and levels have been shown to
correlate with clinical severity. The antibodies inhibit
synaptic transmission at autonomic ganglia. Treatment
is based on case reports showing improvement with
immunomodulatory therapy (Vernino et al., 2000;
Winston and Vernino, 2010; Koike et al., 2013;
Bouxin et al., 2019).
AMYLOIDOSIS
Amyloidosis comprises a group of diseases that results
from the deposition of extracellular amyloid, a collection
of insoluble fibrillary proteins in a b-pleated sheet con-
figuration. There are several different types of amyloid
proteins, some of which deposit in the peripheral nerves
and cause a peripheral polyneuropathy (Wang et al.,
2008). Diagnosis can be made by identifying the amyloid
by biopsy or aspiration of a variety of tissues. The amy-
loid protein has a homogeneous, eosinophilic appearance
under light microscopy and, when stained with Congo
red, demonstrates an apple-green birefringence. There
is a variety of types of amyloidosis that can cause poly-
neuropathy; however, autonomic involvement is usually
seen in hereditary (Plante-Bordeneuve and Said, 2011)
and primary amyloidosis (Gertz, 2013).
126 M. RAFANELLI ET AL.
Table 8.1
Summary of primary and secondary causes of AUD including clinical presentation and cardiovascular manifestations

Primary
etiology Presentation Diagnosis Pathophysiology Treatment

Parkinson’s Slowness of Bradykinesia Loss of dopaminergic Dopamine-enhancing

disease (PD) movement neurons in substantia medications
nigra with rostral
progression over
time
Stiffness of limbs Rigidity Abnormal deposition of Exercise
a-synuclein protein
(Lewy bodies)
Shuffling gait Shuffling gait Postganglionic Symptomatic Rx
sympathetic loss
+/
Tremor +/
Tremor Supportive care
OH-Late Decreased cardiac MIBG
uptake
Multiple Slowness of Bradykinesia Glial inclusions Symptomatic Rx
system movement
atrophy Stiffness of limbs Rigidity Abnormal deposition of Supportive care
(MSA) a-synuclein protein
(Lewy bodies)
Shuffling gait Cerebellar signs Generalized CNS
atrophy
Ataxia Levodopa Preganglionic
unresponsiveness sympathetic neuron
loss
OH early Normal cardiac MIBG
Dementia With Slowness of Significant progressive Abnormal deposition of Dopamine-enhancing
Lewy bodies movement cognitive decline and a-synuclein protein medications (often
(DLB) Parkinsonian signs precipitate
(within 1–2 years of hallucinations early in
disease onset) the disease)
Stiffness of limbs Decreased cardiac MIBG Lewy bodies diffusely Symptomatic Rx
uptake in CNS
Early cognitive Postganglionic Supportive care
impairment sympathetic loss
Mental status
fluctuations
+/

Hallucinations
OH
Pure Lightheadedness; Dysautonomia without Decreased BP elevating
autonomic Faintness motor, sensory, and norepinephrine medications
failure (PAF) cognitive changes synthesis and release
Pain in coat Reduced supine plasma Diffuse loss of Physical counter-
hanger catecholamines sympathetic nerve maneuvers
distribution terminals
Symptoms Decreased cardiac MIBG Abnormal deposition of
relieved when uptake a-synuclein protein
supine in the peripheral
ANS
Postganglionic
sympathetic loss
 AUTONOMIC DYSFUNCTION: DIAGNOSIS AND MANAGEMENT
Familial amyloid polyneuropathies are autosomal-
dominant inherited forms of general amyloidosis, result-
ing from mutations in amyloid precursor proteins
including transthyretin, apolipoprotein A1, or gelsolin.
Most common forms have an age of onset between
20 and 40 years. Prominent dysautonomia accompany-
ing a painful sensorimotor neuropathy often occurs
along with numerous other symptoms. Death often
occurs within 5–15 years after symptom onset. Since
most of the abnormal proteins are secreted by the liver,
liver transplantation is sometimes performed to prolong
survival. (Plante-Bordeneuve and Said, 2011).
Primary amyloidosis, the most common form in the
Western world, is a plasma cell dyscrasia in which
monoclonal light-chains or fragments of light-chains
are produced by the bone marrow. Age of onset is usually
in the sixth or seventh decade. Weight loss and fatigue are
initial common symptoms, with 20% of patients present-
ing with peripheral neuropathy and dysautonomia. Most
cases can be diagnosed by detection of immunoglobulins
and light-chains with immunofixation electrophoresis of
serum or urine. Median survival is 13–35 months. Treat-
ment with melphalan and prednisone or stem cell
transplant may improve survival (Gertz, 2013).
PARANEOPLASTIC SYNDROMES
Paraneoplastic neurologic diseases are very rare neu-
roimmunologic conditions that occur in patients with
cancer. It is thought that antibodies that target neuronal
proteins are expressed by the underlying tumor. Neuro-
logic symptoms often precede the discovery of cancer.
In paraneoplastic autonomic neuropathy, antibodies
are directed at neuronal proteins of the peripheral
ANS. Serum testing may reveal anti-Hu antibodies
(Molinuevo et al., 1998), voltage-gated potassium,
and neuronal calcium channel antibodies (Joubert and
Honnorat, 2015) or ganglionic nicotinic acetylcholine
receptor antibodies (McKeon et al., 2009). Paraneoplas-
tic syndromes are usually associated with small cell lung
cancer and thymomas (Koike et al., 2013). The most
common form largely affects the gastrointestinal system
and is called “paraneoplastic gastroparesis.” Loss of
appetite, early satiety, abdominal pain, constipation,
bloating, and pseudo-obstruction may occur (Chinn
and Schuffler, 1988). Less commonly, a more general-
ized autonomic failure is seen with evidence of failure
of both the sympathetic and parasympathetic nervous
system (Koike et al., 2013).
PATHOPHYSIOLOGY
Autonomic dysfunction is often associated with periph-
eral and cardiac changes in innervation that depend on
the underlying disease. In the current section, we discuss
127
both the peripheral and cardiac changes in patients with
AUD with a summary of the various autonomic tests that
could help with the diagnosis.
Peripheral sympathetic denervation
Changes in plasma norepinephrine (NE) concentra-
tions from the supine to the standing position provide
an indirect way to evaluate sympathetic innervation
in the body as a whole. Normally, the concentration
of NE in plasma doubles within 5 min of standing from
the supine position. Patients with OH due to AUD have
a smaller increase with standing, consistent with
blunted baroreflex-mediated sympatho-excitation
(Goldstein, 2014).
About 40% of patients with PD have evidence of OH
(Goldstein, 2003; Merola et al., 2017). Goldstein et al.
evaluated patients with PD, with or without OH compared
to age-matched healthy volunteers. Supine plasma NE
was lower in patients with OH when compared to
patients without OH (1.40  0.15 vs 2.32  0.26 nmol/L,
P ¼ 0.005). Eleven of the 18 patients without OH had
an increase in plasma NE levels of 60% during orthos-
tasis, whereas none of the 11 patients with OH had this
finding. All patients with PD and OH had abnormal BP
responses to the Valsalva maneuver compared to only 6
of the 23 patients without OH (Goldstein et al., 2002a).
In addition to cardiac sympathetic denervation
(discussed below), Sharabi et al. have shown the pres-
ence of extracardiac involvement in many patients
with PD and OH. The authors measured microdialysate
concentrations of dihydroxyphenylglycol (DHPG), a
neuronal metabolite of NE, in skeletal muscle and the
plasma concentrations of NE and DHPG in response to
intravenous administration of tyramine, yohimbine,
and isoproterenol in patients with PD, PAF, and healthy
controls (Sharabi et al., 2008). Plasma DHPG response to
tyramine provides a measure of NE stores (Bianchetti
et al., 1982). They found that microdialysate concen-
trations of DHPG were similarly low in PD + OH and
PAF patients when compared to controls with minimal
increase following tyramine infusion. Similarly, NE
response to yohimbine and isoproterenol was minimal,
supporting the concept of generalized noradrenergic
denervation in patients with PD + OH, with similar sever-
ity seen in patients with PAF. The authors also investi-
gated if sympathetic denervation was associated with
decreased uptake of catecholamines into storage vesicles
within sympathetic neurons in patients with Lewy
body diseases (Goldstein et al., 2011). They used the
ratio of myocardial 6-[18F]fluoro-dopamine (18F-DA)
to arterial 6-[18F]fluoro-dihydroxyphenylacetic acid
(18F-DOPAC), an 18F-DA metabolite, as an index of
vesicular uptake. They measured these concentrations
128 M. RAFANELLI ET AL.
in patients with PD, PD + OH, PAF (Lewy body dis-
eases), MSA (non-Lewy body disease), and normal con-
trols. Patients with PD + OH or PAF had decreased
vesicular 18F-DA uptake and accelerated 18F-DA loss,
compared to patients with MSA and control subjects.
Their findings of decreased vesicular uptake of neuronal
catecholamines suggest that vesicular monoamine trans-
port might be impaired in patients with Lewy body
diseases.
Cardiac sympathetic denervation
Sympathetic innervation of the heart originates in the
intermediolateral column of the thoracic spinal cord, seg-
ments 1–5. The first synapses form in the upper thoracic
and cervical ganglia. Postganglionic noradrenergic sym-
pathetic fibers accompany the blood vessels to the heart
and enter into the myocardium (Chung and Kim, 2015).
Cardiac sympathetic innervation has been assessed using
different methods including metaiodobenzylguanidine
(MIBG) scintigraphy and 18F-DA positron-emission
tomographic (PET) scanning.
MIBG
Metaiodobenzylguanidine is a pharmacologically inac-
tive urea derivative, which is taken up by the adrenergic
cells via the NE transporter, stored in vesicles, and
secreted in response to different stimuli, such as NE.
MIBG can be labeled with 123-Iodine to become
123
I-MIBG, which is taken up by the postganglionic, pre-
synaptic nerve endings. After depolarization, MIBG is
released into the synaptic cleft, similar to NE, but not
metabolized. 123I-MIBG-uptake has been shown to cor-
relate with adrenergic innervations. Radiolabeled MIBG
is considered a sympathetic neuron imaging agent, that is
useful to study organs that are richly innervated by the
sympathetic nervous system (Chung and Kim, 2015).
The most common semiquantitative indices used to inter-
pret the myocardial innervation images, are the heart to
mediastinum ratio (H/M), which evaluates the degree
of MIBG accumulation in the heart, and the washout rate,
which measures the rate at which MIBG is washed out
between the early and delayed images (Chung and
Kim, 2015).
MIBG scintigraphy has been used to detect and eval-
uate the sympathetic denervation of the heart in conges-
tive cardiomyopathies (Glowniak et al., 1989). In the last
few years it has been reported to be a useful tool for
differentiating various neurologic diseases (Hakusui
et al., 1994). MIBG uptake is decreased in patients with
PD, even in very early stages without clinically signifi-
cant signs or symptoms of AUD, and in patients with
nonmotor symptoms before the occurrence of motor ones
(pre-motor PD), suggesting that it is a good measurement
to detect preclinical-stage PD (Sakakibara et al., 2014).
Furthermore, MIBG uptake has been shown to vary with
the different subtypes of PD. MIBG uptake is sig-
nificantly lower in the akinetic-rigid subtype when com-
pared to the tremor-dominant subtype with a significant
inverse correlation noted between MIBG uptake and
hypokinesia in patients with the mixed and akinetic-rigid
subtypes. The mixed and akinetic-rigid subtypes were
strongly associated with more advanced sympathetic
myocardial degeneration (Chung et al., 2011; Ryu
et al., 2019).
MIBG scintigraphy has also been reported to be
useful in differentiating PD with autonomic failure from
other primary neurodegenerative diseases such as MSA,
particularly the parkinsonian type (Braune et al., 1999).
Given that 123I-MIBG is taken up by postganglionic
nerve endings, patients with PD and autonomic failure
have been shown to have an impaired MIBG uptake,
whereas patients with MSA have a normal uptake.
However, in patients with MSA-parkinsonian type, only
the MIBG washout rate was found to be helpful in
distinguishing these patients from those with PD and
autonomic failure (Chung et al., 2009; Ryu et al.,
2019). MIBG scintigraphy uptake has also been tested
in patients with DLB disease. Compared to patients
with PD, patients with DLB have a significantly lower
MIBG uptake (Oka et al., 2007). In the same study, the
authors also found that other measures of cardiovascular
autonomic function such as baroreflex gain (BRG) and
response to the Valsalva maneuver were reduced in
patients with DLB when compared to controls.
18
F-DA
Cardiac sympathetic denervation in PD has also been
demonstrated through PET scanning after systemic
administration of 18F-DA and assessment of the rate of
entry of NE into the cardiac venous drainage (cardiac
NE spillover) (Goldstein et al., 1997). Patients with
PD and PAF had no detectable 18F-DA-derived radio-
activity in the myocardium, cardiac NE spillover, or
cardiac arteriovenous increments in plasma levels of
levodopa, DHPG, or DOPAC. On the other hand,
patients with MSA and autonomic failure had clearly
visible 18F-DA-derived radioactivity in the left ventricle,
the rate of cardiac NE spillover was normal, and arterial
plasma levels of 18F-DOPAC were higher than in normal
subjects (Goldstein et al., 1997). The involvement of
postganglionic cardiac sympathetic nerves in PD and
PAF, but not in MSA has been confirmed in postmortem
studies (Amino et al., 2005).
A summary of the various autonomic test results in
patients with primary and secondary causes of AUD is
provided in Table 8.2.
 AUTONOMIC DYSFUNCTION: DIAGNOSIS AND MANAGEMENT
Table 8.2
Summary of autonomic test results in patients with primary and secondary causes of AUD
Test PD MSA DLB
Baroreflex function –# # #
Response to Valsalva –# # #
Plasma NE, E
Supine –# – #
Standing –# # #
Cardiac MIBG uptake # – # #
AAG, autoimmune autonomic ganglionopathy; AIDP, acute inflammatory demyelinating polyradiculoneuropathy; DLB, dementia with Lewy
bodies; DM, diabetes mellitus; E, epinephrine; MIBG, metaiodobenzylguanidine; MSA, multiple system atrophy; PAF, pure autonomic failure;
PD, Parkinson’s disease; NE, norepinephrine; #, abnormal test result; –, normal test result.
CARDIOVASCULAR MANIFESTATIONS
Stretch receptors in the wall of the carotid sinuses and
aortic arch provide the central nervous system with a
continuous stream of information on changes in BP,
dynamically modulating the efferent autonomic neural
activity. A rise in BP activates the baroreceptors and
leads to an increased discharge of vagal cardioinhibitory
neurons and a decreased discharge of sympathetic neu-
rons both to the heart and peripheral blood vessels, with
consequent bradycardia, decreased cardiac contractility,
peripheral vascular resistance, and venous return. Con-
versely, a decrease in BP causes less input to the barore-
ceptors resulting in vagal inhibition and increased
sympathetic activity, leading to tachycardia and increased
cardiac contractility, vascular resistance, and venous
return.
There are different methods for assessing the barore-
flex. The most common ones involve measuring changes
in HR following drug-induced or spontaneous changes in
BP. With the modified Oxford technique, vasoactive
agents are infused to increase or decrease BP under con-
tinuous electrocardiogram and beat-to-beat BP monitor-
ing (La Rovere et al., 2008). Arterial BRG is determined
as changes in RR interval/systolic BP. With the sequence
method, spontaneous increases or decreases in BP in
three consecutive beats followed by lengthening or short-
ening in RR intervals are identified. The slope of the
regression line between systolic BP and RR changes
for all identified sequences is averaged and used as an
index of the sensitivity of arterial baroreflex modulation
of HR (Fritsch et al., 1986; Hughson et al., 1993). Other
noninvasive methods include the Valsalva maneuver
where the subject performs forced expiration at the end
of maximal inspiration with continuous analysis of BP
and HR during both the straining phase and release
phase. During the release phase, an increase in venous
return occurs resulting in BP overshoot and reflex HR
129
Paraneoplastic
PAF DM AIDP AAG Amyloidosis syndromes
# # # # # #
# # # # # #
# # –# # – –
# # –# # –# –#
# – – # –
deceleration, which is vagally mediated. Analysis of
the BP and HR changes during the various phases of this
maneuver provides another measure of the baroreflex
(Palmero et al., 1981).
Impairment of the baroreflex could lead to orthostatic
intolerance and inadequate BP response to cardiac
arrhythmias. In the following section, we discuss these
two common problems that are frequently encountered
in patients with AUD.
Orthostatic hypotension
OH is a common cardiovascular disorder that occurs
when adaptive mechanisms for the regulation of ortho-
static BP fail. This regulation is dependent on barore-
flexes, normal blood volume, and defenses against
increased venous pooling (Goldstein et al., 2002b).
A normal hemodynamic response to changes in posture
requires coordination of both the cardiovascular system
and the ANS. Standing results in blood pooling of
approximately 500–1000 mL in the lower extremities
and splanchnic circulation. This pooling triggers an
increase in sympathetic outflow, which in turn increases
peripheral vascular resistance, venous return, and cardiac
output. Inability to increase cardiac output or systemic
vascular resistance, as seen in patients with AUD, could
result in OH (Kanjwal et al., 2015).
The etiology of ANS failure contributing to OH has
been traditionally classified as structural (neurogenic)
or functional (nonneurogenic) (Freeman et al., 2011).
Chronic autonomic failure in primary neurodegenera-
tive disorders such as PD, MSA, and PAF (Goldstein
et al., 2002b; Freeman et al., 2011) and in diseases
with secondary autonomic deficiency such as DM
(Vinik and Ziegler, 2007) and amyloidosis, multiple
sclerosis, and autoimmune diseases results in neuro-
genic OH (Goldstein et al., 2002b; Grubb, 2005;
130 M. RAFANELLI ET AL.
Mandl et al., 2007; Vinik and Ziegler, 2007; Freeman,
2008). Functional or nonneurogenic impairment of
the ANS is often secondary to medication side effects
(e.g., vasodilators, diuretics, chemotherapy agents),
decrease in blood volume, venous pooling, and inotro-
pic and/or chronotropic heart failure (Robertson, 2008;
Goldstein and Sharabi, 2009).
PREVALENCE
The prevalence of OH is 5%–30% depending on age,
type of population studied (e.g., outpatient vs hospital-
ized patients), and comorbidities (Freeman, 2008; Low,
2008). In patients 65 years and older, the reported rates
have been even higher up to 65% and correlated directly
with the number of causative medications (Mader et al.,
1987; Poon and Braun, 2005; Low, 2008). A strong
association has been reported between hypertension
and OH (Strogatz et al., 1991; Raiha et al., 1995;
Fedorowski et al., 2009). In a study assessing the prev-
alence and determinants of OH in middle-aged patients,
Fedorowski et al. found OH in 13.4% of hypertensive
subjects and 5.5% in normotensive subjects. Determi-
nants of OH were sex [female, odds ratio (OR) 2.45,
95% confidence interval (CI) 1.14–5.25, P ¼ 0.022],
reduced glomerular filtration rate [OR (per mL/min/
1.73 m2) 0.97, 95% CI 0.94–0.99, P ¼ 0.002], systolic
BP [OR (per mmHg) 1.02, 95% CI 1.00–1.05,
P ¼ 0.047], diastolic BP [OR (per mmHg) 1.04, 95%
CI 1.00–1.09, P ¼ 0.033], and antihypertensive treat-
ment (OR 0.41, 95% CI 0.18–0.93, P ¼ 0.034)
(Fedorowski et al., 2009).
CLINICAL PRESENTATION
Based on hemodynamic and temporal changes in ortho-
static BP, there are three different clinical variants of OH
that have been proposed, namely, initial, classic, and
delayed forms (Moya et al., 2009; Wieling and Schatz,
2009). Initial OH is exclusively associated with active
standing and is defined as a transient decrease of systolic
BP > 40 mmHg and/or diastolic BP decrease >20 mmHg
within 30 s of standing. Diagnosing initial OH can be
challenging and often requires tilt table testing with
continuous BP monitoring. The postulated mechanism
involves a transient mismatch between cardiac output
and systemic vascular resistance (Wieling et al., 2007;
Fedorowski and Melander, 2013). Classic OH is defined
as a sustained reduction in systolic BP of at least
20 mmHg and/or a decrease in diastolic BP of at least
10 mmHg within 3 min of standing compared with BP
from the sitting or supine position. In patients with supine
hypertension, a reduction in systolic BP of at least
30 mmHg is considered more appropriate criteria for
OH (Freeman et al., 2011). Delayed OH results from a
progressive drop in BP beyond 3 min and sometimes
up to 45 min. It is defined by a decrease in systolic/
diastolic BP of at least 20/10 mmHg in normotensive
patients and at least 30/15 mmHg in patients with hyper-
tension. Patients with delayed OH often have milder, but
prolonged prodromal symptoms. It is often seen in the
older patient with age-related impairment of compensa-
tory reflexes, frequent use of vasodilators and diuretics
and associated comorbidities (e.g., diabetes, hyperten-
sion, and heart failure) (Gibbons and Freeman, 2006;
Madhavan et al., 2008; Moya et al., 2009).
Characteristic symptoms of OH include lightheaded-
ness, visual blurring, dizziness, leg buckling, generalized
weakness, “coat hanger” ache, cognitive slowing, and
gradual or sudden loss of consciousness. Most patients
with OH however, are asymptomatic or have limited
nonspecific symptoms. Thus, OH is often unrecognized
or misdiagnosed.
Patients with OH may experience abnormal responses
to pharmacologic or physiologic challenges (Grubb,
2005; Kanjwal et al., 2015). Heat, fever, alcohol, postex-
ercise period, and immobilization are all conditions that
may predispose patients to peripheral venous pooling
and worsening tolerance of orthostatic stress. Symptoms
are usually more common in the morning and after wak-
ing up. Morning intake of antihypertensive medications
and postprandial hypotension often contribute to the
problem in the early hours of the day resulting in syn-
cope, falls, dizziness, weakness, angina pectoris, and
stroke (Zanasi et al., 2012). Patients with AUD may be
more susceptible to hypotension after consumption of
large meals rich in carbohydrates (Jansen and Lipsitz,
1995). Possible contributors to postprandial hypotension
include inadequate sympathetic nervous system com-
pensation for meal-induced splanchnic blood pooling;
inadequate postprandial increases in cardiac output;
impairments in baroreflex function and peripheral vaso-
constriction; insulin-induced vasodilation, and release
of vasodilatory gastrointestinal peptides (Trahair
et al., 2014).
PROGNOSTIC ASPECTS OF OH
A growing body of evidence from several population-
based studies indicates that OH is a risk factor for
cardiovascular and all-cause mortality, usually due to
underlying causes and associated diseases (Masaki
et al., 1998; Rose et al., 2006; Fedorowski et al.,
2010b; Maule et al., 2012; Fedorowski and Melander,
2013). A recent meta-analysis of prospective observa-
tional studies reported that OH was independently
associated with increased risk of incident coronary
heart disease, heart failure, stroke, and all-cause death.
 AUTONOMIC DYSFUNCTION: DIAGNOSIS AND MANAGEMENT
A post hoc subgroup analysis found a stronger associ-
ation between OH and mortality in the younger cohort
group <65 years of age compared to the older group
(Ricci et al., 2015). Prospective data from the Swedish
Malm€ o Preventive Project reported a twofold higher
risk of death in individuals <42 years of age with
OH (Fedorowski et al., 2010a). Altered autonomic
tone in patients with hypertension and sleep apnea
has been associated with the development of atrial
fibrillation, a known risk factor for cardio-embolic
stroke and heart failure (Hou et al., 2007; Nakagawa
et al., 2009; Jones et al., 2012). The total annual rate
of OH-related hospitalizations in the United States
has been reported to be quite high in the elderly with
a rate of 233 per 100,000 (Shibao et al., 2007). The
elderly with OH have also been found to have a twofold
increase in the incidence of falls (Rubenstein, 2006;
Gangavati et al., 2011).
EVALUATION OF PATIENTS WITH OH
The evaluation of patients with OH should focus on the
underlying treatable conditions that may be either caus-
ative or contributory. Orthostatic vital signs and electro-
cardiogram should be included in all initial assessments.
A thorough medical history including the patient’s pre-
senting symptoms in addition to focusing on any recent
illness or condition that may have exacerbated volume
loss, such as fever, diarrhea, vomiting, or fluid restric-
tion, needs to be obtained. Medical conditions com-
monly seen in patients with OH including heart failure,
hypertension, diabetes, autoimmune disease, renal fail-
ure and neurodegenerative disease should be docu-
mented. A detailed medication list, prescription and
nonprescription, should be obtained to assess for any
medications associated with OH. Laboratory assessment
needs to include hematocrit, electrolytes, blood urea
nitrogen, creatinine, and glucose (Fedorowski and
Melander, 2013).
TREATMENT OPTIONS
The management of OH should be directed toward
correcting any underlying causes, improving functional
status, and reducing the risk of complications. Acute
OH generally resolves with treatment of the underlying
cause. Several new treatment options for chronic OH
have been studied in the past decade. Management
includes both nonpharmacologic and pharmacologic
interventions (Table 8.3).
Nonpharmacologic measures include patient educa-
tion, physical and dietary interventions, avoiding precip-
itating factors, and discontinuation or dosage adjustment
of offending medications. Lifestyle modification is one
of the key elements of nonpharmacologic treatment.
131
BP is influenced by many stimuli in everyday life. Avoid-
ance of prolonged standing and exposure to high envi-
ronmental temperatures (e.g., hot bath, shower, or
sauna) will minimize venous pooling. Arising slowly,
in stages, from supine or sitting to standing is particularly
important in the morning, after meals, and urination/
defecation. Maintaining volume expansion with dietary
intake of 6–10 g of sodium per day in addition to hydra-
tion with a minimum of 1.25–2.50 L of fluid has been
found to be beneficial in order to balance expected
24-h urine losses (Shannon et al., 2002; Humm et al.,
2008). Physical counter pressure maneuvers such as
leg crossing, static handgrip, squatting, and general mus-
cle tensing have been found to increase cardiac output
and systemic BP, thus improving some of the clinical
symptoms associated with OH (van Lieshout et al.,
1992; Clarke et al., 2010; Figueroa et al., 2015). Com-
pression stockings and abdominal binders, which help
minimize peripheral blood pooling have been found to
reduce the degree of orthostatic BP fall and minimize
symptoms in selected patients (Henry et al., 1999;
Podoleanu et al., 2006). Avoiding large meals rich in
carbohydrates and alcohol intake have been found to
reduce postprandial hypotension (Jansen and Lipsitz,
1995; O’Mara and Lyons, 2002). Lastly, a careful adjust-
ment of patients’ medications particularly in the setting
of cardiac and renal disease should be done. The most
common medications associated with OH include
diuretics, antihypertensive medications (particularly
sympathetic blockers), nitrates, a-adrenergic antago-
nists, and antidepressants.
In patients with AUD and supine hypertension, rais-
ing the head of the bed by 10–20 degrees at night reduces
supine BP, decreases nocturnal diuresis, and helps reduce
the OH seen in the early morning hours (Ten Harkel et al.,
1992; van Lieshout et al., 2000). In addition, the use of
short-acting calcium channel blockers or nitroglycerin
patch during the night with its removal 30–60 min before
getting out of bed can help with the management of
supine hypertension. However, the patient should be
informed about the risk of OH should they wake-up in
the middle of the night to go to the bathroom.
Pharmacologic therapies are available if the patient
remains symptomatic despite nonpharmacologic mea-
sures. A step-wise approach is recommended for most
patients with the goal to improve symptoms, while avoid-
ing significant side effects. Midodrine, an a1-adrenergic
agonist, is often used in the treatment of chronic OH. It
has a pressor effect due to both arterial and venous
constriction. One advantage is that it does not cross the
blood–brain–barrier; therefore, sympathomimetic side
effects such as anxiety and tachycardia commonly seen
with adrenergic agents, do not occur (Parsaik et al.,
2013). Supine hypertension is a side effect of midodrine.
132 M. RAFANELLI ET AL.
Table 8.3
Nonpharmacologic and pharmacologic treatment options for chronic orthostatic hypotension

Nonpharmacologic Comments

Withdraw offending medication(s) Either substitute or discontinue if possible

Gradual rising from supine and sitting positions
Small, frequent meals
Avoid prolonged standing in one location
Use physical counter-maneuvers during standing
and with prodromal symptoms
Lower extremity support stockings or sleeves,
waist high if possible
Raise head of bed 10–30 degrees
Increased salt and fluid intake
Particularly in the morning, after meals, and after urination/defecation
Avoid high carbohydrate meals
Move legs up and down; walk
Static handgrip, leg crossing and contraction, squatting, muscle tensing, leg
elevation, bending at waist
Helps reduce peripheral pooling in lower limbs and splanchnic region
Reduction of nocturnal diuresis
6–10 g of sodium per day; 1.5–2 L of fluid per day; careful consideration/
dosing in patients with heart and kidney disease

Pharmacologic Comments

Fludrocortisone (0.05–0.3 mg daily) Mineralocorticoid volume expander

Midodrine (2.5–10 mg 2–3 times/day)
Pyridostigmine (30–60 mg 2–3 times/day)
Droxidopa (100–600 mg 3 times/day)
Increases sodium reabsorption
Need to be monitored for fluid overload and hypokalemia
Direct a-1 adrenoreceptor agonist
Avoid in patients with heart failure, severe coronary artery disease, and urinary
retention
Last dose must be at least 4 h before going to bed due to supine hypertension
Acetylcholinesterase inhibitor
Recommended for neurogenic orthostatic hypotension
Marginal increase in blood pressure
Norepinephrine precursor
Particularly effective in the treatment of neurogenic orthostatic hypotension

As such, this medication should not be used in patients
with severe heart disease or uncontrolled hypertension,
and patients should be instructed to take the last dose at
least 4 h before going to bed (Kaufmann et al., 1988;
Low et al., 1997). Fludrocortisone is a synthetic mineral-
ocorticoid, which reduces salt loss thus increasing blood
volume (Davies et al., 1978). Patients need to be moni-
tored for fluid overload and hypokalemia, particularly
with higher doses. Fludrocortisone is contraindicated in
patients with heart failure, kidney failure, or moderate
to severe hypertension (Hussain et al., 1996). Pyridostig-
mine, an acetylcholinesterase inhibitor, is primarily used
for neurogenic OH. It is postulated that acetylcholinester-
ase inhibition might increase postganglionic release of
NE thus improving OH. Pyridostigmine has been shown
to produce modest improvements in BP (Singer et al.,
2006; Gales and Gales, 2007). Droxidopa, an oral norepi-
nephrine precursor, has been shown to improve symptoms
of OH. It increases the levels of NE in postganglionic
sympathetic neurons causing greater stimulation of
adrenergic receptors. Norepinephrine synthesized from
droxidopa can also function as a circulating hormone
exerting a pressor-like effect (Kaufmann, 2008). Studies
have found that droxidopa was superior to placebo in
the treatment of neurogenic OH secondary to PD, PAF,
MSA, and nondiabetic autonomic neuropathy (Mathias
et al., 2001; Kaufmann et al., 2014; Biaggioni et al.,
2015; Vannorsdall et al., 2015).
In summary, OH is a common condition in the general
population with a higher prevalence in patients with
AUD. Management of symptomatic OH consists of
both nonpharmacologic and pharmacologic methods.
A summary of the available therapies is provided in
Table 8.3.
Cardiac arrhythmias
Hemodynamic consequences of cardiac arrhythmias
are determined by several factors including ventricular
rate, effectiveness of atrial mechanical activity and its
temporal relationship with ventricular contractions, var-
iability in tachycardia cycle length, left ventricular func-
tion, and the overall integrity of the vasomotor control
mechanisms.
Tachycardias are usually associated with a decrease in
BP and increase in cardiac filling pressure. The fall in BP
unloads the arterial baroreceptors with consequent with-
drawal of vagal tone and sympathetic activation, whereas
 AUTONOMIC DYSFUNCTION: DIAGNOSIS AND MANAGEMENT
the increase in cardiac filling pressures results in
decreased vagal tone and withdrawal of sympathetic
activity. We have previously demonstrated that during
both supraventricular and ventricular tachycardia, the
arterial baroreceptors predominate with minimal contri-
bution from the cardiopulmonary baroreceptors leading
to a net increase in peripheral sympathetic nerve activity
(SNA) (Hamdan et al., 1999; Smith et al., 1999; Hamdan
et al., 2001). During simulated supraventricular tachy-
cardia, the largest increase in sympathetic activity was
noted during closely coupled atrial and ventricular sys-
tole presumably due to loss of the atrial contribution to
cardiac filling and its consequences on cardiac output
(Hamdan et al., 2001). During simulated ventricular
tachycardia, the magnitude of sympatho-excitation was
shown to correlate with arterial baroreflex gain assessed
by measuring the increase in SNA for given decrease in
BP using the nitroprusside infusion method (Hamdan
et al., 1999).
In addition to supraventricular and ventricular tachy-
cardias, our group and others have shown that sympa-
thetic activity increases during atrial fibrillation and
cardiac ectopy (Wasmund et al., 2003; Segerson et al.,
2007; Smith et al., 2010). During atrial fibrillation, the
increase in SNA is primarily driven by the variability
in RR intervals with greater increases noted when the
irregularity in the ventricular responses is greater,
despite the absence of a significant change in mean BP
(Wasmund et al., 2003; Segerson et al., 2007). The
postulated mechanism is the unloading of the arterial
baroreceptors during the long RR intervals and associ-
ated reflex increase in SNA. The same is true with
supraventricular and ventricular ectopy where the post-
ectopy pauses result in reflex increase in SNA. Several
investigators including our group have shown that the
magnitude of sympatho-excitation correlated with the
frequency of ectopic beats (Smith et al., 2010). Given
the dominant role the arterial baroreflex plays in deter-
mining hemodynamic outcome during various arrhyth-
mias, it is not surprising that patients with AUD
exhibit poor tolerance to arrhythmias with a higher
incidence of near syncope and syncope.
Aging is associated with an increased prevalence of
both bradyarrhythmias and tachyarrhythmias. This pre-
disposition is the result of age-related structural and func-
tional changes in the cardiovascular system (Kistler et al.,
2004). When the baroreflex is impaired, arrhythmias that
otherwise are well tolerated become a major contributing
factor to higher morbidity and mortality in patients with
AUD. In healthy individuals, the decrease in diastolic
pressure following a premature beat is associated with
a reflex increase in sympathetic activity and a consequent
BP increase (Smith et al., 2010). In patients with AUD,
there is an impairment of this response resulting in
133
inadequate BP recovery leading to near syncope and syn-
cope (Goldstein, 2010). A strong correlation between
atrial ectopy, low baroreflex cardiovagal slope, and
orthostatic changes in BP has been found in patients
who suffer from OH and falls (Goldstein, 2010). Given
the overlap between falls and syncope in the elderly,
interest has emerged in analyzing the presence of asymp-
tomatic arrhythmias in these patients. Atrial fibrillation,
the most common cardiac arrhythmia in adults, has been
linked to recurrent syncope and falls (Ruwald et al.,
2013). Indeed, AF has been found to be an independent
predictor of nonaccidental falls in older adults (Sanders
et al., 2012). This correlation has been recently con-
firmed in a general population cohort, in which adults-
self-reporting syncope and falls were twice as likely to
have AF (Jansen et al., 2015). While this association is
the result of multiple factors including comorbid condi-
tions such as gait and balance impairment and loss of
muscular strength, impairment in the baroreflex is likely
a contributing factor.
CONCLUSION
Primary neurodegenerative disorders such as PD, MSA,
and PAF, and several systemic diseases such as DM,
autoimmune conditions, and paraneoplastic syndromes
can impact the ANS. The aforementioned disorders are
frequently associated with peripheral and/or cardiac
denervation. HR and plasma NE responses to orthostatic
stress are helpful in diagnosing impairment of the baror-
eflex in patients with OH and suspected AUD. Indeed,
the absence of orthostatic increases in NE is commonly
found in patients with Lewy body diseases and OH.
Cardiac sympathetic denervation diagnosed with MIBG
scintigraphy or 18F-DA PET scanning has also been
shown to be helpful in distinguishing preganglionic from
postganglionic involvement and in diagnosing early
stages of neurodegenerative diseases.
Patients with AUD often have impairment of the bar-
oreflex, which is known to play a major role in determin-
ing the hemodynamic outcome during orthostatic stress
and low cardiac output states. It can be assessed by
measuring changes in HR or peripheral SNA following
drug-induced or spontaneous changes in BP. Impairment
of the baroreflex often results in OH and poor tolerance
to cardiac arrhythmias leading to near syncope and
syncope. The treatment of patients with OH can be a
challenge particularly in the presence of supine hyperten-
sion. Indeed, this is a common denominator to many
disorders associated with AUD. Management includes
behavioral and pharmacologic interventions tailored to
the individual patient. Despite all the medical advances
in the field, we remain in dire need of new therapies to
care for patients with AUD.
134 M. RAFANELLI ET AL.
ACKNOWLEDGMENT
This work was supported in part by funds provided from
the Mildred and Marv Conney Chair in Cardiology.
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