Journal of Review Article
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March 2016
From the *Department of
Medicine, MDA/ALS Clinic at
Carilion Clinic, Roanoke, VA;
Virginia Tech Carilion School of
Medicine and Research Institute;
and Department of Medicine,
Carilion Clinic Heart Rhythm
Services; Virginia Tech Carilion
School of Medicine and Research
Institute.
The authors report no conflicts of
interest.
Reprints: Ahmet Z. Burakgaz, MD,
Carilion Clinic, 3 Riverside Circle,
Roanoke, VA 24016 (e-mail:
azburakgazi@carilionclinic.org).
Copyright 2016 Wolters
Kluwer Health, Inc. All rights
reserved.
Copyright 2016 Wolters Kluwer Health, Inc. Unauthorized reproduction of this article is prohibited.
Cardiac Involvement in
Peripheral Neuropathies
Ahmet Z. Burakgazi, MD* and Soufian AlMahameed, MD, FACC
Abstract
Cardiac autonomic neuropathy (CAN) is the least
recognized and understood complication of
peripheral neuropathy. However, because of its
potential adverse effects including sudden death,
CAN is one of the most important forms of
autonomic neuropathies. CAN presents with differ-
ent clinical manifestations including postural
hypotension, exercise intolerance, fluctuation of
blood pressure and heart rate, arrhythmia, and
increased risk of myocardial infarction. In this
article, the prevalence, clinical presentations, and
management of cardiac involvement in certain
peripheral neuropathies, including diabetic neurop-
athy, GuillainBarr syndrome, chronic inflamma-
tory polyneuropathy, human immunodeficiency
virus-associated neuropathy, hereditary neuropa-
thies, and amyloid neuropathy are examined in
detail.
Key Words: cardiac involvement, peripheral neu-
ropathy
( J Clin Neuromusc Dis 2016;17:120128)
INTRODUCTION
Cardiac muscle is an extraordinary
tissue that is made of striated muscle with
an inner conduction system and a pacemaker
that automatically controls the rhythm,
which is further influenced by the auto-
nomic nervous system (ANS).1 Various neu-
ropathies can affect the ANS, including
those that control the heart neural networks
and cause symptoms and complications. Car-
diac autonomic neuropathy (CAN) is the
least recognized and understood complica-
tion of peripheral neuropathy (PN). How-
ever, because of its potential adverse
effects including sudden death, CAN is one
of the most important forms of autonomic
neuropathies.
In this review, we focus on the preva-
lence, clinical characteristics, and management
of cardiac involvement in certain neuropathies
including diabetic neuropathy, GuillainBarr
syndrome (GBS), chronic inflammatory demye-
linating polyneuropathy (CIDP), HIV-associated
neuropathy, hereditary neuropathies, and amy-
loid neuropathy.
DIABETIC NEUROPATHY
Introduction
CAN is an important complication of
diabetes mellitus (DM). CAN affects nearly
20%, although some studies show a higher
prevalence of 34%,2 of all patients with DM and
increases mortality on a significant scale.3 Symp-
toms have a wide range from paroxysmal tachy-
cardia to major cardiovascular events. One of
the dilemmas with CAN is the insidious process
of the nature of the disease in that a patient may
be asymptomatic for a long time.4
CAN in DM is a complex disease and is
the result of various environmental and genetic
factors. Modifiable conditions including dyslipi-
demia, obesity,5 existing cardiovascular disease,
waist circumference, and use of high blood
pressure (BP) medications may increase the risk
of CAN in patients with DM.68 The uncon-
trolled modifiable conditions can increase the
risk of CAN. There is a long list of genes, which
may increase the susceptibility of DM, and sev-
eral genome-wide associated studies have been
conducted in the last decade.9,10 For instance, it
has recently been shown that TCF7L2 genetic
variability may contribute to the development
of CAN.9
The classification of the severity of CAN
can be performed based on the findings of
the San Antonio Conference on Diabetic

Neuropathy (1988) that classifies the severity
into 3 stages (1) early stage: abnormality of
heart rate response during deep breathing
alone; (2) intermediate stage: an abnormality
of Valsalva response; and (3) severe stage:
presence of postural hypotension (systolic BP
drop $20 mm Hg or diastolic BP drop $10
mm Hg associated with symptoms).1113
Pathogenesis
The occurrence of CAN depends on
multiple factors such as poor glycemic con-
trol, the duration of DM, systolic and diastolic
BP changes, and older age.1,14,15 The degree of
glycemic control has an important role in
development and progression of CAN. Poor
glucose control can contribute to CAN by dis-
turbing several biochemical pathways that
cause oxidative stress and impair nerve perfu-
sion.1,6,15 Experimental studies indicate that
increased free oxygen radicals, activation of
the polyol and protein kinase C pathways,
and activation of poly ADP ribosylation may
play critical roles in pathogenesis of CAN
and in neuronal degeneration.1,6,14,15
DM can cause ANS impairment as a long-
term complication. Cerebral vasomotor reactiv-
ity and flow-mediated dilation can be impaired
in DM patients with long-term disease.16 Fur-
thermore, cerebral hemodynamics, systemic
endothelial function, and sympathovagal bal-
ance may be altered in a select population of
well-controlled DM patients with short-term
disease and without CAN.16
Clinical Features
The common clinical manifestations of
CAN are postural hypotension, exercise intol-
erance, intraoperative cardiovascular lability,
silent myocardial ischemia and infarction, and
major cardiovascular events such myocardial
infarction and heart failure.17 Different patho-
physiological mechanisms can cause these
manifestations. For instance, sympathetic and
parasympathetic imbalance can reduce cardiac
output and peripheral blood leading to exer-
cise intolerance in patients with CAN.10,17
Autonomic response of vasoconstriction and
tachycardia to vasodilating effects of anesthesia
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can cause intraoperative cardiovascular March 2016
lability.10,17 Damages in efferent sympathetic
vasomotor fibers, especially in the splanchnic
vasculature and decrease in cutaneous,
splanchnic, and total vascular resistance can
cause postural hypotension.10,17,18
CAN can disturb cardiac function and
cause several complications in cardiovascular
system. CAN can cause arterial stiffness and
reduce myocardial perfusion in patients with
DM.19 CAN blunts heart rate variability
(HRV).10 HRV is considered as a good mea-
sure of CAN in patients with DM, and its
decrease can be associated with increased
risk of mortality and morbidity.20 Diabetic pa-
tients without CAN have higher cardiac sym-
pathetic modulation and preserved HRV.21
Diabetic patients with PN may have lower
HRV indices than patients without PN and
are at higher risk for CAN.22
Diabetic patients with CAN may have
higher left ventricular mass indices and greater
QT dispersion.23 Prolongation of the QT inter-
val is an important indicator of CAN and indi-
cates an imbalance between right and left
sympathetic innervation.24,25 Prolonged QT
interval may increase risk of arrhythmia and
sudden death.25,26
CAN is associated with other macro-
vascular complications such as atherosclero-
sis of the coronary arteries, cerebral arteries,
and large arteries of the lower extremities
and other microvascular complications such
as retinopathy and PN.8,22 CAN may be asso-
ciated with carotid atherosclerosis in patients
with DM.27
CAN may play an additive role in impair-
ment of left ventricle function in patients with
DM or impaired glucose intolerance.28,29 The
presence of CAN may cause more frequent
and more severe forms of left ventricular dia-
stolic dysfunction in patients with DM.28
Diagnosis
The diagnosis of CAN can be difficult.
In general, a diagnosis of CAN can be made
with various tests including HRV tests, pos-
tural BP testing, and Valsalva maneuvers,19
testing a complex set of reflexes involving
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March 2016 both sympathetic and parasympathetic path-
ways to the heart and baroreceptors in the
chest and lungs.4,10 The presence of one
abnormal cardiovagal test is usually enough
to detect possible CAN or early CAN. How-
ever, 2 abnormal cardiovagal tests should be
obtained to confirm the diagnosis.6
Based on the Toronto Consensus con-
clusion, the 5 most sensitive and specific
methods to assess the presence of CAN are
(1) study of HRV using the ratio of the RR
intervals of the electrocardiogram; (2) baror-
eflex sensitivity; (3) muscle sympathetic
nerve activity; (4) measurement of plasma
levels of catecholamines; (5) cardiac sympa-
thetic mapping.30
CAN is often underdiagnosed because
of several factors such as low interest in
unfamiliar complications, disbelief in thera-
peutic options, and lack of education and
training related to necessity of cardiovascular
diagnostic testing. However, more consistent
evidence suggests that CAN may increase
cardiovascular morbidity and mortality in
diabetic patients.30 Therefore, more educa-
tion and training should be provided to physi-
cians to increase awareness of cardiovagal
tests in the diagnosis of CAN.
After the diagnosis of CAN, the pres-
ence and severity of orthostatic hypotension
and abnormal heart rate tests can be used to
follow up the progression of CAN.6 In addi-
tion, HRV is a great marker of ANS function,
and a reduction of HRV is one of sign of early
CAN.10 Thus, HRV monitoring (repeating
HRV test once a year) is recommended to
be performed in all diabetic patients.10 A
decrease in HRV can be the earliest indicator
and predictor of CAN.4,10 Early diagnosis of
CAN is important because it predicts cardio-
vascular events and mortality.31
Treatment
There is no definite cure available for
CAN except for following up and managing
its progression and complications. However,
several modalities have been tried to over-
come its effects. For instance, it was shown
that certain angiotensin-converting enzyme
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inhibitors might prevent or postpone cardiac
autonomic complications of DM.32 It has
been postulated that beta-blocker treatment
could improve autonomic function in diabetic
patients with abnormal albuminuria and an
associated high risk of cardiovascular dis-
ease.10,33 Other studies investigating the
effects of alpha-lipoic acid, Vitamin E and
C-peptide demonstrated that those agents
might improve the prognosis of CAN and its
related complications.6,34 Minocycline is part
of the family of tetracyclines and has been
investigated as a potential cardiovascular ther-
apeutic agents due to its anti-inflammatory,
antiapoptotic, antioxidant, and antienzymatic
properties. A recent study shows that 6-week
treatment of minocycline is safely well toler-
ated and may significantly improve CAN and
PN among patients with DM.35
Besides recommendations in the above
studies, tight metabolic and glycemic control
and increasing awareness of CAN-related symp-
toms and modification of risk factors are the
most effective ways to improve the prognosis
and to manage the complications.6,10 Control
of blood glucose level and high BP is the key
factor that postpone the development of CAN.
Orthostatic hypotension is a late and
challenging complication of CAN.36,37 Non-
pharmacological and pharmacological strate-
gies can be performed in symptomatic
patients.36,37 Nonpharmacological strategies
include increase in fluid and salt intake; the
use of lower extremity stocking socks, eating
smaller and frequent meals; avoidance of sud-
den changes in body posture; avoidance of
drugs precipitants of postural hypotension
such as diuretics, tricyclic antidepressants,
a-adrenoceptor antagonist; performance of
physical countermaneuvers such as leg cross-
ing, stooping, and squatting; and avoidance of
exercise and maneuvers that increase intra-
abdominal and intrathracic pressure.3638 Phar-
macological treatments including midodrine,
clonidine, octreotide, fludrocortisone acetate,
erythropoietin, nonselective beta-blockers,
and pyridostigmine bromide can be used in
patients with nonpharmacological measures
fail to improve symptoms.3641

GBS Introduction
GBS is an acute immune-mediated poly-
neuropathy with different well-described sub-
types.4244 Acute inflammatory demyelinating
polyradiculoneuropathy (AIDP) is the most
common subtype of GBS and accounts for
around 90% of GBS cases in North America
and Europe, whereas acute motor axonal
neuropathy only accounts for approximately
5%10% of GBS cases.42,43 The distribution of
subtypes shows wide variation in different
regions, for example, 30%47% of GBS cases
are the axonal form in Asia, and South and
Central America.42,43 The incidence of GBS is
around 12 cases per 100,000 per year.42,43
GBS-related autonomic complications are
seen around 2/3 of affected cases.42,43 The
presence of autonomic and cardiovascular
involvement is different between the sub-
types. AIDP is usually associated with cardio-
sympathetic hyperactivity and autonomic
dysfunction, whereas acute motor axonal
neuropathy is not generally associated with
marked autonomic dysfunction.45 The cardio-
vascular abnormalities are mostly related to
autonomic fiber involvement.42,45,46
Pathogenesis
AIDP is usually preceded by upper or
gastrointestinal tract infections that are
assumed to trigger an autoimmune process.42
The cross-reaction with shared episodes of
peripheral nerve components is implicated in
the genesis of AIDP. Various antigen ganglio-
side antibody complexes have been demon-
strated in several necropsy and animal
models. Macrophage-medicated invasion or
complement-activated systems can be part of
the underlying immune mechanism. Potential
myocardial involvements in GBS may be
related to cross-reaction of lactose-containing
gangliosides of the heart.42,47
This autoimmune process in AIDP pa-
tients may cause reversible dysfunction of
voltage-gated Na + channels at the nodes of
Ranvier and lead to conduction blocks.42 The
mechanism of depolarization is quite different
in SA and AV nodes, but Na + channel has
a critical role in depolarization and generation
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of the cardiac action potential. In AIDP,
immune response-related channel dysfunction
such as Na + channel may play a role in
rhythm abnormalities.
ANS involvement, particularly sympa-
thetic overactivity rather than parasympa-
thetic hypoactivity, can cause various
cardiovascular complications. Autonomic dys-
function is commonly seen in AIDP. Elevated
levels of epinephrine and norepinephrine in
the plasma and increased 24-hour urine levels
of vanilmandelic acid have been reported in
GBS cases with cardiovascular complications.
Cardiovascular complications may be a result
of increased catecholamine sensitivity in the
denervated organs and impairment of the
carotid sinus reflex.42,45,47,48
Clinical Features, Diagnosis,
and Treatment
A wide spectrum of clinical manifesta-
tion related to autonomic dysfunction is seen
in approximately 60%70% of AIDP cases.42,47
The common cardiovascular complications of
AIDP are rhythm abnormalities, BP variability,
myocardial involvement, acute coronary syn-
drome, and electrocardiographic changes.4648
One of the common rhythm abnormali-
ties is sustained sinus tachycardia. In 1 study,
an increase in the mean heart rate to .125
beats per minute was reported in 25% of the
cases. The increase is usually transient and
does not require any clinical treatment. Sus-
tained sinus tachycardia may occur as a result
of sympathetic hyperactivity.4548 Treatment
with beta-blockers can be problematic because
of bradycardia and hypotension side effects
but should be considered in elderly patients
with coronary artery disease. Atrial and ventric-
ular arrhythmias can be seen in AIDP.
Guideline-directed treatment is suggested in
life-threatening situations related to those ta-
chyarrhythmias.4648 Bradycardia is the most
life-threatening and dangerous cardiovascular
complication of AIDP and can be seen in
approximately 6 of 100 unselected AIDP
cases.49 According to other data, the clinical
spectrums of bradyarrhythmias from sinus bra-
dycardia to asystole were found in 7%34% of
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March 2016 GBS cases.46,48,49 AIDP cases presenting with
severe disability and requiring mechanical ven-
tilation may have more risk to developed seri-
ous bradycardia, but it can be seen in less
severely affected patients as well. AIDP pa-
tients with increased daily systolic BP variation
(.85 mm Hg) have a high risk to develop
bradycardia.46 Early recognition and prediction
of the bradyarrhythmia are extremely impor-
tant to prevent mortal complication. Standard-
ized autonomic testing such as short-term HRV,
carotid pressure, and modified Valsalva maneu-
ver are not useful for early prediction. In addi-
tion, the eyeball pressure testing can be used
as an indicator for threatening serious brady-
cardia in patients with GBS. During the eyeball
pressure testing, moderate pressure is manu-
ally and externally applied on both eyes for
25 seconds or until abnormal bradycardia (hear
rate ,40 beats per minute) develops. A com-
bination of bedside eyeball pressure testing
and heart rate power analysis seems to be an
effective and reliable approach in early detec-
tion of bradyarrhythmias.46,48,49 The administra-
tion of atropine or may be used in serious
cases. The underlying factors such as hypoxia,
medical side effects, and metabolic acidosis
should be corrected aggressively. Cautious tra-
cheal suctioning and avoidance of aggressive
tracheal suctioning may reduce the occurrence
of arrhythmia. In severe bradyarrhythmias
cases, insertion of a transcutaneous pacemaker
can be indicated.50,51
BP variability is another important car-
diovascular complication of AIDP.47,52 It is
related to ANS dysfunction and increased cate-
cholamine levels and sensitivity.4648,53 Owing
to the disturbance of the sympathetic and para-
sympathetic nervous system, AIDP can cause
abnormalities in the baroreceptor reflex path-
way and changes in vascular resistance. Sym-
pathetic overactivity can cause hypertension in
AIDP. Increased renin and atrial natriuretic fac-
tor may contribute to the occurrence of hyper-
tension as well.43,4648,53 Increased BP by more
than 25 mm Hg is frequently seen in all patients
with AIDP, particularly in AIDP cases with
respiratory failure.4,46,47,49,53 There is a positive
correlation between hypertension and severity
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of the disease. Labile BP is a characteristic fea-
ture of AIDP and marked fluctuation of BP is
a bad sign. Close cardiovascular monitoring
should be performed in AIDP patients with
high BP and BP fluctuations. BP fluctuation
and high BP are usually transient in GBS, but
supportive and symptomatic treatment may be
required. Intravenous fluid administration and
low-dose vasopressor therapy may be needed
in hypotensive cases.42,4648,52 Intravenous labe-
talol, esmolol, or nitroprusside may be indi-
cated in hypertensive cases. AIDP cases with
marked BP fluctuation (systolic BP .85 mm
Hg) should be monitored closely for bradycar-
dia and should be investigated with other asso-
ciated conditions including hypoxia, sepsis,
pulmonary thromboembolism, etc.4547,52,54
The myocardium can be affected in
AIDP. The frequency of myocardial involve-
ment is unknown because 2-dimensional
echocardiogram is not performed in AIDP
patients on a regular basis.46,47,52,5456 Myocar-
dial involvements in AIDP may be related to
cross-reaction of lactose-containing ganglio-
sides of the heart or increased catecholamines
levels and sensitivity. Myocardial involvement
can range from asymptomatic myocarditis to
neurogenic stunned myocardium and heart
failure.47,55,56 The mainstay treatment is sup-
portive and symptomatic management. Fortu-
nately, most of these cases are reversible and
recover completely.47,55,56
Another rare and reported complica-
tion of the AIDP is acute coronary syndrome.
Few cases have been reported.47,57 A case of
a patient with AIDP who developed ST-
elevation in the inferolateral leads suggestive
of an acute coronary syndrome was reported.
Cardiac catheterization revealed angiographi-
cally normal coronary arteries, and intracoro-
nary Doppler flow revealed an elevated
baseline coronary flow reserve. No evidence
of myopericarditis was present on 2D echo
and endomyocardial biopsy. The patient had
an uneventful recovery.57
Wide spectrums of morphological elec-
trocardiographic changes are well described
in AIDP.47,50,54 These findings include giant T
waves, prolonged QT intervals, ST-T changes,

U waves, and atrioventricular blocks. 46,47,50,52
The electrocardiogram changes may result
from myocarditis, increased catecholamine
sensitivity, and immune injury of the auto-
nomic nervous system. Further workup
including echocardiogram and cardiac en-
zymes should be performed to investigate pos-
sible underlying myocardial involvement.47,50
HIV-ASSOCIATED NEUROPATHY
Peripheral neuropathies are the most
common neurological complication in HIV/
AIDS.58 Cardiovascular involvement including
autonomic dysfunction is well described in
HIV infection.12,59 As CAN may increase risk
of sudden death, it becomes one of the impor-
tant complications in HIV-infected patients.
The prevalence of CAN in HIV-associated neu-
ropathy shows great variability between 5%
and 77% in the literature.12,59,60 The discrep-
ancy between the studies is related to the def-
inition of autonomic dysfunction and
heterogenicity of the population studied.11,12,59
The QTc interval was measured to
correlate the degree of autonomic neuropa-
thy.25 A significant correlation between scores
of autonomic involvement and OTc interval
prolongation was observed in HIV-positive pa-
tients.25 As patients with prolonged QTc inter-
val have more risk to develop life-threatening
ventricular arrhythmia, these patients should
be followed closely because of increased risk
of sudden death.13,25,59,60
HIV-positive patients can show a signifi-
cantly lower HRV than the healthy population
and can show sympathovagal balance alter-
ation.11,12,59 CAN can be seen at the early stage
of AIDS, but CAN is worse and more frequent
in advance stages of the disease. CAN is more
frequently seen in HIV-infected patients with
lower CD4+ T-lymphocyte counts.11,5860
In patients with CAN, medications and
anesthetic agents that may increase risk of
arrhythmia should be selected and used very
cautiously. Several medications commonly
used in treatment of HIV can be neurotoxic
and may cause some of the abnormalities in
autonomic testing. However, no remarkable
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correlation between the medication and CAN March 2016
has been demonstrated. Antiretroviral ther-
apy (ART) reduces the viral load and slows
down the progression of the disease, thus
ART indirectly reduces the occurrence of
coronary artery disease. Besides ART, symp-
tomatic treatment of arrhythmia and postural
hypotension can be required.11,25,58,60
Chronic Inflammatory
Demyelinating Polyneuropathy
Chronic inflammatory demyelinating pol-
yneuropathy autonomic dysfunction is mild,
limited, and distal postganglionic cholinergic
neuropathy in CIDP.61 Cardiovascular compli-
cations of CIDP are rarely seen when com-
pared with other neuropathies. Myocardial
involvement in CIDP has not been reported
in the literature. Most studies demonstrate that
baroreflex-mediated peripheral vasoconstric-
tion is relatively intact in most CIDP pa-
tients.6163 A retrospective analysis of 47
patients meeting CIDP criteria showed that 3
patients had minimal adrenergic impairment
based on the BP profile on the Valsalva maneu-
ver, and only one of them showed delayed
orthostatic hypotension on head-up tilt.61
Hereditary Peripheral Neuropathy
Hereditary peripheral neuropathies are
a large group of diseases, which are divided
into subgroups depending on clinical pat-
terns, types of inheritance, electrophysiolog-
ical features, metabolic defects, and genetic
features. The most common hereditary PN is
CharcotMarieTooth (CMT) disease.44,64
ANS dysfunctions including reduced sweat-
ing, bladder dysfunction, impotence, fluctua-
tions in blood temperature and BP, and
repeated vomiting can be seen in hereditary
sensory and autonomic neuropathies.65 How-
ever, there is no clear information on preva-
lence and clinic features on cardiac
involvement in hereditary peripheral neurop-
athy including CMT and hereditary sensory
and autonomic neuropathies.
Few studies have been reported.66,67
Sixty-eight patients with CMT were evaluated
prospectively for cardiac involvement.
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March 2016 Cardiac findings were limited to 5 patients
with conduction defects, 2 patients with sup-
raventricular tachycardia, 2 patients with
ischemic heart disease, and 20 with mitral
valve prolapsed.66 In another report, the case
of 2 brothers with CMT presenting with
dilated cardiomyopathy and cardiac conduc-
tion disorder was reported.67
Amyloid Neuropathy
Amyloid proteins are insoluble and
accumulate in tissues. Primary systemic
amyloidosis is characterized by the deposi-
tion of monoclonal immunoglobulin light
chains (AL). In the familial form, the depos-
its are produced from abnormally folded
transthyretin gene products (ATTR).64
Regardless of differences in the substance
of the amyloid deposit, small-fiber neuropa-
thy is seen in Amyloid Light-chain and
Transthyretin-related amyloidosis amyloid-
osis. Amyloid neuropathies are rare but well
known. In both types, amyloid can infiltrate
conduction system and other cardiac struc-
tures such as myocardium, valvular tissues,
and vessels.68,69 The involvement of con-
duction system can cause bundle branch
block, atrioventricular, and sinoatrial block.
Regardless of nerve involvement, amyloid
infiltration can cause cardiomyopathy, val-
vular impairment, and coronary artery dis-
ease that are out of the scope of this
article.68,69
CONCLUSIONS
CAN is the least recognized and under-
stood complications of PN. However, because
of its potential mortal consequences including
sudden cardiovascular deaths, CAN is the one
of the concerning complications of PN. CAD is
most commonly seen in diabetic neuropathy
and GBS. CAN presents with different clinical
manifestations including postural hypoten-
sion, exercise intolerance, increased inci-
dence of coronary artery disease, fluctuation
of heart rate and BP, and arrhythmias. The
diagnosis of CAN at early stage is important to
institute proper clinical management and to
prevent progression of CAN.
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