This review covers the epidemiology, pathophysiology, clinical presentation, and diagnosis
of cardiac autonomic neuropathy (CAN) in diabetes and discusses current evidence on
approaches to prevention and treatment of CAN.
CASE PRESENTATION
A 26-year-old woman with “brittle” type 1 diabetes and severe CAN experienced sudden
cardiac death. She had a 16-year history of poor diabetes control presenting with
wide blood glucose fluctuations, recurrent episodes of severe hypoglycemia, and hypoglycemia
unawareness. Over time she developed persistent orthostatic hypotension with daily
falls in systolic blood pressure ranging from 30–60 mmHg. These episodes had significant
impact on her daily activities and required intermittent therapy with the α-1 agonist
midodrine. Other complications included severe gastroparesis, refractory diarrhea,
and painful diabetic peripheral neuropathy. Her last clinical examination revealed
resting tachycardia with a fixed rate of 115 bpm, supine blood pressure of 110/78
mmHg, which dropped to 70/48 mmHg while standing, symmetrical absent pinprick and
temperature discrimination in stocking distribution, and left Charcot joint. Her last
pertinent laboratory findings were A1C 8.7%, creatinine 1.9 mg/dl, microalbumin/creatinine
496 mg/g, and hemoglobin 10.8 g/dl.
CAN represents a significant cause of morbidity and mortality in diabetic patients
and is associated with a high risk of cardiac arrhythmias and sudden death, possibly
related to silent myocardial ischemia. Therefore, it has important clinical and prognostic
relevance. Recent reports of major clinical trials undermine established thinking
concerning glycemic control and cardiac risk. Thus, a review of this topic is both
timely and important for physicians to better understand how to assess the complexity
of conditions present in patients with diabetes in order to establish safe treatment
targets.
EPIDEMIOLOGY
Diabetes affects more than 23 million people in the U.S. (www.diabetes.org) and an
estimated 250 million worldwide (www.who.int/diabetes). Diabetic neuropathies, including
CAN, are a common chronic complication of type 1 and type 2 diabetes and confer high
morbidity and mortality to diabetic patients. The reported prevalence of CAN varies
greatly depending on the criteria used to identify CAN and the population studied.
CAN prevalence ranges from as low as 2.5% of the primary prevention cohort in the
Diabetes Control and Complications Trial (DCCT) (1) to as high as 90% of patients
with long-standing type 1 diabetes who were potential candidates for a pancreas transplantation
(2). In a large cohort of patients with type 1 and type 2 diabetes, Ziegler et al.
(3), using predefined heart rate variability (HRV) tests and spectral analysis of
the R-R intervals, found that 25.3% of patients with type 1 diabetes and 34.3% of
patients with type 2 diabetes had abnormal findings. Age, sex, and other risk factors
may also influence CAN development.
PATHOGENESIS
In diabetes, CAN is ultimately the result of complex interactions among degree of
glycemic control, disease duration, age-related neuronal attrition, and systolic and
diastolic blood pressure (4,5). Hyperglycemia plays the key role in the activation
of various biochemical pathways related to the metabolic and/or redox state of the
cell, which, in concert with impaired nerve perfusion, contribute to the development
and progression of diabetic neuropathies. Experimental data implicate a number of
pathogenic pathways that may impact autonomic neuronal function in diabetes including:
formation of advanced glycation end products, increased oxidative/nitrosative stress
with increased free radical production, activation of the polyol and protein kinase
C pathways, activation of polyADP ribosylation, and activation of genes involved in
neuronal damage (6
–8). A detailed review of these mechanisms and their complex interactions has been
covered broadly (6
–8) and is beyond the scope of this article.
CAN AND CARDIAC DYSFUNCTION
Autonomic innervation is the primary extrinsic control mechanism regulating HRV and
cardiac performance. It has been shown that chronic hyperglycemia promotes progressive
autonomic neural dysfunction in a manner that parallels the development of peripheral
neuropathy, e.g., beginning distally and progressing proximally. The vagus nerve,
the longest autonomic nerve, mediates ∼75% of all parasympathetic activity. Because
neuropathy is seen first in the longest fibers, the earliest manifestations of autonomic
neuropathy in diabetes tend to be associated with parasympathetic denervation. As
such, the initial development of CAN in diabetes is characterized by early augmentation
of sympathetic tone (9). Our data (10) and those of others (11) confirm that early
in the progression of CAN complicating type 1 diabetes, there is a compensatory increase
in the cardiac sympathetic tone in response to subclinical peripheral denervation.
Sympathetic denervation follows later beginning at the apex of the ventricles and
progressing toward the base (Fig. 1).
Figure 1
The autonomic innervation of the heart and the effects of diabetes. It has been shown
that in diabetes, in a fashion that parallels the development of peripheral neuropathy,
which begins at the tip of the toes and can progress proximally, neuropathy affecting
the heart begins at the apex of the ventricles and progresses toward the base.
The initial augmentation in cardiac sympathetic activity with subsequent abnormal
norepinephrine signaling and metabolism, increased mitochondrial oxidative stress
(12), and calcium-dependent apoptosis (13) may contribute to myocardial injury (12,14)
and may explain the high risk of cardiac events and sudden death in these patients.
The sympathetic imbalance associated with CAN may critically influence myocardial
substrate utilization (15) and contribute to mitochondrial uncoupling (16), regional
ventricular motion abnormalities, functional deficits, and cardiomyopathy (10).
CLINICAL SIGNS
Clinical symptoms of autonomic dysfunction may not appear until long after diabetes
onset. However, subclinical CAN, manifested as changes in HRV, may be detected within
1 year of diagnosis in type 2 diabetes and within 2 years of diagnosis in type 1 diabetes
(17).
Impaired HRV
The earliest clinical indicator of CAN is a decrease in HRV. Variability in the instantaneous
beat-to-beat heart rate intervals is a function of sympathetic and parasympathetic
activity that regulates the cardiac functional response to the body's level of metabolic
activity. In normal individuals the heart rate has a high degree of beat-to-beat variability
and HRV fluctuates with respiration—increasing with inspiration and decreasing with
expiration. Initially, clinical relevance of HRV was identified through observations
that fetal distress is preceded by alterations in beat-to-beat intervals before any
appreciable change occurs in heart rate itself. The serious implications of abnormal
HRV became apparent only in the late 1980s, when it was confirmed that HRV was a strong,
independent predictor of mortality after acute myocardial infarction (18).
Resting tachycardia
Resting heart rates of ∼100 bpm with occasional increments up to 130 bpm usually occur
later in the course of the disease and reflect a relative increase in the sympathetic
tone associated with vagal impairment. However, increased resting heart rate may reflect
other conditions such as anemia or thyroid dysfunction and is not considered to provide
a reliable diagnostic criterion of CAN in the absence of other signs. A fixed heart
rate that is unresponsive to moderate exercise, stress, or sleep indicates almost
complete cardiac denervation (19) and is indicative of severe CAN.
Exercise intolerance
Autonomic dysfunction may impair exercise tolerance and has been shown to reduce heart
rate, blood pressure, and cardiac output responses to exercise (19). It is generally
recommended that diabetic patients suspected to have CAN be tested with a cardiac
stress test before undertaking an exercise program. Patients with CAN need to rely
on their perceived exertion, not heart rate, to avoid hazardous levels of exercise
intensity (19).
Abnormal blood pressure regulation
At night, nondiabetic subjects exhibit a predominance of vagal tone and decreased
sympathetic tone, associated with reduction in nocturnal blood pressure (20). In diabetic
CAN this pattern is altered, resulting in sympathetic predominance during sleep and
subsequent nocturnal hypertension (21). These are associated with a higher frequency
of left ventricular (LV) hypertrophy and both fatal and severe nonfatal cardiovascular
events in diabetic CAN subjects (22,23).
Orthostatic hypotension
In diabetes, orthostatic hypotension occurs largely as a consequence of efferent sympathetic
vasomotor denervation, causing reduced vasoconstriction of the splanchnic and other
peripheral vascular beds (24). Symptoms associated with orthostatic hypotension include:
lightheadness, weakness, faintness, dizziness, visual impairment, and, in most severe
cases, syncope on standing. These symptoms can be aggravated by a number of drugs
including: vasodilators, diuretics, phenothiazines, insulin (through endothelium-dependent
vasodilatation), and tricyclic antidepressants, a class of drugs commonly used for
symptomatic relief of pain associated with painful diabetic neuropathy (19). As illustrated
in the case presentation, orthostatic hypotension is associated with poor quality
of life.
CLINICAL EVALUATION AND DIAGNOSIS CRITERIA
There is no widely accepted single approach to the diagnosis of CAN in diabetes. Assessment
of HRV, orthostatic hypotension, and 24-h blood pressure profiles provides indexes
of both parasympathetic and sympathetic autonomic function and can be used in clinical
settings. Other methods such as cardiac sympathetic imaging, microneurography, occlusion
plethysmography, and baroreflex sensitivity are currently used predominantly in research
settings but may find a place in the clinical assessment of CAN in the future.
HRV
HRV provides a noninvasive and objective method for assessing cardiovagal function
and may be derived from electrocardiogram recordings under paced breathing. Incorporating
respiratory signal analysis enables one to independently measure both sympathetic
and parasympathetic branches of the autonomic nervous system.
During the 1970s, Ewing et al. (25) devised a number of simple bedside tests of short-term
R-R differences to detect CAN in diabetic patients, including: changes in R-R with
deep breathing, which measures sinus arrhythmia during quiet respiration and primarily
reflects parasympathetic function (26); R-R response to standing, which induces reflex
tachycardia followed by bradycardia and is jointly vagal and baroreflex mediated;
and Valsalva ratio, which evaluates cardiovagal function in response to a standardized
increase in intrathoracic pressure (Valsalva maneuver), primarily parasympathetic
mediated (26). These validated tests, described in detail in a statement by the American
Diabetes Association (27), are recommended for CAN diagnosis (7,26
–28) and can be performed in the practitioner's office. The rapid postural changes
that are part of head-up-tilt-table testing, with/without pharmacological provocation,
can be used for the investigation of CAN or of predisposition to neurally mediated
(vasovagal) syncope due to the wide range of changes in the autonomic input to the
heart and in the R-R intervals. This test requires specialized personnel and is not
readily available in general practice.
HRV with deep breathing is the most widely used test of cardiovagal function and has
about ∼80% specificity (29).
The R-R variation can be analyzed in a number of different ways, including heart rate
range, heart period range, standard deviation (SD), E-to-I ratio (ratio of the shortest
R-R during inspiration to the longest R-R during expiration). Calculation of mean
circular resultant computed by vector analysis eliminates the effects of trends in
heart rate over time, attenuating the effect of basal heart rate and ectopic beats
(30). The Valsalva and postural tests are analyzed as the quotient of the largest
and shortest R-R intervals recorded during each respective maneuver.
Normative cutpoints had been recommended originally for interpretation of the various
HRV indexes (25). Recent studies demonstrate that HRV is affected mainly by age, rate
of breathing, and possibly sex (26,30). Therefore, adjustments for these variables
are recommended for higher accuracy (19,26,30).
Cardiovagal function can also be evaluated using statistical indexes in the time and
frequency domains. Time domain measures of the normal R-R intervals include mean normal-to-normal
(NN) interval, mean heart rate, the difference between the longest and shortest NN
interval, and the variation during the difference between night and day heart rate
(18). Twenty-four–hour R-R recordings allow calculation of more complex statistical
time domain measures, such as SD of all normal R-R intervals (SDNN), SD of 5-min average
of normal R-R intervals (SDANN), root–mean square of the difference of successive
R-R intervals (rMSSD), and the number of instances per hour in which two consecutive
R-R intervals differ by >50 ms over 24 h (pNN50). SDNN is thought to represent joint
sympathetic and parasympathetic modulation of HRV, and rMSSD and pNN50 are specific
for the parasympathetic limb (18). The accuracy of these measures can be affected
by various arrhythmias and require normal sinus rhythm and atrioventricular-nodal
function.
Spectral analysis of HRV is another tool to evaluate CAN (19). It decomposes the R-R
signal into a set of sine and cosine waves and estimates the magnitude of variability
as a function of frequency. The main frequency components described are very-low-frequency
components (<0.04 Hz) related to fluctuations in vasomotor tone associated with thermoregulation,
the low-frequency component (0.04–0.15 Hz) associated with the baroreceptor reflex,
and the high-frequency components (0.15–0.4 Hz) related to respiratory activity (19).
It is generally thought that the sympathetic system modulates the lower-frequency
HRV components, whereas the parasympathetic system controls the high-frequency HRV
components. Different mathematical methods have been used to analyze HRV. Fourier
transform is the most commonly chosen due to algorithm simplicity and high processing
speed (18). This method, limited to stationary signals, is based on the assumption
of steady-state conditions discarding any dynamics in the power spectrum and does
not allow a precise detection of a sudden change in autonomous tone or a precise localization
of a particular event in time when examining nonstationary conditions (31). The continuous
wavelet transform equations perform a time-frequency decomposition of the signal yielding
a time-dependent version of the typical low- and high-frequency peaks (31,32). Commercially
available software programs using these methods are available for assessment of HRV
(ANSAR, Philadelphia, PA, and Hokanson, Bellevue, WA).
Orthostatic hypotension
Orthostatic hypotension is documented by a fall >30 mmHg in systolic or >10 mmHg in
diastolic blood pressure in response to a postural change from supine to standing
(19). There are some controversial aspects related to the cut-off value for the diagnostic
fall in systolic blood pressure, i.e., 30 mmHg (7) or 20 mmHg (24,33), despite the
definition provided by an ad hoc consensus committee in 1996 (24). Recent evidence
suggests that postural hypotension has only moderate concordance with HRV in the diagnosis
of CAN (33).
Imaging techniques for CAN
Quantitative scintigraphic assessment of sympathetic innervation of the human heart
is possible with positron emission tomography (PET) and either [123I]meta-iodobenzylguanidine
(MIBG) or [11C]-meta-hydroxy-ephedrine ([11C]HED) (19,34). Deficits of LV [123I]MIBG
and [11C]HED retention have been identified in type 1 and type 2 diabetic subjects
(35
–37) with (35
–37) and without (10) abnormal cardiovascular reflex testing. Metabolically stable
[11C]HED undergoes highly specific uptake into sympathetic nerve varicosities via
norepinephrine transporters, and quantitative [11C]HED retention may be assessed in
480 independent LV regions (34). The striking consistency of the evolution of the
pattern of denervation in type 1 diabetes supports the reliability of [11C]HED to
monitor changes in cardiac sympathetic nerve populations and evaluate early anatomical
regional deficits of sympathetic denervation (10,34,35). As an example, Fig. 2 shows
the polar map analysis of LV [11C]HED retention in subjects with type 1 diabetes expressed
as Z score analysis versus control subjects (10).
Figure 2
Polar maps of [11C]HED retention in normal control subjects (left) and type 1 diabetic
patients with CAN (right). The color table is set to a maximum [11C]HED retention
index value of 0.09 ml blood · min−1 · ml−1 tissue. To quantify the “extent” of cardiac
sympathetic denervation, patients' retention index data are statistically compared
with our normal population database using Z score analysis.
Quantitative regional measurements of myocardial β-adrenoreceptor density can also
be assessed using PET and the high-affinity β-adrenoreceptor radioligand [11C]CGP-12177
(38). However, postsynaptic β-adrenoreceptor density was never assessed in human diabetes.
Baroreflex sensitivity
Baroreflex sensitivity (BRS) is a technique that evaluates the capability to reflexively
increase vagal activity and decrease sympathetic activity in response to a sudden
increase in blood pressure. It is used in research protocols to assess cardiac vagal
and sympathetic baroreflex function and is calculated from the measurement of the
heart rate–blood pressure relation after an intravenous bolus of phenylephrine (39).
The BRS was a significant independent risk predictor of cardiac mortality in the Autonomic
Tone and Reflexes After Myocardial Infarction (ATRAMI) study, a large international
multicenter prospective study of 1,284 patients with a recent myocardial infarction
(39). It has been shown that the analysis of spontaneous baroreflex sequences gives
results equivalent to the pharmacological methods, which lead to development of techniques
based on servoplethysmomanometry that measures blood pressure in the finger on a beat-to-beat
basis (Finapress) (19).
Microneurography
This technique is based on recording electrical activity emitted by peroneal, tibial,
or radial muscle sympathetic nerves and identification of sympathetic bursts. Bursts
have a characteristic shape consisting of a gradual rise and fall that is usually
constrained by the cardiac cycle and at least twice the amplitude of random fluctuations
(40). Recently available fully automated sympathetic neurogram techniques provide
a rapid and objective method that is minimally affected by signal quality and preserves
beat-by-beat sympathetic neurograms (40).
Assessment of symptoms
Symptoms associated with CAN include exercise intolerance, orthostatic intolerance,
and syncope (41). The correlation between symptom scores and deficits is generally
weak in mild CAN, as these symptoms usually occur late in the disease process. Low
et al. (41), using a validated self-report measure of autonomic symptoms in a population-based
study, found that autonomic symptoms were present more commonly in type 1 than in
type 2 diabetes. At least one autonomic symptom was reported in 83% of a large cohort
of patients with type 2 diabetes (42). The risk of CAN as measured by HRV was positively
associated with the number of reported autonomic symptoms (42).
CLINICAL IMPLICATIONS
Mortality risk
CAN is associated with a high risk of cardiac arrhythmias and with sudden death. Longitudinal
studies of subjects with CAN have shown 5-year mortality rates 16–50% in type 1 and
type 2 diabetes, with a high proportion attributed to sudden cardiac death (25,42,43).
In the EURODIAB Prospective Cohort Study of 2,787 type 1 diabetic patients, CAN was
the strongest predictor for mortality during a 7-year follow-up, exceeding the effect
of traditional cardiovascular risk factors (44). The Hoorn study reported that the
presence of diabetic CAN doubled the 9-year mortality risk in an elderly cohort (45).
A meta-analysis of 15 studies including 2,900 subjects with diabetes reported a pooled
relative risk of mortality of 3.45 (95% CI 2.66–4.47) in patients with CAN, with a
progressive increase in the risk with the increase in the number of abnormal CAN function
tests (46). The higher predictive value of an increased number of CAN abnormalities
was confirmed more recently in two other cohorts of type 1 and type 2 diabetes showing
that a combined abnormality in HRV and QT index was a strong predictor of mortality
independent of conventional risk factors (47,48).
The increased mortality risk associated with CAN has important implications for diabetes
management. A feared consequence of rigorous glycemic control is an increased incidence
of hypoglycemia (49,50). Hypoglycemia impairs hormonal and autonomic responses to
subsequent hypoglycemia (51). Hypoglycemia unawareness may promote a reduced threshold
for malignant arrhythmias and subsequent sudden cardiac death, which was a possible
reason for the sudden death experienced by the patient discussed in vignette. Thus,
a recent study reported that exposure to hypoglycemia leads to impaired CAN function
in healthy volunteers (52).
Silent myocardial ischemia and diabetic cardiomyopathy
In a meta-analysis of 12 published studies, Vinik et al. (7) reported a consistent
association between CAN and the presence of silent myocardial ischemia, measured by
exercise stress testing, with point estimates for the prevalence rate ratios from
0.85 to 15.53. In the Detection of Ischemia in Asymptomatic Diabetics (DIAD) study
of 1,123 patients with type 2 diabetes, CAN was a strong predictor of silent ischemia
and subsequent cardiovascular events (53). The association between CAN and silent
ischemia has important implications, as reduced appreciation for ischemic pain impairs
timely recognition of myocardial ischemia or infarction, thereby delaying appropriate
therapy. In patients with diabetes, presence of symptoms such acute onset dyspnea
with/without coughing, severe fatigue, and/or acute onset of nausea and vomiting should
raise a high index of suspicion for an ischemic event and prompt the appropriate measures
(19).
The presence of CAN was also linked to the development of diabetic cardiomyopathy
in type 1 diabetes because in these patients LV dysfunction often precedes or occurs
in the absence of significant coronary artery disease or hypertension. We have identified
diastolic dysfunction early in the course of type 1 diabetes that correlated with
abnormal cardiac sympathetic imaging (10). Further studies are needed to clarify the
complex interactions between CAN, silent myocardial ischemia, and cardiomyopathy in
diabetes.
Intraoperative and perioperative cardiovascular instability
Observations in diabetic patients undergoing general anesthesia reported that individuals
with CAN required vasopressor support more often than those without CAN (19). Individuals
with CAN may experience a greater decline in heart rate and blood pressure during
induction of anesthesia and more severe intraoperative hypothermia resulting in decreased
drug metabolism and impaired wound healing (19).
Stroke
A recent study in 1,458 patients with type 2 diabetes reported that presence of CAN,
assessed by standard HRV testing, was one of the strongest predictors of ischemic
stroke in this cohort together with age and hypertension (54). Earlier reports showed
similar associations (19).
THERAPEUTIC APPROACHES
Glycemic control
The DCCT demonstrated that intensive insulin therapy for type 1 diabetes reduced the
incidence of CAN by 53% compared with conventional therapy (1). The Epidemiology of
Diabetes Interventions and Complications (EDIC) study, the prospective observational
study of the DCCT cohort, has shown persistent beneficial effects of past glucose
control on microvascular complications despite the loss of glycemic separation (55).
Recently we evaluated CAN in 1,226 well-characterized EDIC participants during the
13th and 14th year of EDIC follow-up. We found that during EDIC CAN progressed substantially
in both treatment groups, but the prevalence and incidence of CAN remained significantly
lower in the former intensive group than in the former conventional group, despite
similar levels of glycemic control in the EDIC study (56). Treatment group differences
in the mean A1C level during the DCCT and the EDIC study explained virtually all of
the beneficial effects of intensive versus conventional therapy on risk of incident
CAN, supporting the concept that intensive treatment of type 1 diabetes should be
initiated as early as is safely possible (56).
In type 2 diabetes, the effects of glycemic control are less conclusive. The VA Cooperative
Study demonstrated no difference in the prevalence of autonomic neuropathy in type
2 diabetic patients after 2 years of tight glycemic control compared with those without
tight control (57). On the other hand, the Steno-2 Trial reported that a targeted,
intensive intervention involving glucose control and multiple cardiovascular risk
factors reduced the prevalence of CAN among patients with type 2 diabetes and microalbuminuria
(58).
Other therapies
Data regarding the impact of lifestyle interventions in preventing progression of
CAN are emerging. Strictly supervised endurance training combined with dietary changes
was associated with weight loss and improved HRV in patients with minimal abnormalities
(19). In the Diabetes Prevention Program, indexes of CAN improved most in the lifestyle
modification arm compared with the metformin or placebo arm.
ACE inhibitors, angiotensin receptor blockers, or aldose reductase inhibitors appear
promising but are yet to be validated (19).
Orthostatic hypotension
The treatment of orthostatic hypotension is challenging. Nonpharmacological treatments
include avoidance of sudden changes in body posture to the head-up position; avoiding
medications that aggravate hypotension, such as tricyclic antidepressants and phenothiazines;
eating small, frequent meals to avoid postprandial hypotension; and avoiding activities
that involve straining, since increased intra-abdominal and intra-thoracic pressure
decrease venous return (19). Several physical counter maneuvers, such as leg crossing,
squatting, and muscle pumping can help maintain blood pressure during daily activities
by inducing increased cardiac filling pressures and stroke volume.
PHARMACOLOGICAL TREATMENTS
Midodrine
Midodrine, a peripheral-selective α1-adrenoreceptor agonist is the only Food and Drug
Administration–approved agent for the treatment of orthostatic hypotension in doses
of 2.5–10 mg three times/day. Several double-blind, placebo-controlled studies have
documented its efficacy in the treatment of orthostatic hypotension (7). It does not
cross the blood-brain barrier, resulting in fewer central side effects. The main adverse
effects are piloerection, pruritis, paresthesias, urinary retention, and supine hypertension.
Fludrocortisone acetate
Fludrocortisone acetate, a synthetic mineralocorticoid with a long duration of action,
induces plasma expansion and may enhance the sensitivity of blood vessels to circulating
catecholamines (59). The effects usually occur over a 1- to 2-week period. Supine
hypertension, hypokalemia, and hypomagnesemia may occur. Caution must be used, particularly
in patients with congestive heart failure, to avoid fluid overload. Treatment with
fludrocortisone should begin with 0.05 mg at bedtime and may be titrated gradually
to a maximum of 0.2 mg/day. Doses up to 0.3–0.4 mg used in refractory cases are associated
with high risk for hypokalemia, excessive fluid retention, hypertension, and congestive
heart failure.
Erythropoietin
Erythropoietin may improve orthostatic hypotension, but the mechanism of action for
this pressor effect is still unresolved. Possibilities include the increase in red
cell mass and central blood volume, correction of the normochromic normocytic anemia
that frequently accompanies severe CAN, and direct or indirect neurohumoral effects
on the vascular wall and vascular tone regulation mediated by the interaction between
hemoglobin and the vasodilator nitric oxide (59). Erythropoietin is administered subcutaneously
or intravenously at doses of 25–75 units/kg three times a week until the hematocrit
level approaches normal followed by lower maintenance doses (∼25 units/kg three times/week)
(59).
Nonselective β-blockers
Nonselective β-blockers, particularly those with intrinsic sympathomimetic activity,
may have a limited role in the treatment of orthostatic hypotension (59). The suggested
mechanism of action of these agents is the blockade of vasodilating β-2 receptors
allowing unopposed α-adrenoreceptor–mediated vasoconstriction. To date there is no
clear efficacy evidence in diabetic CAN.
Clonidine
Clonidine, an α-2 antagonist, produces a central sympatholytic effect and a consequent
decrease in blood pressure. Patients with severe CAN have little central sympathetic
efferent activity, and the use of clonidine (0.1–0.6 mg/day) could result in an increase
in venous return without a significant increase in peripheral vascular resistance.
Its use is limited by the inconsistent hypertensive effect and serious side effects.
Somatostatin analogs
Somatostatin analogs (25–200 μg/day) may attenuate orthostatic hypotension in patients
with CAN by inhibiting the release of vasoactive gastrointestinal peptides, enhancing
cardiac output, and increasing forearm and splanchnic vascular resistance. However,
severe cases of hypertension were reported with their use in patients with diabetic
CAN (60).
Pyridostigmine bromide
Pyridostigmine bromide, a cholinesterase inhibitor, was recently shown to ameliorate
orthostatic hypotension by enhancing ganglionic transmission without worsening supine
hypertension (61).
CONCLUSIONS
CAN is a serious chronic complication of diabetes and an independent predictor of
cardiovascular disease mortality. As illustrated by the case vignette and by the evidence
presented in this review, CAN is associated with a poor prognosis and poor quality
of life. Conclusive clinical evidence from randomized prospective trials supports
a central role for hyperglycemia in the pathogenesis of CAN, although other metabolic
and vascular factors contribute to the disease state. The clinical presentation of
CAN comprises a broad constellation of symptoms and deficits. Assessment of HRV is
an easily available tool to document the presence of CAN. Cardiac scintigraphic imaging
with sympathetic analogs offers more sensitive diagnostic alternatives for research
use. The treatment of CAN is challenging. Recent clinical evidence continues to prove
the benefits of glycemic control, while the benefits of lifestyle interventions are
emerging.