Assessment of Cardiovascular Effects in Diabetic Autonomic Neuropathy and
Prognostic Implications
D. J. EWING, M.D.; I. W. CAMPBELL, M.B.; and B. F. CLARKE, M.B.; Edinburgh, Scotland
Cardiovascular effects of diabetic autonomic neuropathy
include postural hypotension, resting tachycardia, and,
possibly, painless myocardial infarction. Involvement of
cardiovascular reflexes in diabetes can be assessed using
simple noninvasive tests: the Valsalva maneuver, beat-to-
beat heart rate variation, the heart rate response to
standing, postural fall in blood pressure, and the
sustained handgrip test. Tests of parasympathetic
function appear to be abnormal more frequently and
earlier in cardiac autonomic involvement, whereas
sympathetic damage usually occurs later and is
associated with clinical symptoms. When test results are
abnormal, in association with symptoms suggestive of
autonomic neuropathy, the prognosis is grave. Some
sudden deaths that occur may be due to abnormal
autonomic reflexes.
A L T H O U G H D A M A G E to autonomic nerves involves al-
most all parts of the body, the effect is most obvious
clinically in the cardiovascular system. T h e cardiovascu-
lar reflex abnormalities associated with diabetes (diabetic
autonomic neuropathy), but not cardiac structural abnor-
malities (diabetic "cardiomyopathy"), will be discussed
below.
Clinical Manifestations
Three cardiovascular abnormalities have usually been
associated with autonomic neuropathy: postural hypoten-
sion, resting tachycardia, and "painless" or "silent" myo-
cardial infarction (1).
POSTURAL HYPOTENSION
Dizziness, faintness, blackouts, or visual impairment
on standing are clinical presentations of postural hypo-
tension, and the most prominent cardiovascular manifes-
tation of autonomic neuropathy. These symptoms may
sometimes be mistakenly thought to represent hypogly-
caemia, but in association with a postural fall in blood
pressure there is usually no doubt about their cause. In
1945 Rundles (2) first linked postural hypotension with
autonomic neuropathy in diabetes, and subsequently
there have been numerous clinical descriptions (1). T h e
blood pressure fall may be worsened by a variety of
drugs, including hypotensive agents, diuretics, tricyclic
antidepressants, phenothiazines, vasodilators, and glyce-
ryl trinitrate (1). Insulin may aggravate postural hypo-
tension, possibly due to decreased venous return or al-
tered capillary endothelial permeability with reduction in
plasma volume, whereas development of congestive car-
diac failure or the nephrotic syndrome ameliorates the
hypotension (1). In our own series of 73 patients (63
males, 11 females), initial clinical features of autonomic
• From the University Department of Medicine and the Diabetic and Dietetic
Department, The Royal Infirmary; Edinburgh, Scotland.
308 Annals of Internal Medicine. 1980;92(Part 2):308-311.
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neuropathy included symptoms of postural hypotension
in 25 patients, of whom 23 had systolic blood pressure
falls of 30 mm Hg or more on standing. Ten subjects had
similar blood pressure falls but were asymptomatic (3).
Those subjects with postural hypotension almost invari-
ably had other abnormalities of cardiovascular reflexes
(see below), and it was the commonest clinical feature,
apart from impotence, in our autonomic neuropathy co-
hort.
The main lesion in postural hypotension is probably in
the efferent limb of the baroreflex arc with damaged sym-
pathetic vasoconstrictor fibres in the splanchnic bed,
muscle, and skin (1). The hypotension may be augmented
by a diminished plasma-renin response to standing, itself
due to impaired sympathetic innervation of the juxta-
glomerular apparatus. Decreased basal and standing plas-
ma noradrenaline may also contribute. Occasionally, ele-
vated noradrenaline on standing has been found in dia-
betics with postural hypotension ("hyperadrenergic" pos-
tural hypotension), but the mechanism for this is not
clear (4).
RESTING T A C H Y C A R D I A
Increased heart rates of 90 to 100 beats per minute
have been seen in diabetic patients with autonomic neu-
ropathy, and sometimes more rapid rates of up to 130
beats per minute occur (1, 5). T h e heart rate pattern of
normal subjects after autonomic blockade may provide
an explanation for this observation. In nine normal sub-
jects (27 to 36 years of age) the mean resting heart rate
was 68 beats per minute, which increased to 104 beats per
minute with atropine alone and then decreased to 95
beats per minute when additional propranolol was given.
Other workers have found similar changes (6). In diabet-
ic patients rapid heart rates due to parasympathetic dam-
age may represent the initial early stage of cardiac auto-
nomic involvement. Later, heart rates similar to that seen
after combined blockade with atropine and propranolol
may occur with additional cardiac sympathetic damage.
PAINLESS OR " S I L E N T " M Y O C A R D I A L INFARCTION
The increased prevalence of myocardial infarction in
diabetic patients has been attributed to autonomic neuro-
pathy (1), and damage to autonomic nerve fibres from the
myocardium in patients dying from painless myocardial
infarction has recently been reported (7). Patients with
florid autonomic neuropathy may, nevertheless, develop
typical cardiac pain during myocardial infarction (8), and
although painless myocardial infarction has been consid-
ered the cause of sudden death in diabetic patients, recent
evidence suggests that abnormal autonomic reflexes may
© 1980 American College of Physicians
 account for some of these deaths (1).
Assessment of Cardiovascular Reflex Involvement in
Diabetes
Before the 1970s most tests to examine the autonomic
nervous system were complex, invasive, and often un-
pleasant. With the realisation that simple tests of cardio-
vascular reflex function could be performed safely, nonin-
vasively, and simply, it has been possible to examine the
cardiovascular aspects of autonomic neuropathy in dia-
betic patients more systematically. Currently there are
five simple tests to assess autonomic neuropathy, based
on cardiovascular reflexes: The first three (the Valsalva
maneuver, beat-to-beat heart rate variation, and the ly-
ing-to-standing heart rate response) assess cardiac para-
sympathetic function; the other two (measurement of
postural hypotension and the response to sustained hand-
grip) only show abnormal results when more widespread
peripheral sympathetic damage is present (5).
VALSALVA MANEUVER
The reflex response to the Valsalva maneuver includes
tachycardia and peripheral vasoconstriction during
strain, followed, after release, by an overshoot rise in
blood pressure and bradycardia. Intra-arterial blood
pressure changes had previously been the standard meth-
od for assessing the Valsalva maneuver, but they must be
measured with invasive procedures. Heart rate changes,
however, give a reliable guide to the associated haemody-
namic events (5) and can be used to measure the re-
sponse. Our technique involves the subject's blowing into
a mouthpiece connected to a manometer held at 40 mm
Hg pressure for 15 s while a continuous ECG is recorded.
The "Valsalva ratio" is then calculated from the ratio of
the longest R-R interval after the maneuver (reflecting
the overshoot bradycardia) to the shortest R-R interval
during the maneuver (reflecting the bradycardia during
strain). A Valsalva ratio of 1.21 or greater is normal, 1.11
to 1.20 is borderline, and 1.10 or less abnormal (9). The
Valsalva maneuver has the advantage of being simple,
easy to perform, noninvasive, and reproducible. It is ef-
fort-dependent and cheating is possible, but, provided
these minor limitations are appreciated, it is a useful test.
Although the bradycardia after strain related to the rest-
ing heart rate has been proposed as a better index (10),
we found that in a group of 59 diabetic patients with
various degrees of autonomic impairment that there was
a very close correlation between the bradycardia and the
Valsalva ratio (r = 0.94), thus indicating that either in-
dex is equally acceptable.
BEAT-TO-BEAT ( R - R INTERVAL) HEART RATE
VARIATION
The beat-to-beat variation is dependent on parasym-
pathetic innervation and is most marked with slow heart
rates or during deep breathing. It is diminished by faster
heart rates, in older subjects, in the presence of cardiac
failure, and after development of intracranial lesions (5).
There are several techniques currently available to mea-
sure beat-to-beat variation.
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During Deep Breathing (11, 12): The subject lies quiet-
ly and breathes deeply at 6 breaths per minute, a rate that
produces maximum variation in heart rate, and an in-
stantaneous heart rate monitor records the difference be-
tween the maximum and minimum heart rates. Fifteen
beats per minute difference or more is normal and 10
beats per minute or less, abnormal (12; see also preceding
paper by Watkins and associates [13]). Two recent elec-
trocardiographic modifications of this technique have
been described. The first measures the "EI ratio"—the
mean of the longest R-R interval during expiration to the
mean of the shortest R-R interval during inspiration (14).
The second modification has been to measure successive
maximum and minimum heart rates from an ECG dur-
ing a period of deep breathing and record the difference
(15).
During Standing, with Measurement of the Standard
Deviation (16): While the subject stands and breathes
quietly for 5 min the ECG is recorded onto magnetic tape
to be analysed later. The standard deviation of the mean
R-R interval over the recorded period is used as a mea-
sure of beat-to-beat heart rate variation. Although this
particular method has been criticised as being insensitive
(10, 17), atropine abolished the R-R interval variation in
normal subjects (5).
During Lying, with Measurement of "Mean Square
Successive Difference" (17): One-hundred fifty consecu-
tive beats are recorded. Each successive R-R interval is
measured and the mean of the squares of the differences
between successive intervals, the "mean square successive
difference," used as a measurement of beat-to-beat varia-
tion.
After a Single Deep Breath: The instantaneous heart
rate response to a single maximum expiration has recent-
ly been described (10), but there have been no detailed
studies to confirm its usefulness as a test.
Comparison of Tests: Beat-to-beat heart rate variation
has been proposed as the most useful diagnostic test of
autonomic neuropathy. This should be viewed with some
caution, however, as our results show that measurements
are not always reproducible in normal subjects (5). We
have recently compared the different techniques, and pre-
liminary results suggest that no one method of analysing
R-R interval variation has any particular advantages.
When beat-to-beat variation in heart rate is abnormal
there is usually no doubt about its significance, but diffi-
culties can arise in the interpretation of borderline abnor-
malities. In this situation a battery of different autonomic
function tests is preferable to relying on one individual
test.
H E A R T R A T E RESPONSE TO S T A N D I N G
Change from horizontal to vertical produces an inte-
grated cardiovascular response, including alterations in
heart rate. There is a characteristic and rapid increase in
heart rate maximal at about the 15th beat after standing,
with a subsequent relative bradycardia maximal at about
the 30th beat. Diabetics with autonomic neuropathy
show only a gradual increase in heart rate (18). Pharma-
cologic studies indicate that this response is mediated by
Ewingetal. • Cardiovascular Effects and Prognosis 309

Figure 1 . Five-year survival curves for age- and sex-matched gener-
al population (o), age- and sex-matched diabetic population (A), 3 3
diabetic patients with normal (°) and 4 0 diabetic patients with ab-
normal (•) autonomic function tests. (Reproduced with permission
from Quarterly Journal of Medicine [ 3 ] ) .
the vagus nerve (18). This reflex response can be simply
quantified with a continuous E C G recording and mea-
surement of the R-R intervals at beats 15 and 30 after
standing, to give the 30/15 ratio. In normal subjects val-
ues are greater than 1.03, whereas in diabetics with auto-
nomic neuropathy values are 1.00 or less (18). The test is
objective, reproducible in normal subjects, and not de-
pendent on age or the resting heart rate. It correlates well
with the Valsalva ratio and beat-to-beat variation in heart
rate (1).
BLOOD PRESSURE RESPONSE TO S T A N D I N G
On standing there is an immediate pooling of blood in
the legs, with a fall in blood pressure. Provided there is
normal baroreflex function, this is rapidly corrected by
peripheral vasoconstriction and tachycardia. Postural hy-
potension is easily detected using a cuff sphygmomanom-
eter, and a fall in systolic blood pressure of 30 mm Hg
upon standing is arbitrarily defined as abnormal (1).
BLOOD PRESSURE RESPONSE TO S U S T A I N E D
M U S C U L A R EXERCISE
Sustained (isometric) muscular exercise normally caus-
es a heart-rate-dependent increase in cardiac output, an
increase in systemic blood pressure, and no change in
peripheral vascular resistance (5). A simple test based on
this reflex uses a handgrip dynamometer standardised at
3 0 % of the maximum voluntary contraction, with mea-
surement of the blood pressure during handgrip (19). Pa-
tients with autonomic neuropathy have an abnormally
small diastolic blood pressure rise. A rise in diastolic
blood pressure of 16 mm Hg or more is defined as nor-
mal, 11 to 15 mm Hg as borderline, and 10 mm Hg or
310 February 1980 • Annals of Internal Medicine • Volume 92 • Number 2 (Part 2)
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less as abnormal. The test is simple and reproducible but
has the disadvantage of being effort dependent.
Abnormal Cardiovascular Reflexes in Diabetes
Cardiovascular reflex abnormalities have been shown
to be present in some diabetic patients at diagnosis, dur-
ing ketoacidosis, without symptoms of autonomic neuro-
pathy, and with symptoms of autonomic neuropathy (1,
5). Abnormalities of cardiovascular reflex function are
therefore more widespread than the symptoms of auto-
nomic neuropathy would suggest.
Results of tests of parasympathetic function are more
commonly found to be abnormal than results of tests of
sympathetic function. In a recent assessment of 61 dia-
betic patients with various degrees of autonomic involve-
ment we found that abnormalities of the Valsalva maneu-
ver, beat-to-beat heart rate variation, and the lying-to-
standing heart rate response were present in 34 patients,
whereas abnormalities of postural hypotension and sus-
tained handgrip were present in 16. Earlier work suggest-
ing that parasympathetic damage occurs more commonly
than sympathetic damage (20) is therefore confirmed. We
and others (21) have also been able to follow the progres-
sion of autonomic function tests with time. Once abnor-
mal, results of autonomic function tests usually stay ab-
normal, whereas some results that were originally normal
become abnormal. In our experience with 38 diabetic pa-
tients who have had at least three assessments of their
autonomic function over 3 years or more, 10 subjects
with initially normal results first developed cardiac para-
sympathetic abnormalities and then widespread sympa-
thetic abnormalities. This suggests not only that para-
sympathetic abnormalities are more widespread, but also
that they occur earlier in the natural history of autonom-
ic neuropathy in diabetes.
Consequences of Abnormal Cardiovascular Reflexes
Cardiovascular reflex damage is assumed to reflect au-
tonomic nervous system damage elsewhere. Symptoms of
autonomic neuropathy other than impotence alone are
usually associated with abnormal autonomic test results
(3, 22). In contrast, subjects with impotence alone usually
have normal cardiovascular autonomic function test re-
sults (3, 22).
In our prospective 5-year follow-up of 73 diabetic pa-
tients with possible autonomic neuropathy, 26 died, and
21 of these had abnormal cardiovascular reflexes at first
testing. The calculated percentage mortality rate at 5
years for patients with symptoms suggestive of autonom-
ic neuropathy but with initally normal autonomic func-
tion test results was 2 1 % (Figure 1). This is not signifi-
cantly different from the increased mortality rate of the
general diabetic population (3). However, in patients with
autonomic symptoms and abnormal autonomic function
test results, the calculated mortality rate was markedly
increased to 5 6 % at 5 years. Of the 21 patients who died,
half died of renal failure but the others died of causes that
might have been attributable to autonomic neuropathy,
and six patients died suddenly.
There was a surprising absence of ischaemic heart dis-
 ease in life or coronary artery disease at post-mortem in
our diabetic patients with autonomic neuropathy who
died suddenly (3, 22). In a retrospective analysis of an-
other group of diabetic patients who died suddenly with
apparent myocardial infarction, this diagnosis could only
be definitely substantiated in one third. In one third there
was not sufficient evidence to make a firm diagnosis, but
in the last third there was no evidence to support the
death certificate diagnosis of myocardial infarction (23).
Several of these deaths were associated with hypoxia. The
sudden deaths both in that study and in our diabetic au-
tonomic neuropathy cohort therefore were probably not
due to myocardial infarction, and in one patient in whom
monitoring of the events was possible there was no evi-
dence of cardiac arrhythmia. To investigate this further
we measured the ventilatory responses to transient hypo-
xia in a group of diabetic patients with and without auto-
nomic neuropathy to assess the integrity of the peripheral
chemoreceptor reflex pathways. N o differences were de-
tected between diabetic patients with and those without
autonomic neuropathy, suggesting that the peripheral re-
flex responses to hypoxia were normal in these subjects
(23). Some other abnormal autonomic reflex mechanism
may explain these deaths, possibly similar to that pro-
posed in tetraplegics (24, 25).
Future directions of research must include a re-exami-
nation of sudden deaths and silent myocardial infarction
in diabetics, investigation of the extent of autonomic
damage, what happens to symptomless patients with au-
tonomic abnormalities, and the ultimate prospect of pre-
ventive drug therapy.
Received 22 October 1979; accepted 8 November 1979.
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