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(Circulation. 1997;96:3766-3773.)
© 1997 American Heart Association, Inc.
Articles |
New Look to an Old Symptom: Angina Pectoris
From the Istituto di Cardiologia, Università Cattolica del Sacro Cuore (F.C.), and the Divisione di Cardiochirurgia, Università Tor Vergata (A.G.), Rome, Italy.
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Abstract |
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Abstract At the turn of this century, it was proposed that ischemic cardiac pain might be related to distension of the ventricular wall ("mechanical hypothesis"). Three decades later, it was hypothesized that ischemic pain might be elicited by the intramyocardial release of pain-producing substances induced by ischemia ("chemical hypothesis"). Studies carried out in the past 10 years have given strong support to the chemical hypothesis, because they have consistently shown that adenosine is a mediator of ischemic cardiac pain. Adenosine-induced ischemic cardiac pain is mediated primarily by stimulation of A1 receptors located in cardiac nerve endings and is potentiated by substance P. Conversely, the magnitude and rate of left ventricular dilation during ischemia do not predict the severity of angina. It is worth noting, however, that stretching of epicardial coronary arteries appears to potentiate the severity of angina caused by myocardial ischemia. The nervous activity generated by myocardial ischemia is modulated in intrinsic cardiac, mediastinal, and thoracic ganglia. Then it is further modulated in the central nervous system and projects bilaterally to the cortex, as demonstrated in humans by positron emission tomography, where it is decoded as a painful sensation. The causes responsible for the lack of angina during myocardial ischemia are probably different in patients who present both pain-free and painful myocardial ischemia, in patients with predominantly painless ischemia, and in diabetic patients.
Key Words: adenosine • angina • coronary disease • receptors
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Causes of Ischemic Cardiac Pain |
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At the turn of this century, Colbeck1 proposed that ischemic cardiac pain might be related to distension of the ventricular wall ("mechanical hypothesis"). Three decades later, Lewis2 hypothesized that ischemic pain might be elicited by the intramyocardial release of pain-producing substances induced by ischemia ("chemical hypothesis"). In the past few years, however, only a few clinical investigations have contributed to clarifying the causes of ischemic cardiac pain.
Mechanical Hypothesis
Davies et al3 showed that dilation of the ventricle
is unlikely to be responsible for angina, because the rate and the
magnitude of left ventricular dilation during
ergonovine-induced or spontaneous transient ischemic episodes
were found to be similar during painful and painless episodes. The
negligible importance of mechanical distortion and distension of
ventricular fibers in the genesis of ischemic
cardiac pain is further supported by the observation that
ventricular dilation, as it occurs during acute
ventricular failure, myocardial biopsy, or valvuloplasty,
does not cause any painful sensation.
Mechanical factors, however, may play a role in the activation of sensory receptors localized at the periarterial level.4 5 Indeed, Tomai et al6 recently found that during coronary angioplasty, for a similar degree of myocardial ischemia on the intracoronary ECG, pain severity was similar when two sequential balloon inflations were carried out at the same pressure, whereas it was greater during the second inflation when the latter was carried out at a higher pressure, thus suggesting that the mechanical distension of the coronary arterial wall can cause pain. This mechanism of cardiac pain may explain the localized chest pain frequently experienced by patients after successful stent implantation in the absence of myocardial ischemia.
Chemical Hypothesis: The Central Role of Adenosine
In the mid 1980s, the intravenous administration of
adenosine was introduced for the detection of coronary
artery disease during perfusion scintigraphy or during
two-dimensional echocardiography and for the
treatment of supraventricular reentry
tachycardia. Sylven et al7 observed that
during adenosine infusion, patients without evidence of
coronary artery disease often complained of a short-lasting
chest pain with features similar to those of ischemic cardiac
pain. Because adenosine is rapidly formed during myocardial
ischemia and released into the vascular bed,8 they
hypothesized that adenosine could be a mediator of
ischemic cardiac pain and tested this hypothesis by assessing
the effects of intravenous boluses of increasing doses of
adenosine in healthy volunteers. Adenosine
administration caused dose-dependent chest pain in all subjects;
furthermore, adenosine-induced pain was increased by
dipyridamole, which reduces adenosine cellular
uptake, and reduced by theophylline, which is a nonspecific
adenosine antagonist. Crea et al9
showed subsequently that in patients with chronic stable angina,
intracoronary infusion of adenosine
consistently caused pain with features identical to those
experienced during daily life episodes of transient myocardial
ischemia but without detectable signs of myocardial
ischemia. Infusion of a similar dose of adenosine into
the right atrium failed to elicit pain, thus proving that the pain
elicited by the intracoronary infusion of adenosine
originated from the heart.
Adenosine-induced cardiac pain is not secondary to myocardial ischemia, because it typically occurs in the absence of ischemialike ECG changes and can be elicited by adenosine infused into angiographically normal coronary branches and vascular beds, such as those supplied by the brachial or the femoral arteries, in which steal-induced ischemia cannot occur.9 10 11 12 Of note, the pain caused by adenosine does not appear to be related to the mechanical distension of periarteriolar nerve endings, because the infusion of nifedipine or papaverine, which produce a comparable degree of vasodilation, do not cause pain.13 Furthermore, adenosine causes pain at doses larger than those that provoke maximal vasodilation.9 In patients with exercise-induced angina, the severity of ischemic cardiac pain is significantly reduced by pretreatment with theophylline, a potent nonselective antagonist of adenosine P1 receptors, in the presence of a similar degree of myocardial ischemia, thus suggesting that endogenous adenosine is at least partially responsible for angina.9 Furthermore, theophylline reduces forearm ischemic pain,14 an effect that cannot be mediated by improvement of an adenosine-induced steal phenomenon.15 Taken together, these observations support the hypothesis that adenosine is an adequate stimulus for cardiac sensory receptors and that endogenous adenosine is a mediator, the first hitherto identified in humans, of cardiac and muscular ischemic pain.
Adenosine-induced pain does not appear to be influenced by ß-blockade, atropine, naloxone, nitroglycerin, nifedipine, clonidine, cyclooxygenase inhibitors, or steroids, whereas it is increased by systemic pretreatment with nicotine, probably because of a central modulation of pain perception.16 17 18 19 Recently, Gaspardone et al20 showed that in humans, the intra-arterial and intracoronary infusion of substance P, a polypeptide present in perivascular nerves and involved in the generation of neurogenic inflammation and in the mechanism of hyperalgesia, does not cause muscular or cardiac pain, yet it enhances adenosine-induced pain. This may help explain the extreme severity of cardiac ischemic pain frequently experienced by patients during myocardial infarction, when a large amount of substance P is probably released into the myocardium because of myocardial necrosis.
Receptors Responsible for Adenosine-Induced Pain
The cardiac effects of adenosine are due to the
stimulation of at least two subtypes (A1 and
A2) of surface membrane P1
receptors.21 22 23 The stimulation of A1
receptors, present in cardiomyocytes and perivascular
sympathetic nerves,23 24 causes
electrophysiological effects25
and inhibits the neuronal release of
catecholamines.23 The stimulation of
A2 receptors, present in endothelial
and vascular smooth muscle cells, causes coronary
vasodilation.26 27 28 29 Although adenosine-induced pain
might be mediated by both theophylline-sensitive A1 and
A2 receptors, early studies suggested that the effects of
adenosine on vascular tone and on pain generation are likely to
be mediated by different receptors. Indeed, monitoring of
coronary sinus blood oxygen saturation during
intracoronary infusion of adenosine revealed that the
doses that cause chest pain are higher than those that cause maximal
coronary dilation.9 13
The identification of the receptor subtype involved in the genesis of adenosine-induced pain has recently been tackled with bamiphylline. This analogue of theophylline has been successfully used to treat bronchial asthma and lung anaphylaxis in young children and infants and chronic obstructive pulmonary disease in adults with an efficacy comparable to that of theophylline but with substantially fewer side effects.30 31 32 33 34 In crude synaptic membranes prepared from rat brain, bamiphylline displaces radioligands from A1 adenosine receptors with a potency similar to that of 8-phenyltheophylline, whereas it shows a negligible potency on A2 adenosine receptors. This results in a high degree of A1 receptor selectivity, indicated by an A2/A1 Ki ratio of 596.35 In humans, Pappagallo et al36 reported that bamiphylline reduces the pain induced by intradermal injection of adenosine but not the A2 receptor–mediated adenosine-induced cutaneous hyperemia, thus suggesting that A1 receptors are involved in cutaneous nociception. Accordingly, Gaspardone et al37 recently found that the intravenous infusion of bamiphylline reduces adenosine-induced muscular and cardiac pain, yet it does not affect adenosine-induced coronary vasodilation. Similarly, it has recently been confirmed that N-0861 (N-6-endonorboran-2-yl-9-methyladenine), a selective A1 adenosine antagonist, at a dose that blocks A1-mediated electrophysiological but not A2-mediated vasodilatory adenosine effects, reduces the pain caused by intravenous administration of adenosine.38 Finally, in patients with exercise-induced angina, bamiphylline reduces the severity of angina normalized for the maximal ST-segment depression, thus suggesting that in humans, the effects of endogenous adenosine on pain generation are mediated primarily by A1 receptors.39
Electrophysiological Demonstration of
the Excitatory Effects of Adenosine on Afferent Nerves
The excitatory effects of adenosine on cardiac
afferent nerves first reported by Uchida et al40 have also
been demonstrated in cultured sensory neurons,41 in the
kidney,42 in the carotid sinus,43 44 and in
muscle.45 More recently, Montano et al46
found that the epicardial application of adenosine results in a
consistent activation of cardiac sympathetic afferent nerves
when their activity is recorded in the third thoracic ramus
communicans of the left sympathetic chain. Moreover, Dibner-Dunlap et
al47 showed that the A1 adenosine
agonist N-5-cyclopentyladenosine elicits a
dose-dependent sympathoexcitatory response
similar to that caused by adenosine, whereas the A2
adenosine agonist
5'-(N-cyclopropyl)carboxamidoadenosine fails to
elicit a sympathoexcitatory response, thus
suggesting that adenosine activates cardiac sympathetic
afferent fibers and leads to a
sympathoexcitatory response because of
activation of A1 adenosine receptors. These
observations are consistent with the early demonstration of
A1 receptors on cardiac afferent
neurons.48
Afferent Code for Ischemic Cardiac Pain
Recording of the electrical activity from cardiac afferent
nerves has shed some light on the nature of the receptors involved in
the production of cardiac pain. According to the "intensity
hypothesis,"49 pain is the result of excessive
stimulation of nonspecific sensory receptors, which also function as
chemoreceptors, mechanoreceptors, or polymodal receptors. According to
the "specificity hypothesis," pain is a result of the excitation
of a specific type of receptor that is stimulated only by noxious
stimuli (hence nociceptor).50 It is well known, for
instance, that on the somatic side there are receptors that appear to
be true nociceptors, because they exhibit no background discharge and
discharge only when stimulated by strong mechanical or thermal
stimuli.51 52 Conversely, on the visceral side, several
experimental studies, based on the recording of the electrical
activity from single-myelinated and
nonmyelinated cardiac sympathetic fibers under normal
hemodynamic conditions, have consistently shown
the presence of a background discharge. The background activity
increases during hemodynamic stress and often also
after chemical stimulation.53 54 55 The consistent
failure to identify fibers without background discharge is considered
an argument against the presence of specific visceral nociceptor
fibers.56 In fact, because nociceptors would serve only to
alert the body to a threat to tissue integrity, they should not have
background activity and should discharge only during potentially
damaging situations. Alternatively, it can be hypothesized that
specific pain receptors are so sparse that they have not been
identified in the experimental models used so far.
A modified version of the intensity hypothesis proposes that cardiac
pain would result from the extreme excitation of a spatially restricted
population of afferent fibers. By contrast, when the activation of the
afferent fibers is widely distributed, some central
inhibitory mechanisms may reduce or prevent
pain.56 57 58 However, the results of a recent study in
patients with chronic stable angina do not support this hypothesis. In
fact, increasing doses of adenosine were randomly infused into
the left anterior descending coronary artery both proximal to
the first diagonal branch and distal to the last diagonal branch. The
infusion of adenosine at the proximal coronary site
consistently caused pain that occurred earlier and was
significantly more severe than that experienced when adenosine
was infused at the distal coronary site.59 These
results indicate that the severity of adenosine-induced pain is
determined primarily by the number of pain receptors stimulated rather
than by the intensity of their stimulation above a certain threshold.
On the basis of present knowledge, it can be hypothesized that
cardiac pain is generated when tonically activated afferent
fibers are stimulated by substances capable of generating a specific
pattern of activation that is decoded by the central nervous system as
pain. Accordingly, in power spectral analysis of activity
generated by dorsal root ganglia cardiac neurons, at least one
adenosine-specific peak occurs at 
40 Hz.60
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Angina Pectoris and Myocardial Ischemia |
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Relations Between Angina and Severity, Duration, and Causes of Ischemia
Myocardial ischemia can manifest as a discomfort having various features or can remain totally silent.61 Painful ischemia is more easily recognized clinically when the pain has all the typical features initially described by Heberden.62 Painless ischemia has been described in all coronary syndromes, including stable angina,63 64 65 unstable and vasospastic angina,66 67 68 69 70 71 72 syndrome X,73 and myocardial infarction.74
The results obtained in patients with angina at rest during continuous ECG and hemodynamic monitoring led to the following conclusions: (1) Transient ischemic episodes lasting <3 minutes and causing an increase of left ventricular pressure <7 mm Hg are typically silent; (2) longer and/or more severe episodes can be either painful or silent even in the same patient; and (3) milder transient ischemic episodes are more likely to be silent than severe ones, although episodes so severe as to cause massive deficit of regional myocardial perfusion and even myocardial infarction can remain completely silent.75 Therefore, in patients with episodes of myocardial ischemia at rest, a critical duration and severity of ischemia is needed for the development of angina.
The causes of ischemia do not influence the features of angina. For instance, patients with chronic stable angina (caused by increased demand) usually have the same type of pain when they develop unstable angina or infarction (caused by thrombosis).61 Some patients with spasm superimposed on a fixed coronary stenosis experience the same type of ischemic cardiac pain during attacks of variant angina at rest with ST-segment elevation (indicative of coronary spasm) and during effort-induced angina with ST-segment depression in the same leads.61
Spatial Relations Between Angina and Ischemia
Location of cardiac pain in somatic regions is determined by the
convergence of visceral and somatic afferents on the same neurons in
the central nervous system.76 Cardiac pain is typically
located in the retrosternal region, but it is also frequently
experienced in the left hemithorax, in the left arm, in the
epigastrium, and in the neck. Less common locations are the right
hemithorax and the right arm. However, there is a great variability in
the location of cardiac pain among different patients.61 A
number of studies have shown that afferent sympathetic fibers are
responsible for the transmission of cardiac pain.57 77 78 79
Other studies have shown that afferent vagal fibers could also be
involved in the transmission of cardiac pain.80 It is
worth noting that intramyocardial nerve fibers run parallel to the
coronary artery branches.81 Furthermore,
experimental studies appear to suggest that afferent sympathetic fibers
would be preferentially located in the anterior cardiac wall, whereas
afferent vagal fibers would be preferentially located in the
inferior wall.82 83 84 Because of this spatial
organization of afferent fibers, ischemic pain originating from
different myocardial regions should have the potential to be
experienced in different somatic regions. Yet, Eriksson et
al85 and Pasceri et al86 found that patients
with anterior or inferior myocardial infarction have a
remarkably similar distribution of ischemic cardiac pain.
Unlike what was observed in patients with acute myocardial infarction,
Lichstein et al,87 who assessed cardiac pain distribution
in relation to the site of coronary occlusion during balloon
angioplasty, found a significant difference in the distribution of pain
during occlusion of the left anterior descending or the right
coronary artery. In their series of patients, left chest pain
had a <10% chance of being present during right coronary
artery occlusion, whereas epigastric pain radiating to the neck or jaw
had a <13% chance of being present during left anterior
descending coronary artery occlusion. The difference between
their results and those obtained in patients with acute myocardial
infarction85 86 is probably accounted for by the more
severe degree of ischemia in patients with myocardial
infarction, which is likely to result in a more extensive stimulation
of afferent fibers.
It is worth noting that sequential adenosine infusion into the
right or left coronary artery in the same patient resulted in a
similar distribution of pain in 75% of the patients, whereas pain
distribution was different in the remaining patients.10
Furthermore, Pasceri et al86 found that 12 of 18 patients
(67%) who had both anterior and inferior myocardial
infarction experienced cardiac ischemic pain in different body
regions, whereas the remaining 33% experienced pain in the same body
region.
Taken together, these findings indicate that the location of ischemic cardiac pain does not allow us to predict the site of myocardial ischemia; yet, in the same patient, different locations of cardiac ischemic pain are likely to be caused by ischemia in different myocardial regions.
Temporal Relations Between Angina and Ischemia
In patients who develop severe transient ischemia, such as
that caused by coronary spasm, angina typically follows the
onset of metabolic, contractile, and electric alterations
by several minutes.3 69 88 This is not the case, however,
for myocardial ischemia of lesser severity. Indeed, during
effort-induced subendocardial ischemia, some patients can
experience angina before the ischemic changes appear on the
surface ECG. This different sequence of events is even more pronounced
in patients with syndrome X, who frequently present with chest pain
in the absence of or before ischemialike ECG
changes.73 These different sequences of events may be in
relation to different mechanisms of ischemia in addition to a
different individual sensitivity to painful cardiac stimuli. Indeed,
during massive transmural ischemia, the deterioration of
myocardial function is very fast because of the accumulation of
anaerobic metabolites in the central core of the
ischemic region and lack of adequate compensatory
hypercontractility; thus, the first marker of
ischemia is an alteration of regional function. Instead, in
syndrome X, in which hypoperfusion is likely to occur in multiple tiny,
sparse regions within the myocardium, the impairment of
regional ventricular function can be very limited because
of both compensatory hypercontractility of adjacent
myocytes and more rapid washout of anaerobic metabolites
that impair ventricular function when they accumulate in
large ischemic regions. Hence, it may be difficult to detect
regional wall motion abnormalities with currently available techniques.
Conversely, the compensatory sustained release of adenosine may
be adequate to stimulate afferent fibers, thus causing pain, which may
be particularly severe in the presence of a generalized high
sensitivity to painful stimuli that is frequently observed in patients
with syndrome X.89
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Lack of Angina During Myocardial Ischemia |
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Lack of angina during myocardial ischemia can simply be due to the short duration and/or lesser severity of myocardial ischemia.75 When ischemia is long and severe enough, various mechanisms can account for the lack of pain. The causes of painless ischemia are probably different (1) in patients who present with both painless and painful myocardial ischemia, (2) in patients with predominantly painless ischemia, and (3) in diabetic patients.
Causes of Lack of Angina in Patients With Both Painful and
Painless Ischemia
In the majority of anginal patients, episodes of painful transient
myocardial ischemia can be followed during the same day, or
even hour, by episodes of similar duration and severity not accompanied
by chest pain. The nervous activity of afferent cardiac fibers is
modulated in intrinsic cardiac ganglia, in mediastinal ganglia, and in
thoracic ganglia (cardiac afferent fibers traveling in sympathetic
nerves) or in the nucleus of the solitary tract (cardiac afferent
fibers traveling in parasympathetic nerves). Then, they are further
modulated in the periaqueductal gray matter, in the hypothalamus, and
in the thalamus. Finally, they project bilaterally to the lateral
basal frontal (Brodmann area 47), mesial orbitofrontal (Brodmann area
10), and ventral cingulate cortices (Brodmann area 25), as recently
demonstrated in humans by positron emission tomography.90
Only when the nervous activity of afferent cardiac fibers generated by
myocardial ischemia reaches the cortex can it be decoded as a
painful sensation.
The response of the intrinsic cardiac ganglia is modified by both excitatory and inhibitory synapses. Indeed, substance P, bradykinin, oxytocin, acetylcholine, nicotine, adenosine, and ATP administered adjacent to in situ intrinsic cardiac neurons have been shown to modify the activity of intrinsic cardiac neurons.91 92 93 Similarly, the epicardial application of substance P and adenosine modifies the activity of dorsal root ganglia neurons.94 More importantly, Armour et al95 demonstrated that the epicardial application of substance P, bradykinin, adenosine, and ATP modifies the activity in nodose ganglion neurons for up to 45 minutes after their application. Of note, in a recent study, Sylven et al96 showed that the infusion of very low doses of adenosine may reduce the severity of exercise-induced angina. Thus, they proposed that adenosine is a neuromodulator that, depending on its concentration and local conditions, could on the one hand stimulate intramyocardial afferent nerves and on the other inhibit afferent impulses originating from the heart, perhaps at the site of cardiac intrinsic ganglia. Taken together, all these observations suggest that ischemic cardiac pain perception depends not only on the generation of a specific signal generated by myocardial ischemia but also on its modulation in intrinsic, mediastinal, and thoracic ganglia, the effect of which is influenced by, among other things, past events.
Further modulation of the nervous activity of afferent cardiac fibers generated by myocardial ischemia can also occur within the central nervous system at the spinal level, according to the gate control theory,97 or at the supraspinal level. However, after they reach the central nervous system, afferent neural impulses generated by myocardial ischemia travel together with other visceral and somatic afferent neural impulses in the spinothalamic tract; therefore, modulation at this level is unlikely to account for the selective inhibition of ischemic cardiac pain that takes place when episodes of transient ischemic episodes of similar duration and severity occur with and without angina in a short period of time.
Causes of Lack of Angina in Patients With Predominantly
Painless Ischemia
In patients who have never experienced angina even during
severe, prolonged ischemia and in those who have predominantly
silent ischemia, the failure to develop pain could be due to
psychological factors that persistently inhibit the perception of pain.
This is suggested by the generalized defective perception of painful
stimuli consistently demonstrated in this subset of patients.
Indeed, patients with totally silent ischemia and those with
predominantly silent ischemia have a significantly higher
threshold and tolerance for painful stimuli than patients with
predominantly painful ischemia when challenged with painful
stimuli, such as forearm ischemia, cold pressor, skin
electrical stimulation,98 99 intravenous
adenosine infusion,9 or dental pulp
stimulation.100 In addition, on a personality inventory
test, patients with silent ischemia recorded significantly
lower scores for nervousness and "excitability," higher scores
for "masculinity," and lower tendency to
complain.98
Endogenous opioids have received considerable attention in relation to the causes of silent ischemia. There are three main groups of endogenous opioids derived from three different precursor molecules: (1) endorphins, which are secreted predominantly by the pituitary gland; (2) enkephalins, secreted mainly by the adrenocortical gland; and (3) dynorphins, whose origin is still poorly known.101 102 103 Endogenous opioids appear to act centrally, provoking a selective suppression of nociceptive dorsal horn–convergent neurons.102 Accordingly, Van Rijn and Rabkin104 reported that naloxone, a potent endorphinergic antagonist, resulted in an earlier appearance of ischemic cardiac pain during treadmill exercise testing in patients with stable angina. However, other studies failed to initiate angina with naloxone in patients with silent myocardial ischemia.105 106 Also controversial are the results of studies in which plasma levels of endogenous endorphins were compared in patients with predominantly painful or painless ischemia.99 107 108 109 110
A common mechanism responsible for the presence of predominantly painless myocardial ischemia may be a selective impairment of the projection to the cortex of the nervous activity generated by myocardial ischemia. Accordingly, a recent study carried out in humans by positron emission tomography showed a much lower cortical activation during myocardial ischemia in patients with a history of painless ischemia than in patients who experienced angina.111
Causes of Lack of Angina in Diabetic Patients
Patients with diabetes mellitus have a higher incidence of
silent myocardial ischemia than nondiabetic
patients.112 Bradley and Partamian113 found
that 33 of 77 diabetic patients who died of acute myocardial infarction
had evidence of at least one healed infarction that was not related to
the patient's clinical history. Bradley and
Schoenfield114 described the presence and severity of
symptoms in 100 diabetic and 100 nondiabetic patients who
presented with myocardial infarction. The study revealed that
severe ischemic cardiac pain was nearly three times as frequent
among nondiabetic patients. Nesto et al115 compared the
results of exercise test in 50 diabetic and 50 nondiabetic patients. In
that study, angina was present in only 14 diabetic patients but in
34 nondiabetic patients, even though the degree of ST-segment
depression was similar in the two groups. The same authors found that
during Holter monitoring, only 5% of transient ischemic
episodes were accompanied by angina in diabetic patients. Finally,
Chiariello et al116 observed that among 51 diabetic
patients with ischemic heart disease, the prevalence of silent
episodes of ST-segment depression during Holter monitoring was higher
than that among 70 nondiabetic patients (35% versus 17%).
Autonomic neuropathy involving cardiac afferent nerves is the most likely explanation of the high incidence of silent ischemia in diabetic patients. In fact, in 5 diabetic patients who died of silent myocardial infarction, Fearman et al117 found that intramyocardial sympathetic and parasympathetic nerves exhibited morphological alterations of diabetic neuropathy characterized by beaded thickening within the nerves, spindle-shaped nerve fibers, fragmentation of nerve fibers, and a decrease in the actual number of neurons. In another study, Niakan et al118 investigated 73 consecutive diabetic patients with peripheral neuropathy. He found ECG evidence of silent myocardial infarction in 5 of 25 patients (20%) with evidence of autonomic nervous system dysfunction but in only 2 of 48 patients (4%) without evidence of autonomic dysfunction. Of note, in a recent study, Caracciolo et al119 failed to find a higher prevalence of silent ischemia during exercise testing in 77 diabetic anginal patients compared with 481 nondiabetic anginal patients. The variable results of different studies may suggest that only a subset of patients with diabetes, probably those with autonomic neuropathy, present a higher prevalence of silent ischemia; hence, the differing results among different studies might be explained by the variable proportions of patients with autonomic neuropathy.
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Footnotes |
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Reprint requests to Filippo Crea, Istituto di Cardiologia, Università Cattolica del Sacro Cuore, L.go A. Gemelli, 8, Rome (Italy).
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References |
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