PET imaging in refractory
angina
Paolo G. Camici
Clinical Sciences Centre and National Heart and Lung Institute,
Faculty of Medicine,
Imperial College of Science, Technology and Medicine, London,
UK
Correspondence: Professor Paolo G. Camici, Clinical
Sciences Centre and National Heart and Lung Institute, Faculty
of Medicine, Imperial College of Science, Technology and Medicine,
London, UK. Tel: +44 20 8383 3186 , fax: +44 20 8383 3742 , e-mail:
paolo.camici@csc.mrc.ac.uk
|
Abstract
Positron emission tomography (PET) is a noninvasive
tool that provides accurate quantitative information on
regional perfusion, metabolism, and autonomic function in
different human organs in vivo. Classically, PET has been
applied to cardiology for the investigation of myocardial
blood flow and flow reserve, and for the assessment of myocardial
glucose utilization and tissue viability. However, PET has
also been applied very successfully to the study of human
brain
function. In this review, the contribution of PET to our
understanding of the pathophysiology of cardiac pain as
well as its role in the assessment of transmyocardial laser
revascularization in patients with refractory angina will
be discussed. The former issue is particularly relevant
in these patients in whom persisting chest pain is the key
feature. Since relief of ischemia is often
technically difficult in refractory angina, a better understanding
of the mechanisms involved in chest pain perception may
help develop alternative therapeutic measures for these
patients.
- Heart Metabol. 2002;16:15–18.
Key words: Coronary
artery disease, angina, brain, cardiac imaging, transmyocardial
laser revascularization
|
Positron emission tomography (PET) is a noninvasive tool that
provides accurate quantitative information on regional perfusion,
metabolism, and autonomic function in different human organs in
vivo. Classically, PET has been applied to cardiology for the
investigation of myocardial blood flow and flow reserve, and for
the assessment of myocardial glucose utilization and tissue viability
[1].
In this brief review, the contribution of PET to our understanding
of the pathophysiology of cardiac pain as well as its role in
the assessment of transmyocardial laser revascularization (TMLR)
in patients with refractory angina will be discussed. The former
issue is particularly relevant in these patients, in whom persisting
chest pain is the key feature. Since relief of ischemia is often
technically difficult in refractory angina, a better understanding
of the mechanisms involved in chest pain perception may help the
development of alternative therapeutic measures for these patients.
Painful and painless myocardial ischemia
Up to 70% of episodes of myocardial ischemia in patients
with coronary artery disease may be asymptomatic; for acute myocardial
infarction, the incidence of painless events is estimated to be
30% [2–6]. Silent ischemia often coexists with
painful ischemia in the same patient, and the evidence suggests
that there is no correlation between the degree of pain and the
severity of the ischemia [2].
The higher incidence of myocardial ischemia in diabetics implicates
peripheral neuropathy in the process; differences in autonomic
nerve function have also been described in nondiabetic patients
with silent myocardial ischemia [3, 4]. Conversely,
silent ischemia can be shown in many nondiabetics with no evidence
of neuropathy.
There is no pathophysiological hypothesis to fully explain these
findings. Such a hypothesis should take into account two interrelated
phenomena. Firstly, the development of ischemia is a dynamic process
in which the determinants of the imbalance between oxygen supply
and demand are not fixed but can be modulated by a number of factors
[5]. Secondly, the sensation of angina pectoris
is the result of activity in neural circuits with potential for
modulation of the message at all levels of the process
[6].
Peripheral mechanisms involved in the
transduction of chest pain perception
An adequate stimulus (eg, mechanical and/or chemical) at the level
of the myocardium will lead to the release of numerous neurotransmitters,
among which adenosine [7] and substance P [8]
have been shown to be particularly important in the case of cardiac
pain. There is disagreement as to whether these ligands activate
receptors on specific nociceptors (specificity theory), or whether
particularly intense stimulation of receptors for other modalities,
such as proprioception, will constitute a nociceptive signal (intensity
theory) [9]. It is important, however, that
we do not label these signals as “painful.” Pain is a conscious
experience triggered by activity in the peripheral nervous system.
Prior to the peripheral signal being processed in the brain, it
is perhaps best thought of as “ischemia-induced afferent activity”
[6].
This afferent activity occurs in anatomically sympathetic fibers,
which have their primary synapses in the dorsal horn of the spinal
cord [10, 11], and vagal fibers, which synapse
firstly in the nucleus of the solitary tract [12].
At these synapses, there is potential for modulation of the message.
Other sensory input to the spinal cord, descending control mechanisms
from the brain, and mechanisms integral to the spinal cord, will
act together to either amplify or diminish ongoing afferent activity
[13]. After the primary synapse, second order neurons ascend
in multiple pathways, including the spinothalamic tract, the spinoamygdaloid
pathway, and the spinohypothalamic pathway [14].
Central nervous pathways mediating anginal
pain
The pain experience is multidimensional, composed of
a sensory-discriminative component (represented by the ability
to identify the stimulus within spatiotemporal and intensive domains)
and a hedonic component (through which the intrusive and unpleasant
qualities of pain are experienced). Additionally, a cognitive
component reflects the ability to evaluate the pain in terms of
the threat that it represents to wellbeing or survival. A great
deal of information on central processing of visceral pain and
angina has been derived from animals, and the following summarizes
this work.
The sensory-discriminative component of the experience is expressed
through the S-1 and S-2 somatosensory cortex and the posterior
cingulate gyrus. These areas receive input from third order neurons
from the ventroposterior lateral thalamus. Arousal, fear, and
autonomic activation are expressed through activity in the reticular
formation, the amygdala, and the hypothalamus. The latter two
areas receive third-order projection fibers from the parabrachial
nuclei of the pons.
Cognitive appraisal occurs in the parietal cortex and the anterior
cingulate cortex. Such appraisal will assess the situation to
be intrusive and threatening, and there will be the appropriate
affective sequelae of difficulty, apprehension, and fear for the
future mediated by increased activity in the prefrontal cortex
and limbic system. These areas receive diffuse projections via
third-order neurons from medial thalamic nuclei [14].
This operational separation of the components of pain helps us
understand the experience, but we must be aware that these are
semantic constructs. The experience of angina is a dynamic, integrated,
subjective phenomenon which is unique to the individual.
PET studies of the central pathways
mediating angina in humans
Recently, PET has been used to trace the central pathways mediating
angina in humans [15]. PET permits noninvasive
assessment of regional cerebral blood flow (rCBF), which is a
reliable indicator of regional cerebral neuronal activity. PET
was used to assess rCBF in patients with stable angina pectoris
and angiographically proven coronary artery disease during dobutamine
stress.
Painful myocardial ischemia
Compared with the resting state, the development of
angina was associated with increased rCBF in the hypothalamus,
periaqueductal gray, bilaterally in the thalamus and lateral prefrontal
cortex, and left inferior anterocaudal cingulate cortex. In contrast,
rCBF was reduced bilaterally in the mid-rostrocaudal cingulate
cortex, fusiform gyrus, and right posterior cingulate, and left
parietal cortices. Thalamic activity could be detected several
minutes after stopping dobutamine infusion and after the disappearance
of anginal pain and ECG changes. Therefore, it is proposed that
the activated central structures constitute the pathways which
map the experience of anginal pain and that the thalamus acts
as a gate to nociceptive information, with activation of many
other areas of the brain being necessary before angina is experienced.
Silent myocardial ischemia
The same PET methodology has been used to study patients
with silent myocardial ischemia [16]. In this
study a difference in the pattern of cerebral cortical activation
was observed when symptomatic patients were compared with those
with silent myocardial ischemia; however, the flow pattern in
the thalamus was similar when the groups were compared. It was
concluded that since bilateral activation of the thalamus can
be shown in both angina and silent ischemia, peripheral nerve
dysfunction cannot serve as a full explanation for silent ischemia.
In addition, activity in the frontal cortex appears necessary
for the sensation of anginal pain.
PET for the assessment of transmyocardial
laser revascularization (TMLR)
TMLR has been proposed for the treatment of refractory angina.
It has been hypothesized that transmural left ventricular channels
created by laser improve myocardial blood flow in the treated
zones. Recently we conducted a study to assess the effect of TMLR
on myocardial blood flow and coronary vasodilator reserve
[17].
We measured myocardial blood flow (ml/min per g) by means of PET
with oxygen-15-labeled water in seven patients with refractory
angina, CCS class 3.6 ± 0.5, on three occasions: before
and at 7.5 ± 2.8 weeks (follow-up 1, FU-1) and at 34.6
± 4.7 weeks (follow-up 2, FU-2) after TMLR performed with
a synchronized high-powered CO2 laser. In each study, myocardial
blood flow was measured at rest and during maximal iv dobutamine.
The coronary vasodilator reserve was computed as dobutamine/rest
myocardial blood flow. After TMLR, the CCS class was 2.2 ±
1.7 at FU-1 and 2.4 ± 1 at FU-2 (P = 0.04 vs pre-TMLR).
Resting myocardial blood flow, both in lasered and nonlasered
regions, was unchanged after TMLR. Dobutamine myocardial blood
flow at baseline was 1.45 ± 0.52 in lasered and 1.55 ±
0.52 in nonlasered regions (P = NS). At FU-1, dobutamine myocardial
blood flow in nonlasered regions had increased significantly to
1.89 ± 0.82 (P < 0.05) and was higher than in lasered
regions (1.51 ± 0.61, P < 0.05 vs nonlasered). At FU-2,
dobutamine myocardial blood flow in nonlasered regions was still
higher than in lasered regions (1.56 ± 0.54 vs 1.21 ±
0.44, P < 0.01). The coronary vasodilator reserve was comparable
in nonlasered and lasered regions at baseline and FU-1, whereas
it was higher in nonlasered regions at FU-2 (1.86 ± 0.67
vs 1.53 ± 0.72, P < 0.05) (Figure 1).
 Figure
1. Coronary vasodilator reserve in lasered and nonlasered
regions at baseline, FU-1, and
FU-2. *P < 0.05. (Adapted from [17].)
In conclusion, TMLR has been shown to reduce angina in severely
diseased patients. The results of our study do not support the
hypothesis that the symptomatic benefit of TMLR can be ascribed
to improved myocardial perfusion or the coronary vasodilator reserve
in the lasered areas.
REFERENCES
1. Camici PG. Positron emission tomography
and myocardial imaging. Heart. 2000;83: 475–480.
Is 'silent' myocardial ischemia really as
severe as symptomatic ischemia? The analytical effect of patient
selection biases.
Klein J, Chao SY, Berman DS, Rozanski A.
Department of Medicine, Cedars-Sinai Medical Center, Los Angeles,
Calif.
BACKGROUND: The clinical significance of exercise-induced chest
pain remains controversial, as reflected by sharply discordant
clinical results within the medical literature. Thus, we developed
a prospective study to compare the functional significance of
silent versus symptomatic ischemia and to evaluate whether patient
selection biases influence this analysis. METHODS AND RESULTS: We
evaluated 117 patients (mean age, 63 +/- 9 years) with ischemic
ST-segment depression during treadmill testing. Each patient
underwent Tl-201 myocardial perfusion single-photon emission
computed tomography (SPECT) after exercise followed by
24-ambulatory ECG monitoring. Patients were divided into silent
versus symptomatic cohorts and were compared for the degree of
hemodynamic, exercise and ambulatory ECG, and thallium
abnormalities during stress testing. Analyses were repeated as the
patient population became increasingly restricted. Compared with
the silent patients, patients with chest pain during exercise had
a shorter exercise duration (P < .009), lower peak heart rate (P =
.009) and double product (P = .005), lower heart rate threshold
for ST depression (P < .05), more episodes of ambulatory
ST-segment depression (P < .05), a higher frequency of ischemia
abnormalities during Tl-201 SPECT (P = .02), and higher summed Tl
reversibility scores (P = .002). As the population became
increasingly restricted, the relative magnitude of differences in
silent versus symptomatic cohorts diminished, whereas the absolute
magnitude of ischemic abnormalities progressively increased in
both cohorts. For example, within the restricted group having
ischemia on both exercise and ambulatory ECG, 50% of the silent
cohort had severe ischemia on Tl SPECT (five or more reversible
defects) and more than one third demonstrated the ominous finding
of transient left ventricular dilation after exercise.
CONCLUSIONS: The induction of chest pain is associated with
substantially more functional abnormalities when it is analyzed in
a relatively "broad-spectrum" coronary artery disease population;
by contrast, chest pain tends to lose its apparent value as a
clinical test parameter when its analysis is restricted to
coronary artery disease populations with a greater a priori
likelihood of manifesting inducible ischemia. These findings may
help resolve some of the previous discordant literature reports.
PMID: 8181118 [PubMed - indexed for MEDLINE]
Comment in:
Detection of silent myocardial ischemia in
diabetes mellitus.
Langer A, Freeman MR, Josse RG, Steiner G, Armstrong PW.
Division of Cardiology, St. Michael's Hospital, Toronto, Ontario,
Canada.
The prevalence of silent myocardial ischemia and its relation to
autonomic dysfunction and pain threshold was studied in 58 men
with diabetes mellitus and without cardiac symptoms. All patients
underwent 48-hour ambulatory electrocardiographic monitoring and
exercise testing after assessment of their autonomic function and
pain threshold. Silent myocardial ischemia, defined as greater
than or equal to 1 mm of ST-segment depression on either exercise
testing or ambulatory electrocardiographic monitoring, was
corroborated by exercise-induced reversible defect(s) on
tomographic thallium scintigraphy. Autonomic function was assessed
by heart rate response to: (1) Valsalva maneuver, (2) deep
breathing, and (3) upright posture, as well as by diastolic blood
pressure response to sustained handgrip and systolic blood
pressure response to upright posture. Autonomic dysfunction was
defined as greater than or equal to 2 abnormal responses. Pain
threshold measurements were performed using electrical cutaneous
stimulation of both forearms. Of the 58 diabetic patients, 21 were
found to have autonomic dysfunction (36%). Silent myocardial
ischemia was detected in 10 patients (17%), and was significantly
more frequent in patients with than without autonomic dysfunction
(38 vs 5%, p = 0.003). There was no difference in the electrical
pain threshold or tolerance in subjects with and without silent
myocardial ischemia. It is concluded that silent myocardial
ischemia in asymptomatic diabetic men occurs frequently and in
association with autonomic dysfunction, suggesting that diabetic
neuropathy may be implicated in the mechanism of silent myocardial
ischemia.
PMID: 2024596 [PubMed - indexed for MEDLINE]
Differences in autonomic nerve function in
patients with silent and symptomatic myocardial ischaemia.
Shakespeare CF, Katritsis D, Crowther A, Cooper IC, Coltart JD,
Webb-Peploe MW.
Cardiac Department, St Thomas' Hospital, London.
BACKGROUND--Autonomic neuropathy provides a mechanism for the
absence of symptoms in silent myocardial ischaemia, but
characterisation of the type of neuropathy is lacking. AIM--To
characterise and compare autonomic nerve function in patients with
silent and symptomatic myocardial ischaemia. METHODS AND
RESULTS--The Valsalva manoeuvre, heart rate variation (HRV) in
response to deep breathing and standing, lower body negative
pressure, isometric handgrip, and the cold pressor test were
performed by patients with silent (n = 25) and symptomatic (n =
25) ambulatory ischaemia and by controls (n = 21). No difference
in parasympathetic efferent function between patients with silent
and symptomatic ischaemia was recorded, but both had significantly
less HRV in response to standing than the controls (p < 0.005 for
silent and p < 0.01 for symptomatic). Patients with silent
ischaemia showed an increased propensity for peripheral
vasodilatation compared with symptomatic patients (p < 0.02) and
controls (p < 0.04). Impaired sympathetic function was found in
patients with pure silent ischaemia (n = 4) compared with the
remaining patients with silent ischaemia whose pain pathways were
presumed to be intact. CONCLUSIONS--Patients with silent ischaemia
and pain pathways presumed to be intact have an enhanced
peripheral vasodilator response, and if this applied to the
coronary vasculature it could provide a mechanism for limiting
ischaemia to below the pain threshold. Patients with pure silent
ischaemia have evidence of sympathetic autonomic dysfunction.
PMID: 8297687 [PubMed - indexed for MEDLINE]
Pathophysiology of angina.
Collins P, Fox KM.
National Heart Hospital, London, UK.
The development and pathophysiology of myocardial ischaemia is a
dynamic process in which increased myocardial oxygen demand or
decreased coronary blood flow are not the sole determinants. Both
these factors are inappropriately altered before, during, or after
the onset of ischaemia, and a vicious cycle ensues. Drug therapy
should be aimed at not only preventing the development of
myocardial ischaemia but also at reversing the abnormal hormonal,
metabolic, and haemodynamic effects.
Publication Types:
PMID: 1967428 [PubMed - indexed for MEDLINE]
Comment in:
Comment on:
Match and mismatch: identifying the neuronal
determinants of pain.
Casey KL.
Neurology Service, Veterans Affairs Medical Center, Ann Arbor, MI
48105, USA.
Despite the increased intensity and sophistication of research on
pain mechanisms in the past three decades, serious uncertainties
remain about the neuronal origin of pain, especially in painful
clinical conditions. Although a positive correlation between
nociceptive afferent activity and the subjective perception of
pain has been seen under controlled experimental conditions,
important mismatches point to the critical importance of central
nervous system processes as determinants of pain. Multiple
peripheral, segmental, and supraspinal neuronal activities control
nociceptive processing at all levels of the neuraxis. Three
studies in this issue highlight the problem of identifying the
neuronal determinants of pain by addressing contrasting
mismatches: angina-like chest pain without an obvious cause and a
potential source of angina (myocardial ischemia) without pain. The
results of these studies suggest that selective visceral
hyperalgesia and hypoalgesia of peripheral or central origin may
be present without other clinical evidence for neurologic
abnormality. Complex mechanisms interacting at several levels of
the nervous system appear to be involved.
Publication Types:
- Comment
- Review
- Review, Tutorial
PMID: 8624067 [PubMed - indexed for MEDLINE]
Comment in:
Role of adenosine in pathogenesis of anginal
pain.
Crea F, Pupita G, Galassi AR, el-Tamimi H, Kaski JC, Davies G,
Maseri A.
Cardiovascular Unit, RPMS-Hammersmith Hospital, London, UK.
The intravenous infusion of adenosine provokes anginalike chest
pain. To establish its origin, an intracoronary infusion of
increasing adenosine concentrations was given in 22 patients with
stable angina pectoris. During adenosine infusion, 20 patients had
chest pain without electrocardiographic signs of ischemia. They
all reported that the chest pain was similar to their usual
anginal pain. In 10 of the 22 patients adenosine was also infused
into the right atrium, but it never produced symptoms at the doses
that had provoked chest pain during intracoronary infusion. In
seven other patients, the intracoronary adenosine infusion was
repeated after intravenous administration of aminophylline, an
antagonist of adenosine P1-receptors. Aminophylline decreased the
severity of adenosine-induced chest pain (assessed with a visual
analog scale) from 42 +/- 22 to 23 +/- 17 mm (p less than 0.002).
In the remaining five of the 22 patients, monitoring of blood
oxygen saturation in the coronary sinus during intracoronary
adenosine administration showed that maximum coronary vasodilation
was achieved at doses lower than those responsible for chest pain.
A single-blind, placebo-controlled, randomized trial of the effect
of aminophylline on exercise-induced chest pain was also performed
in 20 other patients with stable angina. Aminophylline, compared
with placebo, decreased the severity of chest pain at peak
exercise from 67 +/- 21 to 51 +/- 23 mm (p less than 0.02),
despite the achievement of a similar degree of ST-segment
depression. Finally, the effect of intravenous adenosine was
compared in 10 patients with predominantly painful myocardial
ischemia and in 10 patients with predominantly silent
ischemia.(ABSTRACT TRUNCATED AT 250 WORDS)
PMID: 2297824 [PubMed - indexed for MEDLINE]
Substance P potentiates the algogenic effects
of intraarterial infusion of adenosine.
Gaspardone A, Crea F, Tomai F, Iamele M, Crossman DC,
Pappagallo M, Versaci F, Chiariello L, Gioffre PA.
Servizio Speciale di Diagnosi e Cura di Emodinamica, Universita di
Roma Tor Vergata, Italy.
OBJECTIVES. This study investigated whether substance P
potentiates the muscular and cardiac pain caused by the
intraarterial infusion of adenosine, an autocoid known to induce
muscular and cardiac ischemic-like pain in humans. BACKGROUND.
Substance P is involved in the generation of neurogenic
inflammation and causes cutaneous hyperalgesia. Because substance
P is present in perivascular nerves it might also cause muscular
and cardiac hyperalgesia. To test this hypothesis its effects on
adenosine-induced muscular and cardiac pain were investigated in
humans. METHODS. A randomized, crossover study of the algogenic
effects of the intrailiac infusion of increasing scalar doses
(from 125 to 2,000 micrograms/min) of adenosine or substance P
(11.2 pmol/min) for 3 min, followed by the simultaneous infusion
of substance P plus the same doses of adenosine, was carried out
in nine patients with no evidence of peripheral vascular disease.
A similar protocol was carried out by infusing increasing scalar
doses of adenosine (from 50 to 800 micrograms/min) or substance P
(11.2 pmol/min) for 3 min, followed by the simultaneous infusion
of substance P plus the same doses of adenosine, into the left
coronary artery of eight patients with angina. Pain severity,
assessed by a visual analog scale, is presented as median. The
remaining data are presented as mean value +/- 1 SD. RESULTS. All
patients experienced pain during both adenosine and substance P
plus adenosine infusion; no patient experienced pain during the
infusion of substance P alone. During intrailiac infusion, all
patients experienced pain in the right leg that occurred earlier
(207 +/- 152 vs. 321 +/- 154 s, p < 0.05) and was greater (47 vs.
30 mm, p < 0.05) during the simultaneous infusion of substance P
plus adenosine than during the infusion of adenosine. Similarly,
during intracoronary infusion, all patients experienced chest pain
that occurred earlier (409 +/- 242 vs. 596 +/- 210 s, p < 0.05)
and was greater (51 vs. 33 mm, p < 0.05) during the simultaneous
infusion of substance P plus adenosine than during infusion of
adenosine. No patient exhibited electrocardiographic signs of
ischemia. CONCLUSIONS. Substance P does not cause muscular or
cardiac pain, but it provokes muscular and cardiac hyperalgesia.
Publication Types:
- Clinical Trial
- Randomized Controlled Trial
PMID: 7518480 [PubMed - indexed for MEDLINE]
New look to an old symptom: angina pectoris.
Crea F, Gaspardone A.
Istituto di Cardiologia, Universita Cattolica del Sacro Cuore,
Rome, Italy.
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.
Publication Types:
PMID: 9396481 [PubMed - indexed for MEDLINE]
10. White J. Anatomic pathways and physiologic
mechanisms. Circulation. 1957;16:644–655.
11. Malliani A, Pagani M, Lombardi F. Visceral
Versus Somatic Mechanisms. New York, NY: Churchill Livingstone;
1989.
12. Meller S, Gebhart G. Visceral pain: a review
of experimental studies. Neuroscience. 1992;48:501–524.
Pain mechanisms: a new theory.
Melzack R, Wall PD.
Publication Types:
PMID: 5320816 [PubMed - indexed for MEDLINE]
Psychological and neural mechanisms of the
affective dimension of pain.
Price DD.
Department of Oral and Maxillofacial Surgery, University of
Florida, Health Science Center, Post Office Box 100416,
Gainesville, FL 32610-0416, USA. dprice@dental.ufl.edu
The affective dimension of pain is made up of feelings of
unpleasantness and emotions associated with future implications,
termed secondary affect. Experimental and clinical studies show
serial interactions between pain sensation intensity, pain
unpleasantness, and secondary affect. These pain dimensions and
their interactions relate to a central network of brain structures
that processes nociceptive information both in parallel and in
series. Spinal pathways to limbic structures and medial thalamic
nuclei provide direct inputs to brain areas involved in affect.
Another source is from spinal pathways to somatosensory thalamic
and cortical areas and then through a cortico-limbic pathway. The
latter integrates nociceptive input with contextual information
and memory to provide cognitive mediation of pain affect. Both
direct and cortico-limbic pathways converge on the same anterior
cingulate cortical and subcortical structures whose function may
be to establish emotional valence and response priorities.
Publication Types:
PMID: 10846154 [PubMed - indexed for MEDLINE]
Comment in:
Central nervous pathways mediating angina
pectoris.
Rosen SD, Paulesu E, Frith CD, Frackowiak RS, Davies GJ, Jones
T, Camici PG.
Cyclotron Unit, MRC Clinical Sciences Centre, Hammersmith
Hospital, London, UK.
The central nervous pathways of angina pectoris have never been
identified in vivo in man. We used positron emission tomography to
examine the changes in regional cerebral blood flow associated
with angina pectoris. Dynamic positron emission tomography with
15O-labelled water was used in 12 patients with angina and
angiographically proven coronary artery disease to measure
regional cerebral blood flow changes during angina induced by
intravenous dobutamine. All subjects had typical retrosternal
chest pain accompanied by ischaemic electrocardiographic changes
during dobutamine infusion. Compared to the resting state, angina
was associated with increased regional cerebral blood flow in the
hypothalamus (percentage change in regional cerebral blood flow
+6.5 and Z score 7.2) periaquaductal grey (+2.6 and 4.0),
bilaterally in the thalamus (left: +2.7 and 4.3; right +3.7 and
4.7) and lateral prefrontal cortex (left +11.5 and 7.6; right +8.5
and 7.8) and left inferior anterocaudal cingulate cortex (+9.4 and
6.6). In contrast, it was reduced bilaterally in the mid-rostrocaudal
cingulate cortex (left -3.7 and 6.3; right -4.7 and 4.6) and
fusiform gyrus (left -3.2 and 4.0; right -3.3 and 3.7), right
posterior cingulate (-3.9 and 5.8) and left parietal cortices
(-4.8 and 6.3). Several minutes after stopping dobutamine
infusion, when the patients no longer experienced angina and the
electrocardiographic changes had resolved, thalamic, but not
cortical activation could be seen. We propose that the central
structures activated constitute the pathways for perception of
anginal pain and that the thalamus may act as a gate to afferent
pain signals, with cortical activation being necessary for the
sensation of pain. This method of investigation may form a basis
for research into anomalies of visceral pain perception such as
silent myocardial ischaemia.
PMID: 7912763 [PubMed - indexed for MEDLINE]
Comment in:
Comment on:
Silent ischemia as a central problem: regional
brain activation compared in silent and painful myocardial
ischemia.
Rosen SD, Paulesu E, Nihoyannopoulos P, Tousoulis D, Frackowiak
RS, Frith CD, Jones T, Camici PG.
Cyclotron Unit, Hammersmith Hospital, London, United Kingdom.
OBJECTIVE: To test whether the silence of painless myocardial
ischemia is caused by abnormal handling by the central nervous
system of afferent messages from the heart. DESIGN: Nonrandomized
study. SETTING: A tertiary referral center (postgraduate medical
school). PATIENTS: 2 matched groups of nondiabetic patients with
coronary artery disease. Group A consisted of nine patients with
reproducible stress-induced angina; group B consisted of nine
patients with reproducible stress-induced myocardial ischemia but
no angina. INTERVENTIONS: Intravenous placebo infusion and
low-dose (5 and 10 micrograms/ kg per minute) and high-dose (20 to
35 micrograms/kg per minute) dobutamine infusions. MEASUREMENTS:
Positron emission tomography was used to measure regional cerebral
blood flow changes as an index of neuronal activation during
painful and silent myocardial ischemia induced by intravenous
dobutamine. RESULTS: Regional cerebral blood flow changes during
myocardial ischemia were compared with those during baseline
conditions and during placebo infusion. During myocardial
ischemia, regional cerebral blood flow increased bilaterally in
the thalami and prefrontal, basal frontal, and ventral cingulate
corticles in patients in group A. Both thalami were activated in
group B, but cortical activation was limited to the right frontal
region. A formal comparison of groups A and B showed significant
differences (P < 0.01) in activation of the basal frontal cortex,
ventral cingulate cortex, and left temporal pole. In both groups,
thalamic regional cerebral blood flow remained increased after the
symptoms and signs of ischemia had ceased. CONCLUSIONS: Bilateral
activation of the thalamus can be shown in both angina and silent
ischemia; thus, peripheral nerve dysfunction cannot completely
explain silent ischemia. Frontal cortical activation appears to be
necessary for the sensation of pain. Abnormal central processing
of afferent pain messages from the heart may play a determining
role in silent myocardial ischemia.
Publication Types:
PMID: 8624061 [PubMed - indexed for MEDLINE]
Measurement of myocardial blood flow with
positron emission tomography before and after transmyocardial
laser revascularization.
Rimoldi O, Burns SM, Rosen SD, Wistow TE, Schofield PM, Taylor
G, Camici PG.
MRC Cyclotron Unit-Imperial College School of Medicine,
Hammersmith Hospital, London, UK. ornella@cu.rpms.ac.uk
BACKGROUND: Transmyocardial laser revascularization (TMLR) has
been proposed for treatment of refractory angina. It has been
hypothesized that transmural left ventricular channels created by
laser improve myocardial blood flow (MBF) in the treated zones. We
aimed to assess the effect of TMLR on MBF and coronary vasodilator
reserve (CVR). METHODS AND RESULTS: We measured MBF by means of
PET with (15)O-labeled water in 7 patients with refractory angina,
Canadian Cardiovascular Society (CCS) class 3.6+/-0.5, on 3
occasions: before and at 7.5+/-2.8 weeks (FU-1) and 34.6+/-4.7
weeks (FU-2) after TMLR performed with a synchronized,
high-powered CO(2) laser. In each study, MBF was measured at rest
and during maximal intravenous dobutamine. CVR was computed as
dobutamine divided by resting MBF. After TMLR, CCS class was
2.2+/-1.7 at FU-1 and 2.4+/-1 at FU-2 (P=0.04 versus pre-TMLR).
Resting MBF in both lasered and nonlasered regions was unchanged
after TMLR. Dobutamine MBF at baseline was 1.45+/-0.52 and
1.55+/-0.52 mL. min(-1). g(-1) in lasered and nonlasered regions,
respectively (P=NS). At FU-1, dobutamine MBF in nonlasered regions
had increased significantly to 1.89+/-0.82 mL x min(-1) x g(-1)
(P<0.05) and was higher than in lasered regions (1.51+/-0.61 mL x
min(-1) x g(-1); P<0.05 versus nonlasered). At FU-2, dobutamine
MBF in nonlasered regions was still higher than in lasered regions
(1.56+/-0.54 versus 1.21+/-0.44 mL x min(-1) x g(-1); P<0.01). CVR
was comparable in nonlasered and lasered regions at baseline and
FU-1, whereas it was higher in nonlasered regions at FU-2
(1.86+/-0.67 versus 1.53+/-0.72 mL x min(-1) x g(-1); P<0.05).
CONCLUSIONS: TMLR has been shown to reduce angina in severely
diseased patients. The results of our study do not support the
hypothesis that the symptomatic benefit of TMLR can be ascribed to
improved myocardial perfusion or CVR in lasered areas.
PMID: 10567292 [PubMed - indexed for MEDLINE]
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