Inuence of age on pain perception in acute myocardial ischemia: A possible cause

for delayed treatment in elderly patients

H. Rittger
a,
, J. Rieber
b
, O.A. Breithardt
a
, M. Dcker
a
, M. Schmidt
a
, S. Abbara
c
, A.M. Sinha
a
, A. Jakob
a
,
G. Nlker
a
, J. Brachmann
a
a
Med. Klinik II, Klinikum Coburg, Coburg, Germany
b
Medizinische Klinik, Klinikum Innenstadt, Ludwigs-Maximilians-Universitt, Mnchen, Germany
c
Harvard Medical School, Department of Cardiovascular Imaging, Harvard Medical School, Boston, MA, USA
a b s t r a c t a r t i c l e i n f o
Article history:
Received 7 October 2009
Accepted 29 November 2009
Available online 6 January 2010
Keywords:
Acute myocardial infarction
Elderly patients
Reduced pain perception
Time delay
Clinical symptoms
Background: Elderly patients tend to seek later for medical help during myocardial infarction. This may be
caused by impaired pain perception with ageing. The aim of our study was to prospectively evaluate age-
dependent differences in pain perception during temporary induced coronary ischemia.
Methods: In 102 patients (68 male, age 6811 years) undergoing percutaneous coronary intervention,
ischemia was induced by balloon ination for up to 120 s. Time to onset of perceived pain, pain
characteristics and pain severity (0=no pain, 100=worst pain possible) was registered. This was repeated
twice to evaluate ischemic preconditioning. A 12 lead ECG-tracing was simultaneously recorded. Patients
were divided by their median age into 2 groups with comparable demographics: 69 years (group 1) and
N69 years (group 2).
Results: Group 1 patients demonstrated earlier onset of pain (most apparent during the second ination:
3115 s vs. 4626 s; pb0.001), and greater pain severity (ination #1: 6421 vs. 5125 [p=0.017];
#2: 6623vs.5227[p=0.008]; #3: 6323vs. 5424 [p=0.085]). ST-changes did not differ (0.240.10vs.
0.200.14, [p=0.18]; 0.270.17 vs. 0.200.14, [p=0.11]; 0.190.13 vs. 0.160.09; [p=0.32]). Time from
occlusion to onset of ECG changes did not differ between the groups, but increased with repetitive inations
(ination #1: 2911 s vs. 2911 s; #2: 3114 vs. 3311; #3: 3921 vs. 4015 s [increase p=0.017;
pb0.001]).
Conclusion: These data suggest that the perceptionof painfrommyocardial ischemia inthe elderly is signicantly
less severe and delayed compared to younger patients.
2009 Elsevier Ireland Ltd. All rights reserved.
1. Introduction
Exertional angina pectoris (AP) is the main manifestation of
coronary artery disease (CAD) in younger patients, but is less
frequently reported by elderly patients. If AP is present in the elderly,
then this is more often misinterpreted as arthralgia or pulmonary
disease and elderly patients tend to seek later for medical assistance
[13].
The most common symptom of acute ischemia in the elderly,
however, is dyspnoea caused by a transient rise in left ventricular (LV)
pressure during an ischemic event. In the presence of an age-
dependent reduction of LV chamber compliance, this may rapidly
progress to overt heart failure and arrhythmias [46].
The proportion of elderly patients without AP during an acute
coronary syndrome varies between 21% and 68% (7139). This may in
part be explained by an impaired pain perception with ageing, which
may prevent or delay rapid hospital admission in the setting of an ACS.
Impaired pain perception during acute myocardial ischemia in the
elderly has only been described retrospectively, but has not been
investigated experimentally yet.
The aim of this study was (1) to prospectively assess the age
related subjective pain perception induced by temporal myocardial
ischemia during percutaneous coronary intervention (PCI), (2) to
compare subjective pain perception during ischemia with the related
ECG changes, and (3) to compare age-dependent differences in
ischemic preconditioning.
2. Methods
2.1. Patient selection
Written informed consent was obtained prior to the study, which was approved by
an institutional review board (Freiburger Ethik Kommission, Germany).
The study population comprised 102 consecutive patients, admitted to our hospital
for PCI. Inclusion criteria required either a positive stress, AP on exertion [Canadian
Cardiovascular SocietyClass IIIII] or both. Furthermore a signicant proximal or mid-
International Journal of Cardiology 149 (2011) 6367
Corresponding author. Medizinische Klinik II, Ketschendorfer Str. 33, 96450
Coburg, Germany. Tel.: +49 9561 2233215; fax: +49 9561 226490.
E-mail address: rittger@arcor.de (H. Rittger).
0167-5273/$ see front matter 2009 Elsevier Ireland Ltd. All rights reserved.
doi:10.1016/j.ijcard.2009.11.046
Contents lists available at ScienceDirect
International Journal of Cardiology
j our nal homepage: www. el sevi er. com/ l ocat e/ i j car d
vessel coronary lesion (diameter stenosis between 50% and 80% as assessed by
Quantitative Coronary Angiography (QCA)) within a large vessel (vessel diameter
between 3.0 mm and 3.5 mm) as well as sufcient pre-interventional ow (TIMI
scoreN2) [14] was required. Exclusion criteria included ageb18 years and non
reversible wall motion abnormalities as assessed by echo and left ventricular
angiography with an ejection fractionb55%. Patients with an abnormal reaction to
autonomic function tests or nociceptive stimuli, chronic pain syndrome with the need
for analgesic medication, thoracic sensations due to application of contrast medium,
and mental decits were excluded from the study.
The study population was divided into two equally sized groups by the median age.
The elderly patient group included all patients equal to or older than the median age.
2.2. Pain rating
Patients were carefully advised how to rate pain severity and quality. A continuous
numerical rating scale was used to measure pain perception, ranging from 0 (no pain)
to 100 (worst pain possible) [15].
Pain quality was classied into 1.) typical AP without radiation; 2) typical AP with
radiation and 3). epigastric pain and 4.) other pain sensations.
2.3. Assessment of abnormal pain perception
Cold pressor testing (CPT) was applied to identify patients with an abnormal
sensitivity to nociceptive stimuli as previously reported [16]. The apparatus consisted
of a 5 l container lled with ice and water (temperature 04 C). Patients were
instructed to immerse their forearm into the water and to report their pain perception
after 30, 60, 90 and 120 s according to the above described pain rating scale. Patients
with an abnormal pain sensitivity in the CPT (rates below 20 and above 80=average
2D) were excluded.
2.4. Autonomic function test
Autonomic cardiac dysfunction was excluded by a Valsalva test: patients were
connected to a continuous ECG recording and instructed to blow into a mouth-piece
connected to a modied sphygmomanometer and hold a pressure of 40 mm Hg for 15 s.
In patients with normal autonomic regulation blood pressure drops and heart rate rises
during the strain period of the Valsalva maneuver. The presence of autonomic
dysfunction is characterized by a slow fall in blood pressure during the maneuver and a
slow return to baseline after release, with no overshoot rise in blood pressure and no
change in heart rate. This was performed 3 times at 1 min intervals. Results are
expressed as the Valsalva ratio, which is the longest RR-interval after the maneuver to
the shortest RR-interval during the maneuver). Values 1.2 reect normal parasym-
pathetic function [17].
2.5. Conduction of experimental pain testing
Diagnostic angiography was performed in standard projections after intracoronary
injection of 0.2 mg Nitroglycerine with non-ionic iodinated contrast medium
(Ioxaglate, Hexabrix, Guerbet, France). Quantitative coronary angiography (QCA)
was performed with a commercially available and validated QCA system (CAAS II,
Quantcore, Siemens Medical Solutions, Forchheim, Germany) [18].
Then a PCI-balloon (2.53.5 mm, Maverick, Boston Scientic, MA, USA) was
advanced into the stenosed segment and inated with low pressure until distal blood
ow stopped. This was tested under uoroscopy by injection of a small amount of
contrast. Patients were asked to report any pain sensation after balloon ination. Time
to onset of chest pain and pain severity score at onset and after 30, 60, 90 and 120 s of
occlusion were recorded.
After 120 s or after achieving a pain level 80, the balloon was deated. To identify
possible ischemic preconditioning this procedure was repeated twice with ischemia-
free intervals of 120 s. During the procedure a 12-lead-ECG was continuously recorded.
Onset and extent of ST-segment changes in relation to the rst onset of pain and after
30, 60, 90 and 120 s were noted as well as pain quality and pain severity scores at the
time of rst ST-segment changes.
2.6. Statististical analysis
Analysis of categorical and continuous parameters was performed using a
commercial statistical analysis software (SPSS Version 16.0, SPSS, Chicago, Illinois,
USA). All data are presented as meanstandard deviation for continuous data and as
proportions for binary data. A univariate analysis of variance (ANOVA) was applied for
continuous and Chi-square test for categorical variables. An alpha level of 0.05 was used
to determine statistically signicant differences.
3. Results
3.1. Study population
Patient demographic and angiographic characteristics are listed in
Table 1. 148 patients were screened for the study. Due to abnormal
CPT results 21 patients had to be excluded from the study (9 reported
no pain after 120 s, 11 indicated pain valuesN80). In addition 18
patients with values of b1.2 in the autonomic function test were
excluded as well as 7 patients with a pre-interventional TIMI-owb2
in the target vessel. The excluded patient group did not differ
statistically from the study groups regarding gender, age or any of the
other characteristics listed in Table 1. A total of 102 patients (68 male,
mean age 6811 years) were eligible for further testing. PCI was
performed in all cases without complications. There were no major
adverse cardiac events-(MACE, death, myocardial infarction, cere-
brovascular event and urgent revascularization) during initial
hospitalization and 30-day follow-up.
Median age was 69 years. The mean age of group 1 (n=51)
was 59.47.4 years, whereas the mean age of group 2 (n=51) was
76.64.8 years.
Most patients presented with two-vessel-CAD (Table 1). 67 patients
(66%) had a history of prior PCI. In 95 patients (93%) the target lesion
was a de-novo lesion, in 7 patients (7%) an instent-restenosis. Mean
reference vessel diameter was 3.30.33 mm, as assessed by QCA, MLD
was 0.60.7 mm, resulting in a diameter stenosis of 7916%. In 42
cases the treated vessel was the LAD, in 22 cases the circumex artery
and in 38 cases the right coronary artery. There were no signicant
differences noted between the elderly and younger cohort in baseline
demographics except body mass index, which was signicantly higher
in group 1 than in group 2 (28.94.7 kg/m
2
vs. 26.63.7 kg/m
2
[p=0.007]) (Table 1). The study comprised 45 diabetic patients (44%).
There was only a non-signicant trend towards more diabetic patients
in group 2 (n=27; 53%) compared to group 1 (n=18; 35%, p=0.073).
3.2. Pain rating
Pain assessment was performed successfully in 102 patients. In 98
(96%) patients all three predened balloon inations could be
completed whereas in 4 patients only the rst two inations could
be completed due to technical reasons. During repetitive balloon
ination 98 (96%) patients reported pain, four elderly patients (4%)
experienced no pain during balloon ination.
3.2.1. Pain onset
Pain onset occurred 4825 s after the rst balloon ination was
initiated, 3822 s after the second and 4024 s after the third
ination, respectively.
During all three occlusions group 1 experienced pain earlier than
group 2 (Fig. 1). The difference was most apparent during ination
#2 (3115 s vs. 4626 s; pb0.001).
3.2.2. Pain severity
Maximal pain intensity score was 5129 for occlusion 1, 5528
for occlusion 2 and 5229 for occlusion 3. The reported maximum
Table 1
Patient demographics according to age. Absolute and mean values, standard deviations
and proportions are given (BMI = body mass index, LV-EF = left ventricular ejection
fraction, CAD = coronary artery disease, n.s. = not signicant).
Younger patients Older patients p-value
b69.5 years N69.5 years
N 51 51
Age [years] 59.77.4 76.64.8 b0.001
Male 38 (75%) 30 (59%) n.s.
Female 13 (25%) 21 (41%) n.s.
Diabetes mellitus 18 (35%) 27 (53%) n.s
CAD-1 8 (16%) 12 (24%) n.s.
CAD-2 30 (59%) 20 (39%) n.s.
CAD-3 13 (25%) 19 (37%) n.s.
BMI [kg/m
2
] 28.94.7 26.63.7 0.007
LV-EF [%] 66.15.9 66.46.1 n.s.
Vessel diameter [mm] 3.10.3 3.10.3 n.s.
64 H. Rittger et al. / International Journal of Cardiology 149 (2011) 6367
pain ranged from 6524 (group 1) to 4631 (group 2). The highest
value was reached during ination 2 whereas the lowest value was
reached during ination 1.
There was a signicant difference in pain severity across both
groups with higher values in the younger population (occlusion 1:
6421 vs. 5125 [p=0.017]; occlusion 2: 6623 vs.5227
[p=0.008]; occlusion 3: 6323 vs. 5424 [p=0.085], Fig. 2).
There was no signicant intraindividual difference of maximal
pain intensity during the repetitive inations.
Also no signicant differences were observed for the aforemen-
tioned parameters between diabetics and non-diabetics as well as
between men and women (Table 2).
3.2.3. Pain intensity at the point of rst ST-segment changes
Pain intensity at the moment of rst ST-segment changes was 61
for all patients for occlusion 1, 1317 and 1719 for occlusion 2 and 3
respectively. Younger patients experienced more pain at the rst
detectable ECG changes than the elderly, which was statistically
signicant for occlusion 1 and 2 (916 vs. 25, p=0.006; 1818
vs. 713, p=0.002; 2021 vs. 1318; p=0.126).
3.2.4. Pain quality
70 patients (69%) reported typical retrosternal chest pain without
radiation, 14 patients (14%) complained of chest pain accompanied by
radiation to the neck, back or shoulder. 2 patients (2%) complained of
epigastric pain, 12 subjects (11%) reported other pain sensations.
There was no signicant difference between both groups.
3.3. ECG-changes
Of 102 patients 8 ECG tracings could not be analyzed for ST-
Segment changes (technical reasons n=5; left bundle branch block
n=2; pace-maker ECG n=1).
4 subjects of the elderly patient group and 1 of the younger
patients showed ECG changes during balloon inations.
The majority of the patients developed ST-segment elevations (n=
83; 81%), whereas 7 patients (7%) developed ST-segment depression.
3.3.1. Onset and extent of ECG changes
Mean ST-deviation after 120 s were 0.240.10 vs. 0.200.14,
(p=0.18); 0.270.17vs. 0.200.14, (p=0.11); 0.190.13 vs. 0.16
0.09; (p=0.32).
The delay from balloon ination to the onset of ECG changes
showed no signicant difference between both groups but increased
signicantly during the repetitive inations for the younger and
elderly cohort as well (2911 s vs. 2911 s [p=0.88]; 3114 vs.
329, [p=0.5]; 3921 vs. 4015 s [p=0.78]). The increase for
Fig. 1. This gure shows the time to onset of pain for occlusions 1, 2, and 3 stratied into
younger (69 years or less, white column, n=51) and elderly (N69 years, grey column,
n=51) patients. The graph illustrates a signicantly longer time to onset of pain during
occlusions #2 (pb0.001) and occlusion #3 (p=0.05).
Fig. 2. Mean pain ratings on a scale between 0 and 100 after 30 s, 60 s, 90 s, and 120 s of
occlusion time. Panel A shows mean pain ratings and standard deviation for younger
patients, Panel B shows mean pain ratings and standard deviation for elderly patients.
Table 2
Differences for pain onset [s], ECG changes at pain onset [mm], pain severity at pain
onset [sale from 0 to 100] and maximum pain severity for diabetics and non-diabetics
as well as for men and women. There were no signicant differences noted between all
groups.
First
occlusion
Second
occlusion
Third
occlusion
Time of pain onset [s] All patients 48.325.0 38.321.8 39.524.3
Diabetes mellitus 50.524.8 39.423.4 41.227.0
Non diabetes 46.925.2 37.520.8 38.222.1
Male 44.226.4 31.813.2 32.221.4
Female 44.018.0 29.418.0 41.529.5
ST-segment changes
at pain onset [mm]
All patients 0.160.08 0.100.10 0.070.08
Diabetes mellitus 0.130.09 0.110.11 0.090.10
Non diabetes 0.110.08 0.100.10 0.050.07
Male 0.110.08 0.080.09 0.060.08
Female 0.130.09 0.060.09 0.080.10
Pain severity score
at pain onset
All patients 18.48.6 20.114.4 18.79.0
Diabetes mellitus 18.08.0 19.89.7 19.59.6
Non diabetes 18.79.0 20.417.1 18.28.6
Male 19.57.0 17.612.6 18.88.6
Female 23.113.8 21.58.0 17.56.2
Maximum pain
severity score
All patients 58.323.7 59.725.5 58.424.0
Diabetes mellitus 56.922.5 55.524.2 54.724.4
Non diabetes 59.224.6 62.826.2 61.323.6
Male 62.523.0 65.124.8 61.824.9
Female 66.716.1 70.013.5 65.517.5
65 H. Rittger et al. / International Journal of Cardiology 149 (2011) 6367
occlusion 1 to occlusion 2 for group 1 vs. group 2 was p=0.155 vs.
p=0.022 and pb0.001 for occlusion 2 to 3 for both groups (Fig. 3).
4. Discussion
Due to the demographic changes in the industrialized countries,
the number of elderly patients who suffer from CAD and myocardial
infarction continues to rise. Elderly patients have a longer lag time in
seeking medical help compared to younger patients [13] and it has
been speculated that this could be due to an impaired pain perception
in elderly patients [713].
To the best of our knowledge, this is the rst prospective clinical
trial to assess systematically individual pain perception by temporary
coronary artery balloon occlusion in a direct comparison between
younger and elderly patients.
We found a signicant difference in the individual perception of
myocardial ischemia between elderly and younger patients, with a
signicant time lag to the onset of ischemic pain and a signicant
difference in perceived pain intensity.
Another nding of our study is, that objective ischemia patterns
expressed as onset and extent of ST-segment changes showed no
signicant difference between both groups. This implicates, that the
amount of ischemia was actually comparable between the younger
and the older patient cohort. Moreover, our results show that elderly
patients have a comparable amount of ischemia with lower pain levels
at both the onset and the maximum of visible ST-segment changes.
Several studies have demonstrated the atypical features and wide
variety of symptoms in elderly patients with acute myocardial
infarction [79]. A higher prevalence of diabetes and multivessel
diseases, leading to ischemic preconditioning through repetitive
episodes of ischemia or more collateral ow, were suggested as
possible mechanisms. However, we found no related difference
between elderly and younger patients. neither in the prevalence of
diabetes, nor in the prevalence of 1-, 2, and 3-vessel disease therefore
these factors do not explain the observed differences.
Also, we could as expected conrm the previously described
ischemic preconditioning effect with a progressively increasing time
delay from balloon ination to the onset of rst ECG changes after
subsequent coronary occlusions [2022]. However, this effect was
observed in both groups alike and is therefore independent of age, at
least in our experimental model. Interestingly, we found neither a
change in the time delay to onset of pain, nor an effect on pain
intensity as a result of preconditioning by repetitive occlusions in
either patient group.
Our results are consistent with a study by Ambepitiya et al. [19],
who investigated age-associated changes in pain perception by
comparing the time delay between the onset of ST-segment
depression and the onset of AP during exercise stress testing. The
authors found a signicant difference of the mean delay to onset of
pain, which was 49 s in patients aged 70 to 82 years and 30 s in
patients aged 42 to 59 years.
We conclude from these results that there is an age-dependent
reduction in pain sensitivity which is independent of objective signs
of ischemia and of ischemic preconditioning.
The reasons for the diminished pain perception in the elderly
patient cohort remain unclear. Ambepitiya et al. [19] postulated that
this might be caused by peripheral mechanisms such as changes in the
myocardial autonomic nerve endings with blunted ischemic pain
perception, as well as changes in central nervous mechanisms.
Another theory suggested that the higher prevalence of silent
myocardial ischemia and infarction in elderly patients with CAD
may be related to increased levels of endogenous opioids and
increased opioid receptor sensitivity [23]. This explanation does not
appear likely because studies have demonstrated a similar increase in
response of beta-endorphin levels to exercise in both elderly and
younger patients [24] and animal studies show a decrease in opioid
receptor responsiveness with advancing age [25].
The most likely cause therefore seems to be multifactorial in origin
including peripheral altered like impaired autonomic nerve respon-
siveness and central mechanisms.
The impaired pain perception helps to explain the variable clinical
symptoms in elderly patients in an acute ischemic event: elderly
patients are less likely to recognize the ischemia itself, but perceive
more the ischemic consequences like pulmonary congestion or
rhythm disturbances. Mental decits may play a role in the general
population, however, this cannot explain our ndings since patients
with mental decits were not included in this study.
A possible consequence may be the longer delay in seeking
medical assistance after the onset of chest pain as reported by Tresch
et al. [1]. They reported that elderly patients called paramedics on
average 6.5 h after onset of pain, compared to 3.9 h in younger
patients. Sheifer et al. [3] showed in the Cooperative Cardiovascular
Project, that among 102,339 patients older than 65 years with
conrmed acute myocardial infarction, 29.4% arrived at the hospital
N6 h after symptom onset.
Fig. 3. Individual values for the delay of onset of ECG changes for three repetitive
balloon occlusions for younger (A) and older patients age groups (B). The delay
between occlusion 1 and 2 was highly signicant for elderly patients and between
occlusion 2 and 3 highly signicant (p=0.017 and pb0.001 respectively) for both
groups.
66 H. Rittger et al. / International Journal of Cardiology 149 (2011) 6367
Similar to previously published ndings [26] that showed no
differences in the clinical symptoms in AMI between diabetics and
non-diabetics, there were no signicant differences in pain perception
between diabetics and non-diabetics in our study.
5. Limitations
The impact of collaterals may play a major role in this setting but
this question cannot be answered by this trail. Having comparable
groups regarding multivessel disease it seems not likely that this
would have a signicant impact.
Maximum possible ECG changes were not assessable because
balloon ination was stopped according to the protocol at a pain level
of 80. Assessing maximum possible pain intensity could have
inuenced the results but was not in the scope of this clinical study
due to ethical considerations. The observed difference in the time
delay fromonset of induced ischemia to the onset of pain between the
younger and elderly patient cohorts in our experimental setting was
only about 15 s on average. Despite the statistical signicance, this is
obviously a very small difference in absolute terms when compared to
the above cited clinical experience which reports clearly longer delays
in the range of hours. However, this might be explained by our
experimental model with a dened complete cessation of coronary
ow, which rarely occurs in clinical reality. More slowly reduction of
coronary ow by repetitive thrombus formation might have a
signicant impact on the time delay to pain perception and clinical
presentation.
6. Conclusion
Our study demonstrates a signicantly impaired pain sensitivity
during myocardial ischemia in the elderly. We found an age
dependent reduction in perceived pain sensitivity, which is neither
related to the severity of myocardial ischemia as assessed by ECG
changes, nor to ischemic preconditioning. We found no differences in
pain quality between elderly and younger patients.
Acknowledgements
The authors of this manuscript have certied that they comply
with the Principles of Ethical Publishing in the International Journal of
Cardiology [27].
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