Author + information
- Received October 23, 1995
- Revision received May 2, 1996
- Accepted May 13, 1996
- Published online October 1, 1996.
- COLOMBA FALCONE*,
- CARLA AUGUADRO,
- RENATO SCONOCCHIA,
- ORONZO CATALANO,
- MICHAEL OCHAN,
- LUIGI ANGOLI and
- CARLO MONTEMARTINI
- ↵*Address for correspondence: Dr. Colomba Falcone, Department of Cardiology, IRCCS Pol. San Matteo, Piazzale Golgi 1, 27100 Pavia, Italy.
Objectives. This study in patients with coronary artery disease (CAD) sought to 1) determine the dental pain threshold and reaction to tooth pulp stimulation; 2) correlate the clinical, ergometric and angiographic features of patients with and without pain during percutaneous transluminal coronary angioplasty (PTCA) to pulpal test response; 3) verify whether reactivity to dental pulp stimulation could help to identify patients particularly prone to perceiving angina during myocardial ischemia.
Background. Silent myocardial ischemia is frequently observed in patients with CAD. Higher pain thresholds have been documented in asymptomatic subjects, suggesting a generalized hyposensitivity to pain.
Methods. Eighty-six consecutive male patients with reproducible exercise-induced myocardial ischemia and CAD documented by angiography underwent PTCA. A pulpal test was performed in all patients by means of an electrical tooth pulp stimulator.
Results. Seventy-one patients (82.6%) with and 15 (17.4%) without angina during daily life were studied. During the pulpal test, 57 patients (66.2%) reported dental pain, whereas 29 (33.7%) were asymptomatic, even at maximal stimulation of 500 mA. The study cohort was classified into two groups according to the presence (58 patients [group 1]) or absence (28 patients [group 2]) of angina during myocardial ischemia induced by PTCA. Ergometric variables, extent of CAD, presence of ST segment elevation during PTCA, number of inflations, inflation time and maximal inflation pressure were similar in the two patient groups. Dental pain was provoked by pulpal test in 81% of patients with and 36% of patients without symptoms during PTCA (p = 0.0004). The absence of dental pain even at maximal tooth pulp stimulation (500 mA) was observed in 11 (18.9%) patients in group 1 and 18 (64.2%) in group 2. Patients who were asymptomatic during PTCA had a higher mean dental pain threshold, lower mean threshold reaction and lower mean maximal reaction than those who were symptomatic during both PTCA and the pulpal test.
Conclusions. A correlation between the prevalence of symptoms during pulpal test, daily life, exercise-induced myocardial ischemia and PTCA was found. A higher dental pain threshold and lower reactivity characterized those subjects who were prone to silent ischemia both during daily life and during PTCA. Ergometric variables, extent of CAD and techniques used during PTCA were unrelated to the tendency to perceive pain during myocardial ischemia. Response to the pulpal test and the presence of symptoms during daily life were highly related to the presence of angina during PTCA.
Silent myocardial ischemia is frequently observed in patients with coronary artery disease (CAD) both during daily life and during stressor tests [1–5]. Some investigators have reported that the absence of symptoms is frequently associated with ischemia of shorter duration and smaller extension; however, acute ischemia during myocardial infarction and angioplasty-induced coronary occlusion may also not be associated with anginal pain [6–9]. Various mechanisms have been proposed to explain the absence of angina during myocardial ischemia. The endogenous opioid system seems also to play an important role in pain modulation [10–15]. A generalized hyposensitivity to different painful stimuli has been reported in asymptomatic patients, and a higher pain threshold has been demonstrated in such subjects by means of various stimulating techniques. This result suggests that the lack of symptoms may be partly explained by individual differences in pain threshold [16–19].
Dental pulp stimulation may be used to test the pain threshold in humans [19–24]. The electrical pulp stimulation and consequent pain are very brief (a few seconds) and produce no tissue damage. Because the test current can be increased progressively, the pulpal test allows quantification of the pain threshold and avoids interference from superficial sensations that could be triggered by other methods. This study in patients with CAD sought to 1) determine dental pain threshold and reaction to tooth pulp stimulation; 2) correlate the clinical, ergometric and angiographic features of patients with and without symptoms during angioplasty with the pulpal test response; 3) verify whether reactivity to dental pulp stimulation could help to identify patients particularly prone to experience anginal pain during episodes of myocardial ischemia.
Patient selection. Eighty-six consecutive male patients who underwent percutaneous transluminal coronary angioplasty (PTCA) for clinical indications were enrolled in the study. The inclusion criteria were reproducible exercise-induced myocardial ischemia; CAD documented by angiography; PTCA successfully performed in at least one vessel; presence of transmural myocardial ischemia (electrocardiographic [ECG] changes) provoked by PTCA in areas that were not involved in previous myocardial infarction; dental formula suitable for the pulpal test, as indicated by a previous dental checkup.
The study included 71 patients with and 15 without history of angina. Thirty-seven patients had a previous myocardial infarction >6 weeks before the study (2 of 37 patients were symptomless during the acute event). One-vessel disease was documented at angiography in 62 patients and multivessel disease in 24. The dilated vessel was the left anterior descending coronary artery in 50 patients and the right coronary artery in 36. Mean (±SD) ejection fraction calculated by the standard area-length method was 61.7 ± 11.1%, mean left ventricular end-diastolic pressure 17.8 ± 9.9 mm Hg, and mean end-diastolic volume 127.6 ± 50.7 ml. Patients with valvular disease, bundle branch block, congestive heart failure, systemic hypertension, diabetes, peripheral neuropathy or clinical conditions that did not permit temporary withdrawal of antianginal therapy were excluded from the study. All patients enrolled underwent the following tests: bicycle exercise stress test (EST), pulpal test, coronary angiography and PTCA. The tests were performed at pharmacologic washout; calcium channel blocking agents and nitrates were suspended 48 h before the tests. No patient received beta-adrenergic blocking agents or digitalis. Written informed consent was obtained from all patients for each test. The study was approved by the ethics committee of the hospital.
Exercise stress test. A multistage bicycle ergometric stress test was performed 1 to 7 days before PTCA, in the supine position with an initial work load of 25 W and subsequent stepwise increments of 25 W every 3 min at a pedaling frequency of 60 rpm. A 12-lead standard ECG was recorded before the test, every minute during exercise, at peak exercise and every minute during recovery. Leads D3, V5 and V6 were monitored continuously throughout the test and displayed on an oscilloscope. Blood pressure was measured by means of a standard sphygmomanometer at baseline and at 3-min intervals during exercise and recovery. During the test, patients were asked about the presence of chest pain or discomfort. When present, it was quantified on a scale from 1 to 10 and timed in seconds. The test was stopped when moderate to severe angina, dyspnea, exhaustion, major arrhythmias or ST segment depression >3 mm occurred. A positive ECG response was defined as the occurrence of at least 1 mm flat or downsloping ST segment depression for a duration of 0.08 s after the J point. Ischemia threshold was defined as 1-mm ST segment depression. Rate-pressure product (RPP) (Heart rate [beats/min] × systolic blood pressure [mm Hg]) was calculated at baseline, at ischemia and pain thresholds and at peak exercise.
Pulpal test. An electrical tooth pulp stimulator, commonly used in dentistry for diagnosis of pulp disease, was used to determine dental pain threshold. The tooth pulp tester utilized for this study was the same as that used previously ; it is an electronic device that delivers a square-shaped current impulse (plateau 70 ms) of increasing intensity. The stimulator was applied to the tooth through a metal cylinder and was designed to deliver a current impulse of increasing intensity from 10 to 500 mA. As the test current increased, a number from 0 to 9 was displayed on the instrument. All patients had previously undergone a dental checkup to exclude tooth fractures, abrasions, caries, fillings or marked periodontal disease. The test was performed on at least two healthy upper incisors and one inferior incisor. The average of the measurements for the three teeth was used. Patients were instructed to raise their hands at the occurrence of pain or when they wanted the test to be stopped. Dental pain threshold was defined as the minimal current intensity level that elicited any pulp sensation (10 to 500 mA; 1 to 9 on the tester). The highest intensity current (500 mA; 9 on the tester) was applied in all patients. During the test, patients were asked to grade the intensity of pain experienced (reaction) on a scale from 1 to 10; threshold reaction (mean pain intensity at dental pain threshold) and maximal reaction (pain intensity at maximal stimulation) were determined in all patients. The lack of sensation at maximal stimulation was defined as reaction 0. Pulpal test was performed at rest and under comfortable conditions 1 day before PTCA in the morning between 9 and 11 am. The cardiologist who performed PTCA (L.A. or C.M.) was blinded to the response to the pulpal test.
Coronary arteriography. Arteriography was performed using the Sones technique, with multiple views of each vessel being filmed 1 to 15 days before coronary angioplasty. Significant CAD was considered present when ≥50% lumen diameter stenosis was found in a major coronary vessel. Left ventriculography was performed before coronary arteriography in the 30° right anterior oblique projection. Ventricular volumes and ejection fractions were calculated by the standard area-length method.
Percutaneous transluminal coronary angioplasty. Coronary angioplasty was performed in all our patients by the femoral approach, between 9 and 11 am. The procedure is the same as that described in a previous study . During the procedure, the patients were asked about the occurrence of symptoms and, if present, they were reported on a graduated linear scale (1 to 10). Onset of ST segment displacement and any variations were carefully observed and independently estimated by two cardiologists (C.F., C.A.). Coronary angioplasty was performed only in a single vessel in each patient; successful angioplasty was defined as a diameter gain of 20% without complications.
Statistical analysis. Results are presented as mean value ±SD. Statistical significance was tested by means of one-way analysis of variance, the contrast method and linear regression analysis using the computerized SPSS program (Statistical Package for the Social Sciences). The Mann-Whitney test was used for two independent nonparametric samples; p < 0.05 was considered statistically significant.
Clinical features. Of the 86 study patients, 71 (82.6%) reported angina during daily life (7 on effort, 4 at rest and 60 mixed; mean anginal pain intensity 5.2 ± 2.6), and 15 (17.4%) had silent ischemia (3 had a history of syncope, 3 had silent postinfarction myocardial ischemia, and 9 were referred because of silent myocardial ischemia discovered during a routine checkup). All patients had myocardial ischemia during the EST: 32 patients (37.2%) referred for angina (mean anginal pain intensity at peak exercise was 4.0 ± 2.8), whereas 54 (62.8%) were asymptomatic. The RPP at baseline, at ischemia threshold and at peak exercise was 9,292 ± 2,199, 19,601 ± 5,623 and 21,786 ± 5,685 beats/min × mm Hg, respectively. Fifty-seven patients (66.2%) reported dental pain during the pulpal test (mean dental pain threshold 5.7 ± 2.0, mean threshold reaction 3.4 ± 1.5, mean maximal reaction 5.3 ± 2.7), whereas 29 (33.7%) were asymptomatic (threshold 0 and reaction 0 to pulpal test) even at maximal stimulation (500 mA). No significant variations in control heart rate and blood pressure were observed during the procedure.
The study cohort was classified into two groups according to the occurrence of angina during myocardial ischemia induced by coronary angioplasty: Group 1 included 58 patients (67.4%, mean age 53.8 ± 8.6 years) with anginal symptoms, Group 2 included 28 patients (32.5%, mean age 59.2 ± 7.0 years) without symptoms during coronary occlusion. The characteristics of the groups are summarized in Table 1.
Percutaneous transluminal coronary angioplasty. The number of inflations, inflation time and maximal inflation pressure were similar in Groups 1 and 2 (p = NS). No statistical differences in mean baseline heart rate and blood pressure were observed. Mean heart rate and blood pressure values during PTCA were also similar between patients with and without symptoms. Onset of ECG changes was observed at similar inflation pressures in both groups (3.9 ± 1.0 atm for Group 1 vs. 4.1 ± 0.4 atm for Group 2). All patients had transmural ischemia as an inclusion criterion; the presence of ST segment elevation was similar in the two groups, and ECG changes lasted an average of 29 ± 12 s in Group 1 and 23 ± 14 s in Group 2 (p = NS). Anginal pain during PTCA was provoked in 57 (80.2%) of 71 patients with and 1 (6.6%) of 15 without symptoms during daily life. PTCA-related anginal pain appeared in the symptomatic patients at maximal balloon dilation (mean anginal pain intensity 6 ± 2.17). Anginal pain appeared 37 ± 35.7 s from the start of inflation. Absence of anginal pain during PTCA-induced myocardial ischemia was observed in 10 (17.5%) of 57 patients with symptoms at pulpal test. A positive correlation between anginal pain intensity during daily life and PTCA was also found (p = 0.005) (Table 1).
Exercise stress test. Of 32 patients who were symptomatic during the EST, 22 (68.7%) also reported anginal pain during PTCA, whereas the remaining 10 (31.2%) were asymptomatic during PTCA. Of 54 patients without symptoms during the EST, 18 (33.3%) remained asymptomatic, whereas 36 (66.6%) reported pain during PTCA. The intensity of anginal pain and ST segment displacement induced by EST were similar in patients in both groups. The RPP at baseline, at ischemia threshold and at peak exercise also did not differ between the two groups. In patients with symptoms during both PTCA and EST, the pain threshold rate-pressure product was similar to that in patients without symptoms during PTCA but with symptoms during EST. Patients with and without symptoms during EST did not differ with regard to the extent and distribution of CAD (Table 1).
Pulpal test. Dental pain was provoked by pulpal test in 47 (81%) of 58 symptomatic and 10 (35.7%) of 28 asymptomatic patients during PTCA (chi-square 16.93, p = 0.0004). Absence of pain during pulpal test, even at maximal tooth pulp stimulation, was observed in 11 (18.9%) symptomatic and 18 (64.2%) asymptomatic patients during PTCA (Table 1). Asymptomatic patients during PTCA who had pain during dental pulp stimulation had a higher mean dental pain threshold, lower mean threshold reaction and lower mean maximal reaction (7.3 ± 2, 1.9 ± 0.9 and 2.4 ± 1.2, respectively) than patients symptomatic both during PTCA and pulpal test (5.3 ± 1.9, p = 0.0006; 3.7 ± 1.4, p = 0.0001; 6.1 ± 2.6, p = 0.0000, respectively, all by the Mann-Whitney test) (Fig. 1). There was also a correlation between the prevalence of symptoms during daily life, exercise-induced myocardial ischemia, pulpal test and PTCA; 14 (93.3%) of 15 patients without symptoms and 56 (78.8%) of 71 with symptoms during daily life were asymptomatic and symptomatic during pulpal test, respectively. Significant differences in mean dental pain threshold (8.7 ± 1.3 vs. 6.5 ± 2.3, p = 0.0016, Mann-Whitney test), mean threshold reaction (0.3 ± 0.8 vs. 2.6 ± 1.9, p = 0.0000, Mann-Whitney test) and mean maximal reaction (0.5 ± 1.8 vs. 3.9 ± 3.3, p = 0.0001, Mann-Whitney test) between asymptomatic and symptomatic patients during daily life were observed (Fig. 2). Twenty-six patients (81.2%) who reported angina during EST also had dental pain during tooth pulp stimulation; of 54 asymptomatic patients during EST, 23 (42.5%) were also asymptomatic during pulpal test. Of 58 symptomatic patients during PTCA, 22 (37.9%) were also symptomatic during EST and pulpal test; of 28 asymptomatic patients during PTCA, 12 (42.8%) were also asymptomatic during EST and pulpal test. Of 31 patients with silent ischemia during EST and symptoms during pulpal test, 25 (80.6%) reported anginal pain during PTCA.
A multiple regression model was constructed to assess the relative importance of the variables (age, angina during daily life and pulpal test responsiveness) that were significantly different between the two groups of patients for predicting the occurrence of angina during PTCA-induced transmural ischemia. This model showed a stronger statistical power for pulpal test stimulation results. Dental pain threshold, threshold reaction and, above all, maximal reaction could explain ∼30% to 35% of the observed variability in the presence or absence of angina during PTCA-induced myocardial ischemia (adjusted coefficient of determination was, respectively, 0.29, 0.33 and 0.36, p = 0.0000). The inclusion in the model of the patient age increased the predictive power to 38% to 49% (adjusted R2 = 0.39, 0.47 and 0.48, respectively, p = 0.000, 0.0004 and 0.000, respectively).
Angiography. Extent of coronary artery disease, ejection fraction, left ventricular end-diastolic pressure and end-diastolic volume were similar in the two groups of patients (Table 1).
A high incidence of anginal symptoms both in daily life and during PTCA despite a low prevalence of angina during exercise-induced myocardial ischemia was observed in our cohort with CAD. Significant differences in dental pain threshold and reaction were observed between patients with and without symptoms during daily life and PTCA. The prevalence of pain during pulpal test correlates with the prevalence of angina both during daily life and PTCA-induced myocardial ischemia.
Silent ischemia during PTCA, EST and daily life. The prevalence of silent myocardial ischemia varies from 16% to 47% during PTCA and from 32% to 70% during EST [5, 24, 26–34]. In our cohort, 63% of patients were asymptomatic during EST, and only 32.5% did not report angina during PTCA. The variables of the inflation procedure were not correlated with the tendency to perceive pain during myocardial ischemia induced by coronary occlusion. Thus, duration or intensity of ischemia and left ventricular dysfunction are not absolute factors in determining the occurrence of angina, although it has been reported [6, 8, 9]that the absence of pain is frequently associated with myocardial ischemia of shorter duration and smaller extent. The higher prevalence of silent ischemia during exercise could probably be explained by the greater activation of the sympathetic system, resulting from physical stress. Previous studies [35, 36]have demonstrated that activation of the baroceptor reflex arch by pressor agents can induce hyperalgesia in rats, and stimulation of the cardiopulmonary vagal afferents could be responsible for the absence of pain in humans during myocardial ischemia. Sheps et al. suggested that the stimulation of baroceptors may modify the perception of anginal pain. In fact, they found a positive correlation between rest blood pressure and an index of ischemic pain perception . It has also been reported [38–40]that the pain threshold in subjects with essential hypertension was higher than in age-matched normotensive patients. In our cohort the blood pressure values at peak exercise were higher than during balloon occlusion. This finding might confirm the role of the baroceptor regulatory system in the greater prevalence of silent ischemia during exercise. The stronger ischemic stimulus during balloon coronary occlusion may have been the cause of our patients being asymptomatic during exercise but otherwise prone to perceive pain. Twenty-two of the patients who were symptomatic during PTCA reported pain during EST, and 18 of those without symptoms during PTCA were also asymptomatic on EST. A strong correlation between the prevalence of symptoms during daily life and during provoked myocardial ischemia was found. In fact, the majority of symptomatic patients during daily life also had anginal symptoms during PTCA. Moreover, the intensity of angina both during daily life and EST was higher in symptomatic than asymptomatic patients during PTCA. Therefore, individual differences in sensitivity to pain and, above all, an individual variability in pain perception might explain in part the presence or absence of angina during myocardial ischemia.
Pulpal test response and anginal pain perception. Symptomatic patients during myocardial ischemia differ from those with silent ischemia in reactivity to pain. Various studies [17–19, 41, 42]have demonstrated that in patients with silent myocardial ischemia, the mean pain threshold and tolerance in response to electrical skin stimulation and forearm ischemia are significantly higher than in those with symptomatic ischemia. Tooth pulp stimulation has also been used to determine pain threshold in humans, and a fair reproducibility of pulpal test results was found in all studies using the same technique [43–45]. In a previous study that we performed in patients with CAD , tooth pulp stimulation showed significant differences in dental pain threshold and reaction between patients with and without angina during myocardial ischemia. Most patients with silent ischemia during EST did not have pain during pulpal test, even at the highest intensity of test current. Likewise, 80.4% of patients who were symptomatic during exercise also reported pain during dental pulp stimulation . In the present study a correlation was found between dental pain threshold, reaction to pulpal test and angina. A higher dental pain threshold and a lower maximal reaction to pulp stimulation were observed among asymptomatic than symptomatic patients during daily life and PTCA. Dental pain was evoked by tooth pulp stimulation in 81% of symptomatic and 36.8% of asymptomatic patients during PTCA-induced myocardial ischemia. Patients with symptoms during PTCA had significantly a lower mean dental pain threshold and a higher mean threshold reaction and mean maximal reaction at pulpal test than did asymptomatic patients during PTCA. These results suggest that in patients prone to pain, the pulpal test is able to confirm this susceptibility, whereas in those who show a variable reactivity to various painful stimuli, the pulpal test has the same probability to evoke pain. Thus, individual differences in pain perception seem to be an important factor in determining susceptibility to pain.
Previous studies have demonstrated that psychological features may modulate the cardiovascular and neurohumoral responses to noxious stimuli producing discomfort. Personality traits, emotional state, environment or psychological stress, social factors, degree of physical conditioning, amount of exercise and time of day have all been proposed as having a role in pain perception . Different mechanisms have been suggested [10, 19, 38, 49]to explain the hyposensitivity to pain in response to different techniques of pain stimulation: inadequate stimulus, a defect in peripheral pain perception, a defect in central pain sensation transmission, a disturbance in central pain modulation, damage to the cardiac nociceptive pathway by previous infarction or neuropathy and the involvement of the endogenous analgesic system. Many central and peripheral mediators have been recognized as important factors in the modulation of pain, such as endorphins (higher beta-endorphin plasma levels both at baseline and during stress have been documented in asymptomatic patients), metenkephalin, serotonin, catecholamines, gamma-aminobutyric acid and adenosine [14, 15, 25].
A generalized altered perception of noxious stimuli in elderly patients has been reported; in fact age seems to be an independent risk factor for silent myocardial ischemia [46–48]. Our asymptomatic patients undergoing PTCA were on average older than our symptomatic patients; moreover, the inclusion of patient age in the multiple regression model increased the predictivity for the presence or absence of symptoms from 30% to 35% to 38% to 49%.
Variability in response to painful stimuli. An intragroup variability in response to various painful stimuli was observed in our patients. A similar overlap in pain threshold between symptomatic and asymptomatic patients with CAD was previously found [19, 49]; moreover, patients with documented CAD may have both symptomatic and asymptomatic ischemic episodes [4, 6–8, 17–19, 49–51]. Varying concentrations of beta-endorphins in plasma, cerebrospinal fluid and intersynaptic fluid may underlie the varying individual sensitivity to pain. A circadian variation in pain threshold has been also reported ; in patients with variable responses to painful stimuli, both the circadian beta-endorphin secretion and the response to various stressors may undergo periodic variations [52, 53]. A greater instability in beta-endorphin plasma levels among symptomatic patients has been observed . In fact, a significant reduction in beta-endorphin plasma levels during angioplasty has been documented in patients with symptoms, whereas patients with silent ischemia showed more stable values during the procedure . A greater or lesser variation in beta-endorphin plasma levels might explain the presence or absence of angina during different ischemic episodes occurring in the same patient. In the present cohort, only 15% were always asymptomatic (during daily life, EST, PTCA and pulpal test), and this group probably represents truly asymptomatic patients. In contrast, 25.5% of our patients were always symptomatic, and thus they can be considered truly symptomatic. In between these two groups was a continuous spectrum of patients who were sometimes symptomatic and sometimes asymptomatic.
Conclusions. Our results demonstrate the presence of an individual profile for pain perception. A positive correlation between the response to the pulpal test and the presence of angina during myocardial ischemia in patients prone to pain was documented. In fact, a higher dental pain threshold and a lower dental pain reaction characterized the subjects who were prone to silent ischemia. Therefore, pulpal stimulation--a common, simple, brief and safe procedure used in dentistry to determine tooth viability--may find useful application in cardiology by identifying a subgroup of patients at relatively high risk of symptomless acute ischemic events. Patients with a higher pain threshold and lower reactivity on pulpal test constitute a subgroup that should be the focus of particular attention during follow-up. These patients with even severe CAD manifest minimal symptoms, thus lacking the usefulness of angina as a warning. In contrast, patients with a low dental pain threshold and high reactivity to dental pulp stimulation may receive adequate attention and workup by the cardiologist because their disease is more associated with anginal pain, forcing them to seek regular care.
A.1 Abbreviations and Acronyms
CAD = coronary artery disease
ECG = electrocardiogram, electrocardiographic
EST = exercise stress test
PTCA = percutaneous transluminal coronary angioplasty
RPP = rate-pressure product
- Received October 23, 1995.
- Revision received May 2, 1996.
- Accepted May 13, 1996.
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