Safety and feasibility of atropine added in patients with sub-maximal heart rate during exercise myocardial perfusion SPECT
Failure to reach 80% of maximal predicted heart rate (HR) during exercise may render a myocardial perfusion single photon emission computed tomography (SPECT) study non-diagnostic for ischemia detection. We sought to investigate the injection of atropine in patients who fail to achieve 80% of age-predicted HR during exercise performed for myocardial perfusion SPECT (MPS), defining its safety and efficacy to raise HR to adequate levels as well as its effect on MPS interpretation.
Methods and results
Between January 2002 and December 2004, we studied 3,150 consecutive patients (2,253 men and 897 women, mean age 55 ± 6 years) who were referred to a single office-based nuclear cardiology laboratory for MPS using SPECT imaging. One milligram of atropine was administered to patients that were unable to continue because of fatigue before reaching minimal HR, without an ischemic response (group A, n = 397). The scintigraphic results for group A were compared with those of patients who spontaneously achieved target HR (group B, n = 2,753). In group A, mean HR before atropine injection was 119.5 ± 13.6 beats per minute (bpm), and it increased up to 137.3 ± 13.5 bpm after drug administration, with an incremental of 17.8 ± 6.9 bpm (P < 0.0001). The mean percentage of age-related HR achieved in this group was 83.5 ± 8.1%. In 302 of this patients (76.1%) more than 80% of their aged-related HR (86.9 ± 5.1%) was attained. No major adverse effects occurred. When groups A and B were compared, baseline and peak HR, rate pressure product, and maximal metabolic equivalents achieved were higher in group B. There were no significant differences in the percentage of total positive perfusion studies between both groups: 210/397 patients (52.9%) in group A and 1,342/2,753 patients (48.7%) in group B (P = 0.39). Ischemia or ischemia plus scar was found in 112/397 patients (28.2%) in group A and in 923/2,753 patients (33.5%) of group B (P = 0.14).
Atropine added to exercise stress testing in patients who cannot achieve their 80% age-related HR is a safe, well-tolerated, and feasible method for MPS.
KeywordsAtropine Exercise testing Myocardial perfusion SPECT Maximal predicted heart rate
Myocardial perfusion imaging is a vital non-invasive tool for determining the hemodynamic severity of coronary artery disease (CAD). Single photon emission computed tomography (SPECT) images reflect myocardial blood flow at the time of injection, and studies typically are performed both during stress and rest to determine the extent and severity of inducible ischemia.
For assessment during stress, exercise or pharmacologic stress is used . Exercise stress is more physiologic, and some authors have found a higher sensitivity and specificity then with pharmacologic stress . For this reason, maximal subjective stress testing is encouraged whenever possible. However, if exercise capacity is poor, the perfusion study may be sub-optimal [3, 4, 5, 6]. An exercise test result is considered sub-optimal if the patient does not have angina, fatigue, electrocardiographic (ECG) evidence of ischemia, arrhythmias, decrease in blood pressure, or signs of poor perfusion and does not achieve a minimal desirable heart rate (HR) . This minimal HR is considered to be 85% of the patient’s age-predicted HR (220-Age) . Unfortunately, a significant proportion of patients do not reach their HR during exercise . This is probably an increasing phenomenon, as the number of patients with established or suspected CAD shifts to a more aged, obese, and disabled population. A number of factors contribute to the failure to exercise adequately, including physical deconditioning, in addition to β-blockers, peripheral vascular disease, stroke, arthritis, orthopaedic problems, and chronic pulmonary disease, as well as chronotropic incompetence related to depressed cardiac sympathetic tone [10, 11, 12, 13]. Atropine is an anticholinergic drug that cause a rapid increase in HR and has been commonly used as on adjunct to dobutamine in pharmacologic stress protocols [14, 15, 16, 17, 18, 19, 20, 21]. However, atropine administration during exercise has not been extensively studied. We sought to investigate a new alternative. The injection of atropine was given to patients who fail to achieve at least 80% of age-predicted HR during exercise performed for myocardial perfusion SPECT (MPS), and in this way we obtained an increase of HR >85% and at the same time to define its safety and efficacy to raise HR to adequate levels ( >85%) as well as its effect on MPS interpretation.
2 Materials and methods
2.1 Study population
Between January 2002 and December 2004, we studied 3,150 consecutive patients (2,253 men and 897 women, mean age 55 ± 6 years) who were referred to a single office-based nuclear cardiology laboratory (Medicina Nucleare s.r.l., Palermo, Italy) for MPS using SPECT imaging.
The exclusion criteria were acute myocardial infarction in the previous month and inability to perform physical exercise. We also excluded patients with any formal contraindication for atropine, such as glaucoma, obstructive uropathy, or obstructive gastrointestinal disease.
β-blockers or calcium antagonist therapy and apparent poor physical tolerance were non-exclusion criteria.
2.2 Exercise protocol
All of the patients performed maximal or symptom-limited treadmill exercise test according to the Bruce protocol (Marquette Max 1, Jupiter, FL, USA). Blood pressure and 12-lead ECG recording were obtained at rest, at the first and third minute of every stage of exercise, at the end of exercise, at the first and the third minute of the recovery period, and then every 3 min until the electrocardiogram returned to normal. During exercise, 12 leads were continuously monitored. The exercise test results were considered valid whenever the patient’s maximal HR achieved was greater than or equal to 85% of the age-related target [220 beats per minute (bpm)-Age] or the patients have any of the following develop: angina, ST depression >0.2 mV, dyspnea, complex ventricular arrhythmias, a decrease in systolic blood pressure >10 mmHg in two consecutive steps, and fatigue. The presence of angina or ST depression ≥0.1 mV, measured at 80 ms from the J point, were considered as criteria of positivity.
Patients who were unable to continue with further load increments in order to achieve their age-related HR received 1 mg of atropine during the end stage of dynamic exercise (group A, n = 397). We monitored the HR response for the next minute and administered another 0.5 mg of atropine if the target HR was not reached. The maximal dose was 2 mg. After atropine administration, load was maintained, and patients continued to exercise for at least one more minute. Severe adverse events due to atropine were recorded (we did not record minor adverse events such as palpitations or xerostomia). We compared these patients with another group of consecutive non-selected patients who achieved the target HR without atropine (group B, n = 2,753). Experienced staff cardiologists interpreted the exercise tests.
All patients gave written informed consent to undergo the study. The Human Studies Committee of the Buccheri La Ferla Fatebenefratelli Hospital approved this protocol.
2.3 SPECT imaging
Approximately 1 min before the termination of the exercise test, an intravenous dose of 370 MBq of 99 m-technetium tetrofosmin was administered. The acquisition of stress SPECT imaging was started 30 min after the test. Resting studies were performed 72 h after the stress study, 1 h after injection of 370 MBq of tetrofosmin. The same isotope administered during stress was used for rest studies. Each study was performed using a General Electric Millennium gamma camera interfaced to a General Electric Genie computer system (General Electric Medical System, Milwaukee, WI, USA). Image acquisition and interpretation were performed in according to the protocol previously described [22, 23]. For each study, six oblique (short-axis) slices from the apex to the base and three sagittal (vertical long-axis) slices from the septum to the lateral wall were defined. Each of the six short-axis slices was divided into eight equal segments. A total of 47 segments per patient were analysed (after exclusion of the septal part of the to basal slices). The interpretation of the scan was performed by semiquantitatively visual analysis assisted by the circumferential profiles analysis. All tomographic views were reviewed in a side-by-side pair (stress and rest) by an experienced observer who was unaware of the patients’ clinical or ECG data. A reversible perfusion defect was defined as a perfusion defect on stress images that partially or completely resolved at rest images in two or more contiguous segments or slices. This was considered diagnostic of ischemia. A fixed perfusion defect was defined as a perfusion defect on stress images in two or more contiguous segments or slices that persist on rest images. Defects without redistribution were defined as scar. Six major myocardial segments were identified: anterior, inferior, septal anterior, septal posterior, posterolateral, and apical. The following variables were compared between both groups: maximal and percent of age-related HR achieved, systolic peak pressure, baseline and peak rate pressure product, number of metabolic equivalents achieved, and percentage of patients with positive perfusion study results for ischemia, scar, and both together (ischemia plus scar).
2.4 Statistical analysis
Results are expressed as the mean ± standard deviation (SD). Data were analysed by the two-tailed t-test to identify differences between the groups. Nominal data were analysed by the Chi-square test or Fischer’s test. Differences were considered significant at a P-value < 0.05. All analyses were performed using the Statistical Package for Social Sciences (SPSS 11.5) software (SPSS Inc.).
3.1 Baseline clinical characteristics
Baseline clinical characteristics
Group A (atropine)
Group B (no atropine)
Age, years (mean ± SD)
56 ± 1
55.8 ± 8
Male sex (%)
Cigarette smoking (%)
Family history of CAD (%)
Previous AMI (%)
History of PCI (%)
History of bypass surgery (%)
Baseline and maximal hemodynamic parameters
Group A (atropine)
Group B (no atropine)
Baseline HR (bpm)
67.8 ± 12.0
79.7 ± 12.7
Baseline SBP (mmHg)
128.5 ± 24.3
132.6 ± 21.6
Baseline DBP (mmHg)
81.7 ± 13.5
85.2 ± 10.8
9,728.1 ± 2,748.5
10,735.2 ± 2,878.3
Maximal HR (bpm)
137.3 ± 13.5
151.2 ± 19.6
83.5 ± 8.1
91.8 ± 9.7
25,798.3 ± 5,328.5
29,378.7 ± 6,342.7
5.8 ± 2.6
6.9 ± 2.9
Maximal SBP (mmHg)
190.3 ± 35.4
195.3 ± 28.7
Exercise duration (min)
9.8 ± 2.6
10.3 ± 2.3
3.2 Atropine effects
In group A, mean HR before atropine injection was 119.5 ± 13.6 bpm, and it increased up to 137.3 ± 13.5 bpm after drug administration, with an incremental of 17.8 ± 6.9 bpm (P < 0.0001). The usual atropine dose was 1.0 mg. Only 17 patients who did not respond to this initial dose, received the highest dose of atropine up to a maximum of 2 mg, and an extra increment in HR was observed. The mean percentage of age-related HR achieved in this group was 83.5 ± 8.1%. In 302 of this patients (76.1%) more than 80% of their aged-related HR (86.9 ± 5.1%) was attained.
After atropine, arrhythmias were observed in 21 patients (5.3%), 7 (1.7%) with isolated premature ventricular contraction and 13 (3.3%) with premature atrial contraction. Ventricular tachycardia or ventricular fibrillation did not occur. One patient with a history of paroxysmal supraventricular tachycardia, had this arrhythmias develop after atropine injection. The patient had no hemodynamic impairment and reverted to sinus rhythm, after administration of verapamil, during the recovery period. Dry mouth was reported by 129 patients (32.5%) and attributed to atropine effect.
There were significant differences between groups A and B regarding peak HR, peak systolic blood pressure, rate pressure product, percentage of age-related HR, metabolic equivalents achieved, and total exercise time (Table 2). There were no significant differences in chest pain developed: 48 patients (12.1%) in group A and 321 patients (11.6%) in group B (P = 0.8), and in ECG change: mean ST-segment depression was 0.4 ± 1.4 mm in group A and 0.5 ± 1.0 mm in group B (P = 0.079).
Myocardial perfusion study results
Group A (atropine)
Group B (no atropine)
Scar plus ischemia
The maximal heart frequency (HF) and the percentage of the maximal predicted heart rate (MPHR) achieved, in the absence of any other endpoint such as arrhythmias, symptoms, ST changes, or hypotension, are the most frequently used variables to quantify the exercise level.
Failure to achieve an adequate HF during exercise may render a stress myocardial perfusion study non-diagnostic for detection and risk stratification of CAD in absence of clinical or ECG signs of ischemia . Eighty-five percent of the age-related HR is the target HR for the exercise stress test with electrocardiography, but some authors have proposed 80% as target HR for perfusion studies [24, 25]. HR control during exercise is the results of a number of influences mediated by the autonomic nervous system. Some patients have an attenuated HR response to exercise and are unable to reach normal predicted HR. This phenomenon has been called “chronotropic incompetence” and has been correlated with a higher rates of total mortality and incidence of CAD in follow-up [9, 12, 26]. The physiologic mechanism of this response is unclear. Some authors have explained this chronotropic incompetence as a form of sick sinus syndrome. Recently, it has been postulated that this could represent an individual adaptation to exercise through compensatory parasympathetic hyperactivity . The limitation of sub-maximal exercise have been reported in several small studies. Verzijlbergen et al.  have observed that 15 patients with normal planar Tl-201 images after sub-maximal exercise, 6 had myocardial ischemia detected by dipyridamole stress Tl-201. Similar results described McLaughlin et al.  that reported in patients with angiographically documented CAD undergoing planar TL-201 myocardial perfusion imaging, fewer perfusion defects after low-level exercise compared with maximal exercise. These observations were confirmed by Heller et al. , who described that the extent and severity of ischemia detected by planar Tl-201 imaging, postexercise lung uptake, and transient ischemic dilatation of left ventricle were significantly reduced after sub-maximal exercise. Because patients with low HR response during exercise may have either false-negative scans or an underestimated defect extent, and because the presence and extent of stress myocardial perfusion defects are strong determinants of cardiac events and of the need for subsequent cardiac catheterization [27, 28, 29], inappropriate patient management may result. The use of atropine to increase HR during exercise to at least 80% of MPHR may overcome these problems and avoid non-diagnostic MPS studies or reduce the need for repeated exercise or the use of pharmacologic stress as a substitute. Atropine is an excellent drug for achieving a rapid increase in HR through parasympathetic blockade. Given intravenously, atropine decreases sinus node recovery time and improves conduction through the atrioventricular node, resulting in an increase in HR. There is extensive experience in the use of atropine with dobutamine in stress SPECT to increase the HR, with a good safety profile, including a consecutive series of more than 1,000 patients [17, 18, 30]. The addition of atropine during dobutamine infusion results in a higher diagnostic sensitivity for the diagnosis of coronary stenosis and better prognostic data compared with dobutamine alone . Atropine has also been added to pharmacologic echocardiographic stress in different types of patients; it is usually well-tolerated, and the diagnostic ability of the test improves. In our previous study , we used atropine added to dobutamine stress echocardiography to increase the HR response, improving the sensitivity of the test without losing specificity and without severe adverse effects. However, atropine use during exercise has not been extensively studied. Atropine injection results in sufficient stress to accurately evaluate myocardial ischemia not only because of the increase in HR (as HR is one of the major determinants of myocardial oxygen demand) but also because of the increase in the rate pressure product (which correlates fairly well with oxygen consumption during exercise) . In this study, the increase in HR and systolic blood pressure after atropine resulted in a mean rate-pressure product that is similar than that of maximal exercise test. The relatively long duration of atropine effects (30–60 min)  is a potential drawback of its use when compared with vasodilators stress, particularly with adenosine. In this study, atropine injection was well tolerated. There was a moderate frequency of non-life-threatening arrhythmias, and a brief episode of paroxysmal supraventricular tachycardia, which resolved after administration of verapamil. In addition, other side effects from the medication were very uncommon. Our results are similar with those of previous studies showing a low incidence of adverse effects [25, 34].
The primary limitation is that this study was not a “head-to-head” study, as there was no direct comparison in the same group of patients studied on two occasions, with and without atropine (patients not able to reach the minimal target HR, nor any other exercise stress test endpoint). For this reason, the study cannot conclude that there are no differences in the diagnostic capacity between the two groups with the use of atropine. Another limit was the difference in baseline characteristics of the patients. Unfortunately, patients with sub-maximal exercise were receiving more often β-blocker treatment because of previous history of AMI. β-blocker therapy probably was the major factor for high incidence of sub-maximal exercise test and not reaching 80% age-predicted HR. Furthermore, the study does not establish the clinical utility of atropine associated with exercise; rather it defines its safety and feasibility.
This study support the rule that atropine may extend the opportunity to achieve target HR in patients whose exercise HR would otherwise be sub-maximal. In our study, atropine is feasible, safe, and well-tolerated during exercise stress testing with myocardial perfusion studies. The scintigraphic results obtained are comparable to those of patients who can spontaneously achieve the target HR. In agreement with Cosin-Sales and co-authors , further clinical studies with head-to-head comparison and coronary angiography are required to validate these results.
- 4.Verzijlbergen JF, Vermeersch PHMJ, Laarman G, Ascoop CAPL (1991) Inadequate exercise leads to suboptimal imaging. Thallium-201 myocardial perfusion imaging after dipyridamole combined with low-level exercise unmasks ischemia in symptomatic patients with non diagnostic thallium-201 scan who exercise submaximally. J Nucl Med 32:2071–2078PubMedGoogle Scholar
- 14.Sarullo FM, Schicchi R, Schirò M, Shillaci AM, Ascione A, Bonnì G, Americo L, Orlando G, Andolina S, Adamo M, Castello A (1996) Comparative evaluation of dobutamine–atropine stress echocardiography with exercise testing for detection of coronary artery disease [in Italian]. G Ital Cardiol 26:1279–1290PubMedGoogle Scholar
- 22.Elhendy A, Geleijnse ML, van Domburg RT, et al (1997) Comparison of dobutamine stress echocardiography and technetium-99 m sestamibi single-photon emission tomography for the diagnosis of coronary artery disease in hypertensive patients with and without left ventricular hypertrophy. Eur J Nucl Med 25:69–78CrossRefGoogle Scholar
- 23.Sarullo FM, Azzarello V, Sarullo A, Cirino G, Di Pasquale P (2002) Relationship between exercise-induced ST segmental depression and myocardial ischemia assessed by technetium-99 m tetrofosmin SPECT imaging in patients with inferior Q wave myocardial infarction. Int J Cardiovasc Imaging 18(3):195–201PubMedCrossRefGoogle Scholar
- 33.Katzung BG (2001) Basic and clinical pharmacology. McGraw-Hill, New York, p. 115Google Scholar