Author + information
- Received April 14, 1996
- Revision received December 19, 1996
- Accepted January 9, 1997
- Published online April 1, 1997.
- Christine H Attenhofer, MDA,
- Patricia A Pellikka, MD, FACCA,*,
- Robert B McCully, MBChB, FACCA,
- Véronique L Roger, MD, FACCA and
- James B Seward, MD, FACCA
- ↵*Dr. Patricia A. Pellikka, Mayo Clinic, 200 First Street SW, Rochester, Minnesota 55905.
Objectives. This report characterizes the paradoxical sinus deceleration occasionally observed during dobutamine stress testing and determines its relation to myocardial ischemia.
Background. Dobutamine stress echocardiography is widely accepted as a noninvasive tool for evaluating coronary artery disease. With infusion of dobutamine, there is typically a dose-dependent increase in heart rate. However, in some patients, a paradoxical decrease in heart rate has been observed during high dose dobutamine infusion.
Methods. In 181 consecutive patients undergoing both dobutamine stress echocardiography and coronary angiography, electrocardiographic (ECG) data collected during dobutamine infusion were reviewed to identify patients with a decrease in heart rate. The clinical, stress echocardiographic, hemodynamic and angiographic correlates of patients with a decrease in heart rate were reviewed.
Results. A decrease in heart rate ranging from 7 to 64 beats/min occurred during high dose dobutamine infusion in 14 patients (8%, 95% confidence interval [CI] 6% to 10%), including 3 in whom a junctional rhythm developed. The decrease was sudden in five patients (36%, 95% CI 13% to 65%) and gradual in nine (64%, 95% CI 35% to 87%). A decrease in blood pressure (12 patients [86%], 95% CI 57% to 98%) with simultaneous chest pain (7 patients [50%], 95% CI 23% to 77%) and nausea (5 patients [36%], 95% CI 13% to 65%) was common. Significant coronary artery disease (≥50% diameter stenosis) was present in 8 (57%) of 14 patients (95% CI 29% to 82%). Two patients (14%, 95% CI 2% to 43%) had no clinical, ECG or echocardiographic evidence of ischemia and no significant coronary artery disease by angiography. There was no increased incidence of right coronary artery stenosis in patients with paradoxical sinus deceleration.
Conclusions. Paradoxical sinus deceleration occurs in 8% of patients during dobutamine stress testing. Although most often observed in patients with coronary artery disease, it can occur in the absence of ischemia and coronary artery disease, and in some patients may be due to a vasodepressor reflex.
(J Am Coll Cardiol 1997;29:994–9)
© 1997 by the American College of Cardiology
Dobutamine stress echocardiography is widely accepted as a noninvasive tool for evaluating coronary artery disease. The synthetic catecholamine dobutamine has predominant beta1- but also beta2- and alpha-receptor agonistic activity ([1, 2]). During infusion of low doses of dobutamine, the predominant hemodynamic effect is an increase in myocardial contractility; with higher doses, there is a dose-dependent increase in heart rate ([3, 4]). The induction of myocardial ischemia during dobutamine infusion is presumably dependent on achieving a satisfactory chronotropic response. During dobutamine stress echocardiography, an attempt is made to reach a heart rate of at least 85% of the maximal rate predicted for age ().
In some patients we have observed a paradoxical decrease in heart rate during high dose dobutamine infusion. This cardioinhibitory response may be a manifestation of the Bezold-Jarisch reflex. Induction of this reflex increases parasympathetic activity and inhibits sympathetic activity, resulting in bradycardia, which may be accompanied by vasodilation, nausea and hypotension. The Bezold-Jarisch reflex has been stimulated in the settings of myocardial infarction (preferentially inferoposterior location), coronary angiography and vasovagal syncope. Additionally, some drugs, including isoproterenol, can sensitize or desensitize cardiac sensory receptors that have vagal afferent pathways ([6–8]). The purpose of the present study was to characterize the decrease in heart rate that occurs during dobutamine stress echocardiography and to determine its relation to inferoposterior ischemia.
Data from all patients in our database who underwent both dobutamine stress echocardiography and coronary angiography within 6 months (mean [±SD] 24 ± 49 days) at our institution from January 1990 to June 1994 were reviewed. Exclusion criteria were atrial fibrillation and previous or intervening revascularization (coronary artery bypass graft surgery or coronary angioplasty). Of the 181 patients who fulfilled the inclusion criteria, 112 were men and 69 were women (mean age 68 ± 10 years, range 36 to 88). The pertinent medical history, demographics, hemodynamic variables, electrocardiographic (ECG) data and echocardiographic findings were recorded for all patients at the time of stress echocardiography.
1.2 Dobutamine stress echocardiography.
Dobutamine stress echocardiography was performed according to a previously described protocol () in patients abstaining from oral intake for ≥3 h. The beginning infusion rate of dobutamine was 5 μg/kg body weight per min, and the dose was increased every 3 min to 10, 20, 30, 40 and, if needed, 50 μg/kg per min. From January 1992 onward, atropine (in divided doses of 0.25 to 0.5 mg) was administered when the heart rate response to dobutamine infusion of 40 μg/kg per min was inadequate, as judged by the clinician performing the study. Heart rate was recorded every minute during dobutamine infusion and for at least 10 min of recovery. Blood pressure was measured every 3 min; if there was a decrease in systolic blood pressure, measurements were obtained every minute. If systolic blood pressure decreased to ≤90 mm Hg, the patient’s legs were tilted upward to counteract the hypotension. Ejection fraction was calculated according to the modified method of Quinones et al. (). Wall motion was assessed by consensus of two experienced stress echocardiographers who were unaware of the findings of coronary angiography. Regional wall motion analysis was performed semiquantitatively with a 16-segment model of the left ventricle (). Each segment was assigned a score based on its wall motion and thickening, and the wall motion score index was calculated as the sum of the scores divided by the number of visualized segments. The segments were classified into three coronary artery distributions. The anterior regionwas the territory of the left anterior descending coronary artery, and the posterior distributionincluded the left circumflex and right coronary artery territories.
1.2.1 Paradoxical sinus deceleration.
A decrease in heart rate was defined as a decrease >5 beats/min lasting at least 3 min during the continuous incremental dobutamine infusion.
1.3 Coronary angiography.
Coronary angiograms were analyzed by two experienced angiographers who had no knowledge of the clinical data and the results of dobutamine stress echocardiography. They visually estimated the coronary artery narrowing and expressed it as percent stenosis of the lumen diameter. Significant coronary stenosis was defined as ≥50% narrowing of the lumen diameter of the major epicardial coronary arteries or any of their major branches.
1.4 Statistical analysis.
Results are presented as mean value ± SD or frequency expressed as a percentage with 95% confidence intervals. Two-sample ttests or Pearson chi-square tests for 2 × 2 tables were used to assess the association of each variable separately with the presence of a decrease in heart rate.
2.1 Description of sinus deceleration.
Sinus deceleration occurred in 14 patients (8%, 95% confidence interval [CI] 6% to 10%), including 3 in whom a junctional rhythm developed (Table 1andTable 2). These 14 patients had a decrease in heart rate from 7 to 64 beats/min. The decrease occurred at dobutamine doses ranging from 20 to 40 μg/kg per minute; in no patient did heart rate decrease after administration of atropine. The decrease was sudden (the maximal decrease occurred within ≤1 min) in five patients (Patients 2, 5, 7, 10 and 12) and occurred more gradually in the other nine. The minimal heart rate was <60 beats/min in only one patient (Patient 6) (Fig. 1) and was <80 beats/min in five. In nine patients (64%, 95% CI 35% to 87%), the decrease in heart rate was accompanied by a decrease in systolic blood pressure >20 mm Hg. In three of these patients, systolic blood pressure decreased to <90 mm Hg. The decrease in heart rate was interrupted by stopping the dobutamine infusion (in nine patients), increasing the rate of infusion (in one patient) or by injecting atropine (in four patients). Although the dose of dobutamine was increased in six patients, this dose was beneficial in increasing the heart rate in only one. In the four patients (Patients 3, 8, 11 and 14) who received atropine (0.5 to 1.0 mg), heart rate increased by 42 to 82 beats/min (mean 59 ± 20 beats/min) (Fig. 2).
2.2 Clinical variables in patients with and without sinus deceleration (Table 3).
Only 1 of the 14 patients with a decrease in heart rate (7%, 95% CI 0% to 14%) was taking a beta-adrenergic blocker, as opposed to 44 of 167 patients (26%, 95% CI 23% to 29%) with no decrease in heart rate (p = 0.11).
2.3 Stress echocardiographic correlates.
Heart rate, rate-pressure product, symptoms, ECG data and echocardiographic findings for the two groups are summarized in Table 4. Mean ejection fractions in the two groups were similar. In the patients with a decrease in heart rate, ejection fraction at rest ranged from 20% to 70%. The increase in heart rate achieved during dobutamine infusion and the rate-pressure product at peak stress were significantly lower in patients with a decrease in heart rate (p = 0.005 and p = 0.006, respectively). Chest pain occurred significantly more often in the 14 patients with a decrease in heart rate (50%, 95% CI 23% to 77% vs. 22%, 95% CI 19% to 25%, p = 0.02). Nausea was also more common in these 14 patients (36%, 95% CI 13% to 65% vs. 4%, 95% CI 2% to 6%, p = 0.0008). Wall motion score index at peak stress was similar in both groups (p = 0.48).
2.4 Angiographic correlates.
Significant coronary artery disease was present in 154 (85%) of 181 patients (95% CI 82% to 88%) (one-vessel disease in 33, two-vessel disease in 52, three-vessel disease in 70). Twenty-seven patients (15%, 95% CI 12% to 18%) had no significant coronary artery disease. Heart rate decreased in 8 (5%) of 154 patients (95% CI 2% to 9%) with and 6 (22%) of 27 patients (95% CI 9% to 42%) without coronary artery disease. Among patients with a decrease in heart rate during dobutamine stress echocardiography, significant coronary artery disease was less common (57%, 95% CI 29% to 82% vs. 87%, 95% CI 84% to 90%, p = 0.002) (Tables 1–3). Stenosis of the left anterior descending and left circumflex coronary arteries was significantly less frequent (p = 0.04 and p = 0.02, respectively) in patients with than without a decrease in heart rate; however, the incidence of right coronary artery stenosis was similar in both groups (p = 0.21). In one patient (Patient 7) with 50% diameter stenosis of the middle right coronary artery, the dobutamine stress test result was clinically, electrocardiographically and echocardiographically negative for ischemia. In this patient, the test was terminated because of a decrease in blood pressure that accompanied the decrease in heart rate. Target heart rate was not achieved, and the rate-pressure product at peak stress was only 7,395 beats/min × mm Hg. Among patients with a heart rate decrease, three of six patients without significant coronary artery disease (Patients 1, 4 and 5) had 40% diameter stenosis in either the right coronary artery or the left anterior descending coronary artery. Two of these patients (Patients 1 and 5) had rest wall motion abnormalities and new or worsening wall motion abnormalities.
The present study describes the paradoxical sinus deceleration that may occur during dobutamine stress echocardiography. This decrease in heart rate can be sudden or gradual. Sinus deceleration was observed in patients with and without coronary artery disease and inducible myocardial ischemia and was not predictive of the site or the extent of coronary artery disease. Sinus deceleration was frequently accompanied by a decrease in systolic blood pressure, which occurred in 8 (57%) of the 14 patients. In addition, nausea and chest pain were significantly more common in patients with a decrease in heart rate.
3.1 Comparison with previous studies.
Sinus deceleration during dobutamine stress echocardiography has not been extensively described. The first documentation of a decrease in heart rate during dobutamine infusion was found during dobutamine therapy in horses; sinus bradycardia developed in 17% (). Mertes et al. (), reporting on adverse effects during dobutamine stress echocardiography in 1,118 patients, stated that bradycardia was the reason for termination of the test in only 2 patients (0.2%), and junctional rhythm was present in 2.5% of patients; it was not reported how often a decrease in heart rate occurred with or without causing bradycardia. Both Marcovitz et al. () and Rosamond et al. (), analyzing the occurrence of hypotension during dobutamine stress echocardiography, specifically mentioned that a decrease in heart rate was not associated with the decrease in blood pressure and that the mean heart rate was actually higher in patients with a decrease in blood pressure. Analyzing hypotension during dobutamine stress echocardiography, Mazeika et al. (), however, found a concomitant decrease in heart rate in six of seven patients; but they did not report whether heart rate decreased without a decrease in blood pressure. Hopfenspirger et al. () recently reported sinus deceleration of 4 to 38 beats/min during dobutamine–perfusion scintigraphy in 10 (17%) of 58 patients. They found scintigraphic evidence of inferior wall ischemia in all these patients. Coronary angiographic correlation was not available. This finding is in contrast to our experience, in which 6 (43%) of 14 patients did not have significant coronary artery disease. Stenosis of 40% of the lumen diameter was present in three of these patients, two of whom had worsening of wall motion abnormalities with stress. It is conceivable that the angiographic severity of stenosis in these three patients was underestimated or that there was coexistent coronary spasm. However, three patients with paradoxical sinus deceleration had angiographically normal coronary arteries. Thus, inappropriate sinus deceleration during dobutamine infusion cannot be equated with coronary artery disease.
3.2 Mechanism of sinus deceleration.
The triad of bradycardia, hypotension and nausea that we observed in some patients receiving high dose dobutamine could have resulted from stimulation of large-vessel baroreceptors by increased systolic pressure, flow or pulse pressure during the dobutamine infusion (). However, in no patient was the sinus deceleration preceded by a marked increase in blood pressure. A more probable mechanism is activation of the Bezold-Jarisch reflex. This reflex originates in cardiac sensory receptors with nonmyelinated vagal afferent pathways (). The inferoposterior wall of the left ventricle is the principal location of these sensory receptors, which can be stimulated by stretch, chemical substances or drugs; this stimulation results in an increase in parasympathetic activity and an inhibition of sympathetic activity. These effects promote reflex bradycardia, vasodilation and hypotension. In a recent animal study () on the vasodepressor reaction in the rat, in which cardiac volume was reduced by vena cava occlusion, a vasodepressor reaction accompanied by paradoxical bradycardia was induced by infusion of isoproterenol and dobutamine. Induction of a vasodepressor response in humans occurs with the administration of isoproterenol during passive upright tilting in persons with a propensity for syncope. A vasodepressor reaction can occur in any setting with reduced intracardiac volume (as is present during dobutamine stress echocardiography) in combination with beta1-adrenergic stimulation (dobutamine or isoproterenol). Our patients fasted for 3 h before the dobutamine infusion; mild hypovolemia may thus have facilitated the occurrence of this vasodepressor response.
The chronotropic effect of dobutamine may counteract most of the bradycardia it would otherwise induce by sensitizing the cardiac baroreceptors; thus, in many patients, there may be a balance between the positive chronotropic effects of dobutamine and the negatively chronotropic Bezold-Jarisch reflex, attenuating a desirable “normal” increase in heart rate. However, the induction of myocardial ischemia during dobutamine stress echocardiography is presumably dependent on increased heart rate. The paradoxical decrease in heart rate during dobutamine stress echocardiography could potentially result in the underdetection of coronary artery disease. Atropine injection at peak dobutamine infusion is used in patients who do not achieve 85% of the predicted maximal heart rate during dobutamine stress echocardiography (). We have observed that atropine is also effective in augmenting heart rate in patients with a paradoxical bradycardia. Therefore, in the presence of sinus deceleration and in the absence of echocardiographically detectable ischemia, atropine injection should be considered, even if the peak dose of dobutamine has not been given.
3.3 Limitations of the study.
The present study describes a select group of patients who underwent dobutamine stress echocardiography and coronary arteriography. Thus, there is a referral bias, and the incidence of a decrease in heart rate in the general population referred for dobutamine stress echocardiography is unknown. However, we specifically chose only all consecutive patients who underwent coronary angiography to correlate the effect of coronary anatomy with the chronotropic response.
The present study demonstrates that despite continuous high dose dobutamine stress infusion, paradoxical sinus deceleration may occur and is frequently accompanied by nausea and a decrease in systolic blood pressure. This phenomenon is probably mediated by the Bezold-Jarisch reflex. Although paradoxical sinus deceleration most often occurs in the presence of coronary artery disease, it may occur in the absence of inducible myocardial ischemia or angiographic coronary artery disease. This reaction can offset the positive chronotropic effects of dobutamine and can effectively be reversed with atropine.
- confidence interval
- electrocardiogram, electrocardiographic
- Received April 14, 1996.
- Revision received December 19, 1996.
- Accepted January 9, 1997.
- The American College of Cardiology
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