Coronary artery spasm following dobutamine stress echocardiogram

Abstract

A 53-year-old woman with atypical chest pain underwent a dobutamine stress echocardiogram (DSE) and developed a coronary spasm (CS) with severe pain and dramatic ST-segment elevation 9 min after dobutamine infusion was discontinued. The spasm resolved after sublingual nitroglycerin administration. The same-day coronary angiogram showed non-significant stenosis in the three coronary territories. Retrospectively, we found that the patient had vasospastic angina (VSA), a condition that has been strongly associated with the development of dobutamine-induced CS. Mechanisms of dobutamine-induced CS are not fully understood and include endothelial dysfunction leading to deficient nitric oxide-mediated coronary vasodilation in response to increased myocardial oxygen demand as well as imbalance between β1 and β2 adrenergic effects of dobutamine. Dobutamine-induced CS has also been much more frequently reported in patients from Asian descent with VSA. VSA should be systemically recognised in patients considered for DSE and, if present, other modalities of stress imaging should be discussed.

Background

More than 7 million patients with chest pain are evaluated every year in emergency departments (EDs) in the USA.¹ Dobutamine stress echocardiography (DSE) is routinely performed in these patients when they cannot exercise while coronary artery disease (CAD) is suspected.² DSE remains the test of choice to rapidly sort out which patients may have ischaemic heart disease due to the high accuracy of the test, its excellent negative predictive value,² easy accessibility and safety.³ It also avoids radiation compared with radionuclide imaging. However, life-threatening complications of DSE do exist.³ For instance, dobutamine-induced coronary artery spasm (CAS) with ST-segment elevation and acute myocardial ischaemia has been reported,^4–10 typically in patients with significant CAD,^6–9 but also in absence of any significant CAD (ie, coronary stenosis <50%).4–6 8 10 The latter seems to be much more frequent in patients with pre-existing vasospastic angina (VSA).⁵ The objective of this report is to bring attention to DSE-induced CAS, which remains an overlooked, yet potentially life-threatening complication of DSE, even in patients without any significant CAD. Careful attention to symptoms, risk factors and context could help better identify patients with possible VSA in order to select the most appropriate and safest stress test.

Case presentation

A 53-year-old Caucasian woman presented to the ED with a 2-week history of worsening chest and throat tightness. She was an active smoker with a history of hypertension, hyperlipidaemia, chronic myeloid leukaemia on chemotherapy and autoimmune pancreatitis with new onset of steroid-induced diabetes mellitus (blood glucose 551 mg/dL). Of note, thyroid stimulating hormone (TSH) was normal at 2.4 IU/nL. The symptoms occurred both at rest and with daily activities, sometimes after smoking. They were not alleviated with acetaminophen and receded spontaneously after 20 min.

On admission, the ECG demonstrated non-specific repolarisation abnormalities with T-wave inversions in the anterior leads (figure 1). Three serial troponins remained negative, the last one being checked 12 hours after the onset of symptoms. The patient being unable to exercise due to chronic abdominal discomfort and muscle weakness, a DSE was performed. At baseline, no ventricular dysfunction was noted. Intravenous dobutamine was started at 5 µg/kg/min and increased every 3 min to 10, 20, 30, then 40 µg/kg/min and 0.75 mg of atropine was added. The patient had not been taking any beta-blocker before the stress test and none was given during or after the DSE. The test was interrupted when the target heart rate of 142 beats/min was attained, that is, 85% of maximal predicted heart rate,² and was negative for ischaemia. However, 9 min into recovery, the patient developed severe, 10 out of 10 upper chest and throat pain; blood pressure was 111/71 mm Hg and heart rate was 104 beats/min. ECG demonstrated 5 mm ST-segment elevation in the inferior and lateral leads, QRS duration was also increased (figure 2). Symptoms and ECG changes resolved completely within 3 min after sublingual nitroglycerin administration. Patient being restless during this episode, imaging was not possible to obtain.

Figure 1.

Baseline ECG with non-specific T-wave inversions from V₁ to V₄ and D₁, aVL.

Figure 2.

ECG during chest pain, 9 min after the end of dobutamine infusion, showing 5 mm ST-segment elevation in inferior and lateral leads and reciprocal ST-segment depression in anteroseptal leads as well as widening QRS.

Investigations

The same-day coronary angiogram showed non-occlusive coronary disease with 20% stenosis in the proximal left circumflex artery (figure 3), 30% long stenosis in the mid-left anterior descending artery (figure 4) and atherosclerotic plaques with luminal irregularities throughout the right coronary artery (figure 5). Of note, no myocardial bridge or thrombosis was present. Since the diagnosis of dobutamine-induced VSA was the only possible at that point, no additional pharmacological provocation of spasm was attempted.

Figure 3.

Coronary angiogram, right anterior oblique view: 20% stenosis in the proximal left circumflex artery (arrow).

Figure 4.

Coronary angiogram, left anterior oblique view: 30% long plaque in the mid-left anterior descending artery (arrow).

Figure 5.

Coronary angiogram, left anterior oblique view: luminal irregularities in the proximal and mid-right coronary artery (arrows) without significant stenosis.

Treatment

Antispastic therapy, including calcium blocker (diltiazem) and isosorbide mononitrate, was initiated along with smoking cessation.

Outcome and follow-up

The patient reduced smoking and, at 3-month and 1-year follow-ups, reported significant improvement in symptoms.

Discussion

Mechanism of CAS during DSE

In patients unable to perform any meaningful physical activity, dobutamine is used at incremental doses to mimic the effects of exercise on the myocardium. Dobutamine increases myocardial metabolism by exerting most of its inotropic and chronotropic effects through the activation of myocardial β1 receptors, located mostly on epicardial arteries. In addition, β2-receptor activation by dobutamine results in decreased microvascular resistance.¹¹ Dobutamine also activates α1 adrenergic receptors, but any resulting vasoconstricting effect is normally counterbalanced by the β2 activity. The inotropic and chronotropic stimulation results in increased myocardial oxygen demand, in turn leading to higher coronary blood flow, regulated by the release of nitric oxide (NO) by the endothelium.¹² However, in atherosclerotic coronary arteries, a paradoxical vasoconstriction can be produced by dobutamine, even in the absence of significant stenosis, as demonstrated in our patient or other cases reported in the literature.^{4–7 10} Although the putative mechanisms have not been totally elucidated, an imbalance between the β2 and α1 adrenergic effects, as well as loss of NO-mediated vasodilation,^{5 11 12} and production of free radicals⁵ have be proposed to be involved in dopamine-induced CAS. Furthermore, NO-mediated endothelial function is altered in conditions such as diabetes and hypertension.¹²

Prevalence of CAS during DSE

DSE remains a safe and very well-validated test to diagnose myocardial ischaemia; its mortality is less than 0.01%, and the most frequent complications are ventricular and atrial dysrhythmias as well as hypo or hypertension.³ In presence of significant CAD, myocardial ischaemia during DSE manifest most of the time with new regional wall motion abnormalities, with or without ST-segment depression. More rarely, in patients without previous myocardial infarct, symptomatic ST-segment elevation has been observed in 1%–6% of DSE studies and is often a marker of significant CAD.^{6 7} It is therefore recommended to perform a coronary angiogram in symptomatic patients with dobutamine-induced ST elevation.⁷

The prevalence of DSE-induced ST-segment elevation in patients with no significant CAD, resulting from a coronary spasm (CS), is not very well established, varying between 0.14% and 0.4%.⁶ Aboukhoudir et al,⁴ in the largest published prospective study, involving 6061 patients who had a DSE, found that only 3 patients out of 471 (0.6%) with positive DSE presented ST-segment elevation with non-significant CAD. However, when studying patients with variant angina, and with no significant CAD, Kawano et al⁵ found that the prevalence of dobutamine-induced CS was 13.7%, therefore much higher than in the general population, due to the low incidence of variant angina in patients presenting with suspected coronary syndrome. Furthermore, the prevalence of VSA appears much higher in Japanese or Taiwanese populations,¹³ than in Caucasian population,¹⁴ respectively, 40% versus 12%. We have no current information on the risk of DSE-induced spasm in patients suspected of variant angina in the Caucasian population. Consequently, the decision of ordering a DSE in patients suspected of having VSA should be very carefully examined and other modalities of imaging which may carry a lower risk of CAS may be considered. Of note, a vasodilator such as adenosine combined with CT or radionuclide imaging has also been associated with CS,¹⁵ but the prevalence of CAS with adenosine remains unknown.

Late CS following dobutamine infusion

The delayed character of the spasm is actually not unusual after DSE and has been documented after cessation of dobutamine infusion, even in patients who did not receive any beta-blocker.⁸ It appears that in spite of having a very short half-life, dobutamine is still capable of exerting lasting effects on the coronary vasculature, as suggested by the persistent tachycardia in our patient after 9 min. It is therefore crucial to actively monitor patients after DSE for a prolonged period of time. Furthermore, while beta-blockers can reverse dobutamine-induced tachycardia and are frequently used for that purpose in the recovery period after DSE, they may suppress the protective β2 effects of dobutamine that should oppose its α1 adrenergic effect. This effect of beta-blocker agents, by allowing unopposed α1 vasoconstriction, has been suggested to potentially precipitate a fatal outcome in patient with CAD.⁹ Similarly, the administration of β1 selective or non-selective beta-blockers following DSE has been implicated in CAS with severe ventricular arrhythmia in patients with non-significant CAD.¹⁰

Factors contributing to VSA

Table 1 recapitulates 20 case reports related to dobutamine-induced ST-elevation in patients without any significant coronary artery obstruction at the time of the incident. This group reflects a predominance of middle-aged men (mean age 56.8±13.2 years; male to female ratio 2:1), contrary to the female predominance reported in a population with VSA.¹³ Only one patient out of five with a diagnosis of CAD before the DSE had known VSA, that is, a 48-year-old man whose risk factors were not specified. This may suggest a lack of thorough screening for VSA. Among the 16 patients whose cardiovascular risk factors were reported, few were smokers, only three of them, and one was an ex-smoker who quit a year before. Surprisingly, as many as 5 out of 16 patients seemed to have no cardiovascular risk factors at all, yet three out of five had non-significant CAD. Most patients were symptomatic with typical or atypical angina, half of them having either resting symptoms or a combination of resting and exertional angina. Again, this suggests that VSA diagnosis may be largely overlooked before performing a DSE. Baseline ECG demonstrated non-specific ST-T changes, but not always. Although CS was triggered by a variable dose of dobutamine, from 5 µg/kg/min to 40 µg/kg/min, most of the time, the spasm occurred after the peak dose. Atropine was used in 50% of cases to reach the target heart rate. Moreover, in seven patients, a beta-blocker was injected at the end of the test to reverse tachycardia, which may have contributed to trigger the CS. Four patients had a severe complication, that is, ventricular fibrillation occurred in three patients and one of them died,⁹ and another patient had a myocardial infarct due to refractory CS. In retrospect, our patient had features highly suggestive of VSA, for instance, symptoms non-specifically related to exertion. Of note, although VSA is often suggested by resting chest pain, especially when the episodes occur at night or in the early morning hours, the exertional character of symptoms does not exclude the diagnosis, as CS can be triggered by exercise, stress or cold.¹³ She had also non-specific ST changes on the baseline ECG and, similarly to cases reported in table 1, the association of multiple risk factors such as hypertension, dyslipidaemia, diabetes mellitus, obesity, middle age, female gender with chronic inflammatory disease,¹³ not to forget smoking which stands out as the most important risk factor associated with CAS.¹³ Of note, our patient denied using marijuana, cocaine, methamphetamine, vasoconstrictors (found in over-the-counter cold medicines or triptans) or alcohol, which have all been found to be associated with VSA. The existence of CS associated with non-significant CAD is a phenomenon well described in Japanese and Taiwanese populations and it has been suggested that certain genetic characteristics may account for that.¹⁴ However, it is also possible that VSA may be overlooked in the ‘Western’ population, in part due to the lack of current paradigm to try to identify patients with VSA in the ED or other settings, and in part due to the current reticence to perform provocative testing with ergonovine, adenosine or acetylcholine during the coronary angiography.

Table 1.

Recapitulation of literature case reports on dobutamine-induced ST-elevation myocardial infarct (STEMI) or coronary spasm (CS)

Author	Age	Symptoms, h/o CAD or CS	Risk factors	Dob.	Atropine/beta-blocker	ST elev	WMA	CAD or NOCAD	Outcome
Cohen A Lancet 199516	48M	CAD(PCI), CS	N/A	40	Yes/no	Inf+lat At peak	Inf	NOCAD	Resolution with SL nitroglycerin
Mathew J Lancet 199517	69F (AA)	Exertional CP	N/A	40	Yes/no	Inf+ant at peak	Inf	NOCAD	Resolution with SL nitroglycerin
Deligonul U Clin Cardiol 199618	35M	Resting CP	Smoker FH HLP	40	No/no	Inf+lat at peak	NA	NOCAD: RCA plaques LAD 20%	Resolution with SL nitroglycerin
Shaheen J Am Heart J 199619	49M	Inf STEMI, NOCAD	Smoker HLP	40	Yes/no	Inf +V1 at peak	NA	NOCAD: 40%–50% LAD 30%–40% RCA	VF, defibrillation, propranolol for VF
Yamagishi H Jpn Circ J 199820	55F Jpn	Exertional+resting CP	No, h/o breast K	20	No/no	Lat+ant	None	Normal arteries, spasm LCx with dobut	Spontaneous resolution 16 min after termination test
Roffi M Heart 200021	58M	CAD (PCI) exertional+resting CP	HLP, ex-smoker	5–20	No/no	Inf+ant, NSVT	None	NOCAD: 50% D1 40% LAD	Resolution with nasal nitroglycerin
Varga A Am J Med 20009	55M	CAD, CABGx4, exertional CP	N/A	5	No/no	V3-6 ST depress	New postlat akinesis	Autopsy: no acute MI	Metoprolol+nitrates TdP/VF 9 min into recovery, death
Alvarez L Rev Esp Cardiol 200222	37M	Resting CP	Smoker EtOH	40	Yes/propranolol	ST elev	Yes	NOCAD	Resolution with IV nitrates
Ferreira LD Rev Port Cardiol 200423	F	Exertional CP	N/A		N/A	ST elev		Normal arteries
Jiamsripong P. JASE 20078	62M	Pre-op knee surgery	DM HTN HLP	40	Yes/no	12′ into recovery	Apical	CAD: 95% LAD	At 12′: VT, VF, defib resolution with SL nitroglycerin
Ioannides M Int J Cardiol 200824	45M	Exertional epigastric pain	Obesity DM	40	No/no	Ant ST elev+NSVT/MI	Ant+lat	NOCAD	Intravenous nitrates, thrombolysis for refractory CS
Fineschi Eur J Echocardiogr 201125	59M	Resting CP	HLP	40	Yes/metoprolol	Ant+lat 10′ after βb	Anteroseptal	NOCAD: <50% pLAD	Resolution with SL nitroglycerin
	54M	Exertional, atypical CP	None	40	Yes/propranolol	Inf 3′ after βb	Inf+lat	NOCAD: <60% RCA	Emergent Cath, IC nitrates
	65F	h/o CAD resting CP	HTN DM	40	Yes/propranolol	Inf 5′ after βb	Inf+lat	NOCAD: 25% LAD+LCx	Resolution with SL nitroglycerin
Burgos-Rosado PR. Arq Bras Cardiol 201426	55M	NA	Obesity HTN, DM	30	No/metoprolol	Inf+ant no chest pain	Yes	NOCAD	Abundant PVCs
Martinez AM Int J Cardiol 201510	78M	Resting CP	HTN, LBBB	40	Yes/esmolol	Inf, 10′ after βb	No	NOCAD: ecstatic LCx	Resolution with SL nitroglycerin
Poorzand H J Cardiothorac Med 201627	42F	Exertional CP	None	30	No/no	Inf+ant at peak	Yes	NOCAD	Resolution with SL nitroglycerin
Fernandes M J Cardiol Curr Res 201728	79F	Pre-op knee surgery	N None	40	No/no	Inf+ant during recovery	None	NOCAD: plaques LAD	No CP, dyspnoea+hypoTN
Rekik S J Electrocardiol 200929	54M	Exertional+resting CP	None	15	No/no	Inf +V4-6 ST-elev (10 mm)	NA	NOCAD: normal arteries	Intravenous nitrates
Cabani E J Cardiovsc Med 200930	80F	Resting CP	HTN	40	No/metoprolol 3 mg intravenous	Inf ST-elev 30′ after βb	Inf WMA	NOCAD	Resolution with SL nitroglycerin

AA, African-American; ant, anterior; βb, beta-blocker; CABG, coronary artery bypass graft; CAD, coronary artery disease; Cath, catheterisation; CP, chest pain; defib, defibrillation; depress, depression; DM, diabetes mellitus; Dob., dobutamine; F, female; FH, familial history of CAD; HPL, hyperlipidaemia; HTN, hypertension; hypoTN, hypotension; IC, intracoronary; inf, inferior; IV, intravenous; Jpn, Japanese; LAD, left anterior descending artery; lat, lateral; LCx, left circumflex artery; M, male; N/A, not available; NOCAD, non-occlusive coronary artery disease; NSVT, non-sustained VT; PCI, percutaneous coronary intervention; Pre-op, pre-operative; PVCs, premature ventricular complexes; RCA, right coronary artery; SL, sublingual; ST-elev, ST-elevation; TdP, torsades de pointes; VF, ventricular fibrillation; VT, ventricular tachycardia; WMA, wall motion abnormality.

While DSE remains a test routinely ordered to diagnose ischaemic heart disease and is generally safe, it may have under certain circumstances dramatic complications. Indeed, a severe CAS may occur, leading to acute myocardial ischaemia and infarct or ventricular arrhythmia, even in the absence of any significant coronary stenosis. Pre-existing VSA, which appears to be more frequent in patients of Asian descent, should be considered as a major risk factor for developing such a CS. Therefore, patients should be carefully evaluated for possible VSA before any dobutamine stress test. The cardiologist should keep in mind that the presence of mild coronary disease is not a benign finding and may predispose to abnormal vasoreactivity to dobutamine. Furthermore, CS may be delayed, thus a need for prolonged monitoring of patients after a DSE. Nitroglycerin should be administered and beta-blockers should be avoided in case of ST-elevation following DSE. The question remains if dobutamine stress testing should be avoided whenever VSA is suspected, and if, instead, another modality of stress imaging should be favoured.

Learning points.

• Dobutamine can induce a severe coronary spasm during dobutamine stress echocardiogram (DSE) in the absence of significant stenosis.

• Dobutamine-induced coronary spasm can be delayed into recovery from DSE.

• Pre-existing vasospastic angina increases the risk of dobutamine-induced coronary spasm.

• DSE should be avoided in patients with vasospastic angina.