Authors: Ruihai Zhou
Categories: Ischemic Heart Disease, acute coronary syndrome, coronary angiography, myocardial infarction
Source: JACC Case Reports
Authors: Ruihai Zhou
Regadenoson is a selective A2A adenosine receptor agonist vasodilator that is widely used for pharmacologic cardiac stress testing. Although generally considered safe with less side effects than adenosine, regadenoson can have serious side effects. We report here 4 patients who developed ST-segment elevation myocardial infarction (STEMI) or STEMI equivalent due to acute thrombotic occlusion of variable coronary arteries including left main coronary artery, normal and anomalous right coronary artery, and left circumflex coronary artery, with characteristic electrocardiogram abnormalities. The STEMI occurred as early as 1 minute and as late as 30 minutes after regadenoson administration. Therefore, development of localizing acute ST-segment elevation (STE) or STE in aVR with reciprocal ST-segment depression on the electrocardiograms as seen in these cases portends underlying acute coronary obstruction. Attention should also be paid to potential late occurring STEMI. When used in cardiac stress testing, discussing potential serious side effects of regadenoson including STEMI should be part of informed consent.
Cardiac stress testing is an important modality in the diagnosis and prognostication of patients with symptoms suspicious for coronary artery disease (CAD) or with known CAD including those with prior history of coronary revascularization. Cardiac stress testing is also used in the evaluation and risk stratification of patients with heart failure, cardiomyopathy, valvular heart disease, or preoperative evaluation for noncardiac surgery.Take-Home Messages•Report of this case series is intended to raise awareness that regadenoson used in cardiac stress testing can trigger STEMI requiring immediate revascularization.•Regadenoson-triggered STEMI can be recognized by development of localizing STE or STE in aVR lead together with reciprocal ST depression and attention should be paid to potential late occurring STEMI.
Several types of cardiac stress tests are available clinically. Pharmacologic stress testing is often performed when a patient is unable to exercise or has baseline electrocardiogram (ECG) abnormality such as left bundle branch block or ventricular pacing. Vasodilators are usually preferred over inotropic/chronotropic stress agents for pharmacologic radionuclide myocardial perfusion imaging (rMPI). Vasodilators used in rMPI include adenosine, dipyridamole, and regadenoson. Regadenoson produces hyperemia with rapid onset (30 seconds) and lasts longer (approximately 2-5 minutes) than adenosine, permitting more convenient administration (injection over 10 seconds). Regadenoson can also be used for stress cardiovascular magnetic resonance.
Regadenoson has been widely used due to its good tolerability with less side effects than adenosine. Although generally considered safe, regadenoson has contraindications and risk of complications. We here reported a case series of 4 patients who developed ST-segment elevation myocardial infarction (STEMI) or STEMI equivalent that occurred after intravenous administration of regadenoson for pharmacologic rMPI. The report is intended to raise awareness among clinicians of the rare but serious untoward effects of regadenoson in cardiac stress testing.
A 45-year-old man, current cigarette smoker, with no known cardiac disease presented with chest pain. The 12-lead ECG at presentation showed nonspecific ST-segment and T-wave (ST-T) change. He was found to have marginally elevated flat serial cardiac troponin I levels (0.749, 0.809, and 0.72 ng/mL, 6 hours apart; reference range, 0-0.3 ng/mL). The transthoracic echocardiography (TTE) showed left ventricular ejection fraction 55% to 60% with no regional wall motion abnormality, normal right ventricle, and no hemodynamically significant valvular disease. He tested positive for cocaine and cannabinoids on admission. The patient had no recurrent chest pain after admission.
On day 3 of hospitalization, the patient was referred for rMPI for risk stratification. The baseline ECG (Figure 1A, left) showed no dynamic change vs the ECG at presentation. Five minutes after intravenous regadenoson administration, he developed chest pain associated with diaphoresis; the ECGs showed ST-segment elevation (STE) in aVR and aVL, and upsloping (Figure 1A, middle), then downsloping ST-segment depression (STD) (Figure 1A, right) in inferior and lateral leads. Code STEMI was activated, and the patient underwent emergent cardiac catheterization and coronary angiography, which revealed total occlusion of the left main coronary artery (Figure 1B, left) and a lesion in the right posterior descending artery and right-to-left collaterals (Figure 1B, middle). He subsequently underwent percutaneous coronary intervention (PCI) under intra-aortic balloon pump support with placement of a drug-eluting stent (DES) to the left main and ostial left anterior descending (LAD) coronary artery, resulting in no residual stenosis and restoration of TIMI flow grade 3 to the LAD, ramus intermedius artery, and left circumflex (LCx) coronary artery (Figure 1B, right). His chest pain resolved after PCI, and he remained hemodynamically stable after the intra-aortic balloon pump was removed.Figure 1Clinical Data for Patient 1(A) The baseline electrocardiogram (ECG) showed T-wave inversion in lead I and aVL (left panel). Six minutes after regadenoson administration (middle panel) with chest pain, the ECG showed ST-segment elevation (STE) in aVR and aVL (red arrows) and upsloping ST-segment depression (STD) in II, III, aVF and V4-V6 (blue arrows). The ST-segment deviation worsened in amplitude 12 minutes after regadenoson administration (right panel), with persistent STE in aVR and aVL (red arrows), and the STD became downsloping/horizontal (blue arrows). (B) The coronary angiogram showed total occlusion of the left main coronary artery (yellow arrow, left panel) with right to left collateral formation (yellow arrow, middle panel), which was treated successfully with percutaneous coronary intervention (yellow arrow, right panel).
He had another cardiac catheterization and coronary angiography 1.5 years later for chest pain with successful PCI and DES placement to progressing up to 70% to 80% stenosis in the mid right posterior descending artery and the stent previously placed in the left main was patent. He has been well otherwise with regular cardiology follow-up at 4 years since the STEMI.
A 58-year-old man with a history of hypertension, chronic obstructive pulmonary disease, and gout was referred to the cardiology clinic for follow-up after an emergency department (ED) visit. He presented to the ED a month prior with chest pain. The ECG showed no ischemic change. The cardiac troponin I level was within normal range. The patient was discharged from the ED with an outpatient rMPI planned.
The patient underwent rMPI 5 weeks later using regadenoson for pharmacologic stress. He was chest pain–free on arrival. The TTE from earlier that same day showed no significant abnormality. The baseline ECG showed nonspecific ST-segment change (Figure 2A, left). Twenty minutes after intravenous regadenoson administration, he developed substernal chest pressure, but an immediate ECG showed no significant dynamic change vs baseline. However, his chest pain worsened and it was not relieved by sublingual nitroglycerin. He became nauseated and diaphoretic and appeared clammy. The repeat ECG at 27 minutes showed isolated STE in lead III (Figure 2A, middle) and another repeat ECG at 32 minutes showed STE in II, III and aVF, with downsloping STD in aVL and V2 (Figure 2A, right). Code STEMI was activated, and he underwent an emergent coronary angiography, which showed total occlusion from midportion right coronary artery (RCA) with TIMI flow grade 0 distal (Figure 2B, left). He underwent successful primary PCI with a DES placement to the RCA (Figure 2B, middle). The left coronary arteries had no significant obstruction (Figure 2B, right).Figure 2Clinical Data for Patient 2(A) The baseline ECG showed nonspecific ST change (left panel). The ECG obtained 27 minutes after regadenoson administration showed mild STE in III (red arrow, middle panel) but more prominent STE in II, III, and aVF (red arrows, right panel) and downsloping STD in aVL and V2 (blue arrows) 32 minutes after regadenoson administration. (B) The coronary angiogram showed total occlusion of mid right coronary artery (yellow arrow, left panel) treated successfully with percutaneous coronary intervention (yellow arrow, middle panel) and no angiographically significant obstruction in the left coronary arteries (right panel). Abbreviations as in Figure 1.
He has been well, reporting no recurrent cardiac event in the past 18 months with cardiology follow-up.
A 77-year-old woman with a history of diabetes mellitus, hypertension, and breast cancer status post radiation therapy 5 years prior without recurrence presented with intermittent chest pain for 1 week. The cardiac troponin I level was within normal range. The TTE at this presentation was unremarkable. The patient initially declined invasive testing. A pharmacologic nuclear cardiac stress test was performed for risk stratification. The baseline ECG showed sinus rhythm with ST-T change (Figure 3A, left). Approximately 2 minutes after intravenous regadenoson administration, the patient started to have chest pain. The immediate ECG showed isolated STE in lead III and horizontal STD in leads I and aVL (Figure 3A, middle). The patient was given sublingual nitroglycerin 0.4 mg and the chest pain resolved in <2 minutes. The STE in lead III also returned to baseline. However, the chest pain recurred, and the ECG showed STE in II, III, aVF, and V4-V6 (Figure 3A, right). The patient underwent an emergent coronary angiography, which showed subtotal occlusion in the mid portion of the anomalous RCA originating from the left coronary sinus of Valsalva (Figure 3B, left), treated subsequently with PCI with DES placement (Figure 3B, right).Figure 3Clinical Data for Patient 3(A) The baseline ECG showed T-wave inversion in III, aVF, and V3-V6 (left panel). The ECG obtained with chest pain at 3 minutes after regadenoson administration (middle panel) showed STE in lead III (red arrow) and horizontal STD in I and aVL (blue arrows). The ECG at 13 minutes after stress (right panel) showed persistent, more prominent STE in III and new STE in II, aVF, and V4-V6 (red arrows), with downsloping STD in leads I and aVL (blue arrows). (B) The coronary angiogram showed subtotal thrombotic occlusion (yellow arrow) in the mid portion of the anomalous right coronary artery originating from the left coronary sinus of Valsalva (left panel), which was successfully treated with percutaneous coronary intervention (yellow arrow, right panel). Abbreviations as in Figure 1.
The patient has been well since PCI in the past 7.5 years with regular cardiology follow-up.
A 62-year-old woman with a history of CAD status post coronary artery bypass graft (CABG) 20 years prior [left internal mammary artery (LIMA) to LAD, saphenous vein graft (SVG) to RCA, SVG to obtuse marginal artery], PCI to LAD, diabetes mellitus, and hypertension, was admitted for chest and neck pain. She was lost to follow-up for several years before this presentation. She had marginally elevated flat high-sensitivity-cardiac troponin elevation levels (104 and 107 ng/L, 6 hours apart; reference range <34 ng/L). She declined cardiac catheterization but agreed to cardiac stress test for risk stratification before considering invasive study, if needed.
The ECG at baseline showed atrial fibrillation with nonspecific ST-T changes (Figure 4A, left). One minute after intravenous regadenoson administration, the patient developed chest pain. The ECGs obtained immediately and at 5 minutes showed persistent STE in aVR and downsloping STD in multiple leads (Figure 4A, middle and right). The patient underwent immediate coronary and CABG angiography, which showed severe native CAD including chronic total occlusion of the proximal RCA (not shown) and proximal LAD, and acutely occluded proximal LCx (Figure 4B, left), although the LIMA connected to the mid-distal LAD was patent (not shown). The mid-distal LAD had in-stent restenosis. The SVG grafts were all occluded. The patient developed cardiogenic shock and cardiac arrest. She was resuscitated and a percutaneous microaxial ventricular assist device was placed for hemodynamic support. The patient developed ventricular fibrillation treated by electrical shock. She subsequently underwent salvage PCI with DES placement to the occluded LCx resulting in blood flow restoration, although the distal LCx vessels had significant diffuse disease as well (Figure 4B, right).Figure 4Clinical data for Patient 4(A) The baseline ECG showed T-wave inversion in I and aVL (left panel). The ECG obtained with chest pain at 1 minute after stress (middle panel) showed STE in lead aVR (red arrow) and STD and T-wave abnormality in multiple leads, including I, II, aVL, and V2-V6 (blue arrows). The ECG abnormalities (indicated by arrows) persisted with minimal relief by sublingual nitroglycerin at 5 minutes after regadenoson administration (right panel). (B) The coronary angiogram showed severe native coronary artery disease including total acute occlusion of the proximal left circumflex coronary artery (yellow arrow, left panel), treated with percutaneous coronary intervention resulting in restoration of distal flow (yellow arrow, right panel). Abbreviations as in Figure 1.
Unfortunately, the patient was not able to survive to hospital discharge.
Since its approval by the U.S. Food and Drug Administration in 2008, regadenoson has become the most widely used vasodilator in the United States and many other countries for pharmacologic rMPI stress test. The most common side effects from regadenoson are shortness of breath, chest discomfort, headache, and flushing, usually with good tolerability. However, regadenoson can have serious side effects. The U.S. Food and Drug Administration warns that regadenoson and adenosine have rare but serious risks of heart attack and death.^1^ To further raise awareness, a case series is reported of 4 patients who developed STEMI or its equivalent subsequent to intravenous regadenoson administration for rMPI.
It is not rare that dynamic ECG change occurs after intravenous regadenoson administration for cardiac stress tests. However, the clinical significance of the ECG changes alone in patients who undergo pharmacologic stress is not well established due to its low sensitivity and specificity; therefore, pharmacologic stress always combines ECG analysis with an imaging modality. In the reported cases here, the patients developed chest pain with prominent ST-segment deviation. Patient 1 developed acute occlusion of the left main coronary artery, which was reflected on the ECG as STE in aVR and to a lesser extent in aVL along with reciprocal STD in inferior leads (Figure 1). Patients 2 and 3 developed chest pain with localizing inferior STE. The STE was seen more prominently in III than II and aVF, suggestive of RCA vs LCx as the culprit vessel in a right dominant coronary system (Figures 2 and 3), which was seen on the coronary angiogram as anticipated. Patient 4 had known multivessel CAD status post CABG with angiography showing acute occlusion of the codominant LCx (Figure 4), along with known chronic total occlusion of proximal RCA and of mid LAD although with patent LIMA supplying the mid-distal LAD. The mid-distal LAD had diffuse 60% to 70% in-stent restenosis. All the other graft vessels were chronically occluded. The coronary anatomy of patient 4 was equivalent to left main disease, which could explain the ECG findings with STE in aVR with inferior STD, as similarly seen in patient 1 with left main total occlusion. Therefore, in the setting of cardiac stress test using intravenous regadenoson, localizing STE or STE in aVR with STD in reciprocal leads portends underlying acute coronary occlusion warranting immediate attention.
The underlying mechanism by which regadenoson triggered acute myocardial infarction remains elusive. All the 4 cases reported here had angiographic appearance of plaque rupture and acute thrombosis leading to coronary occlusion. The acute occlusion involved various coronary arteries including the left main coronary artery, RCA, LCx, and an anomalous RCA. STEMI is usually caused by sudden plaque rupture with subsequent local platelet activation and coagulation leading to thrombosis and flow compromise. Regadenoson interacts with A2A adenosine receptor causing smooth muscle relaxation leading to vasodilation/hyperemia and coronary steal and sometimes global hypotension. Regadenoson induces perfusion defect in myocardium subtended by a stenosed coronary artery, reflecting the attenuation of coronary flow reserve of stenosed coronary artery as compared with that of the normal coronary artery. Regadenoson was reported to cause direct sympathoexcitation and increase in serum levels of norepinephrine and epinephrine,^2^ which are known factors causing platelet aggregation. In addition, regadenoson may trigger focal coronary vasoconstriction either directly or indirectly, as the chest pain and STE on ECG could be relieved by sublingual nitroglycerin as reported,^3^ which also occurred in patient 3. The sudden change in coronary flow secondary to intravenous regadenoson administration could cause turbulent flow and change in shear stress/force in the diseased artery wall, creating a local milieu provoking plaque destabilization. The vasomotor activity along with the above pathophysiological changes by regadenoson could have triggered plaque rupture, platelet activation, and subsequent thrombotic vessel occlusion. In addition, regadenoson was also reported to cause Takotsubo cardiomyopathy,^4^ which can mimic acute coronary syndrome including STEMI.
Regadenoson has a 3-phase pharmacokinetic and pharmacodynamic profile. The peak plasma concentration is achieved within 1 to 4 minutes after injection. The half-life of regadenoson is 2 to 4 minutes in the initial phase, approximately 30 minutes in the intermediate phase, and approximately 2 hours in the last phase. The initial phase is characterized by a rapid onset of coronary vasodilation, followed by gradual loss of its pharmacodynamic effect, and a prolonged terminal elimination phase.^5^ In these cases, the STEMI that occurred within minutes after the administration of regadenoson was more likely initiated by the vasomotor change corresponding to the phase 1 pharmacokinetic/pharmacodynamics. The STEMI that occurred late, more than 30 minutes after regadenoson injection, falling into the phase 2 pharmacokinetic/pharmacodynamic window, was more likely due to a combination of early vasomotor and subsequent vascular biochemical change in later phases.
Although rare, this case series should further raise the awareness of potential serious side effects of regadenoson including STEMI. The variable temporal pattern of STEMI occurring as early as 1 minute and as late as more than 30 minutes after regadenoson injection warrants close monitoring for potential late STEMI after regadenoson use. When regadenoson is used, serious cardiac events including acute myocardial infarction should be included in the discussion for informed consent before the pharmacologic stress test.
The author has reported that they have no relationships relevant to the contents of this paper to disclose.