Coronary Embolus - interventions.onlinejacc.orginterventions.onlinejacc.org/content/jint/11/2/172.full.pdf · normal underlying vessel or recurrent coronary thrombus. Coronary embolism

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P U B L I S H E D B Y E L S E V I E R

STATE-OF-THE-ART REVIEW

Coronary EmbolusAn Underappreciated Cause of Acute Coronary Syndromes

Claire E. Raphael, MBBS, PHD,a John A. Heit, MD,a,b Guy S. Reeder, MD,a Melanie C. Bois, MD,c

Joseph J. Maleszewski, MD,c R. Thomas Tilbury, MD,a David R. Holmes, JR, MDa

ABSTRACT

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Coronary embolism is the underlying cause of 3% of acute coronary syndromes but is often not considered in the

differential of acute coronary syndromes. It should be suspected in the case of high thrombus burden despite a relatively

normal underlying vessel or recurrent coronary thrombus. Coronary embolism may be direct (from the aortic valve or left

atrial appendage), paroxysmal (from the venous circulation through a patent foramen ovale), or iatrogenic (following

cardiac intervention). Investigations include transesophageal echocardiography to assess the left atrial appendage and

atrial septum and continuous electrocardiographic monitoring to assess for paroxysmal atrial fibrillation. The authors

review the historic and contemporary published data about this important cause of acute coronary syndromes. The authors

propose an investigation and management strategy for work-up and anticoagulation strategy for patients with suspected

coronary embolism. (J Am Coll Cardiol Intv 2018;11:172–80) © 2018 by the American College of Cardiology Foundation.

A lthough coronary embolism is commonlyreported in case studies, it is probablyunder-diagnosed in clinical practice. A recent

retrospective analysis suggested that up to 3% ofacute coronary syndrome (ACS) cases may resultfrom coronary embolism (1). Awareness of the charac-teristics of patients who present with coronary embo-lism and management considerations specific to thiscondition may improve clinical outcome in these pa-tients. We review the published data surroundingcoronary embolism, management, and clinicalimplications.

Coronary embolism is divided into 3 types:1) direct; 2) paradoxical; and 3) iatrogenic, with someoverlap among the categories (2–6). Direct coronaryemboli commonly originate from the left atrialappendage, left ventricle, the aortic or mitral valves,or the proximal coronary artery. Embolic tissue maybe thrombus, valvular material, or even neoplasm.Paradoxical emboli pass through a patent foramen

N 1936-8798/$36.00

m the aDepartment of Cardiovascular Diseases, Mayo Clinic, Rochester,

ernal Medicine, Mayo Clinic, Rochester, Minnesota; and the cDepartment

thors have reported that they have no relationships relevant to the conte

nuscript received April 17, 2017; revised manuscript received August 3, 2

ovale (PFO), atrial septal defect, or pulmonary arte-riovenous malformations from the venous circulationinto the systemic circulation. Most commonly theorigin is from a deep vein (deep venous thrombosis).Iatrogenic emboli may occur following interventionalprocedures, usually valve replacements and coronaryintervention.

DIRECT CORONARY EMBOLISM

Direct coronary embolism may result from thrombusoriginating from the left atrium, left ventricle, orpulmonary veins; endocarditis of the aortic or mitralvalve; and, more rarely, cardiac tumors. Clinicallysignificant coronary embolism has been reported in1.5% of cases with infective endocarditis and micro-emboli to the coronary arteries were present in morethan 60% of cases on postmortem examination (7,8).Although there are no studies that describe risk fac-tors for coronary embolism, systemic embolization of

https://doi.org/10.1016/j.jcin.2017.08.057

Minnesota; bDivision of Hematology, Department of

of Pathology, Mayo Clinic, Rochester, Minnesota. All

nts of this paper to disclose.

017, accepted August 8, 2017.

AB BR E V I A T I O N S

AND ACRONYM S

ACS = acute coronary

syndrome(s)

PFO = patent foramen ovale

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infected vegetation is known to be more common inpatients with endocarditis of the mitral valve, largevegetations (>10 mm in diameter on echocardiogra-phy), and in fungal or staphylococcal infections (9).Embolization of noninfective vegetations caused byautoimmune disease has also been reported (10).Although an uncommon cause of coronary embolism,cardiac myxomas can present with such, particularlywhen the tumors are of the villiform variety (11–13).Coronary emboli may also originate from muralthrombus within the left-sided cardiac chambers.

PARADOXICAL CORONARY EMBOLISM

The incidence of paradoxical coronary embolism isunknown. Case reports include coronary embolioriginating from deep vein thrombosis and evenforeign bodies in the venous circulation (14). Emboligain access to the systemic circuity by passingthrough a PFO or atrial septal defect, and then intothe coronary arteries. Patients with a PFO and majorpulmonary embolus had more than 10-fold increasedmortality compared with those without a PFO in aretrospective series, and this was thought to resultfrom paradoxical emboli to either the coronary or,more commonly, the cerebral circulation (15). Closureof PFOs is easily accomplished percutaneously andclosure devices have recently been approved by theFood and Drug Administration for this indication.Observational data have suggested a benefit ofpercutaneous PFO closure compared with medicaltherapy (16). Randomized trial data have beenhampered by low event rates and did not demon-strate superiority compared with medical therapy onintention-to-treat analysis (17). However, closure wassuperior to medical therapy alone on per-protocolanalysis and subgroup analysis suggested a benefitin patients with large right-to-left shunts and atrialseptal aneurysms, with low rates of risk associatedwith device closure.

IATROGENIC CORONARY EMBOLISM

Embolism of surgical material into the coronary ar-teries may occur at the time of cardiothoracic surgery,during coronary intervention, commonly at the timeof rotablation (18), and also during aortic (19) andmitral (20) valvuloplasty procedures. Clot may formin catheters, particularly during prolonged proced-ures, when full heparinization is not maintained andwhen catheters are not regularly flushed. Coronaryintervention is now the most common cause of cor-onary embolism (6). In the presence of degenerative(calcific) aortic valve disease, even diagnostic

coronary angiography may result in emboli-zation of friable valvular material into acoronary artery (21).

PREVALENCE OF

CORONARY EMBOLISM

The coronary arteries appear relatively protectedanatomically from embolic events compared with theother systemic circulation. Thromboemboli origi-nating in the left ventricle or left atrium mostcommonly pass into the carotids or distal systemiccirculation because these vessels are in a relativelylinear trajectory from the left ventricular outflowtract compared with the coronaries. The acute or rightangle takeoff from the aortic root likely also decreasesthe probability of coronary embolism when comparedwith other systemic embolism.

The prevalence of coronary embolism was firstestimated from autopsy studies. Prizel et al. (22)presented a cohort of 55 patients, representing 13%of the acute myocardial infarctions in an autopsy se-ries, with thrombotic material in the coronary arteriesbut no demonstrable acute plaque rupture, suggest-ing an embolic source. Most had underlying valvularheart disease, cardiomyopathy, or atrial fibrillation.

A large series of all-comers to the catheterizationlaboratory with a first acute myocardial infarctionover a 12-year period demonstrated up to 3% preva-lence of coronary embolism (1). Diagnosis was madeon retrospective examination of diagnostic angiog-raphy and subsequent investigation including echo-cardiography, magnetic resonance imaging, andcomputed tomography. The authors described ascoring system for definite and probable coronaryembolism (Table 1) to diagnose cases that may havebeen misdiagnosed at the time of acute presentation.Most cases with coronary embolism in this series hadatrial fibrillation (73%); however, cardiomyopathyand valvular heart disease were also common. Fifteenpercent of patients had multiple coronary emboli indifferent territories. Concomitant systemic and coro-nary embolism was present in about one-fifth of pa-tients. Following investigation, an intracardiacsource was identified in one-third of patients, mostcommonly within the left atrial appendage, followedby infective endocarditis.

On long-term follow-up, 10% of patients hadrecurrent thromboembolic disease (4% coronaryembolus, 6% stroke). Recurrent events all occurred inpatients with underlying atrial fibrillation. Ten-yearcardiac mortality rate was approximately 50% in thecoronary embolism group compared with <10% in acomparative ACS group without coronary embolism.

TABLE 1 Proposed Scoring System for Diagnosis of Definite and

Probably Coronary Embolus

Major criteria

� Angiographic evidence of coronary embolus/thrombus(e.g., a filling defect, or abrupt occlusion in an artery withoutsignificant atherosclerosis)

� Concomitant coronary emboli in multiple coronary vascularterritories

� Concomitant systemic embolization without left ventricularthrombus attributable to acute myocardial infarction

� Histological evidence of venous origin of coronary embolicmaterial

� Evidence of an embolic source based on TTE, TEE, CT, or MRI(e.g., clot in left atrial appendage)

Minor criteria

� <25% stenosis on angiography in the nonculprit vessels� Atrial fibrillation� Presence of embolic risk factors, cardiomyopathy, rheumatic

heart disease, prosthetic valve, PFO, ASD, history of cardiacsurgery, infective endocarditis, or hypercoagulable state

Patients with 2 or more major criteria, 1 major and 2 minor, or 3 minor criteria wereconsidered to have a definite coronary embolus. Patients with 1 major and 1 minoror 2 minor criteria were considered to have a probable coronary embolus. Adaptedfrom Shibata et al. (1).

ASD ¼ atrial septal defect; CT ¼ computerized tomography; MRI ¼ magneticresonance imaging; PFO ¼ patent foramen ovale; TEE ¼ transesophageal echo-cardiography; TTE ¼ transthoracic echocardiography.

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This may relate to identification bias becausesmall embolic events would not meet the diagnosticcriteria or may suggest larger infarctions in theembolism group compared with the rest of the ACSpopulation.

DIAGNOSIS AND MANAGEMENT OF

ACUTE CORONARY EMBOLISM

Presentation of coronary embolism is difficult todistinguish from atherosclerotic ACS before angiog-raphy. Therefore, initial management with anti-platelet therapy, pain relief, and urgent or emergencycoronary angiography is the same as for any sus-pected ACS case. Angiographically, coronary embo-lism may present with a heavy thrombus burden, asshown in Figure 1A. Smaller emboli may be presentmore distally. Filling defects in multiple coronaryterritories is suggestive of coronary embolism.Although some patients present with a heavythrombus load and no underlying coronary athero-sclerosis, more commonly patients have a degree ofbystander atherosclerosis, making diagnosis morechallenging.

If there is a high thrombus burden, aspirationthrombectomy may be considered. The evidence forthis is controversial because trials have suggested nosignificant benefit in ST-segment elevation myocar-dial infarction and an increased risk of post-procedural stroke (23,24). However, meta-analysis of

individual patient data has suggested there may be asignificant reduction in cardiovascular mortality inselected patients with high thrombus load, albeit witha small but significant increase in stroke risk (25).Thrombectomy trials have usually used aspirationdevices; however, the Angiojet (Boston Scientific,Marlborough, Massachusetts) may have increasedefficacy in restoration of flow and removal of throm-boembolic material (26).

Aspiration allows better assessment of the under-lying coronary artery. If aspiration results in fullrestoration of flow and a normal angiographicappearance, intravascular ultrasound or opticalcomputerized tomography could be used to furtherevaluate the vessel to assess the potential for isolatedplaque erosion versus embolic phenomena. If the ar-tery appears angiographically normal, balloon angio-plasty and stents are not required.

Aspirated material should be sent to pathology forfurther examination that may assist in narrowing thedifferential for thrombus origin. For instance, iden-tification of platelet- and fibrin-rich material isconsistent with acute thrombus from the left heart orproximal coronary artery (Figure 2) and may allowdistinction from a venous paradoxical embolus,which would be more likely to demonstrate organi-zation of the thrombotic material. Less commonly butvital for patient management, embolic material froma neoplasm, foreign material, or infected source(septic emboli) may be identified.

Aspiration may not remove the thrombus entirely,necessitating the use of antiplatelet and anticoagu-lant agents. Intracoronary thrombolytics have beenused to good effect in case studies (27). Infusion ofunfractionated heparin, GPIIb/IIIa agents, or bivalur-udin may be used to manage distal embolus, particu-larly in vessels with reduced distal perfusion (3).However, in the case of more organized thrombus, forexample from paradoxical emboli, these agents maynot be effective.

Following acute intracoronary management, thepatient should be screened for the source of embolicmaterial and for systemic embolism. If paradoxicalembolism is suspected at the time of the angiogram,right heart catheterization may identify intra-atrialcommunication. Transthoracic echocardiographymay allow identification of left ventricular thrombus,whereas transesophageal echocardiography allowsvisualization of the left atrial appendage (Figure 1).Either transesophageal echocardiography or trans-thoracic echocardiography may suggest communica-tion across the atrial septum and bubble studies maybe used to confirm the presence of a PFO. In this case,

FIGURE 1 Angiographic Appearance of Coronary Embolism

(A) Filling defects (arrow) with an acutely occluded vessel. (B) The same vessel following aspiration thrombectomy. (C) Other signs of

coronary thrombus include the “rail road track” sign (arrow)where the embolus is floating in the lumen and contrast dye passes on either side

of the defect. (D) Smaller thrombus in the atrioventricular circumflex artery (arrow) that acutely embolized during transcatheter aortic valve

insertion.

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screening of the venous circulation for deep veinthrombosis or pulmonary embolus may be consideredbased on clinical probability. Coronary embolism iscommonly associated with other systemic embolism.Clinical evidence of stroke was present in 15% of pa-tients presenting with coronary embolism on aretrospective series (1) and prevalence of subclinicalcerebral embolism is likely even higher.

Interestingly, in the cohort study by Shibata et al.(1), most patients with atrial fibrillation and coronaryembolus had a CHADS2 score of 0 or 1. Acute findingof left ventricular or left atrial appendage thrombus isusually treated with anticoagulation, and we suggesttreatment with oral anticoagulation be started even ifthe CHADS2 or CHADS2-VASc score does not meetconventional criteria for anticoagulation (28) becausethese patients remain at increased risk for futurethromboembolic events. The role of left atrialappendage occlusion devices in coronary embolism

has not been studied; however, these may be analternative in these patients if long-term oral anti-coagulation is not suitable.

IS THERE A ROLE FOR THROMBOPHILIA

TESTING IN PATIENTS WITH

CORONARY EMBOLISM?

For clot to form, at least 2 of the conditions ofVirchow triad (Central Illustration, top triangle) mustbe present. For coronary embolism, anatomic factors,such as a PFO, allow transit of clot from the venous tothe arterial circulation and provide an additional riskfactor.

A procoagulant state might reasonably be expectedto increase risk of embolic disease; however, throm-bophilia testing is seldom indicated as part of thediagnostic work-up for coronary embolism. Theinherited thrombophilias have an estimated

FIGURE 2 Coronary Thrombus and Sites of Potential Thromboembolism

(A) Magnetic resonance brain demonstrating multiple small embolic cerebral infarctions. (B) Left atrial appendage with a heavy thrombus

burden. The same patient had multiple presentations with recurrent right coronary artery thromboemboli. (C) Photomicrograph of the

aspirated material from thrombectomy under low-power magnification (hematoxylin and eosin, original magnification �40). (D) Photomi-

crograph of the same specimen at higher power magnification, demonstrating a laminated, platelet- and fibrin-rich thromboembolus (he-

matoxylin and eosin, original magnification �200).

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prevalence of 5% in the general population (29).Although they increase the risk of venous thrombo-embolism, there was no increased risk of arterialthromboembolism in long-term cohort studies ofpatients with inherited thrombophilia (30). Casecontrol studies have suggested a similar prevalenceof protein C, protein S, and antithrombin deficienciesin patients with cryptogenic stroke or myocardialinfarction andmatched control subjects, even in youngpatients (31–33). Development of thrombosis, bothvenous and arterial, is complex and genetic de-terminants are a smaller component of risk comparedwith environmental and acquired risk factors (34).

Because of the rarity of coronary embolic disease,recommendations for thrombophilia testing areextrapolated from the data for strokes of possiblethromboembolic etiology and, to a lesser extent,venous thromboembolism. Routine thrombophiliatesting does not change anticoagulation strategy inmost cases of coronary embolism; however, it shouldbe considered if it is likely to change management ofthe patient.

For most patients with coronary embolism, if therisk of bleeding is low and there are no reversiblerisk factors (Table 2), long-term oral anticoagulationis generally recommended. The recurrence rate for

CENTRAL ILLUSTRATION Anatomic and Pathophysiologic Mechanisms Involved inCoronary Emboli

Raphael, C.E. et al. J Am Coll Cardiol Intv. 2018;11(2):172–80.

For clot to form, at least 2 of the conditions of Virchow triad (top triangle)must be present. For coronary embolism, anatomic factors, such as

a patent foramen ovale, allow transit of clot from the venous to the arterial circulation and provide an additional risk factor. ASD ¼ atrial

septal defect; DVT ¼ deep vein thrombosis; LV ¼ left ventricular; PFO ¼ patent foramen ovale.

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thromboembolic events was 10% (1) on follow-up soa negative thrombophilia screen may even providefalse reassurance (35), because it only tests forknown thrombophilia mutations. If there are con-cerns regarding bleeding risk with long-term oralanticoagulation, thrombophilia testing may be useful

to assess individual patient risk of recurrentthromboembolism.

Young patients, both for coronary embolism andstroke, are a particular area of difficulty with mini-mal data in the stroke data and no data for coronarythromboembolism. Data from stroke suggests that

TABLE 2 Acquired Risk Factors for Thrombophilia

Recent surgery/trauma/fracture

Immobilization

Active cancer

Smoking

Antiphospholipid syndrome

Autoimmune disorders

Myeloproliferative disorders

Prothrombotic chemotherapy agents

Heparin-induced thrombocytopenia

Microalbuminuria/nephrotic syndrome

Pregnancy or post-partum

Oral contraceptive use

Estrogen or progestin therapy

Selective estrogen receptor modulators (e.g., tamoxifen)

Paroxysmal hemoglobinuria

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thromboembolic disease is the underlying cause of20% of strokes in patients younger than 50 yearsof age, largely in patients with first stroke at age<35 (36). Thrombophilia testing has been empiricallyrecommended in patients younger than age 45 with acryptogenic stroke (37); however, there are no datato support improved clinical outcome as a result ofthis testing and we advocate discussion of long-termoral anticoagulation as the first-line managementrecommendation.

Interpretation of thrombophilia testing is complex.Patients are required to be off all anticoagulation andis best performed after the acute phase reaction hasresolved. Novel oral anticoagulants may cause false-positive lupus anticoagulant testing and falsely lowantithrombin activity (38). Additional managementdilemmas are associated with any genetic testing,including management of mutations of unknownsignificance and the anxiety associated with familialtesting.

Full history and clinical examination should assessfor procoagulant risk factors, including signs andsymptoms of active cancer; vasculitis; autoimmunedisease; hyperviscosity syndromes; and infection,including endocarditis and factors increasing risk ofthromboembolism, including immobility and medi-cation use (Table 2). A detailed history of recurrentmiscarriage, previous venous thromboembolism, andarterial thromboembolism should be taken. Bloodtests including erythrocyte sedimentation rate andvasculitis and autoimmune testing where clinicallysuspected should be performed. Management is thenguided by clinical assessment of likelihood of recur-rent embolism.

MANAGEMENT OF CORONARY EMBOLISM:

WHO TO ANTICOAGULATE AND

FOR HOW LONG

Patients presenting with coronary embolism of sus-pected venous origin, either from the history andexamination or from histological examination of theaspirated thrombus, should undergo further work-upto assess for the source and route of paradoxicalembolism, including assessment for PFO and arte-riovenous malformations. Paradoxical embolism ismore difficult to identify and therefore may beunderdiagnosed as a cause of coronary embolism. Inkeeping with the venous thromboembolism guide-lines, management typically is with 3 months of oralanticoagulation in patients with reversible riskfactors (Table 2), such as temporary immobility, post-surgery, and postpartum Idiopathic thromboembo-lism or thromboembolism associated with ongoingprocoagulant states, such as active cancer, are likelyto benefit from long-term oral anticoagulation (38).

Patients with atrial fibrillation had a 10% recur-rence rates in the series by Shibata et al. (1) andshould be offered long-term oral anticoagulation un-less there are contraindications. For all other coro-nary embolism patients, we suggest a period of oralanticoagulation for 3 months in the absence ofongoing procoagulant risk factors (Table 2). For thosewith persistent risk factors, long-term oral anti-coagulation should be considered.

Anticoagulation should be achieved with warfarinor a novel oral anticoagulant rather than antiplateletdrugs. Patients who received a coronary stent at thetime of coronary angiography are more complex.Management may either be with triple therapy or asingle antiplatelet agent coupled with oral anti-coagulation, such as warfarin and clopidogrel. Again,in the absence of guidelines, decisions are at thediscretion of the individual clinician and assessmentof bleeding risk against risk of further thromboem-bolic events.

EMPIRIC RECOMMENDATIONS FOR

INVESTIGATION OF CORONARY EMBOLISM

� History and examination should be performed toassess for evidence of conditions resulting in eithertemporary or sustained increased risk of throm-boembolism (Table 2).

� Patients should be investigated for atrial fibrilla-tion, particularly paroxysmal, with electrocardio-gram telemetry.

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� Patients should be investigated with trans-esophageal echocardiography to assess for leftatrial appendage thrombus or spontaneouscontrast in the left atrial appendage, indicatingincreased predisposition to hemostasis in the leftatrial appendage, PFO, and atrial septal defect.

EMPIRIC RECOMMENDATIONS FOR

TREATMENT OF CORONARY EMBOLISM

� Patients with atrial fibrillation with a low risk ofbleeding should be offered long-term oral anti-coagulation, regardless of the CHADS2-VASc score.

� Patients with recurrent coronary embolism with alow risk of bleeding should be offered long-termoral anticoagulation.

� Patients with a reversible risk factor for thrombo-embolic disease (Table 2) at the time of coronaryembolism that has subsequently resolved shouldreceive oral anticoagulation for 3 months.

� Patients with persistent risk factors for thrombo-embolic disease should be offered long-term oralanticoagulation.

� Patients who underwent percutaneous coronaryintervention (stenting) need to receive antiplateletagents in addition to oral anticoagulation.

� There is no role for routine thrombophilia testingin patients with coronary embolism.

� If there are concerns regarding bleeding risk orpatients are unwilling to take long-term oralanticoagulation, thrombophilia testing may aidindividual risk stratification for recurrentthromboembolism.

CONCLUSIONS

Coronary embolus is an underrecognized cause ofACS. It occurs most commonly following coronaryor surgical intervention. However, spontaneous

embolization of thrombi from the left atrialappendage, left ventricle, or systemic veins (para-doxical) may occur and present as ACS. In the case ofhigh thrombus burden or recurrent thrombus with arelatively normal underlying coronary artery, coro-nary embolism should be suspected. Investigationwith transthoracic and transesophageal echocardiog-raphy may reveal a source of coronary emboli. Aspi-ration thrombectomy should be considered in thepresence of a high thrombus load, whereas distalembolus may be managed with anticoagulation.Following aspiration, if the underlying vessel appearsfree of atherosclerosis, the patient may be managedwith anticoagulation alone. Intravascular ultrasoundor optical computerized tomography may be helpfulin determining if there is underlying atherosclerosisand if percutaneous coronary intervention/balloonangioplasty should be considered. Patients should bescreened for underlying atrial fibrillation and sourcesof embolic material, including left atrial appendagethrombus, left ventricular thrombus, and ater-iovenous communications.

At present, the natural history of coronary embo-lism is not well understood; however, the cardiacmortality rate on a recent cohort study was 50% at10 years, significantly higher than the general ACSpopulation. This suggests these patients requirefurther study to identify the natural history of thecondition and how to optimize management toimprove outcome. We suggest that patients bemanaged with oral anticoagulation for a period of3 months if embolism occurred because of temporaryprocoagulant risk factors, and with long-term oralanticoagulation in the presence of persistent riskfactors, including atrial fibrillation.

ADDRESS FOR CORRESPONDENCE: Dr. David R.Holmes, Jr., Department of Cardiovascular Diseases,Mayo Clinic, 200 First Street SW, Rochester,Minnesota 55905. E-mail: [email protected].

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KEY WORDS coronary embolism, coronaryembolus, paradoxical