Left Atrial Appendage Thrombus and Embolic Stroke: A Case Study

Case

A 65 year-old man presented to the emergency department with a 3-day history of acute-onset confusion and forgetfulness. He had no other past medical history and had never been diagnosed with atrial fibrillation (AF). He took no medications and was a former smoker with a 20 pack-year history. He was admitted to our institution’s stroke unit for further workup.

Initial laboratory evaluation was pertinent for a serum troponin I level of 0.624 ng/ml (normal value is 0.006–0.060 ng/ml) which trended downwards on repeat testing. 12-lead electrocardiography (EKG) demonstrated normal sinus rhythm without ST segment changes or Q waves but there was an elevated p-wave terminal force in lead V1 of 6,400 μv x ms suggestive of atrial dysfunction or “cardiopathy”. Computed tomography (CT) angiography of the head and neck did not reveal evidence of cervical artery stenosis, intracranial stenosis or arterial dissection. Magnetic resonance imaging (MRI) of the brain without gadolinium administration demonstrated multiple infarcts in the territory of the left posterior cerebral artery (PCA) (Figure 1). Transthoracic echocardiography (TTE) revealed an ejection fraction (EF) of 45% with multiple regional wall motion abnormalities consistent with prior myocardial ischemia with normal left atrial volume (51ml). No left atrial appendage (LAA) pathology was identified. The patient’s MRI brain incidentally showed a lesion in the left internal auditory canal and – out of concern for possible metastatic disease – a CT of the chest, abdomen and pelvis was performed with the administration of iodinated contrast. This study revealed a left atrial appendage thrombus (Figure 2A), as well as a large left interpolar renal infarct (Figure 2B) and a 3D spin of the LAA showed a cauliflower morphology (Figure 3) He was started on therapeutic anticoagulation with unfractionated heparin in parallel with warfarin with a goal international normalized ratio of 2–3. He remained in-house until his INR was within the therapeutic range – a total of 7 days. He underwent continuous cardiac telemetry monitoring throughout that entire period with no evidence of atrial fibrillation (AF). He was discharged home with a residual right superior homonymous quadrantonopsia.

Figure 1.

Magnetic resonance imaging of the brain demonstrating multiple infarcts in distribution of the posterior cerebral artery.

Figure 2.

Computed tomography of the chest and abdomen demonstrating A) A left atrial appendage thrombus and B) A left interpolar region infarct.

Figure 3.

3D spin of the left atrial appendage showing a cauliflower morphology with a thrombus (arrow).

Discussion

Embolic stroke of undetermined source (ESUS) describes an infarct with no clear causative mechanism but which appears embolic in nature based on its radiographic appearance.¹ ESUS accounts for up to 25% of all ischemic strokes.¹ Defining an infarct as ESUS rests on excluding hemodynamically-significant cervical or intracranial stenosis as well as high risk cardiac sources of embolization. The patient described was not classified as ESUS given the finding of a LAA thrombus on chest CT. However, in this case the finding of a LAA thrombus was an incidental one and would not have been found as part of the recommended workup for ESUS (EKG, telemetry, and TTE). Another approach in this gentleman’s case that may have yielded the underlying source of thrombus would have been transesophageal echocardiography (TEE).

We hypothesize that this is a case of atrial cardiopathy where atrial dysfunction even in the absence of atrial fibrillation can result in thromboembolism. This patient also had an elevated serum troponin – a finding that has recently been shown to be a marker of cardioembolic stroke. ² The elevated serum troponin in tandem with the wall motion abnormalities observed on TTE evokes a potential non-ST elevation myocardial infarction in this patient. This is less likely, however, given the LAA location of the thrombus which is seen with atrial disease rather than left ventricular location which is typically seen after myocardial infarction. In addition, the patient does not meet criteria for myocardial infarction, as he had no chest pain and ECG changes to suggest ischemia or infarction.

The LAA is the most common location for thrombus formation in patients with AF.³ Additionally, among the group of patients with ESUS, atrial cardiopathy is hypothesized to be a potential etiology of cardioembolism. Atrial cardiopathy describes dysfunction of the left atrium as defined by serum, imaging or electrocardiographic biomarkers⁴, including (1) elevated N-terminal pro-BNP, (2) p-wave terminal force on lead V1 on EKG, (3) and increased left atrial size. A recent retrospective analysis of adults in the Cardiovascular Health Study (without stroke or atrial fibrillation) associated incident stroke with P-wave terminal force on lead V1 (HR 1.04) and serum NT-proBNP (HR 1.09 per doubling of NT-proBNP). Crucially, atrial cardiopathy conveys a liability to thrombus formation in the absence of atrial rhythm disturbances (AF or atrial flutter) and the LAA may be the likely location of the thrombus. Recently, studies have shown lack of a temporal relationship between AF and embolic events, challenging the concept that fibrillation of the atrium is a direct cause of thrombus formation and therefore atrial fibrillation itself may be a biomarker of atrial cardiopathy and not a direct cause of embolic events. Indeed, there may be a reciprocal relationship between left atrial cardiopathy and AF i.e atrial cardiopathy may lead to AF or visa versa.³

Moreover, LAA dysfunction has been suggested to play a role in thrombus formation. Studies have shown that spontaneous echocardiographic contrast, reduced LAA peak flow velocity, and LAA fibrosis has been associated with embolic risk.³ Furthermore, the left atrial appendage has been classified in to 4 morphologies based on its radiographic appearance (in descending order of frequency): chicken wing, cactus, windsock and cauliflower.³ The morphology of the left atrial appendage has been shown to be associated with the risk of embolization with pilot data suggesting that a “non-chicken-wing” morphology is most closely associated with embolic stroke (either ESUS or cardioembolic stroke)⁵, possibly mediated by a lower LAA peak flow velocity in patients with non-chicken wing morphology. The LAA can be challenging to visualize by TTE or transesophageal echocardiography (TEE) owing to its length and varied morphology. Cardiac MRI permits evaluation of the left atrial size and morphology and potentially degree of left atrial fibrosis. ⁶ Atrial fibrosis – as measured via cardiac MRI – is another putative biomarker of left atrium/left atrial appendage dysfunction that increases risk of embolic stroke. A recent study, showed that in patients with ischemic stroke, left atrial fibrosis was more frequently detected in patients with cryptogenic stroke vs. stroke of determined non-cardioembolic mechanism.⁷

These findings were the impetus behind ARCADIA (Atrial Cardiopathy and Antithrombotic Drugs In Prevention After Cryptogenic Stroke (URL: https://clinicaltrials.gov. Unique identifier: NCT03192215)). This is a randomized trial comparing anticoagulation (apixaban) with anti-platelet therapy (aspirin at a dose of 81mg daily) for secondary stroke prevention in patients with recent embolic stroke of undetermined source and evidence of atrial cardiopathy. The hypothesis is supported by a retrospective analysis of the Warfarin Aspirin Recurrent Stroke Study (WARSS) suggested that anticoagulation was superior to anti-platelet therapy for secondary stroke prevention in those patients with an elevated NT-proBNP (>750mg/dl).⁸ By refining a population with cryptogenic stroke and biomarkers of atrial cardiopathy, one can potentially identify a patient most likely to benefit from anticoagulation as opposed to the current recommended therapy of anti-platelet therapy alone. In addition to anticoagulation therapy, occlusion of the LAA– either through an open surgical procedure or via catheter-based approaches – has been suggested as another therapeutic option to reduce stroke risk in AF. The WATCHMAN Left Atrial Appendage Closure Device for Embolic PROTECTion in Patients with Atrial Fibrillation (PROTECT AF) trial ⁹ randomized 707 patients with AF to either warfarin (n=244) or left atrial occlusion via the WATCHMAN device (n=463). This study showed the WATCHMAN device was non-inferior to warfarin in reducing the risk of stroke (both ischemic and hemorrhagic), systemic embolism, or death (4.3% vs. 3.0%; probability of non-inferiority > 0.999). No studies, however, compare WATCHMAN to the direct oral anticoagulants that have a lower risk of stroke and systemic embolism when compared to warfarin and no studies to date investigated WATCHMAN in patients without AF.

TAKE-HOME POINTS.

1. Atrial cardiopathy is a putative stroke mechanism that describes a liability to thrombus formation in the left atrial appendage in the absence of known atrial rhythm disturbances (atrial fibrillation or atrial flutter).

2. Biomakers of left atrial cardiopathy include elevated N-terminal pro-BNP, p-wave terminal force on lead V1 on EKG, increased left atrial size and presence of paroxysmal supraventricular tachycardia.

3. There is likely a reciprocal relationship between atrial cardiopathy and atrial fibrillation with several biological mechanisms proposed by which one worsens the other.

4. Cardiac MRI is an emerging clinical tool that provides good spatial and temporal resolution of the left atrial appendage.

5. ARCADIA is currently randomizing patients with atrial cardiopathy and recent stroke to anti-platelet therapy versus anticoagulation.