https://orcid.org/0000-0002-3494-2958
Abstract
Increased intracardiac thrombus formation in light-chain cardiac amyloidosis (AL-CA) has been associated with thrombotic events such as stroke and high rates of mortality and morbidity.
A 51-year-old man was admitted to the emergency department with a sudden change in consciousness. His emergency brain magnetic resonance imaging showed two foci of cerebral infarction on the bilateral temporal lobes. His electrocardiogram displayed a normal sinus rhythm with low QRS voltage. Transthoracic echocardiography showed concentric thickened ventricles, dilatation of both atria, a left ventricular ejection fraction of 53%, and a Grade 3 diastolic dysfunction. The bull-eye plot on speckle tracking echocardiography displayed a distinctive apical sparing pattern. A serum-free immunoglobulin analysis showed increased lambda-free light chains (295.59 mg/L) with a reduced kappa/lambda ratio (0.08). Light-chain amyloidosis was subsequently confirmed by examining the histology of the abdominal fat-pad tissue. On transoesophageal echocardiography (TEE), an elongated static thrombus and a mobile bouncing oval thrombus were found on the left and right atrial appendages, respectively. Atrial thrombi were managed with a full dose of dabigatran of 150 mg twice daily, which resulted in a complete resolution after 2 months of TEE follow-up.
Complicating intracardiac thrombosis has been considered one of the major contributions of death in cardiac amyloidosis. Transoesophageal echocardiography should be established to aid in the detection and management of atrial thrombus in AL-CA.
Light-chain cardiac amyloidosis (AL-CA) is associated with thrombo-embolism leading to high mortality and morbidity.
Transoesophageal echocardiography aids in the detection and management of atrial thrombi in AL-CA, particularly in those with sinus rhythm.
Although the use of direct oral anticoagulants is understudied in AL-CA, maintenance of anticoagulation therapy after achieving complete resolution of thrombi can be beneficial in terms of secondary prevention in those with associated risks such as persistent low atrial appendage emptying velocity and densely spontaneous echo contrast.
Introduction
Light-chain cardiac amyloidosis (AL-CA) is characterized by an extracellular deposition of abnormal misfolded immunoglobulin light chain in the myocardium. Increased intracardiac thrombus formation, even in patients with sinus rhythm, has been associated with thrombotic events such as stroke and high rates of mortality and morbidity in AL-CA.1,2 However, current published guidelines lack recommendations for screening and detecting thrombi or contributing factors, which lead to thrombus formation by cardiac imaging.3,4 Moreover, data regarding anticoagulation therapy in case of atrial thrombi in cardiac amyloidosis (CA) are scarce. Transoesophageal echocardiography (TEE) is presumed to be the first-line and primary investigation to identify and manage cardiac thrombus in cardiomyopathy, including patients with AL-CA. In this report, we present the case of a patient arriving in the emergency room with stroke, to be subsequently diagnosed with AL-CA by invasive criteria based on current published guidelines.3,4 For example, TEE was used to detect atrial thrombi and guide anticoagulation therapy for the resolution of atrial thrombi and secondary stroke prevention.
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Case presentation
A 51-year-old man was admitted to the emergency department with a sudden change in consciousness. His wife informed that he had lost the ability to identify his family members precisely several hours ago and started to produce obscure speech without any other significant symptoms. On examination, his vital signs were noted with a moderately low blood pressure of 85/57 mmHg, a regular pulse rate of 85 b.p.m., a temperature of 36.8°C, and an SpO2 of 100% on breathing ambient air. No focal neurology was found, and other signs were unremarkable. However, his emergency brain magnetic resonance imaging showed two foci of cerebral infarction on bilateral temporal lobes (Figure 1A and B). Five months prior to this admission, he had been diagnosed with non-obstructive hypertrophic cardiomyopathy and hyperlipidaemia, for which he had been prescribed with metoprolol 50 mg o.d., clopidogrel 75 mg o.d., fenofibrate 145 mg o.d., and atorvastatin/ezetimibe 20/10 mg o.d., and his blood pressure levels had persistently drifted towards the lower end of normal range.
Brain magnetic resonance imaging showed two foci of cerebral infarctions in bilateral temporal lobes (A), cerebrovascular magnetic resonance imaging suggested the occlusion of the M3 branches (B), and 12-lead electrocardiogram indicated a sinus rhythm with some premature atrial beats and low QRS voltages on the limb leads (C).
Electrocardiogram (ECG) displayed a normal sinus rhythm with some atrial premature beats, along with low QRS voltages at the limb leads, and 24 h ECG did not capture any atrial fibrillation (AF) (Figure 1C). N-terminal pro-B-type natriuretic peptide level (971.58 pmol/L) was markedly elevated, while Troponin I level (0.58 ng/mL) was slightly increased. Considering the patient’s medical history of hypertrophic cardiomyopathy with a disproportionately low QRS voltage on the current ECG and a low blood pressure, CA was highly suspected. Transthoracic echocardiography (TTE) showed thickened left and right ventricles, dilated left and right atria, a left ventricular ejection fraction of 53%, and a Grade 3 diastolic dysfunction with an E to A waves’ ratio of 3.11 and an average E/e′ of 18.1. Colour Doppler imaging revealed mild mitral and tricuspid regurgitations with a peak tricuspid regurgitation velocity of 2.84 m/s. Speckle tracking echocardiography revealed a distinctive ‘apical sparing’ or ‘cherry on the top’ pattern on the bull-eye plot and a reduced left atrial reservoir strain of 8% (Figure 2). A serum-free immunoglobulin analysis showed an increased lambda-free light chain (295.59 mg/L) with a reduced kappa/lambda ratio (0.08). Other testing parameters were consistent with a nephrotic syndrome with a total protein level of 12 g on a 24 h-urine collection. Table 1 displays the patient’s comprehensive biochemical test results. Because AL-CA was highly suspected based on previous test results, a diphosphonate scintigraphy was not performed to rule out the transthyretin type. Based on the invasive criteria following current guidelines, AL-CA was confirmed by examining the histology of the abdominal fat-pad tissue (Figure 3), along with typical echocardiographic indices. Bone marrow biopsy was performed to subsequently confirm the diagnosis of multiple myeloma with a 15q22 deletion on G-band staining. Subsequent TEE demonstrated an elongated static thrombus on the left atrial appendage (LAA), which was reasonably likely to constitute the source of this embolic stroke and a mobile bouncing oval thrombus on the right atrial appendage (RAA), along with a spontaneous echo contrast in both atria and low emptying velocities in the LAA (0.25 m/s) and RAA (0.20 m/s) (Figure 4, Supplementary material online, Video S1).
Transthoracic echocardiography showed hypertrophic ventricles and enlarged atria on four-chamber view (A), an abnormally high E/A wave ratio of 3.11 on Doppler imaging (B), ‘apical sparing’ pattern (C), and reduced left atrial strain parameters (D) on speckle tracking echocardiography.
Abdominal fat-pad biopsy result was positive for Congo red staining (A), under polarized light (B), and for lambda light chain with immunofluorescence staining (C).
Thrombi (white arrows) with the presence of spontaneous contrast in the left (A1) and right (B1) atrial appendages on mid-oesophageal two-chamber view (80–90°) and mid-oesophageal bicaval view, respectively. Resolution of thrombi (asterisks) in the left (A2) and right (B2) atrial appendages after 2 months of anticoagulation therapy.
Laboratory data
| Variable | Value | Reference normal range |
|---|---|---|
| Serum | ||
| Free lambda (mg/L) | 295.59 | 3.3–19.4 |
| Free kappa (mg/L) | 25.77 | 5.71–26.3 |
| Ratio of free kappa/lambda | 0.08 | 0.3–1.7 |
| Immunoglobulin A (mg/dL) | 107 | 70–400 |
| Immunoglobulin G (mg/dL) | 293 | 700–1600 |
| Immunoglobulin M (mg/dL) | 110 | 40–230 |
| β2-microglobulin (µg/L) | 6232 | 780–1600 |
| N-terminal pro-B-type natriuretic peptide (pmol/L) | 971.58 | <14.75 |
| Troponin I (ng/mL) | 0.579 | <0.2 |
| Urea (mg/dL) | 32 | 7–20 |
| Creatinine (mg/dL) | 1.2 | 0.7–1.5 |
| Estimated glomerular filtration rate (mL/min/1.73 m2) | 69.6 | ≥90 |
| Sodium (mmol/L) | 139 | 135–150 |
| Potassium (mmol/L) | 4.1 | 3.5–5.5 |
| Chloride (mmol/L) | 107 | 98–106 |
| Aspartate transaminase (U/L) | 49 | 9–48 |
| Alanine transaminase (U/L) | 30 | 5–49 |
| Gamma-glutamyl transferase (U/L) | 447 | 4–38 |
| Total cholesterol (mg/dL) | 231 | 140–239 |
| Low-density lipoprotein cholesterol (mg/dL) | 160 | 90–150 |
| High-density lipoprotein cholesterol (mg/dL) | 34 | >45 |
| Triglyceride (mg/dL) | 282 | 35–160 |
| Albumin (g/dL) | 2.5 | 3.5–5.5 |
| Protein (g/dL) | 4.2 | 6–8 |
| Glucose (mg/dL) | 94 | 70–110 |
| Free thyroxine (pg/mL) | 9.82 | 8–20 |
| Thyroid-stimulating hormone (mIU/L) | 2.22 | 0.4–5 |
| Urine | ||
| 24 h protein (g/24 h) | 12 | 0 |
| Variable | Value | Reference normal range |
|---|---|---|
| Serum | ||
| Free lambda (mg/L) | 295.59 | 3.3–19.4 |
| Free kappa (mg/L) | 25.77 | 5.71–26.3 |
| Ratio of free kappa/lambda | 0.08 | 0.3–1.7 |
| Immunoglobulin A (mg/dL) | 107 | 70–400 |
| Immunoglobulin G (mg/dL) | 293 | 700–1600 |
| Immunoglobulin M (mg/dL) | 110 | 40–230 |
| β2-microglobulin (µg/L) | 6232 | 780–1600 |
| N-terminal pro-B-type natriuretic peptide (pmol/L) | 971.58 | <14.75 |
| Troponin I (ng/mL) | 0.579 | <0.2 |
| Urea (mg/dL) | 32 | 7–20 |
| Creatinine (mg/dL) | 1.2 | 0.7–1.5 |
| Estimated glomerular filtration rate (mL/min/1.73 m2) | 69.6 | ≥90 |
| Sodium (mmol/L) | 139 | 135–150 |
| Potassium (mmol/L) | 4.1 | 3.5–5.5 |
| Chloride (mmol/L) | 107 | 98–106 |
| Aspartate transaminase (U/L) | 49 | 9–48 |
| Alanine transaminase (U/L) | 30 | 5–49 |
| Gamma-glutamyl transferase (U/L) | 447 | 4–38 |
| Total cholesterol (mg/dL) | 231 | 140–239 |
| Low-density lipoprotein cholesterol (mg/dL) | 160 | 90–150 |
| High-density lipoprotein cholesterol (mg/dL) | 34 | >45 |
| Triglyceride (mg/dL) | 282 | 35–160 |
| Albumin (g/dL) | 2.5 | 3.5–5.5 |
| Protein (g/dL) | 4.2 | 6–8 |
| Glucose (mg/dL) | 94 | 70–110 |
| Free thyroxine (pg/mL) | 9.82 | 8–20 |
| Thyroid-stimulating hormone (mIU/L) | 2.22 | 0.4–5 |
| Urine | ||
| 24 h protein (g/24 h) | 12 | 0 |
Bold values indicate abnormal test results.
Laboratory data
| Variable | Value | Reference normal range |
|---|---|---|
| Serum | ||
| Free lambda (mg/L) | 295.59 | 3.3–19.4 |
| Free kappa (mg/L) | 25.77 | 5.71–26.3 |
| Ratio of free kappa/lambda | 0.08 | 0.3–1.7 |
| Immunoglobulin A (mg/dL) | 107 | 70–400 |
| Immunoglobulin G (mg/dL) | 293 | 700–1600 |
| Immunoglobulin M (mg/dL) | 110 | 40–230 |
| β2-microglobulin (µg/L) | 6232 | 780–1600 |
| N-terminal pro-B-type natriuretic peptide (pmol/L) | 971.58 | <14.75 |
| Troponin I (ng/mL) | 0.579 | <0.2 |
| Urea (mg/dL) | 32 | 7–20 |
| Creatinine (mg/dL) | 1.2 | 0.7–1.5 |
| Estimated glomerular filtration rate (mL/min/1.73 m2) | 69.6 | ≥90 |
| Sodium (mmol/L) | 139 | 135–150 |
| Potassium (mmol/L) | 4.1 | 3.5–5.5 |
| Chloride (mmol/L) | 107 | 98–106 |
| Aspartate transaminase (U/L) | 49 | 9–48 |
| Alanine transaminase (U/L) | 30 | 5–49 |
| Gamma-glutamyl transferase (U/L) | 447 | 4–38 |
| Total cholesterol (mg/dL) | 231 | 140–239 |
| Low-density lipoprotein cholesterol (mg/dL) | 160 | 90–150 |
| High-density lipoprotein cholesterol (mg/dL) | 34 | >45 |
| Triglyceride (mg/dL) | 282 | 35–160 |
| Albumin (g/dL) | 2.5 | 3.5–5.5 |
| Protein (g/dL) | 4.2 | 6–8 |
| Glucose (mg/dL) | 94 | 70–110 |
| Free thyroxine (pg/mL) | 9.82 | 8–20 |
| Thyroid-stimulating hormone (mIU/L) | 2.22 | 0.4–5 |
| Urine | ||
| 24 h protein (g/24 h) | 12 | 0 |
| Variable | Value | Reference normal range |
|---|---|---|
| Serum | ||
| Free lambda (mg/L) | 295.59 | 3.3–19.4 |
| Free kappa (mg/L) | 25.77 | 5.71–26.3 |
| Ratio of free kappa/lambda | 0.08 | 0.3–1.7 |
| Immunoglobulin A (mg/dL) | 107 | 70–400 |
| Immunoglobulin G (mg/dL) | 293 | 700–1600 |
| Immunoglobulin M (mg/dL) | 110 | 40–230 |
| β2-microglobulin (µg/L) | 6232 | 780–1600 |
| N-terminal pro-B-type natriuretic peptide (pmol/L) | 971.58 | <14.75 |
| Troponin I (ng/mL) | 0.579 | <0.2 |
| Urea (mg/dL) | 32 | 7–20 |
| Creatinine (mg/dL) | 1.2 | 0.7–1.5 |
| Estimated glomerular filtration rate (mL/min/1.73 m2) | 69.6 | ≥90 |
| Sodium (mmol/L) | 139 | 135–150 |
| Potassium (mmol/L) | 4.1 | 3.5–5.5 |
| Chloride (mmol/L) | 107 | 98–106 |
| Aspartate transaminase (U/L) | 49 | 9–48 |
| Alanine transaminase (U/L) | 30 | 5–49 |
| Gamma-glutamyl transferase (U/L) | 447 | 4–38 |
| Total cholesterol (mg/dL) | 231 | 140–239 |
| Low-density lipoprotein cholesterol (mg/dL) | 160 | 90–150 |
| High-density lipoprotein cholesterol (mg/dL) | 34 | >45 |
| Triglyceride (mg/dL) | 282 | 35–160 |
| Albumin (g/dL) | 2.5 | 3.5–5.5 |
| Protein (g/dL) | 4.2 | 6–8 |
| Glucose (mg/dL) | 94 | 70–110 |
| Free thyroxine (pg/mL) | 9.82 | 8–20 |
| Thyroid-stimulating hormone (mIU/L) | 2.22 | 0.4–5 |
| Urine | ||
| 24 h protein (g/24 h) | 12 | 0 |
Bold values indicate abnormal test results.
After consulting with a haematologist, a regimen with melphalan, dexamethasone, and thalidomide was initiated for the specific treatment of light-chain amyloidosis. Atrial appendages thrombi were managed with a full dose of dabigatran of 150 mg twice daily. The patient was discharged with a minor improvement in his neurologic condition. Two months later, another TEE was performed for evaluating the thrombus status, which showed a complete resolution without any residual thrombi in both atrial appendages. However, due to the persistent presence of spontaneous contrast and low emptying velocities in the atrial appendages on TEE, anticoagulation therapy was continued for the further prevention of thrombus reformation. The patient’s symptoms ameliorated, and he did not suffer from any secondary stroke on follow-up examinations.
Discussion
In summary, we presented a 51-year-old man arriving in the emergency room with cerebral stroke and a history of hypertrophic cardiomyopathy, low blood pressure, low voltage on ECG, and abnormal serum-free light-chain analysis. Those red-flag signs raised a high suspicion for CA and AL-CA was confirmed by a positive fat-pad biopsy and typical echocardiographic findings. Transoesophageal echocardiography was performed to detect thrombi on the LAA and RAAs, which achieved a complete resolution after 2 months of full-dose anticoagulation therapy, and to guide clinical decision on continuing anticoagulation therapy for the prevention of further secondary embolic events.
Cardiac amyloidosis is a disease characterized by an extracellular deposition of insoluble protein called ‘amyloid’, which primarily derives from the breakdown of light chains from plasma cells in the bone marrow (AL-CA), or from the misfolded thyroxine and retinol-transporting protein called ‘transthyretin’ (hereditary or wild-type transthyretin CA). Complicating intracardiac thrombosis, which is not an uncommon finding, has been considered one of the major contributions of death in AL-CA.2,5
In a study examining 116 autopsies of CA including 55 AL-CA, intracardiac thrombosis was found in up to 33%, with a higher incidence of 51% in the light-chain type, and 39.4% had multiple thrombi.2 In those who suffered an embolic event, 82.6% were fatal, with patients primarily suffering from the light chain type and emboli primarily involving the pulmonary artery. Multivariate analyses showed that the two clinical independent factors associated with thrombus formation were AF and AL-CA, while left ventricular diastolic function, higher heart rate, and right ventricular wall thickness were the exclusive echocardiographic parameters related to thrombo-embolism. However, the limitations of this study were the non-inclusion of TEE parameters in analyses due to the limited number of cases examined and the non-evaluation of the effect of anticoagulation therapy. Another study including 156 patients with CA undergoing TTE and TEE found that 27% of the patients had intracardiac thrombi, in which 58 thrombi were detected by TEE, decreasing to only 3 clots by TTE.6 Interestingly, as in our case, 16.7% of the patients who were in sinus rhythm developed atrial thrombosis, supporting the hypothesis of the contribution of more than one mechanism of atrial rhythm disturbance to thrombus formation. The combination of different factors such as hypercoagulable state, endomyocardial injury due to amyloid infiltration, and altered atrial blood stasis could lead to atrial thrombosis even in patients with sinus rhythm or under anticoagulation treatment.7
In a retrospective study including 406 CA patients in five centres, 7.6% of the patients were found to suffer from embolic events, of whom 32.2% were in sinus rhythm.8 The only predictor for the development of the arterial-embolic event in patients with sinus rhythm was a CHA2DS2-VASc score of ≥3. However, due to the retrospective nature of the study and the lack of multivariate analysis, this risk factor should be interpreted with caution while applying it in clinical settings. Another retrospective study including 1911 CA patients showed a disagreed finding, because the CHA2DS2-VASc score did not predict embolic events in patients with sinus rhythm.9 In our case, the patient’s CHA2DS2-VASc score was 0 before this presentation, suggesting that the traditional risk factors may not be sufficient to predict an embolic event in CA. Another case report demonstrated that atrial mechanical dysfunction by a loss of transmitral Doppler A wave and reduced left atrial strain on echocardiography could be linked to atrial thrombus formation and cardioembolic stroke in a CA patient with sinus rhythm and suggested a low threshold of TEE for detecting the embolic source.10 Our patient also yielded a markedly reduced left atrial strain, supporting the incorporation of this parameter along with other TEE indices into a further prospective study to establish a reliable risk score for thrombo-embolism in CA patients with sinus rhythm. A recent retrospective study evaluated 58 patients with CA undergoing direct current electrical cardioversion for atrial arrhythmia. Compared with the control patients, those with CA had a higher rate of cancellation due to intracardiac thrombosis identified on TEE (81 vs. 22%, P = 0.02) despite high rates (31%) of adequate anticoagulation for 3 weeks.11 The results of this study were consistent with others in that low atrial appendage emptying velocity and the presence of spontaneous contrast were common in those with AL-CA and significantly related to the formation of atrial thrombus.6,11 Hence, establishing therapy to target and prevent thrombus in AL-CA should not be based solely on the presence of AF or any rhythm disturbances, but on those high-risk contributing factors also. Of note, although thrombo-embolism can occur in CA patients without AF, there is evidence that in those who suffer from ischaemic stroke, this arrhythmia is frequently detected only after embolic events.9,12 This finding asserts the importance of continuous monitoring and surveillance for AF in CA patients in sinus rhythm.
According to a previous report, the majority of CA patients with thrombosis was managed with warfarin (81%) and a fewer number were controlled with other oral anticoagulated agents.13 However, the effectiveness of each therapy has not been fully examined yet, with a tendency of switching among regimens in those with persistent thrombus, and the resolution rate was reported to be low (43%) after 50 days of the first follow-up. Another recent study showed there was no difference in the incidence rate of embolism and major bleeding events between CA patients with AF treated with vitamin K antagonists and those treated with direct oral anticoagulants; however, anticoagulation therapy was associated with lower embolic events.9 Although guidance on anticoagulation for primary and secondary prevention of stroke in CA was lacking in this study, there was ample evidence to support the significant association between a low atrial appendage emptying velocity or the presence of spontaneous contrast on TEE and the formation of atrial thrombus, and an extended anticoagulation therapy following thrombi resolution in the patient in this study was deemed favourable and reasonable. The fact that there was no recurrent stroke in this patient supports the concept of continuing CA patients on anticoagulation in such high-risk conditions; however, further investigation is warranted.
Our case highlighted a growing need to identify and manage atrial thrombo-embolism in AL-CA patients, which can be accomplished by using a rather widely available TEE. This essential practice should be incorporated into updated guidelines to enable early detection and treatment of such an exceedingly morbid and mortal complication.
Patient perspective
The patient expressed the view that he felt more secure under anticoagulation therapy, acknowledging that such treatment would bring some beneficial effect on the prevention of another embolic attack. He did not have any complaints about long-term anticoagulation.
Lead author biography
Toan Quang Dang completed his residency program in internal medicine led by Sy Van Hoang at the University of Medicine and Pharmacy at Ho Chi Minh City in 2018. He has been working as a general cardiologist and dedicated echocardiographer at Cho Ray Hospital since 2019. He takes special interest in the diagnosis and treatment of cardiomyopathy and heart failure. He is currently training to become an interventional echocardiographer.
Supplementary material
Supplementary material is available at European Heart Journal – Case Reports.
Acknowledgements
None declared.
Slide sets: A fully edited slide set detailing this case and suitable for local presentation is available online as Supplementary data.
Consent: The authors confirm that written consent for submission and publication including images and texts has been obtained from the patient in line with COPE guidance and under the review board of the hospital administration.
Funding: None declared.
References
Author notes
Conflict of interest: None declared.
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