Abstract
Background
Amyloid light chain (AL) amyloidosis is a rapidly progressive disease with significant untreated mortality especially when diagnosis is delayed, making early detection of disease crucial. Various cardiac imaging modalities are emerging as alternatives to echocardiography for the early detection of this disease.
Case Summary
A patient presented with progressive heart failure symptoms and was evaluated with an echocardiogram showing a mildly dilated left ventricle, moderate systolic dysfunction, only mildly increased left ventricular wall thickness, and reduced global longitudinal strain without apical sparing. Cardiac magnetic resonance (CMR) showed diffuse, patchy late gadolinium enhancement. Endomyocardial biopsy confirmed AL cardiac amyloidosis (CA). The patient was treated with guideline-directed medical therapy and chemotherapy agents.
Discussion
Although echocardiography has great utility as a screening tool for cardiac amyloidosis given its widespread availability, this case highlights its potential limitations and emphasizes the importance of CMR for evaluation of dilated cardiomyopathies and CA detection.
Take-Home Messages
CA may present with dilated cardiomyopathy and lack classic echocardiographic features. Early CMR may facilitate timely diagnosis of CA.
Key words: cardiac magnetic resonance, cardiomyopathy, chronic heart failure, imaging, ultrasound
Visual Summary
History of Presentation
A 67-year-old man with a prior history of paroxysmal atrial fibrillation and Crohn disease presented to the cardiology clinic with new-onset exertional dyspnea, leg swelling, chest discomfort, and bendopnea and was found to have new heart failure with reduced ejection fraction (HFrEF). His electrocardiogram showed normal sinus rhythm and voltages (Figure 1A), and an echocardiogram at this time showed mild left ventricular (LV) dilation (LV internal diameter in diastole: 6.0 cm) and mildly increased wall thickness (12 mm) (Figure 1B, Video 1), with an LV ejection fraction of 36.1%. There was global hypokinesis and reduction in global longitudinal strain (GLS) to −14.2% without an apical-sparing pattern (Figure 1C, Video 2). Although attempts were made to initiate goal-directed medical therapy, the patient poorly tolerated sacubitril-valsartan and metoprolol because of symptomatic hypotension and dizziness.
Figure 1.
Electrocardiogram and Transthoracic Echocardiography Findings
(A) 12-lead electrocardiogram (ECG) demonstrating sinus rhythm without low voltage or other classic electrocardiographic cardiac amyloidosis features. (B) Transthoracic echocardiography parasternal long-axis view showing left ventricular dilation (end-diastolic diameter: 56 mm) with only mildly increased left ventricular wall thickness (interventricular septum and posterior wall measuring 12 mm). (C) Global longitudinal strain bull's eye plot demonstrating diffusely reduced strain (global longitudinal strain: −14.2%) without the characteristic apical-sparing pattern.
Past Medical History
For the previous 3 years, the patient had experienced recurrent atrial fibrillation refractory to multiple antiarrhythmics including flecainide and had undergone 2 pulmonary vein isolations. Notable comorbidities include ileocolonic Crohn disease well controlled on a biologic interleukin inhibitor.
Differential Diagnosis
In the context of this patient's long-standing, difficult-to-control atrial fibrillation, tachyarrhythmia-mediated cardiomyopathy was considered to be the most likely etiology of his HFrEF, versus ischemic or other nonischemic cardiomyopathies.
Investigations
A coronary computed tomography angiogram obtained to evaluate for ischemic cardiomyopathy showed nonobstructive coronary artery disease. To evaluate for the etiology of his nonischemic cardiomyopathy, cardiac magnetic resonance (CMR) was then performed, which showed mildly increased wall thickness (Figures 2A and 2B, Video 3), indexed LV end-diastolic volume of 199 mL/m2 consistent with LV dilation, markedly elevated native T1 relaxation times at 1,166 ms (normal: 900-1,100 ms), and extracellular volume at 49% (normal: <29%) (Figures 2C and 2D). Gadolinium kinetics were abnormal with simultaneous nulling of the myocardium and blood pool (Video 4). On late gadolinium enhancement (LGE) imaging, there was diffuse patchy midmyocardial LGE involving the basal and midsegments, most prominently in the septal, inferior, and inferolateral walls (Figures 2C and 2D, Video 5). Overall, this constellation of findings was highly concerning for cardiac amyloidosis (CA). The patient's N-terminal pro–B-type natriuretic peptide was 1,854 pg/mL, troponin T was 62 ng/L, and estimated glomerular filtration rate was 88 mL/min/1.73 m2, corresponding to NAC (National Amyloidosis Centre) stage 1. A comprehensive light chain analysis was obtained, which revealed elevated λ light chains at 9.86 mg/dL and a markedly abnormal kappa/λ light chain ratio of 0.15. Given the light chain positivity, a Tc-PyP scan was deferred in accordance with guidelines, as 20% of patients with amyloid light chain (AL)–CA will have a false-positive examination.1 Based on this, a right heart catheterization with endomyocardial biopsy was performed, confirming AL-CA on mass spectrometry. Notably, a retrospective review of a colonoscopy performed 6 months before the onset of heart failure symptoms had demonstrated perivascular deposits of amyloid throughout the colon and rectum.
Figure 2.
Cardiac Magnetic Resonance Findings
(A) Cardiac magnetic resonance cine imaging in short-axis and 4-chamber views demonstrating left ventricular dilation with mildly increased wall thickness (12 mm). (C and D) Late gadolinium enhancement (LGE) imaging in short-axis and 4-chamber views demonstrating diffuse patchy myocardial enhancement (arrows) involving multiple myocardial segments, consistent with infiltrative cardiomyopathy. (E) Native T1 and (F) extracellular volume (ECV) maps demonstrating markedly increased T1 times and ECV.
Management
The patient's heart failure was managed with appropriate guideline-directed medical therapy with dapagliflozin and spironolactone, with torsemide for congestion. For his AL-CA, he underwent induction therapy with Dara-CyBorD. His disease progressed, and he was treated with lenalidomide followed by elotuzumab, pomalidomide, and dexamethasone.
Outcome and Follow-Up
Unfortunately, despite the above therapies the patient's AL amyloidosis continued to progress with ongoing M-spike, and the patient underwent recent treatment with the novel bispecific antibody teclistamab. His M-spike on follow-up has decreased. He continues to follow up with the advanced heart failure team, who are considering heart transplantation if he achieves AL remission.
Discussion
AL-CA, caused by misfolded immunoglobulin light chains, is a rapidly progressive disease. Mortality rates are highly depending on the stage of disease at diagnosis, highlighting the importance of early identification to avoid delays in treatment initiation. Despite this, the median time from symptom onset to diagnosis is about 2 years.2 As diagnosis of AL-CA requires invasive tissue biopsy, a high index of concern is required, necessitating cardiac imaging techniques that can identify those at high risk who warrant invasive work-up.
Our case highlights an increasingly recognized atypical phenotype of CA. Rather than demonstrating the classic restrictive phenotype characterized by increased wall thickness, preserved ejection fraction, and apical sparing of strain, this patient presented with a markedly different constellation of findings including LV dilation, systolic dysfunction, only mildly increased wall thickness, and absence of apical sparing. This presentation more closely resembles nonischemic dilated cardiomyopathy and therefore carries a high risk of diagnostic delay if clinicians rely on the traditional echocardiographic hallmarks of CA.
Transthoracic echocardiography is the first-line imaging modality for heart disease given its widespread availability and cost-effectiveness. Classic echocardiographic features of CA include increased LV wall thickness, biatrial enlargement, and reduced GLS with relative apical sparing.3 However, these findings may lack sensitivity, particularly early in the disease course.4 GLS with an apical-sparing pattern may additionally have lower sensitivity in AL-CA, and strain quality may be influenced by imaging quality as well as loading conditions.5 These findings are consistent with emerging evidence demonstrating the limitations of traditional echocardiographic markers for CA, including recent multicenter data showing that apical sparing is not universally present.5 In addition, although CA has traditionally been associated with preserved ejection fraction and a restrictive phenotype, increasing recognition of atypical presentations such as HFmrEF (heart failure with mildly reduced ejection fraction) or HFrEF further complicates early diagnosis.6,7 Atypical phenotypes may be more common in the presence of a concomitant cardiomyopathy, such as a tachyarrhythmia-mediated cardiomyopathy in this patient. Emerging artificial intelligence–based echocardiographic tools may help overcome some of these diagnostic limitations by identifying subtle patterns not apparent on conventional assessment, although further research is needed.8
In addition to being a powerful tool for evaluating undifferentiated cardiomyopathies, CMR has emerged as an excellent imaging modality to identify CA. While CMR is always considered appropriate in the evaluation of new cardiomyopathy of unknown etiology, it is specifically useful in CA by confirming the diagnosis in patients with undifferentiated LV hypertrophy or identifying cardiac involvement in patients with known extracardiac AL amyloidosis in whom its presence would affect therapies.1,9 Typical findings of CA include patchy subendocardial-to-transmural LGE, abnormal gadolinium kinetics with early myocardial nulling relative to the blood pool, and markedly elevated native T1/extracellular volume due to extensive extracellular deposition of amyloid fibrils.3 In sarcoidosis or genetic cardiomyopathies, gadolinium kinetics are normal and LGE pattern is typically midmyocardial to subepicardial with patchier distribution. A recent systematic review and meta-analysis comparing the sensitivity and specificity of several imaging modalities in identifying CA showed that CMR may be more accurate than transthoracic echocardiography in diagnosing CA.10 Our case highlights the value of CMR in patients with undifferentiated HFrEF, particularly in those with red flags for CA such as intolerance to guideline-directed medical therapy because of hypotension. This is consistent with the latest expert consensus recommendations, as disease presentation can be highly varied, especially in the early stages, and no existing imaging modality has sufficient sensitivity for early diagnosis individually.1 CMR use may be limited at nonexpert centers or in patient-specific situations such as claustrophobia, poor breath holding technique, or irregular/tachycardic rhythm. Advanced chronic kidney disease was previously considered a relative contraindication to contrast-enhanced CMR; however, the widespread adoption of macrocyclic gadolinium-based contrast agents has markedly reduced the risk of nephrogenic systemic fibrosis, leading to broader use in this population.
Conclusions
Early diagnosis of AL-CA is essential given its rapidly progressive disease course. This case report highlights the potential limitations of relying on traditional echocardiographic features in identifying cardiac amyloidosis, especially early in the disease course, emphasizing the importance of CMR when clinical suspicion is high for this disease.
Visual Summary.
A Patient Presenting With New Heart Failure With Reduced Ejection Fraction Demonstrated an Atypical Echocardiographic Phenotype of Cardiac Amyloidosis Characterized by Left Ventricular Dilation, Only Mildly Increased Wall Thickness, and Absence of Apical Sparing
Cardiac magnetic resonance revealed diffuse patchy late gadolinium enhancement, abnormal gadolinium kinetics, and markedly elevated native T1 and extracellular volume, raising suspicion for cardiac amyloidosis. Subsequent endomyocardial biopsy confirmed AL cardiac amyloidosis. This case highlights the limitations of relying solely on classic echocardiographic findings and emphasizes the role of cardiac magnetic resonance in evaluating unexplained cardiomyopathy when clinical suspicion for cardiac amyloidosis remains high. AL = amyloid light chain; CMR = cardiac magnetic resonance; GLS = global longitudinal strain; LV = left ventricular; MRI = magnetic resonance imaging.
Funding Support and Author Disclosures
The authors have reported that they have no relationships relevant to the contents of this paper to disclose.
Take-Home Messages
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Cardiac amyloidosis may present with dilated cardiomyopathy and lack classic echocardiographic features such as apical sparing.
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In patients with unexplained heart failure, early cardiac magnetic resonance imaging may facilitate timely diagnosis of cardiac amyloidosis.
Footnotes
The authors attest they are in compliance with human studies committees and animal welfare regulations of the authors’ institutions and Food and Drug Administration guidelines, including patient consent where appropriate. For more information, visit the Author Center.
Appendix
For supplemental videos, please see the online version of this paper.
Appendix
Parasternal Long-Axis TTE Video Demonstrating Mildly Increased Wall Thickness With Moderate Systolic Dysfunction
Global Longitudinal Strain Tracking Curve Demonstrating Reduced GLS Without Classic Apical-Sparing Pattern
Four-Chamber CMR Steady-State Free Precession (SSFP) Cine Video Demonstrating Mildly Increased Wall Thickness With Moderate Systolic Dysfunction
Look Locker Sequence Demonstrating Abnormal Gadolinium Kinetics With Simultaneous Nulling of the Blood Pool and Myocardium, Consistent With Cardiac Amyloidosis Pattern
Short-Axis Phase-Sensitive Inversion Recovery (PSIR) LGE Images Demonstrating Diffuse Patchy Midmyocardial LGE Involving the Basal and Midsegments, Most Prominent in the Septal, Inferior, and Inferolateral Walls, a Pattern Consistent With Cardiac Amyloidosis
References
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Associated Data
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Supplementary Materials
Parasternal Long-Axis TTE Video Demonstrating Mildly Increased Wall Thickness With Moderate Systolic Dysfunction
Global Longitudinal Strain Tracking Curve Demonstrating Reduced GLS Without Classic Apical-Sparing Pattern
Four-Chamber CMR Steady-State Free Precession (SSFP) Cine Video Demonstrating Mildly Increased Wall Thickness With Moderate Systolic Dysfunction
Look Locker Sequence Demonstrating Abnormal Gadolinium Kinetics With Simultaneous Nulling of the Blood Pool and Myocardium, Consistent With Cardiac Amyloidosis Pattern
Short-Axis Phase-Sensitive Inversion Recovery (PSIR) LGE Images Demonstrating Diffuse Patchy Midmyocardial LGE Involving the Basal and Midsegments, Most Prominent in the Septal, Inferior, and Inferolateral Walls, a Pattern Consistent With Cardiac Amyloidosis