Accurate differentiation between light-chain (AL) amyloidosis and transthyretin-mediated amyloid cardiomyopathy (ATTR-CM) is critical for effective patient management, as misclassification can delay life-saving therapies for AL amyloidosis or result in unnecessary interventions for ATTR-CM.
These forms of cardiac amyloidosis differ significantly in their pathogenesis, clinical course, and prognosis. AL amyloidosis, caused by misfolded immunoglobulin light chains, is typically more aggressive, presents earlier, and is associated with greater cardiac dysfunction.
On the other hand, ATTR-CM, particularly the wild-type form (wtATTR-CM), mainly affects older men and progresses more slowly, often with conduction abnormalities.
“Recognition of these differences, and the application of multimodal imaging and biomarker strategies, is essential to optimize care and improve outcomes for affected patients,” Hassan Mahmood, MD, and Julius Albert Kato, DO, wrote in a study published in The American Journal of Cardiology.
Read more about ATTR-CM differential diagnosis
Despite these known distinctions, few studies have systematically compared AL amyloidosis and wtATTR-CM across multiple imaging modalities and clinical outcomes in real-world practice.
Furthermore, most available data come from single-center cohorts or highly selected trial populations, limiting broader applicability.
ATTR-CM vs AL Amyloidosis, a Multicenter Evaluation
To address this gap, recent work has evaluated a contemporary, multicenter Southern US cohort using biomarkers, echocardiography, advanced cardiac magnetic resonance imaging (MRI) measures, and adjusted survival analyses, providing a comprehensive and generalizable assessment of subtype-specific differences.
The study revealed important differences in clinical presentation, cardiac structure and function, imaging phenotypes, and outcomes.
In a cohort of 200 patients (50% AL amyloidosis, 50% wtATTR-CM), consistent with prior reports, those with wtATTR-CM were older (mean age, 81 vs 63 years) and predominantly male (88%), whereas the AL amyloidosis group was younger with a more balanced sex distribution (55% male).
These demographic patterns align with the underlying biology of each disease, as wtATTR-CM arises from age-related transthyretin misfolding, while AL amyloidosis results from rapid myocardial deposition of immunoglobulin light chains in the setting of a plasma cell dyscrasia.
Biomarkers and functional indicators of more aggressive AL amyloidosis
AL amyloidosis was associated with more severe cardiac involvement, including significantly higher pro-B-type natriuretic peptide (proBNP, mean, 8827 pg/mL vs 2513 pg/mL) levels and lower left ventricular ejection fraction (LVEF) at baseline (36% vs 52%) and 1 year (33% vs 51%).
Patients with AL amyloidosis also had greater interventricular septal thickness (19 mm vs 14 mm), worse global longitudinal strain (–9.8% vs –13.9%), and slightly higher diastolic dysfunction grade (2.53 vs 2.31).
Imaging phenotypes highlight subtype-specific myocardial involvement
In contrast, wtATTR-CM showed a higher extracellular volume fraction (50% vs 44.1%), reflecting more chronic interstitial infiltration.
Late gadolinium enhancement patterns differed significantly between groups, with subendocardial enhancement predominating in AL amyloidosis and transmural enhancement in wtATTR-CM.
Clinical outcomes demonstrating worse prognosis in AL amyloidosis
Clinically, patients with AL amyloidosis experienced significantly more heart failure hospitalizations (3.3 vs 0.7) and had much higher 2-year mortality (35% vs 5%).
After adjustment for age, sex, baseline LVEF, and proBNP, AL amyloidosis remained an independent predictor of 2-year mortality (hazard ratio, 6.2, 95% confidence interval [CI], 2.5-15.4, P <.01).
Rates of implantable cardioverter-defibrillator insertion were similar between groups, suggesting that arrhythmia risk may not be solely determined by amyloid type.
Multiple myeloma occurred exclusively in the AL cohort (11% vs 0%).
Multiple Myeloma in ATTR-CM: Rare but Possible
Although multiple myeloma occurred exclusively in the AL cohort in the study by Mahmood and Kato, isolated case reports have documented ATTR-CM in patients with plasma cell dyscrasias.
In the Journal of the American College of Cardiology (JACC): Case Reports, Mohamed Ibrahim and colleagues described 2 cases of wtATTR-CM occurring in patients with plasma cell dyscrasias, highlighting the diagnostic challenges and the importance of endomyocardial biopsy in distinguishing ATTR-CM from AL amyloidosis in this clinical context.
Read more about ATTR-CM comorbidities
In these reports, both patients had underlying plasma cell dyscrasias—a 77-year-old woman with overt multiple myeloma and a 73-year-old man with smoldering multiple myeloma—which initially raised suspicion for AL amyloidosis.
Clinical clues
The patients presented with symptoms ranging from exertional intolerance to progressive dyspnea, and cardiac imaging suggested infiltrative cardiomyopathy. Furthermore, both had a remote history of bilateral carpal tunnel syndrome, a finding more commonly associated with ATTR-CM than AL amyloidosis, which provided an early clinical clue for the underlying diagnosis.
“Although bilateral carpal tunnel syndrome is recognized as a manifestation in both AL and ATTR, it is much more prevalent in ATTR patients,” Ibrahim and colleagues said. “The remote history of bilateral carpal tunnel syndrome was more suggestive of ATTR, as carpal tunnel syndrome often predates the diagnosis of ATTR-CM by more than 5 years.”
Imaging findings
Cardiac magnetic resonance imaging showed concentric left ventricular hypertrophy, diffuse subendocardial and midmyocardial late gadolinium enhancement, abnormal myocardial nulling, and reduced left atrial strain.
Additionally, echocardiography demonstrated preserved ejection fraction with abnormal global longitudinal strain and apical sparing patterns.
Initial noninvasive testing was inconclusive. Fat pad aspirates were either negative or, when positive, insufficient for amyloid typing, and technetium-99m-3,3‑diphosphono‑1,2‑propanodicarboxylic acid scintigraphy, although showing myocardial tracer uptake above diagnostic thresholds, could not definitively distinguish ATTR-CM from AL amyloidosis in the setting of a plasma cell disorder.
Definitive diagnosis through endomyocardial biopsy
Definitive diagnosis was established via endomyocardial biopsy, which revealed Congo red-positive amyloid deposits. Laser microdissection with mass spectrometry confirmed transthyretin amyloid, while genetic testing showed no pathogenic TTR variants, confirming wtATTR-CM.
“While left ventricular wall thickness and a remote history of bilateral carpal tunnel syndrome can help distinguish between AL and ATTR, an endomyocardial biopsy remains necessary when cardiac amyloidosis is suspected and concomitant plasma cell dyscrasia is present. This is because [cardiac amyloid radionuclide imaging] can lead to false-positive results in the presence of AL-CM,” Ibrahim and colleagues explained.
Hence, while clinical features, biomarkers, and imaging patterns provide important clues, overlap and the presence of plasma cell disorders can complicate noninvasive diagnosis. Endomyocardial biopsy is essential to confirm amyloid subtype in the presence of a plasma cell dyscrasia, ensuring accurate treatment selection and improving patient outcomes.
Clinicians: Are your patients looking for news and insights on ATTR-CM? Refer them to ATTR-CM Companion.