3 Discordant Extracardiac Amyloid Proteins Highlighting Bystander Deposition in a Case of Light-Chain Amyloid Cardiomyopathy

Abstract

Background

Accurate differentiation of immunoglobulin light-chain (AL) from transthyretin (ATTR) amyloid cardiomyopathy is critical, as misclassification may delay appropriate therapy and worsen outcomes.

Case Summary

An 80-year-old woman with incidental gallbladder AL lambda and ApoA-IV amyloid deposits had elevated cardiac biomarkers and lambda monoclonal gammopathy. Bone marrow biopsy demonstrated AL and ATTR deposits. Echocardiography showed increased wall thickness, apical-sparing strain, and elevated filling pressures. Given these discordant findings, endomyocardial biopsy (EMB) was performed; proteomic analysis confirmed AL lambda deposition without ATTR, prompting anti–plasma cell therapy.

Discussion

This is a rare case of mixed extracardiac amyloid required EMB with proteomic analysis to resolve discordant findings and confirm AL cardiomyopathy.

Take-Home Messages

Amyloid cardiomyopathy subtyping is essential because AL and ATTR amyloidosis treatment differ fundamentally. Underrecognized codeposited “bystander” proteins may confound typing; therefore, discordant extracardiac findings may not represent the myocardial subtype. When uncertainty persists, particularly with monoclonal gammopathy, EMB is essential to define cardiac amyloid subtype.

Visual Abstract

History of Presentation

An 80-year-old woman presented with a 2-year history of NYHA functional class II exertional dyspnea and progressive bilateral lower-extremity edema. She denied chest pain, orthopnea, paroxysmal nocturnal dyspnea, presyncope, or syncope.

On examination, she was alert and in no acute distress. Cardiac auscultation revealed a normal S1 and accentuated S2, with a holosystolic murmur at the left lower sternal border consistent with tricuspid regurgitation. No S3 or S4 was appreciated. Lungs were clear to auscultation. Jugular venous pressure was approximately 8 cm H₂O (5 cm above the sternal angle), and no carotid bruits were present. The abdomen was soft and nontender. Extremities were warm and well perfused, with bilateral pitting edema, more pronounced on the left.

Past Medical History

Her medical history was significant for coronary artery disease complicated by ST-segment elevation myocardial infarction a year ago, treated with drug-eluting stents to the mid-left anterior descending and proximal right coronary arteries. She carried a diagnosis of paroxysmal atrial fibrillation and had previously undergone permanent pacemaker implantation for complete heart block. Additional comorbidities included hypertension, hyperlipidemia, and hypothyroidism.

Her surgical history included gastric bypass and right carpal tunnel release. She also had lumbar spinal stenosis. Importantly, she had no previous hospitalizations for decompensated heart failure. She denied symptoms suggestive of peripheral neuropathy, orthostatic hypotension, gastrointestinal dysmotility, or other manifestations of autonomic dysfunction.

Although several of her comorbidities could contribute to heart failure with preserved ejection fraction, the history of conduction disease and carpal tunnel syndrome raised the possibility of an infiltrative cardiomyopathy.

Differential Diagnosis

Before tissue diagnosis, the differential for exertional dyspnea with preserved ejection fraction included heart failure with preserved ejection fraction related to hypertensive and ischemic heart disease, pulmonary hypertension, right-sided dysfunction, and infiltrative/restrictive cardiomyopathy such as amyloid cardiomyopathy. The coexistence of bilateral carpal tunnel syndrome and complete heart block requiring permanent pacemaker implantation raised suspicion for systemic amyloidosis with cardiac involvement, as both are recognized as clinical red flags.¹ Incidental amyloid deposition on gallbladder pathology substantially increased suspicion for systemic amyloidosis with possible cardiac involvement.

Investigations

The diagnostic evaluation was initiated after incidental findings during cholecystectomy. Gallbladder pathology revealed extensive amyloid deposition involving 2 distinct subtypes: immunoglobulin light-chain amyloidosis lambda–type (AL) and apolipoprotein A-IV amyloidosis (ApoA-IV) codeposition. This unexpected finding prompted a comprehensive hematologic and cardiac workup.

Serum free light-chain analysis demonstrated elevated lambda free light chains (19.6 mg/dL, reference range 0.6700-3.46 mg/dL) with suppressed kappa levels (3.39 mg/dL, reference range 0.6100-4.02 mg/dL), resulting in an abnormal kappa/lambda ratio (0.1730, reference range 0.5700-2.45). Serum protein electrophoresis revealed a minimal monoclonal spike (<0.01 g/dL). Bone marrow biopsy demonstrated 4% plasma cells, consistent with a clonal plasma cell disorder below the threshold for overt multiple myeloma. Importantly, liquid chromatography tandem mass spectrometry was performed and detected a peptide profile consistent with AL lambda–type and transthyretin amyloidosis (ATTR) codeposition within the bone marrow.

Cardiac biomarkers were elevated, with N-terminal pro–B-type natriuretic peptide measuring 1,647 pg/mL and high-sensitivity troponin T 19 ng/L. Electrocardiography revealed an atrial-paced rhythm, right bundle branch block, and left anterior fascicular block. An artificial intelligence–enabled electrocardiographic algorithm estimated a high probability of amyloid cardiomyopathy above the established threshold.

Transthoracic echocardiography revealed findings suspicious for amyloid cardiomyopathy, including reduced global longitudinal strain −17% with relative apical sparing, elevated filling pressures (E/e′ 18; septal e′ 0.05 m/s) and small anterior pericardial effusion. Left ventricular ejection fraction was 51%, with a wall thickness of 11 mm and relative wall thickness of 0.42, consistent with concentric remodeling. Borderline right ventricular enlargement with reduced systolic function, an estimated right ventricular systolic pressure of 48 mm Hg, and mild-to-moderate tricuspid regurgitation were also present.

Although left ventricular wall thickness was not markedly increased, the combination of symptoms, biomarker elevation, conduction disease (history of complete heart block), abnormal strain pattern, and known systemic amyloid deposition strongly suggested cardiac involvement.

Management

The coexistence of multiple extracardiac amyloid subtypes (AL, ATTR, and ApoA-IV) together with a lambda monoclonal gammopathy created substantial diagnostic uncertainty regarding the etiology of cardiac involvement. Accurate myocardial amyloid typing was essential because treatment strategies differ fundamentally between AL and ATTR amyloidosis, and misclassification may lead to inappropriate therapy and delayed treatment. In this setting, neither extracardiac biopsy findings nor noninvasive diagnostic algorithms could reliably determine the cardiac amyloid subtype. Therefore, endomyocardial biopsy (EMB) with proteomic analysis was performed to establish definitive myocardial amyloid typing.

Histopathologic analysis of EMB specimens demonstrated diffuse amyloid deposition involving all fragments. Deposits were predominantly interstitial and pericellular. Moderate vascular amyloid involvement was present and focally obstructive, with focal endocardial deposition. Laser microdissection with mass spectrometry identified AL lambda–type amyloid deposition. No ATTR subtype was detected in myocardial tissue.

This finding established AL lambda–type as the amyloid subtype responsible for myocardial involvement.

Follow-Up

Following definitive subtyping by EMB confirming AL lambda–type cardiomyopathy, the patient was initiated on disease-specific therapy for systemic AL amyloidosis involving the gallbladder, bone marrow, and heart. She began combination treatment with daratumumab, bortezomib, and dexamethasone.

Given the absence of ATTR deposition in myocardial tissue by mass spectrometry, no ATTR-directed therapy was initiated.

She remains under close multidisciplinary follow-up with hematology and an advanced heart failure program. Ongoing management includes serial assessment of light chains, cardiac biomarkers, device surveillance, and optimization of volume status and individualized heart failure with preserved ejection fraction therapy.

Discussion

In this case, the diagnosis of amyloid cardiomyopathy was established following the incidental discovery of amyloid deposition in a gallbladder pathology specimen, which prompted further investigation. In retrospect, the patient had several clinical features suggestive of amyloid cardiomyopathy, including progressive heart failure symptoms with exertional dyspnea and lower-extremity edema. She also had a history of complete heart block requiring permanent pacemaker implantation and bilateral carpal tunnel syndrome, both recognized red flags for amyloidosis.¹ Elevated cardiac biomarkers further increased suspicion for cardiac involvement. Although echocardiography demonstrated features suggestive of amyloid cardiomyopathy, including reduced global longitudinal strain with relative apical sparing and elevated filling pressures, left ventricular wall thickness was not markedly increased, illustrating that cardiac amyloidosis may be present even in the absence of substantial wall thickening.

In patients with suspected amyloid cardiomyopathy, accurate amyloid subtyping is critical as therapeutic strategies diverge substantially between AL and ATTR amyloidosis. AL amyloidosis constitutes a hematologic emergency requiring prompt anti–plasma cell–directed therapy, whereas ATTR cardiomyopathy is treated with transthyretin stabilizers or transthyretin-directed RNA interference therapy. Misclassification may delay appropriate therapy and adversely affect outcomes.^1,2

Current noninvasive diagnostic algorithms for ATTR cardiomyopathy incorporate technetium-labeled bone scintigraphy in patients without evidence of monoclonal gammopathy.³ In this context, grade 2-3 myocardial uptake is highly specific for ATTR cardiomyopathy. However, the presence of a monoclonal protein substantially reduces the specificity of bone scintigraphy because false-positive uptake may occur in AL cardiomyopathy. Consequently, current guidelines emphasize that tissue confirmation is required when monoclonal gammopathy is present to avoid diagnostic misclassification, which is why this patient did not undergo a clinical pyrophosphate scan.4, 5, 6

When extracardiac biopsy results demonstrate discordant amyloid subtypes, determining the myocardial substrate becomes particularly challenging. In such situations, accurate cardiac amyloid typing is essential because therapeutic strategies differ substantially between AL and ATTR disease. Therefore, EMB remains the definitive diagnostic approach when noninvasive evaluation is inconclusive. This case further illustrates the complexity of the amyloid proteome and an important limitation of proteomic analysis. Although proteomic analysis with mass spectrometry is the gold standard for amyloid typing, detected proteins must be interpreted in the context of the clinical phenotype and tissue pathology.⁷ Amyloid deposits may contain both the pathogenic fibril protein and additional codeposited or “bystander” proteins.⁸ ApoA-IV has been described as a potential bystander protein in amyloid deposits, and transthyretin may similarly be detected in non-ATTR amyloidosis.⁸ Therefore, the identification of ApoA-IV and ATTR in extracardiac tissues in this patient did not necessarily establish these proteins as the drivers of cardiac amyloid deposition. Definitive myocardial proteomic analysis demonstrated isolated AL lambda–type involvement of the myocardium, emphasizing the importance of integrating proteomic results with organ-specific clinical assessment.

This case also illustrates the evolving landscape of amyloid detection. Emerging diagnostic tools, including artificial intelligence–enabled electrocardiographic algorithm analysis, may improve early identification of cardiac amyloidosis before overt structural abnormalities become apparent.⁹ Nevertheless, when systemic findings are discordant or when monoclonal gammopathy is present, reliance on imaging alone may be insufficient.

This case highlights several important diagnostic challenges. First, the patient demonstrated multiorgan amyloid deposition with discordant extracardiac subtypes, including AL, ATTR, and ApoA-IV amyloid, complicating interpretation of systemic biopsy findings. Second, the coexistence of monoclonal gammopathy limited the reliability of noninvasive ATTR diagnostic pathways. Third, the echocardiographic phenotype was relatively subtle, without marked ventricular wall thickening, illustrating that amyloid cardiomyopathy may be present even in the absence of classic morphologic features. Fourth, clinical red flags such as conduction system disease and carpal tunnel syndrome represented early manifestation of amyloid infiltration.⁷ Ultimately, this case underscores that in the setting of persistent diagnostic uncertainty, EMB remains the gold standard for establishing myocardial amyloid subtype and guiding disease-specific therapy.^1,2,10

Conclusions

In patients with multiorgan amyloid deposition and monoclonal gammopathy, noninvasive algorithms may be insufficient to determine cardiac amyloid subtype. EMB plays a critical role in establishing definitive diagnosis and guiding appropriate therapy.

Take-Home Messages

• •Amyloid cardiomyopathy subtyping is essential because AL and ATTR amyloidosis treatment differ fundamentally.
• •Underrecognized codeposited “bystander” proteins may confound typing; therefore, discordant extracardiac findings may not represent the myocardial subtype.
• •When uncertainty persists, particularly with monoclonal gammopathy, EMB is essential to define cardiac amyloid subtype.

Visual Summary.

Histopathology Review of the Gallbladder, Bone Marrow, and Endomyocardial Biopsies

AL = immunoglobulin light-chain amyloidosis; ApoA-IV = apolipoprotein A-IV amyloidosis; ATTR = transthyretin amyloidosis.

Funding Support and Author Disclosures

Dr AbouEzzeddine has received consulting income from Alnylam, BridgeBio, Medscape from WebMD, and Pfizer; and research funding from Pfizer Inc. Dr Grogan has received intellectual property for AI-Enabled Amyloid Detection from ECG/Anumana. All other authors have reported that they have no relationships relevant to the contents of this paper to disclose.