Apolipoprotein A-IV Cardiac Amyloidosis Presenting as Massive Ventricular Wall Thickening Mimicking Hypertrophic Cardiomyopathy

Abstract

Background

Apolipoprotein A-IV amyloidosis (AApoAIV) is a rare systemic amyloidosis that can involve the heart and mimic hypertrophic cardiomyopathy.

Case Summary

A 64-year-old woman with presumed hypertrophic cardiomyopathy presented with dyspnea. Imaging showed severe left ventricular wall thickening, outflow tract obstruction, and systolic anterior motion of the mitral valve. Multimodality evaluation suggested infiltrative cardiomyopathy including diffuse late gadolinium enhancement, abnormal nulling, elevated T1 on cardiac magnetic resonance, and an apical-sparing strain pattern on echocardiography. Technetium-99m pyrophosphate scintigraphy demonstrated no myocardial uptake. Endomyocardial biopsy confirmed AApoAIV deposition.

Discussion

AApoAIV cardiac amyloidosis may present with massive left ventricular wall thickening. Discordant noninvasive testing may occur, and endomyocardial biopsy remains essential for diagnosis.

Take-Home Messages

AApoAIV cardiac amyloidosis is a rare infiltrative cardiomyopathy that may mimic hypertrophic cardiomyopathy and follow an indolent course, allowing myocardial infiltration over years. Negative technetium-99m pyrophosphate scintigraphy does not exclude amyloidosis, particularly in non-transthyretin amyloid subtypes like AApoAIV, and tissue diagnosis is required.

Visual Summary

Visual Summary.

Multimodality Clues to a Rare Cardiac Amyloidosis

CMR = cardiac magnetic resonance; ECG = electrocardiography; GLS = global left ventricular longitudinal strain; TTE = transthoracic echocardiography.

History of Presentation

A 64-year-old woman was referred for evaluation of marked biventricular wall thickening. The abnormality was first identified 10 years earlier during a preoperative assessment for lung cancer, when a cardiac murmur prompted a cardiology evaluation. At that time, the patient was completely asymptomatic. The echocardiogram demonstrated severe left ventricular wall thickening, with an interventricular septal thickness of 26 mm, a hyperdynamic left ventricular ejection fraction, dynamic left ventricular outflow tract obstruction with a peak gradient of 70 mm Hg, and systolic anterior motion of the mitral valve with mild mitral regurgitation. Cardiac magnetic resonance (CMR) demonstrated similar findings, and the overall impression at that time was a diagnosis of hypertrophic cardiomyopathy (HCM).

Take-Home Messages

• •Apolipoprotein A-IV amyloidosis cardiac amyloidosis is a rare infiltrative cardiomyopathy that may mimic hypertrophic cardiomyopathy and follow an indolent course, allowing myocardial infiltration over years.
• •Negative technetium-99m pyrophosphate scintigraphy does not exclude amyloidosis, particularly in non-transthyretin amyloid subtypes like apolipoprotein A-IV amyloidosis, and tissue diagnosis is required.

At the time of referral, the patient reported intermittent exertional dyspnea. Symptoms were frequently worse with positional changes and after meals, and she reported postprandial bloating that led her to limit food intake. Her weight had recently remained stable. She also described orthopnea, requiring her to sleep in a recliner for several years. She denied syncope, chest pain, or recent peripheral edema.

On physical examination, the apical impulse was sustained, with palpable S4 and S3 gallops. A grade 1/6 systolic ejection murmur was heard along the left sternal border and did not increase with the Valsalva maneuver. Jugular venous pressure was mildly elevated with rapid descents, and there was no ascites or peripheral edema.

Past Medical History

The patient had a history of HCM with severe biventricular wall thickening. Additional medical history included lung cancer treated with right lobectomy and chemotherapy 10 years earlier, hypothyroidism secondary to Graves disease treated with radioiodine ablation, gout, and chronic kidney disease stage 3b. She also had a remote history of tobacco use (62 pack-years).

Differential Diagnosis

The differential diagnosis included HCM, infiltrative cardiomyopathies such as cardiac amyloidosis, and metabolic or storage disorders including Fabry disease and Danon disease.

Investigations

Initial laboratory evaluation demonstrated a normal complete blood count and electrolyte panel. Renal function was impaired, with a creatinine level of 2.04 mg/dL, corresponding to an estimated glomerular filtration rate of 26 mL/min/1.73 m². The prealbumin level was 30 mg/dL. Screening for light-chain amyloidosis demonstrated mildly elevated kappa free light chains, without evidence of a monoclonal protein in the serum or urine. These findings were attributed to the patient's underlying renal dysfunction. Abdominal fat pad aspiration biopsy was negative for amyloid deposition. Cardiac biomarkers were markedly elevated, with an N-terminal pro–B-type natriuretic peptide level of 31,815 pg/mL and a high-sensitivity troponin T level of 207 ng/L.

Electrocardiography demonstrated sinus rhythm with marked QRS fragmentation and secondary ST-T wave abnormalities. Artificial intelligence–assisted electrocardiogram analysis was positive for HCM and negative for cardiac amyloidosis.^1,2

Transthoracic echocardiography demonstrated a small left ventricular cavity with severe concentric wall thickening and an ejection fraction of 36% with diffuse left ventricular hypokinesis. Global longitudinal strain was markedly reduced at –4.6%, with a characteristic apical sparing pattern. Left ventricular filling pressures were severely elevated. The right ventricle was small with increased wall thickness and moderate-to-severely reduced systolic function. The estimated right ventricular systolic pressure was 64 mm Hg.

To further evaluate transthyretin amyloidosis, technetium-99m pyrophosphate scintigraphy was performed and demonstrated no myocardial radiotracer uptake (Perugini grade 0).

CMR demonstrated severe concentric left ventricular hypertrophy, with a maximum wall thickness of 34 mm. Tissue characterization showed abnormal myocardial nulling kinetics, diffuse late gadolinium enhancement, markedly elevated native T1 values, and increased extracellular volume, findings highly suggestive of cardiac amyloidosis. Other infiltrative cardiomyopathies were considered. Fabry disease was deemed unlikely given the elevated native T1 values, as Fabry disease typically demonstrates reduced native T1. There was no evidence of myocardial edema or iron deposition on T2 mapping or T2∗ imaging. Compared with prior imaging, there was progression of late gadolinium enhancement within the left ventricle and new involvement of the right ventricle.

Right heart catheterization demonstrated severely abnormal hemodynamics. Baseline measurements revealed elevated right atrial pressure (15 mm Hg), right ventricular end-diastolic pressure (20 mm Hg), and severe pulmonary hypertension with pulmonary artery pressures of 88/33 mm Hg (mean 53 mm Hg). The pulmonary capillary wedge pressure was 18 mm Hg. Cardiac output was markedly reduced at 2.05 L/min, with a cardiac index of 1.28 L/min/m². Pulmonary vascular resistance was markedly elevated at 17.07 WU. With administration of inhaled nitric oxide, pulmonary artery pressures changed minimally (84/32 mm Hg, mean 50 mm Hg). Pulmonary capillary wedge pressure increased slightly to 22 mm Hg, whereas cardiac output increased modestly to 2.36 L/min (cardiac index 1.47 L/min/m²). Pulmonary vascular resistance decreased to 11.86 WU.

Endomyocardial biopsy confirmed cardiac amyloidosis due to apolipoprotein A-IV (AApoAIV) deposition. Histologic examination of right ventricular endomyocardial biopsy specimens demonstrated amyloid deposition with an intracellular and extracellular distribution (Figure 1). Vascular and endocardial amyloid was not present. Amyloid typing was performed using liquid chromatography-tandem mass spectrometry on peptides extracted from Congo red–positive microdissected tissue. Proteomic analysis demonstrated a predominance of apolipoprotein A-IV peptides in the absence of another identifiable amyloid precursor protein.

Figure 1.

Histopathologic Findings

(A) Hematoxylin-eosin–stained tissue shows abundant acellular (primarily extracellular) material in a predominately pericellular distribution between the cardiac myocytes. (B) The material shows staining with Congo red and exhibits green birefringence in cross-polarized light, confirming amyloidosis.

Management

After confirmation of AApoAIV cardiac amyloidosis, the diagnosis and prognosis were discussed with the patient. At present, no disease-modifying therapy exists for AApoAIV amyloidosis, and organ transplantation remains the only potential definitive therapy. However, the patient was not considered a candidate for heart transplantation because of severe pulmonary hypertension and significant renal dysfunction.

Management therefore focused on symptom-directed therapy and careful volume management. Given symptomatic improvement with diuresis, a scheduled regimen of furosemide 40 mg daily was recommended with close monitoring of renal function, including repeat laboratory testing within 2 weeks.

Additional guideline-directed heart failure therapies, including angiotensin-converting enzyme inhibitors, angiotensin receptor blockers, angiotensin receptor-neprilysin inhibitors, and sodium-glucose cotransporter-2 inhibitors, were not initiated because of the small ventricular cavity, advanced restrictive physiology, and susceptibility to intravascular volume depletion and renal dysfunction.

Follow-Up

The patient remained clinically stable and continued to work part-time, with follow-up arranged with her local cardiologist and primary care provider. Ongoing management was coordinated with the local care team, with plans for periodic reassessment of symptoms and renal function and consultation as needed.

Discussion

Apolipoprotein-related amyloidoses include hereditary forms, such as variant-associated apolipoprotein A-I amyloidosis (AApoAI), as well as AApoAIV amyloidosis, which appears to occur sporadically and has not been consistently linked to pathogenic genetic variants.³ AApoAI and AApoAIV amyloidosis are rare but increasingly recognized causes of cardiac amyloidosis identified through advanced proteomic typing techniques.^4,5

AApoAIV is typically associated with cardiac involvement and renal dysfunction.^3,5 Cardiac involvement commonly presents with heart failure and classical imaging features of cardiac amyloidosis.³ Patients with AApoAIV cardiac amyloidosis typically demonstrate increased ventricular wall thickness, diffuse myocardial infiltration, elevated extracellular volume on CMR, and a characteristic apical-sparing pattern on strain imaging.^3,5,6

Consistent with these observations, the present case demonstrated progressive myocardial infiltration and severe ventricular wall thickness over more than a decade, reflecting the indolent clinical course described in other apolipoprotein-related amyloidoses.³ Furthermore, survival in AApoAIV amyloidosis appears more favorable than in light-chain amyloidosis, suggesting a comparatively slower disease trajectory.³

This case underscores the diagnostic difficulty in distinguishing infiltrative cardiomyopathy from HCM when ventricular wall thickening is severe. The patient was initially diagnosed with HCM based on severe wall thickening and dynamic left ventricular outflow tract obstruction. However, subsequent multimodality imaging revealed features more consistent with infiltrative cardiomyopathy, including diffuse late gadolinium enhancement, abnormal myocardial nulling kinetics, elevated native T1 values, and an apical-sparing strain pattern, which are characteristic of cardiac amyloidosis.^6,7

Importantly, bone scintigraphy using technetium-labeled tracers demonstrates variable uptake in apolipoprotein amyloidosis. Radiotracer uptake has been described more commonly in AApoAI amyloidosis, whereas AApoAIV cardiac amyloidosis frequently shows absent or minimal uptake, which is consistent with this case.^3,8

Additional diagnostic discordance was observed with artificial intelligence–assisted electrocardiographic analysis, which predicted HCM rather than amyloidosis.^1,2 This discrepancy highlights the limitations of currently available noninvasive diagnostic tools when applied to rare amyloid subtypes that may not exhibit classic phenotypic patterns.

The hemodynamic profile in this patient was notable for severely reduced cardiac output despite preserved ambulatory function. This phenomenon likely reflects gradual physiologic adaptation to chronic low-output states in restrictive cardiomyopathy, allowing patients to maintain functional capacity despite markedly impaired cardiac performance.⁹

Another notable finding in this case was the presence of intracellular amyloid deposition, whereas amyloid fibrils are typically deposited in the extracellular space.¹⁰ In systemic amyloidosis, misfolded proteins aggregate into insoluble fibrils that accumulate predominantly within the extracellular matrix of tissues, leading to progressive organ dysfunction.¹⁰ Intracellular localization is therefore unusual.

Currently, no disease-specific therapy exists for AApoAIV amyloidosis, and treatment remains supportive. Although cardiac transplantation may be considered in selected patients with systemic apolipoprotein amyloidosis, it was not pursued in this case because of severe pulmonary hypertension and renal dysfunction. Management therefore focused on careful volume control and symptom-directed therapy, which remains the cornerstone for advanced restrictive cardiomyopathy.^3,5

Conclusions

This case demonstrates that AApoAIV cardiac amyloidosis may remain clinically indolent for many years despite severe ventricular wall thickening. Discordant findings across imaging modalities, including negative bone scintigraphy and atypical electrocardiographic patterns, may occur with rare amyloid subtypes. In such situations, endomyocardial biopsy with mass spectrometry–based amyloid typing is essential to establish the diagnosis. Recognition of these uncommon amyloid variants is important because they have distinct clinical courses, diagnostic features, and therapeutic implications.

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 artificial intelligence–enabled amyloid detection from electrocardiography/Anumana. All other authors have reported that they have no relationships relevant to the contents of this paper to disclose.