Hereditary Transthyretin Cardiac Amyloidosis With Severe Left Ventricular Outflow Tract Obstruction Mimicking Hypertrophic Obstructive Cardiomyopathy

Abstract

Background

Cardiac amyloidosis may mimic hypertrophic cardiomyopathy; however, severe left ventricular outflow tract (LVOT) obstruction is rarely described in transthyretin (TTR) cardiac amyloidosis.

Case Summary

A 49-year-old man presented with exertional dyspnea and presyncope. Echocardiography demonstrated septal hypertrophy with severe LVOT obstruction, leading to an initial diagnosis of hypertrophic obstructive cardiomyopathy. Persistent symptoms prompted further evaluation. Cardiac magnetic resonance imaging revealed diffuse subendocardial late gadolinium enhancement, whereas bone scintigraphy demonstrated low-grade myocardial uptake. Genetic testing identified a pathogenic TTR variant, and endomyocardial biopsy confirmed TTR amyloidosis (ATTR). Tafamidis therapy was initiated, with clinical improvement during follow-up.

Discussion

Certain hereditary ATTR variants may present with low-grade tracer uptake, emphasizing the importance of tissue confirmation when suspicion persists.

Take-Home Messages

Transthyretin-cardiac amyloidosis may mimic hypertrophic obstructive cardiomyopathy with severe LVOT obstruction. Certain hereditary ATTR variants may demonstrate low-grade tracer uptake on bone scintigraphy. Multimodality imaging, genetic testing, and tissue confirmation are essential when clinical suspicion persists.

Visual Summary

Visual Summary.

Diagnostic and Therapeutic Timeline

This timeline illustrates the diagnostic pathway leading to the identification of hereditary transthyretin cardiac amyloidosis initially misclassified as hypertrophic obstructive cardiomyopathy, highlighting the atypical presentation and the gradual clinical response to disease-specific therapy. 6MWT = 6-minute walk test; ATTR-CA = transthyretin cardiac amyloidosis; CMR = cardiac magnetic resonance; ECG = electrocardiography; GLS = global longitudinal strain; HOCM = hypertrophic obstructive cardiomyopathy; hs-TnT = high-sensitivity troponin; LVH = left ventricular hypertrophy; LVOT = left ventricular outflow tract; NT-proBNP = N-terminal pro–B-type natriuretic peptide; TTE = transthoracic echocardiography.

History of Presentation

A 49-year-old man presented with progressively worsening exertional dyspnea and episodes of presyncope during mild physical activity. On examination, vital signs were within normal limits. Cardiac auscultation revealed a grade 2/6 systolic murmur that increased with standing. An electrocardiogram demonstrated sinus rhythm with left ventricular hypertrophy (LVH) (Figure 1). Transthoracic echocardiography revealed preserved left ventricular systolic function, septal hypertrophy with septal thickness of 16 mm, and systolic anterior motion of the mitral valve, resulting in dynamic left ventricular outflow tract (LVOT) obstruction with a gradient of 70 mm Hg at rest, increasing to 123 mm Hg during the Valsalva maneuver (Figure 2). Based on these findings, the patient was diagnosed with hypertrophic obstructive cardiomyopathy (HOCM), and comprehensive genetic testing was recommended but not completed at that time.

Take-Home Messages

• •Transthyretin cardiac amyloidosis may mimic hypertrophic obstructive cardiomyopathy, and severe left ventricular outflow tract obstruction does not exclude the diagnosis.
• •In certain hereditary transthyretin amyloidosis variants, bone scintigraphy may demonstrate only low-grade tracer uptake, potentially leading to false reassurance and delayed diagnosis.
• •When clinical suspicion persists—particularly in younger patients with left ventricular outflow tract obstruction and systemic features—multimodality imaging, genetic testing, and tissue confirmation are essential to establish the correct diagnosis.

Figure 1.

Electrocardiogram

Electrocardiogram demonstrated normal sinus rhythm with left ventricular hypertrophy, ST-segment depression, and T-wave inversion in the lateral leads, consistent with a left ventricular “strain” pattern.

Figure 2.

Echocardiogram

(A) Parasternal long-axis view shows concentric left ventricular thickening with systolic anterior motion of the mitral valve leaflet. (B) M mode demonstrates systolic anterior motion of the mitral valve leaflet. (C) Continuous-wave Doppler shows dynamic left ventricular outflow tract obstruction with gradient up to 123 mm Hg during the Valsalva maneuver. (D) Global longitudinal strain map demonstrated mildly reduced global longitudinal strain (−16.9%) with apical sparing (“Cherry on top” pattern). ANT = anterior; ANT-LAT = anterolateral; ANT-SEP = anteroseptal; AP2 = apical 2-chamber view; AP3 = apical 3-chamber view (apical long-axis view); AP4 = apical 4-chamber view; endo = endocardial; INF = inferior; INF-LAT = inferolateral; INF-SEP = inferoseptal; LV = left ventricle/left ventricular; peak l strain = peak longitudinal strain; PG = pressure gradient; Vel = velocity.

Past Medical History

The patient had a history of polycystic kidney disease and underwent living donor kidney transplantation, followed by 8 years of immunosuppressive therapy including calcineurin inhibitor therapy (tacrolimus). The postoperative course was complicated by bowel obstruction requiring colectomy. Additional comorbidities included hypertension and dyslipidemia. No relevant family history of cardiomyopathy (CM) was reported.

Investigation

Three years later, in the setting of progressive dyspnea, the patient was referred to a dedicated heart failure clinic for further evaluation. He reported intermittent paresthesia in the hands and feet attributed to peripheral neuropathy. Laboratory tests revealed normal high-sensitivity troponin levels (39.5 ng/L) and elevated N-terminal pro–B-type natriuretic peptide (3,610 pg/mL). Echocardiography demonstrated persistent LVH with an LVOT gradient of 52 mm Hg at rest, enlarged atria, moderate mitral regurgitation, and borderline low global longitudinal strain (GLS) of −16.9% (Figure 2). Cardiac magnetic resonance (CMR) imaging demonstrated preserved left ventricular ejection fraction (66%) with diffuse subendocardial late gadolinium enhancement and increased global T1, raising suspicion for cardiac amyloidosis (CA) (Figure 3). Bone scintigraphy (technetium-99m labeled 3,3-diphosphono-1,2-propanodicarboxylic acid) with single-photon emission computed tomography revealed minor myocardial uptake (Perugini grade 1), inconclusive for transthyretin cardiac amyloidosis (ATTR-CA) (Figure 4). Serum immunofixation electrophoresis and free light chain assay were negative. Genetic testing identified a pathogenic heterozygous transthyretin (TTR) variant (Ser77Tyr; p.Ser97Tyr; c.290C>A), consistent with hereditary transthyretin amyloidosis (ATTR), as well as a pathogenic heterozygous polycystin-1 variant c.7168G>T, consistent with autosomal dominant polycystic kidney disease. Endomyocardial biopsy was subsequently performed, revealing focal interstitial amyloid deposits with positive ATTR immunostaining in areas of amyloid deposition (Figure 5).

Figure 3.

Cardiac Magnetic Resonance Imaging

Late gadolinium enhancement images show diffuse subendocardial late gadolinium enhancement in the 4-chamber view (A) and short-axis view (B). (C and D) T1 mapping shows increased global T1 of 1,353 ms (normal range: 900-1,100 ms).

Figure 4.

Bone Scintigraphy (Technetium-99m Labeled 3,3-Diphosphono-1,2-Propanodicarboxylic Acid)

Axial computed tomography image (A). Fused single-photon emission computed tomography/computed tomography image demonstrates mild myocardial tracer uptake (B). Axial single-photon emission computed tomography image (C). Coronal single-photon emission computed tomography reconstruction (D). Overall findings demonstrate low myocardial uptake, less than rib activity (Perugini grade 1), considered inconclusive for transthyretin cardiac amyloidosis.

Figure 5.

Immunogold Electron Microscopy of Myocardial Biopsy

Uranyl acetate staining demonstrates amyloid fibrils in the myocardial interstitium (A). Anti-transthyretin immunogold labeling shows dense particle deposition over amyloid fibrils (B), compared with non-amyloid areas (C) (49 vs 22 gold particles per image).

Management

Initial management focused on the treatment of presumed HOCM with beta-blockers. Because of intolerance to beta-blockers, therapy was switched to verapamil. Following confirmation of hereditary ATTR, treatment with tafamidis 61 mg daily was initiated, and verapamil was continued at a reduced dose for symptomatic control.

Follow-Up

During 5 years of follow-up, the patient experienced gradual clinical improvement (NYHA functional class II), with an increase in 6-minute walk distance from 500 to 660 m and a reduction in LVOT gradient to 30 mm Hg at rest. This was initially accompanied by a modest worsening in GLS (nadir: 11.5%) and cardiac biomarkers, which subsequently improved with longer-term follow-up.

Discussion

CA is increasingly recognized as a phenotypic mimicker of several cardiac diseases, including hypertrophic cardiomyopathy (HCM),^1,2 yet severe LVOT obstruction is rarely described.³ Exposure to calcineurin inhibitors represents a potential contributor to LVH in this case. Amyloid infiltration of the myocardium leads to increased ventricular wall thickness, restrictive physiology, and conduction abnormalities that may overlap with features traditionally attributed to HCM.² In our case, hereditary ATTR-CA presented with septal hypertrophy, systolic anterior motion of the mitral valve, and severe dynamic LVOT obstruction, initially leading to a diagnosis of HOCM.^3,4

This presentation is consistent with the phenotype described by Rowin et al,⁴ in which ATTR-CA was initially misclassified as HOCM. However, their patients were older, with lower LVOT gradients, lacked electrocardiographic LVH, and demonstrated positive bone scintigraphy (Perugini grade 3). Gupta et al³ also reported patients with ATTR-CA, initially diagnosed with HOCM, with diagnostic delays of up to 34 months, suggesting that the presence of LVOT obstruction may contribute to diagnostic delay.

The unusual presentation in our patient—characterized by younger age, marked LVOT obstruction, electrocardiographic LVH, and low-grade tracer uptake—represents an atypical phenotype that may obscure the diagnosis and likely contributed to the 3-year diagnostic delay. The initial clinical worsening, accompanied by deterioration in cardiac biomarkers and GLS, may reflect ongoing myocardial injury and disease progression.

Hereditary ATTR demonstrates marked geographic variability in the distribution of pathogenic variants. In Israel, the Ser77Tyr (p.Ser97Tyr) TTR mutation, a founder variant prevalent among patients of Yemenite Jewish ancestry, represents the most common pathogenic TTR mutation causing autosomal dominant hereditary ATTR.⁵

Notably, patients carrying this mutation tend to present at a relatively younger age (57.7 ± 5.8 years), with polyneuropathy reported in 78.3% of cases. Bone scintigraphy may have reduced sensitivity in this variant, with approximately 70% of patients demonstrating minimal myocardial tracer uptake despite established CM (Perugini grade <2). In contrast, CMR imaging has shown late gadolinium enhancement suggestive of amyloidosis in 91% of patients.⁵ Consistent with these observations, our patient presented at a relatively young age with peripheral neuropathy and was diagnosed based on characteristic CMR imaging findings despite low-grade tracer uptake on bone scintigraphy.

This case demonstrates the potential limitations of bone scintigraphy in certain ATTR variants. Although CMR imaging may suggest an infiltrative CM, this case further highlights the importance of tissue confirmation in such cases. Even with a pathogenic TTR variant, distinguishing clinically relevant ATTR-CM from HCM may be challenging without biopsy, particularly when bone scintigraphy is nondiagnostic.

Management of CA with LVOT obstruction represents a therapeutic challenge. Standard pharmacologic therapies used in HOCM, including beta-blockers and nondihydropyridine calcium channel blockers, may be poorly tolerated in amyloidosis because of restrictive physiology, autonomic dysfunction, and conduction abnormalities. In addition, certain medications commonly used in HCM, such as verapamil, have been suggested to bind to amyloid fibrils and potentially increase toxicity.⁶ In our case, early intolerance to beta-blockers was observed, whereas treatment with verapamil was surprisingly well tolerated and associated with symptomatic improvement.

Tafamidis stabilizes TTR tetramers and has been shown to improve survival and reduce cardiovascular hospitalizations in ATTR-CA.7, 8, 9 Posthoc analyses further suggest attenuation of progression in echocardiographic parameters such as left ventricular GLS and diastolic function.^7,8 In our patient, Tafamidis therapy was initiated, and clinical stabilization with improved functional capacity and cardiac biomarkers was observed over time. Gradual reduction in the LVOT gradient is unlikely to reflect a structural effect of tafamidis, which primarily functions as a TTR stabilizer, and is more likely related to optimized medical therapy, improved loading conditions, and dynamic factors influencing LVOT obstruction.

This case highlights that CA should be considered in patients with presumed HCM when clinical features are atypical or systemic manifestations are present. Dynamic LVOT obstruction does not exclude CA, even with high gradients. In certain ATTR variants, bone scintigraphy may have limited sensitivity; therefore, persistent clinical suspicion should prompt further evaluation with multimodality imaging, genetic testing, and tissue confirmation. Finally, the combination of a younger age, LVOT obstruction, and intolerance to beta-blockers, especially in Yemenite ancestry, should prompt further assessment for CA since early diagnosis may profoundly affect prognosis.

Conclusions

This case highlights that ATTR-CA may closely mimic HOCM, including severe LVOT obstruction. When clinical suspicion persists, the limitations of bone scintigraphy should be recognized, and further evaluation with multimodality imaging, genetic testing, and tissue confirmation should be considered.

Funding Support and Author Disclosures

The authors have reported that they have no relationships relevant to the contents of this paper to disclose.