Coexistence of Hypertrophic Cardiomyopathy and Hereditary Transthyretin Amyloid Cardiomyopathy

Abstract

Background

Left ventricular wall thickening may result from disease such as hypertrophic cardiomyopathy (HCM) or infiltrative cardiomyopathies such as transthyretin amyloidosis (ATTR). When features of both conditions coexist, distinguishing the dominant pathology can be challenging and may influence management.

Case Summary

A 72-year-old man presented with progressive exertional dyspnea and syncope. He was found to have severe left ventricular outflow tract obstruction with systolic anterior motion of the mitral valve. He experienced marked symptomatic improvement after initiation of mavacamten for presumed HCM. Genetic testing later revealed a pathogenic TTR p.Val50Met variant, and technetium-99m pyrophosphate scintigraphy demonstrated grade 3 myocardial uptake consistent with hereditary ATTR cardiomyopathy. Persistent symptoms led to septal myectomy, which demonstrated marked myocyte hypertrophy and moderate myocardial amyloid deposition but insufficient infiltration to explain the hypertrophy.

Discussion

This case highlights the diagnostic complexity of coexisting HCM and hereditary ATTR cardiomyopathy and underscores the importance of multimodality imaging, genetic testing, and pathologic correlation.

Take-Home Messages

Dynamic left ventricular outflow tract obstruction does not exclude cardiac amyloidosis. Dual cardiomyopathies should be considered when clinical, imaging, and genetic findings appear discordant.

Visual Summary

History of Presentation

A 72-year-old man presented to the cardiology clinic with progressive exertional dyspnea and fatigue over the preceding 2 years. He denied chest pain, orthopnea, paroxysmal nocturnal dyspnea, or lower-extremity edema. He reported a single episode of syncope that occurred while straining. He denied symptoms suggestive of systemic amyloidosis, including carpal tunnel syndrome, spinal stenosis, peripheral neuropathy, tendon rupture, or gastrointestinal manifestations.

On physical examination, vital signs were within normal limits. Examination of the lungs, abdomen, and extremities was unremarkable. Cardiac auscultation revealed a regular rate and rhythm with a grade 2/6 systolic ejection murmur and a holosystolic apical murmur, both of which increased in intensity with the Valsalva maneuver.

Past Medical History

The patient had a history of hypothyroidism treated with thyroid hormone replacement therapy. He had no prior diagnosis of atrial fibrillation, hypertension, or valvular heart disease and no known family history of cardiomyopathy or sudden cardiac death.

Differential Diagnosis

The differential diagnosis for exertional dyspnea with left ventricular wall thickening and dynamic left ventricular outflow tract (LVOT) obstruction included hypertrophic cardiomyopathy (HCM), hypertensive heart disease, infiltrative cardiomyopathies such as cardiac amyloidosis, and valvular heart disease with dynamic obstruction.

Investigations

Laboratory testing revealed normal complete blood count, metabolic panel, thyroid function tests, and lipid profile. Cardiac biomarkers demonstrated increased N-terminal pro–B-type natriuretic peptide of 695 pg/mL (normal: <540 pg/mL) and high-sensitivity troponin T of 32 ng/L (normal: <15 ng/L).

Electrocardiography showed normal sinus rhythm with normal PR, QRS, and QT intervals and no electrocardiographic criteria for left ventricular hypertrophy. Artificial intelligence–based electrocardiographic analysis demonstrated a probability of HCM of 0.003 and a probability of cardiac amyloidosis of 0.0762, both below the established diagnostic significance thresholds.

Transthoracic echocardiography (TTE) demonstrated severe asymmetric left ventricular wall thickening with predominant basal septal involvement (proximal septum measuring 1.7 cm), small left ventricular cavity, no systolic anterior motion (SAM) of the mitral valve, and no significant LVOT obstruction with Valsalva maneuver. Stress TTE showed dynamic LVOT obstruction with maximal peak gradient of 100 mm Hg, associated with SAM and moderate mitral valve regurgitation.

Cardiac magnetic resonance (CMR) demonstrated a maximum diastolic wall thickness of 17 mm in the basal anteroseptum. SAM of the anterior mitral leaflet and chordae was observed, associated with mild eccentric mitral regurgitation (regurgitant volume: 20 mL; regurgitant fraction: 24%) and resting LVOT obstruction. Mild late gadolinium enhancement (LGE) was present in the basal inferolateral and inferior walls (<15% of myocardial mass). The extracellular volume fraction was 27% (upper limit of normal). There was no evidence of abnormal gadolinium kinetics or diffuse fibrosis to suggest an infiltrative cardiomyopathy. Biventricular size and systolic function were normal, with calculated left ventricular ejection fraction of 64% and right ventricular ejection fraction of 61%.

Management

The patient was initially diagnosed with HCM and advised to avoid dehydration and vasodilators. Medical therapy with metoprolol and diltiazem was initiated but resulted in worsening fatigue and dizziness. Given persistent symptoms, treatment with mavacamten 5 mg daily was initiated, resulting in marked symptomatic improvement, with near-complete resolution of dyspnea and fatigue within 19 days.

Because of the prior history of syncope, evaluation for primary prevention implantable cardioverter-defibrillator placement was undertaken. Comprehensive genetic testing using an arrhythmia and cardiomyopathy panel identified a pathogenic variant in the transthyretin gene (TTR p.Val50Met) associated with hereditary transthyretin amyloid cardiomyopathy (ATTRv-CM).

Technetium-99m pyrophosphate scintigraphy, including delayed 3-hour planar and single-photon emission computed tomography imaging, subsequently demonstrated diffuse grade 3 radiotracer uptake throughout the left ventricular myocardium exceeding rib uptake, consistent with transthyretin amyloid cardiomyopathy (ATTR-CM).The diagnosis was therefore revised to ATTRv-CM. Mavacamten was discontinued and tafamidis therapy was initiated. However, the patient experienced recurrence of dyspnea and fatigue. Vutrisiran therapy was subsequently added.

Because of the perceived symptomatic benefit, the patient independently restarted mavacamten. Despite combination therapy with tafamidis, vutrisiran, and mavacamten, he continued to experience NYHA functional class II to III symptoms. He was subsequently referred to a quaternary referral center for further evaluation of suspected HCM and/or ATTRv-CM. Additional diagnostic screening for amyloid light chain amyloidosis was negative, with normal serum free light chains, no monoclonal protein detected on serum or urine immunofixation, and a negative abdominal fat pad aspirate for amyloid deposition.

Repeat TTE on mavacamten demonstrated a hyperdynamic left ventricular ejection fraction with asymmetric left ventricular wall thickening in a sigmoid septal configuration. SAM of the mitral valve was present with moderate mitral regurgitation. Dynamic LVOT obstruction was observed, with a peak gradient of 74 mm Hg during the squat-to-stand maneuver. Diastolic function assessment showed a grade 2/3 left ventricular diastolic dysfunction, consistent with mild to moderately elevated left ventricular filling pressure (mitral inflow E/A ratio of 1.8, medial e′ velocity of 5 cm/s, and left atrial volume index of 46 mL/m²). Global longitudinal strain was −16.4% with relatively preserved apical strain, resulting in an apical sparing pattern.

Given persistent severe LVOT obstruction and symptoms, the patient underwent surgical septal myectomy. Histopathologic examination of the surgical specimen demonstrated marked myocyte hypertrophy without evidence of myocyte disarray, accompanied by mild interstitial fibrosis and moderate endocardial fibrosis. In addition, moderate amyloid deposition was identified (Figure 1). The amyloid deposits were predominantly discrete within the interstitium, with prominent deposition along the endocardial surface corresponding to the region of the SAM contact lesion. However, according to the pathologist, the degree of amyloid infiltration was insufficient to account for the magnitude of septal hypertrophy. These findings supported the coexistence of HCM and ATTRv-CM.

Visual Summary.

Multimodality Evaluation Reveals Coexisting HCM and ATTRv-CM

AI = artificial intelligence; ATTRv-CM = hereditary transthyretin amyloid cardiomyopathy; ECG = electrocardiogram; HCM = hypertrophic cardiomyopathy; LGE = late gadolinium enhancement; LV = left ventricular; LVOT = left ventricular outflow tract; MRI = magnetic resonance imaging; PYP = technetium-99m pyrophosphate scintigraphy; SPECT = single-photon emission computed tomography; TTR = transthyretin.

Figure 1.

Heart, Left Ventricle, Subaortic Septal Myectomy

(A) Hematoxylin and eosin–stained tissue shows moderate acellular material. (B) The material shows staining with Congo red, and it exhibited green birefringence in cross-polarized light, confirming amyloidosis.

Follow-Up

Two months after septal myectomy, the patient reported significant improvement in exercise tolerance while participating in cardiac rehabilitation. Postoperative echocardiography demonstrated resolution of LVOT obstruction and a reduction in mitral regurgitation.

Disease-specific therapy for ATTRv-CM was continued.

Discussion

This case illustrates a complex diagnostic and therapeutic challenge involving the coexistence of HCM and ATTRv-CM.

Although ATTR-CM typically results in restrictive physiology with concentric ventricular thickening, dynamic LVOT obstruction has been described in selected cases. Mechanisms proposed include basal septal hypertrophy, hyperdynamic ventricular function, and SAM of the mitral valve. However, LVOT obstruction in ATTR-CM remains uncommon and is generally less severe than that observed in sarcomeric HCM. Recent reports have indicated that when significant obstruction is present, careful evaluation is required to determine whether additional structural abnormalities, such as coexisting HCM, contribute to the hemodynamic findings.^1,2 In our patient, the severity of obstruction and the dramatic symptomatic response to mavacamten strongly supported a significant contribution from HCM.

Multimodality imaging provided important but somewhat conflicting diagnostic clues. The presence of apical sparing on strain imaging suggested ATTR-CM, while the marked LVOT obstruction and SAM physiology were characteristic of HCM. ATTR-CM can mimic HCM because of overlapping imaging findings, particularly in older patients with unexplained left ventricular wall thickening.³ CMR offered additional tissue characterization, demonstrating mild, regionally distributed LGE without abnormal gadolinium kinetics, findings that were not typical for advanced amyloid infiltration. Although CMR is highly valuable for differentiating HCM from ATTR-CM through assessment of LGE patterns and parametric mapping, there is recognized overlap, which may limit diagnostic specificity.⁴ Genetic testing subsequently identified a pathogenic TTR p.Val50Met variant. Although genetic testing is integral to the evaluation of HCM, its diagnostic yield is modest (approximately 40%), and a significant proportion of patients remain sarcomere-negative despite a phenotypic diagnosis.⁴ Thus, negative genetic testing does not exclude HCM and must be interpreted alongside clinical and imaging features. The definitive imaging clue was provided by technetium-99m pyrophosphate scintigraphy, which demonstrated grade 3 myocardial uptake, confirming the presence of ATTRv-CM.⁵

An additional diagnostic consideration in this case is the observed clinical-biomarker discordance. The absence of clinical congestion, relatively modest cardiac biomarker elevation, and lack of systemic manifestations of amyloidosis argued against advanced ATTR-CM. In ATTR-CM, biomarker levels are typically substantially elevated and correlate with disease burden. In contrast, patients with HCM may exhibit significant structural abnormalities and symptom burden, with comparatively lower biomarker elevations. This relative discordance between symptoms, imaging severity, and biomarker profile in our patient may therefore suggest a contribution from HCM physiology, supporting the possibility of concomitant disease rather than isolated ATTR-CM.

Histopathologic examination following septal myectomy confirmed the coexistence of 2 distinct processes. Absence of myocyte disarray in septal myectomy tissue, as in this case, does not exclude HCM, as prior large series have shown that up to approximately one-fourth of patients with obstructive HCM may lack demonstrable disarray in surgical specimens given sampling limitations.⁶ Although moderate amyloid deposition was identified within the septal myocardium, the extent of infiltration was insufficient to account for the magnitude of septal hypertrophy observed in this patient. Instead, the structural findings were more consistent with a primary HCM with superimposed amyloid deposition. Incidental myocardial amyloid deposition has previously been reported in patients undergoing septal myectomy for HCM. In a series by Helder et al,⁷ amyloid deposition was identified in surgical specimens from patients with HCM undergoing septal myectomy, suggesting that infiltrative processes may coexist with sarcomeric cardiomyopathy in selected cases. More recent studies have also described incidental amyloid deposition in surgical myectomy specimens, further supporting the possibility of dual pathology.⁸

To our knowledge, the coexistence of ATTRv-CM and HCM presenting with severe LVOT obstruction and a marked clinical response to mavacamten has rarely been described. Although rare case reports have described ATTR-CM presenting with asymmetric left ventricular wall thickening and LVOT obstruction resembling HCM, the presence of genetically confirmed ATTRv-CM disease together with classic HCM physiology and pathologic confirmation of both processes remains exceptional.⁹

This case highlights the importance of considering dual cardiomyopathies when imaging, genetic testing, and clinical response to therapy appear discordant. The coexistence of sarcomeric and infiltrative cardiomyopathies, although rare, has important implications for clinical management. Treatment strategies may require a combination of disease-modifying therapies for ATTR-CM, which have been shown to improve outcomes in ATTR-CM, and structural interventions to relieve LVOT obstruction.¹⁰ However, evidence supporting combination ATTR-directed therapies remains limited, and the safety of cardiac myosin inhibitors such as mavacamten in patients with coexisting ATTR-CM is not well established, with potential concerns regarding adverse hemodynamic effects with long-term use.

Conclusions

This case demonstrates the rare coexistence of HCM and ATTRv-CM. The presence of severe LVOT obstruction with a dramatic response to mavacamten initially supported a diagnosis of HCM, while genetic testing and nuclear scintigraphy confirmed ATTRv-CM. Recognition of dual pathology is essential because it may influence both diagnostic interpretation and therapeutic strategy.

Take-Home Messages

• •Dynamic left ventricular outflow tract obstruction does not exclude cardiac amyloidosis.
• •Dual cardiomyopathies should be considered when clinical, imaging, and genetic findings appear discordant.

Funding Support and Author Disclosures

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