Concurrent Use of Tafamidis and Mavacamten for Transthyretin Cardiac Amyloidosis With Severe Outflow Tract Obstruction

Abstract

Background

Cardiac amyloidosis (CA) and hypertrophic cardiomyopathy often manifest with overlapping clinical features, making diagnosis and management challenging.

Case Summary

We describe a 79-year-old man presenting with exertional dyspnea and presyncope who was diagnosed with transthyretin CA with left ventricular outflow tract (LVOT) obstruction and was treated with concurrent mavacamten and tafamidis.

Discussion

There is substantial overlap in the clinical phenotypes of hypertrophic cardiomyopathy and CA, and the presence of hemodynamically significant LVOT does not exclude the possibility of CA as an underlying diagnosis. Endomyocardial biopsy may be required when noninvasive testing is ambiguous or in the presence of overlapping disease features.

Take-Home Messages

Hemodynamically significant LVOT obstruction is a rare but clinically relevant manifestation of CA that may lead to diagnostic ambiguity and difficult management decisions. Tafamidis and mavacamten can be used safely in combination to provide symptom relief and slow disease progression in obstructive transthyretin CA.

Graphical Abstract

History of Presentation

A 79-year-old man was referred to the Johns Hopkins Hypertrophic Cardiomyopathy (HCM) Center for evaluation of possible HCM. He had presented 6 months earlier to a community cardiologist with new symptoms of lower extremity edema and exertional dyspnea. Local echocardiography identified asymmetric septal left ventricular hypertrophy (LVH) (16 mm) with systolic anterior motion of the mitral valve and a pressure gradient in the left ventricular outflow tract (LVOT) of 105 mm Hg, prompting referral to our center. He reported having difficulty with walking on an incline. His vital signs were notable for a blood pressure of 109/70 mm Hg, regular pulse at 73 beats/min, and body mass index of 29.7 kg/m². Cardiac auscultation revealed a harsh, late-peaking 3/6 systolic murmur that increased with Valsalva maneuver; there was trace lower extremity edema and no jugular venous distention.

Take-Home Messages

• •Hemodynamically significant LVOT obstruction is a rare but clinically relevant manifestation of CA that may lead to diagnostic ambiguity and difficult management decisions.
• •Tafamidis and mavacamten can be used safely in combination to provide symptom relief and slow disease progression in obstructive ATTR-CA.

Past Medical History

The patient's other medical history was significant for hyperlipidemia and obstructive sleep apnea. He had no family history of HCM, heart failure, or sudden cardiac death. He had no history of carpal tunnel syndrome or spinal stenosis. His medications included metoprolol succinate 25 mg twice daily, bumetanide 2 mg twice daily, and atorvastatin 10 mg once daily.

Differential Diagnosis

The differential diagnosis for exertional dyspnea included obstructive HCM, coronary artery disease, cardiac amyloidosis (CA), and noncardiac dyspnea.

Investigations

The initial electrocardiogram (ECG) showed normal sinus rhythm but revealed ST-T wave changes and minimal voltage criteria for LVH (Figure 1). Laboratory testing was notable for top normal creatinine (1.2 mg/dL) and elevated pro-B-type natriuretic peptide (3,123 pg/mL). Repeat echocardiogram (Video 1) demonstrated a normal left ventricular ejection fraction (LVEF) of 65% with severe concentric LVH with maximal septal thickness of 2.2 cm in the basal anteroseptum and 1.6 cm in the inferolateral wall (ratio 1.4) (Figure 2A). There was systolic anterior motion of the mitral valve with septal contact and mild posteriorly directed mitral regurgitation. Doppler assessment revealed severe LVOT obstruction at rest (145 mm Hg) (Figure 2B). There was a grade II diastolic filling pattern (pseudonormal) with E/eʹ ratio of 32 suggesting elevated left atrial filling pressure; global longitudinal strain (GLS) was not assessed. Cardiac magnetic resonance confirmed severe LVH (2.8 cm) (Figure 2C) and demonstrated diffuse late gadolinium enhancement (LGE) in a predominantly mid-myocardial pattern affecting 20% to 25% of the left ventricular myocardium by mass (Figure 2D). A 30-gene HCM genetic testing panel revealed no pathologic variants associated with LVH (Invitae).

Figure 1.

Initial Electrocardiogram

Initial electrocardiogram showing sinus rhythm, with borderline criteria for left ventricular hypertrophy and T-wave inversions in the inferior and precordial lateral leads.

Figure 2.

Initial Imaging Evaluation

Initial imaging evaluation (apical 3-chamber, systole) revealed severe concentric left ventricular hypertrophy with systolic anterior motion of the mitral valve and septal contact at rest (red arrow) (A) and severe resting left ventricular outflow tract obstruction (B). Cardiac magnetic resonance confirmed the presence of left ventricular hypertrophy (C) and demonstrated extensive, predominantly mid-myocardial late gadolinium enhancement (D).

Management

Based on the presence of severe LVH, hemodynamically significant LVOT obstruction, and the pattern of mid-myocardial LGE, an initial diagnosis of obstructive HCM was made. After a shared decision making discussion with the patient regarding his NYHA functional class III exertional dyspnea symptoms, treatment with the cardiac myosin inhibitor mavacamten was pursued. Mavacamten was initiated and ultimately titrated to a dose of 5 mg/d. Follow-up echocardiogram after 6 months of treatment revealed normal systolic function with LVEF reduced from baseline (55%) and improvement in both resting (19 mm Hg) and Valsalva provoked (35 mm Hg) gradients across the LVOT (Video 2). GLS was reduced (−6.4%), with relative sparing of the left ventricular apex (Figure 3A). The patient reported moderate improvement, but not resolution, of his exertional dyspnea. He also reported an episode of presyncope that occurred when rising from a seated position. Given his ongoing symptoms, the patient was sent for additional diagnostic evaluation for possible CA. Serum free light chains and protein electrophoresis were within normal limits.^99mTechnetium pyrophosphate scintigraphy nuclear scan was performed, showing grade 3 cardiac uptake and a semiquantitative cardiac-to-contralateral lung uptake ratio of 1.85 (Figure 3B) consistent with transthyretin CA (ATTR-CA). Tafamidis was initiated at a dose of 80 mg/d. Right heart catheterization with endomyocardial biopsy demonstrated normal filling pressures (right atrial pressure: 5 mm Hg; pulmonary artery pressure: 28/12 [17 mm Hg]; pulmonary capillary wedge pressure: 9 mm Hg) with low normal mixed venous saturation of 65% and a reduced Fick cardiac index of 1.9 L/min/m². Histopathology revealed myocyte hypertrophy and focal myocyte disarray with extracellular amyloid deposits and typical apple-green birefringence on Congo red dye staining (Figures 3C and 3D), and mass spectrometry confirmed a diagnosis of ATTR-CA.

Figure 3.

Subsequent Testing for Cardiac Amyloid

Further investigation supported an underlying diagnosis of transthyretin cardiac amyloidosis based on apical sparing on echocardiographic global longitudinal strain analysis (A), pyrophosphate scintigraphy nuclear scan showing increased cardiac uptake (B), and histopathology demonstrating amyloid deposits on Congo red staining (C) with apple-green birefringence (D).

Outcomes and Follow-Up

Based on the reduced cardiac index observed during right heart catheterization, mavacamten was discontinued. Metoprolol was discontinued in the setting of the patient's orthostatic presyncope. Tafamidis was continued. Repeat echocardiography after 8 weeks off of mavacamten demonstrated recurrence of hemodynamically significant LVOT obstruction (77 mm Hg at rest, 88 mm Hg after provocation by Valsalva) with worsening of exertional dyspnea. He was evaluated for septal ablation, but was not a candidate owing to inadequate coronary anatomy. After further shared decision making, mavacamten was resumed at a reduced dose of 2.5 mg/d. Repeat echocardiography showed a stable LVEF (55%), improvement in both resting (20 mm Hg) and Valsalva-provoked (30 mm Hg) gradients across the LVOT, and improvement in his burden of exertional dyspnea.

Discussion

In this report, we describe a patient with severe LVOT obstruction in the setting of biopsy-proven wild-type ATTR-CA who underwent simultaneous treatment with both mavacamten and tafamidis. There were no clinical complications arising from the use of these 2 medications in combination, with the HCM-specific therapy mavacamten relieving hemodynamically significant LVOT obstruction despite an underlying diagnosis of CA.

CA and HCM have overlapping clinical phenotypes, and differentiating between these alternative diagnoses in the evaluation of patients with severe LVH can be difficult. In both conditions, exertional dyspnea is a hallmark presenting symptom. Although patients with wild-type ATTR-CA tend to be older (mean age of 76 years¹), there is a biphasic distribution in the age of HCM presentation, with patients with pathogenic sarcomere- negative HCM in particular presenting later in life. Whereas QRS amplitudes on ECG are classically reduced in CA, ECG-derived LVH criteria are identified in patients with CA and HCM at similar rates and do not distinguish these diagnoses effectively.² Echocardiography also has limited discriminatory power, with patients with ATTR-CA routinely demonstrating HCM-range LVH.³ Whereas the pattern of LVH in CA is more classically concentric with a higher ratio of posterior-to-septal wall thickness, the presence of concentric hypertrophy has low specificity for exclusion of HCM.² GLS is frequently less negative in CA compared with HCM, but these differences may be reduced in obstructive HCM.⁴ Additionally, whereas a pattern of relative apical sparing is more suggestive of CA when present, this finding has low sensitivity, and its absence does not exclude an underlying diagnosis of CA.^2,5 Cardiac magnetic resonance with LGE assessment may also be helpful in some cases, with diffuse subendocardial enhancement suggesting CA and mid-myocardial enhancement of hypertrophied tissue suggesting HCM.⁶ However, as demonstrated by our case, neither finding is definitive or excludes an alternative diagnosis. Myocardial radiotracer uptake on pyrophosphate scintigraphy nuclear scan has high sensitivity and specificity for ATTR-CA,⁷ but has low diagnostic yield when performed in patients who otherwise meet diagnostic criteria for HCM, particularly in the presence of hemodynamically significant LVOT obstruction,⁸ and false-positive results have also been reported in patients with HCM.⁹ Ultimately, definitive endomyocardial biopsy may be required in patients who demonstrate overlapping disease characteristics (eg, a mixed phenotype of HCM and CA) or for whom noninvasive diagnostic testing is ambiguous. Interestingly, although ATTR-CA was definitively confirmed on endomyocardial biopsy for the reported patient, myocyte hypertrophy and focal myocyte disarray were also identified. This raises the possibility that, in this case, LVOT obstruction may have been the result of dual diagnoses of ATTR-CA and HCM rather than ATTR-CA in isolation.

Hemodynamically significant LVOT is a rare but clinically important manifestation of CA with an overall incidence of approximately 3%,¹⁰ the optimal management of which is currently undefined. Patients with CA, particularly patients with advanced disease, may be intolerant of first-line pharmacologic therapy, eg, β-blockers and nondihydropyridine calcium channel blockers, owing to the presence of concomitant restrictive physiology. Invasive septal reduction therapy with either alcohol septal ablation or surgical myectomy may offer effective relief of obstruction.¹⁰ However, patients may not be candidates for invasive treatment owing to older age, high surgical risk, or anatomic considerations. Alternative invasive approaches such as mitral valve transcatheter edge-to-edge repair¹¹ and transcatheter myotomy using septal scoring along the midline endocardium¹² have demonstrated promising early results for relief of LVOT obstruction, but thus far their use remains off-label or experimental, and further study is still required. More recently, mavacamten has emerged as an alternative treatment modality for obstructive HCM,¹³ but its use has not been previously described in CA. Although mavacamten is extensively metabolized by cytochrome P450 enzymes CYP2C19 and CYP3A4 and may thereby be contraindicated or require dose adjustment when used with other medications, there are no known drug-drug interactions between mavacamten and CA disease-modifying medications such as tafamidis. Importantly, whereas the development of new, transient systolic dysfunction (LVEF <50%) has been reported in approximately 5% of patients with HCM receiving mavacamten,^13,14 the currently undefined incidence of mavacamten-associated systolic dysfunction may be higher in patients with obstruction related to ATTR-CA owing to differences in underlying myocardial substrate. Close echocardiographic monitoring and consideration of the use of lower mavacamten dosages should be considered in this population. In the patient described in the present case, mavacamten alleviated LVOT obstruction and symptoms of exertional dyspnea without precipitating systolic dysfunction or clinical heart failure when used over a 6-month period in a patient with ATTR-CA, including during simultaneous treatment with tafamidis. This combination of treatments represents a promising approach to managing severe LVOT obstruction in the context of ATTR-CA, illustrating the need for comprehensive strategies that address both symptom relief and underlying disease mechanisms.

Conclusions

Hemodynamically significant LVOT obstruction is a rare but clinically relevant manifestation of CA that may lead to diagnostic ambiguity and difficult management decisions. Here, we describe a case in which mavacamten was used safely and effectively in a patient with obstructive ATTR-CA, including during simultaneous treatment with tafamidis.

Funding Support and Author Disclosures

Dr Carrick has received funding from the National Institutes of Health (T32HL007227, L30HL165535) and has been a recipient of the Semyon and Janna Friedman Fellowship award. Drs Carrick and Madrazo have received funding from the Talles Family HCM Research Fund. All other authors have reported that they have no relationships relevant to the contents of this paper to disclose.

Appendix

Video 1

Pre-Mavacamten Echocardiography

Transthoracic echocardiography (parasternal long axis, apical 4-chamber) performed before mavacamten treatment demonstrated normal ejection fraction with severe concentric hypertrophy and pronounced systolic motion of the mitral valve with septal contact.

Video 2

Post-Mavacamten Echocardiography

Transthoracic echocardiography (parasternal long axis, apical 4-chamber) performed after 6 months of treatment with mavacamten demonstrated low normal ejection fraction and decreased systolic anterior motion of the mitral valve apparatus.