Sustained Ventricular Tachycardia as the First Presentation of Hereditary Transthyretin Amyloidosis With the Glu109Gln Mutation

Abstract

Background

Transthyretin amyloid cardiomyopathy (ATTR-CM) most commonly presents with heart failure symptoms. Sustained ventricular tachycardia (VT) is an uncommon initial manifestation.

Case Summary

A 57-year-old man presented with hemodynamically unstable monomorphic VT requiring cardioversion. Imaging suggested cardiac amyloidosis and bone scintigraphy demonstrated Perugini grade 3 uptake. Genetic testing revealed a pathogenic p.Glu109Gln variant in the transthyretin gene. An implantable cardioverter-defibrillator (ICD) was implanted, and ATTR-stabilizer therapy was initiated. The patient remains stable without recurrent VT after 2.5 years.

Discussion

This case highlights VT as a rare initial presentation of ATTR-CM and emphasizes the limited evidence guiding the management of ventricular arrhythmias and the role of ICDs in these patients. Notably, the patient remained free of recurrent ventricular arrhythmias and ICD therapies during 2.5 years of follow-up without antiarrhythmic therapy.

Take-Home Messages

VT may represent an atypical presentation of ATTR-CM. Management of ventricular arrhythmias remains individualized due to limited evidence.

Visual Summary

History of Presentation

A 57-year-old man presented with 5 hours of severe palpitations, mild chest pain, and nausea. Initial blood pressure was 140/113 mm Hg. Examination revealed mild volume overload with pulmonary basal crepitations. Electrocardiography showed regular, broad-complex tachycardia with a frequency of approximately 240 beats/min, negative concordance across the precordial leads, and a superior axis consistent with monomorphic ventricular tachycardia (VT) (Figure 1A). Shortly after admission, the patient became hypotensive with a blood pressure of 88/53 mm Hg. Electrical cardioversion restored sinus rhythm (Figure 1B) with clinical stabilization.

Figure 1.

Electrocardiogram at Presentation, After Cardioversion, and During Electrophysiological Study

(A) Electrocardiogram (25 mm/s) at presentation showing monomorphic ventricular tachycardia at 240 beats/min. (B) Electrocardiogram (25 mm/s) after cardioversion showing sinus rhythm at around 80 beats/min with a diffuse pseudo-infarct pattern. (C) Electrocardiogram (50 mm/s) during electrophysiological study showing induced monomorphic ventricular tachycardia. The final QRS complexes reflect burst pacing used for termination of the arrhythmia.

Troponin T and N-terminal pro-B-type natriuretic peptide (NT-proBNP) were elevated to 85 (reference: <19) and 5,471 ng/L (reference: <300), respectively.

Transthoracic echocardiography demonstrated severe left ventricular (LV) hypertrophy with an interventricular septal thickness of 22 mm (Figure 2, Videos 1 and 2). Left ventricular ejection fraction (LVEF) was preserved but LV global longitudinal strain was markedly reduced (−10.1%) with an apical sparing pattern (Figure 2B). Of note, an elongated anterior mitral valve leaflet without systolic anterior motion or LV outflow tract obstruction was observed. The patient was initiated on furosemide 40 mg and metoprolol 50 mg.

Figure 2.

Echocardiography at Presentation

(A) Parasternal long axis image showing severe left ventricular hypertrophy. (B) Bulls-eye plot showing reduced left ventricular global longitudinal strain with a “cherry-on-top” pattern consistent with apical sparing. ANT = anterior; EDV = end-diastolic volume; GS = global strain; INF = inferior; IVSd = interventricular septum thickness, end-diastolic; LAT = lateral; LVIDd = left ventricular internal dimension, end-diastolic; LVPWd = left ventricular posterior wall thickness, end-diastolic; POST = posterior; SEPT = septal.

Past Medical History

The patient had no prior cardiopulmonary disease and was not on any medication. Medical history included bilateral carpal tunnel surgery and multiple trigger finger releases.

He was an avid recreational runner, but over the preceding year he had noticed gradually declining exercise capacity and increasing exertional dyspnea.

Family history was notable for the sudden death of his 76-year-old father, but no history of cardiopulmonary disease. The patient is of Macedonian heritage.

Differential Diagnosis

• 1.Nonobstructive hypertrophic cardiomyopathy
• 2.Cardiac amyloidosis

Investigations

Coronary computed tomography angiography

Coronary computed tomography angiography demonstrated a calcium score of 0 and no evidence of obstructive coronary artery disease.

Cardiac magnetic resonance imaging

Cardiac magnetic resonance imaging showed biventricular hypertrophy and preserved LVEF (Figure 3, Video 3). LV mass index was 122 (normal range: 39-85) g/m² and diffuse subendocardial and septal midmyocardial late gadolinium enhancement was present. Globally, elevated native T1 values of 1,141 (normal range: 900-1,050) milliseconds indicated impaired longitudinal relaxation time. The extracellular volume fraction was 65% (normal range: <30%).

Figure 3.

Cardiac Magnetic Resonance Imaging

(A) 4-chamber view showing biatrial enlargement and severe biventricular hypertrophy. (B) Phase-sensitive inversion recovery image showing diffuse subendocardial and septal midmyocardial late gadolinium enhancement. (C) Native T1 mapping showing severely elevated T1 values in all the myocardium (1,141 milliseconds). (D) Extracellular volume mapping showing a calculated extracellular volume of 65%.

Cardiac amyloidosis evaluation

Technetium-99m–labeled bone scintigraphy with single-photon emission computed tomography/computed tomography demonstrated Perugini grade 3 myocardial uptake (Figure 4). Serum and urine testing showed normal free light chain ratios and no monoclonal protein, excluding light chain amyloidosis. As part of an ongoing clinical trial, an endomyocardial biopsy was obtained. Congo red staining demonstrated extracellular amyloid deposition with characteristic apple-green birefringence under polarized light and subsequent mass spectrometry confirmed the presence of transthyretin amyloid fibrils (Figure 5). Genetic testing later revealed a pathogenic c.325G>C/p.Glu109Gln (formerly Glu89Gln) variant in the transthyretine (TTR) gene, establishing the diagnosis of hereditary transthyretin amyloidosis.

Visual Summary.

Sustained VT Revealing ATTR-CM (Glu109Gln)

ATTR-CM = transthyretin amyloid cardiomyopathy; CMRI = cardiac magnetic resonance imaging; ECV = extracellular volume; EP = electrophysiology; GLS = global longitudinal strain; ICD = implantable cardioverter defibrillator; IVS = interventricular septum; LGE = late gadolinium enhancement; NT-proBNP = N-terminal pro-B-type natriuretic peptide; TnT = troponin T; TTR = transthyretin; VT = ventricular tachycardia.

Figure 4.

Technetium-99m–Labeled Bone Scintigraphy

Technetium-99m–labeled bone scintigraphy showing Perugini grade 3 myocardial uptake.

Figure 5.

Endomyocardial Biopsy With Congo Red Staining

(A) Light microscopy demonstrating extracellular amyloid deposition (salmon-pink areas). (B) Apple-green birefringence of amyloid under polarized light.

Management

Cardiac decompensation was managed with loop diuretic agents. During hospitalization, several episodes of nonsustained VT (up to 17 beats) were observed, although no recurrent sustained VT occurred. Nonsustained VT episodes diminished as the patient achieved euvolemia.

Management of VT

An electrophysiological study demonstrated inducible VT originating from the septal-apical segment of the right ventricular. VT was induced using a pacing protocol with a 500 milliseconds drive cycle length and 3 ventricular extra stimuli delivered from the right ventricular apex (coupling intervals 270, 240, and 290 milliseconds). The induced VT (Figure 1C) was consistent with the presenting arrhythmia, and a dual-chamber implantable cardioverter-defibrillator (ICD) was implanted for secondary prevention. After euvolemia was achieved and nonsustained VT had resolved, beta-blocker therapy was discontinued due to concern for potential intolerance in the setting of transthyretin amyloid cardiomyopathy (ATTR-CM).

Outcome and Follow-Up

The patient was discharged asymptomatic with furosemide 40 mg daily. NT-proBNP had decreased to 1,072 ng/mL and troponin levels were normalized.

At 1-month follow-up, the patient remained asymptomatic with stable biomarkers and no ICD therapies. The patient was started on transthyretin stabilizer therapy.

Given the known mixed cardiac and neurological phenotype associated with the Glu109Gln mutation, neurological and neurophysiological evaluation was performed. Nerve conduction studies, intraepidermal nerve fiber density, cardiovagal tests, and cardiovascular adrenergic tests were normal. A reduced forearm sudomotor response was considered clinically insignificant.

Long-Term Follow-Up

During 2.5 years of follow-up, the patient has remained clinically stable without heart failure hospitalizations or ICD therapies. Remote device monitoring has shown no recurrent sustained ventricular arrhythmias. He remains in NYHA functional class I and National Amyloidosis Center stage I while receiving ATTR-stabilizer therapy and low-dose furosemide. Biomarkers have improved with the most recent NT-proBNP at 503 ng/mL and normal troponin levels.

Two years after the diagnosis, the patient was enrolled in the phase 3 MAGNITUDE (A phase 3, multinational, multicenter, randomized, double-blind, placebo-controlled study to evaluate the efficacy and safety of NTLA-2001 in participants with transthyretin amyloidosis with cardiomyopathy [ATTR-CM]) trial (NCT06128629) evaluating clustered regular interspaced short palindromic repeat (CRISPR)/Cas-9-based transthyretin gene-editing therapy (NTLA-2001).

Cascade genetic screening of the family revealed that the patient’s brother was genotype-negative, whereas his sister was genotype-positive but without clinical manifestations. A genotype-positive cousin was diagnosed with ATTR-CM and is receiving disease-modifying therapy. The cousin’s daughter was genotype-positive but asymptomatic. The patient has 2 preadolescent children who have not yet undergone genetic testing.

Discussion

VT as an atypical presentation of ATTR-CM

This case illustrates an unusual presentation of ATTR-CM with sustained VT as the first clinical manifestation. ATTR-CM typically presents with progressive heart failure symptoms, atrial arrhythmias, or conduction disease in elderly patients.¹ Ventricular arrhythmias are increasingly recognized in patients with ATTR-CM and continuous rhythm monitoring studies have reported nonsustained VT in approximately 20%-40% of patients.^2,3 Despite this, sustained VT as the initial manifestation remains rare, and ATTR-CM may not initially be suspected in younger patients presenting with ventricular arrhythmia.

In this case, additional historical features supported the diagnosis. Bilateral carpal tunnel syndrome and multiple trigger finger procedures represent known extracardiac manifestations of transthyretin amyloidosis.^1,4,5 The patient’s Macedonian ancestry is also consistent with the geographic distribution of hereditary transthyretin variants. Hereditary transthyretin amyloidosis demonstrates marked geographic clustering due to founder genetic variants, and several pathogenic variants are endemic in Mediterranean and Balkan populations.⁶

Management of VT in ATTR-CM

Guidelines directing management of ventricular arrhythmias in ATTR-CM remain limited. Sudden cardiac death in amyloidosis more commonly results from electromechanical dissociation or bradyarrhythmia rather than ventricular tachyarrhythmias, and the role of ICDs in ATTR-CM remains debated.³ Observational studies report appropriate ICD therapies in some patients; however, overall survival benefit is uncertain.³ Consequently, ICD implantation for primary prevention remains controversial.⁷ ICD implantation for secondary prevention after sustained VT or ventricular fibrillation may be considered in selected patients, although evidence is limited and largely derived from patients with light-chain amyloidosis.² Current European Society of Cardiology guidelines provide a Class IIa (Level of Evidence: C) recommendation for secondary prevention ICD implantation in patients with cardiac amyloidosis and life expectancy >1 year.⁸

In the present case, the patient presented with hemodynamically unstable VT and inducible VT during electrophysiological testing. This, along with the patient’s functional status and age, supported ICD implantation for secondary prevention.

Pharmacologic management of VT is also challenged by a lack of evidence. Patients with ATTR-CM often have fixed stroke volume and autonomic dysfunction and may therefore poorly tolerate beta-blocker treatment.¹ However, some patients may tolerate beta-blocker treatment without concerning adverse effects, and 1 large retrospective study found that beta-blocker therapy improved survival in patients with ATTR-CM and reduced LVEF.⁹ In the present case, beta-blocker therapy was initially started but later discontinued due to the absence of recurrent ventricular arrhythmias after volume optimization. Amiodarone may be considered, although evidence for prevention of ventricular arrhythmias in ATTR-CM is limited. Catheter ablation remains controversial but may be considered on a case-by-case basis for drug-refractory ventricular arrhythmias in ATTR-CM.¹⁰ In this case, the reduction in nonsustained VT episodes following volume optimization further suggests that hemodynamic factors may contribute to arrhythmia burden in patients with ATTR-CM.

In the present case, the absence of recurrent VT or ICD therapies during 2.5 years of follow-up, despite no antiarrhythmic therapy, highlights the difficulty of predicting arrhythmic risk in ATTR-CM and supports an individualized management approach.

Conclusions

This case illustrates an unusual presentation of hereditary ATTR-CM with sustained VT as the initial manifestation. In patients with ventricular arrhythmias, ICD implantation for secondary prevention may be considered, although the overall role of ICD therapy in cardiac amyloidosis remains uncertain.

Ethics

The authors confirm that written informed consent for publication of this case report was obtained from the patient in accordance with institutional policies and the principles outlined in the Declaration of Helsinki.

Take-Home Messages

• •Ventricular tachycardia may represent an atypical initial manifestation of transthyretin amyloid cardiomyopathy.
• •Management of ventricular arrhythmias remains uncertain, and implantable cardioverter-defibrillator implantation should be individualized.

Funding Support and Author Disclosures

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

Appendix

Video 1

Echocardiography; Parasternal Long Axis View

Parasternal long axis view demonstrating a severely hypertrophic left ventricular with preserved ejection fraction.

Video 2

Echocardiography; 4-Chamber View

4-chamber view demonstrating bi-atrial enlargement, severe left ventricular hypertrophy, preserved left ventricular ejection fraction, and a slightly elongated anterior mitral valve leaflet.

Video 3

Cardiac Magnetic Resonance Imaging; 4-Chamber View

Cardiac magnetic resonance 4-chamber view demonstrating bi-atrial enlargement, severe biventricular hypertrophy, and preserved biventricular ejection fractions.