Biventricular Arrhythmogenic Cardiomyopathy: Diagnostic Insights from Cardiovascular Magnetic Resonance

Graphical abstract

Highlights

• •ACM is an uncommon but important cause of chest pain.
• •ACM should be suspected in individuals presenting with VAs.
• •Echocardiography should be the initial screening tool for ACM.
• •Three-dimensional TTE or CMR may be considered if clinical suspicion of ACM persists.
• •CMR plays a crucial role in diagnosing and risk-stratifying ACM.

Introduction

Arrhythmogenic cardiomyopathy (ACM) is a rare inherited myocardial disorder that affects the right ventricle (RV), although left ventricle (LV) or biventricular involvement is increasingly recognized.1, 2, 3 Arrhythmogenic cardiomyopathy is associated with an adverse prognosis due to its predisposition to cause dangerous ventricular arrhythmias (VAs) and a high risk of sudden cardiac death (SCD), especially in young individuals.^4,5 We report a case of ACM diagnosis in a patient presenting with atypical chest pain accompanied by VAs, despite the absence of RV abnormalities on two-dimensional (2D) transthoracic echocardiography (TTE).

Case Presentation

A 56-year-old man presented with atypical, sharp chest pains radiating to the left arm. There was a significant family history of coronary artery disease (CAD) and heart failure, but there was no known family history of cardiomyopathy, SCD, or unexplained death. At the age of 27 years old, the patient presented with palpitations and syncope, was diagnosed with Wolff-Parkinson-White syndrome, and underwent catheter ablation. Recently, our patient had experienced a collapse due to ventricular tachycardia with no obvious triggers. Physical examination was unremarkable.

A 12-lead electrocardiogram (ECG) revealed sinus rhythm with T-wave inversion (TWI) in leads V1-V3, and prolonged terminal activation duration (TAD) of QRS (≥55 ms; Figure 1A). Twenty-four-hour ambulatory ECG showed a 6-beat run of ventricular tachycardia and frequent multifocal ventricular ectopics (591 per 24 hours; Figure 1B).

Figure 1.

(A) Twelve-lead ECG demonstrates normal sinus rhythm with TWIs in V1-V3 (dashed green arrow) and TAD of QRS more than 55 ms. (B) Twenty-four-hour ambulatory ECG demonstrates a 6-beat run of ventricular tachycardia (double-headed green arrow).

Routine biochemical testing was within normal limits, including troponin I concentration, although B-type natriuretic peptide levels were mildly elevated (77 ng/L; reference range, <20 ng/L). A recent 2D TTE performed at an external hospital demonstrated a normal left ventricular ejection fraction (56%) with basal inferior hypokinesia, normal size RV (RV basal dimension = 43 mm; RV mid cavity dimension = 32 mm; RV longitudinal dimension = 84 mm on 4-chamber view), and normal right ventricular function, tricuspid annular plane systolic excursion (23 mm), and right ventricular systolic pressure (24 mm Hg; Figure 2, Videos 1-4).

Figure 2.

Two-dimensional TTE, parasternal long-axis (A and B), parasternal short-axis (C and D), right ventricular inflow tract with color-flow Doppler (E and F), and apical 4-chamber (G and H) diastolic (left) and systolic (right) views, demonstrates normal biventricular size and global systolic function. LA, Left atrium; RA, right atrium.

Cardiac computed tomography (CCT) excluded significant CAD but showed areas of subendocardial fatty infiltration in the mid-LV lateral wall as well as fatty infiltration within the RV wall, particularly toward the apex and along the interventricular septum (Figure 3).

Figure 3.

Cardiac computed tomography, left ventricular short-axis (A) and long-axis (B) views, demonstrates dilated RV with biventricular fatty metaplasia (arrows).

Cardiovascular magnetic resonance (CMR; 1.5 Tesla) revealed normal left ventricular volumes and systolic function. There was a focal thinning and akinesis, plus midwall/subepicardial fatty metaplasia of the mid-anterolateral and apical lateral LV wall, surrounded by a black boundary (India ink artifact) in steady-state free precession (SSFP) images (Figure 4A and C, Videos 5-8). These regions exhibited hypointense signal on T1-mapping images (Figure 5A) and hyperintense signal on T2-mapping images (Figure 5B). In addition, there was a focal fibrosis region with increased native myocardial T1 values at the midinferolateral wall (average value, 1,300 ms; Figure 5A). In contrast, the RV was moderately dilated (end-diastolic indexed volume = 140 mL/m²) with features of dysplasia and fatty metaplasia along the right ventricular side of the mid to apical inferoseptum (Figure 4A and D). The RV also showed extensive areas of akinesia and dyskinesia, severely impaired right ventricular ejection fraction (33%), and multiple microaneurysms in SSFP images, also known as the “accordion” sign (Figure 4B and C). Early and late gadolinium enhancement imaging revealed no evidence of intracardiac thrombus (Figure 5C-F). However, late gadolinium enhancement images demonstrated subendocardial/midwall myocardial scarring in the mid and apical lateral LV wall, alongside extensive scarring of the right ventricular free and inferior walls (Video 9). Some of these regions represent areas of fatty metaplasia (Figure 5D-F).

Figure 4.

CMR, balanced SSFP sequence, 4-chamber (A), short-axis (B), 3-chamber (C), and basal RV in-and-out (D) diastolic views, demonstrates abnormal right ventricular contour (black arrows), multiple microaneurysms (yellow arrows), and fatty metaplasia (white arrow). RA, Right atrium.

Figure 5.

CMR, T1 map (A), T2 map (B), early gadolinium enhancement (C), late gadolinium enhancement (D, E, and F) in mid short-axis (A, B, and E), apical 4-chamber (C and D), and RV in-and-out (F) views, demonstrates fatty infiltration in the mid-LV anterolateral wall (green arrow, A); absence of intracardiac thrombi; subendocardial and midwall left ventricular late gadolinium enhancement; extensive RV free and inferior wall late gadolinium enhancement (red arrows; D, E, and F). RA, Right atrium.

Our patient fulfilled most of the Padua criteria for the diagnosis of ACM with biventricular involvement. Subsequently, an implantable cardioverter-defibrillator (ICD) was implanted, and treatment with beta-blockers and amiodarone was initiated.

Discussion

Arrhythmogenic cardiomyopathy is an inherited myocardial disorder that mainly affects the RV, although increasing recognition of left ventricular or biventricular involvement is emerging. Recent reports indicate that ACM with biventricular involvement may be present in approximately 37% to 67% of cases.1, 2, 3 The prevalence of ACM has been estimated at 1 in 1,000 to 1 in 5,000 individuals.⁵ Arrhythmogenic cardiomyopathy is characterized by VAs and a higher risk of SCD in young people.^4,5 Clinical manifestations of ACM are heterogeneous, commonly including palpitations, syncope, VAs, and occasionally atypical chest pain, which may lead to diagnostic confusion with other cardiovascular conditions, particularly CAD.⁶

The diagnosis of ACM is relatively complex and requires integration of structural, functional, electrocardiographic, arrhythmic, and genetic information. Historically, the diagnosis of ACM relied on the 2010 International Task Force criteria.⁷ To address the limitations of these criteria, particularly in recognizing left ventricular involvement, the updated Padua criteria were subsequently proposed.⁸ These criteria assess 5 main aspects: ventricular morphofunctional abnormalities, structural myocardial abnormalities, ECG (re/depolarization) abnormalities, VAs, and family history/genetics.⁸ Two of the criteria with respect to morphofunctional ventricular abnormalities and structural myocardial abnormalities rely heavily on CMR. Although myocardial biopsy can provide histological confirmation of fibrofatty replacement, it is invasive, carries procedural risks, and may not be readily available in many regions.⁸ In this particular case, the patient fulfilled multiple Padua criteria, including morphological-functional and structural abnormalities involving both ventricles, ECG, depolarization and repolarization abnormalities, and documented VAs. While alternative diagnoses such as ablation-related scarring, prior myocarditis, or sarcoidosis⁹ are theoretically possible, the clinical presentation and imaging pattern strongly favor a diagnosis of ACM.

Electrocardiogram remains a fundamental component of diagnosing ACM. Both depolarization and repolarization abnormalities correlate with the extent and distribution of ventricular dilation, dysfunction, and myocardial fibrosis.¹⁰ Key ECG findings in ACM patients consist of TWI, a TAD of more than 55 ms in leads V1-V3, reduced QRS voltages in limb leads, and Epsilon waves.¹⁰ In our patient, TWI and prolonged TAD were consistent with right ventricular involvement. The absence of low QS voltages in the limb leads correlated with the relatively limited extent of left ventricular fibrosis on CMR.

Two-dimensional TTE is considered the first-line imaging modality in suspected ACM and can detect a variety of signs, including ventricular dysfunction, dyskinesia, and hypokinesia; in addition, a mushroom-shaped right ventricular outflow tract may be observed.¹¹ The sensitivity and specificity of 2D TTE vary widely depending on the evaluation criteria and study populations, generally ranging from 55% to 75% and 76% to 95%, respectively.⁷ Furthermore, 2D TTE may not accurately or fully assess the RV compared to three-dimensional TTE, especially regarding right ventricular volume.¹² Therefore, ACM should not be ruled out even if 2D TTE results do not reveal significant abnormalities. Cardiac computed tomography may help identify myocardial fat infiltration and certain cardiac muscle anomalies, but it is not considered a primary diagnostic assessment.¹³ In this case, the CCT scan was performed to exclude CAD in the context of atypical chest pain, a significant family history of CAD, and anterior TWI on the ECG.

Cardiovascular magnetic resonance is currently considered the reference standard for assessing cardiac structure and function, especially of the RV. Diagnostic performance varies depending on the study design and criteria used, but a recent report suggests that CMR has a sensitivity and specificity of 96% and a specificity of up to 100%.² In this patient, CMR revealed both fibrofatty and elevated native T2 values in the regions of the LV lateral wall. Elevated T2 signals suggest myocardial edema or active inflammation,⁹ which has been increasingly recognized in ACM, particularly during the early or “hot phase” of the disease.¹⁴ This finding highlights that ACM is not solely a chronic structural disorder but may also involve ongoing myocardial injury, which could contribute to arrhythmic risk. Differentiating edema from fat is crucial, as fat alone typically is characterized by low native T1 values, the “India ink artifact” on SSFP imaging, and loss of signal on fat-suppressed T2 imaging, whereas edema or fibrosis presents with elevated native T1 and T2 values.⁹ The presence of elevated T2 values in addition to fibrofatty replacement may have prognostic implications, as inflammatory activity in ACM has been linked to increased arrhythmic burden and disease progression.¹⁴ Recognizing these active disease phases may affect clinical decision-making, including timing of ICD or closer rhythm surveillance.¹⁴

Genetic testing also plays an important role in identifying a pathogenic or likely pathogenic variant associated with ACM and contributes to both diagnosis and family screening.^2,14

Arrhythmogenic cardiomyopathy is strongly associated with malignant VAs and SCD in young individuals. One study reported that the average age of young people who died suddenly was approximately 22 years among young victims of SCD due to ACM.¹⁵ The left ventricular involvement, as identified in this case, has been associated with a worse prognosis, necessitating the risk stratification for an ICD.¹

Conclusion

Arrhythmogenic cardiomyopathy is a rare genetically inherited cardiomyopathy with a heterogeneous clinical presentation. It may present with atypical chest pain accompanied by VAs, even when the initial echocardiography appears nondiagnostic. Diagnosing ACM requires a multimodal approach, with CMR as a key component in assessing ventricular structure, function, and myocardial tissue. It should be performed early, even if 2D TTE shows no RV abnormalities.

Ethics Statement

The authors declare that the work described has been carried out in accordance with The Code of Ethics of the World Medical Association (Declaration of Helsinki) for experiments involving humans.

Consent Statement

Complete written informed consent was obtained from the patient (or appropriate parent, guardian, or power of attorney) for the publication of this study and accompanying images.

Funding

The authors declare that this report did not receive any specific grant from funding agencies in the public, commercial, or not-for-profit sectors.

Disclosure Statement

The authors reported no actual or potential conflicts of interest relative to this document.

Supplementary Data

Video 1

Two-dimensional TTE, parasternal long-axis view, demonstrates normal size LV and RV with normal global left ventricular systolic function.

Video 2

Two-dimensional TTE, midventricular parasternal short-axis view, demonstrates normal size LV and RV with normal global left ventricular systolic function.

Video 3

Two-dimensional TTE, right ventricular inflow view with color-flow Doppler, demonstrates normal size RV and right atrium with trace tricuspid regurgitation.

Video 4

Two-dimensional TTE, apical 4-chamber view, demonstrates normal biventricular size and global systolic function.

Video 5

CMR, balanced SSFP sequence, 4-chamber view, demonstrates normal left ventricular size and global systolic function with focal subepicardial fatty metaplasia and akinesis in the midanterolateral wall; the RV is dilated with extensive regions of akinesia and dyskinesia and diffuse right ventricular dysplasia with multiple microaneurysms.

Video 6

CMR, balanced SSFP sequence, short-axis cine stack, demonstrates normal left ventricular size and global systolic function with focal subepicardial fatty metaplasia and akinesis in the midanterolateral wall; the RV is dilated with extensive regions of akinesia and dyskinesia and diffuse right ventricular dysplasia with multiple microaneurysms.

Video 7

CMR, balanced SSFP sequence, 3-chamber view, demonstrates normal left ventricular size and global systolic function with focal subepicardial fatty metaplasia in the apical lateral segment; the right ventricular outflow tract is dilated with a focal right ventricular aneurysm.

Video 8

CMR, balanced SSFP sequence, oblique sagittal right ventricular “in-and-out” view, demonstrates multiple microaneurysms.

Video 9

CMR, late gadolinium enhancement sequence, short-axis stack from base to apex, demonstrates subendocardial and midmyocardial late gadolinium enhancement in the mid to apical lateral LV segment, as well as extensive late gadolinium enhancement involving the RV free and inferior wall segments.