Arrhythmogenic Cardiomyopathy Mimicking Cardiac Amyloidosis with Waldenström Macroglobulinaemia: A Diagnostic Challenge

Arrhythmogenic cardiomyopathy (ACM) is a progressive genetic condition marked by the replacement of the myocardium with fibrofatty tissue. Its clinical presentation varies significantly, ranging from symptomatic arrhythmias and heart failure to sudden cardiac death. While classically right ventricular (RV)-predominant, left-dominant/biventricular phenotypes are increasingly recognized.1 Waldenström's macroglobulinaemia (WM) is a rare, indolent lymphoplasmacytic lymphoma characterized by bone marrow infiltration and elevated serum monoclonal immunoglobulin M (IgM) levels.2 Patients with low-risk WM have a favourable prognosis, with a 5-year survival rate of 87%. In contrast, cardiac amyloidosis is a progressive infiltrative disorder caused by the deposition of amyloid fibrils in cardiac tissue.3 Echocardiographic findings such as left ventricular (LV) wall thickening exceeding 12 mm, accompanied by ‘red flags’ like low/decreased QRS voltage to degree of LV thickness, should raise suspicion for this diagnosis.3 In such cases, comprehensive evaluation integrating multimodality imaging, genetic testing, and hematologic assessment is critical for accurate diagnosis and tailored clinical management. A 59-year-old man with hypertension and a family history of sudden death (brother) presented with recurrent palpitations and syncope over 4 years. Basal electrocardiogram (ECG) showed low QRS voltages in the limb leads and flattened/inverted T-waves in the precordial leads (Figure 1). During palpitations, the ECG revealed non-sustained ventricular tachycardia (VT) with a left bundle branch block (LBBB) morphology (Figure 1). 24-hour Holter monitoring showed 22,148 (28.32%) premature ventricular beats. Transthoracic echocardiography (TTE) demonstrated LV and right atrial dilatation, LV eccentric hypertrophy, apical aneurysm, and reduced left ventricular ejection fraction (LVEF 32%) (Figure 2). Cardiac magnetic resonance (CMR) revealed biventricular dilatation and systolic dysfunction (LVEF 31%, RVEF 27%). A focal ‘crinkling’ of the RV free wall (‘accordion sign’) and a slightly bulging apex were observed (Figure 3). The interventricular septum appeared thickened, and diffuse late gadolinium enhancement (LGE) in the LV and septal myocardium suggested myocardial fibrosis (Figure 3). Genetic testing identified a Desmoglein-2 (DSG2) variant (p.G129D and p.F531C) (Figure 4). The patient was diagnosed with cardiomyopathy and heart failure with reduced ejection fraction (HFrEF). He received an implantable cardioverter defibrillator (ICD), guideline-directed medical therapy (GDMT), and amiodarone. He was readmitted to the hospital due to recurrent VT and ICD shock over the last 2 months. The onset ECG demonstrated a similar non-sustained VT with LBBB morphology. Serum cardiac troponin I was slightly elevated (24.31 ng/L; ULN < 17.5 ng/L), while coronary computed tomography angiography (CTA) excluded significant stenosis (Figure 5). NT-proBNP was 126 pg/mL. An unexpected finding emerged during this hospital stay. Serum immunofixation revealed elevated IgM monoclonal protein (3.97 g/L). Further correlation with the LV hypertrophy with low limb lead voltages, persistent low-level troponin elevation, and diffused LV LGE of the free wall/septum raised suspicion for cardiac amyloidosis. However, further diagnostic investigations including—99mTc-PYP SPECT, serum free light chains (normal κ/λ ratio), and abdominal fat pad aspiration with Congo Red staining—were negative. Bone marrow biopsy revealed lymphoplasmacytic infiltration with negative Congo red staining. TTE showed improved LVEF (50%) but persistent RV abnormalities, including apical aneurysm, thin RV wall (3 mm), and reduced right ventricular fractional area change (RVFAC, 29.8%) (Figure 6, Video S1). The patient's timeline of clinical events and diagnostic tests is shown in Table 1. • ECG: non-sustained VT • 24-hour Holter: 22,148 (28.32%) premature ventricular beats • ECG: non-sustained VT with LBBB morphology + flattened/inverted T-waves (precordial leads) • TTE: ↓LVEF (32%), LV/RA dilatation, LV hypertrophy, apical aneurysm (initially oversight of right heart pathology) • CMR: ↓LVEF (31%)/↓RVEF (27%), ‘accordion sign’, diffuse LGE, biventricular dilatation • Genetic testing: Pathogenic DSG2 variants (p.G129D, p.F531C) Confirmed ACM diagnosis; Initiated ICD + GDMT + amiodarone • ECG: non-sustained VT with LBBB morphology • Elevated troponin I (24.31 ng/L) • Coronary CTA: No significant stenosis Readmission Incident hematologic finding/cardiac amyloid evaluation • ECG: Limb-lead low QRS voltage Serum immunofixation: Monoclonal IgM elevated • BM biopsy: Lymphoplasmacytic infiltration • 99mTc-PYP SPECT: Negative • Serum FLC: Normal κ/λ ratio • Congo red: Negative (fat pad/BM) • TTE: ↑LVEF (50%) but ↓RVFAC (29.8%), RV abnormalities Ruled out cardiac amyloidosis; Confirmed low-risk WM; Radiofrequency ablation recommended but be declined; Continued GDMT + amiodarone • ACM of biventricular phenotype (2020 International Criteria) • Low-risk Waldenström macroglobulinaemia ACM mimicked cardiac amyloidosis; ACM and WM coexistence • ↑LVEF (55%) but ↓RVFAC (28.1%) • No further ICD shocks • Controlled arrhythmias Ultimately, cardiac amyloidosis was excluded, and the patient was diagnosed with ACM of the biventricular phenotype according to the 2020 International Criteria (‘Padua criteria’).4 Simultaneously, he was diagnosed with low-risk WM based on international criteria and International Prognostic Scoring System,2 requiring no specific therapy. Due to frequent VT and ICD shocks, radiofrequency ablation was recommended but declined by the patient. Amiodarone was initiated for VT control alongside continued GDMT. The patient was monitored every 3 months. At 2 years, LVEF improved to 55.0%, but RVFAC declined to 28.1% (Figure 7, Videos S2 and S3). Palpitations were well controlled, ventricular premature beats decreased, and no further ICD shocks occurred. Here, we report an uncommon case of a middle-aged man presenting with VT (LBBB morphology), biventricular dilatation/dysfunction, cardiac hypertrophy, and an apical aneurysm. CMR revealed diffuse LGE, whilst genetic testing identified a DSG2 mutation, confirming ACM. However, incidentally elevated IgM levels and a reduced QRS voltage-to-mass ratio raised suspicion of cardiac amyloidosis. Comprehensive evaluation ultimately excluded amyloidosis, leading to a concurrent diagnosis of low-risk WM. To our knowledge, this represents the first documented case of ACM mimicking cardiac amyloidosis in a patient with WM. ACM is characterized by non-ischaemic myocardial scarring that precipitates ventricular arrhythmias. Diagnosis remains challenging due to overlapping clinical and imaging features with other cardiomyopathies. Initial diagnostic criteria, established in 19945 and revised in 2010,6 focused predominantly on arrhythmogenic right ventricular cardiomyopathy (ARVC). A 2019 expert review confirmed their accuracy for ARVC but highlighted limited sensitivity for left-dominant phenotypes.7 This gap in criteria for left ventricular involvement contributed to decades of underdiagnosis, later addressed by the 2020 Padua criteria encompassing all ACM variants.4 Diagnostic complexity arises from variable test sensitivity and specificity. Comprehensive evaluation—integrating multimodal imaging, genetic testing, and haematological assessment—is essential for overlapping phenotypes. Echocardiography serves as the primary tool for assessing ventricular morphology and function.4 However, its diagnostic accuracy can be limited, particularly in early arrhythmogenic left ventricular cardiomyopathy (ALVC). Right ventricular (RV) evaluation proves especially challenging owing to its retrosternal position and complex geometry. In our case, initial overemphasis on left heart assessment led to oversight of right heart pathology. ECG findings are pivotal. In this case, nonsustained and sustained VT with LBBB morphology, inverted T waves, and frequent ventricular extrasystoles were detected. Although characteristic epsilon waves were absent, the ECG revealed low QRS voltages in the limb leads—a finding reported as highly specific for ARVC with LV involvement,8 yet also highly sensitive (though non-specific) for cardiac amyloidosis.3 This contributed significantly to diagnostic uncertainty. CMR imaging is indispensable for ACM diagnosis, providing detailed visualization of RV and LV morphology, function, and tissue composition. RV wall motion abnormalities (regional akinesia/dyskinesia) on CMR are highly specific.9 However, this patient's CMR complicated diagnosis: (1) biventricular enlargement, (2) RV free wall ‘accordion sign’ and apical aneurysm, (3) interventricular septal thickening, and (4) LGE in the LV wall and septum—all indicative of biventricular involvement. Notably, typical fibrofatty replacement of the RV wall—a hallmark of ARVC—was absent, further challenging the diagnosis. Genetic testing identified a heterozygous pathogenic DSG2 mutation (p.F531C and p.G129D), associated with ARVC. DSG2 mutations link to LV involvement in 5–25% of cases,10 are more prevalent in Asian populations, and often present with a dilated cardiomyopathy phenotype—consistent with this patient's presentation. While identifying a pathogenic desmosomal variant is highly specific for ACM, sensitivity remains incomplete; thus, a negative test does not exclude the diagnosis. Interpretation of ACM genetic testing is complicated by limitations in understanding genetic backgrounds and significant ‘genetic noise’, increasing misdiagnosis risk. Elevated monoclonal immunoglobulin was an incidental finding that raised suspicion for cardiac amyloidosis. As is recognized, cardiac amyloidosis is a progressive infiltrative disease causing heart failure, atrial and ventricular arrhythmias, or conduction disturbances.3 Cardiac manifestations—including discordant QRS voltage relative to increased LV wall thickness, persistent low-level troponin elevation, and diffuse LGE in the LV/septal myocardium—prompted re-evaluation. Consequently, comprehensive investigations (bone marrow biopsy, serum/urine free light chain analysis, immunofixation, and 99mTc-PYP scintigraphy with SPECT) were performed. Cardiac amyloidosis was ultimately excluded, confirming WM. WM, a rare low-grade lymphoplasmacytic lymphoma, features bone marrow infiltration and elevated serum monoclonal IgM.2 To date, no direct association between WM and ACM has been established in published literature. We note, however, that arrhythmias—including VT11 and atrial fibrillation12—have been reported as potential complications of WM therapies, particularly ibrutinib (a Bruton's tyrosine kinase inhibitor). This patient, categorized as low-risk for WM, currently requires no treatment. Thus, no evidence supports an association between WM and cardiac arrhythmias in this context. This report highlights that ACM may present with biventricular features mimicking cardiac amyloidosis. Low limb-lead QRS voltage is non-specific and necessitates context-dependent interpretation. Systematic integration of imaging, genetic, and haematological data is essential to resolve diagnostic uncertainty. The authors reported no relevant disclosures. This work was supported by a grant from the Shandong Provincial Natural Science Foundation (ZR2021MH361) and the National Natural Science Foundation of China (No. 82070453). Video S1. Transthoracic echocardiography showing a localized aneurysm at the right ventricular (RV) apex, thinning of the RV wall, and increased trabecular echoes. Video S2 Two-year follow-up transthoracic echocardiography demonstrating a similar right ventricular morphology compared to baseline. Video S3. Two-year follow-up transthoracic echocardiography revealing improved left ventricular function, now within normal limits. Please note: The publisher is not responsible for the content or functionality of any supporting information supplied by the authors. Any queries (other than missing content) should be directed to the corresponding author for the article.