Late Anthracycline Cardiotoxicity Mimicking Arrhythmogenic Cardiomyopathy in a Young Adult

Abstract

Background

Doxorubicin-induced cardiotoxicity can manifest years after exposure and may mimic other cardiomyopathies in young patients, making the diagnosis of delayed doxorubicin cardiotoxicity challenging in these patients.

Case Summary

A 26-year-old physically active man with childhood Burkitt’s lymphoma treated with doxorubicin (120 mg/m² cumulative) presented with exertional chest discomfort and palpitations. Resting electrocardiogram and ambulatory monitoring were unremarkable. Transthoracic echocardiography demonstrated preserved ejection fraction (55%-60%) but reduced global longitudinal strain (−15%). Cardiac magnetic resonance revealed low-normal biventricular function with nonischemic septal late gadolinium enhancement and reduced strain. Exercise stress testing demonstrated impaired contractile reserve, septal mechanical dyssynchrony, and exercise-induced QRS prolongation. Coronary computed tomography angiography excluded coronary artery disease.

Discussion

This case highlights that anthracycline cardiotoxicity may present late, mimic myocardial ischemia, arrhythmogenic cardiomyopathy, and other cardiomyopathies.

Take-Home Message

A high index of suspicion is required for late cardiotoxicity in young cancer survivors.

Visual Summary

History of Presentation

A 26-year-old physically active man working as a gym instructor presented with several months of exertional chest discomfort and intermittent palpitations. Symptoms occurred during moderate- to high-intensity exercise and resolved with rest. He denied syncope, orthopnea, paroxysmal nocturnal dyspnea, or peripheral edema.

Vital signs were within normal limits. Physical examination was unremarkable, with a normal heart rate and rhythm, no murmurs or signs of heart failure.

Past Medical History

The patient was diagnosed at age 5 with stage III group B Burkitt’s lymphoma involving the chest wall and pleura, initially presenting with dyspnea due to a large malignant pleural effusion. Baseline echocardiography demonstrated hyperdynamic left ventricular function (ejection fraction 81%, fractional shortening 43%) and a small pericardial effusion.

He was treated successfully with protocol 5,961 and rituximab, including anthracycline-based chemotherapy (doxorubicin) with a cumulative dose of 120 mg/m². He remained in remission without recurrence.

The patient has no personal or family history of heart disease.

Differential Diagnosis

The differential diagnosis included:

• 1.Arrhythmogenic right ventricle (RV) cardiomyopathy given RV dilation, late gadolinium enhancement (LGE) on cardiac magnetic resonance (CMR), and exercise-induced conduction abnormalities
• 2.Ischemic heart disease or anomalous aortic origin of a coronary artery, suggested by abnormal stress perfusion findings
• 3.Late anthracycline cardiotoxicity, given prior chemotherapy exposure

Investigations

Resting electrocardiogram demonstrated normal sinus rhythm without repolarization abnormalities. Ambulatory monitoring was performed for 14 days total, revealing rare (<1% of total beats) isolated premature atrial and ventricular complexes without sustained arrhythmias. Patient-triggered symptomatic episodes corresponded to sinus rhythm or isolated premature atrial complexes. Laboratory tests showed normal high-sensitivity troponin and normal N-terminal pro–B-type natriuretic peptide.

Transthoracic echocardiography demonstrated preserved left ventricular ejection fraction (LVEF) of 55%-60%, with reduced global longitudinal strain (−15%, measured using the Philips EPIQ software (Philips HealthCare), Figure 1). Strain imaging was not available from the patient’s baseline childhood study, precluding comparison with pretreatment GLS.

Figure 1.

Transthoracic Echocardiogram With Longitudinal Strain Analysis Showing an Abnormal Global Strain of −15%

CMR imaging showed normal left ventricular volumes with low-normal systolic function (LVEF 56%) and low-normal RV function of 49%. Nonischemic midmyocardial LGE was present in the basal to midinterventricular septum, with additional enhancement at RV insertion sites (Figure 2). There was evidence of hypokinesis of the basal RV-free wall (Video 1). Global longitudinal strain was reduced (−15%, utilizing the Proprietary Software; Circle Cardiovascular Imaging Inc), while extracellular volume fraction was normal (20%). These findings met minor criteria for arrhythmogenic cardiomyopathy.¹

Figure 2.

Cardiac Magnetic Resonance Showing Linear, Nonischemic, Midmyocardial Delayed Enhancement Involving the Basal to Mid Interventricular Septum With Nonischemic Delayed Enhancement of the Inferior Right Ventricular Insertion Site (Red Arrows)

Because the patient reported both exertional chest discomfort and palpitations, exercise nuclear perfusion imaging was selected to reproduce symptoms while simultaneously evaluating exercise capacity, electrocardiographic response, ventricular function, and inducible ischemia. Exercise nuclear stress testing demonstrated a small reversible anteroseptal perfusion defect without infarction, likely representing a false-positive finding (with the patient achieving a peak heart rate of 182 beats/min during exercise corresponding to 93% of his age-predicted maximum heart rate) (Figure 3). There was no systolic augmentation with stress (with an LVEF of 55%), with evidence of septal mechanical dyssynchrony. QRS duration increased at peak exercise, particularly in leads V₁-V₃, corresponding to mechanical dyssynchrony (Figure 4). There was no exercise-inducible ventricular arrhythmia. Functional capacity was preserved, with the patient completing 12 minutes of exercise on the Bruce protocol, which corresponded to the exertional activity performed by the patient on a daily basis.

Visual Summary.

Late Anthracycline Cardiotoxicity Mimicking Arrhythmogenic Cardiomyopathy in a Young Adult

ARVC = arrhythmogenic right ventricular cardiomyopathy; CMR = cardiac magnetic resonance; CT = computed tomography; DMD = Duchenne muscular dystrophy; ECG = electrocardiogram; ECV = extracellular volume; EF = ejection fraction; FS = fractional shortnening; GLS = global longitudinal strain; LGE = late gadolinium enhancement; LVEF = left ventricular ejection fraction; MRI = magnetic resonance imaging; PAC = premature atrial complex; PVC = premature ventricular complexes; RV = right ventricle; RVEF = right ventricle ejection fraction; VT = ventricular tachycardia.

Figure 3.

Abnormal Myocardial Perfusion Study With a Small Region of Mild Ischemia in the Base Anterior/Anteroseptal Region

Figure 4.

Rest and Peak Exercise Electrocardiograms

12-lead electrocardiograms at baseline (A) and peak exercise (B) demonstrating exercise-associated QRS prolongation, predominantly in leads V₁ through V₃.

Coronary computed tomography angiography demonstrated normal coronary anatomy without obstructive disease.

Genetic testing revealed a variant of uncertain significance in the DMD gene, not consistent with the observed phenotype.

Management

The patient was initiated on low-dose lisinopril for early myocardial dysfunction and ventricular remodeling. Beta-blocker therapy was deferred given preserved functional capacity, minimal arrhythmia burden, and concern for exercise limitation. Other components of contemporary heart failure therapy were not initiated because he did not have symptomatic heart failure or unequivocally reduced LVEF, and evidence supporting their use for an isolated imaging-defined late cardiotoxic phenotype remains limited.

Outcome and Follow-Up

At short-term follow-up, the patient remained clinically stable with persistent high functional capacity. A strategy of longitudinal surveillance with serial echocardiography including strain imaging and clinical monitoring was adopted. A repeat CMR in 1 year was recommended to assess for LGE progression.

Discussion

This case highlights a nonclassical presentation of anthracycline cardiotoxicity characterized by significant abnormalities on advanced imaging and stress testing. Importantly, it reinforces that anthracycline-related myocardial injury may manifest years to decades after exposure, even at relatively low cumulative doses, and may present with a phenotype that mimics other cardiomyopathies.^2,3

The Children’s Oncology Group Long-Term Follow-Up Guidelines provide exposure-based recommendations for cardiovascular surveillance among survivors of childhood, adolescent, and young adult cancers.⁴ Anthracycline dose, chest-directed radiation exposure, age at treatment, and associated cardiovascular risk factors inform the recommended frequency of cardiac surveillance. These recommendations principally address routine screening of asymptomatic survivors. New exertional chest discomfort, palpitations, dyspnea, exercise intolerance, or other potentially cardiovascular symptoms should prompt a symptom-directed evaluation regardless of the scheduled surveillance interval. This distinction was particularly relevant in our patient, whose relatively low cumulative anthracycline exposure and preserved LVEF could otherwise have reduced the perceived likelihood of clinically meaningful late treatment-related myocardial injury.

In this patient, reduced global longitudinal strain and nonischemic LGE indicate subclinical myocardial dysfunction and fibrosis despite preserved ejection fraction. The absence of systolic augmentation during exercise further supports impaired contractile reserve, an early marker of myocardial dysfunction that is not captured by resting measurements alone.⁵

The presence of RV dilation, LGE, and RV wall motion abnormalities seen on CMR raised concern for arrhythmogenic cardiomyopathy.¹ However, the pattern of myocardial fibrosis, absence of sustained ventricular arrhythmias, negative genetic testing and family history, and prior anthracycline exposure supported chemotherapy-related cardiotoxicity.⁶ This overlap highlights a critical diagnostic pitfall, particularly in young, highly functional individuals, where cardiotoxicity may masquerade as primary genetic cardiomyopathy. It is important to note that the significance of focal LGE in anthracycline-exposed survivors remains incompletely defined. LGE is absent in many patients with established anthracycline-related dysfunction, and reported enhancement patterns are heterogeneous. Furthermore, there are currently insufficient longitudinal data to support using the presence or progression of LGE alone to guide therapeutic decisions or surveillance strategies.^7,8

Notably, this case occurred at a cumulative anthracycline dose of 120 mg/m², underscoring that cardiotoxicity is not strictly dose-dependent and may occur below traditionally recognized thresholds.⁷ This observation aligns with emerging data suggesting that individual susceptibility can contribute significantly to cardiotoxic risk.^7,9

From a clinical standpoint, this case emphasizes the importance of symptom-guided multimodality evaluation in cancer survivors with suspected late cardiotoxicity. While individual diagnostic studies may appear nondiagnostic or only mildly abnormal in isolation, each modality provided complementary and clinically meaningful information in this patient. Echocardiography with strain imaging identified early myocardial dysfunction despite preserved ejection fraction, CMR characterized myocardial fibrosis and wall motion abnormalities, and exercise stress testing revealed impaired contractile reserve with exercise-induced electrical and mechanical abnormalities. Together, these findings supported the diagnosis of late anthracycline cardiotoxicity after exclusion of competing etiologies.

Most importantly, this case highlights the need for a high index of suspicion for anthracycline cardiotoxicity in young adults presenting with unexplained cardiac symptoms, even decades after treatment. Imaging findings such as reduced strain, focal LGE, or wall motion abnormalities are not specific to anthracycline cardiotoxicity and should not be interpreted in isolation. Rather, the diagnosis should be based on an integrated assessment of treatment exposure, clinical presentation, multimodality imaging, and systematic exclusion of alternative causes.

Conclusions

Anthracycline cardiotoxicity can manifest long after exposure and may mimic other cardiomyopathies, particularly in young adults. Recognition requires multimodality assessment and a sustained clinical index of suspicion.

Funding Support and Author Disclosures

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

Take-Home Messages

• •Anthracycline cardiotoxicity may occur years after exposure and can mimic other cardiomyopathies, even at low cumulative doses.
• •A high index of suspicion and multimodality imaging are essential for diagnosis in young cancer survivors presenting with cardiovascular symptoms.

Appendix

Video 1

Cardiac Magnetic Resonance Showing Hypokinesis of the Basal Right Ventricular Free Wall