Long-term hydroxychloroquine use resulting in cardiomyopathy and conduction abnormalities: a case report

Abstract

Background

Diagnosing the cause of undifferentiated left ventricular hypertrophy (LVH) in a patient with progressive heart failure symptoms can present a diagnostic challenge, with potential for both inherited and acquired aetiologies. Hydroxychloroquine-induced cardiomyopathy (HCQ-CM) is a rare complication of long-term hydroxychloroquine use. This case report highlights its clinical presentation, key differential diagnoses, and treatment strategies.

Case summary

A 56-year-old female with a longstanding history of systemic lupus erythematosus presented with progressive dyspnoea, fatigue, and fluid overload. Initial investigation revealed LVH with restrictive physiology, elevated cardiac biomarkers, and non-specific findings on echocardiography suggestive of an infiltrative cardiomyopathy. The diagnosis remained uncertain until an endomyocardial biopsy (EMB) confirmed HCQ-CM, characterized by the presence of curvilinear inclusion bodies. Following cessation of HCQ, there was a significant clinical improvement, with the patient achieving NYHA class I status at 6 months follow-up.

Conclusion

This case highlights the critical importance of considering HCQ-CM, in the differential diagnosis of unexplained heart failure and LVH in patients on long-term HCQ therapy. A multi-parametric diagnostic approach—including EMB and genetic testing where appropriate—is essential to identify potentially reversible causes of cardiomyopathy and enable timely therapeutic adjustments.

Learning points.

• Understand the potential cardiotoxicity of chronic hydroxychloroquine use.

• Recognize the role of endomyocardial biopsy in establishing the cause of undifferentiated left ventricular hypertrophy.

• Recognize the phenocopy effect between hydroxychloroquine-induced cardiomyopathy and other infiltrative cardiomyopathies, in particular Fabry disease.

Introduction

Hydroxychloroquine (HCQ) is widely used in the management of various autoimmune diseases including systemic lupus erythematosus (SLE) and is generally regarded as safe with a well-established therapeutic profile. However, its long-term use has been sporadically linked to cardiotoxic effects, notably HCQ-induced cardiomyopathy (HCQ-CM), which can mimic other infiltrative cardiomyopathies.¹ In this report, we present a 56-year-old female with a longstanding history of SLE, who developed severe biventricular failure with restrictive physiology and echocardiographic appearances highly suggestive of an infiltrative cardiomyopathy. An endomyocardial biopsy (EMB) confirmed the diagnosis of HCQ-CM, and cessation of HCQ led to significant clinical improvement. This case emphasizes the critical importance of considering drug-induced cardiotoxicity, particularly HCQ-CM, in patients presenting with unexplained heart failure and left ventricular hypertrophy (LVH). Furthermore, this case underscores the necessity for a multimodal diagnostic approach—including EMB and genetic testing where appropriate—to identify potentially reversible causes of cardiomyopathy and enable timely therapeutic adjustments.

Summary figure

Timeline of critical patient events.

Case presentation

A 56-year-old female presented with a 6-month history of progressive dyspnoea on exertion, fatigue, lower limb oedema, abdominal swelling, and weight gain of 5 kg. On physical examination, blood pressure was 122/80 mmHg, heart rate 42 b.p.m., oxygen saturations 97% on room air, and respiratory rate 18 breaths per minute. The jugular venous pressure was elevated at the angle of the mandible, there was pitting oedema to the knees bilaterally, and ascites was present.

The patient was diagnosed with SLE at the age of 28 following a presentation with joint pain, facial rash, and alopecia. Her symptoms resolved with HCQ 400 mg daily which she continued thereafter (estimated cumulative HCQ dose on presentation ∼4000 g—see Summary figure). Advanced membranous lupus nephritis (class V) was diagnosed age 42, and ciclosporin 50 mg bd was added to her medical therapy. Hypertension was diagnosed in her third pregnancy and was difficult to control in recent years, requiring six anti-hypertensive agents at the time of this current presentation.

Electrocardiography demonstrated sinus bradycardia with atrial ectopy and paroxysms of atrial tachycardia, an interventricular conduction delay and low voltage QRS complexes in the inferior and precordial leads (Figure 1A). Transthoracic echocardiography demonstrated normal biventricular cavity size, preserved ejection fraction, and symmetrical LVH (intraventricular septum measuring 1.5 cm and the posterior wall measuring 1.6 cm) with a ground glass appearance of the myocardium (Figure 2A and B). There was severe bi-atrial dilatation, Doppler features of restrictive physiology, and global longitudinal strain was reduced (−12.0%). A complete metabolic panel revealed acute on chronic kidney injury (creatinine 314 µmol/L; baseline creatinine of 130 µmol/L, reference range 45–90 µmol/L). Plasma N-terminal pro-B-type natriuretic peptide (NT-proBNP) was markedly elevated at 48 700 pg/mL (normal range: <300 pg/mL) and high sensitivity troponin was 1110 ng/L (Abbott; normal <16 ng/L). Antinuclear antibody was 30 IU/mL (reference <7 IU/mL) with a homogenous antibody pattern. Markers of SLE disease activity including double stranded DNA antibody titre, C3/C4, antineutrophil cytoplasmic antibody and erythrocyte sedimentation rate were all within normal range. Serum free kappa: lambda ratio was 1.0, and no paraprotein was detected by serum electrophoresis. Alpha-galactosidase A activity was normal. A contrast cardiac magnetic resonance (CMR) could not be performed due to acute renal impairment; however, a CMR conducted 18 months prior, to further investigate LVH seen on echocardiography, did not identify any late enhancement or any other signs of infiltration. Bone scintigraphy (radiopharmaceutical: 99mTc HDP—928 MBq) did not reveal any features indicative of cardiac amyloidosis. An EMB was undertaken given the clinical suspicion for an infiltrative cardiomyopathy. Light microscopy revealed myocyte disarray, variable myocyte thickness, and mild interstitial fibrosis (Figure 3A and B). Some of the myocytes had perinuclear cytoplasmic vacuoles which a Periodic Acid-Schiff stain confirmed were filled with glycogen. A Congo red stain and amyloid P immunohistochemistry were negative. Electron microscopy revealed mildly enlarged myocytes with disrupted myofibrils due to the presence of concentric lamellar structures (myeloid figures) within large lysosomes. Occasional curvilinear bodies and small numbers of myeloid structures within the endothelial cells were also seen. There was no amyloid deposition or electron dense deposits to suggest an immune-mediated injury (Figure 3C and D). Genetic testing for GLA variants was conducted to definitively exclude Fabry disease (FD). A variant combination of unknown significance was identified which was deemed unlikely to be a disease-causing variant. Lyso-ceramide trihexoside levels were found to be within normal limits.

Figure 1.

Electrocardiography demonstrated sinus bradycardia with atrial ectopy, interventricular conduction delay, and low voltage QRS complexes in the inferior and precordial leads (A), paroxysms of atrial tachycardia (B), sinus pause of 4.7 s (C), and non-sustained ventricular tachycardia (D).

Figure 2.

2D echocardiography demonstrates normal biventricular cavity size and symmetrical left ventricular hypertrophy (intraventricular septum measuring 1.5 cm and the posterior wall measuring 1.6 cm) (A). The myocardium has a ground glass appearance (B).

Figure 3.

Light microscopy (A and B) of the endomyocardial biopsy revealed myocyte disarray, variable myocyte thickness, mild interstitial fibrosis, and perinuclear vacuolated cytoplasm which contained glycogen vacuoles on Periodic Acid-Schiff stain. Electron microscopy (C and D) revealed mildly enlarged myocytes with disrupted myofibrils due to variably sized myeloid figures (red arrows) within large lysosomes. Curvilinear bodies (yellow arrows) were present. There was no amyloid deposition and no evidence of immune-mediated injury.

Intravenous diuresis resulted in a favourable clinical response. Beta-blocker therapy was ceased, and all anti-hypertensive agents were discontinued. A diagnosis of HCQ-mediated cardiomyopathy was made, and HCQ was discontinued prior to hospital discharge.

At 6 months of follow-up, the patient remained engaged in a cardiac rehabilitation programme and had achieved NYHA class I status. She was performing 40 min of combined aerobic and weight training exercises during supervised sessions and was able to complete a similar duration of exercise 2–3 times per week at home as part of a structured programme. Renal biochemistry returned to baseline with NT-proBNP levels decreasing significantly to 5730 pg/mL (normal range: <300 pg/mL) and a continued downtrend in troponin was also observed (Figure 4). The patient’s SLE remained quiescent despite HCQ withdrawal.

Figure 4.

Downtrending cardiac biomarkers over a 6-month period following cessation of hydroxychloroquine.

Shortly after her 6-month clinical review, our patient presented with symptomatic sinus node dysfunction, paroxysmal atrial tachycardia, and non-sustained ventricular tachycardia (Figure 1B–D). Electrophysiology studies were performed, revealing the presence of a left atrial tachycardia. A dual chamber permanent pacemaker was implanted, and pharmacological management was initiated for the management of atrial tachycardia.

Discussion

Recently published guidelines recommend using a phenotype-based approach to the diagnosis and evaluation of cardiomyopathies.² Imaging findings are often non-specific in relation to the aetiology of LVH however, and genetic testing and EMB can be instrumental in confirming clinically suspected diagnoses and aiding prognostication in some cases.^2–5

Hypertension is a frequent comorbidity in SLE, driven by multifactorial mechanisms including chronic systemic inflammation, renal involvement (especially lupus nephritis), and endothelial dysfunction.⁶ Long-term use of HCQ in SLE has been associated with improved endothelial function and modest blood pressure-lowering effects, likely mediated by its immunomodulatory and lipid-lowering properties.⁷ However, despite these benefits, HCQ has been linked to a spectrum of cardiac toxicities, including HCQ-CM, conduction abnormalities, QT interval prolongation, and ventricular arrhythmias.⁸ The true incidence of HCQ-CM is not known, and the risk factors remain incompletely characterized however advanced age, female gender, longer duration of therapy, higher cumulative dose/kilogram, pre-existing cardiac disease, and renal impairment are all potential contributors.^1,9

Fabry disease and HCQ-CM are clinical phenocopies, both often presenting with LVH, restrictive physiology, atrial arrhythmia, and conduction disease. Interestingly, the biopsy findings for these two conditions are also strikingly similar with cytoplasmic vacuolization often seen coupled with myelin figures on electron microscopy.¹⁰ The presence of curvilinear inclusion bodies on ultrastructural examination, although not seen in all cases, is characteristic for HCQ-CM and allows a histopathological point of differentiation between the two conditions.^9,11,12 A mechanistic explanation for the phenocopy effect between HCQ-CM and FD likely relates to the inhibitory effect of HCQ on the activity of lysosomal proteins.¹¹ Clinicians should be cautious about attributing clinical and biopsy findings exclusively to HCQ-CM without first ruling out FD, as a missed diagnosis of FD may result in lost opportunities for FD-specific therapy and family screening.

Conclusions

This case highlights the diverse aetiologies of heart failure with LVH, often coexisting with restrictive physiology. Such clinical conundrums require a comprehensive, multi-parametric approach including genetic analysis and EMB where appropriate, to avoid missing potentially reversible diagnoses. Hydroxychloroquine-induced cardiomyopathy is one such clinical rarity that may be easily overlooked, yet a precise diagnosis holds crucial implications for affected patients.

Lead author biography

Dr Timothy Ryan received his medical degree from University College Dublin and completed his cardiology training in Perth, Western Australia. He subsequently undertook fellowships in Electrophysiology and Pacing at Fiona Stanley Hospital, Perth, and Princess Alexandra Hospital, Brisbane. His areas of interest include electrophysiology, heart failure, and device therapy.

Author contributions

Timothy Ryan (Conceptualization [equal], Investigation [equal], Writing—original draft [equal], Writing—review & editing [equal]), Laura Luttrell (Writing—original draft [equal], Writing—review & editing [equal]), Amit Shah (Conceptualization [supporting], Data curation [lead], Writing—review & editing [supporting]), Kaitlyn Lam (Conceptualization [equal], Data curation [equal], Supervision [supporting], Writing—review & editing [supporting]), Peter Dias (Conceptualization [supporting], Data curation [equal], Investigation [lead], Writing—review & editing [supporting]), Aws Jasim (Investigation [equal], Writing—review & editing [supporting]), Andrew Laycock (Data curation [equal], Formal analysis [equal], Investigation [equal], Writing—review & editing [supporting]), and Vimal Patel (Conceptualization [lead], Data curation [equal], Formal analysis [lead], Investigation [equal], Writing—original draft [equal], Writing—review & editing equal])

Consent: Written informed consent was obtained from the patient for publication of this case report, in accordance with the COPE guidelines.

Funding: None declared.

Data availability

All data underlying this article are fully available within the main text and the accompanying Supplementary material. No additional source data were generated or analysed beyond those presented in this case report. Further inquiries can be directed to the corresponding author.