A case of suspected hydroxychloroquine-induced cardiomyopathy: From therapy to toxicity

Abstract

Background

Hydroxychloroquine (HCQ) is a cornerstone treatment for rheumatologic diseases. While it is generally well tolerated, chronic use has rarely been associated with cardiotoxicity. It is believed to occur due to the accumulation of HCQ in lysosomes, which impairs enzyme activity and eventually leads to myocardial fibrosis. Risk factors for HCQ-induced cardiotoxicity include older age, female sex, renal impairment, and prolonged or high cumulative exposure to HCQ.

Case presentation

A 64-year-old female patient with systemic lupus erythematosus and mixed connective tissue disease presented with acute, severe decompensated heart failure that required intubation. She had been taking HCQ (200 mg daily) for 3 years. An echocardiogram 1-year prior showed HFrEF (EF 35% to 40%). Initial workup included a cardiac MRI, which revealed a severely dilated and hypertrophied left ventricle (LVEF 19%). An endomyocardial biopsy confirmed HCQ-induced toxicity, revealing characteristic myeloid bodies. Following discontinuation of HCQ, guideline-directed medical therapy for HFrEF was started. Over the following 9 months, she showed progressive recovery, with LVEF improving from 19% to 50% and NYHA functional class improving from III to II.

Discussion

Hydroxychloroquine (HCQ)-induced cardiomyopathy is often under-recognized, especially in patients with moderate treatment durations, as its presentation can mimic other causes of heart failure. Early recognition is essential, as prompt discontinuation of HCQ may allow for meaningful recovery of cardiac function.

Hydroxychloroquine (HCQ) has been commonly prescribed for autoimmune disease since the 1950s and has generally been well tolerated; however, rare but severe cardiac toxicity has become increasingly relevant. Hydroxychloroquine is a hydroxylated derivative of chloroquine with antimalarial and immunomodulatory properties.¹ It is widely used in rheumatologic conditions such as Systemic Lupus Erythematosus (SLE), rheumatoid arthritis, and mixed connective tissue disease.² Despite its favorable safety profile,² HCQ's recognized adverse effects include retinal toxicity, neuromyopathy, and gastrointestinal disturbance. Less common is cardiac toxicity, which manifests as cardiomyopathy and conduction abnormalities.¹

The pathophysiology of HCQ-induced cardiomyopathy begins with the lysosomotropic accumulation of the weak base within cardiomyocyte lysosomes.³ This accumulation elevates the intralysosomal pH,⁴ which subsequently impairs the function of lysosomal enzymes (e.g., phospholipases and acid hydrolases).⁵ The resulting cascade includes impaired autophagy, resulting in phospholipidosis.4, 6 Ultimately, this process leads to vacuolization, interstitial fibrosis,⁴ and hypertrophy, causing eventual systolic or diastolic dysfunction.⁶ On light microscopy, the histopathology commonly reveals vacuolated myocytes. In contrast, electron microscopy typically reveals myeloid or curvilinear bodies, a pattern analogous to that seen in lysosomal storage disorders.⁷

Clinically, HCQ-cardiotoxicity can present as conduction defects (atrioventricular (AV) block, bundle branch block), arrhythmias, left ventricular hypertrophy, dilated or restrictive cardiomyopathy, and heart failure.⁴ The diagnosis is often challenging because of overlapping features with autoimmune cardiac involvement and other infiltrative diseases (e.g., Fabry disease, amyloidosis).⁴ Early recognition is critical.³ When caught early, prompt drug cessation and heart failure therapy⁸ can reverse dysfunction.⁹ Unfortunately, advanced disease often remains irreversible.2, 7

We report a case of suspected HCQ-induced cardiomyopathy in a 64-year-old woman with SLE following 3 years of HCQ therapy confirmed by endomyocardial biopsy (EMB). The case highlights partial functional recovery achieved after prompt drug discontinuation and optimal heart failure treatment.

Case presentation

A 64-year-old Hispanic woman with nonischemic cardiomyopathy presented to our facility, transferred from an outside hospital for evaluation of acute decompensated heart failure. Her medical history was significant for a 33-year history of mixed connective tissue disease, reclassified as Systemic Lupus Erythematosus (SLE) 3 years prior, with scleroderma overlap. She was first diagnosed with acute-on-chronic combined systolic and diastolic heart failure in July 2024, after presenting with new-onset dyspnea. Echocardiography at that time demonstrated an LVEF of 35% to 40% with grade II diastolic dysfunction, and a nuclear stress test showed extracardiac tracer uptake without evidence of gross ischemia; coronary angiography was normal. Other diagnoses included hypertension, hyperlipidemia, major depressive disorder, interstitial lung disease, pulmonary embolism, and gastroesophageal reflux disease.

Her outpatient medications are summarized in Table 1 and pre-hospitalization was limited in her heart failure-specific therapies. Her immunosuppressive regimen comprised prednisone 20 mg QD (for 6 years), belimumab 10 mg/kg IV monthly, and HCQ 200 mg QD for 3 years.

Table 1.

Medication Regimen Across Clinical Time Points

Medication Class	Medications at Admission	Inpatient GDMT Initiation	Discharge Regimen
Loop diuretic	Bumetanide 1 mg QD	Bumetanide 1 mg QD	Bumetanide 0.5 mg QD
RAAS inhibition	Losartan 50 mg QD	Sacubitril/valsartan 12/13 mg BID	Sacubitril/valsartan 24/26 mg BID
β-blocker	Metoprolol succinate 50 mg AM / 25 mg PM	Metoprolol succinate 12.5 mg QD	Metoprolol succinate 25 mg QD
Mineralocorticoid receptor antagonist	Spironolactone 12.5 mg QD	Spironolactone 25 mg QD	Spironolactone 50 mg QD
SGLT2 inhibitor	Empagliflozin 10 mg QD	Empagliflozin 10 mg QD	Empagliflozin 10 mg QD
Immunosuppression	Prednisone 20 mg QD, Belimumab 10 mg/kg IV monthly, and HCQ 200 mg QD		Prednisone 20 mg QD

The patient presented to an outside hospital in critical condition, acidotic (pH 6.98) with an elevated lactate (5.7 mmol/L). She was acutely hypoxic and hypercapnic, with imaging consistent with multifocal pneumonia and pulmonary edema. She was transferred to the intensive care unit and required intubation. Infectious workup, including bronchoscopy with bronchoalveolar lavage on February 8, 2025, revealed Candida species; she was treated accordingly.

Following the transfer to our facility, exam revealed elevated jugular venous pressure and cool extremities, consistent with a low-output state. Swan-Ganz catheterization on February 9, 2025 showed CVP 5 mmHg, pulmonary artery pressure 30/17 mmHg, PCWP 17 mmHg, and a low SvO2 (31%), suggesting impaired tissue perfusion. Creatinine was 0.58 mg/dL, AST 28 U/L, and ALT 17 U/L. A 12-lead electrocardiogram on February 9, 2025 showed normal sinus rhythm at 66 bpm, with a mildly prolonged corrected QT interval (QTc 459 ms) shown in Figure 1. and nonspecific T-wave abnormalities that had improved compared to a prior study; no high-grade conduction block or arrhythmia was noted. Dobutamine was initiated for hemodynamic support and later discontinued upon improvement, allowing for successful extubation.

Figure 1.

12-lead electrocardiogram showed normal sinus rhythm at 66 bpm, with a mildly prolonged corrected QT interval (QTc 459 ms) and nonspecific T-wave abnormalities. No high-grade conduction block or arrhythmia was noted.

Guideline-directed medical therapy (GDMT) for HFrEF was initiated, also shown in Table 1. Cardiac MRI on February 14, 2025 demonstrated a dilated, hypertrophied left ventricle with depressed global function (LVEF 34%) shown in Figure 2, global hypokinesis with focal anterior wall akinesis, and no late gadolinium enhancement to suggest infarct, scar, or infiltrative process, supporting a nonischemic etiology. Moderate mitral regurgitation was present.

Figure 2.

Cardiac MRI demonstrating a dilated, hypertrophied left ventricle with depressed global function. (A) Short-axis cine image with endocardial (red) and epicardial (green) contours used for volumetric assessment. (B) Four-chamber cine image demonstrating left ventricular dilation.

Given the patient's 3-year history of HCQ use and unexplained worsening nonischemic cardiomyopathy, an endomyocardial biopsy (EMB) was performed on February 17, 2025, at which time echocardiography showed an LVEF 19%. This demonstrated myocyte hypertrophy and interstitial fibrosis with the presence of scattered myeloid bodies and curvilinear figures indicative of chronic changes associated with exposure to hydroxychloroquine, shown in Figure 3, Figure 4. In addition, Congo red stain does not show features of amyloidosis, as shown in Figure 5. Hydroxychloroquine (HCQ) was immediately discontinued.

Figure 3.

Nonspecific myocardial changes characterized by moderate myocyte hypertrophy and patchy, moderate interstitial fibrosis (yellow star). (H&E, 40×).

Figure 4.

Ultrastructural evaluation of endomyocardial biopsy. Panel A (Transmission electron microscopy, ×13,000) demonstrates numerous intracytoplasmic myeloid bodies within cardiomyocytes, reflecting lysosomal accumulation and impaired autophagy (yellow arrows). Panel B (transmission electron microscopy, ×25,000) showing a lamellated curvilinear body within a cardiomyocyte (yellow arrow), a characteristic finding of hydroxychloroquine-induced cardiotoxicity.

Figure 5.

Congo red stain evaluation of endomyocardial biopsy showing no signs of amyloidosis. (Congo red, 40×).

At discharge, her diagnoses included dilated cardiomyopathy, pneumonia, SLE, and severe protein-calorie malnutrition. Discharge medications included the GDMT for heart failure and prednisone, under continued monitoring.

On serial outpatient echocardiography, LVEF improved to 25% by March 26, 2025, 32% by June 2, 2025, and 50% by September 19, 2025. The 4-month follow-up also showed the LV size had reduced to “moderately enlarged.”

Right heart catheterization performed at 3 months showed normal filling pressures (RA 4-5 mmHg; PCWP 9 mmHg) and a normal mean pulmonary artery pressure (18-21 mmHg). Pulmonary vascular resistance was normal (2.1 WU). However, cardiac output was low-normal (4.2 L/min, CI-2.5 L/min/m²), and systemic vascular resistance was elevated (1943).

Discussion

This case presents a biopsy-confirmed HCQ-induced cardiomyopathy occurring after a relatively short duration of therapy, in the setting of pre-existing heart failure. It highlights that although cardiotoxic effects of HCQ are considered rare,⁸ growing evidence suggests it may be under-recognized.⁹ Emphasizing the need for greater recognition of this entity, particularly in patients with rheumatologic disease regardless of therapy duration.1, 3, 5

Hydroxychloroquine-induced cardiotoxicity stems from the drug's lysosomotropic properties, leading to impaired enzyme function, phospholipidosis, and subsequent myocyte vacuolization and interstitial fibrosis.⁴ Electron microscopy classically confirms this mechanism, revealing hallmark findings such as myeloid bodies and curvilinear bodies.⁴ Several risk factors for HCQ cardiomyopathy have been described, including female sex, older age, renal dysfunction, high cumulative dose, and prolonged duration of therapy, with most cases reporting exposure exceeding a decade.⁶ A systematic review of 79 biopsy-confirmed cases of HCQ cardiomyopathy found that 76% of patients were female, with a median age of 56 years.¹⁰ A meta-analysis showed that the average duration of HCQ therapy causing cardiotoxicity was greater than 10 years.¹¹ In contrast to the typically reported timeline, our patient developed advanced cardiomyopathy after only 3 years of HCQ therapy.² We propose that her pre-existing HFrEF significantly increased myocardial vulnerability, lowering the threshold for toxic injury. This observation underscores the limitation of duration-based risk assessment alone and suggests that patients with baseline cardiac disease may represent a particularly susceptible subgroup.²

Diagnosis is challenging.⁵ The clinical presentation may mimic other forms of cardiomyopathy, including autoimmune myocarditis in SLE, viral myocarditis, infiltrative disease such as amyloidosis or Fabry disease, or hypertensive/ischemic cardiomyopathy.⁵ Therefore, the use of multimodal imaging (echocardiography and cardiac MRI) alongside EMB is critical.⁶ For instance, magnetic resonance imaging may demonstrate nonischemic late gadolinium enhancement, LV hypertrophy or dilation, and features that resemble storage disorders.6, 12 In our case, the MRI demonstrated a dilated LV and depressed EF without a perfusion defect. Subsequent EMB confirmed the presence of myeloid inclusions and glycogen accumulation. The diagnosis was strongly supported by the myeloid bodies seen on tissue biopsy. Specifically, ischemia was excluded by normal angiography, and other etiologies were deemed unlikely based on normal coronary anatomy and the lack of indication for viral or genetic testing. This process confirmed HCQ-cardiomyopathy as the most probable cause.

Management is centered on prompt HCQ discontinuation, optimization of heart failure therapy, and close monitoring.⁵ Literature indicates that early recognition and drug cessation may allow for partial or complete recovery, whereas late diagnosis is often associated with progressive disease, transplantation, or death.⁴

In our patient, HCQ discontinuation and initiation of guideline-directed medical therapy were associated with progressive improvement in LVEF, from 19% at the time of biopsy to 50% at 9-month follow-up, with parallel reduction in LV chamber size and global hypokinesis. This recovery was accompanied by clinical improvement in functional status, with NYHA class improving from III during hospitalization to II at follow-up. This sustained, progressive trajectory, rather than an isolated measurement, supports genuine myocardial recovery following HCQ cessation. Although the function remains suboptimal, this finding suggests early remodeling, yet the long-term outlook is uncertain. Had cardiac function failed to improve despite HCQ discontinuation, our approach would have been to pursue further evaluation for advanced heart failure therapies, including consideration of mechanical circulatory support devices or heart transplantation, consistent with our protocol for escalating therapies in patients with advanced heart failure.

While some patients experience a partial reversal of cardiac dysfunction upon drug cessation, others suffer progressive, irreversible myocardial damage. For instance, a recent pediatric case of hydroxychloroquine cardiotoxicity rapidly progressed to end-stage heart failure, highlighting that clinical recovery is not universal and advanced heart failure therapies may ultimately be required.¹³

Ultimately, our patient's presentation underscores the critical importance of restricting HCQ therapy strictly to validated, standard indications such as systemic lupus erythematosus (SLE). While HCQ remains a cornerstone of rheumatologic management, its potential for severe cardiotoxicity must be weighed carefully, particularly when off-label or non-standard utilization is considered. The widespread, unverified deployment of HCQ during the early phases of the COVID-19 pandemic serves as a stark reminder of the dangers associated with using this agent outside of established clinical guidelines without rigorous cardiac oversight.

Due to the rarity of this condition, we recognize the lack of institutionalized surveillance protocols. Which is why, based on our institutional experience, we propose the following recommendations: a baseline echocardiogram prior to initiation of HCQ, with consideration of periodic echocardiographic surveillance in patients who have received therapy for greater than 2 years. For those patients, an annual echocardiogram to assess for changes in ventricular wall thickness and systolic function. Prospective validation of this or similar recommendations in larger cohorts is needed to establish evidence-based surveillance guidelines.

Conclusion

Despite chronic HCQ therapy being considered relatively safe, it can precipitate or exacerbate cardiomyopathy, particularly in patients with pre-existing cardiac dysfunction. Early recognition, exclusion of alternative causes, and EMB confirmation are essential. Clinicians managing rheumatologic patients must carefully weigh the benefits of HCQ against its potential cardiotoxicity. Implementing appropriate cardiac monitoring protocols, especially for at-risk populations, can alter a patient’s outcomes.

Disclosures

This work received no financial support. The authors declare no conflicts of interest.

Patient Consent

Informed consent for publication was obtained from the patient.