Clinical Researcher Providence Health Care Vancouver, British Columbia, Canada
Case background: Hydroxychloroquine is commonly prescribed to treat autoimmune conditions such as rheumatoid arthritis. Although it is generally well tolerated, rare cases of hydroxychloroquine-induced cardiotoxicity have been documented. Hydroxychloroquine-induced cardiomyopathy can resemble infiltrative cardiomyopathies, such as amyloidosis, with overlapping symptoms including conduction abnormalities and ventricular dysfunction. Delayed or missed diagnoses are common due to the nonspecific nature of the symptoms and imaging findings.
A 72-year-old female with a complex medical history, including breast cancer treated with chemotherapy and radiation, renal cell carcinoma treated with nephrectomy, and rheumatoid arthritis treated with hydroxychloroquine, presented with presyncope and was found to have episodes of complete heart block with pauses of up to 15 seconds. Echocardiography demonstrated a left ventricular ejection fraction (LVEF) of 40%, with regional wall motion abnormalities and concentric remodeling. Coronary angiography demonstrated multivessel disease not amenable to revascularization, which was treated medically. She underwent implantation of a biventricular pacemaker. She then began to experience episodes of atypical chest pain, refractory to antianginal therapy. She had multiple ER visits and was noted to have a persistently elevated troponin level, that did not change with chest pain presentations. After a MIBI scan demonstrated anterior wall ischemia, she underwent repeat angiography and was referred for coronary artery bypass surgery, undergoing a four-vessel bypass procedure seven months after her initial presentation. Post-operatively, her echocardiogram showed a small LV with concentric remodeling and an LVEF of 40%. She was referred to the Heart Function Clinic for medication optimization. Her progressive conduction abnormalities and LV dysfunction raised suspicion for underlying amyloidosis. She underwent an amyloidosis workup, including a 99mTc-Pyrophosphate (PYP) scintigraphy, which demonstrated grade 2–3 myocardial uptake, suggestive of transthyretin cardiac amyloidosis. A cardiac MRI showed normal LV size and mild-to-moderately impaired global systolic function, normal segmental wall thickness, normal gadolinium tissue kinetics, a small focus of near-transmural late gadolinium enhancement at the inferior apical segment consistent with prior infarction, and additional enhancement in the adjacent posterior papillary muscle. She had no evidence of monoclonal bands on serum or urine protein electrophoresis, confirmed by immunofixation, or on serum free light chain assay, and light chain amyloidosis (AL) was ruled out. Due to her chronic history of rheumatoid arthritis and hydroxychloroquine use, a right ventricular endomyocardial biopsy was ordered to confirm the presence of amyloid deposition and to rule out hydroxychloroquine-induced cardiomyopathy. The biopsy demonstrated prominent vacuolization of cardiomyocytes in a patchy distribution, intracellular PAS-positive and diastase-resistant granular material within cardiomyocytes, and variable mild cardiomyocyte hypertrophy and patchy mild interstitial fibrosis. No amyloid deposits were identified on Congo red, SAB, or Masson trichrome stains. Electron microscopy revealed abundant myelin figures/zebra bodies within cardiomyocytes, consistent with hydroxychloroquine cardiotoxicity. Hydroxychloroquine was discontinued in August 2024 and replaced by sulfasalazine for her rheumatoid arthritis. Since discontinuing hydroxychloroquine, her symptoms and exercise tolerance have improved considerably. A repeat echocardiogram in January 2025 demonstrated normalization of LV systolic function, with an LVEF of 60%.
Management Challenges: Hydroxychloroquine cardiotoxicity is a rare cause of non-ischemic cardiomyopathy, typically presenting with chest pain, elevated cardiac biomarkers, conduction system disease, ventricular arrhythmias, and biventricular dysfunction. It is often cited as one of the few causes of false-positive results on bone scintigraphy ordered to evaluate transthyretin amyloid cardiomyopathy (ATTR-CM), although, to our knowledge, only three prior case reports exist in the literature. The diagnosis can be confirmed by biopsy, with pathognomonic zebra bodies seen on electron microscopy, although it is most often made as a diagnosis of exclusion without tissue confirmation. Treatment involves withdrawal of hydroxychloroquine therapy and the initiation of guideline-directed medical therapy for left ventricular dysfunction. In the context of the increasing use of nuclear scintigraphy for diagnosing ATTR-CM, this case is particularly timely and reinforces the importance of medication history and the need for awareness of drug-induced cardiotoxicity in the differential diagnosis of nonischemic cardiomyopathy. Given its widespread use, a higher level of suspicion for hydroxychloroquine-cardiotoxicity is warranted in autoimmune disease patients presenting with unexplained cardiomyopathy. Furthermore, this case highlights an important limitation of nuclear scintigraphy in diagnosing ATTR-CM, as false-positive results can occur. A comprehensive evaluation, including additional investigations, is essential to achieve an accurate diagnosis in cases where alternative conditions, such as hydroxychloroquine toxicity or the more common AL amyloidosis, are possible.
