Clinical and experimental insights into hydroxychloroquine-associated electrical abnormalities and cardiomyopathy

AIMS: Hydroxychloroquine (HCQ) is commonly prescribed for malaria and autoimmune diseases, yet its potential for cardiotoxicity remains under-recognized. The objective of this study was to investigate the clinical and experimental features of HCQ-associated cardiotoxicity. METHODS AND RESULTS: We retrospectively analysed 261 HCQ-treated patients, assessing cardiac adverse events and electrocardiographic intervals. Endomyocardial biopsy specimens were examined via transmission electron microscopy. To explore potential pathophysiological correlates, human-induced pluripotent stem cell-derived cardiomyocytes (hiPSC-CMs) were exposed to HCQ, and electrophysiological, ultrastructural, contractile and autophagy-related responses were evaluated. Hydroxychloroquine was discontinued in 14 patients, including 3 patients with clinically significant cardiotoxicity manifesting as heart failure or an isolated conduction abnormality (1.1% of the cohort). QTc intervals increased from a median of 413 ms [interquartile range (IQR), 399-426 ms] pre-treatment to 421 ms (IQR, 407-440 ms) on-treatment (P = 0.003), indicating a modest but statistically significant change. PR interval also increased modestly from 148 ms (IQR, 140-163 ms) to 150 ms (IQR, 142-168 ms) (P = 0.041). In vitro, HCQ exposure in hiPSC-CMs prolonged corrected field potential duration (P = 0.013) and induced arrhythmic activity. Motion analysis demonstrated a reduced peak relaxation velocity (P < 0.01), with concomitant attenuation of contractile function. Transmission electron microscopy showed lamellar inclusions consistent with myelin-like bodies. Hydroxychloroquine exposure significantly increased autophagy-related protein levels, suggesting impaired autophagic degradation. These cellular phenotypes were consistent with clinical manifestations of HCQ-associated electrical abnormalities and cardiomyopathy. CONCLUSION: Hydroxychloroquine therapy was associated with electrical abnormalities and cardiomyopathy. Experimental findings in hiPSC-CMs recapitulated key clinical features and provided biological support for the clinical observations.