Cardiotoxicity

Cardiotoxicity caused by hydroxychloroquine (HCQ) can occur immediately after an overdose (acute) or after long-term use (chronic). The pathophysiology of acute and chronic cardiotoxicity clinical manifestations are different and are outlined below:

HCQ has a dose-related effect on cardiac electrical conduction¹. Acute HCQ cardiotoxicity is defined by a mix of direct cardiovascular effects and electrolyte disturbances with resulting dysrhythmias and is linked to considerable morbidity and mortality¹.

Pathophysiology

HCQ inhibits sodium and potassium channels and antagonises α₁-adrenergic receptors¹. The cardiac potential is affected leading to PR prolongation, QRS complex widening, and QT prolongation^1,2. HCQ also binds to and impedes the function of potassium channels, causing repolarization to be delayed^1,2. Clinically, this causes further QT prolongation and increases the risk of Torsades de pointes². Acute cardiotoxicity also manifests as conduction blocks involving the atrioventricular junction and His-Purkinje system².

After three years of exposure to HCQ, the majority of symptoms of HCQ induced cardiotoxicity appear³.

Pathophysiology

Long-term HCQ use causes the drug to accumulate in lysosomes, where it inhibits phospholipases directly and produces an alkaline change in lysosomal pH³. HCQ also inhibits the activity of lysosomal hydrolase³. These modifications result in accumulation of phospholipids in cardiomyocytes, decreased vesicle fusion and exocytosis, as well as a lysosomal storage disorder^3-4. Lysosomal storage disorder induce cardiomyopathy with concentric hypertrophy and restrictive characteristics, as well as conduction problems, which can lead to heart failure (acute/chronic) and/or recurring syncopal episodes as well as newly developed conduction abnormalities⁴.

References

1. Porta A., Bornstein K., Coye A., Montrief T., Long B., Paris M. Acute chloroquine and hydroxychloroquine toxicity: A review for emergency clinicians. Am J Emerg Med. 2020; 38(10): 2209-2217.

2. Chatre C., Roubille F., Vernhet H., Jorgensen C., Pers YM. Cardiac Complications Attributed to Chloroquine and Hydroxychloroquine: A Systematic Review of the Literature. Drug Safety. 2018; 41(10): 919-931.

3. Yogasundaram H., Putko B.N., Tien J., Paterson D.I., Cujec B., Ringrose J., Oudit G.Y. Hydroxychloroquine-induced cardiomyopathy: case report, pathophysiology, diagnosis and treatment. Can J Cardiol. 2014; 30(12):1706-15.

4. Nair V., Belanger C., Veinot J. Lysosomal storage disorders affecting the heart: a review. Cardiovascular Pathology. 2019; 39: 12-24.