Is hydroxychloroquine associated with an increased risk of vasovagal syncope, particularly in adults with a history of cardiovascular disease or autoimmune disease?

Hydroxychloroquine and Vasovagal Syncope: No Direct Association

Hydroxychloroquine is not associated with vasovagal syncope. The cardiac complications from hydroxychloroquine involve conduction abnormalities, QT prolongation, cardiomyopathy, and heart failure—not vasovagal mechanisms 1, 2, 3.

Understanding the Cardiac Toxicity Profile

Hydroxychloroquine causes dose-dependent cardiotoxicity through lysosomal accumulation of metabolites that alter cellular pH, leading to specific structural and electrical cardiac abnormalities 4:

• Conduction disorders are the predominant cardiac complication, affecting 85% of patients with hydroxychloroquine cardiotoxicity, including bundle branch blocks, QRS widening, and atrioventricular blocks 1, 3
• Cardiomyopathy and heart failure occur in approximately 35% of long-term users who develop cardiotoxicity, typically after median cumulative doses exceeding 1.4 million mg over 10+ years 5, 3
• QT prolongation and torsades de pointes represent the arrhythmic risk, not vasovagal mechanisms 1, 6

Why Vasovagal Syncope Is Not the Mechanism

Vasovagal syncope involves a neurally-mediated reflex causing sudden vasodilation and bradycardia, typically triggered by emotional stress, pain, or orthostatic stress 7, 8. This mechanism is fundamentally different from hydroxychloroquine's cardiotoxic effects:

• Hydroxychloroquine-induced syncope results from structural cardiomyopathy, severe conduction blocks (particularly Mobitz II AV block), or ventricular arrhythmias—not vasovagal reflexes 4, 3
• Vasovagal syncope is a benign reflex present in healthy individuals, occurring spontaneously in approximately 50% of the population during their lifetime 8
• Patients with hydroxychloroquine cardiotoxicity present with progressive cardiac dysfunction, not isolated syncopal episodes characteristic of vasovagal mechanisms 4, 3

Clinical Approach to Syncope in Hydroxychloroquine Users

When evaluating syncope in patients taking hydroxychloroquine, prioritize cardiovascular assessment over vasovagal mechanisms 7:

Immediate Risk Stratification

• Obtain 12-lead ECG immediately to assess for QRS widening, bundle branch blocks, AV blocks, or QTc prolongation >500 ms 7, 1, 6
• Hospitalize patients with documented or suspected ventricular arrhythmia or syncope likely due to cardiac causes 7
• Check electrolytes (potassium, magnesium) as hypokalemia compounds QT prolongation risk and increases torsades de pointes probability 6

High-Risk Features Requiring Urgent Specialist Referral

• Syncope during exercise or with emotional stress suggests arrhythmic etiology, not vasovagal 7
• ECG abnormalities including conduction defects, QTc >500 ms, or ventricular hypertrophy mandate cardiology evaluation 7, 1
• Long-term hydroxychloroquine use (>7 years) with cumulative doses exceeding 1 million mg increases cardiotoxicity risk 5, 3

Diagnostic Workup

• Echocardiography to assess for ventricular hypertrophy, hypokinesia, or reduced ejection fraction characteristic of hydroxychloroquine cardiomyopathy 4, 3
• Ambulatory ECG monitoring (24-48 hour Holter or event recorder) to capture arrhythmias if conduction abnormalities present on baseline ECG 7
• Cardiac MRI plays a crucial role in early detection of hydroxychloroquine cardiotoxicity when structural abnormalities are suspected 4

Critical Management Decisions

Discontinue hydroxychloroquine immediately if any cardiac manifestations are present, as conduction disorders may represent initial manifestations of potentially irreversible toxicity 3:

• Early withdrawal leads to improved ejection fraction and symptom resolution within months in most cases (45% recover normal function) 4, 3
• Delayed recognition results in irreversible damage (13%) or death (31%) in patients with established cardiotoxicity 3
• Cardiac toxicity can be reversible with prompt discontinuation and standard heart failure therapy, particularly when detected early 4, 5

Common Pitfalls to Avoid

• Do not attribute syncope to vasovagal mechanisms in hydroxychloroquine users without excluding cardiac causes through ECG and echocardiography 7
• Do not perform tilt-table testing as first-line investigation for unexplained syncope in these patients—cardiovascular assessment takes priority 7
• Do not overlook dizziness as a potential cardiac symptom; it may represent presyncope from conduction abnormalities or arrhythmias 2
• Do not continue hydroxychloroquine if QTc exceeds 500 ms or any conduction abnormalities develop, as this represents unacceptable arrhythmia risk 6, 3