A 67-year-old woman with rheumatoid arthritis treated with HCQ 200 mg daily for 8 years (cumulative dose 580 g) developed several months of lightheadedness, fatigue, and weakness. Initial electrocardiogram (ECG) showed sinus rhythm. Transthoracic echocardiography (TTE) revealed concentric left ventricular (LV) hypertrophy (septal 13 mm, posterior wall 12 mm), LV mass index 133 g/m², and preserved left ventricular ejection fraction (LVEF) (60%). Cardiac magnetic resonance (CMR) confirmed concentric hypertrophy (maximal wall 13 mm; LV mass 88 g/m²; LVEF 56%), without fibrosis, edema, infiltration, myocarditis, or infarction. ( Figure 1 ) Technetium pyrophosphate scintigraphy excluded transthyretin amyloidosis, and serum free light chains were normal. High-sensitivity troponin remained persistently elevated (293-326 ng/L), B-type natriuretic peptide (BNP) was 203 pg/ml, and Holter monitoring revealed sinus pauses up to 4 seconds. ( Figure 1 )

(A) Cardiac magnetic resonance (CMR) demonstrates concentric left ventricular hypertrophy with preserved systolic function and no late gadolinium enhancement, edema, or infiltrative pattern. (B) Holter monitoring reveals recurrent sinus pauses. (C) Twelve-lead ECG on presentation with cardiogenic shock shows junctional rhythm at 68 bpm with left bundle branch block.

Nine months later she presented in cardiogenic shock. ECG showed junctional rhythm (68 bpm) with new left bundle branch block (QRS 154 ms). ( Figure 1 ) TTE revealed biventricular hypertrophy, LVEF 35%, LV mass index 176 g/m², mild right ventricular dysfunction, and moderate mitral regurgitation and tricuspid regurgitation. Troponin was 2,066 ng/L, NT-proBNP >70,000 pg/ml. Right heart catheterization confirmed low-output restrictive physiology (cardiac index 1.3 L/min/m²). Endomyocardial biopsy demonstrated myocyte vacuolization with lamellar and curvilinear inclusion bodies, confirming HCQ toxicity; HCQ was discontinued. ( Figure 2 )

(A) Medium power photomicrograph of the endomyocardial biopsy demonstrates severe myocyte vacuolization confirming HCQ toxicity (H&E-stained section, 200x original magnification). (B) Electron microscopy of the endomyocardial biopsy reveals lamellar bodies and curvilinear bodies correlating with the light microscopic vacuoles confirming HCQ toxicity (scale bar = 2 microns). (C) Low power photomicrograph of the atrioventricular node (H&E-stained section, 10x original magnification). (D) Medium power photomicrograph demonstrating severe vacuolization of the myocytes of the atrioventricular node with pronounced interstitial fibrosis within the node (H&E-stained section, 40x original magnification).

She required intravenous dobutamine and intra-aortic balloon pump (IABP) support with minimal response, but stabilized with temporary atrial pacing, which improved cardiac output and permitted IABP removal after 48 hours. Following 2 weeks of pacing and inotropes, a leadless atrial pacemaker was implanted. Despite improved hemodynamics, ECG continued to show PR prolongation (256 ms) and QRS widening (162 ms).

One week later, she developed complete heart block with asystolic arrest. Return of spontaneous circulation was achieved after prolonged resuscitation, requiring transvenous ventricular pacing and IABP reinsertion. Despite restored circulation, profound hypoxic brain injury ensued, and care was withdrawn. Autopsy revealed diffuse vacuolar myopathy with extensive involvement of the conduction system, including sinoatrial (SA) and atrioventricular (AV) nodal fibrosis, confirming irreversible HCQ conduction disease. ( Figure 2 )

Question 1

What property of HCQ primarily drives its cardiac toxicity?

A. Preferential accumulation in the mitochondria, inhibiting oxidative enzymes.

B. Weakly basic structure leading to lysosomal ion trapping and impaired autophagy.

C. Rapid renal clearance producing electrolyte disturbances and consequent arrhythmias.

D. Direct calcium-channel inhibition causing negative inotropy.

Correct Answer: B

HCQ is a weakly basic 4-aminoquinoline that becomes protonated at physiologic pH and accumulates in lysosomes through ion trapping. This lysosomal tropism underlies both its therapeutic and toxic effects. Sustained tissue accumulation with a prolonged elimination half-life (∼40-50 days) results in vacuolization, lamellar/curvilinear inclusions, and impaired autophagy. In the heart, these processes affect both myocardium and conduction tissue. Risk factors include long duration (>5 years), high cumulative dose (>500 g), renal impairment, older age, and female sex. In lupus cohorts, abnormal troponin/BNP levels have identified subclinical toxicity in ∼10% of patients, with one-third ultimately confirmed to have HCQ cardiotoxicity.

Question 2

What is increasingly recognized as a primary and mostly irreversible cardiac manifestation of HCQ toxicity?

A. Rapidly reversible restrictive or hypertrophic cardiomyopathy.

B. Myocardial infarction with normal coronaries and microvascular dysfunction.

C. Progressive conduction system disease due to SA and/or AV nodal fibrosis.

D. Acute myocarditis with inflammatory infiltrates containing eosinophils.

Correct Answer: C

Lysosomal dysfunction leads to fibrosis and irreversible conduction loss, as noted in our case. This case underscores the unique vulnerability of the conduction system, which relies heavily on lysosomal clearance. To our knowledge, this is the first autopsy-proven demonstration of SA and AV nodal fibrosis in HCQ toxicity, establishing conduction disease as a primary manifestation with subsequent evidence of myocardial involvement. Analogous mechanisms exist in lysosomal storage diseases such as Danon disease (LAMP2 deficiency) and Fabry’s disease, where conduction abnormalities progress irreversibly despite myocardial recovery. ^, Conduction disturbances, including AV block, bundle branch block, and sinus node dysfunction, have been reported in up to 85% of HCQ cardiotoxicity cases, underscoring their central role.

Question 3

Which management strategy is best supported for preventing adverse outcomes in HCQ-associated conduction disease?

A. Delay pacing until complete heart block develops, as conduction abnormalities reverse following HCQ discontinuation.

B. Rely on CMR imaging as the preferred modality for early detection of myocardial and conduction system involvement.

C. Ensure early ECG surveillance and proactive consideration for dual-chamber or ventricular pacing if evidence of nodal involvement is noted.

D. Exclude HCQ cardiotoxicity when cardiac biomarkers (high-sensitivity troponin, BNP) remain within normal limits.

Correct Answer: C

Diagnosis remains challenging, as CMR is frequently normal in the early stages, and neither this modality nor endomyocardial biopsy reliably detects conduction system involvement. Biopsy by design is confined to the myocardium, limiting diagnostic yield in conduction-predominant phenotypes. Consequently, CMR abnormalities often represent a late manifestation of diffuse myocardial fibrosis. Progressive ECG changes are the earliest—and sometimes only—clue. Even after drug withdrawal, conduction tissue recovery is limited and delayed due to long HCQ washout. Prognosis remains guarded: only 45% improve after drug withdrawal, while many deteriorate with ∼30% mortality—often from irreversible conduction disease that can progress despite biopsy-proven myocyte recovery, sometimes culminating in sudden death despite drug withdrawal. Importantly, no cases of AV conduction recovery have been reported.