Hot hearts on bone scintigraphy are not all amyloidosis: hydroxychloroquine-induced restrictive cardiomyopathy

Abstract

A 70-year old woman with history of longstanding rheumatoid arthritis and recent diagnosis of complete heart block leading to a dualchamber pacemaker im plantation presented to the hospital with several weeks of worsening dyspnoea and lower extremity swelling. On physical exam, she had evidence of both intraand extravascular fluid accumulation as evidenced by elevation in jugular venous pressure and lower extremity oedema. Electrocardiogram demonstrated normal pacemaker function with atrial-sensed, ventricular-paced rhythm. Echocardiography showed moderate-severe increased wall thickness with moderately reduced left ventricular ejection fraction (Supplementary material online, Videos S1-S4). Diastolic parameters were consistent with a Grade III abnormal filling pattern, low mitral annular tissue velocity, and a global longitudinal strain (GLS) of À9.4% with associated relative apical sparing (ratio of apical/basal segments 1.2). Given concern for an infiltrative cardiomyopathy, she underwent 99m technetium pyrophosphate scintigraphy revealing semiquantitative visual Grade 3 and diffuse uptake (Perugini Grade 3) on single-photon emission computed tomography. Serum immunofixation, free light chains, and alpha galactosidase A were normal. Right ventricular biopsy was negative on Congo red staining. Electron microscopy revealed disorganized myofibrils, abundant vacuoles, multiple lamellar inclusion bodies, and curvilinear cytoplasmic bodies, findings that are pathognomonic for hydroxychloroquine-induced restrictive cardiomyopathy (Figure). Hydroxychloroquine was discontinued, and the patient started on guideline directed heart failure therapy. Several months later, repeat echocardiography revealed modest improvement in left ventricular ejection fraction.Hydroxychloroquine accumulates in lysosomes, inhibiting molecular breakdown with resultant accumulation of phospholipids and glycogen. Clinical presentation includes biventricular hypertrophy, restrictive physiology (late-stage), and conduction system abnormalities. Importantly, in an era when bone scintigraphy is being used with increasing frequency to diagnose transthyretin (ATTR) amyloid cardiomyopathy, we hope to raise awareness for the potential of a false-positive result in patients taking hydroxychloroquine.Hydroxychloroquine-induced restrictive cardiomyopathy. (Panel A) Parasternal long-axis and apical views showing left ventricular concentric hypertrophy. (Panel B) Pulsed-wave and tissue Doppler showing a pseudo-normal filling pattern and depressed mitral annular velocity with a normal E/e 0 ratio. (Panel C) Polar map of the left ventricle showing relative apical sparing and a GLS of À9.4%. (Panel D) Diffuse uptake of 99m technetium pyrophosphate on planar imaging and single-photon emission computed tomography. (Panel E) Electron microscopy of a myocardial section obtained from an endomyocardial biopsy showing cytoplasmic changes of the cardiomyocyte including disorganization of myofibrils, lamellar inclusion bodies (red arrows), abundant vacuoles, and curvil...

Diagnostic value of cardiovascular magnetic resonance in comparison to endomyocardial biopsy in cardiac amyloidosis: a multi-centre study

“…Furthermore, Gillmore et al analysed the specificity and PPV of a "positive" bone scintigraphy indicative of CA (defined as cardiac tracer uptake of either grade 2 or 3 vs. grade 0 or 1 as "normal/negative") for ATTR-CA when combined with the absence of monoclonal proteins in N = 374 patients with EMB [12]: they obtained a specificity as well as PPV of 100% for the diagnosis of ATTR-CA. Based on this finding, they established their approach and diagnostic algorithm of bone scintigraphybased non-biopsy diagnosis of ATTR-CA that entered some recommendation papers [24][25][26]-and is questioned by some interesting reports [28,29]. In contrast, in our present study, the combined finding of a "positive" CMR study indicative of CA and "negative" monoclonal protein studies resulted in a similar specificity of 98% and PPV of 99% for the diagnosis of ATTR-CA (compared to biopsy findings).…”

Reversible myocardial oedema due to acute myocardial infarction as differential diagnosis of cardiac transthyretin amyloidosis

“…Myocardial oedema with cardiac uptake of bone‐avid radiotracers due to reperfused myocardial infarction is missing in current consensus papers, diagnostic algorithms, and state‐of‐the art reviews 1,3,5,6 and should be acknowledged as a differential diagnosis for cardiac TTR amyloidosis. In addition, a recent report demonstrated diffuse myocardial uptake of technetium‐99m pyrophosphate in a patient with hydroxychloroquine‐induced restrictive cardiomyopathy 17 …”

“…In addition, a recent report demonstrated diffuse myocardial uptake of technetium-99m pyrophosphate in a patient with hydroxychloroquine-induced restrictive cardiomyopathy. 17…”

Diagnosis and treatment of cardiac amyloidosis: position statement of the German Cardiac Society (DGK)

“…Hence, scintigraphy is a highly valuable diagnostic tool for screening patients with suspected cardiac ATTR amyloidosis and current international guidelines recommend its use early in case of clinical symptoms, ECG, echocardiography, and/or CMR findings suspicious for cardiac amyloidosis [ 87 , 88 ]. However, as outlined by Kittleson et al recently [ 89 ], the test performance of scintigraphy in populations with lower disease prevalence is unknown and the aforementioned positive predictive value of scintigraphy (with the absence of monoclonal gammopathy) of 100% for ATTR is questioned by some recent reports that illustrate possible causes of false-positive 99mTc-PYP scans [ 90 , 91 ]. In addition, first larger studies with a direct comparison of scintigraphic 99m Tc-DPD images with a CMR-based determination of ECV in the same patients suggest that there is a prognostic significance for the more precise CMR-based ECV [ 70 ].…”