Refractory Ventricular Arrhythmias in a Patient With Dilated Cardiomyopathy Caused by a Nonsense Mutation in BAG5

A 14-year-old male patient with no relevant family history was admitted for heart failure (HF). Echocardiography showed a left ventricular (LV) ejection fraction of 18% and a LV diastolic diameter of 58 mm (Supplementary Movie). On cardiac magnetic resonance (CMR) imaging, late gadolinium enhancement was detected in the LV inferolateral wall (Figure A,B). Technetium-99 m tetrofosmin single-photon emission computed tomography (SPECT) also showed a defect within the inferolateral wall (Figure C). The patient’s HF gradually became resistant to conservative therapy including cardiac resynchronization therapy with defibrillator (CRT-D), and he underwent LV assist device (LVAD; HeartMate II) implantation at 19 years old. Despite the mechanical unloading with LVAD, CRT-D often recorded ventricular tachycardia (VT) originated from the LV lateral wall, consistent with the CMR and SPECT findings (Figure D). Frequent hospitalizations were required due to unremitting VT. Finally, he underwent heart transplantation after over 4 years of LVAD implant, which resolved the refractory VT. Exome sequencing revealed a homozygous nonsense mutation in the BAG5 gene (Figure E), which is identical to the causative mutation for dilated cardiomyopathy (DCM) reported by us.¹ BAG5 protein expression was not observed in the patient’s heart tissue (Supplementary Figure A). In addition, a heterozygous frameshift variant in PKP2, a known causative gene for arrhythmogenic right ventricular cardiomyopathy, was identified (Supplementary Figure B), which might have accelerated the arrhythmogenicity in this patient. Patients with juvenile-onset DCM accompanied by refractory VT should be considered for genetic testing.

Figure.

(A,B) Late gadolinium enhancement on cardiac magnetic resonance imaging (arrowheads). (C) Technetium-99 m tetrofosmin single-photon emission computed tomography. (D) Ventricular tachycardia with right bundle-branch block and superior QRS axis, originating from the LV lateral wall. (E) DNA sequence chromatogram of BAG5 showing a homozygous nonsense mutation (c.589C>T), causing a premature stop codon (p.Arg197Ter).

Disclosure

Y.S. is a member of Circulation Journal’s Editorial Team.

IRB Information

This study was approved by the Institutional Review Board of Osaka University (accession no. 680) and followed the principles of the Declaration of Helsinki.

Supplementary Files

Supplementary Movie. Echocardiogram.

Please find supplementary file(s);

https://doi.org/10.1253/circj.CJ-22-0329

Reference

• 1.   Hakui H, Kioka H, Miyashita Y, Nishimura S, Matsuoka K, Kato H, et al. Loss-of-function mutations in the co-chaperone protein BAG5 cause dilated cardiomyopathy requiring heart transplantation. Sci Transl Med 2022; 14: eabf3274.