Dilated Cardiomyopathy Due to BLC2-Associated Athanogene 3 (BAG3) Mutations.

Domínguez F1, Cuenca S2, Bilińska Z3, Toro R4, Villard E5, Barriales-Villa R6, Ochoa JP7, Asselbergs F8, Sammani A9, Franaszczyk M10, Akhtar M11, Coronado-Albi MJ12, Rangel-Sousa D13, Rodriguez-Palomares JF14, Jiménez-Jáimez J15, Garcia-Pinilla JM16, Ripoll-Vera T17, Mogollón-Jiménez MV18, Fontalba-Romero A19, Garcia-Medina D20, Palomino-Doza J21, de Gonzalo-Calvo D22, Cicerchia M23, Salazar-Mendiguchia J23, Salas C24, Pankuweit S25, Hey TM26, Mogensen J26, Barton PJ27, Charron P5, Elliott P11, Garcia-Pavia P28; European Genetic Cardiomyopathies Initiative Investigators.

Abstract

BACKGROUND:

The BAG3 (BLC2-associated athanogene 3) gene codes for an antiapoptotic protein located on the sarcomere Z-disc. Mutations in BAG3 are associated with dilated cardiomyopathy (DCM), but only a small number of cases have been reported to date, and the natural history of BAG3 cardiomyopathy is poorly understood.

OBJECTIVES:

This study sought to describe the phenotype and prognosis of BAG3 mutations in a large multicenter DCM cohort.

METHODS:

The study cohort comprised 129 individuals with a BAG3 mutation (62% males, 35.1 ± 15.0 years of age) followed at 18 European centers. Localization of BAG3 in cardiac tissue was analyzed in patients with truncating BAG3 mutations using immunohistochemistry.

RESULTS:

At first evaluation, 57.4% of patients had DCM. After a median follow-up of 38 months (interquartile range: 7 to 95 months), 68.4% of patients had DCM and 26.1% who were initially phenotype-negative developed DCM. Disease penetrance in individuals >40 years of age was 80% at last evaluation, and there was a trend towards an earlier onset of DCM in men (age 34.6 ± 13.2 years vs. 40.7 ± 12.2 years; p = 0.053). The incidence of adverse cardiac events (death, left ventricular assist device, heart transplantation, and sustained ventricular arrhythmia) was 5.1% per year among individuals with DCM. Male sex, decreased left ventricular ejection fraction. and increased left ventricular end-diastolic diameter were associated with adverse cardiac events. Myocardial tissue from patients with a BAG3 mutation showed myofibril disarray and a relocation of BAG3 protein in the sarcomeric Z-disc.

CONCLUSIONS:

DCM caused by mutations in BAG3 is characterized by high penetrance in carriers >40 years of age and a high risk of progressive heart failure. Male sex, decreased left ventricular ejection fraction, and enlarged left ventricular end-diastolic diameter are associated with adverse outcomes in patients with BAG3 mutations.