Phenotypic spectrum and natural history in BAG3 dilated cardiomyopathy: a contemporary multicenter study

Background

Genetic variants in BAG3 are associated with dilated cardiomyopathy (DCM) and a high risk of heart failure (HF) events. The burden of ventricular arrhythmias and cardiac magnetic resonance (CMR) features in this population remains poorly characterized. The aim of this study is to update and expand on previous observations of BAG3 cardiomyopathy in a large, international, multicenter cohort of BAG3 variant carriers.

Methods

Multicenter observational study including 332 carriers of pathogenic or likely pathogenic BAG3 variants from 36 centers across 3 continents. Both patients with DCM and phenotype-negative (PNeg) individuals were studied. Clinical, electrocardiographic, echocardiographic, and CMR data were collected. Primary outcomes included HF events (HF hospitalization and end-stage HF (ESHF) events: left ventricular assist device implantation, heart transplant (HTx), HF-related mortality) and a composite of major ventricular arrhythmic events (MVA) (sudden cardiac death (SCD), aborted cardiac arrest, ventricular fibrillation (VF), and sustained ventricular tachycardia (SVT)).

Results

At baseline, among 332 carriers (48.8% females, mean age at first evaluation 39.6 +/- 16.5 years), 121 were PNeg, while 211 had DCM. During a median follow-up of 52 months (IQR: 15-125), 27 (22.3%) PNeg carriers developed DCM, and 15 with DCM (7.1%) experienced LVEF normalization. CMR (n=142) revealed a mean LVEF of 41.9% ± 14.7, and late gadolinium enhancement (LGE) was found in 43 % overall and in 19 % of initially PNeg BAG3 carriers with LVEF ≥ 50 %. The most prevalent LGE pattern was mid-wall in 48.4 % of cases (predominantly septal), followed by multifocal (15.9%) and subepicardial (12.9%).

Out of 300 patients with follow-up data, 83 (27.7%) experienced heart failure (HF) admissions, and 53 (17.7%) ESHF events, including 44 heart transplants (14.6%). MVA occurred in 32 patients (10.7%), including 16 SVT (5.3%), 12 VF (4%), and 7 SCD (2.3%). Male gender was associated with a significantly higher risk of ESHF events, whereas MVA were less common and showed no significant difference between males and females (Figure 1).

Conclusions

Carriers of the BAG3 variant face a higher risk of developing heart failure, including hospitalizations and end-stage heart failure (ESHF), especially among males. MVA occurrences are less frequent and show no significant gender difference. LGE in CMR is commonly observed, even in individuals with preserved ejection fraction. These results emphasize the need for gene and sex-specific risk assessment and underscore the importance of CMR for early detection.SexDifferences in MVA & ESHF in BAG3 Carriers