Characteristics and Outcomes of Gene-Elusive Dilated Cardiomyopathy

Background and Aims

Genetic testing in dilated cardiomyopathy (DCM) guides risk stratification and family screening. Likely pathogenic or pathogenic (LP/P) variants are identified in approximately one-third of patients, leaving many without a genetic diagnosis. Cohort studies suggest that ‘gene-elusive’ patients have a lower risk of adverse events. This study aims to better characterise this group and identify factors associated with adverse outcomes.

Methods

Consecutive and unrelated DCM patients undergoing genetic testing and returning no LP/P variants were retrospectively recruited and compared to two control cohorts of DCM patients carrying LP/P variants in LMNA and TTN for a primary composite endpoint of end-stage heart failure (ESHF) or malignant ventricular arrhythmia (MVA).

Results

Among patients without prior MVA, the composite endpoint occurred in 36/423 (8.5%) gene-elusive, 14/39 (35.9%) LMNA and 11/100 (11%) TTN cardiomyopathy patients (log-rank p < 0.001 for LMNA vs gene-elusive and LMNA vs TTN ; p = 0.96 for TTN vs gene-elusive).

For gene-elusive patients, lower left ventricular ejection fraction, larger left ventricular internal diameter in diastole, absence of LBBB and ventricular ectopy on ECG were independent predictors of the primary endpoint. Gene-elusive patients with LBBB had less atrial arrhythmia and a lower burden of ventricular ectopy at baseline and a low risk of the primary composite endpoint (HR 0.3 [0.1-0.8], p-value 0.01).

Conclusions

Gene-elusive DCM patients have a risk of adverse events similar to TTN cardiomyopathy. Gene-elusive patients with LBBB form a particularly low-risk subgroup, likely reflecting a distinct aetiology of left ventricular systolic dysfunction.