Truncating LMNA variants are associated with worse arrhythmic outcomes regardless of variant location, whereas missense variants affecting the tail domain and located in exons 7-12 have better arrhythmic and heart failure (HF) outcomes, according to a large retrospective cohort study published July 2 in JAMA Cardiology.

Ashwin Bhaskaran, MBBS, et al., included 718 patients (mean age 41 years; 53% women) with LMNA cardiomyopathy (mean LVEF 56%) and available variant data from an international registry (since January 2013) and tertiary cardiomyopathy centers (January 2000–June 2017). Among these individuals, 66% had a missense variant; 41% were probands and 60% were relatives.

Results showed that at the 4.2-year follow-up, nearly one-third (n=233) of patients experienced a malignant ventricular arrhythmia (VA), defined as sudden cardiac death (SCD), appropriate ICD therapy or hemodynamically unstable VA, and 15% (n=109) experienced advanced HF, defined as requiring a left ventricular assist device or cardiac implant or non-SCD.

Specifically, in patients with truncating (nonmissence) variants, the risk of VA was higher (hazard ratio [HR], 1.72; p=0.004), but no significant difference existed in advanced HF (HR, 0.94; p=0.77) vs. those with missense variants.

Of note, when stratifying truncating variants by location on the LMNA gene or transcript position, no significant differences in VA or advanced HF events were found. Conversely, on multivariable analysis, missense variants affecting the tail domain of LMNA (HR, 0.35; p=0.02) and located in exons 7-12 (HR, 0.39; p=0.035) had a significantly lower risk of malignant VA.

The study authors write that "overall, the effect and location of LMNA variants can provide hypothesis-generating findings for future precision therapeutics."

In an accompanying editorial comment, Sadiya S. Khan, MD, FACC, et al., write that the high number of VA and advanced HF event rates "underscores the need for clinician, patient, and family awareness for aggressive surveillance, management, and monitoring in those with ... variants in LMNA regardless of the presenting phenotype or lack thereof."