Retrospective comparitive cohort study of laminopathies versus titin mutation cardiomyopathies - an assessment of response to guideline directed medical therapy for heart failure

Background

Non-ischaemic dilated cardiomyopathy (DCM) is estimated to be familial in 30-50% of cases. The commonest genetic causes are variants in the Titin gene (TTN) accounting for 20-25% of cases, and the Lamin A/C gene (LMNA) accounting for 5-8%. The LMNA gene codes for the production of Lamins A and C proteins which are intermediate filament proteins of the cell nucleus envelope. Patients positive for Lamin A/C mutations are at risk of developing a sinister & rapidly progressive cardiology phenotype that has been classically resistant to the disease modifying medical therapy that is available for cardiomyopathies. While diagnostics and management plans are generalised across all causes of DCM, natural history and response to therapy may vary depending on cause.

Aims

To compare baseline findings, natural history and response to treatment between cohorts of patients with LMNA and TTN attending a dedicated inherited cardiac conditions service.

Methods

The cohorts of LMNA and TTN patients were compared with 1:1 matching. Parameters recorded included LV dimensions and ejection fraction [LVEF], late enhancement on CMR, ECG parameters (arrhythmias, conduction delay). The presence of neurological manifestations was noted, and the occurrence of major adverse cardiac events (MACE): death, transplantation, cardiac device implantation. Prescribed medication and response to same over follow up was recorded.

Results

24 LMNA patients were included, the majority of which were male, with a median age at diagnosis of 34. Mean initial EF was 51% falling to 46% at follow-up (P=0.0049). 33% had AV delay. 54% had atrial and 33% ventricular arrhythmia. 54% needed device implantation. 2nd degree of higher AV block was present in 8 patients on follow up. Atrial arrhythmia was identified in 13 (54%) patients and ventricular arrhythmia in 8 (33%) of patients

In comparison the TTN cohort were older with a median age of 41. Mean EF improved from 40% to 46% at follow-up. There was a significant difference in LVEF at diagnosis (p=0.025) between both cohorts. None of the TTN cohort had AV delay (p=0.002), and a lower number of devices were implanted at 25% (p=0.039).

Conclusions

The LMNA cohort displayed a higher rate of needing cardiac device implantation, higher incidence of significant AV conduction disturbance. Interestingly, the LMNA cohort had a higher LVEF at diagnosis. This is likely due to the fact that they present relatively younger and at an earlier disease stage than their counterparts with TTN mutations. This maybe due to the fact that they often present with conduction disturbance or arrhythmia prior to cardiomyopathy and due to the presence of cascade genetic screening programs in inherited cardiac condition centres that allow for earlier familial detection of the condition. Confirming genotype early in the clinical course may facilitate early adoption of invasive strategies for LMNA patients and enhance outcomes.