19 Novel genotype-phenotype correlation in lamin heart disease uncovered using CMR 4D morphological shape analysis

Introduction Truncating (nonsense) variants of the lamin gene (LMNA) are predicted to be more aggressive than missense variants, as are variants upstream as opposed to downstream of its nuclear localization signal (NLS). However, whether impaired myocardial mechanics in vivo is influenced by variant subtype or by their coding DNA location relative to the NLS is unknown. Moreover, whether mechanics is impaired in subclinical LMNA variant carriers is yet to be elucidated. Materials and Methods This multi-centre CMR study (NCT03860454) prospectively recruited 3 cohorts: patients with pathogenic LMNA variants (LMNA); patients with dilated cardiomyopathy but wild-type LMNA gene (DCMwt) and healthy volunteers (Controls). Left ventricular (LV) cines were analysed using 3D feature tracking strain in cvi42 and 3D cartesian coordinates for epi/endocardial meshes were exported. Shapes were reconstructed using generalized procrustes analysis in the size and shape space at homologous times. To compare myocardial mechanics between subjects, procrustes trajectory sizes (PTS) were calculated at each homologous time and for the overall cardiac cycle. Conventional strain metrics (longitudinal, radial, circumferential) were also derived. Results 187 were recruited: 67 LMNA (42% male, 42.1 ±15.2 years)-29 of which had good LV function (i.e., subclinical LMNA carriers); 73 DCMwt (53% male, 45.0 ±15.0 years); and 47 Controls (43% male, 44.1 ±20.2 years). As expected, in LMNA, principal strains were worse compared to Controls but better than in DCMwt (figure 1). Compared to the diastolic reference, LMNA truncating variant carriers had smaller PTS only during systole compared to splice and missense variant carriers suggesting poorer myocardial mechanics (figure 2A). Carriers of an LMNA variant upstream of the NLS had significantly worse myocardial mechanics compared to those with downstream variants (PTS across the whole cardiac cycle 0.16 vs 0.14, p = 0.024; figure 2B). Compared to Controls, subclinical LMNA carriers had smaller (worse) circumferential strain values at the base (by 7% 95% CI: 1–13, p=0.025), mid (by 8% 2–14, p=0.015), and apical segments (by 14% 7–20, ptable 1). Discussion 4-Dimensional procrustes motion analysis of standard CMR cines provides unprecedented insights into myocardial deformation. Applied to lamin heart disease, it links the LMNA genetic landscape to deranged myocardial mechanics, with truncating variants and those upstream of the NLS emerging as particularly aggressive. Moreover, abnormal myocardial mechanics can be detected in subclinical LMNA carriers prior to any decline in ejection fraction. Conclusion In lamin heart disease, myocardial mechanics is impaired in subclinical gene carriers, and it is influenced by the variant subtype. Acknowledgements The authors would like to thank all the study participants for their participation and engagement in this study. Your contribution to science is extremely valued and appreciated. Authors are grateful to their funders: NIHR Rare Disease Translational Research Collaboration, Barts Charity (HeartOME project grant) and SCMR Seed Grant.