The cardiovascular magnetic resonance phenotype of lamin heart disease

Background: Lamin (LMNA) heart disease is characterized by high mortality rate given its propensity to cause severe systolic dysfunction and life-threatening ventricular tachyarrhythmia. We explored its cardiovascular magnetic resonance (CMR) phenotype to discover prognostically useful and subclinical biomarkers. Methods: This prospective multi-centre trial (NCT03860454) recruited four groups of participants: LMNA carriers with preserved left ventricular (LV) ejection fraction (EF) (Lamin+EF); LMNA carriers with reduced LVEF (Lamin–EF); dilated cardiomyopathy with wild-type LMNA (DCMwt); and healthy volunteers (HV). Pathogenicity of all variants was classified according to American College of Medical Genetics guidelines. Phantom-calibrated CMR was used to acquire cines, multiparametric mapping and late gadolinium enhancement (LGE) images. Cines were processed to derive radial, longitudinal, and circumferential strains using feature tracking. LV shapes were reconstructed from cines using generalized Procrustes analysis–an innovative CMR-based four-dimensional (4D) morphofunctional shape analysis. Blood samples at the time of the CMR provided serum troponin levels. Using a major adverse cardiovascular events (MACE) outcome of cardiovascular death, life-threatening ventricular tachyarrhythmia, heart transplantation or atrio-ventricular block requiring pacing, we explored the prognostic value of CMR metrics using Cox regression. Results: 187 were recruited (50% male, mean age 40 years): 29 Lamin+EF (38±14y); 38 Lamin–EF (45±17y); 73 DCMwt (45±15y); 47 HV (44±20y) (Figure 1). Lamin+EF had longer phantom-normalized T2 z-score by 10 units (95% confidence interval [2,20]; p=0.028), higher extracellular volume by 3% ([1,6]; p=0.027), and worse myocardial dynamics (e.g., 11% [7,16] lower circumferential strain) compared to HV (Table 1). Both Lamin+EF and Lamin-EF participants had higher serum levels troponin levels compared to DCMwt (21 vs 5 ng/l, p< 0.001). Over 4-years, 21% of lamin participants and 1% of DCMwt experienced MACE. In lamin participants, each 1% increase in global LGE or LV mass associated with a hazard ratio (HR) for MACE of 1.15 [1.02, 1.30], and 1.05 [1.01,1.10] respectively, while each 1% decrease in procrustes trajectory sizes associated with a HR of 0.99 [0.98,0.99] (all p< 0.025). Conclusion: The CMR phenotype of LMNA carriers with preserved LV systolic function consists of longer T2, higher serum troponin levels, higher ECV and impaired strain. Studying pathways involving myocardial inflammation and extracellular remodeling may yield additional insights into mechanisms behind disease progression. CMR-derived focal fibrosis (Figure 2) and strain biomarkers are prognostic and future studies should explore their added clinical utility beyond the currently available risk prediction tools, none of which currently incorporates CMR metrics.