Prevalence, Genetic Correlates and Prognostic Significance of an Apical Pseudo-Infarct Late Gadolinium Enhancement Pattern in LMNA-Mediated Cardiac Laminopathy
Abstract Body (Do not enter title and authors here): Background: Disease-causative variants in LMNA-encoded lamin A/C cause a genetic cardiomyopathy characterized by atrioventricular (AV) block, atrial fibrillation (AF) and ventricular arrhythmias (VA). Whether domain/variant-specific late gadolinium enhancement (LGE) patterns exist and carry prognostic significance is unclear. Objective: To determine if specific LGE patterns correlate with LMNA variant type/missense variant localization and clinical outcomes in a large cohort of cardiac laminopathy patients. Methods: Retrospectively, 621 genotype-positive arrhythmogenic/dilated cardiomyopathy patients were analyzed to identify those with a disease-causative variant in LMNA-encoded lamin A/C. After exclusion of patients without cardiac magnetic resonance data, pertinent demographic/clinical data was extracted from the electronic medical record. LGE distribution (subepicardial, midmyocardial, subendocardial, transmural) and location (septal, free wall, apical) patterns were analyzed by variant type (missense vs truncating) and missense variant localization (central rod domain vs tail domain) and correlated with advanced heart failure (AHF), MVA, AV block, AF and thromboembolic (TE) events. Results: 70 out of 116 (60%) LMNA variant-positive (mean age 39±12, 43% male and 94% Caucasian) were included. Missense variants localizing to the C-terminal tail region showed a higher prevalence of transmural and apical LGE (Table). Amongst the 5 (7%) patients with this distinct apical pseudo-infarct LGE pattern, p.Arg471His-LMNA was identified in all cases. Among the 48/70 (69%) of patients with clinically manifest disease, p.Arg471His-LMNA-positive patients (n=6) were noted to have an increased prevalence of TE events [3 (50%) vs 5 (12%), 0=0.050] despite a reduced prevalence of AF [2 (33%) vs 32 (76%), p= 0.031]. No difference in AHF or MVA were observed, but AV block was less prevalent [1 (20%) vs 29 (74%), p= 0.029]. Conclusion: p.Arg471His-LMNA causes a distinct apical pseudo-infarct LGE pattern associated with an increased risk of TE events and a decreased prevalence of AV block and AF. Future studies are needed to better refine the role of domain/variant-specific risk-stratification/anticoagulation in cardiac laminopathy.
Castrichini, Matteo
( Mayo Clinic
, Rochester
, Minnesota
, United States
)
Garmany, Ramin
( Mayo Clinic
, Rochester
, Minnesota
, United States
)
Siontis, Konstantinos
( Mayo Clinic
, Rochester
, Minnesota
, United States
)
Ackerman, Michael
( Mayo Clinic
, Rochester
, Minnesota
, United States
)
Giudicessi, John
( Mayo Clinic
, Rochester
, Minnesota
, United States
)
Author Disclosures:
Matteo Castrichini:DO NOT have relevant financial relationships
| Ramin Garmany:DO NOT have relevant financial relationships
| Konstantinos Siontis:No Answer
| Michael Ackerman:DO have relevant financial relationships
;
Consultant:Abbott:Active (exists now)
; Royalties/Patent Beneficiary:Thryv Therapeutics:Active (exists now)
; Royalties/Patent Beneficiary:Pfizer:Past (completed)
; Royalties/Patent Beneficiary:ARMGO Pharma:Active (exists now)
; Royalties/Patent Beneficiary:Anumana:Active (exists now)
; Royalties/Patent Beneficiary:AliveCor:Active (exists now)
; Consultant:Tenaya Therapeutics:Active (exists now)
; Consultant:Solid Biosciences:Active (exists now)
; Consultant:Medtronic:Active (exists now)
; Consultant:Invitae:Active (exists now)
; Consultant:Illumina:Active (exists now)
; Consultant:Daiichi Sankyo:Past (completed)
; Consultant:Bristol Myers Squibb:Active (exists now)
; Consultant:Boston Scientific:Active (exists now)
; Consultant:BioMarin Pharmaceutical:Active (exists now)
| John Giudicessi:DO have relevant financial relationships
;
Consultant:Avidity Biosciences:Active (exists now)
; Other (please indicate in the box next to the company name):Prolaio (equity/royalty sharing):Active (exists now)
; Research Funding (PI or named investigator):Tenaya Therapeutics:Active (exists now)