To recapitulate progressive human dilated cardiomyopathy (DCM) and heart block in the Lmna R225X mutant mice model and investigate the molecular basis of LMNA mutation induced cardiac conduction disorders (CD); To investigate the potential interventional impact of exercise endurance.
Recent pooled cohorts of patients with genetic DCM and in particular in those with Lamin A/C (LMNA) mutations have identified patients at increased risk of SCD and allowed the creation of algorithms to prognosticate SCD risk in mutation carriers.
LMNA chromatin immunoprecipitation-sequencing, reduced representative bisulfite sequencing, and RNA-sequencing were performed in 5 control and 5 LMNA-associated DCM hearts.
LMNA is one of the most frequently mutated genes and should be included in all target gene assessments of end-stage DCM patients until more data are available.
Patients with some mutations in the lamin A/C (LMNA) gene are characterized by the presence of dilated cardiomyopathy (DCM), conduction abnormalities, ventricular tachyarrhythmias (VT), and sudden cardiac death (SCD).
Genes associated predominantly with arrhythmic DCM included LMNA and SCN5A, as well as the more recently-reported DCM disease genes, RBM20, FLNC, and TTN.
Desmosomal and LMNA gene variants identify the subset of DCM patients who are at greatest risk for SCD and life-threatening ventricular arrhythmias, regardless of the left ventricular ejection fraction.
Taken together, our findings suggest that the activation of the PDGF pathway contributes to the pathogenesis of LMNA-related DCM and point to PDGF receptor-β (PDGFRB) as a potential therapeutic target.
Characterised by progressive conduction system disease, arrhythmia and systolic impairment, lamin A/C heart disease is more malignant than other common DCMs due to high event rates even when the left ventricular impairment is mild.
We have previously described 19 pedigrees with apparent lamin (<i>LMNA</i>)-related dilated cardiomyopathy (DCM) manifesting in affected family members across multiple generations.
Using targeted resequencing, we discovered a novel truncating LMNA mutation associated with CCD and DCM in this family characterized by gender differences in clinical severity in LMNA carriers.
TTN truncating variants were the major cause of sporadic DCM (21.4% of sporadic cases) as with Caucasians, whereas LMNA variants, which include a novel recurrent LMNAE115M variant, were the most frequent in familial DCM (24.0% of familial cases) unlike Caucasians.
Mutations in the LMNA gene are a common cause (6-8%) of dilated cardiomyopathy (DCM) leading to heart failure, a growing health care problem worldwide.
Mutations in the lamin A/C gene (LMNA) were associated with dilated cardiomyopathy (DCM) and, recently, were related to severe forms of arrhythmogenic right ventricular cardiomyopathy (ARVC).