LMNA Deficiency Reveals a Role for SK3 Channel Dysfunction in Atrioventricular Block.

BACKGROUND: Atrioventricular block (AVB) is a conduction system disorder that, when severe, results in pacemaker implantation. LMNA mutations affecting the nuclear envelope proteins lamin A/C have been linked to AVB in patients, yet the underlying mechanisms remain largely unclear. The authors identified a nonsense LMNA-R225X mutation in a kindred that was associated with progressive AVB and atrial arrhythmias, followed by left ventricular dysfunction. OBJECTIVES: The aims of this study were to elucidate the mechanisms underlying LMNA-R225X-mediated AVB and to identify novel therapeutic targets for its treatment. METHODS: LMNA-R225X-knock-in mice were generated using clustered regularly interspaced short palindromic repeats/Cas9 technology. Cardiac phenotype was characterized using surface electrocardiography, telemetry electrocardiography, programmed electrical stimulation, and echocardiography. Histology, immunofluorescence staining, Ca2+ imaging, and RNA sequencing were performed to elucidate the mechanistic underpinnings of AVB. RESULTS: Homozygous LMNA-R225X mice displayed bradycardia and first-degree AVB before death at 2 weeks. Similar to patients, R225X-heterozygous mice exhibited age-dependent progressive AVB, ranging from first to second degree, and increased susceptibility to atrial fibrillation, preceding the development of cardiomyopathy. Specific knockdown of LMNA in cardiac conduction system pacemaker cells was sufficient to induce AVB. RNA sequencing analysis of atrioventricular node tissue revealed up-regulation of genes related to fibrosis and cellular hypertrophy, accompanied by down-regulation of the small-conductance calcium-activated potassium channel type 3 (SK3) channel. Ca2+ imaging further demonstrated impaired automaticity of R225X-heterozygous atrioventricular node pacemaker cells. Pharmacologic activation of SK3 channel attenuated AVB in both LMNA deficiency models. CONCLUSIONS: These findings establish a direct role of LMNA deficiency in AVB and reveal the SK3 channel as a therapeutic target for the management of AVB.