Heart Rate Variability as a Prognostic Indicator in DCM Due to Lamin A/C Deficiency

Mutations in the LMNA gene, encoding nuclear lamina proteins, lamins A/C, cause familial dilated cardiomyopathy (DCM) and conduction-system disease. Individuals with LMNA mutations are at increased risk of sudden death but criteria for risk stratification are lacking. Identification of prognostic markers would provide a useful guide for selection of patients for prophylactic therapies, e.g., cardioverter-defibrillator implantation. Analysis of heart rate variability (HRV) has been used for risk stratification in patients with heart failure. We hypothesised that HRV abnormalities might identify a subgroup of individuals with LMNA mutations at increased risk of malignant cardiac arrhythmias. Hence, we performed HRV analysis in heterozygous Lmna knockout (Lmna+/−) mice, which are phenotypically normal at birth but develop DCM and reduced survival with increasing age. Ambulatory ECG recording using telemetry implants were undertaken at 40 weeks of age in male WT (n = 7) and male Lmna+/− (n = 7) mice, and HRV analysed. Thirty seconds of ECG tracing every two hours for 24 h were collected 2–3 days after implantation for analysis. The time-domain and frequency-domain measures of HRV in Lmna+/− mice were similar to that of WT mice. Decreased HRV and abnormal baroreflex function are commonly observed in human heart failure, with a direct relationship between the degree of HRV reduction and the severity of cardiac dysfunction. Although our data does not support this relationship in mice, this may be due to the technical limitations of recording ECG in small animals, and strain-specific differences in autonomic system activity in mice. Prospective evaluation studies of the significance of HRV in genotype-positive individuals with LMNA mutations are warranted.