Cardiac phenotype in familial partial lipodystrophy

Abstract

Objectives: LMNA variants have been previously associated with cardiac abnormalities independent of lipodystrophy. We aimed to assess cardiac impact of familial partial lipodystrophy (FPLD) to understand the role of laminopathy in cardiac manifestations.

Study design: Retrospective cohort study.

Methods: Clinical data from 122 patients (age range: 13-77, 101 females) with FPLD were analysed. Mature human induced pluripotent stem cell-derived cardiomyocytes (hiPSC-CMs) from a patient with an LMNA variant were studied as proof-of-concept for future studies.

Results: Subjects with LMNA variants had a higher prevalence of overall cardiac events than others. The likelihood of having an arrhythmia was significantly higher in patients with LMNA variants (OR: 3.77, 95% CI: 1.45-9.83). These patients were at higher risk for atrial fibrillation or flutter (OR: 5.78, 95% CI: 1.04-32.16). The time to the first arrhythmia was significantly shorter in the LMNA group, with a higher HR of 3.52 (95% CI: 1.34-9.27). Non-codon 482 LMNA variants were more likely to be associated with cardiac events (vs. 482 LMNA: OR: 4.74, 95% CI: 1.41-15.98 for arrhythmia; OR: 17.67, 95% CI: 2.45-127.68 for atrial fibrillation or flutter; OR: 5.71, 95% CI: 1.37-23.76 for conduction disease). LMNA mutant hiPSC-CMs showed a higher frequency of spontaneous activity and shorter action potential duration. Functional syncytia of hiPSC-CMs displayed several rhythm alterations such as early afterdepolarizations, spontaneous quiescence and spontaneous tachyarrhythmia, and significantly slower recovery in chronotropic changes induced by isoproterenol exposure.

Conclusions: Our results highlight the need for vigilant cardiac monitoring in FPLD, especially in patients with LMNA variants who have an increased risk of developing cardiac arrhythmias. In addition, hiPSC-CMs can be studied to understand the basic mechanisms for the arrhythmias in patients with lipodystrophy to understand the impact of specific mutations.

Keywords: LMNA; arrhythmia; atrial fibrillation; conduction disease; lipodystrophy.

FIGURE 1

Kaplan-Meier survival curve showing arrhythmia for LMNA and non-LMNA patients

FIGURE 2

Functional syncytia of mature human induced pluripotent stem cell-derived cardiomyocytes from a patient carrying a variant (LMNA R349W) causative of familial partial lipodystrophy (FPLD) were submitted to optical mapping for assessment of membrane voltage changes. (A) LMNA mutant cardiomyocytes had a higher frequency of spontaneous depolarization in relation to control cell line (MCH) (P < .001). (B) APD80% of repolarization was shorter in cells carrying the LMNA variant. (C) Duration of spontaneous action potential duration at 80% of repolarization was adjusted to the frequency of spontaneous depolarization with Fridericia correction and showed that LMNA mutant cardiomyocytes presented shorter corrected APD80% compared to control cardiomyocytes (P < .001). (D) Additionally, LMNA mutant cardiomyocytes presented several rhythm alterations (red arrows) such as early afterdepolarizations, spontaneous quiescence and spontaneous tachyarrhythmia; none of those were observed in the control cell lines. (E) Finally, both control and LMNA mutant cardiomyocytes showed a positive chronotropic response to isoproterenol. Nevertheless, isoproterenol recovery rate was significantly lower in the LMNA mutant cardiomyocytes