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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., (© 2021 John Wiley & Sons Ltd.)

Objectives: Lipodystrophy syndromes are a group of heterogeneous disorders characterized by adipose tissue loss. Proteinuria is a remarkable finding in previous reports., Study Design: In this multicentre study, prospective follow-up data were collected from 103 subjects with non-HIV-associated lipodystrophy registered in the Turkish Lipodystrophy Study Group database to study renal complications in treatment naïve patients with lipodystrophy., Methods: Main outcome measures included ascertainment of chronic kidney disease (CKD) by studying the level of proteinuria and the estimated glomerular filtration rate (eGFR). Kidney volume was measured. Percutaneous renal biopsies were performed in 9 patients., Results: Seventeen of 37 patients with generalized and 29 of 66 patients with partial lipodystrophy had CKD characterized by proteinuria, of those 12 progressed to renal failure subsequently. The onset of renal complications was significantly earlier in patients with generalized lipodystrophy. Patients with CKD were older and more insulin resistant and had worse metabolic control. Increased kidney volume was associated with poor metabolic control and suppressed leptin levels. Renal biopsies revealed thickening of glomerular basal membranes, mesangial matrix abnormalities, podocyte injury, focal segmental sclerosis, ischaemic changes and tubular abnormalities at various levels. Lipid vacuoles were visualized in electron microscopy images., Conclusions: CKD is conspicuously frequent in patients with lipodystrophy which has an early onset. Renal involvement appears multifactorial. While poorly controlled diabetes caused by severe insulin resistance may drive the disease in some cases, inherent underlying genetic defects may also lead to cell autonomous mechanisms contributory to the pathogenesis of kidney disease., (© 2018 John Wiley & Sons Ltd.)