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OBJECTIVE This study aimed to investigate the shortcoming of BMI as a measurement of adiposity in patients with familial partial lipodystrophy (FPLD). METHODS Two different matching procedures were used to compare 55 FPLD versus control patients with severe obesity (N = 548 patients) to study the relationship between body weight, fat distribution, and metabolic diseases, such as diabetes mellitus, hypertriglyceridemia, and nonalcoholic steatohepatitis. In MATCH1, the patients with FPLD were matched to controls with obesity (OCs) by truncal mass, and in MATCH2, the patients with FPLD were matched to OCs with respect to glucose control. RESULTS With MATCH1, the FPLD group had worse glycemic control (hemoglobin A1c 8.2% ± 1.6% vs. 5.9% ± 0.9%), higher triglycerides (884 ± 1,190 mg/dL vs. 139 ± 79 mg/dL), and lower leptin (20.5 ± 15.8 ng/mL vs. 41.9 ± 29.4 ng/mL, P

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., NIH Clinical and Translational Science AwardsUnited States Department of Health & Human ServicesNational Institutes of Health (NIH) - USA [UL1TR000433]; Nutrition Obesity Research Centers [P30 DK089503]; NIH institutional grantUnited States Department of Health & Human ServicesNational Institutes of Health (NIH) - USA [DK034933]; White Point Foundation of Turkey; Morton S. and Henrietta K. Sellner Professorship in Human Genetics, Infrastructure and data management support has been provided by the NIH Clinical and Translational Science Awards grant UL1TR000433, the Nutrition Obesity Research Centers grant P30 DK089503, and NIH institutional grant DK034933. Finally, the work was supported by generous gifts to the Lipodystrophy Fund at the University of Michigan made by the Sopha family, and the White Point Foundation of Turkey. JWI acknowledges support from the Morton S. and Henrietta K. Sellner Professorship in Human Genetics.