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Leptin is an adipokine that reflects energy storage levels. Patients with obesity have high leptin, hypertension, and increased cardiovascular disease (CVD) risk. In rodents, leptin increases blood pressure (BP), by increasing sympathetic nervous system (SNS) activity, suggesting high leptin may cause hypertension and CVD. Studies of leptin administration in 2 human models of leptin deficiency (weight reduced and congenital leptin deficiency) showed decreased SNS activity in the leptin-deficient state, which increased after leptin replacement. This has clinical relevance as high SNS and low parasympathetic nervous system (PNS) activity correlate with increased risk of hypertension and CVD. In lipodystrophy syndromes adipose tissue is deficient thus leptin is low. We hypothesized that leptin treatment in patients with lipodystrophy would increase SNS activity and BP. SNS and PNS activity in the heart can be assessed using heart rate variability (HRV). The high frequency (HF) component of HRV is directly related to PNS activity whereas the low frequency (LF) component reflects both SNS and PNS. The LF/HF ratio reflects sympathetic-vagal balance. Lower standard deviation of the beat to beat interval (SDNN) inversely correlates with CVD risk. Leptin-naïve patients with lipodystrophy (N=17, 5 generalized, 12 partial) were housed on an inpatient unit for 19 days. Patients were studied without leptin for the first five days. Leptin was administered for the next 14 days. At the end of the OFF-leptin and ON-leptin periods, 24-hr EKG recordings were used to derive HRV parameters and an automated BP monitor measured BP every 30 minutes during the day and every 60 minutes at night. 5 patients had generalized lipodystrophy (median 25th,75th percentile] endogenous leptin [0.5 [0.4, 0.6] ng/mL); 12 had partial lipodystrophy (leptin 7.5 [3.9, 20.3]). In the combined cohort with generalized and partial lipodystrophy, leptin treatment did not alter BP or any measure of autonomic nervous system function after 24 hours, 2 weeks, or 6 months. In exploratory subgroup analyses of generalized vs partial lipodystrophy, those with generalized lipodystrophy had an increase in LF after 2 weeks of leptin and a 4.5 mm Hg increase in systolic BP after 6 months; no changes were observed in those with partial lipodystrophy. Unlike previous human and rodent studies, we did not see increased SNS tone or BP after leptin treatment in patients with lipodystrophy. However, exploratory analyses in patients with generalized lipodystrophy and very low endogenous leptin levels showed small increases in systolic BP and increased LF component of HRV after 2 weeks, which is regulated by both SNS and PNS. This suggests that leptin may alter autonomic function in the transition from very low to normal plasma leptin levels.

SUN-565 The Effect of Leptin Treatment on Blood Pressure and Autonomic Nervous System Function in Patients with Lipodystrophy