Davison, Diane E.

Rationale: The link between obesity, hyperleptinemia, and development of cardiovascular disease is not completely understood. Increases in leptin have been shown to impair leptin signaling via caveolin-1–dependent mechanisms. However, the role of hyperleptinemia versus impaired leptin signaling in adipose tissue is not known. Objective: To determine the presence and significance of leptin-dependent increases in adipose tissue caveolin-1 expression in humans. Methods and Results: We designed a longitudinal study to investigate the effects of increases in leptin on adipose tissue caveolin-1 expression during weight gain in humans. Ten volunteers underwent 8 weeks of overfeeding, during which they gained an average weight of 4.1±1.4 kg, with leptin increases from 7±3.8 to 12±5.7 ng/mL. Weight gain also resulted in changes in adipose tissue caveolin-1 expression, which correlated with increases in leptin (rho=0.79, P =0.01). In cultured human white preadipocytes, leptin increased caveolin-1 expression, which in turn impaired leptin cellular signaling. Functionally, leptin decreased lipid accumulation in differentiating human white preadipocytes, which was prevented by caveolin-1 overexpression. Further, leptin decreased perilipin and fatty acid synthase expression, which play an important role in lipid storage and biogenesis. Conclusions: In healthy humans, increases in leptin, as seen with modest weight gain, may increase caveolin-1 expression in adipose tissue. Increased caveolin-1 expression in turn impairs leptin signaling and attenuates leptin-dependent lowering of intracellular lipid accumulation. Our study suggests a leptin-dependent feedback mechanism that may be essential to facilitate adipocyte lipid storage during weight gain.

Background —Sildenafil citrate is an effective and widely prescribed therapy for erectile dysfunction. Little is known about the effects of sildenafil on neural control of the circulation or about the effects of sildenafil on neurocirculatory stress responses. Methods and Results —We studied 14 normal volunteers (age 32±7 years) who were randomized in a double-blind crossover fashion to receive a single oral dose of sildenafil 100 mg or placebo on 2 separate study days. Blood pressure, heart rate, forearm vascular resistance, muscle sympathetic nerve activity, and plasma catecholamines were measured at baseline and at 30 and 60 minutes after sildenafil and after placebo administration. The effects of sildenafil and placebo on neural and circulatory responses to stressful stimuli (sustained handgrip, maximal forearm ischemia, mental stress, and the cold pressor test) were also evaluated. Blood pressure, heart rate, and forearm vascular resistance after sildenafil and placebo were similar. However, muscle sympathetic nerve activity increased strikingly after sildenafil (by 141±26%, mean±SEM) compared with placebo (3±8%) ( P =0.006); plasma norepinephrine levels also increased by 31±5% after sildenafil administration ( P =0.004). Sympathetic nerve traffic during mental, physical, and cold stresses was 2- to 8-fold higher after sildenafil than with placebo ( P <0.05). Conclusions —Sildenafil causes a marked increase in sympathetic activation, evident both at rest and during stressful stimuli. Sympathetic activation by sildenafil may have implications for understanding cardiovascular events associated with sildenafil use.

Obesity has been associated with increased cardiac sympathetic activation during wakefulness, but the effect on sleep-related sympathetic modulation is not known. The aim of this study was to investigate the effect of fat gain on cardiac autonomic control during wakefulness and sleep in humans. We performed a randomized, controlled study to assess the effects of fat gain on heart rate variability. We recruited 36 healthy volunteers, who were randomized to either a standardized diet to gain ≈4 kg over 8 weeks followed by an 8-week weight loss period (n=20) or to serve as a weight-maintainer control (n=16). An overnight polysomnogram with power spectral analysis of heart rate variability was performed at baseline, after weight gain, and after weight loss to determine the ratio of low-frequency to high-frequency power and to examine the relationship between changes in heart rate variability and changes in insulin, leptin, and adiponectin levels. Mean weight gain was 3.9 kg in the fat gain group versus 0.1 kg in the maintainer group. Low frequency/high frequency increased both during wakefulness and sleep after fat gain and returned to baseline after fat loss in the fat gain group and did not change in the control group. Insulin, leptin, and adiponectin also increased after fat gain and fell after fat loss, but no clear pattern of changes was seen that correlated consistently with changes in heart rate variability. Short-term fat gain in healthy subjects is associated with increased cardiac sympathetic activation during wakefulness and sleep, but the mechanisms remain unclear.

Background— Obstructive sleep apnea (OSA) is associated with recurrent atrial fibrillation (AF) after electrocardioversion. OSA is highly prevalent in patients who are male, obese, and/or hypertensive, but its prevalence in patients with AF is unknown. Methods and Results— We prospectively studied consecutive patients undergoing electrocardioversion for AF (n=151) and consecutive patients without past or current AF referred to a general cardiology practice (n=312). OSA was diagnosed with the Berlin questionnaire, which is validated to identify patients with OSA. We also assessed its accuracy compared with polysomnography in a sample of the study population. Groups were compared with the 2-tailed t , Wilcoxon, and χ 2 tests. Logistic regression modeled the association of AF and OSA after adjustment for relevant covariates. Patients in each group had similar age, gender, body mass index, and rates of diabetes, hypertension, and congestive heart failure. The questionnaire performed with 0.86 sensitivity, 0.89 specificity, and 0.97 positive predictive value in our sample. The proportion of patients with OSA was significantly higher in the AF group than in the general cardiology group (49% versus 32%, P =0.0004). The adjusted odds ratio for the association between AF and OSA was 2.19 (95% CI 1.40 to 3.42, P =0.0006). Conclusions— The novel finding of this study is that a strong association exists between OSA and AF, such that OSA is strikingly more prevalent in patients with AF than in high-risk patients with multiple other cardiovascular diseases. The coinciding epidemics of obesity and AF underscore the clinical importance of these results.

Background— C-reactive protein (CRP) is synthesized from the liver and is regulated by cytokines, especially interleukin-6. Leptin, the adipocyte-derived protein product of the ob gene, is related to amount of body fat. The long form of the leptin receptor resembles cytokine receptors, which include the interleukin-6 receptor. Both leptin and CRP may be increased in women, in obesity, and in inflammation, and both have been linked to cardiovascular pathophysiological processes and increased cardiovascular risk. We tested the hypothesis that leptin is associated with CRP levels independently of the influences of gender, body mass index (BMI), waist-to-hip ratio, and other variables. Methods and Results— We studied 100 healthy volunteers (48 men, and 52 women). For all subjects, leptin was independently associated with CRP after adjustment for age, gender, BMI, waist-to-hip ratio, smoking, and alcohol consumption (F=12.39, P =0.0007). There was a strong and significant positive relationship between leptin and CRP in both women ( R =0.61, P <0.0001) and men ( R =0.55, P <0.0001) considered separately. The association between leptin and CRP was significant even after adjustment for age, BMI, waist-to-hip ratio, smoking, and alcohol consumption in women (F=7.13, P =0.01) and men (F=5.69, P =0.02). When only subjects with BMI <25 kg/m 2 were considered (n=47), CRP was not linked to BMI ( R =0.02, P =0.96), but a significant association between leptin and CRP was still evident ( R =0.55, P <0.0001). Conclusions— Leptin and CRP levels are independently associated in normal humans, providing further evidence linking metabolic and inflammatory cardiovascular disease mechanisms.