The Effect of the Adipocyte-derived Hormone Leptin on Endothelial Function in Healthy Men and in Persons With Known Cardiovascular Disease
试验速览
- 阶段
- 早期 1 期
- 状态
- 已完成
- 发起方
- 入组人数
- 103
- 试验地点
- 2
- 主要终点
- Forearm Blood-flow (FBF)
研究概览
简要总结
Adipose tissue is an active endocrine organ producing several hormones with circulatory and metabolic effects. In 1994, the hormone leptin was discovered. The lack of this hormone explained extreme obesity in rare patients and parenteral substitution restored body weight and metabolic disturbances. It was however soon discovered that most humans had too high levels which were related to development of cardiovascular diseases and diabetes. It was hypothesised that leptin induced vessel dysfunction which could explain this association.
In this study, we wanted to examine the association between leptin and vessel function by using the venous occlusion plethysmography method. We used three protocols to evaluate this association.
First protocol. In ten healthy males, leptin was infused locally in the forearm and forearm blood flow (FBF) was measured.
Second protocol. In ten healthy males, leptin or normal saline was infused locally in the forearm and FBF was measured. Concomitantly, four vasodilatators were infused locally in the forearm in a randomised order and the response (blood flow and fibrinolysis) was measured.
Third protocol. In eighty-three patients with known coronary artery disease, three vasodilators were infused locally in the forearm in a random order and response (FBF and fibrinolysis) was measured. The response was related to endogenous leptin levels.
The two first protocols were performed in Umeå, Sweden whereas the third was performed in Edinburgh, UK, all in 2006.
详细描述
Introduction High BMI and particularly fat mass index are associated with increased risk of coronary artery disease and other cardiovascular conditions, but the underlying mechanisms are not well understood. Endothelial dysfunction precedes atherosclerosis and represents an important link between obesity and cardiovascular events.
The adipose tissue produces cytokines and hormones (adipokines), which, in excess, may promote cardiovascular disease by proinflammatory, prothrombotic, dyslipidemic and atherosclerotic effects.
Leptin is an adipokine with pleiotropic effects and circulating leptin levels are positively associated with the amount of body fat. High plasma leptin levels (hyperleptinemia) associate with the development of atherosclerosis, hypertension and coronary artery disease (CAD). Leptin activates specific leptin receptors expressed, among other tissues, in vascular cells, suggesting that leptin may participate in the development of endothelial dysfunction and atherosclerosis.
However, the net effect of leptin on vasomotor function remains unclear, as both vasodilation and vasoconstriction have been reported. Leptin induces release of nitric oxide (NO) in vitro and elicits endothelium-dependent vasodilation in mice by inducing endothelial expression of NO synthase. In addition, studies in humans have shown that leptin infusion exerts vasodilatation. In contrast, others have shown leptin-induced vasoconstriction in vitro and impaired vasodilatation in dogs. Different mechanisms have been proposed causing increased peripheral vascular resistance, such as vascular inflammation, increased sympathetic nervous system (SNS) activity, increased endothelin-1 (ET-1) production, and decreased nitric oxide (NO) bioavailability.
Hyperleptinemia has been associated to states of altered fibrinolysis, which is common in diabetes, cardiovascular disease and obesity. However, whether leptin directly influences the endogenous fibrinolytic function remains unclear.
研究设计
- 研究类型
- Interventional
- 分配方式
- Randomized
- 干预模型
- Crossover
- 主要目的
- Basic Science
- 盲法
- None
入排标准
- 性别
- All
- 接受健康志愿者
- 是
入选标准
- 未提供
排除标准
- 未提供
研究组 & 干预措施
Leptin infusion
This applies to protocol 1 when 10 healthy men got leptin infused locally in the forearm and forearm blood flow (FBF) was measured. The other forearm was used as the control.
干预措施: Leptin infusion in healthy men (Drug)
Leptin infusion plus vasodilator infusion
This applies to protocol 2 when 10 healthy men got either a background infusion of leptin or saline locally in the forearm when measuring vasoresponse (FBF) to four vasodilatators. Each participant had two examinations with either leptin or saline and the order was randomised. The other forearm was used as the control.
干预措施: Leptin infusion plus vasodilators in healthy men (Drug)
Vasodilator infusion in CAD patients
This applies to protocol 3 when 83 men and women with known CAD (coronary artery disease) got three vasodilators locally infused in the forearm while measuring vasoresponse (FBF). The other forearm was used as the control.
干预措施: Vasodilators in CAD patients (Drug)
结局指标
主要结局
Forearm Blood-flow (FBF)
时间窗: 18 minutes in protocol 1, 3 hours in protocol 2, non-applicable (NA) in protocol 3
The primary outcome in all protocols were local blood-flow in the forearm (FBF). This was measured by venous occlusion plethysmography using mercury-in-silastic strain gauges and the unit is mL/100mL of tissue/min. In protocol 1, the FBF response to increasing levels of leptin was evaluated, In protocol 2, the FBF response to vasodilators on top of leptin or saline infusion was evaluated, and in protocol 3, FBF was measured after infusion of vasodilators and no leptin was given.
次要结局
- Release of Fibrinolytic Variables (Tissue Plasminogen Activator [tPA] and Plasminogen Activator Inhibitor-1 [PAI-1])(18 minutes in protocol 1, 3 hours in protocol 2, NA in protocol 3)
- Leptin(18 minutes in protocol 1, 3 hours in protocol 2, NA in protocol 3)
- Systolic Blood Pressure(18 minutes in protocol 1, 3 hours in protocol 2, NA in protocol 3)
- Heart Rate(18 minutes in protocol 1, 3 hours in protocol 2, NA in protocol 3)
研究者
Stefan Soderberg
Professor
Umeå University