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The role of leptin in endothelial dysfunction and cardiovascular disease
Umeå University, Faculty of Medicine, Department of Public Health and Clinical Medicine.ORCID iD: 253387
2013 (English)Doctoral thesis, comprehensive summary (Other academic)Alternative title
Betydelsen av fetma och fetvävnadsassocierat hormon leptin för endotelial dysfunktion och kardiovaskulär disease (Swedish)
Abstract [en]

Objective:  Obesity has become the leading cause of mortality worldwide; however, the fundamental pathophysiology underlying this association remains unclear. The discovery of adipokines, i.e., cytokines produced by adipose cells (adipocytes), revealed that adipose tissue is a highly endocrine organ, thus opening new lines of investigation. The prototypical adipokine leptin increases in obesity, and leptin receptors are found in vascular cells. However, results are contradictory regarding the role of leptin in vascular and endothelial functions. Leptin has been shown to elicit vasodilatation, but has also been linked with atherosclerotic and thrombotic disease. The main aim of the present thesis was to study the association of circulating levels of leptin with markers of endothelial function, and to analyze the effects of leptin infusion in vivo  on vasomotor function and endogenous fibrinolysis.

Material:  Four associative studies and two interventional studies were conducted. The former included DISARM (studies 1 and 2), the PIVUS study (study 3), and the Scottish post-infarction study (study 4). The DISARM studies and study 4, respectively, recruited 20 men and 83 men and women with stable ischemic heart disease. Study 3 included a random sample of 1016 subjects (54% women, 70 years old) living in the community of Uppsala, Sweden. For the interventional studies (studies 5 and 6), 10 healthy men were recruited for each study.

Methods:  In all studies, endothelial function was estimated based on forearm blood flow (FBF) as measured by strain-gauge venous occlusion plethysmography, at rest or during infusion of vasodilators. In study 3, additional measurement techniques were used, such as brachial ultrasound flow-mediated dilation (FMD) and the aortic augmentation index (AoAIx) by tonometry in the radial artery. Fibrinolytic status was estimated based on basal and stimulated levels of tissue plasminogen activator antigen (t-PA), and by assessment of the endothelial release of t-PA (net t-PA release). Plasma leptin levels were measured by radioimmunoassay. In the associative studies, endothelial function and fibrinolytic status were related to circulating plasma leptin levels. In the experimental studies, exogenous leptin was administered in the brachial artery and endothelial function was assessed by strain-gauge plethysmography

Results:  In elderly men and women, leptin was independently associated with decreased endothelial-dependent and -independent vasodilatation, reflecting disturbed endothelial function in resistance vessels. This association was attenuated after adjustment for BMI, and when analyzed among subjects with high plasma leptin levels. FMD (a measure of endothelial function in conduit vessels) was not associated with leptin. Exogenous leptin infusion did not alter vasomotor tone, but the endothelium-dependent and -independent vasodilatation was impaired during concomitant infusion of leptin and vasodilators. Infused leptin in the forearm did not affect blood pressure or pulse rate. Chronic hyperleptinemia, but not acutely induced hyperleptinemia, was associated with release of endothelial tissue plasminogen activator (net t-PA).

Conclusions:  In humans, leptin was associated with impaired vasodilatation. However, this relationship was blunted after adjustment for BMI, suggesting that leptin could be the mediator between obesity and impaired vascular function. Furthermore, the observed lack of association in hyperleptinemic subjects may reflect a state of leptin resistance. The experimental result showing attenuated vascular reactivity following leptin infusion is in accordance with the results of the associative studies. The augmented net t-PA release in patients with chronic hyperleptinemia may indicate a state of “vascular activation,” which was not observed in healthy endothelium during a short period of leptin infusion. This thesis addresses several controversial issues regarding the action of leptin on vascular tissue in humans. The final results indicate that the in vivo action of leptin on vascularity is complex and mediated by several mechanisms. Our findings suggest that leptin is an important mediator between obesity and endothelial dysfunction, and should stimulate further investigation of this matter.

Place, publisher, year, edition, pages
Umeå: Umeå universitet , 2013. , 116 p.
Series
Umeå University medical dissertations, ISSN 0346-6612 ; 1586
Keyword [en]
leptin, obesity, endothelial dysfunction, cardiovascular disease
National Category
Cardiac and Cardiovascular Systems
Research subject
Cardiology
Identifiers
URN: urn:nbn:se:umu:diva-79823ISBN: 978-91-7459-703-5 (print)OAI: oai:DiVA.org:umu-79823DiVA: diva2:645001
Public defence
2013-09-27, E04, by 6E, Norrlands universitetssjukhus, Umeå, 13:00 (Swedish)
Opponent
Supervisors
Projects
Manuel Cruz Gonzalez
Funder
Swedish Heart Lung Foundation
Available from: 2013-09-06 Created: 2013-09-03 Last updated: 2013-09-06Bibliographically approved
List of papers
1. Ischemic and thrombotic effects of dilute diesel-exhaust inhalation in men with coronary heart disease
Open this publication in new window or tab >>Ischemic and thrombotic effects of dilute diesel-exhaust inhalation in men with coronary heart disease
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2007 (English)In: New England Journal of Medicine, ISSN 0028-4793, E-ISSN 1533-4406, Vol. 357, no 11, 1075-1082 p.Article in journal (Refereed) Published
Abstract [en]

BACKGROUND: Exposure to air pollution from traffic is associated with adverse cardiovascular events. The mechanisms for this association are unknown. We conducted a controlled exposure to dilute diesel exhaust in patients with stable coronary heart disease to determine the direct effect of air pollution on myocardial, vascular, and fibrinolytic function.

METHODS: In a double-blind, randomized, crossover study, 20 men with prior myocardial infarction were exposed, in two separate sessions, to dilute diesel exhaust (300 mug per cubic meter) or filtered air for 1 hour during periods of rest and moderate exercise in a controlled-exposure facility. During the exposure, myocardial ischemia was quantified by ST-segment analysis using continuous 12-lead electrocardiography. Six hours after exposure, vasomotor and fibrinolytic function were assessed by means of intraarterial agonist infusions.

RESULTS: During both exposure sessions, the heart rate increased with exercise (P<0.001); the increase was similar during exposure to diesel exhaust and exposure to filtered air (P=0.67). Exercise-induced ST-segment depression was present in all patients, but there was a greater increase in the ischemic burden during exposure to diesel exhaust (-22+/-4 vs. -8+/-6 millivolt seconds, P<0.001). Exposure to diesel exhaust did not aggravate preexisting vasomotor dysfunction, but it did reduce the acute release of endothelial tissue plasminogen activator (P=0.009; 35% decrease in the area under the curve).

CONCLUSIONS: Brief exposure to dilute diesel exhaust promotes myocardial ischemia and inhibits endogenous fibrinolytic capacity in men with stable coronary heart disease. Our findings point to ischemic and thrombotic mechanisms that may explain in part the observation that exposure to combustion-derived air pollution is associated with adverse cardiovascular events.

Keyword
Air Pollution/*adverse effects, Cardiovascular System/*drug effects/physiopathology, Coronary Disease/*physiopathology, Cross-Over Studies, Double-Blind Method, Environmental Exposure/adverse effects, Exercise/physiology, Fibrinolysis/drug effects, Humans, Inhalation, Male, Middle Aged, Myocardial Infarction, Myocardial Ischemia/*etiology, Particulate Matter/*adverse effects, Thrombosis/etiology, Vasodilator Agents/pharmacology, Vehicle Emissions/*toxicity
National Category
Cardiac and Cardiovascular Systems
Identifiers
urn:nbn:se:umu:diva-18156 (URN)10.1056/NEJMoa066314 (DOI)17855668 (PubMedID)
Available from: 2007-11-28 Created: 2007-11-28 Last updated: 2017-12-14Bibliographically approved
2. Leptin and endothelial function in the elderly: the Prospective Investigation of the Vasculature in Uppsala Seniors (PIVUS) study
Open this publication in new window or tab >>Leptin and endothelial function in the elderly: the Prospective Investigation of the Vasculature in Uppsala Seniors (PIVUS) study
2013 (English)In: Atherosclerosis, ISSN 0021-9150, E-ISSN 1879-1484, Vol. 228, no 2, 485-490 p.Article in journal (Refereed) Published
Abstract [en]

Background: Leptin levels are elevated in obese humans. Several studies have shown an association between hyperleptinemia and development of atherosclerosis and cardiovascular disease (CVD), but the relationship between leptin and vascular function remains unclear.

Aim: To evaluate associations between circulating plasma leptin and measures of vascular function in a large sample of elderly individuals from the community.

Methods: This cross-sectional study included 1016 subjects aged 70 (50% women) from the Prospective Investigation of the Vasculature in Uppsala Seniors (PIVUS). The invasive technique forearm plethysmography with intra-arterial infusions of acetylcholine and sodium nitroprusside was used for estimation of endothelial dependent vasodilatation (EDV) and endothelial independent vasodilatation (EIDV), respectively, in resistance arteries, and the non-invasive technique ultrasound assessed flow mediated vasodilation (FMD) in conduit arteries. The aortic augmentation index (AoAI), a surrogate measure of arterial stiffness, was evaluated by pulse wave analysis. Associations of vascular function, arterial stiffness and blood pressure with leptin were explored.

Results: In sex-adjusted models, high levels of leptin were inversely associated with EDV and EIDV. These associations remained after stratification for sex, traditional risk factors of CVD and insulin resistance, but were attenuated after taking a measure of obesity (body mass index) into account. In addition, leptin associated with arterial stiffness and systolic and diastolic blood pressure.

Conclusion: Hyperleptinemia associated inversely with vasodilatation in resistance arteries. Furthermore, hyperleptinemia associated with arterial stiffness and hypertension. These associations were attenuated after adjusting for body mass index suggesting that leptin may be the mediator between obesity and impaired vascular function. (C) 2013 Elsevier Ireland Ltd. All rights reserved.

Place, publisher, year, edition, pages
Elsevier, 2013
National Category
Cardiac and Cardiovascular Systems
Identifiers
urn:nbn:se:umu:diva-73561 (URN)10.1016/j.atherosclerosis.2013.03.018 (DOI)000319037200031 ()
Available from: 2013-06-25 Created: 2013-06-25 Last updated: 2017-12-06Bibliographically approved
3. Hyperleptinemia is associated with altered endothelial function
Open this publication in new window or tab >>Hyperleptinemia is associated with altered endothelial function
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(English)Manuscript (preprint) (Other academic)
Abstract [en]

Introduction The adipocyte-derived hormone leptin has been associated with increased risk of cardiovascular disease but the underlying mechanisms are unclear. Leptin effects on vascular endothelium may be a key mediator although contradictory results have been presented. We aimed to explore the effects of leptin on endothelial vasomotor and fibrinolytic function in healthy volunteers and patients with coronary heart disease.

Methods and Results The vascular effects of leptin were assessed using venous occlusion plethysmography in healthy volunteers (n=17) and in patients with stable coronary heart disease (CHD) (n=83). In healthy male volunteers, intra-arterial infusion of recombinant human leptin (80, 800 and 8,000 ng/min; n=10) did not affect forearm blood flow or plasma tissue plasminogen activator (tPA) or plasminogen activator inhibitor type 1 (PAI-1) concentrations (all P>0.05).  However, during concomitant co-infusion with leptin (800 ng/min; n=10), induced vasodilatation was reduced (P=0.001), and tPA activity increased (P=0.002). In line with this, patients with coronary heart disease included in the highest tertile of plasma leptin concentrations had reduced substance P-induced vasodilatation (P<0.001), and increased tPA antigen and activity release (p<0.001 and p=0.03 respectively) compared to those in the lowest tertile.

Conclusions Although leptin does not directly affect basal vascular function, acute local and chronic systemic hyperleptinemia are associated with altered endothelial function in healthy volunteers and patients with coronary heart disease respectively. These results support hyperleptinemia as a link between obesity and cardiovascular disease.

Keyword
leptin, obesity, endothelial function, cardiovascular disease
National Category
Cardiac and Cardiovascular Systems
Research subject
Cardiology
Identifiers
urn:nbn:se:umu:diva-79822 (URN)
Projects
Manuel Cruz Gonzalez
Funder
Swedish Heart Lung Foundation
Available from: 2013-09-02 Created: 2013-09-02 Last updated: 2015-04-17Bibliographically approved

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