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Ischemic and thrombotic effects of dilute diesel-exhaust inhalation in men with coronary heart disease
Umeå University, Faculty of Medicine, Department of Public Health and Clinical Medicine, Pulmonary Medicine.
Umeå University, Faculty of Medicine, Department of Public Health and Clinical Medicine, Cardiology. (Kardiologi)
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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.

Place, publisher, year, edition, pages
2007. Vol. 357, no 11, 1075-1082 p.
Keyword [en]
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
URN: urn:nbn:se:umu:diva-18156DOI: 10.1056/NEJMoa066314PubMedID: 17855668OAI: diva2:157829
Available from: 2007-11-28 Created: 2007-11-28 Last updated: 2015-04-17Bibliographically approved
In thesis
1. Respiratory and cardiovascular responses to diesel exhaust exposure
Open this publication in new window or tab >>Respiratory and cardiovascular responses to diesel exhaust exposure
2008 (English)Doctoral thesis, comprehensive summary (Other academic)
Abstract [en]

Background: Exposure to traffic-derived air pollution is associated to high incidence of respiratory and cardio-vascular morbidity and mortality. Diesel engines and fossil fuel contribute to a great amount to the ambient particulate matter pollution. Exposure to diesel exhaust in healthy volunteers is known to cause inflammatory and oxidative responses in the airways. In contrast, very little is known about the air pollution-related mechanisms behind the adverse cardiovascular effects and why patients with cardiorespiratory disease are more susceptible to the adverse effect of particulate matter air pollution.

Methods: Volunteers were exposed to diesel exhaust at a particulate matter concentration of 300 μg/m3 and filtered air for one hour in random order. In studies I-II, patients with moderately severe, stable COPD were examined with lung function, induced sputum and peripheral blood samples. In studies III-V, vascular assessment was performed using venous occlusion plethysmography. Vascular responses to intra-arterially infused endothelial dependent and independent vasodilators were determined, together with endogenous fibrinolysis, systemic inflammation and long-term ECG registration. These vascular studies were carried out in healthy volunteers and patients with stable coronary heart disease.

Results: In healthy subjects, diesel exhaust exposure induced an acute vasomotor dysfunction, which was partly sustained at 24 hours. Endogenous fibrinolysis reflected by tissue plasminogen activator (t-Pa) levels and activity were reduced at 6 hours post exposure both in healthy subjects and patients with stable PCI-treated coronary heart disease. During diesel exhaust exposure, ECG analyses demonstrated significant exerciseinduced ST-T segment depression in patients with coronary heart disease. These findings occurred at a moderately increased heart rate of approximately 90 beats per minute during both diesel and air exposures. The investigated group of stable COPD patients did not demonstrate any further deterioration of lung function, induced sputum or systemic inflammatory parameters within the investigated time frame.

Conclusion: Inhalation of diesel exhaust impaired two important and complementary aspects of vascular function in healthy subjects; regulation of vascular tone and endogenous fibrinolysis. In men with stable coronary heart disease, exposure to diesel exhaust induced signs of myocardial ischemia, along with impaired endogenous fibrinolytic capacity, despite full secondary preventive medication. These exposure studies support the epidemiological evidence of an association between particulate matter air pollution and adverse cardiovascular effects and demonstrate important underlying mechanisms.

Place, publisher, year, edition, pages
Umeå: Lungmedicin, 2008. 81 p.
Umeå University medical dissertations, ISSN 0346-6612 ; 1190
Research subject
Lung Medicine
urn:nbn:se:umu:diva-1670 (URN)978-91-7264-582-0 (ISBN)
Public defence
2008-06-05, Sal E04, 6E, trappa R, NUS, Umeå, 13:00 (English)
Available from: 2008-05-20 Created: 2008-05-20 Last updated: 2010-01-18Bibliographically approved
2. The role of leptin in endothelial dysfunction and cardiovascular disease
Open this publication in new window or tab >>The role of leptin in endothelial dysfunction and cardiovascular disease
2013 (English)Doctoral thesis, comprehensive summary (Other academic)
Alternative title[sv]
Betydelsen av fetma och fetvävnadsassocierat hormon leptin för endotelial dysfunktion och kardiovaskulär disease
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.
Umeå University medical dissertations, ISSN 0346-6612 ; 1586
leptin, obesity, endothelial dysfunction, cardiovascular disease
National Category
Cardiac and Cardiovascular Systems
Research subject
urn:nbn:se:umu:diva-79823 (URN)978-91-7459-703-5 (ISBN)
Public defence
2013-09-27, E04, by 6E, Norrlands universitetssjukhus, Umeå, 13:00 (Swedish)
Manuel Cruz Gonzalez
Swedish Heart Lung Foundation
Available from: 2013-09-06 Created: 2013-09-03 Last updated: 2013-09-06Bibliographically approved

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