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Immobilization as a risk factor for arterial and venous thrombosis
Örebro University, School of Medical Sciences.
2018 (Swedish)Doctoral thesis, comprehensive summary (Other academic)
Abstract [en]

Aim: Immobilization and a sedentary lifestyle are correlated with an elevated risk of both arterial and venous thrombosis. The goal of this research was to investigate whether markers associated with cardiovascular disease risk are altered during long term immobilization in a human model and in the brown bear, which survives annual cycles of long-term immobilization.

Methods: In study populations assigned to 20-60 days of strict head-down-tilt bed rest 24h a day, we analysed blood levels of the emerging cardiovascular disease marker cystatin C, soluble markers of in vivo platelet activation P-selectin and PDGF-BB, and platelet aggregation. Blood samples were taken from free-ranging brown bears in summer and again during hibernation for analysis of lipid profile and platelet aggregation. Histological examination was performed on the left anterior descending coronary artery and aortic arches of bears harvested during the hunting season.

Results: During prolonged bed rest in humans, levels of cystatin C and platelet aggregation remained unchanged, but we observed a significant decrease in platelet activation markers. Brown bear plasma lipids were elevated during hibernation compared with the active state and cholesterol levels were generally considerably higher than normal human values. The arterial specimens showed no signs of atherosclerosis. Platelet aggregation was halved during hibernation compared to the active state.

Conclusions: Long-term immobilization has effects on several cardiovascular risk factors in both humans and bears. Increased knowledge and understanding of the protective mechanisms that allows the brown bear to survive repeated periods of immobilization could contribute to new strategies for prevention and treatment of cardiovascular disease in humans.

Place, publisher, year, edition, pages
Örebro: Örebro University , 2018. , p. 69
Series
Örebro Studies in Medicine, ISSN 1652-4063 ; 179
Keywords [en]
Venous thrombosis, arterial thrombosis, atherosclerosis, cystatin C, cholesterol, platelet activation, platelet aggregation, immobilization
National Category
General Practice
Identifiers
URN: urn:nbn:se:oru:diva-65003ISBN: 978-91-7529-243-4 (print)OAI: oai:DiVA.org:oru-65003DiVA, id: diva2:1182684
Public defence
2018-06-07, Örebro universitet, Campus USÖ, hörsal C3, Södra Grev Rosengatan 32, Örebro, 09:15 (Swedish)
Opponent
Supervisors
Available from: 2018-02-14 Created: 2018-02-14 Last updated: 2018-05-15Bibliographically approved
List of papers
1. Effect of prolonged standardized bed rest on cystatin C and other markers of cardiovascular risk
Open this publication in new window or tab >>Effect of prolonged standardized bed rest on cystatin C and other markers of cardiovascular risk
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2011 (English)In: BMC Physiology, ISSN 1472-6793, E-ISSN 1472-6793, Vol. 11, article id 17Article in journal (Refereed) Published
Abstract [en]

BACKGROUND: Sedentary lifestyle is associated with coronary artery disease but even shorter periods of physical inactivity may increase cardiovascular risk. Cystatin C is independently associated with cardiovascular disease and our objective was to investigate the relation between this novel biomarker and standardized bed rest. Research of immobilization physiology in humans is challenging because good biological models are in short supply. From the Women International Space simulation for Exploration study (WISE) we studied markers of atherosclerosis and kidney function, including cystatin C, in a standardized bed rest study on healthy volunteers. Fifteen healthy female volunteers participated in a 20-day ambulatory control period followed by 60 days of bed rest in head-down tilt position (-6°) 24 h a day, finalized by 20 days of recovery. The subjects were randomized into two groups during bed rest: a control group (n = 8) that remained physically inactive and an exercise group (n = 7) that participated in both supine resistance and aerobic exercise training.

RESULTS: Compared to baseline values there was a statistically significant increase in cystatin C in both groups after bed rest (P < 0.001). Glomerular filtration rate (GFR), calculated by both cystatin C and Cockcroft-Gault equation, decreased after bed rest while there were no differences in creatinine or creatine kinase levels. CRP did not change during bed rest in the exercise group, but there was an increase of CRP in the control group during recovery compared to both the baseline and the bed rest periods. The apo-B/apo-Ai ratio increased during bed rest and decreased again in the recovery period. Subjects experienced a small but statistically significant reduction in weight during bed rest and compared to baseline weights remained lower at day 8 of recovery.

CONCLUSION: During and following prolonged standardized bed rest the concentrations of several clinically relevant cardiovascular risk markers change.

Place, publisher, year, edition, pages
BioMed Central, 2011
National Category
Cardiac and Cardiovascular Systems
Identifiers
urn:nbn:se:oru:diva-66787 (URN)10.1186/1472-6793-11-17 (DOI)22152087 (PubMedID)2-s2.0-83055192077 (Scopus ID)
Available from: 2018-04-26 Created: 2018-04-26 Last updated: 2018-08-27Bibliographically approved
2. Brown Bears (Ursus arctos) Seem Resistant to Atherosclerosis Despite Highly Elevated Plasma Lipids during Hibernation and Active State
Open this publication in new window or tab >>Brown Bears (Ursus arctos) Seem Resistant to Atherosclerosis Despite Highly Elevated Plasma Lipids during Hibernation and Active State
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2012 (English)In: Clinical and Translational Science, ISSN 1752-8054, E-ISSN 1752-8062, Vol. 5, no 3, p. 269-272Article in journal (Refereed) Published
Abstract [en]

Hibernation is an extreme physiological challenge for the brown bear (Ursus arctos) in which metabolism is based mainly on lipids. The study objective was to compare plasma lipids in hibernating and active free-ranging brown bears and relate them to arterial histopathology. Blood was drawn from seven immobilized free-ranging brown bears (three females, 23 years old) during hibernation in February and from the same bears while active in June and analyzed by enzymatic and automated hematology methods within 48 hours of sampling. Left anterior descending coronary arteries and aortic arches from 12 bears (six females, 1.512 years old) killed in hunting were examined by histopathology. Total plasma cholesterol decreased from hibernation to the active period (11.08 +/- 1.04 mmol/L vs. 7.89 +/- 1.96 mmol/L, P= 0.0028) as did triglyceride (3.16 +/- 0.62 mmol/L vs. 1.44 +/- 0.27 mmol/L, P= 0.00012) and LDL cholesterol (4.30 +/- 0.71 mmol/L vs. 2.02 +/- 1.03 mmol/L, P= 0.0075), whereas HDL cholesterol was unchanged. No atherosclerosis, fatty streaks, foam cell infiltration, or inflammation were seen in any arterial samples. Brown bears tolerate elevated cholesterol levels, obesity, physical inactivity, and circulatory slow flow during hibernation without signs of -atherosclerosis. This species might serve as a reverse translational model for atherosclerosis resistance.

Place, publisher, year, edition, pages
Wiley-Blackwell, 2012
Keywords
apolipoproteins, cholesterol, hibernation physiology, triglycerides
National Category
Other Biological Topics
Identifiers
urn:nbn:se:oru:diva-58327 (URN)10.1111/j.1752-8062.2011.00370.x (DOI)000305077100014 ()22686205 (PubMedID)2-s2.0-84862224614 (Scopus ID)
Note

Funding Agencies:

NordForsk (an organization under the Nordic Council of Ministers)  44042

Available from: 2017-06-27 Created: 2017-06-27 Last updated: 2018-08-27Bibliographically approved
3. Downregulation of platelet activation markers during long-term immobilization
Open this publication in new window or tab >>Downregulation of platelet activation markers during long-term immobilization
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2013 (English)In: Platelets, ISSN 0953-7104, E-ISSN 1369-1635, Vol. 24, no 5, p. 369-374Article in journal (Refereed) Published
Abstract [en]

Immobilization and sedentary lifestyle are risk factors for venous thromboembolism and cardiovascular disease, yet little is known about platelet function during long-term physical inactivity. Our aim was to investigate platelet activation markers and their coupling to standardized immobilization: platelet-derived growth factor (PDGF-BB) and P-selectin. We studied 15 healthy females participating in the Women International Space simulation for Exploration study. Following a 20-day ambulatory control period, the subjects underwent 60 days of bed rest in head-down tilt position (-6 degrees) 24 hours a day, finalized by 20 days of recovery. The subjects were randomized into two groups during bed rest: a control group (n = 8) that remained physically inactive and an exercise group (n = 7) that participated in both supine resistance and aerobic exercise training. Blood samples for the analysis of platelet activation markers were collected at baseline (5 days before bed rest), after 44 days of bed rest and 8 days into the recovery period. Compared to baseline, the levels of P-selectin and PDGF-BB decreased after bed rest (by 55%, p = 0.01 and 73%, p < 0.03, respectively) and remained decreased in the recovery period (by 76%, p < 0.001 and 78%, p < 0.02, respectively, compared to baseline). Platelet count (baseline value for the exercise group 260 000/mu l +/- 34 000 and baseline value for the control group 210 000/mu l +/- 30 000) did not change during the bed rest study (two-way repeated measurements ANOVA, p = ns). There were no statistical differences between the physically inactive and the exercise group. During long-term immobilization, a known risk factor for thrombosis, the levels of P-selectin and PDGF-BB decreased. Our findings indicate downregulation of platelet activation during immobilization.

Place, publisher, year, edition, pages
Taylor & Francis, 2013
Keywords
Platelets, P-selectin, PDGF, immobilization, thrombosis
National Category
Hematology Cardiac and Cardiovascular Systems
Identifiers
urn:nbn:se:oru:diva-56417 (URN)10.3109/09537104.2012.715215 (DOI)000321065000005 ()22931233 (PubMedID)2-s2.0-84879764932 (Scopus ID)
Available from: 2017-03-16 Created: 2017-03-16 Last updated: 2018-05-27Bibliographically approved
4. Biochemical Foundations of Health and Energy Conservation in Hibernating Free-Ranging Subadult Brown Bear Ursus arctos
Open this publication in new window or tab >>Biochemical Foundations of Health and Energy Conservation in Hibernating Free-Ranging Subadult Brown Bear Ursus arctos
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2016 (English)In: Journal of Biological Chemistry, ISSN 0021-9258, E-ISSN 1083-351X, Vol. 291, no 43, p. 22509-22523Article in journal (Refereed) Published
Abstract [en]

Brown bears (Ursus arctos) hibernate for 5-7 months without eating, drinking, urinating and defecating at a metabolic rate of only 25% of the summer activity rate. Nonetheless, they emerge healthy and alert in spring. We quantified the biochemical adaptations for hibernation by comparing the proteome, metabolome, and hematologic features of blood from hibernating and active free-ranging subadult brown bears with a focus on conservation of health and energy. We found that total plasma protein concentration increased during hibernation, even though the concentrations of most individual plasma proteins decreased, as did the white blood cell types. Strikingly, antimicrobial defense proteins increased in concentration. Central functions in hibernation involving the coagulation response and protease inhibition, as well as lipid transport and metabolism, were upheld by increased levels of very few key or broad-specificity proteins. The changes in coagulation factor levels matched the changes in activity measurements. A dramatic 45-fold increase in sex-hormone-binding-globulin SHBG levels during hibernation draws, for the first time, attention to its significant but unknown role in maintaining hibernation physiology. We propose that energy for the costly protein synthesis is reduced by three mechanisms, (i) dehydration, which increases protein concentration without de novo synthesis; (ii) reduced protein degradation rates due to a 6 °C reduction in body temperature, and decreased protease activity; and (iii) a marked redistribution of energy resources only increasing de novo synthesis of few key proteins. This comprehensive global data identified novel biochemical strategies for bear adaptations to the extreme condition of hibernation, and have implications for our understanding of physiology in general.

Place, publisher, year, edition, pages
Rockville, USA: American Society for Biochemistry and Molecular Biology, 2016
Keywords
Antimicrobial proteins, blood constituents, coagulation factor, complement system, hibernation physiology, metabolomics, protein turnover, proteomics, sex hormone-binding globulin (SHBG)
National Category
Biochemistry and Molecular Biology
Research subject
Biochemistry
Identifiers
urn:nbn:se:oru:diva-52176 (URN)10.1074/jbc.M116.742916 (DOI)000386760600013 ()27609515 (PubMedID)2-s2.0-84992343533 (Scopus ID)
Note

Funding Agency:

Lundbech Foundation R126-2012-12408

Aalborg University

Available from: 2016-09-21 Created: 2016-09-14 Last updated: 2018-07-16Bibliographically approved
5. Physical inactivity and platelet function in humans and brown bears: A comparative study
Open this publication in new window or tab >>Physical inactivity and platelet function in humans and brown bears: A comparative study
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2018 (English)In: Platelets, ISSN 0953-7104, E-ISSN 1369-1635, Vol. 29, no 1, p. 87-90Article in journal (Refereed) Published
Abstract [en]

Physical inactivity increases the risk of thromboembolism. However, good standardized human models on inactivity are in short supply and experimental models are few.

Our objective was to investigate how standardized bed rest affects platelet aggregation in humans and to investigate if aggregation is altered in a translational model system - the hibernating brown bear (Ursus arctos). We collected blood from (1) healthy male volunteers participating in a 21-day bed rest study in head-down tilt position (-6°) 24 h a day; (2) free-ranging brown bears captured during winter hibernation and again during active state in summer. We analyzed platelet function using multiple electrode platelet aggregometry. In total, 9 healthy male volunteers (age 31.0 ± 6.4 years) and 13 brown bears (7 females and 6 males, age 2.8 ± 0.6 years) were included. In hibernating bears adenosine diphosphate, arachidonic acid, thrombin receptor activating peptide, and collagen impedance aggregometry tests were all halved compared to summer active state. In human volunteers no statistically significant changes were found between baseline and the end of bed rest. In human male volunteers 3 weeks of bed rest did not affect platelet function. In hibernating brown bears platelet aggregation was halved compared to summer and we hypothesize that this is a protective measure to avoid formation of thrombi under periods of low blood flow.

Place, publisher, year, edition, pages
Taylor & Francis, 2018
Keywords
Thrombosis; Platelets; Platelet aggregation; Immobilization
National Category
Physiology Medical Biotechnology (with a focus on Cell Biology (including Stem Cell Biology), Molecular Biology, Microbiology, Biochemistry or Biopharmacy) Hematology
Identifiers
urn:nbn:se:oru:diva-61740 (URN)10.1080/09537104.2017.1336530 (DOI)000423584700015 ()28758823 (PubMedID)2-s2.0-85026519068 (Scopus ID)
Available from: 2017-11-01 Created: 2017-11-01 Last updated: 2018-08-16Bibliographically approved

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