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| 3. |
- Asif, Sana, et al.
(författare)
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Heparinization of cell surfaces with short peptide-conjugated PEG-lipid regulates thromboinflammation in transplantation of human MSCs and hepatocytes
- 2016
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Ingår i: Acta Biomaterialia. - : Elsevier BV. - 1742-7061 .- 1878-7568. ; 35, s. 194-205
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Tidskriftsartikel (refereegranskat)abstract
- Infusion of therapeutic cells into humans is associated with immune responses, including thromboinflammation, which result in a large loss of transplanted cells\ To address these problems, heparinization of the cell surfaces was achieved by a cell-surface modification technique using polyethylene glycol conjugated phospholipid (PEG-lipid) derivatives. A short heparin-binding peptide was conjugated to the PEG-lipid for immobilization of heparin conjugates on the surface of human mesenchymal stem cells (hMSCs) and human hepatocytes. Here three kinds of heparin-binding peptides were used for immobilizing heparin conjugates and examined for the antithrombogenic effects on the cell surface. The heparinized cells were incubated in human whole blood to evaluate their hemocompatibility by measuring blood parameters such as platelet count, coagulation markers, complement markers, and Factor Xa activity. We found that one of the heparin-binding peptides did not show cytotoxicity after the immobilization with heparin conjugates. The degree of binding of the heparin conjugates on the cell surface (analyzed by flow cytometer) depended on the ratio of the active peptide to control peptide. For both human MSCs and hepatocytes in whole-blood experiments, no platelet aggregation was seen in the heparin conjugate-immobilized cell group vs. the controls (non-coated cells or control peptide). Also, the levels of thrombin-antithrombin complex (TAT), C3a, and sC5b-9 were significantly lower than those of the controls, indicating a lower activation of coagulation and complement. Factor Xa analysis indicated that the heparin conjugate was still active on the cell surface at 24 h post-coating. It is possible to immobilize heparin conjugates onto hMSC and human hepatocyte surfaces and thereby protect the cell surfaces from damaging thromboinflammation. Statement of Signigficance We present a promising approach to enhance the biocompatibility of therapeutic cells. Here we used short peptide-conjugated PEG-lipid for cell surface modification and heparin conjugates for the coating of human hepatocytes and MSCs. We screened the short peptides to find higher affinity for heparinization of cell surface and performed hemocompatibility assay of heparinized human hepatocytes and human MSCs in human whole blood. Using heparin-binding peptide with higher affinity, not only coagulation activation but also complement activation was significantly suppressed. Thus, it was possible to protect human hepatocytes and human MSCs from the attack of thromboinflammatory activation, which can contribute to the improvement graft survival. (C) 2016 Acta Materialia Inc. Published by Elsevier Ltd. All rights reserved.
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| 4. |
- Gustafson, Elisabet, et al.
(författare)
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Control of IBMIR Induced by Fresh and Cryopreserved Hepatocytes by Low Molecular Weight Dextran Sulfate Versus Heparin
- 2017
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Ingår i: Cell Transplantation. - : Sage Publications. - 0963-6897 .- 1555-3892. ; 26:1, s. 71-81
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Tidskriftsartikel (refereegranskat)abstract
- Rapid destruction of hepatocytes after hepatocyte transplantation has hampered the application of this procedure clinically. The instant blood-mediated inflammatory reaction (IBMIR) is a plausible underlying cause for this cell loss. The present study was designed to evaluate the capacity of low molecular weight dextran sulfate (LMW-DS) to control these initial reactions from the innate immune system. Fresh and cryopreserved hepatocytes were tested in an in vitro whole-blood model using ABO-compatible blood. The ability to elicit IBMIR and the capacity of LMW-DS (100 mu g/ml) to attenuate the degree of activation of the cascade systems were monitored. The effect was also compared to conventional anticoagulant therapy using unfractionated heparin (1 IU/ml). Both fresh and freeze thawed hepatocytes elicited IBMIR to the same extent. LMW-DS reduced the platelet loss and maintained the cell counts at the same degree as unfractionated heparin, but controlled the coagulation and complement systems significantly more efficiently than heparin. LMW-DS also attenuated the IBMIR elicited by freeze thawed cells. Therefore, LMW-DS inhibits the cascade systems and maintains the cell counts in blood triggered by both fresh and cryopreserved hepatocytes in direct contact with ABO-matched blood. LMW-DS at a previously used and clinically applicable concentration (100 mu g/ml) inhibits IBMIR in vitro and is therefore a potential IBMIR inhibitor in hepatocyte transplantation.
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| 5. |
- Gustafson, Elisabet K., et al.
(författare)
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Exposure of von Willebrand Factor on Isolated Hepatocytes Promotes Tethering of Platelets to the Cell Surface
- 2019
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Ingår i: Transplantation. - : Wolters Kluwer. - 0041-1337 .- 1534-6080. ; 103:8, s. 1630-1638
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Tidskriftsartikel (refereegranskat)abstract
- Background. Hepatocyte transplantation (Hctx) is a potentially attractive method for the treatment of acute liver failure and liver-based metabolic disorders. Unfortunately, the procedure is hampered by the instant blood-mediated inflammatory reaction (IBMIR), a thromboinflammatory response elicited by the vascular innate immune system, causing activation of the coagulation and complement systems and clearance of transplanted cells. Observations have also revealed platelets adhered to the surface of the hepatocytes (Hc). To establish Hctx as a clinical treatment, all factors that trigger IBMIR need to be identified and controlled. This work explores the expression of von Willebrand factor (VWF) on isolated Hc resulting in tethering of platelets. Methods. VWF on Hc was studied by flow cytometry, confocal microscopy, immunoblot, and real-time polymerase chain reaction. Interaction between Hc and platelets was studied in a Chandler loop model. Adhesion of platelets to the hepatocyte surface was demonstrated by flow cytometry and confocal microscopy. Results. Isolated Hc constitutively express VWF on their cell surface and mRNA for VWF was found in the cells. Hc and platelets, independently of coagulation formed complexes, were shown by antibody blocking studies to be dependent on hepatocyte-associated VWF and platelet-bound glycoprotein Ib alpha. Conclusions. VWF on isolated Hc causes, in contact with blood, adhesion of platelets, which thereby forms an ideal surface for coagulation. This phenomenon needs to be considered in hepatocyte-based reconstitution therapy and possibly even in other settings of cell transplantation.
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| 6. |
- Gustafson, Elisabet
(författare)
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Thromboinflammation : in a Model of Hepatocyte Transplantation
- 2016
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Doktorsavhandling (övrigt vetenskapligt/konstnärligt)abstract
- Hepatocyte transplantation is an attractive method for the treatment of metabolic liver disease and acute liver failure. The clinical application of this method has been hampered by a large initial loss of transplanted cells.This thesis has identified and characterized an instant blood-mediated inflammatory reaction (IBMIR), which is a thromboinflammatory response from the innate immunity that may partly explain the observed loss of cells. In vitro perifusion experiments were performed and established that hepatocytes in contact with blood activate the complement and coagulation systems and induce clot formation in conjunction with the recruitment of neutrophils. Within an hour, the hepatocytes were surrounded by platelets and entrapped in a clot infiltrated by neutrophils. Furthermore, hepatocytes expressed tissue factor (TF), and the reactions were shown to be initiated through the TF pathway. Monitoring of hepatocyte transplantation in vivo revealed activation of the same parameters as were noted in vitro.For the first time, von Willebrand factor (vWF) was identified on the hepatocyte surface, being demonstrated by flow cytometry and confocal microscopy. mRNA for vWF was also confirmed in hepatocytes. Complex formation between platelets and hepatocytes was also identified. Addition of antibodies targeting the binding site for vWF on the platelets reduced the complex formation.Two different strategies, systemic and local intervention, were applied to diminish the thromboinflammation elicited from the hepatocytes in contact with ABO-matched blood. Systemic inhibition with LMW-DS, in a clinically applicable dose, was found to be superior in controlling the IBMIR in vitro when compared to heparin. Cryopreserved hepatocytes elicited the IBMIR to the same extent as did fresh hepatocytes, and the IBMIR was equally well controlled with LMW-DS in both cryopreserved and fresh cells.Hepatocytes were coated with two layers of immobilized heparin in an attempt to protect the cells from the IBMIR. In vitro perifusion experiments showed heparinized hepatocytes triggered a significantly lower degree of IBMIR.
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| 7. |
- Hörnsten, Carl, et al.
(författare)
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High blood pressure as a risk factor for incident stroke among very old people : a population-based cohort study
- 2016
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Ingår i: Journal of Hypertension. - 0263-6352 .- 1473-5598. ; 34:10, s. 2059-2065
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Tidskriftsartikel (refereegranskat)abstract
- INTRODUCTION: High blood pressure (BP) increases the risk of stroke, but there is limited evidence from studies including very old people. The aim was to investigate risk factors for incident stroke among very old people.METHODS: A prospective population-based cohort study was performed among participants aged at least 85 years in northern Sweden. The 955 participants were tested at their homes. BP was measured manually after 5-min supine rest. Incident stroke data were collected from medical charts guided by hospital registry, death records, and 5-year reassessments. Cox proportional hazards models were used.RESULTS: The stroke incidence was 33.8/1000 person-years (94 stroke events) during a mean follow-up period of 2.9 years. In a comprehensive multivariate model, atrial fibrillation [hazard ratio 1.85, 95% confidence interval (CI) 1.07-3.19] and higher SBP (hazard ratio 1.19, 95% CI 1.08-1.30 per 10-mmHg increase) were associated with incident stroke overall. However, higher SBP was not associated with incident stroke in participants with SBP less than 140 mmHg (hazard ratio 0.90, 95% CI 0.53-1.53 per 10-mmHg increase). In additional multivariate models, DBP at least 90 mmHg (hazard ratio 2.45, 95% CI 1.47-4.08) and SBP at least 160 mmHg (vs. <140 mmHg; hazard ratio 2.80, 95% CI 1.53-5.14) were associated with incident stroke. The association between BP and incident stroke was not affected by interactions related to sex, dependence in activities of daily living, or cognitive impairment.CONCLUSION: High SBP (≥160 mmHg) and DBP (≥90 mmHg) and atrial fibrillation appeared to be risk factors for incident stroke among very old people.
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| 8. |
- Hörnsten, Carl, 1985-
(författare)
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Stroke and depression in very old age
- 2016
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Doktorsavhandling (övrigt vetenskapligt/konstnärligt)abstract
- Background The prevalence and incidence of stroke are known to increase with age, which, combined with demographic change, means that very old patients with stroke are a growing patient group. Risk factors for incident stroke among very old people have not been widely investigated. The impact of depression on mortality in very old people who have had a stroke also remains unclear. The aim of this thesis was to investigate the risk factors for incident stroke, the epidemiology of stroke and depression, and the consequences of having had a stroke regarding the risk of depression and mortality among very old people.Methods A randomly selected half of 85-, all 90-, and all ≥95-year-olds in certain municipalities in Västerbotten County, Sweden, and Pohjanmaa County, Finland were targeted in a population-based cohort study from 2000-2012. The 65-, 70-, 75-, and 80-year-olds in all the rural and random samples from the urban municipalities in the same counties were furthermore targeted in a survey in 2010.In the cohort study patients were assessed in their homes, by means of the 15-item Geriatric Depression Scale (GDS-15) and other assessment scales, as well as blood pressure measurements, several physical tests, and a review of medical diagnoses appearing in the medical charts. Incident stroke data were collected from medical charts guided by hospital registry records, cause of death records, and reassessments after 5 years. Depression was defined as a GDS-15 score ≥5. A clinical definition of all depressive disorders, based on assessment scale scores and review of medical charts was also used. A specialist in geriatric medicine evaluated the diagnoses. The survey included yes/no questions about stroke and depression status, and the 4-item Geriatric Depression Scale. Associations with mortality and incident stroke were tested using Cox proportional-hazard models. Results In the ≥85-year-olds examined in 2005-2007 (n=601), the stroke prevalence was 21.5%, the prevalence of all depressive disorders was 37.8% and stroke was independently associated with depressive disorders (odds ratio 1.644, p=0.038). The prevalence of depression according to GDS-15 scores was 43.2% in people with stroke compared with 25.0% in people without stroke (p=0.001). However, in ≥85-year-olds examined in Sweden from 2000-2012 (n=955), from all past data collections in the study, depression was not independently associated with incident stroke. In ≥65-year-olds who responded to a survey in 2010 (n=6098), the stroke prevalence rose with age from 4.7% among the 65- to 11.6% among the 80-year-olds (p<0.001). The prevalence of depression rose from 11.0% among the 65- to 18.1% among the 80-year-olds (p<0.001). In the group with stroke, depression was independently associated with dependence in personal activities of daily living and having a life crisis the preceding year, while in the non-stroke group, depression was independently associated with several additional demographic, social and health factors.In ≥85-year-olds examined in 2005-2007 with valid GDS-15 tests (n=452), having had a stroke was associated with increased 5-year mortality [hazard ratio (HR) 1.53, 95% confidence interval (CI) 1.15-2.03]. Having had a stroke and depression was associated with increased 5-year mortality compared with having only stroke (HR 1.90, 95% CI 1.15-3.13), having only depression (HR 1.59, 95% CI 1.03-2.45), and compared with having neither stroke nor depression (HR 2.50, 95% CI 1.69-3.69). Having only stroke without a depression did not increase mortality compared with having neither stroke nor depression.In ≥85-year-olds examined in Sweden from 2000-2012 (n=955), from all past data collections in the study, the stroke incidence was 33.8/1000 person-years during a mean follow-up period of about three years. In a comprehensive multivariate model, atrial fibrillation (HR 1.85, 95% CI 1.07–3.19) and higher systolic blood pressure (SBP; HR 1.19, 95% CI 1.08–1.30 per 10-mmHg increase) were associated with incident stroke overall. In additional multivariate models, diastolic blood pressure (DBP) ≥90 mmHg (HR 2.45, 95% CI 1.47–4.08) and SBP ≥160 mmHg (v. <140 mmHg; HR 2.80, 95% CI 1.53–5.14) were associated with incident stroke.Conclusion The prevalence of both stroke and depression increased with age, and rates were especially high among very old people. Having had a stroke was independently associated with a higher prevalence of depression among very old people, however, depression was not independently associated with a higher incidence of stroke. Having had a stroke was associated with increased all-cause mortality among very old people, but only among those who were also depressed. High SBP (≥160 mmHg), DBP (≥90 mmHg) and atrial fibrillation were the only consistent independent risk factors for incident stroke among very old people.
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| 10. |
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| 11. |
- Li, Man-Bo, et al.
(författare)
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Diastereoselective Cyclobutenol Synthesis : A Heterogeneous Palladium-Catalyzed Oxidative Carbocyclization-Borylation of Enallenols
- 2019
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Ingår i: Chemistry - A European Journal. - : Wiley. - 0947-6539 .- 1521-3765. ; 25:1, s. 210-215
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Tidskriftsartikel (refereegranskat)abstract
- A highly selective and efficient oxidative carbocyclization/borylation of enallenols catalyzed by palladium immobilized on amino-functionalized siliceous mesocellular foam (Pd-AmP-MCF) was developed for diastereoselective cyclobutenol synthesis. The heterogeneous palladium catalyst can be recovered and recycled without any observed loss of activity or selectivity. The high diastereoselectivity of the reaction is proposed to originate from a directing effect of the enallenol hydroxyl group. Optically pure cyclobutenol synthesis was achieved by the heterogeneous strategy by using chiral enallenol obtained from kinetic resolution.
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| 12. |
- Nilsson Ekdahl, Kristina, et al.
(författare)
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Dangerous liaisons : complement, coagulation, and kallikrein/kinin cross-talk act as a linchpin in the events leading to thromboinflammation
- 2016
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Ingår i: Immunological Reviews. - : Wiley. - 0105-2896 .- 1600-065X. ; 274:1, s. 245-269
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Forskningsöversikt (refereegranskat)abstract
- Innate immunity is fundamental to our defense against microorganisms. Physiologically, the intravascular innate immune system acts as a purging system that identifies and removes foreign substances leading to thromboinflammatory responses, tissue remodeling, and repair. It is also a key contributor to the adverse effects observed in many diseases and therapies involving biomaterials and therapeutic cells/organs. The intravascular innate immune system consists of the cascade systems of the blood (the complement, contact, coagulation, and fibrinolytic systems), the blood cells (polymorphonuclear cells, monocytes, platelets), and the endothelial cell lining of the vessels. Activation of the intravascular innate immune system in vivo leads to thromboinflammation that can be activated by several of the system's pathways and that initiates repair after tissue damage and leads to adverse reactions in several disorders and treatment modalities. In this review, we summarize the current knowledge in the field and discuss the obstacles that exist in order to study the cross-talk between the components of the intravascular innate immune system. These include the use of purified in vitro systems, animal models and various types of anticoagulants. In order to avoid some of these obstacles we have developed specialized human whole blood models that allow investigation of the cross-talk between the various cascade systems and the blood cells. We in particular stress that platelets are involved in these interactions and that the lectin pathway of the complement system is an emerging part of innate immunity that interacts with the contact/coagulation system. Understanding the resulting thromboinflammation will allow development of new therapeutic modalities.
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| 13. |
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| 14. |
- Rotundi, Alessandra, et al.
(författare)
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Dust measurements in the coma of comet 67P/Churyumov-Gerasimenko inbound to the Sun
- 2015
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Ingår i: Science. - : American Association for the Advancement of Science (AAAS). - 0036-8075 .- 1095-9203. ; 347:6220
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Tidskriftsartikel (refereegranskat)abstract
- Critical measurements for understanding accretion and the dust/gas ratio in the solar nebula, where planets were forming 4.5 billion years ago, are being obtained by the GIADA (Grain Impact Analyser and Dust Accumulator) experiment on the European Space Agency's Rosetta spacecraft orbiting comet 67P/Churyumov-Gerasimenko. Between 3.6 and 3.4 astronomical units inbound, GIADA and OSIRIS (Optical, Spectroscopic, and Infrared Remote Imaging System) detected 35 outflowing grains of mass 10(-10) to 10(-7) kilograms, and 48 grains of mass 10(-5) to 10(-2) kilograms, respectively. Combined with gas data from the MIRO (Microwave Instrument for the Rosetta Orbiter) and ROSINA (Rosetta Orbiter Spectrometer for Ion and Neutral Analysis) instruments, we find a dust/gas mass ratio of 4 +/- 2 averaged over the sunlit nucleus surface. A cloud of larger grains also encircles the nucleus in bound orbits from the previous perihelion. The largest orbiting clumps are meter-sized, confirming the dust/gas ratio of 3 inferred at perihelion from models of dust comae and trails.
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| 15. |
- Teramura, Yuji, et al.
(författare)
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A cell glue : Inducing cell adhesion using surface modification with cell-penetrating peptide-peg-lipid for 3d cell structures
- 2019
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Ingår i: The Pinnacle of Biomaterials Innovationand Excellence. - : Society for Biomaterials. - 9781510883901 ; , s. 678-
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Konferensbidrag (refereegranskat)abstract
- Statement of Purpose: The ultimate goal of regenerative therapy is the transplantation of functional stem cells-derived tissues and organs to replace those lost as the result of pathology or tissue damage. Since tissues and organs are complicated 3D structures, 3D scaffolds such as decellularized organs and tissues, are required to properly orient living functional cells of different types. 3D scaffolds offer an environment for cell adhesion that differs from that of conventional 2D culture. Therefore, the induction and control of cell attachment, not only to 2D substrate surfaces but also to 3D scaffolds, is of great importance. Here, we propose new type of cell glue made of cell-penetrating peptides (CPP) and PEG-conjugated lipid, which are used for cell-surface modification. PEG-lipid derivatives are incorporated into the lipid bilayer membranes of cells via hydrophobic interactions, and the CPP anchored onto the cell membrane could work as an adhesive domain. In our study, various floating cells, (i.e., T cells, B cells) were used to examine the adhesive efficacy by cell surface modification with CPP-PEG-lipid onto material surface as well as PS microfiber-based 3D scaffolds.
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| 16. |
- Teramura, Yuji, et al.
(författare)
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Cell Adhesion Induced Using Surface Modification with Cell-Penetrating Peptide-Conjugated Poly(ethylene glycol)-Lipid : A New Cell Glue for 3D Cell-Based Structures
- 2017
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Ingår i: ACS Applied Materials and Interfaces. - : American Chemical Society (ACS). - 1944-8244 .- 1944-8252. ; 9:1, s. 244-254
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Tidskriftsartikel (refereegranskat)abstract
- We synthesized a novel material, cell-penetrating peptide conjugated poly(ethylene glycol)-lipid (CPP-PEG-lipid), that can induce the adhesion of floating cells. Firm cell adhesion with spreading could be induced by cell surface modification with the CPP-PEG-lipids. Cell adhesion was induced by CPPs but not by any other cationic short peptides we tested. Here, we demonstrated adherence using the floating cell line CCRF-CEM as well as primary human T cells, B cells, erythrocytes, and hepatocytes. As compared to cells grown in suspension, adherent cells were more rapidly induced to attach to substrates with the cell-surface modification. The critical factor for attachment was localization of CPPs at the cell membrane by PEG-lipids with PEG > 20 kDa. These cationic CPPs on PEG chains were able to interact with substrate surfaces such as polystyrene (PS) surfaces, glass surfaces, and PS microfibers that are negatively charged, inducing firm cell adhesion and cell spreading. Also, as opposed to normal cationic peptides that interact strongly with cell membranes, CPPs were less interactive with the cell surfaces because of their cell-penetrating property, making them more available for adhering cells to the substrate surface. No effects on cell viability or cell proliferation were observed after the induction of cell adhesion. With this technique, cells could be easily immobilized onto PS microfibers, an important step in fabricating 3D cell-based structures. Cells immobilized onto 3D PS microfibers were alive, and human hepatocytes showed normal production of urea and albumin on the microfibers. This method is novel in inducing firm cell adhesion-via a one-step treatment.
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| 17. |
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| 18. |
- Weidung, Bodil, et al.
(författare)
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Blood Pressure, Gait Speed, and Mortality in Very Old Individuals : A Population-Based Cohort Study
- 2015
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Ingår i: Journal of the American Medical Directors Association. - : Elsevier BV. - 1525-8610 .- 1538-9375. ; 16:3, s. 208-214
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Tidskriftsartikel (refereegranskat)abstract
- Objectives: Clinical trials and observational studies have produced contradictory results regarding the association of blood pressure (BP) and mortality in people aged 80 years or older. Gait speed at usual pace has been shown to moderate this association in a population of noninstitutionalized people aged 65 years or older. The aims of this study were to investigate the association of BP with all-cause mortality in a representative sample of people aged 85 years or older and to assess whether gait speed moderates this association.Design, Setting, and Participants: A total of 806 participants in the population-based prospective Umeå 85+/GERDA study aged 85, 90, and 95 years or older.Measurements: Gait speed at usual pace was measured over 2.4 m. The main outcome was hazard ratios (HRs) for all-cause mortality according to systolic and diastolic BP categories in the total sample and in faster-walking (≥0.5 m/s, n = 312) and slower-walking (<0.5 m/s, n = 433) subcohorts; the latter also included habitually nonwalking participants. Comprehensive adjustments were made for sociodemographic and clinical characteristics associated with death.Results: Mean age and baseline systolic and diastolic BP were 89.6 ± 4.6 years, 146.8 ± 23.9 mm Hg, and 74.8 ± 11.1 mm Hg, respectively. Most (n = 561 [69%]) participants were women, 315 (39%) were care facility residents, and 566 (70%) were prescribed BP-lowering drugs. Within 5 years, 490 (61%) participants died. In the total sample and slower-walking subcohort, systolic BP appeared to be inversely associated with mortality, although not independent of adjustments. Among faster-walking participants, mortality risk after adjustment was more than 2 times higher in those with systolic BP of 140 to 149 mm Hg (HR = 2.25, 95% confidence interval [CI] = 1.03–4.94) and 165 mm Hg or higher (HR = 2.13, 95% CI = 1.01–4.49), compared with systolic BP of 126 to 139 mm Hg. Mortality risk was also independently higher in faster-walking participants with diastolic BP higher than 80 mm Hg, compared with diastolic BP of 75 to 80 mm Hg (HR = 1.76, 95% CI = 1.07–2.90).Conclusion: The gait speed threshold of 0.5 m/s may be clinically useful for the distinction of very old people with and without increased all-cause mortality risk due to elevated systolic and diastolic BP.
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| 19. |
- Weidung, Bodil, 1988-
(författare)
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Blood pressure in very old age : determinants, adverse outcomes, and heterogeneity
- 2016
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Doktorsavhandling (övrigt vetenskapligt/konstnärligt)abstract
- Background: High blood pressure (BP) is the leading risk factor for disease and mortality worldwide. However, risks associated with high BP in very old age (≥ 80 or ≥ 85 years) are not entirely understood, as the majority of scientific studies have been performed with younger populations and existing scientific knowledge about very old individuals is sometimes contradictory. Results of previous studies of very old individuals suggest that the associations of BP with mortality and stroke differ with levels of physical and cognitive function. More studies that are representative of very old individuals, including individuals with multimorbidity, that are of adequate size, involve proper adjustment, and investigate non-linear associations, are needed to investigate these issues.Systolic blood pressure (SBP) decline is common among very old individuals and has been shown to precede adverse events. Previous studies have shown that SBP change is associated with baseline SBP, age, and health-related factors, but determinants of SBP change have not been investigated using comprehensive, multivariate models.The three main aims of this thesis were to investigate, in a sample of individuals aged ≥ 85 years, 1) determinants of SBP change, 2) the association of BP with mortality risk and whether this association differs with respect to gait speed and/or Mini-Mental State Examination (MMSE) score, and 3) the association of BP with stroke risk and whether this association differs with respect to the Barthel Activities of Daily Living (ADL) index and/or MMSE score.Methods: The studies conducted for this thesis were based on data from the population-based Umeå 85+/Gerontological regional database study, which provided cross-sectional and longitudinal data on socioeconomic factors, medical conditions, drug prescriptions, and health-related assessments from 2000 to 2015. Participants were aged 85, 90, and ≥ 95 years, and lived in Västerbotten, Sweden, and Österbotten/Pohjanmaa, Finland. Follow-up assessments were conducted after 5 years. Mortality data were collected after 2 and 5 years, and stroke data were collected after 5 years, from death certificates, medical records, population registers, and the inpatient diagnosis register. Comprehensive multivariate models were developed to investigate determinants of SBP change using multiple linear regression, and to investigate associations of mortality and stroke risks with BP using Cox proportional-hazard regression models.Results: Average (± standard deviation) baseline SBP was 146 ± 23 mm Hg, and average diastolic blood pressure (DBP) was 74 ± 11 mm Hg. Within 5 years, 61% of participants had died and 10% had had incident strokes. Among participants followed for 5 years, the average annual SBP decline was 2.6 ± 5.4 mm Hg.In a multivariate model, SBP decline was associated with later investigation year (p = .009), higher baseline SBP (p < .001), baseline antidepressant drug use (p = .011), incident acute myocardial infarction during follow-up (p = .003), use of a new diuretic drug during follow-up (p = .044), and declining Barthel ADL index scores during follow-up (p < .001).In an age- and sex-adjusted analysis of the total sample, mortality risk was decreased in higher (vs. lower) BP categories (SBP ≥ 165 vs. ≤ 125 mm Hg: hazard ratio [HR] .50, p < .001; DBP 70–74 vs. 75–80 mm Hg: HR 1.32, p = .031). In a comprehensively adjusted analysis of the total sample, SBP was not associated significantly with mortality risk. The associations of SBP with mortality in the gait speed < .5 m/s subcohort corresponded with those found in the total sample. In comprehensively adjusted analyses in the gait speed ≥ .5 m/s subcohort, mortality risk increased independently with higher (vs. lower) BP (SBP ≥ 165 vs. 126–139 mm Hg: HR 2.13, p = .048; DBP > 80 vs. 75–80 mm Hg: HR 1.76, p = .026). In comprehensively adjusted analyses in the MMSE score subcohorts, SBP was associated significantly with mortality risk only in the 0–10 MMSE score subcohort; high and low SBP categories were associated independently with increased mortality risk, compared with an intermediary SBP category (SBP ≥ 165 vs. 126–139 mm Hg; HR 4.54, p = .007; SBP ≤ 125 vs. 126–139 mm Hg: HR 2.23, p = .023). Higher BP was associated significantly with increased stroke risk in multivariate models (SBP per 10 mm Hg increment: HR 1.19, p < .001; DBP per 10 mm Hg increment: HR 1.26, p = .013). SBP was not associated with stroke risk in participants with SBP < 140 mm Hg.Interaction effects on the association with mortality were significant between SBP and gait speed (age- and sex-adjusted model: p = .031) but not between SBP and MMSE score. No interaction in the association with stroke was found between any BP measure and Barthel ADL index or MMSE score.Conclusion: The decline in BP in very old age may be explained by health-related factors. Low BP may be a risk marker for short life expectancy, due to morbidity, in the general very old population and among very old individuals with low gait speeds. High BP seems to be an independent risk factor for mortality only in certain groups, which may be distinguished by high gait speed or very severe cognitive impairment. High SBP and DBP seem to increase stroke risk in very old age. These findings may contribute to a better understanding of the risks of adverse outcomes in very old individuals with different BP levels, the importance of comorbidity for these risks, and the etiology of SBP change.
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| 20. |
- Weidung, Bodil, et al.
(författare)
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Systolic blood pressure decline in very old individuals is explained by deteriorating health : Longitudinal changes from Umea85+/GERDA
- 2017
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Ingår i: Medicine. - : Lippincott Williams & Wilkins. - 0025-7974 .- 1536-5964. ; 96:51
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Tidskriftsartikel (refereegranskat)abstract
- Declining systolic blood pressure (SBP) is common in very old age and is associated with adverse events, such as dementia. Knowledge of factors associated with SBP changes could explain the etiology of this decline in SBP. This study investigated longitudinal changes in socioeconomic factors, medical conditions, drug prescriptions, and assessments and their associations with SBP changes among very old followed individuals.The study was based on data from the Umea85+/Gerontological Regional Database (GERDA) cohort study, which provided cross-sectional and longitudinal data on participants aged 85, 90, and 95 years from 2000 to 2015. Follow-up assessments were conducted after 5 years. The main outcome was a change in SBP. Factors associated with SBP changes were assessed using multivariate linear regression models.In the Umea85+/GERDA study, 454 surviving individuals underwent follow-up assessment after 5 years. Of these, 297 had SBP measured at baseline and follow-up. The mean changestandard deviation in SBP was -12 +/- 25mm Hg. SBP decline was associated independently with later investigation year (P=.009), higher baseline SBP (P<.001), baseline antidepressant prescription (P=.011), incident acute myocardial infarction during follow-up (P=.003), new diuretic prescription during follow-up (P=.044), and a decline in the Barthel Activities of Daily Living index at follow-up (P<.001).In conclusion, SBP declines among very old individuals. This decline seems to be associated with initial SBP level, investigation year, and health-related factors.
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| 21. |
- Weidung, Bodil, et al.
(författare)
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The association between SBP and mortality risk differs with level of cognitive function in very old individuals
- 2016
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Ingår i: Journal of Hypertension. - 0263-6352 .- 1473-5598. ; 34:4, s. 745-752
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Tidskriftsartikel (refereegranskat)abstract
- Objective:Cognitive impairment and dementia are highly prevalent in very old populations. Cardiovascular disease is a common cause of death in people with dementia.This study investigated whether the association of blood pressure (BP) with mortality differed with respect to mini-mental state examination (MMSE) score in a representative sample of very old individuals.Methods:The sample consisted of 1115 participants aged 85, 90, and at least 95 years from the Umea85+/GErontological Regional DAtabase cohort study. The main outcome was all-cause mortality within 2 years according to BP and MMSE score, using Cox proportional-hazard regression models adjusted for sociodemographic and clinical characteristics associated with death.Results:Mean age, MMSE score, and SBP and DBP were 89.44.6 years, 21.1 +/- 7.6, 146.1 +/- 23.4mmHg, and 74.1 +/- 11.7mmHg, respectively. Within 2 years, 293 (26%) participants died. BP was not associated independently with mortality risk, except among participants with MMSE scores of 0-10 among whom mortality risk was increased in association with SBP at least 165mmHg and 125mmHg or less, compared with 126-139mmHg (adjusted hazard ratio 4.54, 95% confidence interval=1.52-13.60 and hazard ratio 2.23, 95% confidence interval=1.12-4.45, respectively). In age and sex-adjusted analyses, SBP 125mmHg or less was associated with increased mortality risk in participants with MMSE scores at least 18.Conclusion:In people aged at least 85 years, the association of SBP with mortality appears to differ with respect to MMSE score. Very old individuals with very severe cognitive impairment and low or high BP may have increased mortality risk.
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