The role of inflammation in cardiovascular co-morbidity in psychotic disorders
Prosjekt
- Prosjektnummer
- 2015041
- Ansvarlig person
- Ingrid Dieset
- Institusjon
- Oslo universitetssykehus HF
- Prosjektkategori
- Doktorgradsstipend
- Helsekategori
- Cardiovascular, Inflammatory and Immune System, Mental Health
- Forskningsaktivitet
- 2. Aetiology
Rapporter
Psychotic disorders are increasingly recognized as systemic diseases and in the recent years we have become aware that these patients face an additional burden in terms of cardiovascular and autoimmune diseases implying that disease mechanisms underlying psychotic disorders might involve inflammatory pathways. The overall aim of this PhD-project was to obtain better understanding as to why patients with psychotic disorders face a dramatically increased risk of developing CVD, beyond the risk accounted for by poor life style and environmental factors such as medication, by increasing the knowledge about the relationship between psychotic disorders and increased risk for cardiovascular disease (CVD) and to explore whether dysregulations in the immune system are involved. In particular the project aimed to determine the relationship between peripheral inflammatory activity and CVD risk factors in patients with psychotic disorders, to identify genetic risk involving immune-mediated diseases, CVD risk factors and psychotic disorders and finally to explore whether schizophrenia polygenic risk score is associated with CVD risk factors and markers of peripheral inflammatory activity.
In the first paper which is published in Frontiers in psychiatry, the candidate investigated whether pro-atherogenic lipid ratios differ in patients with psychosis vs. healthy controls, whether several inflammatory markers (high sensitivity C-reactive protein, pentraxin-3, osteoprotegerin, von Willebrand factor, glycoprotein 130, galectin-3, cathepsin S, myeloperoxidase and insulin-like growth factor binding protein 4) were dysregulated in patients with psychosis and if these were associated with increased CVD risk. The results indicated that low-grade inflammation and neutrophil activation may cause increased CVD risk in patients with psychotic disorders. In the second paper which is currently under review, the candidate explored whether leptin, adiponectin or L/A ratio could predict increased CVD in patients with psychotic disorders according to antipsychotic use. Low levels of adiponectin were associated with increased CVD risk regardless of treatment with antipsychotics. In the final paper which is currently in progress, the candidate is exploring a potential relationship between polygenic risk score for schizophrenia and the inflammatory markers (hsCRP and myeloperoxidase) and leptin, adiponectin or L/A ratio as identified in paper I and II.
All in all, this research project has adequately completed the aims that were defined at the onset. The PhD-thesis is somewhat delayed according to the original time line, but the candidate has completed two manuscripts and attended all PhD-courses. The intention is to complete the final paper presenting the results displaying the relationship between polygenic risk score for schizophrenia and inflammatory markers. A complete overview over the results derived from this project will be presented in a PhD dissertation .
The huge gap in life expectancy associated with psychotic disorders is an important public health issue that needs to be addressed. This PhD-project has added to the knowledge about the risk of developing CVD in patients with psychotic disorders, in particular it has uncovered potential mechanisms underlying the increased burden of CVD co-morbidity and consequently increased mortality. Ultimately, increasing this understanding will hopefully help clinicians identify those patients who are at risk of developing CVD so that proper preventive measures can be initiated by the health care system.
Nei
The overall aim for this PhD project is to explore why patients with psychotic disorders face an increased risk of developing cardiovascular disease (CVD), beyond the risk accounted for by poor life style and environmental factors such as medication.Evidence has suggested a link between the immune system and psychotic disorders. Using a translational approach this project explores the nature of the relationship between increased inflammatory activity and the presence of cardio-metabolic risk in patients with schizophrenia and bipolar disorder. By measuring markers of disease state and symptom load in patients with psychotic disorders, peripheral inflammatory markers in plasma as well as mRNA and several cardiovascular- and metabolic risk factors in a large sample (including patients and healthy controls) the project aims at identifying potential mechanisms underlying the excessive CVD risk associated with schizophrenia and bipolar disorder. In 2019 the candidate has identified a substantial increase in CVD risk in terms of higher atherogenic lipid ratios in patients with psychotic disorders, also after adjusting for a range of confounding factors such as antipsychotic medication, overweight, age, insulin resistance and smoking. Results showing that increased lipid ratios in schizophrenia patients are associated with neutrophil activation and oxidative stress are presented in a manuscript which is currently under review.
Nei
The main aim of this PhD-project is to gain knowledge about the underlying mechanisms as to why patients with severe mental disorders face an excessive burden of cardiovascular- and metabolic co-morbidity.The overall aim is to obtain better understanding as to why patients with psychotic disorders face a dramatically increased risk of developing cardiovascular disease (CVD), beyond the risk accounted for by poor life style and environmental factors such as medication. A growing body of literature has suggested a link between the immune system and psychotic disorders. Using a translational approach this project explores the nature of the relationship between increased inflammatory activity and the presence of cardio-metabolic risk in patients with schizophrenia and bipolar disorder. By measuring markers of disease state and symptom load in patients with psychotic disorders, peripheral inflammatory markers in plasma as well as mRNA and several cardiovascular- and metabolic risk factors in a large sample (including patients and healthy controls) the project aims at identifying potential mechanisms underlying the excessive CVD risk associated with schizophrenia and bipolar disorder. The project has identified a substantial increase in CVD risk in terms of higher atherogenic lipid ratios in patients with psychotic disorders, also after adjusting for a range of confounding factors such as antipsychotic medication, overweight, age, insulin resistance and smoking. In addition we have explored the potential role of several inflammatory markers known to be involved in CVD and found that this increase in lipid ratios in particular is associated with neutrophil activation and oxidative stress in patients with schizophrenia. These results are now in the process of being submitted to a peer-reviewed medical journal.
The current PhD project focuses on exploring the potential relationship between inflammatory activity and the presence of cardiovascular risk in patients with psychotic disorders.The overall aim for this PhD project is to obtain better understanding as to why patients with psychotic disorders face a dramatically increased risk of developing cardiovascular disease, beyond the risk accounted for by life style and antipsychotic medication. More specifically, our goal is to explore the role of inflammation in cardiovascular and metabolic co-morbidity in psychotic disorders. The candidate has been gathering data for the project and is now in the process of analyzing the data. The first step will be exploring potential differences in peripheral inflammatory activity in patients with psychotic disorders compared to healthy controls. The candidate is currently investigating a sample with 935 patients with either schizophrenia or bipolar disorder and 611 healthy controls. Preliminary results indicate that markers of vascular remodelling (Galectin 3 and Cathepsin S) are lower in patients compared to the healthy controls. Furthermore, preliminary results show that markers involved in leukocyte activation and vascular inflammation (myeloperoxidase (MPO) and glycoprotein 130 (gp130)) are elevated in the patient group. Preliminary results also indicate an increase in cardiovascular risk factors such as overweight and dyslipidemia in patients with psychotic disorders. The next analytical step will be to explore whether the alterations in inflammatory markers explain some of the excess risk for cardiovascular disease seen in the patient group. We expect the analyses to be concluded and the results to be published within three to four months.
Dette doktorgradsprosjektet er del av et større satsning som søker å kartlegge hvorfor pasienter med psykoselidelser har en betydelig overhyppighet av hjerte-og karsykdom, selv etter at man har tatt høyde for medisiner og miljøfaktorer.Dette doktogradsprosjektet er del av et større prosjekt som søker å kartlegge hvorfor pasienter med psykoselidelser har en betydelig overhyppighet av metabolsk syndrom og hjerte-og karsykdom, selv etter at man har tatt høyde for medisiner og miljøfaktorer. I løpet av 2016 har vi kartlagt immunrelaterte risikofaktorer for diabetes type II hos pasienter med psykosesykdom, samt sammenhengen mellom traumer, overvekt og økt immunaktivering hos pasienter med psykose.
Så langt har vi ved å kartlegge metabolske risikofaktorer, miljøbetingede risikofaktorer som usunn livsstil og røyking, analysere immunrelaterte markører og bruk av registerdata funn som tyder på at økt aktivitet i immunsystemet er assosiert med økt risiko for å utvikle diabetes mellitus type 2. Videre har vi kartlagt barndomtraumer (fysiske og psykiske) hos psykosepasienter og påvist en assosiasjon mellom med overvekt, immunaktivitet (CRP og gp130) og mengden traumebelastning hos disse pasientene. Elina Reponen (doktorgradskandidat med finansiering fra dette HSØ-prosjektet og for tiden i svangerskapspermisjon) har bidratt og er medforfatter på to arbeider som er under ferdigstilling nå. Hun har også gjennomført obligatoriske kurs, inkludert pasienter til prosjektet, samlet inn data og systematisert disse i en database for videre analyser.
Resultatene er så langt oppsummert i to papers som er under arbeid og forventes publisert i løpet av første halvår 2017:
An immune related link between diabetes mellitus type 2 and psychosis, Dieset et al.
Childhood maltreatment severity is associated with elevated C-reactive protein and body mass index in individuals with a psychosis spectrum diagnosis, Aas et al.
Pasientgruppen med psykoselidelser (schizofreni og bipolar lidelse) taper 15-20 leveår sammenlignet med resten av befolkningen og hjerte-kar sykdom utgjør en av årsakene til dette.Bakteppet for studien er at personer med psykoselidelser har økt risiko for metabolsk syndrom og hjerte-kar sykdom utover den risikoen som kan tilskrives usunn livsstil og medisiner. Vi ønsker å undersøke om det foreligger biologiske mekanismer som forklarer denne sammenhengen.
Vi vet følgende:
1. Forskning viser sammenheng mellom ugunstig immunaktivering og hjertekarsykdom.
2. Det er flere studier som viser at det er økt aktivitet i immunsystemet hos pasienter med psykoselidelser. I tillegg viser store genstudier at immunrelaterte gener er potensielle risikogener for schizofreni.
Prosjektets mål er å undersøke:
1. Sammenhengen mellom økt inflammasjon og risiko for hjerte-kar sykdom hos pasienter med psykosesykdommer.
2. Om økt immunaktivitet utgjør en felles årsaksmekanisme for kardiovaskulær sykdom og psykoselidelser.
Prosjektet har foreløpige resultater som viser at det er økte nivåer av YKL-40 (et glykoprotein som predikerer prognose ved hjertesykdom og diabetes type 2) hos pasienter med schizofreni og bipolar lidelse sammenlignet med friske kontrollpersoner. Disse funnene vil bli publisert i løpet av våren 2016.
Det foreligger i tillegg preliminære funn som indikerer sammenheng mellom økte nivåer av andre inflammasjonsmarkører og kardiovaskulære risikofaktorer hos pasienter med schizofreni og bipolar lidelse, disse funnene vil bli publisert i løpet av 2016.
Kandidaten har brukt tiden så langt til å samle data, fullføre obligatoriske doktorgradskurs og undersøke data.
Vitenskapelige artikler
Reponen EJ, Dieset I, Tesli M, Mørch RH, Aas M, Vedal TSJ, Haug E, Drange OK, Steen NE, Hope S, Szabo A, Gohar SM, Wedervang-Resell K, Djurovic S, Melle I, Aukrust P, Andreassen OA, Ueland T
Atherogenic Lipid Ratios Related to Myeloperoxidase and C-Reactive Protein Levels in Psychotic Disorders.
Front Psychiatry 2020;11():672. Epub 2020 jul 10
PMID: 32754070 - Inngår i doktorgradsavhandlingen
Deltagere
- Thor Ueland Medveileder
- Martin Steen Tesli Medveileder
- Ole Andreas Andreassen Medveileder
- Elina Johanna Reponen Doktorgradsstipendiat (finansiert av denne bevilgning)
- Ingrid Dieset Prosjektleder
eRapport er utarbeidet av Sølvi Lerfald og Reidar Thorstensen, Regionalt kompetansesenter for klinisk forskning, Helse Vest RHF, og videreutvikles av de fire RHF-ene i fellesskap, med støtte fra Helse Vest IKT
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