| 1. |
- Aulin, Julia
(author)
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Biomarkers of inflammation in atrial fibrillation
- 2021
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Doctoral thesis (other academic/artistic)abstract
- Atrial fibrillation (AF) is common and associated with increased risk of stroke, heart failure (HF) and mortality. Inflammation is linked to AF.The overall aim of this thesis was to investigate inflammatory activity and cardiovascular outcomes and mortality in patients with AF on effective oral anticoagulation. Levels of the inflammatory biomarkers interleukin 6 (IL-6), C-reactive protein (CRP) and fibrinogen at study entry and serial changes of IL-6 over time were investigated and related to stroke or systemic embolism, mortality and other cardiovascular events, including major bleeding. Associations between IL-6, CRP and biomarkers of cardiorenal dysfunction (NT-proBNP, troponin, GDF-15 and cystatin C) and HF hospitalisation, recurrent HF hospitalisations and mortality, were also investigated in patients with AF stratified for HF symptoms and reduced or preserved ejection fraction.The study populations consisted of patients with AF included in the biomarker substudies of the large multicentre randomised controlled trials RE-LY (n=6,187) and ARISTOTLE (n=14,954) with a median follow-up of 2.0 and 1.9 years, respectively. Repeated IL-6 measurements were available at study entry and at any postbaseline time point at 3, 6 and 12 months in RE-LY (n=2,559), and at study entry and at 2 months in ARISTOTLE (n=4,830). For HF stratification, patients in ARISTOTLE with information on HF symptoms and left ventricular function at study entry and with IL-6, CRP, NT-proBNP, troponin T, GDF-15 and cystatin C available at randomisation (n=11,818) were included.Higher level of IL-6, but not of CRP, was significantly associated with higher risk of mortality in Cox models adjusted for established clinical risk factors and other cardiovascular biomarkers. The level of any of the studied inflammatory biomarkers was not independently associated with any other cardiovascular outcome, including stroke or systemic embolism or major bleeding, in presence of other strong cardiovascular biomarkers. Levels of IL-6 were stable over time and persistent inflammatory activity was associated with increased risk of mortality, independent of clinical risk factors and other prognostic biomarkers. All biomarkers (IL-6, CRP, NT-proBNP, troponin T, GDF-15 and cystatin C) were associated with higher risk of HF hospitalisation and mortality regardless of HF symptoms and reduced or preserved ejection fraction.In conclusion, in anticoagulated patients with AF, higher level of IL-6, but not of CRP, was associated with higher risk of mortality, independent of clinical risk factors and other cardiovascular biomarkers. IL-6 levels were stable over time and provided incremental information on the risk of mortality irrespective of when measured. IL-6 may therefore serve as a risk marker for fatal outcomes. Biomarkers improved the identification of patients with AF at risk of HF in addition to clinical and echocardiography data.
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| 2. |
- Eriksson, Niclas, 1978-
(author)
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On the Prediction of Warfarin Dose
- 2012
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Doctoral thesis (other academic/artistic)abstract
- Warfarin is one of the most widely used anticoagulants in the world. Treatment is complicated by a large inter-individual variation in the dose needed to reach adequate levels of anticoagulation i.e. INR 2.0 – 3.0. The objective of this thesis was to evaluate which factors, mainly genetic but also non-genetic, that affect the response to warfarin in terms of required maintenance dose, efficacy and safety with special focus on warfarin dose prediction.Through candidate gene and genome-wide studies, we have shown that the genes CYP2C9 and VKORC1 are the major determinants of warfarin maintenance dose. By combining the SNPs CYP2C9 *2, CYP2C9 *3 and VKORC1 rs9923231 with the clinical factors age, height, weight, ethnicity, amiodarone and use of inducers (carbamazepine, phenytoin or rifampicin) into a prediction model (the IWPC model) we can explain 43 % to 51 % of the variation in warfarin maintenance dose. Patients requiring doses < 29 mg/week and doses ≥ 49 mg/week benefitted the most from pharmacogenetic dosing. Further, we have shown that the difference across ethnicities in percent variance explained by VKORC1 was largely accounted for by the allele frequency of rs9923231. Other novel genes affecting maintenance dose (NEDD4 and DDHD1), as well as the replicated CYP4F2 gene, have small effects on dose predictions and are not likely to be cost-effective, unless inexpensive genotyping is available.Three types of prediction models for warfarin dosing exist: maintenance dose models, loading dose models and dose revision models. The combination of these three models is currently being used in the warfarin treatment arm of the European Pharmacogenetics of Anticoagulant Therapy (EU-PACT) study. Other clinical trials aiming to prove the clinical validity and utility of pharmacogenetic dosing are also underway.The future of pharmacogenetic warfarin dosing relies on results from these ongoing studies, the availability of inexpensive genotyping and the cost-effectiveness of pharmacogenetic driven warfarin dosing compared with new oral anticoagulant drugs.
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| 3. |
- Folkersen, Lasse, et al.
(author)
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Genomic and drug target evaluation of 90 cardiovascular proteins in 30,931 individuals.
- 2020
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In: Nature metabolism. - : Springer Science and Business Media LLC. - 2522-5812. ; 2:10, s. 1135-1148
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Journal article (peer-reviewed)abstract
- Circulating proteins are vital in human health and disease and are frequently used as biomarkers for clinical decision-making or as targets for pharmacological intervention. Here, we map and replicate protein quantitative trait loci (pQTL) for 90 cardiovascular proteins in over 30,000 individuals, resulting in 451 pQTLs for 85 proteins. For each protein, we further perform pathway mapping to obtain trans-pQTL gene and regulatory designations. We substantiate these regulatory findings with orthogonal evidence for trans-pQTLs using mouse knockdown experiments (ABCA1 and TRIB1) and clinical trial results (chemokine receptors CCR2 and CCR5), with consistent regulation. Finally, we evaluate known drug targets, and suggest new target candidates or repositioning opportunities using Mendelian randomization. This identifies 11 proteins with causal evidence of involvement in human disease that have not previously been targeted, including EGF, IL-16, PAPPA, SPON1, F3, ADM, CASP-8, CHI3L1, CXCL16, GDF15 and MMP-12. Taken together, these findings demonstrate the utility of large-scale mapping of the genetics of the proteome and provide a resource for future precision studies of circulating proteins in human health.
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| 4. |
- Åkerblom, Axel, 1977-
(author)
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Biomarkers of Renal Function in Acute Coronary Syndromes
- 2013
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Doctoral thesis (other academic/artistic)abstract
- The thesis aimed to investigate cystatin C and creatinine-based estimates of glomerular filtration rate (eGFR), both at admission and during follow-up, on the combined endpoint of cardiovascular death and myocardial infarction in patients with acute coronary syndrome (ACS). We also evaluated two cystatin C assays and assessed genetic determinants of cystatin C concentrations.We used the PLATelet inhibition and Patient Outcomes study, where all types of ACS patients (n=18624) were randomized to ticagrelor or clopidogrel treatment. Multivariable Cox regression models, including clinical variables and biomarkers (troponin and NT-proBNP), and c-statistics were calculated.Cystatin C and the creatinine-based CKD-EPI equation exhibited similar significant prognostic impact on the combined endpoint, with Area Under Curves (AUC) 0.6923 and 0.6941, respectively. Follow-up samples of renal biomarkers did not improve risk prediction.Patients randomized to ticagrelor treatment were associated with a non-sustained larger increase in renal markers at discharge, but neither the change nor the difference between the randomized groups affected cardiovascular risk.Two different cystatin C assays exhibited good correlation 0.86 (95% confidence interval 0.85-0.86), however moderate level of agreement. Risk prediction with a combination of creatinine and cystatin C did not outperform the creatinine-based CKD-EPI equation, AUC: 0.6913 and 0.6924, respectively (n=13050).The genetic polymorphism rs6048952 independently affected the cystatin C concentration with mean levels of 0.85mg/L, 0.80mg/L and 0.73mg/L for the A/A, A/G, and G/G genotypes, respectively.The genetic polymorphism did not affect outcome overall, however in the non-ST-elevation ACS subgroup a signal that genetic polymorphism may be associated with cardiovascular death was observed (p=0.002).In conclusion: cystatin C or eGFR, irrespective of equation or assay, are important cardiovascular risk factors in ACS patients. Nonetheless, the incremental value of adding any renal variable, to a multivariable risk model, is small. Further research on the impact of cystatin C genetic polymorphism is warranted.
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| 5. |
- James, Stefan
(author)
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Coagulation, Inflammation and Myocardial Dysfunction in Unstable Coronary Artery Disease and the Influence of Glycoprotein IIb/IIIa Inhibition and Low Molecular Weight Heparin
- 2003
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Doctoral thesis (other academic/artistic)abstract
- Hjärt-kärl sjukdom är den vanligaste dödsorsaken i västvärlden. Samtidigt som antalet patienter med hjärtinfarkt har minskat, har antalet patienter med instabil kranskärlsjukdom d.v.s. svår kärlkramp ökat påtagligt. Diagnosen är nu den vanligaste orsaken till vård på hjärtinfarktavdelningar i Sverige. Modern behandling av instabil kranskärlssjukdom består av en kombination av läkemedel för att minska blodproppsbildning och avlasta hjärtarbetet samt, i de flesta fall, s.k. ballongvidning eller operation av hjärtats kranskärl. Trots stora behandlingsframsteg är risken för hjärtinfarkt och död hög, såväl på kort som lång sikt. Det finns därför ett stort behov av ytterligare förbättrad behandling utan att samtidigt erhålla oacceptabelt hög risk för allvarliga biverkningar. För att erbjuda en effektiv behandling till patienter med hög risk och samtidigt undvika dyr och potentiellt riskfylld behandling till patienter med låg risk behövs också bättre instrument för tidig riskbedömning. Syftet med avhandlingen var att undersöka en stor grupp patienter med instabil kranskärlssjukdom avseende säkerhet och effektivitet av en behandlingskombination av två moderna blodproppshämmande läkemedel, dalteparin och abciximab (ca 1000 patienter). Syftet var också att studera hur denna behandling påverkar system för inflammation och koagulation (ca 400 patienter). Dessutom ville vi värdera hur blodnivåer av markörer för inflammation, hjärtmuskelskada och nedsatt hjärtfunktion kan förutsäga risken för framtida komplikationer (ca 7000 patienter). Tillägg av abciximab till dalteparin minskade inte risken för dödsfall eller hjärtinfarkt inom trettio dagar. Däremot ökade antalet blödningskomplikationer. Totala antalet blödningar var emellertid relativt lågt och behandlingen syntes vara lika säker som kombinationen av abciximab och det internationellt mycket använda blodproppshämmande medlet heparin. Trots den kraftfulla behandlingskombinationen skedde en samtidig aktivering av system för såväl inflammation som koagulation. Detta kan vara en orsak till den observerade avsaknaden av behandlingseffekt av abciximab. Att hindra denna aktivering skulle samtidigt kunna innebära möjligheter för nya behandlingsstrategier. Förhöjda nivåer av markörer för hjärtmuskelskada (troponin T), inflammation (CRP), nedsatt hjärtfunktion (proBNP) eller nedsatt njurfunktion (kreatininclearance) ökade risken för dödlig utgång både på kort och lång sikt, oberoende av andra riskfaktorer. En kombination av två av dessa markörer gav den högsta risken för dödlig utgång. Således dog endast 0.3 % av patienter med låga nivåer av proBNP och normal njurfunktion inom ett år, jämfört med 25.7 % av patienter med höga nivåer av proBNP och nedsatt njurfunktion. Förhöjda nivåer av troponin T eller nedsatt kreatininclearance (men inte av CRP eller proBNP) ökade dessutom risken för hjärtinfarkt. Resultaten i avhandlingsarbetet har givit kliniskt tillämpbar kunskap om hur kärlkrampspatienter med hög respektive låg risk kan selekteras tidigt efter inkomst till sjukhus och ny kunskap om behandlingseffekt av abciximab och dalteparin. Resultaten har redovisats på internationella kongresser och i högt rankade medicinska tidskrifter och har citerats i europeiska och amerikanska ”guidelines” för behandling av instabil kranskärlssjukdom.
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| 6. |
- Varenhorst, Christoph, 1977-
(author)
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Platelet Inhibition in Coronary Artery Disease – Mechanisms and Clinical Importance : Studies with Focus on P2Y12 Inhibition
- 2010
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Doctoral thesis (other academic/artistic)abstract
- Despite the currently recommended dual antiplatelet treatment (DAT) with aspirin and P2Y12 inhibition in patients with coronary artery disease (CAD) there is a risk of adverse clinical outcome. Pharmacodynamic (PD) poor response to clopidogrel occurs in ~ 30% of clopidogrel-treated patients and is associated with an increased risk of recurrent thrombotic events. The aims of this thesis were to compare the PD and pharmacokinetic effects of clopidogrel 600 mg loading dose (LD)/ 75 mg standard maintenance dose (MD) with the novel P2Y12 inhibitor prasugrel 60 mg LD/10 mg MD, in 110 patients with CAD. The mechanisms behind clopidogrel poor response were investigated by assessing the pharmacodynamics after adding clopidogrel active metabolite (AM) and genotyping for variation in CYP-genes involved in thienopyridine metabolism. In another study, we compared the on-clopidogrel platelet reactivity of patients with stent thrombosis (ST) (n=48) or myocardial infarction (MI) (n=30) while on DAT and their matched controls (n=50 + 28). Prasugrel achieved a faster and greater P2Y12-mediated platelet inhibition than clopidogrel measured with light transmission aggregometry, VASP and VerifyNow® P2Y12. Prasugrel’s greater platelet inhibition was associated with higher exposure of AM. The addition of clopidogrel AM led to maximal platelet inhibition in all subjects, suggesting that prasugrel’s greater antiplatelet effect was related to more efficient AM generation compared to that of clopidogrel. Lower levels of AM as well as less platelet inhibition were seen in clopidogrel-treated patients with reduced-metabolizer genotype CYP2C19 compared to those with normal genotype. Patients with ST while on DAT showed higher on-clopidogrel platelet reactivity compared to matched stented controls. Patients with spontaneous MI after stenting did not. In conclusion, these results showed a high rate PD poor response to a high bolus dose of clopidogrel because of a partly genetically caused lower generation of AM which could be overcome by prasugrel treatment. In patients after coronary stenting, clopidogrel poor response was related to ST but not to spontaneous MI, illustrating difficulties in optimizing treatment with clopidogrel based on platelet function or genetic testing in individual patients.
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