Publications from Karolinska Institutet
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    From cytologic features to serum markers: advancing prognostication of uveal melanoma

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    Uveal melanoma (UM) is the most common primary intraocular malignancy in adults. As surveys show, almost all patients diagnosed with UM want prognostic information. However, the tools available today for early prognostication in UM are limited; beyond what information can be obtained by tumor size and location, current methods typically rely on tumor tissue obtained from enucleated eyes or invasive biopsies, or on repeated sampling of peripheral plasma or serum. Therefore, improving the toolbox for prognostication of aggressive vs. less aggressive disease is the focus of this dissertation. In paper I, we explored the scope of digital image analysis of cytologic features in uveal melanoma. We know that cytologic features such as shape and size of tumor cells can predict metastatic death in uveal melanoma. Currently, however, cytologic analysis is conducted manually by visual inspection of pathologists, which is time-consuming and impacts its reproducibility. In this study, we analyzed twelve morphometric variables in a large number of uveal melanoma cells. We then correlated the results with BRCA associated protein-1 (BAP-1) expression and BAP-1 gene mutation status, monosomy 3, gene expression classification as well as patient survival. We demonstrated that digital image analysis of variables describing the shape and size of tumor nuclei correlated to BAP-1 status, to monosomy 3, and to gene expression class. Mean time consumption per tumor was less than 2.5 min. Thus, digital image analysis is a fast and highly reproducible technique, that for the first time allows to objectively quantify cytologic tumor features in large tumors and gives prognostic information on survival in UM. In paper II, we explored if biopsies from posterior UM hold the same prognostic information as tissue from enucleated specimens. We classified BAP-1 expression in transvitreal biopsies of posterior UM and correlated our results with BAP-1 expression in subsequent biopsies. We found that BAP-1 expression in transvitreal biopsies was concordant with BAP-1 in enucleated specimens. Moreover, BAP-1 expression in transvitreal biopsies identified patients with poor metastasis-free survival. Thus, transvitreal biopsies can be a good prognostic tool for patients that do not undergo enucleation. The results also indicate the need to further study BAP-1 expression in even smaller UMs, to infer the tumor size at which loss of BAP-1 starts to occur, and to correlate it with the early seeding of micrometastases. In paper III, we explored prognostic testing on serum samples obtained from patients at diagnosis of uveal melanoma. We first screened for cancer-related proteins by protein profiling in order to find potential biomarkers. Second, we performed ELISA to evaluate the serum levels of the best candidates. Third, receiver operating characteristics were used to define thresholds for metastatic risk. This led to a prognostic test (serUM-Px) that stratifies patients into low, intermediate, and high-risk categories which we tested in a training cohort and validation cohort. We found that serUM-Px is a prognostic test, based on a single peripheral venous blood sample at the time of UM diagnosis, which can be used to stratify patients into low, intermediate and high metastatic risk categories. Thus, this test predicts metastases many years in advance without the need for biopsy or repeated sampling. In paper IV, we wanted to assess the prognostic utility of Tenascin C (TNC) in uveal melanoma. Therefore, we collected peripheral blood samples from 82 patients with small posterior uveal melanomas between 1996 and 1999 as described above for paper III. TNC concentrations were examined 2021. RNA sequencing data of TNC from an additional 80 larger tumors were collected. These levels were subsequently linked with the cumulative incidence of metastasis-related death through competing risk data analysis. In our analysis we observed no significant disparities in tumor size, age at diagnosis, visual acuity, serum protein levels, or treatment modality between patients with above or below median serum or tumor TNC levels. However, above median TNC RNA was associated with BAP1 mutation, monosomy 3, and epitheloid cytomorphology. The competing risk analysis indicated increased metastatic mortality in patients with above median TNC and primary tumor TNC RNA compared to their below median counterparts. We conclude that TNC is a prognostic biomarker in uveal melanoma that exhibits elevated levels in peripheral blood and tumors at diagnosis in patients destined for metastatic death

    Monitoring of the oral anticoagulants apixaban and rivaroxaban to optimize individual safety and efficacy

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    The oral anticoagulants apixaban and rivaroxaban are administered at fixed doses without requiring routine monitoring. However, there is a dose and exposure dependency in efficacy and safety, and monitoring the anticoagulants may improve treatment outcomes. The aim of this thesis was to evaluate different laboratory methods for monitoring apixaban and rivaroxaban and to show the typical exposure levels in patients. Additionally, the study aimed to study the exposure in certain specific populations (i.e. those with obesity and renal impairment), to elucidate whether monitoring would be especially valuable for these patients. In studies I and II, we evaluated various coagulation assays for the monitoring of apixaban and rivaroxaban. While PT-INR (venous) and aPTT were not sensitive enough to be used for this purpose, the anti-Factor Xa assay showed a strong correlation with LC/MS-MS. However, for precise estimations of apixaban/rivaroxaban concentrations in the lower range, LC-MS/MS is the preferred method to use. A large interindividual variability in trough concentrations was observed, 12-fold for apixaban (6-fold within the same dosage group) and 17-fold for rivaroxaban (17-fold for the standard dose and 3- fold for the reduced dose). In study III, we explored the influence of obesity on apixaban trough and peak concentrations. A specific dose recommendation for obese patients may not be necessary given that the concentrations were largely similar to those in matched normal weight patients. However, obese patients exhibited an extensive 18-fold interindividual variability in trough concentrations. Consequently, monitoring apixaban concentrations could be valuable for specific obese patients to ensure optimal treatment outcomes In study IV, we examined the impact of renal function on apixaban exposure in AF patients. Patients with moderate renal impairment had twice as high apixaban trough concentrations compared to patients with normal renal function. This indicates that the recommended 5 mg twice daily dose might be excessive for some patients with moderate renal impairment, and that monitoring ought to be recommended

    Randomised clinical trials with hyperbaric oxygen in COVID-19 and Long COVID : transcriptomic insights into benefits and harms

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    The flow from transcription of genes through translation and processing of proteins is a common basis for all life. Redox homeostasis is crucial for the defence against oxidative stress. We adapt through hormesis; non-lethal stress regulates redox-sensitive systems to maintain homeostasis. If the stress is chronic or acutely overwhelming, the cells can either go into apoptosis or into senescence to maintain homeostasis. Similar effects have been seen with HBOT as with intermittent oxygen deprivation. Hyperbaric oxygen therapy (HBOT) is delivered in a pressure chamber by breathing 100% oxygen intermittently, several times a week, in an ambient pressure equivalent to 10-20 meters of seawater. The aim of this thesis was to evaluate potential harms of HBOT for novel indications and to explore biomarkers in experimental and clinical trials in order to enable future precision medicine. We used methods evaluated on healthy volunteers in randomised clinical trials (RCTs) conducted in compliance with good clinical practice (ICH-GCP). In Paper I, we evaluated Electron paramagnetic resonance (EPR) spectroscopy for measuring reactive oxygen species (ROS) in blood and RNA sequencing (RNAseq) of monocytes in peripheral blood (PBMC), and compared HBOT and HIIT in ten healthy volunteers. We could measure ROS in blood in the same physiological range in both interventions. We also discovered pathways involved in adaption to hypoxia and inflammation that were similar in both interventions. In Papers II and III, we evaluated harms and explored RNAseq in PBMC in an open label RCT where 31 patients with severe COVID- 19 were randomised to HBOT or best practice. We observed similar frequencies of adverse events (AEs) in the two groups and could not see any negative effect on vital signs or oxygenation. We discovered a unique transcriptomic signature in the subjects that had received HBOT. The differentially expressed genes were associated with the unfolded protein response, apoptosis, and immune response. In Paper IV, we evaluated harms and described health related quality of life (HRQoL)in an interim analysis of the first 20 subjects froma placebo controlled RCT where 80 patients with Long COIVD were randomised to HBOT or sham treatment. We reported more AEs than expected and severe physical and mental disabilities with a very poor HRQoL. Most AEs were mild, and all were transient. We have shown that HBOT shares similarities in immune response with HIIT in healthy volunteers. HBOT has a favourable profile of harms and has a potent immunomodulatory effect that is associated with fast recovery for critical COVID-19 patients. HBOT has a favourable profile of harms for patients with post COVID-19 condition. The results provide a base for future clinical trials with HBOT

    Prenatal risk factors for severe cardiovascular diseases up to middle-age : a Nordic collaborative study

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    Background and objectives: Cardiovascular diseases (CVDs) are major causes of death and disability. However, the established traditional risk factors cannot explain a substantial proportion of CVD cases, prompting investigations into novel risk factors. A growing body of evidence underscores the potential role of suboptimal intrauterine conditions on the development of CVD. Nonetheless, our knowledge about the associations between factors contributing to an adverse intrauterine environment and the risk of developing CVD remains limited. The overall objective of this thesis is to enhance our comprehension of the potential role of prenatal risk factors in developing CVD later in life. More specifically, the thesis aims to study the following research questions: (1) Are negative birth outcomes such as preterm birth, being small (SGA) or large (LGA) for gestational age related to the atrial fibrillation risk later in life (Study I)? (2) Is maternal preeclampsia and its subtypes linked to increased risks of stroke and ischemic heart disease in the offspring (Study II)? (3) Is maternal polycystic ovary syndrome (PCOS) associated with the risks of overall CVD and its major subtypes in her offspring (Study III)? and (4) Is prenatal exposure to maternal severe stress related to the risk of heart failure later in life (Study IV)? Methods: We performed four register-based prospective cohort studies, including all live singletons from Denmark (Study I: 1978-2016, Studies II-IV: 1973-2016) and Sweden (Studies I-IV: 1973-2014), and live births from a randomly selected 90% of all births in Finland Studies I and II; 1987-2014). The size of the study population was 8,012,433 in Study I, 8,475,819 in Study II, 6,839,703 in Study III, and 6,758,560 in Study IV. Information on birth outcomes, maternal and offspring's health and covariates were obtained through linkage to population-based socioeconomic and health registers. Each study participant was followed up until the earliest diagnosis of the CVD of interest, emigration, death, or end of follow-up (Denmark: December 31, 2016; Finland: December 31, 2014; Sweden: December 31, 2020), whichever occurred first. We examined the association between prenatal exposures (including preterm birth, SGA, LGA, maternal preeclampsia, PCOS, and severe stress) and CVD outcomes in offspring using multivariable Cox regression models. Furthermore, we used family- based study designs, i.e. sibling and cousin comparison analyses, to account for unmeasured familial genetic and environmental confounders. Additionally, we investigated the mediating roles of abnormal birth outcomes and congenital heart disease in case of some of the observed associations. Results: In Study I, we found that being born preterm or LGA was linked to an increased risk of atrial fibrillation in both childhood and adulthood. The associations persisted in the sibling comparison analyses. In contrast, SGA was related to an increased atrial fibrillation risk in childhood but not in adulthood. In Study II, we found that individuals prenatally exposed to maternal preeclampsia had higher risks of stroke and ischemic heart disease than those unexposed, and that the associations were more pronounced in cases of severe than milder forms of preeclampsia. The associations of the severe forms of maternal preeclampsia with the offspring's risk of stroke remained in the sibling comparison analyses. In Study III, maternal PCOS was associated with elevated risks of overall CVD, hypertensive disease, stroke, and ischemic heart disease in the population analysis; most of these associations, except that observed in case of stroke, remained in the cousin comparison analysis. When investigating the interaction between maternal PCOS and its prevalent comorbidities, we found that individuals born to mothers with both PCOS and its common comorbid conditions, i.e. diabetes, hypertensive disease, or psychiatric disorders, had higher CVD risks than those born to mothers with only PCOS. In Study IV, we found that offspring exposed to maternal loss of a close family member the year prior to or during pregnancy did not have a higher risk of heart failure than those unexposed. However, the severe forms of maternal bereavement, specifically loss due to unnatural causes and loss of a child or partner, were linked to an increased risk of heart failure in the offspring. When splitting follow-up for Studies I-IV at the age of 18, we found that the association between preterm birth and the risk of atrial fibrillation, maternal preeclampsia and the risk of stroke, and severe maternal stress and the risk of heart failure were stronger during childhood than during adulthood. In the mediation analyses, there was some evidence that the association between maternal PCOS and the risk of CVD in offspring was to a modest extent mediated by preterm birth, LGA, and congenital heart disease. In the case of the link between severe maternal stress and the risk of heart failure, we observed considerable contributions from congenital heart disease and preterm birth. Conclusions: This thesis revealed associations of prenatal risk factors with increased risks of CVD up to early middle-age. Specifically, our findings suggest that preterm birth, SGA, and LGA were related to elevated risks of atrial fibrillation. Additionally, maternal preeclampsia, especially its severe types, was associated with elevated risks of stroke and ischemic heart disease in offspring, while maternal PCOS was associated with increased risks of overall CVD and its major types. Moreover, severe maternal stress was associated with an elevated risk of heart failure in offspring. If subsequent studies confirm our findings, early-life prevention and targeted intervention programs may be developed to inform health policies, eventually resulting in a reduced burden of CVD

    The cellular thermal shift assay (CETSA) for elucidating drug mechanism of action and resistance in cancer

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    A complete understanding over drug mechanism of action (MoA) is important when attempting to predict treatment outcome or the presence of resistance in patients. Despite decades of scientific efforts, the MoAs of even some of the oldest and most utilized drugs in cancer therapy today remain only partially understood, while resistance continues to be a frequent and often unpredictable occurrence. The absence of a protein-focused systems-wide characterization of drug-induced changes in cellular states contributes to these gaps in knowledge, as proteins are difficult to study yet they are key players in nearly all cellular processes and the targets for most drugs. The cellular thermal shift assay (CETSA) is a recently introduced method that can directly monitor drug target engagement and drug-induced cellular changes at proteome level in intact living cells. The research presented in this thesis focuses on the protein-centric CETSA approach to charting drug MoA and resistance development by evaluating the drug-induced changes in protein thermal stability for several important cancer drugs utilized in the clinic e.g. pyrimidine analogues, taxanes, or apoptosisblockade releasing compounds in intact living cells or tissues. We report on an extensive set of CETSA responses that reflect on drug-target engagement or other MoA-revealing alterations in cellular processes that are either compound-specific or overlapping between some of the studied drugs. Several of the highlighted proteins or ensembles of proteins show promise for further evaluation as candidate biomarkers for drug efficacy with potential future applications in a clinical setting

    Charting genomic heterogeneity in tumours : from bulk to single cell

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    Tumours do not consist of a single homogeneous population but are complex heterogeneous systems that contain billions of ever-evolving cells with no two tumours being the same. Tumour heterogeneity is present at three levels, 1) inter-patient heterogeneity; 2) intra-patient heterogeneity; and 3) intra-tumour heterogeneity (ITH). Understanding all levels of heterogeneity is crucial for patient prognosis and treatment choice. To this end, we aimed to improve our understanding of all three levels of tumour heterogeneity. In paper I we investigated the prevalence, type, length, and genomic distribution of 853.218 somatic copy number alterations (SCNAs) across 20.249 tumours belonging to 32 cancer types. Based on the 1) number of SCNAs; 2) percentage of the genome altered; and 3) average SCNA size, we found high levels of inter-patient heterogeneity, both between and within cancer types. We found that specific chromosomes were preferentially lost or gained depending on cancer type. Lastly, we detected co-alterations of key oncogenes and TSGs. Taken together, we provided a comprehensive analysis on SCNAs across many cancer types as a valuable resource for the community. In paper II we sought to elucidate intra-patient heterogeneity in non-small cell lung cancer (NSCLC) and their matched brain metastasis (BM). We performed shallow wholegenome sequencing (WGS) on 51 primary NSCLC and matched BM, whole exome sequencing on 40 of the pairs, multi-region sequencing of 15 BMs, and shallow WGS on an additional cohort of 115 BMs. We showed that there is significant intra-patient heterogeneity at the SCNA level, with BM samples showing, on average, more SCNAs compared to their matched NSCLC. In contrast, multi-region sequencing of 15 BMs did not show significant ITH at the level of SCNAs. Finally, we identified putative metastatic driver SCNAs and singlenucleotide variants in key tumour suppressor genes (TSGs) and oncogenes. In paper III we aimed to assess the level of ITH in early localized prostate cancer. We performed organ-wide, multi-region, single-cell DNA sequencing on two prostate midsections. We found transient chromosomal instability (CIN) both in tumour and normal prostate tissue, evidenced by a large number of cells with unique chromosomal (arm) losses and or gains. Furthermore, we found three distinct groups of cells within the prostate: 1) diploid cells; 2) pseudo-diploid cells; and 3) monster cells. We observed an enrichment of diploid cells in normal regions and pseudo-diploid cells in tumour-rich regions, while monster cells were equally distributed over the entire prostate, again suggesting that there were elevated CIN levels across the prostate. Lastly, we detected highly localized subclones that were exclusive to tumour-rich regions and harboured deletions in TSGs that are known to be frequently deleted in prostate cancer. Taken together, with this thesis, I have contributed to advance the understanding of inter-patient, intra-patient, and intra-tumour heterogeneity

    Immune cell-derived adipokines : role in white adipose tissue function and link to metabolic health

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    The white adipose tissue (WAT) is home to a vast array of immune cells that control local homeostasis and metabolism by engaging in intricate crosstalk with adipocytes and their precursors through secreted factors (adipokines). In the obese WAT, these immune cells adopt a pro-inflammatory profile, resulting in a state of chronic low-grade inflammation that can perturb local and systemic metabolic function. This thesis aimed to study physiological and pathological aspects of the interplay between immune cellderived adipokines and processes pertaining to the expansion and metabolic function of the WAT. A postprandial induction of the pro-inflammatory cytokine interleukin (IL)-1b was previously demonstrated in macrophages of the WAT, but not other tissues, hinting to a possible involvement in local energy handling. Therefore, in study I, we employed in vivo and in vitro models to investigate a physiological, metabolic role of IL-1b in the WAT. To our surprise, IL-1 signaling was of minor importance in mature adipocytes. Instead, we identified adipocyte precursors as the major target of IL-1b in the WAT, where it stimulated the formation of new fat cells, a process linked to preserved metabolic health during obesity development. Strikingly distinct effects caused by acute and chronic treatments led us to propose that postprandial surges in IL-1b has a physiological role in promoting healthy WAT expansion but that this effect may be lost in the chronically inflamed obese WAT. Study II set out to identify WAT-secreted factors involved in cardiometabolic diseases of non-obese individuals. An adipokine screen identified the chemokine CCL18 as significantly elevated in cardiometabolic disease groups compared to healthy controls (all non-obese). Further explorations led us to conclude that CCL18 recruits CD4+ T cells and activates them to secrete interferon g and transforming growth factor b1, which in turn stimulate lipolysis of adipocytes, thereby contributing to cardiometabolic disease through release of fatty acids into circulation. Women generally display a healthier metabolic phenotype than men. Whether differences in WAT inflammatory status may account for this is unknown. The antiinflammatory cytokine IL-10 was previously shown to be elevated in WAT of obese women. Study III explored possible sex differences in WAT production of this cytokine. IL-10 secretion and IL-10-producing macrophages were elevated in WAT of obese women, but not men, with type 2 diabetes. Estrogens had no direct effect on IL-10 expression in vitro. This reveals a sex-specific regulation of IL-10 production in obesity, which may provide women with relative protection from obesity-associated inflammation. Overall, this thesis has provided new insights on the complex role of immune cellderived adipokines in metabolism and expansion of the WAT under different contexts, and how this may be linked to metabolic health

    Targeting immune and desmoplastic tumor microenvironment to sensitize gynecological cancer cells to therapy

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    Cancer is a pervasive global threat that manifests with diverse clinical attributes and notable mortality rates, particularly attributable to its metastatic potential in solid cancers. These tumours encompass various types including epithelial cancers like high-grade serous ovarian cancer (HGSC) and mesenchymal cancers like uterine sarcomas (USs). Despite the differing origins of USs and HGSCs, the pivotal concept of the transition between epithelial and mesenchymal states remains remarkably plastic, occurring frequently in these cancers. This plasticity holds immense significance in understanding tumour invasiveness and metastasis. The TME emerges as a crucial influencer as exerting its impact on cancer progression, epithelial-mesenchymal transition (EMT), metastasis, and even chemoresistance. The TME comprises various elements, with the extracellular matrix (ECM) containing structural proteins like collagens, standing out as a key constituent. Moreover, immune cells within the TME, such as lymphocytes and macrophages, actively engage in interactions with both the ECM and cancer cells shaping local responses to kill the cancer cells or support their growth. Understanding the intricate tumour-TME interactions become imperative in formulating effective strategies aimed at modulating the immune response and halting cancer progression. Therefore, a nuanced comprehension of these complexities is crucial in developing strategies to combat cancer effectively. This thesis focuses on identifying TME factors, including ECM components and immune cell interactions in gynaecological cancers for improved precision medicine including immunotherapies and other novel treatments. In Paper I, Uterine sarcomas present distinct immune signatures with prognostic value, independent of tumour type. FOXP3+ cell density and CD8+/FOXP3+ ratio (CFR) correlated with favourable survival in endometrial stromal sarcomas (ESS) and undifferentiated uterine sarcomas (USS). The CFR also highlighted the correlation between CFR high and upregulation of ECM organization pathways. In Paper II conversely, uterine leiomyosarcomas (uLMS) showed distinct behaviours, with lower collagen density and upregulated ECM remodelling enzymes correlating with aggressiveness. MMP-14 and yes-associated protein 1 (YAP) were required for uLMS growth and invasion. In Paper Ⅲ, shifting to HGSC, matrisome, a group of proteins encoded by genes for core ECM proteins 4 (collagens, proteoglycans, and ECM glycoproteins) and ECM-associated proteins (proteins structurally resembling ECM proteins, ECM remodelling enzymes, and secreted factors) in the ECM, showed changes in expression depending on the type of tumour host tissues and after chemotherapy. Collagen VI, among scrutinized proteins, exhibited elevated expression linked to shortened survival in ovarian cancer patients. Mechanistically, collagen VI promoted platinum resistance via the stiffness-dependent β1 integrin-pMLC and YAP/TAZ pathways in HGSC cell lines In summary, this integrated exploration of uterine sarcomas and ovarian cancer provides a comprehensive understating of their TME. The study elucidates diverse immune and molecular features, offering potential prognostic markers and therapeutic targets. The findings underscore the complexity of these gynaecological malignancies, emphasizing the need for tailored approaches in understanding and combating these diseases

    Antigen-presenting autoreactive B cells activate regulatory T cells and suppress autoimmune arthritis in mice

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    B cells undergo several rounds of selection to eliminate potentially pathogenic autoreactive clones, but in contrast to T cells, evidence of positive selection of autoreactive B cells remains moot. Using unique tetramers, we traced natural autoreactive B cells (C1-B) specific for a defined triple-helical epitope on collagen type-II (COL2), constituting a sizeable fraction of the physiological B cell repertoire in mice, rats, and humans. Adoptive transfer of C1-B suppressed arthritis independently of IL10, separating them from IL10-secreting regulatory B cells. Single-cell sequencing revealed an antigen processing and presentation signature, including induced expression of CD72 and CCR7 as surface markers. C1-B presented COL2 to T cells and induced the expansion of regulatory T cells in a contact-dependent manner. CD72 blockade impeded this effect suggesting a new downstream suppressor mechanism that regulates antigen-specific T cell tolerization. Thus, our results indicate that autoreactive antigen-specific naïve B cells tolerize infiltrating T cells against self-antigens to impede the development of tissue-specific autoimmune inflammation.Knut och Alice Wallenbergs Stiftelse (to R. Holmdahl; 2019.0059)Vetenskapsradet (to R.Holmdahl; 2019-01209)Stiftelsen Konung Gustaf V:s 80-arsfondand Karolinska Institutet Foundation Grants for Rheumatology Research 2021 (to M. Aoun; SGI-2022-0862 and 2022-02852,respectively)HORIZON EUROPE Marie Sklodowska-Curie Actions (to A. Coelho and A. Kramer; 765158)Bundesministerium fur Bildung und Forschung (to H. Burkhardt; project 4 01 EC1009C)Publishe

    Cardiovascular magnetic resonance evaluation of effusive and constrictive physiologies

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    This thesis presents an exploration of cardiovascular magnetic resonance (CMR) in the evaluation of effusive and constrictive heart conditions. Central to the thesis is advanced CMR as a diagnostic tool in pericardial effusion and constrictive pericarditis. Studies I and II concern the application of T1 mapping for the characterization of pleural and pericardial effusions and attempts to enhance the understanding of the dynamics of extracellular gadolinium-based contrast agents (GBCA) in effusion fluid. Study II establishes normal T1 values at 1.5 T in the pericardial fluid of healthy individuals, providing a benchmark for future studies. Studies III and IV concern ventricular interdependence, a crucial aspect in evaluating constrictive physiology. Ventricular interdependence is measured by quantifying the respiratory variation in peak early transvalvular blood flow velocities. In Study III, an open-source software tool to perform semi-automated image analysis of real-time phase contrast (RT-PC) images is developed, and normal values are established. In Study IV, the repeatability and reproducibility of the method are tested. This thesis concludes that CMR can become a valuable tool in evaluating pericardial effusion and constrictive pericarditis. Both molecular imaging evaluation of effusive fluids and hemodynamic assessment of ventricular interdependence are feasible using CMR

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