<p>  </p> <p>Cardiovascular disease has been the leading cause of death in the United States for over 70 years. To evaluate the extent and progression of cardiovascular disease, non-invasive imaging techniques are frequently used clinically and pre-clinically. Current echocardiographic and cine magnetic resonance approaches rely on measurements that are typically obtained from two-dimensional images, which assumes uniformity of the structure being evaluated. To explore methods to potentially address these shortcomings, our group has developed and validated high frequency four-dimensional ultrasound techniques as well as created a software toolbox that allows for measurement of myocardial kinematics. In this thesis, I assisted in the application of these methods to two murine models of disease states: myocardial infarction and aortic aneurysm. Another study I aided in focused on cardiac magnetic resonance imaging data from patients with Duchenne muscular dystrophy. From our software, we are able to obtain various strain and strain rate estimates that reveal significant functional changes in infarction and Duchenne muscular dystrophy earlier than standard measurement techniques. Furthermore, we are able to identify vascular expansion, transmural thickening, and changes in hemodynamics prior to aneurysm development. Earlier detection and localization allows for more targeted surveillance and interventions, which ultimately may result in improved clinical outcomes. Ideally, these findings can be used to expand the capabilities of cardiac research and the development of clinically applicable imaging techniques and treatments to better address underlying cardiovascular pathophysiology. </p>

Undersökningen utförs i samarbete med Riksbyggens ombyggnadsavdelning i Jönköping. Riksbyggen är ett kooperativt företag och en av Sveriges största fastighetsförvaltare. Riksbyggens kunder består utav bostadsrättsföreningar, företag och offentliga fastighetsägare. År 2019 släppte byggsektorn ut 21 % av Sveriges växthusgaser och 49% av alla flerbostadshus är byggda mellan 1951 – 1981 (2021). Byggnaderna förbrukar mycket energi och särskilt ventilationssystemen. Dokumentationen av kunskap från olika projekt kan vara obefintlig eller undermåttlig vilket bidrar till att kunskap om energirenovering blir svår att hantera. Målet är att undersöka den ekonomiska lönsamheten och miljöeffekt som energibesparande åtgärder har i ett flerfamiljshus byggd år 1959. Samt att undersöka Riksbyggens och deras externa energisakkunnigas användande av erfarenhetsåterföring i syfte att minska livscykelkostnad och pay-off tid. För att uppnå målet används en kombination av kvalitativa och kvantitativa metoder. Empiri samlas in genom intervju, mätdata, beräkningar samt dokument och ritningar tillhandahållet av Riksbyggen. Beräkningarna svarar på lönsamheten hos de energibesparande åtgärderna och intervjuer används för att kartlägga hur erfarenhetsåterföring används och dess koppling mot livscykelkostnad och pay-off tid hos energirenoveringar. Kvantitativ analysmetod används för åtgärdernas kostnads- och energibesparing där värden jämförs med varandra i grafer och tabeller. För att kartlägga erfarenhetsåterföringen jämförs intervjupersonernas svar med varandra och med det teoretiska ramverket, både leverantör och kund intervjuas för att få båda perspektiv. Enligt utförda beräkningarna besparar alla de planerade åtgärderna totalt 380 MWh fjärrvärme/ år och ökar elbehovet med 55 MWh/ år, kostnadsbesparingen uppgår till 248 000 kr/ år. Pay-off tiden är för värmepumpen 8,4 år och värmepump kombinerat med solceller har en pay-off tid på 9,1 år. Pay-off tiden kombinerat med fönsterbyte är tillsammans 27,6 år. Från intervjuerna framgår det att erfarenhetsåterföring främst sker muntligt i det dagliga arbetet. Resultatet överensstämmer med teorin och den mest givande erfarenhetsåterföringen är enligt intervjudeltagare den utanför egna organisationen med personer med olika befattning. Det främjar utveckling och forskning i branschen samt minskar kostnader och energi. Intervjudeltagarna lägger mycket tid på att dokumentera ekonomisk vinning och det är också det som är den huvudsakliga drivkraften för utveckling enligt teorin. Den ekonomiska besparingen och återbetalningsperioden beräknades bli dyrare än väntat vilken troligen beror på de historiskt höga elpriserna. Men trots höga elpriser är de energibesparande åtgärderna lönsamma och att installera både solceller och frånluftsvärmepump, som i denna undersökning, ger en trygghet i att solceller blir mer lönsamma med stigande elpriser och värmepump med sjunkande elpriser. / The survey is carried out in collaboration with the reconstruction department at Riksbyggen who is a cooperative corporation and one of Sweden’s largest property managers. Riksbyggens customers are housing cooperatives, companies and public property owners. The construction sector emitted 21% in 2019 of Sweden's greenhouse gases and 49% of all apartment buildings were built between 1951 – 1981 (2021), these buildings consume much energy, especially the ventilation systems. Documentation of knowledge from different projects can be none or substandard, which makes knowledge about energy renovation difficult to manage. The goal is to assess the economic profitability and environmental impact of energy saving measures in an apartment building from 1959. And to investigate Riksbyggens external energy specialists use of knowledge transfer to reduce lifecycle costs and pay-off time. To achieve the goal, a combination of qualitative and quantitative methods is used. Empirical data is collected through interviews, measurement data, calculations and documents and drawings provided by Riksbyggen. The calculations are used to answer how profitable the energy saving measures are and the interviews are used to map how knowledge transfer is used regarding savings of costs and energy. To answer the cost measures and energy savings of energy measures, a quantitative analysis method is. To map the feedback of experience, the interviewees' answers compare with each other and with the theoretical framework, both suppliers and customer are interviewed to get both perspectives. According to the performed calculations, the planned measures save a total of about 380 MWh district heating / year and increase the electricity demand by about 55 MWh/ year, the cost savings per year are about 248 000 SEK. The pay-off period of the heating pump is 8,4 years and heating pump combined with solar cells goes up to 9,1 years. The pay-off period including the replacement of new windows goes up to about 27,6 years. From the interviews it appears that knowledge transfer is mainly done orally in the daily work. The results are in line with the theory and the most rewarding knowledge transfer is according to the interviewees, the knowledge transfer their own organization with staff with different types of employment. It promotes development and research in the industry according to the theory and to reduce costs and energy. Interviewees spend a lot of time documenting financial gain and this is also the main driver for development according to the theory. The financial savings and pay-off period are calculated to be more expensive than expected, which is probably due to the historically high energy prices. But despite high prices, the energy-improving measures are profitable and installing both solar cells and an exhaust air heat pump, as in this investigation, provides security that solar cells become more profitable with higher electricity prices and heat pumps with lower electricity prices.

The humerus of a racing horse Thoroughbred is highly susceptible to stress fractures at a characteristic location as a result of cyclic loading. The propensity of a Thoroughbred to exhibit humeral fracture has made equines useful models in the epidemiology of stress fractures. In this study, a racing Thoroughbred humerus was simulated during training using a 3D finite element model in conjunction with a bone remodeling algorithm. Nine muscle forces and two contact forces were applied to the 3-dimensional finite element model, which contains four separate load cases representing fore-stance, mid-stance, aft-stance, and standing. Four different training programs were incorporated into the model, which represent Baseline Layup and Long Layup training programs along with two newly implemented programs for racing, which have an absence of a layup period, last a period of 24 weeks, and a race once every four weeks. Muscle and contact forces were rescaled for all load cases to simulate dirt, turf, and synthetic track surfaces. Bone porosity, damage, and BMU activation frequency were examined at the stress fracture site and compared with a control location called the caudal diaphysis. It was found that race programs exhibited similar remodeling patterns between each other. Damage at the stress fracture site and caudal diaphysis was reduced during all training programs for the turf and synthetic track surfaces with respect to the dirt track surface. Key findings also included changes in bone remodeling at the stress fracture site and caudal diaphysis as a result of turf and synthetic track surfaces. This model can serve as a framework for further studies in human or equine athletes who are susceptible to stress fractures.

Long-duration spaceflight has been shown to have significant, lasting effects on the bone strength of astronauts and to contribute to age-related complications later in life. The microgravity environment of space causes a decrease in daily mechanical loading, which signals a state of disuse to bone cells. This affects the bone remodeling process, which is responsible for maintaining bone mass, causing an increase in damage and a decrease in density. This leads to bone fragility and decreases overall strength, posing a risk for fracture. However, there is little information pertaining to the timeline of bone loss and subsequent fracture risk. This study used finite element analysis to model the human femur, the bone most adversely affected by spaceflight, and to simulate the environments of Earth preflight, a six-month mission on the International Space Station, and one year on Earth postflight. Changes in the properties of cortical and trabecular bone in the femoral neck were measured from the simulations, and used to provide evidence for high fracture risk and to predict when it is most prominent. It was found that a risk for fracture is extremely evident in the femoral neck in both cortical and trabecular bone. Cortical bone in the inferior neck exhibited high magnitudes of damage, while the superior neck suffered the greatest increases in damage that proceeded to increase upon return to Earth. The density of trabecular bone decreased the most significantly and was not fully recovered in the following year. While it is still unclear exactly when these changes cause the greatest risk for fracture, it is possible that they will add to and advance the onset of medical complications such as osteoporosis. Additionally, the results of this study support the claim that the current countermeasure of inflight exercise is insufficient in sustaining bone mass and preserving skeletal health. The effects of long-duration spaceflight on bone health should continue to be investigated especially if future missions are to last as long as one to three years.

Open treatment of condylar head fractures (CHF) is considered controversial. In this retrospective cohort study our primary objective was therefore to assess bone resorption and remodeling as well as patients function after open treatment of CHF in a medium-term follow-up (15.1 ± 2.2 months). We included 18 patients with 25 CHF who underwent open reduction and internal fixation, between 2016 and 2021, in our analysis. The clinical data and cone-beam computed tomography (CBCT) datasets were analyzed. The condylar processes were segmented in the postoperative (T1) and follow-up (T2) CBCT scans. Volumetric and linear bone changes were the primary outcome variables, measured by using a sophisticated 3D-algorithm. The mean condylar head volume decreased non-significantly from 3022.01 ± 825.77 mm3 (T1) to 2878.8 ± 735.60 mm3 (T2; p = 0.52). Morphological alterations indicated remodeling and resorption. The pre-operative maximal interincisal opening (MIO) was 19.75 ± 3.07 mm and significantly improved to 40.47 ± 1.7 mm during follow-up (p = 0.0005). Low rates of postoperative complications were observed. Open reduction of CHF leads to good clinical outcomes and low rates of medium-term complications. This study underlines the feasibility and importance of open treatment of CHF and may help to spread its acceptance as the preferred treatment option.

Mutually linked expression and methylation dynamics in the brain govern genome regulation over the whole lifetime with an impact on cognition, psychological disorders, and cancer. We performed a joint study of gene expression and DNA methylation of brain tissue originating from the human prefrontal cortex of individuals across the lifespan to describe changes in cellular programs and their regulation by epigenetic mechanisms. The analysis considers previous knowledge in terms of functional gene signatures and chromatin states derived from independent studies, aging profiles of a battery of chromatin modifying enzymes, and data of gliomas and neuropsychological disorders for a holistic view on the development and aging of the brain. Expression and methylation changes from babies to elderly adults decompose into different modes associated with the serial activation of (brain) developmental, learning, metabolic and inflammatory functions, where methylation in gene promoters mostly represses transcription. Expression of genes encoding methylome modifying enzymes is very diverse reflecting complex regulations during lifetime which also associates with the marked remodeling of chromatin between permissive and restrictive states. Data of brain cancer and psychotic disorders reveal footprints of pathophysiologies related to brain development and aging. Comparison of aging brains with gliomas supports the view that glioblastoma-like and astrocytoma-like tumors exhibit higher cellular plasticity activated in the developing healthy brain while oligodendrogliomas have a more stable differentiation hierarchy more resembling the aged brain. The balance and specific shifts between volatile and stable and between more irreversible and more plastic epigenomic networks govern the development and aging of healthy and diseased brain.

The tumor microenvironment is a key modulator in cancer progression and has become a novel target in cancer therapy. An increase in hyaluronan (HA) accumulation and metabolism can be found in advancing tumor progression and are often associated with aggressive malignancy, drug resistance and poor prognosis. Wound-healing related myofibroblasts or activated cancer-associated fibroblasts (CAF) are assumed to be the major sources of HA. Both cell types are capable to synthesize new matrix components as well as reorganize the extracellular matrix. However, to which extent myofibroblasts and CAF perform these actions are still unclear. In this work, we investigated the matrix remodeling and HA production potential in normal human dermal fibroblasts (NHFB) and CAF in the absence and presence of transforming growth factor beta -1 (TGF-β1), with TGF-β1 being a major factor of regulating fibroblast differentiation. Three-dimensional (3D) collagen matrix was utilized to mimic the extracellular matrix of the tumor microenvironment. We found that CAF appeared to response insensitively towards TGF-β1 in terms of cell proliferation and matrix remodeling when compared to NHFB. In regards of HA production, we found that both cell types were capable to produce matrix bound HA, rather than a soluble counterpart, in response to TGF-β1. However, activated CAF demonstrated higher HA production when compared to myofibroblasts. The average molecular weight of produced HA was found in the range of 480 kDa for both cells. By analyzing gene expression of HA metabolizing enzymes, namely hyaluronan synthase (HAS1-3) and hyaluronidase (HYAL1-3) isoforms, we found expression of specific isoforms in dependence of TGF-β1 present in both cells. In addition, HAS2 and HYAL1 are highly expressed in CAF, which might contribute to a higher production and degradation of HA in CAF matrix. Overall, our results suggested a distinct behavior of NHFB and CAF in 3D collagen matrices in the presence of TGF-β1 in terms of matrix remodeling and HA production pointing to a specific impact on tumor modulation.

La fibrillation auriculaire (FA) figure parmi les arythmies les plus courantes chez les patients âgés et dont l’incidence augmente avec l’âge. La compréhension des mécanismes liant les caractéristiques tissulaires et le risque de la FA demeure centrale pour l’optimisation du traitement. Les alternances de la durée du potentiel d’action (APD) dans le tissu cardiaque ont été depuis peu documentées comme l’un des phénomènes qui facilitent la FA. Généralement, la FA est associée à de courtes périodes de stimulation électrique. Récemment, la FA a été observée aux longues périodes de stimulation chez les patients atteints de la FA chronique (FAc). Les mécanismes sous-jacents aux alternances d’APD aux longues périodes de stimulation ne sont pas totalement déterminés. En partant d’un modèle mathématique avec le remodelage électrophysiologique associé à la FAc d’un myocyte auriculaire humain, notre objectif était de premièrement identifier ces mécanismes ainsi, nous avons réalisé une analyse de la sensibilité des alternances aux changements des paramètres du modèle. Dix-huit (18) paramètres associés au remodelage de la FA ont été mis à l’échelle entre 30% et 200% de leur valeur de base. Ensuite, nous avons stimulé le tissu à partir de l’électrode de stimulation pendant des périodes de stimulation (CL) comprise entre 700 ms et 350 ms. Les alternances de la durée du potentiel d’action et du calcium intracellulaire (Cai) ont été quantifiées par la suite au point d’enregistrement. On a validé que les alternances d’APD et de Cai étaient significatives seulement pour le changement du paramètre kiCa qui représente la constante d’inactivation des récepteurs ryanodines (RyR). Sachant que ce sont les alternances discordantes qui constituent un substrat pour la FA, nous avons en second lieu, validé la formation des alternances spatialement discordantes aux longues périodes de stimulation lorsque les alternances étaient occasionnées par la diminution de kiCa. Lorsque les alternances discordantes étaient entraînées par l’hétérogénéité de l’inactivation des RyR, le motif des alternances dépendait des conditions initiales de cette hétérogénéité. Nous avons par la suite déterminé les facteurs dynamiques qui modulaient l’apparition des alternances d’APD et de Cai aux périodes de stimulation pour lesquelles les alternances se sont manifestées. On a trouvé que pour notre modèle de FAc avec la diminution de kiCa, les alternances étaient pilotées par le cycle calcique alors que pour le modèle FAc de base, les alternances résultaient des interactions entre le cycle membranaire et calcique. Ces expériences nous ont permis de développer un modèle itéré qui prenait en compte les variables des cycles membranaires, calciques ainsi que le couplage entre ces cycles. L’analyse des données a révélé que le modèle itéré devait être constitué des variables dépendantes suivantes : calcium stocké dans le réticulum sarcoplasmique (SR), calcium cytoplasmique et la durée du potentiel d’action. Notre modèle itéré a pu reproduire les caractéristiques de la dynamique du système représenté par le tissu auriculaire humain avec le remodelage du FAc stimulé périodiquement. / Atrial fibrillation (AF) is one of the most common arrhythmias in elderly patients, and its incidence increases with age. Understanding the mechanisms linking tissue characteristics and the risk of AF remains central to optimising treatment. Action potential duration (APD) alternans in cardiac tissue have recently been documented as one of the phenomena that facilitate AF. Typically, AF is associated with short periods of electrical stimulation. Recently, AF has been observed at long pacing periods in patients with chronic AF (AFc). The mechanisms underlying APD alternans at long pacing periods are not fully determined. Using a mathematical model with the electrophysiological remodeling associated with AFc in a human atrial myocyte, our aim was first to identify these mechanisms and then to analyse the sensitivity of the alternans to changes in the model parameters. Eighteen (18) parameters associated with AF remodelling were scaled between 30% and 200% of their baseline value. The tissue was then paced from the stimulation electrode at pacing periods (CL) between 700 ms and 350 ms. Action potential duration and intracellular calcium (Cai) alternans were subsequently quantified at the recording point. APD and Cai alternans were found to be significant only for the change in the kiCa parameter, which represents the ryanodine receptor (RyR) inactivation constant. Knowing that it is the discordant alternans that constitute a substrate for AF, we secondly validated the formation of spatially discordant alternans at long pacing periods when the alternans were caused by the decrease in kiCa. When the discordant alternans were driven by heterogeneity in RyR inactivation, the pattern of alternans depended on the initial conditions of this heterogeneity. We then determined the dynamic factors that modulated the appearance of APD and Cai alternans at the pacing periods for which the alternans occurred. We found that for our AFc model with the decrease in kiCa, the alternans were driven by the calcium cycle, whereas for the basic AFc model, the alternans resulted from interactions between the membrane and calcium cycles. These experiments enabled us to develop an iterated model that considered the variables of the membrane and calcium cycles, as well as the coupling between these cycles. Analysis of the data revealed that the iterated model should consist of the following dependent variables: calcium load in the sarcoplasmic reticulum (SR), cytoplasmic calcium and the duration of the action potential. Our iterated model was able to reproduce the characteristics of the dynamics of the system represented by human atrial tissue with the electrophysiological remodeling associated with AFc paced periodically.

Cardiovascular disease (CVD) is ranked the second leading cause of death in Canada, with 53,704 heart disease-related deaths documented in 2020 alone. After a patient sustains cardiac injury, such as a myocardial infarction (MI), the heart is often unable to undergo sufficient self-recovery for healthy cardiac regeneration and repair; this is largely attributed to fibrotic tissue development at the injury site and subsequent pathological ventricular remodeling. The prevalence of MI events has created a considerable demand to develop novel strategies for effective and safe post-MI therapies. Research has indicated that post-MI modifications interfere with endogenous cardiac repair mechanisms, resulting in a pathological state. After an infarction, there is an accumulation of methylglyoxal (MG) at the site of injury. It has been suggested that MG contributes to ventricular fibrotic development, however its underlying mechanism remains unclear. Additionally, the effects that the post-MI cardiac environment, specifically MG accumulation, has on post-MI therapies and biomaterials has not been sufficiently established. Accordingly, the primary focus of this research project is to elucidate the effects of MG on the collagen-rich extracellular matrix (ECM) of the heart and key cardiac cells involved in the repair process. Further, the interaction between MG and a promising collagen-based hydrogel therapy is investigated, exploring the effects of MG on the hydrogel’s degradative process. It was found that the MG modification of hydrogels did not alter the degradation rate. Additionally, the degradation products of hydrogels, and MG-modified substrates did not affect the properties and formation of myofibroblasts.

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