Edoxaban for preventing stroke and systemic embolism in people with non-valvular atrial fibrillation: A Single Technology Appraisal. Evidence Review Group Report to NICE

1.1 Edoxaban is recommended, within its marketing authorisation, as an option for preventing stroke and systemic embolism in adults with non-valvular atrial fibrillation with one or more risk factors, including: congestive heart failure hypertension diabetes prior stroke or transient ischaemic attack age 75 years or older

Conversion of a Micro, Glow-Ignition, Two-Stroke Engine from Nitromethane-Methanol Blend Fuel to Military Jet Propellant (JP-8)

The goal of the thesis "Conversion of a Micro, Glow-Ignition, Two-Stroke Engine from Nitromethane-Methanol Blend Fuel to Military Jet Propellant (JP-8)" was to demonstrate the ability to operate a small engine on JP-8 and was completed in two phases. The first phase included choosing, developing a test stand for, and baseline testing a nitromethane-methanol-fueled engine. The chosen engine was an 11.5 cc, glow-ignition, two-stroke engine designed for remote-controlled helicopters. A micro engine test stand was developed to load and motor the engine. Instrumentation specific to the low flow rates and high speeds of the micro engine was developed and used to document engine behavior. The second phase included converting the engine to operate on JP-8, completing JP-8-fueled steady-state testing, and comparing the performance of the JP-8-fueled engine to the nitromethane-methanol-fueled engine. The conversion was accomplished through a novel crankcase heating method; by heating the crankcase for an extended period of time, a flammable fuel-air mixture was generated in the crankcase scavenged engine, which greatly improved starting times. To aid in starting and steady-state operation, yttrium-zirconia impregnated resin (i.e. ceramic coating) was applied to the combustion surfaces. This also improved the starting times of the JP-8-fueled engine and ultimately allowed for a 34-second starting time. Finally, the steady-state data from both the nitromethane-methanol and JP-8-fueled micro engine were compared. The JP-8-fueled engine showed signs of increased engine friction while having higher indicated fuel conversion efficiency and a higher overall system efficiency. The minimal ability of JP-8 to cool the engine via evaporative effects, however, created the necessity of increased cooling air flow. The conclusion reached was that JP-8-fueled micro engines could be viable in application, but not without additional research being conducted on combustion phenomenon and cooling requirements.

Coaching or gaming? Implications of strategy choice for home based stroke rehabilitation

Background: The enduring aging of the world population and prospective increase of age-related chronic diseases urge the implementation of new models for healthcare delivery. One strategy relies on ICT (Information and Communications Technology) home-based solutions allowing clients to pursue their treatments without institutionalization. Stroke survivors are a particular population that could strongly benefit from such solutions, but is not yet clear what the best approach is for bringing forth an adequate and sustainable usage of home-based rehabilitation systems. Here we explore two possible approaches: coaching and gaming. Methods: We performed trials with 20 healthy participants and 5 chronic stroke survivors to study and compare execution of an elbow flexion and extension task when performed within a coaching mode that provides encouragement or within a gaming mode. For each mode we analyzed compliance, arm movement kinematics and task scores. In addition, we assessed the usability and acceptance of the proposed modes through a customized self-report questionnaire. Results: In the healthy participants sample, 13/20 preferred the gaming mode and rated it as being significantly more fun (p < .05), but the feedback delivered by the coaching mode was subjectively perceived as being more useful (p < .01). In addition, the activity level (number of repetitions and total movement of the end effector) was significantly higher (p <.001) during coaching. However, the quality of movements was superior in gaming with a trend towards shorter movement duration (p=.074), significantly shorter travel distance (p <.001), higher movement efficiency (p <.001) and higher performance scores (p <.001). Stroke survivors also showed a trend towards higher activity levels in coaching, but with more movement quality during gaming. Finally, both training modes showed overall high acceptance. Conclusions: Gaming led to higher enjoyment and increased quality in movement execution in healthy participants. However, we observed that game mechanics strongly determined user behavior and limited activity levels. In contrast, coaching generated higher activity levels. Hence, the purpose of treatment and profile of end-users has to be considered when deciding on the most adequate approach for home based stroke rehabilitation.

Protect your body, your temple : Stroke Warning Signs, Symptoms, and Lowering Risk

These bookmarks state: African-Americans face higher risks of stroke. The more risk factors you have, the greater your chances of having a stroke. The best way to prevent a stroke is to reduce your risk factors. Common Risk Factors for Stroke: smoking, high blood pressure, high cholesterol, physical inactivity, obesity/overweight, diabetes. It also lists the warning signs of stroke.

An exploration of treatment burden and patient capacity in people with stroke

Background and aims: Advances in modern medicine have led to improved outcomes after stroke, yet an increased treatment burden has been placed on patients. Treatment burden is the workload of health care for people with chronic illness and the impact that this has on functioning and well-being. Those with comorbidities are likely to be particularly burdened. Excessive treatment burden can negatively affect outcomes. Individuals are likely to differ in their ability to manage health problems and follow treatments, defined as patient capacity. The aim of this thesis was to explore the experience of treatment burden for people who have had a stroke and the factors that influence patient capacity. Methods: There were four phases of research. 1) A systematic review of the qualitative literature that explored the experience of treatment burden for those with stroke. Data were analysed using framework synthesis, underpinned by Normalisation Process Theory (NPT). 2) A cross-sectional study of 1,424,378 participants >18 years, demographically representative of the Scottish population. Binary logistic regression was used to analyse the relationship between stroke and the presence of comorbidities and prescribed medications. 3) Interviews with twenty-nine individuals with stroke, fifteen analysed by framework analysis underpinned by NPT and fourteen by thematic analysis. The experience of treatment burden was explored in depth along with factors that influence patient capacity. 4) Integration of findings in order to create a conceptual model of treatment burden and patient capacity in stroke. Results: Phase 1) A taxonomy of treatment burden in stroke was created. The following broad areas of treatment burden were identified: making sense of stroke management and planning care; interacting with others including health professionals, family and other stroke patients; enacting management strategies; and reflecting on management. Phase 2) 35,690 people (2.5%) had a diagnosis of stroke and of the 39 co-morbidities examined, 35 were significantly more common in those with stroke. The proportion of those with stroke that had >1 additional morbidities present (94.2%) was almost twice that of controls (48%) (odds ratio (OR) adjusted for age, gender and socioeconomic deprivation; 95% confidence interval: 5.18; 4.95-5.43) and 34.5% had 4-6 comorbidities compared to 7.2% of controls (8.59; 8.17-9.04). In the stroke group, 12.6% of people had a record of >11 repeat prescriptions compared to only 1.5% of the control group (OR adjusted for age, gender, deprivation and morbidity count: 15.84; 14.86-16.88). Phase 3) The taxonomy of treatment burden from Phase 1 was verified and expanded. Additionally, treatment burdens were identified as arising from either: the workload of healthcare; or the endurance of care deficiencies. A taxonomy of patient capacity was created. Six factors were identified that influence patient capacity: personal attributes and skills; physical and cognitive abilities; support network; financial status; life workload, and environment. A conceptual model of treatment burden was created. Healthcare workload and the presence of care deficiencies can influence and be influenced by patient capacity. The quality and configuration of health and social care services influences healthcare workload, care deficiencies and patient capacity. Conclusions: This thesis provides important insights into the considerable treatment burden experienced by people who have had a stroke and the factors that affect their capacity to manage health. Multimorbidity and polypharmacy are common in those with stroke and levels of these are high. Findings have important implications for the design of clinical guidelines and healthcare delivery, for example co-ordination of care should be improved, shared decision-making enhanced, and patients better supported following discharge from hospital.

The role of inflammation in vascular function and pregnancy outcome in the pregnant stroke prone spontaneously hypertensive rat

During pregnancy, the maternal cardiovascular system undergoes major adaptation. One of these changes is a 40-50 % increase in circulating blood volume which requires a systemic remodelling of the vasculature in order to regulate maternal blood pressure and maximise blood supply to the developing placenta and fetus. These changes are broadly conserved between humans and rats making them an appropriate pre-clinical model in which to study the underlying mechanisms of pregnancy-dependent cardiovascular remodelling. Whilst women are normally protected against cardiovascular disease; pregnancy marks a period of time where women are susceptible to cardiovascular complications. Cardiovascular disease is the leading cause of maternal mortality in the United Kingdom; in particular hypertensive conditions are among the most common complications of pregnancy. One of the main underlying pathologies of these pregnancy complications is thought to be a failure of the maternal cardiovascular system to adapt. The remodelling of the uterine arteries, which directly supply the maternal-fetal interface, is paramount to a healthy pregnancy. Failure of the uterine arteries to remodel sufficiently can result in a number of obstetric complications such as preeclampsia, fetal growth restriction and spontaneous pregnancy loss. At present, it is poorly understood whether this deficient vascular response is due to a predisposition from existing maternal cardiovascular risk factors, the physiological changes that occur during pregnancy or a combination of both. Previous work in our group employed the stroke prone spontaneously hypertensive rat (SHRSP) as a model to investigate pregnancy-dependent remodelling of the uterine arteries. The SHRSP develops hypertension from 6 weeks of age and can be contrasted with the control strain, the Wistar Kyoto (WKY) rat. The phenotype of the SHRSP is therefore reflective of the clinical situation of maternal chronic hypertension during pregnancy. We showed that the SHRSP exhibited a deficient uterine artery remodelling response with respect to both structure and function accompanied by a reduction in litter size relative to the WKY at gestational day (GD) 18. A previous intervention study using nifedipine in the SHRSP achieved successful blood pressure reduction from 6 weeks of age and throughout pregnancy; however uterine artery remodelling and litter size at GD18 was not improved. We concluded that the abnormal uterine artery remodelling present in the SHRSP was independent of chronic hypertension. From these findings, we hypothesised that the SHRSP could be a novel model of spontaneously deficient uterine artery remodelling in response to pregnancy which was underpinned by other as yet unidentified cardiovascular risk factors. In Chapter 1 of this thesis, I have characterised the maternal, placental and fetal phenotype in pregnant (GD18) SHRSP and WKY. The pregnant SHRSP exhibit features of left ventricular hypertrophy in response to pregnancy and altered expression of maternal plasma biomarkers which have been previously associated with hypertension in human pregnancy. I developed a protocol for accurate dissection of the rat uteroplacental unit using qPCR probes specific for each layer. This allowed me to make an accurate and specific statement about gene expression in the SHRSP GD18 placenta; where oxidative stress related gene markers were increased in the vascular compartments. The majority of SHRSP placenta presented at GD18 with a blackened ring which encircled the tissue. Further investigation of the placenta using western blot for caspase 3 cleavage determined that this was likely due to increased cell death in the SHRSP placenta. The SHRSP also presented with a loss of one particular placental cell type at GD18: the glycogen cells. These cells could have been the target of cell death in the SHRSP placenta or were utilised early in pregnancy as a source of energy due to the deficient uterine artery blood supply. Blastocyst implantation was not altered but resorption rate was increased between SHRSP and WKY; indicating that the reduction in litter size in the SHRSP was primarily due to late (>GD14) pregnancy loss. Fetal growth was not restricted in SHRSP which led to the conclusion that SHRSP sacrifice part of their litter to deliver a smaller number of healthier pups. Activation of the immune system is a common pathway that has been implicated in the development of both hypertension and adverse pregnancy outcome. In Chapter 2, I proposed that this may be a mechanism of interest in SHRSP pregnancy and measured the pro-inflammatory cytokine, TNFα, as a marker of inflammation in pregnant SHRSP and WKY and in the placentas from these animals. TNFα was up-regulated in maternal plasma and urine from the GD18 SHRSP. In addition, TNFα release was increased from the GD18 SHRSP placenta as was the expression of the pro-inflammatory TNFα receptor 1 (Tnfr1). In order to investigate whether this excess TNFα was detrimental to SHRSP pregnancy, a vehicle-controlled intervention study using etanercept (a monoclonal antibody which works as a TNFα antagonist) was carried out. Etanercept treatment at GD0, 6, 12 and 18 resulted in an improvement in pregnancy outcome in the SHRSP with an increased litter size and reduced resorption rate. Furthermore, there was an improved uterine artery function in GD18 SHRSP treated with etanercept which was associated with an improved uterine artery blood flow over the course of gestation. In Chapter 3, I sought to identify the source of this detrimental excess of TNFα by designing a panel for maternal leukocytes in the blood and placenta at GD18. A population of CD3- CD161+ cells, which are defined as rat natural killer (NK) cells, were increased in number in the SHRSP. Intracellular flow cytometry also identified this cell type as a source of excess TNFα in blood and placenta from pregnant SHRSP. I then went on to evaluate the effects of etanercept treatment on these CD3- CD161+ cells and showed that etanercept reduced the expression of CD161 and the cytotoxic molecule, granzyme B, in the NK cells. Thus, etanercept limits the cytotoxicity and potential damaging effect of these NK cells in the SHRSP placenta. Analysing the urinary peptidome has clinical potential to identify novel pathways involved with disease and/or to develop biomarker panels to aid and stratify diagnosis. In Chapter 4, I utilised the SHRSP as a pre-clinical model to identify novel urinary peptides associated with hypertensive pregnancy. Firstly, a characterisation study was carried out in the kidney of the WKY and SHRSP. Urine samples from WKY and SHRSP taken at pre-pregnancy, mid-pregnancy (GD12) and late pregnancy (GD18) were used in the peptidomic screen. In order to capture peptides which were markers of hypertensive pregnancy from the urinary peptidomic data, I focussed on those that were only changed in a strain dependent manner at GD12 and 18 and not pre-pregnancy. Peptide fragments from the uromodulin protein were identified from this analysis to be increased in pregnant SHRSP relative to pregnant WKY. This increase in uromodulin was validated at the SHRSP kidney level using qPCR. Uromodulin has previously been identified to be a candidate molecule involved in systemic arterial hypertension but not in hypertensive pregnancy thus is a promising target for further study. In summary, we have characterised the SHRSP as the first model of maternal chronic hypertension during pregnancy and identified that inflammation mediated by TNFα and NK cells plays a key role in the pathology. The evidence presented in this thesis establishes the SHRSP as a pre-clinical model for pregnancy research and can be continued into clinical studies in pregnant women with chronic hypertension which remains an area of unmet research need.

Coaching or gaming? Implications of strategy choice for home based stroke rehabilitation

Background: The enduring aging of the world population and prospective increase of age-related chronic diseases urge the implementation of new models for healthcare delivery. One strategy relies on ICT (Information and Communications Technology) home-based solutions allowing clients to pursue their treatments without institutionalization. Stroke survivors are a particular population that could strongly benefit from such solutions, but is not yet clear what the best approach is for bringing forth an adequate and sustainable usage of home-based rehabilitation systems. Here we explore two possible approaches: coaching and gaming. Methods: We performed trials with 20 healthy participants and 5 chronic stroke survivors to study and compare execution of an elbow flexion and extension task when performed within a coaching mode that provides encouragement or within a gaming mode. For each mode we analyzed compliance, arm movement kinematics and task scores. In addition, we assessed the usability and acceptance of the proposed modes through a customized self-report questionnaire. Results: In the healthy participants sample, 13/20 preferred the gaming mode and rated it as being significantly more fun (p < .05), but the feedback delivered by the coaching mode was subjectively perceived as being more useful (p < .01). In addition, the activity level (number of repetitions and total movement of the end effector) was significantly higher (p <.001) during coaching. However, the quality of movements was superior in gaming with a trend towards shorter movement duration (p=.074), significantly shorter travel distance (p <.001), higher movement efficiency (p <.001) and higher performance scores (p <.001). Stroke survivors also showed a trend towards higher activity levels in coaching, but with more movement quality during gaming. Finally, both training modes showed overall high acceptance. Conclusions: Gaming led to higher enjoyment and increased quality in movement execution in healthy participants. However, we observed that game mechanics strongly determined user behavior and limited activity levels. In contrast, coaching generated higher activity levels. Hence, the purpose of treatment and profile of end-users has to be considered when deciding on the most adequate approach for home based stroke rehabilitation.

Screening a Case Base for Stroke Disease Detection

Stroke stands for one of the most frequent causes of death, without distinguishing age or genders. Despite representing an expressive mortality fig-ure, the disease also causes long-term disabilities with a huge recovery time, which goes in parallel with costs. However, stroke and health diseases may also be prevented considering illness evidence. Therefore, the present work will start with the development of a decision support system to assess stroke risk, centered on a formal framework based on Logic Programming for knowledge rep-resentation and reasoning, complemented with a Case Based Reasoning (CBR) approach to computing. Indeed, and in order to target practically the CBR cycle, a normalization and an optimization phases were introduced, and clustering methods were used, then reducing the search space and enhancing the cases re-trieval one. On the other hand, and aiming at an improvement of the CBR theo-retical basis, the predicates` attributes were normalized to the interval 0…1, and the extensions of the predicates that match the universe of discourse were re-written, and set not only in terms of an evaluation of its Quality-of-Information (QoI), but also in terms of an assessment of a Degree-of-Confidence (DoC), a measure of one`s confidence that they fit into a given interval, taking into account their domains, i.e., each predicate attribute will be given in terms of a pair (QoI, DoC), a simple and elegant way to represent data or knowledge of the type incomplete, self-contradictory, or even unknown.

Population’s knowledge about cerebrovascular accident (stroke) - passers of the square giraldo in Evora

Stroke is the leading cause of death in Portugal and the Alentejo region. Objective: Describe the population's knowledge about risk factors, signs and symptoms of stroke. Methodology: Quantitative and cross-sectional study. Convenience sample of 207 pedestrians with ages between 16 and 86 years old (M=38,85; SD = 18.93). Results: The pathology is known, the most frequently mentioned sources of information are television and friends. Hypercholesterolemia, heart disease and smoking are the risk factors more set out. The most well known signs are numbness and weakness in the hemisphere and dysarthria. Conclusion: It is necessary to strengthen the role of health services in education about stroke. Knowledge displays weaknesses in appreciation of advanced age and diabetes. Noteworthy is the recognition of the risk associated with tobacco consumption and persistence on it.

Development of a patient-specific model for stroke risk assessment in atrial fibrillation patients

Atrial fibrillation is associated with a five-fold increase in the risk of cerebrovascular events,being responsible of 15-18% of all strokes.The morphological and functional remodelling of the left atrium caused by atrial fibrillation favours blood stasis and, consequently, stroke risk. In this context, several clinical studies suggest that stroke risk stratification could be improved by using haemodynamic information on the left atrium (LA) and the left atrial appendage (LAA). The goal of this study was to develop a personalized computational fluid-dynamics (CFD) model of the left atrium which could clarify the haemodynamic implications of atrial fibrillation on a patient specific basis. The developed CFD model was first applied to better understand the role of LAA in stroke risk. Infact, the interplay of the LAA geometric parameters such as LAA length, tortuosity, surface area and volume with the fluid-dynamics parameters and the effects of the LAA closure have not been investigated. Results demonstrated the capabilities of the CFD model to reproduce the real physiological behaviour of the blood flow dynamics inside the LA and the LAA. Finally, we determined that the fluid-dynamics parameters enhanced in this research project could be used as new quantitative indexes to describe the different types of AF and open new scenarios for the patient-specific stroke risk stratification.

Two stroke cycle, novel combustion concepts and electrification for a new generation of internal combustion engines

The pursuit of decarbonization and increased efficiency in internal combustion engines (ICE) is crucial for reducing pollution in the mobility sector. While electrification is a long-term goal, ICE still has a role to play if coupled with innovative technologies. This research project explores various solutions to enhance ICE efficiency and reduce emissions, including Low Temperature Combustion (LTC), Dual fuel combustion with diesel and natural gas, and hydrogen integration. LTC methods like Dual fuel and Reactivity Controlled Compression Ignition (RCCI) show promise in lowering emissions such as NOx, soot, and CO2. Dual fuel Diesel-Natural Gas with hydrogen addition demonstrates improved efficiency, especially at low loads. RCCI Diesel-Gasoline engines offer increased Brake Thermal Efficiency (BTE) compared to standard diesel engines while reducing specific NOx emissions. The study compares 2-Stroke and 4-Stroke engine layouts, optimizing scavenging systems for both aircraft and vehicle applications. CFD analysis enhances specific power output while addressing injection challenges to prevent exhaust short circuits. Additionally, piston bowl shape optimization in Diesel engines running on Dual fuel (Diesel-Biogas) aims to reduce NOx emissions and enhance thermal efficiency. Unconventional 2-Stroke architectures, such as reverse loop scavenged with valves for high-performance cars, opposed piston engines for electricity generation, and small loop scavenged engines for scooters, are also explored. These innovations, alongside ultra-lean hydrogen combustion, offer diverse pathways toward achieving climate neutrality in the transport sector.

Gli eventi avversi che possono insorgere nel trattamento riabilitativo volto al recupero della deambulazione nel paziente con Stroke: a Scoping Review

Background: I trattamenti volti al recupero della deambulazione nel paziente post stroke sono ampiamente declinati in letteratura, ma vi sono tanti interrogativi per quanto riguarda gli eventi avversi che possono intercorrere in neuroriabilitazione. Dato l’ampio spettro di opzioni terapeutiche in questo ambito, innanzitutto, è utile comprendere quali trattamenti si dimostrano nocivi nella riabilitazione di un paziente così complesso. Obiettivo: l’obiettivo di questa Scoping Review è quello di indagare la presenza di eventi avversi riportati in letteratura che possono insorgere nella riabilitazione volta al recupero del cammino nel paziente post stroke. Inoltre, si cerca di individuare quali strategie terapeutiche non siano applicabili e sicure nell’ambito della neuroriabilitazione. Metodi: la ricerca è avvenuta consultando più banche dati online come Pubmed, Cochrane Library, PEDro, il motore di ricerca Google Scholar; il tutto tramite ricerca manuale bibliografica. Sono stati poi analizzati gli articoli pertinenti rispetto al nostro quesito di partenza, prendendo in considerazione qualsiasi tipologia di studio e senza porre limiti di lingua. Risultati: sono stati individuati 53 articoli secondo i criteri di eleggibilità, di cui: 28 RCT, 8 Systematic Reviews, 7 studi pilota, 4 meta – analisi, 2 studi cross-sectional, 2 studi osservazionali prospettici, 1 studio preliminare e 1 studio post hoc di 2 RCT. Il processo di selezione degli articoli è stato riportato utilizzando un diagramma di flusso, mentre il loro contenuto è sintetizzato in tabella sinottica. Conclusione: L’analisi degli studi segue l’applicazione della stringa di ricerca. Dall’analisi attuale della letteratura non viene evidenziata l’insorgenza di eventi avversi gravi e trattamento-correlati, che fossero responsabili di un cambiamento nella pratica clinica. Sono stati rilevati invece, alcuni eventi avversi di grado lieve o moderato, non sempre direttamente correlabili al trattamento proposto.

Gli effetti della realtà virtuale nel recupero della funzionalità dell’arto superiore in soggetti con esito di stroke in fase cronica: scoping review

Background: L’ictus rappresenta una delle principali patologie neurologiche che causa disabilità a lungo termine con un impatto profondo sulla funzionalità, autonomie della vita quotidiana (ADL) e partecipazione alla vita sociale. Circa il 50% degli individui affetti soffre di deficit cronici dell’arto superiore e solo 1/3 ha un pieno recupero. La realtà virtuale (VR) presenta i presupposti necessari dell’apprendimento motorio come ripetitività, specificità e adattamento del carico di lavoro per favorire la riorganizzazione neurale. Obiettivo: L’obiettivo della scoping review è di svolgere una mappatura della letteratura in cui sia previsto l’impiego della VR come possibile trattamento riabilitativo nel recupero della funzionalità dell’arto superiore in soggetti con esito di stroke in fase cronica, secondo la checklist della PRISMA Extension per le Scoping Review. Disegno dello studio: Sono stati inclusi gli studi pubblicati dall’01 gennaio 2016 al 05 settembre 2022 che prevedessero l’impiego della realtà virtuale, sia immersiva che non immersiva, applicata sull’intero arto superiore nel soggetto con esito di stroke in fase cronica per favorire il recupero della funzionalità dell’arto superiore. I limiti imposti sono: studi in lingua inglese, condotti in un ambiente sanitario con la supervisione di un operatore e il campione coinvolto di età adulta senza ulteriori patologie neurologiche. Le banche dati elettroniche coinvolte sono Pubmed, Cochrane library, PEDro, Scopus e Web of science. Risultati: Sono stati inclusi 5 evidenze scientifiche (1 RCT, 2 trial non controllati e 2 case report) che impiegassero la VR sull’arto superiore e svolgere ADL o attività ludiche nell’ambiente virtuale. Conclusione: Si evince che l’impiego della VR potrebbe favorire il recupero e il mantenimento della funzionalità dell’arto superiore nei soggetti con esito di stroke in fase cronica, ma sono necessari ulteriori studi futuri di maggiore rilevanza e validità scientifica.

Cardiac Magnetic Resonance Assessment Of Interstitial Myocardial Fibrosis And Cardiomyocyte Hypertrophy In Hypertensive Mice Treated With Spironolactone.

Nearly 50% of patients with heart failure (HF) have preserved LV ejection fraction, with interstitial fibrosis and cardiomyocyte hypertrophy as early manifestations of pressure overload. However, methods to assess both tissue characteristics dynamically and noninvasively with therapy are lacking. We measured the effects of mineralocorticoid receptor blockade on tissue phenotypes in LV pressure overload using cardiac magnetic resonance (CMR). Mice were randomized to l-nitro-ω-methyl ester (l-NAME, 3 mg/mL in water; n=22), or l-NAME with spironolactone (50 mg/kg/day in subcutaneous pellets; n=21). Myocardial extracellular volume (ECV; marker of diffuse interstitial fibrosis) and the intracellular lifetime of water (τic; marker of cardiomyocyte hypertrophy) were determined by CMR T1 imaging at baseline and after 7 weeks of therapy alongside histological assessments. Administration of l-NAME induced hypertensive heart disease in mice, with increases in mean arterial pressure, LV mass, ECV, and τic compared with placebo-treated controls, while LV ejection fraction was preserved (>50%). In comparison, animals receiving both spironolactone and l-NAME (l-NAME+S) showed less concentric remodeling, and a lower myocardial ECV and τic, indicating decreased interstitial fibrosis and cardiomyocyte hypertrophy (ECV: 0.43 ± 0.09 for l-NAME versus 0.25 ± 0.03 for l-NAME+S, P<0.001; τic: 0.42 ± 0.11 for l-NAME groups versus 0.12 ± 0.05 for l-NAME+S group). Mice treated with a combination of l-NAME and spironolactone were similar to placebo-treated controls at 7 weeks. Spironolactone attenuates interstitial fibrosis and cardiomyocyte hypertrophy in hypertensive heart disease. CMR can phenotype myocardial tissue remodeling in pressure-overload, furthering our understanding of HF progression.