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1
Bourke, L. T. "Cardiac injury in lupus." Thesis, University College London (University of London), 2014. http://discovery.ucl.ac.uk/1458423/.
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Systemic lupus erythematosus (SLE) carries a significantly enhanced risk of developing cardiovascular disease (CVD) and remains a leading cause of death in these patients, accounting for ~25% of all causes of mortality. Although there is clear evidence li nking accelerated atherosclerosis to SLE (and consequently an increase in cardiovascular events), another factor that may contribute to CVD related morbidity and mortality is reperfusion injury that occurs post - ischaemia. This is termed ischaemic / reperfu sion (I/R) injury and is a known important contributor to the size of the eventual infarct in the heart, which in animal studies has been shown to account for up to 40 - 50% of the final infarct size. Hydroxychloroquine (HCQ), originally an anti - malarial dr ug, is now used to treat autoimmune disorders, including SLE. HCQ has been shown to modulate inflammation in rheumatic diseases such as SLE and rheumatoid arthritis as well as have potential cardiovascular benefits in these patients. One of the keys aims o f this thesis was to explore the potential use of HCQ in reducing cardiac I/R injury. HCQ was found to be cardioprotective in an in vitro neonatal cardiomyocytes simulated I/R injury model as well as in an in vivo cardiac I/R injury model. This was found to be through an ERK - dependent mechanism which was blocked in the presence of the ERK inhibitor U0126 both in vitro and in vivo . Another relevant question addressed in this thesis was if I/R injury is enhanced in lupus. There is evidence from an autoimmune prone mouse model that lupus IgG are pathogenic in mesenteric I/R injury . However, no study as yet has investigated human lupus IgG in a heart model. IgG was purified from the serum of SLE patients (aPL +ve vs aP L – ve), antiphospholipid syndrome (APS) patients, juvenile onset SLE (JSLE) patients and healthy volunteers. The pre - treatment of neonatal rat cardiomyocytes with IgG from all 3 patient groups enhanced simulated I/R injury. However, the most pathogenic wer e those who were aPL positive. Interestingly, JSLE patients who were all aPL negative, enhanced I/R injury to similar levels as those who tested positive in the adult patient cohort. An enhanced p38 MAPK phosphorylation was observed in the presence of aPL positive IgG and this pathogenic effect was blocked in the presence of the p38 inhibitor SB23580. The results ob tained in this thesis have identified a potential role for HCQ in the cardiovascular field as a cardioprotective therapeutic in myocardial I/R injury. Additionally , IgG purified from patients with SLE , APS and JSLE have been shown to accelerate myocardial I/R injury.
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Wall, Johanna Martine. "Trauma-induced secondary cardiac injury." Thesis, Queen Mary, University of London, 2018. http://qmro.qmul.ac.uk/xmlui/handle/123456789/43998.
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Trauma-induced secondary cardiac injury (TISCI) represents an under recognised complication of severe injury with haemorrhage. A limited number of clinical studies have supported the development of adverse cardiac events, such as arrhythmia, in association with biomarker proven TISCI. Pre-clinical studies using small animal models have provided insights into potential mechanisms and key effector molecules involved in the development of TISCI, but there remains a general lack of understanding regarding the in vivo functional implications of this indirect cardiac injury resulting from trauma-haemorrhage. This project aimed to investigate the implications of cardiac injury on myocardial systolic function. A robust, translatable model of TISCI was developed, which reflected the cardiac biomarker profile identified in clinical studies and, for the first time, demonstrated a significant, dose-dependent rise in Heart-type Fatty Acid Binding Protein (H-FABP) in response to trauma-haemorrhage. Non-invasive echocardiography was used to determine the acute myocardial response to injury and haemorrhage and also to assess the response of the left ventricle to resuscitation after an antecedent 60-minute period of trauma-haemorrhage. The functional studies presented here have enabled real time visualisation of the impact of trauma-haemorrhage upon systolic left ventricular function over 1 to 6 hours, both with and without resuscitation. Having established the trends in in vivo systolic function over time, further studies were then conducted to test the combination of adenosine, lidocaine and magnesium (ALM) as a cardiovascular rescue agent in TISCI. ALM, as an adjunct to fluid resuscitation, has shown great promise as a therapeutic agent which improves haemodynamic outcomes, reduces the volume of resuscitation fluid required and favours survival in the murine model of TISCI.
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De’Ath, Henry D. I. "Trauma associated cardiac injury & dysfunction." Thesis, Queen Mary, University of London, 2013. http://qmro.qmul.ac.uk/xmlui/handle/123456789/8466.
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The existence of a trauma induced secondary cardiac injury (TISCI) remains in doubt. The risk factors and pathological processes that lead to its development are not known, whilst the effects of TISCI on injured patient outcome are uncertain. Concurrently, the incidence of coronary heart disease (CHD) in a trauma population and its influence on mortality are inconclusive. The aim of this research project was to address these specific areas of uncertainty. Critically injured patients (n=135) were retrospectively investigated for the incidence and nature of adverse cardiac events (ACEs), and levels of the cardiac specific biomarkers Troponin I, B-type Natriuretic Peptide and Heart-type Fatty Acid Binding Protein were measured. Biomarkers and cardiac events were evaluated against outcome. Thereafter, the relationship of pro-inflammatory cytokines with TISCI was explored. A prospective cohort study of 199 trauma patients followed, to confirm the existence of TISCI and describe its clinical features, risk factors and outcomes. Finally, coronary artery calcium, as a marker of CHD, was evaluated on 432 CT scans of the chest of trauma patients aged 45 years or over, and its association with survival after injury was established. ACEs and early biomarker rises occurred in trauma patients and both were unrelated to the severity of chest injury. Each was associated with higher mortality, and confirmed the existence of TISCI. Risk factors for the development of the condition included increasing age, worsening tissue injury and shock. A relationship with cytokines was demonstrated, and implicated acute inflammation in the pathogenesis of TISCI. Calcification on CT scans revealed the incidence of CHD in an injured cohort approached 70%, although its presence did not impact survival. There exists a trauma induced secondary cardiac injury which was related to poorer outcome. The condition was associated with inflammation. CHD was widespread in older trauma patients but was not associated with increased in-hospital mortality.
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Caroll, Patricia A. "Markers of cardiac injury in ultraendurance runners." Thesis, University of Hawaii at Manoa, 2003. http://hdl.handle.net/10125/6969.
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Wasilewski, Melissa Anne. "ABSENCE OF V1AR ALTERS CARDIAC FUNCTION AT BASELINE AND FOLLOWING ACUTE CARDIAC INJURY." Diss., Temple University Libraries, 2018. http://cdm16002.contentdm.oclc.org/cdm/ref/collection/p245801coll10/id/525634.
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Biomedical SciencesPh.D.
Heart failure (HF) is a prevalent disease affecting over 5.1 million people in the United States and over 23 million people worldwide. Many of the symptoms associated with HF are associated with neurohormonal responses to the decrease in cardiac output and systemic blood pressure, such as the activation of the renin-angiotensin-aldosterone system (RAAS) and the sympathetic nervous system. Current treatment guidelines recommend using drugs that block β-adrenergic receptor (βAR) signaling (e.g. β- blockers) or RAAS signaling (e.g. angiotensin receptor blockers/ARBs or angiotensin converting enzyme inhibitors/ACEi’s) Additionally, clinical studies have demonstrated that drugs blocking these neurohormones from properly signaling have decreased hospitalizations, morbidity, and mortality in these HF patients; and these are the only classes of pharmacological therapies that have been shown to reduce patient mortality. Interestingly, the neurohormone arginine vasopressin (AVP) has been implica
Temple University--Theses
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Maharsy, Wael. "Enhancing Cardiomyocyte Survival in Drug Induced Cardiac Injury." Thèse, Université d'Ottawa / University of Ottawa, 2012. http://hdl.handle.net/10393/23384.
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Cardiotoxicity associated with many cancer drugs is a critical issue facing physicians these days and a huge hurdle that must be overcome for a side effects-free cancer therapy. Survival of cardiac myocytes is compromised upon the exposure to certain chemotherapeutic drugs. Unfortunately, the mechanisms implicated in cardiac toxicity and the pathways governing myocyte survival are poorly understood. The following thesis addresses the mechanisms underlying the cardiotoxicity of two anticancer drugs, doxorubicin (DOX) and Imatinib mesylate (Gleevec). Transcription factor GATA-4, has recently emerged as an indispensable factor in the adult heart adaptive response and cardiomyocyte survival. Therefore, the specific aim of this project was to determine the role of GATA-4, its upstream regulators, as well as partners in survival. A combination of cell and molecular techniques done on in vivo, and ex vivo models were utilized to tackle these issues. In this study, we confirmed the cardiotoxicity of the anticancer drug, Imatinib mesylate and found to be age dependent. GATA-4, already known to be implicated in DOX-induced toxicity, was confirmed as an Imatinib target. At the molecular level, we identified IGF-1 and AKT as upstream regulators of GATA-4. Moreover, we confirmed ZFP260 (PEX-1), a key regulator of the cardiac hypertrophic response, as a GATA-4 collaborator in common prosurvival pathways. Collectively, these results provide new insights on the mechanisms underlying drug-induced cardiotoxicity and raise the exciting possibility that cancer drugs are negatively affecting the same prosurvival pathway(s), in which GATA-4 is a critical component. Therapeutic interventions aimed at enhancing GATA-4 activity may be interesting to consider in the context of treatments with anticancer drugs.
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Patel, Nikil. "Causes of brain injury associated with cardiac interventions." Thesis, University of Leicester, 2015. http://hdl.handle.net/2381/33073.
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Background& Objective: Brain injury after cardiac surgery is a serious concern for patients and their families. Thousands of air bubbles enter the cerebral circulation during cardiac surgery, but whether these are harmful to the brain and impact adversely on cognition remains subject of speculation. The purpose of this study was to use MRI to characterise new and pre-existing cerebral ischaemic lesions in patients undergoing cardiac surgery, and to test whether the accumulation of new lesions adversely affects cognition. This study also draws upon recent advances in intra-operative bubble sizing to investigate whether high volumes of macro-bubbles have potential to result in new MRI lesions or increased risk of cognitive decline following surgery. Methods: The burden of pre-existing versus new ischaemic lesions was quantified based on analysis of 3T MR images and compared with the results of cognitive testing. Intraoperative Doppler ultrasound recordings were used to estimate the number, volume and diameters of bubbles entering the middle cerebral artery during surgery for comparison with MRI and cognitive outcome. Results: Post-operative lesions were identified in 31% of patients. Patients with pre-existing lesions were 10 times more likely to receive new lesions after surgery. Forty six percent of patients experienced postoperative cognitive decline, which was independent of whether new lesions were present. Intra-cardiac patients received over 16 times the total volume of air, 7 times as many macro-bubbles, 5 times as many emboli following aortic cross-clamp removal, and over twice as many emboli overall than CABG patients, but there were no significant differences in MRI or cognitive outcome. Conclusions: New MRI lesions and high numbers of intra-operative macro-bubbles are common during cardiac surgery, but we found no evidence of any adverse effect on cognition.
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Naganathar, Sriveena. "Trauma induced secondary cardiac injury clinical manifestations and underlying mechanisms." Thesis, Queen Mary, University of London, 2018. http://qmro.qmul.ac.uk/xmlui/handle/123456789/54467.
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Since 1933, studies have explored the concept of trauma induced secondary cardiac injury (TISCI), yet till 2012, it had not been defined as the incidence of cardiac events and rise in cardiac biomarkers following traumatic injury. Despite, improvements in early outcomes, trauma patients have reduced long-term mortality with cardiac disease being the major contributor. Although many putative mechanisms have been suggested for TISCI, the underpinning pathophysiology still remains unclear. In this thesis, a prospective study of 290 critically injured patients identifies a 13% incidence of adverse cardiac events (ACE) with consistently raised serum h-FABP levels in these patients. H-FABP was found to be a good predictor of ACE through ROC analysis and a h-FABP of 16.8 ng/ml used to define trauma induced secondary cardiac injury (TISCI). TISCI was associated with longer hospital stay and higher mortality. Patients who developed ACE had higher plasma levels of adrenaline and noradrenaline with a correlating increase in plasma h-FABP. On multivariate analysis, hypertension was the only independent risk factors for ACE. The increase in serum cardiac biomarkers was reflected by an increase in serum h- FABP in our group's trauma hemorrhage murine models. The hearts of these models were used in the experiments that form the last experimental chapter of this thesis. Protein expression studies confirm this increase in serum h-FABP by evidence of concurrent leaching in the cardiac tissue, along with Troponin I. Myocardial injury was evident on electron microscopy with evidence of interstitial and organelle oedema, myofibrillar degeneration, nuclear condensation and changes in mitochondrial morphology. Immunohistochemistry and western blotting protein studies demonstrate the translocation of the mitochondrial death-related protein AIF to the cytosol and nucleus, where it becomes its active pro-apoptotic form. This thesis propositions the utility of the cardiac biomarker h-FABP in predicting ACE and outcomes in critically injured patients. Although increasing serum noradrenaline and adrenaline levels are associated with higher incidence of ACE and biochemical evidence of cardiac injury with rising h-FABP levels, multivariate analysis negates their value as independent predictors of ACE. Leaching out of the proteins h-FABP and Troponin I in the murine cardiac tissue confirmed the value of serum measurements of these proteins as markers of cardiac injury. This was associated with widespread ultrastructural myocardial damage in the TH mice with changes in mitochondrial morphology. The mitochondrial damage seen is associated with the translocation of the mitochondrial death-related protein AIF to the cytosol and the nucleus where I propose its canonical signaling leading to nuclear degradation and cell death is the driver of cardiac dysfunction.
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Hiraumi, Yoshimi. "Granulocyte colony-stimulating factor protects cardiac mitochondria in the early phase of cardiac injury." Kyoto University, 2009. http://hdl.handle.net/2433/126456.
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Khan, Areeg Ismail Ahmed Abdulla. "Novel translational strategies to treat cardiac injury and dysfunction." Thesis, Queen Mary, University of London, 2014. http://qmro.qmul.ac.uk/xmlui/handle/123456789/8445.
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There is ample evidence of the crucial role of PI3K/Akt dependent signalling in cardiac function, cellular growth and cell apoptosis. The PI3K/Akt pathway mediates cardioprotective effects in experimental models of cardiovascular disease. For example, activation of this pathway ameliorates the sepsis-induced cardiac dysfunction, whereas its activation in myocardial ischaemia/reperfusion (I/R) limits cardiac injury. This thesis investigates the role of two drugs, which activate the PI3K/Aktpathway, namely the haematopoietic cytokine erythropoietin and the anti-malarial drug artesunate, in a mouse animal model of experimental sepsis-induced cardiac dysfunction and in a rat model of regional myocardial I/R injury, respectively. Using a clinically relevant model of caecal ligation and puncture in mice, I demonstrated that aged (8 months) C57BL/6 mice (receiving fluid resuscitation and antibiotic therapy) developed significant cardiac dysfunction (within 24 h), while younger mice (2 months) did not. Erythropoietin attenuated the impaired systolic contractility (in vivo and ex vivo) caused by endotoxaemia (lipopolysacchride 9 mg kg-1; young mice) and sepsis (aged mice). These beneficial effects were associated with activation of Akt and endothelial nitric oxide synthase survival pathways and inhibition of the glycogen synthase kinase 3β, nuclear factor-κB and interleukin 1β pro-inflammatory pathways, secondary to activation of the β-common receptor. A single bolus administration of artesunate at the start of reperfusion in a rat model of myocardial I/R significantly attenuated the infarct size. This effect was mediated via activation of pro-survival pathways (PI3K/Akt and ERK 1/2 and STAT-3) and inhibition of the glycogen synthase kinase 3β and nuclear factor-κB pro-inflammatory pathways. Thus, in this thesis I have demonstrated that pharmacological activation of the PI3K/Akt pathway by erythropoietin and artesunate in sepsis and myocardial I/R, respectively, plays a vital role in the amelioration of cardiac dysfunction and injury.
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Coetzee, Ettienne. "Myocardial injury after non-cardiac surgery: A prevalence study." Master's thesis, University of Cape Town, 2018. http://hdl.handle.net/11427/29298.
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Background
Worldwide, the number of patients suffering from surgical complications account for a significant burden on healthcare systems. Myocardial injury after non-cardiac surgery (MINS) is a new entity that has recently been identified as an independent risk factor associated with 30-day all-cause mortality. The risk of death increases approximately 10 fold following MINS in the perioperative period. Diagnosing myocardial injury in nonsurgical patients often relies on specific symptomatology and clinical findings combined with special investigations. However, in surgical patients, more than 80% of patients with postoperative myocardial injury will be asymptomatic, and hence the majority of diagnoses will be missed. Studies identifying the prevalence and risk factors for MINS have been conducted in countries with a different surgical population to South Africa. The primary outcome of this study was to investigate the prevalence of MINS after non-cardiac, elective, elevated risk surgery in South Africa.
Methods
Patients undergoing elevated risk, elective, non-cardiac surgery ≥ 45 years of age were enrolled via convenience sampling. The new 5th generation, high sensitivity cardiac troponin T (hscTnT) blood test was used to identify MINS. Blood samples were taken between 24 to 72 hours after surgery. Exclusion criteria included patients with known renal disease, a recent cardiac event, pulmonary embolism or sepsis. Results A total of 244 patients were included in the study. The prevalence of MINS was 4.9% (95% CI 2.2-7.6) which was not significantly different (p=0.078) to reports from international prospective observational studies.
Conclusion
Elective, elevated risk surgical patients in South Africa have a similar incidence of MINS when compared to patients from international studies. As the risk profile of South African patients is significantly lower than other similar international observational studies, it is possible that the prevalence of MINS is more common in South Africa, when patients are adjusted for cardiovascular risk profile. The burden of MINS on public health morbidity is therefore likely to be proportionally more in South Africa when compared to international reports. This may suggest that the calibration of international cardiovascular risk prediction models is incorrect for South African patients, or there are confounding comorbidities which should be included in South African cardiovascular risk prediction models. Larger studies are required to confirm this hypothesis however, and should also aim to address the need for appropriate cardiovascular risk predicting models in South Africa, to ensure timeous identification of patients at risk of MINS.
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Qureshi, Muhammad Saqib Hayat. "Endothelial homeostasis and post-cardiac surgery inflammatory organ injury." Thesis, University of Leicester, 2016. http://hdl.handle.net/2381/37617.
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This thesis evaluates three most important etiological factors for organ injury namely, intravenous fluid, cardiopulmonary bypass (CPB) and blood transfusion, and considers their effects on endothelial dysfunction. This thesis evaluates 1. The safety of current fluid therapy, 2. The effects of novel versus established volume expanders on endothelial function and Acute Kidney Injury (AKI), 3. The effect of Sildenafil on renal glycocalyx in post-CPB AKI and 4. The effect of standard and modified red cell transfusions on lung and kidney injury. Using a systematic assessment of randomised controlled trials comparing colloids and crystalloids, we found that Hydroxyethylstarches are associated with increased risk of mortality and AKI. On the contrary, there was no evidence that Gelatins, Dextrans and Crystalloids were associated with increased harm. We evaluated the supremacy of novel AQIX RS-1® for intravenous resuscitation in a swine model of general anesthesia but failed to show its superiority as an endothelial and organ protective agent compared to Hartmann’s solution. We characterized that CPB mediated AKI is associated with modifications of Glycosaminoglycans and core protein components of Glycocalyx, but also that CPB induces detrimental changes in endothelial surface markers; vWF, Thrombomodulin, VE-Cadherin. These structural modifications caused direct reduction in Nitric Oxide bioavailability, renal artery vasomotor function and invoked AKI in swine. Post CPB-AKI was prevented by restoration of depleted NO bioavailability using Sildenafil Citrate without restoration of glomerular endothelial membrane (GEM) constituents. We explored the pathogenesis of Transfusion Related Acute Lung Injury (TRALI) and implicate alterations in red cell metabolomics; endothelial dysfunction, inflammation, microparticles and labile Iron and use a translational porcine model of TRALI to test red cell Rejuvenation coupled with red cell washing as a promising therapy. The work in this thesis has supported or generated ideas of novel pragmatic randomised clinical trials that seek to make direct difference in outcomes after cardiac surgery.
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Yamada, Tetsu. "Impact of the cardiac arrest mode on cardiac death donor lungs." Kyoto University, 2015. http://hdl.handle.net/2433/200492.
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Mörtberg, Erik. "Assessment of the Cerebral Ischemic/Reperfusion Injury after Cardiac Arrest." Doctoral thesis, Uppsala universitet, Anestesiologi och intensivvård, 2010. http://urn.kb.se/resolve?urn=urn:nbn:se:uu:diva-132681.
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The cerebral damage after cardiac arrest is thought to arise both from the ischemia during the cardiac arrest but also during reperfusion. It is the degree of cerebral damage which determines the outcome in patients. This thesis focuses on the cerebral damage after cardiac arrest. In two animal studies, positron emission tomography (PET) was used to measure cerebral blood flow, oxygen metabolism and oxygen extraction in the brain. After restoration of spontaneous circulation (ROSC) from five or ten minutes of cardiac arrest there was an immediate hyperperfusion, followed by a hypoperfusion which was most evident in the cortex. The oxygen metabolism decreased after ROSC with the lowest values in the cortex. The oxygen extraction was high at 60 minutes after ROSC, indicating an ischemic situation. After ten minutes of cardiac arrest, there was a hyperperfusion in the cerebellum. In 31 patients resuscitated after cardiac arrest and treated with hypothermia for 24 hours, blood samples were collected from admission until 108 hours after ROSC. The samples were analyzed for different biomarkers in order to test the predictive value of the biomarkers. The patients were assessed regarding their neurological outcome at discharge from the intensive care unit and after six months. Brain derived neurotrophic factor (BDNF) and glial fibrillary acidic protein (GFAP) was not associated with outcome. Neuron specific enolase (NSE) concentrations were higher among those with a poor outcome with a sensitivity of 57% and a specificity of 93% when sampled 96 hours after ROSC. S-100B was very accurate in predicting outcome; after 24 hours after ROSC it predicted a poor outcome with a sensitivity of 87% and a specificity of 100%. Tau protein predicted a poor outcome after 96 hours after ROSC with a sensitivity of 71% and a specificity of 93%.
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Burton, James O. "The mechanisms and consequences of haemodialysis induced acute cardiac injury." Thesis, University of Nottingham, 2009. http://eprints.nottingham.ac.uk/10662/.
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Patients on dialysis are subject to a hugely elevated risk of cardiovascular mortality. Incidence and prevalence of, and mortality and morbidity from heart failure is significantly higher in the haemodialysis population than the general population as a whole. This thesis describes research work focusing on the large scale haemodynamic changes that occur during haemodialysis and how they may negatively impact on the cardiovascular system. Our results show that the haemodynamic disturbances which occur during haemodialysis are capable of causing a reduction in myocardial blood flow sufficient in magnitude to induce myocardial ischaemia. This is associated with a matched reduction in regional left ventricular (LV) function and is entirely in keeping with other published work describing haemodialysis induced myocardial stunning reflecting subclinical myocardial ischaemia (myocardial stunning). In addition, we now know that this phenomenon of haemodialysis induced myocardial ischaemia and stunning is common and associated with both short and long term complications including ventricular arrhythmias, left ventricular dysfunction, an increased hazard of death and time to first cardiovascular event. This is pertinent as in non-dialysis patients repeated episodes of myocardial stunning lead to chronic heart failure, and in dialysis patients the presence of LV dysfunction dramatically increases the risk of death. We also identified a number of factors associated with the presence of myocardial stunning including age, raised biochemical markers of cardiac damage (troponin-T), higher ultrafiltration volumes and lower intradialytic blood pressure. This is of crucial importance as ultrafiltration volumes and intradialytic haemodynamics are potentially modifiable risk factors that could provide targets for dialysis based interventions aimed at improving cardiovascular outcomes in the haemodialysis population.
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O'Brien, Nicole Wadsworth. "Cardiac ischemia reperfusion injury and the role of neutral sphingomyelinase /." Diss., Connect to a 24 p. preview or request complete full text in PDF format. Access restricted to UC campuses, 2003. http://wwwlib.umi.com/cr/ucsd/fullcit?p3077801.
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Limchaiyawat, Pauline Tessalee. "The role of Chromogranin A in cardiac ischemic reperfusion injury." Diss., Connect to a 24 p. preview or request complete full text in PDF format. Access restricted to UC campuses, 2008. http://wwwlib.umi.com/cr/ucsd/fullcit?p1457303.
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Thesis (M.S.)--University of California, San Diego, 2008.Title from first page of PDF file (viewed November 6, 2008). Available via ProQuest Digital Dissertations. Includes bibliographical references (p. 46-50).
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Duan, Qiming. "Cardiac Na/K-ATPase in Ischemia-Reperfusion Injury and Cardioprotection." University of Toledo Health Science Campus / OhioLINK, 2014. http://rave.ohiolink.edu/etdc/view?acc_num=mco1388151402.
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Sakai, Tetsuro. "Autologous heart cell transplantation improves cardiac function after myocardlal injury." Kyoto University, 2001. http://hdl.handle.net/2433/150591.
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Wilson, Michelle. "The psychosocial outcome of anoxic brain injury following cardiac arrest." Thesis, University of Lincoln, 2012. http://eprints.lincoln.ac.uk/18966/.
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Aim of the study The psychosocial outcome of anoxic brain injury following cardiac arrest is a relatively under researched, but clinically important area. The aim of the current study was to add to the limited existing literature exploring the psychosocial outcome for cardiac arrest survivors, but specifically explore if there is a greater impact on psychosocial outcome in individuals experiencing anoxic brain injury as a result. Methods A range of self report measures were used to compare the quality of life, social functioning and symptoms of anxiety, depression and post traumatic stress of individuals with and without anoxic brain injury following cardiac arrest. Measures of subjective memory and executive difficulties were also used to investigate whether psychosocial difficulties were associated with subjective cognitive difficulties. Participants took part in the study between six months and four years post cardiac arrest. A MANOVA was used as a primary method of analysis. Results There was a significant multivariate difference between the two groups; with individuals with anoxia reporting more psychosocial difficulties than the nonanoxia group. Participants in the anoxia group had more social functioning difficulties and more anxiety, depression and post traumatic stress symptoms. There was no significant difference in self-reported quality of life between the two groups, although better quality of life was associated with better social functioning and fewer anxiety, depression and post traumatic stress symptoms. Although there was no significant difference between the two groups in regard to self-reported cognitive difficulties, fewer reported difficulties were also significantly associated with better quality of life, better social functioning and fewer anxiety, depression and post traumatic stress symptoms. There was no significant association with psychosocial outcome and time since cardiac arrest and no significant gender differences. Conclusion As the first known study to compare outcome for cardiac arrest survivors with anoxia with those without, the results suggest psychosocial outcome is worse for individuals with anoxia. Individuals with anoxia experience significantly more social functioning difficulties and symptoms of anxiety, depression and post traumatic stress. It is suggested that the difference is due to a combination of neuropsychological, social and psychological factors resulting from anoxic brain injury following cardiac arrest, however further research is required to explore the contributing factors in more depth.
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Reed, Grant William. "Associations Between Cardiac Troponin, Mechanism of Myocardial Injury, and Long-Term Mortality After Non-Cardiac Vascular Surgery." Case Western Reserve University School of Graduate Studies / OhioLINK, 2017. http://rave.ohiolink.edu/etdc/view?acc_num=case1491571890479287.
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Von, Oppell Ulrich O. "Myocardial protection during cardiac surgery." Thesis, University of Cape Town, 1992. http://hdl.handle.net/11427/25887.
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Castellan, Raphaël Fabrice Paul. "Macrophage-derived WNTs in normal cardiac growth and regeneration following injury." Thesis, University of Edinburgh, 2017. http://hdl.handle.net/1842/28808.
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Unlike other regenerative organs such as the liver, the adult mammalian heart does not regenerate tissue lost following injury such as myocardial infarction (MI). Instead a non-contractile fibrous scar develops that in the longer term leads to the development of heart failure (HF). In contrast to the adult, neonatal mammals, including mice and man, retain potent cardiac regenerative capacities and can replace myocardium lost following injury. Understanding the mechanisms underlying scar free repair in the neonate may help in development of new approaches to reduce the impact of myocardial injury in adults. In this thesis MI was induced by coronary artery ligation in mice at post-natal day 1 (P1). Novel electrocardiogram gated high resolution cardiac ultrasound was developed to permit non-invasive confirmation of injury 1 day later and regeneration 21 days later by loss, then restoration, of contractile function. Macrophages (MФ) play important roles in organ growth and homeostasis, and are required for scar-free regeneration of the neonatal mouse heart following MI. WNTs are secreted lipophilic proteins with multiple roles in development. MФ-derived WNTs are essential for scar free tissue regeneration following injury in the kidney, liver, and gut, but their role in the heart is unknown. The primary aim of this thesis was to investigate the role of MФ, and in particular MФ-derived WNTs in determining normal growth of the myocardium from neonate to adult and also in regeneration of the neonatal heart following injury. In wild-type neonatal mouse hearts, Csf1r-expressing cells density (mostly macrophages) was consistent across all time points studied. Three populations of resident cardiac mononuclear phagocytes were identified by flow cytometry: F4/80hi, CD11blo, Ly6C-ve - F4/80lo, CD11bhi, Ly6C-ve - F4/80lo, CD11bhi, Ly6C+ve. F4/80hi, CD11blo, Ly6C-ve cells were hypothesised to correspond to yolk-sac derived mononuclear phagocytes and F4/80lo, CD11bhi, Ly6C-ve - F4/80lo, CD11bhi, Ly6C+ve to foetal liver/bone marrow derived mononuclear phagocytes. Three phases of myocardial growth were identified by ultrasound and histological techniques: hyperplastic (P2-P8, with increased Ki67 and cardiac troponin immunopositive cells), hypertrophic/reorganisation (P8-P21, with increasing cardiomyocyte size and no change in left ventricle wall thickness), and finally hypertrophic solely (P21-P42, with increasing cardiomyocyte size and left ventricle wall thickness). Average coronary vessel size was shown to decrease between P2 and P8 whilst vessel density was increased. The number of α-smooth muscle actin (αSMA) coated vessels greatly increased between P8 and P42, indicating vessel maturation. Throughout all phases cardiac systolic function was maintained at steady state. Diastolic function was however shown to mature from a foetal to an adult pattern between P2 and P8, with reversal of the E:A wave ratio on Doppler ultrasound. In mice globally deficient in MФ due to a germline knock-out of the Csf1r gene (Csf1rnull mice), both body and heart weights were decreased from P7 onwards. The number of proliferating (Ki67+ve) cardiomyocytes at P1 and P7 was unchanged in Csf1r-null mice but there was a trend towards decreased cardiomyocyte size at P7, suggesting an influence on hypertrophic rather than hyperplastic growth of the myocardium. There was also a trend for slowed vascular network maturation, with a delay in the shift from large to smaller vessels in hearts from Csf1r-null mice. In mice with MФ-directed (Csf1r-icre mediated) depletion of Porcupine (Porcn), a gene encoding an enzyme required for WNT acylation and secretion cardiac growth, vascularisation, fibrosis and function were all similar in Cre-ve and Cre+ve animals until P41, when cardiomyocyte size and cardiac systolic function were both significantly increased in Cre+ve animals. However, the underlying mechanism is unknown. In the neonatal mice, Csf1r expressing cells, mostly MФ, were identified in association with regenerating myocardium after induction of MI at P1. Flow cytometry data showed that by P7 the putative resident yolk-sac derived population had mostly disappeared from the heart and was replaced by F4/80lo cells, similar to the pattern reported in the adult. In the regenerating myocardium, Axin2 expression was increased consistent with activation of canonical Wnt signalling. Expression of Wnt5b and Fzd2 receptor, both associated with fibrosis, was significantly increased relative to age matched uninjured hearts. MФ-directed depletion of Porcn did not influence either the functional decrease at day 1 or recovery at day 21 following induction of MI at P1. Coronary re-vascularisation was also unaffected by the genotype. However, retention of intra-myocardial fibrosis (picrosirius red staining) was significantly increased in hearts at day 21 post-MI from mice with MФ-directed depletion of Porcn. MФ-derived WNTs are therefore required for scar-free wound healing in the heart, as they are in the liver and the kidney where they regulate matrix metalloproteinase activity. In summary, novel ECG-gated high-resolution in vivo ultrasound developed in this project has allowed characterisation of cardiac structure and function during early post-natal growth and following injury and regeneration in neonatal mice. The resident MФ population of the heart is established pre-natally, and may play a role in determining maturation of the developing vascular network, although this does not involve MФ-derived Wnt signalling. Following MI, the MФ population may expand from bone marrow cells and MФ accumulate around the regenerating tissue. MФ derived WNTs are not required for regeneration of the neonatal myocardium but do have a role in ensuring scar free wound healing and this merits further investigation.
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Amaro, Emilie, Stephen Pophal, and Jozef Zoldos. "Vascular Reconstruction in a Neonate after Iatrogenic Injury during Cardiac Catheterization." LIPPINCOTT WILLIAMS & WILKINS, 2017. http://hdl.handle.net/10150/627070.
Full textAbstract:
As technology and interventional techniques continue to evolve, both the volume and complexity of cardiac catheterizations will increase, leading to a rise in the number of complications. One of the most morbid complications of cardiac catheterization is vascular injury. We report the case of a 31-day-old, 3.0-kg infant with hypoplastic left heart syndrome who experienced a left common iliac artery disruption during cardiac catheterization resulting in a retroperitoneal hemorrhage. The extent of the vascular injury combined with the vessel caliber posed a technically challenging surgical scenario. Ultimately, the vascular supply to the left lower extremity was reconstructed by the plastic surgery team with a reverse autologous vein graft. To our knowledge, this multidisciplinary approach with the involvement of plastic surgery represents a unique case.
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Champattanachai, Voraratt. "Effects of hexosamine biosynthesis on an in vitro model of cardiac ischemia." Thesis, Birmingham, Ala. : University of Alabama at Birmingham, 2008. https://www.mhsl.uab.edu/dt/2008d/champattanachai.pdf.
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Lucien, Jamie George. "The necrotic and apoptotic injury of cardiac xenotransplants caused by human serum." Thesis, National Library of Canada = Bibliothèque nationale du Canada, 2001. http://www.collectionscanada.ca/obj/s4/f2/dsk3/ftp04/NQ58625.pdf.
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Deye, Nicolas. "Cardiac Arrest-Induced Brain Injury : Diagnostic And Prognostic Values of Circulating Biomarkers." Thesis, Sorbonne Paris Cité, 2018. http://www.theses.fr/2018USPCC150.
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Le pronostic de l’arrêt cardiaque (AC) reste dramatique. Diagnostiquer sa cause rapidement et prédire précocement son pronostic ("pronostication") de manière fiable permettrait de mieux guider les traitements initiaux, en évitant de traiter futilement les patients avec faible probabilité d’évolution favorable ou à l’inverse de permettre d’intensifier le traitement de patients avec forte probabilité d’évolution favorable. Les biomarqueurs, dont l’utilité diagnostique et pronostique reste débattue, semblent actuellement insuffisamment sensibles et précis, surtout dans les 1ères heures après la reprise de l’activité circulatoire spontanée (RACS). Dans l’algorithme pronostique, seule la Neuron Specific Enolase (NSE) est validée après le 3ème jour post-AC et en 2ème intention. Notre première étude a montré que la valeur diagnostique des biomarqueurs "spécifiques" des lésions cérébrales en post-AC (protéine S100B : S100 et surtout NSE) était insuffisante, à l’admission en réanimation, pour étayer précisément le diagnostic de cause neurologique d’AC. Si la coronarographie précoce est l’outil diagnostique de référence de l’AC de probable cause cardiaque, les biomarqueurs ne peuvent remplacer le scanner cérébral pour diagnostiquer une cause neurologique d’AC. La deuxième étude a évalué, au 1er jour post-AC, S100 et NSE avec 2 témoins d’œdème cérébral proposés comme outils pronostiques : le diamètre de l’enveloppe du nerf optique (DENO) par échographie et le rapport de dédifférenciation substance grise / substance blanche (DSG/B) par scanner cérébral. Même si une relation directe ne peut être affirmée formellement entre ces paramètres, l’élargissement du DENO à J1 post-AC était corrélé aux lésions cérébrales, surtout l’œdème cérébral et les lésions neuronales suspectés sur l’élévation de la NSE (à l’admission et à J1) et la baisse de DSG/B. Si NSE, DSG/B et DENO à J1 étaient liés, S100, plus spécifique de la glie, n’était pas corrélée au DENO ni au DSG/B. NSE et S100 à l’admission, à J1 et J2 post-RACS et DENO à J1 étaient associées à la mortalité hospitalière. La troisième étude évaluait la valeur pronostique des biomarqueurs à la phase précoce de l’AC (NSE et S100 étant prélevées en médiane 220 min après la RASC). S100, réalisée en aveugle des cliniciens, était le biomarqueur le plus précis à l’admission en réanimation pour prédire correctement le pronostic défavorable à la sortie de l’hôpital et à 3 mois après AC, par rapport au lactate, pH et créatininémie, et surtout à la NSE. Les variations de S100 dans le temps permettaient d’affiner cette prédiction. S100 à l’admission était un facteur indépendant du pronostic défavorable à la sortie de l’hôpital, avec la durée sans massage cardiaque, le rythme initial non-choquable, le lactate initial et la présence de convulsion clinique. Selon les recommandations, la pronostication nécessite théoriquement d’être différée et multimodale, les biomarqueurs seuls n’étant pas recommandés, surtout précocement. Les biomarqueurs ne peuvent constituer une alternative, en comparaison à l’imagerie, pour l’aide diagnostique de la cause d’AC. A l’inverse, certains biomarqueurs comme la S100 après admission pourraient facilement et spécifiquement discriminer les AC ayant une certitude de pronostic défavorable. Associée à d’autres outils prédictifs clinico-radiologiques, la S100 pourrait être incorporée dans des algorithmes permettant de guider les thérapeutiques initiales. Une pronostication correcte précoce pourrait éviter des traitements invasifs inutiles, ou au contraire optimiser certaines thérapeutiques agressives. Le choix de méthodes recommandées et automatisées de contrôle ciblé de la température, très efficaces mais invasives et onéreuses, ou l’indication d’utiliser -ou pas- une assistance cardio-circulatoire extra-corporelle pourrait bénéficier d’une telle stratégie précoce de sélection des patientsOutcome of cardiac arrest (CA) remains dramatic. To quickly diagnose the cause of CA and establish a reliable outcome prediction (prognostication) as early as possible could help to guide initial treatments. It could avoid futile treatments in patients with low chance of survival or of good neurological recovery, or conversely allow treatment optimization in patients expected to have a high likelihood of good neurological outcome. Usefulness of biomarkers to guide clinicians in finding the CA diagnosis and helping prognostication is debated. Biomarkers are considered as not sensitive and accurate enough, especially within the first hours after return of spontaneous circulation (ROSC). Their use is only recommended in prognostication for Neuron Specific Enolase (NSE) as a second line tool and after the third day from CA. Our first study confirmed that biomarkers “specific” of brain injury (S100B protein: S100 and moreover NSE) cannot sufficiently discriminate the neurological cause of CA on ICU admission. If early coronary angiogram is the standard for diagnosing a probable cardiac cause of CA, biomarkers cannot replace brain computed-tomography (CT) in CA from a neurological cause. The second study evaluated, during the 1st day after ROSC, the link between biomarkers (S100 and NSE) and 2 surrogates of brain oedema recently proposed as outcome predictors: echography of the optic nerve sheath diameter (ONSD), and grey to white matter attenuation ratio (GWR) on brain CT-scan. Even though we cannot conclude on a definitive relationship between these parameters, ONSD enlargement at day 1 was associated with specific brain damage after CA, such as brain oedema and mostly axonal injuries, as reflected by increases in NSE (on admission and at day 1) and low GWR measurements. Whereas NSE, GWR and ONSD at day 1 were correlated, S100, which is more specific of glial injuries, did not reach significance. NSE and S100 on admission, at days 1 and 2 after ROSC, as well as ONSD at day 1, were associated with survival at hospital discharge. The third study evaluated the prognostic value of several biomarkers in the early phase after CA (NSE and S100 being sampled at median 220 min after ROSC). S100, blinded to physicians, was the biomarker with the best accuracy after ICU admission to correctly predict unfavourable outcome at hospital discharge and at 3 months after CA, compared with all other biomarkers such as lactate, pH, creatinine, and especially NSE. S100 variations during the first day after admission refined prognostication. Initial S100 was an early independent predictive factor associated with unfavourable outcome at hospital discharge, with the no-flow duration, initial lactate value, initial non-shockable rhythm, and the presence of clinical seizure. According to guidelines, prognostication theoretically needs to be delayed and multimodal, biomarkers alone not being recommended especially in the early phase after CA. Biomarkers cannot seem to be an alternative option compared to imaging to precisely diagnose the CA cause. By contrast, some biomarkers, such as S100 after admission, could easily and specifically discriminate CA patients with certainty of unfavourable outcome. Associated with other predictive tools (clinical or using imaging), biomarkers could interestingly be incorporated in early decisional algorithms to optimally guide initial therapies. This correct patient classification could help to avoid unuseful treatments versus to maximize aggressive therapies. The choice of recommended servo-controlled targeted temperature management devices, very efficient but invasive and expensive, or the indication -or not- of a cardio-circulatory assist device implementation should be guided in the early stage after ROSC using this simple strategy of patient selection
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Hobbs, Daniel. "PATHOGENIC ROLE OF PHOSPHODIESTERASE TYPE 5 UPREGULATION IN CARDIAC ISCHEMIA/REPERFUSION INJURY." VCU Scholars Compass, 2010. http://scholarscompass.vcu.edu/etd/106.
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Phosphodiesterase Type 5 (PDE5) inhibitors are cardioprotective against ischemia/reperfusion (I/R) injury. However, it remains uncertain if I/R affects PDE5. We hypothesized that generation of reactive oxygen species (ROS) during I/R leads to upregulation of PDE5, which contributes to pathological changes following acute myocardial infarction (AMI). Adult male ICR mice were subjected to 30 minutes of in vivo or ex vivo I/R. To examine the role of ROS, a subset of hearts were perfused with 100 µM hydrogen peroxide (H2O2). Expression and activity of PDE5, pPDE5, and cGMP-dependent protein kinase (PKG) were measured by Western blots and spectrophotometric assay. The results show that ischemia and I/R significantly increased expression of PDE5. H2O2 had no effect on PDE5 expression and activity but significantly increased PKG activity. We conclude that acute cardiac ischemia or I/R upregulate PDE5 independent of oxidant stress in the heart.
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McCracken, Laura A. "Cardiac function and physical activity participation in individuals with spinal cord injury." Thesis, University of British Columbia, 2017. http://hdl.handle.net/2429/61357.
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Individuals with spinal cord injury (SCI) are at greatly increased risk of cardiovascular disease (CVD). This is likely due to physical inactivity and impaired sympathetic control of the heart and blood vessels, resulting in cardiovascular dysfunction. Cardiovascular dysfunction in individuals with SCI is associated with injury level, whereby individuals with higher lesions exhibit greater dysfunction. In people without SCI, cardiac dysfunction predicts CVD. The studies that have investigated cardiac indices in individuals with SCI tend to agree that cardiac atrophy and impaired systolic function occur following SCI. Physical activity is a key method to decrease CVD risk and improve cardiac function, yet few studies have examined the relationship between cardiac function and physical activity in individuals with SCI. Those that have investigated this relationship have used subjective measures of physical activity. The current guidelines for physical activity participation for individuals with SCI were based on a systematic review of the evidence on the benefits of physical activity, yet there was inadequate evidence to prescribe activity intensity and duration to improve cardiovascular health in this population. Individuals with SCI also experience numerous barriers and facilitators to physical activity participation that affect their ability to meet the guideline recommendations. The objectives of this thesis, therefore, were: 1) to objectively measure physical activity in individuals with SCI, using wrist-worn accelerometry during a six-day physical activity monitoring period, and to evaluate the utility of group based wrist accelerometry cut-points to estimate physical activity intensity by comparing MVPA determined by individual cut-points to MVPA determined by group-based cut-points; 2) to determine the relationship between objectively measured physical activity and cardiac structure and function in individuals with SCI across a range of injury levels, and 3) to explore the barriers and facilitators to physical activity participation experienced by individuals with SCI during a six-day physical activity monitoring period.Education, Faculty of
Kinesiology, School of
Graduate
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NAGATA, KOHZO, TOYOAKI MUROHARA, MASAAKI MIYACHI, MAYUKO OHTAKE, KOJI TSUBOI, MASAFUMI OHTAKE, KEIJI TAKAHASHI, ERIKA IWASE, TAMAYO MURASE, and TAKUYA HATTORI. "Glucocorticoid-Induced Hypertension and Cardiac Injury: Effects of Mineralocorticoid and Glucocorticoid Receptor Antagonism." Nagoya University School of Medicine, 2013. http://hdl.handle.net/2237/17604.
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Southworth, Richard. "Tolerance of the immature myocardium to ischaemia-reperfusion injury : the importance of a favourable antioxidant/free radical balance." Thesis, King's College London (University of London), 1998. http://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.286204.
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Hunter, Arwen Leigh. "The role of peri-transplant ischemia and reperfusion injury in cardiac allograft vasculopathy." Thesis, University of British Columbia, 2008. http://hdl.handle.net/2429/2503.
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Heart transplantation is often the only therapeutic option for patients with end stage heart disease. Allograft organs are in short supply. Thus, preserving the life of a grafted organ is extremely important. Cardiac allograft vasculopathy (CAV) is an expression of chronic rejection that accounts for the greatest loss of graft function in transplanted hearts. Peri-transplant ischemia/reperfusion (I/R)-injury occurs during transplantation when blood flow is stopped to remove the heart from the donor and then is reinstated upon implantation of the donor heart into the recipient. This oxidative injury contributes to vascular dysfunction and CAV. In this dissertation, I hypothesize that prevention and/or reduction of I/R during transplantation reduces post-transplant vascular dysfunction and CAV. In this regard, myself and my colleagues examined the roles of apoptosis repressor with caspase recruitment domain (ARC) and cytochrome p450 (CYP) 2C enzymes in UR-induced vascular dysfunction and CAV.
ARC expression was detected in endothelial cells (ECs) and smooth muscle cells (SMCs); however, increased levels of ARC do not protect against oxidant injury. ARC overexpression did protect against oxidant-induced cell death in H9c2 rat embryonic myoblasts. We observed that ARC-overexpression prevented H9c2 differentiation into muscle cells. With our focus on vascular injury, we turned our attention to the CYP 2C enzymes. Both endothelium-dependent and independent vascular function was impaired following I/R. Pre-treatment with the CYP 2C inhibitor sulfaphenazole (SP) restored endothelial sensitivity to acetylcholine, but did not restore sensitivity to endothelium-independent vasodilators. Rat heterotopic heart transplants were performed with rats being treated with SP or vector control prior to surgery. Rats treated with SP showed significantly reduced luminal narrowing and had decreased SMC proliferation, oxidant and interferon-y levels. No differences were detected in immune infiltration or apoptosis. Complementary studies in cultured vascular cells revealed that CYP 2C9 expression decreased viability and increased ROS production following hypoxia and re-oxygenation in ECs but not in SMCs.
In summary, we did not detect protection of vascular cells by ARC, but did discover a novel role for ARC in differentiation. CYP 2C contributes to post-ischemic vascular dysfunction and CAV through increased oxidative stress and endothelial dysfunction.
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Ahmed, Ishtiaq M. "Studies on the role of inflammation and stem cells in cardiac ischaemic injury." Thesis, Durham University, 2008. http://etheses.dur.ac.uk/2177/.
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The regenerative capacity of human myocardium is unable to compensate adequately forth significant loss of heart muscle that occurs in acute myocardial infarction (Ml). However, recent studies indicate that the adult heart may contain populations of cells that have stem cell characteristics and which could have regenerative potential. In order to better examine the biology of such cells, this study developed a mouse model of MI that combined low mortality, reproducible infarct size and the opportunity for reperfusion studies. One potential barrier to the expression of regenerative capacity at the time of acute Ml is inflammation, which, as well as contributing to myocardial injury, may prevent the activation and function of putative stem cells. The C5/C5a axis in the complement cascade is a key mediator of the inflammatory events involved in MI and therefore represents an attractive target. An antibody to the C5a receptor was used in vivo in the murine model of MI. Although the neutrophil infiltration at the time of MI was significantly reduced (p<0.05), the size of MI was unchanged in comparison to control, suggesting that other regenerative strategies must be explored. Therefore in pursuit of a mechanism by which the heart may regenerate, cells were isolated and assayed in vitro for their stem cell capacity. Cells expressing platelet derived growth factor receptor alpha (PDGFRA) were candidates for such stem cells, both as these are present in the proepicardium and epicardium in the embryo, and that Pdgfra(^+) mice demonstrate cardiac abnormalities. A combined approach was employed, using genetically modified mice expressing Green Fluorescence Protein (GFP) under the transcriptional control of the Pdgfra locus, expression of surface antigens as well as the ability of candidate stem cells to demonstrate self renewal and proliferation in a colony forming unit fibroblast assay (CFU-F). A Sca-1(^+) /PECAM˙/PDGFRA(^GFP+) fraction isolated from the adult heart was found to be enriched for colony forming activity. Two populations were found which formed colonies, the PDGFRA(^GFPHIGH) population which had 'stem cell' like properties in terms of proliferation, prolonged self renewal and multipotent in vitro differentiation, and the PDGFRA (^GFPMEDIUM) population which had 'progenitor cell' like properties in that although it had proliferative ability, the potential of this population to continue to self renew and differentiate into multiple lineages was limited. The number of candidate stem cells and progenitor cells in the heart increased post infarct as evidenced by an increase in number of PDGFRA (^GFPHIGH) and PDGFRA (^GFPMEDIUM) cells, together with a greater colony forming ability of the PDGFRA (^GEPHIGH) cells. These effects were magnified in a proregenerative transgenic model, Pdgfra (^GFP/+) ;mlGF, in which there was over expression of insulin-like growth factor 1 (IGF-1), supporting the argument that Sca-1(^+) /PECAM˙/PDGFRA(^GFP+) cells may have a role to play in the regenerative capacity of the adult heart.
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Gallagher, Sean. "Reducing acute kidney injury in patients with chronic kidney disease undergoing cardiac surgery." Thesis, Queen Mary, University of London, 2014. http://qmro.qmul.ac.uk/xmlui/handle/123456789/8669.
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Patients with chronic kidney disease (CKD) are a group with a markedly increased risk of adverse events following cardiac surgery. A particular problem for these patients is the development of post-operative acute kidney injury (AKI), which is associated with a significant increase in morbidity and mortality. Currently, there are no effective therapies proven to modify AKI in patients undergoing cardiac surgery. This thesis has three parts. The first describes an analysis of the Barts Health NHS Trust cardiac surgical dataset. Specifically, outcomes of patients with CKD and AKI were examined. The second describes a randomized control trial that examined the effect of remote ischaemic preconditioning (RIPC) upon AKI and myocardial injury in patients with CKD undergoing coronary artery bypass graft surgery (CABG). The final part describes the development of a panel of AKI biomarkers to allow the accurate prediction of AKI in patients with CKD undergoing CABG. The aims of this thesis were: 1. In our local cardiac surgical cohort, a. To assess the effects of CKD upon outcomes after CABG. b. To asses the prognostic importance of AKI after CABG. 2. To assess the potential for RIPC to reduce AKI and myocardial injury in patients with CKD undergoing CABG. 3. To investigate the diagnostic performance of serum and urine AKI biomarkers in a population of patients with CKD undergoing CABG. Analysis of the Barts Health NHS Trust cardiac surgical dataset confirmed that patients with CKD account for almost one-third of patients undergoing CABG. However, these patients account for a disproportionate two-thirds of all early mortality. CKD was also independently associated with late mortality after CABG. AKI was common in these patients. AKI was associated with late mortality even after accounting for pre-operative comorbidity and surgical complexity. In the randomized control trial, RIPC showed no effect upon the incidence of AKI or myocardial injury in the. 86 patients with CKD recruited. Secondary analysis of serum and urine biomarkers collected found change in serum cystatin C and NGAL as impressive predictors of AKI in patients with CKD. They allowed accurate early prediction of AKI more than 24 hours before diagnosis was possible using serum creatinine.
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HOUSE, STACEY LYNN. "ROLE OF FIBROBLAST GROWTH FACTOR 2 IN CARDIAC ISCHEMIA-REPERFUSION INJURY AND HYPERTROPHY." University of Cincinnati / OhioLINK, 2005. http://rave.ohiolink.edu/etdc/view?acc_num=ucin1132336027.
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Zhang, Hongyu. "INCREASING MYOCYTE CONTRACTILITY EXACERBATES CARDIAC INJURY AND PUMP DYSFUNCTION AND ABLATION OF PHOSPHORYLATION." Diss., Temple University Libraries, 2010. http://cdm16002.contentdm.oclc.org/cdm/ref/collection/p245801coll10/id/90859.
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PhysiologyPh.D.
Myocardial infarction (MI) leads to heart failure (HF) and premature death. The respective roles of myocyte death and depressed myocyte contractility in the induction of HF after MI have not been clearly defined. Cardiac ryanodine receptor (RyR2) has been linked to cardiac arrhythmias and HF. It has been controversial that protein kinase A (PKA) hyperphosphorylation of the RyR2 at a single residue, Ser-2808 is a critical mediator of progressive cardiac dysfunction after MI. We developed two mouse models. In one model with beta2a (LTCC subunit) overexpression we could prevent depressed myocyte contractility after MI and use it to test the idea that preventing depression of myocyte Ca2+ handling defects could avert post MI cardiac pump dysfunction. In the other model, mice with Ser2808 in RyR2 replaced by alanine (S2808A) to prevent the phosphorylation at this site were used to determine whether loss of functional PKA phosphorylation site at Ser2808 could protect against cardiac dysfunction progression after MI. beta2a myocytes had increased Ca2+ current; contraction and Ca2+ transients (versus controls) and beta2a hearts had increased performance before MI. After MI, ventricular dilation, myocyte hypertrophy, and depressed cardiac pump function was greater in beta2a versus control hearts. There was also an increased rate of myocyte death in beta2a hearts after MI and survival was significantly reduced in these animals. We concluded that maintaining myocyte contractility after MI, by increasing Ca2+ influx, depresses rather than improves cardiac pump function. Baseline cardiac function was similar in wild type (WT) and RyR-S2808A mice before MI. After MI, there was no significant difference between WT and RyR-S2808A mice in EF and FS at 4 weeks. ICa-L € in WT and RyR-S2808A myocytes was not significantly different. There were significant ISO responses in all myocytes, and no appreciable differences in responsiveness were found. Contractions and Ca2+ transients were not significantly different in WT and RyR-S2808A myocytes after MI. In conclusion, preventing PKA phosphorylation of RyR at Ser2808 after MI does not protect the heart or its myocytes. The role of RyR phosphorylation at other sites on abnormal Ca2+ handling in diseased hearts is yet to be defined.
Temple University--Theses
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Patel, Nishith N. "Novel renoprotective strategies for the prevention of acute kidney injury following cardiac surgery." Thesis, University of Bristol, 2013. http://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.683689.
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Acute kidney injury (AKI) following cardiac surgelY is common, is associated with a 4-fold increased risk of in-hospital death, a doubling of healthcare costs and prolonged hospital stay. The aim of this thesis was to develop novel renoprotective strategies by systematically reviewing current preventative sh·ategies, developing a large animal model of post-cardiopulmonalY bypass (CPB) AKI and assessing the interaction of red blood cell (RBC) transfusion and CPB in the pathogenesis of AKI. This thesis has found that cUlTently there are no effective renoprotective strategies for the prevention of post-CPB AKI. By developing a novel large animal porcine recovery model, we have shown that post-CPB AKI is characterised by endothelial injury, activation and dysfunction, nitric oxide depletion, inflammation, tubular epithelial cell stress and apoptosis with no evidence of acute tubular necrosis. Targeting endothelial pathways using Sitaxsentan sodium, an endothelin-A receptor antagonist, and Sildenafil citrate, a phosphodiesterase-5 inhibitor given intravenously at the start of CPB prevented AKI. Contrary to observational studies, we found that allogeneic porcine RBC transfusion did not cause AKI. Instead RBC transfusion prevented post-CPB AKI by reversing haemodilutional anaemia and improving systemic haemodynamics in the porcine model. However, RBC transfusion did cause Transfusion-Related Acute Lung Injury (TRALI). The severity of TRALI was storage dependent and therefore older RBCs caused greater injUly than younger RBCs. RBC transfusion in the presence of CPB exacerbated TRALI. TRALI was characterised by endothelial activation, inflammation, platelet activation and dysfunction, and coagulopathy. Washing of old, stored RBCs ameliorated TRALI. This thesis has contributed two novel large animal recovery models: a model of postCPB AKI and a model ofTRALI. These models have been utilised as platforms for the development of novel organ protection strategies. This thesis has identified three such strategies that can be rapidly translated into clinical trials, namely, endothelin-A receptor antagonism using Sitaxsentan sodium, phosphodiesterase-5 inhibition using sildenafil citrate and washing of stored human RBCs prior to transfusion.
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Befroy, Douglas Eugene. "Osmotic shock : modulation of contractile function, pHâ†i and ischaemic damage in the perfused guinea-pig heart." Thesis, University of Oxford, 2000. http://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.326024.
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Ciucci, Giulio. "Engineered heart tissues to investigate the role of mechanical loading and injury in cardiomyocyte proliferation." Doctoral thesis, Università degli studi di Trento, 2021. http://hdl.handle.net/11572/312213.
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Myocardial infarction is one of the most severe acute pathologies of the cardiovascular system. The adult mammalian heart is indeed unable to regenerate most of the lost cardiomyocytes (CMs) after cardiac injury. The loss of cardiomyocytes and the myocardial scarring after myocardial infarction eventually compromise contractility of the remaining myocardium, leading to heart failure. Therefore, promoting heart regeneration is one of the most crucial therapeutic targets in cardiovascular medicine. The lack of regenerative response is due to the loss of proliferative capacity of adult CMs which in mice occurs seven days after birth. One of the events which occur at birth in neonatal hearts is a sudden increase in mechanical loading that may contribute to switching mammal CMs phenotype from neonatal proliferative to adult postmitotic. Therefore, understanding the role of mechanotransduction in regulating the balance between CM proliferation and maturation may bring us to the identification of unknown mediators and new potential strategies to induce cardiac regeneration. Regulation of mechanical load in bi-dimensional cultures of CMs can be achieved in different ways, however, the poor degree of CM maturation that can be reached in a culture dish together with the lack of a tridimensional structure represent a major limitation to performing mechanotransduction studies. In our work we developed a novel system to study mechanotransduction of CMs based on 3D culture of cardiac cells, called engineered heart tissues (EHTs), that allow us to reduce or increase mechanical loading easily. We show that the three-dimensional setting of the culture leads to an improvement of CM maturation that may be reversed by mechanical unloading inducing cell proliferation. On the other hand, a persisting overload stimulus eventually induces CM switch to a more mature phenotype with a low degree of proliferation.
Also, we have focused our work on developing an EHT-based model able to recapitulate the adult infarct injury in order to investigate the biology of cardiac regeneration in this setting. Specifically, we set up a cryoinjury protocol that is relatively easy and reproducible. Cryoinjury produces a localized injury without
compromising EHT’s structural integrity. Indeed, all the EHTs subjected to cryoinjury preserved their contractile activity and did not show any significant change in shape. Considering that EHTs are unpurified cardiac culture rich in fibroblast and endothelial cells, we observed that cryoinjury induce fibroblast proliferation and activation together with a lack of proliferative response of the cardiomyocytes which is, on the other hand, present in the early phase of EHT’s development, similarly to what has been shown in mice and rats after myocardial infarction, highlighting the robustness of our cryoinjury approach as a model to investigate cardiac regeneration.
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Speakman, Elisabeth Anne. "The fall in cardiac output after a scald burn injury to the anaesthetised rat." Thesis, University of Southampton, 1989. http://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.328547.
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Prakash, Meeta B. "Deletion of Cardiac miR-17-92 Cluster Increases Ischemia/ Reperfusion Injury via PTEN Upregulation." VCU Scholars Compass, 2017. http://scholarscompass.vcu.edu/etd/4956.
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The miR-17- 92 cluster is necessary for cell proliferation and development of the cardiovascular system. Deletion of this cluster leads to death in neonatal mice. The role of this cluster still needs to be defined following ischemia and reperfusion. Methods and Results: Adult male mice were injected with Tamoxifen- was to induce inducible cardiac-specific miR-17- 92-deficient (miR-17- 92-def: MCM:TG:miR-17- 92 flox/flox ) and wild type (WT: MCM:NTG:miR-17-92 flox/flox ) mice were subjected to 30 minutes of myocardial ischemia via left anterior descending coronary artery ligation followed by reperfusion for 24 hours. Post I/R survival (48%) and ejection fraction were reduced, while myocardial infarct size enlarged in miR-17- 92-deficient mice as compared to WT mice (survival: 71%). Necrosis (trypan blue staining) and apoptosis (TUNEL assay) both were higher in adult cardiomyocytes isolated from miR-17- 92-deficient mice as compared to WT mice subjected to simulated ischemia/reoxygenation with a concomitant reduction of mitochondrial membrane potential (JC1 staining). The electron transport chain was compromised through dysregulation of glutamate+malate as complex I substrate and malate dehydrogenase in the hearts of miR-17- 92-deficient mice compared to WT. After 4 hours of reperfusion, PTEN expression, a downstream target of miR-20A, increased, while phosphorylation of AKT reduced in the hearts of miR-17- 92-deficient mice in comparison to WT. The induced knockdown of cardiac miR-17- 92 increases myocardial I/R injury by ceasing suppression of PTEN, leading to decreased concentrations of AKT and mitochondrial dysfunction. These results suggest that innovative therapeutic strategies can focus on genetic upregulation of miR-17- 92 in patients with coronary artery disease.
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Angert, David W. "Repair of the Injured Adult Heart Involves Resident Cardiac Stem Cell Derived New Myocytes." Diss., Temple University Libraries, 2011. http://cdm16002.contentdm.oclc.org/cdm/ref/collection/p245801coll10/id/125347.
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PhysiologyPh.D.
The ability of the adult heart to generate new myocytes after injury is not established. Our purpose was to determine if the adult heart has the capacity to generate new myocytes after injury, and to gain insight into their source. Cardiac injury was induced in the adult feline heart by infusing Isoproterenol (ISO) for 10 days with minipumps and then animals were allowed to recover for 7 or 28 days. Cardiac function was measured with echocardiography and proliferative cells were identified by nuclear incorporation of 5-bromodeoxyuridine (BrdU; 7 day minipump infusion). BrdU was infused for 7 days before euthanasia at Day 10 (injury), Day 17 (early recovery), and Day 38 (late recovery) and, with a separate group of animals, was infused during injury and removed at Day 10, with animals euthanized at Day 38 for a pulse-chase experiment. Isoproterenol caused a reduction in cardiac function with evidence of myocyte loss from necrosis. During the injury phase there was a significant increase in the number of proliferative cells in the atria and ventricle, including an increase in cKit+/BrdU+ proliferative cardiac precursor cells, but there was no increase in the number of BrdU+ new myocytes (Day 10). During the first seven days of recovery (Day 17) there was a significant reduction in cellular proliferation (total BrdU+ nuclei, including cKit+/BrdU+ proliferative cardiac precursor cells) but a significant increase in BrdU+ myocytes. There was modest improvement in cardiac structure and function during recovery. At Day 38 (late recovery), overall cell proliferation (BrdU+ cells) was not different than control (BrdU infused from Days 31-38); however, increased numbers of ("bright") BrdU+ myocytes were found at Day 38 in the pulse-chase experiment, when BrdU was infused during injury (and removed at Day 10). Some of the newly formed myocytes (from the pulse-chase group; Day 38), derived from BrdU+ cardiac precursors appear to be transiently proliferative (between Days 10-38) producing a population of "dimly" BrdU+ myocytes in our pulse-chase protocol (BrdU infused during injury, Days 3-10, and removed at Day 10, with heart explant at Day 38). No significant numbers of "dimly" BrdU+ nuclei were found in any of the hearts in which BrdU was infused for 7 days prior to the animal being euthanized (Control, Day 10, Day 17, Day 38). These observations are most consistent with the conclusions stated. Our results also suggest that myocyte regeneration, as defined by BrdU+ myocytes, was more robust in the atria than the ventricle. The reasons for these differences are not clear and deserve additional study. If true, our findings suggest that cardiac precursors isolated and expanded from atrial tissue might be a better source of cells for autologous cardiac cell therapy. In summary, our data shows that the adult heart has the ability to generate new myocytes after injury, suggests that ISO injury activates cardiac precursor cells that can differentiate into new myocytes during cardiac repair, but that the environment of the ISO injured heart blunts the differentiation of cardiac precursors into functional new myocytes. The contribution of new myocytes to improved function of the ventricle would appear to be small, unless we have underestimated the number of these cells. This is quite possible, and further study is warranted to incorporate the number of "dimly" BrdU+ myocytes that may have undergone a proliferative phase as a progenitor cell and/or as an immature cardiac myocyte. Further understanding the factors that limit endogenous new myocyte formation could significantly contribute to new therapeutic applications and improve the quality of life, and potentially the lifespan, of patients in heart failure.
Temple University--Theses
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Gates, Phillip Ellis. "Echocardiographic determination of left ventricular adaptation to upper body exercise." Thesis, Manchester Metropolitan University, 2000. http://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.312114.
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Varga, Anita. "Use of Cardiac Troponin I for Early Detection of Myocardial Damage in Dairy Cows." The Ohio State University, 2008. http://rave.ohiolink.edu/etdc/view?acc_num=osu1229644005.
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Nakajima, Daisuke. "Reconditioning Lungs Donated After Cardiac Death Using Short-Term Hypothermic Machine Perfusion." Kyoto University, 2016. http://hdl.handle.net/2433/216177.
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MAEKAWA, Atsuo, Jong-Kook LEE, Keiko MIWA, Takashi NAGAYA, Yuichi UEDA, and Itsuo KODAMA. "Overexpression of Calpastatin Ameliorates Functional Recovery from Ischemic Injury in the Rat Heart." Research Institute of Environmental Medicine, Nagoya University, 2002. http://hdl.handle.net/2237/2793.
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Xie, Lifang. "Proteomic and Microarray Identification of Novel Cardiac Specific Indicators of Oxidative Injury and Mechanism of Action." Diss., The University of Arizona, 2007. http://hdl.handle.net/10150/195214.
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Cardiovascular disease (CVD) is the leading cause of death in the United States. Oxidative stress plays an important role in the pathogenesis of CVD. Heart failure is the end point of many forms of CVD. The purpose of this study is to identify novel cardiac specific indicators of oxidative injury useful for early and convenient diagnosis of heart failure.To determine the most suitable method for identification of non-invasive oxidative injury indicators in general, human diploid fibroblasts (HDFs) were treated with H2O2 for collection of mRNA, cell lysates and conditioned media to perform cDNA microarray and LC-MS/MS based Multidimensional Protein Identification Technology (MudPIT) analyses. Electron Spray Ionization (ESI)-LC-MS/MS analysis of the conditioned media led to the finding of IGFBP-6 as a non-invasive biomarker of cell oxidative injuy in vitro and in vivo. The data obtained from this study indicate that proteomic analysis of conditioned media is useful to identify non-invasive biomarkers valuable for diagnosis or management of diseases.Cardiomyocyts (CMCs) and Cardiac fibroblasts (CFs) in culture were used to identify cardiac specific indicators of oxidative stress. Increased level of Cystatin C was detected in the conditioned medium of CMCs due to H2O2 treatment. In vivo models of oxidative stress were used to validate the increase of Cystatin C. Cystatin C levels increased in the plasma of mice with doxorubicin induced cardiomyopathy and coronary artery occlusion induced myocardial infarction (MI). These data indicate that Cystatin C can be a potential indicator of CMC oxidative injury in vitro and in vivo.Cystatin C is a cysteine protease inhibitor. The finding that oxidative stress induces Cystatin C led us to investigate a novel pathway regulating cardiac extracellular matrix (ECM) with CFs in culture, increased levels of ECM protein and decreased levels of Cathepsin B (CTB) protein and activity were detected upon Cystatin C treatment. With coronary artery occlusion induced MI mouse model, increased levels of Cystatin C and ECM protein and decreased levels of CTB protein and activity were detected in the infarcted area of the myocardium. These data indicate that Cystatin C serves as a potential fibrotic factor during myocardial remodeling.
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McCormick, James. "The role of the signal transducer and activator of transcription-1 in cardiac ischaemia-reperfusion injury." Thesis, University College London (University of London), 2006. http://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.433160.
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Gibbons, Patric. "Follow Your Heart: Evaluating Cardiac Function to Predict Outcomes Among ICU Patients with Traumatic Brain Injury." eScholarship@UMMS, 2018. https://escholarship.umassmed.edu/gsbs_diss/977.
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Introduction: Traumatic Brain Injury (TBI) remains a significant public health burden in the United States. Persons afflicted with more severe TBIs are usually admitted to an ICU, where they are at risk for a number of complications throughout their hospitalization. Recent literature has attempted to describe such complications from a cardiovascular perspective as part of a “cardio-cerebral syndrome.” We described the frequency of cardiac complications in the ICU among patients with a TBI and compared patients with and without measured cardiac dysfunction. We investigated the potential impact of cardiac dysfunction on in-hospital mortality.
Methods: This was a retrospective review of a prospective cohort study in adult ICU patients with moderate-to-severe TBI (GCS≤12). We measured cardiac dysfunction using initial EKG echocardiography findings and peak serum troponin levels during hospitalization. Primary outcome was in-hospital mortality for patients with and without cardiac dysfunction using multivariable adjusted Cox Proportional Hazards Regression. Secondary outcomes examined the relationship between severity of brain injury and degree of cardiac dysfunction.
Results: Ordinal logistic regression showed patients with more indicators of cardiac injury were significantly more likely to have greater brain injury as reflected by lower GCS scores (OR 0.76; 95%CI 0.58-0.99). There was a significantly increased multivariable adjusted risk of dying for each increase in measured cardiac injury (HR 2.41; 95% CI 1.29-4.53).
Conclusions: Cardiac dysfunction was frequently observed in patients with TBI and we showed an association between increasing TBI severity and development of cardiac injury. Cardiovascular dysfunction was associated with an increased risk of in-hospital death. Adverse outcomes from TBI could potentially be mediated by cardiac injury, which could be used as a target for therapeutic intervention.
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Sturz, Gregory R. "SILDENAFIL ATTENUATES ETHANOL-INDUCED CARDIOMYOCYTE INJURY AND PRESERVES CARDIAC FUNCTION THROUGH PROTEIN KINASE G-DEPENDENT SIGNALING." VCU Scholars Compass, 2013. http://scholarscompass.vcu.edu/etd/2999.
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Background: Ethanol is a cardiotoxic substance that damages the heart by increasing apoptosis, free radical formation and calcium overloading. Consequently, there is an increase in cell death leaving fewer functioning myocytes leading to heart failure. Sildenafil is a phosphodiesterase type-5 (PDE-5) inhibitor approved for treatment of erectile dysfunction. Studies from our lab have demonstrated that PDE-5 inhibition reduces myocardial infarct size and attenuates post-ischemic cardiac dysfunction in both ischemia-reperfusion and permanent coronary artery ligation models. Therefore, in the present study, we hypothesized that treatment with sildenafil will prevent cardiotoxicity associated with acute alcohol exposure by reducing myocyte apoptosis and preserving cardiac function through PKG signaling. Methods and Results: Adult cardiomyocytes were isolated and treated with 100 mM of 100% ethanol ± 10 µM sildenafil. At 24 hours necrosis was assessed via trypan blue exclusion assay, JC-1 staining assessed mitochondrial membrane potential and ROS production was measured by DCF fluorescence. At 48 hours apoptosis was assessed by TUNEL assay. Ethanol increased the rate of necrotic and apoptotic cell death. This was attenuated by co-treatment with sildenafil. Ethanol disrupted the mitochondrial membrane potential and increased ROS production. Sildenafil preserved mitochondrial membrane potential and attenuated ROS production. Treatment of myocytes with 5-HD, a mitochondrial K+atp channel antagonist, blocked the protective effect of sildenafil. Knockdown of PKG using adenoviral siRNA blocked the protective effect of sildenafil, while overexpression of PKG1α conferred protection against ethanol cytotoxicity. To further demonstrate the effect of sildenafil ethanol-cardiotoxicity in vivo, mice were treated with ethanol (3 g/kg/day) with or without sildenafil (0.7 mg/kg) by i.p. injection for three consecutive days. After treatment, the animals were sacrificed and the hearts removed and perfused on a Langendorff system to measure function. After functional analysis, apoptosis and PKG activity was measured in the heart samples. Ethanol decreased the rate-force product and increased myocardial apoptosis. Sildenafil preserved cardiac function and significantly reduced apoptosis. Sildenafil treated myocardium also showed an increase in PKG activity. Conclusion: Sildenafil attenuates the toxic effect of ethanol by reducing apoptosis and maintaining the mitochondrial integrity in cardiomyocytes. Sildenafil also preserved cardiac function in ethanol-treated mice. Protein kinase G-dependent signaling plays a critical role in attenuating cardiotoxic effect of ethanol.