Background: Myocardial injury affects up to one in three patients undergoing non-cardiac surgery. However, very little is known about the underlying pathophysiology. In the general population, patients with elevated resting heart rate are at increased risk of cardiac events, mortality, heart failure and autonomic dysfunction, while hypertension is a well described risk factor for cardiovascular disease. I hypothesised that common abnormalities of heart rate or blood pressure were associated with myocardial injury after non-cardiac surgery. Methods: This thesis comprises a series of secondary analyses of data from five prospective multi-centre epidemiological studies of surgical patients. The main outcome of interest was myocardial injury, defined using objective measurement of cardiac troponin. I used logistic regression analysis to test for association between exposures and outcomes. Results: In a large international cohort, patients with high preoperative heart rate had increased risk of myocardial injury and patients with very low preoperative heart rate had reduced risk of myocardial injury. Patients with elevated preoperative pulse pressure had increased risk of myocardial injury, independent of existing hypertension or systolic blood pressure. High heart rate, or high or low systolic blood pressure during surgery, was associated with increased risk of myocardial injury. In a separate study, elevated preoperative heart rate was associated with cardiopulmonary and autonomic dysfunction, and reduced left ventricular stroke volume, suggestive of heart failure. Finally, autonomic dysfunction, identified using cardiopulmonary exercise testing, was associated with elevated preoperative heart rate, elevated plasma NT-Pro-BNP (indicative of heart failure) and postoperative myocardial injury. Conclusions: Elevated preoperative heart rate, autonomic dysfunction and subclinical heart failure may be part of a common phenotype associated with perioperative myocardial injury. Further research is needed to characterise the pathological processes responsible for myocardial injury, and to identify potential therapeutic targets.

Myocardial injury after noncardiac surgery (MINS) is common in patients undergoing inpatient noncardiac surgery and has been shown to adversely impact short- and long-term patient prognosis. Most MINS events are asymptomatic and systematic troponin measurement early after surgery is of paramount importance to detect these events. The largest study to determine thresholds and prognostic importance of MINS used troponin T and high-sensitivity troponin T. There is limited information on how to diagnose MINS using high-sensitivity troponin I (hsTnI). How to predict who is at higher risk of MINS and would benefit the most from troponin monitoring, and how to manage patients who suffer a MINS are also areas that need further research. This thesis presents studies that inform on these knowledge gaps. Chapter 2 describes the result of a large prospective cohort of patients undergoing noncardiac surgery which determined the utility of preoperative N-Terminal pro-B type Natriuretic Peptide to predict 30-day MINS and vascular death, in addition to clinical evaluation. Chapter 3 uses data collected as part of a large prospective cohort with a nested biobank to determine thresholds of hsTnI that can predict major cardiovascular events in patients who underwent noncardiac surgery and be used to diagnosis MINS using hsTnI. Chapter 4 details the methods of an international, multicentre, randomized placebo-controlled trial (MANAGE Trial) determining the impact of dabigatran, a blood thinner, and using a partial factorial design, of omeprazole, a gastric acid reducing drug, on the occurrence of major vascular and upper gastrointestinal events in patients who suffered a MINS and are followed for up to 2 years. Chapter 5 presents the results of the omeprazole component of the MANAGE Trial. Chapter 6 discusses the key findings of the thesis and future research directions. / Thesis / Doctor of Philosophy (PhD) / Damage to the heart muscle occurring after a noncardiac surgery, called myocardial injury after noncardiac surgery (MINS), occurs frequently and negatively impacts patient’s short- and long-term health and survival. Most patients who suffer a MINS do not present symptoms suggestive of heart problems. Blood tests obtained after surgery measuring troponins, a marker of heart damage, is necessary to detect which patients are having MINS. Different troponin tests are available, including a test called high-sensitivity troponin I, for which there is limited information on how to diagnose MINS using this test. How to predict who is at higher risk of MINS and how to treat patients who suffered a MINS are also areas that need further research. This thesis presents studies that inform on these knowledge gaps.

No description available.

Asthma affects 5%-10% of adults in the United States. Older adults (< 65 years) with asthma have higher rates of fatal asthma than younger adults. The occurrence of a respiratory emergency, such as status asthmaticus, would seem likely to create a situation of cardiopulmonary dysfunction conducive to myocardial ischemia. However, multiple studies of fatal or near-fatal asthma have failed to incriminate myocardial infarction as a contributing factor. We report a patient without underlying coronary artery disease who sustained myocardial injury consistent with myocardial ischemia and infarction during status asthmaticus while receiving recommended treatment without intravenous sympathomimetics or theophylline.

No description available.

<p>Radiation therapy can cause acute toxicity and long-term side effects in normal tissues. Because part of the acute toxicity of radiation is due to p53-mediated apoptosis, blocking p53 during irradiation can protect some normal tissues from acute radiation injury and might improve the therapeutic ratio of radiation therapy. However, the mechanisms by which p53 regulates late effects of radiation are not well understood. Here, I utilized genetically engineered mouse models to dissect the role of p53 in regulating two of the most clinically significant late effects of radiation: radiation-induced carcinogenesis and radiation-induced myocardial injury. </p><p> It has been well characterized that mice with one allele of p53 permanently deleted are sensitized to radiation-induced cancer. Therefore, temporary inhibition of blocking p53 during irradiation could promote malignant transformation. Experiments with mice lacking functional p53 in which p53 protein can be temporarily restored during total-body irradiation (TBI) suggest that the radiation-induced p53 response does not contribute to p53-mediated tumor suppression. Here, I performed reciprocal experiments and temporarily turned p53 off during TBI using transgenic mice with reversible RNA interference against p53. I found that temporary knockdown of p53 during TBI not only ameliorated acute hematopoietic toxicity, but in both Kras wild-type and tumor-prone KrasLA1 mice also prevented lymphoma development. Mechanistic studies show that p53 knockdown during TBI improves survival of hematopoietic stem and progenitor cells (HSPCs), which maintains HSPC quiescence and prevents accelerated repopulation of surviving cells. Moreover, using an in vivo competition assay I found that temporary knockdown of p53 during TBI maintains the fitness of p53 wild-type HSPCs to prevent the expansion of irradiated mutant cells. Taken together, our data demonstrate that p53 functions during TBI to promote lymphoma formation by facilitating the expansion of irradiated HSPCs with adaptive mutations. </p><p> p53 functions in the heart to promote myocardial injury after multiple types of stress, including ischemic injury, pressure overload and doxorubicin-induced oxidative stress. However, how p53 regulates radiation-induced myocardial injury, which develops after radiation therapy, is not well understood. Here, I utilized the Cre-loxP system to demonstrate that p53 functions in endothelial cells to protect mice from myocardial injury after a single dose of 12 Gy or 10 daily fractions of 3 Gy whole-heart irradiation (WHI). Mice in which both alleles of p53 are deleted in endothelial cells succumbed to heart failure after WHI due to myocardial necrosis, systolic dysfunction and cardiac hypertrophy. Moreover, the onset of cardiac dysfunction was preceded by alterations in myocardial vascular permeability and density. Mechanistic studies using primary cardiac endothelial cells (CECs) irradiated in vitro indicate that p53 signals to cause a mitotic arrest and protects CECs against radiation-induced mitotic catastrophe. Furthermore, mice lacking the cyclin-dependent kinase inhibitor p21, which is a transcriptional target of p53, are also sensitized to myocardial injury after 12 Gy WHI. Together, our results demonstrate that the p53/p21 axis functions to prevent radiation-induced myocardial injury in mice. Our findings raise the possibility that when combining radiation therapy with inhibitors of p53 or other components of the DNA damage response that regulate mitotic arrest, patients may experience increased radiation-related heart disease. </p><p> Taken together, our results demonstrate crucial but distinct roles of p53 in regulating late effects of radiation: p53-mediated apoptosis promotes radiation-induced lymphomagenesis, but p53-mediated cell cycle arrest prevents radiation-induced myocardial injury. These findings indicate that p53 may generally play a protective role from radiation, particularly at high doses, in cells where p53 activation is uncoupled from the induction of the intrinsic pathway of apoptosis. Therefore, selectively inhibiting p53-mediated apoptosis may be a promising approach to ameliorate acute radiation toxicity without exacerbating late effects of radiation.</p> / Dissertation

No description available.

<p>Worldwide, more than 2 million patients die within 30 days after noncardiac surgery anually. Postoperative ischemic myocardial injury is frequent, however, no consensus exists about its definition.</p> <p><strong>Objective: </strong>to develop a term Myocardial Injury after Noncardiac Surgery (MINS) caused by myocardial ischemia, requiring at least, troponin T (TnT) elevation, and with prognostic relevance at 30 days after surgery.</p> <p><strong>Methods: </strong>we performed a prospective study including 15,167 patients ³45 years-old undergoing noncardiac surgery, who had fourth-generation TnT measurements during the first 3 postoperative days. We undertook Cox regression analyses with 30-day mortality after surgery as the dependent variable, using different TnT thresholds, clinical features and several perioperative variables. Non-ischemic etiologies were excluded. Furthermore, we developed a scoring system to predict risk in MINS patients.</p> <p><strong>Results:</strong> MINS was defined as TnT ≥0.03 ng/mL with or without clinical features, and it was an independent predictor of 30-day mortality (adjusted HR 3.82, CI 95% 2.84-5.10). We determined that MINS incidence was 8%, its population attributable risk 33.7%, and 30-days mortality rate 9.6%. Patients did not experience ischemic symptoms in 84% of MINS cases. Additionally, we developed a scoring system in patients suffering MINS with 3 independent predictors of death (age ≥75 years, new ST elevation or left bundle branch block, and anterior location of ECG changes),</p> <p><strong>Conclusion: </strong>Among patients undergoing noncardiac surgery, we defined MINS based on a TnT threshold ≥0.03 ng/mL. Mostly, MINS patients were asymptomatic. Therefore, this strongly suggests the importance of a troponin monitoring during the first few days after surgery.</p> / Master of Health Sciences (MSc)

Fundação de Apoio a Pesquisa e à Inovação Tecnológica do Estado de Sergipe - FAPITEC/SE / Cardiovascular diseases are the leading cause of death worldwide, and myocardial infarction (MI) is one of the most devastating. Cardiac ischemia-reperfusion injury represents a major threat to human health, contributing to adverse cardiovascular effects.However, although reperfusion of the ischemic heart is essential to reduce myocardial damage, restoration of blood flow may, paradoxically, amplify cellular damage.The recognition that pathological events occurring both in ischemia and reperfusion contribute to tissue injury leads to accelerated efforts to identify mechanisms of IR injury in the hope of identifying new treatments that may limit injury induced by blood reduction flow and / or damage produced by reperfusion.Myrtenol is a monoterpene with multiple pharmacological activities. However, although monoterpenes have been proposed to play beneficial roles in a variety of cardiac disorders, pharmacological actions of myrtenol in the heart are not yet reported. Hence, the aim of this study was to evaluate whether myrtenol promotes cardioprotection against myocardial ischemia-reperfusion (IR) injury, and the mechanisms involved in these effects. Male Wistar rats were orally treated for seven consecutive days with solution (NaCl 0.9% 0.20 ml + DMSO 0.05 ml), myrtenol (50 mg/kg) or N-acetyl cysteine (1.200 mg/kg, NAC).Subsequently, the hearts were submitted to cardiac IR injury, through the aortic perfusion flow system of the langedorff type, contractile parameters such as left ventricular pressure (PVE), maximum rise/down velocity of left intraventricular pressure (dP/dt), heart rate (HR), electrocardiographic parameters, HR, PR interval and duration of the QRS complex, measured the activity of Lactate Dehydrogenase (LDH), determined the severity of cardiac arrhythmias (ASI). The oxidative stress was evaluated on the basis of the determination of total hydroperoxides, total sulfhydryl (SH) groups, measurements of the reactive oxygen species (ROS) generation, the carbonylated proteins, the activity of the endogenous antioxidant enzymes: superoxide dismutase (SOD), catalase (CAT) , glutathione peroxidase (GPx) and glutathione reductase (GR), and the infarct area. The apoptosis pathway was investigated by the expression of Bax and Bcl-2 proteins and in situ apoptosis was studied from the TUNEL assay. Here, we show that the severe impairment of contractile performance induced by IR was significantly prevented by myrtenol or NAC. Moreover, Myrtenol abolished aberrant electrocardiographic waveform (ST-segment elevation), as well as reduced life-threatening arrhythmias and infarct size induced by IR injury. Importantly, myrtenol fully prevented the massive increase of cardiac reactive oxygen species generation and oxidative stress damage. Accordingly, myrtenol restored the impairment of endogenous antioxidant enzymes (superoxide dismutase, catalase, glutathione peroxidase and reductase) activities and balance of pro- and anti-apoptotic pathways (Bax and Blc-2), associated with decreased TUNEL-positive apoptotic cells. Taken together, our data show that myrtenol promotes cardioprotection against IR injury through attenuation of oxidative stress and inhibition of pro-apoptotic pathway. / A lesão de isquemia-reperfusão cardíaca representa um grande dano à saúde humana contribuindo para efeitos cardiovasculares adversos. Embora a reperfusão do coração isquêmico seja essencial para reduzir o dano miocárdico em processo de isquemia, a restauração do fluxo sanguíneo pode, paradoxalmente, amplificar o dano celular. Não existem metodologias de intervenção clínica que tratem a origem dos eventos celulares que levam ao dano celular observado. Neste contexto, o mirtenol é um monoterpeno com múltiplas atividades farmacológicas e estudos sugerem que esta molécula possa atuar em eventos que culminam na prevenção da lesão tissular. Assim, o objetivo deste estudo foi avaliar se o mirtenol promove a cardioproteção contra a lesão de isquemia-reperfusão cardíaca (IR) e os mecanismos envolvidos nesses efeitos. Para este estudo, ratos Wistar machos foram pré-tratados por via oral durante sete dias consecutivos com solução salina (NaCl 0,9% 0,20 ml + DMSO 0,05 mL), mirtenol (50 mg / kg) ou N-acetil cisteína (NAC) (1.200 mg / kg). Posteriormente, os corações foram submetidos à lesão de IR cardíaca, por meio do sistema de perfusão aórtica de fluxo constate do tipo Langedorff. Foram obtidos os parâmetros contráteis tais como pressão ventricular esquerda (PVE), derivadas máxima (+dP/dt) e mínima (-dP/dt) da PVE, frequência cardíaca (FC), parâmetros eletrocardiográficos, como FC, intervalo PR e a duração do complexo QRS. Além disso, foi mensurado a atividade da lactato desidrogenase (LDH) determinado o índice de severidade das arritmias cardíacas (ISA) e a área de infarto. O estresse oxidativo foi avaliado com base na determinação de hidroperóxidos totais, grupamento sulfidrilas totais, ainda foram mensuradas as espécies reativas de oxigênio (EROs), as proteínas carboniladas e determinada a atividade das enzimas antioxidantes endógenas: superóxido dismutase (SOD), catalase (CAT), glutationa peroxidase (GPx) e glutationa redutase (GR), e a área de infarto. A apoptose celular foi investigada mediante a expressão das proteínas Bax e Bcl-2 e a apoptose in situ foi avaliada pelo método TUNEL. Mostramos que o comprometimento severo do desempenho contrátil induzido pela IR foi prevenido de forma significativa pelo mirtenol e NAC. Além disso, que o mirtenol preveniu a forma de onda eletrocardiográfica discrepante (elevação do segmento ST), bem como, reduziu as arritmias fatais e o tamanho da área do infarto induzido pela lesão de IR. Relevantemente, o mirtenol impediu o aumento de superóxido e danos cardíacos que poderiam ser causados pelo estresse oxidativo. Consequentemente, o mirtenol restaurou a atividade das enzimas antioxidantes endógenas e o equilíbrio das vias pró e antiapoptóticas (Bax e Blc-2), associado à diminuição das células apoptóticas TUNEL-positivas. Em conjunto, nossos dados mostram que o mirtenol promove a cardioproteção contra lesão de IR através da atenuação do estresse oxidativo e inibição da via pró-apoptótica. / Aracaju

Myocardial injury is the leading cause of death in Europe following non-cardiac surgery. Its causes, diagnosis, and treatment are still under investigation by the scientific community. Some research groups have hypothesized a connection between myocardial injury and hypotension during surgery. This thesis investigated the development of a machine learning binary classifier to make a diagnosis of myocardial injury from a set of patients undergoing non-cardiac surgery. Furthermore, it aimed to clarify the potential of hypotension as a predictor of the pathology. After an evaluation of the requirements that the model had to meet, it was decided to use a decision tree. 4 features were selected combining ANOVA and the domain knowledge of the doctors. The classifier obtained a F1 macro-score of 0.68, showing to have potential in classifying patients as positive or negative. Among the selected features, hypotension obtained the lowest predictive power. Despite the performance of the model, further research is needed to validate the results across different populations and to investigate the use of hypotension as a predictor of myocardial injury. / Myokardiell skada är den främsta dödsorsaken i Europa efter icke-kardiell kirurgi. Dess orsaker, diagnos och behandling är fortfarande under utredning av vetenskapssamfundet. Vissa forskargrupper har hypotiserat om ett samband mellan myokardiell skada och hypotoni under operationen. Denna avhandling undersökte utvecklingen av en binär klassificerare med maskininlärning för att ställa diagnos på myokardiell skada hos en grupp patienter som genomgick icke-kardiell kirurgi. Dessutom syftade den till att klargöra hypotoniens potentiella betydelse som en prediktor för sjukdomen. Efter en utvärdering av modellens krav beslutades det att använda ett beslutsträd. Fyra egenskaper valdes ut genom att kombinera ANOVA och läkarnas domänkunskap. Klassificeraren uppnådde en F1-makropoäng på 0,68 och visade potential att klassificera patienter som positiva eller negativa. Bland de valda egenskaperna hade hypotension den lägsta prediktiva förmågan. Trots modellens prestanda behövs ytterligare forskning för att validera resultaten i olika populationer och undersöka användningen av hypotension som en prediktor för myokardiell skada.