Obesity has reached worldwide epidemic proportions and with this increased incidence of obesity, comes an increase in incidence of the comorbidities associated with obesity such as diabetes and cardiovascular disease (CVD). The underlying mechanisms which connect these diseases are still poorly understood. One system which has been shown to be up-regulated in the setting of obesity and diabetes is that of the G-protein coupled receptor-55/Lysophosphatidylinositol (GPR55/LPI). Despite being upregulated in the setting of obesity, the function of GPR55 in obesity and other disease states remains elusive. Therefore, the present study aimed to 1) investigate the role of GPR55 in obesity by characterising the phenotype of the GPR55 knockout (GPR55-/-) mouse when challenged with a high fat diet (HFD) intervention, 2) elucidate any effect of the GPR55 knockout and HFD intervention on the myocardial infarct size sustained following a period of ischaemia/reperfusion (I/R) and 3) make use of an in vitro model to elucidate the mechanisms by which changes occur in the adipose tissue of mice fed a HFD. GPR55-/- mice fed a HFD for 12-weeks gained significantly more weight in the form of fat mass, compared to wild-type (WT) controls and consequently become obese. Obese GPR55-/- mice displayed hypertrophic adipose tissue concurrent with the significant dysregulation of plasma lipids, increases in specific circulating LPI species, increased lipid deposition within the liver and a change in adipose tissue gene expression profile. These changes were not observed in GPR55-/- mice fed a standard diet or WT mice fed a HFD. Following a period of I/R, the myocardial infarct size in hearts from WT HFD fed mice was significantly smaller than in hearts from WT standard diet fed mice. This reduction in infarct size due to HFD intervention was not dependent on RISK-pathway activation and was not observed in hearts from GPR55-/- mice, therefore demonstrating that the cardio-protective effect of a HFD on infarct size is dependent on GPR55. In vitro studies using 3T3-L1 cells determined that the changes in adipose tissue gene expression of HFD fed mice was not due to enhanced stimulation with LPI or via hypoxic mechanisms. The results of these studies demonstrate that GPR55 has an anti-obesity function in vivo and also mediates the cardio-protective effect of a HFD on myocardial infarct size, through currently unknown mechanisms.

Chui Wai Leung. / Thesis (M.Sc.)--Chinese University of Hong Kong, 1996. / Includes bibliographical references (leaves 120-126). / List of tables and figures --- p.1 / Declaration --- p.6 / Acknowledgments --- p.7 / Summary --- p.8 / Chapter Chapter 1: --- Introduction --- p.10 / Chapter 1.1 --- Acute Myocardial Infarction (AMI) / Chapter 1.2 --- Diagnosis of AMI / Chapter 1.2.1 --- Clinical Signs / Chapter 1.2.2 --- Electrocardiogram (ECG) / Chapter 1.2.3 --- Cardiac enzymes / Chapter 1.3 --- "CKMB,a marker of choice" / Chapter 1.4 --- "Troponin-T, another candidate marker" / Chapter 1.5 --- Objectives / Chapter Chapter 2: --- Analytical evaluation of CKMB measurement by the four methods --- p.20 / Chapter 2.1 --- Analytical methods / Chapter 2.1.1 --- Assay for total creatine kinase / Chapter 2.1.2 --- Assay for CKMB / Chapter 2.1.2.1 --- CKMB mass concentration assay / Chapter 2.1.2.2 --- CKMB EEC & immunoinhibition activity assay / Chapter 2.1.2.3 --- CKMB activity concentration assay1 / Chapter 2.1.2.4 --- CKMB activity concentration assay2 / Chapter 2.2 --- Precision / Chapter 2.3 --- Accuracy / Chapter 2.4 --- Linearity / Chapter 2.5 --- Recovery / Chapter 2.6 --- Interference / Chapter 2.6.1 --- Effect of haemolysis / Chapter 2.6.2 --- Effect of turbidity / Chapter 2.6.3 --- Effect of bilirubin / Chapter 2.7 --- Stability / Chapter Chapter 3 : --- Correlation among the four methods of CKMB measurement --- p.61 / Chapter Chapter 4 : --- Establishment of reference ranges for the four methods of CKMB measurement --- p.71 / Chapter Chapter 5: --- Information on the Qualitative Troponin-T Rapid Assay® --- p.80 / Chapter Chapter 6 : --- Clinical Evaluation of CKMB and Troponin-T in detection of AMI --- p.82 / Chapter 6.1 --- Material and Methods / Chapter 6.1.1 --- Subjects / Chapter 6.1.2 --- Specimens / Chapter 6.1.3 --- Criteria for diagnosis / Chapter 6.1.4 --- Analytical methods / Chapter 6.1.5 --- Statistical methods / Chapter 6.2 --- Results / Chapter 6.3 --- Discussion / Chapter Chapter 7 : --- General Discussion --- p.105 / Appendix 1: study protocol sheet --- p.113 / Appendix 2: diagnostic criteria for a definite AMI --- p.115 / Appendix 3: criteria for exclusion of AMI --- p.117 / Appendix 4: enzyme criteria --- p.118 / References --- p.120

Abstrakt Bakgrund: Hjärtinfarkt kan vara livshotande och kräver omedelbar sjukhusvård. För att reducera skada på hjärtat är det viktig att patienten kommer till omedelbar reperfusionsbehandling. Om symtom inte känns eller relateras till hjärtat, kan det göra att personen avvaktar med att söka vård och därmed försenas diagnos och behandling vilket kan leda en till ökad risk för att dö. För att öka kunskapen inom detta område vill vi med vår analys undersöka patienters upplevelse av symtom vid en akut hjärtinfarkt. Syfte: Att undersöka patientens upplevelse av symtom vid en akut hjärtinfarkt. Metod: En integrativ litteraturöversikt genomfördes vilken baserades på sökningar i Cinahl och Pubmed. Nio vetenskapliga artiklar med både kvalitativ och kvantitativ ansats valdes ut. Resultat: Studierna visade stor variation av patienternas upplevda symtom och symtomdebutens karaktär. Det fanns även skillnader mellan förväntade och upplevda symtom och resultatet visade att det råder en generell kunskapsbrist om AMI symtom bland allmänheten. Detta sammantaget leder till fördröjning i patienternas beslutsprocess för att uppsöka vård och behandling. Slutsats: Om tiden till behandling kortas, kan det leda till stora förbättringar vad gäller personens hälsa, välmående och livskvalitet. Det borde därmed finnas ett stort intresse att investera i strategier för att öka kunskapen om de olika och varierande symtom vid akut hjärtinfarkt hos allmänheten och även hos yrkesverksamma inom vård- och omsorg.

Acute myocardial infarction is the commonest cause of death in firefighters, accounting for 45% of all deaths on duty. Compared with an average life expectancy of 77 years in the general population, the average age of cardiovascular death in firefighters is 50 years suggesting that occupational hazards are responsible for premature disease. The risk of acute myocardial infarction is increased 12- to 136-fold during rescue and firefighting duties, and is likely to reflect a combination of factors including strenuous physical exertion, mental stress, heat and pollutant exposure. Previous studies have established that the duties of a firefighter, in particular fire suppression, put inordinate strain on the cardiovascular system yet the exact mechanisms underlying the increased risk of myocardial infarction remain poorly defined. In a series of studies, I assessed the effect of occupation-specific risk factors on cardiovascular health in a combination of controlled and real-life studies in order to better define these mechanisms, hypothesising that exposure to high temperatures, strenuous physical exertion, psychological stress and air pollution either alone or in combination caused vascular dysfunction and thrombosis. In order to assess if firefighters had a greater cumulative risk of cardiovascular disease due to their occupation at baseline, I assessed the cardiovascular function of group of healthy, off-duty firefighters and compared this to a group of healthy age- and sex-matched off-duty police officers; an occupational group with similar responsibilities but a much lower risk of on-duty cardiovascular events. I was able to demonstrate that traditional cardiovascular risk factors, vascular endothelial function and thrombogenicity were similar in the two groups concluding that the excess of cardiovascular events and deaths in on-duty firefighters are due to the acute and transient effects of strenuous physical exertion, psychological stress, heat and exposure to air pollutants. Having established that off-duty firefighters had no apparent increased risk of cardiovascular events, I then went on to clarify the effects of combustion derived air pollution in the form of wood smoke on the cardiovascular system. The suppression of wildland or forest fires is globally the single most important duty of the fire service. Previous work within our institution has demonstrated the adverse effects of combustion derived air pollution, in the form of diesel exhaust, on the cardiovascular system. In a similar fashion, I assessed the effect of a wood smoke inhalation in a group of healthy off-duty firefighters by performing controlled exposures to wood smoke utilising a unique and well characterised facility. Interestingly, unlike diesel-exhaust, the exposure to wood smoke had no adverse effect on vascular endothelial function or thrombogenicity in this group concluding that cardiovascular events during wildland fire suppression may not be directly related to wood smoke inhalation but instead precipitated by other mechanisms such as strenuous physical exertion or dehydration. Latterly, I proceeded to evaluate the effects of strenuous physical exertion and heat exposure by comprehensively assessing a number of cardiovascular end points following controlled exposure to a fire simulation activity in a group of healthy, off-duty firefighters. I was able to demonstrate that exposure to extreme heat and physical exertion impaired vasomotor function and increased thrombus formation. Moreover, I demonstrated cardiac troponin concentrations increased suggesting that fire suppression activity may cause myocardial injury. These important findings suggest pathogenic mechanisms to explain the association between fire suppression activity and acute myocardial infarction. In the final phase of work, I endeavoured to assess the effects of real-life firefighter activities on the cardiovascular system. In an ambitious study, I attempted to undertake a comprehensive assessment of cardiovascular function in healthy firefighters following three periods of duty: fire suppression, alarm response and non-emergency activity. I was unable to complete enough studies to adequately power an analysis and draw any firm conclusions about the effect of these duties on cardiovascular health. Further work is required in a real-world setting to more clearly define the occupational risk factors underlying the increased risk of cardiovascular events associated with specific firefighter duties Understanding the biological mechanisms and environmental factors that predispose firefighters to cardiovascular events is essential if we are to develop effective methods for the prevention of acute myocardial infarction on-duty. This body of work has greatly improved the understanding of the mechanisms underlying the increased risk of cardiovascular events on duty and calls for the immediate evaluation of current practice in order to minimise risk to firefighters in the future. Examples of where improvements should be made include strategies to ensure adequate hydration and cooling following exposure to heat and physical exertion, change to working patterns to limit the duration of extreme exposures, and education, training and screening programmes to reduce the impact of traditional and occupational cardiovascular risk factors.

<p>Akut hjärt-kärlsjukdom orsakar mer än hälften av alla dödsfall i Sverige. Många patienter med akut hjärtinfarkt uppvisar inte de klassiska symtom som vanligtvis förknippas med sjukdomen utan har en mer atypisk symtombild. Syftet med litteraturstudien var att beskriva vikten av god kunskap och kännedom om den varierande symtombild som kan förekomma vid hjärtinfarkt, sett ur ett omvårdnadsperspektiv. I metoden har 23 vetenskapliga artiklar bearbetats. Resultatet visade att förekomst av atypiska symtom var vanligare hos kvinnor, äldre och diabetiker. Män upplevde framförallt bröstsmärta, smärtutstrålning till armar och svettning. Kvinnor uppvisade bröstsmärta i mindre omfattning men upplevde däremot mer andnöd, rygg- och nacksmärta, besvär från mag-tarmkanalen, trötthet och orkeslöshet. Varningssymtom förekom hos ett stort antal patienter och framförallt hos kvinnor. Patienterna uppfattade och uttryckte sina besvär på olika sätt, vilket påverkade deras beslut att söka vård. Sjuksköterskans roll ansågs vara att informera patienter, speciellt de med högre risk att uppvisa atypiska symtom samt allmänheten om den annorlunda symtombild som kan förekomma. Sjuksköterskor måste ha god kunskap och kännedom om olikheter i symtombild hos olika patientgrupper. De bör vara lyhörda och ha en klinisk blick samt förstå vikten av god framförhållning och beredskap för ett adekvat omhändertagande. I framtiden måste kunskapen utökas och spridas bland allmänheten. Vidare forskning i ämnet är önskvärt ur ett sjuksköterskeperspektiv.</p>

Akut hjärt-kärlsjukdom orsakar mer än hälften av alla dödsfall i Sverige. Många patienter med akut hjärtinfarkt uppvisar inte de klassiska symtom som vanligtvis förknippas med sjukdomen utan har en mer atypisk symtombild. Syftet med litteraturstudien var att beskriva vikten av god kunskap och kännedom om den varierande symtombild som kan förekomma vid hjärtinfarkt, sett ur ett omvårdnadsperspektiv. I metoden har 23 vetenskapliga artiklar bearbetats. Resultatet visade att förekomst av atypiska symtom var vanligare hos kvinnor, äldre och diabetiker. Män upplevde framförallt bröstsmärta, smärtutstrålning till armar och svettning. Kvinnor uppvisade bröstsmärta i mindre omfattning men upplevde däremot mer andnöd, rygg- och nacksmärta, besvär från mag-tarmkanalen, trötthet och orkeslöshet. Varningssymtom förekom hos ett stort antal patienter och framförallt hos kvinnor. Patienterna uppfattade och uttryckte sina besvär på olika sätt, vilket påverkade deras beslut att söka vård. Sjuksköterskans roll ansågs vara att informera patienter, speciellt de med högre risk att uppvisa atypiska symtom samt allmänheten om den annorlunda symtombild som kan förekomma. Sjuksköterskor måste ha god kunskap och kännedom om olikheter i symtombild hos olika patientgrupper. De bör vara lyhörda och ha en klinisk blick samt förstå vikten av god framförhållning och beredskap för ett adekvat omhändertagande. I framtiden måste kunskapen utökas och spridas bland allmänheten. Vidare forskning i ämnet är önskvärt ur ett sjuksköterskeperspektiv.

The treatment of acute myocardial infarction (AMI) has undergone a tremendous development during the last decades, and the most important factor is probably the introduction of reperfusion therapy aimed at preventing or limiting the myocardial injury. It is of vital importance that patients with AMI are adequately monitored regarding the development of ECG changes during and after treatment to identify successful or failed reperfusion and to detect episodes of recurrent ischemia. Vectorcardiography (VCG) is one method for this purpose. This series of studies was aimed at evaluating VCG as a method for detecting reperfusion and recurrent ischemia in patients with ST-elevation AMI who were treated with different reperfusion strategies. Specific changes in the VCG during the initial treatment phase, “reperfusion peaks,” were examined in detail. The influence of the fibrinolytic system and von Willebrand factor (vWF) on successful reperfusion and subsequent AMI and death after thrombolytic treatment with streptokinase (SK) was another main objective. From the data in these studies it can be concluded that: VCG is a relevant and easily used method for ischemia-monitoring in patients with AMI. A specific sign, the reperfusion peak, is associated with vectorcardiographic signs of reperfusion. This sign is observed both in patients treated with primary coronary angioplasty and in those who are treated with fibrinolytic agents. The reperfusion peak is associated with successful reperfusion and with larger infarcts, but by itself, the parameter has little prognostic significance. The recognition of the reperfusion peak is important since it can mimic severe ischemia. In an unfortunate situation the incorrect interpretation of the VCG could lead to premature treatment decisions that might even be harmful to the patient. Streptokinase treatment of patients with AMI induced profound changes in the fibrinolytic system and vWF. A high tissue plasminogen activator (tPA) activity level (&gt;25 U/mL) early after the start of treatment, reflecting the fibrinolytic activity obtained by the given drug, was associated with successful reperfusion. Pre-existing neutralizing antibodies to SK were found to varying degrees in the previously SK-treated patients. No association between SK-neutralizing antibodies and the result of the treatment regarding successful reperfusion as judged by VCG was seen. Pre-treatment levels of tPA activity, PAI-1 activity, PAI-1 mass-concentration and vWF had no correlation with the success of reperfusion therapy with SK or on the incidence of recurrent ischemia during the first 24 hours. Recurrent ischemia, however, was shown to be an independent risk factor for death within the first 1 year. Elevated levels of PAI-1 mass-concentration, and to some extent PAI-1 activity, after the start of SK treatment, were associated with a higher risk for death at one year, though not at five years.

This thesis describes the development of new magnetic resonance imaging (MRI) methods to characterize cardiac tissue with myocardial infarction (MI). Wall motion imaging (for visualizing myocardial contraction) and viability imaging (to identify MI) are two components of cardiac tissue characterization used for prognosis and treatment planning. MRI-based wall motion and viability methods are considered the gold standard in imaging, and characterization of MRI viability images has been correlated with inducibility for ventricular tachycardia (VT). However, viability imaging with MRI has limitations such as difficulty visualizing the blood-infarct border. Wall motion and viability images are acquired separately, each requiring cardiac gating and breath holds, leading to long scan times. A novel multi-contrast delayed enhancement (MCDE) sequence was developed that simultaneously acquires wall motion and viability images. In a patient study, the MCDE sequence was demonstrated to provide improved visualization of MI compared to the conventional inversion-recovery gradient echo (IR-GRE) sequence, particularly for small infarcts adjacent to the blood pool. MCDE images also provided accurate wall motion images that could be used to calculate the left ventricular ejection fraction. An image processing algorithm was developed to analyze MCDE images to segment and classify the infarct gray zone, which is hypothesized to represent heterogeneous infarct responsible for causing VT. In a study of 15 patients with MI, the MCDE-derived gray zone was shown to be less sensitive to image noise than the IR-GRE-derived gray zone, and did not require manual contours of the blood pool which contributes to additional variability in the IR-GRE gray zone analysis. Finally, a real-time delayed enhancement (RT-DE) method was developed to provide black-blood viability images without requiring cardiac gating or breath holds. RT-DE imaging was shown to have a high sensitivity for detecting MI in a study of 23 patients. The methods described in this thesis help expand the patient population that can undergo a cardiac viability exam and help improve the visualization of myocardial infarct. Further modifications in the pulse sequences to improve the temporal and spatial resolutions are proposed with the goal of predicting and guiding treatment of ventricular tachycardia resulting from myocardial infarct.

Remote ischemic preconditioning (rIPC) through transient limb ischemia induces potent cardioprotection against ischemia reperfusion (IR) injury. I examined the delayed phase of protection that appears 24 hours after the initial rIPC stimulus. The primary objective of this study was to establish a mode of sedation and control treatment for delayed rIPC experiments. I used an ex-vivo, Langendorff isolated-mouse heart preparation of IR injury to examine the delayed effects of an intra-peritoneal (IP) injection, sodium-pentobarbital (SP), halothane and nitrous oxide (N2O) anesthesia on post-ischemic cardiac function. Each anesthetic method improved left-ventricular function after IR injury. SP and halothane anesthesia also reduced LV infarct size. Delayed cardioprotection after IP injections was associated with an increase in phosphorylated-Akt levels. The present study shows that IP injections and inhalational anesthesia invoke cardioprotection and, therefore, indicates that these modes of sedation should not be used as control treatments for studies examining the delayed rIPC phenotype.

Remote ischemic preconditioning (rIPC) through transient limb ischemia induces potent cardioprotection against ischemia reperfusion (IR) injury. I examined the delayed phase of protection that appears 24 hours after the initial rIPC stimulus. The primary objective of this study was to establish a mode of sedation and control treatment for delayed rIPC experiments. I used an ex-vivo, Langendorff isolated-mouse heart preparation of IR injury to examine the delayed effects of an intra-peritoneal (IP) injection, sodium-pentobarbital (SP), halothane and nitrous oxide (N2O) anesthesia on post-ischemic cardiac function. Each anesthetic method improved left-ventricular function after IR injury. SP and halothane anesthesia also reduced LV infarct size. Delayed cardioprotection after IP injections was associated with an increase in phosphorylated-Akt levels. The present study shows that IP injections and inhalational anesthesia invoke cardioprotection and, therefore, indicates that these modes of sedation should not be used as control treatments for studies examining the delayed rIPC phenotype.