Ambulanspersonal skall i sitt dagliga arbete lyfta och behandla patienter. I varje ambulans finns två ambulanssjukvårdare (kan även vara sjuksköterskor med eller utan specialistutbildningar) som har genomgått ett lyftprov som bekräftar att de på två man klarar att lyfta en patient som väger 90kg. Då en patient väger 150kg (gravt obes patient) eller mer blir det problematiskt, både ergonomiskt och medicintekniskt. Antalet överviktiga ökar, även de som räknas som gravt obesa. Syftet med denna uppsats vara att beskriva ambulanspersonalens erfarenheter då det gäller ambulanstransport av gravt obesa patienter.Enkäter besvarades anonymt av personal på en ambulansstation i södra Sverige. Svarsfrekvensen blev 29 av 55 personal efter att ett påminnelsebrev delats ut. Svaren bearbetades med beskrivande statistik. Resultatet visade att det inte fanns en fullt fungerande rutin för gravt obesa patienter. Personalen ansåg överlag att hjälpmedel inte var tillräckliga för att snabbt och säkert kunna transportera patienter med en vikt över 150kg till sjukhuset. Förbättring av rutiner samt hjälpmedel skulle kunde minska riskerna för skador hos personal samt innebära en bättre och säkrare vård vid transport till sjukhus.

Nível elevado de homocisteína (Hcy) no plasma é considerado fator de risco de doença cardiovascular. Consumo reduzido de vitaminas B6, B12 e ácido fólico tem sido relacionado com hiperhomocisteinemia. O objetivo desse estudo foi verificar o consumo de vitaminas B6, B12 e ácido fólico nas populações urbana e rural, bem como a correlação dos níveis plasmáticos dessas vitaminas com os níveis plasmáticos de Hcy. Também determinamos os níveis séricos de lipídeos e avaliamos o risco cardiovascular das populações frente a hiperlipemia. O consumo de B6 e ácido fólico é maior na população urbana, com p=0,00 e p=0,04 respectivamente, sendo o consumo de B12 maior na população rural, com p=0,47. As correlações são significativamente negativa entre Hcy e as vitaminas B12 e ácido fólico . A população rural apresenta Hcy com valor médio de 16,5±9,2µmol/L, classificada como hiperhomocisteinemia moderada, e a população urbana 12,8±5,5 µmol/L, o qual está dentro da faixa de referência. O valor médio de LDL sérica é maior na população urbana (3,4±0,8mmoI/L) do que na população rural (2,8±0,9mmoI/L), com valor de p=0,00. Como fator de risco cardiovascular, consideramos Hcy plasmática >14µmol/L e LDL sérica >3,38mmol/L. Neste caso, 41,4% da população rural e 7,4% população urbana apresentam Hcy maior que 14µmol/L. O inverso ocorre em relação a LDL, onde 43,2% da população urbana e 11% na população rural apresentam níveis acima de 3,38mmol/L. Concluímos que o risco cardiovascular decorrente de hiperhomocisteinemia é maior na população rural que na urbana e este risco poderia reduzir mediante o consumo de vitaminas. / Elevated levels of plasma homocysteine (Hey) are considered a risk factor for cardiovascular diseases. Low intake of vitamins 86, 812 and folic acid have been related to hyperhomocysteinemia. The purpose of the present study is to determine the consumption of the vitamins B6, B12 and folic acid in two Brazilian urban and rural populations, along with the plasmatic levels of these vitamins and plasmatic homocysteine. In addition, the serum levels of lipids have been determined to evaluate the cardiovascular risk in the two populations regarding their hyperlipidemie comdition. The consumption of B6 and folic acid is higher in the urban population (p=0.00 and p=0.04 respective/y), while the consumption of B12 is not significantly different (p=0.47). There is a negative correlation between B12 and folic acid with Hcy. The rural population shows mean Hcy value of 16.5±9.2µmol/L and is classified as having moderate hyperhomocysteinemia, while for the urban population, the mean value is 12.8±5.5µmol/L and is well within the normal range. The mean value of the serum LDL is higher in the urban population (3.4±0.8mmol/L) compared to the rural population (2.8±0.9mmol/lL) with a significance of p=0.00. Plasma Hcy values >14µmol/L and serum LDL >3.38mmol/L were considered as the risk factors for cardiovascular disease. With in the reference values, 41.4% of the rural population and 7.4% of the urban population showa Hcy as a risk factor. For LDL, the inverse is true, i.e 43.2% of urban and 11% of the rural population are at risk. We conclude that the cardiovascular risk arising from hyperhomocysteinemia is higher in the rural population and that this can be reduced by increased consumption of vitamins.

Este estudo teve por objetivo avaliar a prevalência de doença periodontal e risco de doença cardiovascular estratificado pelos métodos de Framingham e PROCAM em uma amostra de sujeitos do Instituto Dante Pazzanese de Cardiologia. Trata-se de um estudo de prevalência com 56 sujeitos do gênero masculino de 45 a 70 anos dos Ambulatórios de Coronariopatia e Cardiologia do Esporte que aceitaram participar voluntariamente e tiveram os dados coletados da anamnese, do exame clínico global e periodontal e de análises laboratoriais. Os parâmetros clínicos periodontais foram: Registro Periodontal Simplificado (PSR), Índice Comunitário de Necessidades de Tratamento Periodontal (CPITN), Índice de Placa (IP), Índice de sangramento sulcular à sondagem (IS), Profundidade de Sondagem (PS), nível de inserção clínica periodontal (NIC) e Retração Gengival (RG). Avaliaram-se também na anamnese e no exame clínico global a idade, etnia, escolaridade, estado civil, hábitos alimentares, pressão arterial pulsátil, índice de massa corpórea (IMC), tabagismo, histórico familiar de cardiopatias, atividade física semanal e presença de doenças sistêmicas. Na avaliação laboratorial analisamos Glicemia, Triglicérides, Lipoproteína de Alta (HDL) e Baixa (LDL) Densidade, Colesterol Total e Proteína C Reativa. Os dados laboratoriais e clínicos foram utilizados como base de cálculo do logaritmo de estratificação de risco de doença cardiovascular nos métodos de Framingham e PROCAM. Foi então realizada a análise univariada e de freqüência para cada dado coletado, como também foi analisada a correlação entre os métodos periodontais e de estratificação de risco de doença cardiovascular. Finalizando com a análise de correlação da prevalência de doença periodontal com o risco de doença cardiovascular. Foi estabelecido o nível de significância de 5%. Os sujeitos do ambulatório de Coronariopatia apresentaram maior risco de doença cardiovascular calculado pelos métodos de Framingham e PROCAM (T1=1,212, p=0,048; T1=1,843, p=0,045), índice de massa corporal e concentração plasmática de proteína C reativa, menor intervalo de temporal de atividade física semanal do que os sujeitos do ambulatório de Cardiologia do Esporte. Nos parâmetros periodontais os sujeitos do ambulatório de Coronariopatia apresentaram maior freqüência de periodontite moderada no exame de PSR, maior índice de placa, índice de sangramento sulcular, perda de inserção clínica e profundidade de sondagem do que nos sujeitos do ambulatório de Cardiologia do Esporte. A prevalência de doença periodontal foi significantemente maior nos sujeitos com maior risco de doença cardiovascular estratificado nos métodos de Framingham e PROCAM (r=0,786/Framingham; r=0,823/PROCAM). / Oral infection models have emerged as useful tools to study the hypothesis that infection and inflammatory reaction is a independent cardiovascular disease (CVD) risk factor. Periodontal infections are a leading culprit, with studies reporting associations between periodontal disease and CVD, but this studies the periodontal diagnosis and coronary risk show substantial variations. This study aimed to analyze the different methods of periodontal diagnosis (Periodontal Screening and Recording - PSR and Clinical Attachment Loss - CAL) and correlation with Framingham and PROCAM coronary risk. The result shown strong and significant associations between periodontal diagnosis (r=0,812) and coronary risk (r=0,786/Framingham; r=0,823/PROCAM). Evidence continues to support an association among periodontal infections, atherosclerosis and vascular disease in different periodontal diagnosis and coronary risk stratification methods.

Background: Age-standardised mortality rates for cardiovascular disease (CVD) are generally higher among men than women, prompting suggestions that reproductive factors may be partly responsible. Moreover, there have been major changes in women’s reproductive patterns and CVD rates in China over the last few decades, but the association between them is still poorly understood. Objectives: To start addressing these issues, this thesis examines the secular trends and correlates of age at menarche and menopause (the major physiological events defining a woman’s reproductive window), as well as their association with blood pressure and anthropometry in 302,180 women born in 1930-74 from 10 areas across China using cross-sectional demographic, behavioural, physical and reproductive data from the China Kadoorie Biobank. Results: Mean age at menarche decreased by 2 years over a 44-year period (1930-1974), with the exception of an increase of about 1 year for women exposed to the Great Chinese Famine in early adolescence. No other factor showed as large an effect on age at menarche. Among women aged >57 years at the baseline, mean age at menopause increased by 1.4 years over a 21-year period (1930-1951) and was significantly associated with several reproductive and behavioural factors, notably gravidity (2 years later menopause) and smoking (6 months earlier menopause). Blood pressure and anthropometry were weakly inversely associated with age at menarche (0.2mmHg and 0.2kg/m² lower per year later menarche) and even more weakly positively associated with age at menopause (0.06mmHg and 0.04kg/m² higher per year later menopause). These trends and associations all varied to some extent by area and socioeconomic status. (All p-values <0.0001) Conclusion: This study adds new information on the secular trends and correlates of age at menarche and menopause in a large Chinese population born around the mid-20th century and provides a basis for further prospective work on the association of reproductive history with the incidence of CVD in China.

<strong>Background:</strong> Stroke is a leading cause of disability and premature death in China and blood pressure is widely considered to be a major cause. Despite this, substantial uncertainty remains about the shape and strength of the association between blood pressure and stroke pathological types in China. <strong>Methods:</strong> Information from the China Kadoorie Biobank study (a prospective cohort study of 0.5 million men and women in China recruited during 2004-8) was used to relate usual blood pressure to risk of stroke, by stroke pathological type (cerebral infarction [ischaemic stroke], intracerebral haemorrhage and subarachnoid haemorrhage). Prospective analyses excluded participants with a history of vascular disease recorded at baseline; involved correction for regression dilution bias; used incident stroke events for which the diagnosis involved a head CT or MRI scan; and, assessed for confounding and effect modification by major vascular risk factors. These prospective analyses were informed by a set of prior analyses, including: a description of baseline associations between blood pressure and other vascular risk factors, to identify potential confounders; analyses of resurvey blood pressure data from ~20_000 participants, to assess regression dilution bias; and analyses of stroke follow-up data, involving an adjudication ‘sub-study’ performed specifically as part of this thesis, to evaluate the diagnostic accuracy of incident stroke events (~1000 events were adjudicated). <strong>Results:</strong> During 2.1 million person-years at risk, there were 5783 incident stroke events. At ages 40-79 years, the proportional difference in risk of both cerebral infarction and intracerebral haemorrhage associated with a given absolute difference in usual blood pressure was constant throughout the range of blood pressures examined (SBP 120-170 mm Hg, DBP 70-100 mm Hg). Overall, the strength of association was approximately 1.5-times greater for intracerebral haemorrhage than for the other stroke pathological types: 10 mm Hg higher usual SBP was associated with 82% (95% CI: 76%-89%) higher risk of intracerebral haemorrhage, 47% (44%- 50%) higher risk of cerebral infarction and 52% (35%-71%) higher risk of subarachnoid haemorrhage (the overall mean age at event for each stroke pathological type was ~60 years). For both cerebral infarction and intracerebral haemorrhage, there was strong evidence of major effect modification by age and to a lesser extent by a number of other vascular risk factors. The associations by age were around a third as extreme at age 70-79 years than at 40-49 years. The annual absolute differences in risk associated with a given absolute increase in usual blood pressure, however, were greater at older age. <strong>Conclusions:</strong> In Chinese adults, usual blood pressure was strongly and positively related to risk of all stroke pathological types. The strength of association was greater for intracerebral haemorrhage than other stroke pathological types. For both cerebral infarction and intracerebral haemorrhage, there was evidence of major effect modification by age. The overall effect of blood pressure on stroke risk was much greater than estimated by previous prospective studies in China, particularly for intracerebral haemorrhage.

Coronary atherosclerotic plaque rupture is a critical event during atherosclerosis disease progression. Clinical consequences of atherosclerotic plaque rupture vary from asymptomatic to acute arterial thrombosis, yet the mechanisms underpinning such divergent biological response remain poorly understood. Novel biological signatures of plaque rupture will confer further insights into the dynamic responses triggered by plaque rupture event(s), and may provide alternative strategies for modulation of this prevalent disease. This thesis aims to investigate the events that accompany coronary plaque rupture and their relations to subsequent, downstream systemic effects. In a prospective clinical study of patients undergoing non-emergency percutaneous coronary intervention (PCI), stenting induced plaque disruption was used as a model of plaque rupture in vivo. Optical coherence tomography (OCT) imaging of the plaque lesion was performed prior to stenting, followed by serial blood sampling from targeted anatomical sites in reference to the plaque disruption event. Coronary plaque debris were also retrieved in a controlled manner. Analysis of candidate markers demonstrated a role of matrix metalloproteinase 9 (MMP9) in the systemic response to plaque disruption. Local and systemic elevations of MMP9 were observed promptly after plaque disruption. The systemic release of MMP9 was independent to the myocardial injury and systemic inflammation as a result of PCI. OCT analysis further suggested that plaque morphology may be a determining factor in the subsequent MMP9 release, as the disruption of lipid rich plaque(s) resulted in more acute elevation 'of ~1'MP9 when compared to disruption of non-lipid lesions. Changes of systemic MMP9 served as an index of response to the stent induced plaque disruption. Subjects with divergent MMP9 responses to the plaque disruption event were put forward for further comprehensive investigation during the discovery phase, using mass spectrometry techniques to investigate the lipidomic, metabolomics, and proteomic signatures of plaque disruption. Coronary atherosclerotic plaque disruption was associated with immediate changes in the plasma lipidomics and metabolomics profiles, which had distinct relations to the subsequent systemic MMP9 release. Coronary plaque debris provided a "catalogue" of proteins which could be acutely liberated into systemic circulation. Several such novel proteins were detected in circulation after plaque disruption, which triggered disparate responses in known canonical pathways. Evidence from this thesis implicates the role of liver X receptor / retinoic acid receptor pathway (LXR/RXR) as a key mediator to the divergent systemic responses after plaque disruption, and pinpoints a direction for future investigations.

The research in this thesis investigated the role of the hypoxia-inducible factor (HIF) family of transcription factors in metabolism and cardiopulmonary physiology. Specifically, the effects of HIF on ventilatory control, carotid body morphology, and cardiac metabolism and function were studied using a murine model of a genetic disorder of oxygen sensing known as Chuvash polycythaemia. HIF coordinates oxygen-regulated gene expression throughout all organ systems, thereby orchestrating cellular, tissue and systemic responses to hypoxia. HIF is primarily regulated by oxygen-dependent prolyl hydroxylase-domain enzymes (PHDs) that initiate its degradation via the von Hippel-Lindau protein (VHL). In Chuvash polycythaemia, a homozygous VHL mutation in humans causes generalised stabilisation of HIF in euoxia, resulting in profound changes in cardiopulmonary physiology, exercise and metabolism. The Chuvash mouse model provides an opportunity to further characterise the role of HIF in different organ systems. Chapter 2 of this thesis introduces the murine model, demonstrating an increase in haemoglobin and haematocrit in the Chuvash mice as well as a marked reduction in body weight. Chapter 3 describes the ventilatory and carotid body study. Chuvash mice were shown to have elevated baseline ventilation in euoxia and marked ventilatory sensitivity to hypoxia. These findings were accompanied by changes within the carotid body, including hyperplasia, hypertrophy and altered ultrastructure of the oxygen-sensing type I cells. Chapter 4 of this thesis describes the study into cardiac metabolism, energetics and function. Chuvash hearts were found to have increased glycolytic flux and lactate production (the latter both in and ex vivo), with altered myocardial energetics. Despite this, left ventricular function remained normal, although in vivo cine MRI revealed clear evidence of pulmonary hypertension and right ventricular hypertrophy. Overall, this thesis provides evidence that the PHD-VHL-HIF axis plays a major role in calibrating the hypoxic response in the principal organ systems responsible for oxygen uptake, delivery and utilisation.

Visit-to-visit variability in blood pressure (BP) increases stroke risk, independent of mean BP. However, its physiological validity, the ideal method of measurement and the mechanisms increasing cardiovascular risk are unclear. In meta-analyses of individual patient data, I pooled associations between BP variability and risk of stroke, all cardiovascular events and death. I then determined antihypertensive drug-class differences in cardiovascular risk, intra-individual (I-VR) and inter-individual BP variability (M-VR). In 500 Oxford Vascular Study (OXVASC) patients undergoing thrice-daily home (HBPM) and awake ambulatory monitoring (ABPM), associations between mean, maximum or variability in BP (CV-BP) were determined with premorbid BP, hypertensive arteriopathy (creatinine, aortic stiffness, cognitive impairment, stroke versus TIA and leukoaraiosis) and cardiovascular events. In 200 patients, I determined associations with pulsatility or stiffness (pulse wave velocity) in cerebral and aortic vessels. There was a 21% and 27% increased risk of stroke and myocardial infarction per standard deviation of CV-SBP in 318700 patients, independent of mean SBP. In 244,479 patients, SBP variability was reduced by CCBs and diuretics within (I-VR=0.89, 95% CI=0.82-0.96, p=0.0001) and between individuals (M-VR 0.83, 0.77-0.89, p<0.0001), especially in the first year of treatment, explaining drug class differences in stroke risk (OR=0.76, 0.68-0.87, p<0.0001). In OXVASC, drug class differences on day-to-day SBP variability were greatest immediately after waking. Residual hypertension after treatment on HBPM but not ABPM (BP>135/85) predicted recurrent cardiovascular events (HR 2.82, 1.44-5.51, p=0.002 vs. 1.48, 0.68-3.23, p=0.33), reflecting stronger associations with premorbid BP and hypertensive arteriopathy, due largely to inaccuracy of ABPM in patients aged >65 years. Furthermore, day-to-day maximum and CV-SBP were associated with premorbid BP, hypertensive arteriopathy and cardiovascular events, with no additional predictive value of mean SBP when analysed with maximum SBP. Maximum SBP was greater in men and CV-SBP in women, whilst age and creatinine determined both. Increased stroke risk may partly be due to the association between BP variability and cerebral pulsatility, which was correlated with leukoaraiosis (p=0.01) and determined by aortic stiffness (p=0.016) and pulsatility (p<0.001). BP variability is clinically significant and physiologically valid, and is treatable with CCBs and diuretics. After TIA or minor stroke, HBPM best identifies residual hypertension and demonstrates the predictive value of BP variability and maximum BP, but associated arterial changes might explain some of the increased stroke risk.

Intradialytic Hypotension (IDH) is the commonest complication of maintenance haemodialysis and is associated with increased morbidity and mortality. However, there is no standardised definition of IDH, making comparisons between studies difficult. This observational study with a total of 80 patients and over 600 dialysis sessions showed a poor correlation between symptoms and hypotension. Importantly, patients experienced low blood pressure without symptoms, so continuous intradialytic blood pressure monitoring is required to identify this asymptomatic group. In light of these findings, a revised definition of IDH is suggested. This study also aimed to identify predictors of IDH that could be detected in sufficient time to allow a mitigating intervention. A novel non-invasive alternative for continuous blood pressure monitoring is introduced which uses intra-fistula pressure data from the sensors sited in the extracorporeal circuit of the dialysis machine. Results show that in the majority of patients, changes in intra-fistula pressure correlate with blood pressure measurements obtained by a standard oscillometric device. To investigate whether IDH can be predicted, a photoplethysmogram (PPG) waveform was obtained from a pulse oximeter attached to the finger or ear. Continuous PPG monitoring of patients with IDH during dialysis demonstrated that some IDH episodes were predictable using the variation in the PPG baseline with respiration as a surrogate for low blood volume. Additionally, the area under the curve of the PPG waveform can be used as a surrogate for cardiac output and peripheral vascular tone, resulting in a reasonable predictor for potentially critical changes in blood pressure during dialysis. Individually, the novel metrics described here are limited in their identification of IDH in all patients affected, but in combination they may be used to develop a multi-parameter predictive model. The relative merits of personalised versus population-based models are explored and a conclusion is drawn that personalised multi-parameter data fusion modelling for haemodialysis patients would be an important area for future work.

Aortic dissection is a detrimental disease with a high mortality. However, the mechanisms regulating the susceptibility to aortic dissection remain unknown. We hypothesize that endothelial oxidative stress due to the activation of the reactive oxygen species (ROS)-generating Nox2 enzyme may play an important role in the development of aortic dissection. To investigate this, we generated transgenic mice (C57BL/6J background) with endothelial specific over-expression of Nox2 (Nox2 Tg) under the control of a tie-2 promoter. Expression of the human Nox2 transgene was confirmed by qRT-PCR to be found only in endothelial cells (EC) isolated from transgenic mice, and not in Wt EC or vascular smooth muscle cells (VSMC) and macrophages isolated from either genotype. Wild-type (Wt) littermates and Nox2 Tg male mice (22-24 weeks old, n=11) were treated with saline or Ang II (1mg/kg/day) via subcutaneous mini-pump for 28 days. There was no significant difference in the pressor responses to Ang II between Wt and Nox2 Tg mice (Wt 121±7mmHg vs. Nox2-Tg 122±6mmHg). However, 5/11 Nox2 Tg mice developed aortic dissections compared to 0/11 Wt mice (P<0.05). Immunohistochemistry revealed significant increases in endothelial VCAM-1 expression, MMP activity and CD45+ inflammatory cell recruitment in the aortas of Nox2 Tg mice after 5 days of Ang II infusion. Inflammatory cell recruitment was confirmed by FACS analysis of cells from digested aortas (P<0.05). Explanted aortas from Nox2-Tg mice had significantly greater secreted pro-inflammatory cytokine, Cyclophilin A (CypA) both at baseline and after 5 days of Ang II infusion compared to Wt littermates. Compared to primary Wt EC and VSMC, Nox2-Tg primary EC, but not primary VSMC, had increased ROS production which was accompanied by increased endothelial CypA secretion and ERK1/2 activation. Furthermore, conditioned media from Nox2-Tg EC induced greater ERK1/2 phosphorylation compared to conditioned media from Wt controls. Knockdown of CypA from sEND.1 endothelial conditioned media by siRNA knockdown abolished VSMC Erk1/2 phosphorylation. In conclusion, we demonstrate for the first time that a specific increase in endothelial ROS through the over-expression of Nox2 was sufficient to induce aortic dissection in response to Ang II stimulation. Endothelial secreted CypA could be the signalling mechanism by which increased endothelial ROS regulates the inflammatory response and the susceptibility to aortic dissection.