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It is becoming increasingly evident that the development of atherosclerotic coronary heart disease (CHD) can largely be regulated by lifestyle and dietary choices. The type of fatty acids regularly consumed may promote or prevent atherogenesis. Flaxseed, the richest plant source of the omega-3 fatty acid alpha-linolenic acid (ALA) is thought to protect against atherosclerotic disease. However, the mechanism(s) by which flaxseed exerts these anti-atherogenic effects requires further investigation. Alternatively, there are dietary fatty acids that are thought to induce significant deleterious effects upon our cardiovascular health. Epidemiological evidence associates dietary trans fatty acids (TFAs) with atherosclerotic CHD. This evidence has largely focused on the main source of TFAs in the North American diet, industrially hydrogenated vegetable shortening (iTFAs). It is assumed that TFAs stimulate atherosclerosis but the only studies to date have shown no effect of TFAs on atherosclerosis. Even less is known of the impact of naturally occurring TFAs from dairy and meat products of ruminant animals (rTFAs) on atherosclerotic disease. We investigated the effects of flaxseed supplementation on atherosclerosis and vascular function in two animal models, the hypercholesterolemic rabbit and the cholesterol fed, low density lipoprotein receptor (LDLr-/-) deficient mouse. New Zealand White rabbits and LDLr-/- mice were fed a diet containing flaxseed in the absence or presence of dietary cholesterol for a period of 6 to 24 weeks. We found that dietary flaxseed inhibits the atherogenic effects of a high cholesterol diet in both animal models. The anti-atherogenic effect was achieved in the mouse model through a capacity to lower circulating cholesterol levels and at a cellular level by inhibiting cell proliferation and inflammation. This reduction is also associated with an improved vascular relaxation response as demonstrated in the rabbit model. We also investigated the effects of consuming TFAs from two sources, industrially hydrogenated iTFAs rich in elaidic TFA (C18:1t-9) or naturally-occurring ruminant rTFAs rich in vaccenic TFA (C18:1t-11), on atherosclerotic development in the LDLr-/- mouse in the presence or absence of elevated dietary cholesterol. Our results demonstrate that consuming iTFAs dose dependently initiates atherosclerotic development but not beyond the effects of dietary cholesterol alone. However, consuming rTFAs rich in vaccenic acid protects against hyperlipidemia and atherosclerosis in the presence or absence of dietary cholesterol. The effects of combining dietary flaxseed and iTFAs in the diet were also examined in this model. Adding whole ground flaxseed or flaxseed oil (ALA) to diets containing low and high doses of iTFAs completely prevented atherosclerotic development in the absence of dietary cholesterol. Flaxseed was also able to partially prevent atherosclerosis caused by iTFAs and cholesterol. Our results suggest that the omega-3 ALA fatty acid rich content of flaxseed is mainly responsible for the anti-atherogenic effects of flaxseed. Our results highlight potential mechanisms for the beneficial effects of dietary flaxseed and the mixed effects of TFAs on cardiovascular health and underscore the need for further basic and clinical investigations.

Considerable interest has focused on the influence of dietary fat quality on cardiovascular disease (CVD) risk. Increasingly, novel dietary oils rich in oleic acid and alpha-linolenic acid (ALA) are being developed and marketed with an aim to improve fatty acid intakes and reduce CVD risk. The objective of this research was to investigate the efficacy of high-oleic canola oil (HOCO) alone, or blended with flaxseed oil (FXCO), on traditional and emerging clinical biomarkers of CVD risk. An additional aim was to study the influence of dietary and genetic factors on metabolism of 13C-ALA to long-chain PUFA. Using a diet-controlled randomized crossover design, thirty-six hypercholesterolaemic subjects consumed three isoenergetic diets for 28 days each containing ~36% energy from fat, of which 70% was provided by HOCO, FXCO, or a Western dietary fat blend (WD; control). Endpoint measures revealed reductions (P<0.001) in serum lipid concentrations, including a 7.4% and 15.1% decrease in LDL-cholesterol after HOCO and FXCO diets, respectively, as compared with the WD control. Moreover, a reduction (P=0.023) in plasma E-selectin concentration was found after the FXCO diet compared with the WD control. Consumption of the dietary oils failed to alter whole-body fat oxidation or energy expenditure, nor lead to alterations in body composition. FXCO diet increased (P<0.001) plasma ALA ~5-fold, EPA ~3-fold, and DPA ~1.5-fold, but did not modulate DHA levels compared with the WD control. At 24 and 48 hours the amount of administered 13C-ALA recovered as plasma 13C-EPA and 13C-DPA was lower (P<0.001) after FXCO diet compared with HOCO and WD diets, suggesting decreased ALA conversion efficiency with very high intakes of dietary ALA. No difference in plasma 13C-DHA enrichment was observed across diets. Moreover, minor alleles of selected single nucleotide polymorphisms in the FADS1/FADS2 gene cluster were associated with reduced (P<0.05) plasma fatty acid compositions and apparent conversion of 13C-ALA. However, increased consumption of ALA in the FXCO diet compensated for lower levels of EPA in minor allele homozygotes. Taken together, substitution of dietary fats common to WD with both HOCO and FXCO represents an effective strategy to target several biomarkers for CVD risk reduction.

Background - Mobile health (mHealth) interventions to promote medication adherence have shown promise; among patients primarily diagnosed with Coronary Heart Disease (CHD), however, there is a lack of evidence for nurse-led mHealth interventions, in this particular group in Iran. Aim - To refine and evaluate a pre-developed nurse-led mHealth intervention to promote cardiovascular medication adherence in Iranian adult, male and female Cardiac Rehabilitation (CR) outpatients. Methods - A quantitative-dominant mixed methods study was conducted drawing upon the Medical Research Council’s (MRC) Framework on the development and evaluation of complex interventions. Phase 1 comprised of a self-completion CHD patients’ survey (n=123) and three focus groups with cardiac nurses (n=23) within three public university-affiliated hospitals in Tehran, which in turn informed Phase 2 (the exploratory trial phase). The automated Short Message Service (SMS) medication reminder was designed based on the dimensions of adherence suggested by the World Health Organisation (WHO) and Bandura’ Self-efficacy Theory. The intervention was refined according to the findings from Phase 1 and then piloted in an Iranian CR setting. Seventy eight CHD patients who were 18 years or older, and had mobile phone access were recruited and randomised to receive either daily SMS reminders (n=39) or usual care (n=39) for 12 weeks. The primary outcome was the effect on cardiovascular medication adherence as measured by the self-reported Morisky Medication Adherence Scale; secondary outcomes explored the feasibility of the mHealth intervention, intervention effect on medication adherence selfefficacy, cardiac ejection fraction, cardiac functional capacity, hospital readmission/ death rate and health-related quality of life. Patient acceptability was assessed through completion of a post-intervention survey. Results - Feasibility was evidenced by high ownership of mobile phones in CHD patients, high application of SMS messaging, positive patients’ perception about the intervention, suboptimal cardiovascular medication adherence and patients’ high interest in receiving SMS reminders for their medications. Participants in the intervention group showed higher self-reporting of medication adherence compared to the usual care group χ2 (2) = 23.447; P < 0.001. The Relative Risk (RR) was indicated that it was 2.19 times more likely for the control group to be less adherent to their medications than the intervention group (RR = 2.19; 95% Confidence Interval (CI) 1.5 - 3.19). All secondary outcomes improved in the intervention group at the end of the study. Acceptability was evidenced by participants who received the intervention reporting that they perceived the SMS reminders useful. Conclusion - The SMS medication reminder intervention was well accepted and feasible with significantly higher reporting of medication adherence in Iranian CHD patients. Effect sizes were established for use in future follow-up evaluations of the mHealth intervention.

Fetal exposure to excess glucocorticoid is associated with low birth weight and increased cardiovascular disease risk in first generation offspring. Such phenotypes can be produced experimentally through the administration of the synthetic glucocorticoid dexamethasone (Dex) to pregnant rats during the last week of gestation. These ‘programmed effects’ can be transmitted to a second generation through both maternal and paternal lines. The overall hypothesis for this thesis was that the transmission of programmed effects through the male line may result from alterations in fetal germ cells, which form sperm in adulthood. Epigenetic reprogramming of germ cells is characterised by the genome-wide erasure and subsequent re-establishment of 5-methylcytosine (5mC), however this process has not previously been described for the rat. Furthermore, the involvement of more recently identified cytosine modifications; 5-hydroxymethylcytosine (5hmC), 5- formylcytosine (5fC) and 5-carboxylcytosine (5caC), has not been characterised during germ cell ontogeny. Using immunofluorescence to study DNA modifications during late gestation I identified that 5hmC, 5fC and 5caC were present between e14.5 and e16.5 but absent thereafter. In contrast, 5mC was absent during this time but remethylation was noted from e19.5 onwards. Prenatal Dex exposure was associated with the presence of significantly more 5mC-positive germ cells at e19.5 relative to controls. This difference did not persist at e20.5 suggesting that Dex exposure promotes premature global remethylation. The mechanisms for this are unclear since there were no differences between groups in the localisation of the DNA methyltransferases DNMT3a and 3b, or in markers of normal testis maturation. To enable the study of gene-specific changes in DNA methylation in the germline a colony of Germ Cell Specific-Enhanced Green Fluorescent Protein (GCS-EGFP) rats was established and characterised. GCS-EGFP rats had a transgenerational decrease in pup weight with Dex exposure, as in Wistar rats. The expression of both established and novel candidate genes was compared between strains. Multiple genes across different pathways had altered expression, with some affected in both Wistar and GCS-EGFP rats, whilst other differences were strain-specific. Enhanced Reduced Representation Bisulfite Sequencing was performed on liver and fetal germ cells from males exposed to Dex in utero to explore effects on DNA methylation. These studies confirm that epigenetic reprogramming occurs in the rat and that this process may be susceptible to modification by prenatal Dex exposure. GCS-EGFP rats also exhibited a Dex programming phenotype, with decreased pup weight and altered liver gene expression. The use of this unique strain of rats will permit dissection of the mechanisms for the transmission of programmed phenotypes across generations.

Made available in DSpace on 2014-06-11T19:25:19Z (GMT). No. of bitstreams: 0 Previous issue date: 2011-02-28Bitstream added on 2014-06-13T20:53:03Z : No. of bitstreams: 1 morais_mgt_me_botfm.pdf: 1390196 bytes, checksum: 479c99fbe7320445854c3f31cf0ad4ee (MD5) / Universidade Estadual Paulista (UNESP) / Apresentamos nesta dissertação, uma revisão dos estudos epidemiológicos e econômicos mostrando a doença cardiovascular como a grande pandemia do século XXI, tanto dos países desenvolvidos como naqueles em desenvolvimento. Colocamos em foco a necessidade de estudar-se a epidemiologia cardiovascular, que consiste na busca das causas de mudança da condição de saúde ou doença, nos seus fatores de risco e nos esforços para a preservação da saúde. Além das perspectivas epidemiológicas, há de se comentar as econômicas e sociais que seguem as primeiras uma vez que pessoas cada vez mais jovens adoecem causando um déficit na população economicamente ativa. Hoje a doença cardiovascular consome muitos recursos, saber quanto custa ao serviço público, com dados claros e fidedignos é a única forma de evitar um caos nos sistemas de saúde de todo o mundo. A grande maioria dos dados disponíveis hoje necessita de aperfeiçoamento para serem utilizados com êxito. No Brasil a criação do Sistema Único de Saúde SUS em 1988 norteada com os princípios da universalidade e da equidade, juntamente com os avanços tecnológicos e escassez de recursos, exige uma otimização dos recursos disponíveis sem, entretanto alterar a qualidade da assistência á saúde. Quando analisamos os gastos do SUS em saúde, observamos um incremento anual crescente, especialmente quando falamos das doenças cardiovasculares. Em 2007 foram registradas 1.157.509 internações por DCV no Sistema Único de Saúde (SUS) que custaram aos cofres públicos R$ 1.468.441.279,46. Em novembro de 2009 ocorreram 91.970 internações por DCV, resultando em um custo de R$ 165.461.644,33 (DATASUS). Os gastos continuam aumentando ano após ano de forma desastrosa. Sendo assim caracterizamos o gasto com as DCV especificamente... / We presented in this dissertation, a review of epidemiologic and economic studies showing the cardiovascular disease as the great pandemic of the XXI century much of the developed countries as in developing countries. We focuses the need to study the cardiovascular epidemiology, which consists in finding the causes of change in health condition or disease, in its risk factors and efforts to preserve health. Apart from the epidemiological perspective, we should also comment on the economic and social that follows the first since more and more young people become ill, causing a deficit in the economically active population. Today, cardiovascular disease consumes too many resources, how much it costs to public service, with clear and reliable data is the only way to avoid chaos in health systems around the world. The vast majority of data available today need improvement to be used successfully. In Brazil, the creation of the Sistema Único de Saúde in 1988 SUS guided with the principles of universality and equity, along with technological advances and dwindling resources, requires an optimization of available resources without however changing the quality of healthcare. When we analyze SUS expenses on health, we observe a growing annual increase, especially when it comes to cardiovascular diseases. In 2007 we registered 1,157,509 admissions for CVD in the Sistema Único de Saúde (SUS) that cost the public treasury R$ 1,468,441,279.46. In November 2009 there were 91,970 admissions for CVD, resulting in a cost of R$ 165,461,644.33 (DATASUS). Expenses continue to increase year after year in a disastrous way. Therefore we characterize the CVD expenses specifically heart disease by the government through a retrospective study, with descriptive purpose, developed within the specialty of cardiology where numerical data... (Complete abstract click electronic access below)

Calcium (Ca) intakes may affect cardiovascular disease risk by altering body weight/fat and serum lipid profile, but results have been inconsistent and the underlying mechanisms are not well understood. Thus, the effects of dietary Ca on body composition and lipid metabolism were examined in male Sprague-Dawley rats. Rats were fed high-fat, high-energy diets containing (g/kg) low (0.75Ca, 0.86 ± 0.05; 2Ca, 2.26 ± 0.02), normal (5Ca, 5.55 ± 0.08) or high (10Ca,11.03 ± 0.17; 20Ca, 21.79 ± 0.15) Ca for 10 weeks. At the end of the study the 0.75Ca group had lower (p < 0.05) body weight and fat mass compared to other groups. Rats fed the high Ca diets had lower serum total and LDL cholesterol compared to rats fed normal or low Ca. Liver total cholesterol was lower in rats fed high compared to low Ca. In general, liver mRNA expression of the LDLR and genes involved in cholesterol synthesis (HMGCR and HMGCS1), fatty acid oxidation (CPT2) and cholesterol esterification (ACAT2) were higher in rats fed higher Ca. Apparent digestibility of total trans, saturated, monounsaturated and polyunsaturated fatty acids was lower in rats fed the high compared to the low Ca diets, but the differences were greatest for trans and saturated fatty acids. Fecal excretion of cholesterol and total bile acids was highest in rats fed the 20Ca diet. The results suggest little effect of dietary Ca on body composition unless Ca intakes are very low. Decreased bile acid reabsorption and reduced absorption of neutral sterols and trans and saturated fatty acids may contribute to the improved serum lipid profile in rats fed higher Ca.

Chronic kidney disease (CKD) is an important independent risk factor in the development of cardiovascular disease (CVD). Indeed, patients with CKD are far more likely to die from CVD than reach end stage renal disease. Conventional cardiovascular risk factors and co-morbidity contribute to this increased risk of CVD. However, emerging evidence suggests other novel factors including inflammation, oxidative stress, and a shift in the balance of the vasodilator nitric oxide and vasoconstrictor endothelin system, are also important contributors. Despite increasing evidence that the endothelin system plays an important role in the development of CKD and CVD, there has been little research examining possible therapeutic benefits of its modification in patients with CKD. The overall aims of the work presented within this thesis were to examine CVD risk in patients with renal impairment and then to see what impact chronic inhibition of the endothelin system would have on risk factors for CVD and CKD progression. In the first two studies I examined markers of arterial stiffness (AS) and endothelial function in a cohort of patients with immune-mediated renal disease. I was able to show in the acute setting that improvement in renal function following treatment for these conditions leads to significant improvements in AS. Interestingly, in patients who were in remission from their renal disease, only classical cardiovascular risk factors appear to be linked to AS. In the next study I was able to prove that sitaxsentan, a selective oral ETA antagonist, did not cause functional blockade of the ETB receptor in man. This was the first study of its kind to confirm that a “selective” endothelin antagonist truly is selective in vivo: a finding that will allow more accurate mechanistic investigation of the ET system. In the final studies, I showed that in subjects with stable non-diabetic proteinuric CKD, chronic selective ETA receptor antagonism reduces blood pressure and AS, and that these systemic benefits are associated with an increase in renal blood flow and reduction in proteinuria. The reduction in proteinuria is most likely haemodynamic and linked to a fall in GFR and filtration fraction, similar to what is seen with ACE inhibitors. Importantly, these benefits were seen in patients already taking maximally tolerated renin-angiotensin aldosterone system blockade, suggesting that chronic endothelin antagonism could be an important future therapy in the management of CKD. In summary, I have shown that renal impairment can directly affect markers of arterial function and by inference increase the risk of CVD. Chronic antagonism of the endothelin system with ETA receptor blockers would appear to improve many of these biomarkers, including reductions in BP, AS and proteinuria. There were no adverse effects reported in these studies, suggesting that selective ETA antagonism may be safe enough for clinical development in CKD patients. Further larger clinical trials are warranted.

Today, it is estimated that 35 million people are living with human immunodeficiency virus (HIV). Since its initial discovery in 1981, researchers and medical providers have worked endless hours to understand the pathology, transmission, and medical management of HIV. In the early days of HIV, life expectancy after diagnosis was 10 years. However, after the development of zidovudine (AZT) in 1987, life expectancy of HIV patients began to slowly increase, albeit still lower than that of the general population. The development of AZT opened the door for more antiretroviral drugs and more drug classes. Now, patients undergo a triple drug regimen to manage HIV. These patients are able to maintain viral suppression and are no longer experiencing opportunistic infection or other AIDS-related conditions. While HIV is medically managed, this is a chronic condition and to-date, not cured. As opposed to opportunistic infections and other AIDS-related conditions, patients are succumbing to non-AIDs related conditions such as renal, neurological, bone disorders, and liver complications. The leading non-AIDs related condition is cardiovascular disease (CVD). Even with viral suppression, HIV infection itself contributes to the pathology and development of atherosclerosis and CVD. It is clear that chronic immune activation, HIV proteins, and dyslipidemia appear to be key factors in CVD development. Since the life expectancy of HIV patients has increased, physicians are now seeing an older generation of HIV patients. Medical providers are shifting focus toward understanding the long-term effects of not just HIV, but antiretroviral therapy (ART) as well. It appears that drug interactions and long-term toxicity augment CVD development. Protease inhibitors (PIs), compared to other ART drug classes, appear to increase the risk of atherosclerosis, especially through dyslipidemia. Due to management of HIV being life-long, compliance is difficult because of high pill burden, drug-drug interactions, and drug side effects. This can result in drug failure leading HIV patients to switch to second-line ART regimens. PIs are a common component of second-line ART regimens. Compared to other ART drugs, PIs have a high genetic barrier to resistance. However, PIs have a low bioavailability requiring high dosage and/or boosting with ritonavir (RTV). Lopinavir (LPV) boosted with RTV (LPV/r) is a favorable PI as it is used in a combination pill and is the most cost effective. However, multiple studies have shown LPV/r correlates more to CVD compared to other PIs. Patients on LPV/r exhibit an increased intima-medial thickening, a hallmark characteristic of atherosclerosis and an increased risk for myocardial infarction. Unfortunately, researchers are greatly conflicted as to why this is and in general why PIs increase the risk of CVD. Future medical treatment for HIV is complex and requires long-term medical management. In recent years, integrase inhibitors (IIs) have exhibited promise to provide better lipid profiles while maintaining viral suppression. However, as this drug class is relatively new and expensive, the financial burden on HIV patients is high. The next step toward addressing the global health issue of HIV is understanding the exact mechanism of how PIs contribute to CVD. This will not only increase the life expectancy of HIV patients, but reduce drug toxicity, non-AIDS related conditions, and increase adherence and viral suppression. It is clear that future research must be focused on understanding the role PIs have in CVD development. Physicians are seeing an older generation of HIV patients, and a vast majority are on second-line regimens. By understanding this relationship, researchers could design alternative drugs to manage CVD risk, by modifying current PIs or designing entirely new drugs.

Dravet syndrome (DS) is a severe form of pediatric epilepsy with characterizations of pharmacoresistant seizures and developmental delay. A rarer variant of the DS model is caused by heterozygous loss-of-function mutations in SCN1B, which is essential in regulating sodium channel gating, expression, localization, and the firing of action potentials. Mutations in SCN1B result in severe seizures as well as a higher risk of Sudden Unexpected Death in EPilepsy (SUDEP). Factors underlying SUDEP are poorly understood, although cardiac arrythmias have been implicated. Acebutolol (ACE) is a common beta-blocker used in the treatment of arrhythmias and hypertension. We hypothesized that treating mice with ACE will decrease cardiac arrhythmias and the incidence of SUDEP, prolonging lifespan of Scn1b null mice. Wild-type (WT) and null (KO) mice were given daily injections of 10 mg/kg ACE or saline starting at postnatal day 15 (after typical seizure onset) either during the day (09:00) or at night (21:00). ECG was recorded daily including a baseline and a 20-minute post injection measurement to analyze the long-term and acute effects of treatment. 20 minutes following ACE injection, KO mice displayed a significant reduction in heart rate compared to WT (38% vs. 11%). Interestingly, HR the day prior to death consistently dropped ~50% (average 414 bpm to 193 bpm) in our saline group; this was prevented in KO animals treated with ACE (421 bpm). A modest, but significant, increase in survival curves in our KO animals was observed compared to saline treated mice for those given injections during the day (a 2 day increase in median survival). In addition, in this group, the onset of animal death was delayed. Surprisingly, in the mice injected during the night hours, there was a trend towards a decrease in lifespan. From these findings there is a notable hypersensitivity to ACE in this DS model. Leading up to death, we believe it is possible ACE assisted in decreased cardiovascular deficits that could lead to SUDEP and contributed to the modest increased lifespan. While we are still seeing death in the ACE treated group because of unnoticed, prolonged seizures, or other mechanisms of SUDEP. In addition, our results demonstrate the importance of timing in delivery of drugs targeted at SUDEP. Further work includes testing this hypothesis by adding 24 hour drug delivery or an anti-epileptic drug to see if lifespan is further affected is warranted.