Atherosclerosis, one of the major causative factors of cardiovascular diseases (CVD), is thought to be initiated by oxidative stress. Particular attention has been paid to the atherogenic effects of oxidative damage on low density lipoproteins (LDL). Current research shows that dietary antioxidant supplementation protects against oxidative stress, and therefore may present preventative measures and treatments for patients with diseases influenced by oxidative stress. Isoflavones found in soy, such as genistein and daidzein are reported to have potent antioxidant properties and have been shown to inhibit LDL oxidation in vitro. Although there is a strong base of data that supports the correlation between soy consumption, cholesterol reduction and cardiovascular protection, it remains to be elucidated whether it is the soy protein, the isoflavone, or a combination of both that confers benefits. This study investigated the effect of isoflavone supplementation on the following parameters: plasma genestein levels, oxidized LDL levels, plasma cholesterol, vitamin E, and C-reactive protein. Elevated serum cholesterol and C-reactive protein (CRP) have been identified as risk factors for cardiovascular disease. In a randomized, double-blind, placebo-controlled study, 150 mg/d isoflavone was supplemented for four weeks by 30 healthy, yet sedentary male subjects who underwent 30 minute exercise sessions at 80% VO2pk before and after a 28 day period of supplementation. The purpose of the exercise was to induce oxidative stress. The average plasma genistein and daidzein concentrations increased significantly after isoflavone supplementation from 0 ng/ml to 561.6 ± 39.3 and 466.3 ± 35.5 ng/ ml (SE) respectively (P < 0.0001), compared to 0 ng/ml in the placebo group throughout the study. There was no significant beneficial effect of isoflavone supplementation on oxidized LDL, plasma vitamin E concentrations, total cholesterol, LDL, HDL, or triglycerides. Isoflavone supplementation resulted in an average increase in CRP levels by 44% (P = 0.014), which was opposite from expectations. This study supports the theory that it may not be soy isoflavones alone that benefit lipid profiles, or offer protection from oxidative stress. / Master of Science

No / The National Audit Office (NAO) has produced prescribing indicators that Primary Care Trusts (PCTs) can use to judge their performance. One of the indicators is for the antiplatelet clopidogrel, measured as defined daily dose (DDD) per cardiovascular Specific Therapeutic Age Related Prescribing Unit (STAR-PU). Clopidogrel is used as an indicator because it is a more expensive medicine than the alternative (aspirin) and there may be scope for cost reduction. We aimed to establish if the NAO indicator for clopidogrel prescribing is a valid measure of prescribing performance. Methods Prescribing data for 152 PCTs and a range of explanatory variables were obtained. Correlation between variables was determined. A regression analysis was conducted to compare the dependent variable (prescribing) with the explanatory variables identified. Results The percentage of patients on the coronary heart disease register and Index of Multiple Deprivation explained 30% of the variation in prescribing (DDD/STAR-PU) between PCTs. Even though DDD/STAR-PU is adjusted for age and sex other measures of need still have an impact on prescribing. Conclusions Using DDD/STAR-PU alone as a prescribing indicator might misidentify some PCTs, which are under- and over-using clopidogrel. Poor ranking against other PCTs using the NAO indicator should be fully explored taking into account other variables (cardiovascular morbidity and deprivation) before any corrective action is taken.

No / To provide an insight into the process of patients receiving Health Checks and to determine the extent to which patients were supported to reduce the risks of developing cardiovascular disease through behaviour change. Semi-structured qualitative interviews were undertaken with 45 patients about their initial experiences of undertaking a Health Check. They were followed up 1 year later to assess whether the behavioural changes reported after the Health Check had been maintained. Patients expressed a need for individualized support in order to stay motivated and to adopt long-term diet and lifestyle changes. Those involved in the delivery of the programme need to adopt a consistent approach in terms of explaining the purpose of the Health Check, communicating risk and consider the challenges and the barriers that influence behaviour change. / National Institute for Health Research' Research for Patient Benefit Programme. Grant Number: PB-PG-0609-19169. University of York

Yes / MicroRNAs are short, non-coding RNAs that target messenger RNAs for degradation. miR-145 is a vascular-enriched microRNA that is important for smooth muscle cell (SMC) differentiation. Under healthy circumstances, SMC exist in a contractile, differentiated phenotype promoted by miR-145. In cases of disease or injury, SMC can undergo reversible dedifferentiation into a synthetic phenotype, accompanied by inhibition of miR-145 expression. Vascular disorders such as atherosclerosis and neointimal hyperplasia are characterised by aberrant phenotypic switching in SMC. This review will summarise the physiological roles of miR-145 in vascular SMC, including the molecular regulation of differentiation, proliferation and migration. Furthermore, it will discuss the different ways in which miR-145 can be dysregulated and the downstream impact this has on the progression of vascular pathologies. Finally, it will discuss whether miR-145 may be suitable for use as a biomarker of vascular disease.

Introduction: Cardiovascular disease (CVD) risk assessment is becoming increasingly common in routine clinical practice. Consequently many individuals are likely to be identified as being at increased CVD risk and risk reducing strategies implemented with a view to preventing future CVD. There are many steps along the pathway from CVD risk assessment to the prevention of CVD events. First, CVD risk needs to be accurately estimated using an appropriate CVD risk calculator. Secondly CVD risk information needs to be effectively communicated to the individual identified as being at increased risk. Thirdly, the risk information communicated needs to be capable of motivating behaviour change and finally behaviour change needs to result in a reduction in CVD risk. The evidence base for many of these steps has yet to be fully established. Aims: The overall aims of this work were first to adapt the United Kingdom Prospective Diabetes Study (UKPDS) Risk Engine to better display risk and achievable risk. Secondly to investigate lay perceptions of risk and to develop two interventions designed to reduce CVD risk. The two interventions were a personalised 10-year CVD risk estimate and a brief lifestyle advice intervention. Finally, the capacity of these interventions to increase physical activity and improve CVD risk factors in adults at increased CVD risk was tested. Methods: Three focus groups were held to investigate lay perceptions of risk and to inform the design of the UKPDS Risk Engine interface and a brief lifestyle advice intervention designed to motivate risk reducing behaviours. The two interventions were then tested in a 2x2 factorial randomised controlled trial. Results: The focus group results demonstrated that public interest and understanding of risk was high. In addition participants expressed clear views regarding how risk information and lifestyle advice should be presented. 194 participants at increased 10-year CVD risk (≥ 20%) were recruited from 4 Oxfordshire general practices. Neither a personalised 10-year CVD risk estimate nor a brief lifestyle advice intervention was capable of increasing physical activity or reducing estimated 10-year CVD risk in this group. Conclusions: Whilst public interest in CVD risk appeared to be high this study was unable to demonstrate that a 10-year personalised CVD risk estimate or a brief lifestyle advice intervention was able to increase physical activity in adults at increased CVD risk.

The prevalence of obesity in both the developed and developing world have increased, which leads to diverse health outcomes and is placing a heavy burden on the economy. Abdominal obesity proved to be one of the main features in predicting metabolic and cardiovascular disease (CVD) risk and may be the link that unifies the metabolic syndrome (MS) through pro-inflammatory pathways. While the pathogenesis of the MS and each of its components are complex and not well understood, abdominal obesity remains the mechanism that relates to increased lipolysis causing the liver to increase blood glucose and very low lipoprotein output. This in turns leads to raised blood glucose, triglycerides, low-density lipoprotein cholesterol (LDL-C), blood pressure and inflammatory markers (C-reactive protein, interleukin-6 and tumor necrosis factor-a) and decreased high-density lipoprotein cholesterol (HDL-C). Prevention of the metabolic syndrome and treatment of its main characteristics are now considered of utmost importance in order to combat the increased CVD risk and all-cause mortality. Decreasing sedentary behaviour through regular physical activity is a key element in successful treatment of obesity through an increase in energy expenditure, but the ability to decrease low-grade systemic inflammation may be an even greater outcome. Aims The aims of this study was firstly, to determine by means of a literature review, how obesity could be related to a state of chronic systemic inflammation (increased CRP and IL-6). Secondly to determine whether physical activity could serve as a suitable method to decrease inflammation associated with obesity and related disorders. Thirdly to determine if abdominal obesity is a predictor of the metabolic syndrome and CVD and finally, to determine if measures of obesity can predict risk for the metabolic syndrome and CVD risk. Methods For this review study, a computer-assisted literature search were utilized to identify research published between 1990 and 2005. the following databases were utilized for the search: NEXUS, Science Direct, PubMed and Medline. Keywords related to obesity (abdominal obesity, overweight), metabolic syndrome (insulin resistance syndrome, dysmetabolic syndrome, syndrome X), cardiovascular disease (coronary heart disease, coronary artery disease), cardiovascular risk factors (hypertension, dyslipidemia, diabetes mellitus, physical activity), inflammatory markers (CRP, IL-6, chronic low-grade inflammation) and physical activity (fitness, exercise and training) were included as part of the search, including the references identified by previous reviewers (not identified as part of the computerized literature search). Results and conclusions Several research studies concluded that obesity could be an inflammatory disorder due to low-grade systemic inflammation. Adipose tissue is known to be a sectretory organ producing cytokines, acute phase reactants and other circulating factors. The synthesis of adipose tissue TNF-a could induce the production of IL-6, CRP and other acute phase reactants. CRP is a acute phase reactant, synthesized primarily in hepatocytes and secreted by the liver in response to a variety of inflammatory cytokines of which IL-6 and TNF-a are mainly involved. CRP increases rapidly in response to trauma, inflammation and infection. Thus, enhanced levels of CRP can be used as a marker of inflammation. Several studies of large population cohorts provide evidence for an inverse, independent dose-response relation between plasma CRP concentration and level of physical activity in both men and women. Trends for decreased IL-6, TNF-a and CRP concentrations were linear with increasing amounts of reported exercise in most of the research studies, physical activity proved effective in lowering measures of adiposity (BMI, WHR, WC and percentage body fat) and obesity related inflammatory markers (CRP & IL-6). Thereby indicating a potential anti-inflammatory effect. In the studies reviewed in this article abdominal obesity is identified as a predictor and independent risk factor for CVD in both men and women. High levels of deep abdominal fat have also been correlated with components of the metabolic syndrome, glucose intolerance, hyperinsulinemia, hypertension, diabetes, increases in plasma triglyceride levels and a decrease in HDL-C levels (dyslipidemia) in many of the studies. Prospective epidemiological studies have revealed that abdominal obesity (determined by WC and WHR) conveys an independent prediction of CVD risk and is more relevant compared to general obesity (determined by BMI). Abdominal fat has been linked to metabolic risk factors like high systolic blood pressure, atherogenic dyslipidemia, with increased serum TG and decreased HDL-C, and glucose intolerance. Although magnetic resonance imaging (MRI) and computerized tomography (CT) have been used successfully in many studies to measure adipose compartments of the abdomen (subcutaneous and visceral fat), anthropometrical measures like WHR and WC have been proven to be an effective measure in predicting the metabolic syndrome. WC has also been included in the metabolic syndrome definitions of the WHO, ATP Ill and new IDF. / The prevalence of obesity in both the developed and developing world have increased, which leads to diverse health outcomes and is placing a heavy burden on the economy. Abdominal obesity proved to be one of the main features in predicting metabolic and cardiovascular disease (CVD) risk and may be the link that unifies the metabolic syndrome (MS) through pro-inflammatory pathways. While the pathogenesis of the MS and each of its components are complex and not well understood, abdominal obesity remains the mechanism that relates to increased lipolysis causing the liver to increase blood glucose and very low lipoprotein output. This in turns leads to raised blood glucose, triglycerides, low-density lipoprotein cholesterol (LDL-C), blood pressure and inflammatory markers (C-reactive protein, interleukin-6 and tumor necrosis factor-a) and decreased high-density lipoprotein cholesterol (HDL-C). Prevention of the metabolic syndrome and treatment of its main characteristics are now considered of utmost importance in order to combat the increased CVD risk and all-cause mortality. Decreasing sedentary behaviour through regular physical activity is a key element in successful treatment of obesity through an increase in energy expenditure, but the ability to decrease low-grade systemic inflammation may be an even greater outcome. Aims The aims of this study was firstly, to determine by means of a literature review, how obesity could be related to a state of chronic systemic inflammation (increased CRP and IL-6). Secondly to determine whether physical activity could serve as a suitable method to decrease inflammation associated with obesity and related disorders. Thirdly to determine if abdominal obesity is a predictor of the metabolic syndrome and CVD and finally, to determine if measures of obesity can predict risk for the metabolic syndrome and CVD risk. Methods For this review study, a computer-assisted literature search were utilized to identify research published between 1990 and 2005. the following databases were utilized for the search: NEXUS, Science Direct, PubMed and Medline. Keywords related to obesity (abdominal obesity, overweight), metabolic syndrome (insulin resistance syndrome, dysmetabolic syndrome, syndrome X), cardiovascular disease (coronary heart disease, coronary artery disease), cardiovascular risk factors (hypertension, dyslipidemia, diabetes mellitus, physical activity), inflammatory markers (CRP, IL-6, chronic low-grade inflammation) and physical activity (fitness, exercise and training) were included as part of the search, including the references identified by previous reviewers (not identified as part of the computerized literature search). Results and conclusions Several research studies concluded that obesity could be an inflammatory disorder due to low-grade systemic inflammation. Adipose tissue is known to be a sectretory organ producing cytokines, acute phase reactants and other circulating factors. The synthesis of adipose tissue TNF-a could induce the production of IL-6, CRP and other acute phase reactants. CRP is a acute phase reactant, synthesized primarily in hepatocytes and secreted by the liver in response to a variety of inflammatory cytokines of which IL-6 and TNF-a are mainly involved. CRP increases rapidly in response to trauma, inflammation and infection. Thus, enhanced levels of CRP can be used as a marker of inflammation. Several studies of large population cohorts provide evidence for an inverse, independent dose-response relation between plasma CRP concentration and level of physical activity in both men and women. Trends for decreased IL-6, TNF-a and CRP concentrations were linear with increasing amounts of reported exercise in most of the research studies, physical activity proved effective in lowering measures of adiposity (BMI, WHR, WC and percentage body fat) and obesity related inflammatory markers (CRP & IL-6). Thereby indicating a potential anti-inflammatory effect. In the studies reviewed in this article abdominal obesity is identified as a predictor and independent risk factor for CVD in both men and women. High levels of deep abdominal fat have also been correlated with components of the metabolic syndrome, glucose intolerance, hyperinsulinemia, hypertension, diabetes, increases in plasma triglyceride levels and a decrease in HDL-C levels (dyslipidemia) in many of the studies. Prospective epidemiological studies have revealed that abdominal obesity (determined by WC and WHR) conveys an independent prediction of CVD risk and is more relevant compared to general obesity (determined by BMI). Abdominal fat has been linked to metabolic risk factors like high systolic blood pressure, atherogenic dyslipidemia, with increased serum TG and decreased HDL-C, and glucose intolerance. Although magnetic resonance imaging (MRI) and computerized tomography (CT) have been used successfully in many studies to measure adipose compartments of the abdomen (subcutaneous and visceral fat), anthropometrical measures like WHR and WC have been proven to be an effective measure in predicting the metabolic syndrome. WC has also been included in the metabolic syndrome definitions of the WHO, ATP Ill and new IDF. / Thesis (M.A. (Human Movement Science))--North-West University, Potchefstroom Campus, 2006.

The prevalence of obesity in both the developed and developing world have increased, which leads to diverse health outcomes and is placing a heavy burden on the economy. Abdominal obesity proved to be one of the main features in predicting metabolic and cardiovascular disease (CVD) risk and may be the link that unifies the metabolic syndrome (MS) through pro-inflammatory pathways. While the pathogenesis of the MS and each of its components are complex and not well understood, abdominal obesity remains the mechanism that relates to increased lipolysis causing the liver to increase blood glucose and very low lipoprotein output. This in turns leads to raised blood glucose, triglycerides, low-density lipoprotein cholesterol (LDL-C), blood pressure and inflammatory markers (C-reactive protein, interleukin-6 and tumor necrosis factor-a) and decreased high-density lipoprotein cholesterol (HDL-C). Prevention of the metabolic syndrome and treatment of its main characteristics are now considered of utmost importance in order to combat the increased CVD risk and all-cause mortality. Decreasing sedentary behaviour through regular physical activity is a key element in successful treatment of obesity through an increase in energy expenditure, but the ability to decrease low-grade systemic inflammation may be an even greater outcome. Aims The aims of this study was firstly, to determine by means of a literature review, how obesity could be related to a state of chronic systemic inflammation (increased CRP and IL-6). Secondly to determine whether physical activity could serve as a suitable method to decrease inflammation associated with obesity and related disorders. Thirdly to determine if abdominal obesity is a predictor of the metabolic syndrome and CVD and finally, to determine if measures of obesity can predict risk for the metabolic syndrome and CVD risk. Methods For this review study, a computer-assisted literature search were utilized to identify research published between 1990 and 2005. the following databases were utilized for the search: NEXUS, Science Direct, PubMed and Medline. Keywords related to obesity (abdominal obesity, overweight), metabolic syndrome (insulin resistance syndrome, dysmetabolic syndrome, syndrome X), cardiovascular disease (coronary heart disease, coronary artery disease), cardiovascular risk factors (hypertension, dyslipidemia, diabetes mellitus, physical activity), inflammatory markers (CRP, IL-6, chronic low-grade inflammation) and physical activity (fitness, exercise and training) were included as part of the search, including the references identified by previous reviewers (not identified as part of the computerized literature search). Results and conclusions Several research studies concluded that obesity could be an inflammatory disorder due to low-grade systemic inflammation. Adipose tissue is known to be a sectretory organ producing cytokines, acute phase reactants and other circulating factors. The synthesis of adipose tissue TNF-a could induce the production of IL-6, CRP and other acute phase reactants. CRP is a acute phase reactant, synthesized primarily in hepatocytes and secreted by the liver in response to a variety of inflammatory cytokines of which IL-6 and TNF-a are mainly involved. CRP increases rapidly in response to trauma, inflammation and infection. Thus, enhanced levels of CRP can be used as a marker of inflammation. Several studies of large population cohorts provide evidence for an inverse, independent dose-response relation between plasma CRP concentration and level of physical activity in both men and women. Trends for decreased IL-6, TNF-a and CRP concentrations were linear with increasing amounts of reported exercise in most of the research studies, physical activity proved effective in lowering measures of adiposity (BMI, WHR, WC and percentage body fat) and obesity related inflammatory markers (CRP & IL-6). Thereby indicating a potential anti-inflammatory effect. In the studies reviewed in this article abdominal obesity is identified as a predictor and independent risk factor for CVD in both men and women. High levels of deep abdominal fat have also been correlated with components of the metabolic syndrome, glucose intolerance, hyperinsulinemia, hypertension, diabetes, increases in plasma triglyceride levels and a decrease in HDL-C levels (dyslipidemia) in many of the studies. Prospective epidemiological studies have revealed that abdominal obesity (determined by WC and WHR) conveys an independent prediction of CVD risk and is more relevant compared to general obesity (determined by BMI). Abdominal fat has been linked to metabolic risk factors like high systolic blood pressure, atherogenic dyslipidemia, with increased serum TG and decreased HDL-C, and glucose intolerance. Although magnetic resonance imaging (MRI) and computerized tomography (CT) have been used successfully in many studies to measure adipose compartments of the abdomen (subcutaneous and visceral fat), anthropometrical measures like WHR and WC have been proven to be an effective measure in predicting the metabolic syndrome. WC has also been included in the metabolic syndrome definitions of the WHO, ATP Ill and new IDF. / The prevalence of obesity in both the developed and developing world have increased, which leads to diverse health outcomes and is placing a heavy burden on the economy. Abdominal obesity proved to be one of the main features in predicting metabolic and cardiovascular disease (CVD) risk and may be the link that unifies the metabolic syndrome (MS) through pro-inflammatory pathways. While the pathogenesis of the MS and each of its components are complex and not well understood, abdominal obesity remains the mechanism that relates to increased lipolysis causing the liver to increase blood glucose and very low lipoprotein output. This in turns leads to raised blood glucose, triglycerides, low-density lipoprotein cholesterol (LDL-C), blood pressure and inflammatory markers (C-reactive protein, interleukin-6 and tumor necrosis factor-a) and decreased high-density lipoprotein cholesterol (HDL-C). Prevention of the metabolic syndrome and treatment of its main characteristics are now considered of utmost importance in order to combat the increased CVD risk and all-cause mortality. Decreasing sedentary behaviour through regular physical activity is a key element in successful treatment of obesity through an increase in energy expenditure, but the ability to decrease low-grade systemic inflammation may be an even greater outcome. Aims The aims of this study was firstly, to determine by means of a literature review, how obesity could be related to a state of chronic systemic inflammation (increased CRP and IL-6). Secondly to determine whether physical activity could serve as a suitable method to decrease inflammation associated with obesity and related disorders. Thirdly to determine if abdominal obesity is a predictor of the metabolic syndrome and CVD and finally, to determine if measures of obesity can predict risk for the metabolic syndrome and CVD risk. Methods For this review study, a computer-assisted literature search were utilized to identify research published between 1990 and 2005. the following databases were utilized for the search: NEXUS, Science Direct, PubMed and Medline. Keywords related to obesity (abdominal obesity, overweight), metabolic syndrome (insulin resistance syndrome, dysmetabolic syndrome, syndrome X), cardiovascular disease (coronary heart disease, coronary artery disease), cardiovascular risk factors (hypertension, dyslipidemia, diabetes mellitus, physical activity), inflammatory markers (CRP, IL-6, chronic low-grade inflammation) and physical activity (fitness, exercise and training) were included as part of the search, including the references identified by previous reviewers (not identified as part of the computerized literature search). Results and conclusions Several research studies concluded that obesity could be an inflammatory disorder due to low-grade systemic inflammation. Adipose tissue is known to be a sectretory organ producing cytokines, acute phase reactants and other circulating factors. The synthesis of adipose tissue TNF-a could induce the production of IL-6, CRP and other acute phase reactants. CRP is a acute phase reactant, synthesized primarily in hepatocytes and secreted by the liver in response to a variety of inflammatory cytokines of which IL-6 and TNF-a are mainly involved. CRP increases rapidly in response to trauma, inflammation and infection. Thus, enhanced levels of CRP can be used as a marker of inflammation. Several studies of large population cohorts provide evidence for an inverse, independent dose-response relation between plasma CRP concentration and level of physical activity in both men and women. Trends for decreased IL-6, TNF-a and CRP concentrations were linear with increasing amounts of reported exercise in most of the research studies, physical activity proved effective in lowering measures of adiposity (BMI, WHR, WC and percentage body fat) and obesity related inflammatory markers (CRP & IL-6). Thereby indicating a potential anti-inflammatory effect. In the studies reviewed in this article abdominal obesity is identified as a predictor and independent risk factor for CVD in both men and women. High levels of deep abdominal fat have also been correlated with components of the metabolic syndrome, glucose intolerance, hyperinsulinemia, hypertension, diabetes, increases in plasma triglyceride levels and a decrease in HDL-C levels (dyslipidemia) in many of the studies. Prospective epidemiological studies have revealed that abdominal obesity (determined by WC and WHR) conveys an independent prediction of CVD risk and is more relevant compared to general obesity (determined by BMI). Abdominal fat has been linked to metabolic risk factors like high systolic blood pressure, atherogenic dyslipidemia, with increased serum TG and decreased HDL-C, and glucose intolerance. Although magnetic resonance imaging (MRI) and computerized tomography (CT) have been used successfully in many studies to measure adipose compartments of the abdomen (subcutaneous and visceral fat), anthropometrical measures like WHR and WC have been proven to be an effective measure in predicting the metabolic syndrome. WC has also been included in the metabolic syndrome definitions of the WHO, ATP Ill and new IDF. / Thesis (M.A. (Human Movement Science))--North-West University, Potchefstroom Campus, 2006.

In a replicating cell, the ataxia telangiectasia mutated kinase (ATM) gene induces DNA repair or cell cycle arrest in response to DNA damage. Mutations in the ATM gene have been shown to predispose individuals to insulin resistance and cardiovascular disease (CVD). CVD is a leading cause of death in the United States and diabetes has recently been identified as an increased risk factor for CVD. Diastolic dysfunction is an early indicator of CVD in diabetics. This can be caused by cardiac fibrosis or hypertrophic cardiomyopathy. Studies have also shown that females with diabetes are at an increased risk for CVD when compared to diabetic males. Therefore, the effects of ATM deficiency on diabetic heart function in both male and female mice were studied. Mice with two normal copies (WT) and one mutate copy (hKO) for the ATM gene were treated with 150 mg/kg body weight dose of streptozotocin (STZ) at ten months of age to induce diabetes. Three days following, blood glucose levels were measured. Mice with blood glucose levels above 300 mg/dL were considered diabetic and used for the study. The animals were followed over a time period of two months. Echocardiography was used to examine cardiac function. Blood flow velocity and ventricular filling parameters were measured in ATM WT and hKO diabetic mice. Contraction and relaxation times of the left ventricle were also measured in these mice. The animals were euthanized at two months post-treatment. Echocardiography revealed that ATM deficiency resulted in a greater increase in systolic function in hKO diabetic females compared to non-diabetic females with the same genotype. Systolic function in WT-diabetic female mice was not higher in non-diabetic females however it was higher compared to WT diabetic males. Interestingly, WT-diabetic female mice also experienced a higher systolic function compared to hKO-diabetic females. Doppler blood flow velocity patterns will be analyzed to determine ATM effects on diastolic dysfunction. These findings should help to better understand the physiological changes the ATM gene has in diabetic cardiomyopathy. It should also help identify if ATM deficiency is a risk factor for diabetics who also suffer from cardiovascular disease.

Cardiovascular disease is the leading cause of death with over 600,000 deaths per year. A key feature of heart failure is over stimulation of the beta-adrenergic receptors. Over stimulation of these receptors leads to changes in contractility of the heart, which can eventually lead to myocardial remodeling such as cardiomyocyte cell death (apoptosis). Prolonged activation and injury of the heart stimulates fibroblasts to repair the injured site and can lead to stiffening and scar formation. These changes in the heart are heightened in post-menopausal women as estrogen is depleted. Clinical trials have shown that estrogen has cardioprotective effects through its receptors: estrogen receptor alpha (ER-α) and estrogen receptor beta (ER-β). Though estrogen has been shown to be cardioprotective, studies have shown that hormone replacement therapy had little to no benefit to postmenopausal women with heart disease. These discrepancies lead to the need for more studies on how estrogen can protect the heart against failure. We therefore, examined the effects of estrogen deficiency and its role on cardiac structure and function following chronic β-adrenergic stimulation. Female mice (4 months of age) were treated with isoproterenol (ISO) (400μg/kg/h, subcutaneously) for 7 days one month after bilateral ovariectomy (OVX) at 3 months of age. Echocardiography and pulse wave doppler analysis was performed to examine cardiac function. Animals were then euthanized and hearts were isolated and paraffin embedded for histology analysis. Fibrosis was analyzed using Masson’s trichrome staining and apoptosis was analyzed with TUNEL assay. Ovariectomy did result in significant compromised cardiac function and ISO treatment exacerbated these results. Results from the echocardiography exam showed that ISO increased left ventricular diameter and that ovariectomy increased the diameter in a similar manner. Ovariectomized mice treated with ISO showed even greater increases in left ventricular diameter. The Doppler pattern results also showed a significant decrease in contraction time in the ISO and OVX+ISO groups compared to the OVX group alone. Surprisingly, Masson’s trichrome staining showed no significant change between the SHAM and ISO treated groups. The low amount of fibrosis could be attributed to the length of the ISO treatment. One-month post-ovariectomy may not be long enough to cause significant estrogen loss for the heart with effects on fibrosis. Extending the length of time post-ovariectomy before beginning isoproterenol treatment will be important to study the effects of estrogen loss on heart failure over time. We will analyze cardiac apoptosis and hypertrophy as further indicators of cardiac remodeling following ovariectomy and chronic beta-adrenergic stimulation. The results of this work can provide new information on heart disease in post menopausal women and alternative drug targets.

Cardiovascular disease (CVD) is the leading cause of death in the United States. A common feature in most cardiac pathologies is the dysregulation of beta-adrenergic receptors (β-AR) and changes in the extracellular matrix (ECM). The ECM maintains strength and normal organization of cardiac tissue, while fibrosis (connective tissue scarring) is necessary for repair of damaged cardiac tissue. However, the dysregulation of the ECM leads to a number of cardiac disease pathologies. Osteopontin (OPN) is a protein with diverse biological functions in regulating the ECM such as bone resorption and calcification, wound healing, cell adhesion, cell survival, and apoptosis. OPN is expressed at low levels in the heart but increases with injury by promoting collagen synthesis, cardiac fibroblast growth, and adhesions to ECM proteins. Furthermore, as the heart ages, increases in ECM reorganization leads to cardiac damage and failure. Several studies have examined the role of OPN in the heart, but to date, no studies exist on the role of OPN in response to β-AR signaling and cardiac remodeling or the role that aging plays in this response. The goal of this study was to examine the effects of OPN on cardiac ECM remodeling following chronic beta-adrenergic stimulation. We proposed that OPN expression increases cardiac remodeling and dysfunction following ISO treatment in the aging heart evidenced by increased fibrosis. For this study, young (4 months) and middle age (14 months) mice with (WT) and without (KO) the OPN gene were treated with isoproterenol (ISO) for 28 days. Echocardiography was used to assess cardiac function. Mice were euthanized, and the hearts were analyzed for fibrosis using Masson’s Trichrome Staining. Results showed ISO increased fibrosis in the WT-ISO, but not KO-ISO compared to the respective controls (SHAM, no ISO treatment) for the middle age mice (p≤0.05). Furthermore, the aged WT-ISO group exhibited a 3-fold increase in fibrosis compared to the young WT-ISO group. Results from echocardiography will be analyzed and we expect to see compromised cardiac function in the WT-ISO groups compared to KO-ISO groups. OPN is currently being examined as a potential biomarker in heart failure. The results from this study will provide new insight on changes in the cardiac vasculature in the aging heart following injury and the role OPN plays in this process.