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Cardiovascular disease (CVD) is a major cause of mortality and morbidity worldwide, often with heart failure as the terminal stage. Clinical studies have associated elevated levels of trimethylamine N-oxide (TMAO), a gut-derived metabolite, with adverse outcomes of CVD. As of today, TMAO's effects on cardiac structure and function are not well understood. In this study, both male and female TMAO-treated hearts showed functional deficits based on electrocardiography and echocardiography results. Immunohistochemistry results showed signs of hypertrophic cardiomyopathy in TMAO-treated male hearts while female TMAO-treated hearts showed signs of dilated cardiomyopathy. Neither TMAO group showed signs of fibrosis. Overproduction of reactive oxygen species was only observed in male TMAO-treated hearts. At the level of individual cardiomyocytes, significant delays in time to reach maximum contraction and dilation were only seen in TMAO-treated male hearts along with higher contractile force. Overall, TMAO-treated hearts show significant functional deficits with altered structure in a sex-specific way. Our study utilizes a variety of methods to comprehensively characterize features of TMAO-induced heart failure in both males and females which extends our current knowledge from human clinical associations. / Master of Science / Cardiovascular disease (CVD) is a major cause of mortality and morbidity worldwide, often with heart failure as the terminal stage. Clinical studies have associated elevated levels of trimethylamine N-oxide (TMAO), a compound derived from eggs, red meat and seafood, with adverse outcomes of CVD. As of today, TMAO's impact on the heart is not well understood. After supplementing mice with TMAO, we discovered deficiencies in heart function coupled with altered heart structure showing signs of hypertrophic cardiomyopathy in males and dilated cardiomyopathy in females. In-depth experiments suggest that TMAO-induced cell stress could be a potential underlying cause of previously mentioned changes but the specific mechanisms require further investigation. Overall, TMAO-treated hearts show significant functional deficits with altered structure in a sex-specific way. Our study utilizes a variety of methods to characterize features of TMAO-induced heart failure aiming to unravel relevant biological changes in both male and female mice which extends our knowledge from human clinical associations.

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The heart rate variability (HRV) signal has been employed as a measure of sympathovagal balance in the human autonomic nervous system (ANS). It is known that aging affects the functional characteristics of the ANS. It has been suggested that complexity as measured by nonlinear dynamical indices, decays with age. We developed several algorithms and test protocols to characterize nonlinear dynamics in the HRV signal and to test the hypothesis that aging reduces the complexity within the HRV signal. Continuous HRV signal was obtained from 93 healthy subjects (41 males and 52 females) ranging in age between 5 and 78 years under controlled laboratory conditions in supine state. Subjects were from pediatric (PED, 5-12 years, n=15, 9 male, 6 female), adolescent (ADO, 13-17 years, n=16, 6 male, 10 female), adult (ADL, 18-30 years, n=22, 12 male, 10 female), middle aged (MDA, 31-60 years, n=21, 8 male, 13 female) and elderly (ELD, 61+ years, n=19, 6 male, 13 female) age groups. The length of data was 1000 or more R-R intervals for adequate computation. Stationary Holter HRV data from these controls were also used for the present study. Our results are as follows: There is a continuous systematic decay in the power-law scaling (beta), which decreases from -1.162 ± 0.388 for the PED group to -1.95 ± 0.6 for the ELD group (F = 6.649, p < 0.001; R = 0.475, p < 0.001. Approximate entropy (ApEn) decreases with age from 1.456 ± 0.093 for the PED group to 1.272 ± 0.135 for the ELD group (F = 7.82, p < 0.001; R = 0.519, p < 0.001. The detrended fluctuation analysis (DFA) of short-term data yielded an increase in short-range DFA scaling exponent (alpha)1 from 0.774 ± 0.204 for the PED group to 1.138 ± 0.289 for the ELD group (F = 7.535, p < 0.001), and in long-range DFA scaling exponent (alpha)2 increased from 0.667 ± 0.082 for the PED group to 0.86 ± 0.172 for the ELD group (F= 4.841,p < 0.001). The detrended fluctuation analysis (DFA) of long-term data yielded an increase in short-range DFA scaling exponent (alpha)1 from 1.052 ± 0.218 for the PED group to 1.204 ± 0.205 for the ELD group (F = 1.922), and in long-range DFA scaling exponent (alpha)2 increased from 0.961 ± 0.081 for the PED group to 1.076 ± 0.102 for the ELD group (F = 4.06, p < 0.01). Surrogate data analysis demonstrated that the hypothesis that the HRV signal is generated by a linear stochastic process is not always rejected. In summary, the HRV signal lends itself to an analysis using nonlinear dynamical methods and studies in patients may yield useful clinical information in the future. / Thesis / Master of Engineering (ME)

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Typescript (photocopy). / Digitized by Kansas Correctional Industries

Call number: LD2668 .T4 1933 W54

Background/Aims. Understanding the fundamental mechanisms underlying the development of congenital heart disease and cardiomyopathies is a goal of researchers worldwide, with the ultimate goal being the establishment of effective therapeutics for the amelioration of cardiac dysfunction. Unfortunately these disorders are often polygenic in aetiology, making it difficult for researchers to probe complex interactions that may contribute to the severity of the disease. Over the last decade, the adult fruit fly (Drosophila melanogaster) has emerged as an invaluable tool with which to study the genetic and molecular mechanisms underlying heart function. The aim of my thesis research was to establish the adult fruit fly as a model of human heart function, and to exploit this powerful genetic system to screen for conserved genes affecting the development and function of its cardiac syncytium. Methodology/Results Baseline measures of heart function and other factors contributing to variability in heart function (i.e. age, temperature, and the time of day) were assessed to establish the adult Drosophila heart model. I then performed an a priori RNAi screen, knocking down expression of individual conserved genes via cardiomyocyte-specific overexpression utilising the yeast GAL4/UAS system. Heart-specific ablation of Fermitin 1 and Fermitin 2 (Fit1, Fit2), the two Drosophila orthologs of Kindlin 2 (Kind2, a gene thought to be important for cardiomyocyte-cardiomyocyte junction integrity in human myocardium), caused severe cardiomyopathy characterised by the failure of cardiomyocytes to develop as a functional syncytium and loss of synchrony between cardiomyocytes. I generated a null allele of Fit1 via P-element mobilisation, but this had no impact on heart development or function. Similarly, the silencing of Fit2 failed to affect heart development or function. In contrast, the silencing of Fit2 in the cardiomyocytes of Fit1-null flies disrupted syncytium development, leading to severe cardiomyopathy. Temperature-sensitive cardiac-specific GAL4/GAL80ts lines were also generated, and knockdown of Fit (Fit1 and Fit2) function at different developmental stages was assessed. I observed the strongest effects of Fit knockdown on adult cardiac morphology during stages of heart development and remodelling, with significant cardiomyocyte decoupling. After 3-weeks of Fit knockdown during adulthood, cardiomyocytes were significantly decoupled, and these hearts were significantly arrhythmic compared to control animals. Conclusions/Discussion. My data provide clarity about the role of Kind2 by demonstrating a cell autonomous role for this family in the development of a functional cardiac syncytium in Drosophila. My findings also show that the Fermitins can functionally compensate for each other in order to control syncytium development. Therefore, my thesis demonstrates the power of the fruit fly as a model of human cardiac physiology, and supports the concept that abnormalities in cardiomyocyte KIND2 expression or function may contribute to cardiomyopathies in humans.

There is now unequivocal evidence that dietary behaviour is related to illness and risk of chronic diseases such as cardiovascular disease and cancer. Attempts to improve the nation's diet are based on providing information, assuming that given more information, the public will choose healthier diets. Many studies indicate, however, that nutrition knowledge has little association with dietary behaviour; but a review of the literature reveals that nutrition knowledge has been inadequately measured. In addition, dietary behaviour has been assessed in terms of food intake and not in relation to changes in, or readiness to change, food intake. Following the Introduction, this research begins, in Chapter 2, by reviewing the literature measuring nutrition knowledge. It is found that while many studies measure knowledge, typically the measure forms only part of the study which assesses either a particular subpopulation or a particular aspect of nutrition. In consequence, questionnaires are designed for a one-off and specific purpose and little attention is paid to the psychometric properties of the instrument. Dietary behaviour is measured with one of the well-established methods of assessing intake, the problems of which are acknowledged in the literature. Chapter 3 describes these methods with their shortcomings and use in psychological research. In response to these reviews, a comprehensive nutrition knowledge questionnaire was developed (in 1994) and intake was conceptualised in terms of dietary change, in keeping with psychologists' role in nutrition. Following the development and pilot study of this questionnaire (Chapter 4), its validity and reliability were assessed further in Chapter 5, with positive results. Significant differences were found between criterion groups (dietetic and computer science students), providing evidence of construct validity. Internal consistency correlations ranged from 0.50 to 0.92 and test-retest reliability correlations ranged from 0.80 to 0.98. This measure was then used (Chapter 6) to assess the level of nutrition knowledge among a large representative sample of British adults in a postal survey (in 1995). Nutrition knowledge was found to be poor concerning the dietary recommendations for meat, starchy foods, fruit and vegetables; the different types of fat (saturated, poly- and monounsaturated); and associations between diet and diseases, such as fruit and vegetables, heart disease and cancer. Both stages of change (using Prochaska and DiClemente's model) and consumption of fat, fruit and vegetables (to test the stages' validity) were also assessed as measures of dietary behaviour. Most respondents replied that they had been limiting their fat intake for more than 6 months, but not been thinking of increasing their fruit and vegetable intake. Multivariate analyses showed that being female, having more educational qualifications and being in a higher socioeconomic class were predictive of knowing more about nutrition and having a healthier dietary behaviour. Relationships between nutrition knowledge, stages of change and dietary intake were examined in Chapter 7 and significant associations identified. In contrast to this cross-sectional research, the final study in Chapter 8 was longitudinal and examined changes in nutrition knowledge and dietary behaviour over a one-year period (from 1993 to 1994). This study aimed to provide information on the extent to which healthier changes in dietary intake are related to increases in nutrition knowledge. While changes occurred in dietary intake (fat and sugar intake decreased significantly, the increases in fruit and vegetable consumption were insignificant), knowledge scores remained unchanged. The final chapter discusses the key findings of this research, its implications and areas worthy of future investigation. For example, the results from this research suggest that knowledge is an important factor in food choice and should not be discounted as a part of health promotion. It may also be useful to integrate the construct of knowledge into the social cognition models of dietary choice or indeed to develop a new model to include knowledge along with motivational constructs from the social cognition models.

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