Background: Non ST-elevation Acute Coronary Syndromes are the most frequent manifestations of acute ischemic heart disease. Gender differences in treatment intensity, including differences in level of care, have been reported. Also differences in benefit from certain treatments, especially invasive treatment, have been discussed. Finally, difference in outcome between men and women, have been proposed. Results have been inconsistent, partly depending on if and how adjustment for differences in background characteristics has been made. The aims of the studies in this thesis were to assess differences between the genders in baseline characteristics, level of care, medical treatment and non-invasive and invasive cardiac procedures. The aims were also to determine gender differences in short and long-term mortality, including impact of level of care, and to determine differences between the genders in benefit from an invasive strategy, with special reference to benefit in women. Method: We used prospectively collected data from the RIKS-HIA registry in two studies (Paper I and IV). In one study we merged data from patients admitted to general wards in the south-east region of Sweden (The AKUT registry), with data from patients admitted to CCU´s (RIKS-HIA) at participating hospitals during the same time (Paper II). We also randomly assigned women to a routine invasive or a selective invasive treatment strategy, and performed a meta-analysis, to determine gender differences in benefit from a routine invasive strategy (Paper III). Results: Women were older than men and more likely to have a history of diabetes and hypertension, while men were more likely to have a history of myocardial infarction and revascularisation. Women were also more likely to have normal coronary arteries on the angiogram. After adjustment for baseline differences there were only minor, and directionally inconsistent, differences between women and men in pharmacological treatment. Men were more often referred for coronary angiography, even after adjustment. While CABG-rate was lower in women, after adjustment PCI-rate was similar or even higher compared to men. After adjustment for differences in age, longterm outcome was better in women. In our small but randomised trial there was no benefit from a routine invasive strategy in women. A meta-analysis indicated interaction between gender and treatment strategy, with lack of benefit in women, in contrast to in men. However, our large observational study indicated no gender difference with an invasive strategy. Moreover, benefit was similar in women and men with invasive treatment. Conclusion: There are substantial differences between women and men in baseline characteristics that affect management and outcome more than gender per se. After adjustment women have better long-term outcome than men. There appear to be a difference in benefit from a routine invasive strategy between the genders, with less benefit in women, but in routine clinical management there was no difference between women and men managed with an invasive strategy.

Diss. (sammanfattning) Uppsala : Uppsala universitet, 2005. / Härtill 4 uppsatser.

Thesis (Ph. D.)--University of Wisconsin--Madison, 1984. / Typescript. Vita. eContent provider-neutral record in process. Description based on print version record. Includes bibliographical references.

Introduction Infective endocarditis is a microbial infection of the endothelial surface of the heart, predominantly the heart valves, that is associated with high mortality and morbidity. Few contemporary data exist regarding affected children in our context. Aims and Objectives: We aimed to describe the profile and treatment outcomes of infant and childhood endocarditis at our facilities. Methods: This is a retrospective review of infants and children with endocarditis at two public-sector hospitals in the Western Cape Province of South Africa over a 5-year period. Patients with “definite” and “possible” endocarditis according to Modified Duke Criteria were included in the review. Results: Forty-nine patients were identified for inclusion; 64% of patients met “definite” and 36% “possible” criteria. The in-hospital mortality rate was 20%; 53% of patients underwent surgery with a post-operative mortality rate of 7.7%. The median interval from diagnosis to surgery was 20 days (interquartile range 9-47 days). Valve replacement occurred in 28% and valve repair in 58%. There was a significant reduction in valvular dysfunction in patients undergoing surgery and only a marginal improvement in patients treated medically. Overall, 43% of patients had some degree of residual valvular dysfunction. Conclusion: Endocarditis is a serious disease with a high in-hospital mortality and presents challenges in making an accurate diagnosis. Despite a significant reduction in valvular dysfunction, a portion of patients had residual valvular dysfunction. Early surgery is associated with a lower mortality rate, but a higher rate of valve replacement when compared to delayed surgery.

Biomarkers are used in clinical and research settings to enable prevention, subtype disease, quantify severity, guide treatment, and prioritize therapeutic targets. Large scale high throughput platforms have allowed for measurement of high quantities of proteins in large epidemiologic samples. By combining proteomic assays with results from genomic platforms, biological insights can be gleaned to facilitate clinical relevance of emerging markers. In Study 1, we used the Prospective Urban Rural Epidemiology (PURE) study analyzed in a case-cohort fashion to evaluate the importance of angiotensin-converting enzyme 2 (ACE2) as a cardiometabolic risk marker. Using long-run prospective data, we showed ACE2 predicted incident diabetes, cardiovascular disease, and death beyond traditional cardiac risk factors. In Study 2, we evaluate M-CSF as a causal driver of vascular disease using a similar case-cohort design. We find M-CSF is a strong predictor of stroke, myocardial infarction, heart failure, and death. Using Mendelian randomization, an approach that leverages genetic variants as instrumental variables, we find M-CSF is not only associated with cardiovascular disease and death, but is also a causal driver of the development of vascular disease. In a subsequent Mendelian randomization analysis, we find that body-mass index correlates with increased plasma M-CSF, indicating that M-CSF may play a mediating role between BMI and cardiovascular disease. Finally, in Study 3, we use polygenic risk scores to agnostically prioritize among a set of 539 plasma proteins which ones are dysregulated early in the heart failure disease course. We identify 7 proteins representing a diverse set of pathways including IL6 (Interleukin 6), HGF (Hepatocyte growth factor), and CPM (Carboxypeptidase M) as markers associated with both incident heart failure as well as genetic predisposition to heart failure. Of the 7 identified proteins, 3 maintained prognostic significance for death and hospitalization in those with heart failure (IL6, KIM1, HGF). / Thesis / Doctor of Philosophy (PhD) / Finding risk factors for heart disease can assist in efforts to prevent disease and prioritize targets for treatment. Advances in the ability to measure entities like proteins and genetic markers at scale allow researchers to evaluate these new risk factors in large databases. We take advantage of these advances in technology to uncover new insights in global studies with participants representing 5 continents. In Study 1, we performed a comprehensive evaluation of the emerging biomarker angiotensin-converting enzyme 2 (ACE2) wherein we evaluated the association of ACE2 with future risk of cardiometabolic events, but also gained insights into possible drivers of plasma protein concentration. In Study 2, we employ a similar analytic profiling of the biomarker macrophage-colony stimulating factor (M-CSF). Available evidence is conflicting as it relates to whether M-CSF serves a harmful or beneficial role in the development of cardiovascular disease. We perform an analysis examining the upstream determinants and downstream consequences of M-CSF levels. In Study 3, we adopt an approach to identify early markers of heart failure by using genetic predisposition to heart failure as an additional filter for biomarker relevance. Overall, this work relies on complementary approaches to better understand risk factors evaluated in large global databases including the Prospective Urban Rural Epidemiology study and Global Congestive Heart Failure study.

The metabolic syndrome (MS), consequent upon the pandemic of obesity and diabetes, is associated with an increased risk for cardiovascular (CV) disease. Development of sub-clinical cardiac structural and functional changes associated with CV disease risk factors may be detected on echocardiography. The extent to which these structural changes and CV risk factors are dependent on genetic factors is not clearly established. This project was designed to investigate the relationship between CV disease risk factors, cardiac structural and functional changes and underlying genetic abnormalities. Specifically, the risk factor profile and the presence of the MS were determined. This was then correlated with the echocardiographic findings and gene polymorphisms. Method: A randomly selected cohort of 1428 subjects from the Phoenix community was studied. Demographic data was collected using the WHO STEPS instrument. Blood samples for biochemistry and genetic analysis, together with anthropometric measurements, were collected. Blood pressure and echocardiography was performed on all subjects. The metabolic syndrome was classified according to the National Cholesterol Education Panel (NECP) Adult Treatment Panel III (ATP III) and International Diabetes Federation (IDF) criteria. The Lipoprotein Lipase and Human Paraoxonase-1 genes were genotyped on a Light Cycler 480 Real-Time PCR instrument, using allele-specific probes and sequencing. Results: There was a high prevalence of CV risk factors in this sample; particularly increased waist circumference (79%), obesity (64%) insulin resistance (58%) and hypertension (50%) across the age groups. This translated into a high prevalence of MS (38% using NCEP ATPIII and 46% using IDF criteria). There were significant echocardiographic differences between subjects with and without MS for chamber dimensions (p<0.001), left ventricular wall thickness (p<0.001) and mass (p<0.001), diastolic indices (E-wave {p<0.001}, trans-mitral ratio {p=0.017}) and sub-epicardial adipose tissue (SEAT) thickness (p<0.001). Stepwise multivariate analysis identified age (95% CI 0.975; 0.998), gender (95%CI 0.48; 0.9) and hypertension (95% CI 0.53; 0.99) as independent risk factors for diastolic abnormalities. Logistic regression identified age as the most significant contributor to diastolic abnormalities (OR=1.02; 95%CI 1.009; 1.03; Wald=13.4), followed by the waist circumference (OR=1.025; 95%CI 1.014; 1.037) and BMI (OR=1.075; 95% CI 1.035; 1.117). Genetic analysis showed significant associations between the heterozygous variant of Q192R genotype (PON-1 gene) and elevated HDL levels and also between this variant and obese women (p= <0.05). Conclusion: The high prevalence of CV risk factors and MS in this community has reached epidemic proportions. Although the MS was associated with significant remodelling of cardiac structure, alteration of diastolic indices and increased sub-epicardial adipose tissue thickness, BMI and waist circumference were stronger promoters of altered cardiac physiology. This augurs poorly for this population group unless intervention is introduced to address the markedly high prevalence of these culprit drivers. / Thesis (Ph.D.)-University of KwaZulu-Natal, Durban, 2013.

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