<p>In the past two decades studies have indicated that oral health might be associated with the prevalence for cardiovascular disease (CVD), although the biological link still remains unknown. Bacteria and inflammatory mediators causing periodontal disease have also been suggested to influence the progression of atherosclerosis.</p><p>The aims of this thesis were to study oral inflammation and associations between different oral health parameters and CVD. </p><p>Inflammatory mediators such as interleukin-1 (IL-1) as well as bone resorption activity (BRA) were significantly higher in gingival crevicular fluid (GCF) from sites with periodontal disease compared to healthy sites. Treatment resulted in a reduction of BRA as well as the levels of IL-1 for most of the diseased pockets. The levels of IL-1 were not correlated to the amount of BRA.</p><p>Number of teeth (NT) was consistently associated to CVD and was the only oral health parameter that related to all-cause mortality and mortality in CVD in a dose-dependent manner. Subjects with <10 teeth had a 7-fold increase risk for mortality in coronary heart disease compared to those with >25 teeth. Furthermore, NT was also significantly associated to the levels of leukocytes and to the metabolic syndrome, which consists of a combination of cardiovascular risk factors.</p><p>Other investigated oral health parameters, such as severity of periodontal disease, number of deepened pockets, and bleeding on probing, were not related to CVD in a consistent way.</p><p> Oral health parameters as well as myocardial infarction (MI) were related to serum antibody levels against Porphyromonas gingivalis (Pg), indicating that Pg might be a link between oral health and MI.</p><p>In conclusion, treatment reduced the increased levels of IL-1 and BRA in GCF from sites with periodontal disease. Oral health was associated to CVD with number of teeth being the only oral health parameter that consistently was associated to CVD. Serum antibody levels against P. gingivalis were related to myocardial infarction (MI) as well as to oral health parameters, suggesting that this bacteria could be a link between oral health and CVD.</p>

Cardiovascular disease is a large problem in the intensive care unit (ICU) due to its high prevalence in modern society. In the ICU, intensive monitoring is required to help diagnose cardiac and circulatory dysfunction. However, complex interactions between the patient, disease, and treatment can hide the underlying disorder. As a result, clinical staff must often rely on their skill, intuition, and experience to choose therapy, increasing variability in care and patient outcome. To simplify this clinical scenario, model-based methods have been created to track subject-specific disease and treatment dependent changes in patient condition, using only clinically available measurements. The approach has been tested in two pig studies on acute pulmonary embolism and septic shock and in a human study on surgical recovery from mitral valve replacement. The model-based method was able to track known pathophysiological changes in the subjects and identified key determinants of cardiovascular health such as cardiac preload, afterload, and contractility. These metrics, which can be otherwise difficult to determine clinically, can be used to help provide targets for goal-directed therapies to help provide deliver the optimal level of therapy to the patient. Hence, this model-based approach provides a feasible and potentially practical means of improving patient care in the ICU.

Background In patients with diabetes mellitus (DM) or chronic kidney disease (CKD), established cardiovascular disease (CVD) is associated with an increased risk of recurrent events and poor outcome. Ischemic stroke after an acute myocardial infarction (AMI) is a devastating event that carries high risks of decreased patient independence and death. Among patients with DM or CKD, the risk of an ischemic stroke within a year following an AMI is not known. Improved risk factor control is required to reduce the likelihood of CVD recurrence. Guidelines recommend target lipid profile and blood pressure values; however, data show that these targets are often not met. Therefore, there remains an urgent need for improved cardiovascular secondary preventive follow- up. Aims The aims of the present studies were to define trends in the incidence and predictors of ischemic stroke after an AMI in patients with DM or CKD. Furthermore to assess whether secondary preventive follow-up with nurse-based telephone follow-up including medication titration after CVD improves risk factor values in patients with DM or CKD and to investigate if this method performs better than usual care to implement a new treatment guideline in diabetic patients. Methods To assess the risk of post-AMI ischemic stroke, patient data were obtained from the Swedish Register of Information and Knowledge about Swedish Heart Intensive Care Admissions (RIKS-HIA). In separate studies, we compared a total of 173 233 AMI patients with and without DM, and 118 434 AMI patients with and without CKD. Within the nurse-based age-independent intervention to limit evolution of disease (NAILED) trial, we investigated a nurse-based cardiovascular secondary preventive follow-up protocol. Patients with acute coronary syndrome, stroke, or transient ischemic attack were randomized to receive either nurse-based telephone follow-up (intervention) or usual care (control). Low-density lipoprotein (LDL-C) levels and blood pressure (BP) were measured at 1 month (baseline) and 12 months post- discharge. Intervention patients with above-target baseline values received medication titration to achieve treatment goals, while the measurements for control patients were forwarded to their general practitioners for assessment. We calculated the changes in LDL-C level and BP between baseline and 12 months post-discharge, and compared  these changes between 225 intervention patients and 215 control patients with concurrent DM or CKD. During the course of the NAILED trial, new secondary preventive guidelines for DM patients were released, including a new LDL-C target value. To assess adherence to the new guidelines within the NAILED trial, we compared LDL-C levels in the 101 intervention patients and 100 control patients with DM. Results Ischemic stroke after AMI The rates of ischemic stroke within one-year after admission for an AMI decreased over time, from 7.1% in 1998–2000 to 4.7% in 2007–2008 among DM patients, and from 4.2% to 3.7% during the same time periods for non-diabetic patients. Lower stroke risk was associated with percutaneous coronary intervention (PCI) and initiation of secondary preventive treatments in-hospital. In-hospital ischemic stroke occurred in 2.3% of CKD patients and 1.2% of non-CKD patients, with no change in these incidences over time. The rates of one-year post- discharge ischemic stroke decreased between 2003–2004 and 2009–2010 from 4.1% to 2.5% among CKD patients, and from 2.0% to 1.3% among non-CKD patients. Lower rates of post-discharge stroke were associated with PCI and statins. Cardiovascular secondary preventive follow-up Among DM and CKD patients with above-target baseline values in the NAILED trial, the median LDL-C value at 12 months was 2.2 versus 3.0 mmol/L (p&lt;0.001) and median systolic BP was 140 versus 145 mmHg (p=0.26) for intervention and control patients, respectively. Before the guideline change, 96% of the intervention and 70% of the control patients reached the target LDL-C value (p&lt;0.001). After the guideline change, the corresponding respective proportions were 65% and 36% (p&lt;0.001). Conclusion Ischemic stroke is a fairly common post-AMI complication among patients with DM and CKD. This risk of stroke has decreased during recent years, possibly due to the increased use of evidence-based therapies. Compared with usual care, cardiovascular secondary prevention including nurse-based telephone follow-up improved LDL-C values at 12 months after discharge in patients with DM or CVD, and led to more efficient implementation of new secondary preventive guidelines.

Periodontal diseases may increase risk of vascular calcification in cardiovascular diseases but the potential mechanisms are not defined. Fetuin, a naturally-occurring serum glycoprotein in humans, protects against ectopic arterial calcification. We considered that patients with periodontitis could be at increased risk of developing calcifying atheromas because periodontal-disease associated enzymes may enter the circulation and subsequently degrade fetuin, thereby disrupting its ability to inhibit calcification. By in silico investigation, MMP -3 and -7 were predicted to cleave fetuin but only MMP-7 actually degraded human fetuin in vitro. MMP-7 degradation of fetuin was time- and concentration- dependent and was inhibited by an MMP Inhibitor. By mass spectrometry the presence of novel, MMP-7-mediated cleavage sites in fetuin were found. Fetuin bound tightly to MMP-7 (kd =2.96 x 10-9 M). The degradation of fetuin by MMP-7 could explain, at least in part, the apparent association between periodontal diseases and calcifying atheromas.

Periodontal diseases may increase risk of vascular calcification in cardiovascular diseases but the potential mechanisms are not defined. Fetuin, a naturally-occurring serum glycoprotein in humans, protects against ectopic arterial calcification. We considered that patients with periodontitis could be at increased risk of developing calcifying atheromas because periodontal-disease associated enzymes may enter the circulation and subsequently degrade fetuin, thereby disrupting its ability to inhibit calcification. By in silico investigation, MMP -3 and -7 were predicted to cleave fetuin but only MMP-7 actually degraded human fetuin in vitro. MMP-7 degradation of fetuin was time- and concentration- dependent and was inhibited by an MMP Inhibitor. By mass spectrometry the presence of novel, MMP-7-mediated cleavage sites in fetuin were found. Fetuin bound tightly to MMP-7 (kd =2.96 x 10-9 M). The degradation of fetuin by MMP-7 could explain, at least in part, the apparent association between periodontal diseases and calcifying atheromas.

Introduction: Cardiovascular disease (CVD) is the leading cause of global mortality and its prevalence is increasing among black South Africans in spite of their favourable lipid profile. Apolipoprotein E (ApoE) is a well-described risk factor for CVD and certain polymorphisms within this gene alter the lipid profile. The author hypothesised that there are population-specific effects within the ApoE gene that are responsible for the favourable lipid profile observed in black South Africans whose effects are being altered by environmental factors. Objectives: The main aim of this study was to investigate the associations between specific ApoE single nucleotide polymorphisms (SNPs) and the lipid profile of a black South African population, taking into account certain environmental and phenotypic factors in order to explore the interaction effects between these variables. Methods: Genotyping within this cross-sectional study (n=1 588), nested within the Prospective Urban and Rural Epidemiology (PURE) study, was achieved using Illumina‘s® GoldenGate Genotyping Assay with VeraCode® technology on the BeadXpress® platform (proprietary multiplex fluorescent hybridisation assays on a bead array substrate) or the Bio-Rad CFX Manager© (version 2.0). The Konelab20i™ auto analyser was used for quantitative determination of serum total cholesterol; high-density lipoprotein cholesterol (HDL-C) and triglyceride (TG) concentrations. Low-density lipoprotein cholesterol concentrations were estimated by the Friedewald equation. Results: All SNPs adhered to the assumptions of the Hardy-Weinberg equilibrium, yet the frequency of the SNPs often differed from that reported in other ethnic groups. The well-reported rs429358 and rs7412 SNPs (as the constituent SNPs of the haplotype-genotypes) presented with the strongest associations with various components of the blood lipid profile in the black South African cohort under investigation. Two gene-environment (rs405509 and rs7412) interaction effects on TG remained significant after conducting post hoc tests. Two genotype-phenotype interaction effects between the rs7412 SNP and body mass index and gamma-glutamyl transferase on the HDL-C concentrations remained significant after conducting post hoc tests. Conclusions: The variety of associations between these particular SNPs and the blood lipid profile determined in the present cohort strongly indicates that it is integral to any public health investigation into CVD development that these SNPs be investigated. This study further produced greater insight into the biological mechanisms underlying serum lipid and cholesterol concentrations in a black South African population. Therefore, from these results it is evident that the lipid profile of black South Africans is most definitely influenced by not only genetic variations in the ApoE gene and certain environmental factors, but by the interaction between these factors as well. The present study is the largest study to date to investigate the effect of polymorphisms in the ApoE gene on the lipid profile of black South Africans. / MSc (Nutrition), North-West University, Potchefstroom Campus, 2014

The aim of this thesis was to investigate socio-economic status in relation to morbidity and mortality, in particular cardiovascular disease among women using data from two population based studies from Sweden. The secondary aim was to explore mechanisms potentially linking socio-economic status to health, assessing for example dental, dietary, and lifestyle factors. Samples: The Population Study of Women in Gothenburg Sweden was begun in 1968-69. A representative random sample of 1,622 women was selected according to date of birth and within the strata 38, 46, 50, 54, and 60 years of age; the participation rate was 90 percent. The Gerontological and Geriatric Population Studies in Gothenburg (H-70) are based on representative samples of 70-year olds from Göteborg, Sweden who participated in a series of cross sectional and longitudinal studies between1971 and 2000. Participation rates ranged from 86 percent for men and 83 percent for women in the 1901/2 birth cohort to 65 percent for men and 69 percent for women in the 1930 birth cohort. Main results: High socio-economic status was associated with a decreased risk for cardiovascular disease [RR 0.49; CI 0.24 – 0.99] in middle aged women independently of risk factors such as smoking and obesity;moreover opposing monotonic trends were seen for mortality from cancer and cardiovascular disease in relation to socio-economic status. Tooth loss, a proxy for cumulative lifetime oral infection was also associated with an increased risk for cardiovascular disease in women independently of socio-economic factors such as the husband’s occupational category, income, and educational level. Among 70-year old cohorts, later-born women were heavier and had higher body mass index than earlier-born women within the high education group only. However, secular increases in waist-hip ratio were seen in both educational groups. Compared to earlier-born cohorts of 70-year old men, later-born cohorts had higher body mass index and cholesterol levels across social strata, and heart disease and diabetes mellitus became more prevalent. Among the elderly, secular trends indicated greater improvements in cardiovascular risk factors among women than men, with exception to smoking and alcohol consumption. Diet quality and food selection were assessed in relation to socio-economic status in the youngest cohort of 70-year olds born in 1930. Socio-economic disparities in diet quality were detected in men but not in women. Conclusions: From a public health perspective, it is suggested that risk factor patterns should be investigated in association with socio-economic status in order to expose health inequalities, and to develop more equitable interventions for cardiovascular disease prevention.

Coronary heart disease rates show substantial geographic variation in England, which could be due to environmental variables (e.g. climate, air quality) or behavioural risk factors for coronary heart disease within populations. Previous work investigating this geographic variation has either used ecological analysis (i.e. areas as units of observation) or individual-level analysis. Ecological studies have been unable to account adequately for differences in behavioural risk factors within populations; individual-level studies have been under-powered at the area-level to include all potentially explanatory environmental variables. This thesis reports on ecological multi-level and spatial error regression analyses of coronary heart disease mortality and hospitalisation rates for all wards in England using environmental variables and synthetic estimates of the prevalence of behavioural risk factors as explanatory variables. Existing sets of synthetic estimates were subjected to studies of their validity. Validated synthetic estimates of the prevalence of smoking, low fruit and vegetable consumption, raised blood pressure, obesity and raised cholesterol were combined into a single index of unhealthy lifestyle to take account of collinearity between them. Final models successfully explained around 80% of large scale geographic variation (i.e. variation between wards in different areas of the country) in mortality rates for coronary heart disease and 60% in hospitalisation rates, and around 20% of the small scale geographic variation (i.e. variation between wards in close proximity) in mortality rates, and 30% in hospitalisation rates. The climate explained around 15% of large scale geographic variation in coronary heart disease rates after adjustment for the index of unhealthy lifestyle and socioeconomic deprivation. Urbanicity and air pollution explained a small amount of small scale geographic variation in coronary heart disease rates. The majority of explained geographic variation was due to the index of unhealthy lifestyle and deprivation. The results of this thesis confirm and extend findings from the British Regional Heart Study, report on the validity of synthetic estimates currently used to guide healthcare resource allocation, and introduce an index of unhealthy lifestyle that could be used in future ecological studies of chronic disease.

Cardiovascular magnetic resonance imaging (MRI) is a well established technique in clinical cardiology. Different MRI sequences are routinely used to assess cardiac anatomy, function, viability and other parameters that aid diagnosing cardiac disease. Conversely, cardiac magnetic resonance spectroscopy (MRS), the only available method for a non-invasive study of human cardiac metabolism, has not evolved into a clinical tool yet. The combination of both techniques holds great potential to gain insight into the causality of cardiomyopathy diseases or other medical conditions with high cardiovascular risk profile, like diabetes or obesity and improve the clinical management of cardiac diseases. Nowadays, high field clinical MR systems have the great potential of improving the low spatial and temporal resolution and reproducibility of MRS. The aim of this thesis was to develop and implement a cardiac 1H-MRS method at 3 T that can be applied in clinical routine for the assessment of creatine and lipid levels in the human myocardium. The methodological developments to advance cardiac MRS are presented first. A robust 1H-MRS method comprising an optimized single-voxel technique, phased-array coil combination routine, optimized water suppression, breath-hold averaging and post-processing methods were developed. First, reproducibility and feasibility of the method were validated in vivo by acquiring 1H-MRS of the liver in almost one hundred healthy subjects. Subsequently, myocardial lipids levels were obtained in healthy volunteers by single breath-hold 1H-MRS triggered to mid-diastole, showing good reproducibility in an acquisition time less than 12 s. The good spectral resolution achieved using this method was demonstrated by the ability to differentiate for the first time two pools of myocardial lipids in spectra from the septum of patients with suspected myocardial lipid excess. Finally, creatine levels for healthy volunteers were investigated using multiple breath-hold acquisitions. Thus, this study shows the practicality and feasibility to incorporate this rapid cardiac 1H-MRS method into clinical studies of the human myocardium.

Introduction: Some past breast cancer radiotherapy regimens led to an increased risk of death from heart disease. Although heart dose from breast cancer radiotherapy has generally reduced over the past few decades, there may still be some cardiac risk. Estimation of future risk for women irradiated today requires both measurement of their cardiac dose and dose-response relationships, which depend on cardiac dosimetry of past regimens, in conjunction with long-term follow-up data. Methods: Virtual simulation and computed tomography 3-dimensional treatment planning on a representative patient were used to estimate mean heart and coronary artery doses for women irradiated since 1950 in 71 randomised trials in the Early Breast Cancer Trialists’ Collaborative Group (EBCTCG) overview. Patient-to-patient variability in cardiac dose was assessed. Heart and coronary artery doses were also calculated for breast cancer radiotherapy regimens used since the 1950s in Sweden. Cardiac doses from contemporary (year 2006) radiotherapy were assessed for 55 patients who received tangential breast cancer irradiation at a large UK radiotherapy centre. The maximum heart distance (i.e. the maximum distance between the anterior cardiac contour and the posterior tangential field edges) was measured for the left-sided patients, and its value as a predictor of cardiac doses assessed. Results: Mean heart dose for women irradiated in the EBCTCG trials varied from <1 to 18 Gray, and mean coronary artery dose from <1 to 57 Gray. Patient-to-patient variability was moderate. Mean heart dose for women irradiated in Sweden since the 1950s varied from <1 to 24 Gray, and mean coronary artery dose from <1 to 46 Gray. Heart dose from tangential irradiation has reduced over the past four decades. However, mean heart dose for left-sided patients irradiated in 2006 was 2 Gray and around half of them still received >20 Gray to parts of the heart and left anterior descending coronary artery. For these patients, maximum heart distance was a reliable predictor of cardiac doses. For the other patients, mean heart dose varied little and was usually less than 2 Gray. Conclusions: Cardiac doses from breast cancer radiotherapy can be estimated reliably and are now available for use in deriving dose-response relationships in the EBCTCG data and in a Scandinavian case-control study. Cardiac dose has reduced over the past four decades. Therefore the cardiac risk is also likely to have reduced. Nevertheless, for some patients, parts of the heart still receive >20 Gray in the year 2006.