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Systemic lupus erythematosus (SLE) is associated with premature onset of coronary heart disease and endothelial dysfunction. To date the mechanisms underlying this remain unclear. We hypothesise there is premature biological ageing in patients with SLE as evidenced by a reduction in the mean telomere length of PBMC. Premature biological ageing is also evident in the vasculature of patients with SLE and reflected by relatively shortened telomeres of cells involved in vascular repair and regeneration i.e. endothelial progenitor cells (EPC). Furthermore, senescent EPC result in cellular imbalance with a relatively reduced number and/or function of circulating healthy EPC. We studied 200 SLE patients longitudinally over an average of 5.8 (5.2, 6.3) years and demonstrated progression of carotid plaque burden in 17.5%. Baseline traditional CHD risk factors did not influence plaque progression. We measured CD34/CD133+ EPC using flow cytometry in 54 SLE patients and 49 controls in cross-sectional study and demonstrated no significant difference between the groups. We further investigated number and function of EPC by enumerating colony-forming unit (CFU) in culture in 39 SLE patients and 27 controls and demonstrated a significant reduction in CFU number in SLE [median (IQR) CFU 5.7 (2.3, 8.0) in SLE vs. 10.0 (5.7, 15.0) in controls; p= 0.0016] and this difference was particularly marked in those under the age of 40 years [4 (2, 8) vs. 10.5 (7, 19), p= 0.03]. We measured relative telomere length of PBMC in SLE compared to age-matched controls using real-time qPCR in a cross-sectional study and demonstrated a significant reduction in SLE patients [0.97 (0.47, 1.57) and 1.53 (0.82, 2.29), p = P = 0.0008]. Further, telomere length of DNA extracted from CFU after 7 days in culture was quantified in a preliminary study of 5 SLE patients and 5 controls and demonstrated a trend to telomere length reduction in SLE patients. In conclusion there was evidence of significant progression of carotid plaque is in this cohort of female SLE patients. Further there is evidence of abnormal endothelial repair and premature senescence in SLE. Results support the hypothesis that there is a premature senescent phenotype in SLE and as such may present a novel therapeutic target to attenuate the risk of CHD in SLE.

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Background: Despite the ongoing pandemic attributed to an infectious disease (SAR-CoV-2), non-infectious diseases-primarily cardiovascular diseases (CVD) remain the leading cause of death globally accounting for 655,000 annual deaths in the United States (U.S.). Additionally, CVD significantly impacts the quality of life attributing to total healthcare expenditure of $214 billion per year, of which $138 billion are attributed to the loss of productivity due to poor quality of life. The study's purpose is to assess the impact of CVD on the general health of adults in the U.S. Question: What is the effect of CVD including angina, coronary heart disease, heart attack, and stroke on the general health of adults residing in the U.S.? Methods: Study data included 418,268 adults who participated in the Behavioral Risk Factor Surveillance System (BRFSS) during 2019. The study outcome was general health status of U.S. adults categorized into excellent, very good, good, fair, and poor groups. Predictor variables included responses to the diagnosis of angina/coronary heart disease (CHD), heart attack (HD), and stroke during the respective years Other covariates included participants' demographics (age, education, and annual household income). Logistic regression models were conducted to estimate the association of CVD and other covariates with general health of U.S. adults adjusting for other confounders. Results: After applying the study criteria, the final study sample included 355,391 participants. Poor general health status was reported among 83,882 study participants (19.6%). The odds of reporting a poor general health status were 2.7 times (adjusted OR (aOR) 2.70, 95% CI 2.56-2.78), 2 times (aOR: 2.04, 95% CI 1.96-2.08), and 2.6 times (aOR 2.56, 95% CI 2.50-2.70) more likely among participants who had CHD, HD, and stroke respectively compared to participants who did not have such conditions. The odds of reporting a poor general health status was 4% less likely among males compared to females (aOR 0.96, 95% CI 0.94-0.98). For every 5-year increase in age, the odds reporting poor general health status increased by 5% (aOR: 1.05, 95% CI 1.045-1.052). Participants earning $50,000 or more income were 68% less likely to report poor general health status compared with those earning less than $50,000 (aOR: 0.32, 95% CI 0.31- 0.33). Furthermore, participants with above high school education were 42% less likely to indicate poor general health status than those with high school or less education (aOR: 0.58, 95% CI 0.57-0.59). Conclusion: The study findings provide subjective evidence about poor health status among U.S. adults diagnosed with CVD. Future studies are warranted to substantiate this evidence using objective measures and adjusting for other unmeasured cofounders. Public Health Implications: While the nation continues to shift its strategies in addressing the COVID-19 pandemic and other emerging infectious diseases, there is a need for continued effort to address the prevention of CVD and other non-communicable diseases and reduce its impact among adults in the United States.

Abstract: Cardiovascular disease (CVD) is the leading cause of death in the United States (US). One of the most important things primary care providers (PCP) can do to prevent CVD is using primary prevention treatments. In the practice where the project was implemented, a standardized process was not in place for identifying at-risk patients. Without this, there is no way to identify if providers were adequately assessing patients for atherosclerotic cardiovascular disease (ASCVD) risk by considering their risk-enhancing factors. One way to identify appropriate patients is by completing ASCVD risk calculation using the ASCVD Risk Estimator Plus from the American College of Cardiology and the American Heart Association. In addition, 2018 Guidelines for Cholesterol Management recommend ASCVD risk calculation on all patients 40-79. The use of this tool is free to both patients and providers through a website or mobile app. The calculator can be integrated into the Electronic Health Record (EHR) to improve ease of use however, that does not come standard. Therefore, ASCVD risk calculation was performed on all patients aged 40-79 presenting for a fasting lab visit (FLV) at a primary care practice comprised of 3 clinics in East Tennessee between January 17, 2022 and February 28, 2022. Excluded patients included: patients outside of the age range, who did not have a lipid level done at their FLV, or who had a total cholesterol (TC) level greater than 320mg/dL. Once calculation was performed, results were given to the patient’s PCP for medical decision making on primary prevention treatment. After providers were given the results, chart reviews were completed to assess for primary prevention treatment initiations or increases within three months of receiving the results. Preliminary results show that a total of 443 patients presented for a FLV during the timeframe. A total of 132 patients were ineligible due to age (n=70), not having a lipid level completed (n=61) or having a TC level greater than 320 mg/dL (n=1). A total of 133 patients did not show or rescheduled their FLV. Chart reviews are just beginning, and insufficient data is currently available regarding intervention results. Limitations to this project include: all participants were Caucasian therefore, result may not be applicable to a more diverse population, the project was completed during a pandemic where patients were hesitant to come into the office, even for FLV, and a considerable number of patients who risk calculation could not be completed on. Having ASCVD calculation integrated within the EHR could promote use by providers. Future long-term research is needed to identify the accuracy of this calculator. This calculator has been modified based on research. However, research to identify the accuracy could lead to modification of the calculation to provide the most accurate result possible. One way this can be done is through use of the calculator by providers across the US.

Osteoarthritis (OA) is a prevalent and progressive musculoskeletal condition characterized by the degradation of the cartilage and bone and is often comorbid with cardiovascular disease (CVD), with both disease prevalence’s increasing with age. Several factors, such as the site of OA and the menopause transition, are known to independently influence both conditions. OA and CVD share overlapping risk factors and proposed mechanisms, though it is not well understood how these mechanisms influence the risk of comorbidity. This thesis examines the relationship of CVD risk factors, sites of OA, and menopausal variables on CVD risk in individuals with OA. The first aim of this thesis was to examine preclinical markers of CVD risk, namely the carotid intima-media thickness (cIMT) and cardiovascular risk scores, the Framingham risk score (FRS) and the InterHeart risk score (IHRS), in individuals with and without OA to examine differences in CVD risk profiles. Additional considerations were given to the site of OA, as well as non-specific CVD risk factors (such as social disadvantage and frailty). Risk factors were compared between age- and sex-matched individuals with and without OA and between weight-bearing and non-weight bearing OA. Individuals with OA had significantly greater cIMT, FRS, and IHRS, though no differences were found when comparing the site of OA. Unadjusted and multivariate adjusted odds ratios (OR) calculated odds of CVD at 3-year follow-up in the same cohorts. There was a significantly unadjusted (p<0.001, OR:1.70) and adjusted (p<0.001, OR ranging from 1.67-1.70) influence of OA diagnosis on odds of CVD at 3-year follow-up. There was no significant unadjusted or adjusted difference in odds of CVD at 3-year follow-up when comparing different sites of OA (p ranging from 0.24-0.75, OR ranging from 0.69-0.71). The second aim of this thesis was to study CVD risk in post-menopausal women. CVD risk factors and the IHRS were used to calculate differences between age-matched post-menopausal women. Unadjusted and multivariable adjusted ORs calculated odds of CVD at 3-year follow-up. There was a significant unadjusted influence of OA diagnosis (p=0.03, OR:1.34) on CVD outcomes, though the effect of OA diagnosis became non-significant after adjusting for the IHRS (p=0.25, OR:1.36) and the IHRS with menopausal variables (p=0.22, OR:1.40). Although OA is a multifaceted condition, it has often been viewed as a joint-centric disease. The elevated risk of CVD individuals with OA suggests that additional aspects of the OA pathology, such as inflammation and frailty, may drive the increase in risk of CVD independent of age, sex, or menopausal status. / Thesis / Master of Science (MSc) / Osteoarthritis (OA) and cardiovascular disease (CVD) are two of the most prevalent comorbidities that affect the aging population. Surrogate measures of CVD, such as CVD risk scores and carotid intima-media thickness, have rarely been examined in individuals with OA despite studies showing elevated CVD risk in individuals with OA. We used baseline and 3-year follow-up data collected by the Canadian Longitudinal Study on Aging to study CVD risk factors in older individuals with and without OA, with considerations given to the site of OA and to menopause, which are additional non-modifiable factors known to influence vascular outcomes. We hypothesized that individuals with OA have greater CVD risk and odds of developing CVD compared to individuals without OA. We found that individuals with OA have greater CVD risk and odds of developing CVD at 3-year follow-up, with no influence of OA site on CVD outcomes, and post-menopausal women with OA have greater odds of developing CVD than post-menopausal women without OA. Our findings suggests that aspects of the OA pathology play a role in increasing CVD risk, which are partially explained through shared risk factors and etiology.

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