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Patients infected with the human immunodeficiency virus (HIV+) are living longer and at heightened risk for developing cardiovascular events (CVEs). Commonly used prediction tools appear to misrepresent their CVE risk to varying degrees and in varying directions. Inclusion of markers of cellular infection, chronic immune activation and/or systemic inflammation into risk models might provide better predictive accuracy. Observational studies assessing the relationship of high-sensitivity C-reactive protein (hs-CRP) to CVE in HIV+ patients have reported inconsistent findings. This review of published studies attempted to determine if the available evidence supports its potential use in new models for stable, treated HIV+ patients. We searched the PubMed database using keywords and combinations of "HIV" AND "cardiovascular risk" AND "CRP". Papers presenting original analyses, associating hs-CRP concentration as an independent variable to hard cardiovascular outcomes (myocardial infarction and cardiovascular death), or to hard CVE as part of a composite endpoint, were included. Five observational studies met inclusion/exclusion criteria for review. Three papers identified an association between elevated hs-CRP and CVE, while two others failed to find any significant association. All reports were heterogeneous in terms of independent variables, controls, and designs. The larger and more rigorous studies, employing higher rates of confounder controls and more objective endpoints in their composites, showed positive associations. Though not conclusive, the preponderance of the evidence at this time supports CRP as a potentially valuable factor to be studied in prospective cardiovascular risk prediction investigations in HIV+ patients.

Hypertension is a major public health issue impacting one in two adults in the United States and accounts for 10 million deaths each year worldwide. It is a leading risk factor for multiple diseases, including stroke, myocardial infarction, chronic kidney disease, and peripheral artery disease. The prevalence of hypertension increases with age in both sexes. In addition, aging is associated with significantly higher hypertension-related morbidity and mortality and insufficient control of high blood pressure. Critically, menopause is linked to a 2-fold increase in hypertension risk and premenopausal women have lower hypertension rates compared to men of similar age. Increased sympathetic nervous system activity, inflammation, and remodeling of large arteries like the aorta have been implicated in both normal aging and the pathophysiology of hypertension. Despite extensive hypertension research and the rapidly growing aging population, only 4% of hypertension studies focus on aging. Increased molecular insight into the mechanisms mediating arterial remodeling in age-dependent hypertension could uncover potential therapeutics for more targeted treatment of hypertension. In this thesis, Sprague Dawley rats were used in the models of normal aging and norepinephrine-induced hypertension to investigate the complex interplay between aging, sympathetic nervous system activity, and inflammation in arterial remodeling in age-dependent hypertension and potential sex differences. Our key findings from the abdominal aorta and renal artery are (1) Sex-dependent changes in the phosphorylation of c-Src kinase and ERK1/2, and expression of caveolin-1, (2) Altered expression of alpha-SMA and MHY-11, (3) Partial recapitulation of aged hypertensive phenotype in the abdominal aorta of young male rats following NE-infusion. Our proteomic and phosphoproteomic analyses of the aorta of young normotensive and aged hypertensive male rats have identified 58 differentially expressed proteins and 39 differentially phosphorylated proteins. Proteome analysis further revealed that the proteins in extracellular matrix, actin cytoskeleton and inflammatory pathways were the top affected proteins or pathways. Moreover, in phosphoproteome analysis, major differences were found in neurons, synapse structures, vascular smooth muscle cells, and focal adhesions. Notably, approximately two-thirds of differentially phosphorylated proteins (22 out of 39) were found to be at neurons and synapses. In the assessment of inflammatory mediators, we found that increases in multiple homeostatic cytokines including, CCL21, MMP2, and osteopontin were associated with the aortic remodeling in age-dependent hypertension. Collectively, these results support a model in which aging, increased sympathetic nervous system activity, and inflammation contribute to arterial remodeling in age-dependent hypertension. / 2024-11-02T00:00:00Z

BACKGROUND: Type 2 diabetes (T2DM) is a metabolic disease that arises from insulin resistance and facilitates progression to cardiovascular consequences including myocardial infarction, coronary artery disease, and stroke. A contributor to the cardiovascular complications seen in T2DM is endothelial dysfunction. From a molecular standpoint, studies have shown that the pathophysiology of T2DM involves an altered metabolic milieu and increased oxidative stress, which both arise from insulin resistance, and lead to endothelial dysfunction. There is still much to discover on the pathways that are altered in this disease. Proteomics is a rapidly improving technique that can elucidate the differences in serum biomarkers, and their relationship to vascular endothelial health to further understand the pathophysiology of T2DM. OBJECTIVE: To evaluate the proteomic background and the implicated pathways in T2DM, and to understand how these biomarkers are associated with endothelial cell phenotype and systemic vascular function. METHODS: Age and sex similar individuals with T2DM and control individuals without T2DM between the ages of 30 and 80 were enrolled in this study. Blood was obtained for blood glucose and insulin levels and two proteomics panels assessing 192 serum biomarkers. Baseline vascular measures were obtained including blood pressure, heart rate, and flow-mediated dilation. Endothelial cells collected from participants were stimulated with insulin ex vivo and stained with phosphorylated endothelial nitric oxide synthase (p-eNOS) to measure changes in the insulin-mediated eNOS pathway. Associations between biomarker levels and insulin-stimulated p-eNOS levels were evaluated. RESULTS: The present study includes 69 subjects including 37 subjects with T2DM (age 57±8 years, 41% female) and 32 control subjects (age 53±9 years, 38% female). Measures of vascular health showed evidence of impairment in patients with T2DM including higher pulse pressure (56±12 mmHg versus 48±11 mmHg, p=0.02) and lower flow-mediated dilation (6.04±3.41% versus 9.1±4.4%, p=0.01). The proteomic panels revealed 24 serum biomarkers that were significantly upregulated and 2 that were significantly downregulated (adjusted p<0.05) in patients with T2DM compared to nondiabetic controls. These biomarkers are mainly involved in metabolism, vascular and fluid homeostasis, immune response, and apoptosis. Endothelial cell phenotype was abnormal in patients with T2DM compared to controls: mean fold change in insulin-stimulated p-eNOS was 0.34±0.07 for nondiabetic controls and -0.14±0.03 (p=0.01) for patients with T2DM. Renin and Adrenomedullin were significantly associated with lower insulin stimulated p-eNOS activation (r=-0.38, r=-0.27, and p=0.004, p=0.049 respectively). Whereas Chymotrypsin C (r=0.37, p=0.006), Paraoxonase 3 (r=0.35, p=0.009), Lipoprotein Lipase (r=0.34, p=0.01), and Superoxide Dismutase 2 (r=0.31, p=0.02) were significantly associated with higher insulin stimulated p-eNOS activation. CONCLUSIONS: We found associations between serum biomarker levels and insulin-stimulated p-eNOS levels which showed that there is a relationship between altered biomarkers and endothelial cell phenotype. Patients with T2DM had worse vascular endothelial health as shown by measures of endothelial dysfunction and arterial stiffness. Endothelial cell insulin resistance was present in patients with T2DM. In the same group, serum biomarkers showed elevated adiposity, inflammation and oxidative stress, and upregulation of the renin-angiotensin-aldosterone system.

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Introduction: The placenta is essential for fetal development and pregnancy prolongation. Its dysfunction can lead to short and long-term health consequences for mother and child. A subset of diseases resulting from placental dysfunction have been collectively termed placental-mediated diseases (PMD) - which includes the common and serious hypertensive disorder of pregnancy preeclampsia (PE), among others. PMDs are independent risk factors for maternal cardiovascular disease (CVD) in later life. This thesis presents a multi-pronged body of work, which includes: 1) A systematic review, aimed at summarizing the current state of knowledge on the risk for future maternal CVD after PMDs; 2) A cohort study, aimed at assessing the utility of placenta pathology examination at delivery to identify women at high lifetime risk for CVD following PE; and 3) An assessment of an immunohistochemistry screening panel for 3 placenta protein markers of interest, aimed at determining if these markers can accurately identify women deemed to be at high-risk for future CVD following a PE pregnancy. Methods: 1) We searched 4 databases for observational studies evaluating clinical and biochemical markers of CVD risk and/or a subsequent calculated risk score based on these parameters in women with a history of PMD. We excluded interventional studies and studies measuring these outcomes during or prior to pregnancy. 2) A cohort study was established across two clinical sites (Kingston, Ottawa), in which patients with PE (N=85) underwent cardiovascular risk assessments at 6-months postpartum. The placentas from these pregnancies also underwent detailed placenta histopathology examination to determine the presence, absence, and severity of 35 distinct placental lesions. The associations between distinct placental lesions and estimated lifetime cardiovascular risk were evaluated by odds ratios (OR) and receiver operator curve analysis (ROC). 3) Immunohistochemistry (IHC) analysis was performed on placental samples from a subset of the previously described cohort (N=41; Ottawa site only). Protein expression for FLT-1, ENG, and CD68 was quantified. Using a multivariate logistic regression model, the association between placenta protein expression, with and without clinical and placenta pathology findings, and cardiovascular risk was assessed. Results: 1) The search yielded 11,039 articles of which 104 met our inclusion criteria. All PMD types demonstrated evidence of increased CVD risk markers at varying timepoints postpartum. At least one study per PMD type had non-optimal measures of systolic blood pressure, BMI, and total cholesterol. 2) In the analysis of placenta pathology lesions within the cohort of individuals with PE, lesions of maternal vascular malperfusion (MVM) were found to be associated with elevated life-time risk for maternal CVD at 6 months postpartum (OR: 3.10[1.20-7.92]). We also found that adding these lesions to a logistic regression model improved the predictive accuracy for elevated maternal lifetime CVD risk (AUC: 73.0, sensitivity: 78.4%, specificity: 51.6%). 3) Individually, no significant differences were found in FLT-1, ENG, and CD68 expression between the individuals deemed to be at high and low-risk for lifetime CVD. Although, when added to a model that included placenta pathology lesions and clinical data the predictive accuracy for elevated maternal lifetime CVD risk increased (AUC: 1.0, sensitivity: 100%, specificity: 100%). Conclusions: In conclusion, this thesis provides further evidence of the utility of assessing placenta features in the prediction of future maternal CVD. This is evidenced by the association between PMDs, placental pathology, and placental protein biomarkers with elevated risk profiles for lifetime CVD. Thus, specific placental phenotypes of PMDs may be at increased risk for CVD. The use of placental data should be further explored as a triage strategy to identify these high-priority of women following delivery.

Cardiac diseases such as myocardial infarction (MI) can lead to adverse remodeling and impaired contractility of the heart due to widespread cardiomyocyte death in the damaged area. Current therapies focus on improving heart contractility and minimizing fibrosis with modest cardiac regeneration, but MI patients can still progress to heart failure (HF). There is a dire need for clinical therapies that can replace the lost myocardium, specifically by the induction of new myocyte formation from pre-existing cardiomyocytes. Many studies have shown terminally differentiated myocytes can re-enter the cell cycle and divide through manipulations of the cardiomyocyte cell cycle, signaling pathways, endogenous genes, and environmental factors. However, these approaches result in minimal myocyte renewal or cardiomegaly due to hyperactivation of cardiomyocyte proliferation. Finding the optimal treatment that will replenish cardiomyocyte numbers without causing tumorigenesis is a major challenge in the field. Another controversy is the inability to clearly define cardiomyocyte division versus myocyte DNA synthesis due to limited methods. A recent study suggests that systemic hypoxemia in adult male mice can induce cardiac myocytes to proliferate. The goal of the present experiments was to confirm these results, provide new insights on the mechanisms that induce cardiomyocyte cell cycle re-entry, and to determine if hypoxemia also induces cardiomyocyte proliferation and division in female mice. EdU mini pumps were implanted in 3-month-old, male and female C57BL/6 mice. Mice were then placed in a hypoxia chamber and the oxygen was lowered by 1% every day for 14 days to reach 7% oxygen. The animals remained in 7% inspired oxygen for 2 weeks before terminal studies. Myocyte cell cycle re-entry and division was also studied with a mosaic analysis with double markers (MADM) mouse model. MADM mice were exposed to hypoxia at 7% Oxygen as described above. Hypoxia induced cardiac hypertrophy in both left ventricular (LV) and right ventricular (RV) myocytes, with LV myocytes lengthening and RV myocytes widening and lengthening. Hypoxia induced a small increase in cardiomyocytes undergoing DNA synthesis (EdU+) in male and female C57BL/6 mice. Hypoxia induced a significant increase in myocyte cell cycle re-entry in MADM mice, but few myocytes synthesized new DNA (EdU+) and completed cytokinesis. RNA-sequencing showed upregulation in mitotic cell cycle processes but a downregulation of promoter genes for G1 to S phase transition in hypoxic mice when compared to control mice. There was also proliferation of non-myocyte cells and mild cardiac remodeling in hypoxic mice that did not disrupt cardiac function. Male and female mice exhibited similar gene expression profiles following hypoxia. Thus, systemic hypoxia induces adult cardiac myocyte cell cycle re-entry, but very few adult myocytes progress through the cell cycle to synthesize new DNA and divide into two daughter cells. / Biomedical Sciences

Bakgrund: Hjärt-kärlsjukdom är den största dödsorsaken globalt och den vanligaste dödsorsaken hos både kvinnor och män i Sverige. Primärvården och således distriktssköterskan har en viktig funktion när det gäller att arbeta förebyggande med hjärt-kärlsjukdom, och med ett hälsofrämjande synsätt utgöra ett stöd för alla människor oavsett ålder, bakgrund och sjukdom. Syfte: Syftet med studien var att beskriva distriktssköterskors och sjuksköterskors erfarenheter av att arbeta förebyggande med hjärt-kärlsjukdom inom primärvården. Metod: Studien hade en deskriptiv design med en kvalitativ ansats. Data har samlats in genom semistrukturerade intervjuer utifrån en sammanställd intervjuguide med öppna frågor. Totalt deltog åtta distriktssköterskor och en sjuksköterska som arbetade inom primärvården. Huvudresultat: I studien framkom att deltagarna upplevde det förebyggande arbetet som väldigt viktigt samtidigt som det var utmanande och begränsades av olika hinder och skillnader i förutsättningar. Deltagarna beskrev att innebörden att arbeta förebyggande med hjärt-kärlsjukdom handlade om att identifiera levnadsvanor, samtala om livsstilsförändring, motivera till livsstilsförändring samt följa patienter över tid och hålla koll på deras parametrar och prover. Deltagarna beskrev vidare att de mest fördelaktiga förutsättningar att arbeta förebyggande fanns om arbetet skedde på en specialistmottagning, såsom en diabetes- eller hypertonimottagning där det fanns mer tid samt möjlighet att lägga upp arbetet mer fritt. Slutsats: Deltagarna i föreliggande studie beskrev det förebyggande arbetet som viktigt men utmanande. Hinder i det förebyggande arbetet beskrevs som tids- och resursbrist samt kunskapsbrist. Föreliggande studie kan bidra genom att belysa distriktssköterskors erfarenheter av att arbeta förebyggande med hjärt-kärlsjukdom och på sikt förbättra deras förutsättningar. / Background: Cardiovascular disease is the biggest cause of death globally and the most common cause of death in both women and men in Sweden. Primary care and thus the primary health care nurse have an important function when it comes to health prevention work with cardiovascular disease, and with a health-promoting approach provide support for all people regardless of age, background and illness. Purpose: The purpose of this study was to describe the primary health care nurses' and nurses` experiences of health prevention work with cardiovascular disease in primary care. Method: The study had a descriptive design with a qualitative approach. Data has been collected through semi-structured interviews based on a compiled interview guide with open questions. A total of eight primary health care nurses and one nurse who worked in primary care participated. Main findings: The study showed that the participants felt that it was very important to work with health prevention, at the same time as it was challenging and limited by various obstacles and differences in conditions. The participants described that the meaning of health prevention work with cardiovascular disease was about identifying lifestyle habits, talking about lifestyle change, motivating lifestyle change and following patients over time and keeping track of their parameters and samples. The participants further described the most favourable conditions for working with health prevention were if the work took place in a specialist reception, such as a diabetes- or hypertension reception where there was more time and the opportunity to schedule the work more freely. Conclusion: The participants in the present study described that working with health prevention was important but challenging. Obstacles in working with health prevention were described as lack of time and resources as well as a lack of knowledge. The present study can contribute by highlighting the experiences of primary health care nurses`  and nurses in health prevention work with cardiovascular disease and in the long term improving their conditions.

A Calibrated Cuff Plethysmography device was built, tested for verification, and used to experiment on human subjects to measure the cardiovascular response of consuming a beet supplement, specifically looking at arterial compliance and pressure-area curves. Each subject was tested four times. A baseline was measured under normal conditions and after five-minute hyperemia conditions. 10 subjects were given 6 ounces of water mixed with either purple Kool-Aid (control), a SuperBeets supplement, or a SuperBeets Sport supplement and after 45 minutes, measurements were taken undergoing normal and hyperemia conditions once more. The verification testing demonstrated the calibration of the device was effectively able to measure volume changes using a stationary metal pipe and IV bag, showing an average percent error of 3.11%. Data collected during the patient experiment resulted in the expected arterial compliance curves as well as pressure-area curves, when measurements were taken properly, and the subject didn’t move. These tests were able to validate the use of the device for measuring arterial compliance and seeing distinctions between normal and hyperemic conditions. However, many issues were presented and are thoroughly addressed in this paper for future research using the same device.