Indiana University-Purdue University Indianapolis (IUPUI) / Obesity increases cardiovascular disease risk and is associated with factors of the “metabolic syndrome” (MetS), a disorder including hypertension, hypercholesterolemia and/or impaired glucose tolerance. Expanding adipose and subsequent inflammation is implicated in vascular dysfunction in MetS. Perivascular adipose tissue (PVAT) surrounds virtually every artery and is capable of releasing factors that influence vascular reactivity, but the effects of PVAT in the coronary circulation are unknown. Accordingly, the goal of this investigation was to delineate mechanisms by which lean vs. MetS coronary PVAT influences vasomotor tone and the coronary PVAT proteome. We tested the hypothesis that MetS alters the functional expression and vascular contractile effects of coronary PVAT in an Ossabaw swine model of the MetS. Utilizing isometric tension measurements of coronary arteries in the absence and presence of PVAT, we revealed the vascular effects of PVAT vary according to anatomical location as coronary and mesenteric, but not subcutaneous adipose tissue augmented coronary artery contractions to KCl. Factors released from coronary PVAT increase baseline tension and potentiate constriction of isolated coronary arteries relative to the amount of adipose tissue present. The effects of coronary PVAT are elevated in the setting of MetS and occur independent of endothelial function. MetS is also associated with substantial alterations in the coronary PVAT proteome and underlying increases in vascular smooth muscle Ca2+ handling via CaV1.2 channels, H2O2-sensitive K+ channels and/or upstream mediators of these ion channels. Rho-kinase signaling participates in the increase in coronary artery contractions to PVAT in lean, but not MetS swine. These data provide novel evidence that the vascular effects of PVAT vary according to anatomic location and are influenced by the MetS phenotype.

Indiana University-Purdue University Indianapolis (IUPUI) / Epidemiologic studies suggest that depression is an independent risk factor for cardiovascular disease (CVD). Although several possible mediators of this association have been proposed, few studies have examined the role of moderators. Accordingly, I examined adverse childhood experiences (ACE) as a potential moderator of the depression-CVD association, given that individuals with a history of ACE show a greater inflammatory response to depression, and inflammation plays a role in the development of CVD. Data from Waves 1 and 2 of the National Epidemiologic Survey on Alcohol and Related Conditions (NESARC) were analyzed. Participants were 29,282 adults (58% female, 42% non–white) aged 18–97 years, free of CVD diagnoses at baseline. Lifetime depressive disorder (LDD) was assessed by the Alcohol Use Disorder and Associated Disabilities Interview Schedule–IV (AUDADIS–IV), and adverse childhood experiences (abuse, neglect, and household dysfunction), and CVD were assessed during separate interviews. The primary outcome was incident CVD (n = 1,255), defined as nonfatal arteriosclerosis, angina pectoris, myocardial infarction, and/or stroke reported during the Wave 2 interviews. All analyses were adjusted for demographic and traditional CVD risk factors. Logistic regression models revealed that both LDD (OR = 1.44, 95% CI: 1.28–1.62, p < .001) and any ACE (OR = 1.25, 95% CI: 1.16–1.35, p < .001) were independent predictors of incident CVD. Interactions between LDD x any ACE (p = .024), LDD x neglect (p = .003), and LDD x household dysfunction (p < .001), but not LDD x abuse (p = 0.16), were detected. Analyses stratified by the ACE variables revealed that LDD was a predictor of incident CVD among adults with a history of (1) any ACE (OR = 1.51, 95% CI: 1.32–1.73, p < .001), but not among those without a history (OR = 1.15, 95% CI: 0.87–1.50, p = .332); (2) neglect (OR = 1.59, 95% CI: 1.36–1.87, p < .001) and among those without a history (OR = 1.25, 95% CI: 1.07–1.62, p = .005); (3) household dysfunction (OR = 1.73, 95% CI: 1.46–2.04, p < .001), but not among those without a history (OR = 1.18, 95% CI: 0.96–1.43, p = .11). Overall, the present findings suggest that depression may be a stronger risk factor for CVD among adults with a history of ACE, especially neglect and household dysfunction, than among adults who did not have these experiences.

Indiana University-Purdue University Indianapolis (IUPUI) / Neurofibromatosis Type 1 (NF1) is a genetic disorder resulting from mutations in the NF1 tumor suppressor gene. Neurofibromin is the protein product of NF1 and functions as a negative regulator of Ras activity in both hematopoietic and vascular wall cells, which are critical for maintaining blood vessel homeostasis. NF1 patients are predisposed to chronic inflammation and premature cardiovascular disease, including development of large arterial aneurysms, which may result in sudden death secondary to their rupture. However, the molecular pathogenesis of NF1 aneurysm formation is completely unknown. Utilizing a novel model of Nf1 murine aneurysm formation, we demonstrate that heterozygous inactivation of Nf1 (Nf1+/-) results in enhanced aneurysm formation with myeloid cell infiltration and increased reactive oxygen species in the vessel wall. Using cell lineage-restricted transgenic mice, we show that loss of a single Nf1 allele in myeloid cells is sufficient to recapitulate the Nf1+/- aneurysm phenotype in vivo. Additionally, oral administration of simvastatin, a statin with antioxidant and anti-inflammatory effects, significantly reduced aneurysm formation in Nf1+/- mice. Finally, the antioxidant apocynin was administered orally and also resulted in a significant reduction of Nf1+/- aneurysms. These data provide genetic and pharmacologic evidence that neurofibromin-deficient myeloid cells are the central cellular triggers for aneurysm formation in a novel model of NF1 vascular disease, implicated oxidative stress as the key biochemical mechanisms of NF1 aneurysm formation and provide a potential therapeutic target for NF1 vasculopathy.

Indiana University-Purdue University Indianapolis (IUPUI) / Recent advancements in the management of systemic glucose regulation in obesity/T2DM include drug therapies designed to utilize components of the incretin system specifically related to glucagon-like peptide 1 (GLP-1). More recently, GLP-1 has been investigated for potential cardioprotective effects. Several investigations have revealed that acute/sub-acute intravenous administration of GLP-1 significantly reduces myocardial infarct size following ischemia/reperfusion injury and improves cardiac contractile function in the settings of coronary artery disease, myocardial ischemia/reperfusion injury, and heart failure. Despite an abundance of data indicating that intravenous infusion of GLP-1 is cardioprotective, information has been lacking on the cardiac effects of iv GLP-1 in the MetS or T2DM population. Some important questions this study aimed to address are 1) what are the direct, dose-dependent cardiac effects of GLP-1 in-vivo 2) are the cardiac effects influenced by cardiac demand (MVO2) and/or ischemia, 3) does GLP-1 effect myocardial blood flow, glucose uptake or total oxidative metabolism in human subjects, and 4) are the cardiac effects of GLP-1 treatment impaired in the settings of obesity/MetS and T2DM. Initial studies conducted in canines demonstrated that GLP-1 had no direct effect on coronary blood flow in-vivo or vasomotor tone in-vitro, but preferentially increased myocardial glucose uptake in ischemic myocardium independent of effects on cardiac contractile function or coronary blood flow. Parallel translational studies conducted in the humans and Ossabaw swine demonstrate that iv GLP-1 significantly increases myocardial glucose uptake at rest and in response to increases in cardiac demand (MVO2) in lean subjects, but not in the settings of obesity/MetS and T2DM. Further investigation in isolated cardiac tissue from lean and obese/MetS swine indicate that this impairment in GLP-1 responsiveness is related to attenuated activation of p38-MAPK, independent of alterations in GLP-1 receptor expression or PKA-dependent signaling. Our results indicate that the affects of GLP-1 to reduce cardiac damage and increase left ventricular performance may be impaired by obesity/MetS and T2DM.

The study was aimed at furthering the health objectives of the government's Reconstruction and Development Programme (ANC 1994b) in the area of primary health care. . The purpose of the study was to examine the possible reduction of medical scheme claims for cardiovascular disease by means of primary health care, so that medical scheme benefits do not become exhausted so rapidly. The overall outcome of the study showed that if cardiovascular disease could be diagnosed and treated early, the financial benefits could be substantial. This was illustrated by the comparison of primary, secondary and tertiary treatment of cardiovascular disease using case studies over a period of one year. Recommendations centered around nurse-based primary health care for cardiovascular disease and the cost-effective management of the medical scheme. It was concluded that as a result of nurse-based primary health care, costs could be contained so that medical scheme benefits would not become exhausted so rapidly. / Health Studies / M.A. (Nursing Science)

The study was aimed at furthering the health objectives of the government's Reconstruction and Development Programme (ANC 1994b) in the area of primary health care. . The purpose of the study was to examine the possible reduction of medical scheme claims for cardiovascular disease by means of primary health care, so that medical scheme benefits do not become exhausted so rapidly. The overall outcome of the study showed that if cardiovascular disease could be diagnosed and treated early, the financial benefits could be substantial. This was illustrated by the comparison of primary, secondary and tertiary treatment of cardiovascular disease using case studies over a period of one year. Recommendations centered around nurse-based primary health care for cardiovascular disease and the cost-effective management of the medical scheme. It was concluded that as a result of nurse-based primary health care, costs could be contained so that medical scheme benefits would not become exhausted so rapidly. / Health Studies / M.A. (Nursing Science)

Indiana University-Purdue University Indianapolis (IUPUI) / Peripheral arterial disease is caused by plaque buildup in the peripheral arteries. Standard treatments are available when the blockage is proximal and focal, however when distal and diffuse the same type of the treatment options are not beneficial due to the diseased locations. Restoration of blood flow and further salvaging of the limb in these patients can occur in a retrograde manner through the venous system, called retroperfusion or arteriovenous reversal. Retroperfusion has been explored over the last century, where early side to side artery to venous connections had issues with valve competency prohibiting distal flows, edema buildup, and heart failure. However, more recent clinical studies create a bypass to a foot vein to ensure distal flows, and though the results have been promising, it requires a lengthy invasive procedure. It is our belief that the concerns of both retroperfusion approaches can be overcome in a minimally invasive/catheter based approach in which the catheter is engineered to a specific resistance that avoids edema and the perfusion location allows for valves to be passable and flow to reach distally. In this approach, the pressure flow relations were characterized in the retroperfused venous system in ex-vivo canine legs to locate the optimal perfusion location followed by in-vivo validation of canines. Six canines were acutely injured for 1-3 hours by surgical ligation of the terminal aorta and both external iliac arteries. Retroperfusion was successfully performed on five of the dogs at the venous popliteal bifurcation for approximately one hour, where flow rates at peak pressures reached near half of forward flow (37±3 vs. 84±27ml/min) and from which the slope of the P/F curves displayed a retro venous vasculature resistance that was used to calculate the optimal catheter resistance. To assess differences in regional perfusion, microspheres were passed during retroperfusion and compared to baseline microspheres passed arterially prior to occlusion in which the ratio of retroperfusion and forward perfusion levels were near the ratio of reversed and forward venous flow (0.44) throughout the limb. Decreases in critical metabolites during injury trended towards normal levels post-retroperfusion. By identifying the popliteal bifurication as a perfusion site to restore blood flow in the entirety of the distal ischemic limb, showing reversal of injury, and knowing what catheter resistances to target for further chronic studies, steps towards controlled retroperfusion and thus more efficient treatment options can be made for severe PAD patients.