Browsing by Subject "Atherosclerosis"

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Algal derivative rhamnan sulfate reduces vascular inflammation and atherosclerotic plaque formation
(2022-05) Patil, Nikita P.; Baker, Aaron Blair; Rausch, Manuel; Tanaka, Hirofumi; Ghosh, Debadyuti
The glycocalyx, an interior lining of blood vessels, forms a barrier against atherosclerotic risk factors. It is degraded during plaque development, allowing cholesterol deposition and inflammation in the intima. Rhamnan sulfate (RS), a polysaccharide from green seaweed, resembles heparan sulfate, a component of the glycocalyx which can replace and rejuvenate the glycocalyx to enhance barrier function and prevent plaque formation. In vitro, we tested the interaction of RS with vascular cells and its effects on their proliferation, migration and inhibition of the NF-κb pathway. We also tested the effects of RS on glycocalyx stiffness and thickness post-inflammation. In vivo, we conducted a study in female and male ApoE [superscript -/-] mice on a high fat diet where RS treatment was provided orally. We found that RS decreased growth factor induced proliferation and migration of endothelial and vascular smooth muscle cells. It also decreased the activation of NF-κb in response to TNF-α treatment while binding to NF-κb subunits. Mechanical properties of the glycocalyx could be restored with RS under certain inflammatory conditions. ApoE [superscript -/-] mice, oral consumption of RS decreased cholesterol levels in the plasma in female mice and plaque area in both female and male mice. In livers of these mice, RS treatment showed significant differences in genes related to metabolism, circadian rhythm and lipid regulation between high fat diet and RS groups and male and female mice.
Cerebrovascular dysfunction : associations with midlife risk factors
(2021-05-08) Gourley, Drew David; Tanaka, Hirofumi, Ph. D.; Haley, Andreana P; Kohl, Harold W; Lalande, Sophie
While age has the strongest associations with the development of dementia, a myriad of modifiable cardiovascular risk factors exacerbates and accelerate such risk. Identifying the individual and combined effect earlier in life is crucial to reduce their impact and to introduce positive changes in health behaviors. This dissertation focused on associations between traditional cardiovascular risk factors as well as novel measures of vascular pathology to identify negative functional and structural changes in the brain and cerebrovascular circulation. The rationale for these projects is that continued investigation on the impact of individual and aggregate risk from various cardiovascular risk factors will help target early changes in structure and function that contribute to late life cognitive decline. Once clinical deficits are present, it is often too late to intervene. Therefore, the target population was placed on early to late middle-aged adults between 40-64. In the first study, cross-sectional associations between a midlife dementia risk score composed of cardiovascular risk factors and measures of structural integrity in the brain were investigated. We measured the association between two algorithm-based risk scores used to assess dementia and vascular risk with neuroimaging and cognitive measures in middle-aged, cognitively intact adults. The primary findings of the first study were that the dementia risk score was negatively associated with cortical thickness in the superior frontal gyrus and parahippocampal gyrus as well as memory. These findings provide insight into early pathological changes that occur even among low-risk adults. In the second study, we investigated if subclinical elevations in blood glucose concentration were associated with an early marker of cognitive dysfunction, functional connectivity, and whether this relation was modified by physical fitness or physical activity status. We determined the moderating effect of physical fitness on the association between elevated plasma glucose and functional connectivity. We found there was no direct effect of elevated plasma glucose or insulin resistance with functional connectivity between the medial prefrontal cortex and posterior cingulate cortex, and that neither physical fitness nor physical activity status moderated this association. This suggests that there is a threshold at which elevations in metabolic factors influence connectivity. For the last study, we examined the association between midlife extracranial and peripheral atherosclerosis with late-life intracranial atherosclerosis using a novel magnetic resonance angiography technique. Using the community-based Atherosclerosis Risk in Communities study, we examined the association between various measures of extracranial and peripheral atherosclerosis and late-life intracranial atherosclerosis. We found that carotid intima media thickness was associated with greater odds of intracranial plaque presence and a greater burden of intracranial atherosclerotic disease. Taken together, our findings emphasize the importance of improving lifestyle behaviors at midlife as well as before the emergence of clinical pathology, such as diabetes, to reduce risk of late life dysfunction.
Characterization of atherosclerotic plaques using ultrasound guided intravascular photoacoustic imaging
(2011-05) Wang, Bo, 1981-; Emelianov, Stanislav Y.; Sokolov, Konstantin; Smalling, Richard; Litovsky, Silvio; Dunn, Andrew; Aglyamov, Salavat
Rupture of atherosclerotic plaque is closely related to plaque composition. Currently, plaque composition cannot be clinically characterized by any imaging modality. The objective of this dissertation is to use a recently developed imaging modality – ultrasound-guided intravascular photoacoustic (IVPA) imaging – to detect the distribution of two critical components in atherosclerotic plaques: lipid and phagocytically active macrophages. Under the guidance of intravascular ultrasound imaging, spectroscopic IVPA imaging is capable of detecting the spatially resolving optical absorption property inside a vessel wall. In this study, contrast in spectroscopic IVPA imaging was provided by either the endogenous optical property of lipid or optically absorbing contrast agent such as gold nanoparticles (Au NPs). Using a rabbit model of atherosclerosis, this dissertation demonstrated that ultrasound guided spectroscopic IVPA imaging could simultaneously image lipid deposits as well as macrophages labeled in vivo with Au NPs. Information of macrophage activity around lipid rich plaques may help to identify rupture-prone or vulnerable plaques. The results show that ultrasound guided IVPA imaging is promising for detecting plaque composition in vivo. Clinical use of ultrasound guided IVPA imaging may significantly improve the accuracy of diagnosis and lead to more effective treatments of atherosclerosis.
The effects of prolonged sitting and acute exercise on postprandial plasma triglyceride concentration
(2011-12) Kim, Il-Young, 1973-; Coyle, Edward F., 1952-; Ivy, John L.; Tanaka, Hirofumi; Hamilton, Marc T.; Brothers, Robert M.
These studies investigated the effect of physical inactivity (prolonged sitting) and physical activity (walking, standing, and moderate intensity exercise) on postprandial plasma triglyceride concentration (PPTG). In the first study, we evaluated the effect of low intensity intermittent walking at ~25% VO₂max (WALK) and energy-matched moderate intensity running at ~65% VO₂max (RUN) on PPTG, compared to a sitting control (SIT). RUN reduced incremental area under the curves for plasma triglyceride concentration (TG AUC[subscript I]), compared to WALK by 17.3% (p = 0.04) and SIT by 27% (p [less than] 0.001). The reduced TG AUC[subscript I] in RUN was accompanied by enhanced whole body insulin sensitivity, compared to WALK and SIT (for both, p [less than] 0.05). Whole body postprandial fat oxidation at rest following a high fat test meal intake was enhanced in RUN by 31% (P [less than] 0.001) and to a lesser extent in WALK by 8.4% (p [less than] 0.005), compared to SIT. In the second study, we evaluated 1) the effect of 2 days of prolonged sitting on PPTG, and 2) the effect of 4 days of SIT on the ability of an acute bout of exercise to reduce PPTG, compared to the same days of active walking and standing with calorically balanced diet (WALK+B). To distinguish the effect of prolonged sitting from the excess calorie effect, we had a sitting condition with calorically balanced diet (SIT+B) in addition to a sitting condition with hypercaloric diet (SIT+H). Following 2 days of respective food and activity control, WALK+B was lower in TG AUC[subscript T] by 21.3% and AUC[subscript I] by 17.4%, compared to SIT+H (for both, p [less than] 0.005). WALK+B was lower than SIT+B for TG AUC[subscript T] by 17.7% (p = 0.165) and AUC[subscript I] by 23.5% (p = 0.145) although statistical significance was not achieved. Remarkably, an acute exercise following 4 days of either SIT+H or SIT+B failed to reduce both TG AUC[subscript T] and AUC[subscript I], compared to SIT+B in HFTT1. The same exercise following 4 days of WALK+B, however, reduced both TG AUC[subscript T] by 29% and TG AUC[subscript I] by 32% in HFTT2, compared to SIT+B in HFTT1 (for both, p [less than] 0.02). Further, both SIT conditions reduced relative whole body fat oxidation in favor of increases in carbohydrate oxidation, compared to WALK+B by more than 40% in both HFTT1 and HFTT2. Taken together, our data suggest that 1) exercise intensity plays an independent role with higher intensity being more effective than lower intensity exercise in reducing PPTG, and 2) prolonged sitting with excess energy intake amplifies PPTG and prolonged sitting impairs the ability of an acute bout of moderate intensity exercise to reduce PPTG. This emphasizes the importance of regular participation in moderate-to-vigorous intensity exercise and reducing sitting time by increasing non-exercise physical activities (i.e., walking and standing) for the favorable postprandial metabolic health from the individual and public health perspectives.
Effects of prolonged sitting on normal, exercise-induced metabolic improvements
(2017-08-08) Akins, John David; Coyle, Edward F., 1952-
Cardiovascular disease (CVD) is an ever-growing cause of mortality and has been coupled with a rise in sedentary behavior. A vast majority of people spend their time physically inactive with the occasional bout of acute exercise. Generally, acute exercise is able to improve postprandial lipemia (PPL), a risk factor for CVD. However, research is beginning to suggest that sedentary behavior might abolish the metabolic benefits normally seen from exercise. This study set out to elucidate the impact of an acute bout of exercise on PPL after four days of prolonged sitting (~13.5 h/day). Subjects participated in a counterbalanced, crossover study in which they completed two trials: prolonged sitting without exercise (SIT) and prolonged sitting with a one-hour bout of treadmill exercise (SIT+EX). Following each trial, plasma triglycerides and glucose were obtained and substrate oxidation via indirect calorimetry was collected to be analyzed for possible improvements caused by exercise. No differences (p>0.05) were found in triglyceride or glucose response during the high fat tolerance test, evidenced by triglyceride or glucose AUCₜ or AUCᵢ, or fat oxidation as measured by indirect calorimetry between trials. While the triglyceride temporal response was similar to expectation with a rise to peak around hour 3-4 postprandial, a noticeably flatter and more prolonged response was seen in the glucose temporal response. This lack of difference between trials comes with similar activity except for the one-hour bout of exercise. The results from this study suggest that prolonged sitting imposes some sort of resistance to the normal improvement in PPL and fat oxidation after acute exercise. This suggests that physical inactivity (e.g. prolonged sitting) creates a condition whereby people are resistant to the normal metabolic improvements in fat metabolism that are derived from a bout of acute exercise
Intravascular photoacoustics as a theranostic platform for atherosclerosis
(2014-08) Yeager, Douglas Edward; Emelianov, Stanislav Y.; Baker, Aaron; Sessler, Jonathan; Smalling, Richard; Sokolov, Konstantin
The persistence of high global mortality rates directly attributable to cardiovascular disease drives ongoing research into novel approaches for improved diagnosis and treatment of its primary underlying cause, atherosclerosis. Combined intravascular ultrasound and photoacoustic (IVUS/IVPA) imaging is one such modality, actively being developed as a tool for improved characterization of high-risk atherosclerotic plaques. The pathophysiology associated with progression and destabilization of atherosclerotic plaques leads to characteristic changes in arterial morphology and composition. IVUS/IVPA imaging seeks to expand upon the ability of clinically utilized intravascular ultrasound (IVUS) imaging to assess vessel anatomy by adding improved sensitivity to image the underlying cellular and molecular composition through intravascular photoacoustic (IVPA) imaging of either endogenous chromophores (e.g. lipid) or exogenously delivered contrast agents. This dissertation focuses on the expansion of IVUS/IVPA imaging using exogenous contrast agents to enable the detection and subsequent optically-triggered therapy of atherosclerotic plaques. The passive extravasation and aggregation of systemically injected plasmonic gold nanorods absorbing within the near infrared tissue optical window within plaques of atherosclerotic rabbit models is first demonstrated, along with the ability to localize the contrast agents using ex vivo IVUS/IVPA imaging. The motivation for nanoparticle labeling of atherosclerosis is then expanded from that of purely image contrast agents to vehicles for image-guided, dual-modality phototherapy. The integrated IVUS/IVPA imaging catheter is utilized for photothermal delivery with simultaneous IVPA temperature monitoring using the high optical absorption of gold nanorod contrast agents to enable localized heating. Subsequently, the potential role for IVUS/IVPA-guided phototherapy is further expanded through the characterization and in vitro assessment of novel multifunctional theranostic nanoparticles comprised of a gold nanorod core with a degradable, photosensitizer-doped silica shell. Together, the results presented within this dissertation provide a framework for ongoing research into the expansion of IVUS/IVPA imaging as a platform for complimentary diagnosis and local treatment of atherosclerotic plaques using multifunctional theranostic nanoparticle contrast agents.
Photoacoustic image guidance and tissue characterization in cardiovascular applications
(2016-12) Dana, Nicholas Pacheco; Suggs, Laura J.; Emelianov, Stanislav Y.; Dunn, Andrew; Tunnell, James; Bouchard, Richard
Collectively, cardiovascular diseases continue to be the leading cause of death, across nations and across decades. Improved diagnostic imaging methods offer promise to alleviate the morbidity associated with these diseases. Photoacoustic (PA) imaging is one such method, poised to make a significant impact on cardiovascular imaging, both as a research tool, as well as a clinical imaging modality. Offering the potential of molecular imaging in real-time, PA methods have been demonstrated in proof-of-concept studies tracking myocyte calcium dynamics. These results open the door to non-invasive longitudinal assessment of cardiac electrophysiological function, with implications for drug and contrast agent development. PA image guidance has also been extended to the characterization of cardiac radiofrequency ablation lesions. This method has been demonstrated to utilize endogenous chromophore changes resulting from ablation for the generation of depth-resolved tissue characterization maps, capable of assessing lesion extent. The technique has been subsequently validated by assessing high-intensity focused ultrasound ablation lesions in myocardium, with the hope for offering thermographic capabilities as well. While PA imaging offers such promise in cardiac ablation procedures, it is also in the process of clinical translation for image guidance and characterization in coronary artery disease applications. Research has shown, using Monte Carlo optical modeling, that using a simple dual-wavelength PA imaging technique has great potential for successful visualization of atherosclerotic plaques across multiple tissue types and at clinically relevant multiple millimeters of depth. Collectively these results offer a suite of PA imaging tools with the potential for molecular and thermographic imaging across a broad range of cardiovascular applications.
Textured thin metal shells on metal oxide nanoparticles with strong NIR absorbance and high magnetization for imaging and therapy
(2010-12) Ma, Li, doctor of chemical engineering; Feldman, Marc David; Johnston, Keith P., 1955-; Milner, Thomas E.; Sokolov, Konstantin V.; Mullins, C. B.; Hwang, Gyeong S.
The ability of sub 100 nm nanoparticles to target and modulate the biology of cells will enable major advancements in cellular imaging and therapy in cancer and atherosclerosis. A key challenge is to load an extremely high degree of targeting, imaging, and therapeutic functionality into small, yet stable particles. A general mechanism is presented for thin autocatalytic growth on nanoparticle substrates (TAGS), as demonstrated for a homologous series of < 5 nm textured Au coatings on < 42 nm iron oxide cluster cores. Very low Au supersaturation levels are utilized to prevent commonly encountered excessive autocatalytic growth that otherwise produce thick shells. The degree of separation of nucleation to form the seeds from growth is utilized to control the morphology and uniformity of the thin Au coatings. The thin and asymmetric Au shells produce strong near infrared (NIR) absorbance with a cross section of ~10⁻¹⁴ m², whereas the high magnetic content per particles provides strong r2 spin-spin magnetic relaxivity of 200 mM⁻¹s⁻¹. TAGS may be generalized to a wide variety of substrates and high energy coatings to form core-shell nanoparticles of interest in a variety of applications as diverse as catalysis and bionanotechnology. High uptake of the nanoclusters by macrophages is facilitated by the dextran coating, producing intense NIR contrast both in cell culture and an in vivo rabbit model of atherosclerosis. A novel conjugation technique further allows covalent binding of anti-epidermal growth factor receptor (EGFR) monoclonal antibody (Ab) to the nanoclusters for highly selective targeting to EGFR over expressing cancer cells. AlexaFluor 488 tagged Ab nanocluster conjugates were prepared to correlate the number of conjugated Abs with the hydrodynamic diameter. The high targeting efficacy was evaluated by dark field reflectance imaging and atomic absorbance spectrometry (AAS). Colocalization of the nanoparticles by dual mode in-vitro imaging with dark field and fluorescence microscopy demonstrates the Abs remained attached to the Au surfaces. The extremely high curvature of the Au shells with features below 5 nm influence the spacing and orientations of the Abs on the surface, which has the potential to have a marked effect on biological pathways within cells. These targeted small multifunctional nanoclusters may solve some key molecular imaging challenges for cancer and atherosclerosis.
Validity of digital thermal monitoring techniques to assess vascular reactivity following finger and brachial occlusion
(2020-06-23) Heath, Melanie Ann; Tanaka, Hirofumi, Ph. D.
Digital thermal monitoring (DTM) using the VENDYS-II device is an alternative, fully automated and noninvasive methodology to evaluate endothelial function using temperature change on finger as a surrogate measure of the magnitude of vascular reactivity index (VRI). Due to the simplicity, it could provide a more feasible technique to assess vascular endothelial function in the clinical setting. A most recent modification to the technique includes the application of occlusion cuff at the base of a finger. Therefore, the purpose of this study is to assess the validity of the VENDYS-II device compared with the standard flow-mediated dilation (FMD) protocol. Thirty-eight (22 males; 38±15 years) participants varying widely in age, health status, ethnicity, and socioeconomic status were studied. Occlusion cuff was placed over the right antecubital fossa or at the base of the right index finger. Temperature monitors were placed on bilateral index fingers to assess change in temperature throughout 5-minute occlusion and recovery phases. FMD was obtained simultaneously using high-resolution ultrasound. Shear rate total area under the curve (SR [subscript AUC]) was calculated for 180 cardiac cycles following cuff release. Mean brachial artery FMD was 7.5±2.2% and mean SR [subscript AUC] was 43,924±10,256. SR [subscript AUC] was significantly correlated with VRI obtained from brachial occlusion (r=0.34; p<0.05), but more strongly correlated with finger occlusion VRI (r=0.43; p<0.05) (Figure 1). Inversely, brachial FMD was more strongly correlated with brachial occlusion VRI (r=0.69; p<0.05), than finger occlusion VRI (r=0.53; p<0.05). VRI values obtained with the finger occlusion (1.58±0.29 AU) were not significantly different from VRI measured with the brachial artery occlusion (1.55±0.26 AU) (p=0.47), and both VRI values were moderately correlated with each other (r=0.25; p=0.47) Therefore, finger-based VRI may be a valid and novel alternative measure of endothelial function that is more suitable than the standard FMD or hyperemic shear rate for the assessment of endothelial function in the routine clinical setting.