京都大学 / 新制・課程博士 / 博士(医学) / 甲第23057号 / 医博第4684号 / 新制||医||1048(附属図書館) / 京都大学大学院医学研究科医学専攻 / (主査)教授 森田 智視, 教授 湊谷 謙司, 教授 川上 浩司 / 学位規則第4条第1項該当 / Doctor of Medical Science / Kyoto University / DFAM

Background: Glycation influences the ultrastructure and clot kinetics of fibrin clots due to the post-translational modifications in fibrinogen. Methylglyoxal (MG) is used to measure the level of glycation which has been associated with the pathogenesis of type 2 diabetes Melilites (T2DM) and coronary heart disease (CHD). The aim of the study was to determine the role of MG on clot kinetics and fibrin clot structure in CHD patients with and without T2DM to provide insight into the mechanism of pathogenesis of atherosclerosis in T2DM which results in the development of CHD. Methodology: Scanning electron microscopy (SEM) was used to evaluate the morphology of fibrin clots. Thromboelastography (TEG) was used to assess the physiological clot properties (kinetics). Enzyme-linked immunosorbent assay (ELISA) was used to determine the levels of methylglyoxal-adducts. Results: The morphology of clots from controls analysed using SEM showed thick and thin fibres which created an organised mesh of fibrin fibres. In T2DM, CHD with T2DM and CHD some alterations in the morphology were observed. The ultrastructure micrographs in CHD shows that some of the fibrin fibres formed have individual fibres with both thick and thin fibres as well as a thick mass of fibres with a net-like structure that forms dense-matted deposits. In addition, the fibrin fibres are not organised. The densitometry analysis between controls and patient groups’ (CHD: mean (standard deviation) 0.42±0.11; CHD+T2DM: 0.31±0.08 and T2DM: 0.29±0.08) was found to be significantly lower in all groups compared to the control which had a mean of 0.57±0.1, p<0.0001. There are no significant differences in the alpha angle between CHD, T2DM, CHD with T2DM and controls (60.88±2.321˚ vs. 60.81±2.385˚ vs. 59.09± 3.185˚ vs. 66.47±1.300˚, p=0.5279). There was no significant difference found in the K-value between T2DM, CHD with T2DM, CHD and control subjects (3.458±0.446mins vs. 5.118±1.589mins vs. 3.758±0.450mins vs. 2.839±0.2156mins, p=0.0102). The maximum amplitude was higher in T2DM patients compared to CHD, CHD with T2DM and controls (40.51±1.914mm vs. 34.10±2.127mm vs. 33.12±3.365mm vs. 33.60±1.525mm, p=0.0102). The MRTG was higher in CHD compared to T2DM, CHD 4 with T2DM and controls (10.74±3.335 dyn cm-2 s -1 vs. 4.268±0.690 dyn cm-2 s -1 vs. 5.046± 0.927 dyn cm-2 s -1 vs. 6.535±0.664 dyn cm-2 s -1 , p=0.0096). The reaction time was higher in CHD with T2DM patients compared to T2DM, CHD and controls (32.58±4.005min vs. 23.92±2.793min vs. 21.29± 2.383min vs. 8.322±0.886min, p<0.0001). There was no significant difference found in the TTG between T2DM, CHD with T2DM, CHD and control subjects (231.3±28.68 dyn cm-2 vs. 258.5±38.15 dyn cm2 vs. 343.7±71.92 dyn cm-2 vs. 287.7±21.37 dyn cm-2 , p=0.8421). The TMRTG was higher in T2DM patients compared to T2DM, CHD with T2DM, CHD and controls (23.91±2.409mins vs. 20.46±3.411mins vs. 14.14±1.287mins vs. 10.16±0.751mins, p<0.0001). To assess if an association between MG-adducts and clot kinetics exists, the Spearman r correlation was completed for each clot parameter. The reaction time (p=0.0047, 95% CI: 0.138 to 0.665) and time taken before maximum speed of the clot growth to be achieved (p=0.3958, 95% CI: 0.072 to 0.644) was significant. This indicates the relationship between the parameters i.e., the higher the level of MGadducts present, the longer it takes for clotting to begin and reach maximum speed of formation. Conclusion: This study showed that there are ultrastructural differences in fibrin fibres formed in CHD patients with T2DM. The viscoelastic parameters indicated that haemostasis was irregular in CHD and T2DM. The levels of MG-adducts were much higher in T2DM, CHD with T2DM and CHD and may be a contributing factor to the pathogenesis associated with altered coagulation in these patients. / Dissertation (MSc (Physiology))--University of Pretoria, 2020. / NRF / Physiology / MSc (Physiology) / Unrestricted

Atherosclerosis begins in the teenage years and progresses over time in susceptible individuals. It is unknown, however, whether coronary angiography in middle-aged adults showing no evidence of atherosclerosis identifies individuals at low risk for subsequent development of coronary artery disease (CAD). We identified 4068 patients ≥40 years of age who had at least two coronary angiograms between January 1, 1990 and March 31, 2011. Of these, 227 patients (5.8%) had no CAD and 251 patients (6.4%) had mild atherosclerotic disease (stenosis <30%) on the initial angiogram. Patients in the normal-angiogram group were younger, more often female, and less likely to use tobacco than patients in the mild-atherosclerosis group, while rates of diabetes and hypertension were the same. Angiographic evidence of any CAD and obstructive CAD was apparent in 26% and 4.8%, respectively of the normal-angiogram group on subsequent angiography performed 75 ± 46 months later. Myocardial infarction and revascularization occurred in 4.8% and 3.5%, respectively. Progression of CAD (odds ratio ≤ 10.2), development of obstructive CAD (odds ratio ≤ 8.9), myocardial infarction (odds ratio ≤ 2.7), and revascularization (odds ratio ≤ 8.4) were more frequent in the mild-atherosclerosis group. In summary, 26% of middle-aged adults with a normal coronary angiogram who had subsequent angiography for clinical reasons developed CAD, although the annual rates of myocardial infarction or revascularization were very low. Even mild atherosclerosis on the initial angiogram increased the rate of progression of CAD by 10-fold and the rate of revascularization by 8-fold.

BACKGROUND: Recent studies indicate that the use of ankle-brachial index (ABI) measurements helps identify patients with peripheral arterial disease. Previous research also reveals a relationship between peripheral arterial disease and higher incidence of cardiac mortality and morbidity. PURPOSE: The purpose of this study was to investigate the correlation of a low ABI (<0.90 mm Hg) with coronary artery disease, diabetes, hypercholesterolemia, body mass index greater than 25, a sedentary lifestyle, smoking, and carotid artery disease. METHODS: A descriptive correlational design was used to study a population (N = 810) of fairly healthy women who self-selected to undergo cardiovascular screening that they paid for out of pocket. Cardiac disease and most of the data on risk factors were obtained using questionnaires. Carotid artery stenosis was determined by ultrasound. Hypotheses were tested using χ and independent t test. RESULTS: A statistically significant relationship was found between a low ABI and the presence of moderate to severe carotid artery stenosis (χ = 5.90, P = .015). A low ABI (<0.90 mm Hg) was not significantly related to cardiac disease (χ = 0.83, P = .362), diabetes (χ = 1.82, P = .177), hypercholesterolemia (χ = 0.01, P = .930), claudication (χ = 2.06, P = .151), physical activity (χ = 1.17, P = .884), or body mass index (t = 1.12, P = .270). CONCLUSION: The significant relationship between low ABI and carotid artery stenosis illustrates that atherosclerosis occurs in multiple arterial beds simultaneously. The lack of association between ABI and the other variables probably reflects the self-report nature of the data collected on these variables. Ankle-brachial index measurements may be useful in future research as a tool for early recognition of cardiovascular disease.

Purpose of Review: Patients with stable coronary artery disease (CAD) and a high risk of bleeding are not ideal candidates for a polymer-based drug-eluting stent (DES) because it requires 6–12 months of dual antiplatelet therapy (DAPT) following percutaneous coronary intervention (PCI). The purpose of this review is to assess the angiographic and clinical outcomes of polymer-free drug-coated stents (PF-DCS) in stable CAD patients with a high bleeding risk. Recent Findings: Several randomized controlled trials (RCTs) have compared angiographic and clinical outcomes of PF-DCS with bare-metal stents (BMS), permanent polymer (PP)-DES, or biodegradable polymer (BP)-DES. However, none of these studies particularly recruited patients with stable CAD and a high risk of bleeding. Furthermore, there are limited data available on duration of DAPT following PF-DCS placement. Summary: PF-DCS has a better efficacy and similar safety as compared with BMS. PF-DCS with dual drug is noninferior to currently available PP-DES. Further RCTs are needed to assess the safety and efficacy of PF-DCS to BP-DES and PP-DES comparing shorter to standard durations of DAPT.

Indiana University-Purdue University Indianapolis (IUPUI) / Metabolic syndrome (MetS) affects 1/3 of all Americans and is the clustering of three or more of the following cardiometabolic risk factors: obesity, hypertension, dyslipidemia, glucose intolerance, and insulin resistance. MetS drastically increases the incidence of coronary artery disease (CAD), which is the leading cause of mortality globally. A cornerstone of CAD is arterial remodeling associated with coronary smooth muscle (CSM) cytodifferentiation from a contractile phenotype to proliferative and osteogenic phenotypes. This cytodifferentiation is tightly coupled to changes in intracellular Ca2+ handling that regulate several key cellular functions, including contraction, transcription, proliferation, and migration. Our group has recently elucidated the time course of Ca2+ dysregulation during MetS-induced CAD development. Ca2+ transport mechanisms, including voltage-gated calcium channels, sarcoplasmic reticulum (SR) Ca2+ store, and sarco-endoplasmic reticulum Ca2+ ATPase (SERCA), are enhanced in early, mild disease and diminished in late, severe disease in the Ossabaw miniature swine. Using this well-characterized large animal model, I tested the hypothesis that this Ca2+ dysregulation pattern occurs in multiple etiologies of CAD, including diabetes and aging. The fluorescent intracellular Ca2+ ([Ca2+]i) indicator fura-2 was utilized to measure [Ca2+]i handling in CSM from lean and diseased swine. I found that [Ca2+]i handling is enhanced in mild disease with minimal CSM phenotypic switching and diminished in severe disease with greater phenotypic switching, regardless of CAD etiology. We are confident of the translatability of this research, as the Ca2+ influx, SR Ca2+ store, and SERCA functional changes in CSM of humans with CAD are similar to those found in Ossabaw swine with MetS. Single-cell RNA sequencing revealed that CSM cells from an organ culture model of CAD exhibited many different phenotypes, indicating that phenotypic modulation is not a discreet event, but a continuum. Transcriptomic analysis revealed differential expression of many genes that are involved in the osteogenic signaling pathway and in cellular inflammatory responses across phenotypes. These genes may be another regulatory mechanism common to the different CAD etiologies. This study is the first to show that CSM Ca2+ dysregulation is common among different CAD etiologies in a clinically relevant animal model.

京都大学 / 0048 / 新制・課程博士 / 博士(医学) / 甲第19549号 / 医博第4056号 / 新制||医||1012(附属図書館) / 32585 / 京都大学大学院医学研究科医学専攻 / (主査)教授 福原 俊一, 教授 吉村 長久, 教授 山下 潤 / 学位規則第4条第1項該当 / Doctor of Medical Science / Kyoto University / DFAM

京都大学 / 0048 / 新制・論文博士 / 博士(医学) / 乙第13050号 / 論医博第2116号 / 新制||医||1017(附属図書館) / 33140 / (主査)教授 柳田 素子, 教授 長船 健二, 教授 福原 俊一 / 学位規則第4条第2項該当 / Doctor of Medical Science / Kyoto University / DFAM

No description available.

No description available.