Pulmonary artery hypertension (PAH), which is diagnosed by an abnormal increase of blood pressure in the pulmonary artery, can be a severe disease, leading to heart failure. In recent years, medical imaging, such as echocardiography, magnetic resonance imaging (MRI), and computed tomography (CT), has been widely used due to its non-invasive property. Right pulmonary artery (RPA) wall distensibility derived from CT angiography was reported to serve as a reliabile marker for the diagnosis of PAH. This study presented a robust method for automatic segmentation of artery based on CT angiography. The algorithm can be divided into two steps: generation of initial contour and refinement of edge. In the first step, a series of original images at different cardiac phases were thresholded to retrieve appropriate intensity window of vessels, followed by the determination of initial contours by a series of morphological image processing on the binary images with two simple manual initializations. Initial contours without touching can be taken as the final results of segmentation, when others need further refinement of edge. In the second step, the center of vessel was automatically located by an ellipse fitting method and then the ray casting algorithm was applied to search for possible edge. Disconnected segments of edge will be linked to complete the vessel segmentation. Furthermore, cross-sectional areas of arteries at different cardiac phases can be measured and used to obtain distensibility. In this study, artery wall distensibility of patients and healthy subjects was evaluated on four vessels, including aorta, main pulmonary artery, right and left pulmonary artery. In addition, segmentation results of five subjects were compared with those obtained by manual selection to evaluate the reliability of the proposed method.

Biological materials are complex hierarchical systems subjected to external stimuli like mechanical forces, chemical potentials and electrical signals. A deeper understanding of the behavior of these materials is required for the response characterization of healthy and diseased conditions. The primary aim of this dissertation is to study the mechanics of biological materials like cells and tissues from a computational perspective and relate its behavior with experimental works, so as to provide a framework for the identification and treatment of pathological conditions like cancer and vascular diseases. The first step towards understanding the behavior of a biological cell is to comprehend its response to external mechanical stimuli. Experimentally derived material properties of cells have found to vary by orders of magnitude even for the same cell type. The primary cause of such disparity is attributed to the stimulation process, and the theoretical models used to interpret the experimental data. The variations in mechanical properties obtained from the experimental and theoretical studies can be overcome only through the development of a sound mathematical framework correlating the derived mechanical property with the cellular structure. Such a formulation accounting for the inhomogeneity of the cytoplasm due to stress fibers and actin cortex is developed in this work using Mori-Tanaka method of homogenization. Mechanical modeling of single cells would be extremely useful in understanding its behavior in an experimental setup. Characterization of in-vivo response of cells requires mathematical modeling of the embedding environment like fibers and fluids, which forms the extra cellular matrix. Studies on fluid-tissue interactions in biomechanics have primarily relied on either an iterative solution of the individual solid or tissue phases or a sequential solution of the entire domain using a coupled algorithm. In this dissertation, a new computational methodology for the analysis of fluid-tissue interaction problem is presented. The modeling procedure is based on a biphasic representation of fluid and tissue domain, consisting of fluid and solid phases. The biphasic-fluid interaction model is also implemented to study the transfer of low-density lipoprotein from the blood to the arterial wall, and also the nutrient transfer in the tissue scaffolds of a bioreactor.

Background: The presence of calcified deposits in the coronary arteries has become established as a marker of coronary atherosclerosis. Design and Setting: Single medical center observational study. Study objective: 1) To determine the sensitivity and specificity of coronary calcium by cinefluoroscopy (CF) and to validate the reliability of CF in the angiographic detection of > 50% coronary artery stenosis. 2) To assess the financial benefit of adding CF-determined coronary calcium into the self-paid executive physical examination items. 3) To evaluate whether an algorithm using CF to assess coronary calcium has potential as an initial cost-effective testing pathway for diagnosis of > 50% coronary artery stenosis. Methods: Between November 1, 2004 and April 25, 2005, 333 patients who underwent angiography for diagnosis of and determine the extent of coronary artery disease were enrolled in the study. All patients received CF to determine presence or absence of calcium in the coronary artery system prior to selective angiography. Sensitivity and specificity were then obtained to confirm CF as a reliable non-invasive test for diagnosing > 50% coronary artery stenosis. Direct cost, total cost and estimated profit were calculated with and without the cost of cardiac catheterization laboratory at Chang Gung Memorial Hospital, which has an average of 475 patients/month who undergo self-paid executive physical examinations. Direct cost, total cost and estimated loss of coronary calcium by electron beam computed tomography (EBCT) were calculated for the acquisition of an EBCT machine by Chang Gung Memorial Hospital. A test model was applied to examine the costs and cost-effectiveness of the following diagnostic modalities: the traditional treadmill exercise (TMET); stress thallium and positron emission tomography (THALLIUM); coronary calcium by EBCT calcium score > 0 and > 168; and, coronary calcium by CF for diagnosis of obstructive coronary artery disease (CAD) as a function of pretest likelihood (i.e., prevalence) of disease. Results: Two hundred fifty three men and 80 women were enrolled in this study (mean age, 63.9+11.4 years; age range, 35-90 years). Sensitivity and specificity of CF in the detection of patients with angiographically coronary artery stenosis >50% were 96% and 86%, respectively. The profit accrued from implementing the CF test at Chang Gung Memorial Hospital, including the cost of the cardiac catheterization laboratory, was NT$329/patient. At 475 patients per month, this test will produce revenue of NT$156,275/month or NT$1,875,300/year. The profit achieved by implementing the CF test at Chang Gung Memorial Hospital, excluding the cost of the cardiac catheterization laboratory was NT$838.7/patient, or NT$398,382.5/month and NT$4,780,590/year. Conversely, implementing the EBCT test will cost Chang Gung Memorial Hospital NT$ 1,124,990/month or NT$ 13,499,880/year. With disease prevalence at < 0.7, CF examination was the most cost-efficient initial diagnostic testing pathway. However, for the group with prevalence at 1.0, the highest group, initial angiography with no prior non-invasive testing was the most cost-effective strategy for diagnosis of obstructive coronary artery disease. Conclusion: 1) Calcium detection with CF is a highly sensitive and moderately specific test, and a simple, inexpensive, and safe technique for identifying CAD. 2) Instituting CF as a screening test for self-paid executive physical examinations would result in considerable profit for the hospital. Conversely, establishing an EBCT program will produce a substantial financial loss. 3) For patients evaluated for obstructive CAD, a test pathway utilizing CF to detect coronary artery calcium as an initial non-invasive test minimized direct costs and maximized cost-effectiveness. Cinefluoroscopy has been neglected as a noninvasive technique for diagnosis of coronary stenosis and is sufficiently promising to warrant increased clinical use.

Previous studies show that coronary artery disease (CAD) is a multi-factors and chronic inflammatory disease, and is associated with lipid metabolism. IL-1ra is a naturally occurring anti-inflammatory molecules that block the action of IL-1. However, little is known about the imbalance between IL-1ra and inflammatory mediators in CAD. We attempted to investigate the relationships between inflammatory mediators and serum IL-1ra levels in patients with CAD. In 95 patients with angiographically defined CAD, and 70 healthy controls were studied in a case-control manner. Serum levels of cytokines and the risk factor of CAD were examined. Polymorphisms for IL-1ra gene were detected by PCR, and genotypes and allelic frequencies in both groups were compared. Our major finding include: (1) The risk factors such as elevated BMI, systolic BP, smoking, hypertension, blood glucose, and TG was more frequently found in the CAD group than the control group ( p < 0.001). However, the HDL-C and bilirubin were significantly higher in control group than the CAD group. (2) The relative risk of those in the highest quartile of ratio of LDL-C to HDL-C, TC to HDL-C, and TG to HDL-C were significantly elevated. ( OR = 2.98, p < 0.01; OR = 5.31, p <0.001; OR = 8.43, p < 0.001 respectively) (3) Five different inflammatory markers were significantly elevated including IL-1ra, hs-CRP, IL-6, leukocyte count, and neutrophil percentage between healthy controls and CAD patients. ( p < 0.01) (4) Levels of IL-1ra and other variables such as blood glucose, BMI, TG, IL-6, hs-CRP, and leukocyte count has significantly correlated, and were inversed correlation in bilirubin, and HDL-C in all study subjects. ( p < 0.01) (5) In the multiple logistic regression analysis, adjustment was made for variables. The relative risk of CAD for the highest quartile of IL-1ra, as compared with the lowest quartile, had an Odds ratio 2.57 ( 95% confidence intervals, 1.12 - 5.91, p = 0.026 ) increase in risk for CAD. (6) Similar results were obtained hs-CRP, IL-6 in the highest quartile were increase risk for future CAD. ( OR = 5.86 and 5.79 respectively; p < 0.001) (7) The join effect cytokines of hs-CRP, IL-6, IL-1ra concentrations may play important role in CAD risk. ( OR = 10.19, p < 0.001 ) (8) In addition, IL-1ra allele 2 genotype and allelic frequencies were no significant association with increase in IL-1ra with CAD. In conclusion, we find a significant association of elevated IL-1ra levels in the patients with CAD. Thus, these results support the hypothesis that inflammation, anti-inflammation cytokines and lipoprotein metabolism provide a useful marker for predicting the development of CAD events.

Kawasaki disease (KD) is the most common cause of paediatric acquired heart disease which may be attributed to the combined effects of infection, immunological response, and genetic susceptibility. Acute coronary artery lesions (CALs) develop in 20-48 % KD children. In addition, chronic CALs develop in approximately 20-30% of untreated KD children. Although KD children treated with IVIG, 2-6% still develop chronic CALs. According to recent epidemiological studies, Asian populations have a much higher incidence of KD. Taiwan has the third highest annual incidence in the world (69 per 100,000 children < 5 years of age between 2003 and 2006). Several studies have shown that KD patients spontaneously produce high levels of IL- 10. Plasma or serum IL-10 levels of KD children in acute phase were nearly 8-33 fold and 4-5 fold higher than those of healthy controls and those of the acute febrile children, respectively. The elevated IL-10 levels during the acute phase of KD not only decreased during subacute and convalescent phase, but also decreased immediately after IVIG administration, coincidently rapid improvement of inflammatory symptoms. The above studies show a correlation of high IL-10 levels with inflammatory features of KD, but do not answer the question of whether high levels of IL-10 may be simply a byproduct of acute KD, or whether it may play a role in the pathogenesis of KD. Therefore, a family-based linkage study of 134 case-parents trios, a case-control study of 247 KD children and 129 normal controls, and a matched case-control study of 76 KD cases with acute coronary artery lesions (CALs) and 76 KD controls without acute CALs were carried out to evaluate the association of genetic single nucleotide polymorphisms (SNP) in IL-10 promoter (-1082, -819, and -592) with the risk of KD and acute CALs. Based on the Transmission Disequilibrium test (TDT) results, significant undertransmission of haplotype ATA and overtransmission of haplotype (ACC+GCC) were found for KD (p = 0.023 and 0.011, respectively), even after 1,000 times permutation (p = 0.026 and 0.010, respectively). In addition, the TC and CC genotype of IL-10-819T>C were significantly associated with the decreased risk of acute CALs (AOR, 0.93; 95% CI, 0.47-1.81 and AOR, 0.07; 95% CI, 0.01-0.62, respectively), as compared to TT genotype. The carries of AC and CC genotype in IL-10-592A>C were with significantly decreased risk of acute CALs (AOR, 0.90; 95%CI, 0.46-1.75 and AOR, 0.17; 95%CI, 0.03-0.87, respectively), as compared to those with AA genotype. Furthermore, as compared with ATA/ATA diplotype, GCC+ACC/GCC+ACC diplotype of IL10 was associated with the decreased risk of acute CALs (AOR, 0.18; 95% CI, 0.04-0.72). In conclusion, the haplotype and diplotype of IL10-1082/-819/-592 were significant differences in the transmission in KD families and that the IL10-819 and -592 SNPs played important role for the sequelae of acute CALs.

The impact of percutaneous renal artery angioplasty and stenting (PTRAS) for treatment of atherosclerotic renal artery stenosis (ARAS) is not fully understood, especially in patients with chronic kidney disease (CKD). We performed a retrospective cohort study of patients with significant ARAS and moderate to severe chronic kidney disease (estimated GFR 15-60 ml/min/1.73m2) who were treated medically or with PTRAS. The primary endpoint of this study was change in renal function over the first year after treatment. Secondary endpoints included hemodynamic outcomes, antihypertensive medication doses, end stage renal disease (ESRD), and death. We reviewed all patients with a diagnosis of significant ARAS and impaired GFR treated between 1997-2007 in the Veterans Affairs Connecticut Healthcare System (VACHS). A total of 118 patients met inclusion criteria (71 medical treatment, 47 PTRAS), with an average follow-up of 34 months. The students t-test was used to compare baseline characteristics, as well as renal and hemodynamic endpoints between the two treatment groups. The cohort had a mean age of 73 ± 9 years and average baseline GFR of 37.2 ± 14.9 ml/min/1.73m2. Demographic, clinical and laboratory characteristics at baseline were similar between the two groups, with the exception of higher diastolic blood pressure in the stent group at baseline (75 versus 70 mmHg, p=0.028). No statistically significant difference was found between the two treatment groups for any renal endpoints. After a steady decline in GFR in both the medical treatment and stent groups during the 12 months preceding diagnosis (-4.2 versus -4.0 ml/min/1.73m2, p=0.911), GFR stabilized in both groups over the year following diagnosis (decline in GFR of -1.6 versus -1.4 ml/min/1.73m2, p=0.938). Multivariate models did not reveal an association between treatment modality and percent change in GFR during follow-up. No difference was found in blood pressure outcomes at 12 months between the medical and stent groups. Antihypertensive therapy, measured in defined daily doses (DDDs), was significantly higher in the medical treatment group at 12 months (4.5 versus 3.5 DDDs, p=0.048), but lost significance thereafter. In addition, the number of deaths was significantly higher in the stented group on univariate analysis, although this did not remain significant on multivariable Cox analysis. No difference was found between treatment groups in the development of ESRD. These data suggest that, among patients with ARAS and CKD, medical therapy and renal artery stenting are comparable in stabilizing renal function.

Mental stress ischemia (MSI) is associated with poor prognosis for coronary artery disease (CAD) and is amenable to treatment, yet no easily administered test exists to diagnose it. Given the known increase in systemic vascular tone in response to stress, we studied the ability of peripheral arterial tonometry (PAT), a noninvasive functional measure of arterial tone, to predict those vulnerable to MSI. Seventy-seven patients with chronic stable CAD were subjected to mental stress with concomitant assessment of myocardial perfusion and pulse wave amplitude. Nuclear perfusion imaging was used to document MSI, and PAT was used to measure pulse wave and microarterial tone. A ratio of PAT measurements during stress to those before stress was used to characterize vascular responses. Serum catecholamines and endothelin-1 (ET-1) were simultaneously measured. Subjects who experienced MSI had a lower average PAT ratio than those who did not (0.76 ¡À 0.04 vs. 0.91 ¡À 0.05, P = 0.03). A receiver operating characteristics curve for PAT ratio predicting MSI had an area under the curve of 0.613 (standard error, 0.065, one-sided P = 0.04). Maxima of sensitivity and specificity were observed at a threshold of 0.78 to define an abnormal PAT ratio. Cross-tabulation of groups above and below this threshold with groups of subjects with and without MSI showed a significant predictive relationship between PAT ratio and MSI (P = 0.03). Subjects at or below this threshold (¡Ü0.78) displayed a significant increase in norepinephrine levels during mental stress (235 pg/ml at baseline, 259 pg/ml during mental stress, P = 0.007). Subjects above this threshold (>0.78) displayed a significant decline in their ET-1 levels 24 hours after mental stress (1.15 pg/ml after mental stress, 0.93 pg/ml 24 hours later, P = 0.01), while those at or below threshold had a continued increase. PAT ratio is a complex functional measure of peripheral arterial tone that significantly predicts the occurrence of MSI. It may have clinical value as an easily administered screening test for MSI.

Thesis--University of Kentucky (M.S.), 2003. / Title from document title page. Document formatted into pages; contains viii, 86 p. : ill. Includes abstract and vita. Includes bibliographical references (p. 82-85).

Flow-mediated dilation (FMD) is used as a surrogate marker for endothelial function, a subclinical indicator of coronary artery disease (CAD) and for that reason; FMD is commonly used to compare endothelial function across groups differing in age and number and/or type of CAD risk factors. The traditional calculation of FMD involves arterial diameter prior to cuff inflation and then peak arterial diameter following cuff release. Generally, arterial response during cuff inflation is not taken into consideration. The aims of the present study were to determine 1) if there were differences in brachial artery response, more specifically vasoconstriction, during cuff inflation in a diverse population of subjects, 2) if variability existed, the resulting impact on the calculation of traditional FMD, and 3) if arterial stiffness was a physiological determinant in this process. A total of 84 subjects, varying in age (18-62 years) and CAD risk factor profiles were studied. Low flow-mediated constriction (L-FMC), during cuff inflation, traditional FMD, and modified FMD, which accounts for L-FMC, were calculated to investigate brachial artery response during all three stages of the FMD measurement. Subjects ≥ 50 years old had lower FMD response compared with those ≤ 35 years old but only the modified FMD was statistically significant. The same effect was seen when comparing healthy subjects to those with multiple risk factors for CAD; there was an attenuated FMD response that only reached statistical significance with modified FMD. L-FMC was modestly but significantly associated with FMD. L-FMC was weakly but positively correlated with brachial pulse wave velocity (PWV). Our results indicate that modified FMD, which takes into consideration brachial response to cuff inflation, may be a more sensitive indicator of endothelial dysfunction and that arterial stiffening may be a physiological determinant in this process. / text

published_or_final_version / abstract / toc / Physiology / Doctoral / Doctor of Philosophy