Genetic polymorphism of apolipoprotein (apo) E has been shown to account for a significant amount of variance in plasma lipid and lipoprotein levels, thereby contributing to the incidence of cardiovascular disease across populations. In this cross-sectional study apo E genotypes were determined in a sample of 173 healthy, middle-aged Indian women using a restriction isotyping method, in which DNA was amplified by PCR and the Cfol restricted DNA fragments were separated on a polyacrylamide gel, allowing unambiguous typing of the common apo E genotypes. Considering the three common alleles, e2, e3 and e4, a reduced frequency of the e2 allele was observed in the study population in comparison to other populations around the world. This finding underlines the heterogeneity of apo E allele frequencies in different populations. This study also investigated possible effects of apo E genotype on lipoprotein changes in this sample of women spanning the menopause. Apo E polymorphism was associated with significant differences in plasma lipid levels. Notably, total and low density lipoprotein cholesterol and more especially plasma triglyceride concentrations were increased in carriers of the e3/4 genotype. Two-way analysis of variance of the effect of apo E genotype and menopausal status on the lipid profile showed no significant interaction effect, indicating that the effects of apo E genotype on the lipid profile do not differ significantly between premenopausal and postmenopausal women. Age and to a lesser extent the waist hip ratio also correlated with lipid concentrations, but menopausal status had no apparent effect in this sample. This study confirms the potentially deleterious effect of the e4 allele, in a vulnerable population. The reduced occurrence of the E2 isoform, which is considered to offer a measure of protection against cardiovascular disease, may contribute to the relatively high incidence of coronary heart disease in the South African Indian population. However, the relatively low incidence of the e2 allele may protect this population against the occurrence of type III hyperlipoproteinaemia precipitated by diabetes and obesity in e2/2 homozygotes. / Thesis (M.Med.)-University of Natal, Durban, 1993.

Thirty-one college age females enrolled in aerobic dance conditioning classes were subjects. The purposes were to determine if aerobic dance is sufficiently vigorous to elicit a heart rate capable of producing a training effect and to determine whether a training effect heart rate level can be maintained. The narco-biosystems telemetry was used to monitor heart rates. Each subject performed one aerobic dance at three trials. Twelve-minute run/walk pretests and post-tests were given to assign fitness levels. Results of the study indicate that aerobic dance is an effective cardiovascular training program. Resting heart rates decreased, fitness levels improved, and training intensity heart rates were elicited and maintained at each of the trials.

M.A. / Please refer to full text to view abstract

Though several clinical monitoring ways exist and have been applied to detect cardiac atril fibrillation (A-Fib) and other arrhythmia, these medical interventions and the ensuing clinical treatments are after the fact and costly. Current portable healthcare monitoring systems come in the form of Ambulatory Event Monitors. They are small, battery-operated electrocardiograph devices used to record the heart's rhythm and activity. However, they are not energy-aware ; they are not personalized ; they require long battery life, and ultimately fall short on delivering real-time continuous detection of arrhythmia and specifically progressive development of cardiac A-Fib. The focus of this dissertation is the design of a class of adaptive and efficient energy-aware real-time detection models for monitoring, early real-time detection and reporting of progressive development of cardiac A-Fib.... The design promises to have a greater positive public health impact from predicting A-Fib and providing a viable approach to meeting the energy needs of current and future real-time monitoring, detecting and reporting required in wearable computing healthcare applications that are constrained by scarce energy resources. / by Redjem Bouhenguel. / Thesis (Ph.D.)--Florida Atlantic University, 2012. / Includes bibliography. / Mode of access: World Wide Web. / System requirements: Adobe Reader.

Restrictive cardiomyopathy (RCM) is a heart muscle disease, characterized by diastolic dysfunction. The present dissertation is to understand the mechanisms underlyijng the initiation of diastolic dysfunction and the fast disease progression to early death in a RCM mouse model, the transgenic cTnI193His mouse... These data showed that myocardial ischemia occurred after diastolic dysfunction and before systolic dysfunction which proceeded congestive heart failure. The results demonstrate that myocardial ischemia causing cardiomycete death is a link between the initial diastolic dysfunction and late-stage systolic dysfunction, and accelerates the disease progression to fatal heart failure in the early age. / by Yuejin Li. / Thesis (Ph.D.)--Florida Atlantic University, 2011. / Includes bibliography. / Mode of access: World Wide Web. / System requirements: Adobe Reader.

Endothelial dysfunction (ED) is associated with many cardiovascular conditions including hypertension and hyperhomocysteinemia. The decreased bioavailability of nitric oxide and increased oxidative stress are the hallmarks of ED. Apart from the mainstream Western medicine treatment, Chinese medical interventions have also demonstrated their capacity in dealing with a great variety of cardiovascular conditions. The effectiveness of acupuncture on hypertension has been recognized by the World Health Organization but the underlying mechanisms have hitherto remained largely obscure. A commonly prescribed Chinese herb, the Root of Rhodiola rosea has been used to treatment a wide range of cardiovascular conditions but its effect on ED is also unclear. In this thesis, we have explored the effects and the underlying mechanism of these two important Chinese medical interventions. / In the first part, we have performed an acupuncture study on hypertensive animals. Eighteen weeks old adult Wistor Kyoto Rats (WKYs) and Spontaneously Hypertensive Rats (SHRs) were divided into WKY control, SHR control, Sham-acupuncture and real acupuncture groups. Electroacupuncture was performed on acupoints ST36 and LR3 in the real acupuncture group for 6 weeks. The blood pressure at the end of the treatment was lowered in acupuncture group when compared with SHR control and sham-acupuncture group. Serum angiotensin II level in SHR controls was higher than that in WKY control and acupuncture treatment significantly attenuated it. Dihydroethidium (DHE) imaging showed that the reactive oxygen species (ROS) level was reduced in the aortas and carotid arteries of acupuncture treated SHR. Biochemical assays showed that acupuncture inhibited the nicotinamide adenine dinucleotide phosphate (NADPH) oxidase activity and enhanced antioxidant capacity. In functional studies, the endothelial dependent relaxation of aorta rings and carotid arteries to acetylcholine were improved in acupuncture group. SHRs received acupuncture also expressed a elevation of eNOS and peNOS level and inhibition of nitrotyrosine level in Western blotting assay. The nitrate/nitrite level in aortic tissue was also increased by acupuncture. The findings concluded that one of the possible mechanisms of acupuncture in lowering blood pressure involved the improvement of oxidative stress, nitric oxide bioavailability and endothelium functions. / In the second part, we have studied the effects of salidroside, an active ingredient of the root of Rhodiola rosea with documented antioxidative, antihypoxia and neuroprotective properties on homocysteine induced ED. Functional studies on the rat aortas were performed to delineate the vascular effect of salidroside. Exposure to homocysteine attenuated endothelium-dependent relaxations in rat aortas while salidroside pretreatment rescued it. DHE imaging revealed that salidroside inhibited homocysteine-induced elevation in ROS production in both aortas and cultured endothelial cells. Western blot analysis showed that salidroside increased the phosphorylation of eNOS which was diminished by homocysteine in endothelial cells. Moreover, salidroside inhibited the NOX2 expression which was promoted by homocysteine in aorta tissue. The findings suggested that salidroside was effective in preserving the NO bioavailability and reducing ROS level, thereby protecting against homocysteine-induced impairment of ED. / We have successfully demonstrated the two Chinese medicine modalities, i.e. acupuncture and salidroside, a naturally occurring chemical compound isolated from Rhodiola rosea, delivered beneficial effects on ED, and both of them exert anti-oxidative effects for their action. Our experimental findings have enhanced the prospective of using Chinese medical interventions to manage oxidative stress-associated cardiovascular conditions and also helped put the clinical use of Chinese medical interventions on a more scientific footing. / 內皮功能失調與很多心血管系統疾病，包括高血壓和高半胱氨酸過高症有著十分密切的關系，一氧化氮供應減少與氧化應激增加均為這病理現象的一個特徵。除了主流的西方醫學治療方法外，中醫藥也一直表現出對各種心血管系統疾病有著明顯的療效。其中以針灸治療高血壓雖然己被世界衛生組織認可為一有效之療法，然而其療效原理卻並未被完全了解。另外，中草藥當中的紅景天，其對心血管疾病的療效亦非常顯著，唯其對內皮功能失調之影響卻仍有待查証。在這部論文當中，作者將會對以上兩項中醫藥治療方法的原理作出深入探討。 / 在第一部份的實驗當中，作者對自發性高血壓的大鼠施行了針灸治療。把十八週歲的自發性高血壓大鼠與京都種大鼠分為1)京都種大鼠對照組 2)自發性高血壓大鼠對照組 3)假針組針針刺組。針刺組中所使用的方案乃於足三里和太沖施行為期六週的電針治療。治療後針刺組的血壓相對於高血壓大鼠對照組和假針組均有明顯下降。同時針刺組大鼠血液中的血管緊張素II亦明顯降低。顯微鏡螢光造影發現於主動脈與頸動脈組織中，超氧化因子數量於針刺後均低於另外兩組高血壓大鼠對照組與假針組。另外實驗結果亦發現尼克酰胺腺嘌呤二核苷酸磷酸氧化酶的活動於針刺後下降，而抗氧化總容量則有所提升。另一方面，血管功能測試則顯示在針刺組內，由乙酰胆碱所引發的血管舒張比對照所產生的有所增加。而內皮一氧化氮酶和磷化皮內皮一氧化氮酶於血管中的表達則於針刺治療後有所增加，反觀硝基酪氨酸的含量則於針刺後減少。針刺對於血管組織中的亚硝酸盐/硝酸盐含量均有刺激作用。綜合而言，針刺能透過抑制氧化應激從而增加血管中一氧化氮的含量，最後達至內皮功能改善而降低血壓。 / 在第二部份，作者對中藥紅景天內其中一種活性成份紅景天苷對半胱氨酸所引起的內皮功能損傷進行研究。血管功能測試顯示半胱氨酸抑制了由乙酰胆碱所引發的血管舒張，而紅景天苷則能有效逆轉該抑制作用。顯微鏡螢光造影則發現紅景天苷能壓制由半胱氨酸所刺激的超氧化因子，另一方面能增加由半胱氨酸所抑制的磷化皮內皮一氧化氮酶的表達。尼克酰胺腺嘌呤二核苷酸磷酸氧化酶為超氧化因子的其中一個主要來源，半胱氨酸被發現會對其當中NOX2亞組的表達有刺激作用，而紅景天苷則能減少其表達。實驗結果顯示紅景天苷對半胱氨酸所引起的內皮功能損傷有顯著保護作用，其原理則與減少氧化因子從而增加一氧化氮的含量有密切關系。 / 整體而言，本論文成功顯示針灸與紅景天苷兩項中醫藥治療方案均能夠透過抑制超氧化因子而改善內皮功能捐傷。實驗結果加強了中醫藥於治療氧化應激相關的心血管疾病的應用，為中醫藥發展提供堅實的科學基礎。 / Leung, Sin Bond. / Thesis (Ph.D.)--Chinese University of Hong Kong, 2014. / Includes bibliographical references. / Abstracts also in Chinese. / Title from PDF title page (viewed on 01, November, 2016). / Detailed summary in vernacular field only. / Detailed summary in vernacular field only. / Detailed summary in vernacular field only. / Detailed summary in vernacular field only.

目的1)發現與中風相闋的視網膜特徵2) 利用視網膜特徵建立統計模型對老年人中風風險進行分類。 / 方法:配對病例對照研究。病例為中風患者，一部分中風患者來自於糖尿病眼病的篩查項目，另外一部分是腦內科的中風患者。對照是沒有中風的老年人。對照來自糖尿病眼病篩查項目內沒有患中風的患者及在眼科門診沒有中風及特殊眼病的患者。對照與病例在年齡及是否患有糖尿病進行匹配。所有研究對象均來自香港威爾斯親王醫院。我們收集所有研究對象的中風危險因素，包括年齡，性別，吸煙，及是否患有糖尿病，高血壓，缺血性心髒病，心房顫動，高血脂。所有研究對象的彩色視網膜照片都被採集。我們應用軟件“ImageJ"分析並記錄視網膜動靜脈直徑，血管分叉係數，分叉角度，分叉對稱性，視乳頭周長。我們也記錄其他視網膜特徵，如動靜脈壓跡，出血，硬性滲出，動脈阻塞及血管彎曲性。獨立t檢驗用於對連續變量的單因素分析，卡方檢驗用於對分類變量的單因素分析。Logistic 回歸用於建立統計模型對中風風險進行分類。所有統計方法均應用SPSS16.0 軟件。 / 結果:本研究納入122 中風患者及122 例患者做對照。每組分別有81 例糖尿病患者， 41 例非糖尿病患者。視網膜特徵包括動靜脈直徑，血管彎曲度，出血，硬性滲出，動靜脈壓跡在兩組中有顯著性差異。我們建立風險模型對兩組患者進行風險分類。分類準確度最高達的模型裡面包括的因子有：1)中風相關危險因素包括:高血壓，糖尿病，心房顫動2) 視網膜特徵包括:動脈直徑，血管彎曲性，出血，動靜脈壓跡跟靜脈對稱性；3) 視網膜特徵間的交立作用包括:動脈直徑與靜脈對稱性，動脈直徑與出血，靜脈對稱性與血管彎曲度。分類的準確度為80 .4%。只包括視網膜特徵的分類模型的準確度為74.5% 。 / 結論:彩色視網膜照相可成為中風風險的分類工具。與中風相關的視網膜特徵包括血管直徑，血管彎曲度，血管對稱性，出血，動靜脈壓跡。視網膜特徵與中風之間的聯繫存在交互作用。 / Objective: 1) To detect retina characteristics that associated with stroke; 2) To develop a statistics model with variables of retina characteristics for classifying patients with stroke from those without stroke in aged population. / Method: Matched case control study. Patients with stroke from the diabetic retinopathy screening program and stroke patients from Acute Stroke Unit were selected as stroke cases. Controls (patients without history of stroke) with matched diabetes status and age were selected from the diabetic retinopathy screening program and eye outpatient clinics. All subjects in this study were from Prince of Wales Hospital, Hong Kong. Risk factors of stroke from all subjects were collected, including age, gender, diabetes, hypertension, hyperlipidemia, history of ischemic heart disease, atrial fibrillation and smoking. Color retina images of each subject were collected and analyzed. The retina characteristics, including diameters of arterioles and venules, bifurcation coefficients, bifurcation angles, branch symmetry, optic disc perimeter were extracted from the color retina images by software "ImageJ". Other retina characteristics including arteriole-venule nicking, hemorrhages, exudates, arteriole occlusion, and vessel tortuosity were also recorded. Independent t test and Chi-squire test were used to compare the continuous and categorical retina characteristics respectively between patients with stroke and those without stroke. Logistic model combining the risk factors of stroke and retina characteristics was established to classify patients with stroke from those without stroke. All data analysis was by SPSS 16.0. / Results: there were 122 stroke cases and 122 controls recruited in this study. There were 41 patients without diabetes and 81 patients with diabetes in each group. Retina characteristics including diameters of arterioles and venules, vessel tortuosity, hemorrhages, exudates, arteriole-venule nicking were significantly different between the two groups. We established risk models to classify patients with stroke from those without stroke. The risk model with highest accuracy of classification included 1) stroke risk factors including hypertension, diabetes and atrial fibrillation; 2) retina characteristics, including arteriole diameters, vessel tortuosity, hemorrhages, arteriolevenule nicking and venule symmetry; 3)interaction between retina characteristics, including arteriole diameters by venule symmetry, arteriole diameters by hemorrhage,and venule symmetry by vessel tortuosity. The accuracy of classification was 80.4%. Using retinal characteristics alone achieved an accuracy of 74.5%. / Conclusion: color retina images are a potential tool for stroke risk stratification. Useful characteristics found in the retinal images included vessel diameters, vessel tortuosity, vessel symmetry, hemorrhage, arteriole-venule nicking. The association between the retinal characteristic and stroke was modified by other retinal characteristics. / Detailed summary in vernacular field only. / Detailed summary in vernacular field only. / Detailed summary in vernacular field only. / Detailed summary in vernacular field only. / Li, Qing. / Thesis (Ph.D.)--Chinese University of Hong Kong, 2012. / Includes bibliographical references (leaves 139-148). / Electronic reproduction. Hong Kong : Chinese University of Hong Kong, [2012] System requirements: Adobe Acrobat Reader. Available via World Wide Web. / Abstract also in Chinese. / Abstract (English) --- p.i / Abstract (Chinese) --- p.iii / Acknoledgements --- p.v / Chapter Chapter 1 --- Introduction and review of the Literature --- p.1 / Chapter Section 1: --- Stroke prevention and risk assessment tools --- p.1 / Chapter Section 2: --- Rationale of relationship of vascular circulation between retina and brain --- p.9 / Chapter Section 3: --- Manifestation of hypertensive retinopathy and diabetic retinopathy --- p.12 / Chapter Section 4: --- Retina characteristics related to stroke --- p.15 / Chapter Section 5: --- How to make retina as a tool of risk stratification for stroke --- p.28 / Chapter Section 6: --- Rationale to do study to further explore the useful information in color retina images to make it as tool for stroke risk stratification --- p.31 / Chapter Chapter 2 --- Research hypothesis and general design --- p.33 / Chapter Chapter 3 --- Methods of retia characteristics extraction --- p.34 / Chapter Chapter 4 --- A Study of the Reliability of manual measurement of Retinal characteristics using ImageJ --- p.46 / Chapter Chapter 5 --- A study of comparison of retina characteristics between patients with stroke and patients without stroke --- p.55 / Chapter Section 1: --- Method --- p.56 / Chapter Section 2: --- Result-univariate analysis --- p.62 / Chapter Section 3: --- Results-stratification analysis --- p.68 / Chapter Section 4: --- Result-risk model building for stroke risk stratification --- p.79 / Chapter Chapter 6: --- Discussion --- p.118 / Chapter Chapter 7: --- Limitation of this study --- p.133 / Chapter Chapter 8: --- Future development and application of the study results --- p.134 / Appendix --- p.136 / Reference --- p.139

Cardiovascular disease (CVD) is broadly characterized by a loss of global function, exacerbated by a very limited ability for the heart to regenerate itself following injury. CVD remains the leading cause of death in the United States and the leading citation in hospital discharges. The overall concept of this dissertation is to investigate the use of biophysical signals that drive physiologic maturation of myocardium, and lead to its deterioration in disease. By incorporating biophysical signaling into cardiac tissue engineering methods, the aim is to generate high fidelity engineered platforms for cell delivery and maturation of surrogate muscle, while understanding the cues that lead to pathological cell fate in disease. The first part of this thesis describes the development of a composite scaffold, derived from human myocardium, to use as a delivery platform of mesenchymal stem cells to the heart. Through biochemical signaling, we are able to modulate MSC phenotype, and propose a mechanism through which angio- and arteriogenesis of the heart leading to global functional improvements, following myocardial infarction, may be attributed. We further demonstrate cardioprotection of host myocardium in a setting of acute injury by exploiting non-invasive radioimaging techniques. The mechanism through which we can attribute cell mobilization to the infarct bed is further explored in patient-derived myocardium, to understand how this pathway remains relevant in chronic heart failure. The second focus of the thesis is the use of electro-mechanical stimulation to generate high fidelity Engineered Heart Muscle (EHM). We report that electro-mechanical stimulation of EHM at near-physiologic frequency leads to development and maturation of Calcium handling and the T- tubular network, as well as improved functionality and positive force frequency relationship. Lastly, we return to human myocardium as platform understand regulation of cardiomyocyte function by the extracellular matrix. Here, we seek to understand how the ECM from different disease states (eg. non-diseased, ischemic, non-ischemic) affects cell phenotype. Specifically, can bona fide engineered myocardium successfully integrate and remodel diseased ECM? Using stem cell derived cardiomyocytes and patient-derived decellularized myocardium to generated engineered myocardium (hhEMs), we report that hhEMs mimic native myogenic expression patterns representative of their failing- and non-failing heart tissue.

Cardiovascular disease (CVD) consistently ranks among the leading causes of death in the United States. The most common subtype of CVD, ischemic heart disease, is a frequent precursor of myocardial infarction and heart failure, most commonly affecting the left ventricle (LV). Today, echocardiography is regarded as the gold standard in screening, diagnosis, and monitoring of LV dysfunction. But while global assessment of LV function tends to be quantitative, cardiologists with specific expertise still perform many regional evaluations subjectively. However, a more objective and quantitative measure of regional function – myocardial strain – has been developed and widely studied using 2D echocardiography. With recent developments in real-time 3D echocardiography (RT3DE), it has become possible to measure strain in its native 3D orientation as well. Our laboratory’s earlier work introduced the Optical Flow (OF) method of strain analysis, which was validated on simulated echocardiograms as well as through animal studies. The principal goal of this thesis is to translate this OF-based method of strain estimation from the research setting to the patient’s bedside. We have performed a series of studies to evaluate the feasibility, accuracy, and reproducibility of OF-based myocardial strain estimation in a routine clinical setting. The first investigation focused on the optimization of RT3DE acquisition and the OF processing pipeline for use in human subjects. Subsequently, we evaluated the capacity of this technique to distinguish abnormal strain patterns in patients with CVD and varying degrees of LV dysfunction. Our analysis revealed that segmental strain measures obtained by OF may have better sensitivity and specificity than the more commonly used global LV strains. Our third validation study examined the reproducibility of these strain measures in both healthy and diseased populations. We established that OF-based strain measures demonstrate repeatability comparable to that achieved by the latest commercial software commonly used in clinical research to estimate 2D or 3D strain. These studies were driven in large part by the absence of a ground truth or accepted gold standard of 3D strain measurements in the human LV. However, cardiac magnetic resonance imaging has had considerable success in measuring some forms of strain in the human LV. We therefore began to develop an image-processing pipeline to derive strain estimates from a new pulse sequence called 3D-DENSE. We further sought to improve the OF pipeline by automating the process of tracking the LV border. To this end, we developed a level-set based technique which tracks the LV endocardium. Our evaluation of its performance on RT3DE data confirmed that this method performs within the limits of inter-observer variability. Overall, our pilot studies of OF-based strain estimation demonstrate that the technique possesses several promising features for improving cardiologists’ ability to quantify and interpret the complex three-dimensional deformations of the human LV.

The mechanical contraction of the heart is tightly coupled to rapid and concerted electrical excitation of the cardiac muscle. This electrical activity is facilitated by a highly synchronized conduction system consisting of channels, pumps, and transporters that facilitate the flow of charged ions between cellular compartments, the cytoplasm, and the interstitial fluid between cells. The biophysical properties of these membrane proteins have been studied for many years, but their role in the generation of potentially lethal cardiac arrhythmias and their interactions with drugs remains an important field of research. The cardiac isoform of the voltage-gated Na+-channel, Nav1.5, has garnered widespread interest because of its role in the generation of electrical impulses in the cardiac myocyte, its association with congenital conduction disorders and acquired cardiac arrhythmias, and its unique pharmacological properties. The Congenital Long QT Syndrome Type 3 (LQT3) arises from heritable mutations in SCN5A - the gene encoding Nav1.5 - that disrupt the inactivation process responsible for imparting a refractory period and that often cause a sustained depolarizing late current (INaL). The gain of function depolarizing currents arising from LQT3 mutant channels cause a prolongation of the ventricular action potential and leave patients susceptible to asynchronous electrical activity, ventricular arrhythmias, and sudden cardiac death. The disruption of channel inactivation can arise through a wide range of modalities, including changes in inactivation voltage-dependence and kinetics, and has been shown to occur with varying degrees of severity. Because of this range of phenotypes there is heterogeneity in the risk factors for arrhythmia and sudden cardiac death and in the utility of Na+-channel blocking antiarrhythmic drugs. Moreover, INaL has been implicated as a proarrhythmic and potentiating factor in several acquired cardiac ailments including heart failure, ischemia, and hypertrophy. There is therefore a large unmet need for improved understanding of INaL and mechanisms of its selective inhibition, and LQT3 mutant channels provide a reliable experimental model for this class of cardiac arrhythmias. This study will employ a combination of electrophysiological and computational methods to unravel mechanisms by which mutant Nav1.5 produces pro-arrhythmic currents and the interactions of different disease-causing mutant channels with a set of clinically relevant antiarrhythmic drugs. Chapter 1 of this study presents a functional characterization of one LQT3 mutation, F1473C, that was discovered in a patient with severe QT prolongation, frequent ventricular arrhythmias, and a poor response to pharmacological intervention. This mutation gives rise to INaL by a mechanism that is functionally distinct from the mechanism discovered previously in the canonical LQT3 mutation, ΔKPQ (1505-1507del), and causes a unique response to channel inhibitors. In order to better understand the mechanisms of this divergent pharmacology, Chapter 2 presents the development of a series of computational models which explore the gating dysfunctions that cause INaL and how these pathological changes can influence the predicted safety and efficacy of pharmacological intervention. These models predict that the majority of mutation- specific drug effects can be attributed to differential mutant channel gating, but raise the possibility that mutations may directly alter the physical chemical interaction between drugs and channels. Finally, Chapter 3 presents an attempt to explore this possibility using an innovative chemical biology technique - the site-specific incorporation of unnatural amino acids - that allows for the measurement of precise chemical interactions hypothesized to vary in a mutation-dependent manner. The findings presented in this work promote the need for patient-specific screening of antiarrhythmic agents and lay the groundwork for the use of in silico systems analysis of cardiovascular pharmacology.