Cardiovascular diseases are the leading cause of death worldwide, and are estimated to kill over 17 million people each year, about 31% of all deaths. In the clinic, the first diagnostic procedure for a suspected cardiac abnormality is often acquisition of an electrocardiogram (ECG), which measures the electrical potential of the heart at the body surface. Understanding the mechanisms underlying generation of the ECG waveforms is crucial for optimal clinical benefit. Computer simulations possess several strengths as a tool to gain this understanding, particularly in terms of human-specificity, flexibility, repeatability, and ethics. The ventricles make up the majority of the cardiac volume and are therefore responsible for the majority of ECG waveforms. Ventricular disorders are the most life-threatening, because the ventricles are responsible for pumping blood to the body. Due to their size it has only recently become possible to perform biophysically detailed simulations of the ventricles and torso using supercomputers. In this thesis, multiscale, mathematical models of the ventricles and torso using the Chaste software library are simulated on high performance computing systems. A description is included of the performance enhancements made in Chaste to improve resource efficiency and accelerate job turnaround, particularly in data storage and the auxiliary tasks of post-processing and data conversion. A novel model of ventricular activation is presented and parametrized using multi-modal human data, and successfully used to simulate normal and pathological QRS complexes. Similarly, repolarization gradients are imposed based on the literature and result in a variety of T waves. Finally, the developed human whole-ventricular and torso models are utilized to gain new insights into possible ionic mechanisms underlying the clinical manifestations of the early repolarization syndrome. Overall, this thesis presents a novel framework for simulation of the human ECG using high performance computers, with possible applications in basic science and computational medicine.

Congenital increase in cardiac outflow tract resistance would lead to chronic ventricular pressure overloading, and eventually ventricular hypertrophy and dysfunction. Conventional echocardiographic assessment of global ventricular systolic and diastolic function is far from ideal because of the lack of sensitivity. There is a pressing need in developing a clinical tool to unveil the degree of myocardial dysfunction as well as to monitor the treatment effect in these patients. M-mode and tissue Doppler recordings of the left and right atrioventricular rings' motion in a longitudinal cardiac axis allowed us to assess segmental ventricular function in a more sensitive and specific way. This thesis aimed to assess ventricular long axis function in patients with congenital outflow tract obstructions. It is based on the anatomical observation that a major part of long axis function is subtended by subendocardial fibers, and the hypothesis that the function of these fibers might be more sensitive to effect of pressure overload than circumferential ones. / Normal values for left and right ventricular (RV) long axis function (in left, septal and tricuspid sites of atrioventricular rings) were first established by studying normal healthy volunteers without cardiovascular diseases with M-mode and pulse wave (PW) tissue Doppler Imaging (TDI). These values included: / 1) M-mode derived systolic amplitude of motion (displacement) / 2) Any long axis incoordination (long axis shortening after end of ejection which was reported as a sign of coronary ischemia after excluding interventricular conduction abnormalities) / 3) TDI-derived peak systolic and diastolic velocities. / The following groups of patients with congenital outflow tract obstructions were therefore studied: / 1) Congenital aortic valve stenosis and subaortic stenosis (21 patients, study 1). / 2) Congenital coarctation of aorta (23 patients, study 2). / 3) Congenital pulmonary valve stenosis (43 patients, study 3). / Study 1 investigated the presence of "isolated" diastolic disease, defined as reduced long axis early diastolic velocity with normal systolic velocity in 21 young patients with congenital aortic valve stenosis (AVS). Most patients with normal left ventricular (LV) ejection fractions in fact had depressed long axis systolic velocities. This work demonstrated the selective sensitivity of long axis function in unveiling myocardial dysfunction in AVS patients. Moreover, good correlation was found between long axis systolic and diastolic velocities which suggested isolated diastolic disease is unlikely. / Patients with coarctation of aorta (CoA) are often less symptomatic (fewer reported chest pain or heart failure) that AVS patients despite having similar degree of outflow resistance. Study 2 addressed such phenomenon by studying the long axis function in 23 CoA patients and the results were compared to 23 AVS patients and normal controls. This work again confirmed the presence of LV long axis impairment in patients with chronic increase in LV afterload. Moreover, a worse deterioration of LV long axis function and a higher prevalence of long axis incoordination independent of LV outflow resistance is seen in patients with proximally increased LV afterload (AVS) compared with distal disease (CoA) that might account for their difference in clinical behavior. / Data are scant to address the impact of chronic increase in RV outflow resistance on RV diastolic performance. Study 3 evaluated the relationship of restrictive RV physiology (defined as the presence of antegrade pulmonary arterial flow in late diastole measured by conventional PW Doppler echocardiography) to RV long axis function and patients' symptoms in 43 patients with pulmonary valve stenosis (PVS). Restrictive RV physiology was found in 42% studied patients who were more symptomatic and had more severe RV long axis dysfunction. This work implied regular follow-up of adult PVS patients using simple qualitative RV Doppler echocardiographic measurements should guide toward early identification of myocardial dysfunction and the need for removal of outflow tract obstruction before irreversible damage occurs. / Given the selective sensitivity of long axis function in assessing myocardial damage In patients with pressure overloaded ventricle, I further studied the effect of interventions on change of long axis behavior in patients with CoA: / 1) Before and 14 month after successful endovascular stenting (21 patients, study 4). / 2) Long term follow up after surgical correction, by either angioplasty or endovascular stenting (80 patients, study 5). / Study 4 prospectively evaluated the effect of endovascular stenting on intermediate-term biventricular function in 21 adults with CoA and the results were compared with surgically repaired patients and normal controls. LV long axis disturbances were improved with sparing of RV long axis function after intervention. Subclinical myocardial dysfunction was observed in both stented and repaired patients compared with normal controls. This work supported aortic stenting in patients with anatomically suitable lesions. It also prompted further studies on the clinical significance of persistent myocardial dysfunction in "corrected" CoA patients. / In study 5, I went on to examine the prevalence of LV long axis diastole dysfunction (defined as septal PW TDI early diastolic velocity 8cm/s) in a relatively large cohort of CoA patients (n=80) and its relationships to patient demo graphics and aortic elastic properties. Forty-seven patients (59%) were found to have LV long axis dysfunction. As a group, they were older when received treatment and had higher ascending aortic stiffness indices despite similar systemic blood pressure, prevalence of anti-hypertensive use and associated bicuspid aortic valve as compared to other CoA patients. This work addressed the age at intervention and increased aortic stiffness are important determinants of persistent myocardial dysfunction after intervention. Intervention at an early age before structural damage to proximal aorta and appropriate medications to reduce central aortic stiffness might preserve LV long axis function in "corrected" CoA patients and further improve their long term prognosis. / CONCLUSIONS: / In conclusion, conventional global echocardiographic assessment is inadequate for assessing patients with congenital outflow tract obstructions. Segmental ventricular long axis function is frequently abnormal at rest in these patients. The site of these disturbances corresponds to the ventricle that is subjected to pressure overloading. Assessment of long axis function is simple and sensitive. It has considerable potential in investigating the natural course of myocardial damage, to clarify the basis of abnormal ventricular function, particularly during diastole and to evaluate treatment effect on myocardial recovery in patients with congenital outflow tract obstructions. Further studies should focus on the role of long axis function in determining prognosis for these patients. / Lam, Yat Yin. / "November 2011." / Thesis (M.D.)--Chinese University of Hong Kong, 2012. / Includes bibliographical references (leaves 134-160). / ABSTRACT --- p.1 / Chapter PART1 --- HISTORIC REVIEW --- p.5 / Chapter Chapter1 --- VENTRICULAR OUTFLOW TRACT OBSTRUCTION SYNDROME --- p. 6 / Chapter 1.1 --- BACKGROUND --- p.7 / Chapter 1.2 --- AORTIC VALVULAR STENOSIS --- p.8 / Chapter 1.2.1 --- Anatomy pathophysiology and clinical features --- p.8 / Chapter 1.2.2 --- Investigations --- p.9 / Chapter 1.2.3 --- Treatment --- p.9 / Chapter 1.3 --- COARCTATION OF AORTA --- p.9 / Chapter 1.3.1 --- Anatomy pathophysiology and clinical features --- p.9 / Chapter 1.3.2 --- Investigations --- p.11 / Chapter 1.3.3 --- Treatment --- p.11 / Chapter 1.4 --- PULMONARY VALVULAR STENOSIS --- p.12 / Chapter 1.4.1 --- Anatomy pathophysiology and clinical features --- p.12 / Chapter 1.4.2 --- Investigations --- p.13 / Chapter 1.4.3 --- Treatment --- p.13 / Chapter Chapter2 --- VENTRICULAR RESPONSE TO HIGH AFTERLOAD --- p.14 / Chapter 2.1 --- VENTRICULAR ADAPTATION IN AORTIC VALVULAR STENOSIS --- p.15 / Chapter 2.2 --- VASCULAR STIFFENING AORTIC COARCTATION --- p.17 / Chapter 2.3 --- VENTRICULAR ADAPTATION IN PULMONARY VALVULAR STENOSIS --- p.18 / Chapter 2.4 --- LIMITATIONS OF CONVENTIONAL ECHOCARDIOGRAPHY --- p.19 / Chapter Chapter3 --- MYOCARDIAL FIBER ARCHITECTURE AND LONG AXIS FUNCTION --- p.21 / Chapter 3.1 --- MYOCARDIAL FIBER STRUCTURE AND LONG AXIS FUNCTION --- p.22 / Chapter 3.2 --- NOMRAL LONG AXIS EXCURSION AND TIMING --- p.25 / Chapter 3.3 --- QUANTIFICATION OF LONG AXIS MOTIONS --- p.26 / Chapter 3.3.1 --- M-mode --- p.26 / Chapter 3.3.2 --- Clinical applications of atrio-ventricular plane displacement --- p.27 / Chapter 3.3.3 --- Tissue Doppler Imaging --- p.28 / Chapter 3.3.4 --- Clinical application of tissue Doppler imaging --- p.30 / Chapter 3.3.5 --- Limitations of M-mode and TDI in the assessment of long axis function --- p.31 / Chapter Chapter4 --- HYPOTHESIS AND SPECIFIC OBJECTIVES OF THE THESIS --- p.32 / Chapter 4.1 --- INTRODUCTION --- p.33 / Chapter 4.2 --- HYPOTHESIS --- p.34 / Chapter Chapter5 --- METHODOLOGY --- p.35 / Chapter 5.1 --- STUDY PATIENTS --- p.36 / Chapter 5.1.1 --- Patients with ventricular outflow tract obstruction --- p.36 / Chapter 5.1.2 --- Normal controls --- p.36 / Chapter 5.2 --- CLINICAL ASSESSMENT --- p.37 / Chapter 5.3 --- ECHO CARDIOGRAPHIC ASSESSMENT --- p.37 / Chapter 5.3.1 --- Imaging acquisition protocol --- p.37 / Chapter 5.3.2 --- Assessment of severity of outflow tract obstruction --- p.38 / Chapter 5.3.3 --- Assessment of global ventricular structure and function --- p.40 / Chapter 5.3.4 --- Assessment of long axis function --- p.42 / Chapter 5.3.5 --- Evaluation of restrictive RV physiology in PVS patients --- p.42 / Chapter 5.3.6 --- Determination of aortic elastic properties in CoA patients --- p.43 / Chapter 5.3.7 --- Reproducibility --- p.45 / Chapter 5.4 --- CARDIAC CATHETERIZATON AND ENDOVASCULAR STENTING FOR COARCTATION OF AORTA --- p.45 / Chapter 5.5 --- STATISTICS --- p.46 / Chapter PART 2 --- CLINICAL STUDIES --- p.48 / Chapter Chapter6 --- "ISOLATED" DIASTOLIC DYSFUNCTION IN LEFT VENTRICULAR OUTFLOW TRACT OBSTRUCTION --- p.49 / Chapter 6.1 --- INTRODUCTION --- p.50 / Chapter 6.2 --- METHODS --- p.50 / Chapter 6.2.1 --- Study population --- p.50 / Chapter 6.2.2 --- Echocardiographic examination --- p.51 / Chapter 6.2.3 --- Reproducibility --- p.51 / Chapter 6.2.4 --- Statistics --- p.51 / Chapter 6.3 --- RESULTS --- p.52 / Chapter 6.3.1 --- Baseline characteristics --- p.52 / Chapter 6.3.2 --- Echocardiographic measurements --- p.52 / Chapter 6.3.3 --- Correlation analysis between long axis variables --- p.55 / Chapter 6.3.4 --- Reproduci bility --- p.58 / Chapter 6.4 --- DISCUSSION --- p.58 / Chapter 6.4.1 --- Selective sensitivity oflong axis function --- p.58 / Chapter 6.4.2 --- Close coupling of long axis systolic and diastolic function --- p.59 / Chapter 6.4.3 --- Limitations --- p.60 / Chapter 6.5 --- CONCLUSIONS --- p.61 / Chapter Chapter7 --- EFFECT OF CHRONIC AFTERLOAD INCREASE ON LEFT VENTRICULAR MYOCARDIAL FUNCTION IN PATIENTS WITH CONGENITAL LEFT-SIDED OBSTRUCTIVE LESIONS --- p.62 / Chapter 7.1 --- INTRODUCTION --- p.63 / Chapter 7.2 --- METHODS --- p.63 / Chapter 7.2.1 --- Study population --- p.63 / Chapter 7.2.2 --- Echocardiographic examination --- p.64 / Chapter 7.2.3 --- Reproducibility --- p.65 / Chapter 7.2.4 --- Statistics --- p.65 / Chapter 7.3 --- RESULTS --- p.66 / Chapter 7.3.1 --- Baseline characteristics --- p.66 / Chapter 7.3.2 --- Patients versus controls --- p.66 / Chapter 7.3.3 --- Aortic valvular stenosis versus coarctation patients --- p.70 / Chapter 7.3.4 --- Reproducibility --- p.70 / Chapter 7.4 --- DISCUSSION --- p.72 / Chapter 7.4.1 --- Long axis function in patients with increased LV afterload --- p.72 / Chapter 7.4.2 --- Difference between aortic valvular stenosis and coarctation patients --- p.72 / Chapter 7.4.3 --- Limitations --- p.74 / Chapter 7.5 --- CONCLUSIONS --- p.74 / Chapter Chapter8 --- RESTRICTIVE RIGHT VENTRICULAR PHYSIOLOGY: ITS PRESENCE AND SYMPTOMATIC CONTRIBUTION IN PATIENTS WITH PULMONARY STENOSIS --- p.75 / Chapter 8.1 --- INTRODUCTION --- p.76 / Chapter 8.2 --- METHODS --- p.77 / Chapter 8.2.1 --- Study population --- p.77 / Chapter 8.2.2 --- Echocardiographic examination --- p.77 / Chapter 8.2.3 --- Reproducibility --- p.78 / Chapter 8.2.4 --- Statistics --- p.78 / Chapter 8.3 --- RESULTS --- p.79 / Chapter 8.3.1 --- Baseline characteristics --- p.79 / Chapter 8.3.2 --- Patients versus controls --- p.81 / Chapter 8.3.3 --- Comparison between patient groups --- p.81 / Chapter 8.3.4 --- Predictors for symptoms --- p.84 / Chapter 8.3.5 --- Reproducibility --- p.85 / Chapter 8.4 --- DISCUSSION --- p.85 / Chapter 8.4.1 --- Main findings --- p.85 / Chapter 8.4.2 --- Characterization of diastolic performance in pulmonary valvuar stenosis patients --- p.85 / Chapter 8.4.3 --- Mechanism for restrictive RV physiology in PVS patients --- p.87 / Chapter 8.4.4 --- Study inlplications --- p.89 / Chapter 8.4.5 --- Limitations --- p.90 / Chapter 8.5 --- CONCLUSIONS --- p.90 / Chapter Chapter9 --- EFFECT OF ENDOVASCULAR STENTING OF AORTIC COARCTATION ON BIVENTRlCULAR FUNCTION IN ADULTS --- p.91 / Chapter 9.1 --- INTRODUCTION --- p.92 / Chapter 9.2 --- METHODS --- p.92 / Chapter 9.2.1 --- Study population --- p.92 / Chapter 9.2.2 --- Implantation procedure --- p.93 / Chapter 9.2.3 --- Echocardiographic examination --- p.94 / Chapter 9.2.4 --- Reproducibility --- p.94 / Chapter 9.2.5 --- Statistics --- p.95 / Chapter 9.3 --- RESULTS --- p.95 / Chapter 9.3.1 --- Baseline characteristics --- p.95 / Chapter 9.3.2 --- Blood pressure data --- p.96 / Chapter 9.3.3 --- Echocardiographic measurements --- p.97 / Chapter 9.3.3.1 --- Pre-stenting versus post-stenting (group 1) --- p.97 / Chapter 9.3.3.2 --- Stenting (group 1) versus post-surgical repair (group 2) --- p.101 / Chapter 9.3.3.3 --- Coarctation patients (group 1 post-stenting and group 2) versus control (group 3) --- p.101 / Chapter 9.3.4 --- Reproducibility --- p.101 / Chapter 9.4 --- DISCUSSION --- p.103 / Chapter 9.4.1 --- Main findings --- p.103 / Chapter 9.4.2 --- Potential impact of stenting on cardiovascular outcome --- p.103 / Chapter 9.4.2.1 --- BP control --- p.103 / Chapter 9.4.2.2 --- LV mass and long axis function --- p.104 / Chapter 9.4.3 --- RV function after stenting --- p.105 / Chapter 9.4.4 --- Subclinical LV myocardial function in coarctation patients --- p.105 / Chapter 9.4.5 --- Limitations --- p.106 / Chapter 9.5 --- CONCLUSIONS --- p.107 / Chapter Chapter10 --- LEFT VENTRICULAR LONG AXIS DYSFUNCTION IN ADULTS WITH "CORRECTED" AORTIC COARCTATION IS RELATED TO AN OLDER AGE AT INTERVENTION AND INCREASED AORTIC STIFFNESS --- p.108 / Chapter 10.1 --- INTRODUCTION --- p.109 / Chapter 10.2 --- METHODS --- p.110 / Chapter 10.2.1 --- Study population --- p.110 / Chapter 10.2.2 --- Echocardiographic examination --- p.111 / Chapter 10.2.3 --- Reproducibility --- p.111 / Chapter 10.2.4 --- Statistics --- p.112 / Chapter 10.3 --- RESULTS --- p.112 / Chapter 10.3.1 --- Patients versus controls --- p.112 / Chapter 10.3.2 --- Patients with long axis dysfunction (LAD) versus without LAD --- p.113 / Chapter 10.3.3 --- Predictors of LAD --- p.117 / Chapter 10.3.4 --- Reproducibility --- p.120 / Chapter 10.4 --- DISCUSSION --- p.120 / Chapter 10.4.1 --- Main findings --- p.120 / Chapter 10.4.2 --- LV dysfunction and adverse remodeling in "corrected" aortic coarctation --- p.120 / Chapter 10.4.3 --- Mechanism behind LV dysfunction in "corrected" aortic coarctation --- p.121 / Chapter 10.4.4 --- Study implications --- p.124 / Chapter 10.4.5 --- Limitations --- p.124 / Chapter 10.5 --- CONCLUSIONS --- p.125 / Chapter Chapter 11 --- DISCUSSION --- p.126 / Chapter 11.1 --- DISCUSSION --- p.127 / Chapter 11.2 --- LIMITATIONS --- p.129 / Chapter 11.3 --- THE FUTURE --- p.129 / Chapter Chapter12 --- CONCLUSIONS --- p.131 / APPENDIX --- p.133 / BIBLIOGRAPHY --- p.134

The projects of this thesis examine the complex interaction between isotonic exercise, functional capacity, exercise-induced myocardial ischaemia, severity of regurgitation and left ventricular function in patients with significant chronic mitral regurgitation. The concept of left ventricular contractile reserve, i.e. the ability of the left ventricle to increase its contractility and decrease its end systolic volume with isotonic exercise, is explored. In patients with chronic isolated mitral regurgitation without coronary disease, isotonic exercise was associated with a slight decrease in left ventricular end diastolic volume but a marked decrease in end systolic volume, resulting in a significant increase in the stroke volume and ejection fraction. Early after uncomplicated mitral valve repair surgery, there was a significant decrease in the left ventricular ejection fraction with a proportion of the patients developing left ventricular dysfunction despite a normal pre-operative ejection fraction. When different pre-operative echocardiographic indices of left ventricular function were evaluated for their ability to predict left ventricular function after mitral valve repair, the exercise indices were found to be superior to resting indices. Left ventricular end systolic volume immediately after exercise was found to be the best predictor. The optimal cut-off was at 25 ml/m2, which had a sensitivity and specificity of 83% in predicting early post-operative left ventricular dysfunction. Exercise indices appeared to be superior to resting indices in identifying patients with persistent left ventricular dysfunction &lt1 year after mitral valve repair. The concept of contractile reserve was further examined by estimating the left ventricular stroke work from simplified pressure-volume loops, which were constructed from non-invasively obtained parameters with geometric assumptions. Left ventricular stroke work immediately after exercise, but not at rest, was found to be significantly lower in patients with latent left ventricular dysfunction. Patients without latent ventricular dysfunction had similar increases in stroke work with exercise compared with healthy normal subjects. The ability of the left ventricle to increase its stroke work with exercise, a measure of the contractile reserve, was correlated with the left ventricular ejection fraction after mitral valve repair. A numerical model was constructed using the clinical data as input parameters. The results from the numerical model were similar to that obtained from the clinical study, testifying that the observation made in the clinical study was valid and independent of the geometric assumptions made in constructing the simplified pressure-volume loops. Left ventricular pressure-volume loops under different loading conditions were plotted from simultaneously measured left ventricular pressure and volume to measure the left ventricular end systolic elastance (Ees) and preload recruitable stroke work relationship (MSW). Despite normal or near normal haemodynamics at rest, a significant proportion of the study patients were found to have impaired left ventricular contractility, as measured by Ees, consistent with a state of latent left ventricular dysfunction. Exercise indices of left ventricular function were better correlated with Ees and MSW than resting indices. There were highly significant inverse relationships between end systolic volume index immediately after exercise and Ees and MSW. Moreover, there was a significant powered relationship between MSW and exercise left ventricular ejection fraction. There was no such relationship between Ees or MSW and any of the resting echocardiographic indices of left ventricular function. Furthermore, the optimal diagnostic cut-off level of end systolic volume index after exercise at 25 ml/m2 accurately identified those with impaired left ventricular contractility as defined by an Ees of &gt 2 mmHg/ml. In patients with chronic organic mitral regurgitation with ejection fraction of &lt 50%, objectively measured functional capacity, VO2max, was correlated with exercise cardiac output, patient age and gender but not to the severity of the mitral regurgitation or the resting left ventricular function. The VO2max of these patients were significantly lower than that of age and gender-matched healthy controls despite these patients' relative lack of subjective symptoms. There were significant individual variations in the response of the severity of the mitral regurgitation to isotonic exercise. Patients whose regurgitant stroke volume increased had a lower exercise cardiac output than those whose regurgitant stroke volume decreased. Such variability was also seen with the response of the left ventricular function to exercise. Patients whose left ventricular end systolic volume increased with exercise, i.e. patients with a limited contractile reserve, had a lower exercise cardiac output and lower VO2max than those whose end systolic volume decreased with exercise. The determinants of exercise capacity were then examined in patients with functional mitral regurgitation and left ventricular dysfunction. VO2max of these patients was correlated with exercise cardiac output and exercise left ventricular ejection fraction, a situation similar to that seen in patients with organic mitral regurgitation and normal left ventricular function. Furthermore, indices of left ventricular systolic function at rest and pulsed wave Doppler indices of diastolic function showed no significant correlations with VO2max. The determinants of VO2max remained unchanged in these patients after four weeks of supervised exercise training. The four weeks of exercise training resulted in a significant decrease in left ventricular end systolic volume, a trend towards an increase in left ventricular ejection fraction and some restoration of the contractile reserve. The total exercise time almost doubled. However, this dramatic improvement in total exercise time was accompanied only by non-significant increases in VO2max and left ventricular ejection fraction. Therefore, the benefits of exercise training in these patients may involve more than just central mechanisms. Exercise induced myocardial ischaemia may also contribute to a limited left ventricular contractile reserve in patients with mitral regurgitation. Electrocardiographic changes at rest are commonly seen in patients with mitral regurgitation due to mitral valve prolapse. These resting electrocardiographic changes make exercise electrocardiography uninterpretable for exercise-induced ischaemia. Exercise electrocardiographic changes are also commonly encountered in these patients despite the absence of coronary artery disease and a normal resting electrocardiogram, making exercise electrocardiography unreliable as a non-invasive screening test for coronary artery disease. In these patients, exercise echocardiography was slightly more sensitive but significantly more specific in diagnosing significant coronary artery disease. The overall accuracy and the positive predictive value were significantly higher for exercise echocardiography than for exercise electrocardiography. The &quotcost-effectiveness&quot of different diagnostic strategies for coronary artery disease in patients with mitral valve prolapse was examined based on the results of the clinical study. Strategies involving exercise electrocardiography as part of the screening test were costly and were associated with a high false negative rate. Strategies involving exercise echocardiography were more accurate and less costly but the initial costs of exercise echocardiography for all patients meant that the overall costs were still considerable. Assessing the pre-test probability of coronary artery disease in these patients and using exercise echocardiography as the initial test for patients with at least a moderate pre-test probability of coronary artery disease seemed to result in the best compromise between cost and effectiveness. The studies of this thesis have shown that a limited cardiac contractile reserve is a sign of latent ventricular dysfunction in patients with chronic mitral regurgitation. The presence of a limited contractile reserve can be used to predict left ventricular dysfunction after mitral valve repair. The concept of a limited contractile reserve is further supported by the finding of a limited increase in left ventricular stroke work with exercise from a theoretical as well as a numerical model of left ventricular pressure-volume loops. Exercise echocardiographic indices show better correlations to invasively measured Ees and MSW than resting indices. VO2max in these patients is determined more by their ability to increase their forward cardiac output with exercise and not by the regurgitant volumes. Exercise training in patients with left ventricular dysfunction and functional mitral regurgitation results in some restoration of contractile reserve. Exercise echocardiography is also a reliable and cost-effective test in the non-invasive screening for coronary artery disease in these patients. Based on the results of the studies in the thesis, one can incorporate exercise echocardiography as one of the important assessment tools in the management of patients with significant mitral regurgitation as it allows measurement of left ventricular volumes and assessment of contractile reserve. Further studies are needed to examine whether a policy of monitoring of contractile reserve in these patients to guide therapy and surgical referral will result in a better preservation of long term left ventricular function, an improvement in functional capacity and patient outcome.

Diss. (sammanfattning) Stockholm : Karolinska institutet, 2009. / Härtill 5 uppsatser.

published_or_final_version / Medical Sciences / Master / Master of Medical Sciences

No description available.

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Diss. (sammanfattning) Göteborg : Göteborgs universitet, 2008. / Härtill 4 uppsatser.

Thesis (Ph. D.)--University of Washington, 2000. / Vita. Includes bibliographical references (leaves 147-157).