Information was collected in an eight and a half month prospective study about 358 recent cardiac disease-related cardiac arrest cases which were attended by personnel from the Provincial Ambulance Service in the Lower Mainland of British Columbia. When possible, advanced life support personnel (EMA Ills), regular ambulance attendants (EMA Ms) and Fire Department staff are dispatched to cardiac arrest calls. At the time of this study some areas in the region did not have advanced life support coverage, and some cardiac arrest calls occurred while the EMA Ills were already engaged with another case. Such calls, attended by EMA lis, but not by EMA Ills, served as the comparison group for paramedic performance in this study. Patient outcomes were compared at admission to hospital and at discharge from hospital for the group of patients treated by EMA Ms and the group of patients treated by EMA Ills, or by a combination of EMA Ills and EMA Ms. Strongly significant differences in initial outcome (hospital admission) were found between the two patient groups, with EMA IM patients faring better (p.=0.002). Marginally significant differences in final outcome (discharge alive) between the two patient groups were found, with the EMA III group again doing better (p.=0.10). Whether or not the receiving hospital had a coronary care unit was not associated with a difference in initial (p.=0.45) or final outcome (p.=1.0) for the entire group of patients in the study. Short time in arrest without CPR was associated with better initial outcome (p.=0.00), and with better final outcome (p.=0.01) for all patients. in the study, as was short time to definitive care (initial outcome p.=0.001; final outcome p.=0.03). EMA II patients had a better chance of survival when they arrested during attendance by EMA lis than they did when they were found in arrest. This study suggests that significantly more cardiac arrest victims reach hospital alive, and more survive to be discharged alive from hospital, when their prehospital treatment is provided by advanced life support personnel than when it is provided by regular ambulance personnel. / Medicine, Faculty of / Population and Public Health (SPPH), School of / Graduate

published_or_final_version / Nursing Studies / Master / Master of Nursing

Like any muscle, cardiac contraction is evoked by action potentials. In the healthy heart, atrial and ventricular activation occur through impulse conduction via the rapid conduction system. Normal cardiac function requires a highly synchronized series of mechanical events occurring in the atria and the ventricles. This synchronization is achieved by rapid conduction of action potentials through the electrical conduction system, which leads to coordinated mechanical activation and deactivation of the myocardium — a process known as electromechanical coupling. As a result of this coordinated electromechanical coupling, the left ventricle functions efficiently as a pump. On the contrary, asynchronous electrical activation leads to asynchronous contraction. The presence of a bundle branch block or other intraventricular conduction delay can worsen heart failure due to systolic dysfunction by causing ventricular dyssynchrony, thereby inducing regional loading disparities and reducing the efficiency of contraction. Consistent with the idea that ventricular dyssynchrony exacerbates left ventricular dysfunction is the observation that a variety of hemodynamic benefits follow the correction of dyssynchrony with cardiac resynchronization therapy (CRT) using biventricular pacing. With decades of research on electromechanical coupling in the heart, it is now recognized that (1) cardiac dyssynchrony worsens ventricular efficiency and contributes to the progression of systolic heart failure; (2) cardiac dyssynchrony can be accurately assessed by echocardiography; (3) cardiac dyssynchrony independently predicts worse prognosis in patients with systolic heart failure; and (4) CRT has established as an effective treatment for systolic heart failure, leading to improved symptomatic status and better survival. / Concerning the subject of cardiac dyssynchrony there are still a lot of unanswered questions which are important to complete understanding of disease mechanisms of heart failure and hence to develop better treatment strategies. First, patients with heart failure but with a preserved ejection fraction (HFPEF) constitutes about half of the heart failure occurrence. Yet, it is not completely understood whether cardiac dyssynchrony, as a potential pathogenic mechanism and therapeutic target, is present in these patients. Second, the heart and circulation is a dynamic system. Nevertheless, scarce data exists on how cardiac dyssynchrony alters in response to exercise and other hemodynamic stressors in patients with heart failure. The potential clinical significance of dynamic dyssynchrony is unknown. Furthermore, identification of precipitating factors of acute hemodynamic decompensation in heart failure is important to prevent recurrent acute exacerbation and hospitalization. Cardiac dyssynchrony has been suspected to be an insidious, potentially correctable trigger of acute decompensated heart failure (ADHF), but scientific evidence is limited. Last but not least, about 30% of the CRT recipients did not respond to the treatment. It was proposed that inadequate optimization of atrioventricular (AV) synchronization is the most common contributory factor, hence the routine practice of AV optimization after CRT implantation. But again, electromechanical coupling is a dynamic process. It is uncertain, however, whether AV optimization should be performed at rest or during exercise to achieve optimal hemodynamic and clinical benefit. / In Part I of this thesis, I will review the literature on heart failure, cardiac dyssynchrony, and exercise impact on the cardiovascular system. In Chapter 1, the definition, clinical classification, and epidemiology of heart failure, as well as the biomechanical model for heart failure progression will be discussed. In Chapter 2, the literature on the normal and pathological electromechanical coupling mechanism, the clinical implication of dyssynchrony in heart failure, and the effect of CRT will be reviewed. In Chapter 3, I will discuss the current understanding of the physiologic effect of exercise, heart rate and stress on cardiac function and synchronicity. In Part II, the hypotheses (Chapter 4) and general objectives (Chapter 5) of the studies included in this thesis will be specified. In Part III, I will describe in detail the general methodology used inthese studies including the study population involved (Chapter 6), the echocardiographic techniques (Chapter 7), and the exercise/pharmacological stress protocols (Chapter 8) used in these studies. / Part IV will be a thorough and logical reporting of the background, methods, findings, discussion, and conclusion of each of the clinical studies of this thesis. Chapter 9, 10 and 11 will focus on patients with preserved ejection fraction and Chapter 12 and 13 will attempt to fill the gap of knowledge of cardiac dyssynchrony in patients with systolic heart failure. / In the study discussed in Chapter 9, the prevalence of left ventricular mechanical dyssynchrony in coronary artery disease with preserved ejection fraction was evaluated. Ninety-four consecutive patients with chronic coronary artery disease and preserved ejection fraction (≥50%) were evaluated using echocardiography with tissue Doppler imaging and compared to 217 patients with depressed ejection fraction and (<50%) and 117 healthy subjects. Left ventricular systolic and diastolic dyssynchrony were determined by measuring the standard deviations of peak systolic (Ts-SD) and early diastolic myocardial (Te-SD) velocities, respectively, using a six-basal/six-mid-segmental model. In patients with coronary artery disease and preserved ejection fraction, both Ts-SD (32.2±17.3 compared with 17.7±8.6 ms; p<0.05) and Te-SD (26.2±13.6 compared with 20.3±8.1 ms; p<0.05) were significantly prolonged when compared with controls, although they were less prolonged than patients with coronary artery disease and depressed ejection fraction (Ts-SD, 37.8±16.5 ms; and Te-SD, 36.0±23.9 ms; both p<0.005). Patients with preserved ejection fraction who had no prior myocardial infarction had Ts-SD (32.9±17.5 ms) and Te-SD (28.6±14.8 ms) prolonged to a similar extent (p=NS) to those with prior myocardial infarction (Ts-SD, 28.4±16.8 ms; and Te-SD, 25.5±15.0 ms). Patients with class III/IV angina or multi-vessel disease were associated with more severe mechanical dyssynchrony (P<0.05). Furthermore, the majority of patients with mechanical dyssynchrony had narrow QRS complexes in those with preserved ejection fraction. This is in contrast with patients with depressed ejection fraction in whom systolic and diastolic dyssynchrony were more commonly associated with wide QRS complexes. / In Chapter 10, focus will be shifted to patients with acute coronary syndrome complicated by acute HFPEF. One hundred two patients presenting with acute coronary syndrome (ejection fraction ≥50%) and 104 healthy controls were studied using tissue Doppler imaging: group 1 (n=55) had HFPEF on presentation and group 2 (n=47) had no clinical HFPEF. Te-SD was found to be greater in group 1 (33±13 ms) than group 2 (21±9 ms) (p<0.001), and diastolic mechanical dyssynchrony was evident in 35% of patients in group 1 but in only 9% in group 2 (p<0.001). Worsening of the diastolic dysfunction grade was associated with a parallel increase in Te-SD (grades 0, 1, 2, and 3: 16±3 ms, 21±5 ms, 28±9 ms, and 41±17 ms, respectively; p<0.001). Te-SD correlated negatively with mean early diastolic basal myocardial velocity (Em) (r=-0.56, p<0.001) and positively with peak mitral inflow velocity of the early rapid-filling wave/Em (r=0.69, p<0.001). Multivariate analysis identified peak mitral inflow velocity of the early rapid-filling wave/Em as the only variable independently associated with HFPEF [odd sratio (OR)=1.48, p=0.001]. When peak mitral inflow velocity of the early rapid-filling wave/Em was excluded from the model, Te-SD (OR=1.13, p<0.001) and mean Em (odds ratio=0.37, p<0.001) became independently associated with HFPEF. / In Chapter 11, I will evaluate the impact of hemodynamic stress on left ventricular dyssynchrony and the relationship and predictive value of dynamic changes of left ventricular dyssynchrony on hypertensive HFPEF. In this study, a total of 131 subjects including 47 hypertensive HFPEF patients, 34 hypertensive patients with left ventricular hypertrophy without HFPEF, and 50 normal controls were studied by dobutamine stress echocardiography with tissue Doppler imaging. In normal controls, systolic and diastolic dyssynchrony did not develop during stress. The prevalence of resting systolic (36.2% vs. 38.2%, p=0.85) and diastolic (34.0% vs. 29.4%, p=0.66) dyssynchrony was similar in patients with HFPEF and left ventricular hypertrophy. During stress, the prevalence of systolic and diastolic dyssynchrony increased dramatically to 85.1% and 87.2%, respectively, in patients with HFPEF, but only 52.9% and 58.8% in patients with left ventricular hypertrophy (p<0.005). In HFPEF group, stress-induced increase in mean systolic basal myocardial velocity (Sm) was significantly blunted (2.8±2.0 vs. 4.2±2.4 cm/s, p=0.004), and the increase was abolished for mean Em (-0.3±2.5 vs. 2.4±3.4 cm/s, p<0.001). On multivariate analysis, stress-induced changes in mean Em (OR=0.69, p=0.004) and mean Sm (OR=0.56, p=0.004), and diastolic (OR=4.6, p=0.005) and systolic dyssynchrony during stress (OR=4.3, p=0.038) were independent determinants for occurrence of HFPEF. / In Chapter 12, the role of dyssynchrony in patients with systolic heart failure presentating with acute decompensation (ADHF) will be studied. In this study, it was hypothesized that acute left ventricular systolic dyssynchrony might be a hidden triggering mechanism for ADHF. Echocardiography with tissue Doppler imaging was performed in 145 subjects with systolic heart failure (ejection fraction <50%), including 84 consecutive patients presented with ADHF requiring hospitalization, comparing them to 61 chronic stable heart failure patients who had no heart failure exacerbation or hospitalization in the past 6 months. The ADHF group was observed to have higher heart rate on admission than patients with stable heart failure (82±15 vs 68±13 bpm, P<0.001), greater left ventricular wall thicknesses and mass (all P<0.05), and mitral regurgitation was more common (71% vs 46%, P<0.0001; ERO=0.12±0.11 vs 0.02±0.04 cm2, P<0.0001), but the overall severity of mitral regurgitation was mild or moderate. Despite no difference in ejection fraction, the ADHF group had significantly lower mean Sm (2.7±0.9 cm/s vs 3.0±0.9 cm/s, P=0.04). The Ts-SD was significantly prolonged in the ADHF group compared to patients with stable heart failure (44.7±16.6 vs 33.4±17.7 ms, P=0.0001). Significant left ventricular systolic dyssynchrony was evident in 75% (63 of 84) of patients of the ADHF group, compared to only 44% (27 of 61) of patients with chronic stable heart failure (P=0.0002). / In Chapter 13, I will focus on the role of dynamic AV dyssynchrony during exercise in patients with systolic heart failure who receive CRT. AV delay in CRT recipients are typically optimised at rest. However, there are limited data on the impact of exercise-induced changes in heart rate on the optimal AV delay and left ventricular function. In this study, AV delays were serially programmed in 41 CRT patients with intrinsic sinus rhythm at rest and during two stages of supine bicycle exercise with heart rates at 20 bpm (stage I) and 40 bpm (stage II) above baseline. The optimal AV delay during exercise was determined by the iterative method to maximise cardiac output using Doppler echocardiography. Results were compared to physiological change in PR intervals in 56 normal controls during treadmill exercise. The optimal AV delay was progressively shortened (p<0.05) with escalating exercise level (baseline: 123±26 ms vs. stage I: 102±24 ms vs stage II: 70±22 ms, p<0.05). AV delay optimisation led to a significantly higher cardiac output than without optimisation did during stage I (6.2±1.2 l/min vs. 5.2±1.2 l/min, p<0.001) and stage II (6.8±1.6 l/min vs. 5.9±1.3 l/min, p<0.001) exercise. A linear inverse relationship existed between optimal AV delays and heart rates in CRT patients (AV delay=241-1.61 x heart rate, R²=0.639, p<0.001) and healthy controls (R²=0.646, p<0.001), but the slope of regression was significantly steeper in CRT patients (p<0.001). / In conclusion, the works included in this thesis provide new evidence that left ventricular mechanical dyssynchrony is common in patients with coronary artery disease and preserved ejection fraction, even in patients without prior myocardial infarction or evidence of eletromechanical delay. In particular, left ventricular diastolic mechanical dyssynchrony may impair diastolic function and contribute to the pathophysiology of HFPEF during acute coronary syndrome. Moreover, dynamic dyssynchrony and impaired myocardial longitudinal function reserve during stress may contribute importantly to the pathophysiology of hypertensive HFPEF. In patients with heart failure and reduced ejection fraction, a high prevalence of left ventricular systolic dyssynchrony during acute decompensation suggests that acute or dynamic left ventricular systolic dyssynchrony may be an important precipitating factor and a potential therapeutic target. Progressive shortening of hemodynamically optimal AV delay with increasing heart rate during exercise suggests that dyssynchrony is dynamic and there may be a need for programming of rate-adaptive AV delay in CRT recipients to optimise clinical response. I believe this work will provide new understanding of the prevalence, mechanism, and clinical significance of cardiac dyssynchrony in heart failure. / Lee, Pui Wai. / Thesis (M.D.))--Chinese University of Hong Kong, 2015. / Includes bibliographical references (leaves 138-174). / Title from PDF title page (viewed on 24, October, 2016).

儘管心力衰竭的診斷和治療已取得了長足進步，但是心力衰竭依然是目前主要的致殘和致死病因。而且，隨著人口的老齡化，心力衰竭的發病率不斷上升。然而心力衰竭的快速診斷、心功能評價以及患者的危險分層依然面臨眾多挑戰。Acoustic cardiography 是一項經濟簡單的新技術。憑藉獨有的雙功能感測器，這項技術可以同時評估收縮間期（systolic time intervals）以及舒張期心音（diastolic heart sounds）。這項技術提供的主要參數包括：第三心音分數（S3 score；第三心音存在的可能性），電機械時間（EMAT, electromechanical activation time；從心電圖Q 波到心音圖第一心音的時間）及電機械時間比例（%EMAT；電機械時間占整個心動週期的比例），收縮障礙指數（SDI, systolic dysfunctionindex）。本論文主要涵蓋Acoustic cardiography 在心力衰竭患者中如下三個方面 的應用： / 一、心力衰竭的診斷和不同亞型的識別 / 本研究入組了 94 名高血壓但無心力衰竭患者、109 名射血分數正常的心力衰竭患者以及89 名射血分數減低的心力衰竭患者，我們發現%EMAT 可以鑒別射血分數正常的心力衰竭和高血壓患者。另一方面，SDI 是鑒別分射血分數正常和射血分數減低患者的最好指標。 / 二、心力衰竭患者心功能障礙嚴重程度評估 / 此研究共招募 94 名高血壓患者和127 名射血分數減低的心力衰竭患者。結果顯示：SDI 可以鑒別射血分數減低的心力衰竭和高血壓患者。亞組分析顯示：SDI 可以區分射血分數嚴重減低和中度減低的心力衰竭患者；S3 score 可以識別伴舒張功能嚴重障礙的心力衰竭患者。 / 三、心力衰竭患者的危險分層 / 共計 474 名心力衰竭患者被納入此研究，平均隨訪時間484±316 天，169名患者死亡，其中125 名死於心臟病。SDI 和S3 score 都是全因死亡率的獨立預測因數；Kaplan Meier 分析顯示：SDI ≥ 5 或S3 score ≥ 4.12 的心力衰竭患者的生存率顯著降低。 / 通過以上三個方面的研究，我們發現這項新技術有助於（1）心力衰竭的診斷和不同亞型的識別；（2）評估心力衰竭患者的心功能障礙嚴重程度，進而發現其中的高危人群；（3）心力衰竭患者的危險分層。因此，這項新技術有望在心力衰竭患者的管理中扮演早期診斷、評估以及危險分層的重要角色。 / Despite recent advances in its management, heart failure remains a major cause of disability and death and its prevalence is still increasing as the population ages. However, rapid and accurate bedside diagnosis, evaluation as well as risk stratification of heart failure still remain challenging. / Acoustic cardiography (AUDICOR, Inovise Medical, Inc., Portland, OR, USA) is a novel and user friendly equipment which can be used in a wide variety of clinical conditions. With proprietary dual-functional sensors, this technology permits simultaneous acquisition of detailed information regarding systolic time intervals and diastolic heart sounds and provides a computerized interpretation of the findings. Major acoustic cardiographic parameters include S3 score (probability that the third heart sound exists), electromechanical activation time (EMAT, interval from Q wave to the first heart sound; %EMAT is the proportion of cardiac cycle that EMAT occupies), and systolic dysfunction index (SDI= exp [S3 score/10] x QRS interval x QR interval x %EMAT).This thesis will cover 3 aspects of clinical application of acoustic cardiography in heart failure patients. / I. Identification of heart failure and its phenotypes / We performed one study involving 94 patients with hypertension without heart failure, 109 patients with heart failure with normal ejection fraction (HFNEF, EF > 50%) and 89 patients with heart failure and reduced ejection fraction (HFREF, EF < 50%). We found that %EMAT significantly differentiated HFNEF from hypertension. Whereas SDI out-performed the other acoustic cardiographic parameters in differentiating HFREF from HFNEF. / II. Assessment of HFREF patients at high risk by evaluating the severity of left ventricular (LV) systolic and diastolic dysfunction / Ninety-four hypertensive patients without heart failure and 127 HFREF patients (EF < 50%) were consecutively recruited for the study. SDI significantly differentiated HFREF from hypertension. In subgroup analysis, SDI discriminated HFREF patients with severely impaired EF (EF ≤ 35%) from those with moderately impaired EF (35% < EF <50%). S3 score > 4.67 identified HFREF patients with restrictive LV filling pattern. / III. Risk stratification in patients with heart failure / A total of 474 patients hospitalized for heart failure were enrolled into our study. During a mean follow-up time of 484±316 days, 169 (35.7%) patients died and 125 (26.4%) of them died of cardiac causes. After controlling for other potential confounders, we found that S3 score ≥ 4.12, and SDI ≥ 5 were both independent predictors for all-cause mortality. Kaplan-Meier analysis showed that heart failure patients with SDI ≥ 5 or S3 score ≥ 4.12 had a significantly lower survival rate than those with lower SDI or S3 score. / In summary, this bedside technology offers a wide variety of clinical applications in (1) identification of heart failure and its phenotypes; (2) assessmet of HFREF patients at high risk by evaluating the severity of LV systolic and diastolic dysfunction; (3) risk stratification in patients with heart failure. Thus, acoustic cardiography is likely to be helpful in the management of heart failure patients, acting as an early detection, evaluation and risk-stratification tool. / Detailed summary in vernacular field only. / Detailed summary in vernacular field only. / Detailed summary in vernacular field only. / Detailed summary in vernacular field only. / Detailed summary in vernacular field only. / Detailed summary in vernacular field only. / Detailed summary in vernacular field only. / Detailed summary in vernacular field only. / Wang, Shang. / Thesis (Ph.D.)--Chinese University of Hong Kong, 2012. / Includes bibliographical references (leaves 123-135). / Abstract also in Chinese. / DECLARATION OF ORIGINALITY --- p.i / ACKNOWLEDGEMENTS --- p.ii / PUBLICATIONS RELATED TO THIS THESIS --- p.iv / Full publications --- p.iv / Conference presentations --- p.v / TABLE OF CONTENTS --- p.vi / LIST OF TABLES --- p.xi / LIST OF FIGURES --- p.xiii / LIST OF ABBREVIATIONS --- p.xv / ABSTRACT --- p.xviii / 論文摘要 --- p.xx / Chapter PART I --- LITERATURE REVIEW --- p.1 / Chapter Chapter 1 --- Introduction to Acoustic Cardiography --- p.2 / Chapter 1.1 --- History of auscultation, phonocardiography --- p.2 / Chapter 1.2 --- STIs --- p.3 / Chapter 1.2.1 --- Conventional STIs --- p.3 / Chapter 1.1.2 --- Echocardiographic STI --- p.5 / Chapter 1.3 --- Acoustic cardiography --- p.7 / Chapter 1.3.1 --- ECG parameters of acoustic cardiography --- p.11 / Chapter 1.3.2 --- Systolic parameters of acoustic cardiography --- p.12 / Chapter 1.3.3 --- Diastolic Parameters of acoustic cardiography --- p.13 / Chapter 1.4 --- Comparison between acoustic cardiography and traditional phonocardiography --- p.19 / Chapter Chapter 2 --- Clinical Application of Acoustic Cardiography --- p.27 / Chapter 2.1 --- Mechanism of generation of S3 and S4 --- p.27 / Chapter 2.2 --- Prevalence of S3 and S4 --- p.28 / Chapter 2.3 --- Clinical auscultation of S3 and S4 problems --- p.29 / Chapter 2.4 --- Rapid identification of heart failure or LV dysfunction --- p.32 / Chapter 2.4.1 --- S3 and S4 --- p.32 / Chapter 2.4.2 --- EMAT --- p.33 / Chapter 2.4.3 --- SDI --- p.34 / Chapter 2.4.5 --- Other derived acoustic cardiographic parameters --- p.34 / Chapter 2.5 --- Predicting elevated LV filling pressure --- p.35 / Chapter 2.6 --- Improving diagnostic utility of BNP in detection of heart failure or LV dysfunction --- p.36 / Chapter 2.7 --- Hemodynamic correlations of acoustic cardiographic parameters --- p.37 / Chapter 2.8 --- Prognostic value of acoustic cardiography --- p.38 / Chapter 2.9 --- Cardiac resynchronization therapy --- p.39 / Chapter 2.10 --- Detection of ischemia --- p.40 / Conclusions --- p.42 / Chapter PART II --- STUDIES ON APPLICATION OF ACOUSTIC CARDIOGRAPHY --- p.48 / Chapter Chapter 3 --- Acoustic Cardiography Helps to Identify Heart Failure and Its Phenotypes --- p.49 / Introduction --- p.49 / Methods --- p.50 / Participants and study design --- p.50 / Echocardiography --- p.51 / Acoustic cardiography --- p.52 / Assessment of reproducibility --- p.55 / Statistical analysis --- p.55 / Results --- p.56 / Characteristics of study subjects --- p.56 / Acoustic cardiographic and echocardiographic characteristics --- p.59 / Diagnostic characteristics of acoustic cardiography --- p.64 / Analysis of covariance results --- p.68 / Inter-operator reproducibility --- p.68 / Discussion --- p.68 / Chapter Chapter 4 --- Rapid Bedside Identification of High-Risk Population in Heart Failure with Reduced Ejection Fraction by Acoustic Cardiography --- p.72 / Introduction --- p.72 / Methods --- p.73 / Study population --- p.73 / Echocardiography --- p.73 / Acoustic cardiography --- p.74 / Assessment of reproducibility --- p.74 / Statistical analysis --- p.74 / Results --- p.75 / Baseline characteristics of study subjects --- p.75 / Acoustic cardiographic and echocardiographic characteristics --- p.78 / Diagnostic test characteristics of acoustic cardiography --- p.84 / Analysis of covariance results --- p.89 / Inter-operator reproducibility --- p.89 / Discussion --- p.89 / Chapter Chapter 5 --- Prognostic value of Acoustic Cardiography in Risk Stratification of Patients With Heart Failure --- p.93 / Introduction --- p.93 / Methods --- p.94 / Study population --- p.94 / Acoustic cardiography --- p.94 / Echocardiography --- p.94 / Endpoint --- p.95 / Assessment of reproducibility --- p.95 / Statistical analysis --- p.95 / Results --- p.96 / Study population --- p.96 / All-cause mortality --- p.100 / Cardiac death --- p.100 / Subgroup analysis in 232 patients undergoing echocardiography --- p.107 / Inter-operator reproducibility --- p.107 / Discussion --- p.114 / Strengths and potential limitations --- p.115 / Chapter PART III --- CONCLUSIONS --- p.117 / Chapter Chapter 6 --- Summary of the Present Studies --- p.118 / Chapter I. --- Identification of heart failure and its phenotypes --- p.118 / Chapter II. --- Assessment of HFREF patients at high risk by evaluating the severity of LV systolic and diastolic dysfunction --- p.119 / Chapter III. --- Risk stratification in patients with heart failure --- p.119 / Chapter Chapter 7 --- Future Research Directions --- p.121 / References --- p.123

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

Thesis (M.Sc. (Chemical Pathology) --University of Limpopo, 2013 / Cardiovascular diseases (CVDs) are among one of the well documented conditions and pose a significant health burden in the world as they areconsidered to be of adult onset. However, recent studies have shown that in developed countries CVD risk factors are becoming prevalent in young people which isof great concern. Therefore, the aim of this study was to determine if CVD risk factors are present in young subjects aged 15-20 years of age residing in a rural area of a developing country. Methods: Subjects aged between 15-20 years who participated in the “Gene - Environment interaction project” were included in this sub-study. Total cholesterol, triglycerides, HDL-cholesterol, LDLcholesterol, insulin, glucose, creatinine, Lp(a), apoB, apoA-1 and hs-CRPwere determined. Blood pressure, physical activity (number of steps/day), weight, height, waist circumference and hip circumference were obtained from the database. Subjects with CRP levels above 10mg/L and creatinine levels above 130 mmol/L were excluded. Results: The present study showed an overall high prevalence of some CVD risk factors. There was high prevalence of insulin resistance (23.0% in females and 34.7% in males), and high hs-CRP (18.4% in females, 12.9% in males). The prevalence of low HDL-C levels was high (55.2% in females and 16.8 % in males), however, the prevalence of abnormal levels of other lipids such as total cholesterol/HDL-cholesterol ratio was low in both males and females. The prevalence of an increased apoB/apoA ratio was significantly higher in females 26.4% compared to males 7.9%. The prevalence of overweight (12.6%) and obesity (9.2%) was higher in females than in males (overweight 1%, obesity 0 %). The prevalence of hypertension was comparable between the two genders (5.7% in females and 10.9 % in males). Conclusion: The results showed a relatively high prevalence of non-traditional risk factors for cardiovascular diseases in adolescents residing in a rural area, Limpopo Province, while the prevalence of traditional risk factors such as total cholesterol and triglycerides was low.

A Tissue Engineering (TE) approach to heart valve replacement has the aim of producing an implant that is identical to healthy tissue in morphology, function and immune recognition. The aim is to harvest tissue from a patient, establish cells in culture from this tissue and then use these cells to grow a new tissue in a desired shape for the implant. The scaffold material that supports the growth of cells into a desired shape may be composed of a biodegradable polymer that degrades over time, so that the final engineered implant is composed entirely of living tissue. The approach used at Swinburne University was to induce the desired mechanical and functional properties of tissue and is to be developed in an environment subjected to flow stresses that mimicked the haemodynamic forces that natural tissue experiences. The full attainment of natural biomechanical and morphological properties of a TE structure has not as yet been demonstrated. In this thesis a review of Tissue Engineering of Heart Valves (TEHVs) is presented followed by an assessment of biocompatible materials currently used for TEHVs. The thrust of the work was the design and development of a Bioreactor (BR) system, capable of simulating the corresponding haemodynamic forces in vitro so that long-term cultivation of TEHVs and/or other structures can be mimicked. A full description of the developed BR and the verification of its functionality under various physiological conditions using Laser Doppler Anemometry (LDA) are given. An analysis of the fluid flow and shear stress forces in and around a heart valve scaffold is also provided. Finally, preliminary results related to a fabricated aortic TEHV-scaffold and the developed cell culture systems are presented and discussed. Attempts to establish viable cell lines from ovine cardiac tissue are also reported.

Thesis (Ph. D.)--School of Electrical and Computer Engineering, Georgia Institute of Technology, 2004. Directed by Paul J. Benkeser. / Vita. Includes bibliographical references.

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