CUHK electronic theses & dissertations collection

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