Thesis (Ph. D.)--University of Hong Kong, 2000. / Includes bibliographical references (leaves 140-173).

Abstract Introduction The study aimed to assess and improve the quality of care for congestive cardiac failure in a public sector, primary health care setting, in Cape Town. There is currently no literature available on the quality of care for the management of congestive cardiac failure in primary health care in South Africa. Methods A disease register was constructed by identifying patients prescribed Furosemide and checking the medical records. Altogether 95 patients with CCF were identified. The study followed the usual steps for a quality improvement cycle: Formation of an audit team; agreeing on criteria based on current CCF guidelines; collection of data from medical records to measure the criteria; analysis and feedback of results to the staff; critical reflection, planning and implementing change; re-audit of the medical records. Results There was a mean age of 63.4 years, 21% were male and 75% were females. The results of the initial audit revealed suboptimal management of patients diagnosed with CCF: 53% had an aetiological diagnosis recorded in the clinical notes, 24% had a documented functional capacity, 12% of patients had documented precipitating/exacerbating factors, 58% had fluid status documented, and 37% had documentation of their cardiac rate and rhythm. The intervention consisted of feedback on the audit results and critical reflection with the relevant staff members. The doctors were provided with a printed protocol to refer to for the management of CCF. Clinicians were resistant to change and to taking on new tasks in relation to the management of patients with CCF and decided to only focus on improving the clinical assessment of patients. The results of the re-audit after 5-months in 40 patients demonstrated improvement in the clinical assessment criteria: 95% of the patients had an aetiological diagnosis recorded in the notes, 50% had a documented functional capacity, 42% had documented precipitating/exacerbating factors documented, 72% had their fluid status documented, and 85% of patients had their cardiac rate and rhythm documented. None of the five assessment criteria were met at baseline but post-intervention three of the five met the target set and all showed substantial improvement. There was no improvement noted in any of the other criteria, which were not specifically focused on in the plan to improve clinical practice. Conclusion The current quality of care for CCF in primary health care is poor and needs to be improved. The quality improvement cycle led to substantial improvement in the clinical assessment of patients with CCF. Recommendations are made regarding future criteria, which could be included in local audit tools.

Hypertension is associated with marked cardiac sympathetic over-activity and end organ hyper-responsiveness. The sympathetic dysfunction is caused by aberrant calcium (Ca²⁺) handling resulting in enhanced neurotransmission. However, it remains unclear whether the sympathetic neuron or the myocytes is the primary driver behind the initiation and maintenance of the autonomic phenotype. The work in this thesis characterises the Ca²⁺ dysfunction and regulation at the membrane level. Further, it employs physiologically coupled sympathetic neurons and ventricular myocytes to determine the cellular driver of cardiac dysautonomia in the pro-hypertensive state. <b>Chapter 1</b> provides a general overview of the field of autonomic hypertension with a specific focus on the sympathetic control of cardiac excitability. In particular, the role of Ca²⁺ and cyclic nucleotides in the facilitation of neurotransmission are explored. <b>Chapter 2</b> details the methods used in this thesis. It provides rationale for the approaches taken to record membrane Ca2+ currents, cyclic adenosine monophosphate (cAMP) levels and cAMP-activated protein kinase (PKA) activity, and the development and uses of a co-culture of coupled sympathetic neurons and ventricular myocytes. <b>Chapter 3</b> describes the successful development of an effective voltage clamp method to isolate whole cell Ca²⁺ currents in sympathetic neurons. It details the issue of space clamp problem when using this technique on peripheral neurons and provides experimental guidance on how to quantify and limit theses issues. <b>Chapter 4</b> identifies that the pro-hypertensive four-week old neurons from the spontaneously hypertensive rat (SHR) have significantly larger whole cell Ca²⁺ currents when compared to normotensive (Wistar Kyoto-WKY) neurons, that are largely N-type in nature. Restoring the cGMP cyclic nucleotide dysfunction seen in these cells, rescues the ion channel phenotype and bring the Ca²⁺ down to levels seen in the normotensive WKY neuron. Further, it identifies that phosphodiesterase (PDE) 2A inhibition differentially affects the currents in the WKY and SHR, further supporting the notion of PDE2A dominance. <b>Chapter 5</b> identifies the presence and functional relevance of cGMP cross-talk with the cAMP-PKA pathway in sympathetic neurons. This cross talk is significantly altered in the pro-hypertensive state, via the differential involvement of PDEs. It functionally identifies the presence of PDE3 and PDE2A and provides further evidence that these enzymes could be dysregulated in pro-hypertensive neurons. <b>Chapter 6</b> describes the use of a co-culture model of ventricular myocytes and sympathetic neurons. Physiological stimulation of the sympathetic neuron with nicotine whilst monitoring cAMP levels in the myocytes confirms that the cellular phenotypes seen in the individual cells are functionally present in the co-culture. Using cross-cultures, it identifies the neuron as the principal driver behind the cardiac sympathetic responses observed in pro-hypertension. The results provide evidence for a dominant role played by the neuron in driving the adrenergic phenotype seen in cardiovascular disease and highlights the potential of using healthy neurons to turn down the gain of neurotransmission, akin to a smart pre-synaptic &beta;-blocker. <b>Chapter 7</b> forms the concluding discussion that summarises the main findings of this thesis and attempt to place it in a clinical context, and highlights avenues of further research. In particular, the possibility of using a cell therapeutic approach to treat sympathetic hyperactivity.

No description available.

Background-Emergency 9-1-1 callers use a wide range of terms to describe abnormal breathing in persons with out-of-hospital cardiac arrest (OHCA). These breathing descriptors can obstruct the telephone cardiopulmonary resuscitation (CPR) process. Methods and Results-We conducted an observational study of emergency call audio recordings linked to confirmed OHCAs in a statewide Utstein-style database. Breathing descriptors fell into 1 of 8 groups (eg, gasping, snoring). We divided the study population into groups with and without descriptors for abnormal breathing to investigate the impact of these descriptors on patient outcomes and telephone CPR process. Callers used descriptors in 459 of 2411 cases (19.0%) between October 1, 2010, and December 31, 2014. Survival outcome was better when the caller used a breathing descriptor (19.6% versus 8.8%, P<0.0001), with an odds ratio of 1.63 (95% confidence interval, 1.17-2.25). After exclusions, 379 of 459 cases were eligible for process analysis. When callers described abnormal breathing, the rates of telecommunicator OHCA recognition, CPR instruction, and telephone CPR were lower than when callers did not use a breathing descriptor (79.7% versus 93.0%, P<0.0001; 65.4% versus 72.5%, P=0.0078; and 60.2% versus 66.9%, P=0.0123, respectively). The time interval between call receipt and OHCA recognition was longer when the caller used a breathing descriptor (118.5 versus 73.5 seconds, P<0.0001). Conclusions-Descriptors of abnormal breathing are associated with improved outcomes but also with delays in the identification of OHCA. Familiarizing telecommunicators with these descriptors may improve the telephone CPR process including OHCA recognition for patients with increased probability of survival.

No description available.

Heart failure patients have dysfunction of the cardiac conduction system that contributes to a high burden of arrhythmias including atrial fibrillation and sudden cardiac death. Heart failure has been associated with the inflammatory response, but it is unknown if inflammation is playing a role in the remodelling of the cardiac conduction system in heart failure. Inflammation has been shown to be present in the myocardium from failing hearts and it is known to have detrimental effects on cardiac function, inducing fibrosis, remodelling of ion channels and even arrhythmias. However, the effect of inflammation on the cardiac conduction system has not been investigated. The aims of this study were to determine if there is an increase of pro-inflammatory cytokines and inflammatory cells in the cardiac conduction system in heart failure. In addition, to identify if there is possible inflammation-associated fibrosis and apoptosis in the cardiac conduction system in heart failure. To test these aims, three models of heart failure were used: a rat model of pulmonary arterial hypertension, a rabbit model of congestive heart failure and a rat model of myocardial infarction. In the rat model of pulmonary arterial hypertension there was a bradycardia, a prolongation of the QT interval, and an increase in the atrioventricular and ventricular refractory periods, suggesting electrical remodelling in these animals. The rats with pulmonary arterial hypertension displayed an increase in pro-inflammatory cytokines such as interleukins 1β and TGFβ in the right side of the heart, including the sinoatrial node and right Purkinje fibres of the cardiac conduction system. In addition, in these areas, there was an increase in components of the extracellular matrix, including fibronectin, collagen I and vimentin. Histology revealed regions of non-myocyte nuclei, only in the right ventricle of the rats with pulmonary arterial hypertension. Immunohistochemistry demonstrated patches of CD68 and vimentin expression (markers for macrophages and fibroblasts, respectively) in the right side of the heart in these animals. TUNEL staining also revealed an increase in apoptosis in the right side of the heart. In the rabbit model of congestive heart failure, the region most affected by inflammation was the right atrium, while few changes were measured in the ventricles or cardiac conduction system. Although these results are surprising, it is suggested that the atria could be more sensitive to the physical stretch produced in this model. In the rat model of myocardial infarction, there were regions of non-myocyte nuclei in the border zone. This region also had increases in pro-inflammatory and fibrosis markers. In conclusion, this work has presented the novel finding that there can be inflammation in the cardiac conduction system in heart failure. This could be contributing to the arrhythmias seen in heart failure patients. This could possibly lead the way to anti-inflammatories as a possible novel therapeutic for heart failure patients.

Cardiovascular disease is prevalent across the western world and is a major cause of morbidity and mortality, accounting for approximately a third of all fatalities. Investigating the heart by simulating its electrophysiology via the aid of mathematical models has advanced significantly over the past 60 years and is now a well established field. While much of the research focus is placed on the ventricles, the study of the atria is in comparison neglected. Therefore this Thesis is focused on the genesis and maintenance of atrial fibrillation (AF). A series of case studies are performed whereby established biophysically detailed mathematical models are implemented and modified to incorporate electrophysical alterations of atrial cells resulting from a variety of external conditions. The opening section of this Thesis is dedicated to developing a background to the field, including a discussion into the clinical aspect of the diagnosis and management of AF. The suitability of two atrial cell models is discussed and the development of single cell, 1D, 2D, and 3D multi-scale simulation protocols are described in detail. In addition measurements taken to quantify the arrhythmogenic properties of the cells susceptibility to AF are outlined. The second section is focused on the incorporation of conditions thought to enhance atrial tissues ability to initiate and maintain the genesis of AF. Included is a case study into the missence S140G gene mutation, and elevated physiological levels of the hormone Homocystein. The third section investigates the effectiveness of well established and widely used pharmacological treatments such as Beta-Blockers. In addition possible avenues of investigations for the development of atrial specific drugs are explored. These include blocking of the ultra rapid potassium channel and a more novel target for therapy via the targeting of 5HT4 receptors; which is transcribed solely in the atria and alters the electrophysical properties of the L-type Calcium current. The final part of this Thesis is dedicated to the development of a 2D atrial sheet model which includes electrical and spatial heterogeneities via the inclusion of multiple cell types and basic fiber orientation respectively. This allows for an investigation into the role that heterogeneities play in role genesis and maintenance of AF. The main finding of this Thesis is that alterations to the electrophysiology of atrial cells, due to external factors, can be successfully simulated via the implementation of mathematically detailed atrial cell models. It is concluded that simulations of the KENQ1 mutation and elevated levels of Homocystein successfully reproduce conditions which increase the onset of AF. Established treatments such as Beta-Blockers are found to have limited effectiveness. Possible theoretical treatments, such as the blocking of IKur, are found to provide a small amount of therapeutic benefit. In contrast, investigations into the effects of Serotonin were inconclusive. The study into the 2D atria indicated the importance that heterogeneities play in atria. The conclusions show that models provide a powerful tool when investigating how changes to electrophysiology of cells are manifested at a multi-scale level. The models also have their limitations and require further advancement to improve their accuracy.

Several studies have been carried out recently with the aim of achieving cardiac modelling of the whole heart for a full heartbeat. However, within the context of the Galerkin method, those simulations require high computational demand, ranging from 16 - 200 CPUs, and long calculation time, lasting from 1 h - 50 h. To solve this problem, this research proposes to make use of a Reduced Order Method (ROM) called the Proper Orthogonal Decomposition with Interpolation method (PODI) to achieve real-time modelling with an adequate level of solution accuracy. The idea behind this method is to first construct a database of pre-computed full-scale solutions using the Element-free Galerkin method (EFG) and then project a selected subset of these solutions to a low dimensional space. Using the Moving Least Square method (MLS), an interpolation is carried out for the problem-at-hand, before the resulting coefficients are projected back to the original high dimensional solution space. The aim of this project is to tackle real-time modelling of a patient-specific heart for a full heartbeat in different stages, namely: modelling (i) the diastolic filling with variations of material properties, (ii) the isovolumetric contraction (IVC), ejection and isovolumetric relation (IVR) with arbitrary time evolutions, and (iii) variations in heart anatomy. For the diastolic filling, computations are carried out on a bi-ventricle model (BV) to investigate the performance and accuracy for varying the material parameters. The PODI calculations of the LV are completed within 14 s on a normal desktop machine with a relative L₂-error norm of 6x10⁻³. These calculations are about 2050 times faster than EFG, with each displacement step generated at a calculation frequency of 1074 Hz. An error sensitivity analysis is consequently carried out to find the most sensitive parameter and optimum dataset to be selected for the PODI calculation. In the second phase of the research, a so-called "time standardisation scheme" is adopted to model a full heartbeat cycle. This is due to the simulation of the IVC, ejection, and IVR phases being carried out using a displacement-driven calculation method which does not use uniform simulation steps across datasets. Generated results are accurate, with the PODI calculations being 2200 faster than EFG. The PODI method is, in the third phase of this work, extended to deal with arbitrary heart meshes by developing a method called "Degrees of freedom standardisation" (DOFS). DOFS consists of using a template mesh over which all dataset result fields are projected. Once the result fields are standardised, they are consequently used for the PODI calculation, before the PODI solution is projected back to the mesh of the problem-at-hand. The first template mesh to be considered is a cube mesh. However, it is found to produce results with high errors and non-physical behaviour. The second template mesh used is a heart template. In this case, a preprocessing step is required where a non-rigid transformation based on the coherent point drift method is used to transform all dataset hearts onto the heart template. The heart template approach generated a PODI solution of higher accuracy at a relatively low computational time. Following these encouraging results, a final investigation is carried out where the PODI method is coupled with a computationally expensive gradient-based optimisation method called the Levenberg- Marquardt (PODI-LVM) method. It is then compared against the full-scale simulation one where the EFG is used with the Levenberg-Marquardt method (EFG-LVM). In this case, the PODI-LVM simulations are 1025 times faster than the EFG-LVM, while its error is less than 1%. It is also observed that since the PODI database is built using EFG simulations, the PODI-LVM behaves similarly to the EFG-LVM one.

The present study was designed to explore the protective effects of melatonin and its analogs, 6-hydroxymelatonin and 8-methoxy-2-propionamidotetralin, on the survival of doxorubicin-treated mice and on doxorubicin-induced cardiac dysfunction, ultrastructural alterations, and apoptosis in mouse hearts. Whereas 60% of the mice treated with doxorubicin (25 mg/kg ip) died in 5 days, almost all the doxorubicin-treated mice survived when melatonin or 6-hydroxymelatonin (10 mg/l) was administered in their drinking water. Perfusion of mouse hearts with 5 μM doxorubicin for 60 min led to a 50% suppression of heart rate × left ventricular developed pressure and a 50% reduction of coronary flow. Exposure of hearts to 1 μM melatonin or 6-hydroxymelatonin reversed doxorubicin-induced cardiac dysfunction. 8-Methoxy-2-propionamidotetralin had no protective effects on animal survival and on in vitro cardiac function. Infusion of melatonin or 6-hydroxymelatonin (2.5 μg/h) significantly attenuated doxorubicin-induced cardiac dysfunction, ultrastructural alterations, and apoptosis in mouse hearts. Neither melatonin nor 6-hydroxymelatonin compromised the antitumor activity of doxorubicin in cultured PC-3 cells. These results suggest that melatonin protect against doxorubicin-induced cardiotoxicity without interfering with its antitumor effect.