University of Macau / Institute of Chinese Medical Sciences

Diss. (sammanfattning) Stockholm : Karol. inst. / Härtill 5 uppsatser.

Thesis (Ph. D.)--University of Wisconsin--Madison, 1975. / Typescript. Vita. eContent provider-neutral record in process. Description based on print version record. Bibliography: leaves 102-112.

Includes bibliographical references (leaves 147-180). / Chronic valvular heart disease is characterised by compensatory mechanisms that result in a long asymptomatic phase associated with variable disease progression. After the development of symptoms or left ventricular dysfunction, mortality is high without surgical intervention. Currently there is no known medical therapy that influences disease progression or clinical outcome. While the development of symptoms or left ventricular dysfunction are the cardinal indications for valve surgery, routine echocardiography may not detect early left ventricular dysfunction and the development of early symptoms may not be appreciated. Numerous studies demonstrate that increased natriuretic peptide plasma levels, including atrial natriuretic peptide (ANP), B-type natriuretic peptide (BNP) and amino-terminal BNP (N-BNP) reflect left ventricular dysfunction, correlate with symptoms of cardiac failure and are independent prognostic markers for clinical outcomes in diverse cardiac conditions, but very few studies address natriuretic peptides in patients with valvular heart disease. The aims of this thesis are firstly, to determine the clinical utility of measuring natriuretic peptide plasma levels in patients with valvular heart disease, and secondly, to provide supportive biochemical evidence to established histological evidence that aortic stenosis is an inflammatory disease. One hundred and sixty three patients with chronic valvular heart disease, including aortic stenosis (n=74), aortic regurgitation (n=40) and mitral regurgitation (n=49) underwent independent assessment of symptoms, transthoracic echocardiography and measurement of plasma levels of ANP, BNP and N-BNP. Natriuretic peptide levels were significantly higher in symptomatic compared with asymptomatic patients after adjustment for echocardiographic measures of disease severity and left ventricular function. Of 29 asymptomatic patients with aortic stenosis followed for a mean of 18 months, patients with an N-BNF level above the normal range or with a greater increase in N-BNP/year were at increased risk of symptomatic deterioration. In 33 patients with aortic stenosis who underwent aortic valve replacement, N-BNP levels decreased and symptoms consistently improved by 6 months postoperatively in patients with a preoperative N-BNP level above the normal range, but N-BNP levels did not decrease and symptoms less reliably improved in patients with a preoperative N-BNP level within normal limits. In contrast to the established theory that aortic stenosis is a degenerative process not amenable to medical therapy, recent histological studies suggest that aortic stenosis may be an inflammatory disease with similarities to coronary atherosclerosis. To further address this issue, high sensitivity C-reactive protein (CRP) was measured in 20 patients with non-rheumatic aortic stenosis, 19 patients with non-rheumatic aortic regurgitation and 31 healthy controls, as well as 6 months after valve replacement in aortic stenosis. CRP was significantly increased in aortic stenosis, but not aortic regurgitation compared with controls and decreased after valve replacement in aortic stenosis. These observations are consistent with histological evidence that the aortic valve is the site of active inflammation. In conclusion, measurement of plasma natriuretic peptide levels complement clinical and echocardiographic evaluation of patients with valvular heart disease and may assist with the timing of valve surgery. Novel evidence that aortic stenosis may be an inflammatory disease is presented and suggests further studies are required to determine whether agents with anti-inflammatory actions may have a role in delaying disease progression. Following on the studies presented in this thesis, a large multicentre study has commenced in New Zealand to confirm these findings that has the potential to change clinical practice.

Background and hypothesis: Standard pharmacological treatment for heart failure improves cardiac remodelling and survival in the setting of chronic heart failure, but is suboptimal in cases of acute heart failure (AHF). Peripartum cardiomyopathy (PPCM), de-novo hypotension (often due to haemorrhagic shock), and Takotsubo cardiomyopathy (TC) are conditions which have acute onset of heart failure, and often present with high mortality rates. In patients treated for these pathologies, a variation in the heart rate is observed and could potentially be used as a target to improve the treatment of AHF. We therefore questioned whether the use of a sinoatrial node inhibitor (ivabradine) to modulate heart rate may improve outcomes in AHF. Objectives and methods: Our objectives were 3-fold: (1) to explore the effect of a standard treatment strategy on heart rate in a South African cohort of PPCM patients after 6 and 12 months follow-up. (2) To explore the effect of ivabradine, a sinoatrial node inhibitor in an established signal transducer and activator of transcription 3 (STAT3) knockout mouse model of PPCM (with 3 consecutive pregnancies). Mice were fed ivabradine for 30 days (10mg/kg/day in drinking water), following the 3rd weaning. Trans-thoracic echocardiograms (TTE) were done at the end of the 3rd weaning, and after 30 days of treatment with ivabradine. Hearts were harvested after the second TTE for histology staining and messenger ribonucleic acid (mRNA) quantitation of transcripts involved in heart failure. (3) To explore the role of the sinoatrial node inhibitor in an ex-vivo model of de-novo AHF due to hypotension, and a newly developed ex-vivo model of TC. In the AHF model, hearts were stabilised before administering Ivabradine (3μM) in a buffer containing high free fatty-acids at a low pressure (to mimic hypotension/ haemorrhage shock conditions). A pressure- sensing balloon in the left ventricle measured heart rate, diastolic and systolic pressure, left ventricular developed pressure, rate pressure products and functional recovery. In the TC model, hearts were stabilised, then given a buffer with high free fatty-acid content and 10 times a physiological dose of adrenaline to mimic the adrenergic response seen in TC. Thereafter, hearts were restored to stabilisation pressure and substrate for recovery. Results: (1) Clinical outcomes indicated that patients on maximum standard therapy improved symptomatically and on the New York Heart Association scale. However, heart rates of PPCM patients remained elevated after 6 months of treatment. (2) In PPCM mice, a treatment with ivabradine was associated with reduced fibrotic infiltration in cardiac tissue and with a decrease in levels of atrial natriuretic peptide and Fibronectin mRNAs. (3) Both hypotensive AHF and TC models showed a tendency toward better cardiac function with ivabradine at the end of the acute phases. This advantage was lost after withdrawal of ivabradine during recovery. Conclusion: In South African women with PPCM treated with standard therapy, heart rate remains elevated, therefore suggesting that these women may benefit from the use of ivabradine as an additional therapy, particularly in patients who may be intolerant to β-blockers. The long-term use of ivabradine in the setting of cardiac dysfunction appears to have beneficial effects on remodelling, as treatment with ivabradine in our mouse PPCM model showed reduced cardiac fibrosis. The ex-vivo models of hypotensive AHF and TC both showed benefit in reducing heart rate during the acute phases, and hold the potential of being an intervention therapy to improve the outcome in patients who are brought to hospital while still in the acute phase.

Includes abstract. / Includes bibliographical references (p.127-140). / Tuberculous (TB) pericarditis is associated with a mortality rate of 17-40% despite treatment with anti-tuberculosis drugs. The complications of TB pericarditis that confer mortality and morbidity are pericardial tamponade, effusive constrictive pericarditis, and constrictive pericarditis. Whilst the diagnosis and treatment of pericardial tamponade and constriction are well established, there is a paucity of evidence on the frequency and significance of tuberculous effusive constrictive pericarditis. The primary purpose of this work was to determine the prevalence, predictors, fractal (geometric) structure, biomarker signature, and outcome of effusive constrictive TB pericarditis.

Background: Little is known about the mechanisms, clinical characteristics, natural history and outcomes of cardiomyopathy amongst Africans. Familial aggregation of cardiomyopathy has not been studied systematically in an African setting. Further, it is not clear whether the various phenotypic expressions of cardiomyopathy represent disparate clinical entities, or whether they are merely different forms of the same disease manifested differently in different circumstances. Methods: Two cohorts of patients with cardiomyopathy were utilised for this study: (1) patients with cardiomyopathy seen at the specialist cardiomyopathy clinic at Groote Schuur Hospital, Cape Town between February 1, 1996 and December 31, 2009; and (2) a group of hypertrophic cardiomyopathy (HCM) patients and first degree relatives seen in a specialist cardiogenetic clinic at Tygerberg Hospital, who underwent cardiovascular magnetic resonance (CMR) imaging at Groote Schuur Hospital.

Tuberculosis is the most common cause of pericarditis in Africa. The dual human immunodeficiency virus (HIV)-tuberculosis epidemics are major contributors to the burden of extra-pulmonary tuberculosis, including tuberculous pericarditis. Mortality rates remain unacceptably high. Atrial fibrillation (AF) is the most common sustained arrhythmia encountered in clinical practice. It is associated with increased cardiovascular mortality and morbidity, as well as complications related to thromboembolic disease and haemodynamic instability. Similarly, atrial flutter (AFL) is a common macro-reentry arrhythmia, often associated with AF and its complications. While there is a recognized association between atrial fibrillation and / or atrial flutter (AF/AFL) and tuberculous pericarditis, there are limited data regarding the prevalence, determinants, natural history, and outcomes of AF/AFL in tuberculous pericarditis. Hypothesis: In patients with tuberculous pericarditis, AF/AFL is common, and when compared to tuberculous pericarditis patients that are in sinus rhythm, is associated with increased morbidity and mortality. Aims In participants with tuberculous pericarditis enrolled into the Investigation of the Management of Pericarditis (IMPI) trial, we intend to: 1. Estimate the prevalence of AF/AFL 2. Describe the natural history of AF/AFL 3. Identify clinical, biochemical and, echocardiographic predictors of AF/AFL 4. Determine the clinical impact of AF/AFL.

Includes abstract. / Includes bibliographical references. / Tachycardia-induced cardiomyopathy (TIC) is a reversible cause of LV systolic dysfunction that can complicate any supraventricular or ventricular tachyarrhythmia. This study is the first to compare features of pure and impure TIC. We found that impure TIC may develop more quickly than pure TIC, as impure TIC patients have a shorter duration and more severe symptoms at presentation, which suggests that underlying structural heart disease is a risk factor in the pathogenesis of TIC.

The pleiotropic cytokine tumour necrosis factor alpha (TNFα) is produced by the heart in response to the ischaemic preconditioning (PC) stimulus. We hypothesised that this endogenously produced peptide may play a role in activating the ischaemic PC mediated tolerance towards a subsequent ischaemic insult in muscle cells. To test this and to delineate the downstream signalling cascades mediating this programme we developed classic PC protocols in adherent mature murine C2C12 myotubes and in human cardiac derived Girardi cell lines. The C2C12 myotubes were preconditioned using either one hour of simulated ischaemia (SI) or the PC-mimetic adenosine (0.1 mM) or TNFα (0.5 ng/ml) followed by one hour of reoxygenation followed by an eight hour SI insult. Cell viability was assessed by measuring lactate dehydrogenase (LOH) release. Simulated ischaemia (SI), PC, adenosine and TNFα activated the PC programme and increased cell viability by 40±3%, 28±5% and 36±4% respectively compared to the SI controls (p<0.005 in all experiments, n≥4 x 6 well plates in all groups). Cell viability was also evaluated by the measurement of propidium iodide uptake on flow cytometry. Preconditioning and TNFα enhanced cell viability with a reduction in propidium iodide uptake by 28% and 41 % respectively versus the ischaemic controls. To evaluate whether TNFα activation of the nuclear regulatory protein nuclear factor kappa B (NFₖ B) mediates this myocyte protection, the NFₖ B antagonists diethyldithiocarbamate (DDTC 10mM) or sodium salicylate (SA 100μM) were co-administered with TNFα. The myocyte protective effect of TNF a was significantly decrease with both antagonists, although not completely inhibited/blocked (DDTC - attenuated cell viability by 62 ±6% and SA by 45 ±5% compared to the TNFα preconditioned cells (p <0.05 vs SI controls and p<0.05 vs TNFα PC, with either antagonists). To confirm these data, TNFα was used as a PC-mimetic in the isolated Langendorff perfused rat heart (Langendorff) preparation. Infarct size was used as the end point. In parallel with cell culture studies, TNFα again conferred preconditioning induced cardioprotection with partial abrogation of these effects with the pharmacological antagonists of NFₖ B. Thus, TNFα administration mimics the cytoprotective effects of ischaemic PC in cardiac, skeletal myocytes and in the isolated perfused rat heart. Moreover, these data support the role of TNFα production as an endogenous paracrine / autocrine signalling peptide which promotes myocyte cellular survival, in part, through activation of NFₖ B.