Browsing by Author "Sack, Michael N"

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    Neurohormonal and inflammatory markers in valvular heart disease
    (2004) Gerber, Ivor Leslie; Stewart Ralph; Sack, Michael N
    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.
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    Preconditioning and augmented preconditioning via manipulation of metabolic and signalling pathways in the rat heart
    (2000) Makaula, Siyanda S S; Opie, Lionel H; Sack, Michael N
    Cardiac ischaemic preconditioning (IPC) describes a biological phenomenon whereby a short ischaemic stimulus confers protection to the heart against subsequent prolonged ischaemia and reperfusion injury. Understanding this survival programme will enable us to augment tissue tolerance against cell death. Ischaemic preconditioning is poorly understood, however, certain metabolic events and activation intracellular signalling events are known to trigger this cardioprotection. The purpose of this study was to investigate the metabolic and intracellular signalling events which occur during ischaemic preconditioning and their effects on improvement of contractile recovery following an ischaemia/reperfusion insult.
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    The protective role of tumour necrosis factor alpha in the heart
    (2002) Meiring, James Justus; Sack, Michael N
    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.
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    The role of sublethal stress on mitochondria and the development of cardiac preconditioning
    (2003) Minners, Jan O; Opie, Lionel H; Sack, Michael N
    Cardiac preconditioning describes a cell survival program whereby a trigger renders the heart partially resistant to subsequent ischaemia/reperfusion induced cell death.