Clinical and Immunopathological Aspects of Heart Damage in Dogs Infected with Trypanosoma brucei

Veterinary science, Animal diseases

Ndung'u, Joseph Mathu

University:University of Glasgow

关键词: Veterinary science, Animal diseases;   

Others  :  http://theses.gla.ac.uk/78081/1/11007360.pdf

来源: University of Glasgow

【 摘 要 】

In an attempt to increase the understanding of the mechanisms of cardiac damage in African trypanosomiasis, a group of beagle dogs were infected with Trypanosoma brucei. Cardiac involvement during the course of the disease was monitored using various non-invasive techniques, including auscultation, palpation, echocardiography and electrocardiography (ECG). Parasitological, haematological, endocrinological and biochemical studies were carried out. Two dogs per time point were euthanised at mid-infection on days 10 and 15, and in the terminal stages on days 21, 22 and 26, and tissue samples taken from the heart for histological, histochemical, transmission electron microscopical and immunofluorescence investigations. The dogs developed an acute disease syndrome, characterised by high parasitaemia, persistent fever, increased plasma levels of acute phase proteins, severe anaemia, lymph node and splenic enlargement, wasting and weight loss. If the dogs were not treated or the experiments terminated by humane euthanasia, death would have invariably occurred during week 4 of infection. Clinical evidence of cardiac damage was demonstrated from the end of week 1 by echocardiography and ECG. The clinical signs included tachycardia, incompetence of all the cardiac valves, and first degree heart block. With progress of the disease, second degree and in some cases complete heart block developed. Towards the end of week 3 and beginning of week 4, cardiac performance deteriorated, as demonstrated by a reduction in left ventricular function, bradycardia, and accumulation of pericardial effusion. Histological and ultrastructural studies confirmed a severe pancarditis involving the myocardium, the cardiac valves, and the vasculature. Deposition of fibrinogen and sparse quantities of IgG, IgM and C3 was demonstrated in perivascular and interstitial spaces. A terminal fall in plasma levels of the cardiac hormone atrial natriuretic factor (ANF) occurred, and was associated with decreased numbers, sizes and electron density of the atrial storage granules. The low plasma levels of ANF were accompanied by an inverse increase in plasma renin activity, an indication that the dogs at that time were incapable of controlling blood volume. From the end of week 2 of infection, a gradually developing hyperlipidaemia and intense deposition of lipids in the myocardium and infiltrating macrophages was demonstrated for the first time. It is possible that cachectin/tumour necrosis factor (TNF) was contributing to the hyperlipidaemic state, following the detection of increased cachectin/TNF activity in monocytes from infected dogs. The presence of large numbers of trypanosomes, infiltrating cells that consisted mainly of macrophages, neutrophils, plasma cells and a few lymphocytes, in areas of extensive myocardial damage indicated that tissue damage was initiated by excessive immunological responses by the host to this highly antigenic parasite. Tissue damage was probably exacerbated by accumulation of toxic and biologically active substances released from dead trypanosomes and autolysing inflammatory cells, following obstruction of the lymphatic vessels draining the heart. Anaemia, vascular damage and interstitial oedema reduced tissue perfusion and increased the incidence of myocardial ischaemia. The presence of lipid deposits in ischaemic myocardium indicated that they too could be playing a major role in the pathogenesis of tissue damage. Further, the presence of mesangial deposits of immune complexes in the kidneys confirmed their presence in the circulation, indicating that immune complexes played a role in the pathogenesis of general tissue damage. Intravenous treatment of terminally ill dogs with the trypanocidal drug suramin at 10 to 20 mg/kg was usually unsuccessful. In most cases, a post-treatment reaction, with increased severity of heart damage, was observed. Nevertheless, the survival period of the dogs was prolonged, precipitating a condition of chronic cardiac failure. The dogs that survived longest were those that were best able to control anaemia after treatment. When a group of infected dogs were treated with the non-steroidal anti-inflammatory drugs (NSAIDs) cyclosporin A and azathioprine, or a combination of azathioprine and prednisolone, the severity of cardiac damage was reduced, despite intense trypanosome infiltration in the myocardium. These results confirmed the immunological and inflammatory nature of the cardiac disease induced by T. brucei. It would appear that if such drugs were used as an adjunct to trypanocidal drug treatment, the severity of post-treatment myocardial damage, and possibly general tissue damage, might have been reduced. The present work has conclusively demonstrated that cardiac damage in canine trypanosomiasis caused by T. brucei is mainly immunologically mediated. The similarity of the disease to human African trypanosomiasis indicated that cardiac damage in humans could be mediated through similar mechanisms. The future of the dog as large monogastric animal model for studying cardiac damage in African trypanosomiasis is promising.