Tick paralysis caused by the Australian paralysis tick, Ixodes holocyclus, is a significant cause of morbidity and mortality of companion animals in Australia. Previous work on tick paralysis in dogs concluded that factors other than respiratory muscle paralysis lead to death, and hypertension, believed to be produced by autonomic dysfunction and excess sympathetic stimulation, was thought to be important in the pathophysiology. However, the conclusions of this early work have been recently questioned. The aim of the studies presented in this thesis was to determine the cardiovascular effects produced by the toxin(s) of I.holocyclus.
The cardiovascular systems of dogs with naturally-occurring tick paralysis were studied over the course of the condition and following clinical recovery by ultrasonic Doppler to determine systolic blood pressure, determination of several blood parameters, radiography, echocardiography, electrocardiography, and in selected dogs, bronchoalveolar lavage.
Left-sided congestive heart failure and pulmonary oedema was identified in dogs with tick paralysis which had pulmonary venous congestion and peribronchial fluid infiltration in the presence of left-ventricular dysfunction (predominantly diastolic) and normotension. Pulmonary oedema fluid, retrieved by bronchoalveolar lavage from dogs with tick paralysis, had a low protein concentration consistent with a cardiac cause. A fluid shift from the vasculature to the interstitium, as pulmonary oedema developed, was reflected by a change in packed cell volume and a reduction in R wave amplitude on electrocardiography. Dogs with tick paralysis had changes in plasma renin and aldosterone indicative of early activation of the renin-angiotensin-aldosterone system, and changes in plasma catecholamines reflecting sympathetic activation due to heart failure. Elevations of blood lactate in dogs severely affected by tick paralysis reflected accompanying tissue hypoxia.
Dogs with tick paralysis had prolonged corrected QT intervals on electrocardiography, reflecting delayed cardiac repolarisation, predisposing to development of polymorphic ventricular tachycardia and sudden death.
In vitro experiments on isolated rat cardiovascular tissues were performed to determine the direct cellular effects of the toxin, to assess the ability of tick antitoxin serum to alter the toxin's effects and to elucidate the toxin's mechanism of action. The toxin reduced the rate of contraction (negative chronotropy) of spontaneously beating right atria, and increased the force of contraction (positive inotropy) and prolonged the time for relaxation (positive lusitropy) of electrically stimulated left ventricular papillary muscles. It also produced contraction of thoracic aortic rings. Electrophysiology studies identified that the toxin prolonged the action potential duration of left ventricular papillary myocytes. Tick antitoxin serum was unable to prevent or reverse the mechanical effects of the toxin on any of these cardiovascular tissues.
The mechanism by which the toxin produced positive inotropy and prolonged the action potential duration in left ventricular papillary muscles was by blockage of the transient outward rectifying and delayed outward rectifying potassium channels. Positive lusitropy was also mediated by toxin action on these potassium channels but other mechanisms, such as interference with calcium cycling or alteration of calcium sensitivity, must also be involved. Although not studied, the responses of the right atria and vascular smooth muscle may also be attributed to toxic action on the potassium channels.
The mechanical response of the heart to the toxin differed between in vivo and in vitro. The toxin's positive inotropic effect on isolated left ventricular papillary muscles was not observed in dogs with tick paralysis. However, the toxin's positive lusitropic effect in vitro was reflected in dogs with tick paralysis by the reduction in diastolic left ventricular chamber dimension and by the proposed diastolic dysfunction. The negative chronotropic effect of the toxin in vitro was not observed in dogs with tick paralysis, which had elevated heart rates. Similarly, the toxin contracted the thoracic aortic rings in vitro but systolic blood pressure of dogs with tick paralysis was unchanged. These discrepancies may occur because some of the cellular effects of the toxin are masked in the animal by reflex mechanisms and compensatory changes, or because the toxin may have multiple effects.
The effect of the toxin on the electrical activity of the heart to delay cardiac repolarisation was consistent in vitro, where action potential duration was prolonged, and in vivo, where the QT interval was prolonged.
The toxin did not produce any structural damage to the heart; normal serum cardiac troponin-T and lactate dehydrogenase isoenzyme-1 levels as well as normal histological and ultrastructural examinations of the myocardium were seen in animals with tick paralysis. However, the effect of the toxin on the electrical activity of the heart, as indicated by QT prolongation in dogs, persisted some time after clinical recovery.