Anthrax Toxins Induce Shock in Rats by Depressed Cardiac Ventricular Function

Abstract

Anthrax infections are frequently associated with severe and often irreversible hypotensive shock. The isolated toxic proteins of Bacillus anthracis produce a non-cytokine-mediated hypotension in rats by unknown mechanisms. These observations suggest the anthrax toxins have direct cardiovascular effects. Here, we characterize these effects. As a first step, we administered systemically anthrax lethal toxin (LeTx) and edema toxin (EdTx) to cohorts of three to twelve rats at different doses and determined the time of onset, degree of hypotension and mortality. We measured serum concentrations of the protective antigen (PA) toxin component at various time points after infusion. Peak serum levels of PA were in the µg/mL range with half-lives of 10–20 minutes. With doses that produced hypotension with delayed lethality, we then gave bolus intravenous infusions of toxins to groups of four to six instrumented rats and continuously monitored blood pressure by telemetry. Finally, the same doses used in the telemetry experiments were given to additional groups of four rats, and echocardiography was performed pretreatment and one, two, three and twenty-four hours post-treatment. LeTx and EdTx each produced hypotension. We observed a doubling of the velocity of propagation and 20% increases in left ventricular diastolic and systolic areas in LeTx-treated rats, but not in EdTx-treated rats. EdTx-but not LeTx-treated rats showed a significant increase in heart rate. These results indicate that LeTx reduced left ventricular systolic function and EdTx reduced preload. Uptake of toxins occurs readily into tissues with biological effects occurring within minutes to hours of serum toxin concentrations in the µg/mL range. LeTx and EdTx yield an irreversible shock with subsequent death. These findings should provide a basis for the rational design of drug interventions to reduce the dismal prognosis of systemic anthrax infections.

Anthrax edema toxin has cAMP-mediated stimulatory effects and high-dose lethal toxin has depressant effects in an isolated perfused rat heart model

“…In these same models, lethal toxin produced gradual hypotension not initially associated with tachycardia and progressive (over days) decreases in LVEF (30). Thus, consistent with findings from other laboratories, shock with lethal toxin may be related in part to myocardial dysfunction (9,22,36,37).…”

“…In these same models, lethal toxin produced gradual hypotension not initially associated with tachycardia and progressive (over days) decreases in LVEF (30). Thus, consistent with findings from other laboratories, shock with lethal toxin may be related in part to myocardial dysfunction (9,22,36,37).It is presently unclear, however, whether edema toxin and lethal toxin alter myocardial function directly or indirectly via their effects on preload or afterload. Therefore, we investigated edema toxin and lethal toxin in a constantpressure isolated perfused Sprague-Dawley rat heart model.…”

“…In this and a canine model, lethal toxin decreased LV function (4,36,37). This group concluded that edema toxin's recognized effect on tissue edema formation likely reduced preload and induced secondary hypotension and tachycardia.…”

“…One group (36,37) has shown that rapid edema toxin administration in rats produces hypotension and tachycardia and reduced left ventricular (LV) volumes but not other cardiac parameters. In this and a canine model, lethal toxin decreased LV function (4,36,37).…”

Defensive strategies of Bacillus anthracis that promote a fatal disease

“…Hypotension may be a result of increased vascular permeability -lethal toxin has been reported to induce endothelial barrier dysfunction and endothelial cell death. A direct affect of lethal toxin on cardiac function may also contribute to hypotension and host death [27].…”