Abstract 3361: Progressive Left Ventricle, Myocyte Dysfunction, and Heart Failure in the Lethality of Anthrax Toxin in Conscious Dogs

Abstract

Background . Bacillus anthracis ( BA ) infection is a cause of human and animal disease and associated with biowarfare. Although circulatory shock related to anthrax lethal toxin (LeTx) may play a primary role in lethality due to BA infection, its mechanisms are unclear. Methods . Six chronically-instrumented conscious dogs were assigned to receive a bolus injection of LeTx (10 ml saline with equivalent doses PA/LF, about 0.265 mg/kg, iv, n = 2) or saline (10 ml, iv, n = 4). Hemodynamic, left ventricular (LV) systolic and diastolic responses were determined periodically until 96 hours (h) in both groups. LV biopsies were performed at about 98H (before death). Isolated myocyte contractile function and histopathological alterations were determined. Results . Compared with control, in LeTx-treated animals, there were progressive decreases in LV contractility and slowed LV relaxation during the transition from LV dysfunction to heart failure (HF) over 96–98H. The cardiac depression was apparent about 6 – 8H after LeTx, but progressed through the subsequent 72–98H. At 72H after LeTx, heart rate (LeTx:129vsControl:95 bpm), LV end-diastolic pressure (P) (21vs9 mmHg), and the time constant of relaxation (40.9vs29.7 ms) were increased with markedly reduced ejection fraction, stroke volume (SV, 8.4vs15.8 ml), and end-systolic P (92vs118 mmHg). Moreover, LV contractility was decreased 49% (E ES , 4.1vs8.2 mmHg/ml and M SW , 44.9vs88.9 mmHg) with rightward shifts of LV P-V loops. At 96H, M SW , SV, and EF were further decreased accompanied by the development of severe HF. Pathologic finding of LV dilatation was associated with significantly increased length of LV myocytes (201±11vs122±13 μm). In LeTx-treated myocytes, there were about 46% reductions in cell contraction (79.0±9.7vs146.2±11.4 μm/s) and relaxation, respectively. LeTx produced lethality in dogs 4 days after LeTx treatment with similar time courses to those previously reported in man. Conclusions . LeTx causes direct and time-dependent progressive decrease in LV contractility, slow relaxation, cardiomyocyte dysfunction, LV, and myocyte remodeling and leads to HF, which suggests that the heart could be the primary target for the action of LeTx and plays an important role in lethality due to BA infection.