Decreased ventricular contractility during sepsis lasts much longer than the half-lives of inflammatory mediators that have been suggested to be myocardial depressant factors. Our hypothesis is that blood-borne factors may also cause myocardial structural changes, including damage and death of myocytes, associated with decreased ventricular contractility. We tested this hypothesis in an isolated rabbit heart perfused by a support rabbit. Support rabbits received 1 mg/kg endotoxin i.v. over 30 min (endotoxin group, n = 7) or vehicle (control group, n = 6). The slope of the end-systolic pressure-volume relationship, Emax, was used to measure contractility of the isolated heart. Five hours after endotoxin infusion, Emax decreased by 17 +/- 7% (P < 0.03) compared with 0 +/- 2% in the control group. Quantitative morphometric analysis of isolated hearts from the endotoxin group demonstrated an increased volume fraction of myocardial capillaries occupied by leukocytes (15.7 +/- 3.5 vs. 3.0 +/- 0.7% in the control group, P < 0.05), structurally abnormal myocytes (7.6 +/- 3.6 vs. 0.8 +/- 0.4%, P < 0.05), and interstitial edema (23.2 +/- 5.2 vs. 14.3 +/- 2.1%, P < 0.05). We conclude that blood-borne factors cause myocardial structural changes that may contribute to decreased ventricular contractility and may explain the prolonged decrease in ventricular contractility during sepsis.