SURGERY 231 ENDOTOXIN (or lipopolysaccharide, LPS) from gram-negative bacteria is a prime trigger of the sys- temic inflammatory response. Severe sepsis or sep- tic shock occurs in more than 500,000 patients each year in the United States alone, nearly half of whom die. 1 In addition to septic cardiomyopathy and heart failure, LPS has been linked to multiple organ dysfunction in conjunction with cardiopul- monary bypass. 2 During experimental endotoxemia, systolic dys- function, reduced contractile reserve, and ventric- ular dilation can be observed within 1 to 4 hours; these occur in the absence of systemic acidosis, hypotension, or decreased coronary perfusion. 3,4 Isolated muscle and cardiomyocyte preparations also demonstrate early and progressive LPS- induced contractile dysfunction. 5 Exact mecha- nisms of this rapid LPS-induced dysfunction are unknown. Although specific receptor-mediated signals (primarily via CD14 receptors) have been identified for monocytes and other cell types, the LPS signal cascade in cardiomyocytes is unclear. Myocardial tumor necrosis factor alpha (TNF- α) gene expression and production, respectively, can be detected within 30 and 60 to 75 minutes of LPS treatment. 6 Beginning several hours after LPS exposure, multiple mediators including TNF- α, interleukin-1, interleukin-6, platelet-activating fac- tor, and nitric oxide (NO) are likely to adversely affect myocardial function. 2,7,8 Both harmful and protective roles have been ascribed to inflammato- ry-induced myocardial NO. 9 Other studies have reported significant myocardial depression result- Increased myocardial calcium cycling and reduced myofilament calcium sensitivity in early endotoxemia Koh Takeuchi, MD, Pedro J. del Nido, MD, Andra E. Ibrahim, MD, Dimitrios N. Poutias, BS, Paul Glynn, PhD, Hung Cao-Danh, PhD, Douglas B. Cowan, PhD, and Francis X. McGowan Jr, MD Boston, Mass Background. Mechanisms of cardiac dysfunction during endotoxemia are multiple and their targets uncertain. This study tested the hypothesis that endotoxin (LPS) induces abnormal calcium-activated contractile force in the heart. Methods. Adult rabbits were given LPS intravenously; 2 hours later hearts were studied in the Langendorff mode. Measurements included peak developed pressure (PDP), myocardial oxygen consump- tion (MVO 2 ), high-energy phosphates by 31 P-NMR, and beat-to-beat intracellular calcium (Ca i ) by fluo- rescence spectroscopy. Myofibrillar calcium sensitivity was assessed from the relationship of PDP to Ca i and the rate of diastolic Ca i removal (τCa) was quantified. Results. Force-calcium relationships were markedly depressed in LPS hearts despite increased Ca i . MVO 2 was increased in parallel with increased Ca i . Taken together, these data denote myofilament calcium insensitivity and mechanical inefficiency. τCa was markedly prolonged in LPS hearts, indicating impaired calcium reuptake and/ or extrusion. High-energy phosphates and intracellular pH were unaf- fected by LPS; however, inorganic phosphate (P i ) was significantly increased. Dobutamine further in creased Ca i and MVO 2 in LPS hearts without significantly improving calcium-activated force. Pyruvate, an inotrope that reduces P i , significantly improved contractility in LPS hearts. Conclusions. Endotoxemia rapidly induced futile calcium cycling and reduced myofibrillar calcium sen- sitivity. This state was resistant to β-agonist inotropic stimulation; inotropes that normalize the calcium- force relationship may be more effective. (Surgery 1999;126:231-8.) From the Departments of Anesthesiology and Cardiothoracic Surgery, Harvard Medical School and Children’s Hospital, Boston, Mass Supported in part by NIH grants HL-52589 (F.X.M.) and HL- 42607 (P.J.D.). Presented at the 60th Annual Meeting of the Society of University Surgeons, New Orleans, La, Feb 11-13, 1999. Reprint requests: Francis X. McGowan, Jr, MD, Cardiac Anesthesia Service, Children’s Hospital, 300 Longwood Ave, Boston, MA 02115. Copyright © 1999 by Mosby, Inc. 0039-6060/ 99/ $8.00 + 0 11/ 6/ 98928