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. 1985 Oct;76(4):1539–1553. doi: 10.1172/JCI112135

A circulating myocardial depressant substance in humans with septic shock. Septic shock patients with a reduced ejection fraction have a circulating factor that depresses in vitro myocardial cell performance.

J E Parrillo, C Burch, J H Shelhamer, M M Parker, C Natanson, W Schuette
PMCID: PMC424125  PMID: 4056039

Abstract

We have previously described a subpopulation of patients with septic shock who had a reversible depression of radionuclide-determined left ventricular ejection fraction (EF). To investigate the mechanism of this myocardial depression, an in vitro model of mammalian myocardial cell performance was established employing primary spontaneously beating rat myocardial cells. The contraction of a single cardiac cell was quantitated by recording the changes in area occupied by the cell during contraction and relaxation. In 20 septic shock patients during the acute phase, the mean left ventricular EF was decreased (mean = 0.33, normal mean = 0.50), and serum obtained during this acute phase induced a mean (+/- standard error of the mean) 33 +/- 4% decrease in extent and 25 +/- 4% decrease in velocity of myocardial cell shortening during contraction (P less than 0.001). In contrast, serum obtained from 11 of these same patients before shock (n = 2) or after recovery (n = 9) of the left ventricular EF (mean = 0.50) showed a return toward normal in extent and velocity of shortening (P less than 0.001). Sera from 17 critically ill nonseptic patients, from 10 patients with structural heart disease as a cause for a depressed EF, and from 12 healthy laboratory personnel, induced no significant changes in in vitro myocardial cell performance. In 20 patients during the acute phase of septic shock, the decreased EF in vivo demonstrated a significant correlation (r = +0.52, P less than 0.01) with a decrease in the extent of myocardial cell shortening in vitro. The quantitative and temporal correlation between the decreased left ventricular EF and this serum myocardial depressant substance argues for a pathophysiologic role for this depressant substance in producing the reversible cardiomyopathy seen during septic shock in humans.

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Selected References

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  1. Barry W. H., Pitzen R., Protas K., Harrison D. C. Inotropic effects of different calcium ion concentration on the embryonic chick ventricle. Comparison of single cultured cells and intact muscle strips. Circ Res. 1975 Jun;36(6):727–734. doi: 10.1161/01.res.36.6.727. [DOI] [PubMed] [Google Scholar]
  2. Biedert S., Barry W. H., Smith T. W. Inotropic effects and changes in sodium and calcium contents associated with inhibition of monovalent cation active transport by ouabain in cultured myocardial cells. J Gen Physiol. 1979 Oct;74(4):479–494. doi: 10.1085/jgp.74.4.479. [DOI] [PMC free article] [PubMed] [Google Scholar]
  3. Boder G. B., Harley R. J., Johnson I. S. Recording system for monitoring automaticity of heart cells in culture. Nature. 1971 Jun 25;231(5304):531–532. doi: 10.1038/231531a0. [DOI] [PubMed] [Google Scholar]
  4. Borer J. S., Bacharach S. L., Green M. V., Kent K. M., Epstein S. E., Johnston G. S. Real-time radionuclide cineangiography in the noninvasive evaluation of global and regional left ventricular function at rest and during exercise in patients with coronary-artery disease. N Engl J Med. 1977 Apr 14;296(15):839–844. doi: 10.1056/NEJM197704142961503. [DOI] [PubMed] [Google Scholar]
  5. Calvin J. E., Driedger A. A., Sibbald W. J. An assessment of myocardial function in human sepsis utilizing ECG gated cardiac scintigraphy. Chest. 1981 Nov;80(5):579–586. doi: 10.1378/chest.80.5.579. [DOI] [PubMed] [Google Scholar]
  6. Carli A., Auclair M. C., Bleichner G., Weber S., Lechat P., Monsallier J. F. Inhibited response to isoproterenol and altered action potential of beating rat heart cells by human serum in septic shock. Circ Shock. 1978;5(1):85–94. [PubMed] [Google Scholar]
  7. Carli A., Auclair M. C., Vernimmen C., Jourdon P. Reversal by calcium of rat heart cell dysfunction induced by human sera in septic shock. Circ Shock. 1979;6(2):147–147. [PubMed] [Google Scholar]
  8. Clowes G. H., Jr, Farrington G. H., Zuschneid W., Cossette G. R., Saravis C. Circulating factors in the etiology of pulmonary insufficiency and right heart failure accompanying severe sepsis (peritonitis). Ann Surg. 1970 May;171(5):663–678. doi: 10.1097/00000658-197005000-00005. [DOI] [PMC free article] [PubMed] [Google Scholar]
  9. Clowes G. H., Jr, George B. C., Villee C. A., Jr, Saravis C. A. Muscle proteolysis induced by a circulating peptide in patients with sepsis or trauma. N Engl J Med. 1983 Mar 10;308(10):545–552. doi: 10.1056/NEJM198303103081001. [DOI] [PubMed] [Google Scholar]
  10. DeHann R. L. Regulation of spontaneous activity and growth of embryonic chick heart cells in tissue culture. Dev Biol. 1967 Sep;16(3):216–249. doi: 10.1016/0012-1606(67)90025-5. [DOI] [PubMed] [Google Scholar]
  11. Glucksman E. E., Lefer A. M. Effects of a myocardial depressant factor on isolated vascular smooth muscle. Am J Physiol. 1971 Jun;220(6):1581–1585. doi: 10.1152/ajplegacy.1971.220.6.1581. [DOI] [PubMed] [Google Scholar]
  12. Greene L. J., Shapanka R., Glenn T. M., Lefer A. M. Isolation of myocardial depressant factor from plasma of dogs in hemorrhagic shock. Biochim Biophys Acta. 1977 Mar 28;491(1):275–285. doi: 10.1016/0005-2795(77)90063-0. [DOI] [PubMed] [Google Scholar]
  13. HARARY I., FARLEY B. In vitro studies of single isolated beating heart cells. Science. 1960 Jun 3;131(3414):1674–1675. doi: 10.1126/science.131.3414.1674. [DOI] [PubMed] [Google Scholar]
  14. HARARY I., FARLEY B. In vitro studies on single beating rat heart cells. I. Growth and organization. Exp Cell Res. 1963 Feb;29:451–465. doi: 10.1016/s0014-4827(63)80008-7. [DOI] [PubMed] [Google Scholar]
  15. Harary I., McCarl R., Farley B. Studies in vitro on single beating rat heart cells. IX. The restoration of beating by serum lipids and fatty acids. Biochim Biophys Acta. 1966 Jan 25;115(1):15–22. doi: 10.1016/0304-4165(66)90043-2. [DOI] [PubMed] [Google Scholar]
  16. Harris P. J., Harrell F. E., Jr, Lee K. L., Behar V. S., Rosati R. A. Survival in medically treated coronary artery disease. Circulation. 1979 Dec;60(6):1259–1269. doi: 10.1161/01.cir.60.6.1259. [DOI] [PubMed] [Google Scholar]
  17. Hess M. L., Hastillo A., Greenfield L. J. Spectrum of cardiovascular function during gram-negative sepsis. Prog Cardiovasc Dis. 1981 Jan-Feb;23(4):279–298. doi: 10.1016/0033-0620(81)90017-7. [DOI] [PubMed] [Google Scholar]
  18. Hinshaw L. B. Myocardial function in endotoxin shock. Circ Shock Suppl. 1979;1:43–51. [PubMed] [Google Scholar]
  19. Lefer A. M., Martin J. Origin of myocardial depressant factor in shock. Am J Physiol. 1970 May;218(5):1423–1427. doi: 10.1152/ajplegacy.1970.218.5.1423. [DOI] [PubMed] [Google Scholar]
  20. Lefer A. M. Role of a myocardial depressant factor in the pathogenesis of circulatory shock. Fed Proc. 1970 Nov-Dec;29(6):1836–1847. [PubMed] [Google Scholar]
  21. Lefer A. M. The pathophysiologic role of myocardial depressant factor as a mediator of circulatory shock. Klin Wochenschr. 1982 Jul 15;60(14):713–716. doi: 10.1007/BF01716561. [DOI] [PubMed] [Google Scholar]
  22. MACLEAN L. D., SPINK W. W., VISSCHER M. B., WEIL M. H. Studies on the circulatory changes in the dog produced by endotoxin from gram-negative microorganisms. J Clin Invest. 1956 Nov;35(11):1191–1198. doi: 10.1172/JCI103373. [DOI] [PMC free article] [PubMed] [Google Scholar]
  23. MacLean L. D., Mulligan W. G., McLean A. P., Duff J. H. Patterns of septic shock in man--a detailed study of 56 patients. Ann Surg. 1967 Oct;166(4):543–562. doi: 10.1097/00000658-196710000-00004. [DOI] [PMC free article] [PubMed] [Google Scholar]
  24. McCabe W. R., Kreger B. E., Johns M. Type-specific and cross-reactive antibodies in gram-negative bacteremia. N Engl J Med. 1972 Aug 10;287(6):261–267. doi: 10.1056/NEJM197208102870601. [DOI] [PubMed] [Google Scholar]
  25. McConn R., Greineder J. K., Wasserman F., Clowes G. H., Jr Is there a humoral factor that depresses ventricular function in sepsis? Circ Shock Suppl. 1979;1:9–22. [PubMed] [Google Scholar]
  26. Nishijima H., Weil M. H., Shubin H., Cavanilles J. Hemodynamic and metabolic studies on shock associated with gram negative bacteremia. Medicine (Baltimore) 1973 Jul;52(4):287–294. doi: 10.1097/00005792-197307000-00007. [DOI] [PubMed] [Google Scholar]
  27. Parker M. M., Shelhamer J. H., Bacharach S. L., Green M. V., Natanson C., Frederick T. M., Damske B. A., Parrillo J. E. Profound but reversible myocardial depression in patients with septic shock. Ann Intern Med. 1984 Apr;100(4):483–490. doi: 10.7326/0003-4819-100-4-483. [DOI] [PubMed] [Google Scholar]
  28. Parrillo J. E. Cardiovascular dysfunction in septic shock: new insights into a deadly disease. Int J Cardiol. 1985 Mar;7(3):314–321. doi: 10.1016/0167-5273(85)90059-2. [DOI] [PubMed] [Google Scholar]
  29. Sibbald W. J., Paterson N. A., Holliday R. L., Anderson R. A., Lobb T. R., Duff J. H. Pulmonary hypertension in sepsis: measurement by the pulmonary arterial diastolic-pulmonary wedge pressure gradient and the influence of passive and active factors. Chest. 1978 May;73(5):583–591. doi: 10.1378/chest.73.5.583. [DOI] [PubMed] [Google Scholar]
  30. Siegel J. H., Greenspan M., Del Guercio L. R. Abnormal vascular tone, defective oxygen transport and myocardial failure in human septic shock. Ann Surg. 1967 Apr;165(4):504–517. doi: 10.1097/00000658-196704000-00002. [DOI] [PMC free article] [PubMed] [Google Scholar]
  31. Thompson E. J., Wilson S. H., Schuette W. H., Whitehouse W. C., Nirenberg M. W. Measurement of the rate and velocity of movement by single heart cells in culture. Am J Cardiol. 1973 Aug;32(2):162–166. doi: 10.1016/s0002-9149(73)80115-8. [DOI] [PubMed] [Google Scholar]
  32. UDHOJI V. N., WEIL M. H. HEMODYNAMIC AND METABOLIC STUDIES ON SHOCK ASSOCIATED WITH BACTEREMIA. OBSERVATIONS ON 16 PATIENTS. Ann Intern Med. 1965 May;62:966–978. doi: 10.7326/0003-4819-62-5-966. [DOI] [PubMed] [Google Scholar]
  33. WAISBREN B. A. Bacteremia due to gram-negative bacilli other than the Salmonella; a clinical and therapeutic study. AMA Arch Intern Med. 1951 Oct;88(4):467–488. doi: 10.1001/archinte.1951.03810100051005. [DOI] [PubMed] [Google Scholar]
  34. Wangensteen S. L., Ramey W. G., Ferguson W. W., Starling J. R. Plasma myocardial depressant activity (shock factor) identified as salt in the cat papillary muscle bioassay system. J Trauma. 1973 Mar;13(3):181–194. doi: 10.1097/00005373-197303000-00001. [DOI] [PubMed] [Google Scholar]
  35. Weisel R. D., Vito L., Dennis R. C., Valeri C. R., Hechtman H. B. Myocardial depression during sepsis. Am J Surg. 1977 Apr;133(4):512–521. doi: 10.1016/0002-9610(77)90141-6. [DOI] [PubMed] [Google Scholar]
  36. Winslow E. J., Loeb H. S., Rahimtoola S. H., Kamath S., Gunnar R. M. Hemodynamic studies and results of therapy in 50 patients with bacteremic shock. Am J Med. 1973 Apr;54(4):421–432. doi: 10.1016/0002-9343(73)90038-7. [DOI] [PubMed] [Google Scholar]
  37. Wolff S. M., Bennett J. V. Editorial: Gram-negative-rod bacteremia. N Engl J Med. 1974 Oct 3;291(14):733–734. doi: 10.1056/NEJM197410032911411. [DOI] [PubMed] [Google Scholar]

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