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. 1992 Mar;89(3):932–938. doi: 10.1172/JCI115674

Abnormalities in intracellular calcium regulation and contractile function in myocardium from dogs with pacing-induced heart failure.

C L Perreault 1, R P Shannon 1, K Komamura 1, S F Vatner 1, J P Morgan 1
PMCID: PMC442940  PMID: 1311723

Abstract

24 d of rapid ventricular pacing induced dilated cardiomyopathy with both systolic and diastolic dysfunction in conscious, chronically instrumented dogs. We studied mechanical properties and intracellular calcium (Ca2+i) transients of trabeculae carneae isolated from 15 control dogs (n = 32) and 11 dogs with pacing-induced cardiac failure (n = 26). Muscles were stretched to maximum length at 30 degrees C and stimulated at 0.33 Hz; a subset (n = 17 control, n = 17 myopathic) was loaded with the [Ca2+]i indicator aequorin. Peak tension was depressed in the myopathic muscles, even in the presence of maximally effective (i.e., 16 mM) [Ca2+] in the perfusate. However, peak [Ca2+]i was similar (0.80 +/- 0.13 vs. 0.71 +/- 0.05 microM; [Ca2+]o = 2.5 mM), suggesting that a decrease in Cai2+ availability was not responsible for the decreased contractility. The time for decline from the peak of the Cai2+ transient was prolonged in the myopathic group, which correlated with prolongation of isometric contraction and relaxation. However, similar end-diastolic [Ca2+]i was achieved in both groups (0.29 +/- 0.05 vs. 0.31 +/- 0.02 microM), indicating that Cai2+ homeostasis can be maintained in myopathic hearts. The inotropic response of the myopathic muscles to milrinone was depressed compared with the controls. However, when cAMP production was stimulated by pretreatment with forskolin, the response of the myopathic muscles to milrinone was improved. Our findings provide direct evidence that abnormal [Ca2+]i handling is an important cause of contractile dysfunction in dogs with pacing-induced heart failure and suggest that deficient production of cAMP may be an important cause of these changes in excitation-contraction coupling.

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Selected References

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  1. Allen D. G., Blinks J. R. Calcium transients in aequorin-injected frog cardiac muscle. Nature. 1978 Jun 15;273(5663):509–513. doi: 10.1038/273509a0. [DOI] [PubMed] [Google Scholar]
  2. Allen D. G., Lee J. A., Smith G. L. The consequences of simulated ischaemia on intracellular Ca2+ and tension in isolated ferret ventricular muscle. J Physiol. 1989 Mar;410:297–323. doi: 10.1113/jphysiol.1989.sp017534. [DOI] [PMC free article] [PubMed] [Google Scholar]
  3. Alpert N. R., Mulieri L. A. Functional consequences of altered cardiac myosin isoenzymes. Med Sci Sports Exerc. 1986 Jun;18(3):309–313. doi: 10.1249/00005768-198606000-00009. [DOI] [PubMed] [Google Scholar]
  4. Bing O. H., Brooks W. W., Conrad C. H., Sen S., Perreault C. L., Morgan J. P. Intracellular calcium transients in myocardium from spontaneously hypertensive rats during the transition to heart failure. Circ Res. 1991 May;68(5):1390–1400. doi: 10.1161/01.res.68.5.1390. [DOI] [PubMed] [Google Scholar]
  5. Böhm M., Gierschik P., Jakobs K. H., Pieske B., Schnabel P., Ungerer M., Erdmann E. Increase of Gi alpha in human hearts with dilated but not ischemic cardiomyopathy. Circulation. 1990 Oct;82(4):1249–1265. doi: 10.1161/01.cir.82.4.1249. [DOI] [PubMed] [Google Scholar]
  6. Dhalla N. S., Zhao D. Possible role of sarcolemmal Ca2+/Mg2+ ATPase in heart function. Magnes Res. 1989 Sep;2(3):161–172. [PubMed] [Google Scholar]
  7. Erdmann E., Böhm M. Positive inotropic stimulation in the normal and insufficient human myocardium. Basic Res Cardiol. 1989;84 (Suppl 1):125–133. doi: 10.1007/BF02650352. [DOI] [PubMed] [Google Scholar]
  8. Feldman A. M., Tena R. G., Kessler P. D., Weisman H. F., Schulman S. P., Blumenthal R. S., Jackson D. G., Van Dop C. Diminished beta-adrenergic receptor responsiveness and cardiac dilation in hearts of myopathic Syrian hamsters (BIO 53.58) are associated with a functional abnormality of the G stimulatory protein. Circulation. 1990 Apr;81(4):1341–1352. doi: 10.1161/01.cir.81.4.1341. [DOI] [PubMed] [Google Scholar]
  9. Feldman M. D., Copelas L., Gwathmey J. K., Phillips P., Warren S. E., Schoen F. J., Grossman W., Morgan J. P. Deficient production of cyclic AMP: pharmacologic evidence of an important cause of contractile dysfunction in patients with end-stage heart failure. Circulation. 1987 Feb;75(2):331–339. doi: 10.1161/01.cir.75.2.331. [DOI] [PubMed] [Google Scholar]
  10. Gwathmey J. K., Copelas L., MacKinnon R., Schoen F. J., Feldman M. D., Grossman W., Morgan J. P. Abnormal intracellular calcium handling in myocardium from patients with end-stage heart failure. Circ Res. 1987 Jul;61(1):70–76. doi: 10.1161/01.res.61.1.70. [DOI] [PubMed] [Google Scholar]
  11. Gwathmey J. K., Slawsky M. T., Hajjar R. J., Briggs G. M., Morgan J. P. Role of intracellular calcium handling in force-interval relationships of human ventricular myocardium. J Clin Invest. 1990 May;85(5):1599–1613. doi: 10.1172/JCI114611. [DOI] [PMC free article] [PubMed] [Google Scholar]
  12. Ingwall J. S., Atkinson D. E., Clarke K., Fetters J. K. Energetic correlates of cardiac failure: changes in the creatine kinase system in the failing myocardium. Eur Heart J. 1990 Apr;11 (Suppl B):108–115. doi: 10.1093/eurheartj/11.suppl_b.108. [DOI] [PubMed] [Google Scholar]
  13. Katz A. M. Cyclic adenosine monophosphate effects on the myocardium: a man who blows hot and cold with one breath. J Am Coll Cardiol. 1983 Jul;2(1):143–149. doi: 10.1016/s0735-1097(83)80387-8. [DOI] [PubMed] [Google Scholar]
  14. Katz A. M. Energy requirements of contraction and relaxation: implications for inotropic stimulation of the failing heart. Basic Res Cardiol. 1989;84 (Suppl 1):47–53. doi: 10.1007/BF02650346. [DOI] [PubMed] [Google Scholar]
  15. Kihara Y., Grossman W., Morgan J. P. Direct measurement of changes in intracellular calcium transients during hypoxia, ischemia, and reperfusion of the intact mammalian heart. Circ Res. 1989 Oct;65(4):1029–1044. doi: 10.1161/01.res.65.4.1029. [DOI] [PubMed] [Google Scholar]
  16. Kihara Y., Morgan J. P. A comparative study of three methods for intracellular loading of the calcium indicator aequorin in ferret papillary muscles. Biochem Biophys Res Commun. 1989 Jul 14;162(1):402–407. doi: 10.1016/0006-291x(89)92011-1. [DOI] [PubMed] [Google Scholar]
  17. Kohmoto O., Spitzer K. W., Movsesian M. A., Barry W. H. Effects of intracellular acidosis on [Ca2+]i transients, transsarcolemmal Ca2+ fluxes, and contraction in ventricular myocytes. Circ Res. 1990 Mar;66(3):622–632. doi: 10.1161/01.res.66.3.622. [DOI] [PubMed] [Google Scholar]
  18. Longabaugh J. P., Vatner D. E., Vatner S. F., Homcy C. J. Decreased stimulatory guanosine triphosphate binding protein in dogs with pressure-overload left ventricular failure. J Clin Invest. 1988 Feb;81(2):420–424. doi: 10.1172/JCI113335. [DOI] [PMC free article] [PubMed] [Google Scholar]
  19. MacKinnon R., Gwathmey J. K., Allen P. D., Briggs G. M., Morgan J. P. Modulation by the thyroid state of intracellular calcium and contractility in ferret ventricular muscle. Circ Res. 1988 Dec;63(6):1080–1089. doi: 10.1161/01.res.63.6.1080. [DOI] [PubMed] [Google Scholar]
  20. Mercadier J. J., Bouveret P., Gorza L., Schiaffino S., Clark W. A., Zak R., Swynghedauw B., Schwartz K. Myosin isoenzymes in normal and hypertrophied human ventricular myocardium. Circ Res. 1983 Jul;53(1):52–62. doi: 10.1161/01.res.53.1.52. [DOI] [PubMed] [Google Scholar]
  21. Mercadier J. J., Lompré A. M., Duc P., Boheler K. R., Fraysse J. B., Wisnewsky C., Allen P. D., Komajda M., Schwartz K. Altered sarcoplasmic reticulum Ca2(+)-ATPase gene expression in the human ventricle during end-stage heart failure. J Clin Invest. 1990 Jan;85(1):305–309. doi: 10.1172/JCI114429. [DOI] [PMC free article] [PubMed] [Google Scholar]
  22. Morano I., Arndt H., Gärtner C., Rüegg J. C. Skinned fibers of human atrium and ventricle: myosin isoenzymes and contractility. Circ Res. 1988 Mar;62(3):632–639. doi: 10.1161/01.res.62.3.632. [DOI] [PubMed] [Google Scholar]
  23. Näbauer M., Böhm M., Brown L., Diet F., Eichhorn M., Kemkes B., Pieske B., Erdmann E. Positive inotropic effects in isolated ventricular myocardium from non-failing and terminally failing human hearts. Eur J Clin Invest. 1988 Dec;18(6):600–606. doi: 10.1111/j.1365-2362.1988.tb01274.x. [DOI] [PubMed] [Google Scholar]
  24. O'Brien P. J., Ianuzzo C. D., Moe G. W., Stopps T. P., Armstrong P. W. Rapid ventricular pacing of dogs to heart failure: biochemical and physiological studies. Can J Physiol Pharmacol. 1990 Jan;68(1):34–39. doi: 10.1139/y90-004. [DOI] [PubMed] [Google Scholar]
  25. Opie L. H. Role of cyclic nucleotides in heart metabolism. Cardiovasc Res. 1982 Sep;16(9):483–507. doi: 10.1093/cvr/16.9.483. [DOI] [PubMed] [Google Scholar]
  26. Panagia V., Lee S. L., Singh A., Pierce G. N., Jasmin G., Dhalla N. S. Impairment of mitochondrial and sarcoplasmic reticular functions during the development of heart failure in cardiomyopathic (UM-X7.1) hamsters. Can J Cardiol. 1986 Jul-Aug;2(4):236–247. [PubMed] [Google Scholar]
  27. Perreault C. L., Bing O. H., Brooks W. W., Ransil B. J., Morgan J. P. Differential effects of cardiac hypertrophy and failure on right versus left ventricular calcium activation. Circ Res. 1990 Sep;67(3):707–712. doi: 10.1161/01.res.67.3.707. [DOI] [PubMed] [Google Scholar]
  28. Perreault C. L., Meuse A. J., Bentivegna L. A., Morgan J. P. Abnormal intracellular calcium handling in acute and chronic heart failure: role in systolic and diastolic dysfunction. Eur Heart J. 1990 May;11 (Suppl 100):8–21. doi: 10.1093/eurheartj/11.suppl_c.8. [DOI] [PubMed] [Google Scholar]
  29. Poole-Wilson P. A. Regulation of intracellular pH in the myocardium; relevance to pathology. Mol Cell Biochem. 1989 Sep 7;89(2):151–155. doi: 10.1007/BF00220768. [DOI] [PubMed] [Google Scholar]
  30. Rouleau J. L., Paradis P., Shenasa H., Juneau C. Faster time to peak tension and velocity of shortening in right versus left ventricular trabeculae and papillary muscles of dogs. Circ Res. 1986 Nov;59(5):556–561. doi: 10.1161/01.res.59.5.556. [DOI] [PubMed] [Google Scholar]
  31. Weber K. T., Pick R., Silver M. A., Moe G. W., Janicki J. S., Zucker I. H., Armstrong P. W. Fibrillar collagen and remodeling of dilated canine left ventricle. Circulation. 1990 Oct;82(4):1387–1401. doi: 10.1161/01.cir.82.4.1387. [DOI] [PubMed] [Google Scholar]
  32. Wisenbaugh T., Allen P., Cooper G., 4th, Holzgrefe H., Beller G., Carabello B. Contractile function, myosin ATPase activity and isozymes in the hypertrophied pig left ventricle after a chronic progressive pressure overload. Circ Res. 1983 Sep;53(3):332–341. doi: 10.1161/01.res.53.3.332. [DOI] [PubMed] [Google Scholar]
  33. de la Bastie D., Levitsky D., Rappaport L., Mercadier J. J., Marotte F., Wisnewsky C., Brovkovich V., Schwartz K., Lompré A. M. Function of the sarcoplasmic reticulum and expression of its Ca2(+)-ATPase gene in pressure overload-induced cardiac hypertrophy in the rat. Circ Res. 1990 Feb;66(2):554–564. doi: 10.1161/01.res.66.2.554. [DOI] [PubMed] [Google Scholar]

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