Decrease in Myocardial Ryanodine Receptors and Altered Excitation-Contraction Coupling Early in the Development of Heart Failure

Vatner, Dorothy E. MD
Sato, Naoki MD
Kiuchi, Kaname MD
Shannon, Richard P. MD
Vatner, Stephen F. MD

Departments of Medicine, Harvard Medical School, Brigham and Women's Hospital (N.S., K.K., S.F.V.), and Beth Israel Hospital (R.P.S.), Boston, Mass; the New England Regional Primate Research Center, Southborough, Mass; and the Children's Service, Massachusetts General Hospital (D.E.V.), Boston.

Correspondence to Dorothy E. Vatner, MD, New England Regional Primate Research Center, One Pine Hill Dr, PO Box 9102, Southborough, MA 01772-9102.

Received February 22, 1994; revision accepted May 6, 1994.

Circulation 90(3):p 1423-1430, September 1994.

Background

Rapid ventricular pacing for 1 day reduced myocardial contractile function without inducing heart failure in conscious, chronically instrumented dogs. After 4 to 7 weeks of pacing, myocardial contractility was depressed further and overt signs of congestive heart failure, eg, ascites, dyspnea, and edema, were evident.

Methods and Results

The mechanical restitution response, a physiological index of calcium release, was depressed at 1 day of rapid ventricular pacing. Postextrasystolic potentiation was also depressed by a similar amount, 14±3%, at 1 day after pacing. The response to isoproterenol 0.2 μg/kg per minute was depressed by a significantly greater amount (P<.05), 52±7%, at 1 day after pacing. ³H-ryanodine receptor binding fell from 1013±25 to 808±42 fmol/mg after 1 day of pacing and remained depressed at similar levels (782±61 fmol/mg) at 4 to 7 weeks when heart failure was manifest. Ryanodine receptor affinity was unchanged from control values. Neither dihydropyridine binding nor affinity for ³H-PN200-110 was changed from control levels. Within 5 days after recovery from 1 day of pacing, physiological responses to isoproterenol, postextrasystolic potentiation, and mechanical restitution recovered, as did ³H-ryanodine binding density.

Conclusions

These findings suggest that the changes in excitation-contraction coupling and potentially the sarcoplasmic reticulum calcium release channel occur early in the development of heart failure and therefore may be important in the pathogenesis of the contractile abnormalities in this disease state.