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(Circulation. 1997;96:1495-1500.)
© 1997 American Heart Association, Inc.

Articles

Troponin I Phosphorylation in the Normal and Failing Adult Human Heart

Geza S. Bodor, MD; Annette E. Oakeley; Paul D. Allen, MD, PhD; Dan L. Crimmins, PhD; Jack H. Ladenson, PhD; ; Page A. W. Anderson, MD

From the Department of Laboratories (G.S.B.), Denver Health Medical Center, Denver, Colo; the Department of Pediatrics (A.E.O., P.A.W.A.), Duke University Medical Center, Durham, NC; the Department of Anesthesiology (P.D.A.), Brigham and Women's Hospital, Boston, Mass; and the Department of Pathology (G.S.B., D.L.C., J.H.L.), Division of Laboratory Medicine, Washington University, St Louis, Mo.

Correspondence to Page A.W. Anderson, MD, Department of Pediatrics, PO Box 3218, Duke University Medical Center, Durham, NC 27710. E-mail ander005{at}mc.duke.edu

Background In the failing human heart myofibrillar calcium sensitivity of tension development is greater and maximal myofibrillar ATPase activity is less than in the normal heart. Phosphorylation of the cardiac troponin I (cTnI)–specific NH₂-terminus decreases myofilament sensitivity to calcium, while phosphorylation of other cTnI sites decreases maximal myofibrillar ATPase activity.

Methods and Results We examined cTnI phosphorylation in left ventricular myocardium collected from failing hearts at the time of transplant (n=20) and normal hearts from trauma victims (n=24). The relative amounts of actin, tropomyosin, and TnI did not differ between failing and normal myocardium. Using Western blot analysis with a monoclonal antibody (MAb) that recognizes the striated muscle TnI isoforms, we confirmed that the adult human heart expresses only cTnI. A cTnI-specific MAb recognized two bands of cTnI, designated cTnI₁ and cTnI₂, while a MAb whose epitope is located in the cTnI-specific NH₂-terminus recognized only cTnI₁. Alkaline phosphatase decreased the relative amount of cTnI₁, while protein kinase A and protein kinase C increased cTnI₁. The percentage of cTnI made up of cTnI₁, the phosphorylated form of TnI, is greater in the normal than the failing human heart (P<.001).

Conclusions This phosphorylation difference could underlie the reported greater myofibrillar calcium sensitivity of failing myocardium. The functional consequence of this difference may be an adaptive or maladaptive response to the lower and longer calcium concentration transient of the failing heart, eg, enhancing force development or producing ventricular diastolic dysfunction.

Key Words: heart failure • calcium • myocardial contraction • myocardium • cardiomyopathy

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