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Am J Physiol Heart Circ Physiol (August 25, 2006). doi:10.1152/ajpheart.00283.2006
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Submitted on March 17, 2006
Accepted on August 22, 2006

Heart failure-associated alterations in troponin I phosphorylation impair ventricular relaxation-afterload and force-frequency responses and systolic function

Kenneth C. Bilchick1, Jennifer G Duncan2, Rajashree Ravi3, Eiki Takimoto1, Hunter C. Champion1, Wei Dong Gao4, Linda B. Stull3, David A. Kass1, and Anne M Murphy3*

1 Medicine, Johns Hopkins University, Baltimore, Maryland, United States
2 Baltimore, Maryland, United States; Anesthesiology and Critical Care Medicine, Johns Hopkins University, Baltimore, Maryland, United States
3 Pediatrics, Johns Hopkins University, Baltimore, Maryland, United States
4 Anesthesiology and Critical Care Medicine, Johns Hopkins University, Baltimore, Maryland, United States

* To whom correspondence should be addressed. E-mail: murphy{at}jhmi.edu.

Recent studies have found that selective stimulation of troponin I (TnI)- protein kinase A (PKA) phosphorylation enhances heart-rate dependent inotropy and blunts relaxation delay coupled to increased afterload. However, in failing hearts, TnI phosphorylation by PKA declines while protein kinase C (PKC) activity is enhanced, potentially augmenting TnI PKC phosphorylation. Accordingly, we hypothesized that these site-specific changes deleteriously affect both rate responsive cardiac function and afterload dependence of relaxation, both prominent phenotypic features of the failing heart. A transgenic (TG) mouse model was generated in which PKA-TnI sites were mutated to mimic partial dephosphorylation (Ser22 to Ala; Ser23 to Asp), and dominant PKC sites mutated to mimic constitutive phosphorylation (Ser42 and Ser44 to Asp). The two highest expressing lines were further characterized. TG mice had reduced fractional shortening 34.7+1.4% vs. 41.3+2.0%, p=0.018 and slight chamber dilation on echocardiography. In vivo cardiac pressure-volume (PV) studies revealed near doubling of isovolumic relaxation prolongation with increasing afterload in TG animals (p < 0.001), and this remained elevated despite isoproterenol infusion (PKA stimulation). Increasing heart rate from 400-700 bpm elevated contractility 13% in TG hearts, nearly half the response observed in NTG animals (p = 0.005). This blunted frequency response was normalized by isoproterenol infusion. Abnormal TnI phosphorylation observed in cardiac failure may explain exacerbated relaxation delay in response to increased afterload and contribute to blunted chronotropic reserve.




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