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This Article Full Text Full Text (PDF) All Versions of this Article: 575/1/201    most recent jphysiol.2006.107557v1 Services Email this article to a friend Similar articles in this journal Similar articles in PubMed Alert me to new issues of the journal Download to citation manager Citing Articles Citing Articles via HighWire Citing Articles via Google Scholar Google Scholar Articles by Sirenko, S. G. Articles by Knollmann, B. C. Search for Related Content PubMed PubMed Citation Articles by Sirenko, S. G. Articles by Knollmann, B. C. Related Collections Cardiovascular

¹ Department of Pharmacology, Georgetown University Medical Center, Washington, DC, USA
² Department of Molecular and Cellular Pharmacology, University of Miami School of Medicine, Miami, FL, USA
³ Division of Clinical Pharmacology and Oates Institute for Experimental Therapeutics, Departments of Medicine and Pharmacology, Vanderbilt University Medical Center, Nashville, TN, USA

Troponin T (TnT) mutations that cause familial hypertrophic cardiomyopathy (FHC) and sudden cardiac death frequently increase myofilament Ca²⁺ sensitivity, suggesting that their Ca²⁺-sensitizing effect contributes importantly to the FHC pathogenesis. To test this hypothesis, we compared transgenic mice expressing the Ca²⁺-sensitizing TnT-I79N mutant (I79N), which causes a high rate of sudden cardiac death in patients, with mice expressing the more benign TnT-R278C mutant (R278C) that does not affect myofilament Ca²⁺ sensitivity. Acutely increasing myofilament Ca²⁺ sensitivity with EMD57033 served as a positive control. Isovolumically contracting hearts were compared over a range of loading conditions (Frank-Starling curve). Consistent with their increased myofilament Ca²⁺ sensitivity, I79N-Tg hearts demonstrated significantly higher systolic performance at low perfusate [Ca²⁺] compared with R278C-Tg hearts, which were not statistically different from control hearts expressing either human wild-type TnT or no transgene (CON). Diastolic function was impaired in both FHC mutants (time to 90% relaxation: I79N 48 ± 1.0 ms, n = 10 or R278C 47 ± 0.4 ms, n = 7, versus CON 44 ± 1.0 ms, n = 20, P < 0.05). In the presence of isoproterenol, almost all contractile parameters of R278C hearts became indistinguishable from control hearts, whereas both systolic and diastolic function of I79N hearts significantly worsened (end-diastolic pressure: I79N 20 ± 4 mmHg versus CON 13 ± 2 mmHg or R278C 11 ± 2 mmHg, P < 0.05). The Ca²⁺ sensitizer EMD57033 produced an even greater contractile dysfunction than the I79N mutation at fast pacing rates. In vivo, maximal exercise tolerance was significantly impaired only in I79N mice. Pretreatment with ß-adrenergic receptor antagonists abolished differences in exercise tolerance. In conclusion, the Ca²⁺-sensitizing effects of TnT mutations may reduce the responsiveness of mouse hearts to inotropic stimuli.

(Received 13 February 2006; accepted after revision 9 June 2006; first published online 15 June 2006)
Corresponding author B. C. Knollmann: Oates Institute for Experimental Therapeutics, Vanderbilt University School of Medicine, Division of Clinical Pharmacology, 1265 Medical Research Building IV, Nashville, TN 37232-0575, USA. Email: bjorn.knollmann{at}vanderbilt.edu

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