Advanced

Improved mechanoenergetics and cardiac rest and reserve function of in vivo failing heart by calcium sensitizer EMD-57033

Senzaki, H; Isoda, T; Paolocci, N; Ekelund, Ulf LU ; Hare, J M and Kass, D A (2000) In Circulation 101(9). p.1040-1048
Abstract
BACKGROUND: Myofilament Ca(2+) sensitizers enhance contractility but can adversely alter diastolic function through sensitization to low intracellular Ca(2+) concentration. Concomitant phosphodiesterase III inhibition (PDE3I) may offset diastolic changes but limit the mechanoenergetic benefits. We tested whether selective Ca(2+) sensitization in vivo with the use of EMD-57033 enhances both systolic and diastolic function in failing hearts at minimal energetic cost. METHODS AND RESULTS: Pressure-dimension data were measured with sonomicrometry/micromanometry in conscious dogs before (CON, n=9) and after tachycardia-induced heart failure (HF, n=11). In contrast to blunted dobutamine (DOB) responses in HF, low-dose EMD-57033 (0.4 mg. kg(-1).... (More)
BACKGROUND: Myofilament Ca(2+) sensitizers enhance contractility but can adversely alter diastolic function through sensitization to low intracellular Ca(2+) concentration. Concomitant phosphodiesterase III inhibition (PDE3I) may offset diastolic changes but limit the mechanoenergetic benefits. We tested whether selective Ca(2+) sensitization in vivo with the use of EMD-57033 enhances both systolic and diastolic function in failing hearts at minimal energetic cost. METHODS AND RESULTS: Pressure-dimension data were measured with sonomicrometry/micromanometry in conscious dogs before (CON, n=9) and after tachycardia-induced heart failure (HF, n=11). In contrast to blunted dobutamine (DOB) responses in HF, low-dose EMD-57033 (0.4 mg. kg(-1). min(-1) for 20 minutes) markedly enhanced contractility, doubling end-systolic elastance and raising fractional shortening similarly in CON-treated and HF hearts. EMD-57033 effects were achieved at a reduced heart rate, without vasodilation. EMD-57033 augmented blunted heart rate-dependent contractility responses in HF at a rate of twice that of DOB, despite matched basal inotropic responses. EMD-57033 also improved diastolic function, lowering left ventricular end-diastolic pressure and increasing the filling rate. At equipotent inotropic doses and matched preload, EMD-57033 lowered the oxygen cost of contractility by -11.4+/-5.8%, whereas it rose 64+/-18% with DOB (P=0.001) and 28+/-11% with milrinone. Doubling EMD-57033 dose further augmented positive inotropy in CON and HF, accompanied by vasodilation, increased heart rate, and other changes consistent with PDE3I coactivity, but the oxygen cost of contractility remained improved compared with the use of DOB. CONCLUSIONS: Selective Ca(2+) sensitization with minimal PDE3I in vivo is achieved with the use of EMD-57033, improving basal and rate-stimulated contractility and mechanoenergetics of HF without compromising diastolic function. Despite PDE3I activity at higher doses, energetic benefits persist. (Less)
Please use this url to cite or link to this publication:
author
organization
publishing date
type
Contribution to journal
publication status
published
subject
in
Circulation
volume
101
issue
9
pages
1040 - 1048
publisher
Lippincott Williams and Wilkins
external identifiers
  • pmid:10704173
  • scopus:0034006394
ISSN
1524-4539
language
English
LU publication?
yes
id
394d08a1-322c-4e41-87e7-818c1a9cbdba (old id 1117176)
alternative location
http://circ.ahajournals.org/cgi/content/abstract/101/9/1040
date added to LUP
2008-07-03 09:11:57
date last changed
2017-02-05 04:17:18
@article{394d08a1-322c-4e41-87e7-818c1a9cbdba,
  abstract     = {BACKGROUND: Myofilament Ca(2+) sensitizers enhance contractility but can adversely alter diastolic function through sensitization to low intracellular Ca(2+) concentration. Concomitant phosphodiesterase III inhibition (PDE3I) may offset diastolic changes but limit the mechanoenergetic benefits. We tested whether selective Ca(2+) sensitization in vivo with the use of EMD-57033 enhances both systolic and diastolic function in failing hearts at minimal energetic cost. METHODS AND RESULTS: Pressure-dimension data were measured with sonomicrometry/micromanometry in conscious dogs before (CON, n=9) and after tachycardia-induced heart failure (HF, n=11). In contrast to blunted dobutamine (DOB) responses in HF, low-dose EMD-57033 (0.4 mg. kg(-1). min(-1) for 20 minutes) markedly enhanced contractility, doubling end-systolic elastance and raising fractional shortening similarly in CON-treated and HF hearts. EMD-57033 effects were achieved at a reduced heart rate, without vasodilation. EMD-57033 augmented blunted heart rate-dependent contractility responses in HF at a rate of twice that of DOB, despite matched basal inotropic responses. EMD-57033 also improved diastolic function, lowering left ventricular end-diastolic pressure and increasing the filling rate. At equipotent inotropic doses and matched preload, EMD-57033 lowered the oxygen cost of contractility by -11.4+/-5.8%, whereas it rose 64+/-18% with DOB (P=0.001) and 28+/-11% with milrinone. Doubling EMD-57033 dose further augmented positive inotropy in CON and HF, accompanied by vasodilation, increased heart rate, and other changes consistent with PDE3I coactivity, but the oxygen cost of contractility remained improved compared with the use of DOB. CONCLUSIONS: Selective Ca(2+) sensitization with minimal PDE3I in vivo is achieved with the use of EMD-57033, improving basal and rate-stimulated contractility and mechanoenergetics of HF without compromising diastolic function. Despite PDE3I activity at higher doses, energetic benefits persist.},
  author       = {Senzaki, H and Isoda, T and Paolocci, N and Ekelund, Ulf and Hare, J M and Kass, D A},
  issn         = {1524-4539},
  language     = {eng},
  number       = {9},
  pages        = {1040--1048},
  publisher    = {Lippincott Williams and Wilkins},
  series       = {Circulation},
  title        = {Improved mechanoenergetics and cardiac rest and reserve function of in vivo failing heart by calcium sensitizer EMD-57033},
  volume       = {101},
  year         = {2000},
}