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

Hideaki Senzaki, Takayoshi Isoda, Nazareno Paolocci, Ulf Ekelund, Joshua Hare, David A. Kass

Research output: Contribution to journalArticle

57 Citations (Scopus)

Abstract

Background - Myofilament Ca2+ sensitizers enhance contractility but can adversely alter diastolic function through sensitization to low intracellular Ca2+ concentration. Concomitant phosphodiesterase III inhibition (PDE3I) may offset diastolic changes but limit the mechanoenergetic benefits. We tested whether selective Ca2+ 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 Ca2+ 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.

Original languageEnglish
Pages (from-to)1040-1048
Number of pages9
JournalCirculation
Volume101
Issue number9
StatePublished - Mar 7 2000
Externally publishedYes

Fingerprint

EMD 53998
Calcium
Dobutamine
Heart Rate
Costs and Cost Analysis
Vasodilation
Type 3 Cyclic Nucleotide Phosphodiesterases
Milrinone
Oxygen
Myofibrils
Left Ventricular Function

Keywords

  • Calcium
  • Contractility
  • Diastole
  • Heart failure
  • Mechanics

ASJC Scopus subject areas

  • Physiology
  • Cardiology and Cardiovascular Medicine

Cite this

Senzaki, H., Isoda, T., Paolocci, N., Ekelund, U., Hare, J., & Kass, D. A. (2000). Improved mechanoenergetics and cardiac rest and reserve function of in vivo failing heart by calcium sensitizer EMD-57033. Circulation, 101(9), 1040-1048.

Improved mechanoenergetics and cardiac rest and reserve function of in vivo failing heart by calcium sensitizer EMD-57033. / Senzaki, Hideaki; Isoda, Takayoshi; Paolocci, Nazareno; Ekelund, Ulf; Hare, Joshua; Kass, David A.

In: Circulation, Vol. 101, No. 9, 07.03.2000, p. 1040-1048.

Research output: Contribution to journalArticle

Senzaki, H, Isoda, T, Paolocci, N, Ekelund, U, Hare, J & Kass, DA 2000, 'Improved mechanoenergetics and cardiac rest and reserve function of in vivo failing heart by calcium sensitizer EMD-57033', Circulation, vol. 101, no. 9, pp. 1040-1048.
Senzaki, Hideaki ; Isoda, Takayoshi ; Paolocci, Nazareno ; Ekelund, Ulf ; Hare, Joshua ; Kass, David A. / Improved mechanoenergetics and cardiac rest and reserve function of in vivo failing heart by calcium sensitizer EMD-57033. In: Circulation. 2000 ; Vol. 101, No. 9. pp. 1040-1048.
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abstract = "Background - Myofilament Ca2+ sensitizers enhance contractility but can adversely alter diastolic function through sensitization to low intracellular Ca2+ concentration. Concomitant phosphodiesterase III inhibition (PDE3I) may offset diastolic changes but limit the mechanoenergetic benefits. We tested whether selective Ca2+ 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 Ca2+ 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.",
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AU - Paolocci, Nazareno

AU - Ekelund, Ulf

AU - Hare, Joshua

AU - Kass, David A.

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N2 - Background - Myofilament Ca2+ sensitizers enhance contractility but can adversely alter diastolic function through sensitization to low intracellular Ca2+ concentration. Concomitant phosphodiesterase III inhibition (PDE3I) may offset diastolic changes but limit the mechanoenergetic benefits. We tested whether selective Ca2+ 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 Ca2+ 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.

AB - Background - Myofilament Ca2+ sensitizers enhance contractility but can adversely alter diastolic function through sensitization to low intracellular Ca2+ concentration. Concomitant phosphodiesterase III inhibition (PDE3I) may offset diastolic changes but limit the mechanoenergetic benefits. We tested whether selective Ca2+ 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 Ca2+ 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.

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