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February 6, 2003Circulation ResearchOpen Access

Insulin-Like Growth Factor-1 Exerts Ca 2+ -Dependent Positive Inotropic Effects in Failing Human Myocardium

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Why the study?

Does IGF-1 exert positive inotropic effects in isolated failing human myocardium?

Population

Isolated trabeculae or cardiomyocytes from 46 end-stage failing human hearts

Comparison

Insulin-like growth factor-1 0.001 to 0.2… vs Baseline values and various pharmacological…

Design

Preclinical

Authors

DLDirk von LewinskiHeart Failure & TransplantKVKerstin VoßUniversity of GöttingenSHSwen HülsmannUniversity of Göttingen

Discussion

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Implication

Hypothesis-generating for IGF-1 inotropy; requires human validation before any clinical consideration.

Key Points

  • To determine the acute inotropic responses and signal transduction mechanisms mediated by insulin-like growth factor-1 in failing human myocardium.
  • Tested isolated trabeculae and single cardiomyocytes harvested from 46 patients with end-stage heart failure.
  • Measured isometric twitch force at 37°C, intracellular Ca2+ transients via aequorin, sarcoplasmic reticulum Ca2+ content via rapid cooling contractures, and L-type Ca2+ currents via whole-cell voltage clamp across IGF-1 concentrations (0.001 to 0.2 µmol/L).
  • Assessed signaling mechanisms using pharmacologic inhibitors of the IGF-1 receptor, PI3-kinase, protein kinase C, L-type Ca2+ channels, Na+-H+ exchange, and reverse-mode Na+-Ca2+ exchange.
  • IGF-1 produced concentration-dependent positive inotropic effects, with twitch force peaking at 133 ± 4% of baseline at 0.1 µmol/L (P<0.05); this effect was prevented by IGF-1 receptor blockade or PI3-kinase inhibition.
  • IGF-1 (0.1 µmol/L) increased L-type Ca2+ current amplitude by 24 ± 7% (P<0.05), and L-type channel blockade with diltiazem blunted the inotropic response by approximately 50%.
  • Inhibition of protein kinase C, Na+-H+ exchange, or reverse-mode Na+-Ca2+ exchange reduced the inotropic response to IGF-1 by 60% to 70%, whereas sarcoplasmic reticulum blockade had no effect.

Structured PICO

Does IGF-1 exert positive inotropic effects in isolated failing human myocardium?

P
Population
Isolated trabeculae or cardiomyocytes from 46 end-stage failing human hearts
I
Intervention
Insulin-like growth factor-1 (IGF-1) 0.001 to 0.2 micromol/L
C
Comparator
Baseline values and various pharmacological blockers (alphaIR3, wortmannin, diltiazem, GF109203X, HOE642, KB-R7943)
O
Outcome
Isometric twitch force, intracellular Ca2+ transients, sarcoplasmic reticulum (SR) Ca2+ content, L-type Ca2+ current, and cAMP concentrationssurrogate

IGF-1 exerts Ca2+-dependent positive inotropic effects in failing human myocardium via IGF-1 receptors and a PI3-kinase-dependent pathway.

Cite This Study

Lewinski et al. (2003) studied this question.

synapsesocial.com/papers/6a70021ba528af2d65c34699https://doi.org/10.1161/01.res.0000051885.70159.12

Topics

Heart failureHFrEF treatment
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Also Consider

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