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Heart rate reduction by ivabradine improves aortic compliance in apolipoprotein E-deficient mice

Florian Custodis1, Peter Fries, Andreas Müller

  • 1Kliniken für Innere Medizin III, Kardiologie, Angiologie und Internistische Intensivmedizin, Universitätsklinikum des Saarlandes, Homburg/Saar, Germany. florian.custodis@uks.eu

Journal of Vascular Research
|July 5, 2012
PubMed

Insights

Heart rate reduction using ivabradine improved aortic compliance in mice lacking apolipoprotein E. This suggests potential therapeutic benefits for cardiovascular health by targeting heart rate and vascular mechanisms.

Area of Science:

  • Cardiovascular Physiology
  • Pharmacology
  • Molecular Biology

Background:

  • Impaired vascular compliance is a significant risk factor for cardiovascular mortality.
  • The precise impact of heart rate on vascular compliance remains incompletely understood.
  • Apolipoprotein E-deficient (ApoE(-)/(-)) mice serve as a model for atherosclerosis and cardiovascular disease.

Purpose of the Study:

  • To investigate the effects of heart rate reduction (HRR) induced by If current inhibition on aortic compliance.
  • To elucidate the underlying molecular mechanisms responsible for these effects in ApoE(-)/(-) mice.

Main Methods:

  • Apolipoprotein E-deficient (ApoE(-)/(-)) and wild-type (WT) mice were administered ivabradine or vehicle for six weeks.
  • Ascending aortic compliance was quantitatively assessed using Magnetic Resonance Imaging (MRI).
  • Molecular analyses included protein and mRNA expression of the angiotensin II type 1 (AT1) receptor, and assays for oxidative stress markers.

Main Results:

  • Ivabradine significantly reduced heart rate in both WT and ApoE(-)/(-) mice.
  • ApoE(-)/(-) mice exhibited diminished distensibility and circumferential strain compared to WT controls.
  • HRR via ivabradine enhanced aortic distensibility and strain in ApoE(-)/(-) mice, with no effect in WT mice.
  • Ivabradine treatment led to decreased AT1 receptor expression, reduced rac1-GTPase activity, and inhibited p47(phox) translocation in ApoE(-)/(-) mice.
  • HRR demonstrated anti-inflammatory effects, indicated by reduced aortic mRNA expression of IL-6, TNF-alpha, and TGF-beta in ApoE(-)/(-) mice.

Conclusions:

  • Heart rate reduction achieved with ivabradine effectively improves vascular compliance in the context of atherosclerosis (ApoE(-)/(-)) mice.
  • Key mechanisms mediating these improvements include the downregulation of the AT1 receptor, attenuation of oxidative stress, and modulation of inflammatory cytokine expression.
  • These findings highlight a potential therapeutic strategy for enhancing vascular health through heart rate modulation.
Abstract

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