Preclinical Research
Short-Term Administration of Serelaxin Produces Predominantly Vascular Benefits in the Angiotensin II/L-NAME Chronic Heart Failure Model

https://doi.org/10.1016/j.jacbts.2017.03.011Get rights and content
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Highlights

  • Temporary administration of recombinant relaxin-2 (serelaxin) in patients hospitalized with HF was associated with improved mortality 6 months after discharge.

  • The specific effects of serelaxin on vascular and myocardial structure and function in HF have not been studied.

  • In mice subjected to continuous 28-day heart failure stimulus of AngII and L-NAME, serelaxin was administered for 3 days (days 7 to 9), and both the acute effects during serelaxin infusion and the delayed effects after termination of serelaxin on cardiovascular structure and function were studied.

  • Temporary serelaxin improved vascular fibrosis and myocardial capillary density and reduced resistance vessel constriction to potassium chloride during administration. These effects unexpectedly persisted 19 days after discontinuation of serelaxin, despite continued exposure to AngII/L-NAME. Serelaxin did not alter cardiac hypertrophy, geometry, or dysfunction at either time point.

  • These findings support that serelaxin predominantly affects vascular structure and function in the setting of HF.

Summary

In patients hospitalized with acute heart failure, temporary serelaxin infusion reduced 6-month mortality through unknown mechanisms. This study therefore explored the cardiovascular effects of temporary serelaxin administration in mice subjected to the angiotensin II (AngII)/L-NG-nitroarginine methyl ester (L-NAME) heart failure model, both during serelaxin infusion and 19 days post–serelaxin infusion. Serelaxin administration did not alter AngII/L-NAME-induced cardiac hypertrophy, geometry, or dysfunction. However, serelaxin-treated mice had reduced perivascular left ventricular fibrosis and preserved left ventricular capillary density at both time points. Furthermore, resistance vessels from serelaxin-treated mice displayed decreased potassium chloride–induced constriction and reduced aortic fibrosis. These findings suggest that serelaxin improves outcomes in patients through vascular-protective effects.

Key Words

heart failure
relaxin
vascular function

Abbreviations and Acronyms

AngII
angiotensin II
HF
heart failure
L-NAME
L-NG-nitroarginine methyl ester
LV
left ventricular
SBP
systolic blood pressure

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This study was funded by Novartis Pharmaceuticals through an investigator initiated study award (RLX030AUSNC14T). The authors have reported that they have no relationships relevant to the contents of this paper to disclose. Drs. Jaffe and Blanton contributed equally to this work.

All authors attest they are in compliance with human studies committees and animal welfare regulations of the authors’ institutions and Food and Drug Administration guidelines, including patient consent where appropriate. For more information, visit the JACC: Basic to Translational Science author instructions page.