Reduced ambient temperature exacerbates SIRS-induced cardiac autonomic dysregulation and myocardial dysfunction in mice

  • Bernadin Ndongson-Dongmo
  • Guang-Ping Lang
  • Odeta Mece
  • Nadine Hechaichi
  • Trim Lajqi
  • Dirk Hoyer
  • Michael Brodhun
  • Regine Heller
  • Reinhard Wetzker
  • Marcus Franz
  • Finn Olav Levy
  • Reinhard BauerEmail author
Original Contribution


Sepsis-induced myocardial depression (SIMD) is an early and frequent consequence of the infection-induced systemic inflammatory response syndrome. In homiotherms, variations in ambient temperature (Ta) outside the thermoneutral zone induce thermoregulatory responses mainly driven by a gradually increased sympathetic activity, which may affect disease severity. We hypothesized that thermoregulatory responses upon reduced Ta exposition aggravate SIMD in mice. Mice were kept at neutral Ta (30 ± 0.5 °C), moderately lowered Ta (26 ± 0.5 °C) or markedly lowered Ta (22 ± 0.5 °C), exposed to lipopolysaccharide- (LPS, 10 µg/g, from Escherichia coli serotype 055:B5, single intraperitoneal injection) evoked shock and monitored for survival, cardiac autonomic nervous system function and left ventricular performance. Primary adult cardiomyocytes and heart tissue derived from treated mice were analyzed for inflammatory responses and signaling pathways of myocardial contractility. We show that a moderate reduction of Ta to 26 °C led to a 40% increased mortality of LPS-treated mice when compared to control mice and that a marked reduction of Ta to 22 °C resulted in an early mortality of all mice. Mice kept at 26 °C exhibited increased heart rate and altered indices of heart rate variability (HRV), indicating sympathovagal imbalance along with aggravated LPS-induced SIMD. This SIMD was associated with reduced myocardial β-adrenergic receptor expression and suppressed adrenergic signaling, as well as with increased myocardial iNOS expression, nitrotyrosine formation and leukocyte invasion as well as enhanced apoptosis and appearance of contraction band necrosis in heart tissue. While ineffective separately, combined treatment with the β2-adrenergic receptor (AR) antagonist ICI 118551 (10 ng/gbw) and the inducible nitric oxide synthase (iNOS) inhibitor 1400 W (5 µg/gbw) reversed the increase in LPS-induced mortality and aggravation of SIMD at reduced Ta. Thus, consequences of thermoregulatory adaptation in response to ambient temperatures below the thermoneutral range increase the mortality from LPS-evoked shock and markedly prolong impaired myocardial function. These changes are mitigated by combined β2-AR and iNOS inhibition.


Myocardial contractility Autonomic nervous system Acute inflammation Ambient temperature iNOS 



The authors acknowledge Mrs. R.-M. Zimmer and Mr. A. Gloria for skillful technical assistance, and Dr. Helen Morrisson for her collegial review of the manuscript.


The study was supported by the German Federal Ministry of Education and Research [B.N.-D., N.H., R.H.] [BMBF; Grant FKZ 01EO1002; Center for Sepsis Control and Care], the Deutsche Forschungsgemeinschaft [R.H., R.B.] [DFG, Grant RTG 1715, Grant RTG 2155], the Research Council of Norway (Grant 205167), Stiftelsen Kristian Gerhard Jebsen, the Anders Jahre foundation for the promotion of science, the Family Blix foundation, the Simon Fougner Hartmann Family foundation, and Grants from the University of Oslo [F.O.L.]. B.N.-D. received funding from the European Union Seventh Framework Programme (FP7-PEOPLE-2013-COFUND) under Grant agreement no 609020-Scientia Fellows, G.-P.L. received a Scholarship by the China Scholarship Council.

Compliance with ethical standards.

Conflict of interest

The authors declare that they have no competing interest.

Supplementary material

395_2019_734_MOESM1_ESM.docx (642 kb)
Supplementary material 1 (DOCX 641 kb)


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Copyright information

© Springer-Verlag GmbH Germany, part of Springer Nature 2019

Authors and Affiliations

  • Bernadin Ndongson-Dongmo
    • 1
    • 2
  • Guang-Ping Lang
    • 1
  • Odeta Mece
    • 1
    • 3
  • Nadine Hechaichi
    • 4
    • 9
  • Trim Lajqi
    • 1
  • Dirk Hoyer
    • 5
  • Michael Brodhun
    • 6
  • Regine Heller
    • 1
    • 4
  • Reinhard Wetzker
    • 1
    • 7
  • Marcus Franz
    • 8
  • Finn Olav Levy
    • 2
  • Reinhard Bauer
    • 1
    Email author
  1. 1.Institute of Molecular Cell Biology, Jena University HospitalFriedrich Schiller UniversityJenaGermany
  2. 2.Department of PharmacologyUniversity of Oslo and Oslo University HospitalOsloNorway
  3. 3.Laboratory of Cell Death Research and Therapy, Department of Cellular and Molecular MedicineKU LeuvenLouvainBelgium
  4. 4.Integrated Research and Treatment Center, Center for Sepsis Control and CareJena University HospitalJenaGermany
  5. 5.Biomagnetic Center, Hans Berger Clinic for Neurology, Jena University HospitalFriedrich Schiller UniversityJenaGermany
  6. 6.Department of PathologyHelios-Klinikum ErfurtErfurtGermany
  7. 7.Department of Anesthesiology and Intensive Care Medicine, Jena University HospitalFriedrich Schiller UniversityJenaGermany
  8. 8.Department of Internal Medicine I, Jena University HospitalFriedrich Schiller UniversityJenaGermany
  9. 9.Occlutech GmbHJenaGermany

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