Reduced ambient temperature exacerbates SIRS-induced cardiac autonomic dysregulation and myocardial dysfunction in mice
Abstract
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.
Keywords
Myocardial contractility Autonomic nervous system Acute inflammation Ambient temperature iNOSNotes
Acknowledgements
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.
Funding
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
References
- 1.Task Force of the European Society of Cardiology and the North American Society of Pacing and Electrophysiology (1996) Heart rate variability: standards of measurement, physiological interpretation and clinical use. Circulation 93:1043–1065CrossRefGoogle Scholar
- 2.Angus DC, van der Poll T (2013) Severe sepsis and septic shock. N Engl J Med 369:840–851. https://doi.org/10.1056/NEJMra1208623 CrossRefPubMedPubMedCentralGoogle Scholar
- 3.Aragones J, Fraisl P, Baes M, Carmeliet P (2009) Oxygen sensors at the crossroad of metabolism. Cell Metab 9:11–22. https://doi.org/10.1016/j.cmet.2008.10.001 CrossRefPubMedGoogle Scholar
- 4.Balligand JL, Feron O, Dessy C (2009) eNOS activation by physical forces: from short-term regulation of contraction to chronic remodeling of cardiovascular tissues. Physiol Rev 89:481–534. https://doi.org/10.1152/physrev.00042.2007 CrossRefPubMedGoogle Scholar
- 5.Beesley SJ, Weber G, Sarge T, Nikravan S, Grissom CK, Lanspa MJ, Shahul S, Brown SM (2018) Septic cardiomyopathy. Crit Care Med 46:625–634. https://doi.org/10.1097/CCM.0000000000002851 CrossRefPubMedGoogle Scholar
- 6.Bers DM (2002) Cardiac excitation–contraction coupling. Nature 415:198–205. https://doi.org/10.1038/415198a CrossRefPubMedGoogle Scholar
- 7.Bierhaus A, Humpert PM, Nawroth PP (2006) Linking stress to inflammation. Anesthesiol Clin 24:325–340. https://doi.org/10.1016/j.atc.2006.01.001 CrossRefPubMedGoogle Scholar
- 8.Blouin CC, Page EL, Soucy GM, Richard DE (2004) Hypoxic gene activation by lipopolysaccharide in macrophages: implication of hypoxia-inducible factor 1alpha. Blood 103:1124–1130. https://doi.org/10.1182/blood-2003-07-2427 CrossRefPubMedGoogle Scholar
- 9.Botker HE, Hausenloy D, Andreadou I, Antonucci S, Boengler K, Davidson SM, Deshwal S, Devaux Y, Di Lisa F, Di Sante M, Efentakis P, Femmino S, Garcia-Dorado D, Giricz Z, Ibanez B, Iliodromitis E, Kaludercic N, Kleinbongard P, Neuhauser M, Ovize M, Pagliaro P, Rahbek-Schmidt M, Ruiz-Meana M, Schluter KD, Schulz R, Skyschally A, Wilder C, Yellon DM, Ferdinandy P, Heusch G (2018) Practical guidelines for rigor and reproducibility in preclinical and clinical studies on cardioprotection. Basic Res Cardiol 113:39. https://doi.org/10.1007/s00395-018-0696-8 CrossRefPubMedPubMedCentralGoogle Scholar
- 10.Brodhun M, Fritz H, Walter B, Antonow-Schlorke I, Reinhart K, Zwiener U, Bauer R, Patt S (2001) Immunomorphological sequelae of severe brain injury induced by fluid-percussion in juvenile pigs—effects of mild hypothermia. Acta Neuropathol 101:424–434PubMedGoogle Scholar
- 11.Cannavo A, Rengo G, Liccardo D, Pun A, Gao E, George AJ, Gambino G, Rapacciuolo A, Leosco D, Ibanez B, Ferrara N, Paolocci N, Koch WJ (2017) beta1-blockade prevents post-ischemic myocardial decompensation via beta3AR-dependent protective sphingosine-1 phosphate signaling. J Am Coll Cardiol 70:182–192. https://doi.org/10.1016/j.jacc.2017.05.020 CrossRefPubMedPubMedCentralGoogle Scholar
- 12.Chavez LO, Leon M, Einav S, Varon J (2017) Editor’s choice—inside the cold heart: a review of therapeutic hypothermia cardioprotection. Eur Heart J Acute Cardiovasc Care 6:130–141. https://doi.org/10.1177/2048872615624242 CrossRefPubMedGoogle Scholar
- 13.Chen M, Sato PY, Chuprun JK, Peroutka RJ, Otis NJ, Ibetti J, Pan S, Sheu SS, Gao E, Koch WJ (2013) Prodeath signaling of G protein-coupled receptor kinase 2 in cardiac myocytes after ischemic stress occurs via extracellular signal-regulated kinase-dependent heat shock protein 90-mediated mitochondrial targeting. Circ Res 112:1121–1134. https://doi.org/10.1161/CIRCRESAHA.112.300754 CrossRefPubMedPubMedCentralGoogle Scholar
- 14.Chen Q, Chen T, Li W, Zhang W, Zhu J, Li Y, Huang Y, Shen Y, Yu C (2012) Mycoepoxydiene inhibits lipopolysaccharide-induced inflammatory responses through the suppression of TRAF6 polyubiquitination [corrected]. PLoS One 7:e44890. https://doi.org/10.1371/journal.pone.0044890 CrossRefPubMedPubMedCentralGoogle Scholar
- 15.Connelly L, Madhani M, Hobbs AJ (2005) Resistance to endotoxic shock in endothelial nitric-oxide synthase (eNOS) knock-out mice: a pro-inflammatory role for eNOS-derived no in vivo. J Biol Chem 280:10040–10046. https://doi.org/10.1074/jbc.M411991200 CrossRefPubMedGoogle Scholar
- 16.CotEU EP (2010) Directive 2010/63/EU of the European Parliament and of the council on the protection of animals used for scientific purposes. Off J Eur Union L 276:33–79Google Scholar
- 17.Cumming J, Purdue GF, Hunt JL, O’Keefe GE (2001) Objective estimates of the incidence and consequences of multiple organ dysfunction and sepsis after burn trauma. J Trauma 50:510–515. https://doi.org/10.1097/00005373-200103000-00016 CrossRefPubMedGoogle Scholar
- 18.Cunnion RE, Schaer GL, Parker MM, Natanson C, Parrillo JE (1986) The coronary circulation in human septic shock. Circulation 73:637–644CrossRefGoogle Scholar
- 19.Dash R, Mitsutake Y, Pyun WB, Dawoud F, Lyons J, Tachibana A, Yahagi K, Matsuura Y, Kolodgie FD, Virmani R, McConnell MV, Illindala U, Ikeno F, Yeung A (2018) Dose-dependent cardioprotection of moderate (32 degrees C) versus mild (35 degrees C) therapeutic hypothermia in porcine acute myocardial infarction. JACC Cardiovasc Interv 11:195–205. https://doi.org/10.1016/j.jcin.2017.08.056 CrossRefPubMedPubMedCentralGoogle Scholar
- 20.De Giorgi A, Fabbian F, Pala M, Parisi C, Misurati E, Molino C, Boccafogli A, Tiseo R, Gamberini S, Salmi R, Portaluppi F, Manfredini R (2015) Takotsubo cardiomyopathy and acute infectious diseases: a mini-review of case reports. Angiology 66:257–261. https://doi.org/10.1177/0003319714523673 CrossRefPubMedGoogle Scholar
- 21.Eckle T, Kohler D, Lehmann R, El Kasmi K, Eltzschig HK (2008) Hypoxia-inducible factor-1 is central to cardioprotection: a new paradigm for ischemic preconditioning. Circulation 118:166–175. https://doi.org/10.1161/CIRCULATIONAHA.107.758516 CrossRefPubMedGoogle Scholar
- 22.Finkel MS, Oddis CV, Jacob TD, Watkins SC, Hattler BG, Simmons RL (1992) Negative inotropic effects of cytokines on the heart mediated by nitric oxide. Science 257:387–389. https://doi.org/10.1126/science.1631560 CrossRefPubMedGoogle Scholar
- 23.Fleischmann C, Scherag A, Adhikari NK, Hartog CS, Tsaganos T, Schlattmann P, Angus DC, Reinhart K, International Forum of Acute Care T (2016) Assessment of global incidence and mortality of hospital-treated sepsis. Current estimates and limitations. Am J Respir Crit Care Med 193:259–272. https://doi.org/10.1164/rccm.201504-0781oc CrossRefPubMedGoogle Scholar
- 24.Goldstein DS (2013) Differential responses of components of the autonomic nervous system. Handb Clin Neurol 117:13–22. https://doi.org/10.1016/B978-0-444-53491-0.00002-X CrossRefPubMedGoogle Scholar
- 25.Gonnert FA, Recknagel P, Seidel M, Jbeily N, Dahlke K, Bockmeyer CL, Winning J, Losche W, Claus RA, Bauer M (2011) Characteristics of clinical sepsis reflected in a reliable and reproducible rodent sepsis model. J Surg Res 170:e123–e134. https://doi.org/10.1016/j.jss.2011.05.019 CrossRefPubMedGoogle Scholar
- 26.Gordon CJ (2012) Thermal physiology of laboratory mice: defining thermoneutrality. J Therm Biol 37:654–685. https://doi.org/10.1016/j.jtherbio.2012.08.004 CrossRefGoogle Scholar
- 27.Gordon CJ (2017) The mouse thermoregulatory system: its impact on translating biomedical data to humans. Physiol Behav 179:55–66. https://doi.org/10.1016/j.physbeh.2017.05.026 CrossRefPubMedPubMedCentralGoogle Scholar
- 28.Gordon CJ, Becker P, Ali JS (1998) Behavioral thermoregulatory responses of single- and group-housed mice. Physiol Behav 65:255–262. https://doi.org/10.1016/S0031-9384(98)00148-6 CrossRefPubMedGoogle Scholar
- 29.Gottlieb RA, Mentzer RM (2010) Autophagy during cardiac stress: joys and frustrations of autophagy. Annu Rev Physiol 72:45–59. https://doi.org/10.1146/annurev-physiol-021909-135757 CrossRefPubMedPubMedCentralGoogle Scholar
- 30.Gottlieb RA, Mentzer RM Jr (2013) Autophagy: an affair of the heart. Heart Fail Rev 18:575–584. https://doi.org/10.1007/s10741-012-9367-2 CrossRefPubMedGoogle Scholar
- 31.Groeneveld AB, van Lambalgen AA, van den Bos GC, Bronsveld W, Nauta JJ, Thijs LG (1991) Maldistribution of heterogeneous coronary blood flow during canine endotoxin shock. Cardiovasc Res 25:80–88CrossRefGoogle Scholar
- 32.Hankenson FC, Marx JO, Gordon CJ, David JM (2018) Effects of rodent thermoregulation on animal models in the research environment. Comp Med. https://doi.org/10.30802/aalas-cm-18-000049 CrossRefPubMedPubMedCentralGoogle Scholar
- 33.Heusch G (2012) HIF-1alpha and paradoxical phenomena in cardioprotection. Cardiovasc Res 96:214–215. https://doi.org/10.1093/cvr/cvs145 (discussion 216–219) CrossRefPubMedGoogle Scholar
- 34.Heusch G (2015) Molecular basis of cardioprotection: signal transduction in ischemic pre-, post-, and remote conditioning. Circ Res 116:674–699. https://doi.org/10.1161/CIRCRESAHA.116.305348 CrossRefPubMedGoogle Scholar
- 35.Heusch G (2017) Critical issues for the translation of cardioprotection. Circ Res 120:1477–1486. https://doi.org/10.1161/CIRCRESAHA.117.310820 CrossRefPubMedGoogle Scholar
- 36.Heusch G (2017) There is more to beta-blockade than just blockade of beta-receptors: a case for cardioprotective cross-signaling. J Am Coll Cardiol 70:193–195. https://doi.org/10.1016/j.jacc.2017.05.017 CrossRefPubMedGoogle Scholar
- 37.Heusch G, Schulz R, Rahimtoola SH (2005) Myocardial hibernation: a delicate balance. Am J Physiol Heart Circ Physiol 288:H984–H999. https://doi.org/10.1152/ajpheart.01109.2004 CrossRefPubMedGoogle Scholar
- 38.Hsieh CH, Pai PY, Hsueh HW, Yuan SS, Hsieh YC (2011) Complete induction of autophagy is essential for cardioprotection in sepsis. Ann Surg 253:1190–1200. https://doi.org/10.1097/SLA.0b013e318214b67e CrossRefPubMedGoogle Scholar
- 39.Huang CH, Chiang CY, Pen RH, Tsai MS, Chen HW, Hsu CY, Wang TD, Ma MH, Chen SC, Chen WJ (2015) Hypothermia treatment preserves mitochondrial integrity and viability of cardiomyocytes after ischaemic reperfusion injury. Injury 46:233–239. https://doi.org/10.1016/j.injury.2014.10.055 CrossRefPubMedGoogle Scholar
- 40.Huang CH, Tsai MS, Chiang CY, Su YJ, Wang TD, Chang WT, Chen HW, Chen WJ (2015) Activation of mitochondrial STAT-3 and reduced mitochondria damage during hypothermia treatment for post-cardiac arrest myocardial dysfunction. Basic Res Cardiol 110:59. https://doi.org/10.1007/s00395-015-0516-3 CrossRefPubMedGoogle Scholar
- 41.Hylander BL, Gordon CJ, Repasky EA (2019) Manipulation of ambient housing temperature to study the impact of chronic stress on immunity and cancer in mice. J Immunol 202:631–636. https://doi.org/10.4049/jimmunol.1800621 CrossRefPubMedGoogle Scholar
- 42.Imbrogno S, Gattuso A, Mazza R, Angelone T, Cerra MC (2015) beta3-AR and the vertebrate heart: a comparative view. Acta Physiol (Oxf) 214:158–175. https://doi.org/10.1111/apha.12493 CrossRefGoogle Scholar
- 43.Jones SP, Tang XL, Guo Y, Steenbergen C, Lefer DJ, Kukreja RC, Kong M, Li Q, Bhushan S, Zhu X, Du J, Nong Y, Stowers HL, Kondo K, Hunt GN, Goodchild TT, Orr A, Chang CC, Ockaili R, Salloum FN, Bolli R (2015) The NHLBI-sponsored Consortium for preclinicAl assESsment of cARdioprotective therapies (CAESAR): a new paradigm for rigorous, accurate, and reproducible evaluation of putative infarct-sparing interventions in mice, rabbits, and pigs. Circ Res 116:572–586. https://doi.org/10.1161/CIRCRESAHA.116.305462 CrossRefPubMedGoogle Scholar
- 44.Karp CL (2012) Unstressing intemperate models: how cold stress undermines mouse modeling. J Exp Med 209:1069–1074. https://doi.org/10.1084/jem.20120988 CrossRefPubMedPubMedCentralGoogle Scholar
- 45.Kass DA, Beyar R, Lankford E, Heard M, Maughan WL, Sagawa K (1989) Influence of contractile state on curvilinearity of in situ end-systolic pressure–volume relations. Circulation 79:167–178CrossRefGoogle Scholar
- 46.Keipert S, Jastroch M (2014) Brite/beige fat and UCP1—is it thermogenesis? Biochim Biophys Acta 1837:1075–1082. https://doi.org/10.1016/j.bbabio.2014.02.008 CrossRefPubMedGoogle Scholar
- 47.Khoynezhad A, Jalali Z, Tortolani AJ (2007) A synopsis of research in cardiac apoptosis and its application to congestive heart failure. Tex Heart Inst J 34:352–359PubMedPubMedCentralGoogle Scholar
- 48.Kohr MJ, Roof SR, Zweier JL, Ziolo MT (2012) Modulation of myocardial contraction by peroxynitrite. Front Physiol 3:468. https://doi.org/10.3389/fphys.2012.00468 CrossRefPubMedPubMedCentralGoogle Scholar
- 49.Lange M, Connelly R, Traber DL, Hamahata A, Nakano Y, Esechie A, Jonkam C, von Borzyskowski S, Traber LD, Schmalstieg FC, Herndon DN, Enkhbaatar P (2010) Time course of nitric oxide synthases, nitrosative stress, and poly(ADP ribosylation) in an ovine sepsis model. Crit Care 14:R129. https://doi.org/10.1186/cc9097 CrossRefPubMedPubMedCentralGoogle Scholar
- 50.Laupland KB, Zahar JR, Adrie C, Minet C, Vesin A, Goldgran-Toledano D, Azoulay E, Garrouste-Orgeas M, Cohen Y, Schwebel C, Jamali S, Darmon M, Dumenil AS, Kallel H, Souweine B, Timsit JF (2012) Severe hypothermia increases the risk for intensive care unit-acquired infection. Clin Infect Dis 54:1064–1070. https://doi.org/10.1093/cid/cir1033 CrossRefPubMedGoogle Scholar
- 51.Lefkowitz RJ, Shenoy SK (2005) Transduction of receptor signals by beta-arrestins. Science 308:512–517. https://doi.org/10.1126/science.1109237 CrossRefPubMedGoogle Scholar
- 52.Levy RJ, Piel DA, Acton PD, Zhou R, Ferrari VA, Karp JS, Deutschman CS (2005) Evidence of myocardial hibernation in the septic heart. Crit Care Med 33:2752–2756CrossRefGoogle Scholar
- 53.Li F, Lang F, Zhang H, Xu L, Wang Y, Zhai C, Hao E (2017) Apigenin alleviates endotoxin-induced myocardial toxicity by modulating inflammation, oxidative stress, and autophagy. Oxid Med Cell Longev 2017:2302896. https://doi.org/10.1155/2017/2302896 CrossRefPubMedPubMedCentralGoogle Scholar
- 54.Liang J, Yin K, Cao X, Han Z, Huang Q, Zhang L, Ma W, Ding F, Bi C, Feng D, Pan Z, Liu Y (2017) Attenuation of low ambient temperature-induced myocardial hypertrophy by atorvastatin via promoting Bcl-2 expression. Cell Physiol Biochem 41:286–295. https://doi.org/10.1159/000456111 CrossRefPubMedGoogle Scholar
- 55.Lindsey ML, Bolli R, Canty JM Jr, Du XJ, Frangogiannis NG, Frantz S, Gourdie RG, Holmes JW, Jones SP, Kloner RA, Lefer DJ, Liao R, Murphy E, Ping P, Przyklenk K, Recchia FA, Schwartz Longacre L, Ripplinger CM, Van Eyk JE, Heusch G (2018) Guidelines for experimental models of myocardial ischemia and infarction. Am J Physiol Heart Circ Physiol 314:H812–H838. https://doi.org/10.1152/ajpheart.00335.2017 CrossRefPubMedPubMedCentralGoogle Scholar
- 56.Livak KJ, Schmittgen TD (2001) Analysis of relative gene expression data using real-time quantitative PCR and the 2(-Delta Delta C(T)) method. Methods 25:402–408. https://doi.org/10.1006/meth.2001.1262 CrossRefGoogle Scholar
- 57.Louch WE, Sheehan KA, Wolska BM (2011) Methods in cardiomyocyte isolation, culture, and gene transfer. J Mol Cell Cardiol 51:288–298. https://doi.org/10.1016/j.yjmcc.2011.06.012 CrossRefPubMedPubMedCentralGoogle Scholar
- 58.Lu S, Xu D (2013) Cold stress accentuates pressure overload-induced cardiac hypertrophy and contractile dysfunction: role of TRPV1/AMPK-mediated autophagy. Biochem Biophys Res Commun 442:8–15. https://doi.org/10.1016/j.bbrc.2013.10.128 CrossRefPubMedGoogle Scholar
- 59.Madorin WS, Rui T, Sugimoto N, Handa O, Cepinskas G, Kvietys PR (2004) Cardiac myocytes activated by septic plasma promote neutrophil transendothelial migration: role of platelet-activating factor and the chemokines LIX and KC. Circ Res 94:944–951. https://doi.org/10.1161/01.RES.0000124395.20249.AE CrossRefPubMedGoogle Scholar
- 60.Mayr M, May D, Gordon O, Madhu B, Gilon D, Yin X, Xing Q, Drozdov I, Ainali C, Tsoka S, Xu Q, Griffiths J, Horrevoets A, Keshet E (2011) Metabolic homeostasis is maintained in myocardial hibernation by adaptive changes in the transcriptome and proteome. J Mol Cell Cardiol 50:982–990. https://doi.org/10.1016/j.yjmcc.2011.02.010 CrossRefPubMedPubMedCentralGoogle Scholar
- 61.Merx MW, Weber C (2007) Sepsis and the heart. Circulation 116:793–802. https://doi.org/10.1161/CIRCULATIONAHA.106.678359 CrossRefPubMedGoogle Scholar
- 62.Mi Z, Rapisarda A, Taylor L, Brooks A, Creighton-Gutteridge M, Melillo G, Varesio L (2008) Synergystic induction of HIF-1alpha transcriptional activity by hypoxia and lipopolysaccharide in macrophages. Cell Cycle 7:232–241. https://doi.org/10.4161/cc.7.2.5193 CrossRefPubMedGoogle Scholar
- 63.Morin P Jr, Storey KB (2005) Cloning and expression of hypoxia-inducible factor 1alpha from the hibernating ground squirrel, Spermophilus tridecemlineatus. Biochim Biophys Acta 1729:32–40. https://doi.org/10.1016/j.bbaexp.2005.02.009 CrossRefPubMedGoogle Scholar
- 64.Nakamura K (2011) Central circuitries for body temperature regulation and fever. Am J Physiol Regul Integr Comp Physiol 301:R1207–R1228. https://doi.org/10.1152/ajpregu.00109.2011 CrossRefPubMedGoogle Scholar
- 65.Ndongson-Dongmo B, Heller R, Hoyer D, Brodhun M, Bauer M, Winning J, Hirsch E, Wetzker R, Schlattmann P, Bauer R (2015) Phosphoinositide 3-kinase gamma controls inflammation-induced myocardial depression via sequential cAMP and iNOS signalling. Cardiovasc Res 108:243–253. https://doi.org/10.1093/cvr/cvv217 CrossRefPubMedGoogle Scholar
- 66.Nef HM, Mollmann H, Akashi YJ, Hamm CW (2010) Mechanisms of stress (Takotsubo) cardiomyopathy. Nat Rev Cardiol 7:187–193. https://doi.org/10.1038/nrcardio.2010.16 CrossRefPubMedGoogle Scholar
- 67.Ning XH, Chi EY, Buroker NE, Chen SH, Xu CS, Tien YT, Hyyti OM, Ge M, Portman MA (2007) Moderate hypothermia (30 degrees C) maintains myocardial integrity and modifies response of cell survival proteins after reperfusion. Am J Physiol Heart Circ Physiol 293:H2119–H2128. https://doi.org/10.1152/ajpheart.00123.2007 CrossRefPubMedGoogle Scholar
- 68.Ning XH, Xu CS, Song YC, Xiao Y, Hu YJ, Lupinetti FM, Portman MA (1998) Hypothermia preserves function and signaling for mitochondrial biogenesis during subsequent ischemia. Am J Physiol 274:H786–H793PubMedGoogle Scholar
- 69.Nishida K, Otsu K (2016) Autophagy during cardiac remodeling. J Mol Cell Cardiol 95:11–18. https://doi.org/10.1016/j.yjmcc.2015.12.003 CrossRefPubMedGoogle Scholar
- 70.Nishida K, Taneike M, Otsu K (2015) The role of autophagic degradation in the heart. J Mol Cell Cardiol 78:73–79. https://doi.org/10.1016/j.yjmcc.2014.09.029 CrossRefPubMedGoogle Scholar
- 71.Nishida K, Yamaguchi O, Otsu K (2008) Crosstalk between autophagy and apoptosis in heart disease. Circ Res 103:343–351. https://doi.org/10.1161/CIRCRESAHA.108.175448 CrossRefPubMedGoogle Scholar
- 72.NRC (2011) Guide for the care and use of laboratory animals. The National Academy Press, Washington, DCGoogle Scholar
- 73.Okla M, Wang W, Kang I, Pashaj A, Carr T, Chung S (2015) Activation of Toll-like receptor 4 (TLR4) attenuates adaptive thermogenesis via endoplasmic reticulum stress. J Biol Chem 290:26476–26490. https://doi.org/10.1074/jbc.M115.677724 CrossRefPubMedPubMedCentralGoogle Scholar
- 74.Otake H, Shite J, Paredes OL, Shinke T, Yoshikawa R, Tanino Y, Watanabe S, Ozawa T, Matsumoto D, Ogasawara D, Yokoyama M (2007) Catheter-based transcoronary myocardial hypothermia attenuates arrhythmia and myocardial necrosis in pigs with acute myocardial infarction. J Am Coll Cardiol 49:250–260. https://doi.org/10.1016/j.jacc.2006.06.080 CrossRefPubMedGoogle Scholar
- 75.Overton JM (2010) Phenotyping small animals as models for the human metabolic syndrome: thermoneutrality matters. Int J Obes (Lond) 34(Suppl 2):S53–S58. https://doi.org/10.1038/ijo.2010.240 CrossRefGoogle Scholar
- 76.Pacher P, Nagayama T, Mukhopadhyay P, Batkai S, Kass DA (2008) Measurement of cardiac function using pressure–volume conductance catheter technique in mice and rats. Nat Protoc 3:1422–1434. https://doi.org/10.1038/nprot.2008.138 CrossRefPubMedPubMedCentralGoogle Scholar
- 77.Perez-Schindler J, Philp A, Hernandez-Cascales J (2013) Pathophysiological relevance of the cardiac beta2-adrenergic receptor and its potential as a therapeutic target to improve cardiac function. Eur J Pharmacol 698:39–47. https://doi.org/10.1016/j.ejphar.2012.11.001 CrossRefPubMedGoogle Scholar
- 78.Peyssonnaux C, Cejudo-Martin P, Doedens A, Zinkernagel AS, Johnson RS, Nizet V (2007) Cutting edge: essential role of hypoxia inducible factor-1alpha in development of lipopolysaccharide-induced sepsis. J Immunol 178:7516–7519. https://doi.org/10.4049/jimmunol.178.12.7516 CrossRefPubMedGoogle Scholar
- 79.Polderman KH, Herold I (2009) Therapeutic hypothermia and controlled normothermia in the intensive care unit: practical considerations, side effects, and cooling methods. Crit Care Med 37:1101–1120. https://doi.org/10.1097/CCM.0b013e3181962ad5 CrossRefPubMedGoogle Scholar
- 80.Rudiger A, Singer M (2007) Mechanisms of sepsis-induced cardiac dysfunction. Crit Care Med 35:1599–1608. https://doi.org/10.1097/01.CCM.0000266683.64081.02 CrossRefPubMedGoogle Scholar
- 81.Rudiger A, Singer M (2013) The heart in sepsis: from basic mechanisms to clinical management. Curr Vasc Pharmacol 11:187–195. https://doi.org/10.2174/1570161111311020008 CrossRefPubMedGoogle Scholar
- 82.Sato PY, Chuprun JK, Schwartz M, Koch WJ (2015) The evolving impact of g protein-coupled receptor kinases in cardiac health and disease. Physiol Rev 95:377–404. https://doi.org/10.1152/physrev.00015.2014 CrossRefPubMedPubMedCentralGoogle Scholar
- 83.Schmittinger CA, Dunser MW, Torgersen C, Luckner G, Lorenz I, Schmid S, Joannidis M, Moser P, Hasibeder WR, Halabi M, Steger CM (2013) Histologic pathologies of the myocardium in septic shock: a prospective observational study. Shock 39:329–335. https://doi.org/10.1097/SHK.0b013e318289376b CrossRefPubMedGoogle Scholar
- 84.Schmittinger CA, Wurzinger B, Deutinger M, Wohlmuth C, Knotzer H, Torgersen C, Dunser MW, Hasibeder WR (2010) How to protect the heart in septic shock: a hypothesis on the pathophysiology and treatment of septic heart failure. Med Hypotheses 74:460–465. https://doi.org/10.1016/j.mehy.2009.10.012 CrossRefPubMedGoogle Scholar
- 85.Schortgen F (2012) Fever in sepsis. Minerva Anestesiol 78:1254–1264PubMedGoogle Scholar
- 86.Semenza GL (1999) Regulation of mammalian O2 homeostasis by hypoxia-inducible factor 1. Annu Rev Cell Dev Biol 15:551–578. https://doi.org/10.1146/annurev.cellbio.15.1.551 CrossRefPubMedGoogle Scholar
- 87.Semenza GL (2012) Shifting paradigms for ischaemic preconditioning. Cardiovasc Res 96:216–219. https://doi.org/10.1093/cvr/cvs145 CrossRefGoogle Scholar
- 88.Singer M, Deutschman CS, Seymour CW, Shankar-Hari M, Annane D, Bauer M, Bellomo R, Bernard GR, Chiche JD, Coopersmith CM, Hotchkiss RS, Levy MM, Marshall JC, Martin GS, Opal SM, Rubenfeld GD, van der Poll T, Vincent JL, Angus DC (2016) The third international consensus definitions for sepsis and septic shock (Sepsis-3). JAMA 315:801–810. https://doi.org/10.1001/jama.2016.0287 CrossRefPubMedPubMedCentralGoogle Scholar
- 89.Soreide K (2014) Clinical and translational aspects of hypothermia in major trauma patients: from pathophysiology to prevention, prognosis and potential preservation. Injury 45:647–654. https://doi.org/10.1016/j.injury.2012.12.027 CrossRefPubMedGoogle Scholar
- 90.Standage SW, Waworuntu RL, Delaney MA, Maskal SM, Bennion BG, Duffield JS, Parks WC, Liles WC, McGuire JK (2016) Nonhematopoietic peroxisome proliferator-activated receptor-alpha protects against cardiac injury and enhances survival in experimental polymicrobial sepsis. Crit Care Med 44:e594–e603. https://doi.org/10.1097/CCM.0000000000001585 CrossRefPubMedPubMedCentralGoogle Scholar
- 91.Steendijk P, Baan J (2000) Comparison of intravenous and pulmonary artery injections of hypertonic saline for the assessment of conductance catheter parallel conductance. Cardiovasc Res 46:82–89CrossRefGoogle Scholar
- 92.Stein B, Frank P, Schmitz W, Scholz H, Thoenes M (1996) Endotoxin and cytokines induce direct cardiodepressive effects in mammalian cardiomyocytes via induction of nitric oxide synthase. J Mol Cell Cardiol 28:1631–1639. https://doi.org/10.1006/jmcc.1996.0153 CrossRefPubMedGoogle Scholar
- 93.Swoap SJ, Li C, Wess J, Parsons AD, Williams TD, Overton JM (2008) Vagal tone dominates autonomic control of mouse heart rate at thermoneutrality. Am J Physiol Heart Circ Physiol 294:H1581–H1588. https://doi.org/10.1152/ajpheart.01000.2007 CrossRefPubMedGoogle Scholar
- 94.Szentirmai E, Krueger JM (2014) Sickness behaviour after lipopolysaccharide treatment in ghrelin deficient mice. Brain Behav Immun 36:200–206. https://doi.org/10.1016/j.bbi.2013.11.017 CrossRefPubMedGoogle Scholar
- 95.Tan CL, Knight ZA (2018) Regulation of body temperature by the nervous system. Neuron 98:31–48. https://doi.org/10.1016/j.neuron.2018.02.022 CrossRefPubMedPubMedCentralGoogle Scholar
- 96.Thireau J, Zhang BL, Poisson D, Babuty D (2008) Heart rate variability in mice: a theoretical and practical guide. Exp Physiol 93:83–94. https://doi.org/10.1113/expphysiol.2007.040733 CrossRefPubMedGoogle Scholar
- 97.Thoresen M, Satas S, Loberg EM, Whitelaw A, Acolet D, Lindgren C, Penrice J, Robertson N, Haug E, Steen PA (2001) Twenty-four hours of mild hypothermia in unsedated newborn pigs starting after a severe global hypoxic-ischemic insult is not neuroprotective. Pediatr Res 50:405–411. https://doi.org/10.1203/00006450-200109000-00017 CrossRefPubMedGoogle Scholar
- 98.Tissier R, Chenoune M, Pons S, Zini R, Darbera L, Lidouren F, Ghaleh B, Berdeaux A, Morin D (2013) Mild hypothermia reduces per-ischemic reactive oxygen species production and preserves mitochondrial respiratory complexes. Resuscitation 84:249–255. https://doi.org/10.1016/j.resuscitation.2012.06.030 CrossRefPubMedGoogle Scholar
- 99.Tissier R, Couvreur N, Ghaleh B, Bruneval P, Lidouren F, Morin D, Zini R, Bize A, Chenoune M, Belair MF, Mandet C, Douheret M, Dubois-Rande JL, Parker JC, Cohen MV, Downey JM, Berdeaux A (2009) Rapid cooling preserves the ischaemic myocardium against mitochondrial damage and left ventricular dysfunction. Cardiovasc Res 83:345–353. https://doi.org/10.1093/cvr/cvp046 CrossRefPubMedPubMedCentralGoogle Scholar
- 100.Tissier R, Ghaleh B, Cohen MV, Downey JM, Berdeaux A (2012) Myocardial protection with mild hypothermia. Cardiovasc Res 94:217–225. https://doi.org/10.1093/cvr/cvr315 CrossRefPubMedGoogle Scholar
- 101.Tooley JR, Satas S, Porter H, Silver IA, Thoresen M (2003) Head cooling with mild systemic hypothermia in anesthetized piglets is neuroprotective. Ann Neurol 53:65–72. https://doi.org/10.1002/ana.10402 CrossRefPubMedGoogle Scholar
- 102.Trappanese DM, Liu Y, McCormick RC, Cannavo A, Nanayakkara G, Baskharoun MM, Jarrett H, Woitek FJ, Tillson DM, Dillon AR, Recchia FA, Balligand JL, Houser SR, Koch WJ, Dell’Italia LJ, Tsai EJ (2015) Chronic beta1-adrenergic blockade enhances myocardial beta3-adrenergic coupling with nitric oxide-cGMP signaling in a canine model of chronic volume overload: new insight into mechanisms of cardiac benefit with selective beta1-blocker therapy. Basic Res Cardiol 110:456. https://doi.org/10.1007/s00395-014-0456-3 CrossRefPubMedGoogle Scholar
- 103.van de Sandt AM, Windler R, Godecke A, Ohlig J, Zander S, Reinartz M, Graf J, van Faassen EE, Rassaf T, Schrader J, Kelm M, Merx MW (2013) Endothelial NOS (NOS3) impairs myocardial function in developing sepsis. Basic Res Cardiol 108:330. https://doi.org/10.1007/s00395-013-0330-8 CrossRefPubMedPubMedCentralGoogle Scholar
- 104.Van Lambalgen AA, van Kraats AA, Mulder MF, Teerlink T, van den Bos GC (1994) High-energy phosphates in heart, liver, kidney, and skeletal muscle of endotoxemic rats. Am J Physiol 266:H1581–H1587. https://doi.org/10.1152/ajpheart.1994.266.4.H1581 CrossRefPubMedGoogle Scholar
- 105.Vo PA, Lad B, Tomlinson JA, Francis S, Ahluwalia A (2005) autoregulatory role of endothelium-derived nitric oxide (NO) on Lipopolysaccharide-induced vascular inducible NO synthase expression and function. J Biol Chem 280:7236–7243. https://doi.org/10.1074/jbc.M411317200 CrossRefPubMedGoogle Scholar
- 106.Werdan K, Oelke A, Hettwer S, Nuding S, Bubel S, Hoke R, Russ M, Lautenschlager C, Mueller-Werdan U, Ebelt H (2011) Septic cardiomyopathy: hemodynamic quantification, occurrence, and prognostic implications. Clin Res Cardiol 100:661–668. https://doi.org/10.1007/s00392-011-0292-5 CrossRefPubMedGoogle Scholar
- 107.Wilhelm J, Hettwer S, Schuermann M, Bagger S, Gerhardt F, Mundt S, Muschik S, Zimmermann J, Amoury M, Ebelt H, Werdan K (2014) Elevated troponin in septic patients in the emergency department: frequency, causes, and prognostic implications. Clin Res Cardiol 103:561–567. https://doi.org/10.1007/s00392-014-0684-4 CrossRefPubMedGoogle Scholar
- 108.Willis MS, Schisler JC, Portbury AL, Patterson C (2009) Build it up-Tear it down: protein quality control in the cardiac sarcomere. Cardiovasc Res 81:439–448. https://doi.org/10.1093/cvr/cvn289 CrossRefPubMedGoogle Scholar
- 109.Yang X, Liu Y, Yang XM, Hu F, Cui L, Swingle MR, Honkanen RE, Soltani P, Tissier R, Cohen MV, Downey JM (2011) Cardioprotection by mild hypothermia during ischemia involves preservation of ERK activity. Basic Res Cardiol 106:421–430. https://doi.org/10.1007/s00395-011-0165-0 CrossRefPubMedPubMedCentralGoogle Scholar
- 110.Ye L, Wu J, Cohen P, Kazak L, Khandekar MJ, Jedrychowski MP, Zeng X, Gygi SP, Spiegelman BM (2013) Fat cells directly sense temperature to activate thermogenesis. Proc Natl Acad Sci USA 110:12480–12485. https://doi.org/10.1073/pnas.1310261110 CrossRefPubMedGoogle Scholar
- 111.Young PJ, Saxena M, Beasley R, Bellomo R, Bailey M, Pilcher D, Finfer S, Harrison D, Myburgh J, Rowan K (2012) Early peak temperature and mortality in critically ill patients with or without infection. Intensive Care Med 38:437–444. https://doi.org/10.1007/s00134-012-2478-3 CrossRefGoogle Scholar
- 112.Zaglia T, Milan G, Franzoso M, Bertaggia E, Pianca N, Piasentini E, Voltarelli VA, Chiavegato D, Brum PC, Glass DJ, Schiaffino S, Sandri M, Mongillo M (2013) Cardiac sympathetic neurons provide trophic signal to the heart via beta2-adrenoceptor-dependent regulation of proteolysis. Cardiovasc Res 97:240–250. https://doi.org/10.1093/cvr/cvs320 CrossRefPubMedGoogle Scholar
- 113.Zaky A, Deem S, Bendjelid K, Treggiari MM (2014) Characterization of cardiac dysfunction in sepsis: an ongoing challenge. Shock 41:12–24. https://doi.org/10.1097/SHK.0000000000000065 CrossRefPubMedGoogle Scholar