Cardiovascular Research Advance Access [Accepted Manuscript] published online on February 5, 2009
Cardiovascular Research, doi:10.1093/cvr/cvp046
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Rapid cooling preserves the ischemic myocardium against mitochondrial damage and left ventricular dysfunction
1 INSERM U955, Equipe 3, Créteil, F-94010, France.
2 Université Paris 12, Faculté de Médecine, Créteil, F-94010, France.
3 Ecole Nationale Vétérinaire d'Alfort, Maisons-Alfort, F-94704, France.
4 INSERM UMRs872, Institut des Cordeliers, Paris, F-75005, France.
5 Department of Physiology, University of South Alabama, College of Medicine, Mobile, AL36688, USA.
6 Department of Medicine, University of South Alabama, College of Medicine, Mobile, AL36688, USA.
Corresponding author: Alain Berdeaux INSERM U955 Faculté de Médecine Paris 12 8 rue du Général Sarrail 94010 Créteil cedex, France Tel: +33.1.49.81.36.51 ; Fax: +33.1.48.99.17.77 E-mail: alain.berdeaux{at}inserm.fr
Aims: We investigated whether rapid cooling instituted by total liquid ventilation (TLV) improves cardiac and mitochondrial function in rabbits submitted to ischemia-reperfusion.
Methods: Rabbits were chronically instrumented with a coronary artery occluder and myocardial ultrasonic crystals for assessment of segment length shortening. Two weeks later they were reanesthetized and underwent either a normothermic 30-min coronary artery occlusion (CAO) (Control group, n = 7) or a comparable CAO with cooling initiated by a 10-min hypothermic TLV and maintained by a cold blanket placed on the skin. Cooling was initiated after 5 or 15-min of CAO (Hypo-TLV and Hypo-TLV15' groups, n = 6 and 5, respectively). A last group underwent normothermic TLV during CAO (Normo-TLV group, n = 6). Wall motion was measured in the conscious state over 3 days of reperfusion before infarct size evaluation and histology. Additional experiments were done for myocardial sampling in anesthetized rabbits for mitochondrial studies.
Results: The Hypo-TLV procedure induced a rapid decrease in myocardial temperature to 32-34°C. Throughout reperfusion, segment length shortening was significantly increased in Hypo-TLV and Hypo-TLV15' vs Control and Normo-TLV (15.1 ± 3.3%, 16.4 ± 2.3%, 1.8 ± 0.6% and 1.1 ± 0.8% at 72 h, respectively). Infarct sizes were also considerably attenuated in Hypo-TLV and Hypo-TLV15' vs Control and Normo-TLV (4 ± 1%, 11 ± 5%, 39 ± 2% and 42 ± 5% infarction of risk zones, respectively). Mitochondrial function in myocardial samples obtained at the end of ischemia or after 10 min of reperfusion was improved by Hypo-TLV with respect to ADP-stimulated respiration and calcium-induced opening of mitochondrial permeability transition pores (mPTP). Calcium concentration opening mPTP was, e.g., increased at the end of ischemia in the risk zone in Hypo-TLV vs Control (157 ± 12 vs 86 ± 12 µM). Histology and electron microscopy also revealed better preservation of lungs and of cardiomyocyte ultrastructure in Hypo-TLV as compared to Control.
Conclusion: Institution of rapid cooling by TLV during ischemia reduces infarct size as well as other sequelae of ischemia such as post-ischemic contractile and mitochondrial dysfunction.
KEYWORDS Cooling; Contractile function; Mitochondria; Infarction; Total liquid ventilation
Time for primary review: 25 Days
* both authors contributed equally to this work
Authorship: Conception, analysis and interpretation of data: R. Tissier, N. Couvreur, P. Bruneval, F. Lidouren, D. Morin, R. Zini, A. Bizé, M. Chenoune, M-F. Bélair, C. Mandet, M. Douheret, A. Berdeaux. Drafting of the manuscript and critical revision for intellectual content: R. Tissier, B. Ghaleh, J-L. Dubois-Randé, J.C. Parker, M.V. Cohen, J.M. Downey, A. Berdeaux.