Newly Published
Critical Care Medicine  |   April 2017
Up-regulation of Intracellular Calcium Handling Underlies the Recovery of Endotoxemic Cardiomyopathy in Mice
Author Notes
  • From the Department of Medicine, Section of Cardiovascular Medicine, Boston University Medical Center, Boston, Massachusetts (J.C.M., J.H., N.K., E.J.M., D.A.S., W.S.C., I.A.H.); Department of Radiology, Boston University Medical Center, Boston, Massachusetts (E.J.M.); Department of Anesthesiology, Critical Care and Pain Medicine, Massachusetts General Hospital, Boston, Massachusetts (I.A.H.); and Harvard University Medical School, Boston, Massachusetts (I.A.H.).
  • Preliminary results have been presented in abstract form at the annual meeting of the Biophysical Society in San Francisco, California, February 14 to 19, 2014.
    Preliminary results have been presented in abstract form at the annual meeting of the Biophysical Society in San Francisco, California, February 14 to 19, 2014.×
  • Submitted for publication July 3, 2016. Accepted for publication February 27, 2017.
    Submitted for publication July 3, 2016. Accepted for publication February 27, 2017.×
  • Acknowledgments: The idea behind this study came during a discussion with the late Kenneth D. Bloch, M.D., Professor of Anesthesiology, Harvard University, Boston, Massachusetts.
    Acknowledgments: The idea behind this study came during a discussion with the late Kenneth D. Bloch, M.D., Professor of Anesthesiology, Harvard University, Boston, Massachusetts.×
  • Research Support: Supported by grant Nos. HL-061639 and HL-064750 from the National Institutes of Health, Bethesda, Maryland (to Dr. Colucci); contract No. N01-HV-28178 from the National Heart, Lung, and Blood Institute–sponsored Boston University Cardiovascular Proteomics Center, Boston, Massachusetts (to Dr. Colucci); grant No. K08GM096082 from the National Institute of General Medical Sciences, Bethesda, Maryland, and support from the Department of Anesthesia, Critical Care and Pain Medicine, Massachusetts General Hospital, Boston, Massachusetts (to Dr. Hobai). Other support includes Student Research Awards from Boston University, Boston, Massachusetts (to J. C. Morse).
    Research Support: Supported by grant Nos. HL-061639 and HL-064750 from the National Institutes of Health, Bethesda, Maryland (to Dr. Colucci); contract No. N01-HV-28178 from the National Heart, Lung, and Blood Institute–sponsored Boston University Cardiovascular Proteomics Center, Boston, Massachusetts (to Dr. Colucci); grant No. K08GM096082 from the National Institute of General Medical Sciences, Bethesda, Maryland, and support from the Department of Anesthesia, Critical Care and Pain Medicine, Massachusetts General Hospital, Boston, Massachusetts (to Dr. Hobai). Other support includes Student Research Awards from Boston University, Boston, Massachusetts (to J. C. Morse).×
  • Competing Interests: The authors declare no competing interests.
    Competing Interests: The authors declare no competing interests.×
  • Correspondence: Address correspondence to Dr. Hobai: Department of Anesthesia, Critical Care and Pain Medicine, Massachusetts General Hospital, 55 Fruit Street, GRB 444, Boston, Massachusetts 02114. ihobai@partners.org. Information on purchasing reprints may be found at www.anesthesiology.org or on the masthead page at the beginning of this issue. Anesthesiology’s articles are made freely accessible to all readers, for personal use only, 6 months from the cover date of the issue.
Article Information
Critical Care Medicine / Cardiovascular Anesthesia / Critical Care / Pharmacology
Critical Care Medicine   |   April 2017
Up-regulation of Intracellular Calcium Handling Underlies the Recovery of Endotoxemic Cardiomyopathy in Mice
Anesthesiology Newly Published on April 20, 2017. doi:10.1097/ALN.0000000000001627
Anesthesiology Newly Published on April 20, 2017. doi:10.1097/ALN.0000000000001627
Abstract

Background: In surviving patients, sepsis-induced cardiomyopathy is spontaneously reversible. In the absence of any experimental data, it is generally thought that cardiac recovery in sepsis simply follows the remission of systemic inflammation. Here the authors aimed to identify the myocardial mechanisms underlying cardiac recovery in endotoxemic mice.

Methods: Male C57BL/6 mice were challenged with lipopolysaccharide (7 μg/g, intraperitoneally) and followed for 12 days. The authors assessed survival, cardiac function by echocardiography, sarcomere shortening, and calcium transients (with fura-2-acetoxymethyl ester) in electrically paced cardiomyocytes (5 Hz, 37°C) and myocardial protein expression by immunoblotting.

Results: Left ventricular ejection fraction, cardiomyocyte sarcomere shortening, and calcium transients were depressed 12 h after lipopolysaccharide challenge, started to recover by 24 h (day 1), and were back to baseline at day 3. The recovery of calcium transients at day 3 was associated with the up-regulation of the sarcoplasmic reticulum calcium pump to 139 ± 19% (mean ± SD) of baseline and phospholamban down-regulation to 35 ± 20% of baseline. At day 6, calcium transients were increased to 123 ± 31% of baseline, associated with increased sarcoplasmic reticulum calcium load (to 126 ± 32% of baseline, as measured with caffeine) and inhibition of sodium/calcium exchange (to 48 ± 12% of baseline).

Conclusions: In mice surviving lipopolysaccharide challenge, the natural recovery of cardiac contractility was associated with the up-regulation of cardiomyocyte calcium handling above baseline levels, indicating the presence of an active myocardial recovery process, which included sarcoplasmic reticulum calcium pump activation, the down-regulation of phospholamban, and sodium/calcium exchange inhibition.