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Reduced Myocardial Mitochondrial ROS Production in Mechanically Unloaded Hearts

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Abstract

Mechanical ventricular unloading in advanced heart failure (HF) has been shown to induce reverse remodeling in myocardial tissues. Little is known about the impact of ventricular unloading on myocardial energy metabolism. We hypothesized that left ventricular unloading reduces myocardial mitochondrial reactive oxygen species (ROS) production and improves mitochondrial coupling efficiency in patients suffering from advanced HF. Left ventricular tissue specimens were harvested from explanted hearts at the time of transplantation. We compared myocardial metabolism in explanted hearts supported with an unloading ventricular assist device prior to transplantation (LVAD-HTX; n = 9) with tissue specimens of unsupported failing hearts (HTX; n = 6). Myocardial mitochondrial ROS production was decreased by 40% in LVAD-HTX compared to HTX patients (1.5 ± 0.3 vs. 0.9 ± 0.1 pmol/(s/mg); p < 0.05). High-resolution respirometry revealed increased mitochondrial coupling efficiency in LVAD-HTX patients (respiratory/control ratio 1.7 ± 0.2 vs. 1.2 ± 0.2; p < 0.05). In conclusion, ventricular unloading is related to decreased mitochondrial ROS production and increased coupling efficiency in myocardium of human failing hearts, suggesting a novel pathomechanism of unloading-associated cardioprotection.

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References

  1. Dayer, M., & Cowie, M. R. (2004). Heart failure: diagnosis and healthcare burden. Clinical Medicine (London, England), 4(1), 13–18.

    Article  PubMed Central  Google Scholar 

  2. Braunwald, E. (2013). Heart failure. JACC Heart Fail, 1(1), 1–20.

    Article  Google Scholar 

  3. Ponikowski, P., et al. (2016). ESC Guidelines for the diagnosis and treatment of acute and chronic heart failure: The Task Force for the diagnosis and treatment of acute and chronic heart failure of the European Society of Cardiology (ESC). Developed with the special contribution of the Heart Failure Association (HFA) of the ESC. European Journal of Heart Failure, 18(8), 891–975.

    Article  PubMed  Google Scholar 

  4. Deng, M. C., et al. (2004). Mechanical circulatory support device database of the International Society for Heart and Lung Transplantation: second annual report—2004. The Journal of Heart and Lung Transplantation, 23(9), 1027–1034.

    Article  PubMed  Google Scholar 

  5. Burkhoff, D., Klotz, S., & Mancini, D. M. (2006). LVAD-induced reverse remodeling: basic and clinical implications for myocardial recovery. Journal of Cardiac Failure, 12(3), 227–239.

    Article  PubMed  Google Scholar 

  6. Klotz, S., et al. (2004). Left ventricular pressure and volume unloading during pulsatile versus nonpulsatile left ventricular assist device support. The Annals of Thoracic Surgery, 77(1), 143–9; discussion 149-50.

    Article  PubMed  Google Scholar 

  7. Ponikowski, P., et al. (2016). ESC Guidelines for the diagnosis and treatment of acute and chronic heart failure: The Task Force for the diagnosis and treatment of acute and chronic heart failure of the European Society of Cardiology (ESC)Developed with the special contribution of the Heart Failure Association (HFA) of the ESC. European Heart Journal, 37(27), 2129–2200.

    Article  PubMed  Google Scholar 

  8. Levin, H. R., et al. (1995). Reversal of chronic ventricular dilation in patients with end-stage cardiomyopathy by prolonged mechanical unloading. Circulation, 91(11), 2717–2720.

    Article  CAS  PubMed  Google Scholar 

  9. de Jonge, N., et al. (2002). Left ventricular assist device in end-stage heart failure: persistence of structural myocyte damage after unloading. An immunohistochemical analysis of the contractile myofilaments. Journal of the American College of Cardiology, 39(6), 963–969.

    Article  PubMed  Google Scholar 

  10. Vatta, M., et al. (2002). Molecular remodelling of dystrophin in patients with end-stage cardiomyopathies and reversal in patients on assistance-device therapy. Lancet, 359(9310), 936–941.

    Article  CAS  PubMed  Google Scholar 

  11. Bayeva, M., Gheorghiade, M., & Ardehali, H. (2013). Mitochondria as a therapeutic target in heart failure. Journal of the American College of Cardiology, 61(6), 599–610.

    Article  CAS  PubMed  Google Scholar 

  12. Lee, S. H., et al. (1998). Improvement of myocardial mitochondrial function after hemodynamic support with left ventricular assist devices in patients with heart failure. The Journal of Thoracic and Cardiovascular Surgery, 116(2), 344–349.

    Article  CAS  PubMed  Google Scholar 

  13. Nagoshi, T., et al. (2011). Optimization of cardiac metabolism in heart failure. Current Pharmaceutical Design, 17(35), 3846–3853.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  14. Holzem, K. M., et al. (2016). Mitochondrial structure and function are not different between nonfailing donor and end-stage failing human hearts. The FASEB Journal, 30(8), 2698–2707.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  15. Stride, N., et al. (2013). Decreased mitochondrial oxidative phosphorylation capacity in the human heart with left ventricular systolic dysfunction. European Journal of Heart Failure, 15(2), 150–157.

    Article  CAS  PubMed  Google Scholar 

  16. Tsutsui, H., Kinugawa, S., & Matsushima, S. (2011). Oxidative stress and heart failure. American Journal of Physiology. Heart and Circulatory Physiology, 301(6), H2181–H2190.

    Article  CAS  PubMed  Google Scholar 

  17. Mondal, N. K., et al. (2013). Oxidative stress, DNA damage and repair in heart failure patients after implantation of continuous flow left ventricular assist devices. International Journal of Medical Sciences, 10(7), 883–893.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  18. Templeton, D. L., et al. (2012). Effects of left ventricular assist device (LVAD) placement on myocardial oxidative stress markers. Heart, Lung & Circulation, 21(9), 586–597.

    Article  CAS  Google Scholar 

  19. Koliaki, C., et al. (2015). Adaptation of hepatic mitochondrial function in humans with non-alcoholic fatty liver is lost in steatohepatitis. Cell Metabolism, 21(5), 739–746.

    Article  CAS  PubMed  Google Scholar 

  20. Szendroedi, J., Phielix, E., & Roden, M. (2011). The role of mitochondria in insulin resistance and type 2 diabetes mellitus. Nature Reviews. Endocrinology, 8(2), 92–103.

    Article  CAS  PubMed  Google Scholar 

  21. Pesta, D., & Gnaiger, E. (2012). High-resolution respirometry: OXPHOS protocols for human cells and permeabilized fibers from small biopsies of human muscle. Methods in Molecular Biology, 810, 25–58.

    Article  CAS  PubMed  Google Scholar 

  22. Gnaiger, E. (2008). Polarographic oxygen sensors, the oxygraph, and high-resolution respirometry to assess mitochondrial function. In Drug-induced mitochondrial dysfunction (pp. 325–352).

    Chapter  Google Scholar 

  23. Gnaiger, E. (2009). Capacity of oxidative phosphorylation in human skeletal muscle: new perspectives of mitochondrial physiology. The International Journal of Biochemistry & Cell Biology, 41(10), 1837–1845.

    Article  CAS  Google Scholar 

  24. Krumschnabel, G., et al. (2015). Simultaneous high-resolution measurement of mitochondrial respiration and hydrogen peroxide production. Methods in Molecular Biology, 1264, 245–261.

    Article  CAS  PubMed  Google Scholar 

  25. Makrecka-Kuka, M., Krumschnabel, G., & Gnaiger, E. (2015). High-resolution respirometry for simultaneous measurement of oxygen and hydrogen peroxide fluxes in permeabilized cells, tissue homogenate and isolated mitochondria. Biomolecules, 5(3), 1319–1338.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  26. Fleckenstein-Elsen, M., et al. (2016). Eicosapentaenoic acid and arachidonic acid differentially regulate adipogenesis, acquisition of a brite phenotype and mitochondrial function in primary human adipocytes. Molecular Nutrition & Food Research, 60(9), 2065–2075.

    Article  CAS  Google Scholar 

  27. Larsen, S., et al. (2012). Biomarkers of mitochondrial content in skeletal muscle of healthy young human subjects. The Journal of Physiology, 590(14), 3349–3360.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  28. Lemieux, H., et al. (2011). Mitochondrial respiratory control and early defects of oxidative phosphorylation in the failing human heart. The International Journal of Biochemistry & Cell Biology, 43(12), 1729–1738.

    Article  CAS  Google Scholar 

  29. Dipla, K., et al. (1998). Myocyte recovery after mechanical circulatory support in humans with end-stage heart failure. Circulation, 97(23), 2316–2322.

    Article  CAS  PubMed  Google Scholar 

  30. Heerdt, P. M., et al. (2002). Disease-specific remodeling of cardiac mitochondria after a left ventricular assist device. The Annals of Thoracic Surgery, 73(4), 1216–1221.

    Article  PubMed  Google Scholar 

  31. Razeghi, P., et al. (2002). Downregulation of metabolic gene expression in failing human heart before and after mechanical unloading. Cardiology, 97(4), 203–209.

    Article  CAS  PubMed  Google Scholar 

  32. Keith, M., et al. (1998). Increased oxidative stress in patients with congestive heart failure 11This study was supported by a grant jointly sponsored by the Medical Research Council of Canada, Ottawa and Bayer pharmaceuticals, Etobicoke, Ontario, Canada. Journal of the American College of Cardiology, 31(6), 1352–1356.

    Article  CAS  PubMed  Google Scholar 

  33. Ide, T., et al. (2001). Mitochondrial DNA damage and dysfunction associated with oxidative stress in failing hearts after myocardial infarction. Circulation Research, 88(5), 529–535.

    Article  CAS  PubMed  Google Scholar 

  34. Sawyer, D. B., et al. (2002). Role of oxidative stress in myocardial hypertrophy and failure. Journal of Molecular and Cellular Cardiology, 34(4), 379–388.

    Article  CAS  PubMed  Google Scholar 

  35. Caruso, R., et al. (2012). Severity of oxidative stress and inflammatory activation in end-stage heart failure patients are unaltered after 1 month of left ventricular mechanical assistance. Cytokine, 59(1), 138–144.

    Article  CAS  PubMed  Google Scholar 

  36. Stanley, B. A., et al. (2011). Thioredoxin reductase-2 is essential for keeping low levels of H(2)O(2) emission from isolated heart mitochondria. The Journal of Biological Chemistry, 286(38), 33669–33677.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  37. Aon, M. A., et al. (2012). Glutathione/thioredoxin systems modulate mitochondrial H2O2 emission: an experimental-computational study. The Journal of General Physiology, 139(6), 479–491.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  38. Molina, A. J., et al. (2016). Skeletal muscle mitochondrial content, oxidative capacity, and Mfn2 expression are reduced in older patients with heart failure and preserved ejection fraction and are related to exercise intolerance. JACC Heart Fail, 4(8), 636–645.

    Article  PubMed  PubMed Central  Google Scholar 

  39. Melenovsky, V., et al. (2017). Myocardial iron content and mitochondrial function in human heart failure: a direct tissue analysis. European Journal of Heart Failure, 19(4), 522–530.

    Article  CAS  PubMed  Google Scholar 

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Author notes

  1. Daniel Scheiber and Elric Zweck contributed equally to this work.

Authors and Affiliations

  1. Division of Cardiology, Pulmonology and Vascular Medicine, Medical Faculty, Heinrich Heine University, Düsseldorf, Germany

    Daniel Scheiber, Elric Zweck, Patrick Horn, Sophie Albermann, Maryna Masyuk, Malte Kelm & Ralf Westenfeld

  2. Institute for Clinical Diabetology, German Diabetes Center, Leibniz Center for Diabetes Research, Heinrich Heine University, Düsseldorf, Germany

    Daniel Scheiber, Elric Zweck, Tomas Jelenik, Sophie Albermann, Michael Roden & Julia Szendroedi

  3. German Center for Diabetes Research (DZD e.V.), München-Neuherberg, Partner Düsseldorf, Düsseldorf, Germany

    Daniel Scheiber, Elric Zweck, Tomas Jelenik, Sophie Albermann, Michael Roden & Julia Szendroedi

  4. Clinic for Cardiovascular Surgery, Medical Faculty, Heinrich Heine University, Düsseldorf, Germany

    Udo Boeken & Diyar Saeed

  5. Cardiovascular Research Institute Duesseldorf, Medical Faculty, Heinrich Heine University, Düsseldorf, Germany

    Malte Kelm

  6. Department of Endocrinology and Diabetology, Medical Faculty, Heinrich Heine University, Düsseldorf, Germany

    Michael Roden & Julia Szendroedi

Authors
  1. Daniel Scheiber
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  2. Elric Zweck
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  3. Tomas Jelenik
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  9. Malte Kelm
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  10. Michael Roden
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Correspondence to Ralf Westenfeld.

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Associate Editor Daniel P. Judge oversaw the review of this article

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Scheiber, D., Zweck, E., Jelenik, T. et al. Reduced Myocardial Mitochondrial ROS Production in Mechanically Unloaded Hearts. J. of Cardiovasc. Trans. Res. 12, 107–115 (2019). https://doi.org/10.1007/s12265-018-9803-3

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  • DOI: https://doi.org/10.1007/s12265-018-9803-3

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