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Sunitinib does not attenuate contractile force following a period of ischemia in isolated human cardiac muscle

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Abstract

Concerns have been raised about the development of heart failure in patients treated for cancer with angiogenesis inhibitors, such as the tyrosine kinase inhibitor sunitinib. Patients with previous coronary artery disease and hypertension have an increased risk of developing heart failure. Therefore, we studied the effect of sunitinib on the contractility of isolated human atrial trabeculae and the effect on recovery after ischemic stimulation. After informed consent, the atrial appendage of patients undergoing cardiac surgery was harvested and isolated trabeculae were placed in an organ bath with a force transducer. During electrical stimulation, contractile force was measured during normal pacing or after simulated ischemia. Of each patient, one trabecula was perfused with control and one with sunitinib. Contractile force (expressed as percentage of baseline force) declined over time to 57 ± 8 and 73 ± 20 % after 150 min of stimulation for solvent- and sunitinib-treated trabeculae, respectively (mean ± SE; n = 8; p > 0.1). After simulated ischemia and reperfusion, contractile force was 40 ± 6 % in the control compared to 39 ± 6 % in the sunitinib-treated trabeculae during the last final 5 min of reperfusion (n = 12; p > 0.1). Sunitinib at low, but clinically relevant, concentrations does not have a direct effect on function of human atrial cardiomyocytes nor does it attenuate the recovery in contractile force of atrial cardiomyocytes after a period of ischemia. A direct and acute toxic effect on cardiomyocytes does not explain the development of heart failure in patients treated with sunitinib.

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Acknowledgments

The authors would like to thank Petra van den Broek (Radboud University Medical Center) for the measurement (LCMS) of sunitinib in the perfusate, and we would like to thank the surgeons and secretariat of the Department of Cardiothoracic Surgery (Radboud University Medical Center) for the assistance in recruiting patients and the harvesting of atrial tissue. The study was funded by the Dutch Cancer Society.

Conflict of interest

The authors declare that they have no conflict of interest.

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Authors and Affiliations

  1. Department of Pharmacology-Toxicology, Radboud University Medical Center, PO BOX 9101, 6500 HB, Nijmegen, The Netherlands

    Anna M. J. Thijs, Saloua El Messaoudi, Johanna C. M. Vos, Alfons C. Wouterse, Vivienne Verweij & Gerard A. Rongen

  2. Department of Medical Oncology, Radboud University Medical Center, Nijmegen, The Netherlands

    Anna M. J. Thijs, Carla M. L. van Herpen & Winette T. A. van der Graaf

  3. Department of Cardio-thoracic Surgery, Radboud University Medical Center, Nijmegen, The Netherlands

    Henry van Swieten & Luc Noyez

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  1. Anna M. J. Thijs
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  2. Saloua El Messaoudi
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  3. Johanna C. M. Vos
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  4. Alfons C. Wouterse
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Correspondence to Anna M. J. Thijs.

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Thijs, A.M.J., El Messaoudi, S., Vos, J.C.M. et al. Sunitinib does not attenuate contractile force following a period of ischemia in isolated human cardiac muscle. Targ Oncol 10, 439–443 (2015). https://doi.org/10.1007/s11523-014-0351-8

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  • DOI: https://doi.org/10.1007/s11523-014-0351-8

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