title: Sunitinib does not attenuate contractile force following a period of ischemia in isolated human cardiac muscle.
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.
authors.affiliation: Department of Pharmacology-Toxicology, Radboud University Medical Center, PO BOX 9101, 6500 HB, Nijmegen, The Netherlands, Annemarie.Thijs@radboudumc.nl.
authors.forename: Anna M J
authors.initials: AM
authors.lastname: Thijs
authors.forename: Saloua
authors.initials: S
authors.lastname: El Messaoudi
authors.forename: Johanna C M
authors.initials: JC
authors.lastname: Vos
authors.forename: Alfons C
authors.initials: AC
authors.lastname: Wouterse
authors.forename: Vivienne
authors.initials: V
authors.lastname: Verweij
authors.forename: Henry
authors.initials: H
authors.lastname: van Swieten
authors.forename: Carla M L
authors.initials: CM
authors.lastname: van Herpen
authors.forename: Winette T A
authors.initials: WT
authors.lastname: van der Graaf
authors.forename: Luc
authors.initials: L
authors.lastname: Noyez
authors.forename: Gerard A
authors.initials: GA
authors.lastname: Rongen
mesh_terms: D000328:Adult; D000368:Aged; D001026:Coronary Artery Bypass; D004558:Electric Stimulation; D005260:Female; D006325:Heart Atria / Q000187:drug effects*; D006333:Heart Failure / Q000139:chemically induced / Q000503:physiopathology; D006801:Humans; D007211:Indoles / Q000009:adverse effects / Q000627:therapeutic use*; D007511:Ischemia / Q000188:drug therapy*; D008297:Male; D008875:Middle Aged; D009200:Myocardial Contraction / Q000187:drug effects*; D009206:Myocardium / Q000473:pathology*; D011758:Pyrroles / Q000009:adverse effects / Q000627:therapeutic use*; D015427:Reperfusion Injury; D012997:Solvents / Q000737:chemistry; D000077210:Sunitinib; D042461:Vascular Endothelial Growth Factor A / Q000378:metabolism
chemical_list: D007211:Indoles; D011758:Pyrroles; D012997:Solvents; C467484:VEGFA protein, human; D042461:Vascular Endothelial Growth Factor A; D000077210:Sunitinib