title: Cardiotoxicity associated with tyrosine kinase inhibitor sunitinib.
abstract: BACKGROUND
  Sunitinib, a multitargeted tyrosine-kinase inhibitor, which is approved by both US and European Commission regulatory agencies for clinical use, extends survival of patients with metastatic renal-cell carcinoma and gastrointestinal stromal tumours, but concerns have arisen about its cardiac safety. We therefore assessed the cardiovascular risk associated with sunitinib in patients with metastatic gastrointestinal stromal tumours.
  
  
  METHODS
  We retrospectively reviewed all cardiovascular events in 75 patients with imatinib-resistant, metastatic, gastrointestinal stromal tumours who had been enrolled in a phase I/II trial investigating the efficacy of sunitinib. The composite cardiovascular endpoint was cardiac death, myocardial infarction, and congestive heart failure. We also examined sunitinib's effects on left ventricular ejection fraction (LVEF) and blood pressure. We investigated potential mechanisms of sunitinib-associated cardiac effects by studies in isolated rat cardiomyocytes and in mice.
  
  
  RESULTS
  Eight of 75 (11%) patients given repeating cycles of sunitinib in the phase I/II trial had a cardiovascular event, with congestive heart failure recorded in six of 75 (8%). Ten of 36 (28%) patients treated at the approved sunitinib dose had absolute LVEF reductions in ejection fraction (EF) of at least 10%, and seven of 36 (19%) had LVEF reductions of 15 EF% or more. Sunitinib induced increases in mean systolic and diastolic blood pressure, and 35 of 75 (47%) individuals developed hypertension (>150/100 mm Hg). Congestive heart failure and left ventricular dysfunction generally responded to sunitinib being withheld and institution of medical management. Sunitinib caused mitochondrial injury and cardiomyocyte apoptosis in mice and in cultured rat cardiomyocytes.
  
  
  CONCLUSIONS
  Left ventricular dysfunction might be due, in part, to direct cardiomyocyte toxicity, exacerbated by hypertension. Patients treated with sunitinib should be closely monitored for hypertension and LVEF reduction, especially those with a history of coronary artery disease or cardiac risk factors.
authors: Department of Cardiology, Children's Hospital Boston and Harvard Medical School, Boston, MA 02115, USA.
authors: Tammy F
authors: TF
authors: Chu
authors: Maria A
authors: MA
authors: Rupnick
authors: Risto
authors: R
authors: Kerkela
authors: Susan M
authors: SM
authors: Dallabrida
authors: David
authors: D
authors: Zurakowski
authors: Lisa
authors: L
authors: Nguyen
authors: Kathleen
authors: K
authors: Woulfe
authors: Elke
authors: E
authors: Pravda
authors: Flavia
authors: F
authors: Cassiola
authors: Jayesh
authors: J
authors: Desai
authors: Suzanne
authors: S
authors: George
authors: Jeffrey A
authors: JA
authors: Morgan
authors: David M
authors: DM
authors: Harris
authors: Nesreen S
authors: NS
authors: Ismail
authors: Jey-Hsin
authors: JH
authors: Chen
authors: Frederick J
authors: FJ
authors: Schoen
authors: Annick D
authors: AD
authors: Van den Abbeele
authors: George D
authors: GD
authors: Demetri
authors: Thomas
authors: T
authors: Force
authors: Ming Hui
authors: MH
authors: Chen
mesh_terms: D000818:Animals; D000970:Antineoplastic Agents / Q000009:adverse effects* / Q000627:therapeutic use; D001794:Blood Pressure / Q000187:drug effects; D005260:Female; D046152:Gastrointestinal Stromal Tumors / Q000188:drug therapy; D006333:Heart Failure / Q000139:chemically induced*; D006801:Humans; D007211:Indoles / Q000009:adverse effects* / Q000627:therapeutic use; D008297:Male; D051379:Mice; D008875:Middle Aged; D015337:Multicenter Studies as Topic; D011505:Protein-Tyrosine Kinases / Q000037:antagonists & inhibitors; D011758:Pyrroles / Q000009:adverse effects* / Q000627:therapeutic use; D051381:Rats; D012189:Retrospective Studies; D013318:Stroke Volume / Q000187:drug effects; D000077210:Sunitinib
chemical_list: D000970:Antineoplastic Agents; D007211:Indoles; D011758:Pyrroles; D011505:Protein-Tyrosine Kinases; D000077210:Sunitinib