Genetic and ethnic modulation of cardiovascular toxicity of vascular endothelial growth factor inhibitors

Ann Med. 2018 Feb;50(1):46-56. doi: 10.1080/07853890.2017.1383629. Epub 2017 Sep 27.

Abstract

Vascular endothelial growth factor (VEGF) inhibitors, including monoclonal antibodies and tyrosine kinase inhibitors (TKIs), are important as anticancer treatments through curbing tumour angiogenesis and growth. VEGF inhibitors have significant cardiovascular effects. By blocking VEGF receptors, ligands, or signal pathways, VEGF inhibitors disturb the balance between vasodilation and vasoconstriction, undermine endothelial cell integrity, and activate cardiomyocyte apoptosis. VEGF inhibitors increase risks of hypertension, heart failure, thromboembolism and arrhythmia. Genetic and geographic studies showed that genetic polymorphisms likely play significant predictive or prognostic roles in cardiovascular toxicity associated with VEGF inhibitors. This review updates current understandings of VEGF inhibitors on cardiovascular toxicity, explores potential mechanisms, and clarifies whether genetic or ethnic factors contribute to their adverse effects. Key Messages VEGF inhibitors disturb the balance between vasodilation and vasoconstriction, undermine endothelial cell integrity and activate cardiomyocyte apoptosis. VEGF inhibitors increase risks of hypertension, heart failure, thromboembolism and arrhythmia. Genetic and geographic studies showed that genetic polymorphisms likely play significant predictive or prognostic roles in cardiovascular toxicity associated with VEGF inhibitors.

Keywords: Angiogenesis inhibitors; antibodies; cardiotoxicity; cardiovascular system; ethnic groups; tyrosine kinase inhibitors; vascular endothelial growth factors.

Publication types

  • Review

MeSH terms

  • Antibodies, Monoclonal / adverse effects
  • Apoptosis
  • Arrhythmias, Cardiac / chemically induced
  • Cardiovascular System / drug effects*
  • Drug-Related Side Effects and Adverse Reactions / ethnology*
  • Drug-Related Side Effects and Adverse Reactions / genetics*
  • Heart Failure / chemically induced
  • Humans
  • Hypertension / chemically induced
  • Myocytes, Cardiac / drug effects
  • Myocytes, Cardiac / pathology
  • Neovascularization, Pathologic
  • Polymorphism, Genetic / genetics
  • Pyrazoles / adverse effects
  • Pyrimidines / adverse effects
  • Receptors, Vascular Endothelial Growth Factor
  • Signal Transduction / drug effects
  • Thromboembolism / chemically induced
  • Vascular Endothelial Growth Factor A / antagonists & inhibitors*
  • Vasoconstriction / drug effects
  • Vasodilation / drug effects

Substances

  • 4-amino-5-(4-methylphenyl)-7-(tert-butyl)pyrazolo(3,4-d)pyrimidine
  • Antibodies, Monoclonal
  • Pyrazoles
  • Pyrimidines
  • Vascular Endothelial Growth Factor A
  • Receptors, Vascular Endothelial Growth Factor