Drug Safety

, Volume 36, Issue 5, pp 295–316 | Cite as

Cardiovascular Safety of Tyrosine Kinase Inhibitors: With a Special Focus on Cardiac Repolarisation (QT Interval)

  • Rashmi R. ShahEmail author
  • Joel Morganroth
  • Devron R. Shah
Review Article


The development of tyrosine kinase inhibitors (TKI) represents a major milestone in oncology. However, their use has been found to be associated with serious toxicities that impinge on various vital organs including the heart. Sixteen TKIs have been approved for use in oncology as of 30 September 2012, and a large number of others are in development or under regulatory review. Cardiovascular safety of medicinal products is a major public health issue that has concerned all the stakeholders. This review focuses on three specific cardiovascular safety aspects of TKIs, namely their propensity to induce QT interval prolongation, left ventricular (LV) dysfunction and hypertension (both systemic and pulmonary). Analyses of information in drug labels, the data submitted to the regulatory authorities and the published literature show that a number of TKIs are associated with these undesirable effects. Whereas LV dysfunction and systemic hypertension are on-target effects related to the inhibition of ligand-related signalling pathways, QT interval prolongation appears to be an off-target class III electrophysiologic effect, possibly related to the presence of a fluorine-based pharmacophore. If not adequately managed, these cardiovascular effects significantly increase the morbidity and mortality in a population already at high risk. Hitherto, the QT effect of most QT-prolonging TKIs (except lapatinib, nilotinib, sunitinib and vandetanib) is relatively mild at clinical doses and has not led to appreciable morbidity clinically. In contrast, LV dysfunction and untreated hypertension have resulted in significant morbidity. Inevitably, dilemmas arise in determining the risk/benefit of a TKI therapy in an individual patient who develops any of these effects following the treatment of the TKI-sensitive cancer. QT interval prolongation, hypertension and LV dysfunction can be managed effectively by using reliable methods of measurement and careful monitoring of patients whose clinical management requires optimisation by a close collaboration between an oncologist and a cardiologist, an evolving subspecialty referred to as cardio-oncology. Despite their potential adverse clinical impact, the effects of TKIs on hypertension and LV function are generally inadequately characterised during their development. As has been the case with QT liability of drugs, there is now a persuasive case for a regulatory requirement to study TKIs systematically for these effects. Furthermore, since most of these novel drugs are studied in trials with relatively small sample sizes and approved on an expedited basis, there is also a compelling case for their effective pharmacovigilance and on-going reassessment of their risk/benefit after approval.


Imatinib Sorafenib Sunitinib Pulmonary Arterial Hypertension Gefitinib 
These keywords were added by machine and not by the authors. This process is experimental and the keywords may be updated as the learning algorithm improves.


Conflict of interest

The authors have no conflicts of interest that are directly relevant to the content of this review and have not received any financial support for writing it. RRS was formerly a Senior Clinical Assessor at the Medicines and Healthcare products Regulatory Agency (MHRA), London, UK, and the ICH E14 Topic Leader, representing the EU. JM is the Chief Cardiac Consultant to eResearchTechnology Inc. (eRT), Philadelphia, PA, USA, which provides cardiac safety services to drug development companies. Both RRS and JM now provide expert consultancy services on QT liability of drugs and development of new drugs to a number of pharmaceutical companies. DRS is a first-year house officer at a district general hospital and has no consultancy relationships.


  1. 1.
    Krause DS, Van Etten RA. Tyrosine kinases as targets for cancer therapy. N Engl J Med. 2005;353:172–87.PubMedCrossRefGoogle Scholar
  2. 2.
    Strevel EL, Siu LL. Cardiovascular toxicity of molecularly targeted agents. Eur J Cancer. 2009;45(Suppl 1):318–31.PubMedCrossRefGoogle Scholar
  3. 3.
    des Guetz G, Uzzan B, Chouahnia K, et al. Cardiovascular toxicity of anti-angiogenic drugs. Target Oncol. 2011;6:197–202.PubMedCrossRefGoogle Scholar
  4. 4.
    Shah RR. The significance of QT interval in drug development. Br J Clin Pharmacol. 2002;54:188–202.PubMedCrossRefGoogle Scholar
  5. 5.
    Shah RR. Cardiac repolarisation and drug regulation: assessing cardiac safety 10 years after the CPMP guidance. Drug Saf. 2007;30:1093–110.PubMedCrossRefGoogle Scholar
  6. 6.
    Shah RR. Drug-induced QT interval prolongation: does ethnicity of the thorough QT study population matter? Br J Clin Pharmacol. 2013;75:347–58.PubMedCrossRefGoogle Scholar
  7. 7.
    Committee for Medicinal Products for Human Use. ICH note for guidance: the nonclinical evaluation of the potential for delayed ventricular repolarization (QT interval prolongation) by human pharmaceuticals (ICH S7B) (CHMP/ICH/423/02). EMA, London (2005). (Accessed Sep 22 2012).
  8. 8.
    Committee for Medicinal Products for Human Use. ICH note for guidance: the clinical evaluation of QT/QTc interval prolongation and proarrhythmic potential for non-antiarrhythmic drugs (ICH E14) (CHMP/ICH/2/04). EMA, London (2005). (Accessed Sep 22 2012).
  9. 9.
    Strevel EL, Ing DJ, Siu LL. Molecularly targeted oncology therapeutics and prolongation of the QT interval. J Clin Oncol. 2007;25:3362–71.PubMedCrossRefGoogle Scholar
  10. 10.
    Ederhy S, Cohen A, Dufaitre G, et al. QT interval prolongation among patients treated with angiogenesis inhibitors. Target Oncol. 2009;4:89–97.PubMedCrossRefGoogle Scholar
  11. 11.
    Garcia-Alvarez A, Garcia-Albeniz X, Esteve J, Rovira M, et al. Cardiotoxicity of tyrosine-kinase-targeting drugs. Cardiovasc Hematol Agents Med Chem. 2010;8:11–21.PubMedCrossRefGoogle Scholar
  12. 12.
    Force T, Kolaja KL. Cardiotoxicity of kinase inhibitors: the prediction and translation of preclinical models to clinical outcomes. Nat Rev Drug Discov. 2011;10:111–26.PubMedCrossRefGoogle Scholar
  13. 13.
    Qi WX, Min DL, Shen Z, et al. Risk of venous thromboembolic events associated with VEGFR-TKIs: a systematic review and meta-analysis. Int J Cancer 2012 (Epub ahead of print).Google Scholar
  14. 14.
    Sonpavde G, Je Y, Schutz F, et al. Venous thromboembolic events with vascular endothelial growth factor receptor tyrosine kinase inhibitors: a systematic review and meta-analysis of randomized clinical trials. Crit Rev Oncol Hematol. 2013 (Epub ahead of print).Google Scholar
  15. 15.
    Choueiri TK, Schutz FA, Je Y, et al. Risk of arterial thromboembolic events with sunitinib and sorafenib: a systematic review and meta-analysis of clinical trials. J Clin Oncol. 2010;28:2280–5.PubMedCrossRefGoogle Scholar
  16. 16.
    Schutz FA, Je Y, Richards CJ, et al. Meta-analysis of randomized controlled trials for the incidence and risk of treatment-related mortality in patients with cancer treated with vascular endothelial growth factor tyrosine kinase inhibitors. J Clin Oncol. 2012;30:871–7.PubMedCrossRefGoogle Scholar
  17. 17.
    Food and Drug Administration Product Reviews and Labels. (Accessed Oct 28 2012).
  18. 18.
    Food and Drug Administration Oncologic Drugs Advisory Committee Documents. (Accessed Oct 28 2012).
  19. 19.
    European Medicines Agency European Public Assessment Reports Assessment History and Product Information. (Accessed Oct 28 2012).
  20. 20.
    Health Canada Summary Basis of Decision. (Accessed Oct 28 2012).
  21. 21.
    National Cancer Institute NCI Drug Dictionary. (Accessed Oct 28 2012). doi: 10.1007/s40264-013-0050-x
  22. 22.
    Chen MH, Kerkela R, Force T. Mechanisms of cardiomyopathy associated with tyrosine kinase inhibitor cancer therapeutics. Circulation. 2008;118:84–95.PubMedCrossRefGoogle Scholar
  23. 23.
    Force T. Introduction to cardiotoxicity reviews. Circ Res. 2010;106:19–20.PubMedCrossRefGoogle Scholar
  24. 24.
    Scheffler M, Di Gion P, Doroshyenko O, et al. Clinical pharmacokinetics of tyrosine kinase inhibitors: focus on 4-anilinoquinazolines. Clin Pharmacokinet. 2011;50:371–403.PubMedCrossRefGoogle Scholar
  25. 25.
    Di Gion P, Kanefendt F, Lindauer A, et al. Clinical pharmacokinetics of tyrosine kinase inhibitors: focus on pyrimidines, pyridines and pyrroles. Clin Pharmacokinet. 2011;50:551–603.PubMedCrossRefGoogle Scholar
  26. 26.
    Zhang J, Yang PL, Gray NS. Targeting cancer with small molecule kinase inhibitors. Nat Rev Cancer. 2009;9:28–39.PubMedCrossRefGoogle Scholar
  27. 27.
    van Cruijsen H, van der Veldt A, Hoekman K. Tyrosine kinase inhibitors of VEGF receptors: clinical issues and remaining questions. Front Biosci. 2009;14:2248–68.PubMedCrossRefGoogle Scholar
  28. 28.
    Roodhart JM, Langenberg MH, Witteveen E, et al. The molecular basis of class side effects due to treatment with inhibitors of the VEGF/VEGFR pathway. Curr Clin Pharmacol. 2008;3:132–43.PubMedCrossRefGoogle Scholar
  29. 29.
    Shah DR, Shah RR, Morganroth J. Tyrosine kinase inhibitors: Their on-target toxicities as potential indicators of efficacy. Drug Saf. 2013 (in press).Google Scholar
  30. 30.
    Asnacios A, Naveau S, Perlemuter G. Gastrointestinal toxicities of novel agents in cancer therapy. Eur J Cancer. 2009;45(Suppl 1):332–42.PubMedCrossRefGoogle Scholar
  31. 31.
    Dienstmann R, Braña I, Rodon J, et al. Toxicity as a biomarker of efficacy of molecular targeted therapies: focus on EGFR and VEGF inhibiting anticancer drugs. Oncologist. 2011;16:1729–40.PubMedCrossRefGoogle Scholar
  32. 32.
    Lu Z, Wu CY, Jiang YP, et al. Suppression of phosphoinositide 3-kinase signalling and alteration of multiple ion currents in drug-induced long QT syndrome. Sci Transl Med. 2012;4:131ra50.PubMedCrossRefGoogle Scholar
  33. 33.
    Amir E, Seruga B, Martinez-Lopez J, et al. Oncogenic targets, magnitude of benefit, and market pricing of antineoplastic drugs. J Clin Oncol. 2011;29:2543–9.PubMedCrossRefGoogle Scholar
  34. 34.
    Shah RR, Roberts SA, Shah DR. A fresh perspective on comparing the FDA and the CHMP/EMA: approval of antineoplastic tyrosine kinase inhibitors. Br J Clin Pharmacol. 2013. doi: 10.1111/bcp.12085.
  35. 35.
    Sanguinetti MC, Jiang C, Curran ME, et al. A mechanistic link between an inherited and an acquired cardiac arrhythmia: HERG encodes the IKr potassium channel. Cell. 1995;81:299–307.PubMedCrossRefGoogle Scholar
  36. 36.
    Vandenberg JI, Perry MD, Perrin MJ, et al. hERG K(+) channels: structure, function, and clinical significance. Physiol Rev. 2012;92:1393–478.PubMedCrossRefGoogle Scholar
  37. 37.
    Milon D, Daubert JC, Saint-Marc C, et al. Torsade depointes. Apropos of 54 cases [Article in French]. Ann Fr Anesth Reanim. 1982;1:513–20.PubMedCrossRefGoogle Scholar
  38. 38.
    Salle P, Rey JL, Bernasconi P, et al. Torsades de pointe. Apropos of 60 cases. Ann Cardiol Angeiol (Paris). 1985;34:381–8.Google Scholar
  39. 39.
    Fung MC, Hsiao-hui Wu H, Kwong K, et al. Evaluation of the profile of patients with QTc prolongation in spontaneous adverse event reporting over the past three decades—1969–98. Pharmacoepidemiol Drug Saf. 2000;9(Suppl 1):S24.Google Scholar
  40. 40.
    Garnett CE, Beasley N, Bhattaram VA, et al. Concentration-QT relationships play a key role in the evaluation of proarrhythmic risk during regulatory review. J Clin Pharmacol. 2008;48:13–8.PubMedCrossRefGoogle Scholar
  41. 41.
    Rock EP, Finkle J, Fingert HJ, et al. Assessing proarrhythmic potential of drugs when optimal studies are infeasible. Am Heart J. 2009;157:827–36.PubMedCrossRefGoogle Scholar
  42. 42.
    Morganroth J, Shah RR, Scott JW. Evaluation and management of cardiac safety using the electrocardiogram in oncology clinical trials: focus on cardiac repolarization (QTc interval). Clin Pharmacol Ther. 2010;87:166–74.PubMedCrossRefGoogle Scholar
  43. 43.
    Shah RR, Morganroth J. Early investigation of QTc liability: the role of multiple ascending dose (MAD) study. Drug Saf. 2012;35:695–709.PubMedGoogle Scholar
  44. 44.
    Piekarz RL, Frye AR, Wright JJ, et al. Cardiac studies in patients treated with depsipeptide, FK228, in a phase II trial for T-cell lymphoma. Clin Cancer Res. 2006;12:3762–73.PubMedCrossRefGoogle Scholar
  45. 45.
    Varterasian M, Meyer M, Fingert H, et al. Baseline heart rate-corrected QT and eligibility for clinical trials in oncology. J Clin Oncol. 2003;21:3378–9.PubMedCrossRefGoogle Scholar
  46. 46.
    Dong Q, Fu XX, Du LL, et al. Blocking of the human ether-à-go-go-related gene channel by imatinib mesylate. Biol Pharm Bull. 2013;36:268–75.PubMedCrossRefGoogle Scholar
  47. 47.
    Dogan E, Yorgun H, Petekkaya I, et al. Evaluation of cardiac safety of lapatinib therapy for ErbB2-positive metastatic breast cancer: a single center experience. Med Oncol. 2012;29:3232–9.PubMedCrossRefGoogle Scholar
  48. 48.
    Baselga J, Bradbury I, Eidtmann H, et al. Lapatinib with trastuzumab for HER2-positive early breast cancer (NeoALTTO): a randomised, open-label, multicentre, phase 3 trial. Lancet. 2012;379:633–40.PubMedCrossRefGoogle Scholar
  49. 49.
    Kim TD, le Coutre P, Schwarz M, et al. Clinical cardiac safety profile of nilotinib. Haematologica. 2012;97:883–9.PubMedCrossRefGoogle Scholar
  50. 50.
    AstraZeneca CAPRELSA REMS Program. (Accessed Jan 20 2013).
  51. 51.
    Leboulleux S, Bastholt L, Krause T, et al. Vandetanib in locally advanced or metastatic differentiated thyroid cancer: a randomised, double-blind, phase 2 trial. Lancet Oncol. 2012;13:897–905.PubMedCrossRefGoogle Scholar
  52. 52.
    Zang J, Wu S, Tang L, et al. Incidence and risk of QTc interval prolongation among cancer patients treated with vandetanib: a systematic review and meta-analysis. PLoS One. 2012;7:e30353.PubMedCrossRefGoogle Scholar
  53. 53.
    Barros F, Gomez-Varela D, Viloria CG, et al. Modulation of human erg K+ channel gating by activation of a G protein-coupled receptor and protein kinase C. J Physiol. 1998;511(Pt 2):333–46.PubMedCrossRefGoogle Scholar
  54. 54.
    Thomas D, Zhang W, Karle CA, et al. Deletion of protein kinase A phosphorylation sites in the HERG potassium channel inhibits activation shift by protein kinase A. J Biol Chem. 1999;274:27457–62.PubMedCrossRefGoogle Scholar
  55. 55.
    Kiehn J, Karle C, Thomas D, et al. HERG potassium channel activation is shifted by phorbol esters via protein kinase A-dependent pathways. J Biol Chem. 1998;273:25285–91.PubMedCrossRefGoogle Scholar
  56. 56.
    Davis MJ, Wu X, Nurkiewicz TR, et al. Regulation of ion channels by protein tyrosine phosphorylation. Am J Physiol Heart Circ Physiol. 2001;281:H1835–62.PubMedGoogle Scholar
  57. 57.
    Marx SO, Kurokawa J, Reiken S, et al. Requirement of a macromolecular signalling complex for beta adrenergic receptor modulation of the KCNQ1-KCNE1 potassium channel. Science. 2002;295:496–9.PubMedCrossRefGoogle Scholar
  58. 58.
    Chen J, Sroubek J, Krishnan Y, et al. PKA phosphorylation of HERG protein regulates the rate of channel synthesis. Am J Physiol Heart Circ Physiol. 2009;296:H1244–54.PubMedCrossRefGoogle Scholar
  59. 59.
    Sroubek J, McDonald TV. Protein kinase A activity at the endoplasmic reticulum surface is responsible for augmentation of human ether-a-go-go-related gene product (HERG). J Biol Chem. 2011;286:21927–36.PubMedCrossRefGoogle Scholar
  60. 60.
    Krishnan Y, Li Y, Zheng R, et al. Mechanisms underlying the protein-kinase mediated regulation of the HERG potassium channel synthesis. Biochim Biophys Acta. 2012;1823:1273–84.PubMedCrossRefGoogle Scholar
  61. 61.
    Zhang Y, Wang H, Wang J, et al. Normal function of HERG K+ channels expressed in HEK293 cells requires basal protein kinase B activity. FEBS Lett. 2003;534:125–32.PubMedCrossRefGoogle Scholar
  62. 62.
    Zhang DY, Wang Y, Lau CP, et al. Both EGFR kinase and Src-related tyrosine kinases regulate human ether-à-go-go-related gene potassium channels. Cell Signal. 2008;20:1815–21.PubMedCrossRefGoogle Scholar
  63. 63.
    Himmel HM, Hoffmann M. QTc shortening with a new investigational cancer drug: a brief case study. J Pharmacol Toxicol Methods. 2010;62:72–81.PubMedCrossRefGoogle Scholar
  64. 64.
    Morgan TK Jr, Sullivan ME. An overview of class III electrophysiological agents: a new generation of antiarrhythmic therapy. Prog Med Chem. 1992;29:65–108.PubMedCrossRefGoogle Scholar
  65. 65.
    Park BK, Kitteringham NR. Effects of fluorine substitution on drug metabolism: pharmacological and toxicological implications. Drug Metab Rev. 1994;26:605–43.PubMedCrossRefGoogle Scholar
  66. 66.
    Park BK, Kitteringham NR, O’Neill PM. Metabolism of fluorine-containing drugs. Annu Rev Pharmacol Toxicol. 2001;41:443–70.PubMedCrossRefGoogle Scholar
  67. 67.
    Elice F, Rodeghiero F, Falanga A, et al. Thrombosis associated with angiogenesis inhibitors. Best Pract Res Clin Haematol. 2009;22:115–28.PubMedCrossRefGoogle Scholar
  68. 68.
    Girardi F, Franceschi E, Brandes AA. Cardiovascular safety of VEGF-targeting therapies: current evidence and handling strategies. Oncologist. 2010;15:683–94.PubMedCrossRefGoogle Scholar
  69. 69.
    Minami M, Matsumoto S, Horiuchi H. Cardiovascular side-effects of modern cancer therapy. Circ J. 2010;74:1779–86.PubMedCrossRefGoogle Scholar
  70. 70.
    Keefe D, Bowen J, Gibson R, et al. Noncardiac vascular toxicities of vascular endothelial growth factor inhibitors in advanced cancer: a review. Oncologist. 2011;16:432–44.PubMedCrossRefGoogle Scholar
  71. 71.
    Mellor HR, Bell AR, Valentin JP, et al. Cardiotoxicity associated with targeting kinase pathways in cancer. Toxicol Sci. 2011;120:14–32.PubMedCrossRefGoogle Scholar
  72. 72.
    Sonpavde G, Bellmunt J, Schutz F, et al. The double edged sword of bleeding and clotting from VEGF inhibition in renal cancer patients. Curr Oncol Rep. 2012;14:295–306.PubMedCrossRefGoogle Scholar
  73. 73.
    Mir O, Ropert S, Alexandre J, et al. Hypertension as a surrogate marker for the activity of anti-VEGF agents. Ann Oncol. 2009;20:967–70.PubMedCrossRefGoogle Scholar
  74. 74.
    Chu TF, Rupnick MA, Kerkela R, et al. Cardiotoxicity associated with tyrosine kinase inhibitor sunitinib. Lancet. 2007;370:2011–9.PubMedCrossRefGoogle Scholar
  75. 75.
    Qi WX, Shen Z, Lin F, et al. Incidence and risk of hypertension with vandetanib in cancer patients: a systematic review and meta-analysis of clinical trials. Br J Clin Pharmacol. 2012;75:919–30.CrossRefGoogle Scholar
  76. 76.
    Robinson ES, Khankin EV, Karumanchi SA, et al. Hypertension induced by vascular endothelial growth factor signalling pathway inhibition: mechanism and potential use as a biomarker. Semin Nephrol. 2010;30:591–601.PubMedCrossRefGoogle Scholar
  77. 77.
    Maitland ML, Kasza KE, Karrison T, et al. Ambulatory monitoring detects sorafenib-induced blood pressure elevations on the first day of treatment. Clin Cancer Res. 2009;15:6250–7.PubMedCrossRefGoogle Scholar
  78. 78.
    Veronese ML, Mosenkis A, Flaherty KT, et al. Mechanisms of hypertension associated with BAY 43-9006. J Clin Oncol. 2006;24:1363–9.PubMedCrossRefGoogle Scholar
  79. 79.
    Kim JJ, Vaziri SA, Rini BI, et al. Association of VEGF and VEGFR2 single nucleotide polymorphisms with hypertension and clinical outcome in metastatic clear cell renal cell carcinoma patients treated with sunitinib. Cancer. 2012;118:1946–54.PubMedCrossRefGoogle Scholar
  80. 80.
    Steeghs N, Gelderblom H, Roodt JO, et al. Hypertension and rarefaction during treatment with telatinib, a small molecule angiogenesis inhibitor. Clin Cancer Res. 2008;14:3470–6.PubMedCrossRefGoogle Scholar
  81. 81.
    GlaxoSmilthKline Clinical Study Register A meta-analysis of the cumulative incidence of hypertension in the first month of treatment with pazopanib across three RCC studies: VEG102616, VEG105192 and VEG107769 (Study number 115227). (Accessed Oct 25 2012).
  82. 82.
    Quintás-Cardama A, Kantarjian H, O’brien S, et al. Pleural effusion in patients with chronic myelogenous leukemia treated with dasatinib after imatinib failure. J Clin Oncol. 2007;25:3908–14.PubMedCrossRefGoogle Scholar
  83. 83.
    Guignabert C, Montani D. Key roles of Src family tyrosine kinases in the integrity of the pulmonary vascular bed. Eur Respir J. 2013;41:3–4.PubMedCrossRefGoogle Scholar
  84. 84.
    Pullamsetti SS, Berghausen EM, Dabral S, et al. Role of Src tyrosine kinases in experimental pulmonary hypertension. Arterioscler Thromb Vasc Biol. 2012;32:1354–65.PubMedCrossRefGoogle Scholar
  85. 85.
    Schermuly RT, Dony E, Ghofrani HA, et al. Reversal of experimental pulmonary hypertension by PDGF inhibition. J Clin Invest. 2005;115:2811–21.PubMedCrossRefGoogle Scholar
  86. 86.
    Ghofrani HA, Seeger W, Grimminger F. Imatinib for the treatment of pulmonary arterial hypertension. N Engl J Med. 2005;353:1412–3.PubMedCrossRefGoogle Scholar
  87. 87.
    Tapper EB, Knowles D, Heffron T, et al. Portopulmonary hypertension: imatinib as a novel treatment and the Emory experience with this condition. Transplant Proc. 2009;41:1969–71.PubMedCrossRefGoogle Scholar
  88. 88.
    ten Freyhaus H, Dumitrescu D, Bovenschulte H, et al. Significant improvement of right ventricular function by imatinib mesylate in scleroderma-associated pulmonary arterial hypertension. Clin Res Cardiol. 2009;98:265–7.PubMedCrossRefGoogle Scholar
  89. 89.
    Chhina MK, Nargues W, Grant GM, et al. Evaluation of imatinib mesylate in the treatment of pulmonary arterial hypertension. Future Cardiol. 2010;6:19–35.PubMedCrossRefGoogle Scholar
  90. 90.
    ten Freyhaus H, Dumitrescu D, Berghausen E, et al. Imatinib mesylate for the treatment of pulmonary arterial hypertension. Expert Opin Investig Drugs. 2012;21:119–34.PubMedCrossRefGoogle Scholar
  91. 91.
    Antoniu SA. Targeting PDGF pathway in pulmonary arterial hypertension. Expert Opin Ther Targets. 2012;16:1055–63.PubMedCrossRefGoogle Scholar
  92. 92.
    Ghofrani HA, Morrell NW, Hoeper MM, et al. Imatinib in pulmonary arterial hypertension patients with inadequate response to established therapy. Am J Respir Crit Care Med. 2010;182:1171–7.PubMedCrossRefGoogle Scholar
  93. 93.
    Hatano M, Yao A, Shiga T, et al. Imatinib mesylate has the potential to exert its efficacy by down-regulating the plasma concentration of platelet-derived growth factor in patients with pulmonary arterial hypertension. Int Heart J. 2010;51:272–6.PubMedCrossRefGoogle Scholar
  94. 94.
    Ciuclan L, Bonneau O, Hussey M, et al. A novel murine model of severe pulmonary arterial hypertension. Am J Respir Crit Care Med. 2011;184:1171–82.PubMedCrossRefGoogle Scholar
  95. 95.
    Ciuclan L, Hussey MJ, Burton V, et al. Imatinib attenuates hypoxia-induced pulmonary arterial hypertension pathology via reduction in 5-hydroxytryptamine through inhibition of tryptophan hydroxylase 1 expression. Am J Respir Crit Care Med. 2013;187:78–89.PubMedCrossRefGoogle Scholar
  96. 96.
    Kojonazarov B, Sydykov A, Pullamsetti SS, et al. Effects of multikinase inhibitors on pressure overload-induced right ventricular remodeling. Int J Cardiol. 2012 (Epub ahead of print).Google Scholar
  97. 97.
    Schmidinger M, Zielinski CC, Vogl UM, et al. Cardiac toxicity of sunitinib and sorafenib in patients with metastatic renal cell carcinoma. J Clin Oncol. 2008;26:5204–12.PubMedCrossRefGoogle Scholar
  98. 98.
    Kerkelä R, Grazette L, Yacobi R, et al. Cardiotoxicity of the cancer therapeutic agent imatinib mesylate. Nat Med. 2006;12:908–16.PubMedCrossRefGoogle Scholar
  99. 99.
    Lenihan DJ, Cardinale D, Cipolla CM. The compelling need for a cardiology and oncology partnership and the birth of the International CardiOncology Society. Prog Cardiovasc Dis. 2010;53:88–93.PubMedCrossRefGoogle Scholar
  100. 100.
    Cheng H, Force T. Why do kinase inhibitors cause cardiotoxicity and what can be done about it? Prog Cardiovasc Dis. 2010;53:114–20.PubMedCrossRefGoogle Scholar
  101. 101.
    Dasanu CA, Padmanabhan P, Clark BA 3rd, et al. Cardiovascular toxicity associated with small molecule tyrosine kinase inhibitors currently in clinical use. Expert Opin Drug Saf. 2012;11:445–57.PubMedCrossRefGoogle Scholar
  102. 102.
    Montaigne D, Hurt C, Neviere R. Mitochondria death/survival signalling pathways in cardiotoxicity induced by anthracyclines and anticancer-targeted therapies. Biochem Res Int. 2012;Article ID 951539.Google Scholar
  103. 103.
    Van den Akker NM, Winkel LC, Nisancioglu MH, et al. PDGF-B signalling is important for murine cardiac development: its role in developing atrioventricular valves, coronaries, and cardiac innervation. Dev Dyn. 2008;237:494–503.PubMedCrossRefGoogle Scholar
  104. 104.
    Cheng H, Kari G, Dicker AP, et al. A novel preclinical strategy for identifying cardiotoxic kinase inhibitors and mechanisms of cardiotoxicity. Circ Res. 2011;109:1401–9.PubMedCrossRefGoogle Scholar
  105. 105.
    Force T, Krause DS, Van Etten RA. Molecular mechanisms of cardiotoxicity of tyrosine kinase inhibitors. Nat Rev Cancer. 2007;7:332–44.PubMedCrossRefGoogle Scholar
  106. 106.
    Kerkela R, Woulfe KC, Durand JB, et al. Sunitinib-induced cardiotoxicity is mediated by off-target inhibition of AMP-activated protein kinase. Clin Transl Sci. 2009;2:15–25.PubMedCrossRefGoogle Scholar
  107. 107.
    Hasinoff BB. The cardiotoxicity and myocyte damage caused by small molecule anticancer tyrosine kinase inhibitors is correlated with lack of target specificity. Toxicol Appl Pharmacol. 2010;244:190–5.PubMedCrossRefGoogle Scholar
  108. 108.
    Hasinoff BB, Patel D. Mechanisms of myocyte cytotoxicity induced by the multikinase inhibitor sorafenib. Cardiovasc Toxicol. 2010;10:1–8.PubMedCrossRefGoogle Scholar
  109. 109.
    Hasinoff BB, Patel D. The lack of target specificity of small molecule anticancer kinase inhibitors is correlated with their ability to damage myocytes in vitro. Toxicol Appl Pharmacol. 2010;249:132–9.PubMedCrossRefGoogle Scholar
  110. 110.
    Subbiah IM, Lenihan DJ, Tsimberidou AM. Cardiovascular toxicity profiles of vascular-disrupting agents. Oncologist. 2011;16:1120–30.PubMedCrossRefGoogle Scholar
  111. 111.
    Force T, Kerkela R. Cardiotoxicity of the new cancer therapeutics- mechanisms of, and approaches to, the problem. Drug Discov Today. 2008;13:778–84.PubMedCrossRefGoogle Scholar
  112. 112.
    Yang B, Papoian T. Tyrosine kinase inhibitor (TKI)-induced cardiotoxicity: approaches to narrow the gaps between preclinical safety evaluation and clinical outcome. J Appl Toxicol. 2012 (Epub ahead of print).Google Scholar
  113. 113.
    Eschenhagen T, Force T, Ewer MS, et al. Cardiovascular side effects of cancer therapies: a position statement from the Heart Failure Association of the European Society of Cardiology. Eur J Heart Fail. 2011;13:1–10.PubMedCrossRefGoogle Scholar
  114. 114.
    Steingart RM, Bakris GL, Chen HX, et al. Management of cardiac toxicity in patients receiving vascular endothelial growth factor signalling pathway inhibitors. Am Heart J. 2012;163:156–63.PubMedCrossRefGoogle Scholar

Copyright information

© Springer International Publishing Switzerland 2013

Authors and Affiliations

  • Rashmi R. Shah
    • 1
    Email author
  • Joel Morganroth
    • 2
  • Devron R. Shah
    • 1
  1. 1.Rashmi Shah Consultancy Ltd.BuckinghamshireUK
  2. 2.eResearch TechnologyPhiladelphiaUSA

Personalised recommendations