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  • Review Article
  • Published:

Cardiotoxicity of kinase inhibitors: the prediction and translation of preclinical models to clinical outcomes

This article has been updated

Key Points

  • The development of kinase inhibitors — which predominantly target kinases that are dysregulated in various cancers — is a rapidly growing area of drug discovery.

  • The vast majority of approved kinase inhibitors and drugs in development target the ATP binding pocket. However, the conservation of the ATP binding pocket among kinases can mean that inhibitors can also inhibit unintended kinases, and if any of these kinases serve important functions in the heart, off-target cardiotoxicity can result.

  • Many of the pathways that regulate cancer cell survival also regulate essential processes in cardiomyocytes, including survival. So, although inhibiting those kinases in the cancer is beneficial, inhibiting them in the cardiomyocyte may not be.

  • Although clinically important cardiotoxicity appears to be limited to only a few currently marketed agents, a big concern is the large number of drugs in development, many of which are multi-targeted and either intentionally or unintentionally inhibit pathways that maintain cardiomyocyte homeostasis. Thus, it is imperative to develop strategies that accurately identify problematic agents early in the drug development process.

  • In this Review we discuss the growing connection between preclinical models of kinase inhibitor-induced cardiotoxicity and clinical safety. We discuss the challenges of making safe and selective inhibitors of a kinase by examining the cardiac effects of sunitinib. We also explore the field of genetically modified mouse models and discuss their merits in predicting more effectively which kinase inhibitors may have the potential to cause cardiotoxicity. Additionally in vitro models used to predict cardiotoxicity are reviewed, with emphasis on human stem cell-derived cardiomyocytes. Lastly, we conclude with future perspectives on clinical studies, including biomarkers and imaging.

Abstract

Targeted therapeutics, particularly those that inhibit the activity of protein kinases that are mutated and/or overexpressed in cancer, have revolutionized the treatment of some cancers and improved survival rates in many others. Although these agents dominate drug development in cancer, significant toxicities, including cardiotoxicity, have emerged. In this Review, we examine the underlying mechanisms that result in on-target or off-target cardiotoxicities of small molecule kinase inhibitors. We also discuss how well the various preclinical safety models and strategies might predict clinical cardiotoxicity. It is hoped that a thorough understanding of the mechanisms underlying cardiotoxicity will lead to the development of safe, effective drugs and consequently, fewer costly surprises as agents progress through clinical trials.

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Figure 1: Crucial signalling pathways in the heart and consequences of their activation or inhibition.

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  • 27 October 2011

    This has been corrected on both the html and pdf versions.

References

  1. Cohen, P. The role of protein phosphorylation in human health and disease. The Sir Hans Krebs Medal Lecture. Eur. J. Biochem. 268, 5001–5010 (2001).

    Article  CAS  PubMed  Google Scholar 

  2. Verkhivker, G. M. Exploring sequence-structure relationships in the tyrosine kinome space: functional classification of the binding specificity mechanisms for cancer therapeutics. Bioinformatics 23, 1919–1926 (2007).

    Article  CAS  PubMed  Google Scholar 

  3. Giamas, G. et al. Kinases as targets in the treatment of solid tumors. Cell. Signal. 22, 984–1002 (2010).

    Article  CAS  PubMed  Google Scholar 

  4. Zsila, F., Fitos, I., Bencze, G., Keri, G. & Orfi, L. Determination of human serum α1-acid glycoprotein and albumin binding of various marketed and preclinical kinase inhibitors. Curr. Med. Chem. 16, 1964–1977 (2009).

    Article  CAS  PubMed  Google Scholar 

  5. Cheng, H. & Force, T. Molecular mechanisms of cardiovascular toxicity of targeted cancer therapeutics. Circ. Res. 106, 21–34 (2010).

    Article  CAS  PubMed  Google Scholar 

  6. Chu, T. F. et al. Cardiotoxicity associated with tyrosine kinase inhibitor sunitinib. Lancet 370, 2011–2019 (2007).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  7. Perez, E. A. et al. Cardiac safety of lapatinib: pooled analysis of 3,689 patients enrolled in clinical trials. Mayo Clin. Proc. 83, 679–686 (2008).

    Article  PubMed  Google Scholar 

  8. Ohren, J. F. et al. Structures of human MAP kinase kinase 1 (MEK1) and MEK2 describe novel noncompetitive kinase inhibition. Nature Struct. Mol. Biol. 11, 1192–1197 (2004).

    Article  CAS  Google Scholar 

  9. Okram, B. et al. A general strategy for creating “inactive-conformation” Abl inhibitors. Chem. Biol. 13, 779–786 (2006).

    Article  CAS  PubMed  Google Scholar 

  10. Sebolt-Leopold, J. S. et al. Blockade of the MAP kinase pathway suppresses growth of colon tumors in vivo. Nature Med. 5, 810–816 (1999).

    Article  CAS  PubMed  Google Scholar 

  11. Zhang, J., Yang, P. L. & Gray, N. S. Targeting cancer with small molecule kinase inhibitors. Nature Rev. Cancer 9, 28–39 (2009).

    Article  CAS  Google Scholar 

  12. Morphy, R. Selectively nonselective kinase inhibition: striking the right balance. J. Med. Chem. 53, 1413–1437 (2010).

    Article  CAS  PubMed  Google Scholar 

  13. Bhargava, P. VEGF kinase inhibitors: how do they cause hypertension? Am. J. Physiol. Regul. Integr Comp. Physiol. 297, R1–R5 (2009).

    Article  CAS  PubMed  Google Scholar 

  14. Liu, P., Cheng, H., Roberts, T. M. & Zhao, J. J. Targeting the phosphoinositide 3-kinase pathway in cancer. Nature Rev. Drug. Discov. 8, 627–644 (2009).

    Article  CAS  Google Scholar 

  15. Matsui, T. et al. Akt activation preserves cardiac function and prevents injury after transient cardiac ischemia in vivo. Circulation 104, 330–335 (2001).

    Article  CAS  PubMed  Google Scholar 

  16. Bantscheff, M. et al. Quantitative chemical proteomics reveals mechanisms of action of clinical ABL kinase inhibitors. Nature Biotech. 25, 1035–1044 (2007). A definitive application of open-ended proteomic technology used to gain insight into off-target effects of kinase inhibitors. This approach underscores the inherent challenges in being able to identify mechanisms of toxicity.

    Article  CAS  Google Scholar 

  17. Meissner, K. et al. The ATP-binding cassette transporter ABCG2 (BCRP), a marker for side population stem cells, is expressed in human heart. J. Histochem. Cytochem. 54, 215–221 (2006).

    Article  CAS  PubMed  Google Scholar 

  18. Kerkela, R. et al. Sunitinib-induced cardiotoxicity is mediated by off-target inhibition of AMP-activated protein kinase. Clin. Transl. Sci. 2, 15–25 (2009).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  19. Thirunavukkarasu, M. et al. VEGFR1 (Flt-1+/−) gene knockout leads to the disruption of VEGF-mediated signaling through the nitric oxide/heme oxygenase pathway in ischemic preconditioned myocardium. Free. Radic. Biol. Med. 42, 1487–1495 (2007).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  20. Thirunavukkarasu, M. et al. Heterozygous disruption of Flk-1 receptor leads to myocardial ischaemia reperfusion injury in mice: application of affymetrix gene chip analysis. J. Cell. Mol. Med. 12, 1284–1302 (2008).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  21. Chintalgattu, V. et al. Cardiomyocyte PDGFR-β signaling is an essential component of the mouse cardiac response to load-induced stress. J. Clin. Invest. 120, 472–484 (2010).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  22. Izumiya, Y. et al. Vascular endothelial growth factor blockade promotes the transition from compensatory cardiac hypertrophy to failure in response to pressure overload. Hypertension 47, 887–893 (2006).

    Article  CAS  PubMed  Google Scholar 

  23. Orphanos, G. S., Ioannidis, G. N. & Ardavanis, A. G. Cardiotoxicity induced by tyrosine kinase inhibitors. Acta Oncol. 48, 964–970 (2009).

    Article  CAS  PubMed  Google Scholar 

  24. Karaman, M. W. et al. A quantitative analysis of kinase inhibitor selectivity. Nature Biotech. 26, 127–132 (2008). The technology described in this study opened the door for broad scale assessment of competitive inhibition of kinase inhibitors, thereby immediately allowing one to understand the challenges associated with making selective kinase inhibitors.

    Article  CAS  Google Scholar 

  25. Liu, L. et al. Hypoxia-induced energy stress regulates mRNA translation and cell growth. Mol. Cell 21, 521–531 (2006).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  26. Shell, S. A. et al. Activation of AMPK is necessary for killing cancer cells and sparing cardiac cells. Cell Cycle 7, 1769–1775 (2008).

    Article  CAS  PubMed  Google Scholar 

  27. Rixe, O., Billemont, B. & Izzedine, H. Hypertension as a predictive factor of sunitinib activity. Ann. Oncol. 18, 1117 (2007).

    Article  CAS  PubMed  Google Scholar 

  28. Bono, P. et al. Hypertension and clinical benefit of bevacizumab in the treatment of advanced renal cell carcinoma. Ann. Oncol. 20, 393–394 (2009).

    Article  CAS  PubMed  Google Scholar 

  29. Rini, B. I. et al. Antitumor activity and biomarker analysis of sunitinib in patients with bevacizumab-refractory metastatic renal cell carcinoma. J. Clin. Oncol. 26, 3743–3748 (2008).

    Article  CAS  PubMed  Google Scholar 

  30. Goodwin, R. et al. Treatment-emergent hypertension and outcomes in patients with advanced non-small-cell lung cancer receiving chemotherapy with or without the vascular endothelial growth factor receptor inhibitor cediranib: NCIC Clinical Trials Group Study BR24. Ann. Oncol. 21, 2220–2226 (2010).

    Article  CAS  PubMed  Google Scholar 

  31. Hasinoff, B. B. The cardiotoxicity and myocyte damage caused by small molecule anticancer tyrosine kinase inhibitors is correlated with lack of target specificity. Toxicol. Appl. Pharmacol. 244, 190–195 (2010).

    Article  CAS  PubMed  Google Scholar 

  32. Fabian, M. A. et al. A small molecule-kinase interaction map for clinical kinase inhibitors. Nature Biotech. 23, 329–336 (2005).

    Article  CAS  Google Scholar 

  33. Olaharski, A. J. et al. Identification of a kinase profile that predicts chromosome damage induced by small molecule kinase inhibitors. PLoS Comput. Biol. 5, e1000446 (2009).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  34. Bergmann, O. et al. Evidence for cardiomyocyte renewal in humans. Science 324, 98–102 (2009). A revolutionary application of airborne radiation; the assessment of radioisotopes in human tissues to estimate proliferation rates. This work definitively shows that the myocardium exhibits a baseline proliferation and has ushered out the notion that the adult heart is forever postmitotic.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  35. Padin-Iruegas, M. E. et al. Cardiac progenitor cells and biotinylated insulin-like growth factor-1 nanofibers improve endogenous and exogenous myocardial regeneration after infarction. Circulation 120, 876–887 (2009).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  36. De Angelis, A. et al. Anthracycline cardiomyopathy is mediated by depletion of the cardiac stem cell pool and is rescued by restoration of progenitor cell function. Circulation 121, 276–292 (2010). A thorough demonstration of the use of exogenous stem cells to attenuate cardiotoxicity induced by doxorubicin. These data provide rationale for the hypothesis that the stem cell compartment in the heart is a target of toxicity. This hypothesis was put forth to explain the increased incidence of heart failure in doxorubicin-treated children.

    Article  CAS  PubMed  Google Scholar 

  37. Kajstura, J. et al. Cardiac stem cells and myocardial disease. J. Mol. Cell. Cardiol. 45, 505–513 (2008).

    Article  CAS  PubMed  Google Scholar 

  38. Huang, C. et al. Juvenile exposure to anthracyclines impairs cardiac progenitor cell function and vascularization resulting in greater susceptibility to stress-induced myocardial injury in adult mice. Circulation 121, 675–683 (2010).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  39. Lipshultz, S. E. Exposure to anthracyclines during childhood causes cardiac injury. Semin. Oncol. 33, S8–S14 (2006).

    Article  CAS  PubMed  Google Scholar 

  40. Li, M. et al. c-kit is required for cardiomyocyte terminal differentiation. Circ. Res. 102, 677–685 (2008).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  41. Crone, S. A. et al. ErbB2 is essential in the prevention of dilated cardiomyopathy. Nature Med. 8, 459–465 (2002).

    Article  CAS  PubMed  Google Scholar 

  42. Harris, I. S. et al. Raf-1 kinase is required for cardiac hypertrophy and cardiomyocyte survival in response to pressure overload. Circulation 110, 718–723 (2004).

    Article  CAS  PubMed  Google Scholar 

  43. Lin, R. C. et al. PI3K(p110α) protects against myocardial infarction-induced heart failure: identification of PI3K-regulated miRNA and mRNA. Arterioscler. Thromb. Vasc. Biol. 30, 724–732 (2010).

    Article  CAS  PubMed  Google Scholar 

  44. Sano, M. et al. p53-induced inhibition of Hif-1 causes cardiac dysfunction during pressure overload. Nature 446, 444–448 (2007).

    Article  CAS  PubMed  Google Scholar 

  45. Adams, R. H. et al. Essential role of p38α MAP kinase in placental but not embryonic cardiovascular development. Mol. Cell 6, 109–116 (2000).

    Article  CAS  PubMed  Google Scholar 

  46. Molkentin, J. D. & Robbins, J. With great power comes great responsibility: using mouse genetics to study cardiac hypertrophy and failure. J. Mol. Cell. Cardiol. 46, 130–136 (2009). A well-written review about the necessity to understand in deeper detail how transgenic and knockout mice are created, in order to effectively interpret the phenotype that is observed. Specific emphasis is placed on genetically modified mice and their role in understanding cardiac biology.

    Article  CAS  PubMed  Google Scholar 

  47. Braam, S. R., Passier, R. & Mummery, C. L. Cardiomyocytes from human pluripotent stem cells in regenerative medicine and drug discovery. Trends Pharmacol. Sci. 30, 536–545 (2009).

    Article  CAS  PubMed  Google Scholar 

  48. Braam, S. R. et al. Prediction of drug-induced cardiotoxicity using human embryonic stem cell-derived cardiomyocytes. Stem Cell Res. 4, 107–116 (2010). One of the first articles to use stem cell-derived cardiomyocytes as a model for assessing cardio-active compounds.

    Article  CAS  PubMed  Google Scholar 

  49. Marroquin, L. D., Hynes, J., Dykens, J. A., Jamieson, J. D. & Will, Y. Circumventing the Crabtree effect: replacing media glucose with galactose increases susceptibility of HepG2 cells to mitochondrial toxicants. Toxicol. Sci. 97, 539–547 (2007).

    Article  CAS  PubMed  Google Scholar 

  50. Kimes, B. W. & Brandt, B. L. Properties of a clonal muscle cell line from rat heart. Exp. Cell Res. 98, 367–381 (1976).

    Article  CAS  PubMed  Google Scholar 

  51. Merten, K. E., Jiang, Y., Feng, W. & Kang, Y. J. Calcineurin activation is not necessary for doxorubicin-induced hypertrophy in H9c2 embryonic rat cardiac cells: involvement of the phosphoinositide 3-kinase-Akt pathway. J. Pharmacol. Exp. Ther. 319, 934–940 (2006).

    Article  CAS  PubMed  Google Scholar 

  52. Wang, Y. J. et al. Time-dependent block of ultrarapid-delayed rectifier K+ currents by aconitine, a potent cardiotoxin, in heart-derived H9c2 myoblasts and in neonatal rat ventricular myocytes. Toxicol. Sci. 106, 454–463 (2008).

    Article  CAS  PubMed  Google Scholar 

  53. Will, Y. et al. Effect of the multitargeted tyrosine kinase inhibitors imatinib, dasatinib, sunitinib, and sorafenib on mitochondrial function in isolated rat heart mitochondria and H9c2 cells. Toxicol. Sci. 106, 153–161 (2008).

    Article  CAS  PubMed  Google Scholar 

  54. Simpson, P., McGrath, A. & Savion, S. Myocyte hypertrophy in neonatal rat heart cultures and its regulation by serum and by catecholamines. Circ. Res. 51, 787–801 (1982).

    Article  CAS  PubMed  Google Scholar 

  55. Simpson, P. & Savion, S. Differentiation of rat myocytes in single cell cultures with and without proliferating nonmyocardial cells. Cross-striations, ultrastructure, and chronotropic response to isoproterenol. Circ. Res. 50, 101–116 (1982).

    Article  CAS  PubMed  Google Scholar 

  56. Kerkela, R. et al. Cardiotoxicity of the cancer therapeutic agent imatinib mesylate. Nature Med. 12, 908–916 (2006). The first paper describing the cardiotoxicity of kinase inhibitors. The results in this paper changed the approach for assessing cardiotoxicity of kinase inhibitors.

    Article  CAS  PubMed  Google Scholar 

  57. Hasinoff, B. B., Patel, D. & O'Hara, K. A. Mechanisms of myocyte cytotoxicity induced by the multiple receptor tyrosine kinase inhibitor sunitinib. Mol. Pharmacol. 74, 1722–1728 (2008).

    Article  CAS  PubMed  Google Scholar 

  58. Zhang, J. et al. Functional cardiomyocytes derived from human induced pluripotent stem cells. Circ. Res. 104, e30–e41 (2009).

    CAS  PubMed  PubMed Central  Google Scholar 

  59. Itskovitz-Eldor, J. et al. Differentiation of human embryonic stem cells into embryoid bodies compromising the three embryonic germ layers. Mol. Med. 6, 88–95 (2000).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  60. Kehat, I. et al. Electromechanical integration of cardiomyocytes derived from human embryonic stem cells. Nature Biotech. 22, 1282–1289 (2004).

    Article  CAS  Google Scholar 

  61. Satin, J. et al. Calcium handling in human embryonic stem cell-derived cardiomyocytes. Stem Cells 26, 1961–1972 (2008).

    Article  CAS  PubMed  Google Scholar 

  62. Vidarsson, H., Hyllner, J. & Sartipy, P. Differentiation of human embryonic stem cells to cardiomyocytes for in vitro and in vivo applications. Stem Cell Rev. 6, 108–120 (2010).

    Article  Google Scholar 

  63. Liang, H. et al. Human and murine embryonic stem cell-derived cardiomyocytes serve together as a valuable model for drug safety screening. Cell Physiol. Biochem. 25, 459–466 (2010).

    Article  CAS  PubMed  Google Scholar 

  64. Hill, A. J., Teraoka, H., Heideman, W. & Peterson, R. E. Zebrafish as a model vertebrate for investigating chemical toxicity. Toxicol. Sci. 86, 6–19 (2005).

    Article  CAS  PubMed  Google Scholar 

  65. Jopling, C. et al. Zebrafish heart regeneration occurs by cardiomyocyte dedifferentiation and proliferation. Nature 464, 606–609 (2010).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  66. Baker, K., Warren, K. S., Yellen, G. & Fishman, M. C. Defective “pacemaker” current (Ih) in a zebrafish mutant with a slow heart rate. Proc. Natl Acad. Sci. USA 94, 4554–4559 (1997).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  67. Eimon, P. M. & Rubinstein, A. L. The use of in vivo zebrafish assays in drug toxicity screening. Expert Opin. Drug. Metab. Toxicol. 5, 393–401 (2009).

    Article  CAS  PubMed  Google Scholar 

  68. Pugach, E. K., Li, P., White, R. & Zon, L. Retro-orbital injection in adult zebrafish. J. Vis. Exp. 34, 1645 (2009).

    Google Scholar 

  69. Wenner, M. The most transparent research. Nature Med. 15, 1106–1109 (2009).

    Article  CAS  PubMed  Google Scholar 

  70. Herman, E. H. & Ferrans, V. J. Pretreatment with ICRF-187 provides long-lasting protection against chronic daunorubicin cardiotoxicity in rabbits. Cancer Chemother. Pharmacol. 16, 102–106 (1986).

    Article  CAS  PubMed  Google Scholar 

  71. Herman, E. H., Ferrans, V. J., Jordan, W. & Ardalan, B. Reduction of chronic daunorubicin cardiotoxicity by ICRF-187 in rabbits. Res. Commun. Chem. Pathol. Pharmacol. 31, 85–97 (1981).

    CAS  PubMed  Google Scholar 

  72. Herman, E. H. & Ferrans, V. J. Preclinical animal models of cardiac protection from anthracycline-induced cardiotoxicity. Semin. Oncol. 25, 15–21 (1998).

    CAS  PubMed  Google Scholar 

  73. Fernandez, A. et al. An anticancer C-Kit kinase inhibitor is reengineered to make it more active and less cardiotoxic. J. Clin. Invest. 117, 4044–4054 (2007).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  74. Olson, H. et al. Concordance of the toxicity of pharmaceuticals in humans and in animals. Regul. Toxicol. Pharmacol. 32, 56–67 (2000).

    Article  CAS  PubMed  Google Scholar 

  75. Takahashi, K. et al. Induction of pluripotent stem cells from adult human fibroblasts by defined factors. Cell 131, 861–872 (2007).

    Article  CAS  PubMed  Google Scholar 

  76. Yu, J. et al. Induced pluripotent stem cell lines derived from human somatic cells. Science 318, 1917–1920 (2007).

    Article  CAS  PubMed  Google Scholar 

  77. Eschenhagen, T. 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 13, 1–10 (2011).

    Article  PubMed  Google Scholar 

  78. Zhang, L. & Dokainish, H. Echocardiography in the assessment of heart failure. Minerva Cardioangiol. 57, 457–466 (2009).

    CAS  PubMed  Google Scholar 

  79. Apple, F. S. A new season for cardiac troponin assays: it's time to keep a scorecard. Clin. Chem. 55, 1303–1306 (2009).

    Article  CAS  PubMed  Google Scholar 

  80. Apple, F. High-sensitivity cardiac troponin assays: what analytical and clinical issues need to be addressed before introduction into clinical practice? Clin. Chem. 56, 886–891 (2010).

    Article  CAS  Google Scholar 

  81. Polena, S. et al. Troponin I as a marker of doxorubicin induced cardiotoxicity. Proc. West. Pharmacol. Soc. 48, 142–144 (2005).

    CAS  PubMed  Google Scholar 

  82. Cardinale, D. et al. Prevention of high-dose chemotherapy-induced cardiotoxicity in high-risk patients by angiotensin-converting enzyme inhibition. Circulation 114, 2474–2481 (2006).

    Article  CAS  PubMed  Google Scholar 

  83. Cardinale, D. et al. Trastuzumab-induced cardiotoxicity: clinical and prognostic implications of troponin I evaluation. J. Clin. Oncol. 28, 3910–3916 (2010).

    Article  CAS  PubMed  Google Scholar 

  84. Henderson, I. C. et al. Randomized clinical trial comparing mitoxantrone with doxorubicin in previously treated patients with metastatic breast cancer. J. Clin. Oncol. 7, 560–571 (1989).

    Article  CAS  PubMed  Google Scholar 

  85. Mordente, A., Meucci, E., Silvestrini, A., Martorana, G. E. & Giardina, B. New developments in anthracycline-induced cardiotoxicity. Curr. Med. Chem. 16, 1656–1672 (2009).

    Article  CAS  PubMed  Google Scholar 

  86. Lewis, G. D., Asnani, A. & Gerszten, R. E. Application of metabolomics to cardiovascular biomarker and pathway discovery. Am. Coll. Cardiol. 52, 117–123 (2008).

    Article  CAS  Google Scholar 

  87. Lewis, G. D. et al. Metabolic signatures of exercise in human plasma. Sci. Transl. Med. 2, 33–37 (2010).

    Article  CAS  Google Scholar 

  88. Olson, E. N. A decade of discoveries in cardiac biology. Nature Med. 10, 467–474 (2004).

    Article  CAS  PubMed  Google Scholar 

  89. Brini, M. & Carafoli, E. Calcium pumps in health and disease. Physiol. Rev. 89, 1341–1378 (2009).

    Article  CAS  PubMed  Google Scholar 

  90. Swain, J. L., Sabina, R. L., McHale, P. A., Greenfield, J. C. Jr & Holmes, E. W. Prolonged myocardial nucleotide depletion after brief ischemia in the open-chest dog. Am. J. Physiol. 242, H818–H826 (1982).

    CAS  PubMed  Google Scholar 

  91. Khouri, E. M., Gregg, D. E. & Rayford, C. R. Effect of exercise on cardiac output, left coronary flow and myocardial metabolism in the unanesthetized dog. Circ. Res. 17, 427–437 (1965).

    Article  CAS  PubMed  Google Scholar 

  92. Barry, S. P., Davidson, S. M. & Townsend, P. A. Molecular regulation of cardiac hypertrophy. Int. J. Biochem. Cell. Biol. 40, 2023–2039 (2008).

    Article  CAS  PubMed  Google Scholar 

  93. Oliveira, R. S. et al. Cardiac anti-remodelling effect of aerobic training is associated with a reduction in the calcineurin/NFAT signalling pathway in heart failure mice. J. Physiol. 587, 3899–3910 (2009).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  94. Zhang, T. et al. CaMKIIδ isoforms differentially affect calcium handling but similarly regulate HDAC/MEF2 transcriptional responses. J. Biol. Chem. 282, 35078–35087 (2007).

    Article  CAS  PubMed  Google Scholar 

  95. Zhang, T. et al. Phospholamban ablation rescues sarcoplasmic reticulum Ca2+ handling but exacerbates cardiac dysfunction in CaMKIIδC transgenic mice. Circ. Res. 106, 354–362 (2010).

    Article  CAS  PubMed  Google Scholar 

  96. Vittone, L., Mundina-Weilenmann, C. & Mattiazzi, A. Phospholamban phosphorylation by CaMKII under pathophysiological conditions. Front. Biosci. 13, 5988–6005 (2008).

    Article  CAS  PubMed  Google Scholar 

  97. Ghoreschi, K., Laurence, A. & O'Shea, J. J. Selectivity and therapeutic inhibition of kinases: to be or not to be? Nature Immunol. 10, 356–360 (2009).

    Article  CAS  Google Scholar 

  98. Louvet, C. et al. Tyrosine kinase inhibitors reverse type 1 diabetes in nonobese diabetic mice. Proc. Natl Acad. Sci. USA 105, 18895–18900 (2008).

    Article  PubMed  PubMed Central  Google Scholar 

  99. Mariani, S. et al. Imatinib does not substantially modify the glycemic profile in patients with chronic myeloid leukaemia. Leuk. Res. 34, e5–e7 (2010).

    Article  CAS  PubMed  Google Scholar 

  100. Agostino, N. et al. Effect of the tyrosine kinase inhibitors (sunitinib, sorafenib, dasatinib, and imatinib) on blood glucose levels in diabetic and nondiabetic patients in general clinical practice. J. Oncol. Pharm. Pract. 4 Aug 2010 (doi:10.1177/1078155210378913).

  101. Schermuly, R. T. et al. Reversal of experimental pulmonary hypertension by PDGF inhibition. J. Clin. Invest. 115, 2811–2821 (2005).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  102. Klein, M. et al. Combined tyrosine and serine/threonine kinase inhibition by sorafenib prevents progression of experimental pulmonary hypertension and myocardial remodeling. Circulation 118, 2081–2090 (2008).

    Article  CAS  PubMed  Google Scholar 

  103. Ghofrani, H. A. et al. Imatinib in pulmonary arterial hypertension patients with inadequate response to established therapy. Am. J. Respir. Crit. Care Med. 182, 1171–1177 (2010).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  104. Wang, C. H. et al. Stem cell factor deficiency is vasculoprotective: unraveling a new therapeutic potential of imatinib mesylate. Circ. Res. 99, 617–625 (2006).

    Article  CAS  PubMed  Google Scholar 

  105. Makiyama, Y. et al. Imatinib mesilate inhibits neointimal hyperplasia via growth inhibition of vascular smooth muscle cells in a rat model of balloon injury. Tohoku J. Exp. Med. 215, 299–306 (2008).

    Article  CAS  PubMed  Google Scholar 

  106. Ayach, B. B. et al. Stem cell factor receptor induces progenitor and natural killer cell-mediated cardiac survival and repair after myocardial infarction. Proc. Natl Acad. Sci. USA 103, 2304–2309 (2006).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  107. Force, T. et al. Research priorities in hypertrophic cardiomyopathy: report of a working group of the National Heart, Lung, and Blood Institute. Circulation 122, 1130–1133 (2010).

    Article  PubMed  PubMed Central  Google Scholar 

  108. Ahmad, F. et al. Increased α2 subunit-associated AMPK activity and PRKAG2 cardiomyopathy. Circulation 112, 3140–3148 (2005).

    Article  CAS  PubMed  Google Scholar 

  109. Tao, R., Zhang, J., Vessey, D. A., Honbo, N. & Karliner, J. S. Deletion of the sphingosine kinase-1 gene influences cell fate during hypoxia and glucose deprivation in adult mouse cardiomyocytes. Cardiovasc. Res. 74, 56–63 (2007).

    Article  CAS  PubMed  Google Scholar 

  110. Moga, M. A., Nakamura, T. & Robbins, J. Genetic approaches for changing the heart and dissecting complex syndromes. J. Mol. Cell. Cardiol. 45, 148–155 (2008).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  111. Aoki, Y., Niihori, T., Narumi, Y., Kure, S. & Matsubara, Y. The RAS/MAPK syndromes: novel roles of the RAS pathway in human genetic disorders. Hum. Mutat. 29, 992–1006 (2008).

    Article  CAS  PubMed  Google Scholar 

  112. Gelb, B. D. & Tartaglia, M. Noonan syndrome and related disorders: dysregulated RAS-mitogen activated protein kinase signal transduction. Hum. Mol. Genet. 15,R220–R226 (2006).

    Article  CAS  Google Scholar 

  113. Yamaguchi, O. et al. Cardiac-specific disruption of the c-raf-1 gene induces cardiac dysfunction and apoptosis. J. Clin. Invest. 114, 937–943 (2004).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  114. McMullen, J. R. & Jay, P. Y. PI3K(p110α) inhibitors as anti-cancer agents: minding the heart. Cell Cycle 6, 910–913 (2007).

    Article  CAS  PubMed  Google Scholar 

  115. McMullen, J. R. et al. Protective effects of exercise and phosphoinositide 3-kinase(p110α) signaling in dilated and hypertrophic cardiomyopathy. Proc. Natl Acad. Sci. USA 104, 612–617 (2007).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  116. Rose, R. A., Kabir, M. G. & Backx, P. H. Altered heart rate and sinoatrial node function in mice lacking the cAMP regulator phosphoinositide 3-kinase-γ. Circ. Res. 101, 1274–1282 (2007).

    Article  CAS  PubMed  Google Scholar 

  117. Oudit, G. Y. et al. Phosphoinositide 3-kinase-γ-deficient mice are protected from isoproterenol-induced heart failure. Circulation 108, 2147–2152 (2003).

    Article  CAS  PubMed  Google Scholar 

  118. Oudit, G. Y. et al. The role of phosphoinositide-3 kinase and PTEN in cardiovascular physiology and disease. J. Mol. Cell. Cardiol. 37, 449–471 (2004).

    Article  CAS  PubMed  Google Scholar 

  119. Mora, A. et al. Deficiency of PDK1 in cardiac muscle results in heart failure and increased sensitivity to hypoxia. EMBO J. 22, 4666–4676 (2003).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  120. DeBosch, B. et al. Akt1 is required for physiological cardiac growth. Circulation 113, 2097–2104 (2006).

    Article  CAS  PubMed  Google Scholar 

  121. DeBosch, B., Sambandam, N., Weinheimer, C., Courtois, M. & Muslin, A. J. Akt2 regulates cardiac metabolism and cardiomyocyte survival. J. Biol. Chem. 281, 32841–32851 (2006).

    Article  CAS  PubMed  Google Scholar 

  122. Lee, C. H., Inoki, K. & Guan, K. L. mTOR pathway as a target in tissue hypertrophy. Annu. Rev. Pharmacol. Toxicol. 47, 443–467 (2007).

    Article  CAS  PubMed  Google Scholar 

  123. Ciuffreda, L., Di Sanza, C., Incani, U. C. & Milella, M. The mTOR pathway: a new target in cancer therapy. Curr. Cancer Drug Targets 10, 10484–10495 (2010).

    Article  Google Scholar 

  124. Blair, E. et al. Mutations in the γ2 subunit of AMP-activated protein kinase cause familial hypertrophic cardiomyopathy: evidence for the central role of energy compromise in disease pathogenesis. Hum. Mol. Genet. 10, 1215–1220 (2001).

    Article  CAS  PubMed  Google Scholar 

  125. Zhang, P. et al. AMP activated protein kinase-α2 deficiency exacerbates pressure-overload-induced left ventricular hypertrophy and dysfunction in mice. Hypertension 52, 918–924 (2008).

    Article  CAS  PubMed  Google Scholar 

  126. Matsuda, T. et al. Distinct roles of GSK-3α and GSK-3β phosphorylation in the heart under pressure overload. Proc. Natl Acad. Sci. USA 105, 20900–20905 (2008).

    Article  PubMed  PubMed Central  Google Scholar 

  127. Kerkela, R. et al. Deletion of GSK-3β in mice leads to hypertrophic cardiomyopathy secondary to cardiomyoblast hyperproliferation. J. Clin. Invest. 118, 3609–3618 (2008).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  128. Woulfe, K. C. et al. Glycogen synthase kinase-3β regulates post-myocardial infarction remodeling and stress-induced cardiomyocyte proliferation in vivo. Circ. Res. 106, 1635–1645 (2010).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  129. Barriere, C. et al. Mice thrive without Cdk4 and Cdk2. Mol. Oncol. 1, 72–83 (2007).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  130. Liem, D. A. et al. Cyclin-dependent kinase 2 signaling regulates myocardial ischemia/reperfusion injury. J. Mol. Cell. Cardiol. 45, 610–616 (2008).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  131. Perez Fidalgo, J. A., Roda, D., Rosello, S., Rodriguez-Braun, E. & Cervantes, A. Aurora kinase inhibitors: a new class of drugs targeting the regulatory mitotic system. Clin. Transl. Oncol. 11, 787–798 (2009).

    Article  CAS  PubMed  Google Scholar 

  132. Lapenna, S. & Giordano, A. Cell cycle kinases as therapeutic targets for cancer. Nature Rev. Drug. Discov. 8, 547–566 (2009).

    Article  CAS  Google Scholar 

  133. Chopra, P., Sethi, G., Dastidar, S. G. & Ray, A. Polo-like kinase inhibitors: an emerging opportunity for cancer therapeutics. Expert Opin. Investig. Drugs 19, 27–43 (2010).

    Article  CAS  PubMed  Google Scholar 

  134. Noma, T. et al. β-arrestin-mediated β1-adrenergic receptor transactivation of the EGFR confers cardioprotection. J. Clin. Invest. 117, 2445–2458 (2007).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  135. De Keulenaer, G. W., Doggen, K. & Lemmens, K. The vulnerability of the heart as a pluricellular paracrine organ: lessons from unexpected triggers of heart failure in targeted ErbB2 anticancer therapy. Circ. Res. 106, 35–46 (2010).

    Article  CAS  PubMed  Google Scholar 

  136. Iwamoto, R. et al. Heparin-binding EGF-like growth factor and ErbB signaling is essential for heart function. Proc. Natl Acad. Sci. USA 100, 3221–3226 (2003).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  137. Liu, F. F. et al. Heterozygous knockout of neuregulin-1 gene in mice exacerbates doxorubicin-induced heart failure. Am. J. Physiol. 289, H660–H666 (2005).

    CAS  Google Scholar 

  138. Garcia-Rivello, H. et al. Dilated cardiomyopathy in Erb-b4-deficient ventricular muscle. Am. J. Physiol. 289, H1153–H1160 (2005).

    CAS  Google Scholar 

  139. Fazel, S. et al. Cardioprotective c-kit+ cells are from the bone marrow and regulate the myocardial balance of angiogenic cytokines. J. Clin. Invest. 116, 1865–1877 (2006).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  140. Hilfiker-Kleiner, D., Limbourg, A. & Drexler, H. STAT3-mediated activation of myocardial capillary growth. Trends Cardiovas. Med. 15, 152–157 (2005).

    Article  CAS  Google Scholar 

  141. Kunisada, K. et al. Signal transducer and activator of transcription 3 in the heart transduces not only a hypertrophic signal but a protective signal against doxorubicin-induced cardiomyopathy. Proc. Natl Acad. Sci. USA 97, 315–319 (2000).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  142. Barry, S. P., Townsend, P. A., Latchman, D. S. & Stephanou, A. Role of the JAK-STAT pathway in myocardial injury. Trends Mol. Med. 13, 82–89 (2007).

    Article  CAS  PubMed  Google Scholar 

  143. Peng, X. et al. Inactivation of focal adhesion kinase in cardiomyocytes promotes eccentric cardiac hypertrophy and fibrosis in mice. J. Clin. Invest. 116, 217–227 (2006).

    Article  CAS  PubMed  Google Scholar 

  144. O'Cochlain, D. F. et al. Transgenic overexpression of human DMPK accumulates into hypertrophic cardiomyopathy, myotonic myopathy and hypotension traits of myotonic dystrophy. Hum. Mol. Genet. 13, 2505–2518 (2004).

    Article  CAS  PubMed  Google Scholar 

  145. Honda, H. et al. Heart-specific activation of LTK results in cardiac hypertrophy, cardiomyocyte degeneration and gene reprogramming in transgenic mice. Oncogene 18, 3821–3830 (1999).

    Article  CAS  PubMed  Google Scholar 

  146. Shi, J., Zhang, Y. W., Yang, Y., Zhang, L. & Wei, L. ROCK1 plays an essential role in the transition from cardiac hypertrophy to failure in mice. J. Mol. Cell Cardiol. 49, 819–828 (2010).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  147. Zhang, Y. M. et al. Targeted deletion of ROCK1 protects the heart against pressure overload by inhibiting reactive fibrosis. FASEB J. 20, 916–925 (2006).

    Article  CAS  PubMed  Google Scholar 

  148. Ikeda, Y. et al. Cardiac-specific deletion of LKB1 leads to hypertrophy and dysfunction. J. Biol. Chem. 284, 35839–35849 (2009).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  149. Zheng, M. et al. Cardiac-specific ablation of Cypher leads to a severe form of dilated cardiomyopathy with premature death. Hum. Mol. Genet. 18, 701–713 (2009).

    Article  CAS  PubMed  Google Scholar 

  150. Lorenz, K., Schmitt, J. P., Schmitteckert, E. M. & Lohse, M. J. A new type of ERK1/2 autophosphorylation causes cardiac hypertrophy. Nature Med. 15, 75–83 (2009).

    Article  CAS  PubMed  Google Scholar 

  151. Lips, D. J. et al. MEK1-ERK2 signaling pathway protects myocardium from ischemic injury in vivo. Circulation 109, 1938–1941 (2004).

    Article  CAS  PubMed  Google Scholar 

  152. Kehat, I. & Molkentin, J. D. Extracellular signal-regulated kinase 1/2 (ERK1/2) signaling in cardiac hypertrophy. Ann. NY Acad. Sci. 1188, 96–102 (2010).

    Article  CAS  PubMed  Google Scholar 

  153. Nakamura, T. et al. Mediating ERK 1/2 signaling rescues congenital heart defects in a mouse model of Noonan syndrome. J. Clin. Invest. 117, 2123–2132 (2007).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  154. Liu, Q. et al. PKCα, but not PKCβ or PKCγ, regulates contractility and heart failure susceptibility: implications for ruboxistaurin as a novel therapeutic approach. Circ. Res. 105, 194–200 (2009).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  155. Takimoto, E. et al. Regulator of G protein signaling 2 mediates cardiac compensation to pressure overload and antihypertrophic effects of PDE5 inhibition in mice. J. Clin. Invest. 119, 408–420 (2009).

    CAS  PubMed  PubMed Central  Google Scholar 

  156. Guazzi, M., Vicenzi, M., Arena, R. & Guazzi, M. D. PDE5-inhibition with sildenafil improves left ventricular diastolic function, cardiac geometry and clinical status in patients with stable systolic heart failure: results of a 1-year prospective, randomized, rlacebo-controlled study. Circ. Heart Fail. 29 Oct 2010 (doi:10.1161/circheartfailure.110.944694).

  157. Muraski, J. A. et al. Pim-1 regulates cardiomyocyte survival downstream of Akt. Nature Med. 13, 1467–1475 (2007).

    Article  CAS  PubMed  Google Scholar 

  158. Sag, C. M. et al. Calcium/calmodulin-dependent protein kinase II contributes to cardiac arrhythmogenesis in heart failure. Circ. Heart Fail. 2, 664–675 (2009).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  159. Ling, H. et al. Requirement for Ca2+/calmodulin-dependent kinase II in the transition from pressure overload-induced cardiac hypertrophy to heart failure in mice. J. Clin. Invest. 119, 1230–1240 (2009).

    Article  PubMed  PubMed Central  Google Scholar 

  160. Lymperopoulos, A. et al. Reduction of sympathetic activity via adrenal-targeted GRK2 gene deletion attenuates heart failure progression and improves cardiac function after myocardial infarction. J. Biol. Chem. 285, 16378–16386 (2010).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  161. Eckhart, A. D. et al. Hybrid transgenic mice reveal in vivo specificity of G protein-coupled receptor kinases in the heart. Circ. Res. 86, 43–50 (2000).

    Article  CAS  PubMed  Google Scholar 

  162. Yamaguchi, O. et al. Targeted deletion of apoptosis signal-regulating kinase 1 attenuates left ventricular remodeling. Proc. Natl Acad. Sci. USA 100, 15883–15888 (2003).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  163. Taniike, M. et al. Apoptosis signal-regulating kinase 1/p38 signaling pathway negatively regulates physiological hypertrophy. Circulation 117, 545–552 (2008).

    Article  CAS  PubMed  Google Scholar 

  164. Hescheler, J. et al. Morphological, biochemical, and electrophysiological characterization of a clonal cell (H9c2) line from rat heart. Circ. Res. 69, 1476–1486 (1991).

    Article  CAS  PubMed  Google Scholar 

  165. Zordoky, B. N. & El-Kadi, A. O. H9c2 cell line is a valuable in vitro model to study the drug metabolizing enzymes in the heart. J. Pharmacol. Toxicol. Methods 56, 317–322 (2007).

    Article  CAS  PubMed  Google Scholar 

  166. Field, L. J. Atrial natriuretic factor-SV40 T antigen transgenes produce tumors and cardiac arrhythmias in mice. Science 239, 1029–1033 (1988).

    Article  CAS  PubMed  Google Scholar 

  167. White, S. M., Constantin, P. E. & Claycomb, W. C. Cardiac physiology at the cellular level: use of cultured HL-1 cardiomyocytes for studies of cardiac muscle cell structure and function. Am. J. Physiol. 286, H823–H829 (2004).

    CAS  Google Scholar 

  168. Eimre, M. et al. Distinct organization of energy metabolism in HL-1 cardiac cell line and cardiomyocytes. Biochim. Biophys. Acta 1777, 514–524 (2008).

    Article  CAS  PubMed  Google Scholar 

  169. Fritzsche, M., Fredriksson, J. M., Carlsson, M. & Mandenius, C. F. A cell-based sensor system for toxicity testing using multiwavelength fluorescence spectroscopy. Anal. Biochem. 387, 271–275 (2009).

    Article  CAS  PubMed  Google Scholar 

  170. Zhang, Y., Nuglozeh, E., Toure, F., Schmidt, A. M. & Vunjak-Novakovic, G. Controllable expansion of primary cardiomyocytes by reversible immortalization. Hum. Gene Ther. 20, 1687–1696 (2009).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  171. Pentassuglia, L. et al. Inhibition of ErbB2/neuregulin signaling augments paclitaxel-induced cardiotoxicity in adult ventricular myocytes. Exp. Cell Res. 313, 1588–1601 (2007).

    Article  CAS  PubMed  Google Scholar 

  172. Deng, X. F., Rokosh, D. G. & Simpson, P. C. Autonomous and growth factor-induced hypertrophy in cultured neonatal mouse cardiac myocytes. Comparison with rat. Circ. Res. 87, 781–788 (2000).

    Article  CAS  PubMed  Google Scholar 

  173. Gussak, I., Chaitman, B. R., Kopecky, S. L. & Nerbonne, J. M. Rapid ventricular repolarization in rodents: electrocardiographic manifestations, molecular mechanisms, and clinical insights. J. Electrocardiol. 33, 159–170 (2000).

    Article  CAS  PubMed  Google Scholar 

  174. Brouillette, J., Clark, R. B., Giles, W. R. & Fiset, C. Functional properties of K+ currents in adult mouse ventricular myocytes. J. Physiol. 559, 777–798 (2004).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  175. Volz, A., Piper, H. M., Siegmund, B. & Schwartz, P. Longevity of adult ventricular rat heart muscle cells in serum-free primary culture. J. Mol. Cell. Cardiol. 23, 161–173 (1991).

    Article  CAS  PubMed  Google Scholar 

  176. Ellingsen, O. et al. Adult rat ventricular myocytes cultured in defined medium: phenotype and electromechanical function. Am. J. Physiol. 265, H747–H754 (1993).

    CAS  PubMed  Google Scholar 

  177. Bistola, V. et al. Long-term primary cultures of human adult atrial cardiac myocytes: cell viability, structural properties and BNP secretion in vitro. Int. J. Cardiol. 131, 113–122 (2008).

    Article  PubMed  Google Scholar 

  178. Benardeau, A. et al. Primary culture of human atrial myocytes is associated with the appearance of structural and functional characteristics of immature myocardium. J. Mol. Cell. Cardiol. 29, 1307–1320 (1997).

    Article  CAS  PubMed  Google Scholar 

  179. Li, R. K. et al. Human pediatric and adult ventricular cardiomyocytes in culture: assessment of phenotypic changes with passaging. Cardiovasc. Res. 32, 362–373 (1996).

    Article  CAS  PubMed  Google Scholar 

  180. Davidson, M. M. et al. Novel cell lines derived from adult human ventricular cardiomyocytes. J. Mol. Cell. Cardiol. 39, 133–147 (2005).

    Article  CAS  PubMed  Google Scholar 

  181. Zhou, J. et al. GSK-3α directly regulates β adrenergic signaling and the response of the heart to hemodynamic stress in mice. J. Clin. Invest. 120, 2280–2291 (2010).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  182. Kondo, R. P. et al. Comparison of contraction and calcium handling between right and left ventricular myocytes from adult mouse heart: a role for repolarization waveform. J. Physiol. 571, 131–46 (2006).

    Article  CAS  PubMed  Google Scholar 

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Thomas Force is a consultant to GlaxoSmithKline, for issues surrounding cardiotoxicity of kinase inhibitors.

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Glossary

Regular type radionuclide ventriculography

The use of radionuclides to study left ventricular function.

Multi-targeted

Intentionally designed kinase inhibitor of more than one kinase.

Cardiac stress

Either increased demand (for example, hypertension) or reduced supply (for example, ischaemia) of oxygen to the heart.

Class effect

A toxicity or pharmacological outcome that occurs with all molecules that inhibit a particular target (for example, all β-adrenergic receptor antagonists lead to heart rate slowing).

Side population

A form of stem cell that is characterized by a specific pattern using fluorescent activated sorting.

Hoechst dye

A family of fluorescent stains used for labelling DNA and detecting and/or separating cell populations of interest.

Pressure load

A pressure load on the heart can be induced by anything that raises blood pressure. Experimentally, this typically means constricting the transverse aorta or infusing a drug (for example, angiotensin II).

Mitochondrial permeability transition pore

A regulatory opening within the mitochondria induced by certain types of cellular stress (for example, oxidant stress or ischemia). This results in loss of mitochondrial membrane integrity and swelling, ultimately inducing cell death.

Stem/progenitor cell compartment

The small population of undifferentiated cells within a tissue that has the potential to regenerate and replenish the dying cells of an organ.

Anthracycline

A class of drugs (of which doxorubicin is a member) used extensively in treatment of various cancers.

Pressure overload

A consequence of thoracic aortic constriction, resulting in increased blood pressure and subsequent cardiac hypertrophy and LV dysfunction.

Thoracic aortic constriction

A surgical procedure in which the aorta is banded, creating an acute and usually severe increase in blood pressure.

HERG

The human ether-a-go-go gene HERG (also known as KCNH2) codes for a specific potassium ion channel. Mutations in the gene cause one form of hereditary long QT syndrome.

Phenocopies

A phenotype or trait that is similar among different individuals.

Noonan, Costello and Cranio-facio-cutaneous syndromes

A group of syndromes that affect a number of organ systems and cause severe cardiac hypertrophy.

Ischaemia–reperfusion injury

A complex phenomenon that occurs when the blood supply from an organ is restored after a period of ischaemia.

Endoplasmic reticulum stress

A conserved response to excessive misfolded proteins resulting in an effort to repair and correct the situation; failing to do so leads to programmed cell death.

ABL

An oncogene associated with chronic myelogenous leukaemia.

Embyroid bodies

Aggregates of differentiating and undifferentiated cells formed from embryonic stem cells.

IKr

The inward delayed rectifier potassium current that is regulated in humans by HERG and is responsible for repolarization of cardiac action potential.

Tissue Doppler imaging/strain rate

A form of cardiac ultrasound used to assess functional parameters of the direction and speed of blood flow.

Hazard ratio

An explanatory factor used to assess the risk of a given event or disease.

B-type natriuretic peptide

A protein secreted from the heart in response to stress, including stretch.

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Force, T., Kolaja, K. Cardiotoxicity of kinase inhibitors: the prediction and translation of preclinical models to clinical outcomes. Nat Rev Drug Discov 10, 111–126 (2011). https://doi.org/10.1038/nrd3252

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