Guidelines for Translational Research in Heart Failure

  • Enrique Lara-Pezzi
  • Philippe Menasché
  • Jean-Hugues Trouvin
  • Lina Badimón
  • John P. A. Ioannidis
  • Joseph C. Wu
  • Joseph A. Hill
  • Walter J. Koch
  • Albert F. De Felice
  • Peter de Waele
  • Valérie Steenwinckel
  • Roger J. Hajjar
  • Andreas M. Zeiher


Heart failure (HF) remains a major cause of death and hospitalization worldwide. Despite medical advances, the prognosis of HF remains poor and new therapeutic approaches are urgently needed. The development of new therapies for HF is hindered by inappropriate or incomplete preclinical studies. In these guidelines, we present a number of recommendations to enhance similarity between HF animal models and the human condition in order to reduce the chances of failure in subsequent clinical trials. We propose different approaches to address safety as well as efficacy of new therapeutic products. We also propose that good practice rules are followed from the outset so that the chances of eventual approval by regulatory agencies increase. We hope that these guidelines will help improve the translation of results from animal models to humans and thereby contribute to more successful clinical trials and development of new therapies for HF.


Guidelines Heart failure Animal models New therapies Preclinical studies Clinical trials Good laboratory practice Induced pluripotent stem cells Toxicity 



Angiotensin-converting enzyme


Absorption, distribution, metabolism, excretion


Active pharmacological product


Angiotensin II receptor blocker


Advanced therapy medicinal products


Area under the curve


Coronary artery disease


Clustered regularly interspaced short palindromic repeats


Dilated cardiomyopathy


European Medicines Agency


Food and Drug Administration


Good laboratory practice


Good manufacturing practice


Heart failure


Heart failure with preserved ejection fraction


Investigational new drugs


Left anterior descending


Left ventricle


Market authorization


Myocardial infarction


No observed adverse effect level


Percutaneous coronary intervention






Programmed electrical stimulation


Proof of concept


Standard of care


Transverse aortic constriction


  1. 1.
    Go, A. S., Mozaffarian, D., Roger, V. L., Benjamin, E. J., Berry, J. D., Blaha, M. J., Dai, S., Ford, E. S., et al. (2014). Heart disease and stroke statistics—2014 update: a report from the American Heart Association. Circulation, 129, e28–e292.PubMedGoogle Scholar
  2. 2.
    Krum, H., & Abraham, W. T. (2009). Heart failure. Lancet, 373, 941–955.PubMedGoogle Scholar
  3. 3.
    Mcmurray, J. J. V., Packer, M., Desai, A. S., Gong, J., Lefkowitz, M. P., Rizkala, A. R., Rouleau, J. L., Shi, V. C., et al. (2014). Angiotensin-neprilysin inhibition enalapril in heart failure. New England Journal of Medicine, 371, 993–1004.PubMedGoogle Scholar
  4. 4.
    Molloy, G. J., O'carroll, R. E., Witham, M. D., & Mcmurdo, M. E. T. (2012). Interventions to enhance adherence to medications in patients with heart failure: a systematic review. Circulation. Heart Failure, 5, 126–133.PubMedGoogle Scholar
  5. 5.
    Adler, E. D., Goldfinger, J. Z., Kalman, J., Park, M. E., & Meier, D. E. (2009). Palliative care in the treatment of advanced heart failure. Circulation, 120, 2597–2606.PubMedGoogle Scholar
  6. 6.
    Kandala, J., Altman, R., Park, M., & Singh, J. (2012). Clinical, laboratory, and pacing predictors of CRT response. Journal of Cardiovascular Translational Research, 5, 196–212.PubMedGoogle Scholar
  7. 7.
    Birks, E. J., Tansley, P. D., Hardy, J., Bowles, C. T., Burke, M., Banner, N. R., Khaghani, A., & Yacoub, M. H. (2006). Reversal of heart failure using a combination of left ventricular assist device (LVAD) and pharmacologic therapy. New England Journal of Medicine, 355, 1873–1884.PubMedGoogle Scholar
  8. 8.
    Owan, T. E., Hodge, D. O., Herges, R. M., Jacobsen, S. J., Roger, V. L., & Redfield, M. M. (2006). Trends in prevalence and outcome of heart failure with preserved ejection fraction. New England Journal of Medicine, 355, 251–259.PubMedGoogle Scholar
  9. 9.
    Zile, M., & Baicu, C. (2013). Biomarkers of diastolic dysfunction and myocardial fibrosis: application to heart failure with a preserved ejection fraction. Journal of Cardiovascular Translational Research, 6, 501–515.PubMedGoogle Scholar
  10. 10.
    Chalmers, I., Bracken, M. B., Djulbegovic, B., Garattini, S., Grant, J., Gülmezoglu, A. M., Howells, D. W., Ioannidis, J. P. A., et al. (2014). How to increase value and reduce waste when research priorities are set. Lancet, 383, 156–165.PubMedGoogle Scholar
  11. 11.
    Contopoulos-Ioannidis, D. G., Ntzani, E. E., & Ioannidis, J. P. A. (2003). Translation of highly promising basic science research into clinical applications. American Journal of Medicine, 114, 477–484.PubMedGoogle Scholar
  12. 12.
    Schwartz Longacre, L., Kloner, R. A., Arai, A. E., Baines, C. P., Bolli, R., Braunwald, E., Downey, J., Gibbons, R. J., et al. (2011). New horizons in cardioprotection: recommendations from the 2010 National Heart, Lung, and Blood Institute Workshop. Circulation, 124, 1172–1179.PubMedGoogle Scholar
  13. 13.
    Sharma, K., & Kass, D. A. (2014). Heart failure with preserved ejection fraction: mechanisms, clinical features, and therapies. Circulation Research, 115, 79–96.PubMedGoogle Scholar
  14. 14.
    Henderson, V. C., Kimmelman, J., Fergusson, D., Grimshaw, J. M., & Hackam, D. G. (2013). Threats to validity in the design and conduct of preclinical efficacy studies: a systematic review of guidelines for in vivo animal experiments. PLoS Medicine, 10, e1001489.PubMedCentralPubMedGoogle Scholar
  15. 15.
    Investigators TCaSTC. (1989). Preliminary report: effect of encainide and flecainide on mortality in a randomized trial of arrhythmia suppression after myocardial infarction. New England Journal of Medicine, 321, 406–412.Google Scholar
  16. 16.
    Breckenridge, R. (2010). Heart failure and mouse models. Disease Models & Mechanisms, 3, 138–143.Google Scholar
  17. 17.
    Houser, S. R., Margulies, K. B., Murphy, A. M., Spinale, F. G., Francis, G. S., Prabhu, S. D., Rockman, H. A., Kass, D. A., et al. (2012). Animal models of heart failure: a scientific statement from the American Heart Association. Circulation Research, 111, 131–150.PubMedGoogle Scholar
  18. 18.
    Rockman, H. A., Ross, R. S., Harris, A. N., Knowlton, K. U., Steinhelper, M. E., Field, L. J., Ross, J., & Chien, K. R. (1991). Segregation of atrial-specific and inducible expression of an atrial natriuretic factor transgene in an in vivo murine model of cardiac hypertrophy. Proceedings of the National Academy of Sciences of the United States of America, 88, 8277–8281.PubMedCentralPubMedGoogle Scholar
  19. 19.
    Van Berlo, J. H., Maillet, M., & Molkentin, J. D. (2013). Signaling effectors underlying pathologic growth and remodeling of the heart. Journal of Clinical Investigation, 123, 37–45.PubMedCentralPubMedGoogle Scholar
  20. 20.
    Gao, E., Lei, Y. H., Shang, X., Huang, Z. M., Zuo, L., Boucher, M., Fan, Q., Chuprun, J. K., et al. (2010). A novel and efficient model of coronary artery ligation and myocardial infarction in the mouse. Circulation Research, 107, 1445–1453.PubMedCentralPubMedGoogle Scholar
  21. 21.
    Vander Heide, R. S., & Steenbergen, C. (2013). Cardioprotection and myocardial reperfusion: pitfalls to clinical application. Circulation Research, 113, 464–477.PubMedGoogle Scholar
  22. 22.
    Rockman, H. A., Chien, K. R., Choi, D.-J., Iaccarino, G., Hunter, J. J., Ross, J., Lefkowitz, R. J., & Koch, W. J. (1998). Expression of a β-adrenergic receptor kinase 1 inhibitor prevents the development of myocardial failure in gene-targeted mice. Proceedings of the National Academy of Sciences of the United States of America, 95, 7000–7005.PubMedCentralPubMedGoogle Scholar
  23. 23.
    Rengo, G., Lymperopoulos, A., Zincarelli, C., Donniacuo, M., Soltys, S., Rabinowitz, J. E., & Koch, W. J. (2009). Myocardial adeno-associated virus serotype-6-βARKct gene therapy improves cardiac function and normalizes the neurohormonal axis in chronic heart failure. Circulation, 119, 89–98.PubMedCentralPubMedGoogle Scholar
  24. 24.
    Thai, H., Guarraia, D., Johnson, N., Goldman, S., & Gaballa, M. A. (2007). Valsartan therapy in heart failure after myocardial infarction: the role of endothelial dependent relaxation. Journal of Cardiovascular Pharmacology, 50, 703–707. doi:10.1097/FJC.1090b1013e318159378b.PubMedGoogle Scholar
  25. 25.
    Defelice, A., Harris, A., Frering, R., & Horan, P. (1989). Beneficial hemodynamic effects of milrinone and enalapril in conscious rats with healed myocardial infarction. European Journal of Pharmacology, 167, 211–220.PubMedGoogle Scholar
  26. 26.
    Gavras, H., Faxon, D. P., Berkoben, J., Brunner, H. R., & Ryan, T. J. (1978). Angiotensin converting enzyme inhibition in patients with congestive heart failure. Circulation, 58, 770–776.PubMedGoogle Scholar
  27. 27.
    Pfeffer, J. M., Pfeffer, M. A., & Braunwald, E. (1985). Influence of chronic captopril therapy on the infarcted left ventricle of the rat. Circulation Research, 57, 84–95.PubMedGoogle Scholar
  28. 28.
    Jeremy, R. W., Allman, K. C., Bautovitch, G., & Harris, P. J. (1989). Patterns of left ventricular dilation during the six months after myocardial infarction. Journal of the American College of Cardiology, 13, 304–310.PubMedGoogle Scholar
  29. 29.
    Sweet, C. S., Ludden, C. T., Stabilito, I. I., Emmert, S. E., & Heyse, J. F. (1988). Beneficial effects of milrinone and enalapril on long-term survival of rats with healed myocardial infarction. European Journal of Pharmacology, 147, 29–37.PubMedGoogle Scholar
  30. 30.
    The Solvd Investigators. (1991). Effect of enalapril on survival in patients with reduced left ventricular ejection fractions and congestive heart failure. New England Journal of Medicine, 325, 293–302.Google Scholar
  31. 31.
    Defelice, A., Fein, S., Daudiss, K., Frering, R., & Horan, P. (1989). Beneficial hemodynamic effects of milrinone in conscious rabbits with chronic aortic regurgitation. Journal of Cardiovascular Pharmacology, 14, 659–665.PubMedGoogle Scholar
  32. 32.
    Bers, D. M. (2008). Calcium cycling and signaling in cardiac myocytes. Annual Review of Physiology, 70, 23–49.PubMedGoogle Scholar
  33. 33.
    Vimercati, C., Qanud, K., Mitacchione, G., Sosnowska, D., Ungvari, Z., Sarnari, R., Mania, D., Patel, N., et al. (2014). Beneficial effects of acute inhibition of the oxidative pentose phosphate pathway in the failing heart. American Journal of Physiology. Heart and Circulatory Physiology, 306, H709–H717.PubMedCentralPubMedGoogle Scholar
  34. 34.
    Bank, A., Gage, R., & Burns, K. (2012). Right ventricular pacing, mechanical dyssynchrony, and heart failure. Journal of Cardiovascular Translational Research, 5, 219–231.PubMedGoogle Scholar
  35. 35.
    Pleger, S. T., Shan, C., Ksienzyk, J., Bekeredjian, R., Boekstegers, P., Hinkel, R., Schinkel, S., Leuchs, B., et al. (2011). Cardiac AAV9-S100A1 gene therapy rescues post-ischemic heart failure in a preclinical large animal model. Science Translational Medicine, 3, 92ra64.PubMedCentralPubMedGoogle Scholar
  36. 36.
    Tilemann, L., Lee, A., Ishikawa, K., Aguero, J., Rapti, K., Santos-Gallego, C., Kohlbrenner, E., Fish, K. M., et al. (2013). SUMO-1 gene transfer improves cardiac function in a large-animal model of heart failure. Science Translational Medicine, 5, 211ra159.PubMedGoogle Scholar
  37. 37.
    Sabbah, H. N., Tocchetti, C. G., Wang, M., Daya, S., Gupta, R. C., Tunin, R. S., Mazhari, R., Takimoto, E., et al. (2013). Nitroxyl (HNO): a novel approach for the acute treatment of heart failure. Circulation. Heart Failure, 6, 1250–1258.PubMedCentralPubMedGoogle Scholar
  38. 38.
    Liu, Y., Dillon, A. R., Tillson, M., Makarewich, C., Nguyen, V., Dell'italia, L., Sabri, A. K., Rizzo, V., et al. (2013). Volume overload induces differential spatiotemporal regulation of myocardial soluble guanylyl cyclase in eccentric hypertrophy and heart failure. Journal of Molecular and Cellular Cardiology, 60, 72–83.PubMedCentralPubMedGoogle Scholar
  39. 39.
    Kawase, Y., Ly, H. Q., Prunier, F., Lebeche, D., Shi, Y., Jin, H., Hadri, L., Yoneyama, R., et al. (2008). Reversal of cardiac dysfunction after long-term expression of SERCA2a by gene transfer in a pre-clinical model of heart failure. Journal of the American College of Cardiology, 51, 1112–1119.PubMedGoogle Scholar
  40. 40.
    Prunier, F., Kawase, Y., Gianni, D., Scapin, C., Danik, S. B., Ellinor, P. T., Hajjar, R. J., & Del Monte, F. (2008). Prevention of ventricular arrhythmias with sarcoplasmic reticulum Ca2+ ATPase pump overexpression in a porcine model of ischemia reperfusion. Circulation, 118, 614–624.PubMedGoogle Scholar
  41. 41.
    Xie, M., Kong, Y., Tan, W., May, H., Battiprolu, P. K., Pedrozo, Z., Wang, Z. V., Morales, C., et al. (2014). Histone deacetylase inhibition blunts ischemia/reperfusion injury by inducing cardiomyocyte autophagy. Circulation, 129, 1139–1151.PubMedGoogle Scholar
  42. 42.
    Kou, W., Nelson, S., Lynch, J., Montgomery, D., Dicarlo, L., & Lucchesi, B. (1987). Effect of flecainide acetate on prevention of electrical induction of ventricular tachycardia and occurrence of ischemic ventricular fibrillation during the early postmyocardial infarction period: evaluation in a conscious canine model of sudden death. Journal of the American College of Cardiology, 9, 359–365.PubMedGoogle Scholar
  43. 43.
    Kaiser, R. A., Lyons, J. M., Duffy, J. Y., Wagner, C. J., Mclean, K. M., O'neill, T. P., Pearl, J. M., & Molkentin, J. D. (2005). Inhibition of p38 reduces myocardial infarction injury in the mouse but not pig after ischemia-reperfusion. American Journal of Physiology. Heart and Circulatory Physiology, 289, H2747–H2751.PubMedGoogle Scholar
  44. 44.
    Van Den Borne, S. W. M., De Schans, V., VaM, S. A. E., Vervoort-Peters, H. T. M., Lijnen, P. M., Cleutjens, J. P. M., Smits, J. F. M., Daemen, M. J. P., et al. (2009). Mouse strain determines the outcome of wound healing after myocardial infarction. Cardiovascular Research, 84, 273–282.PubMedGoogle Scholar
  45. 45.
    Seeger, F. H., Tonn, T., Krzossok, N., Zeiher, A. M., & Dimmeler, S. (2007). Cell isolation procedures matter: a comparison of different isolation protocols of bone marrow mononuclear cells used for cell therapy in patients with acute myocardial infarction. European Heart Journal, 28, 766–772.PubMedGoogle Scholar
  46. 46.
    Hood, L., & Tian, Q. (2012). Systems approaches to biology and disease enable translational systems medicine. Genomics, Proteomics & Bioinformatics, 10, 181–185.Google Scholar
  47. 47.
    Raake, P. W., Vinge, L. E., Gao, E., Boucher, M., Rengo, G., Chen, X., Degeorge, B. R., Matkovich, S., et al. (2008). G protein-coupled receptor kinase 2 ablation in cardiac myocytes before or after myocardial infarction prevents heart failure. Circulation Research, 103, 413–422.PubMedCentralPubMedGoogle Scholar
  48. 48.
    Leinwand, L. A. (2003). Sex is a potent modifier of the cardiovascular system. Journal of Clinical Investigation, 112, 302–307.PubMedCentralPubMedGoogle Scholar
  49. 49.
    Council NR (2001). Guide for care and use of laboratory animals 8th Edition.Google Scholar
  50. 50.
    U.S. Food and Drug Administration (2010). General considerations for animal studies for cardiovascular devices.
  51. 51.
    Peterson, E., Augenstein, J., Tanis, D., & Augenstein, D. (1981). Noise raises blood pressure without impairing auditory sensitivity. Science, 211, 1450–1452.PubMedGoogle Scholar
  52. 52.
    Tucker, D., Johnson, A. (1984). Influence of neonatal handling on blood pressure, locomotor activity, and preweanling heart rate in spontaneously hypertensive and Wistar Kyoto rats. 17:587–600.Google Scholar
  53. 53.
    Maury, E., Ramsey, K. M., & Bass, J. (2010). Circadian rhythms and metabolic syndrome: from experimental genetics to human disease. Circulation Research, 106, 447–462.PubMedCentralPubMedGoogle Scholar
  54. 54.
    Durgan, D. J., Pulinilkunnil, T., Villegas-Montoya, C., Garvey, M. E., Frangogiannis, N. G., Michael, L. H., Chow, C.-W., Dyck, J. R. B., et al. (2010). Short communication: ischemia/reperfusion tolerance is time-of-day-dependent: mediation by the cardiomyocyte circadian clock. Circulation Research, 106, 546–550.PubMedCentralPubMedGoogle Scholar
  55. 55.
    Shimizu, T., Nakai, K., Morimoto, Y., Ishihara, M., Oishi, H., Kikuchi, M., & Arai, H. (2009). Simple rabbit model of vulnerable atherosclerotic plaque. Neurologia Medico-Chirurgica, 49, 327–332.PubMedGoogle Scholar
  56. 56.
    Aikawa, M., Sugiyama, S., Hill, C. C., Voglic, S. J., Rabkin, E., Fukumoto, Y., Schoen, F. J., Witztum, J. L., et al. (2002). Lipid lowering reduces oxidative stress and endothelial cell activation in rabbit atheroma. Circulation, 106, 1390–1396.PubMedGoogle Scholar
  57. 57.
    Bustos, C., Hernández-Presa, M. A., Ortego, M., Tuñón, J., Ortega, L., Pérez, F., Díaz, C., Hernández, G., et al. (1998). HMG-CoA reductase inhibition by atorvastatin reduces neointimal inflammation in a rabbit model of atherosclerosis. Journal of the American College of Cardiology, 32, 2057–2064.PubMedGoogle Scholar
  58. 58.
    Largo, R., Sánchez-Pernaute, O., Marcos, M. E., Moreno-Rubio, J., Aparicio, C., Granado, R., Ortega, L., Egido, J., et al. (2008). Chronic arthritis aggravates vascular lesions in rabbits with atherosclerosis: a novel model of atherosclerosis associated with chronic inflammation. Arthritis and Rheumatism, 58, 2723–2734.PubMedGoogle Scholar
  59. 59.
    Reagan-Shaw, S., Nihal, M., & Ahmad, N. (2008). Dose translation from animal to human studies revisited. FASEB Journal, 22, 659–661.PubMedGoogle Scholar
  60. 60.
    Behfar, A., Latere, J.-P., Bartunek, J., Homsy, C., Daro, D., Crespo-Diaz, R. J., Stalboerger, P. G., Steenwinckel, V., et al. (2013). Optimized delivery system achieves enhanced endomyocardial stem cell retention. Circulation. Cardiovascular Interventions, 6, 710–718.PubMedCentralPubMedGoogle Scholar
  61. 61.
    Douglas, P. S., Decara, J. M., Devereux, R. B., Duckworth, S., Gardin, J. M., Jaber, W. A., Morehead, A. J., Oh, J. K., et al. (2009). Echocardiographic imaging in clinical trials: American Society of Echocardiography Standards for Echocardiography Core Laboratories: endorsed by the American College of Cardiology Foundation. Journal of the American Society of Echocardiography, 22, 755–765.PubMedGoogle Scholar
  62. 62.
    Bellenger, N. G., Burgess, M. I., Ray, S. G., Lahiri, A., Coats, A. J. S., Cleland, J. G. F., & Pennell, D. J. (2000). Comparison of left ventricular ejection fraction and volumes in heart failure by echocardiography, radionuclide ventriculography and cardiovascular magnetic resonance. Are they interchangeable? European Heart Journal, 21, 1387–1396.PubMedGoogle Scholar
  63. 63.
    Lang, R. M., Bierig, M., Devereux, R. B., Flachskampf, F. A., Foster, E., Pellikka, P. A., Picard, M. H., Roman, M. J., et al. (2005). Recommendations for chamber quantification: a report from the American Society of Echocardiography's Guidelines and Standards Committee and the Chamber Quantification Writing Group, developed in conjunction with the European Association of Echocardiography, a branch of the European Society of Cardiology. Journal of the American Society of Echocardiography, 18, 1440–1463.PubMedGoogle Scholar
  64. 64.
    Dorosz, J. L., Lezotte, D. C., Weitzenkamp, D. A., Allen, L. A., & Salcedo, E. E. (2012). Performance of 3-dimensional echocardiography in measuring left ventricular volumes and ejection fraction: a systematic review and meta-analysis. Journal of the American College of Cardiology, 59, 1799–1808.PubMedCentralPubMedGoogle Scholar
  65. 65.
    Tee, M., Noble, J. A., & Bluemke, D. A. (2013). Imaging techniques for cardiac strain and deformation: comparison of echocardiography, cardiac magnetic resonance and cardiac computed tomography. Expert Review of Cardiovascular Therapy, 11, 221–231.PubMedGoogle Scholar
  66. 66.
    Gorcsan Iii, J., & Tanaka, H. (2011). Echocardiographic assessment of myocardial strain. Journal of the American College of Cardiology, 58, 1401–1413.Google Scholar
  67. 67.
    Thavendiranathan, P., Poulin, F., Lim, K.-D., Plana, J. C., Woo, A., & Marwick, T. H. (2014). Use of myocardial strain imaging by echocardiography for the early detection of cardiotoxicity in patients during and after cancer chemotherapy: a systematic review. Journal of the American College of Cardiology, 63, 2751–2768.PubMedGoogle Scholar
  68. 68.
    Chemaly, E. R., Chaanine, A. H., Sakata, S., & Hajjar, R. J. (2012). Stroke volume-to-wall stress ratio as a load-adjusted and stiffness-adjusted indicator of ventricular systolic performance in chronic loading. Journal of Applied Physiology, 113, 1267–1284.PubMedCentralPubMedGoogle Scholar
  69. 69.
    Ishikawa, K., Chemaly, E. R., Tilemann, L., Fish, K., Ladage, D., Aguero, J., Vahl, T., Santos-Gallego, C., et al. (2012). Assessing left ventricular systolic dysfunction after myocardial infarction: are ejection fraction and dP/dtmax complementary or redundant? American Journal of Physiology. Heart and Circulatory Physiology, 302, H1423–H1428.PubMedCentralPubMedGoogle Scholar
  70. 70.
    Nagueh, S. F., Appleton, C. P., Gillebert, T. C., Marino, P. N., Oh, J. K., Smiseth, O. A., Waggoner, A. D., Flachskampf, F. A., et al. (2009). Recommendations for the evaluation of left ventricular diastolic function by echocardiography. Journal of the American Society of Echocardiography, 22, 107–133.PubMedGoogle Scholar
  71. 71.
    Enriquez-Sarano, M., Akins, C. W., & Vahanian, A. (2009). Mitral regurgitation. Lancet, 373, 1382–1394.PubMedGoogle Scholar
  72. 72.
    Ibanez, B., Prat-Gonzalez, S., Speidl, W. S., Vilahur, G., Pinero, A., Cimmino, G., Garcia, M. J., Fuster, V., et al. (2007). Early metoprolol administration before coronary reperfusion results in increased myocardial salvage: analysis of ischemic myocardium at risk using cardiac magnetic resonance. Circulation, 115, 2909–2916.PubMedGoogle Scholar
  73. 73.
    Neilan, T. G., Coelho-Filho, O. R., Shah, R. V., Abbasi, S. A., Heydari, B., Watanabe, E., Chen, Y., Mandry, D., et al. (2013). Myocardial extracellular volume fraction from T1 measurements in healthy volunteers and mice: relationship to aging and cardiac dimensions. JACC. Cardiovascular Imaging, 6, 672–683.PubMedCentralPubMedGoogle Scholar
  74. 74.
    Panse, K., Felkin, L., López-Olañeta, M., Gómez-Salinero, J., Villalba, M., Muñoz, L., Nakamura, K., Shimano, M., et al. (2012). Follistatin-like 3 mediates paracrine fibroblast activation by cardiomyocytes. Journal of Cardiovascular Translational Research, 5, 814–826.PubMedGoogle Scholar
  75. 75.
    Felkin, L. E., Narita, T., Germack, R., Shintani, Y., Takahashi, K., Sarathchandra, P., López-Olañeta, M. M., Gómez-Salinero, J. M., et al. (2011). Calcineurin splicing variant CnAβ1 improves cardiac function after myocardial infarction without inducing hypertrophy. Circulation, 123, 2838–2847.PubMedGoogle Scholar
  76. 76.
    López-Olañeta, M. M., Villalba, M., Gómez-Salinero, J. M., Jiménez-Borreguero, L. J., Breckenridge, R., Ortiz-Sánchez, P., García-Pavía, P., Ibáñez, B., et al. (2014). Induction of the calcineurin variant CnAβ1 after myocardial infarction reduces post-infarction ventricular remodelling by promoting infarct vascularization. Cardiovascular Research, 102, 396–406.PubMedGoogle Scholar
  77. 77.
    Felkin, L., Lara-Pezzi, E., Hall, J., Birks, E., & Barton, P. (2011). Reverse remodelling and recovery from heart failure are associated with complex patterns of gene expression. Journal of Cardiovascular Translational Research, 4, 321–331.PubMedGoogle Scholar
  78. 78.
    Choudhary, R., Iqbal, N., Khusro, F., Higginbotham, E., Green, E., & Maisel, A. (2013). Heart failure biomarkers. Journal of Cardiovascular Translational Research, 6, 471–484.PubMedGoogle Scholar
  79. 79.
    Vilahur, G., Cubedo, J., Casani, L., Padro, T., Sabate-Tenas, M., Badimon, J. J., & Badimon, L. (2013). Reperfusion-triggered stress protein response in the myocardium is blocked by post-conditioning. Systems biology pathway analysis highlights the key role of the canonical aryl-hydrocarbon receptor pathway. European Heart Journal, 34, 2082–2093.PubMedGoogle Scholar
  80. 80.
    Barth, A., Chakir, K., Kass, D., & Tomaselli, G. (2012). Transcriptome, proteome, and metabolome in dyssynchronous heart failure and CRT. Journal of Cardiovascular Translational Research, 5, 180–187.PubMedGoogle Scholar
  81. 81.
    Bravo, P., & Bengel, F. (2011). The role of cardiac PET in translating basic science into the clinical arena. Journal of Cardiovascular Translational Research, 4, 425–436.PubMedGoogle Scholar
  82. 82.
    Schroeder, M. A., Lau, A. Z., Chen, A. P., Gu, Y., Nagendran, J., Barry, J., Hu, X., Dyck, J. R. B., et al. (2013). Hyperpolarized 13C magnetic resonance reveals early- and late-onset changes to in vivo pyruvate metabolism in the failing heart. European Journal of Heart Failure, 15, 130–140.PubMedCentralPubMedGoogle Scholar
  83. 83.
    Defelice, A., Frering, R., & Horan, P. (1989). Time course of hemodynamic changes in rats with healed severe myocardial infarction. American Journal of Physiology, 257, H289–H296.PubMedGoogle Scholar
  84. 84.
    Ioannidis, J. P. A. (2005). Why most published research findings are false. PLoS Medicine, 2, e124.PubMedCentralPubMedGoogle Scholar
  85. 85.
    Ioannidis, J. P. A. (2008). Why most discovered true associations are inflated. Epidemiology, 19, 640–648. doi:10.1097/EDE.0b1013e31818131e7.PubMedGoogle Scholar
  86. 86.
    Nishida, K., Michael, G., Dobrev, D., & Nattel, S. (2010). Animal models for atrial fibrillation: clinical insights and scientific opportunities. Europace, 12, 160–172.PubMedGoogle Scholar
  87. 87.
    Morgan, S. J., Elangbam, C. S., Berens, S., Janovitz, E., Vitsky, A., Zabka, T., & Conour, L. (2013). Use of animal models of human disease for nonclinical safety assessment of novel pharmaceuticals. Toxicologic Pathology, 41, 508–518.PubMedGoogle Scholar
  88. 88.
    Schreiner, K., Voss, F., Senges, J., Becker, R., Kraft, P., Bauer, A., Kelemen, K., Kuebler, W., et al. (2004). Tridimensional activation patterns of acquired torsade-de-pointes-tachycardias in dogs with chronic AV-block. Basic Research in Cardiology, 99, 288–298.PubMedGoogle Scholar
  89. 89.
    Vrána, M., Fejfar, Z., Netu'sil, M., Blazek, Z., & Trcka, V. (1978). Stimulation threshold studies and the effect of antiarrhythmic drugs. Basic Research in Cardiology, 73, 618–676.PubMedGoogle Scholar
  90. 90.
    Fazekas, T., Scherlag, B., Mabo, P., Patterson, E., & Lazzara, R. (1994). Facilitation of reentry by lidocaine in canine myocardial infarction. Acta Physiologica Hungarica, 82, 201–213.PubMedGoogle Scholar
  91. 91.
    Táborský, M., Heinc, P., & Doupal, V. (2010). Antiarrhythmic agents vs implantable cardioverter-defibrillators in the prevention of sudden cardiac death: finally resolved issue? Kardiologia in Review International Medicine, 12, 26–31.Google Scholar
  92. 92.
    Zbinden, G. (1993). The concept of multispecies testing in industrial toxicology. Regulatory Toxicology and Pharmacology, 17, 85–94.PubMedGoogle Scholar
  93. 93.
    Cohn, J. N., Goldstein, S. O., Greenberg, B. H., Lorell, B. H., Bourge, R. C., Jaski, B. E., Gottlieb, S. O., Mcgrew, F., et al. (1998). A dose-dependent increase in mortality with vesnarinone among patients with severe heart failure. New England Journal of Medicine, 339, 1810–1816.PubMedGoogle Scholar
  94. 94.
    Boulaksil, M., Jungschleger, J. G., Antoons, G., Houtman, M. J. C., De Boer, T. P., Wilders, R., Beekman, J. D., Maessen, J. G., et al. (2011). Drug-induced torsade de pointes arrhythmias in the chronic AV block dog are perpetuated by focal activity. Circulation. Arrhythmia and Electrophysiology, 4, 566–576.PubMedGoogle Scholar
  95. 95.
    Kozhevnikov, D. O., Yamamoto, K., Robotis, D., Restivo, M., & El-Sherif, N. (2002). Electrophysiological mechanism of enhanced susceptibility of hypertrophied heart to acquired torsade de pointes arrhythmias: tridimensional mapping of activation and recovery pattern. Circulation, 105, 1128–1134.PubMedGoogle Scholar
  96. 96.
    Hernandez, R., Mann, D. E., Breckinridge, S., Williams, G. R., & Reiter, M. J. (1989). Effects of flecainide on defibrillation thresholds in the anesthetized dog. Journal of the American College of Cardiology, 14, 777–781.PubMedGoogle Scholar
  97. 97.
    Nicholson, C., Jackman, S., & Wilke, R. (1989). Ability of denbufylline to inhibit cyclic nucleotide phosphodiesterase and its affinity for adenosine receptor and adenosine reuptake site. British Journal of Pharmacology, 97, 889–900.PubMedCentralPubMedGoogle Scholar
  98. 98.
    Desjardins, S., & Cauchy, M. J. (1995). Comparative cardiac effects of milrinone and sodium nitroprusside in rats. Drug and Chemical Toxicology, 18, 43–59.PubMedGoogle Scholar
  99. 99.
    Alousi, A., Canter, J., & Montenaro, M. (1983). Cardiotonic activity of milrinone, a new potent cardiac bipyridine, on the normal and failing heart of experimental animals. Journal of Clinical Pharmacology, 5, 792–803.Google Scholar
  100. 100.
    Lynch, J., Uprichard, A., Frye, J., Driscoll, E., Kitzen, J., & Lucchesi, B. (1989). Effects of the positive inotropic agents milrinone and pimobendan on the development of lethal ischemic arrhythmias in conscious dogs with recent myocardial infarction. Journal of Cardiovascular Pharmacology, 14, 585–597.PubMedGoogle Scholar
  101. 101.
    U.S. Food and Drug Administration (2013). Code of Federal Regulations. Good Laboratory Practice for nonclinical laboratory studies.
  102. 102.
    Commission E (2001). Directive 2001/83/EC of the European Parliament and of the Council on the Community code relating to medicinal products for human use.
  103. 103.
    Abbasalizadeh, S., & Baharvand, H. (2013). Technological progress and challenges towards cGMP manufacturing of human pluripotent stem cells based therapeutic products for allogeneic and autologous cell therapies. Biotechnology Advances, 31, 1600–1623.PubMedGoogle Scholar
  104. 104.
    European Commission (2001). Directive 2001/83 and its annex I on the Community code relating to medicinal products for human use.
  105. 105.
    International Conference on Harmonisation. Harmonized tripartite guideline on preclinical safety evaluation of biotechnology-derived pharmaceuticals S6(R1) (1997)
  106. 106.
    Takahashi, K., Tanabe, K., Ohnuki, M., Narita, M., Ichisaka, T., Tomoda, K., & Yamanaka, S. (2007). Induction of pluripotent stem cells from adult human fibroblasts by defined factors. Cell, 131, 861–872.PubMedGoogle Scholar
  107. 107.
    Burridge, P. W., Keller, G., Gold, J. D., & Wu, J. C. (2012). Production of de novo cardiomyocytes: human pluripotent stem cell differentiation and direct reprogramming. Cell Stem Cell, 10, 16–28.PubMedCentralPubMedGoogle Scholar
  108. 108.
    Matsa, E., Sallam, K., & Wu, J. C. (2014). Cardiac stem cell biology: glimpse of the past, present, and future. Circulation Research, 114, 21–27.PubMedGoogle Scholar
  109. 109.
    Montserrat, N., Bahima, E., Batlle, L., Häfner, S., Rodrigues, A., González, F., & Belmonte, J. (2011). Generation of pig iPS cells: a model for cell therapy. Journal of Cardiovascular Translational Research, 4, 121–130.PubMedGoogle Scholar
  110. 110.
    Mordwinkin, N. M., Lee, A. S., & Wu, J. C. (2013). Patient-specific stem cells and cardiovascular drug discovery. JAMA : The Journal of the American Medical Association, 310, 2039–2040.Google Scholar
  111. 111.
    Mordwinkin, N., Burridge, P., & Wu, J. (2013). A review of human pluripotent stem cell-derived cardiomyocytes for high-throughput drug discovery, cardiotoxicity screening, and publication standards. Journal of Cardiovascular Translational Research, 6, 22–30.PubMedCentralPubMedGoogle Scholar
  112. 112.
    Paul, S. M., Mytelka, D. S., Dunwiddie, C. T., Persinger, C. C., Munos, B. H., Lindborg, S. R., & Schacht, A. L. (2010). How to improve R&D productivity: the pharmaceutical industry's grand challenge. Nature Reviews Drug Discovery, 9, 203–214.PubMedGoogle Scholar
  113. 113.
    Scannell, J. W., Blanckley, A., Boldon, H., & Warrington, B. (2012). Diagnosing the decline in pharmaceutical R&D efficiency. Nature Reviews Drug Discovery, 11, 191–200.PubMedGoogle Scholar
  114. 114.
    Matsa, E., & Denning, C. (2012). In vitro uses of human pluripotent stem cell-derived cardiomyocytes. Journal of Cardiovascular Translational Research, 5, 581–592.PubMedGoogle Scholar
  115. 115.
    Yazawa, M., & Dolmetsch, R. (2013). Modeling Timothy syndrome with iPS cells. Journal of Cardiovascular Translational Research, 6, 1–9.PubMedCentralPubMedGoogle Scholar
  116. 116.
    Moretti, A., Bellin, M., Welling, A., Jung, C. B., Lam, J. T., Bott-Flugel, L., Dorn, T., Goedel, A., et al. (2010). Patient-specific induced pluripotent stem-cell models for long-QT syndrome. New England Journal of Medicine, 363, 1397–1409.PubMedGoogle Scholar
  117. 117.
    Wang, Y., Liang, P., Lan, F., Wu, H., Lisowski, L., Gu, M., Hu, S., Kay, M. A. et al. (2014). Genome editing of isogenic human induced pluripotent stem cells recapitulates long QT phenotype for drug testing. Journal of the American College of Cardiology.Google Scholar
  118. 118.
    Sun, N., Yazawa, M., Liu, J., Han, L., Sanchez-Freire, V., Abilez, O. J., Navarrete, E. G., Hu, S., et al. (2012). Patient-specific induced pluripotent stem cells as a model for familial dilated cardiomyopathy. Science Translational Medicine, 4, 130ra147.Google Scholar
  119. 119.
    Lan, F., Lee, A. S., Liang, P., Sanchez-Freire, V., Nguyen, P. K., Wang, L., Han, L., Yen, M., et al. (2013). Abnormal calcium handling properties underlie familial hypertrophic cardiomyopathy pathology in patient-specific induced pluripotent stem cells. Cell Stem Cell, 12, 101–113.PubMedCentralPubMedGoogle Scholar
  120. 120.
    Carvajal-Vergara, X., Sevilla, A., D'souza, S. L., Ang, Y. S., Schaniel, C., Lee, D. F., Yang, L., Kaplan, A. D., et al. (2010). Patient-specific induced pluripotent stem-cell-derived models of LEOPARD syndrome. Nature, 465, 808–812.PubMedCentralPubMedGoogle Scholar
  121. 121.
    Matsa, E., Burridge, P. W., & Wu, J. C. (2014). Human stem cells for modeling heart disease and for drug discovery. Science Translational Medicine, 6, 239ps236.Google Scholar
  122. 122.
    Glasziou, P., Altman, D. G., Bossuyt, P., Boutron, I., Clarke, M., Julious, S., Michie, S., Moher, D., et al. (2014). Reducing waste from incomplete or unusable reports of biomedical research. Lancet, 383, 267–276.PubMedGoogle Scholar
  123. 123.
    Kilkenny, C., Browne, W. J., Cuthill, I. C., Emerson, M., & Altman, D. G. (2010). Improving bioscience research reporting: the ARRIVE guidelines for reporting animal research. PLoS Biology, 8, e1000412.PubMedCentralPubMedGoogle Scholar
  124. 124.
    Simera, I., Moher, D., Hoey, J., Schulz, K. F., & Altman, D. G. (2010). A catalogue of reporting guidelines for health research. European Journal of Clinical Investigation, 40, 35–53.PubMedGoogle Scholar

Copyright information

© Springer Science+Business Media New York 2015

Authors and Affiliations

  • Enrique Lara-Pezzi
    • 1
  • Philippe Menasché
    • 2
  • Jean-Hugues Trouvin
    • 3
    • 4
  • Lina Badimón
    • 5
  • John P. A. Ioannidis
    • 6
  • Joseph C. Wu
    • 7
  • Joseph A. Hill
    • 8
    • 14
  • Walter J. Koch
    • 9
  • Albert F. De Felice
    • 10
  • Peter de Waele
    • 11
  • Valérie Steenwinckel
    • 11
  • Roger J. Hajjar
    • 12
  • Andreas M. Zeiher
    • 13
  1. 1.Cardiovascular Development and Repair DepartmentCentro Nacional de Investigaciones Cardiovasculares (CNIC)MadridSpain
  2. 2.Assistance Publique-Hôpitaux de ParisHôpital Européen Georges Pompidou Department of Cardiovascular SurgeryParisFrance
  3. 3.School of Pharmacy, Department on Health Security and Public HealthUniversity Paris Sorbonne CitéParisFrance
  4. 4.Committee for Advanced Therapies, European Medicines AgencyLondonUK
  5. 5.Cardiovascular Research Center (CSIC-ICCC)Hospital de la Santa Creu i Sant-Pau (IIB-Sant Pau)BarcelonaSpain
  6. 6.Stanford Prevention Research Center, Department of Medicine and Division of Epidemiology, Department of Health Research and PolicyStanford UniversityStanfordUSA
  7. 7.Stanford Cardiovascular Institute, School of MedicineStanford UniversityStanfordUSA
  8. 8.Department of Internal Medicine (Cardiology)University of Texas Southwestern Medical CenterDallasUSA
  9. 9.Department of Pharmacology, Center for Translational MedicineTemple UniversityPhiladelphiaUSA
  10. 10.Division of Cardiovascular Drug ProductsUS Food and Drug AdministrationSilver SpringUSA
  11. 11.Cardio3 BioSciences S.A.Mont-Saint-GuibertFrance
  12. 12.Cardiovascular Research Center, Department of CardiologyMount Sinai School of MedicineNew YorkUSA
  13. 13.Department of Cardiology, Internal Medicine IIIJ. W. Goethe University Hospital FrankfurtFrankfurt am MainGermany
  14. 14.Department of Molecular BiologyUniversity of Texas Southwestern Medical CenterDallasUSA

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