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Abstract

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.

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Abbreviations

ACE:

Angiotensin-converting enzyme

ADME:

Absorption, distribution, metabolism, excretion

API:

Active pharmacological product

ARB:

Angiotensin II receptor blocker

ATMP:

Advanced therapy medicinal products

AUC:

Area under the curve

CAD:

Coronary artery disease

CRISPR:

Clustered regularly interspaced short palindromic repeats

DCM:

Dilated cardiomyopathy

EMA:

European Medicines Agency

FDA:

Food and Drug Administration

GLP:

Good laboratory practice

GMP:

Good manufacturing practice

HF:

Heart failure

HFpEF:

Heart failure with preserved ejection fraction

INDs:

Investigational new drugs

LAD:

Left anterior descending

LV:

Left ventricle

MA:

Market authorization

MI:

Myocardial infarction

NOAEL:

No observed adverse effect level

PCI:

Percutaneous coronary intervention

PD:

Pharmacodynamic

PDE:

Phosphodiesterase

PES:

Programmed electrical stimulation

POC:

Proof of concept

SOC:

Standard of care

TAC:

Transverse aortic constriction

References

  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.

    PubMed  Google Scholar 

  2. Krum, H., & Abraham, W. T. (2009). Heart failure. Lancet, 373, 941–955.

    PubMed  Google Scholar 

  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.

    CAS  PubMed  Google Scholar 

  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.

    PubMed  Google Scholar 

  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.

    PubMed  Google Scholar 

  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.

    PubMed  Google Scholar 

  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.

    CAS  PubMed  Google Scholar 

  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.

    CAS  PubMed  Google Scholar 

  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.

    PubMed  Google Scholar 

  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.

    PubMed  Google Scholar 

  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.

    PubMed  Google Scholar 

  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.

    PubMed  Google Scholar 

  13. Sharma, K., & Kass, D. A. (2014). Heart failure with preserved ejection fraction: mechanisms, clinical features, and therapies. Circulation Research, 115, 79–96.

    CAS  PubMed  Google Scholar 

  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.

    PubMed Central  PubMed  Google Scholar 

  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. Breckenridge, R. (2010). Heart failure and mouse models. Disease Models & Mechanisms, 3, 138–143.

    Google Scholar 

  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.

    CAS  PubMed  Google Scholar 

  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.

    PubMed Central  CAS  PubMed  Google Scholar 

  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.

    PubMed Central  PubMed  Google Scholar 

  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.

    PubMed Central  CAS  PubMed  Google Scholar 

  21. Vander Heide, R. S., & Steenbergen, C. (2013). Cardioprotection and myocardial reperfusion: pitfalls to clinical application. Circulation Research, 113, 464–477.

    CAS  PubMed  Google Scholar 

  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.

    PubMed Central  CAS  PubMed  Google Scholar 

  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.

    PubMed Central  CAS  PubMed  Google Scholar 

  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.

    CAS  PubMed  Google Scholar 

  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.

    CAS  PubMed  Google Scholar 

  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.

    CAS  PubMed  Google Scholar 

  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.

    CAS  PubMed  Google Scholar 

  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.

    CAS  PubMed  Google Scholar 

  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.

    CAS  PubMed  Google Scholar 

  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. 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.

    CAS  PubMed  Google Scholar 

  32. Bers, D. M. (2008). Calcium cycling and signaling in cardiac myocytes. Annual Review of Physiology, 70, 23–49.

    CAS  PubMed  Google Scholar 

  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.

    PubMed Central  CAS  PubMed  Google Scholar 

  34. Bank, A., Gage, R., & Burns, K. (2012). Right ventricular pacing, mechanical dyssynchrony, and heart failure. Journal of Cardiovascular Translational Research, 5, 219–231.

    PubMed  Google Scholar 

  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.

    PubMed Central  CAS  PubMed  Google Scholar 

  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.

    PubMed  Google Scholar 

  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.

    PubMed Central  CAS  PubMed  Google Scholar 

  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.

    PubMed Central  CAS  PubMed  Google Scholar 

  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.

    CAS  PubMed  Google Scholar 

  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.

    CAS  PubMed  Google Scholar 

  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.

    CAS  PubMed  Google Scholar 

  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.

    CAS  PubMed  Google Scholar 

  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.

    CAS  PubMed  Google Scholar 

  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.

    PubMed  Google Scholar 

  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.

    PubMed  Google Scholar 

  46. Hood, L., & Tian, Q. (2012). Systems approaches to biology and disease enable translational systems medicine. Genomics, Proteomics & Bioinformatics, 10, 181–185.

    CAS  Google Scholar 

  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.

    PubMed Central  CAS  PubMed  Google Scholar 

  48. Leinwand, L. A. (2003). Sex is a potent modifier of the cardiovascular system. Journal of Clinical Investigation, 112, 302–307.

    PubMed Central  CAS  PubMed  Google Scholar 

  49. Council NR (2001). Guide for care and use of laboratory animals 8th Edition.

  50. U.S. Food and Drug Administration (2010). General considerations for animal studies for cardiovascular devices. http://www.fda.gov/medicaldevices/deviceregulationandguidance/guidancedocuments/ucm220760.htm.

  51. Peterson, E., Augenstein, J., Tanis, D., & Augenstein, D. (1981). Noise raises blood pressure without impairing auditory sensitivity. Science, 211, 1450–1452.

    CAS  PubMed  Google Scholar 

  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.

  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.

    PubMed Central  CAS  PubMed  Google Scholar 

  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.

    PubMed Central  CAS  PubMed  Google Scholar 

  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.

    PubMed  Google Scholar 

  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.

    CAS  PubMed  Google Scholar 

  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.

    CAS  PubMed  Google Scholar 

  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.

    PubMed  Google Scholar 

  59. Reagan-Shaw, S., Nihal, M., & Ahmad, N. (2008). Dose translation from animal to human studies revisited. FASEB Journal, 22, 659–661.

    CAS  PubMed  Google Scholar 

  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.

    PubMed Central  CAS  PubMed  Google Scholar 

  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.

    PubMed  Google Scholar 

  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.

    CAS  PubMed  Google Scholar 

  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.

    PubMed  Google Scholar 

  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.

    PubMed Central  PubMed  Google Scholar 

  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.

    CAS  PubMed  Google Scholar 

  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. 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.

    PubMed  Google Scholar 

  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.

    PubMed Central  PubMed  Google Scholar 

  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.

    PubMed Central  CAS  PubMed  Google Scholar 

  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.

    PubMed  Google Scholar 

  71. Enriquez-Sarano, M., Akins, C. W., & Vahanian, A. (2009). Mitral regurgitation. Lancet, 373, 1382–1394.

    PubMed  Google Scholar 

  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.

    CAS  PubMed  Google Scholar 

  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.

    PubMed Central  PubMed  Google Scholar 

  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.

    PubMed  Google Scholar 

  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.

    CAS  PubMed  Google Scholar 

  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.

    PubMed  Google Scholar 

  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.

    PubMed  Google Scholar 

  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.

    PubMed  Google Scholar 

  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.

    CAS  PubMed  Google Scholar 

  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.

    PubMed  Google Scholar 

  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.

    PubMed  Google Scholar 

  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.

    PubMed Central  CAS  PubMed  Google Scholar 

  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.

    CAS  PubMed  Google Scholar 

  84. Ioannidis, J. P. A. (2005). Why most published research findings are false. PLoS Medicine, 2, e124.

    PubMed Central  PubMed  Google Scholar 

  85. Ioannidis, J. P. A. (2008). Why most discovered true associations are inflated. Epidemiology, 19, 640–648. doi:10.1097/EDE.0b1013e31818131e7.

    PubMed  Google Scholar 

  86. Nishida, K., Michael, G., Dobrev, D., & Nattel, S. (2010). Animal models for atrial fibrillation: clinical insights and scientific opportunities. Europace, 12, 160–172.

    PubMed  Google Scholar 

  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.

    PubMed  Google Scholar 

  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.

    PubMed  Google Scholar 

  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.

    PubMed  Google Scholar 

  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.

    CAS  PubMed  Google Scholar 

  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. Zbinden, G. (1993). The concept of multispecies testing in industrial toxicology. Regulatory Toxicology and Pharmacology, 17, 85–94.

    CAS  PubMed  Google Scholar 

  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.

    CAS  PubMed  Google Scholar 

  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.

    CAS  PubMed  Google Scholar 

  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.

    PubMed  Google Scholar 

  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.

    CAS  PubMed  Google Scholar 

  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.

    PubMed Central  CAS  PubMed  Google Scholar 

  98. Desjardins, S., & Cauchy, M. J. (1995). Comparative cardiac effects of milrinone and sodium nitroprusside in rats. Drug and Chemical Toxicology, 18, 43–59.

    CAS  PubMed  Google Scholar 

  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.

    CAS  Google Scholar 

  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.

    CAS  PubMed  Google Scholar 

  101. U.S. Food and Drug Administration (2013). Code of Federal Regulations. Good Laboratory Practice for nonclinical laboratory studies. http://www.accessdata.fda.gov/scripts/cdrh/cfdocs/cfcfr/CFRSearch.cfm?CFRPart=58&showFR=1.

  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. http://ec.europa.eu/health/files/eudralex/vol-1/dir_2001_83_cons/dir2001_83_cons_20081230_en.pdf.

  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.

    CAS  PubMed  Google Scholar 

  104. European Commission (2001). Directive 2001/83 and its annex I on the Community code relating to medicinal products for human use. http://ec.europa.eu/health/files/eudralex/vol-1/dir_2001_83_cons/dir2001_83_cons_20081230_en.pdf.

  105. International Conference on Harmonisation. Harmonized tripartite guideline on preclinical safety evaluation of biotechnology-derived pharmaceuticals S6(R1) (1997) http://www.ich.org/fileadmin/Public_Web_Site/ICH_Products/Guidelines/Safety/S6_R1/Step4/S6_R1_Guideline.pdf.

  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.

    CAS  PubMed  Google Scholar 

  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.

    PubMed Central  CAS  PubMed  Google Scholar 

  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.

    CAS  PubMed  Google Scholar 

  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.

    PubMed  Google Scholar 

  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.

    CAS  Google Scholar 

  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.

    PubMed Central  PubMed  Google Scholar 

  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.

    CAS  PubMed  Google Scholar 

  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.

    CAS  PubMed  Google Scholar 

  114. Matsa, E., & Denning, C. (2012). In vitro uses of human pluripotent stem cell-derived cardiomyocytes. Journal of Cardiovascular Translational Research, 5, 581–592.

    PubMed  Google Scholar 

  115. Yazawa, M., & Dolmetsch, R. (2013). Modeling Timothy syndrome with iPS cells. Journal of Cardiovascular Translational Research, 6, 1–9.

    PubMed Central  PubMed  Google Scholar 

  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.

    CAS  PubMed  Google Scholar 

  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.

  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. 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.

    PubMed Central  CAS  PubMed  Google Scholar 

  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.

    PubMed Central  CAS  PubMed  Google Scholar 

  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. 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.

    PubMed  Google Scholar 

  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.

    PubMed Central  PubMed  Google Scholar 

  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.

    CAS  PubMed  Google Scholar 

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Acknowledgments

We are grateful to María Villalba Orero (CNIC, Madrid, Spain) for critical reading of the manuscript.

Sources of Funding

E.L.-P. was supported by grants from the European Union’s FP7 (CardioNeT-ITN-289600, CardioNext-ITN-608027), from the Spanish Ministry of Economy (SAF2012-31451), and from the Regional Government of Madrid (2010-BMD-2321 “Fibroteam”). The CNIC is supported by the Spanish Ministry of Economy and by the Pro-CNIC Foundation. J.A.H. was supported by grants from NIH (HL-120732; HL100401), AHA (14SFRN20740000), CPRIT (RP110486P3), and the Leducq Foundation (11CVD04). LB is supported by MINECO-SAF 2013-42962R, Instituto Carlos III (TERCEL-RD-12/00190026 and RIC12/00420024), and FP7-IMI-JU-SAFET-115003 by from the European Union.

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The authors have no conflict of interest.

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Correspondence to Enrique Lara-Pezzi.

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Associate Editor Lorrie Kirshenbaum oversaw the review of this article

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Lara-Pezzi, E., Menasché, P., Trouvin, JH. et al. Guidelines for Translational Research in Heart Failure. J. of Cardiovasc. Trans. Res. 8, 3–22 (2015). https://doi.org/10.1007/s12265-015-9606-8

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