1. Tomaselli, G. F., Beuckelmann, D. J., Calkins, H. G., Berger, R. D., Kessler, P. D., Lawrence, J. H., Kass, D., Feldman, A. M., and Marban, E. (1994) Sudden cardiac death in heart failure. The role of abnormal repolarization. Circulation 90, 2534-2539
2. Avery, C. L., Loehr, L. R., Baggett, C., Chang, P. P., Kucharska-Newton, A. M., Matsushita, K., Rosamond, W. D., and Heiss, G. (2012) The population burden of heart failure attributable to modifiable risk factors: the ARIC (Atherosclerosis Risk in Communities) study. J Am Coll Cardiol 60, 1640-1646
3. Mozaffarian, D., Benjamin, E. J., Go, A. S., Arnett, D. K., Blaha, M. J., Cushman, M., Das, S. R., de Ferranti, S., Despres, J. P., Fullerton, H. J., Howard, V. J., Huffman, M. D., Isasi, C. R., Jimenez, M. C., Judd, S. E., Kissela, B. M., Lichtman, J. H., Lisabeth, L. D., Liu, S., Mackey, R. H., Magid, D. J., McGuire, D. K., Mohler, E. R., 3rd, Moy, C. S., Muntner, P., Mussolino, M. E., Nasir, K., Neumar, R. W., Nichol, G., Palaniappan, L., Pandey, D. K., Reeves, M. J., Rodriguez, C. J., Rosamond, W., Sorlie, P. D., Stein, J., Towfighi, A., Turan, T. N., Virani, S. S., Woo, D., Yeh, R. W., Turner, M. B., American Heart Association Statistics, C., and Stroke Statistics, S. (2016) Heart Disease and Stroke Statistics-2016 Update: A Report From the American Heart Association. Circulation 133, e38-360
4. Collaborators, G. B. D. C. o. D. (2018) Global, regional, and national age-sex-specific mortality for 282 causes of death in 195 countries and territories, 1980-2017: a systematic analysis for the Global Burden of Disease Study 2017. Lancet 392, 1736-1788
5. Jones, N. R., Roalfe, A. K., Adoki, I., Hobbs, F. D. R., and Taylor, C. J. (2019) Survival of patients with chronic heart failure in the community: a systematic review and meta- analysis. Eur J Heart Fail 21, 1306-1325
6. Virani, S. S., Alonso, A., Aparicio, H. J., Benjamin, E. J., Bittencourt, M. S., Callaway, C. W., Carson, A. P., Chamberlain, A. M., Cheng, S., Delling, F. N., Elkind, M. S. V., Evenson, K. R., Ferguson, J. F., Gupta, D. K., Khan, S. S., Kissela, B. M., Knutson, K. L., Lee, C. D., Lewis, T. T., Liu, J., Loop, M. S., Lutsey, P. L., Ma, J., Mackey, J., Martin, S. S., Matchar, D. B., Mussolino, M. E., Navaneethan, S. D., Perak, A. M., Roth, G. A., Samad, Z., Satou, G. M., Schroeder, E. B., Shah, S. H., Shay, C. M., Stokes, A., VanWagner, L. B., Wang, N. Y., Tsao, C. W., American Heart Association Council on, E., Prevention Statistics, C., and Stroke Statistics, S. (2021) Heart Disease and Stroke Statistics-2021 Update: A Report From the American Heart Association. Circulation 143, e254-e743
7. Okura, Y., Ramadan, M. M., Ohno, Y., Mitsuma, W., Tanaka, K., Ito, M., Suzuki, K., Tanabe, N., Kodama, M., and Aizawa, Y. (2008) Impending epidemic: future projection of heart failure in Japan to the year 2055. Circ J 72, 489-491
8. Conrad, N., Judge, A., Tran, J., Mohseni, H., Hedgecott, D., Crespillo, A. P., Allison, M., Hemingway, H., Cleland, J. G., McMurray, J. J. V., and Rahimi, K. (2018) Temporal trends and patterns in heart failure incidence: a population-based study of 4 million individuals. Lancet 391, 572-580
9. Groenewegen, A., Rutten, F. H., Mosterd, A., and Hoes, A. W. (2020) Epidemiology of heart failure. Eur J Heart Fail 22, 1342-1356
10. Dunlay, S. M., Weston, S. A., Jacobsen, S. J., and Roger, V. L. (2009) Risk factors for heart failure: a population-based case-control study. Am J Med 122, 1023-1028
11. Johns, E. J., Kopp, U. C., and DiBona, G. F. (2011) Neural control of renal function. Compr Physiol 1, 731-767
12. Bouhnik, J., Galen, F. X., Menard, J., Corvol, P., Seyer, R., Fehrentz, J. A., Nguyen, D. L., Fulcrand, P., and Castro, B. (1987) Production and characterization of human renin antibodies with region-oriented synthetic peptides. J Biol Chem 262, 2913-2918
13. Drenjancevic-Peric, I., Jelakovic, B., Lombard, J. H., Kunert, M. P., Kibel, A., and Gros, M. (2011) High-salt diet and hypertension: focus on the renin-angiotensin system. Kidney Blood Press Res 34, 1-11
14. Verdecchia, P., Angeli, F., Mazzotta, G., Gentile, G., and Reboldi, G. (2008) The renin angiotensin system in the development of cardiovascular disease: role of aliskiren in risk reduction. Vasc Health Risk Manag 4, 971-981
15. Crisan, D., and Carr, J. (2000) Angiotensin I-converting enzyme: genotype and disease associations. J Mol Diagn 2, 105-115
16. Bernstein, K. E., Gonzalez-Villalobos, R. A., Giani, J. F., Shah, K., Bernstein, E., Janjulia, T., Koronyo, Y., Shi, P. D., Koronyo-Hamaoui, M., Fuchs, S., and Shen, X. Z. (2014) Angiotensin-converting enzyme overexpression in myelocytes enhances the immune response. Biol Chem 395, 1173-1178
17. Patel, S., Rauf, A., Khan, H., and Abu-Izneid, T. (2017) Renin-angiotensin-aldosterone (RAAS): The ubiquitous system for homeostasis and pathologies. Biomed Pharmacother 94, 317-325
18. Matsumoto, R., Yoshiyama, M., Omura, T., Kim, S., Nakamura, Y., Izumi, Y., Akioka, K., Iwao, H., Takeuchi, K., and Yoshikawa, J. (2004) Effects of aldosterone receptor antagonist and angiotensin II type I receptor blocker on cardiac transcriptional factors and mRNA expression in rats with myocardial infarction. Circ J 68, 376-382
19. Pourdjabbar, A., Parker, T. G., Nguyen, Q. T., Desjardins, J. F., Lapointe, N., Tsoporis, J. N., and Rouleau, J. L. (2005) Effects of pre-, peri-, and postmyocardial infarction treatment with losartan in rats: effect of dose on survival, ventricular arrhythmias, function, and remodeling. Am J Physiol Heart Circ Physiol 288, H1997-2005
20. Mann, D. L., and Bristow, M. R. (2005) Mechanisms and models in heart failure: the biomechanical model and beyond. Circulation 111, 2837-2849
21. Schrier, R. W., and Abraham, W. T. (1999) Hormones and hemodynamics in heart failure. N Engl J Med 341, 577-585
22. Cohn, J. N., Tognoni, G., and Valsartan Heart Failure Trial, I. (2001) A randomized trial of the angiotensin-receptor blocker valsartan in chronic heart failure. N Engl J Med 345, 1667-1675
23. Group, T. C. T. S. (1987) Effects of enalapril on mortality in severe congestive heart failure. Results of the Cooperative North Scandinavian Enalapril Survival Study (CONSENSUS). N Engl J Med 316, 1429-1435
24. Pfeffer, M. A., Braunwald, E., Moye, L. A., Basta, L., Brown, E. J., Jr., Cuddy, T. E., Davis, B. R., Geltman, E. M., Goldman, S., Flaker, G. C., and et al. (1992) Effect of captopril on mortality and morbidity in patients with left ventricular dysfunction after myocardial infarction. Results of the survival and ventricular enlargement trial. The SAVE Investigators. N Engl J Med 327, 669-677
25. Pfeffer, M. A., Swedberg, K., Granger, C. B., Held, P., McMurray, J. J., Michelson, E. L., Olofsson, B., Ostergren, J., Yusuf, S., Pocock, S., Investigators, C., and Committees. (2003) Effects of candesartan on mortality and morbidity in patients with chronic heart failure: the CHARM-Overall programme. Lancet 362, 759-766
26. Ferrario, C. M. (2010) Addressing the theoretical and clinical advantages of combination therapy with inhibitors of the renin-angiotensin-aldosterone system: antihypertensive effects and benefits beyond BP control. Life Sci 86, 289-299
27. Fisher, N. D., and Hollenberg, N. K. (2005) Renin inhibition: what are the therapeutic opportunities? J Am Soc Nephrol 16, 592-599
28. Stanton, A. (2003) Potential of renin inhibition in cardiovascular disease. J Renin Angiotensin Aldosterone Syst 4, 6-10
29. Gross, F., Lazar, J., and Orth, H. (1972) Inhibition of the renin-angiotensinogen reaction by pepstatin. Science 175, 656
30. Sielecki, A. R., Hayakawa, K., Fujinaga, M., Murphy, M. E., Fraser, M., Muir, A. K., Carilli, C. T., Lewicki, J. A., Baxter, J. D., and James, M. N. (1989) Structure of recombinant human renin, a target for cardiovascular-active drugs, at 2.5 A resolution. Science 243, 1346-1351
31. Ramya, K., Suresh, R., Kumar, H. Y., Kumar, B. R. P., and Murthy, N. B. S. (2020) Decades-old renin inhibitors are still struggling to find a niche in antihypertensive therapy. A fleeting look at the old and the promising new molecules. Bioorg Med Chem 28, 115466
32. Vaidyanathan, S., Jarugula, V., Dieterich, H. A., Howard, D., and Dole, W. P. (2008) Clinical pharmacokinetics and pharmacodynamics of aliskiren. Clin Pharmacokinet 47, 515-531
33. Imaeda, Y., Tokuhara, H., Fukase, Y., Kanagawa, R., Kajimoto, Y., Kusumoto, K., Kondo, M., Snell, G., Behnke, C. A., and Kuroita, T. (2016) Discovery of TAK-272: A Novel, Potent, and Orally Active Renin Inhibitor. ACS Med Chem Lett 7, 933-938
34. Matsuno, K., Kuroda, S., Tanaka, S., Nakamichi, H., Kagawa, T., and Koumura, E. (2018) Pharmacokinetics, Pharmacodynamics and Safety of a Single Dose of Imarikiren, a Novel Renin Inhibitor, in Healthy Male Subjects. Basic Clin Pharmacol Toxicol 123, 607-614
35. Ito, S., Kagawa, T., Saiki, T., Shimizu, K., Kuroda, S., Sano, Y., and Umeda, Y. (2019) Efficacy and Safety of Imarikiren in Patients with Type 2 Diabetes and Microalbuminuria: A Randomized, Controlled Trial. Clin J Am Soc Nephrol 14, 354-363
36. Silva, K. A. S., and Emter, C. A. (2020) Large Animal Models of Heart Failure: A Translational Bridge to Clinical Success. JACC Basic Transl Sci 5, 840-856
37. Riehle, C., and Bauersachs, J. (2019) Small animal models of heart failure. Cardiovasc Res 115, 1838-1849
38. Balakumar, P., Singh, A. P., and Singh, M. (2007) Rodent models of heart failure. J Pharmacol Toxicol Methods 56, 1-10
39. Pfeffer, M. A., Pfeffer, J. M., Fishbein, M. C., Fletcher, P. J., Spadaro, J., Kloner, R. A., and Braunwald, E. (1979) Myocardial infarct size and ventricular function in rats. Circ Res 44, 503-512
40. Francis, J., Weiss, R. M., Wei, S. G., Johnson, A. K., and Felder, R. B. (2001) Progression of heart failure after myocardial infarction in the rat. Am J Physiol Regul Integr Comp Physiol 281, R1734-1745
41. Bayat, H., Swaney, J. S., Ander, A. N., Dalton, N., Kennedy, B. P., Hammond, H. K., and Roth, D. M. (2002) Progressive heart failure after myocardial infarction in mice. Basic Res Cardiol 97, 206-213
42. Lutgens, E., Daemen, M. J., de Muinck, E. D., Debets, J., Leenders, P., and Smits, J. F. (1999) Chronic myocardial infarction in the mouse: cardiac structural and functional changes. Cardiovasc Res 41, 586-593
43. Monnet, E., and Chachques, J. C. (2005) Animal models of heart failure: what is new? Ann Thorac Surg 79, 1445-1453
44. Abbate, A., Scarpa, S., Santini, D., Palleiro, J., Vasaturo, F., Miller, J., Morales, C., Vetrovec, G. W., and Baldi, A. (2006) Myocardial expression of survivin, an apoptosis inhibitor, in aging and heart failure. An experimental study in the spontaneously hypertensive rat. Int J Cardiol 111, 371-376
45. Sicard, P., Oudot, A., Guilland, J. C., Moreau, D., Vergely, C., and Rochette, L. (2006) Dissociation between vascular oxidative stress and cardiovascular function in Wistar Kyoto and spontaneously hypertensive rats. Vascul Pharmacol 45, 112-121
46. Fukamizu, A., Sugimura, K., Takimoto, E., Sugiyama, F., Seo, M. S., Takahashi, S., Hatae, T., Kajiwara, N., Yagami, K., and Murakami, K. (1993) Chimeric renin-angiotensin system demonstrates sustained increase in blood pressure of transgenic mice carrying both human renin and human angiotensinogen genes. J Biol Chem 268, 11617-11621
47. Cho, M. C., Rapacciuolo, A., Koch, W. J., Kobayashi, Y., Jones, L. R., and Rockman, H. A. (1999) Defective beta-adrenergic receptor signaling precedes the development of dilated cardiomyopathy in transgenic mice with calsequestrin overexpression. J Biol Chem 274, 22251-22256
48. Jones, L. R., Suzuki, Y. J., Wang, W., Kobayashi, Y. M., Ramesh, V., Franzini-Armstrong, C., Cleemann, L., and Morad, M. (1998) Regulation of Ca2+ signaling in transgenic mouse cardiac myocytes overexpressing calsequestrin. J Clin Invest 101, 1385-1393
49. Kaneko, M., Satomi, T., Fujiwara, S., Uchiyama, H., Kusumoto, K., and Nishimoto, T. (2016) AT1 receptor blocker azilsartan medoxomil normalizes plasma miR-146a and miR- 342-3p in a murine heart failure model. Biomarkers, 1-8
50. Harding, V. B., Jones, L. R., Lefkowitz, R. J., Koch, W. J., and Rockman, H. A. (2001) Cardiac beta ARK1 inhibition prolongs survival and augments beta blocker therapy in a mouse model of severe heart failure. Proc Natl Acad Sci U S A 98, 5809-5814
51. Rashikh, A., Ahmad, S. J., Pillai, K. K., Kohli, K., and Najmi, A. K. (2012) Aliskiren attenuates myocardial apoptosis and oxidative stress in chronic murine model of cardiomyopathy. Biomed Pharmacother 66, 138-143
52. Weng, L. Q., Zhang, W. B., Ye, Y., Yin, P. P., Yuan, J., Wang, X. X., Kang, L., Jiang, S. S., You, J. Y., Wu, J., Gong, H., Ge, J. B., and Zou, Y. Z. (2014) Aliskiren ameliorates pressure overload-induced heart hypertrophy and fibrosis in mice. Acta Pharmacol Sin 35, 1005- 1014
53. Westermann, D., Riad, A., Lettau, O., Roks, A., Savvatis, K., Becher, P. M., Escher, F., Jan Danser, A. H., Schultheiss, H. P., and Tschope, C. (2008) Renin inhibition improves cardiac function and remodeling after myocardial infarction independent of blood pressure. Hypertension 52, 1068-1075
54. McMurray, J. J., Pitt, B., Latini, R., Maggioni, A. P., Solomon, S. D., Keefe, D. L., Ford, J., Verma, A., Lewsey, J., and Aliskiren Observation of Heart Failure Treatment, I. (2008) Effects of the oral direct renin inhibitor aliskiren in patients with symptomatic heart failure. Circ Heart Fail 1, 17-24
55. McMurray, J. J., Krum, H., Abraham, W. T., Dickstein, K., Kober, L. V., Desai, A. S., Solomon, S. D., Greenlaw, N., Ali, M. A., Chiang, Y., Shao, Q., Tarnesby, G., Massie, B. M., and Investigators, A. C. (2016) Aliskiren, Enalapril, or Aliskiren and Enalapril in Heart Failure. N Engl J Med 374, 1521-1532
56. Gunther, S., Baba, H. A., Hauptmann, S., Holzhausen, H. J., Grossmann, C., Punkt, K., Kusche, T., Jones, L. R., Gergs, U., and Neumann, J. (2010) Losartan reduces mortality in a genetic model of heart failure. Naunyn Schmiedebergs Arch Pharmacol 382, 265-278
57. Pilz, B., Shagdarsuren, E., Wellner, M., Fiebeler, A., Dechend, R., Gratze, P., Meiners, S., Feldman, D. L., Webb, R. L., Garrelds, I. M., Jan Danser, A. H., Luft, F. C., and Muller, D. N. (2005) Aliskiren, a human renin inhibitor, ameliorates cardiac and renal damage in double-transgenic rats. Hypertension 46, 569-576
58. Wong, P. C., Price, W. A., Jr., Chiu, A. T., Carini, D. J., Duncia, J. V., Johnson, A. L., Wexler, R. R., and Timmermans, P. B. (1990) Nonpeptide angiotensin II receptor antagonists. Studies with EXP9270 and DuP 753. Hypertension 15, 823-834
59. Christen, Y., Waeber, B., Nussberger, J., Porchet, M., Borland, R. M., Lee, R. J., Maggon, K., Shum, L., Timmermans, P. B., and Brunner, H. R. (1991) Oral administration of DuP 753, a specific angiotensin II receptor antagonist, to normal male volunteers. Inhibition of pressor response to exogenous angiotensin I and II. Circulation 83, 1333-1342
60. Dobaczewski, M., Chen, W., and Frangogiannis, N. G. (2011) Transforming growth factor (TGF)-beta signaling in cardiac remodeling. J Mol Cell Cardiol 51, 600-606
61. Li, J., Philip, J. L., Xu, X., Theccanat, T., Abdur Razzaque, M., and Akhter, S. A. (2014) beta-Arrestins regulate human cardiac fibroblast transformation and collagen synthesis in adverse ventricular remodeling. J Mol Cell Cardiol 76, 73-83
62. Annes, J. P., Munger, J. S., and Rifkin, D. B. (2003) Making sense of latent TGFbeta activation. J Cell Sci 116, 217-224
63. Akki, A., Zhang, M., Murdoch, C., Brewer, A., and Shah, A. M. (2009) NADPH oxidase signaling and cardiac myocyte function. J Mol Cell Cardiol 47, 15-22
64. Ago, T., Kuroda, J., Pain, J., Fu, C., Li, H., and Sadoshima, J. (2010) Upregulation of Nox4 by hypertrophic stimuli promotes apoptosis and mitochondrial dysfunction in cardiac myocytes. Circ Res 106, 1253-1264
65. Seshiah, P. N. (2002) Angiotensin II Stimulation of NAD(P)H Oxidase Activity: Upstream Mediators. Circ Res 91, 406-413
66. Bai, F., Pang, X. F., Zhang, L. H., Wang, N. P., McKallip, R. J., Garner, R. E., and Zhao, Z. Q. (2016) Angiotensin II AT1 receptor alters ACE2 activity, eNOS expression and CD44-hyaluronan interaction in rats with hypertension and myocardial fibrosis. Life Sci 153, 141-152
67. Zhuo, J. L., Mendelsohn, F. A., and Ohishi, M. (2002) Perindopril alters vascular angiotensin-converting enzyme, AT(1) receptor, and nitric oxide synthase expression in patients with coronary heart disease. Hypertension 39, 634-638
68. Jones, S. P., Greer, J. J., van Haperen, R., Duncker, D. J., de Crom, R., and Lefer, D. J. (2003) Endothelial nitric oxide synthase overexpression attenuates congestive heart failure in mice. Proc Natl Acad Sci U S A 100, 4891-4896
69. Buczko, W., and Hermanowicz, J. M. (2008) Pharmacokinetics and pharmacodynamics of aliskiren, an oral direct renin inhibitor. Pharmacol Rep 60, 623-631
70. Solomon, S. D., Shin, S. H., Shah, A., Skali, H., Desai, A., Kober, L., Maggioni, A. P., Rouleau, J. L., Kelly, R. Y., Hester, A., McMurray, J. J., Pfeffer, M. A., and Aliskiren Study in Post, M. I. P. t. R. R. I. (2011) Effect of the direct renin inhibitor aliskiren on left ventricular remodelling following myocardial infarction with systolic dysfunction. Eur Heart J 32, 1227-1234
71. Gheorghiade, M., Bohm, M., Greene, S. J., Fonarow, G. C., Lewis, E. F., Zannad, F., Solomon, S. D., Baschiera, F., Botha, J., Hua, T. A., Gimpelewicz, C. R., Jaumont, X., Lesogor, A., Maggioni, A. P., Investigators, A., and Coordinators. (2013) Effect of aliskiren on postdischarge mortality and heart failure readmissions among patients hospitalized for heart failure: the ASTRONAUT randomized trial. JAMA 309, 1125-1135
72. Oh, B. H., Mitchell, J., Herron, J. R., Chung, J., Khan, M., and Keefe, D. L. (2007) Aliskiren, an oral renin inhibitor, provides dose-dependent efficacy and sustained 24-hour blood pressure control in patients with hypertension. J Am Coll Cardiol 49, 1157-1163
73. Parodi-Rullan, R., Barreto-Torres, G., Ruiz, L., Casasnovas, J., and Javadov, S. (2012) Direct renin inhibition exerts an anti-hypertrophic effect associated with improved mitochondrial function in post-infarction heart failure in diabetic rats. Cell Physiol Biochem 29, 841-850
74. Zhi, H., Luptak, I., Alreja, G., Shi, J., Guan, J., Metes-Kosik, N., and Joseph, J. (2013) Effects of direct Renin inhibition on myocardial fibrosis and cardiac fibroblast function. PLoS One 8, e81612
75. Wood, J. M., Stanton, J. L., and Hofbauer, K. G. (1987) Inhibitors of renin as potential therapeutic agents. J Enzyme Inhib 1, 169-185
76. Bohlender, J., Fukamizu, A., Lippoldt, A., Nomura, T., Dietz, R., Menard, J., Murakami, K., Luft, F. C., and Ganten, D. (1997) High human renin hypertension in transgenic rats. Hypertension 29, 428-434
77. Savoia, C., Arrabito, E., Parente, R., Sada, L., Madaro, L., Nicoletti, C., Zezza, L., Alonzo, A., Rubattu, S., Michelini, S., Muller, D. N., and Volpe, M. (2013) The direct renin inhibitor aliskiren improves vascular remodelling in transgenic rats harbouring human renin and angiotensinogen genes. Clin Sci (Lond) 125, 183-189
78. Hara, T., Nishimura, S., Yamamoto, T., Kajimoto, Y., Kusumoto, K., Kanagawa, R., Ikeda, S., and Nishimoto, T. (2018) TAK-272 (imarikiren), a novel renin inhibitor, improves cardiac remodeling and mortality in a murine heart failure model. PLoS One 13, e0202176
79. Levine, T. B., Francis, G. S., Goldsmith, S. R., Simon, A. B., and Cohn, J. N. (1982) Activity of the sympathetic nervous system and renin-angiotensin system assessed by plasma hormone levels and their relation to hemodynamic abnormalities in congestive heart failure. Am J Cardiol 49, 1659-1666
80. Francis, G. S., Benedict, C., Johnstone, D. E., Kirlin, P. C., Nicklas, J., Liang, C. S., Kubo, S. H., Rudin-Toretsky, E., and Yusuf, S. (1990) Comparison of neuroendocrine activation in patients with left ventricular dysfunction with and without congestive heart failure. A substudy of the Studies of Left Ventricular Dysfunction (SOLVD). Circulation 82, 1724- 1729
81. SCOHIA Pharma, I. (2021) Pipeline (https://www.scohia.com/eng/sys/pipeline/).
82. Shanghai Pharmaceuticals Holding Co., L. (2018) Safety and Efficacy of SPH3127 on Treating Mild-moderate Essential Hypertension Patients (ClinicalTrials.gov Identifier: NCT03756103).
83. Kanda, E., Kashihara, N., Matsushita, K., Usui, T., Okada, H., Iseki, K., Mikami, K., Tanaka, T., Wada, T., Watada, H., Ueki, K., Nangaku, M., and Research Working Group for Establishing Guidelines for Clinical Evaluation of Chronic Kidney, D. (2018) Guidelines for clinical evaluation of chronic kidney disease : AMED research on regulatory science of pharmaceuticals and medical devices. Clin Exp Nephrol 22, 1446-1475
84. Bottari, S. P., Taylor, V., King, I. N., Bogdal, Y., Whitebread, S., and de Gasparo, M. (1991) Angiotensin II AT2 receptors do not interact with guanine nucleotide binding proteins. Eur J Pharmacol 207, 157-163
85. Hansen, J. L., Servant, G., Baranski, T. J., Fujita, T., Iiri, T., and Sheikh, S. P. (2000) Functional reconstitution of the angiotensin II type 2 receptor and G(i) activation. Circ Res 87, 753-759
86. Zhang, H., Han, G. W., Batyuk, A., Ishchenko, A., White, K. L., Patel, N., Sadybekov, A., Zamlynny, B., Rudd, M. T., Hollenstein, K., Tolstikova, A., White, T. A., Hunter, M. S., Weierstall, U., Liu, W., Babaoglu, K., Moore, E. L., Katz, R. D., Shipman, J. M., Garcia- Calvo, M., Sharma, S., Sheth, P., Soisson, S. M., Stevens, R. C., Katritch, V., and Cherezov, V. (2017) Structural basis for selectivity and diversity in angiotensin II receptors. Nature 544, 327-332
87. Paz Ocaranza, M., Riquelme, J. A., Garcia, L., Jalil, J. E., Chiong, M., Santos, R. A. S., and Lavandero, S. (2020) Counter-regulatory renin-angiotensin system in cardiovascular disease. Nat Rev Cardiol 17, 116-129
88. Leonhardt, J., Villela, D. C., Teichmann, A., Munter, L. M., Mayer, M. C., Mardahl, M., Kirsch, S., Namsolleck, P., Lucht, K., Benz, V., Alenina, N., Daniell, N., Horiuchi, M., Iwai, M., Multhaup, G., Schulein, R., Bader, M., Santos, R. A., Unger, T., and Steckelings, U. M. (2017) Evidence for Heterodimerization and Functional Interaction of the Angiotensin Type 2 Receptor and the Receptor MAS. Hypertension 69, 1128-1135
89. Villela, D., Leonhardt, J., Patel, N., Joseph, J., Kirsch, S., Hallberg, A., Unger, T., Bader, M., Santos, R. A., Sumners, C., and Steckelings, U. M. (2015) Angiotensin type 2 receptor (AT2R) and receptor Mas: a complex liaison. Clin Sci (Lond) 128, 227-234
90. Kaschina, E., Namsolleck, P., and Unger, T. (2017) AT2 receptors in cardiovascular and renal diseases. Pharmacol Res 125, 39-47
91. Ocaranza, M. P., and Jalil, J. E. (2012) Protective Role of the ACE2/Ang-(1-9) Axis in Cardiovascular Remodeling. Int J Hypertens 2012, 594361
92. Wagenaar, G. T., Laghmani el, H., Fidder, M., Sengers, R. M., de Visser, Y. P., de Vries, L., Rink, R., Roks, A. J., Folkerts, G., and Walther, F. J. (2013) Agonists of MAS oncogene and angiotensin II type 2 receptors attenuate cardiopulmonary disease in rats with neonatal hyperoxia-induced lung injury. Am J Physiol Lung Cell Mol Physiol 305, L341- 351
93. Pharma, V. (2021) Safety, Efficacy and Pharmacokinetics of C21 in Subjects With IPF (ClinicalTrials.gov Identifier: NCT04533022).
94. Juillerat-Jeanneret, L. (2020) The Other Angiotensin II Receptor: AT2R as a Therapeutic Target. J Med Chem 63, 1978-1995
95. Imai, Y., Kuba, K., and Penninger, J. M. (2008) The discovery of angiotensin-converting enzyme 2 and its role in acute lung injury in mice. Exp Physiol 93, 543-548
96. Yamazato, Y., Ferreira, A. J., Hong, K. H., Sriramula, S., Francis, J., Yamazato, M., Yuan, L., Bradford, C. N., Shenoy, V., Oh, S. P., Katovich, M. J., and Raizada, M. K. (2009) Prevention of pulmonary hypertension by Angiotensin-converting enzyme 2 gene transfer. Hypertension 54, 365-371
97. Ferreira, A. J., Shenoy, V., Yamazato, Y., Sriramula, S., Francis, J., Yuan, L., Castellano, R. K., Ostrov, D. A., Oh, S. P., Katovich, M. J., and Raizada, M. K. (2009) Evidence for angiotensin-converting enzyme 2 as a therapeutic target for the prevention of pulmonary hypertension. Am J Respir Crit Care Med 179, 1048-1054
98. Li, G., Zhang, H., Zhao, L., Zhang, Y., Yan, D., and Liu, Y. (2017) Angiotensin-converting enzyme 2 activation ameliorates pulmonary endothelial dysfunction in rats with pulmonary arterial hypertension through mediating phosphorylation of endothelial nitric oxide synthase. J Am Soc Hypertens 11, 842-852
99. Epelman, S., Tang, W. H., Chen, S. Y., Van Lente, F., Francis, G. S., and Sen, S. (2008) Detection of soluble angiotensin-converting enzyme 2 in heart failure: insights into the endogenous counter-regulatory pathway of the renin-angiotensin-aldosterone system. J Am Coll Cardiol 52, 750-754
100. Johnson, J. A., West, J., Maynard, K. B., and Hemnes, A. R. (2011) ACE2 improves right ventricular function in a pressure overload model. PLoS One 6, e20828
101. Rathinasabapathy, A., Bryant, A. J., Suzuki, T., Moore, C., Shay, S., Gladson, S., West, J. D., and Carrier, E. J. (2018) rhACE2 Therapy Modifies Bleomycin-Induced Pulmonary Hypertension via Rescue of Vascular Remodeling. Front Physiol 9, 271
102. Hemnes, A. R., Rathinasabapathy, A., Austin, E. A., Brittain, E. L., Carrier, E. J., Chen, X., Fessel, J. P., Fike, C. D., Fong, P., Fortune, N., Gerszten, R. E., Johnson, J. A., Kaplowitz, M., Newman, J. H., Piana, R., Pugh, M. E., Rice, T. W., Robbins, I. M., Wheeler, L., Yu, C., Loyd, J. E., and West, J. (2018) A potential therapeutic role for angiotensin- converting enzyme 2 in human pulmonary arterial hypertension. Eur Respir J 51
103. Khan, A., Benthin, C., Zeno, B., Albertson, T. E., Boyd, J., Christie, J. D., Hall, R., Poirier, G., Ronco, J. J., Tidswell, M., Hardes, K., Powley, W. M., Wright, T. J., Siederer, S. K., Fairman, D. A., Lipson, D. A., Bayliffe, A. I., and Lazaar, A. L. (2017) A pilot clinical trial of recombinant human angiotensin-converting enzyme 2 in acute respiratory distress syndrome. Crit Care 21, 234
104. Organization, W. H. (2021) WHO Coronavirus (COVID-19) Dashboard (https://covid19.who.int/).
105. Hoffmann, M., Kleine-Weber, H., Schroeder, S., Kruger, N., Herrler, T., Erichsen, S., Schiergens, T. S., Herrler, G., Wu, N. H., Nitsche, A., Muller, M. A., Drosten, C., and Pohlmann, S. (2020) SARS-CoV-2 Cell Entry Depends on ACE2 and TMPRSS2 and Is Blocked by a Clinically Proven Protease Inhibitor. Cell 181, 271-280 e278
106. Kai, H., and Kai, M. (2020) Interactions of coronaviruses with ACE2, angiotensin II, and RAS inhibitors-lessons from available evidence and insights into COVID-19. Hypertens Res 43, 648-654
107. Baral, R., Tsampasian, V., Debski, M., Moran, B., Garg, P., Clark, A., and Vassiliou, V. S. (2021) Association Between Renin-Angiotensin-Aldosterone System Inhibitors and Clinical Outcomes in Patients With COVID-19: A Systematic Review and Meta-analysis. JAMA Netw Open 4, e213594
108. Lee, T., Cau, A., Cheng, M. P., Levin, A., Lee, T. C., Vinh, D. C., Lamontagne, F., Singer, J., Walley, K. R., Murthy, S., Patrick, D., Rewa, O. G., Winston, B. W., Marshall, J., Boyd, J., Tran, K., Kalil, A., McCuloh, R., Fowler, R., Luther, J. M., Russell, J. A., and CORONA, A. R. (2021) Angiotensin Receptor Blockers and Angiotensin Converting Enzyme Inhibitors in Covid-19 -Meta-Analysis/Meta-Regression Adjusted for Confounding Factors. CJC Open
109. Iheanacho, C. O., Odili, V. U., and Eze, U. I. H. (2021) Risk of SARS-CoV-2 infection and COVID-19 prognosis with the use of renin-angiotensin-aldosterone system (RAAS) inhibitors: a systematic review. Futur J Pharm Sci 7, 73
110. Kuba, K., Imai, Y., Rao, S., Gao, H., Guo, F., Guan, B., Huan, Y., Yang, P., Zhang, Y., Deng, W., Bao, L., Zhang, B., Liu, G., Wang, Z., Chappell, M., Liu, Y., Zheng, D., Leibbrandt, A., Wada, T., Slutsky, A. S., Liu, D., Qin, C., Jiang, C., and Penninger, J. M. (2005) A crucial role of angiotensin converting enzyme 2 (ACE2) in SARS coronavirus- induced lung injury. Nat Med 11, 875-879
111. Krishnamurthy, S., Lockey, R. F., and Kolliputi, N. (2021) Soluble ACE2 as a potential therapy for COVID-19. Am J Physiol Cell Physiol 320, C279-C281
112. Monteil, V., Kwon, H., Prado, P., Hagelkruys, A., Wimmer, R. A., Stahl, M., Leopoldi, A., Garreta, E., Hurtado Del Pozo, C., Prosper, F., Romero, J. P., Wirnsberger, G., Zhang, H., Slutsky, A. S., Conder, R., Montserrat, N., Mirazimi, A., and Penninger, J. M. (2020) Inhibition of SARS-CoV-2 Infections in Engineered Human Tissues Using Clinical-Grade Soluble Human ACE2. Cell 181, 905-913 e907
113. AG, A. B. (2020) APEIRON Biologics: Patient recruitment completed in Phase II COVID-19 Clinical Trial of APN01 (https://www.apeiron-biologics.com/wp- content/uploads/20201204_APEIRON_LPI_Covid-trial_ENG_FINAL.pdf).
114. Zoufaly, A., Poglitsch, M., Aberle, J. H., Hoepler, W., Seitz, T., Traugott, M., Grieb, A., Pawelka, E., Laferl, H., Wenisch, C., Neuhold, S., Haider, D., Stiasny, K., Bergthaler, A., Puchhammer-Stoeckl, E., Mirazimi, A., Montserrat, N., Zhang, H., Slutsky, A. S., and Penninger, J. M. (2020) Human recombinant soluble ACE2 in severe COVID-19. Lancet Respir Med 8, 1154-1158
115. Tatemoto, K., Hosoya, M., Habata, Y., Fujii, R., Kakegawa, T., Zou, M. X., Kawamata, Y., Fukusumi, S., Hinuma, S., Kitada, C., Kurokawa, T., Onda, H., and Fujino, M. (1998) Isolation and characterization of a novel endogenous peptide ligand for the human APJ receptor. Biochem Biophys Res Commun 251, 471-476
116. O'Dowd, B. F., Heiber, M., Chan, A., Heng, H. H., Tsui, L. C., Kennedy, J. L., Shi, X., Petronis, A., George, S. R., and Nguyen, T. (1993) A human gene that shows identity with the gene encoding the angiotensin receptor is located on chromosome 11. Gene 136, 355- 360
117. Lee, D. K., Cheng, R., Nguyen, T., Fan, T., Kariyawasam, A. P., Liu, Y., Osmond, D. H., George, S. R., and O'Dowd, B. F. (2000) Characterization of apelin, the ligand for the APJ receptor. J Neurochem 74, 34-41
118. Habata, Y., Fujii, R., Hosoya, M., Fukusumi, S., Kawamata, Y., Hinuma, S., Kitada, C., Nishizawa, N., Murosaki, S., Kurokawa, T., Onda, H., Tatemoto, K., and Fujino, M. (1999) Apelin, the natural ligand of the orphan receptor APJ, is abundantly secreted in the colostrum. Biochim Biophys Acta 1452, 25-35
119. Maguire, J. J., Kleinz, M. J., Pitkin, S. L., and Davenport, A. P. (2009) [Pyr1]apelin-13 identified as the predominant apelin isoform in the human heart: vasoactive mechanisms and inotropic action in disease. Hypertension 54, 598-604
120. Zhen, E. Y., Higgs, R. E., and Gutierrez, J. A. (2013) Pyroglutamyl apelin-13 identified as the major apelin isoform in human plasma. Anal Biochem 442, 1-9
121. Wysocka, M. B., Pietraszek-Gremplewicz, K., and Nowak, D. (2018) The Role of Apelin in Cardiovascular Diseases, Obesity and Cancer. Front Physiol 9, 557
122. Japp, A. G., Cruden, N. L., Amer, D. A., Li, V. K., Goudie, E. B., Johnston, N. R., Sharma, S., Neilson, I., Webb, D. J., Megson, I. L., Flapan, A. D., and Newby, D. E. (2008) Vascular effects of apelin in vivo in man. J Am Coll Cardiol 52, 908-913
123. Japp, A. G., Cruden, N. L., Barnes, G., van Gemeren, N., Mathews, J., Adamson, J., Johnston, N. R., Denvir, M. A., Megson, I. L., Flapan, A. D., and Newby, D. E. (2010) Acute cardiovascular effects of apelin in humans: potential role in patients with chronic heart failure. Circulation 121, 1818-1827
124. Ishida, J., Hashimoto, T., Hashimoto, Y., Nishiwaki, S., Iguchi, T., Harada, S., Sugaya, T., Matsuzaki, H., Yamamoto, R., Shiota, N., Okunishi, H., Kihara, M., Umemura, S., Sugiyama, F., Yagami, K., Kasuya, Y., Mochizuki, N., and Fukamizu, A. (2004) Regulatory roles for APJ, a seven-transmembrane receptor related to angiotensin-type 1 receptor in blood pressure in vivo. J Biol Chem 279, 26274-26279
125. Zhong, J. C., Yu, X. Y., Huang, Y., Yung, L. M., Lau, C. W., and Lin, S. G. (2007) Apelin modulates aortic vascular tone via endothelial nitric oxide synthase phosphorylation pathway in diabetic mice. Cardiovasc Res 74, 388-395
126. Vickers, C., Hales, P., Kaushik, V., Dick, L., Gavin, J., Tang, J., Godbout, K., Parsons, T., Baronas, E., Hsieh, F., Acton, S., Patane, M., Nichols, A., and Tummino, P. (2002) Hydrolysis of biological peptides by human angiotensin-converting enzyme-related carboxypeptidase. J Biol Chem 277, 14838-14843
127. Sato, T., Suzuki, T., Watanabe, H., Kadowaki, A., Fukamizu, A., Liu, P. P., Kimura, A., Ito, H., Penninger, J. M., Imai, Y., and Kuba, K. (2013) Apelin is a positive regulator of ACE2 in failing hearts. J Clin Invest 123, 5203-5211
128. Chun, H. J., Ali, Z. A., Kojima, Y., Kundu, R. K., Sheikh, A. Y., Agrawal, R., Zheng, L., Leeper, N. J., Pearl, N. E., Patterson, A. J., Anderson, J. P., Tsao, P. S., Lenardo, M. J., Ashley, E. A., and Quertermous, T. (2008) Apelin signaling antagonizes Ang II effects in mouse models of atherosclerosis. J Clin Invest 118, 3343-3354
129. Siddiquee, K., Hampton, J., McAnally, D., May, L., and Smith, L. (2013) The apelin receptor inhibits the angiotensin II type 1 receptor via allosteric trans-inhibition. Br J Pharmacol 168, 1104-1117
130. Kleinz, M. J., and Davenport, A. P. (2004) Immunocytochemical localization of the endogenous vasoactive peptide apelin to human vascular and endocardial endothelial cells. Regul Pept 118, 119-125
131. Szokodi, I., Tavi, P., Foldes, G., Voutilainen-Myllyla, S., Ilves, M., Tokola, H., Pikkarainen, S., Piuhola, J., Rysa, J., Toth, M., and Ruskoaho, H. (2002) Apelin, the novel endogenous ligand of the orphan receptor APJ, regulates cardiac contractility. Circ Res 91, 434-440
132. Tatemoto, K., Takayama, K., Zou, M. X., Kumaki, I., Zhang, W., Kumano, K., and Fujimiya, M. (2001) The novel peptide apelin lowers blood pressure via a nitric oxide- dependent mechanism. Regul Pept 99, 87-92
133. Foldes, G., Horkay, F., Szokodi, I., Vuolteenaho, O., Ilves, M., Lindstedt, K. A., Mayranpaa, M., Sarman, B., Seres, L., Skoumal, R., Lako-Futo, Z., deChatel, R., Ruskoaho, H., and Toth, M. (2003) Circulating and cardiac levels of apelin, the novel ligand of the orphan receptor APJ, in patients with heart failure. Biochem Biophys Res Commun 308, 480-485
134. Azizi, Y., Faghihi, M., Imani, A., Roghani, M., and Nazari, A. (2013) Post-infarct treatment with [Pyr1]-apelin-13 reduces myocardial damage through reduction of oxidative injury and nitric oxide enhancement in the rat model of myocardial infarction. Peptides 46, 76-82
135. Foussal, C., Lairez, O., Calise, D., Pathak, A., Guilbeau-Frugier, C., Valet, P., Parini, A., and Kunduzova, O. (2010) Activation of catalase by apelin prevents oxidative stress-linked cardiac hypertrophy. FEBS Lett 584, 2363-2370
136. Pharmaceuticals, N. (2021) A Study of CLR325 in Chronic Stable Heart Failure Patients. (ClinicalTrials.gov Identifier: NCT02696967).
137. Amgen. (2019) Study to Evaluate the Safety and Tolerability of AMG 986 in Healthy Subjects and Heart Failure Patients (ClinicalTrials.gov Identifier: NCT03276728).
138. Squibb, B.-M. (2021) A Study of BMS-986224 in Healthy Subjects and Heart Failure Patients With Reduced Ejection Fraction (ClinicalTrials.gov Identifier: NCT03281122).
139. Cruden, N. L., Fox, K. A., Ludlam, C. A., Johnston, N. R., and Newby, D. E. (2004) Neutral endopeptidase inhibition augments vascular actions of bradykinin in patients treated with angiotensin-converting enzyme inhibition. Hypertension 44, 913-918
140. Rademaker, M. T., Charles, C. J., Espiner, E. A., Nicholls, M. G., Richards, A. M., and Kosoglou, T. (1996) Neutral endopeptidase inhibition: augmented atrial and brain natriuretic peptide, haemodynamic and natriuretic responses in ovine heart failure. Clin Sci (Lond) 91, 283-291
141. Wilkinson, I. B., McEniery, C. M., Bongaerts, K. H., MacCallum, H., Webb, D. J., and Cockcroft, J. R. (2001) Adrenomedullin (ADM) in the human forearm vascular bed: effect of neutral endopeptidase inhibition and comparison with proadrenomedullin NH2- terminal 20 peptide (PAMP). Br J Clin Pharmacol 52, 159-164
142. Maric, C., Zheng, W., and Walther, T. (2006) Interactions between angiotensin ll and atrial natriuretic peptide in renomedullary interstitial cells: the role of neutral endopeptidase. Nephron Physiol 103, p149-156
143. Rice, G. I., Thomas, D. A., Grant, P. J., Turner, A. J., and Hooper, N. M. (2004) Evaluation of angiotensin-converting enzyme (ACE), its homologue ACE2 and neprilysin in angiotensin peptide metabolism. Biochem J 383, 45-51
144. McMurray, J. J., Packer, M., Desai, A. S., Gong, J., Lefkowitz, M. P., Rizkala, A. R., Rouleau, J. L., Shi, V. C., Solomon, S. D., Swedberg, K., Zile, M. R., Investigators, P.-H., and Committees. (2014) Angiotensin-neprilysin inhibition versus enalapril in heart failure. N Engl J Med 371, 993-1004
145. Solomon, S. D., McMurray, J. J. V., Anand, I. S., Ge, J., Lam, C. S. P., Maggioni, A. P., Martinez, F., Packer, M., Pfeffer, M. A., Pieske, B., Redfield, M. M., Rouleau, J. L., van Veldhuisen, D. J., Zannad, F., Zile, M. R., Desai, A. S., Claggett, B., Jhund, P. S., Boytsov, S. A., Comin-Colet, J., Cleland, J., Dungen, H. D., Goncalvesova, E., Katova, T., Kerr Saraiva, J. F., Lelonek, M., Merkely, B., Senni, M., Shah, S. J., Zhou, J., Rizkala, A. R., Gong, J., Shi, V. C., Lefkowitz, M. P., Investigators, P.-H., and Committees. (2019) Angiotensin-Neprilysin Inhibition in Heart Failure with Preserved Ejection Fraction. N Engl J Med 381, 1609-1620
146. McMurray, J. J. V., Jackson, A. M., Lam, C. S. P., Redfield, M. M., Anand, I. S., Ge, J., Lefkowitz, M. P., Maggioni, A. P., Martinez, F., Packer, M., Pfeffer, M. A., Pieske, B., Rizkala, A. R., Sabarwal, S. V., Shah, A. M., Shah, S. J., Shi, V. C., van Veldhuisen, D. J., Zannad, F., Zile, M. R., Cikes, M., Goncalvesova, E., Katova, T., Kosztin, A., Lelonek, M., Sweitzer, N., Vardeny, O., Claggett, B., Jhund, P. S., and Solomon, S. D. (2020) Effects of Sacubitril-Valsartan Versus Valsartan in Women Compared With Men With Heart Failure and Preserved Ejection Fraction: Insights From PARAGON-HF. Circulation 141, 338-351
147. AG, N. (2021) Full Year 2020 Product Sales (https://www.novartis.com/investors/financial-data/product-sales).
148. Zinman, B., Wanner, C., Lachin, J. M., Fitchett, D., Bluhmki, E., Hantel, S., Mattheus, M., Devins, T., Johansen, O. E., Woerle, H. J., Broedl, U. C., Inzucchi, S. E., and Investigators, E.-R. O. (2015) Empagliflozin, Cardiovascular Outcomes, and Mortality in Type 2 Diabetes. N Engl J Med 373, 2117-2128
149. Neal, B., Perkovic, V., Mahaffey, K. W., de Zeeuw, D., Fulcher, G., Erondu, N., Shaw, W., Law, G., Desai, M., Matthews, D. R., and Group, C. P. C. (2017) Canagliflozin and Cardiovascular and Renal Events in Type 2 Diabetes. N Engl J Med 377, 644-657
150. Wiviott, S. D., Raz, I., Bonaca, M. P., Mosenzon, O., Kato, E. T., Cahn, A., Silverman, M. G., Zelniker, T. A., Kuder, J. F., Murphy, S. A., Bhatt, D. L., Leiter, L. A., McGuire, D. K., Wilding, J. P. H., Ruff, C. T., Gause-Nilsson, I. A. M., Fredriksson, M., Johansson, P. A., Langkilde, A. M., Sabatine, M. S., and Investigators, D.-T. (2019) Dapagliflozin and Cardiovascular Outcomes in Type 2 Diabetes. N Engl J Med 380, 347-357
151. McMurray, J. J. V., Solomon, S. D., Inzucchi, S. E., Kober, L., Kosiborod, M. N., Martinez, F. A., Ponikowski, P., Sabatine, M. S., Anand, I. S., Belohlavek, J., Bohm, M., Chiang, C. E., Chopra, V. K., de Boer, R. A., Desai, A. S., Diez, M., Drozdz, J., Dukat, A., Ge, J., Howlett, J. G., Katova, T., Kitakaze, M., Ljungman, C. E. A., Merkely, B., Nicolau, J. C., O'Meara, E., Petrie, M. C., Vinh, P. N., Schou, M., Tereshchenko, S., Verma, S., Held, C., DeMets, D. L., Docherty, K. F., Jhund, P. S., Bengtsson, O., Sjostrand, M., Langkilde, A. M., Committees, D.-H. T., and Investigators. (2019) Dapagliflozin in Patients with Heart Failure and Reduced Ejection Fraction. N Engl J Med 381, 1995-2008
152. Packer, M., Anker, S. D., Butler, J., Filippatos, G., Pocock, S. J., Carson, P., Januzzi, J., Verma, S., Tsutsui, H., Brueckmann, M., Jamal, W., Kimura, K., Schnee, J., Zeller, C., Cotton, D., Bocchi, E., Bohm, M., Choi, D. J., Chopra, V., Chuquiure, E., Giannetti, N., Janssens, S., Zhang, J., Gonzalez Juanatey, J. R., Kaul, S., Brunner-La Rocca, H. P., Merkely, B., Nicholls, S. J., Perrone, S., Pina, I., Ponikowski, P., Sattar, N., Senni, M., Seronde, M. F., Spinar, J., Squire, I., Taddei, S., Wanner, C., Zannad, F., and Investigators, E. M.-R. T. (2020) Cardiovascular and Renal Outcomes with Empagliflozin in Heart Failure. N Engl J Med 383, 1413-1424
153. Staels, B. (2017) Cardiovascular Protection by Sodium Glucose Cotransporter 2 Inhibitors: Potential Mechanisms. Am J Med 130, S30-S39
154. Ohara, K., Masuda, T., Murakami, T., Imai, T., Yoshizawa, H., Nakagawa, S., Okada, M., Miki, A., Myoga, A., Sugase, T., Sekiguchi, C., Miyazawa, Y., Maeshima, A., Akimoto, T., Saito, O., Muto, S., and Nagata, D. (2019) Effects of the sodium-glucose cotransporter 2 inhibitor dapagliflozin on fluid distribution: A comparison study with furosemide and tolvaptan. Nephrology (Carlton) 24, 904-911
155. Ceriello, A., Genovese, S., Mannucci, E., and Gronda, E. (2016) Glucagon and heart in type 2 diabetes: new perspectives. Cardiovasc Diabetol 15, 123
156. Ferrannini, E., Mark, M., and Mayoux, E. (2016) CV Protection in the EMPA-REG OUTCOME Trial: A "Thrifty Substrate" Hypothesis. Diabetes Care 39, 1108-1114
157. PLC, A. (2021) Full-year 2020 results (https://www.astrazeneca.com/content/dam/az/PDF/2020/full-year/Full- year_2020_results_announcement.pdf).
158. Ingelheim, B. (2021) Annual Report 2020 (https://annualreport.boehringer-ingelheim.com/fileadmin/downloads/en/bi_finanzbericht_2020_en.pdf).
159. AstraZeneca. (2018) Dapagliflozin Evaluation to Improve the LIVEs of Patients With PReserved Ejection Fraction Heart Failure. (DELIVER) (ClinicalTrials.gov Identifier: NCT03619213).
160. Anker, S. D., Butler, J., Filippatos, G. S., Jamal, W., Salsali, A., Schnee, J., Kimura, K., Zeller, C., George, J., Brueckmann, M., Zannad, F., Packer, M., Committees, E. M.-P. T., and Investigators. (2019) Evaluation of the effects of sodium-glucose co-transporter 2 inhibition with empagliflozin on morbidity and mortality in patients with chronic heart failure and a preserved ejection fraction: rationale for and design of the EMPEROR- Preserved Trial. Eur J Heart Fail 21, 1279-1287
161. Talman, V., and Ruskoaho, H. (2016) Cardiac fibrosis in myocardial infarction-from repair and remodeling to regeneration. Cell Tissue Res 365, 563-581
162. Bergmann, O., Bhardwaj, R. D., Bernard, S., Zdunek, S., Barnabe-Heider, F., Walsh, S., Zupicich, J., Alkass, K., Buchholz, B. A., Druid, H., Jovinge, S., and Frisen, J. (2009) Evidence for cardiomyocyte renewal in humans. Science 324, 98-102
163. Sadek, H., and Olson, E. N. (2020) Toward the Goal of Human Heart Regeneration. Cell Stem Cell 26, 7-16
164. Ieda, M., Fu, J. D., Delgado-Olguin, P., Vedantham, V., Hayashi, Y., Bruneau, B. G., and Srivastava, D. (2010) Direct reprogramming of fibroblasts into functional cardiomyocytes by defined factors. Cell 142, 375-386
165. Miyamoto, K., Akiyama, M., Tamura, F., Isomi, M., Yamakawa, H., Sadahiro, T., Muraoka, N., Kojima, H., Haginiwa, S., Kurotsu, S., Tani, H., Wang, L., Qian, L., Inoue, M., Ide, Y., Kurokawa, J., Yamamoto, T., Seki, T., Aeba, R., Yamagishi, H., Fukuda, K., and Ieda, M. (2018) Direct In Vivo Reprogramming with Sendai Virus Vectors Improves Cardiac Function after Myocardial Infarction. Cell Stem Cell 22, 91-103 e105
166. Nam, Y. J., Song, K., Luo, X., Daniel, E., Lambeth, K., West, K., Hill, J. A., DiMaio, J. M., Baker, L. A., Bassel-Duby, R., and Olson, E. N. (2013) Reprogramming of human fibroblasts toward a cardiac fate. Proc Natl Acad Sci U S A 110, 5588-5593
167. Mahmoudi, S., Mancini, E., Xu, L., Moore, A., Jahanbani, F., Hebestreit, K., Srinivasan, R., Li, X., Devarajan, K., Prelot, L., Ang, C. E., Shibuya, Y., Benayoun, B. A., Chang, A. L. S., Wernig, M., Wysocka, J., Longaker, M. T., Snyder, M. P., and Brunet, A. (2019) Heterogeneity in old fibroblasts is linked to variability in reprogramming and wound healing. Nature 574, 553-558
168. Takahashi, K., and Yamanaka, S. (2006) Induction of pluripotent stem cells from mouse embryonic and adult fibroblast cultures by defined factors. Cell 126, 663-676
169. Mazzola, M., and Di Pasquale, E. (2020) Toward Cardiac Regeneration: Combination of Pluripotent Stem Cell-Based Therapies and Bioengineering Strategies. Front Bioeng Biotechnol 8, 455
170. Chong, J. J., Yang, X., Don, C. W., Minami, E., Liu, Y. W., Weyers, J. J., Mahoney, W. M., Van Biber, B., Cook, S. M., Palpant, N. J., Gantz, J. A., Fugate, J. A., Muskheli, V., Gough, G. M., Vogel, K. W., Astley, C. A., Hotchkiss, C. E., Baldessari, A., Pabon, L., Reinecke, H., Gill, E. A., Nelson, V., Kiem, H. P., Laflamme, M. A., and Murry, C. E. (2014) Human embryonic-stem-cell-derived cardiomyocytes regenerate non-human primate hearts. Nature 510, 273-277
171. Zhu, K., Wu, Q., Ni, C., Zhang, P., Zhong, Z., Wu, Y., Wang, Y., Xu, Y., Kong, M., Cheng, H., Tao, Z., Yang, Q., Liang, H., Jiang, Y., Li, Q., Zhao, J., Huang, J., Zhang, F., Chen, Q., Li, Y., Chen, J., Zhu, W., Yu, H., Zhang, J., Yang, H. T., Hu, X., and Wang, J. (2018) Lack of Remuscularization Following Transplantation of Human Embryonic Stem Cell-Derived Cardiovascular Progenitor Cells in Infarcted Nonhuman Primates. Circ Res 122, 958-969
172. (2013) 再生医療を国民が迅速かつ安全に受けられるようにするための施策の総合的な推進に関する法律(https://www.mhlw.go.jp/file/06-Seisakujouhou-10800000- Iseikyoku/0000150832.pdf).
173. Toda, K. (2019) Clinical trial of human (allogeneic) iPS cell-derived cardiomyocytes sheet for ischemic cardiomyopathy (Trial ID: jRCT2053190081).
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