The SGLT2 inhibitor empagliflozin reduces mortality and prevents progression in experimental pulmonary hypertension

Biochemical and Biophysical Research Communications

Volumn 524, Issue 1, 2020, Pages 50-56

  Chowdhury, Biswajit ^a   Luu, Albert Z ^a,b   Luu, Vincent Z ^a,b   Kabir, M Golam ^a   Pan, Yi ^a   Teoh, Hwee ^a   Quan, Adrian ^a   Sabongui, Sandra ^a   Al Omran, Mohammed ^a,b,c   Bhatt, Deepak L ^d   Mazer, C David ^a,b,c   Connelly, Kim A ^b,c   Verma, Subodh ^a,b,c   Hess, David A ^a,b,e,f  

^a ST MICHAEL'S HOSPITAL   (Canada)

^b UNIVERSITY OF TORONTO   (Canada)

^c UNIVERSITY OF TORONTO   (Canada)

^d HARVARD MEDICAL SCHOOL   (United States)

^e ROBARTS RESEARCH INSTITUTE   (Canada)

^f UNIVERSITY OF WESTERN ONTARIO   (Canada)

Author keywords

Empagliflozin; Pulmonary arterial hypertension; Vascular remodeling

Indexed keywords

EMPAGLIFLOZIN; MONOCROTALINE; BENZHYDRYL DERIVATIVE; GLUCOSIDE;

ANIMAL EXPERIMENT; ANIMAL MODEL; ANIMAL TISSUE; APOPTOSIS; ARTERIAL WALL THICKENING; ARTICLE; CONTROLLED STUDY; DISEASE EXACERBATION; DRUG EFFECT; DRUG MECHANISM; EXPERIMENTAL PULMONARY HYPERTENSION; HEART FUNCTION; HEART MUSCLE FIBROSIS; HEART RIGHT VENTRICLE HYPERTROPHY; LUNG ARTERIOLE; LUNG ARTERY PRESSURE; LUNG BLOOD VESSEL; LUNG HEMODYNAMICS; MALE; MORTALITY; NONHUMAN; PRIORITY JOURNAL; RAT; SURVIVAL; SYSTOLIC BLOOD PRESSURE; VASCULAR REMODELING; ANIMAL; BLOOD PRESSURE; FIBROSIS; HEART VENTRICLE; HEMODYNAMICS; HUMAN; LUNG; METABOLISM; NON INSULIN DEPENDENT DIABETES MELLITUS; PATHOLOGY; PHARMACOLOGY; PULMONARY ARTERY; PULMONARY HYPERTENSION; RISK ASSESSMENT; SPRAGUE DAWLEY RAT;

ANIMALS; BENZHYDRYL COMPOUNDS; BLOOD PRESSURE; DIABETES MELLITUS, TYPE 2; FIBROSIS; GLUCOSIDES; HEART VENTRICLES; HEMODYNAMICS; HUMANS; HYPERTROPHY, RIGHT VENTRICULAR; LUNG; MALE; MODELS, ANIMAL; MONOCROTALINE; MORTALITY; PULMONARY ARTERIAL HYPERTENSION; PULMONARY ARTERY; RATS, SPRAGUE-DAWLEY; RISK ASSESSMENT; SODIUM-GLUCOSE TRANSPORTER 2 INHIBITORS; VASCULAR REMODELING;

EID: 85078589768     PISSN: 0006291X     EISSN: 10902104     Source Type: Journal    
DOI: 10.1016/j.bbrc.2020.01.015     Document Type: Article

References (41)

1. Zelt, J.G.E., Chaudhary, K.R., Cadete, V.J., Mielniczuk, L.M., Stewart, D.J., Medical therapy for heart failure associated with pulmonary hypertension. Circ. Res. 124 (2019), 1551–1567, 10.1161/CIRCRESAHA.118.313650.
2. Sikirica, M., Iorga, S.R., Bancroft, T., Potash, J., The economic burden of pulmonary arterial hypertension (PAH) in the US on payers and patients. BMC Health Serv. Res., 14, 2014, 676, 10.1186/s12913-014-0676-0.
3. McLaughlin, V., Bacchetta, M., Badesch, D., Benza, R., Burger, C., Chin, K., Frantz, R., Frost, A., Hemnes, A., Kim, N.H., Rosenzweig, E.B., Rubin, L., Update on pulmonary arterial hypertension research: proceedings from a meeting of experts. Curr. Med. Res. Opin. 34 (2018), 263–273, 10.1080/03007995.2017.1404974.
4. Kirson, N.Y., Birnbaum, H.G., Ivanova, J.I., Waldman, T., Joish, V., Williamson, T., Prevalence of pulmonary arterial hypertension and chronic thromboembolic pulmonary hypertension in the United States. Curr. Med. Res. Opin. 27 (2011), 1763–1768, 10.1185/03007995.2011.604310.
5. Badesch, D.B., Raskob, G.E., Elliott, C.G., Krichman, A.M., Farber, H.W., Frost, A.E., Barst, R.J., Benza, R.L., Liou, T.G., Turner, M., Giles, S., Feldkircher, K., Miller, D.P., McGoon, M.D., Pulmonary arterial hypertension. Chest 137 (2010), 376–387, 10.1378/chest.09-1140.
6. Humbert, M., Sitbon, O., Chaouat, A., Bertocchi, M., Habib, G., Gressin, V., Yaïci, A., Weitzenblum, E., Cordier, J.-F., Chabot, F., Dromer, C., Pison, C., Reynaud-Gaubert, M., Haloun, A., Laurent, M., Hachulla, E., Cottin, V., Degano, B., Jaïs, X., Montani, D., Souza, R., Simonneau, G., Survival in patients with idiopathic, familial, and anorexigen-associated pulmonary arterial hypertension in the modern management era. Circulation 122 (2010), 156–163, 10.1161/CIRCULATIONAHA.109.911818.
7. McLaughlin, V.V., McGoon, M.D., Pulmonary arterial hypertension. Circulation 114 (2006), 1417–1431, 10.1161/CIRCULATIONAHA.104.503540.
8. Prins, K.W., Thenappan, T., World Health organization group I pulmonary hypertension: epidemiology and pathophysiology. Cardiol. Clin. 34 (2016), 363–374, 10.1016/j.ccl.2016.04.001.
9. Hassoun, P.M., Mouthon, L., Barberà, J.A., Eddahibi, S., Flores, S.C., Grimminger, F., Jones, P.L., Maitland, M.L., Michelakis, E.D., Morrell, N.W., Newman, J.H., Rabinovitch, M., Schermuly, R., Stenmark, K.R., Voelkel, N.F., Yuan, J.X.-J., Humbert, M., Inflammation, growth factors, and pulmonary vascular remodeling. J. Am. Coll. Cardiol. 54 (2009), S10–S19, 10.1016/j.jacc.2009.04.006.
10. 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., EMPA-REG OUTCOME Investigators, empagliflozin, cardiovascular outcomes, and mortality in type 2 diabetes. N. Engl. J. Med. 373 (2015), 2117–2128, 10.1056/NEJMoa1504720.
11. Wanner, C., Inzucchi, S.E., Zinman, B., Empagliflozin and progression of kidney disease in type 2 diabetes. N. Engl. J. Med. 375 (2016), 1799–1802, 10.1056/NEJMc1611290.
12. Hess, D.A., Terenzi, D.C., Trac, J.Z., Quan, A., Mason, T., Al-Omran, M., Bhatt, D.L., Dhingra, N., Rotstein, O.D., Leiter, L.A., Zinman, B., Sabongui, S., Yan, A.T., Teoh, H., Mazer, C.D., Connelly, K.A., Verma, S., SGLT2 inhibition with empagliflozin increases circulating provascular progenitor cells in people with type 2 diabetes mellitus. Cell Metabol. 30 (2019), 609–613, 10.1016/j.cmet.2019.08.015.
13. Umar, S., Iorga, A., Matori, H., Nadadur, R.D., Li, J., Maltese, F., Van Der Laarse, A., Eghbali, M., Estrogen rescues preexisting severe pulmonary hypertension in rats. Am. J. Respir. Crit. Care Med. 184 (2011), 715–723, 10.1164/rccm.201101-0078OC.
14. Pullamsetti, S.S., Doebele, C., Fischer, A., Savai, R., Kojonazarov, B., Dahal, B.K., Ghofrani, H.A., Weissmann, N., Grimminger, F., Bonauer, A., Seeger, W., Zeiher, A.M., Dimmeler, S., Schermuly, R.T., Inhibition of microRNA-17 improves lung and heart function in experimental pulmonary hypertension. Am. J. Respir. Crit. Care Med. 185 (2012), 409–419, 10.1164/rccm.201106-1093OC.
15. Cowan, K.N., Heilbut, A., Humpl, T., Lam, C., Ito, S., Rabinovitch, M., Complete reversal of fatal pulmonary hypertension in rats by a serine elastase inhibitor. Nat. Med. 6 (2000), 698–702, 10.1038/76282.
16. Schermuly, R.T., Dony, E., Ghofrani, H.A., Pullamsetti, S., Savai, R., Roth, M., Sydykov, A., Lai, Y.J., Weissmann, N., Seeger, W., Grimminger, F., Reversal of experimental pulmonary hypertension by PDGF inhibition. J. Clin. Investig. 115 (2005), 2811–2821, 10.1172/JCI24838.
17. Connelly, K.A., Prior, D.L., Kelly, D.J., Feneley, M.P., Krum, H., Gilbert, R.E., Load-sensitive measures may overestimate global systolic function in the presence of left ventricular hypertrophy: a comparison with load-insensitive measures. Am. J. Physiol. Cell Physiol. 290 (2006), H1699–H1705.
18. Gao, H., Cheng, Y., Zong, L., Huang, L., Qiao, C., Li, W., Gong, B., Hu, J., Liu, H., Wang, X., Zhao, C., Aspirin attenuates monocrotaline-induced pulmonary arterial hypertension in rats by suppressing the ERK/MAPK pathway. Clin. Exp. Hypertens. 39 (2017), 34–41, 10.1080/10641963.2016.1210620.
19. Walia, J.S., Altaleb, N., Bello, A., Kruck, C., LaFave, M.C., Varshney, G.K., Burgess, S.M., Chowdhury, B., Hurlbut, D., Hemming, R., Kobinger, G.P., Triggs-Raine, B., Long-term correction of sandhoff disease following Intravenous delivery of rAAV9 to mouse neonates. Mol. Ther. 23 (2015), 414–422, 10.1038/mt.2014.240.
20. Ramadan, A., Singh, K.K., Quan, A., Plant, P.J., Al-Omran, M., Teoh, H., Verma, S., Loss of vascular smooth muscle cell autophagy exacerbates angiotensin II-associated aortic remodeling. J. Vasc. Surg. 68 (2018), 859–871, 10.1016/j.jvs.2017.08.086.
21. Dromparis, P., Paulin, R., Stenson, T.H., Haromy, A., Sutendra, G., Michelakis, E.D., Attenuating endoplasmic reticulum stress as a novel therapeutic strategy in pulmonary hypertension. Circulation 127 (2013), 115–125, 10.1161/CIRCULATIONAHA.112.133413.
22. Zhou, L., Chen, Z., Vanderslice, P., So, S.-P., Ruan, K.-H., Willerson, J.T., Dixon, R.A.F., Endothelial-like progenitor cells engineered to produce prostacyclin rescue monocrotaline-induced pulmonary arterial hypertension and provide right ventricle benefits. Circulation 128 (2013), 982–994, 10.1161/CIRCULATIONAHA.113.003139.
23. McMurtry, M.S., Bonnet, S., Wu, X., Dyck, J.R.B., Haromy, A., Hashimoto, K., Michelakis, E.D., Dichloroacetate prevents and reverses pulmonary hypertension by inducing pulmonary artery smooth muscle cell apoptosis. Circ. Res. 95 (2004), 830–840, 10.1161/01.RES.0000145360.16770.9f.
24. Tossavainen, E., Söderberg, S., Grönlund, C., Gonzalez, M., Henein, M.Y., Lindqvist, P., Pulmonary artery acceleration time in identifying pulmonary hypertension patients with raised pulmonary vascular resistance. Eur. Heart J. Cardiovasc. Imaging. 14 (2013), 890–897, 10.1093/ehjci/jes309.
25. Cheng, Y., Yu, M., Xu, J., He, M., Wang, H., Kong, H., Xie, W., Inhibition of Shp2 ameliorates monocrotaline-induced pulmonary arterial hypertension in rats. BMC Pulm. Med., 18, 2018, 130, 10.1186/s12890-018-0700-y.
26. Wang, Z., Chesler, N.C., Pulmonary vascular wall stiffness: an important contributor to the increased right ventricular afterload with pulmonary hypertension. Pulm. Circ. 1 (2011), 212–223, 10.4103/2045-8932.83453.
27. Hill, N.S., Gillespie, M.N., McMurtry, I.F., Fifty years of monocrotaline-induced pulmonary hypertension: what has it meant to the field?. Chest 152 (2017), 1106–1108, 10.1016/j.chest.2017.10.007.
28. Gomez-Arroyo, J.G., Farkas, L., Alhussaini, A.A., Farkas, D., Kraskauskas, D., Voelkel, N.F., Bogaard, H.J., The monocrotaline model of pulmonary hypertension in perspective. Am. J. Physiol. Lung Cell Mol. Physiol. 302 (2012), L363–L369, 10.1152/ajplung.00212.2011.
29. Lee, M.-Y., Tsai, K.-B., Hsu, J.-H., Shin, S.-J., Wu, J.-R., Yeh, J.-L., Liraglutide prevents and reverses monocrotaline-induced pulmonary arterial hypertension by suppressing ET-1 and enhancing eNOS/sGC/PKG pathways. Sci. Rep., 6, 2016, 31788, 10.1038/srep31788.
30. Ramos, M.F., Lamé, M.W., Segall, H.J., Wilson, D.W., Smad signaling in the rat model of monocrotaline pulmonary hypertension. Toxicol. Pathol. 36 (2008), 311–320, 10.1177/0192623307311402.
31. Zhang, Z., Zhang, L., Sun, C., Kong, F., Wang, J., Xin, Q., Jiang, W., Li, K., Chen, O., Luan, Y., Baicalin attenuates monocrotaline-induced pulmonary hypertension through bone morphogenetic protein signaling pathway. Oncotarget 8 (2017), 63430–63441, 10.18632/oncotarget.18825.
32. Hoeper, M.M., Barst, R.J., Bourge, R.C., Feldman, J., Frost, A.E., Galié, N., Gómez-Sánchez, M.A., Grimminger, F., Grünig, E., Hassoun, P.M., Morrell, N.W., Peacock, A.J., Satoh, T., Simonneau, G., Tapson, V.F., Torres, F., Lawrence, D., Quinn, D.A., Ghofrani, H.-A., Imatinib mesylate as add-on therapy for pulmonary arterial hypertension. Circulation 127 (2013), 1128–1138, 10.1161/CIRCULATIONAHA.112.000765.
33. Colvin, K.L., Yeager, M.E., Animal models of pulmonary hypertension: matching disease mechanisms to etiology of the human disease. J. Pulm. Respir. Med., 4, 2014, 10.4172/2161-105X.1000198.
34. Barst, R.J., McGoon, M., Torbicki, A., Sitbon, O., Krowka, M.J., Olschewski, H., Gaine, S., Diagnosis and differential assessment of pulmonary arterial hypertension. J. Am. Coll. Cardiol. 43 (2004), S40–S47, 10.1016/j.jacc.2004.02.032.
35. Thenappan, T., Ormiston, M.L., Ryan, J.J., Archer, S.L., Pulmonary arterial hypertension: pathogenesis and clinical management. BMJ, 360, 2018, j5492, 10.1136/bmj.j5492.
36. Fitchett, D., McKnight, J., Lee, J., George, J., Mattheus, M., Woerle, H.J., Inzucchi, S.E., Empagliflozin reduces heart failure irrespective of control of blood pressure, low density lipoprotein cholesterol and HbA1c. Eur. Heart J., 38, 2017, 10.1093/eurheartj/ehx502.P4903 ehx493.P4903.
37. Yurista, S.R., Silljé, H.H.W., Oberdorf-Maass, S.U., Schouten, E.M., Pavez Giani, M.G., Hillebrands, J.L., van Goor, H., van Veldhuisen, D.J., de Boer, R.A., Westenbrink, B.D., Sodium–glucose co-transporter 2 inhibition with empagliflozin improves cardiac function in non-diabetic rats with left ventricular dysfunction after myocardial infarction. Eur. J. Heart Fail. 21 (2019), 862–873, 10.1002/ejhf.1473.
38. Lopaschuk, G.D., Verma, S., Empagliflozin's fuel hypothesis: not so soon. Cell Metabol. 24 (2016), 200–202, 10.1016/j.cmet.2016.07.018.
39. Ferrannini, E., Mark, M., Mayoux, E., CV protection in the EMPA-REG OUTCOME trial: a thrifty substrate hypothesis. Diabetes Care 39 (2016), 1108–1114, 10.2337/dc16-0330.
40. Baartscheer, A., Schumacher, C.A., Wüst, R.C.I., Fiolet, J.W.T., Stienen, G.J.M., Coronel, R., Zuurbier, C.J., Empagliflozin decreases myocardial cytoplasmic Na+ through inhibition of the cardiac Na+/H+ exchanger in rats and rabbits. Diabetologia 60 (2017), 568–573, 10.1007/s00125-016-4134-x.
41. Verma, S., Rawat, S., Ho, K.L., Wagg, C.S., Zhang, L., Teoh, H., Dyck, J.E., Uddin, G.M., Oudit, G.Y., Mayoux, E., Lehrke, M., Marx, N., Lopaschuk, G.D., Empagliflozin increases cardiac energy production in diabetes: novel translational insights into the heart failure benefits of SGLT2 inhibitors. JACC. Basic to Transl. Sci. 3 (2018), 575–587, 10.1016/j.jacbts.2018.07.006.