Sodium-Glucose Cotransporter 2 Inhibitors and Cardiac Remodeling.
Cardiac remodeling
HFpEF
HFrEF
Heart failure
Mechanisms
SGLT2 inhibitors
SGLT2i
Journal
Journal of cardiovascular translational research
ISSN: 1937-5395
Titre abrégé: J Cardiovasc Transl Res
Pays: United States
ID NLM: 101468585
Informations de publication
Date de publication:
10 2022
10 2022
Historique:
received:
24
12
2021
accepted:
14
02
2022
pubmed:
16
3
2022
medline:
3
11
2022
entrez:
15
3
2022
Statut:
ppublish
Résumé
Sodium-glucose cotransporter 2 (SGLT2) inhibitors have evident cardiovascular benefits in patients with type 2 diabetes with or at high risk for atherosclerotic cardiovascular disease, heart failure with reduced ejection fraction, heart failure with preserved ejection fraction (only empagliflozin and dapagliflozin have been investigated in this group so far), and chronic kidney disease. Prevention and reversal of adverse cardiac remodeling is one of the mechanisms by which SGLT2 inhibitors may exert cardiovascular benefits, especially heart failure-related outcomes. Cardiac remodeling encompasses molecular, cellular, and interstitial changes that result in favorable changes in the mass, geometry, size, and function of the heart. The pathophysiological mechanisms of adverse cardiac remodeling are related to increased apoptosis and necrosis, decreased autophagy, impairments of myocardial oxygen supply and demand, and altered energy metabolism. Herein, the accumulating evidence from animal and human studies is reviewed investigating the effects of SGLT2 inhibitors on these mechanisms of cardiac remodeling.
Identifiants
pubmed: 35290593
doi: 10.1007/s12265-022-10220-5
pii: 10.1007/s12265-022-10220-5
doi:
Substances chimiques
Sodium-Glucose Transporter 2 Inhibitors
0
Glucose
IY9XDZ35W2
Sodium
9NEZ333N27
Types de publication
Journal Article
Review
Research Support, N.I.H., Extramural
Research Support, Non-U.S. Gov't
Langues
eng
Sous-ensembles de citation
IM
Pagination
944-956Subventions
Organisme : NHLBI NIH HHS
ID : T32 HL007604
Pays : United States
Organisme : NHLBI NIH HHS
ID : K23 HL151744
Pays : United States
Informations de copyright
© 2022. The Author(s), under exclusive licence to Springer Science+Business Media, LLC, part of Springer Nature.
Références
Salah, H. M., Al’Aref, S. J., Khan, M. S., et al. (2021). Effect of sodium-glucose cotransporter 2 inhibitors on cardiovascular and kidney outcomes-Systematic review and meta-analysis of randomized placebo-controlled trials. American Heart Journal, 232, 10–22.
pubmed: 33214130
doi: 10.1016/j.ahj.2020.10.064
Salah, H. M., Al’Aref, S. J., Khan, M. S., et al. (2021). Effects of sodium-glucose cotransporter 1 and 2 inhibitors on cardiovascular and kidney outcomes in type 2 diabetes: A meta-analysis update. American Heart Journal, 233, 86–91.
pubmed: 33385359
doi: 10.1016/j.ahj.2020.12.007
McGuire, D. K., Shih, W. J., Cosentino, F., et al. (2021). Association of SGLT2 inhibitors with cardiovascular and kidney outcomes in patients with type 2 diabetes: A meta-analysis. JAMA Cardiology., 6(2), 148–158.
pubmed: 33031522
doi: 10.1001/jamacardio.2020.4511
Zannad, F., Ferreira, J. P., Pocock, S. J., et al. (2020). SGLT2 inhibitors in patients with heart failure with reduced ejection fraction: A meta-analysis of the EMPEROR-Reduced and DAPA-HF trials. The Lancet., 396(10254), 819–829.
doi: 10.1016/S0140-6736(20)31824-9
Ghezzi, C., Loo, D. D. F., & Wright, E. M. (2018). Physiology of renal glucose handling via SGLT1, SGLT2 and GLUT2. Diabetologia, 61(10), 2087–2097.
pubmed: 30132032
pmcid: 6133168
doi: 10.1007/s00125-018-4656-5
Zhou, L., Cryan, E. V., D’Andrea, M. R., Belkowski, S., Conway, B. R., & Demarest, K. T. (2003). Human cardiomyocytes express high level of Na+/glucose cotransporter 1 (SGLT1). Journal of Cellular Biochemistry, 90(2), 339–346.
pubmed: 14505350
doi: 10.1002/jcb.10631
Vrhovac, I., Balen Eror, D., Klessen, D., et al. (2015). Localizations of Na(+)-D-glucose cotransporters SGLT1 and SGLT2 in human kidney and of SGLT1 in human small intestine, liver, lung, and heart. Pflugers Archiv. European Journal of Physiology, 467(9), 1881–1898.
pubmed: 25304002
doi: 10.1007/s00424-014-1619-7
Georgianos, P. I., & Agarwal, R. (2019). Ambulatory blood pressure reduction with SGLT-2 inhibitors: Dose-response meta-analysis and comparative evaluation with low-dose hydrochlorothiazide. Diabetes Care, 42(4), 693–700.
pubmed: 30894383
pmcid: 6429633
doi: 10.2337/dc18-2207
Kawasoe, S., Maruguchi, Y., Kajiya, S., et al. (2017). Mechanism of the blood pressure-lowering effect of sodium-glucose cotransporter 2 inhibitors in obese patients with type 2 diabetes. BMC Pharmacology and Toxicology, 18(1), 23.
pubmed: 28391776
pmcid: 5385592
doi: 10.1186/s40360-017-0125-x
Lopaschuk, G. D., & Verma, S. (2020). Mechanisms of cardiovascular benefits of sodium glucose co-transporter 2 (SGLT2) inhibitors: A state-of-the-art review. JACC Basic to Translational Science, 5(6), 632–644.
pubmed: 32613148
pmcid: 7315190
doi: 10.1016/j.jacbts.2020.02.004
Pereira, M. J., & Eriksson, J. W. (2019). Emerging role of SGLT-2 inhibitors for the treatment of obesity. Drugs, 79(3), 219–230.
pubmed: 30701480
pmcid: 6394798
doi: 10.1007/s40265-019-1057-0
Heerspink, H. J., Perkins, B. A., Fitchett, D. H., Husain, M., & Cherney, D. Z. (2016). Sodium glucose cotransporter 2 inhibitors in the treatment of diabetes mellitus: Cardiovascular and kidney effects, potential mechanisms, and clinical applications. Circulation, 134(10), 752–772.
pubmed: 27470878
doi: 10.1161/CIRCULATIONAHA.116.021887
Vallon, V., & Verma, S. (2021). Effects of SGLT2 inhibitors on kidney and cardiovascular function. Annual Review of Physiology, 83, 503–528.
pubmed: 33197224
doi: 10.1146/annurev-physiol-031620-095920
Packer, M., Anker, S. D., Butler, J., et al. (2020). Cardiovascular and renal outcomes with empagliflozin in heart failure. New England Journal of Medicine, 383(15), 1413–1424.
pubmed: 32865377
doi: 10.1056/NEJMoa2022190
McMurray, J. J. V., Docherty, K. F., & Jhund, P. S. (2020). Dapagliflozin in patients with heart failure and reduced ejection fraction. Reply. New England Journal of Medicine, 382(10), 973.
Verma, S., McGuire, D. K., & Kosiborod, M. N. (2020). Twotales: One story. Circulation, 142(23), 2201–2204.
pubmed: 32969716
doi: 10.1161/CIRCULATIONAHA.120.051122
Anker, S. D., Butler, J., Filippatos, G., et al. (2021). Empagliflozin in heart failure with a preserved ejection fraction. New England Journal of Medicine., 385(16), 1451–1461.
pubmed: 34449189
doi: 10.1056/NEJMoa2107038
Butler, J., Packer, M., Filippatos, G., et al. (2021). Effect of empagliflozin in patients with heart failure across the spectrum of left ventricular ejection fraction. European Heart Journal
Parizo, J. T., Goldhaber-Fiebert, J. D., Salomon, J. A., et al. (2021). Cost-effectiveness of Dapagliflozin for treatment of patients with heart failure with reduced ejection fraction. JAMA Cardiology
Bhatt, D. L., Szarek, M., Steg, P. G., et al. (2020). Sotagliflozin in patients with diabetes and recent worsening heart failure. New England Journal of Medicine., 384(2), 117–128.
pubmed: 33200892
doi: 10.1056/NEJMoa2030183
Bhatt, D. L., Szarek, M., Pitt, B., et al. (2020). Sotagliflozin in patients with diabetes and chronic kidney disease. New England Journal of Medicine., 384(2), 129–139.
pubmed: 33200891
doi: 10.1056/NEJMoa2030186
Heerspink, H. J. L., Stefánsson, B. V., Correa-Rotter, R., et al. (2020). Dapagliflozin in patients with chronic kidney disease. New England Journal of Medicine., 383(15), 1436–1446.
pubmed: 32970396
doi: 10.1056/NEJMoa2024816
Cannon, C. P., Pratley, R., Dagogo-Jack, S., et al. (2020). Cardiovascular outcomes with ertugliflozin in type 2 diabetes. New England Journal of Medicine., 383(15), 1425–1435.
pubmed: 32966714
doi: 10.1056/NEJMoa2004967
Cohn, J. N., Ferrari, R., & Sharpe, N. (2000). Cardiac remodeling—concepts and clinical implications: A consensus paper from an international forum on cardiac remodeling. Behalf of an International Forum on Cardiac Remodeling. Journal of the American College of Cardiology, 35(3), 569–582.
pubmed: 10716457
doi: 10.1016/S0735-1097(99)00630-0
Azevedo, P. S., Polegato, B. F., Minicucci, M. F., Paiva, S. A. R., & Zornoff, L. A. M. (2016). Cardiac remodeling: Concepts, clinical impact, pathophysiological mechanisms and pharmacologic treatment. Arquivos Brasileiros de Cardiologia, 106(1), 62–69.
pubmed: 26647721
pmcid: 4728597
Konstam, M. A., Kramer, D. G., Patel, A. R., Maron, M. S., & Udelson, J. E. (2011). Left ventricular remodeling in heart failure: Current concepts in clinical significance and assessment. JACC: Cardiovascular Imaging, 4(1), 98–108.
pubmed: 21232712
Azevedo, P. S., Polegato, B. F., Minicucci, M. F., Paiva, S. A., & Zornoff, L. A. (2016). Cardiac remodeling: Concepts, clinical impact, pathophysiological mechanisms and pharmacologic treatment. Arquivos Brasileiros de Cardiologia, 106(1), 62–69.
pubmed: 26647721
pmcid: 4728597
Kurosaki, E., & Ogasawara, H. (2013). Ipragliflozin and other sodium–glucose cotransporter-2 (SGLT2) inhibitors in the treatment of type 2 diabetes: Preclinical and clinical data. Pharmacology & Therapeutics., 139(1), 51–59.
doi: 10.1016/j.pharmthera.2013.04.003
Hammoudi, N., Jeong, D., Singh, R., et al. (2017). Empagliflozin improves left ventricular diastolic dysfunction in a genetic model of type 2 diabetes. Cardiovascular Drugs and Therapy, 31(3), 233–246.
pubmed: 28643218
pmcid: 6681671
doi: 10.1007/s10557-017-6734-1
Shiojima, I., Sato, K., Izumiya, Y., et al. (2005). Disruption of coordinated cardiac hypertrophy and angiogenesis contributes to the transition to heart failure. The Journal of Clinical Investigation, 115(8), 2108–2118.
pubmed: 16075055
pmcid: 1180541
doi: 10.1172/JCI24682
Younis, F., Leor, J., Abassi, Z., et al. (2018). Beneficial effect of the SGLT2 inhibitor empagliflozin on glucose homeostasis and cardiovascular parameters in the cohen rosenthal diabetic hypertensive (CRDH) rat. Journal of Cardiovascular Pharmacology and Therapeutics., 23(4), 358–371.
pubmed: 29627992
doi: 10.1177/1074248418763808
Park, S. H., Farooq, M. A., Gaertner, S., et al. (2020). Empagliflozin improved systolic blood pressure, endothelial dysfunction and heart remodeling in the metabolic syndrome ZSF1 rat. Cardiovascular Diabetology, 19(1), 19.
pubmed: 32070346
pmcid: 7026972
doi: 10.1186/s12933-020-00997-7
Weir-McCall, J. R., Lambert, M., Gandy, S. J., et al. (2018). Systemic arteriosclerosis is associated with left ventricular remodeling but not atherosclerosis: A TASCFORCE study. Journal of Cardiovascular Magnetic Resonance, 20(1), 7.
pubmed: 29382349
pmcid: 5791244
doi: 10.1186/s12968-018-0428-0
Santos-Gallego, C. G., Requena-Ibanez, J. A., San Antonio, R., et al. (2019). Empagliflozin ameliorates adverse left ventricular remodeling in nondiabetic heart failure by enhancing myocardial energetics. Journal of the American College of Cardiology, 73(15), 1931–1944.
pubmed: 30999996
doi: 10.1016/j.jacc.2019.01.056
Santos-Gallego, C. G., Requena-Ibanez, J. A., Antonio, R. S., et al. (2021). Empagliflozin ameliorates diastolic dysfunction and left ventricular fibrosis/stiffness in nondiabetic heart failure. JACC: Cardiovascular Imaging, 14(2), 393–407.
pubmed: 33129742
Paulus, W. J., & Tschöpe, C. (2013). A novel paradigm for heart failure with preserved ejection fraction: Comorbidities drive myocardial dysfunction and remodeling through coronary microvascular endothelial inflammation. Journal of the American College of Cardiology., 62(4), 263–271.
pubmed: 23684677
doi: 10.1016/j.jacc.2013.02.092
Yurista, S. R., Silljé, H. H. W., Oberdorf-Maass, S. U., et al. (2019). Sodium-glucose co-transporter 2 inhibition with empagliflozin improves cardiac function in non-diabetic rats with left ventricular dysfunction after myocardial infarction. European Journal of Heart Failure, 21(7), 862–873.
pubmed: 31033127
doi: 10.1002/ejhf.1473
Connelly, K. A., Zhang, Y., Desjardins, J. F., et al. (2020). Load-independent effects of empagliflozin contribute to improved cardiac function in experimental heart failure with reduced ejection fraction. Cardiovascular Diabetology, 19(1), 13.
pubmed: 32035482
pmcid: 7007658
doi: 10.1186/s12933-020-0994-y
Byrne, N. J., Parajuli, N., Levasseur, J. L., et al. (2017). Empagliflozin prevents worsening of cardiac function in an experimental model of pressure overload-induced heart failure. JACC Basic to Translational Science, 2(4), 347–354.
pubmed: 30062155
pmcid: 6034464
doi: 10.1016/j.jacbts.2017.07.003
Connelly, K. A., Zhang, Y., Visram, A., et al. (2019). Empagliflozin improves diastolic function in a nondiabetic rodent model of heart failure with preserved ejection fraction. JACC Basic to Translational Science, 4(1), 27–37.
pubmed: 30847416
pmcid: 6390677
doi: 10.1016/j.jacbts.2018.11.010
Bode, D., Semmler, L., Wakula, P., et al. (2021). Dual SGLT-1 and SGLT-2 inhibition improves left atrial dysfunction in HFpEF. Cardiovascular Diabetology, 20(1), 7.
pubmed: 33413413
pmcid: 7792219
doi: 10.1186/s12933-020-01208-z
Zhang, N., Feng, B., Ma, X., Sun, K., Xu, G., & Zhou, Y. (2019). Dapagliflozin improves left ventricular remodeling and aorta sympathetic tone in a pig model of heart failure with preserved ejection fraction. Cardiovascular Diabetology, 18(1), 107.
pubmed: 31429767
pmcid: 6702744
doi: 10.1186/s12933-019-0914-1
Connelly, K. A., Zhang, Y., Desjardins, J. F., Thai, K., & Gilbert, R. E. (2018). Dual inhibition of sodium-glucose linked cotransporters 1 and 2 exacerbates cardiac dysfunction following experimental myocardial infarction. Cardiovascular Diabetology, 17(1), 99.
pubmed: 29981571
pmcid: 6035399
doi: 10.1186/s12933-018-0741-9
Kang, S., Verma, S., Hassanabad, A. F., et al. (2020). Direct effects of empagliflozin on extracellular matrix remodelling in human cardiac myofibroblasts: Novel translational clues to explain EMPA-REG OUTCOME results. Canadian Journal of Cardiology, 36(4), 543–553.
pubmed: 31837891
doi: 10.1016/j.cjca.2019.08.033
Verma, S., Mazer, C. D., Yan, A. T., et al. (2019). Effect of empagliflozin on left ventricular mass in patients with type 2 diabetes mellitus and coronary artery disease. Circulation, 140(21), 1693–1702.
pubmed: 31434508
doi: 10.1161/CIRCULATIONAHA.119.042375
Mason, T., Coelho-Filho, O. R., Verma, S., et al. (2021). Empagliflozin reduces myocardial extracellular volume in patients with type 2 diabetes and coronary artery disease. JACC Cardiovasc Imaging
Shim, C. Y., Seo, J., Cho, I., et al. (2021). Randomized, Controlled trial to evaluate the effect of dapagliflozin on left ventricular diastolic function in patients with type 2 diabetes mellitus. Circulation, 143(5), 510–512.
pubmed: 33186508
doi: 10.1161/CIRCULATIONAHA.120.051992
Brown, A. J. M., Gandy, S., McCrimmon, R., Houston, J. G., Struthers, A. D., & Lang, C. C. (2020). A randomized controlled trial of dapagliflozin on left ventricular hypertrophy in people with type two diabetes: The DAPA-LVH trial. European Heart Journal., 41(36), 3421–3432.
pubmed: 32578850
pmcid: 8202417
doi: 10.1093/eurheartj/ehaa419
Nagai, T., Anzai, T., Kaneko, H., et al. (2011). C-reactive protein overexpression exacerbates pressure overload-induced cardiac remodeling through enhanced inflammatory response. Hypertension, 57(2), 208–215.
pubmed: 21220701
doi: 10.1161/HYPERTENSIONAHA.110.158915
Santos-Gallego, C. G., Vargas-Delgado, A. P., Requena-Ibanez, J. A., et al. (2021). Randomized trial of empagliflozin in nondiabetic patients with heart failure and reduced ejection fraction. Journal of the American College of Cardiology., 77(3), 243–255.
pubmed: 33197559
doi: 10.1016/j.jacc.2020.11.008
Lee, M. M. Y., Brooksbank, K. J. M., Wetherall, K., et al. (2021). Effect of empagliflozin on left ventricular volumes in patients with type 2 diabetes, or prediabetes, and heart failure with reduced ejection fraction (SUGAR-DM-HF). Circulation, 143(6), 516–525.
pubmed: 33186500
doi: 10.1161/CIRCULATIONAHA.120.052186
Omar, M., Jensen, J., Ali, M., et al. (2021). Associations of empagliflozin with left ventricular volumes, mass, and function in patients with heart failure and reduced ejection fraction: A substudy of the empire HF randomized clinical trial. JAMA Cardiology
Singh, J. S. S., Mordi, I. R., Vickneson, K., et al. (2020). Dapagliflozin versus placebo on left ventricular remodeling in patients with diabetes and heart failure: The REFORM trial. Diabetes Care, 43(6), 1356–1359.
pubmed: 32245746
pmcid: 7245350
doi: 10.2337/dc19-2187
Nassif, M. E., Qintar, M., Windsor, S. L., et al. (2021). Empagliflozin effects on pulmonary artery pressure in patients with heart failure. Circulation, 143(17), 1673–1686.
pubmed: 33550815
doi: 10.1161/CIRCULATIONAHA.120.052503
Wang, C., & Wang, X. (2015). The interplay between autophagy and the ubiquitin-proteasome system in cardiac proteotoxicity. Biochimica et Biophysica Acta, 1852(2), 188–194.
pubmed: 25092168
doi: 10.1016/j.bbadis.2014.07.028
Tarone, G., & Brancaccio, M. (2014). Keep your heart in shape: Molecular chaperone networks for treating heart disease. Cardiovascular Research, 102(3), 346–361.
pubmed: 24585203
doi: 10.1093/cvr/cvu049
Burchfield, J. S., Xie, M., & Hill, J. A. (2013). Pathological ventricular remodeling: Mechanisms: Part 1 of 2. Circulation, 128(4), 388–400.
pubmed: 23877061
pmcid: 3801217
doi: 10.1161/CIRCULATIONAHA.113.001878
Shirakabe, A., Zhai, P., Ikeda, Y., et al. (2016). Drp1-dependent mitochondrial autophagy plays a protective role against pressure overload-induced mitochondrial dysfunction and heart failure. Circulation, 133(13), 1249–1263.
pubmed: 26915633
pmcid: 4811679
doi: 10.1161/CIRCULATIONAHA.115.020502
Nakai, A., Yamaguchi, O., Takeda, T., et al. (2007). The role of autophagy in cardiomyocytes in the basal state and in response to hemodynamic stress. Nature Medicine, 13(5), 619–624.
pubmed: 17450150
doi: 10.1038/nm1574
Nishida, K., Kyoi, S., Yamaguchi, O., Sadoshima, J., & Otsu, K. (2009). The role of autophagy in the heart. Cell Death & Differentiation., 16(1), 31–38.
doi: 10.1038/cdd.2008.163
Mancini, S. J., Boyd, D., Katwan, O. J., et al. (2018). Canagliflozin inhibits interleukin-1beta-stimulated cytokine and chemokine secretion in vascular endothelial cells by AMP-activated protein kinase-dependent and -independent mechanisms. Science and Reports, 8(1), 5276.
doi: 10.1038/s41598-018-23420-4
Hawley, S. A., Ford, R. J., Smith, B. K., et al. (2016). The Na+/glucose cotransporter inhibitor canagliflozin activates AMPK by inhibiting mitochondrial function and increasing cellular AMP levels. Diabetes, 65(9), 2784–2794.
pubmed: 27381369
doi: 10.2337/db16-0058
Sayour, A. A., Korkmaz-Icoz, S., Loganathan, S., et al. (2019). Acute canagliflozin treatment protects against in vivo myocardial ischemia-reperfusion injury in non-diabetic male rats and enhances endothelium-dependent vasorelaxation. Journal of Translational Medicine, 17(1), 127.
pubmed: 30992077
pmcid: 6469222
doi: 10.1186/s12967-019-1881-8
Inoue, M. K., Matsunaga, Y., Nakatsu, Y., et al. (2019). Possible involvement of normalized Pin1 expression level and AMPK activation in the molecular mechanisms underlying renal protective effects of SGLT2 inhibitors in mice. Diabetology and Metabolic Syndrome, 11, 57.
pubmed: 31367234
pmcid: 6647324
doi: 10.1186/s13098-019-0454-6
Lu, Q., Liu, J., Li, X., et al. (2020). Empagliflozin attenuates ischemia and reperfusion injury through LKB1/AMPK signaling pathway. Molecular and Cellular Endocrinology, 501, 110642.
pubmed: 31759100
doi: 10.1016/j.mce.2019.110642
Kim, J. W., Lee, Y. J., You, Y. H., et al. (2018). Effect of sodium-glucose cotransporter 2 inhibitor, empagliflozin, and alpha-glucosidase inhibitor, voglibose, on hepatic steatosis in an animal model of type 2 diabetes. Journal of Cellular Biochemistry
Ye, Y., Jia, X., Bajaj, M., & Birnbaum, Y. (2018). Dapagliflozin attenuates Na(+)/H(+) exchanger-1 in cardiofibroblasts via AMPK activation. Cardiovascular Drugs and Therapy, 32(6), 553–558.
pubmed: 30367338
doi: 10.1007/s10557-018-6837-3
Kim, S., Jo, C. H., & Kim, G. H. (2019). Effects of empagliflozin on nondiabetic salt-sensitive hypertension in uninephrectomized rats. Hypertension Research, 42(12), 1905–1915.
pubmed: 31537914
pmcid: 8075936
doi: 10.1038/s41440-019-0326-3
Chang, Y. K., Choi, H., Jeong, J. Y., et al. (2016). Dapagliflozin, SGLT2 inhibitor, attenuates renal ischemia-reperfusion injury. PLoS One., 11(7), e0158810.
pubmed: 27391020
pmcid: 4938401
doi: 10.1371/journal.pone.0158810
Packer, M. (2020). Autophagy stimulation and intracellular sodium reduction as mediators of the cardioprotective effect of sodium–glucose cotransporter 2 inhibitors. European Journal of Heart Failure., 22(4), 618–628.
pubmed: 32037659
doi: 10.1002/ejhf.1732
Packer, M. (2020). SGLT2 inhibitors produce cardiorenal benefits by promoting adaptive cellular reprogramming to induce a state of fasting mimicry: A paradigm shift in understanding their mechanism of action. Diabetes Care, 43(3), 508–511.
pubmed: 32079684
doi: 10.2337/dci19-0074
Takimoto, E., & Kass, D. A. (2007). Role of oxidative stress in cardiac hypertrophy and remodeling. Hypertension, 49(2), 241–248.
pubmed: 17190878
doi: 10.1161/01.HYP.0000254415.31362.a7
Sabri, A., Hughie, H. H., & Lucchesi, P. A. (2003). Regulation of hypertrophic and apoptotic signaling pathways by reactive oxygen species in cardiac myocytes. Antioxidants & Redox Signaling, 5(6), 731–740.
doi: 10.1089/152308603770380034
Rababa’h, A. M., Guillory, A. N., Mustafa, R., & Hijjawi, T. (2018). Oxidative stress and cardiac remodeling: An updated edge. Current Cardiology Reviews, 14(1), 53–59.
pubmed: 29332590
pmcid: 5872263
doi: 10.2174/1573403X14666180111145207
Li, C., Zhang, J., Xue, M., et al. (2019). SGLT2 inhibition with empagliflozin attenuates myocardial oxidative stress and fibrosis in diabetic mice heart. Cardiovascular Diabetology, 18(1), 15.
pubmed: 30710997
pmcid: 6359811
doi: 10.1186/s12933-019-0816-2
Campos, D. H., Leopoldo, A. S., Lima-Leopoldo, A. P., et al. (2014). Obesity preserves myocardial function during blockade of the glycolytic pathway. Arquivos Brasileiros de Cardiologia, 103(4), 330–337.
pubmed: 25352507
pmcid: 4206364
Santos, P. P., Oliveira, F., Ferreira, V. C., et al. (2014). The role of lipotoxicity in smoke cardiomyopathy. PLoS One, 9(12), e113739.
pubmed: 25462161
pmcid: 4252176
doi: 10.1371/journal.pone.0113739
Ferrannini, E., Mark, M., & Mayoux, E. (2016). CV Protection in the EMPA-REG OUTCOME Trial: A “thrifty substrate” hypothesis. Diabetes Care, 39(7), 1108–1114.
pubmed: 27289126
doi: 10.2337/dc16-0330
Byrne, N. J., Soni, S., Takahara, S., et al. (2020). Chronically elevating circulating ketones can reduce cardiac inflammation and blunt the development of heart failure. Circulation: Heart Failure, 13(6), e006573.
Maejima, Y. (2019). SGLT2 inhibitors play a salutary role in heart failure via modulation of the mitochondrial function. Frontiers in Cardiovascular Medicine, 6, 186.
pubmed: 31970162
doi: 10.3389/fcvm.2019.00186
Daniele, G., Xiong, J., Solis-Herrera, C., et al. (2016). Dapagliflozin enhances fat oxidation and ketone production in patients with type 2 diabetes. Diabetes Care, 39(11), 2036–2041.
pubmed: 27561923
pmcid: 5079607
doi: 10.2337/dc15-2688
Cai, T., Ke, Q., Fang, Y., et al. (2020). Sodium-glucose cotransporter 2 inhibition suppresses HIF-1alpha-mediated metabolic switch from lipid oxidation to glycolysis in kidney tubule cells of diabetic mice. Cell Death & Disease, 11(5), 390.
doi: 10.1038/s41419-020-2544-7
Lauritsen, K. M., Nielsen, B. R. R., Tolbod, L. P., et al. (2021). SGLT2 inhibition does not affect myocardial fatty acid oxidation or uptake, but reduces myocardial glucose uptake and blood flow in individuals with type 2 diabetes: A randomized double-blind, placebo-controlled crossover trial. Diabetes, 70(3), 800–808.
pubmed: 33334875
doi: 10.2337/db20-0921
Verma, S., Rawat, S., Ho, K. L., et al. (2018). Empagliflozin increases cardiac energy production in diabetes: Novel translational insights into the heart failure benefits of SGLT2 inhibitors. JACC Basic to Translational Science, 3(5), 575–587.
pubmed: 30456329
pmcid: 6234616
doi: 10.1016/j.jacbts.2018.07.006
Olgar, Y., Tuncay, E., Degirmenci, S., et al. (2020). Ageing-associated increase in SGLT2 disrupts mitochondrial/sarcoplasmic reticulum Ca(2+) homeostasis and promotes cardiac dysfunction. Journal of Cellular and Molecular Medicine, 24(15), 8567–8578.
pubmed: 32652890
pmcid: 7412693
doi: 10.1111/jcmm.15483
Takagi, S., Li, J., Takagaki, Y., et al. (2018). Ipragliflozin improves mitochondrial abnormalities in renal tubules induced by a high-fat diet. Journal of Diabetes Investigation, 9(5), 1025–1032.
pubmed: 29352520
pmcid: 6123054
doi: 10.1111/jdi.12802
Sun, M., Chen, M., Dawood, F., et al. (2007). Tumor necrosis factor-alpha mediates cardiac remodeling and ventricular dysfunction after pressure overload state. Circulation, 115(11), 1398–1407.
pubmed: 17353445
doi: 10.1161/CIRCULATIONAHA.106.643585
Schirone, L., Forte, M., Palmerio, S., et al. (2017). A review of the molecular mechanisms underlying the development and progression of cardiac remodeling. Oxidative Medicine and Cellular Longevity, 2017, 3920195.
pubmed: 28751931
pmcid: 5511646
doi: 10.1155/2017/3920195
Heerspink, H. J. L., Perco, P., Mulder, S., et al. (2019). Canagliflozin reduces inflammation and fibrosis biomarkers: A potential mechanism of action for beneficial effects of SGLT2 inhibitors in diabetic kidney disease. Diabetologia, 62(7), 1154–1166.
pubmed: 31001673
pmcid: 6560022
doi: 10.1007/s00125-019-4859-4
Kim, S. R., Lee, S. G., Kim, S. H., et al. (2020). SGLT2 inhibition modulates NLRP3 inflammasome activity via ketones and insulin in diabetes with cardiovascular disease. Nature Communications, 11(1), 2127.
pubmed: 32358544
pmcid: 7195385
doi: 10.1038/s41467-020-15983-6
Sokolova, M., Sjaastad, I., Louwe, M. C., et al. (2019). NLRP3 inflammasome promotes myocardial remodeling during diet-induced obesity. Frontiers in Immunology, 10, 1621.
pubmed: 31379826
pmcid: 6648799
doi: 10.3389/fimmu.2019.01621
Byrne, N. J., Matsumura, N., Maayah, Z. H., et al. (2020). Empagliflozin blunts worsening cardiac dysfunction associated with reduced NLRP3 (nucleotide-binding domain-like receptor protein 3) inflammasome activation in heart failure. Circulation: Heart Failure, 13(1), e006277.
Yerra, V. G., Batchu, S. N., Kabir, G., et al. (2021). Empagliflozin disrupts a Tnfrsf12a-mediated feed forward loop that promotes left ventricular hypertrophy. Cardiovascular Drugs and Therapy
Camici, P. G., & Lorenzoni, R. (1994). Microcirculation and remodelling. Cardiologia, 39(12 Suppl 1), 197–201.
pubmed: 7634267
Miličić, D., Jakuš, N., & Fabijanović, D. (2018). Microcirculation and heart failure. Current Pharmaceutical Design, 24(25), 2954–2959.
pubmed: 29938612
doi: 10.2174/1381612824666180625143232
Adingupu, D. D., Göpel, S. O., Grönros, J., et al. (2019). SGLT2 inhibition with empagliflozin improves coronary microvascular function and cardiac contractility in prediabetic ob/ob(-/-) mice. Cardiovascular Diabetology, 18(1), 16.
pubmed: 30732594
pmcid: 6366096
doi: 10.1186/s12933-019-0820-6
Juni, R. P., Kuster, D. W. D., Goebel, M., et al. (2019). Cardiac microvascular endothelial enhancement of cardiomyocyte function is impaired by inflammation and restored by empagliflozin. JACC Basic to Translational Science., 4(5), 575–591.
pubmed: 31768475
pmcid: 6872802
doi: 10.1016/j.jacbts.2019.04.003
Ott, C., Jumar, A., Striepe, K., et al. (2017). A randomised study of the impact of the SGLT2 inhibitor dapagliflozin on microvascular and macrovascular circulation. Cardiovascular Diabetology, 16(1), 26.
pubmed: 28231831
pmcid: 5324272
doi: 10.1186/s12933-017-0510-1
Herat, L. Y., Magno, A. L., Rudnicka, C., et al. (2020). SGLT2 inhibitor-induced sympathoinhibition: A novel mechanism for cardiorenal protection. JACC Basic to Translational Science, 5(2), 169–179.
pubmed: 32140623
pmcid: 7046513
doi: 10.1016/j.jacbts.2019.11.007
Verma, S. (2020). Are the cardiorenal benefits of SGLT2 inhibitors due to inhibition of the sympathetic nervous system? JACC Basic to Translational Science, 5(2), 180–182.
pubmed: 32142070
pmcid: 7046535
doi: 10.1016/j.jacbts.2020.01.011
Shimizu, W., Kubota, Y., Hoshika, Y., et al. (2020). Effects of empagliflozin versus placebo on cardiac sympathetic activity in acute myocardial infarction patients with type 2 diabetes mellitus: The EMBODY trial. Cardiovascular Diabetology., 19(1), 148.
pubmed: 32977831
pmcid: 7519555
doi: 10.1186/s12933-020-01127-z
Spiegel, J. (2010). Diagnostic and pathophysiological impact of myocardial MIBG scintigraphy in Parkinson’s disease. Parkinson’s Disease, 2010, 295346.
pubmed: 20975774
Garg, V., Verma, S., Connelly, K. A., et al. (2020). Does empagliflozin modulate the autonomic nervous system among individuals with type 2 diabetes and coronary artery disease? The EMPA-HEART CardioLink-6 Holter analysis. Metabology Open, 7, 100039.
doi: 10.1016/j.metop.2020.100039
Sag, C. M., Wagner, S., & Maier, L. S. (2013). Role of oxidants on calcium and sodium movement in healthy and diseased cardiac myocytes. Free Radical Biology & Medicine, 63, 338–349.
doi: 10.1016/j.freeradbiomed.2013.05.035
Makielski, J. C. (2016). Late sodium current: A mechanism for angina, heart failure, and arrhythmia. Trends in Cardiovascular Medicine, 26(2), 115–122.
pubmed: 26092781
doi: 10.1016/j.tcm.2015.05.006
Philippaert K, Kalyaanamoorthy S, Fatehi M, et al. The cardiac late sodium channel current is a molecular target for the sodium-glucose co-transporter 2 inhibitor empagliflozin. Circulation.0(0).
Uthman, L., Baartscheer, A., Bleijlevens, B., et al. (2018). Class effects of SGLT2 inhibitors in mouse cardiomyocytes and hearts: Inhibition of Na(+)/H(+) exchanger, lowering of cytosolic Na(+) and vasodilation. Diabetologia, 61(3), 722–726.
pubmed: 29197997
doi: 10.1007/s00125-017-4509-7
Baartscheer, A., Schumacher, C. A., Wüst, R. C., et al. (2017). Empagliflozin decreases myocardial cytoplasmic Na(+) through inhibition of the cardiac Na(+)/H(+) exchanger in rats and rabbits. Diabetologia, 60(3), 568–573.
pubmed: 27752710
doi: 10.1007/s00125-016-4134-x
Chung, Y. J., Park, K. C., Tokar, S., et al. (2020). Off-target effects of sodium-glucose co-transporter 2 blockers: Empagliflozin does not inhibit Na+/H+ exchanger-1 or lower [Na+]i in the heart. Cardiovascular Research
Tomek, J., & Bub, G. (2017). Hypertension-induced remodelling: On the interactions of cardiac risk factors. Journal of Physiology, 595(12), 4027–4036.
pubmed: 28217927
pmcid: 5471416
doi: 10.1113/JP273043
González, A., Ravassa, S., López, B., et al. (2018). Myocardial remodeling in hypertension. Hypertension, 72(3), 549–558.
pubmed: 30354762
doi: 10.1161/HYPERTENSIONAHA.118.11125
Tikkanen, I., Narko, K., Zeller, C., et al. (2015). Empagliflozin reduces blood pressure in patients with type 2 diabetes and hypertension. Diabetes Care, 38(3), 420–428.
pubmed: 25271206
doi: 10.2337/dc14-1096
Majewski, C., & Bakris, G. L. (2015). Blood pressure reduction: An added benefit of sodium–glucose cotransporter 2 inhibitors in patients with type 2 diabetes. Diabetes Care, 38(3), 429–430.
pubmed: 25715414
pmcid: 4876696
doi: 10.2337/dc14-1596
Oliva, R. V., & Bakris, G. L. (2014). Blood pressure effects of sodium-glucose co-transport 2 (SGLT2) inhibitors. Journal of the American Society of Hypertension, 8(5), 330–339.
pubmed: 24631482
doi: 10.1016/j.jash.2014.02.003
Kario, K., Okada, K., Kato, M., et al. (2019). Twenty-four-hour blood pressure-lowering effect of a sodium-glucose cotransporter 2 inhibitor in patients with diabetes and uncontrolled nocturnal hypertension. Circulation, 139(18), 2089–2097.
doi: 10.1161/CIRCULATIONAHA.118.037076
Kaesler, N., Babler, A., Floege, J., & Kramann, R. (2020). Cardiac remodeling in chronic kidney disease. Toxins (Basel), 12(3).
Rasić, S., Kulenović, I., Haracić, A., & Catović, A. (2004). Left ventricular hypertrophy and risk factors for its development in uraemic patients. Bosnian Journal of Basic Medical Sciences, 4(1), 34–40.
pubmed: 15628978
pmcid: 7245531
doi: 10.17305/bjbms.2004.3458
Kramann, R., Erpenbeck, J., Schneider, R. K., et al. (2014). Speckle tracking echocardiography detects uremic cardiomyopathy early and predicts cardiovascular mortality in ESRD. Journal of the American Society of Nephrology, 25(10), 2351–2365.
pubmed: 24700873
pmcid: 4178432
doi: 10.1681/ASN.2013070734
Heerspink, H. J. L., Stefansson, B. V., Correa-Rotter, R., et al. (2020). Dapagliflozin in patients with chronic kidney disease. New England Journal of Medicine, 383(15), 1436–1446.
pubmed: 32970396
doi: 10.1056/NEJMoa2024816
Perkovic, V., Jardine, M. J., Neal, B., et al. (2019). Canagliflozin and renal outcomes in type 2 diabetes and nephropathy. New England Journal of Medicine, 380(24), 2295–2306.
pubmed: 30990260
doi: 10.1056/NEJMoa1811744
Simon, T. G., Bamira, D. G., Chung, R. T., Weiner, R. B., & Corey, K. E. (2017). Nonalcoholic steatohepatitis is associated with cardiac remodeling and dysfunction. Obesity (Silver Spring), 25(8), 1313–1316.
doi: 10.1002/oby.21879
Salah, H. M., Pandey, A., Soloveva, A., et al. (2021). Relationship of nonalcoholic fatty liver disease and heart failure with preserved ejection fraction. JACC Basic to Translational Science, 6(11), 918–932.
pubmed: 34869957
pmcid: 8617573
doi: 10.1016/j.jacbts.2021.07.010
Xing, B., Zhao, Y., Dong, B., Zhou, Y., Lv, W., & Zhao, W. (2020). Effects of sodium-glucose cotransporter 2 inhibitors on non-alcoholic fatty liver disease in patients with type 2 diabetes: A meta-analysis of randomized controlled trials. Journal of Diabetes Investigation, 11(5), 1238–1247.
pubmed: 32083798
pmcid: 7477503
doi: 10.1111/jdi.13237
Nishiya, D., Omura, T., Shimada, K., et al. (2006). Effects of erythropoietin on cardiac remodeling after myocardial infarction. Journal of Pharmacological Sciences, 101(1), 31–39.
pubmed: 16717399
doi: 10.1254/jphs.FP0050966
Sano, M., & Goto, S. (2019). Possible mechanism of hematocrit elevation by sodium glucose cotransporter 2 inhibitors and associated beneficial renal and cardiovascular effects. Circulation, 139(17), 1985–1987.
pubmed: 31009585
doi: 10.1161/CIRCULATIONAHA.118.038881
Mazer, C. D., Hare, G. M. T., Connelly, P. W., et al. (2020). Effect of empagliflozin on erythropoietin levels, iron stores, and red blood cell morphology in patients with type 2 diabetes mellitus and coronary artery disease. Circulation, 141(8), 704–707.
pubmed: 31707794
doi: 10.1161/CIRCULATIONAHA.119.044235
Maruyama, T., Takashima, H., Oguma, H., et al. (2019). Canagliflozin improves erythropoiesis in diabetes patients with anemia of chronic kidney disease. Diabetes Technology & Therapeutics, 21(12), 713–720.
doi: 10.1089/dia.2019.0212