Rationale for the Use of Pirfenidone in Heart Failure With Preserved Ejection Fraction

Francesca Graziani, Rosa Lillo, Filippo Crea, Francesca Graziani, Rosa Lillo, Filippo Crea

Abstract

Heart failure with preserved ejection fraction (HFpEF) is a major public health problem with growing prevalence and poor outcomes, mainly due to the lack of an effective treatment. HFpEF pathophysiology is heterogeneous and complex. Recently a "new paradigm" has been proposed, suggesting that cardiovascular and non-cardiovascular coexisting comorbidities lead to a systemic inflammatory state, perturbing the physiology of the endothelium and the perivascular environment and engaging molecular pathways that ultimately converge to myocardial fibrosis. If inflammation and fibrosis are the "fil rouge" in the heterogeneous spectrum of HFpEF, anti-fibrotic and anti-inflammatory drugs may have a role in its treatment. Pirfenidone is an orally bioavailable drug with antifibrotic and anti-inflammatory properties already approved for the treatment of idiopathic pulmonary fibrosis. Pirfenidone has been recently tested in animal models of myocardial fibrosis with promising results. Here we will review the rationale underlying the potential therapeutic effect of Pirfenidone in HFpEF.

Keywords: heart failure; heart failure with preserved ejection fraction; idiopatic pulmonary fibrosis; inflammation; pirfenidone.

Conflict of interest statement

The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.

Copyright © 2021 Graziani, Lillo and Crea.

Figures

Figure 1
Figure 1
Comorbidity-Driven Microvascular Inflammation Theory in HFpEF. Accumulated risk factors as well as cardiac and non-cardiac comorbidities lead to a systemic inflammatory state and coronary microvascular inflammation. The endothelial dysfunction and perturbation of the physiology of the perivascular environment engage molecular pathways that ultimately converge to microvascular dysfunction and myocardial fibrosis causing HFpEF.
Figure 2
Figure 2
Common pathways between HFpEF and IPF and potential role of Pirfenidone as treatment for both diseases. Repetitive lung injuries over a genetically susceptible alveolar epithelium, activates inflammatory pathways and the overproduction of pro-fibrotic mediators like transforming growth factor (TGF)-β, enhancing fibroblast recruitment, and conversion to myofibroblast. Similarly, HFpEF comorbidities trigger microvascular inflammation converging to myocardial fibrosis. Pirfenidone, an antifibrotic and anti-inflammatory drug approved for clinical use in IPF, may be proposed for HFpEF treatment.

References

    1. Ponikowski P, Voors AA, Anker SD, Bueno H, Cleland JG, Coats AJ, et al. . 2016 ESC Guidelines for the diagnosis treatment of acute chronic heart failure: The Task Force for the diagnosis treatment of acute chronic heart failure of the European Society of Cardiology (ESC). Developed with the special contribution of the Heart Failure Association (HFA) of the ESC. Eur J Heart Fail. (2016) 18:891–975. 10.1093/eurheartj/ehw128
    1. D'Amario D, Migliaro S, Borovac JA, Restivo A, Vergallo R, Galli M, et al. . Microvascular dysfunction in heart failure with preserved ejection fraction. Front Physiol. (2019) 10:1347. 10.3389/fphys.2019.01347
    1. Owan TE, Hodge DO, Herges RM, Jacobsen SJ, Roger VL, Redfield MM. Trends in prevalence and outcome of heart failure with preserved ejection fraction. N Engl J Med. (2006) 355:251–9. 10.1056/NEJMoa052256
    1. Pfeffer MA, Shah AM, Borlaug BA. Heart failure with preserved ejection fraction in perspective. Circ Res. (2019) 124:1598–617. 10.1161/CIRCRESAHA.119.313572
    1. Burlew BS, Weber KT. Cardiac fibrosis as a cause of diastolic dysfunction. Herz. (2002) 27:92–8. 10.1007/s00059-002-2354-y
    1. Zile MR, Baicu CF. Biomarkers of diastolic dysfunction and myocardial fibrosis: application to heart failure with a preserved ejection fraction. J Cardiovasc Transl Res. (2013) 6:501–15. 10.1007/s12265-013-9472-1
    1. Graziani F, Varone F, Crea F, Richeldi L. Treating heart failure with preserved ejection fraction: learning from pulmonary fibrosis. Eur J Heart Fail. (2018) 20:1385–91. 10.1002/ejhf.1286
    1. Jaroch J, Łoboz-Grudzień K. Novel paradigms for heart failure with preserved ejection fraction. Przegl Lek. (2016) 73:413–8.
    1. Paulus WJ, Tschöpe C. A novel paradigm for heart failure with preserved ejection fraction: comorbidities drive myocardial dysfunction and remodeling through coronary microvascular endothelial inflammation. J Am Coll Cardiol. (2013) 62:263–71. 10.1016/j.jacc.2013.02.092
    1. Westermann D, Kasner M, Steendijk P, Spillmann F, Riad A, Weitmann K, et al. . Role of left ventricular stiffness in heart failure with normal ejection fraction. Circulation. (2008) 117:2051–60. 10.1161/CIRCULATIONAHA.107.716886
    1. Díez J. Profibrotic effects of angiotensin II in the heart: a matter of mediators. Hypertension. (2004) 43:1164–5. 10.1161/01.HYP.0000128620.57061.67
    1. Ammar KA, Redfield MM, Mahoney DW, Johnson M, Jacobsen SJ, Rodeheffer RJ. Central obesity: association with left ventricular dysfunction and mortality in the community. Am Heart J. (2008) 156:975–81. 10.1016/j.ahj.2008.06.018
    1. Redfield MM, Jacobsen SJ, Burnett JC, Jr, Mahoney DW, Bailey KR, Rodeheffer RJ. Burden of systolic and diastolic ventricular dysfunction in the community: appreciating the scope of the heart failure epidemic. JAMA. (2003) 289:194–202. 10.1001/jama.289.2.194
    1. Westermann D, Lindner D, Kasner M, Zietsch C, Savvatis K, Escher F, et al. . Cardiac inflammation contributes to changes in the extracellular matrix in patients with heart failure and normal ejection fraction. Circ Heart Fail. (2011) 4:44–52. 10.1161/CIRCHEARTFAILURE.109.931451
    1. Hage C, Michaëlsson E, Kull B, Miliotis T, Svedlund S, Linde C, et al. . Myeloperoxidase and related biomarkers are suggestive footprints of endothelial microvascular inflammation in HFpEF patients. ESC Heart Fail. (2020) 7:1534–46. 10.1002/ehf2.12700
    1. Matsubara J, Sugiyama S, Nozaki T, Sugamura K, Konishi M, Ohba K, et al. . Pentraxin 3 is a new inflammatory marker correlated with left ventricular diastolic dysfunction and heart failure with normal ejection fraction. J Am Coll Cardiol. (2011) 57:861–9. 10.1016/j.jacc.2010.10.018
    1. Edelmann F, Holzendorf V, Wachter R, Nolte K, Schmidt AG, Kraigher-Krainer E, et al. . Galectin-3 in patients with heart failure with preserved ejection fraction: results from the Aldo-DHF trial. Eur J Heart Fail. (2015) 17:214–23. 10.1002/ejhf.203
    1. Shah KB, Kop WJ, Christenson RH, Diercks DB, Henderson S, Hanson K, et al. . Prognostic utility of ST2 in patients with acute dyspnea and preserved left ventricular ejection fraction. Clin Chem. (2011) 57:874–82. 10.1373/clinchem.2010.159277
    1. Yamamoto E, Hirata Y, Tokitsu T, Kusaka H, Tabata N, Tsujita K, et al. . The clinical significance of plasma neopterin in heart failure with preserved left ventricular ejection fraction. ESC Heart Fail. (2016) 3:53–9. 10.1002/ehf2.12070
    1. Tromp J, Khan MAF, Mentz RJ, O'connor CM, Metra M, Dittrich HC, et al. . Biomarker profiles of acute heart failure patients with a mid-range ejection fraction. JACC Heart Fail. (2017) 5:507–17. 10.1016/j.jchf.2017.04.007
    1. Sanders-van Wijk S, Tromp J, Beussink-Nelson L, Hage C, Svedlund S, Saraste A, et al. . Proteomic evaluation of the comorbidity-inflammation paradigm in heart failure with preserved ejection fraction: results from the PROMIS-HFpEF study. Circulation. (2020) 142:2029–44. 10.1161/CIRCULATIONAHA.120.045810
    1. Crea F, Bairey Merz CN, Beltrame JF, Kaski JC, Ogawa H, Ong P, et al. . Coronary vasomotion disorders international study group (COVADIS). The parallel tales of microvascular angina and heart failure with preserved ejection fraction: a paradigm shift. Eur Heart J. (2017) 38:473–7. 10.1093/eurheartj/ehw461
    1. Pepine CJ, Petersen JW, Bairey Merz CN. A microvascular-myocardial diastolic dysfunctional state and risk for mental stress ischemia. A revised concept of ischemia during daily life. JACC Cardiovasc Imaging. (2014) 7:362–5. 10.1016/j.jcmg.2013.11.009
    1. Ikonomidis I, Tzortzis S, Triantafyllidi H, Parissis J, Papadopoulos C, Venetsanou K, et al. . Association of impaired left ventricular twisting-untwisting with vascular dysfunction, neurohumoral activation and impaired exercise capacity in hypertensive heart disease. Eur J Heart Fail. (2015) 17:1240–51. 10.1002/ejhf.403
    1. Mohammed SF, Hussain S, Mirzoyev SA, Edwards WD, Maleszewski JJ, Redfield MM. Coronary microvascular rarefaction and myocardial fibrosis in heart failure with preserved ejection fraction. Circulation. (2015) 131:550–9. 10.1161/CIRCULATIONAHA.114.009625
    1. Shah SJ, Lam CSP, Svedlund S, Saraste A, Hage C, Tan RS, et al. . Prevalence and correlates of coronary microvascular dysfunction in heart failure with preserved ejection fraction: PROMIS-HFpEF. Eur Heart J. (2018) 39:3439–50. 10.1093/eurheartj/ehy531
    1. Hage C, Svedlund S, Saraste A, Faxén UL, Benson L, Fermer ML, et al. . Association of coronary microvascular dysfunction with heart failure hospitalizations and mortality in heart failure with preserved ejection fraction: a follow-up in the PROMIS-HFpEF study. J Card Fail. (2020) 26:1016–21. 10.1016/j.cardfail.2020.08.010
    1. Taqueti VR, Solomon SD, Shah AM, Desai AS, Groarke JD, Osborne MT, et al. . Coronary microvascular dysfunction and future risk of heart failure with preserved ejection fraction. Eur Heart J. (2018) 39:840–9. 10.1093/eurheartj/ehx721
    1. Schelbert EB, Fridman Y, Wong TC, Abu Daya H, Piehler KM, Kadakkal A, et al. . Temporal relation between myocardial fibrosis and heart failure with preserved ejection fraction: association with baseline disease severity and subsequent outcome. JAMA Cardiol. (2017) 2:995–1006. 10.1001/jamacardio.2017.2511
    1. Zile MR, Baicu CF, Ikonomidis JS, Stroud RE, Nietert PJ, Bradshaw AD, et al. . Myocardial stiffness in patients with heart failure and a preserved ejection fraction: contributions of collagen and titin. Circulation. (2015) 131:1247–59. 10.1161/CIRCULATIONAHA.114.013215
    1. Rommel KP, von Roeder M, Latuscynski K, Oberueck C, Blazek S, Fengler K, et al. . Extracellular volume fraction for characterization of patients with heart failure and preserved ejection fraction. J Am Coll Cardiol. (2016) 67:1815–25. 10.1016/j.jacc.2016.02.018
    1. Schelbert EB, Wong TC, Gheorghiade M. Think small and examine the constituents of left ventricular hypertrophy and heart failure: cardiomyocytes versus fibroblasts, collagen, and capillaries in the interstitium. J Am Heart Assoc. (2015) 4:e002491. 10.1161/JAHA.115.002491
    1. Roy C, Slimani A, de Meester C, Amzulescu M, Pasquet A, Vancraeynest D, et al. . Associations and prognostic significance of diffuse myocardial fibrosis by cardiovascular magnetic resonance in heart failure with preserved ejection fraction. J Cardiovasc Magn Reson. (2018) 20:55. 10.1186/s12968-018-0477-4
    1. Borbély A, van der Velden J, Papp Z, Bronzwaer JG, Edes I, Stienen GJ, et al. . Cardiomyocyte stiffness in diastolic heart failure. Circulation. (2005) 111:774–81. 10.1161/01.CIR.0000155257.33485.6D
    1. Hara H, Takeda N, Komuro I. Pathophysiology and therapeutic potential of cardiac fibrosis. Inflamm Regen. (2017) 37:13. 10.1186/s41232-017-0046-5
    1. Wei C, Kim IK, Kumar S, Jayasinghe S, Hong N, Castoldi G, et al. . NF-κB mediated miR-26a regulation in cardiac fibrosis. J Cell Physiol. (2013) 228:1433–42. 10.1002/jcp.24296
    1. Liang H, Xu C, Pan Z, Zhang Y, Xu Z, Chen Y, et al. . The antifibrotic effects and mechanisms of microRNA-26a action in idiopathic pulmonary fibrosis. Mol Ther. (2014) 22:1122–33. 10.1038/mt.2014.42
    1. Cushing L, Kuang PP, Qian J, Shao F, Wu J, Little F, et al. . miR-29 is a major regulator of genes associated with pulmonary fibrosis. Am J Respir Cell Mol Biol. (2011) 45:287–94. 10.1165/rcmb.2010-0323OC
    1. Sassi Y, Avramopoulos P, Ramanujam D, Grüter L, Werfel S, Giosele S, et al. . Cardiac myocyte miR-29 promotes pathological remodeling of the heart by activating Wnt signaling. Nat Commun. (2017) 8:1614. 10.1038/s41467-017-01737-4
    1. Wyman AE, Noor Z, Fishelevich R, Lockatell V, Shah NG, Todd NW, et al. . Sirtuin 7 is decreased in pulmonary fibrosis and regulates the fibrotic phenotype of lung fibroblasts. Am J Physiol Lung Cell Mol Physiol. (2017) 312:L945–58. 10.1152/ajplung.00473.2016
    1. Araki S, Izumiya Y, Rokutanda T, Ianni A, Hanatani S, Kimura Y, et al. . Sirt7 contributes to myocardial tissue repair by maintaining transforming growth factor-β signaling pathway. Circulation. (2015) 132:1081–93. 10.1161/CIRCULATIONAHA.114.014821
    1. Cappetta D, Esposito G, Piegari E, Russo R, Ciuffreda LP, Rivellino A, et al. . SIRT1 activation attenuates diastolic dysfunction by reducing cardiac fibrosis in a model of anthracycline cardiomyopathy. Int J Cardiol. (2016) 205:99–110. 10.1016/j.ijcard.2015.12.008
    1. Rong L, Wu J, Wang W, Zhao RP, Xu XW, Hu D. Sirt 1 activator attenuates thebleomycin-induced lung fibrosis in mice via inhibiting epithelial-to-mesenchymal transition (EMT). Eur Rev Med Pharmacol Sci. (2016) 20:2144–50.
    1. Bindu S, Pillai VB, Kanwal A, Samant S, Mutlu GM, Verdin E, et al. . SIRT3 blocks myofibroblast differentiation and pulmonary fibrosis by preventing mitochondrial DNA damage. Am J Physiol Lung Cell Mol Physiol. (2017) 312:L68–78. 10.1152/ajplung.00188.2016
    1. Guo X, Yan F, Shan X, Li J, Yang Y, Zhang J, et al. . SIRT3 inhibits Ang II-induced transdifferentiation of cardiac fibroblasts through β-catenin/PPAR-γ signaling. Life Sci. (2017) 186:111–7. 10.1016/j.lfs.2017.07.030
    1. Zhang ZZ, Cheng YW, Jin HY, Chang Q, Shang QH, Xu YL, et al. . The sirtuin 6 prevents angiotensin II-mediated myocardial fibrosis and injury by targeting AMPK-ACE2 signaling. Oncotarget. (2017) 8:72302–14. 10.18632/oncotarget.20305
    1. Tian K, Chen P, Liu Z, Si S, Zhang Q, Mou Y, et al. . Sirtuin 6 inhibits epithelial to mesenchymal transition during idiopathic pulmonary fibrosis via inactivating TGF-β1/Smad3 signaling. Oncotarget. (2017) 8:61011–24. 10.18632/oncotarget.17723
    1. Cunningham JW, Claggett BL, O'Meara E, Prescott MF, Pfeffer MA, Shah SJ, et al. . Effect of sacubitril/valsartan on biomarkers of extracellular matrix regulation in patients with HFpEF. J Am Coll Cardiol. (2020) 76:503–14. 10.1016/j.jacc.2020.05.072
    1. Cleland JG, Tendera M, Adamus J, Freemantle N, Polonski L, Taylor J. PEP-CHF investigators. The perindopril in elderly people with chronic heart failure (PEP-CHF) study. Eur Heart J. (2006) 27:2338–45. 10.1093/eurheartj/ehl250
    1. Massie BM, Carson PE, McMurray JJ, Komajda M, McKelvie R, Zile MR, et al. . I-PRESERVE investigators. Irbesartan in patients with heart failure and preserved ejection fraction. N Engl J Med. (2008) 359:2456–67. 10.1056/NEJMoa0805450
    1. Yusuf S, Pfeffer MA, Swedberg K, Granger CB, Held P, McMurray JJ, et al. . CHARM investigators and committees. Effects of candesartan in patients with chronic heart failure and preserved left-ventricular ejection fraction: the CHARM-Preserved Trial. Lancet. (2003) 362:777–81. 10.1016/S0140-6736(03)14285-7
    1. Kitzman DW, Hundley WG, Brubaker PH, Morgan TM, Moore JB, Stewart KP, et al. . A randomized double-blind trial of enalapril in older patients with heart failure and preserved ejection fraction: effects on exercise tolerance and arterial distensibility. Circ Heart Fail. (2010) 3:477–85. 10.1161/CIRCHEARTFAILURE.109.898916
    1. Conraads VM, Metra M, Kamp O, De Keulenaer GW, Pieske B, Zamorano J, et al. . Effects of the long-term administration of nebivolol on the clinical symptoms, exercise capacity, and left ventricular function of patients with diastolic dysfunction: results of the ELANDD study. Eur J Heart Fail. (2012) 14:219–25. 10.1093/eurjhf/hfr161
    1. Yamamoto K, Origasa H, Hori M, J-DHF Investigators. Effects of carvedilol on heart failure with preserved ejection fraction: the Japanese Diastolic Heart Failure Study (J-DHF). Eur J Heart Fail. (2013) 15:110–8. 10.1093/eurjhf/hfs141
    1. Edelmann F, Wachter R, Schmidt AG, Kraigher-Krainer E, Colantonio C, Kamke W, et al. . Aldo-DHF Investigators. Effect of spironolactone on diastolic function and exercise capacity in patients with heart failure with preserved ejection fraction: the Aldo-DHF randomized controlled trial. JAMA. (2013) 309:781–91. 10.1001/jama.2013.905
    1. Pitt B, Pfeffer MA, Assmann SF, Boineau R, Anand IS, Claggett B. Spironolactone for heart failure with preserved ejection fraction. N Engl J Med. (2014) 370:1383–92. 10.1056/NEJMoa1313731
    1. Solomon SD, McMurray JJV, Anand IS, Ge J, Lam CSP, Maggioni AP. Angiotensin-neprilysin inhibition in heart failure with preserved ejection fraction. N Engl J Med. (2019) 381:1609–20. 10.1056/NEJMoa1908655
    1. Wachter R, Shah SJ, Cowie MR, Szecsödy P, Shi V, Ibram G, et al. . Angiotensin receptor neprilysin inhibition versus individualized RAAS blockade: design and rationale of the PARALLAX trial. ESC Heart Fail. (2020) 7:856–64. 10.1002/ehf2.12694
    1. Ahmed A, Rich MW, Fleg JL, Zile MR, Young JB, Kitzman DW, et al. . Effects of digoxin on morbidity and mortality in diastolic heart failure: the ancillary digitalis investigation group trial. Circulation. (2006) 114:397–403. 10.1161/CIRCULATIONAHA.106.628347
    1. Komajda M, Isnard R, Cohen-Solal A, Metra M, Pieske B, Ponikowski P, et al. . prEserveD left ventricular ejectIon fraction chronic heart Failure with ivabradine studY (EDIFY) Investigators. Effect of ivabradine in patients with heart failure with preserved ejection fraction: the EDIFY randomized placebo-controlled trial. Eur J Heart Fail. (2017) 19:1495–503. 10.1002/ejhf.876
    1. Shah SJ, Voors AA, McMurray JJV, Kitzman DW, Viethen T, Bomfim Wirtz A, et al. . Effect of neladenoson bialanate on exercise capacity among patients with heart failure with preserved ejection fraction: a randomized clinical trial. JAMA. (2019) 321:2101–12. 10.1001/jama.2019.6717
    1. Redfield MM, Anstrom KJ, Levine JA, Koepp GA, Borlaug BA, Chen HH, et al. . Isosorbide mononitrate in heart failure with preserved ejection fraction. N Engl J Med. (2015) 373:2314–24. 10.1056/NEJMoa1510774
    1. Borlaug BA, Anstrom KJ, Lewis GD, Shah SJ, Levine JA, Koepp GA, et al. . Effect of inorganic nitrite vs placebo on exercise capacity among patients with heart failure with preserved ejection fraction: the INDIE-HFpEF randomized clinical trial. JAMA. (2018) 320:1764–73. 10.1001/jama.2018.14852
    1. Redfield MM, Chen HH, Borlaug BA, Semigran MJ, Lee KL, Lewis G, et al. . RELAX trial. Effect of phosphodiesterase-5 inhibition on exercise capacity and clinical status in heart failure with preserved ejection fraction: a randomized clinical trial. JAMA. (2013) 309:1268–77. 10.1001/jama.2013.2024
    1. Hoendermis ES, Liu LC, Hummel YM, van der Meer P, de Boer RA, Berger RM, et al. . Effects of sildenafil on invasive haemodynamics and exercise capacity in heart failure patients with preserved ejection fraction and pulmonary hypertension: a randomized controlled trial. Eur Heart J. (2015) 36:2565–73. 10.1093/eurheartj/ehv336
    1. Pieske B, Maggioni AP, Lam CSP, Pieske-Kraigher E, Filippatos G, Butler J, et al. . Vericiguat in patients with worsening chronic heart failure and preserved ejection fraction: results of the SOluble guanylate Cyclase stimulatoR in heArT failurE patientS with PRESERVED EF (SOCRATES-PRESERVED) study. Eur Heart J. (2017) 38:1119–27. 10.1093/eurheartj/ehw593
    1. Armstrong PW, Lam CSP, Anstrom KJ, Ezekowitz J, Hernandez AF, O'Connor CM, et al. . VITALITY-HFpEF study group. Effect of vericiguat vs placebo on quality of life in patients with heart failure and preserved ejection fraction: the VITALITY-HFpEF randomized clinical trial. JAMA. (2020) 324:1512–21. 10.1001/jama.2020.15922
    1. Udelson JE, Lewis GD, Shah SJ, Zile MR, Redfield MM, Burnett J, Jr, et al. . Effect of praliciguat on peak rate of oxygen consumption in patients with heart failure with preserved ejection fraction: the CAPACITY HFpEF randomized clinical trial. JAMA. (2020) 324:1522–31. 10.1001/jama.2020.16641
    1. Glezeva N, Baugh JA. Role of inflammation in the pathogenesis of heart failure with preserved ejection fraction and its potential as a therapeutic target. Heart Fail Rev. (2014) 19:681–94. 10.1007/s10741-013-9405-8
    1. Van Tassell BW, Arena R, Biondi-Zoccai G, Canada JM, Oddi C, Abouzaki NA, et al. . Effects of interleukin-1 blockade with anakinra on aerobic exercise capacity in patients with heart failure and preserved ejection fraction (from the D-HART pilot study). Am J Cardiol. (2014) 113:321–7. 10.1016/j.amjcard.2013.08.047
    1. Van Tassell BW, Trankle CR, Canada JM, Carbone S, Buckley L, Kadariya D, et al. . IL-1 blockade in patients with heart failure with preserved ejection fraction. Circ Heart Fail. (2018) 11:e005036. 10.1161/CIRCHEARTFAILURE.118.005036
    1. Del Buono MG, Iannaccone G, Scacciavillani R, Carbone S, Camilli M, Niccoli G, et al. . Heart failure with preserved ejection fraction diagnosis and treatment: an updated review of the evidence. Prog Cardiovasc Dis. (2020) 63:570–84. 10.1016/j.pcad.2020.04.011
    1. Wiviott SD, Raz I, Bonaca MP, Mosenzon O, Kato ET, Cahn A, et al. . Dapagliflozin and cardiovascular outcomes in type 2 diabetes. N Engl J Med. (2019) 380:347–57. 10.1056/NEJMoa1812389
    1. Zinman B, Wanner C, Lachin JM, Fitchett D, Bluhmki E, Hantel S, et al. . Empagliflozin, cardiovascular outcomes, and mortality in type 2 diabetes. N Engl J Med. (2015) 373:2117–28. 10.1056/NEJMoa1504720
    1. Juni RP, Kuster DWD, Goebel M, Helmes M, Musters RJP, van der Velden J, et al. . Cardiac microvascular endothelial enhancement of cardiomyocyte function is impaired by inflammation and restored by empagliflozin. JACC Basic Transl Sci. (2019) 4:575–91. 10.1016/j.jacbts.2019.04.003
    1. Cappetta D, De Angelis A, Ciuffreda LP, Coppini R, Cozzolino A, Miccichè A, et al. . Amelioration of diastolic dysfunction by dapagliflozin in a non-diabetic model involves coronary endothelium. Pharmacol Res. (2020) 157:104781. 10.1016/j.phrs.2020.104781
    1. Richeldi L, Yasothan U, Kirkpatrick P. Pirfenidone. Nat Rev Drug Discov. (2011) 10:489–90. 10.1038/nrd3495
    1. Togami K, Kanehira Y, Tada H. Pharmacokinetic evaluation of tissue distribution of pirfenidone and its metabolites for idiopathic pulmonary fibrosis therapy. Biopharm Drug Dispos. (2015) 36:205–15. 10.1002/bdd.1932
    1. Aimo A, Cerbai E, Bartolucci G, Adamo L, Barison A, Lo Surdo G, et al. . Pirfenidone is a cardioprotective drug: mechanisms of action and preclinical evidence. Pharmacol Res. (2020) 155:104694. 10.1016/j.phrs.2020.104694
    1. Cottin V, Koschel D, Günther A, Albera C, Azuma A, Sköld CM, et al. . Long-term safety of pirfenidone: results of the prospective, observational PASSPORT study. ERJ Open Res. (2018) 4:00084–2018. 10.1183/23120541.00084-2018
    1. Shi Q, Liu X, Bai Y, Cui C, Li J, Li Y, et al. . In vitro effects of pirfenidone on cardiac fibroblasts: proliferation, myofibroblast differentiation, migration and cytokine secretion. PLoS ONE. (2011) 6:e28134. 10.1371/journal.pone.0028134
    1. Wang Y, Wu Y, Chen J, Zhao S, Li H. Pirfenidone attenuates cardiac fibrosis in a mouse model of TAC-induced left ventricular remodeling by suppressing NLRP3 inflammasome formation. Cardiology. (2013) 126:1–11. 10.1159/000351179
    1. Giri SN, Al-Bayati MA, Du X, Schelegle E, Mohr FC, Margolin SB. Amelioration of doxorubicin-induced cardiac and renal toxicity by pirfenidone in rats. Cancer Chemother Pharmacol. (2004) 53:141–50. 10.1007/s00280-003-0703-z
    1. Van Erp C, Irwin NG, Hoey AJ. Long-term administration of pirfenidone improves cardiac function in mdx mice. Muscle Nerve. (2006) 34:327–34. 10.1002/mus.20590
    1. Hisatomi K, Mukae H, Sakamoto N, Ishimatsu Y, Kakugawa T, Hara S, et al. . Pirfenidone inhibits TGF-β1-induced over-expression of collagen type I and heat shock protein 47 in A549 cells. BMC Pulm Med. (2012) 12:24. 10.1186/1471-2466-12-24
    1. Miric G, Dallemagne C, Endre Z, Margolin S, Taylor SM, Brown L. Reversal of cardiac and renal fibrosis by pirfenidone and spironolactone in streptozotocin-diabetic rats. Br J Pharmacol. (2001) 133:687–94. 10.1038/sj.bjp.0704131
    1. Mirkovic S, Seymour AM, Fenning A, Strachan A, Margolin SB, Taylor SM, et al. . Attenuation of cardiac fibrosis by pirfenidone and amiloride in DOCA-salt hypertensive rats. Br J Pharmacol. (2002) 135:961–8. 10.1038/sj.bjp.0704539
    1. Yamazaki T, Yamashita N, Izumi Y, Nakamura Y, Shiota M, Hanatani A, et al. . The antifibrotic agent pirfenidone inhibits angiotensin II-induced cardiac hypertrophy in mice. Hypertens Res. (2012) 35:34–40. 10.1038/hr.2011.139
    1. Yamagami K, Oka T, Wang Q, Ishizu T, Lee JK, Miwa K, et al. . Pirfenidone exhibits cardioprotective effects by regulating myocardial fibrosis and vascular permeability in pressure-overloaded hearts. Am J Physiol Heart Circ Physiol. (2015) 309:H512–22. 10.1152/ajpheart.00137.2015
    1. Lee KW, Everett TH, IV, Rahmutula D, Guerra JM, Wilson E, Ding C, et al. . Pirfenidone prevents the development of a vulnerable substrate for atrial fibrillation in a canine model of heart failure. Circulation. (2006) 114:1703–12. 10.1161/CIRCULATIONAHA.106.624320
    1. Nguyen DT, Ding C, Wilson E, Marcus GM, Olgin JE. Pirfenidone mitigates left ventricular fibrosis and dysfunction after myocardial infarction and reduces arrhythmias. Heart Rhythm. (2010) 7:1438–45. 10.1016/j.hrthm.2010.04.030
    1. Lewis GA, Schelbert EB, Naish JH, Bedson E, Dodd S, Eccleson H, et al. . Pirfenidone in heart failure with preserved ejection fraction-rationale and design of the PIROUETTE trial. Cardiovasc Drugs Ther. (2019) 33:461–70. 10.1007/s10557-019-06876-y
    1. Alansari S, Southern B, Riaz H, Sharma V, Borowski A, Tang W. Responses to pirfenidone treatment in patients with idiopathic pulmonary fibrosis is not associated with changes in echocardiographic parameters of left ventricular structure and function. J Card Fail. (2019) 25:S27. 10.1016/j.cardfail.2019.07.074
    1. AlAnsari S, Southern BD, Sharma V, Mahalwar G, Tang WHW. Pirfenidone is associated with decreased indexed end diastolic and systolic volumes in patients with HFpEF and a known history of idiopathic pulmonary fibrosis. J Card Fail. (2020) 26:S25. 10.1016/j.cardfail.2020.09.080

Source: PubMed

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