Molecular Mechanisms for Pathophysiology and Therapy of Cardiac Dysfunction in Heart Failure
Abstract
Extensive work over the past 6 decades in the field of cardiovascular medicine has revealed that haemodynamic, hormonal, metabolic, cellular and molecular mechanisms of heart failure are not only complex but are also dependent upon the type and stage of heart disease. Although various agents such as β-adrenoreceptor blockers, angiotensin converting enzyme inhibitors, angiotensin II receptor antagonists and vasodilators are available for the treatment of heart failure, these interventions delay the progression of heart failure without reducing mortality and morbidity. In this article, literature on the pathophysiology of heart failure due to myocardial infarction and haemodynamic overload to identify molecular targets for future drug development is reviewed. Particularly, objective was to focus on the mechanisms of heart failure involving pathways for the generation of oxidative stress, myocardial inflammation and Ca2+-handling abnormalities. It is evident that elevated levels of plasma vasoactive hormones and growth factors as well as increased preload and afterload play critical roles in stimulating various signal transduction pathways for the occurrence of increased ventricular wall stress, cardiac remodelling and subsequent cardiac dysfunction. These alterations are associated with development of oxidative stress, myocardial inflammation, endothelial dysfunction, metabolic defects, intracellular Ca2+-handling abnormalities, apoptosis, fibrosis and changes in the extracellular matrix. In view of such pathogenic abnormalities in failing hearts, it is suggested these parameters may serve as excellent targets for drug development for the therapy of heart failure. In addition, there occurs activation of proteases and phospholipases as well as depression in cardiac gene expression for the induction of subcellular remodelling in failing hearts and thus interventions affecting these parameters may also be considered to exert beneficial effects in heart failure. There is also an urgent need to develop some existing and newer agents such as metabolic inhibitors, antioxidants and sodium-glucose cotransporter-2 inhibitors as well as gene and RNA based therapies for the treatment of heart failure.
References
Smith, WM. Epidemiology of congestive heart failure. Am J Cardiol. 1985;55(2):3A-8A. doi: 10.1016/0002-9149(85)90789-1.
Parmley, WW. Pathophysiology of congestive heart failure. Am J Cardiol. 1985;56(2):7A-11A. doi: 10.1016/0002-9149(85)91199-3.
Brophy, JM. Epidemiology of congestive heart failure. Canadian data from 1970 to 1989. Can J Cardiol. 1992; 8(5):495-8. PMID: 1617529.
Dhalla NS, Afzal N, Beamish RE, Naimark B, Takeda N, Nagano M. Pathophysiology of cardiac dysfunction in congestive heart failure. Can J Cardiol. 1993;9(10):873-87. PMID: 8281476.
Cohn JN, Ferrari R, Sharpe N. Cardiac remodeling--concepts and clinical implications: a consensus paper from an international forum on cardiac remodeling. Behalf of an International Forum on Cardiac Remodeling. J Am Coll Cardiol. 2000;35(3):569-82. doi: 10.1016/s0735-1097(99)00630-0.
Jessup M, Brozena S. Heart failure. N Engl J Med. 2003;348(20):2007-18. doi: 10.1056/NEJMra021498.
Dhalla NS, Dent MR, Tappia PS, Sethi R, Barta J, Goyal RK. Subcellular remodeling as a viable target for the treatment of congestive heart failure. J Cardiovasc Pharmacol Ther. 2006;11(1):31-45. doi: 10.1177/107424840601100103.
Dhalla NS, Rangi S, Babick AP, Zieroth S, Elimban V. Cardiac remodeling and subcellular defects in heart failure due to myocardial infarction and aging. Heart Fail Rev. 2012;17(4-5):671-81. doi: 10.1007/s10741-011-9278-7.
Francis GS. Development of arrhythmias in the patient with congestive heart failure: pathophysiology, prevalence and prognosis. Am J Cardiol. 1986;57(3):3B-7B. doi: 10.1016/0002-9149(86)90991-4.
Packer M. Neurohormonal interactions and adaptations in congestive heart failure. Circulation. 1988;77(4):721-30. doi: 10.1161/01.cir.77.4.721.
Dhalla NS, Elimban V, Shah AK, Nusier M. Mechanisms of cardiac dysfunction in heart failure due to myocardial infarction. J Integ Cardiol Open Access. 2019;2(4):2674-89. doi:10.31487/j.JICOA.2019.04.12.
Dhalla NS, Bhullar SK, Shah AK. Future scope and challenges for congestive heart failure: moving toward development of pharmacotherapy. Can J Physiol Pharmacol. 2022;100(9):834-47. doi: 10.1139/cjpp-2022-0154.
Dhalla NS, Mota KO, Elimban V, Shah AK, de Vasconcelos CML, Bhullar SK. Role of vasoactive hormone-induced signal transduction in cardiac hypertrophy and heart failure. Cells. 2024;13(10):856. doi: 10.3390/cells13100856.
Roger VL, Go AS, Lloyd-Jones DM, Benjamin EJ, Berry JD, Borden WB, et al. American Heart Association Statistics Committee and Stroke Statistics Subcommittee. Heart disease and stroke statistics--2012 update: a report from the American Heart Association. Circulation. 2012;125(1):e2-e220. doi: 10.1161/CIR.0b013e31823ac046.
Heidenreich PA, Albert NM, Allen LA, Bluemke DA, Butler J, Fonarow GC, et al. Forecasting the impact of heart failure in the United States: a policy statement from the American Heart Association. Circ Heart Fail. 2013;6(3):606-19. doi: 10.1161/HHF.0b013e318291329a.
Felker GM, Thompson RE, Hare JM, Hruban RH, Clemetson DE, Howard DL, et al. Underlying causes and long-term survival in patients with initially unexplained cardiomyopathy. N Engl J Med. 2000;342(15):1077-84. doi: 10.1056/NEJM200004133421502.
Levy D, Kenchaiah S, Larson MG, Benjamin EJ, Kupka MJ, Ho KK, et al. Long-term trends in the incidence of and survival with heart failure. N Engl J Med. 2002;347(18):1397-402. doi: 10.1056/NEJMoa020265.
McMurray JJ, Stewart S. Epidemiology, aetiology, and prognosis of heart failure. Heart. 2000;83(5):596-602. doi: 10.1136/heart.83.5.596.
Lloyd-Jones DM, Larson MG, Leip EP, Beiser A, D'Agostino RB, Kannel WB, Murabito JM, et al. Lifetime risk for developing congestive heart failure: the Framingham Heart Study. Circulation. 2002;106(24):3068-72. doi: 10.1161/01.cir.0000039105.49749.6f.
Maillet M, van Berlo JH, Molkentin JD. Molecular basis of physiological heart growth: fundamental concepts and new players. Nat Rev Mol Cell Biol. 2013;14(1):38-48. doi: 10.1038/nrm3495.
Lyon RC, Zanella F, Omens JH, Sheikh F. Mechanotransduction in cardiac hypertrophy and failure. Circ Res. 2015;116(8):1462-76. doi: 10.1161/CIRCRESAHA.116.304937.
Bernardo BC, Weeks KL, Pretorius L, McMullen JR. Molecular distinction between physiological and pathological cardiac hypertrophy: experimental findings and therapeutic strategies. Pharmacol Ther. 2010;128(1):191-227. doi: 10.1016/j.pharmthera.2010.04.005.
Molkentin JD, Dorn GW 2nd. Cytoplasmic signaling pathways that regulate cardiac hypertrophy. Annu Rev Physiol. 2001;63:391-426. doi: 10.1146/annurev.physiol.63.1.391.
Shimizu I, Minamino T. Physiological and pathological cardiac hypertrophy. J Mol Cell Cardiol. 2016;97:245-62. doi: 10.1016/j.yjmcc.2016.06.001.
Wikman-Coffelt J, Parmley WW, Mason DT. The cardiac hypertrophy process. Analyses of factors determining pathological vs. physiological development. Circ Res. 1979;45(6):697-707. doi: 10.1161/01.res.45.6.697.
Dhalla NS, Heyliger CE, Beamish RE, Innes IR. Pathophysiological aspects of myocardial hypertrophy. Can J Cardiol. 1987;3(4):183-96. PMID: 3036324.
Heineke J, Molkentin JD. Regulation of cardiac hypertrophy by intracellular signalling pathways. Nat Rev Mol Cell Biol. 2006;7(8):589-600. doi: 10.1038/nrm1983.
Oldfield CJ, Duhamel TA, Dhalla NS. Mechanisms for the transition from physiological to pathological cardiac hypertrophy. Can J Physiol Pharmacol. 2020;98(2):74-84. doi: 10.1139/cjpp-2019-0566.
Olson RE. Myocardial metabolism in congestive heart failure. J Chronic Dis. 1959;9(5):442-64. doi: 10.1016/0021-9681(59)90172-9.
Dhalla NS, Saini-Chohan HK, Rodriguez-Leyva D, Elimban V, Dent MR, Tappia PS. Subcellular remodelling may induce cardiac dysfunction in congestive heart failure. Cardiovasc Res. 2009;81(3):429-38. doi: 10.1093/cvr/cvn281.
Dhalla NS, Das PK, Sharma GP. Subcellular basis of cardiac contractile failure. J Mol Cell Cardiol. 1978;10(4):363-85. doi: 10.1016/0022-2828(78)90384-x.
Pfeffer MA, Braunwald E. Ventricular remodeling after myocardial infarction. Experimental observations and clinical implications. Circulation. 1990;81(4):1161-72. doi: 10.1161/01.cir.81.4.1161.
Opie LH, Commerford PJ, Gersh BJ, Pfeffer MA. Controversies in ventricular remodelling. Lancet. 2006;367(9507):356-67. doi: 10.1016/S0140-6736(06)68074-4.
Machackova J, Barta J, Dhalla NS. Myofibrillar remodeling in cardiac hypertrophy, heart failure and cardiomyopathies. Can J Cardiol. 2006;22(11):953-68. doi: 10.1016/s0828-282x(06)70315-4.
Sabbah HN, Goldstein S. Ventricular remodelling: consequences and therapy. Eur Heart J. 1993;14 Suppl C:24-9. doi: 10.1093/eurheartj/14.suppl_c.24.
Mudd JO, Kass DA. Tackling heart failure in the twenty-first century. Nature. 2008;451(7181):919-28. doi: 10.1038/nature06798.
Burchfield JS, Xie M, Hill JA. Pathological ventricular remodeling: mechanisms: part 1 of 2. Circulation. 2013;128(4):388-400. doi: 10.1161/CIRCULATIONAHA.113.001878.
Gaasch WH. Diagnosis and treatment of heart failure based on left ventricular systolic or diastolic dysfunction. JAMA. 1994;271(16):1276-80. PMID: 8151903.
Zile MR, Baicu CF, Gaasch WH. Diastolic heart failure--abnormalities in active relaxation and passive stiffness of the left ventricle. N Engl J Med. 2004;350(19):1953-9. doi: 10.1056/NEJMoa032566.
Zile MR, Gottdiener JS, Hetzel SJ, McMurray JJ, Komajda M, McKelvie R, et al. Prevalence and significance of alterations in cardiac structure and function in patients with heart failure and a preserved ejection fraction. Circulation. 2011;124(23):2491-501. doi: 10.1161/CIRCULATIONAHA.110.011031.
Zile MR, Kjellstrom B, Bennett T, Cho Y, Baicu CF, Aaron MF, et al. Effects of exercise on left ventricular systolic and diastolic properties in patients with heart failure and a preserved ejection fraction versus heart failure and a reduced ejection fraction. Circ Heart Fail. 2013;6(3):508-16. doi: 10.1161/CIRCHEARTFAILURE.112.000216.
Borlaug BA, Paulus WJ. Heart failure with preserved ejection fraction: pathophysiology, diagnosis, and treatment. Eur Heart J. 2011;32(6):670-9. doi: 10.1093/eurheartj/ehq426.
Ho JE, Lyass A, Lee DS, Vasan RS, Kannel WB, Larson MG, Levy D. Predictors of new-onset heart failure: differences in preserved versus reduced ejection fraction. Circ Heart Fail. 2013;6(2):279-86. doi: 10.1161/CIRCHEARTFAILURE.112.972828.
Borbély A, van der Velden J, Papp Z, Bronzwaer JG, Edes I, Stienen GJ, Paulus WJ. Cardiomyocyte stiffness in diastolic heart failure. Circulation. 2005;111(6):774-81. doi: 10.1161/01.CIR.0000155257.33485.6D.
Upadhya B, Haykowsky MJ, Kitzman DW. Therapy for heart failure with preserved ejection fraction: current status, unique challenges, and future directions. Heart Fail Rev. 2018;23(5):609-29. doi: 10.1007/s10741-018-9714-z.
Packer M. Drugs that ameliorate epicardial adipose tissue inflammation may have discordant effects in heart failure with a preserved ejection fraction as compared with a reduced ejection fraction. J Card Fail. 2019;25(12):986-1003. doi: 10.1016/j.cardfail.2019.09.002.
Pitt B, Pfeffer MA, Assmann SF, Boineau R, Anand IS, Claggett B, et al. Spironolactone for heart failure with preserved ejection fraction. N Engl J Med. 2014;370(15):1383-92. doi: 10.1056/NEJMoa1313731.
Kjeldsen SE, von Lueder TG, Smiseth OA, Wachtell K, Mistry N, Westheim AS, et al. Medical therapies for heart failure with preserved ejection fraction. Hypertension. 2020;75(1):23-32. doi: 10.1161/HYPERTENSIONAHA.119.14057.
Vaduganathan M, Claggett BL, Desai AS, Anker SD, Perrone SV, Janssens S, et al. Prior heart failure hospitalization, clinical outcomes, and response to sacubitril/valsartan compared with valsartan in HFpEF. J Am Coll Cardiol. 2020;75(3):245-54. doi: 10.1016/j.jacc.2019.11.003.
Anker SD, Butler J, Filippatos G, Ferreira JP, Bocchi E, Böhm M, et al. Empagliflozin in heart failure with a preserved ejection fraction. N Engl J Med. 2021;385(16):1451-61. doi: 10.1056/NEJMoa2107038.
Bhatt DL, Szarek M, Steg PG, Cannon CP, Leiter LA, McGuire DK, et al. Sotagliflozin in patients with diabetes and recent worsening heart failure. N Engl J Med. 2021;384(2):117-28. doi: 10.1056/NEJMoa2030183.
Nassif ME, Windsor SL, Borlaug BA, Kitzman DW, Shah SJ, Tang F, et al. The SGLT2 inhibitor dapagliflozin in heart failure with preserved ejection fraction: a multicenter randomized trial. Nat Med. 2021;27(11):1954-60. doi: 10.1038/s41591-021-01536-x.
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(3):251-9. doi: 10.1056/NEJMoa052256.
Guo X, Saini HK, Wang J, Gupta SK, Goyal RK, Dhalla NS. Prevention of remodeling in congestive heart failure due to myocardial infarction by blockade of the renin-angiotensin system. Expert Rev Cardiovasc Ther. 2005;3(4):717-32. doi: 10.1586/14779072.3.4.717.
Ju H, Zhao S, Jassal DS, Dixon IM. Effect of AT1 receptor blockade on cardiac collagen remodeling after myocardial infarction. Cardiovasc Res. 1997;35(2):223-32. doi: 10.1016/s0008-6363(97)00130-2.
Rouleau JL. The neurohormonal hypothesis and the treatment of heart failure. Can J Cardiol. 1996; 12: 3F–8F.
Rehsia NS, Dhalla NS. Mechanisms of the beneficial effects of beta-adrenoceptor antagonists in congestive heart failure. Exp Clin Cardiol. 2010;15(4):e86-95. PMID: 21264074.
Sabbah HN, Shimoyama H, Kono T, Gupta RC, Sharov VG, Scicli G, et al. Effects of long-term monotherapy with enalapril, metoprolol, and digoxin on the progression of left ventricular dysfunction and dilation in dogs with reduced ejection fraction. Circulation. 1994;89(6):2852-9. doi: 10.1161/01.cir.89.6.2852.
Pandey AK, Dhingra NK, Hibino M, Gupta V, Verma S. Sodium-glucose cotransporter 2 inhibitors in heart failure with reduced or preserved ejection fraction: a meta-analysis. ESC Heart Fail. 2022;9(2):942-6. doi: 10.1002/ehf2.13805.
Spertus JA, Birmingham MC, Nassif M, Damaraju CV, Abbate A, Butler J, et al. The SGLT2 inhibitor canagliflozin in heart failure: the CHIEF-HF remote, patient-centered randomized trial. Nat Med. 2022;28(4):809-13. doi: 10.1038/s41591-022-01703-8.
Heath R, Johnsen H, Strain WD, Evans M. Emerging horizons in heart failure with preserved ejection fraction: the role of SGLT2 inhibitors. Diabetes Ther. 2022;13(2):241-50. doi: 10.1007/s13300-022-01204-4.
Neri M, Fineschi V, Di Paolo M, Pomara C, Riezzo I, Turillazzi E, Cerretani D. Cardiac oxidative stress and inflammatory cytokines response after myocardial infarction. Curr Vasc Pharmacol. 2015;13(1):26-36. doi: 10.2174/15701611113119990003.
van der Pol A, van Gilst WH, Voors AA, van der Meer P. Treating oxidative stress in heart failure: past, present and future. Eur J Heart Fail. 2019;21(4):425-35. doi: 10.1002/ejhf.1320.
Sia YT, Lapointe N, Parker TG, Tsoporis JN, Deschepper CF, Calderone A, et al. Beneficial effects of long-term use of the antioxidant probucol in heart failure in the rat. Circulation. 2002;105(21):2549-55. doi: 10.1161/01.cir.0000016721.84535.00.
Ayoub KF, Pothineni NVK, Rutland J, Ding Z, Mehta JL. Immunity, inflammation, and oxidative stress in heart failure: emerging molecular targets. Cardiovasc Drugs Ther. 2017;31(5-6):593-608. doi: 10.1007/s10557-017-6752-z.
Milinković I, Polovina M, Simeunović DS, Ašanin M, Seferović PM. Oxidative stress and inflammation in heart failure: The best is yet to come. Eur J Prev Cardiol. 2020;27(5):490-3. doi: 10.1177/2047487319900294.
Rehsia NS, Dhalla NS. Potential of endothelin-1 and vasopressin antagonists for the treatment of congestive heart failure. Heart Fail Rev. 2010;15(1):85-101. doi: 10.1007/s10741-009-9152-z.
Lopaschuk GD, Ussher JR, Folmes CD, Jaswal JS, Stanley WC. Myocardial fatty acid metabolism in health and disease. Physiol Rev. 2010;90(1):207-58. doi: 10.1152/physrev.00015.2009.
Schmidt-Schweda S, Holubarsch C. First clinical trial with etomoxir in patients with chronic congestive heart failure. Clin Sci (Lond). 2000;99(1):27-35. doi: 10.1042/CS19990235.
English JM, Cobb MH. Pharmacological inhibitors of MAPK pathways. Trends Pharmacol Sci. 2002;23(1):40-5. doi: 10.1016/s0165-6147(00)01865-4.
Dhalla NS, Müller AL. Protein kinases as drug development targets for heart disease therapy. Pharmaceuticals (Basel). 2010;3(7):2111-45. doi: 10.3390/ph3072111.
Grossman W. Cardiac hypertrophy: useful adaptation or pathologic process? Am J Med. 1980;69(4):576-84. doi: 10.1016/0002-9343(80)90471-4.
Packer M. The neurohormonal hypothesis: a theory to explain the mechanism of disease progression in heart failure. J Am Coll Cardiol. 1992;20(1):248-54. doi: 10.1016/0735-1097(92)90167-l.
Weber KT, Sun Y, Guarda E. Structural remodeling in hypertensive heart disease and the role of hormones. Hypertension. 1994;23(6 Pt 2):869-77. doi: 10.1161/01.hyp.23.6.869.
Parmley WW. Neuroendocrine changes in heart failure and their clinical relevance. Clin Cardiol. 1995;18(8):440-5. doi: 10.1002/clc.4960180804.
Nicholls DP, Onuoha GN, McDowell G, Elborn JS, Riley MS, Nugent AM, et al. Neuroendocrine changes in chronic cardiac failure. Basic Res Cardiol. 1996;91 Suppl 1:13-20. doi: 10.1007/BF00810519.
Tarzami ST. Chemokines and inflammation in heart disease: adaptive or maladaptive? Int J Clin Exp Med. 2011;4(1):74-80. PMID: 21394288.
Zhang H, Dhalla NS. The role of pro-inflammatory cytokines in the pathogenesis of cardiovascular disease. Int J Mol Sci. 2024;25(2):1082. doi: 10.3390/ijms25021082.
Dhalla NS, Dent MR, Tappia PS, Sethi R, Barta J, Goyal RK. Subcellular remodeling as a viable target for the treatment of congestive heart failure. J Cardiovasc Pharmacol Ther. 2006;11(1):31-45. doi: 10.1177/107424840601100103.
Sawyer DB, Siwik DA, Xiao L, Pimentel DR, Singh K, Colucci WS. Role of oxidative stress in myocardial hypertrophy and failure. J Mol Cell Cardiol. 2002;34(4):379-88. doi: 10.1006/jmcc.2002.1526.
Keith M, Geranmayegan A, Sole MJ, Kurian R, Robinson A, Omran AS, Jeejeebhoy KN. Increased oxidative stress in patients with congestive heart failure. J Am Coll Cardiol. 1998;31(6):1352-6. doi: 10.1016/s0735-1097(98)00101-6.
Dhalla NS, Elmoselhi AB, Hata T, Makino N. Status of myocardial antioxidants in ischemia-reperfusion injury. Cardiovasc Res. 2000;47(3):446-56. doi: 10.1016/s0008-6363(00)00078-x.
Dhalla NS, Temsah RM, Netticadan T. Role of oxidative stress in cardiovascular diseases. J Hypertens. 2000;18(6):655-73. doi: 10.1097/00004872-200018060-00002.
Mialet-Perez J, Santin Y, Parini A. Monoamine oxidase-A, serotonin and norepinephrine: synergistic players in cardiac physiology and pathology. J Neural Transm (Vienna). 2018;125(11):1627-34. doi: 10.1007/s00702-018-1908-y.
Looi YH, Grieve DJ, Siva A, Walker SJ, Anilkumar N, Cave AC, et al. Involvement of Nox2 NADPH oxidase in adverse cardiac remodeling after myocardial infarction. Hypertension. 2008;51(2):319-25. doi: 10.1161/HYPERTENSIONAHA.107.101980.
Murdoch CE, Zhang M, Cave AC, Shah AM. NADPH oxidase-dependent redox signalling in cardiac hypertrophy, remodelling and failure. Cardiovasc Res. 2006;71(2):208-15. doi: 10.1016/j.cardiores.2006.03.016.
Lassègue B, San Martín A, Griendling KK. Biochemistry, physiology, and pathophysiology of NADPH oxidases in the cardiovascular system. Circ Res. 2012;110(10):1364-90. doi: 10.1161/CIRCRESAHA.111.243972.
Shah AK, Bhullar SK, Elimban V, Dhalla NS. Oxidative stress as a cechanism for functional alterations in cardiac hypertrophy and heart failure. Antioxidants (Basel). 2021;10(6):931. doi: 10.3390/antiox10060931.
Umbarkar P, Singh S, Arkat S, Bodhankar SL, Lohidasan S, Sitasawad SL. Monoamine oxidase-A is an important source of oxidative stress and promotes cardiac dysfunction, apoptosis, and fibrosis in diabetic cardiomyopathy. Free Radic Biol Med. 2015;87:263-73. doi: 10.1016/j.freeradbiomed.2015.06.025.
Dammanahalli KJ, Sun Z. Endothelins and NADPH oxidases in the cardiovascular system. Clin Exp Pharmacol Physiol. 2008;35(1):2-6. doi: 10.1111/j.1440-1681.2007.04830.x.
Backs J, Backs T, Neef S, Kreusser MM, Lehmann LH, Patrick DM, et al. The delta isoform of CaM kinase II is required for pathological cardiac hypertrophy and remodeling after pressure overload. Proc Natl Acad Sci U S A. 2009;106(7):2342-7. doi: 10.1073/pnas.0813013106.
van Heerebeek L, Borbély A, Niessen HW, Bronzwaer JG, van der Velden J, Stienen GJ, et al. Myocardial structure and function differ in systolic and diastolic heart failure. Circulation. 2006;113(16):1966-73. doi: 10.1161/CIRCULATIONAHA.105.587519.
Selby DE, Palmer BM, LeWinter MM, Meyer M. Tachycardia-induced diastolic dysfunction and resting tone in myocardium from patients with a normal ejection fraction. J Am Coll Cardiol. 2011;58(2):147-54. doi: 10.1016/j.jacc.2010.10.069.
Shimizu I, Minamino T, Toko H, Okada S, Ikeda H, Yasuda N, et al. Excessive cardiac insulin signaling exacerbates systolic dysfunction induced by pressure overload in rodents. J Clin Invest. 2010;120(5):1506-14. doi: 10.1172/JCI40096.
Parodi EM, Kuhn B. Signalling between microvascular endothelium and cardiomyocytes through neuregulin. Cardiovasc Res. 2014;102(2):194-204. doi: 10.1093/cvr/cvu021.
Ruetten H, Dimmeler S, Gehring D, Ihling C, Zeiher AM. Concentric left ventricular remodeling in endothelial nitric oxide synthase knockout mice by chronic pressure overload. Cardiovasc Res. 2005;66(3):444-53. doi: 10.1016/j.cardiores.2005.01.021.
Agapitov AV, Haynes WG. Role of endothelin in cardiovascular disease. J Renin Angiotensin Aldosterone Syst. 2002;3(1):1-15. doi: 10.3317/jraas.2002.001.
Davenport AP, Hyndman KA, Dhaun N, Southan C, Kohan DE, Pollock JS, et al. Endothelin. Pharmacol Rev. 2016;68(2):357-418. doi: 10.1124/pr.115.011833.
Margulies KB, Hildebrand FL Jr, Lerman A, Perrella MA, Burnett JC Jr. Increased endothelin in experimental heart failure. Circulation. 1990;82(6):2226-30. doi: 10.1161/01.cir.82.6.2226.
Wu C, Zhang Z, Zhang W, Liu X. Mitochondrial dysfunction and mitochondrial therapies in heart failure. Pharmacol Res. 2022;175:106038. doi: 10.1016/j.phrs.2021.106038.
Zhou B, Tian R. Mitochondrial dysfunction in pathophysiology of heart failure. J Clin Invest. 2018;128(9):3716-26. doi: 10.1172/JCI120849.
Keshavarz-Bahaghighat H, Darwesh AM, Sosnowski DK, Seubert JM. Mitochondrial dysfunction and inflammaging in heart failure: novel roles of CYP-derived epoxylipids. Cells. 2020;9(7):1565. doi: 10.3390/cells9071565.
Kumar AA, Kelly DP, Chirinos JA. Mitochondrial dysfunction in heart failure with preserved ejection fraction. Circulation. 2019;139(11):1435-50. doi: 10.1161/CIRCULATIONAHA.118.036259.
Hinton A Jr, Claypool SM, Neikirk K, Senoo N, Wanjalla CN, Kirabo A, Williams CR. Mitochondrial structure and function in human heart failure. Circ Res. 2024;135(2):372-96. doi: 10.1161/CIRCRESAHA.124.323800.
Bhattarai N, Scott I. In the heart and beyond: Mitochondrial dysfunction in heart failure with preserved ejection fraction (HFpEF). Curr Opin Pharmacol. 2024;76:102461. doi: 10.1016/j.coph.2024.102461.
Bhullar SK, Dhalla NS. Status of mitochondrial oxidative phosphorylation during the development of heart failure. Antioxidants (Basel). 2023;12(11):1941. doi: 10.3390/antiox12111941.
Mongirdienė A, Liuizė A, Karčiauskaitė D, Mazgelytė E, Liekis A, Sadauskienė I. Relationship between oxidative stress and left ventricle markers in patients with chronic heart failure. Cells. 2023;12(5):803. doi: 10.3390/cells12050803.
Dhalla NS, Elimban V, Bartekova M, Adameova A. Involvement of oxidative stress in the development of subcellular defects and heart disease. Biomedicines. 2022;10(2):393. doi: 10.3390/biomedicines10020393.
Barteková M, Adameová A, Görbe A, Ferenczyová K, Pecháňová O, Lazou A, et al. Natural and synthetic antioxidants targeting cardiac oxidative stress and redox signaling in cardiometabolic diseases. Free Radic Biol Med. 2021;169:446-77. doi: 10.1016/j.freeradbiomed.2021.03.045.
Argirò A, Ding J, Adler E. Gene therapy for heart failure and cardiomyopathies. Rev Esp Cardiol (Engl Ed). 2023;76(12):1042-54. English, Spanish. doi: 10.1016/j.rec.2023.06.009.
Greenberg B. Gene therapy for heart failure. J Cardiol. 2015;66(3):195-200. doi: 10.1016/j.jjcc.2015.02.006.
Korpela H, Järveläinen N, Siimes S, Lampela J, Airaksinen J, Valli K, et al. Gene therapy for ischaemic heart disease and heart failure. J Intern Med. 2021;290(3):567-82. doi: 10.1111/joim.13308.
Gabisonia K, Recchia FA. Gene therapy for heart failure: new perspectives. Curr Heart Fail Rep. 2018;15(6):340-9. doi: 10.1007/s11897-018-0410-z.
Wang J, Shi Q, Wang Y, Dawson LW, Ciampa G, Zhao W, et al. Gene therapy with the N-terminus of junctophilin-2 improves heart failure in mice. Circ Res. 2022;130(9):1306-17. doi: 10.1161/CIRCRESAHA.121.320680.
Hsu A, Duan Q, Day DS, Luo X, McMahon S, Huang Y, et al. Targeting transcription in heart failure via CDK7/12/13 inhibition. Nat Commun. 2022;13(1):4345. doi: 10.1038/s41467-022-31541-8.
Lucas T, Bonauer A, Dimmeler S. RNA therapeutics in cardiovascular disease. Circ Res. 2018;123(2):205-20. doi: 10.1161/CIRCRESAHA.117.311311.
Saddique MN, Qadri M, Ain NU, Farhan E, Shahid F, Benyamin J, et al. Safety and effectiveness of interference RNA (RNAi) based therapeutics in cardiac failure: A systematic review. Heart Lung. 2024;68:298-304. doi: 10.1016/j.hrtlng.2024.08.015.
Dave P, Anand P, Kothawala A, Srikaram P, Shastri D, Uddin A, et al. RNA interference therapeutics for hereditary amyloidosis: A narrative review of clinical trial outcomes and future directions. Cureus. 2024;16(6):e62981. doi: 10.7759/cureus.62981.
Packer M, Butler J, Zannad F, Filippatos G, Ferreira JP, Pocock SJ, et al. Effect of empagliflozin on worsening heart failure events in patients with heart failure and preserved ejection fraction: EMPEROR-Preserved Trial. Circulation. 2021;144(16):1284-94. doi: 10.1161/CIRCULATIONAHA.121.056824.
Borlaug BA, Paulus WJ. Heart failure with preserved ejection fraction: pathophysiology, diagnosis, and treatment. Eur Heart J. 2011;32(6):670-9. doi: 10.1093/eurheartj/ehq426.
Omote K, Verbrugge FH, Borlaug BA. Heart failure with preserved ejection fraction: mechanisms and treatment strategies. Annu Rev Med. 2022;73:321-37. doi: 10.1146/annurev-med-042220-022745.
Omar M, Jensen J, Ali M, Frederiksen PH, Kistorp C, Videbæk L, et al. 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 Cardiol. 2021;6(7):836-40. doi: 10.1001/jamacardio.2020.6827.
Vaduganathan M, Docherty KF, Claggett BL, Jhund PS, de Boer RA, Hernandez AF, et al. SGLT-2 inhibitors in patients with heart failure: a comprehensive meta-analysis of five randomised controlled trials. Lancet. 2022;400(10354):757-67. doi: 10.1016/S0140-6736(22)01429-5.
Das US, Paul A, Banerjee S. SGLT2 inhibitors in heart failure with reduced ejection fraction. Egypt Heart J. 2021;73(1):93. doi: 10.1186/s43044-021-00218-w.
Tomasoni D, Fonarow GC, Adamo M, Anker SD, Butler J, Coats AJS, et al. Sodium-glucose co-transporter 2 inhibitors as an early, first-line therapy in patients with heart failure and reduced ejection fraction. Eur J Heart Fail. 2022;24(3):431-41. doi: 10.1002/ejhf.2397.
Zannad F, Macari S. Drug treatment with empagliflozin lowered risk for hospitalization in people with heart failure with reduced ejection fraction: plain language summary of the EMPEROR-Reduced study. Future Cardiol. 2023;19(13):625-30. doi: 10.2217/fca-2023-0090.
Solomon SD, de Boer RA, DeMets D, Hernandez AF, Inzucchi SE, Kosiborod MN, et al. Dapagliflozin in heart failure with preserved and mildly reduced ejection fraction: rationale and design of the DELIVER trial. Eur J Heart Fail. 2021;23(7):1217-25. doi: 10.1002/ejhf.2249.
Wang Y, Gao T, Meng C, Li S, Bi L, Geng Y, Zhang P. Sodium-glucose co-transporter 2 inhibitors in heart failure with mildly reduced or preserved ejection fraction: an updated systematic review and meta-analysis. Eur J Med Res. 2022;27(1):314. doi: 10.1186/s40001-022-00945-z.
Shang Z, Wang X, Gao W. Heart failure with mildly reduced ejection fraction: emerging frontiers in clinical characteristics, prognosis, and treatment. Rev Cardiovasc Med. 2022;23(1):30. doi: 10.31083/j.rcm2301030.
Talha KM, Butler J. Breakthroughs in the treatment of heart failure with mildly reduced and preserved ejection fraction. Clin Cardiol. 2022;45 Suppl 1(Suppl 1):S31-S39. doi: 10.1002/clc.23846.
Xiang B, Zhang R, Wu X, Zhou X. Optimal pharmacologic treatment of heart failure with preserved and mildly reduced ejection fraction: A Meta-analysis. JAMA Netw Open. 2022;5(9):e2231963. doi: 10.1001/jamanetworkopen.2022.31963.
Arnold SV, Silverman DN, Gosch K, Nassif ME, Infeld M, Litwin S, et al. Beta-blocker use and heart failure outcomes in mildly reduced and preserved ejection fraction. JACC Heart Fail. 2023;11(8 Pt 1):893-900. doi: 10.1016/j.jchf.2023.03.017.
Vaduganathan M, Mentz RJ, Claggett BL, Miao ZM, Kulac IJ, Ward JH, et al. Sacubitril/valsartan in heart failure with mildly reduced or preserved ejection fraction: a pre-specified participant-level pooled analysis of PARAGLIDE-HF and PARAGON-HF. Eur Heart J. 2023;44(31):2982-93. doi: 10.1093/eurheartj/ehad344.
Packer M, McMurray JJV. Rapid evidence-based sequencing of foundational drugs for heart failure and a reduced ejection fraction. Eur J Heart Fail. 2021;23(6):882-94. doi: 10.1002/ejhf.2149.
Lin Y, Zhang H, Zhao S, Chen L, Li J, Wang X, Tian W. The efficacy and safety of the combined therapy of sodium-glucose co-transporter-2 inhibitors and angiotensin receptor-neprilysin inhibitor in patients with heart failure with reduced ejection fraction: A meta-analysis of the EMPEROR-reduced and DAPA-HF sub-analysis. Front Cardiovasc Med. 2022;9:882089. doi: 10.3389/fcvm.2022.882089.
Bozkurt B. Contemporary pharmacological treatment and management of heart failure. Nat Rev Cardiol. 2024;21(8):545-55. doi: 10.1038/s41569-024-00997-0.
Cotter G, Davison BA, Mebazaa A, Takagi K, Novosadova M, Freund Y, et al. Medical therapy of heart failure with reduced ejection fraction-A call for comparative research. J Clin Med. 2021;10(9):1803. doi: 10.3390/jcm10091803.
Narayan SI, Terre GV, Amin R, Shanghavi KV, Chandrashekar G, Ghouse F, et al. The pathophysiology and new advancements in the pharmacologic and exercise-based management of heart failure with reduced ejection fraction: A narrative review. Cureus. 2023;15(9):e45719. doi: 10.7759/cureus.45719.
Murphy SP, Ibrahim NE, Januzzi JL Jr. Heart failure with eeduced ejection fraction: A review. JAMA. 2020;324(5):488-504. doi: 10.1001/jama.2020.10262.
Kura B, Bagchi AK, Singal PK, Barancik M, LeBaron TW, Valachova K, et al. Molecular hydrogen: potential in mitigating oxidative-stress-induced radiation injury. Can J Physiol Pharmacol. 2019;97(4):287-92. doi: 10.1139/cjpp-2018-0604.
Slezak J, Kura B, LeBaron TW, Singal PK, Buday J, Barancik M. Oxidative stress and pathways of molecular hydrogen effects in medicine. Curr Pharm Des. 2021;27(5):610-25. doi: 10.2174/1381612826666200821114016.
LeBaron TW, Kura B, Kalocayova B, Tribulova N, Slezak J. A new approach for the prevention and treatment of cardiovascular disorders. Molecular hydrogen significantly reduces the effects of oxidative stress. Molecules. 2019;24(11):2076. doi: 10.3390/molecules24112076.
Singh RB, Sumbalova Z, Fatima G, Mojto V, Fedacko J, Tarnava A, et al. Effects of molecular hydrogen in the pathophysiology and management of cardiovascular and metabolic diseases. Rev Cardiovasc Med. 2024;25(1):33. doi: 10.31083/j.rcm2501033.
Kura B, Slezak J. The protective role of molecular hydrogen in ischemia/reperfusion injury. Int J Mol Sci. 2024;25(14):7884. doi: 10.3390/ijms25147884.
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