Treatment of patients with heart failure and preserved ejection fraction: reliance on clinical phenotypes

The article discusses the problem of improving the effectiveness of treatment of heart failure with preserved left ventricular ejection fraction (HFpEF). The relative "failure" of early studies with renin-angiotensin-aldosterone system inhibitors was largely due to the lack of understanding that patients with HFpEF represent a heterogeneous group with various etiological factors and pathogenetic mechanisms of the disease. Therefore, the so-called personalized approach should be used in the treatment of these patients. This approach is based on the identification of clearly defined disease phenotypes, each characterized by a set of demographic, pathogenetic, and clinical characteristics. Based on the literature and own experience, the authors consider four main phenotypes of HFpEF: 1) phenotype with brain natriuretic peptide “deficiency” syndrome associated with moderate/severe left ventricular hypertrophy; 2) cardiometabolic phenotype; 3) phenotype with mixed pulmonary hypertension and right ventricular failure; and 4) cardiac amyloidosis phenotype. In the treatment of patients with phenotype 1, it seems preferable to use the valsartan + sacubitril (possibly in combination with spironolactone) combination treatment; with phenotype 2, the empagliflozin treatment is the best; with phenotype 3, the phosphodiesterase type 5 inhibitor sildenafil; and with phenotype 4, transthyretin stabilizers. Certain features of different phenotypes overlap and may change as the disease progresses. Nevertheless, the isolation of these phenotypes is advisable to prioritize the choice of drug therapy. Thus, the diuretic treatment (preferably torasemide) should be considered in the presence of congestion, regardless of the HFpEF phenotype; the valsartan + sacubitril and spironolactone treatment is appropriate not only in the shortage of brain natriuretic peptide but also in the presence of concentric left ventricular hypertrophy (except for the amyloidosis phenotype); and the treatment with empagliflozin and statins may be considered in all situations where pro-inflammatory mechanisms are involved.

1. McDonagh TA, Metra M, Adamo M, Gardner RS, Baumbach A, Böhm M et al. 2021 ESC Guidelines for the diagnosis and treatment of acute and chronic heart failure: Developed by the Task Force for the diagnosis and treatment of acute and chronic heart failure of the European Society of Cardiology (ESC). With the special contribution of the Heart Failure Association (HFA) of the ESC. European Journal of Heart Failure. 2022;24(1):4–131. DOI: 10.1002/ejhf.2333

2. Cleland JGF, Tendera M, Adamus J, Freemantle N, Gray CS, Lye M et al. Perindopril for elderly people with chronic heart failure: the PEP-CHF study. European Journal of Heart Failure. 1999;1(3):211–7. DOI: 10.1016/S1388-9842(99)00039-2

3. Massie BM, Carson PE, McMurray JJ, Komajda M, McKelvie R, Zile MR et al. Irbesartan in Patients with Heart Failure and Preserved Ejection Fraction. New England Journal of Medicine. 2008;359(23):2456–67. DOI: 10.1056/NEJMoa0805450

4. Yusuf S, Pfeffer MA, Swedberg K, Granger CB, Held P, McMurray JJ et al. Effects of candesartan in patients with chronic heart failure and preserved left-ventricular ejection fraction: the CHARM-Preserved Trial. The Lancet. 2003;362(9386):777–81. DOI: 10.1016/S0140-6736(03)14285-7

5. Pitt B, Pfeffer MA, Assmann SF, Boineau R, Anand IS, Claggett B et al. Spironolactone for Heart Failure with Preserved Ejection Fraction. New England Journal of Medicine. 2014;370(15):1383–92. DOI: 10.1056/NEJMoa1313731

6. Pfeffer MA, Braunwald E. Treatment of Heart Failure With Preserved Ejection Fraction: Reflections on Its Treatment With an Aldosterone Antagonist. JAMA Cardiology. 2016;1(1):7–8. DOI: 10.1001/jamacardio.2015.0356

7. McMurray JJV, Packer M, Desai AS, Gong J, Lefkowitz MP, Rizkala AR et al. Angiotensin–niprilysin Inhibition versus enalapril in heart failure. New England Journal of Medicine. 2014;371(11):993–1004. DOI: 10.1056/NEJMoa1409077

8. Solomon SD, McMurray JJV, Anand IS, Ge J, Lam CSP, Maggioni AP et al. Angiotensin–Neprilysin Inhibition in Heart Failure with Preserved Ejection Fraction. New England Journal of Medicine. 2019;381(17):1609–20. DOI: 10.1056/NEJMoa1908655

9. Anker SD, Butler J, Filippatos G, Ferreira JP, Bocchi E, Böhm M et al. Empagliflozin in Heart Failure with a Preserved Ejection Fraction. New England Journal of Medicine. 2021;385(16):1451–61. DOI: 10.1056/NEJMoa2107038

10. Shah SJ, Borlaug BA, Kitzman DW, McCulloch AD, Blaxall BC, Agarwal R et al. Research Priorities for Heart Failure With Preserved Ejection Fraction: National Heart, Lung and Blood Institute Working Group Summary. Circulation. 2020;141(12):1001–26. DOI: 10.1161/CIRCULATIONAHA.119.041886

11. Shah SJ. Precision Medicine for Heart Failure with Preserved Ejection Fraction: An Overview. Journal of Cardiovascular Translational Research. 2017;10(3):233–44. DOI: 10.1007/s12265-017-9756-y

12. Zhu K, Ma T, Su Y, Pan X, Huang R, Zhang F et al. Heart Failure With Mid-range Ejection Fraction: Every Coin Has Two Sides. Frontiers in Cardiovascular Medicine. 2021;8:683418. DOI: 10.3389/fcvm.2021.683418

13. Uijl A, Savarese G, Vaartjes I, Dahlström U, Brugts JJ, Linssen GCM et al. Identification of distinct phenotypic clusters in heart failure with preserved ejection fraction. European Journal of Heart Failure. 2021;23(6):973–82. DOI: 10.1002/ejhf.2169

14. Ovchinnikov A.G., Gvozdeva A.D., Blankova Z.N., Borisov A.A., Ageev F.T. The Role of Neprilysin Inhibitors in the Treatment of Heart Failure with Preserved Ejection Fraction. Kardiologiia. 2020;60(11):117–27. DOI: 10.18087/cardio.2020.11.n1352

15. Ovchinnikov A.G., Gvozdeva A.D., Potekhina A.V., Vitsenya M.V., Ageev F.T. Potential of valsartan+sacubitril therapy in hypertensive heart disease. Russian Journal of Cardiology. 2021;26(7):80– 91. DOI: 10.15829/1560-4071-2021-4568

16. Gvozdeva AD, Ovchinnikov AG, Blankova ZN, Borisov AA, Ageev FT. Angiotensin neprilysin inhibition in HFpEF and advanced left ventricular hypertrophy: the rationale, design, and preliminary results of a randomized open-label pilot study. P.233381. European Journal of Heart Failure. 2021;23(Suppl S2):2–322. [Av. at: https://esc365.escardio.org/presentation/233381]. DOI: 10.1002/ejhf.2297

17. Svirida O.N., Ovchinnikov A.G., Ageev F.T. Influence of candesartan and its combination with spironolactone on left ventricular diastolic function and level of collagen balance’s biochemical markers in patients with chronic heart failure and preserved left ventricular systolic function. Russian Heart Failure Journal. 2010;11(5):263–75.

18. 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. Journal of the American College of Cardiology. 2020;76(5):503–14. DOI: 10.1016/j.jacc.2020.05.072

19. Paulus WJ, Tschope C. 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. 2013;62(4):263–71. DOI: 10.1016/j.jacc.2013.02.092

20. Ovchinnikov A.G., Potekhina A.V., Ozhereljeva M.V., Ageev F.T. Left ventricular dysfunction in hypertensive heart: Current view of the pathogenesis and treatment. Kardiologiia. 2017;57(S2):367– 82. DOI: 10.18087/cardio.2393

21. Sinha A, Rahman H, Webb A, Shah AM, Perera D. Untangling the pathophysiologic link between coronary microvascular dysfunction and heart failure with preserved ejection fraction. European Heart Journal. 2021;42(43):4431–41. DOI: 10.1093/eurheartj/ehab653

22. Ovchinnikov AG, Arefieva TI, Potekhina AV, Filatova AYu, Ageev FT, Boytsov SА. The Molecular and Cellular Mechanisms Associated with a Microvascular Inflammation in the Pathogenesis of Heart Failure with Preserved Ejection Fraction. Acta Naturae. 2020;12(2):40–51. DOI: 10.32607/actanaturae.10990

23. Pabel S, Wagner S, Bollenberg H, Bengel P, Kovács Á, Schach C et al. Empagliflozin directly improves diastolic function in human heart failure. European Journal of Heart Failure. 2018;20(12):1690–700. DOI: 10.1002/ejhf.1328

24. Kolijn D, Pabel S, Tian Y, Lódi M, Herwig M, Carrizzo A et al. Empagliflozin improves endothelial and cardiomyocyte function in human heart failure with preserved ejection fraction via reduced pro-inflammatory-oxidative pathways and protein kinase Gα oxidation. Cardiovascular Research. 2021;117(2):495–507. DOI: 10.1093/cvr/cvaa123

25. Habibi J, Aroor AR, Sowers JR, Jia G, Hayden MR, Garro M et al. Sodium glucose transporter 2 (SGLT2) inhibition with empagliflozin improves cardiac diastolic function in a female rodent model of diabetes. Cardiovascular Diabetology. 2017;16(1):9. DOI: 10.1186/s12933-016-0489-z

26. Lin B, Koibuchi N, Hasegawa Y, Sueta D, Toyama K, Uekawa K et al. Glycemic control with empagliflozin, a novel selective SGLT2 inhibitor, ameliorates cardiovascular injury and cognitive dysfunction in obese and type 2 diabetic mice. Cardiovascular Diabetology. 2014;13(1):148. DOI: 10.1186/s12933-014-0148-1

27. Ovchinnikov A.G., Borisov A.A., Zherebchikova K.Yu., Ryabtseva O.Yu., Gvozdeva A.D., Masenko V.P. et al. Empagliflozin in heart failure patients with preserved ejection fraction and diabetes mellitus type 2. (Results of a pilot prospective randomized trial). Russian Cardiology Bulletin. 2021;16(3):60–73. DOI: 10.17116/Cardiobulletin20211603160

28. Ramasubbu K, Estep J, White DL, Deswal A, Mann DL. Experimental and clinical basis for the use of statins in patients with ischemic and nonischemic cardiomyopathy. Journal of the American College of Cardiology. 2008;51(4):415–26. DOI: 10.1016/j.jacc.2007.10.009

29. Antoniades C, Bakogiannis C, Leeson P, Guzik TJ, Zhang M-H, Tousoulis D et al. Rapid, direct effects of statin treatment on arterial redox state and nitric oxide bioavailability in human atherosclerosis via tetrahydrobiopterin-mediated endothelial nitric oxide synthase coupling. Circulation. 2011;124(3):335–45. DOI: 10.1161/CIRCULATIONAHA.110.985150

30. Akahori H, Tsujino T, Naito Y, Matsumoto M, Sasaki N, Iwasaku T et al. Atorvastatin ameliorates cardiac fibrosis and improves left ventricular diastolic function in hypertensive diastolic heart failure model rats. Journal of Hypertension. 2014;32(7):1534–41. DOI: 10.1097/HJH.0000000000000184

31. Bielecka-Dabrowa A, Bytyçi I, Von Haehling S, Anker S, Jozwiak J, Rysz J et al. Association of statin use and clinical outcomes in heart failure patients: a systematic review and meta-analysis. Lipids in Health and Disease. 2019;18(1):188. DOI: 10.1186/s12944-019-1135-z

32. Ovchinnikov AG, Dreeva ZV, Potekhina AV, Arefieva TI, Masenko VP, Ageev FT. Statins improves functional capacity and restores LV diastolic reserve in patients with heart failure with preserved left ventricular ejection fraction. European Journal of Heart Failure. 2019;21(Suppl S1):418. DOI: 10.1002/ejhf.1488

33. Ovchinnikov AG, Ojerelyeva MV, Ageev FT. Hypertensive left ventricular hypertrophy is a risk factor for the development of a HFPEF but not a depressed left ventricular ejection fraction within eight years. European Journal of Heart Failure. 2017;19(Suppl S1):328

34. Ovchinnikov A.G., Ozhereleva M. V., Masenko V.P., Ageev F.T. Structure and function features and adverse prognostic factors of compensated hypertensive heart disease. Russian Heart Journal. 2017;16(3):185–96.

35. Ovchinnikov A.G., Gavryushina S.V., Ageev F.T. Pulmonary hypertension associated with diastolic heart failure: pathogenesis, diagnosis, treatment. Russian Heart Failure Journal. 2016;17(2):114– 29. DOI: 10.18087/rhfj.2016.2.2210

36. Ovchinnikov A.G., Potekhina A.V., Ibragimova N.M., Barabanova E.A., Yushchyuk E.N., Ageev F.T. Mechanisms of exercise intolerance in patients with heart failure and preserved ejection fraction. Part II: The role of right heart chambers, vascular system and skeletal muscles. Kardiologiia. 2019;59(8S):4–14. DOI: 10.18087/cardio.n393

37. Ovchinnikov A.G., Azizova A.G., Masenko V.P., Shatalina L.S., Ageev F.T. The effect of loop diuretics on the clinical course, the filling pressure of the left ventricle in patients with compensated NSFW and high filling pressure of the LV. Russian Heart Failure Journal. 2012;13(6):320–33.

38. Belyavskiy E, Ovchinnikov AG, Potekhina AV, Ageev FT, Edelmann F. Phosphodiesterase 5 inhibitor sildenafil in patients with heart failure with preserved ejection fraction and combined pre- and postcapillary pulmonary hypertension: a randomized open-label pilot study. BMC Cardiovascular Disorders. 2020;20(1):408. DOI: 10.1186/s12872-020-01671-2

39. Guazzi M, Vicenzi M, Arena R, Guazzi MD. Pulmonary Hypertension in Heart Failure with Preserved Ejection Fraction: A Target of Phosphodiesterase-5 Inhibition in a 1-Year Study. Circulation. 2011;124(2):164–74. DOI: 10.1161/CIRCULATIONAHA.110.983866

40. Guazzi M, Borlaug BA. Pulmonary Hypertension Due to Left Heart Disease. Circulation. 2012;126(8):975–90. DOI: 10.1161/CIRCULATIONAHA.111.085761

41. Opitz CF, Hoeper MM, Gibbs JSR, Kaemmerer H, Pepke-Zaba J, Coghlan JG et al. Pre-Capillary, Combined, and Post-Capillary Pulmonary Hypertension. Journal of the American College of Cardiology. 2016;68(4):368–78. DOI: 10.1016/j.jacc.2016.05.047

42. Kramer T, Dumitrescu D, Gerhardt F, Orlova K, ten Freyhaus H, Hellmich M et al. Therapeutic potential of phosphodiesterase type 5 inhibitors in heart failure with preserved ejection fraction and combined post- and pre-capillary pulmonary hypertension. International Journal of Cardiology. 2019;283:152–8. DOI: 10.1016/j.ijcard.2018.12.078

43. Siddiqi OK, Ruberg FL. Cardiac amyloidosis: An update on pathophysiology, diagnosis, and treatment. Trends in Cardiovascular Medicine. 2018;28(1):10–21. DOI: 10.1016/j.tcm.2017.07.004

44. Nativi-Nicolau J, Maurer MS. Amyloidosis cardiomyopathy: update in the diagnosis and treatment of the most common types. Current Opinion in Cardiology. 2018;33(5):571–9. DOI: 10.1097/HCO.0000000000000547

45. González-López E, Gallego-Delgado M, Guzzo-Merello G, de Harodel Moral FJ, Cobo-Marcos M, Robles C et al. Wild-type transthyretin amyloidosis as a cause of heart failure with preserved ejection fraction. European Heart Journal. 2015;36(38):2585–94. DOI: 10.1093/eurheartj/ehv338

46. Castaño A, Narotsky DL, Hamid N, Khalique OK, Morgenstern R, DeLuca A et al. Unveiling transthyretin cardiac amyloidosis and its predictors among elderly patients with severe aortic stenosis undergoing transcatheter aortic valve replacement. European Heart Journal. 2017;38(38):2879–87. DOI: 10.1093/eurheartj/ehx350

47. Maurer MS, Schwartz JH, Gundapaneni B, Elliott PM, Merlini G, Waddington-Cruz M et al. Tafamidis Treatment for Patients with Transthyretin Amyloid Cardiomyopathy. New England Journal of Medicine. 2018;379(11):1007–16. DOI: 10.1056/NEJMoa1805689