Korean Circ J.  2023 Jul;53(7):425-451. 10.4070/kcj.2023.0114.

Korean Society of Heart Failure Guidelines for the Management of Heart Failure: Management of the Underlying Etiologies and Comorbidities of Heart Failure

• Park SM
• Lee SY
• Jung MH
• Youn JC
• Kim D
• Cho JY
• Cho DH
• Hyun J
• Cho HJ
• Park SM
• Choi JO
• Chung WJ
• Kang SM
• Yoo BS
• on behalf of Committee of Clinical Practice Guidelines, Korean Society of Heart Failure

• KMID: 2545130
• DOI: http://doi.org/10.4070/kcj.2023.0114

Abstract

Most patients with heart failure (HF) have multiple comorbidities, which impact their quality of life, aggravate HF, and increase mortality. Cardiovascular comorbidities include systemic and pulmonary hypertension, ischemic and valvular heart diseases, and atrial fibrillation. Non-cardiovascular comorbidities include diabetes mellitus (DM), chronic kidney and pulmonary diseases, iron deficiency and anemia, and sleep apnea. In patients with HF with hypertension and left ventricular hypertrophy, renin-angiotensin system inhibitors combined with calcium channel blockers and/or diuretics is an effective treatment regimen. Measurement of pulmonary vascular resistance via right heart catheterization is recommended for patients with HF considered suitable for implantation of mechanical circulatory support devices or as heart transplantation candidates. Coronary angiography remains the gold standard for the diagnosis and reperfusion in patients with HF and angina pectoris refractory to antianginal medications. In patients with HF and atrial fibrillation, longterm anticoagulants are recommended according to the CHA 2 DS 2 -VASc scores. Valvular heart diseases should be treated medically and/or surgically. In patients with HF and DM, metformin is relatively safer; thiazolidinediones cause fluid retention and should be avoided in patients with HF and dyspnea. In renal insufficiency, both volume status and cardiac performance are important for therapy guidance. In patients with HF and pulmonary disease, beta-blockers are underused, which may be related to increased mortality. In patients with HF and anemia, iron supplementation can help improve symptoms. In obstructive sleep apnea, continuous positive airway pressure therapy helps avoid severe nocturnal hypoxia. Appropriate management of comorbidities is important for improving clinical outcomes in patients with HF.

Keyword

Heart failure; Guideline; Comorbidity; Disease management

Figure

• 

  Figure 1 Various cardiovascular and non-cardiovascular underlying etiologies and comorbidities of heart failure.Red and blue circles indicate cardiovascular and non-cardiovascular comorbidities respectively.

• 

  Figure 2 Algorithm for right heart catheterization in patients with severe heart failure.Cpc-PH = combined postcapillary and precapillary pulmonary hypertension; Ipc-PH = isolated postcapillary pulmonary hypertension; LVAD = left ventricular assist device; PA = pulmonary artery; PCWP = pulmonary capillary wedge pressure; PVR = pulmonary vascular resistance; WU = Wood units.*Values for recently updated 2022 European Society of Cardiology and the European Respiratory Society guideline for pulmonary hypertension.

• 

  Figure 3 Recommendations for the treatment of ventricular arrhythmia in patients with heart failure.DC = direct current; GDMT = guideline-directed medical therapy; ICD = implantable cardioverter-defibrillator; VT = ventricular tachycardia.

Reference

1. Lopez AD, Mathers CD, Ezzati M, Jamison DT, Murray CJ. Global and regional burden of disease and risk factors, 2001: systematic analysis of population health data. Lancet. 2006; 367:1747–1757. PMID: 16731270.

2. Feigin VL, Roth GA, Naghavi M, et al. Global burden of stroke and risk factors in 188 countries, during 1990-2013: a systematic analysis for the Global Burden of Disease Study 2013. Lancet Neurol. 2016; 15:913–924. PMID: 27291521.

3. Oh GC, Cho HJ. Blood pressure and heart failure. Clin Hypertens. 2020; 26:1. PMID: 31908841.

4. Stewart Coats AJ. Common co-morbidities in heart failure - diabetes, functional mitral regurgitation and sleep apnoea. Int J Heart Fail. 2019; 1:25–41. PMID: 36262740.

5. Sawamura A, Kajiura H, Sumi T, et al. Clinical impact of worsening renal function in elderly patients with acute decompensated heart failure. Int J Heart Fail. 2021; 3:128–137. PMID: 36262877.

6. Choi DJ, Han S, Jeon ES, et al. Characteristics, outcomes and predictors of long-term mortality for patients hospitalized for acute heart failure: a report from the Korean Heart Failure Registry. Korean Circ J. 2011; 41:363–371. PMID: 21860637.

7. Lee SE, Lee HY, Cho HJ, et al. Clinical characteristics and outcome of acute heart failure in Korea: results from the Korean Acute Heart Failure Registry (KorAHF). Korean Circ J. 2017; 47:341–353. PMID: 28567084.

8. SPRINT Research Group. Wright JT Jr, Williamson JD, et al. A randomized trial of intensive versus standard blood-pressure control. N Engl J Med. 2015; 373:2103–2116. PMID: 26551272.

9. Heart Failure Society of America. Lindenfeld J, Albert NM, et al. HFSA 2010 comprehensive heart failure practice guideline. J Card Fail. 2010; 16:e1–e194. PMID: 20610207.

10. Williams B, Mancia G, Spiering W, et al. 2018 ESC/ESH Guidelines for the management of arterial hypertension. Eur Heart J. 2018; 39:3021–3104. PMID: 30165516.

11. Lee HY, Shin J, Kim GH, et al. 2018 Korean Society of Hypertension Guidelines for the management of hypertension: part II-diagnosis and treatment of hypertension. Clin Hypertens. 2019; 25:20. PMID: 31388453.

12. McDonagh TA, Metra M, Adamo M, et al. 2021 ESC Guidelines for the diagnosis and treatment of acute and chronic heart failure. Eur Heart J. 2021; 42:3599–3726. PMID: 34447992.

13. Packer M, O’Connor CM, Ghali JK, et al. Effect of amlodipine on morbidity and mortality in severe chronic heart failure. N Engl J Med. 1996; 335:1107–1114. PMID: 8813041.

14. Cohn JN, Pfeffer MA, Rouleau J, et al. Adverse mortality effect of central sympathetic inhibition with sustained-release moxonidine in patients with heart failure (MOXCON). Eur J Heart Fail. 2003; 5:659–667. PMID: 14607206.

15. Fagard RH, Celis H, Thijs L, Wouters S. Regression of left ventricular mass by antihypertensive treatment: a meta-analysis of randomized comparative studies. Hypertension. 2009; 54:1084–1091. PMID: 19770405.

16. Simonneau G, Montani D, Celermajer DS, et al. Haemodynamic definitions and updated clinical classification of pulmonary hypertension. Eur Respir J. 2019; 53:1801913. PMID: 30545968.

17. Jang AY, Park SJ, Chung WJ. Pulmonary hypertension in heart failure. Int J Heart Fail. 2021; 3:147–159. PMID: 36262642.

18. O’Sullivan CJ, Wenaweser P, Ceylan O, et al. Effect of pulmonary hypertension hemodynamic presentation on clinical outcomes in patients with severe symptomatic aortic valve stenosis undergoing transcatheter aortic valve implantation: insights from the new proposed pulmonary hypertension classification. Circ Cardiovasc Interv. 2015; 8:e002358. PMID: 26156149.

19. Fang JC, DeMarco T, Givertz MM, et al. World Health Organization Pulmonary Hypertension group 2: pulmonary hypertension due to left heart disease in the adult--a summary statement from the Pulmonary Hypertension Council of the International Society for Heart and Lung Transplantation. J Heart Lung Transplant. 2012; 31:913–933. PMID: 22884380.

20. Mikus E, Stepanenko A, Krabatsch T, et al. Reversibility of fixed pulmonary hypertension in left ventricular assist device support recipients. Eur J Cardiothorac Surg. 2011; 40:971–977. PMID: 21354812.

21. Zimpfer D, Zrunek P, Roethy W, et al. Left ventricular assist devices decrease fixed pulmonary hypertension in cardiac transplant candidates. J Thorac Cardiovasc Surg. 2007; 133:689–695. PMID: 17320566.

22. Kumarasinghe G, Jain P, Jabbour A, et al. Comparison of continuous-flow ventricular assist device therapy with intensive medical therapy in fixed pulmonary hypertension secondary to advanced left heart failure. ESC Heart Fail. 2018; 5:695–702. PMID: 29573567.

23. Hünlich M, Lubos E, Beuthner BE, et al. Acute and long-term hemodynamic effects of MitraClip implantation on a preexisting secondary right heart failure. BioMed Res Int. 2018; 2018:6817832. PMID: 29725600.

24. Pons J, Leblanc MH, Bernier M, et al. Effects of chronic sildenafil use on pulmonary hemodynamics and clinical outcomes in heart transplantation. J Heart Lung Transplant. 2012; 31:1281–1287. PMID: 23127754.

25. Sueta CA, Gheorghiade M, Adams KF Jr, et al. Safety and efficacy of epoprostenol in patients with severe congestive heart failure. Am J Cardiol. 1995; 75:34A–43A. PMID: 7801861.

26. Califf RM, Adams KF, McKenna WJ, et al. A randomized controlled trial of epoprostenol therapy for severe congestive heart failure: the Flolan International Randomized Survival Trial (FIRST). Am Heart J. 1997; 134:44–54. PMID: 9266782.

27. Bonderman D, Ghio S, Felix SB, et al. Riociguat for patients with pulmonary hypertension caused by systolic left ventricular dysfunction: a phase IIb double-blind, randomized, placebo-controlled, dose-ranging hemodynamic study. Circulation. 2013; 128:502–511. PMID: 23775260.

28. Bonderman D, Pretsch I, Steringer-Mascherbauer R, et al. Acute hemodynamic effects of riociguat in patients with pulmonary hypertension associated with diastolic heart failure (DILATE-1): a randomized, double-blind, placebo-controlled, single-dose study. Chest. 2014; 146:1274–1285. PMID: 24991733.

29. Packer M, McMurray J, Massie BM, et al. Clinical effects of endothelin receptor antagonism with bosentan in patients with severe chronic heart failure: results of a pilot study. J Card Fail. 2005; 11:12–20. PMID: 15704058.

30. Packer M, McMurray JJV, Krum H, et al. Long-term effect of endothelin receptor antagonism with bosentan on the morbidity and mortality of patients with severe chronic heart failure: primary results of the ENABLE trials. JACC Heart Fail. 2017; 5:317–326. PMID: 28449795.

31. Vachiéry JL, Delcroix M, Al-Hiti H, et al. Macitentan in pulmonary hypertension due to left ventricular dysfunction. Eur Respir J. 2018; 51:1701886. PMID: 29437943.

32. Lee SE, Lee HY, Cho HJ, et al. Reverse J-curve relationship between on-treatment blood pressure and mortality in patients with heart failure. JACC Heart Fail. 2017; 5:810–819. PMID: 29096790.

33. Fonarow GC, Heywood JT, Heidenreich PA, Lopatin M, Yancy CW. ADHERE Scientific Advisory Committee and Investigators. Temporal trends in clinical characteristics, treatments, and outcomes for heart failure hospitalizations, 2002 to 2004: findings from Acute Decompensated Heart Failure National Registry (ADHERE). Am Heart J. 2007; 153:1021–1028. PMID: 17540205.

34. Tsuyuki RT, McKelvie RS, Arnold JM, et al. Acute precipitants of congestive heart failure exacerbations. Arch Intern Med. 2001; 161:2337–2342. PMID: 11606149.

35. Jolicœur EM, Dunning A, Castelvecchio S, et al. Importance of angina in patients with coronary disease, heart failure, and left ventricular systolic dysfunction: insights from STICH. J Am Coll Cardiol. 2015; 66:2092–2100. PMID: 26541919.

36. Ponikowski P, Voors AA, Anker SD, et al. 2016 ESC Guidelines for the diagnosis and treatment of acute and chronic heart failure: The Task Force for the diagnosis and treatment of acute and 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 Heart J. 2016; 37:2129–2200. PMID: 27206819.

37. SHEP Cooperative Research Group. Prevention of stroke by antihypertensive drug treatment in older persons with isolated systolic hypertension. Final results of the Systolic Hypertension in the Elderly Program (SHEP). JAMA. 1991; 265:3255–3264. PMID: 2046107.

38. Dahlöf B, Lindholm LH, Hansson L, Scherstén B, Ekbom T, Wester PO. Morbidity and mortality in the Swedish Trial in Old Patients with Hypertension (STOP-Hypertension). Lancet. 1991; 338:1281–1285. PMID: 1682683.

39. Uretsky BF, Young JB, Shahidi FE, Yellen LG, Harrison MC, Jolly MK. Randomized study assessing the effect of digoxin withdrawal in patients with mild to moderate chronic congestive heart failure: results of the PROVED trial. PROVED Investigative Group. J Am Coll Cardiol. 1993; 22:955–962. PMID: 8409069.

40. Bugiardini R, Cenko E, Yoon J, et al. Concerns about the use of digoxin in acute coronary syndromes. Eur Heart J Cardiovasc Pharmacother. 2022; 8:474–482. PMID: 34251454.

41. Su JB, Cazorla O, Blot S, et al. Bradykinin restores left ventricular function, sarcomeric protein phosphorylation, and e/nNOS levels in dogs with Duchenne muscular dystrophy cardiomyopathy. Cardiovasc Res. 2012; 95:86–96. PMID: 22562664.

42. Mancini GB, Henry GC, Macaya C, et al. Angiotensin-converting enzyme inhibition with quinapril improves endothelial vasomotor dysfunction in patients with coronary artery disease. The TREND (Trial on Reversing ENdothelial Dysfunction) Study. Circulation. 1996; 94:258–265. PMID: 8759064.

43. Andreotti F, Kluft C, Davies GJ, Huisman LG, de Bart AC, Maseri A. Effect of propranolol (long-acting) on the circadian fluctuation of tissue-plasminogen activator and plasminogen activator inhibitor-1. Am J Cardiol. 1991; 68:1295–1299. PMID: 1951115.

44. Cleland JG, Pennel D, Ray S, et al. The carvedilol hibernation reversible ischaemia trial; marker of success (CHRISTMAS). Eur J Heart Fail. 1999; 1:191–196. PMID: 10937930.

45. Goldstein RE, Boccuzzi SJ, Cruess D, Nattel S. Diltiazem increases late-onset congestive heart failure in postinfarction patients with early reduction in ejection fraction. The Adverse Experience Committee; and the Multicenter Diltiazem Postinfarction Research Group. Circulation. 1991; 83:52–60. PMID: 1984898.

46. Cleland JG, Bulpitt CJ, Falk RH, et al. Is aspirin safe for patients with heart failure? Br Heart J. 1995; 74:215–219. PMID: 7547012.

47. Klimt CR, Knatterud GL, Stamler J, Meier P. Persantine-Aspirin Reinfarction Study. Part II. Secondary coronary prevention with persantine and aspirin. J Am Coll Cardiol. 1986; 7:251–269. PMID: 2868029.

48. Cleland JG, John J, Dhawan J, Clark A. What is the optimal medical management of ischaemic heart failure? Br Med Bull. 2001; 59:135–158. PMID: 11756208.

49. Andreassen AK, Nordøy I, Simonsen S, et al. Levels of circulating adhesion molecules in congestive heart failure and after heart transplantation. Am J Cardiol. 1998; 81:604–608. PMID: 9514458.

50. Malinin AI, Oshrine BR, Sane DC, O’Connor CM, Serebruany VL. Does heart failure etiology, New York Heart Association class, or ejection fraction affect the ability of clopidogrel to inhibit heightened platelet activity? Blood Coagul Fibrinolysis. 2007; 18:91–96. PMID: 17287623.

51. Serebruany VL. Clopidogrel and heart failure survival: missed opportunity or wrong turn? J Am Coll Cardiol. 2010; 55:1308–1309. PMID: 20338490.

52. Hofman-Bang C, Rehnqvist N, Swedberg K, Wiklund I, Aström H. Coenzyme Q10 as an adjunctive in the treatment of chronic congestive heart failure. The Q10 Study Group. J Card Fail. 1995; 1:101–107. PMID: 9420639.

53. Kjekshus J, Pedersen TR, Olsson AG, Faergeman O, Pyörälä K. The effects of simvastatin on the incidence of heart failure in patients with coronary heart disease. J Card Fail. 1997; 3:249–254. PMID: 9547437.

54. Tavazzi L, Maggioni AP, Marchioli R, et al. Effect of rosuvastatin in patients with chronic heart failure (the GISSI-HF trial): a randomised, double-blind, placebo-controlled trial. Lancet. 2008; 372:1231–1239. PMID: 18757089.

55. Gullestad L, Ueland T, Kjekshus J, et al. Galectin-3 predicts response to statin therapy in the Controlled Rosuvastatin Multinational Trial in Heart Failure (CORONA). Eur Heart J. 2012; 33:2290–2296. PMID: 22513778.

56. Perera D, Clayton T, O’Kane PD, Greenwood JP. Percutaneous revascularization for ischemic left ventricular dysfunction. N Engl J Med. 2022; 387:1351–1360. PMID: 36027563.

57. Velazquez EJ, Lee KL, Deja MA, et al. Coronary-artery bypass surgery in patients with left ventricular dysfunction. N Engl J Med. 2011; 364:1607–1616. PMID: 21463150.

58. Mehta RH, Grab JD, O’Brien SM, et al. Clinical characteristics and in-hospital outcomes of patients with cardiogenic shock undergoing coronary artery bypass surgery: insights from the Society of Thoracic Surgeons National Cardiac Database. Circulation. 2008; 117:876–885. PMID: 18250266.

59. Kapur NK, Davila CD. Timing, timing, timing: the emerging concept of the ‘door to support’ time for cardiogenic shock. Eur Heart J. 2017; 38:3532–3534. PMID: 29020366.

60. Esposito ML, Kapur NK. Acute mechanical circulatory support for cardiogenic shock: the “door to support” time. F1000 Res. 2017; 6:737.

61. Lee SE, Cho HJ, Lee HY, et al. A multicentre cohort study of acute heart failure syndromes in Korea: rationale, design, and interim observations of the Korean Acute Heart Failure (KorAHF) registry. Eur J Heart Fail. 2014; 16:700–708. PMID: 24797348.

62. Ruff CT, Giugliano RP, Braunwald E, et al. Comparison of the efficacy and safety of new oral anticoagulants with warfarin in patients with atrial fibrillation: a meta-analysis of randomised trials. Lancet. 2014; 383:955–962. PMID: 24315724.

63. Van Gelder IC, Groenveld HF, Crijns HJ, et al. Lenient versus strict rate control in patients with atrial fibrillation. N Engl J Med. 2010; 362:1363–1373. PMID: 20231232.

64. Van Gelder IC, Rienstra M, Crijns HJ, Olshansky B. Rate control in atrial fibrillation. Lancet. 2016; 388:818–828. PMID: 27560277.

65. Kotecha D, Flather MD, Altman DG, et al. Heart rate and rhythm and the benefit of beta-blockers in patients with heart failure. J Am Coll Cardiol. 2017; 69:2885–2896. PMID: 28467883.

66. Kotecha D, Bunting KV, Gill SK, et al. Effect of digoxin vs bisoprolol for heart rate control in atrial fibrillation on patient-reported quality of life: the RATE-AF randomized clinical trial. JAMA. 2020; 324:2497–2508. PMID: 33351042.

67. Hofmann R, Steinwender C, Kammler J, Kypta A, Leisch F. Effects of a high dose intravenous bolus amiodarone in patients with atrial fibrillation and a rapid ventricular rate. Int J Cardiol. 2006; 110:27–32. PMID: 16046015.

68. Wood MA, Brown-Mahoney C, Kay GN, Ellenbogen KA. Clinical outcomes after ablation and pacing therapy for atrial fibrillation : a meta-analysis. Circulation. 2000; 101:1138–1144. PMID: 10715260.

69. Gasparini M, Kloppe A, Lunati M, et al. Atrioventricular junction ablation in patients with atrial fibrillation treated with cardiac resynchronization therapy: positive impact on ventricular arrhythmias, implantable cardioverter-defibrillator therapies and hospitalizations. Eur J Heart Fail. 2018; 20:1472–1481. PMID: 29251799.

70. Lim KT, Davis MJ, Powell A, et al. Ablate and pace strategy for atrial fibrillation: long-term outcome of AIRCRAFT trial. Europace. 2007; 9:498–505. PMID: 17491103.

71. Packer DL, Piccini JP, Monahan KH, et al. Ablation versus drug therapy for atrial fibrillation in heart failure: results from the CABANA trial. Circulation. 2021; 143:1377–1390. PMID: 33554614.

72. Zafari AM, Zarter SK, Heggen V, et al. A program encouraging early defibrillation results in improved in-hospital resuscitation efficacy. J Am Coll Cardiol. 2004; 44:846–852. PMID: 15312869.

73. Kudenchuk PJ, Brown SP, Daya M, et al. Amiodarone, lidocaine, or placebo in out-of-hospital cardiac arrest. N Engl J Med. 2016; 374:1711–1722. PMID: 27043165.

74. Kudenchuk PJ, Cobb LA, Copass MK, et al. Amiodarone for resuscitation after out-of-hospital cardiac arrest due to ventricular fibrillation. N Engl J Med. 1999; 341:871–878. PMID: 10486418.

75. Tung R, Vaseghi M, Frankel DS, et al. Freedom from recurrent ventricular tachycardia after catheter ablation is associated with improved survival in patients with structural heart disease: an International VT Ablation Center Collaborative Group study. Heart Rhythm. 2015; 12:1997–2007. PMID: 26031376.

76. Kuck KH, Schaumann A, Eckardt L, et al. Catheter ablation of stable ventricular tachycardia before defibrillator implantation in patients with coronary heart disease (VTACH): a multicentre randomised controlled trial. Lancet. 2010; 375:31–40. PMID: 20109864.

77. Zeppenfeld K, Tfelt-Hansen J, de Riva M, et al. 2022 ESC Guidelines for the management of patients with ventricular arrhythmias and the prevention of sudden cardiac death. Eur Heart J. 2022; 43:3997–4126. PMID: 36017572.

78. Connolly SJ, Dorian P, Roberts RS, et al. Comparison of beta-blockers, amiodarone plus beta-blockers, or sotalol for prevention of shocks from implantable cardioverter defibrillators: the OPTIC Study: a randomized trial. JAMA. 2006; 295:165–171. PMID: 16403928.

79. Sapp JL, Wells GA, Parkash R, et al. Ventricular Tachycardia Ablation versus Escalation of Antiarrhythmic Drugs. N Engl J Med. 2016; 375:111–121. PMID: 27149033.

80. Ataklte F, Erqou S, Laukkanen J, Kaptoge S. Meta-analysis of ventricular premature complexes and their relation to cardiac mortality in general populations. Am J Cardiol. 2013; 112:1263–1270. PMID: 23927786.

81. Lin CY, Chang SL, Lin YJ, et al. Long-term outcome of multiform premature ventricular complexes in structurally normal heart. Int J Cardiol. 2015; 180:80–85. PMID: 25438221.

82. Lee GK, Klarich KW, Grogan M, Cha YM. Premature ventricular contraction-induced cardiomyopathy: a treatable condition. Circ Arrhythm Electrophysiol. 2012; 5:229–236. PMID: 22334430.

83. Singh SN, Fletcher RD, Fisher SG, et al. Amiodarone in patients with congestive heart failure and asymptomatic ventricular arrhythmia. Survival Trial of Antiarrhythmic Therapy in Congestive Heart Failure. N Engl J Med. 1995; 333:77–82. PMID: 7539890.

84. Penela D, Acosta J, Aguinaga L, et al. Ablation of frequent PVC in patients meeting criteria for primary prevention ICD implant: safety of withholding the implant. Heart Rhythm. 2015; 12:2434–2442. PMID: 26385530.

85. Berruezo A, Penela D, Jáuregui B, et al. Mortality and morbidity reduction after frequent premature ventricular complexes ablation in patients with left ventricular systolic dysfunction. Europace. 2019; 21:1079–1087. PMID: 30904923.

86. Stockburger M, Gómez-Doblas JJ, Lamas G, et al. Preventing ventricular dysfunction in pacemaker patients without advanced heart failure: results from a multicentre international randomized trial (PREVENT-HF). Eur J Heart Fail. 2011; 13:633–641. PMID: 21613427.

87. Sweeney MO, Bank AJ, Nsah E, et al. Minimizing ventricular pacing to reduce atrial fibrillation in sinus-node disease. N Engl J Med. 2007; 357:1000–1008. PMID: 17804844.

88. Stockburger M, Boveda S, Moreno J, et al. Long-term clinical effects of ventricular pacing reduction with a changeover mode to minimize ventricular pacing in a general pacemaker population. Eur Heart J. 2015; 36:151–157. PMID: 25179761.

89. Sweeney MO, Hellkamp AS, Ellenbogen KA, et al. Adverse effect of ventricular pacing on heart failure and atrial fibrillation among patients with normal baseline QRS duration in a clinical trial of pacemaker therapy for sinus node dysfunction. Circulation. 2003; 107:2932–2937. PMID: 12782566.

90. Curtis AB, Worley SJ, Adamson PB, et al. Biventricular pacing for atrioventricular block and systolic dysfunction. N Engl J Med. 2013; 368:1585–1593. PMID: 23614585.

91. Brignole M, Botto G, Mont L, et al. Cardiac resynchronization therapy in patients undergoing atrioventricular junction ablation for permanent atrial fibrillation: a randomized trial. Eur Heart J. 2011; 32:2420–2429. PMID: 21606084.

92. Yu CM, Chan JY, Zhang Q, et al. Biventricular pacing in patients with bradycardia and normal ejection fraction. N Engl J Med. 2009; 361:2123–2134. PMID: 19915220.

93. Otto CM, Nishimura RA, Bonow RO, et al. 2020 ACC/AHA Guideline for the management of patients with valvular heart disease: executive summary: a report of the American College of Cardiology/American Heart Association Joint Committee on Clinical Practice Guidelines. Circulation. 2021; 143:e35–e71. PMID: 33332149.

94. Vahanian A, Beyersdorf F, Praz F, et al. 2021 ESC/EACTS Guidelines for the management of valvular heart disease. Eur Heart J. 2022; 43:561–632. PMID: 34453165.

95. Chaliki HP, Mohty D, Avierinos JF, et al. Outcomes after aortic valve replacement in patients with severe aortic regurgitation and markedly reduced left ventricular function. Circulation. 2002; 106:2687–2693. PMID: 12438294.

96. Tornos P, Sambola A, Permanyer-Miralda G, Evangelista A, Gomez Z, Soler-Soler J. Long-term outcome of surgically treated aortic regurgitation: influence of guideline adherence toward early surgery. J Am Coll Cardiol. 2006; 47:1012–1017. PMID: 16516086.

97. Obadia JF, Messika-Zeitoun D, Leurent G, et al. Percutaneous repair or medical treatment for secondary mitral regurgitation. N Engl J Med. 2018; 379:2297–2306. PMID: 30145927.

98. Stone GW, Lindenfeld J, Abraham WT, et al. Transcatheter mitral-valve repair in patients with heart failure. N Engl J Med. 2018; 379:2307–2318. PMID: 30280640.

99. Zack CJ, Fender EA, Chandrashekar P, et al. National trends and outcomes in isolated tricuspid valve surgery. J Am Coll Cardiol. 2017; 70:2953–2960. PMID: 29241483.

100. Lee HY. Heart failure and diabetes mellitus: dangerous liaisons. Int J Heart Fail. 2022; 4:163–174. PMID: 36381018.

101. Bhatt DL, Szarek M, Steg PG, et al. Sotagliflozin in patients with diabetes and recent worsening heart failure. N Engl J Med. 2021; 384:117–128. PMID: 33200892.

102. Anker SD, Butler J, Filippatos G, et al. Empagliflozin in heart failure with a preserved ejection fraction. N Engl J Med. 2021; 385:1451–1461. PMID: 34449189.

103. McMurray JJV, Solomon SD, Inzucchi SE, et al. Dapagliflozin in patients with heart failure and reduced ejection fraction. N Engl J Med. 2019; 381:1995–2008. PMID: 31535829.

104. Perkovic V, Jardine MJ, Neal B, et al. Canagliflozin and renal outcomes in type 2 diabetes and nephropathy. N Engl J Med. 2019; 380:2295–2306. PMID: 30990260.

105. Zinman B, Wanner C, Lachin JM, et al. Empagliflozin, cardiovascular outcomes, and mortality in type 2 diabetes. N Engl J Med. 2015; 373:2117–2128. PMID: 26378978.

106. Solomon SD, McMurray JJV, Claggett B, et al. Dapagliflozin in heart failure with mildly reduced or preserved ejection fraction. N Engl J Med. 2022; 387:1089–1098. PMID: 36027570.

107. Neal B, Perkovic V, Mahaffey KW, et al. Canagliflozin and cardiovascular and renal events in type 2 diabetes. N Engl J Med. 2017; 377:644–657. PMID: 28605608.

108. Wiviott SD, Raz I, Bonaca MP, et al. Dapagliflozin and cardiovascular outcomes in type 2 diabetes. N Engl J Med. 2019; 380:347–357. PMID: 30415602.

109. Packer M, Butler J, Zannad F, et al. Effect of empagliflozin on worsening heart failure events in patients with heart failure and preserved ejection fraction: EMPEROR-Preserved trial. Circulation. 2021; 144:1284–1294. PMID: 34459213.

110. Kato ET, Kimura T. Sodium-glucose co-transporters-2 inhibitors and heart failure: state of the art review and future potentials. Int J Heart Fail. 2020; 2:12–22. PMID: 36263075.

111. Packer M, Anker SD, Butler J, et al. Cardiovascular and renal outcomes with empagliflozin in heart failure. N Engl J Med. 2020; 383:1413–1424. PMID: 32865377.

112. Damman K, Gori M, Claggett B, et al. Renal effects and associated outcomes during angiotensin-neprilysin inhibition in heart failure. JACC Heart Fail. 2018; 6:489–498. PMID: 29655829.

113. Jang SY, Yang DH. Prognostic and therapeutic implications of renal insufficiency in heart failure. Int J Heart Fail. 2022; 4:75–90. PMID: 36263106.

114. Bart BA, Goldsmith SR, Lee KL, et al. Ultrafiltration in decompensated heart failure with cardiorenal syndrome. N Engl J Med. 2012; 367:2296–2304. PMID: 23131078.

115. Urso C, Brucculeri S, Caimi G. Acid-base and electrolyte abnormalities in heart failure: pathophysiology and implications. Heart Fail Rev. 2015; 20:493–503. PMID: 25820346.

116. Canepa M, Franssen FM, Olschewski H, et al. Diagnostic and therapeutic gaps in patients with heart failure and chronic obstructive pulmonary disease. JACC Heart Fail. 2019; 7:823–833. PMID: 31521680.

117. Massone C, Cavalchini A, Clapasson A, Nunzi E. Hypopigmented macules: leprosy, atopy or pityriasis versicolor? G Ital Dermatol Venereol. 2010; 145:779–782. PMID: 21139555.

118. Halpin DM, Criner GJ, Papi A, et al. Global initiative for the diagnosis, management, and prevention of chronic obstructive lung disease. The 2020 GOLD science committee report on COVID-19 and chronic obstructive pulmonary disease. Am J Respir Crit Care Med. 2021; 203:24–36. PMID: 33146552.

119. Reddel HK, Bacharier LB, Bateman ED, et al. Global Initiative for Asthma Strategy 2021: executive summary and rationale for key changes. J Allergy Clin Immunol Pract. 2022; 10:S1–18. PMID: 34718211.

120. Klip IT, Comin-Colet J, Voors AA, et al. Iron deficiency in chronic heart failure: an international pooled analysis. Am Heart J. 2013; 165:575–582.e3. PMID: 23537975.

121. Anand IS. Anemia and chronic heart failure implications and treatment options. J Am Coll Cardiol. 2008; 52:501–511. PMID: 18687241.

122. Lim EA, Sohn HS, Lee H, Choi SE. Cost-utility of ferric carboxymaltose (Ferinject^®) for iron-deficiency anemia patients with chronic heart failure in South Korea. Cost Eff Resour Alloc. 2014; 12:19. PMID: 25278814.

123. Sharma R, Francis DP, Pitt B, Poole-Wilson PA, Coats AJ, Anker SD. Haemoglobin predicts survival in patients with chronic heart failure: a substudy of the ELITE II trial. Eur Heart J. 2004; 25:1021–1028. PMID: 15191772.

124. Tang YD, Katz SD. Anemia in chronic heart failure: prevalence, etiology, clinical correlates, and treatment options. Circulation. 2006; 113:2454–2461. PMID: 16717164.

125. Martens P, Nijst P, Verbrugge FH, Smeets K, Dupont M, Mullens W. Impact of iron deficiency on exercise capacity and outcome in heart failure with reduced, mid-range and preserved ejection fraction. Acta Cardiol. 2018; 73:115–123. PMID: 28730869.

126. Jankowska EA, Rozentryt P, Witkowska A, et al. Iron deficiency predicts impaired exercise capacity in patients with systolic chronic heart failure. J Card Fail. 2011; 17:899–906. PMID: 22041326.

127. Enjuanes C, Klip IT, Bruguera J, et al. Iron deficiency and health-related quality of life in chronic heart failure: results from a multicenter European study. Int J Cardiol. 2014; 174:268–275. PMID: 24768464.

128. Anand IS, Gupta P. Anemia and iron deficiency in heart failure: current concepts and emerging therapies. Circulation. 2018; 138:80–98. PMID: 29967232.

129. Silverberg DS, Wexler D, Blum M, et al. The use of subcutaneous erythropoietin and intravenous iron for the treatment of the anemia of severe, resistant congestive heart failure improves cardiac and renal function and functional cardiac class, and markedly reduces hospitalizations. J Am Coll Cardiol. 2000; 35:1737–1744. PMID: 10841219.

130. Parissis JT, Kourea K, Panou F, et al. Effects of darbepoetin alpha on right and left ventricular systolic and diastolic function in anemic patients with chronic heart failure secondary to ischemic or idiopathic dilated cardiomyopathy. Am Heart J. 2008; 155:751.e1–751.e7.

131. van Veldhuisen DJ, Dickstein K, Cohen-Solal A, et al. Randomized, double-blind, placebo-controlled study to evaluate the effect of two dosing regimens of darbepoetin alfa in patients with heart failure and anaemia. Eur Heart J. 2007; 28:2208–2216. PMID: 17681958.

132. Ghali JK, Anand IS, Abraham WT, et al. Randomized double-blind trial of darbepoetin alfa in patients with symptomatic heart failure and anemia. Circulation. 2008; 117:526–535. PMID: 18195176.

133. Swedberg K, Young JB, Anand IS, et al. Treatment of anemia with darbepoetin alfa in systolic heart failure. N Engl J Med. 2013; 368:1210–1219. PMID: 23473338.

134. Okonko DO, Grzeslo A, Witkowski T, et al. Effect of intravenous iron sucrose on exercise tolerance in anemic and nonanemic patients with symptomatic chronic heart failure and iron deficiency FERRIC-HF: a randomized, controlled, observer-blinded trial. J Am Coll Cardiol. 2008; 51:103–112. PMID: 18191732.

135. Toblli JE, Lombraña A, Duarte P, Di Gennaro F. Intravenous iron reduces NT-pro-brain natriuretic peptide in anemic patients with chronic heart failure and renal insufficiency. J Am Coll Cardiol. 2007; 50:1657–1665. PMID: 17950147.

136. Anker SD, Comin Colet J, Filippatos G, et al. Ferric carboxymaltose in patients with heart failure and iron deficiency. N Engl J Med. 2009; 361:2436–2448. PMID: 19920054.

137. Ponikowski P, van Veldhuisen DJ, Comin-Colet J, et al. Beneficial effects of long-term intravenous iron therapy with ferric carboxymaltose in patients with symptomatic heart failure and iron deficiency. Eur Heart J. 2015; 36:657–668. PMID: 25176939.

138. Ponikowski P, Kirwan BA, Anker SD, et al. Ferric carboxymaltose for iron deficiency at discharge after acute heart failure: a multicentre, double-blind, randomised, controlled trial. Lancet. 2020; 396:1895–1904. PMID: 33197395.

139. Lewis GD, Malhotra R, Hernandez AF, et al. Effect of oral iron repletion on exercise capacity in patients with heart failure with reduced ejection fraction and iron deficiency: the IRONOUT HF randomized clinical trial. JAMA. 2017; 317:1958–1966. PMID: 28510680.

140. Lewis GD, Semigran MJ, Givertz MM, et al. Oral iron therapy for heart failure with reduced ejection fraction: design and rationale for oral iron repletion effects on oxygen uptake in heart failure. Circ Heart Fail. 2016; 9:e000345. PMID: 27140203.

141. Young T, Finn L, Peppard PE, et al. Sleep disordered breathing and mortality: eighteen-year follow-up of the Wisconsin sleep cohort. Sleep. 2008; 31:1071–1078. PMID: 18714778.

142. Young T, Palta M, Dempsey J, Skatrud J, Weber S, Badr S. The occurrence of sleep-disordered breathing among middle-aged adults. N Engl J Med. 1993; 328:1230–1235. PMID: 8464434.

143. Gottlieb DJ, Yenokyan G, Newman AB, et al. Prospective study of obstructive sleep apnea and incident coronary heart disease and heart failure: the sleep heart health study. Circulation. 2010; 122:352–360. PMID: 20625114.

144. Randerath W, Verbraecken J, Andreas S, et al. Definition, discrimination, diagnosis and treatment of central breathing disturbances during sleep. Eur Respir J. 2017; 49:1600959. PMID: 27920092.

145. Elias RM, Chan CT, Paul N, et al. Relationship of pharyngeal water content and jugular volume with severity of obstructive sleep apnea in renal failure. Nephrol Dial Transplant. 2013; 28:937–944. PMID: 23136217.

146. Arzt M, Young T, Finn L, et al. Sleepiness and sleep in patients with both systolic heart failure and obstructive sleep apnea. Arch Intern Med. 2006; 166:1716–1722. PMID: 16983049.

147. Egea CJ, Aizpuru F, Pinto JA, et al. Cardiac function after CPAP therapy in patients with chronic heart failure and sleep apnea: a multicenter study. Sleep Med. 2008; 9:660–666. PMID: 17904420.

148. Smith LA, Vennelle M, Gardner RS, et al. Auto-titrating continuous positive airway pressure therapy in patients with chronic heart failure and obstructive sleep apnoea: a randomized placebo-controlled trial. Eur Heart J. 2007; 28:1221–1227. PMID: 17470670.

149. Pearse SG, Cowie MR. Sleep-disordered breathing in heart failure. Eur J Heart Fail. 2016; 18:353–361. PMID: 26869027.

150. Cowie MR, Woehrle H, Wegscheider K, et al. Adaptive Servo-Ventilation for central sleep apnea in systolic heart failure. N Engl J Med. 2015; 373:1095–1105. PMID: 26323938.

151. Angermann CE, Ertl G. Depression, anxiety, and cognitive impairment : comorbid mental health disorders in heart failure. Curr Heart Fail Rep. 2018; 15:398–410. PMID: 30402659.

152. Sbolli M, Fiuzat M, Cani D, O’Connor CM. Depression and heart failure: the lonely comorbidity. Eur J Heart Fail. 2020; 22:2007–2017. PMID: 32468714.

153. Angermann CE, Gelbrich G, Störk S, et al. Effect of escitalopram on all-cause mortality and hospitalization in patients with heart failure and depression: the MOOD-HF randomized clinical trial. JAMA. 2016; 315:2683–2693. PMID: 27367876.

154. Čelutkienė J, Vaitkevičius A, Jakštienė S, Jatužis D. Expert opinion-cognitive decline in heart failure: more attention is needed. Card Fail Rev. 2016; 2:106–109. PMID: 28785462.

155. Lee KS, Choi JO, Jeon ES, et al. Distinct factors associated with better self-care in heart failure patients with and without mild cognitive impairment. J Cardiovasc Nurs. 2019; 34:440–447. PMID: 31373955.

156. Corrigendum to 'Risk stratification and management of women with cardiomyopathy/heart failure planning pregnancy or presenting during/after pregnancy: a position statement from the Heart Failure Association of the European Society of Cardiology Study Group on Peripartum Cardiomyopathy' [Eur J Heart Fail 2021;23:527-540]. Eur J Heart Fail. 2022; 24:733.

157. Mehta LS, Warnes CA, Bradley E, et al. Cardiovascular considerations in caring for pregnant patients: a scientific statement from the American Heart Association. Circulation. 2020; 141:e884–e903. PMID: 32362133.

158. Regitz-Zagrosek V, Roos-Hesselink JW, Bauersachs J, et al. 2018 ESC Guidelines for the management of cardiovascular diseases during pregnancy. Eur Heart J. 2018; 39:3165–3241. PMID: 30165544.

159. Davis MB, Arany Z, McNamara DM, Goland S, Elkayam U. Peripartum cardiomyopathy: JACC state-of-the-art review. J Am Coll Cardiol. 2020; 75:207–221. PMID: 31948651.

160. Regitz-Zagrosek V. Sex and gender differences in heart failure. Int J Heart Fail. 2020; 2:157–181. PMID: 36262368.

161. Sliwa K, Petrie MC, van der Meer P, et al. Clinical presentation, management, and 6-month outcomes in women with peripartum cardiomyopathy: an ESC EORP registry. Eur Heart J. 2020; 41:3787–3797. PMID: 32840318.

162. Moulig V, Pfeffer TJ, Ricke-Hoch M, et al. Long-term follow-up in peripartum cardiomyopathy patients with contemporary treatment: low mortality, high cardiac recovery, but significant cardiovascular co-morbidities. Eur J Heart Fail. 2019; 21:1534–1542. PMID: 31724271.

163. Kim H, Chung WB, Cho KI, et al. Diagnosis, treatment, and prevention of cardiovascular toxicity related to anti-cancer treatment in clinical practice: an opinion paper from the Working Group on Cardio-Oncology of the Korean Society of Echocardiography. J Cardiovasc Ultrasound. 2018; 26:1–25. PMID: 29629020.

164. Čelutkienė J, Pudil R, López-Fernández T, et al. Role of cardiovascular imaging in cancer patients receiving cardiotoxic therapies: a position statement on behalf of the Heart Failure Association (HFA), the European Association of Cardiovascular Imaging (EACVI) and the Cardio-Oncology Council of the European Society of Cardiology (ESC). Eur J Heart Fail. 2020; 22:1504–1524. PMID: 32621569.

165. Thavendiranathan P, Negishi T, Somerset E, et al. Strain-Guided Management of potentially cardiotoxic cancer therapy. J Am Coll Cardiol. 2021; 77:392–401. PMID: 33220426.

166. Awadalla M, Mahmood SS, Groarke JD, et al. Global longitudinal strain and cardiac events in patients with immune checkpoint inhibitor-related myocarditis. J Am Coll Cardiol. 2020; 75:467–478. PMID: 32029128.

167. Guglin M, Krischer J, Tamura R, et al. Randomized trial of lisinopril versus carvedilol to prevent trastuzumab cardiotoxicity in patients with breast cancer. J Am Coll Cardiol. 2019; 73:2859–2868. PMID: 31171092.