The year 2017 in cardiology: heart failure

    Authors

    • Lars H. Lund — Stockholm, Sweden
    • Lars Køber — University of Copenhagen, Denmark
    • Karl Swedberg — University of Gothenburg, Gothenburg, Sweden
    • Frank Ruschitzka — University Heart Centre Zurich, Zürich, Switzerland

    DOI

    https://doi.org/10.15836/ccar2018.154

    Full Text

    ## Preamble The 2016 European Society of Cardiology (ESC) heart failure (HF) guidelines brought to the fore new recommendations for the management of HF with reduced ejection fraction (HFrEF; EF 2, 6MWT, KCCQ score, or NT-proBNP levels. (70) ## Acute heart failure On the basis of the ACS concept of ‘time is muscle’, (1) the initial presentation of acutely decompensated HF may represent a period of substantial myocardial vulnerability. (71) As such, the early intervention with an intravenous vasodilator has been proposed as a therapeutic goal to reduce cardiac-wall stress and myocardial injury, and ultimately long-term prognosis in patients with AHF. (71) In the TRUE-AHF trial, a randomized, double-blind, parallel-group, placebo-controlled, event-driven trial, however, ularitide given at a median of 6 h after evaluation did not reduce the composite endpoint of 48 h clinical course and 15 month CV mortality. (72) Similarly, early administration of serelaxin did not improve the composite endpoint of worsening HF at 5 days or CV death at 6 months in RELAX-AHF2. (73) Interestingly, an observational study suggested that treatment with intravenous loop diuretic within 1-h of presentation to the emergency department was associated with lower in-hospital mortality, (74) but the observational nature of this study precludes any conclusions regarding optimal type or timing of AHF interventions. In BLAST-AHF, a biased ligand of the angiotensin II type 1 receptor did not reduce dyspnoea, worsening HF or hospital length of stay. (75) Another concept is early aldosterone inhibition, but in ATHENA-HF, 100 mg of spironolactone compared to placebo did not improve natriuretic peptides or clinical measures. (76) Thus by end of 2017, numerous interventional strategies in AHF have failed, including continuous diuretics infusion, ultrafiltration, vasodilators and inotropes. ## Advanced heart failure In patients with severe refractory symptoms despite optimal medical management, quality of life and prognosis are dismal. The remaining options include heart transplantation (HTx), durable mechanical circulatory support (MCS), and palliation. After 30 years of remarkable success of HFrEF drug trials, (1, 2) it is notable that In 2017 we celebrate 50 years since the first HTx performed in 1967, and indeed the establishment of HTx as an option paved way for the worldwide HF referral centres and research programs that brought us the subsequent advances in HF pharmacotherapy. Similarly, implantable left ventricular assist devices (LVADs) were introduced already in the 1960s. In recent years, outcomes with HTx (77) and with LVAD both as bridge to transplantation and as destination therapy (78) have improved worldwide. However, HTx is associated with complications and studies are suggesting immunosuppression should be more individualized. (79) The number of HTx procedures performed are stagnant (77) and LVAD use is increasing only modestly. (78) Despite remarkable effect on mortality, LVADs are still limited by complications. Modern small centrifugal continuous flow LVADs appear to reduce the risk of thrombosis in the device, (80) but concerns over stroke and bleeding, right ventricular failure, and infection through the external driveline remain. In the PAL-HF trial, interdisciplinary palliative care compared with usual care showed benefits in quality of life, anxiety, depression, and spiritual well-being (**Figure 3**). (81) It is increasingly recognized that the scarcity of donor organs and the still high cost and complications with durable MCS demand especially careful selection, considering both indications and benefits as well as contraindications and risks. Figure 3. In PAL-HF trial, palliative vas significantly superior to usual care in improving quality of life. ## Novel interventional strategies As much as we need to focus on optimal utilization of existing therapy, HF remains a chronic, incurable, generally irreversible, and still debilitating syndrome, and novel inventive approaches have continued appeal. A new myosin activator which improves impaired contractility, omecamtiv mecarbil, was studied in the phase II study COSMIC-HF. (82) Titration guided by pharmacokinetics resulted in improved cardiac function and decreased NT-proBNP. (82) A Phase III trial is ongoing. Stem cell therapy has generally proven disappointing, but in the exploratory REGENERATE-IHD and CHART-1, intramyocardial injection of autologous bone-marrow derived cells in ischaemic cardiomyopathy appeared safe and improved EF, New York Heart Association (NYHA) class and NT-proBNP, and left ventricular (LV) end-systolic and diastolic volumes. (83–85) Novel radiocarbon (14C) techniques allow assessment of cardiomyocyte turnover dynamics and may provide a future foundation for regenerative strategies. (86) The ESC Task Force for stem cells in myocardial infarction and HF (87) and a global position statement on cardiovascular regenerative medicine (88) outline challenges for the stem cell field, and standardization of animal models, clinical trials and regulatory procedures are put forth as necessary for future success. Gene ‘editing’ targeting Clustered Regularly Interspaced Short Palindromic Repeats (CRISPR) is a promising technique with broad applications that has been used e.g. to edit hypertrophic cardiomyopathy causing genes in human embryos. (89) ## Conclusions This has been another year with many new trials reporting in HF. However, none of them will change clinical practise at present. A major challenge for the practising physician is to make sure that eligible patients with HFrEF receive guideline recommended care, and a major challenge for the HF community is to develop effective interventions in HFpEF and AHF. ## Acknowledgments The mention of trade names, commercial products organizations, and the inclusion of advertisements in the journal does not imply endorsement by the European Heart Journal, the editors, the editorial board, Oxford University Press or the organization to which the authors are affiliated. The editors and publishers have taken all reasonable precautions to verify drug names and doses, the results of experimental work and clinical findings published in the journal. The ultimate responsibility for the use and dosage of drugs mentioned in the journal and in interpretation of published material lies with the medical practitioner, and the editors and publisher cannot accept liability for damages arising from any error or omissions in the journal. Please inform the editors of any errors. The opinions expressed in the European Heart Journal are those of the authors and contributors, and do not necessarily reflect those of the European Society of Cardiology, the editors, the editorial board, Oxford University Press or the organization to which the authors are affiliated. OUP and the ESC are not responsible or in any way liable for the accuracy of the translation, for any errors, omissions or inaccuracies, or for any consequences arising therefore. Nina Jakuš and Ivo Darko Gabrić solely responsible for the translation published in this reprint. Translation edited by: Mario Ivanuša. Language editing: Tomislav Salopek.

    Literature

    1. Ponikowski P, Voors AA, Anker SD, Bueno H, Cleland JG, Coats AJ, 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: 2129–200. https://doi.org/10.1002/ejhf.592
    2. McMurray JJ. Improving outcomes in heart failure: a personal perspective. Eur Heart J. 2015;36:3467–70. https://doi.org/10.1093/eurheartj/ehv565
    3. Docherty KF, Campbell RT, Jhund PS, Petrie MC, McMurray JJV. How robust are clinical trials in heart failure? Eur Heart J. 2017;38:338–45. https://pubmed.ncbi.nlm.nih.gov/27742808/
    4. Ouwerkerk W, Voors AA, Anker SD, Cleland JG, Dickstein K, Filippatos G, et al. Determinants and clinical outcome of uptitration of ACE-inhibitors and beta-blockers in patients with heart failure: a prospective European study. Eur Heart J. 2017;38:1883–90. https://doi.org/10.1093/eurheartj/ehx026
    5. Chioncel O, Mebazaa A, Harjola VP, Coats AJ, Piepoli MF, Crespo-Leiro MG, et al. ESC Heart Failure Long-Term RegistryInvestigators. Clinical phenotypes and outcome of patients hospitalized for acute heart failure: the ESC Heart Failure Long-Term Registry. Eur J Heart Fail. 2017;19:1242–54. https://doi.org/10.1002/ejhf.890
    6. Crespo-Leiro MG, Anker SD, Maggioni AP, Coats AJ, Filippatos G, Ruschitzka F, et al. European Society of Cardiology Heart Failure Long-Term Registry (ESC-HF-LT): 1-year follow-up outcomes and differences across regions. Eur J Heart Fail. 2016;18:613–25. https://doi.org/10.1002/ejhf.566
    7. Thorvaldsen T, Benson L, Dahlstrom U, Edner M, Lund LH. Use of evidence-based therapy and survival in heart failure in Sweden 2003-2012. Eur J Heart Fail. 2016;18:503–11. https://doi.org/10.1002/ejhf.496
    8. Aldahl M, Jensen AS, Davidsen L, Eriksen MA, Møller Hansen S, Nielsen BJ, et al. Associations of serum potassium levels with mortality in chronic heart failure patients. Eur Heart J. 2017;38:2890–6. https://doi.org/10.1093/eurheartj/ehx460
    9. Ferreira JP, Rossignol P, Machu JL, Sharma A, Girerd N, Anker SD, et al. Mineralocorticoid receptor antagonist pattern of use in heart failure with reduced ejection fraction: findings from BIOSTAT-CHF. Eur J Heart Fail. 2017;19:1284–93. https://doi.org/10.1002/ejhf.900
    10. Böhm M, Komajda M, Borer JS, Ford I, Maack C, Tavazzi L, et al. SHIFT Investigators. Duration of chronic heart failure affects outcomes with preserved effects of heart rate reduction with ivabradine: findings from SHIFT. Eur J Heart Fail. 2018 Feb;20(2):373–81. https://doi.org/10.1002/ejhf.1021
    11. Desai AS, Claggett BL, Packer M, Zile MR, Rouleau JL, Swedberg K, et al. PARADIGM-HF Investigators. Influence of Sacubitril/Valsartan (LCZ696) on 30-day readmission after heart failure hospitalization. J Am Coll Cardiol. 2016;68:241–8. https://doi.org/10.1016/j.jacc.2016.04.047
    12. Scuffham PA, Ball J, Horowitz JD, Wong C, Newton PJ, Macdonald P, et al. WHICH? II Trail Investigators. Standard vs. intensified management of heart failure to reduce healthcare costs: results of a multicentre, randomized controlled trial. Eur Heart J. 2017;38:2340–8. https://doi.org/10.1093/eurheartj/ehx259
    13. Felker GM, Anstrom KJ, Adams KF, Ezekowitz JA, Fiuzat M, Houston-Miller N, et al. Effect of natriuretic peptide-guided therapy on hospitalization or cardiovascular mortality in high-risk patients with heart failure and reduced ejection fraction: a randomized clinical trial. JAMA. 2017;318:713–20. https://doi.org/10.1001/jama.2017.10565
    14. Morgan JM, Kitt S, Gill J, McComb JM, Ng GA, Raftery J, et al. Remote management of heart failure using implantable electronic devices. Eur Heart J. 2017;38:2352–60. https://doi.org/10.1093/eurheartj/ehx227
    15. Boehmer JP, Hariharan R, Devecchi FG, Smith AL, Molon G, Capucci A, et al. A multisensor algorithm predicts heart failure events in patients with implanted devices: results from the MultiSENSE Study. JACC Heart Fail. 2017;5:216–25. https://doi.org/10.1016/j.jchf.2016.12.011
    16. Zeitler EP, Friedman DJ, Daubert JP, Al-Khatib SM, Solomon SD, Biton Y, et al. Multiple comorbidities and response to cardiac resynchronization therapy: MADIT-CRT long-term follow-up. J Am Coll Cardiol. 2017;69:2369–79. https://doi.org/10.1016/j.jacc.2017.03.531
    17. Lund LH, Braunschweig F, Benson L, Stahlberg M, Dahlstrom U, Linde C. Association between demographic, organizational, clinical, and socio-economic characteristics and underutilization of cardiac resynchronization therapy: results from the Swedish Heart Failure Registry. Eur J Heart Fail. 2017;19:1270–9. https://doi.org/10.1002/ejhf.781
    18. Komajda M, Cowie MR, Tavazzi L, Ponikowski P, Anker SD, Filippatos GS. QUALIFY Investigators. Physicians’ guideline adherence is associated with better prognosis in outpatients with heart failure with reduced ejection fraction: the QUALIFY international registry. Eur J Heart Fail. 2017;19:1414–23. https://doi.org/10.1002/ejhf.887
    19. Lund LH, Carrero JJ, Farahmand B, Henriksson KM, Jonsson Å, Jernberg T, et al. Association between enrolment in a heart failure quality registry and subsequent mortality—a nationwide cohort study. Eur J Heart Fail. 2017 Sep;19(9):1107–16. https://doi.org/10.1002/ejhf.762
    20. van der Bijl P, Khidir M, Leung M, Mertens B, Ajmone Marsan N, Delgado V, et al. Impact of QRS complex duration and morphology on left ventricular reverse remodelling and left ventricular function improvement after cardiac resynchronization therapy. Eur J Heart Fail. 2017;19:1145–51. https://doi.org/10.1002/ejhf.769
    21. Linde C, Abraham WT, Gold MR, Daubert JC, Tang ASL, Young JB, et al. Predictors of short-term clinical response to cardiac resynchronization therapy. Eur J Heart Fail. 2017;19:1056–63. https://doi.org/10.1002/ejhf.795
    22. Brugada J, Delnoy PP, Brachmann J, Reynolds D, Padeletti L, Noelker G, et al. Contractility sensor-guided optimization of cardiac resynchronization therapy: results from the RESPOND-CRT trial. Eur Heart J. 2017;38:730–8. https://pubmed.ncbi.nlm.nih.gov/27941020/
    23. Bertini M, Mele D, Malagu M, Fiorencis A, Toselli T, Casadei F, et al. Cardiac resynchronization therapy guided by multimodality cardiac imaging. Eur J Heart Fail. 2016;18:1375–82. https://doi.org/10.1002/ejhf.605
    24. Sommer A, Kronborg MB, Norgaard BL, Poulsen SH, Bouchelouche K, Bottcher M, et al. Multimodality imaging-guided left ventricular lead placement in cardiac resynchronization therapy: a randomized controlled trial. Eur J Heart Fail. 2016;18:1365–74. https://doi.org/10.1002/ejhf.530
    25. Burns KV, Gage RM, Curtin AE, Gorcsan J, Bank AJ. Left ventricular-only pacing in heart failure patients with normal atrioventricular conduction improves global function and left ventricular regional mechanics compared with biventricular pacing: an adaptive cardiac resynchronization therapy sub-study. Eur J Heart Fail. 2017;19:1335–43. https://doi.org/10.1002/ejhf.906
    26. Boriani G. How to RESPOND to the quest to increase the effectiveness of cardiac resynchronization therapy? Eur Heart J. 2017;38:739–41. https://pubmed.ncbi.nlm.nih.gov/28025193/
    27. Gyöngyösi M, Winkler J, Ramos I, Do QT, Firat H, McDonald K, et al. Myocardial fibrosis: biomedical research from bench to bedside. Eur J Heart Fail. 2017;19:177–91. https://doi.org/10.1002/ejhf.696
    28. Køber L, Thune JJ, Nielsen JC, Haarbo J, Videbaek L, Korup E, et al. DANISH Investigators. Defibrillator implantation in patients with nonischemic systolic heart failure. N Engl J Med. 2016;375:1221–30. https://doi.org/10.1056/NEJMoa1608029
    29. Elming MB, Nielsen JC, Haarbo J, Videbæk L, Korup E, Signorovitch J, et al. Age and outcomes of primary prevention implantable cardioverter-defibrillators in patients with nonischemic systolic heart failure. Circulation. 2017;136:1772–80. https://doi.org/10.1161/CIRCULATIONAHA.117.028829
    30. Daimee UA, Vermilye K, Rosero S, Schuger CD, Daubert JP, Zareba W, et al. Heart failure severity, inappropriate ICD therapy, and novel ICD programming: a MADIT-RIT substudy. Pacing Clin Electrophysiol. 2017;40:1405–11. https://doi.org/10.1111/pace.13216
    31. Golwala H, Bajaj NS, Arora G, Arora P. Implantable cardioverter-defibrillator for nonischemic cardiomyopathy: an updated meta-analysis. Circulation. 2017;135:201–3. https://doi.org/10.1161/CIRCULATIONAHA.116.026056
    32. Kolodziejczak M, Andreotti F, Kowalewski M, Buffon A, Ciccone MM, Parati G, et al. Implantable cardioverter-defibrillators for primary prevention in patients with ischemic or nonischemic cardiomyopathy: a systematic review and meta-analysis. Ann Intern Med. 2017;167:103–11. https://doi.org/10.7326/M17-0120
    33. Shun-Shin MJ, Zheng SL, Cole GD, Howard JP, Whinnett ZI, Francis DP. Implantable cardioverter defibrillators for primary prevention of death in left ventricular dysfunction with and without ischaemic heart disease: a meta-analysis of 8567 patients in the 11 trials. Eur Heart J. 2017;38:1738–46. https://doi.org/10.1093/eurheartj/ehx028
    34. Stavrakis S, Asad Z, Reynolds D. Implantable cardioverter defibrillators for primary prevention of mortality in patients with nonischemic cardiomyopathy: a meta-analysis of randomized controlled trials. J Cardiovasc Electrophysiol. 2017;28:659–65. https://doi.org/10.1111/jce.13204
    35. Shen L, Jhund PS, Petrie MC, Claggett BL, Barlera S, Cleland JGF, et al. Declining risk of sudden death in heart failure. N Engl J Med. 2017;377:41–51. https://doi.org/10.1056/NEJMoa1609758
    36. Aro AL, Reinier K, Rusinaru C, Uy-Evanado A, Darouian N, Phan D, et al. Electrical risk score beyond the left ventricular ejection fraction: prediction of sudden cardiac death in the Oregon Sudden Unexpected Death Study and the Atherosclerosis Risk in Communities Study. Eur Heart J. 2017;38:3017–25. https://doi.org/10.1093/eurheartj/ehx331
    37. Bilchick KC, Wang Y, Cheng A, Curtis JP, Dharmarajan K, Stukenborg GJ, et al. Seattle Heart Failure and Proportional Risk Models Predict Benefit From Implantable Cardioverter-Defibrillators. J Am Coll Cardiol. 2017;69:2606–18. https://doi.org/10.1016/j.jacc.2017.03.568
    38. Rizas KD, McNitt S, Hamm W, Massberg S, Kaab S, Zareba W, et al. Prediction of sudden and non-sudden cardiac death in post-infarction patients with reduced left ventricular ejection fraction by periodic repolarization dynamics: MADIT-II substudy. Eur Heart J. 2017;38:2110–8. https://doi.org/10.1093/eurheartj/ehx161
    39. 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. https://doi.org/10.1002/ejhf.876
    40. Pitt B, Pfeffer MA, Assmann SF, Boineau R, Anand IS, Claggett B, et al. TOPCAT Investigators. Spironolactone for heart failure with preserved ejection fraction. N Engl J Med. 2014;370:1383–92. https://doi.org/10.1056/NEJMoa1313731
    41. Pfeffer MA, Claggett B, Assmann SF, Boineau R, Anand IS, Clausell N, et al. Regional variation in patients and outcomes in the treatment of preserved cardiac function heart failure with an aldosterone antagonist (TOPCAT) trial. Circulation. 2015;131:34–42. https://doi.org/10.1161/CIRCULATIONAHA.114.013255
    42. Girerd N, Ferreira JP, Rossignol P, Zannad F. A tentative interpretation of the TOPCAT trial based on randomized evidence from the brain natriuretic peptide stratum analysis. Eur J Heart Fail. 2016;18:1411–4. https://doi.org/10.1002/ejhf.621
    43. Desai AS, Jhund PS. After TOPCAT: what to do now in heart failure with preserved ejection fraction. Eur Heart J. 2016;37:3135–40. https://doi.org/10.1093/eurheartj/ehw114
    44. Anand IS, Rector TS, Cleland JG, Kuskowski M, McKelvie RS, Persson H, et al. Prognostic value of baseline plasma amino-terminal pro-brain natriuretic peptide and its interactions with irbesartan treatment effects in patients with heart failure and preserved ejection fraction: findings from the I-PRESERVE trial. Circ Heart Fail. 2011;4:569–77. https://doi.org/10.1161/CIRCHEARTFAILURE.111.962654
    45. Anand IS, Claggett B, Liu J, Shah AM, Rector TS, Shah SJ, et al. Interaction between spironolactone and natriuretic peptides in patients with heart failure and preserved ejection fraction: from the TOPCAT trial. JACC Heart Fail. 2017;5:241–52. https://doi.org/10.1016/j.jchf.2016.11.015
    46. Lund LH, Oldgren J, James S. Registry-based pragmatic trials in heart failure: current experience and future directions. Curr Heart Fail Rep. 2017;14:59–70. https://doi.org/10.1007/s11897-017-0325-0
    47. Rastogi A, Novak E, Platts AE, Mann DL. Epidemiology, pathophysiology and clinical outcomes for heart failure patients with a mid-range ejection fraction. Eur J Heart Fail. 2017 Dec;19(12):1597–605. https://doi.org/10.1002/ejhf.879
    48. Vedin O, Lam CSP, Koh AS, Benson L, Teng THK, Tay WT, et al. Significance of ischemic heart disease in patients with heart failure and preserved, midrange, and reduced ejection fraction: a nationwide cohort study. Circ Heart Fail. 2017 Jun;10(6):e003875. https://doi.org/10.1161/CIRCHEARTFAILURE.117.003875
    49. Bax JJ, Delgado V, Sogaard P, Singh JP, Abraham WT, Borer JS, et al. Prognostic implications of left ventricular global longitudinal strain in heart failure patients with narrow QRS complex treated with cardiac resynchronization therapy: a subanalysis of the randomized EchoCRT trial. Eur Heart J. 2017;38:720–6. https://pubmed.ncbi.nlm.nih.gov/28426885/
    50. Tops LF, Delgado V, Marsan NA, Bax JJ. Myocardial strain to detect subtle left ventricular systolic dysfunction. Eur J Heart Fail. 2017;19:307–13. https://doi.org/10.1002/ejhf.694
    51. Lund LH. The Inescapable Heterogeneity of Heart Failure. J Card Fail. 2017;23:351–2. https://doi.org/10.1016/j.cardfail.2017.03.007
    52. Löfman I, Szummer K, Dahlstrom U, Jernberg T, Lund LH. Associations with and prognostic impact of chronic kidney disease in heart failure with preserved, mid-range, and reduced ejection fraction. Eur J Heart Fail. 2017 Dec;19(12):1606–14. https://doi.org/10.1002/ejhf.821
    53. Chioncel O, Lainscak M, Seferovic PM, Anker SD, Crespo-Leiro MG, Harjola VP, et al. Epidemiology and one-year outcomes in patients with chronic heart failure and preserved, mid-range and reduced ejection fraction: an analysis of the ESC Heart Failure Long-Term Registry. Eur J Heart Fail. 2017 Dec;19(12):1574–85. https://doi.org/10.1002/ejhf.813
    54. Sartipy U, Dahlstrom U, Fu M, Lund LH. Atrial fibrillation in heart failure with preserved, mid-range, and reduced ejection fraction. JACC Heart Fail. 2017;5:565–74. https://doi.org/10.1016/j.jchf.2017.05.001
    55. Tsuji K, Sakata Y, Nochioka K, Miura M, Yamauchi T, Onose T, et al. CHART-2 Investigators. Characterization of heart failure patients with mid-range left ventricular ejection fraction-a report from the CHART-2 Study. Eur J Heart Fail. 2017;19:1258–69. https://doi.org/10.1002/ejhf.807
    56. Lupón J, Diez-Lopez C, de Antonio M, Domingo M, Zamora E, Moliner P, et al. Recovered heart failure with reduced ejection fraction and outcomes: a prospective study. Eur J Heart Fail. 2017 Dec;19(12):1615–23. https://doi.org/10.1002/ejhf.824
    57. Rickenbacher P, Kaufmann BA, Maeder MT, Bernheim A, Goetschalckx K, Pfister O, et al. TIME-CHF Investigators. Heart failure with mid-range ejection fraction: a distinct clinical entity? Insights from the Trial of Intensified versus standard Medical therapy in Elderly patients with Congestive Heart Failure (TIME-CHF). Eur J Heart Fail. 2017 Dec;19(12):1586–96. https://doi.org/10.1002/ejhf.798
    58. Cleland JGF, Bunting KV, Flather MD, Altman DG, Holmes J, Coats AJS, et al. Beta-blockers for heart failure with reduced, mid-range, and preserved ejection fraction: an individual patient-level analysis of double-blind randomized trials. Eur Heart J. 2018 Jan 1;39(1):26–35. https://doi.org/10.1093/eurheartj/ehx564
    59. Lund LH, Claggett B, Liu J, Lam CS, Swedberg K, Yusuf S, et al. Heart failure with mid ejection fraction in CHARM: characteristics, outcomes and effect of candesartan across the entire EF spectrum. Eur J Heart Fail. 2018 Feb 12;•••: [Epub ahead of print]. https://doi.org/10.1002/ejhf.1149
    60. 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. https://doi.org/10.1056/NEJMoa1504720
    61. Neal B, Perkovic V, Mahaffey KW, de Zeeuw D, Fulcher G, Erondu N, et al. Canagliflozin and cardiovascular and renal events in type 2 diabetes. N Engl J Med. 2017;377:644–57. https://doi.org/10.1056/NEJMoa1611925
    62. Savarese G, D’Amore C, Federici M, De Martino F, Dellegrottaglie S, Marciano C, et al. Effects of dipeptidyl peptidase 4 Inhibitors and Sodium-Glucose Linked coTransporter-2 Inhibitors on cardiovascular events in patients with type 2 diabetes mellitus: a meta-analysis. Int J Cardiol. 2016;220:595–601. https://doi.org/10.1016/j.ijcard.2016.06.208
    63. Fitchett DH, Udell JA, Inzucchi SE. Heart failure outcomes in clinical trials of glucose-lowering agents in patients with diabetes. Eur J Heart Fail. 2017;19:43–53. https://doi.org/10.1002/ejhf.633
    64. Butler J, Hamo CE, Filippatos G, Pocock SJ, Bernstein RA, Brueckmann M, et al. The potential role and rationale for treatment of heart failure with sodium-glucose co-transporter 2 inhibitors. Eur J Heart Fail. 2017;19:1390–400. https://doi.org/10.1002/ejhf.933
    65. Marrouche NF. Catheter Ablation versus Standard conventional Treatment in patients with LEft ventricular dysfunction and Atrial Fibrillation (CASTLE-AF). Hot Line - Late Breaking Clinical Trials 1 on Sunday 27 August, ESC 2017. Available at:. https://congress365.escardio.org/Presentation/162165#.WsCJ2C92CqQ
    66. van Gelder I. Risk factor driven upstream atrial fibrillation therapy improves sinus rhythm maintenance (RACE 3). Hot Line—Late Breaking Clinical Trials 1 on Sunday 27 August, ESC 2017. Available at:. https://www.escardio.org/The-ESC/Press-Office/Press-releases/risk-factor-driven-upstream-atrial-fibrillation-therapy-improves-sinus-rhythm-maintenance
    67. Zhabyeyev P, Oudit GY. Unravelling the molecular basis for cardiac iron metabolism and deficiency in heart failure. Eur Heart J. 2017;38:373–5. https://pubmed.ncbi.nlm.nih.gov/27651442/
    68. Haddad S, Wang Y, Galy B, Korf-Klingebiel M, Hirsch V, Baru AM, et al. Iron-regulatory proteins secure iron availability in cardiomyocytes to prevent heart failure. Eur Heart J. 2017;38:362–72. https://pubmed.ncbi.nlm.nih.gov/27545647/
    69. Anker SD, Kirwan BA, van Veldhuisen DJ, Filippatos G, Comin-Colet J, Ruschitzka F, et al. Effects of ferric carboxymaltose on hospitalisations and mortality rates in iron-deficient heart failure patients: an individual patient data meta-analysis. Eur J Heart Fail. 2018 Jan;20(1):125–33. https://doi.org/10.1002/ejhf.823
    70. Lewis GD, Malhotra R, Hernandez AF, McNulty SE, Smith A, Felker GM, 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;317:1958–66. https://doi.org/10.1001/jama.2017.5427
    71. Packer M, Holcomb R, Abraham WT, Anker S, Dickstein K, Filippatos G, et al. Rationale for and design of the TRUE-AHF trial: the effects of ularitide on the short-term clinical course and long-term mortality of patients with acute heart failure. Eur J Heart Fail. 2017;19:673–81. https://doi.org/10.1002/ejhf.698
    72. Packer M, O’Connor C, McMurray JJV, Wittes J, Abraham WT, Anker SD, et al. TRUE-AHF Investigators. Effect of ularitide on cardiovascular mortality in acute heart failure. N Engl J Med. 2017;376:1956–64. https://doi.org/10.1056/NEJMoa1601895
    73. Teerlink JR, Voors AA, Ponikowski P, Pang PS, Greenberg BH, Filippatos G, et al. Serelaxin in addition to standard therapy in acute heart failure: rationale and design of the RELAX-AHF-2 study. Eur J Heart Fail. 2017;19:800–9. https://doi.org/10.1002/ejhf.830
    74. Matsue Y, Damman K, Voors AA, Kagiyama N, Yamaguchi T, Kuroda S, et al. Time-to-furosemide treatment and mortality in patients hospitalized with acute heart failure. J Am Coll Cardiol. 2017;69:3042–51. https://doi.org/10.1016/j.jacc.2017.04.042
    75. Pang PS, Butler J, Collins SP, Cotter G, Davison BA, Ezekowitz JA, et al. Biased ligand of the angiotensin II type 1 receptor in patients with acute heart failure: a randomized, double-blind, placebo-controlled, phase IIB, dose ranging trial (BLAST-AHF). Eur Heart J. 2017;38:2364–73. https://doi.org/10.1093/eurheartj/ehx196
    76. Butler J, Anstrom KJ, Felker GM, Givertz MM, Kalogeropoulos AP, Konstam MA, et al. Efficacy and safety of spironolactone in acute heart failure: the ATHENA-HF randomized clinical trial. JAMA Cardiol. 2017 Sep 1;2(9):950–8. https://doi.org/10.1001/jamacardio.2017.2198
    77. Lund LH, Khush KK, Cherikh WS, Goldfarb S, Kucheryavaya AY, Levvey BJ, et al. The Registry of the International Society for Heart and Lung Transplantation: Thirty-fourth Adult Heart Transplantation Report-2017; focus theme: allograft ischemic time. J Heart Lung Transplant. 2017;36:1037–46. https://doi.org/10.1016/j.healun.2017.07.019
    78. Kirklin JK, Cantor R, Mohacsi P, Gummert J, De By T, Hannan MM, et al. First Annual IMACS Report: a global International Society for Heart and Lung Transplantation Registry for mechanical circulatory support. J Heart Lung Transplant. 2016;35:407–12. https://doi.org/10.1016/j.healun.2016.01.002
    79. Wever-Pinzon O, Edwards LB, Taylor DO, Kfoury AG, Drakos SG, Selzman CH, et al. Association of recipient age and causes of heart transplant mortality: implications for personalization of post-transplant management-An analysis of the International Society for Heart and Lung Transplantation Registry. J Heart Lung Transplant. 2017;36:407–17. https://doi.org/10.1016/j.healun.2016.08.008
    80. Mehra MR, Naka Y, Uriel N, Goldstein DJ, Cleveland JC, Colombo PC, et al. MOMENTUM 3 Investigators. A fully magnetically levitated circulatory pump for advanced heart failure. N Engl J Med. 2017;376:440–50. https://doi.org/10.1056/NEJMoa1610426
    81. Rogers JG, Patel CB, Mentz RJ, Granger BB, Steinhauser KE, Fiuzat M, et al. Palliative care in heart failure: the PAL-HF randomized, controlled clinical trial. J Am Coll Cardiol. 2017;70:331–41. https://doi.org/10.1016/j.jacc.2017.05.030
    82. Teerlink JR, Felker GM, McMurray JJ, Solomon SD, Adams KF, Cleland JG, et al. COSMIC-HF Investigators. Chronic Oral Study of Myosin Activation to Increase Contractility in Heart Failure (COSMIC-HF): a phase 2, pharmacokinetic, randomised, placebo-controlled trial. Lancet. 2016;388:2895–903. https://doi.org/10.1016/S0140-6736(16)32049-9
    83. Choudhury T, Mozid A, Hamshere S, Yeo C, Pellaton C, Arnous S, et al. An exploratory randomized control study of combination cytokine and adult autologous bone marrow progenitor cell administration in patients with ischaemic cardiomyopathy: the REGENERATE-IHD clinical trial. Eur J Heart Fail. 2017;19:138–47. https://doi.org/10.1002/ejhf.676
    84. Bartunek J, Terzic A, Davison BA, Filippatos GS, Radovanovic S, Beleslin B, et al. CHART-1 Program. Cardiopoietic cell therapy for advanced ischaemic heart failure: results at 39 weeks of the prospective, randomized, double blind, sham-controlled CHART-1 clinical trial. Eur Heart J. 2017;38:648–60. https://pubmed.ncbi.nlm.nih.gov/28025189/
    85. Teerlink JR, Metra M, Filippatos GS, Davison BA, Bartunek J, Terzic A, et al. CHART-1 Investigators. Benefit of cardiopoietic mesenchymal stem cell therapy on left ventricular remodelling: results from the Congestive Heart Failure Cardiopoietic Regenerative Therapy (CHART-1) study. Eur J Heart Fail. 2017;19:1520–9. https://doi.org/10.1002/ejhf.898
    86. Lázár E, Sadek HA, Bergmann O. Cardiomyocyte renewal in the human heart: insights from the fall-out. Eur Heart J. 2017;38:2333–42. https://doi.org/10.1093/eurheartj/ehx343
    87. Mathur A, Fernandez-Aviles F, Dimmeler S, Hauskeller C, Janssens S, Menasche P, et al. BAMI Investigators. The consensus of the Task Force of the European Society of Cardiology concerning the clinical investigation of the use of autologous adult stem cells for the treatment of acute myocardial infarction and heart failure: update 2016. Eur Heart J. 2017;38:2930–5. https://doi.org/10.1093/eurheartj/ehw640
    88. Fernández-Avilés F, Sanz-Ruiz R, Climent AM, Badimon L, Bolli R, Charron D, et al. TACTICS (Transnational Alliance for Regenerative Therapies in Cardiovascular Syndromes) Writing Group; Authors/Task Force Members. Chairpersons; Basic Research Subcommittee; Translational Research Subcommittee; Challenges of Cardiovascular Regenerative Medicine Subcommittee; Tissue Engineering Subcommittee; Delivery, Navigation, Tracking and Assessment Subcommittee; Clinical Trials Subcommittee; Regulatory and funding strategies subcommittee; Delivery, Navigation, Tracking and Assessment Subcommittee. Global position paper on cardiovascular regenerative medicine. Eur Heart J. 2017 Sep 1;38(33):2532–46. https://doi.org/10.1093/eurheartj/ehx248
    89. Ma H, Marti-Gutierrez N, Park SW, Wu J, Lee Y, Suzuki K, et al. Correction of a pathogenic gene mutation in human embryos. Nature. 2017;548:413–9. https://doi.org/10.1038/nature23305
    Cardiologia Croatica
    Back to search

    The year 2017 in cardiology: heart failure

    Review Article
    Issue3-4
    Published
    Pages154-164
    PDF via DOIhttps://doi.org/10.15836/ccar2018.154

    Authors

    Lars H. Lund*Stockholm, Sweden
    Lars KøberUniversity of Copenhagen, Denmark
    Karl SwedbergUniversity of Gothenburg, Gothenburg, Sweden
    Frank RuschitzkaUniversity Heart Centre Zurich, Zürich, Switzerland

    *Correspondence email: lars.lund@ki.se

    Full Text

    Preamble

    The 2016 European Society of Cardiology (ESC) heart failure (HF) guidelines brought to the fore new recommendations for the management of HF with reduced ejection fraction (HFrEF; EF <40%); introduced a new term: HF with mid-range EF (HFmrEF) for the previously denoted ‘grey area’ corresponding to EF 40–49%; highlighted the continued lack of evidence based interventions in HFmrEF and HF with preserved EF (HFpEF; EF ≥50%); and introduced the concept of early intervention in acute HF (AHF). Here we summarize data from autumn 2016 to autumn 2017 that analyse implementation and utilization of existing proven therapy in HFrEF; additional neutral trials in HFpEF but detailed characterization of and potential efficacy of therapy in HFmrEF; further disappointing trials in AHF; and growing evidence in favour of treating comorbidities.

    Heart failure with reduced ejection fraction treatment: implemetation and optimal utilization of existing therapy

    Drug therapy

    The last 30 years have seen a remarkable series of successful randomized trials in HFrEF, which have brought to clinical use multiple interventions that improve symptoms and quality of life and reduce HF hospitalization and/or mortality. (1, 2) While success of even large-scale outcome trials often depend on a small number of events and has been traditionally defined by statistical P-values, a novel measure of the robustness (or fragility) of the results of a clinical trial has been recently introduced. The fragility index (FI) describes the number of non-events that need to become events in order to render a trial result non-significant thus indicating how many patients would be required to convert a trial from being statistically significant to not significant. In a humbling analysis of 25 randomized controlled trials (RCT) with median sample size 2331 and primary events 688, the median FI was 26, and it was less than 10 in one-third of trials, (3) suggesting they may be less robust than we commonly assume.

    Nevertheless, a greater concern is that existing therapy is not optimally utilized in the real world. Although angiotensin-converting enzyme inhibitors (ACEi)/angiotensin receptor blockers (ARBs) and β-blockers appear to be used in 80–90% of patients with HFrEF even in real-world settings, dosing is sub-optimal, which is associated with higher mortality and HF hospitalization. (4) Recent data from the ESC HF Long-Term Registry (selected European sites) suggest that mineralocorticoid receptor antagonists (MRAs) are used in only two-third of patients with HFrEF (5, 6) and in the non-selective Swedish HF Registry, in less than one-third. (7) Chronic kidney disease and hyperkalaemia are common in HF (8) and reasons for MRA under-use appear to be perceived risk of or actual hyperkalaemia and worsening renal function. (9) More novel drugs such as ivabradine and sacubitril/valsartan may be deferred due to clinician inertia, even though they have demonstrated benefit regardless of HF duration (10) and very early after initiation. (11)

    How can appropriate utilization be improved? One appealing strategy is monitoring. However, intensified management using home visits and structured telephone support did not reduce recurrent hospitalization, mortality or costs. (12) In the large and much anticipated Guiding Evidence Based Therapy Using Biomarker Intensified Treatment in Heart Failure (GUIDE-IT) trial a strategy of aiming for an NT-proBNP <1000 ng/L vs. usual care did not reduce cardiovascular (CV) death or first or total HF hospitalizations, or even NT-proBNP levels. (13) In Remote Management of Heart Failure Using Implantable Electronic Devices (REM-HF), remote monitoring using implantable devices did not improve outcomes. (14) In the MultiSENSE study, the HeartLogic algorithm using implantable device data predicted HF decompensation (15) but has still to be shown to improve outcomes.

    Another strategy concerns improving the organization and prioritization of care. The use of devices is highly variable but overall underutilized. (7) Although, cardiac resynchronization therapy (CRT) benefit does not appear compromised by comorbidity burden, (16) it is conceivable that older and comorbid patients are less prioritized. In Sweden, non-use appears due to poor access to cardiology specialists rather than clinical variables. (17) In the international QUALIFY registry, guideline adherence was associated with improved outcomes. (18) A large Swedish study showed that enrolment vs. non-enrolment in the non-selective but voluntary Swedish Heart Failure Registry was associated with a 35% lower risk of death, and that the strongest explanatory factor was greater use of HF and CV medications in patients enrolled in the registry. (19)

    Cardiac rhythm management devices

    Implantable cardioverter-defibrillators (ICDs) and CRT improve outcomes in selected patients with HFrEF in multiple randomized clinical trials. These recent successes notwithstanding, a substantial number of patients receiving an ICD and/or CRTs do not benefit from the device thus highlighting the need for improvement in patient selection. Longer QRS duration, left bundle branch block morphology, and lower LVEF remain the most important independent predictor of response to CRT. (20, 21) In the RESPOND-CRT trial, non-response was ameliorated by an echo-guided optimization of atrioventricular (AV) and ventriculoventricular (VV) intervals. (22) Multimodality cardiac imaging strategies for lead placement, and possibly, left ventricular-only pacing, may increase CRT response. (23–25) But given the many factors involved in CRT response and outcomes, predicting CRT response remains elusive and the potential for larger multi parametric big-data approaches should be considered for future trials. (26, 27)

    The 2016 ESC guidelines recommend primary prevention ICD in both ischaemic and non-ischaemic cardiomyopathy. (1) This was called into doubt by DANISH, (28) where primary prevention ICD in non-ischaemic cardiomyopathy reduced sudden cardiac death but not all-cause death. In a secondary analysis, the association between ICD and survival decreased with age, and a cut-off of 70 years was suggested to yield the highest survival for the population as a whole. (29) Furthermore, inappropriate ICD therapy appears more likely in patients with more severe HF. (30) At the same time, in the last year, several meta-analyses point to a distinct reduction in both sudden and all-cause death. (31–34) Patients in these meta-analyses may have had less effective medical therapy than contemporary patients. Indeed, a large analysis form 12 clinical trials suggested that the rates of sudden death have declined over time (Figure 1), (35) which would be consistent with potentially lower benefit of primary prevention ICD in patients with contemporary treatment. Furthermore, benefits may differ substantially depending on e.g. age (28) and concomitant use of CRT, and in several recent studies multivariable prediction models were used to refine sudden death risk prediction and ICD benefit. (36–38)

    Figure 1. Rates of sudden death per 100 patient-years in heart failure with reduced ejection fraction trials.

    Heart failure with preserved ejection fraction

    Controversy remains as to whether HFpEF is a variant of HFrEF, a distinct entity, or merely a consequence of ageing and related comorbidities. It is associated with lower CV risk than HFrEF but it is indisputable that in the real world, it has the same overall mortality as HFrEF and is increasing more rapidly in prevalence. (1) Previous trials of ACEi, ARBs, and nitrates have been disappointing. (1) Recently, in EDIFY, ivabradine did not improve 6MWT, NT-proBNP, or E/e’. (39) In Treatment of Preserved Cardiac Function Heart Failure with an Aldosterone Antagonist (TOPCAT), spironolactone was overall not effective (40) but regional analyses suggested a potential effect in North and South America. (41) Perhaps more importantly, in the pre-specified stratum including patients based on NT-proBNP levels, consistent with confirmed HF, spironolactone was effective. (42) Interestingly, in both TOPCAT and I-PRESERVE, treatment was more effective in patients with lower natriuretic peptide levels. (43–45) So as we struggle in HFpEF trial design to ensure presence of HF and to enrich for HF events by requiring elevated NPs, as NPs go too high, the syndrome may be less amenable to intervention. Now, MRAs will be reassessed in a large pragmatic trial including patients with both HFpEF and HFmrEF. (46)

    Heart failure with mid-range ejection fraction

    The 2016 ESC guidelines introduced a new term HFmrEF, corresponding to the previously denoted ‘grey area’ EF 40–49%. (1) However, EF is not an ideal marker to classify HF, and EF may change with treatment and time. (47) A recent study suggested that 17-34% of patients with HFrEF or HFmrEF improve to a higher category, and that this, as expected, was more common in the absence of ischaemic heart disease. (48) Other modalities may refine characterization of HF, such as global longitudinal strain, (49, 50) but their impact in clinical routine remains to be seen. Given the heterogeneity of HF and difficulty characterizing HF, in particular with preserved EF, multimarker personalized approaches to HF, as occurs in oncology, may improve characterization and classification in HF. (27, 51)

    But EF remains the most commonly used classifier and the fact remains: EF 40–49% is not normal but there is no evidence based therapy, and further research is needed in this group, (1) comprising more than 20% of patients with HF. (52, 53) Extensive work during the last year suggest that although HFmrEF may be intermediate regarding some characteristics, (54–57) it resembles HFrEF regarding age, preponderance of male sex, greater prevalence of ischaemic heart disease (48) and greater prognostic impact of chronic kidney disease. (52) Recent studies also suggest that standard HF therapy may be effective in HFmrEF. In an individual patient-level meta-analysis from RCTs, β-blockers were not effective in atrial fibrillation (AF), but in sinus rhythm, they reduced all-cause and CV mortality in HFrEF and HFmrEF but not HFpEF (Figure 2). (58) Similarly, in a posthoc analysis from Candesartan in Heart failure – Assessment of moRtality and Morbidity (CHARM), candesartan reduced the composite of CV death and HF hospitalization in HFrEF (where 57% received concomitant ACEi), and HFmrEF (27% ACEi) but not HFpEF (16% ACEi). (59) Currently, drugs recommended in HFrEF are not recommended in HFmrEF, but these data suggest that they may be effective, and novel pragmatic trials should test this hypothesis. (46)

    Figure 2. All-cause mortality (A) and cardiovascular mortality (B) in patients with sinus rhythm and heart failure with different ejection fraction categories treated with β-blockers vs. placebo. From an individual patient-level analysis of double-blind randomized trials. (58) This Figure has been reprinted with permission of Oxford University Press on behalf of European Society of Cardiology.

    Comorbidities

    In diabetes mellitus, SGLT2 inhibitors modestly lower HbA1c. But in EMPA-REG (10% HF at baseline), empagliflozin reduced HF hospitalization by 35%, (60) and in CANVAS (14% HF at baseline), canagliflozin reduced HF hospitalization by 33%. (61) This has generated considerable interest in SGLT2 and also SGLT2/1 inhibition in HF (62, 63) and several trial programs are underway (64) to address whether SGLT2/1 inhibitors in combination with diuretics can improve outcomes in prevalent HF, with HFrEF, HFmrEF, and/or HFpEF, and with and without diabetes.

    Recent real-world data suggest that AF is more common in HF than previously believed, at 53% in HFrEF, 60% in HFmrEF and 63% in HFpEF in one generalizable study. (54) In CASTLE-AF, catheter ablation in patients with HFrEF (EF <35%) and paroxysmal or persistent AF appeared to reduce combined HF hospitalization and all-cause mortality (65) although these result have not yet been published. In RACE 3, in patients with HF and persistent AF who underwent electrical cardioversion, a concomitant strategy of cardiac rehabilitation, statins, an ACEi or ARB, and an MRA, resulted in maintained sinus rhythm at 1 year in 75% of patients, compared with 63% in the usual care group. (66)

    Iron deficiency affects as many as half of patients with HFrEF, irrespective of anaemia, (67) and recent animal studies suggest that this occurs through impaired cardiomyocyte mitochondrial respiration and adaptation to increases in workload. (68) Intravenous iron treatment results in considerable improvements in 6MWT and quality of life, and a meta-analysis suggest that it also reduced HF hospitalization. (69) It would be appealing to treat with oral rather than intravenous iron, but bioavailability is low and the large IRONOUT-HF trial showed that oral iron did not improve peak VO2, 6MWT, KCCQ score, or NT-proBNP levels. (70)

    Acute heart failure

    On the basis of the ACS concept of ‘time is muscle’, (1) the initial presentation of acutely decompensated HF may represent a period of substantial myocardial vulnerability. (71) As such, the early intervention with an intravenous vasodilator has been proposed as a therapeutic goal to reduce cardiac-wall stress and myocardial injury, and ultimately long-term prognosis in patients with AHF. (71)

    In the TRUE-AHF trial, a randomized, double-blind, parallel-group, placebo-controlled, event-driven trial, however, ularitide given at a median of 6 h after evaluation did not reduce the composite endpoint of 48 h clinical course and 15 month CV mortality. (72) Similarly, early administration of serelaxin did not improve the composite endpoint of worsening HF at 5 days or CV death at 6 months in RELAX-AHF2. (73) Interestingly, an observational study suggested that treatment with intravenous loop diuretic within 1-h of presentation to the emergency department was associated with lower in-hospital mortality, (74) but the observational nature of this study precludes any conclusions regarding optimal type or timing of AHF interventions.

    In BLAST-AHF, a biased ligand of the angiotensin II type 1 receptor did not reduce dyspnoea, worsening HF or hospital length of stay. (75) Another concept is early aldosterone inhibition, but in ATHENA-HF, 100 mg of spironolactone compared to placebo did not improve natriuretic peptides or clinical measures. (76) Thus by end of 2017, numerous interventional strategies in AHF have failed, including continuous diuretics infusion, ultrafiltration, vasodilators and inotropes.

    Advanced heart failure

    In patients with severe refractory symptoms despite optimal medical management, quality of life and prognosis are dismal. The remaining options include heart transplantation (HTx), durable mechanical circulatory support (MCS), and palliation. After 30 years of remarkable success of HFrEF drug trials, (1, 2) it is notable that In 2017 we celebrate 50 years since the first HTx performed in 1967, and indeed the establishment of HTx as an option paved way for the worldwide HF referral centres and research programs that brought us the subsequent advances in HF pharmacotherapy.

    Similarly, implantable left ventricular assist devices (LVADs) were introduced already in the 1960s. In recent years, outcomes with HTx (77) and with LVAD both as bridge to transplantation and as destination therapy (78) have improved worldwide. However, HTx is associated with complications and studies are suggesting immunosuppression should be more individualized. (79) The number of HTx procedures performed are stagnant (77) and LVAD use is increasing only modestly. (78) Despite remarkable effect on mortality, LVADs are still limited by complications. Modern small centrifugal continuous flow LVADs appear to reduce the risk of thrombosis in the device, (80) but concerns over stroke and bleeding, right ventricular failure, and infection through the external driveline remain.

    In the PAL-HF trial, interdisciplinary palliative care compared with usual care showed benefits in quality of life, anxiety, depression, and spiritual well-being (Figure 3). (81) It is increasingly recognized that the scarcity of donor organs and the still high cost and complications with durable MCS demand especially careful selection, considering both indications and benefits as well as contraindications and risks.

    Figure 3. In PAL-HF trial, palliative vas significantly superior to usual care in improving quality of life.

    Novel interventional strategies

    As much as we need to focus on optimal utilization of existing therapy, HF remains a chronic, incurable, generally irreversible, and still debilitating syndrome, and novel inventive approaches have continued appeal. A new myosin activator which improves impaired contractility, omecamtiv mecarbil, was studied in the phase II study COSMIC-HF. (82) Titration guided by pharmacokinetics resulted in improved cardiac function and decreased NT-proBNP. (82) A Phase III trial is ongoing. Stem cell therapy has generally proven disappointing, but in the exploratory REGENERATE-IHD and CHART-1, intramyocardial injection of autologous bone-marrow derived cells in ischaemic cardiomyopathy appeared safe and improved EF, New York Heart Association (NYHA) class and NT-proBNP, and left ventricular (LV) end-systolic and diastolic volumes. (83–85) Novel radiocarbon (14C) techniques allow assessment of cardiomyocyte turnover dynamics and may provide a future foundation for regenerative strategies. (86) The ESC Task Force for stem cells in myocardial infarction and HF (87) and a global position statement on cardiovascular regenerative medicine (88) outline challenges for the stem cell field, and standardization of animal models, clinical trials and regulatory procedures are put forth as necessary for future success. Gene ‘editing’ targeting Clustered Regularly Interspaced Short Palindromic Repeats (CRISPR) is a promising technique with broad applications that has been used e.g. to edit hypertrophic cardiomyopathy causing genes in human embryos. (89)

    Conclusions

    This has been another year with many new trials reporting in HF. However, none of them will change clinical practise at present. A major challenge for the practising physician is to make sure that eligible patients with HFrEF receive guideline recommended care, and a major challenge for the HF community is to develop effective interventions in HFpEF and AHF.

    Acknowledgments

    The mention of trade names, commercial products organizations, and the inclusion of advertisements in the journal does not imply endorsement by the European Heart Journal, the editors, the editorial board, Oxford University Press or the organization to which the authors are affiliated. The editors and publishers have taken all reasonable precautions to verify drug names and doses, the results of experimental work and clinical findings published in the journal. The ultimate responsibility for the use and dosage of drugs mentioned in the journal and in interpretation of published material lies with the medical practitioner, and the editors and publisher cannot accept liability for damages arising from any error or omissions in the journal. Please inform the editors of any errors.

    The opinions expressed in the European Heart Journal are those of the authors and contributors, and do not necessarily reflect those of the European Society of Cardiology, the editors, the editorial board, Oxford University Press or the organization to which the authors are affiliated.

    OUP and the ESC are not responsible or in any way liable for the accuracy of the translation, for any errors, omissions or inaccuracies, or for any consequences arising therefore. Nina Jakuš and Ivo Darko Gabrić solely responsible for the translation published in this reprint. Translation edited by: Mario Ivanuša. Language editing: Tomislav Salopek.

    Literature

    1. 1.
      Ponikowski P, Voors AA, Anker SD, Bueno H, Cleland JG, Coats AJ, 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: 2129–200.DOI
    2. 2.
      McMurray JJ. Improving outcomes in heart failure: a personal perspective. Eur Heart J. 2015;36:3467–70.DOI
    3. 3.
      Docherty KF, Campbell RT, Jhund PS, Petrie MC, McMurray JJV. How robust are clinical trials in heart failure? Eur Heart J. 2017;38:338–45.PubMed
    4. 4.
      Ouwerkerk W, Voors AA, Anker SD, Cleland JG, Dickstein K, Filippatos G, et al. Determinants and clinical outcome of uptitration of ACE-inhibitors and beta-blockers in patients with heart failure: a prospective European study. Eur Heart J. 2017;38:1883–90.DOI
    5. 5.
      Chioncel O, Mebazaa A, Harjola VP, Coats AJ, Piepoli MF, Crespo-Leiro MG, et al. ESC Heart Failure Long-Term RegistryInvestigators. Clinical phenotypes and outcome of patients hospitalized for acute heart failure: the ESC Heart Failure Long-Term Registry. Eur J Heart Fail. 2017;19:1242–54.DOI
    6. 6.
      Crespo-Leiro MG, Anker SD, Maggioni AP, Coats AJ, Filippatos G, Ruschitzka F, et al. European Society of Cardiology Heart Failure Long-Term Registry (ESC-HF-LT): 1-year follow-up outcomes and differences across regions. Eur J Heart Fail. 2016;18:613–25.DOI
    7. 7.
      Thorvaldsen T, Benson L, Dahlstrom U, Edner M, Lund LH. Use of evidence-based therapy and survival in heart failure in Sweden 2003-2012. Eur J Heart Fail. 2016;18:503–11.DOI
    8. 8.
      Aldahl M, Jensen AS, Davidsen L, Eriksen MA, Møller Hansen S, Nielsen BJ, et al. Associations of serum potassium levels with mortality in chronic heart failure patients. Eur Heart J. 2017;38:2890–6.DOI
    9. 9.
      Ferreira JP, Rossignol P, Machu JL, Sharma A, Girerd N, Anker SD, et al. Mineralocorticoid receptor antagonist pattern of use in heart failure with reduced ejection fraction: findings from BIOSTAT-CHF. Eur J Heart Fail. 2017;19:1284–93.DOI
    10. 10.
      Böhm M, Komajda M, Borer JS, Ford I, Maack C, Tavazzi L, et al. SHIFT Investigators. Duration of chronic heart failure affects outcomes with preserved effects of heart rate reduction with ivabradine: findings from SHIFT. Eur J Heart Fail. 2018 Feb;20(2):373–81.DOI
    11. 11.
      Desai AS, Claggett BL, Packer M, Zile MR, Rouleau JL, Swedberg K, et al. PARADIGM-HF Investigators. Influence of Sacubitril/Valsartan (LCZ696) on 30-day readmission after heart failure hospitalization. J Am Coll Cardiol. 2016;68:241–8.DOI
    12. 12.
      Scuffham PA, Ball J, Horowitz JD, Wong C, Newton PJ, Macdonald P, et al. WHICH? II Trail Investigators. Standard vs. intensified management of heart failure to reduce healthcare costs: results of a multicentre, randomized controlled trial. Eur Heart J. 2017;38:2340–8.DOI
    13. 13.
      Felker GM, Anstrom KJ, Adams KF, Ezekowitz JA, Fiuzat M, Houston-Miller N, et al. Effect of natriuretic peptide-guided therapy on hospitalization or cardiovascular mortality in high-risk patients with heart failure and reduced ejection fraction: a randomized clinical trial. JAMA. 2017;318:713–20.DOI
    14. 14.
      Morgan JM, Kitt S, Gill J, McComb JM, Ng GA, Raftery J, et al. Remote management of heart failure using implantable electronic devices. Eur Heart J. 2017;38:2352–60.DOI
    15. 15.
      Boehmer JP, Hariharan R, Devecchi FG, Smith AL, Molon G, Capucci A, et al. A multisensor algorithm predicts heart failure events in patients with implanted devices: results from the MultiSENSE Study. JACC Heart Fail. 2017;5:216–25.DOI
    16. 16.
      Zeitler EP, Friedman DJ, Daubert JP, Al-Khatib SM, Solomon SD, Biton Y, et al. Multiple comorbidities and response to cardiac resynchronization therapy: MADIT-CRT long-term follow-up. J Am Coll Cardiol. 2017;69:2369–79.DOI
    17. 17.
      Lund LH, Braunschweig F, Benson L, Stahlberg M, Dahlstrom U, Linde C. Association between demographic, organizational, clinical, and socio-economic characteristics and underutilization of cardiac resynchronization therapy: results from the Swedish Heart Failure Registry. Eur J Heart Fail. 2017;19:1270–9.DOI
    18. 18.
      Komajda M, Cowie MR, Tavazzi L, Ponikowski P, Anker SD, Filippatos GS. QUALIFY Investigators. Physicians’ guideline adherence is associated with better prognosis in outpatients with heart failure with reduced ejection fraction: the QUALIFY international registry. Eur J Heart Fail. 2017;19:1414–23.DOI
    19. 19.
      Lund LH, Carrero JJ, Farahmand B, Henriksson KM, Jonsson Å, Jernberg T, et al. Association between enrolment in a heart failure quality registry and subsequent mortality—a nationwide cohort study. Eur J Heart Fail. 2017 Sep;19(9):1107–16.DOI
    20. 20.
      van der Bijl P, Khidir M, Leung M, Mertens B, Ajmone Marsan N, Delgado V, et al. Impact of QRS complex duration and morphology on left ventricular reverse remodelling and left ventricular function improvement after cardiac resynchronization therapy. Eur J Heart Fail. 2017;19:1145–51.DOI
    21. 21.
      Linde C, Abraham WT, Gold MR, Daubert JC, Tang ASL, Young JB, et al. Predictors of short-term clinical response to cardiac resynchronization therapy. Eur J Heart Fail. 2017;19:1056–63.DOI
    22. 22.
      Brugada J, Delnoy PP, Brachmann J, Reynolds D, Padeletti L, Noelker G, et al. Contractility sensor-guided optimization of cardiac resynchronization therapy: results from the RESPOND-CRT trial. Eur Heart J. 2017;38:730–8.PubMed
    23. 23.
      Bertini M, Mele D, Malagu M, Fiorencis A, Toselli T, Casadei F, et al. Cardiac resynchronization therapy guided by multimodality cardiac imaging. Eur J Heart Fail. 2016;18:1375–82.DOI
    24. 24.
      Sommer A, Kronborg MB, Norgaard BL, Poulsen SH, Bouchelouche K, Bottcher M, et al. Multimodality imaging-guided left ventricular lead placement in cardiac resynchronization therapy: a randomized controlled trial. Eur J Heart Fail. 2016;18:1365–74.DOI
    25. 25.
      Burns KV, Gage RM, Curtin AE, Gorcsan J, Bank AJ. Left ventricular-only pacing in heart failure patients with normal atrioventricular conduction improves global function and left ventricular regional mechanics compared with biventricular pacing: an adaptive cardiac resynchronization therapy sub-study. Eur J Heart Fail. 2017;19:1335–43.DOI
    26. 26.
      Boriani G. How to RESPOND to the quest to increase the effectiveness of cardiac resynchronization therapy? Eur Heart J. 2017;38:739–41.PubMed
    27. 27.
      Gyöngyösi M, Winkler J, Ramos I, Do QT, Firat H, McDonald K, et al. Myocardial fibrosis: biomedical research from bench to bedside. Eur J Heart Fail. 2017;19:177–91.DOI
    28. 28.
      Køber L, Thune JJ, Nielsen JC, Haarbo J, Videbaek L, Korup E, et al. DANISH Investigators. Defibrillator implantation in patients with nonischemic systolic heart failure. N Engl J Med. 2016;375:1221–30.DOI
    29. 29.
      Elming MB, Nielsen JC, Haarbo J, Videbæk L, Korup E, Signorovitch J, et al. Age and outcomes of primary prevention implantable cardioverter-defibrillators in patients with nonischemic systolic heart failure. Circulation. 2017;136:1772–80.DOI
    30. 30.
      Daimee UA, Vermilye K, Rosero S, Schuger CD, Daubert JP, Zareba W, et al. Heart failure severity, inappropriate ICD therapy, and novel ICD programming: a MADIT-RIT substudy. Pacing Clin Electrophysiol. 2017;40:1405–11.DOI
    31. 31.
      Golwala H, Bajaj NS, Arora G, Arora P. Implantable cardioverter-defibrillator for nonischemic cardiomyopathy: an updated meta-analysis. Circulation. 2017;135:201–3.DOI
    32. 32.
      Kolodziejczak M, Andreotti F, Kowalewski M, Buffon A, Ciccone MM, Parati G, et al. Implantable cardioverter-defibrillators for primary prevention in patients with ischemic or nonischemic cardiomyopathy: a systematic review and meta-analysis. Ann Intern Med. 2017;167:103–11.DOI
    33. 33.
      Shun-Shin MJ, Zheng SL, Cole GD, Howard JP, Whinnett ZI, Francis DP. Implantable cardioverter defibrillators for primary prevention of death in left ventricular dysfunction with and without ischaemic heart disease: a meta-analysis of 8567 patients in the 11 trials. Eur Heart J. 2017;38:1738–46.DOI
    34. 34.
      Stavrakis S, Asad Z, Reynolds D. Implantable cardioverter defibrillators for primary prevention of mortality in patients with nonischemic cardiomyopathy: a meta-analysis of randomized controlled trials. J Cardiovasc Electrophysiol. 2017;28:659–65.DOI
    35. 35.
      Shen L, Jhund PS, Petrie MC, Claggett BL, Barlera S, Cleland JGF, et al. Declining risk of sudden death in heart failure. N Engl J Med. 2017;377:41–51.DOI
    36. 36.
      Aro AL, Reinier K, Rusinaru C, Uy-Evanado A, Darouian N, Phan D, et al. Electrical risk score beyond the left ventricular ejection fraction: prediction of sudden cardiac death in the Oregon Sudden Unexpected Death Study and the Atherosclerosis Risk in Communities Study. Eur Heart J. 2017;38:3017–25.DOI
    37. 37.
      Bilchick KC, Wang Y, Cheng A, Curtis JP, Dharmarajan K, Stukenborg GJ, et al. Seattle Heart Failure and Proportional Risk Models Predict Benefit From Implantable Cardioverter-Defibrillators. J Am Coll Cardiol. 2017;69:2606–18.DOI
    38. 38.
      Rizas KD, McNitt S, Hamm W, Massberg S, Kaab S, Zareba W, et al. Prediction of sudden and non-sudden cardiac death in post-infarction patients with reduced left ventricular ejection fraction by periodic repolarization dynamics: MADIT-II substudy. Eur Heart J. 2017;38:2110–8.DOI
    39. 39.
      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.DOI
    40. 40.
      Pitt B, Pfeffer MA, Assmann SF, Boineau R, Anand IS, Claggett B, et al. TOPCAT Investigators. Spironolactone for heart failure with preserved ejection fraction. N Engl J Med. 2014;370:1383–92.DOI
    41. 41.
      Pfeffer MA, Claggett B, Assmann SF, Boineau R, Anand IS, Clausell N, et al. Regional variation in patients and outcomes in the treatment of preserved cardiac function heart failure with an aldosterone antagonist (TOPCAT) trial. Circulation. 2015;131:34–42.DOI
    42. 42.
      Girerd N, Ferreira JP, Rossignol P, Zannad F. A tentative interpretation of the TOPCAT trial based on randomized evidence from the brain natriuretic peptide stratum analysis. Eur J Heart Fail. 2016;18:1411–4.DOI
    43. 43.
      Desai AS, Jhund PS. After TOPCAT: what to do now in heart failure with preserved ejection fraction. Eur Heart J. 2016;37:3135–40.DOI
    44. 44.
      Anand IS, Rector TS, Cleland JG, Kuskowski M, McKelvie RS, Persson H, et al. Prognostic value of baseline plasma amino-terminal pro-brain natriuretic peptide and its interactions with irbesartan treatment effects in patients with heart failure and preserved ejection fraction: findings from the I-PRESERVE trial. Circ Heart Fail. 2011;4:569–77.DOI
    45. 45.
      Anand IS, Claggett B, Liu J, Shah AM, Rector TS, Shah SJ, et al. Interaction between spironolactone and natriuretic peptides in patients with heart failure and preserved ejection fraction: from the TOPCAT trial. JACC Heart Fail. 2017;5:241–52.DOI
    46. 46.
      Lund LH, Oldgren J, James S. Registry-based pragmatic trials in heart failure: current experience and future directions. Curr Heart Fail Rep. 2017;14:59–70.DOI
    47. 47.
      Rastogi A, Novak E, Platts AE, Mann DL. Epidemiology, pathophysiology and clinical outcomes for heart failure patients with a mid-range ejection fraction. Eur J Heart Fail. 2017 Dec;19(12):1597–605.DOI
    48. 48.
      Vedin O, Lam CSP, Koh AS, Benson L, Teng THK, Tay WT, et al. Significance of ischemic heart disease in patients with heart failure and preserved, midrange, and reduced ejection fraction: a nationwide cohort study. Circ Heart Fail. 2017 Jun;10(6):e003875.DOI
    49. 49.
      Bax JJ, Delgado V, Sogaard P, Singh JP, Abraham WT, Borer JS, et al. Prognostic implications of left ventricular global longitudinal strain in heart failure patients with narrow QRS complex treated with cardiac resynchronization therapy: a subanalysis of the randomized EchoCRT trial. Eur Heart J. 2017;38:720–6.PubMed
    50. 50.
      Tops LF, Delgado V, Marsan NA, Bax JJ. Myocardial strain to detect subtle left ventricular systolic dysfunction. Eur J Heart Fail. 2017;19:307–13.DOI
    51. 51.
      Lund LH. The Inescapable Heterogeneity of Heart Failure. J Card Fail. 2017;23:351–2.DOI
    52. 52.
      Löfman I, Szummer K, Dahlstrom U, Jernberg T, Lund LH. Associations with and prognostic impact of chronic kidney disease in heart failure with preserved, mid-range, and reduced ejection fraction. Eur J Heart Fail. 2017 Dec;19(12):1606–14.DOI
    53. 53.
      Chioncel O, Lainscak M, Seferovic PM, Anker SD, Crespo-Leiro MG, Harjola VP, et al. Epidemiology and one-year outcomes in patients with chronic heart failure and preserved, mid-range and reduced ejection fraction: an analysis of the ESC Heart Failure Long-Term Registry. Eur J Heart Fail. 2017 Dec;19(12):1574–85.DOI
    54. 54.
      Sartipy U, Dahlstrom U, Fu M, Lund LH. Atrial fibrillation in heart failure with preserved, mid-range, and reduced ejection fraction. JACC Heart Fail. 2017;5:565–74.DOI
    55. 55.
      Tsuji K, Sakata Y, Nochioka K, Miura M, Yamauchi T, Onose T, et al. CHART-2 Investigators. Characterization of heart failure patients with mid-range left ventricular ejection fraction-a report from the CHART-2 Study. Eur J Heart Fail. 2017;19:1258–69.DOI
    56. 56.
      Lupón J, Diez-Lopez C, de Antonio M, Domingo M, Zamora E, Moliner P, et al. Recovered heart failure with reduced ejection fraction and outcomes: a prospective study. Eur J Heart Fail. 2017 Dec;19(12):1615–23.DOI
    57. 57.
      Rickenbacher P, Kaufmann BA, Maeder MT, Bernheim A, Goetschalckx K, Pfister O, et al. TIME-CHF Investigators. Heart failure with mid-range ejection fraction: a distinct clinical entity? Insights from the Trial of Intensified versus standard Medical therapy in Elderly patients with Congestive Heart Failure (TIME-CHF). Eur J Heart Fail. 2017 Dec;19(12):1586–96.DOI
    58. 58.
      Cleland JGF, Bunting KV, Flather MD, Altman DG, Holmes J, Coats AJS, et al. Beta-blockers for heart failure with reduced, mid-range, and preserved ejection fraction: an individual patient-level analysis of double-blind randomized trials. Eur Heart J. 2018 Jan 1;39(1):26–35.DOI
    59. 59.
      Lund LH, Claggett B, Liu J, Lam CS, Swedberg K, Yusuf S, et al. Heart failure with mid ejection fraction in CHARM: characteristics, outcomes and effect of candesartan across the entire EF spectrum. Eur J Heart Fail. 2018 Feb 12;•••: [Epub ahead of print].DOI
    60. 60.
      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.DOI
    61. 61.
      Neal B, Perkovic V, Mahaffey KW, de Zeeuw D, Fulcher G, Erondu N, et al. Canagliflozin and cardiovascular and renal events in type 2 diabetes. N Engl J Med. 2017;377:644–57.DOI
    62. 62.
      Savarese G, D’Amore C, Federici M, De Martino F, Dellegrottaglie S, Marciano C, et al. Effects of dipeptidyl peptidase 4 Inhibitors and Sodium-Glucose Linked coTransporter-2 Inhibitors on cardiovascular events in patients with type 2 diabetes mellitus: a meta-analysis. Int J Cardiol. 2016;220:595–601.DOI
    63. 63.
      Fitchett DH, Udell JA, Inzucchi SE. Heart failure outcomes in clinical trials of glucose-lowering agents in patients with diabetes. Eur J Heart Fail. 2017;19:43–53.DOI
    64. 64.
      Butler J, Hamo CE, Filippatos G, Pocock SJ, Bernstein RA, Brueckmann M, et al. The potential role and rationale for treatment of heart failure with sodium-glucose co-transporter 2 inhibitors. Eur J Heart Fail. 2017;19:1390–400.DOI
    65. 65.
      Marrouche NF. Catheter Ablation versus Standard conventional Treatment in patients with LEft ventricular dysfunction and Atrial Fibrillation (CASTLE-AF). Hot Line - Late Breaking Clinical Trials 1 on Sunday 27 August, ESC 2017. Available at:.Link
    66. 66.
      van Gelder I. Risk factor driven upstream atrial fibrillation therapy improves sinus rhythm maintenance (RACE 3). Hot Line—Late Breaking Clinical Trials 1 on Sunday 27 August, ESC 2017. Available at:.Link
    67. 67.
      Zhabyeyev P, Oudit GY. Unravelling the molecular basis for cardiac iron metabolism and deficiency in heart failure. Eur Heart J. 2017;38:373–5.PubMed
    68. 68.
      Haddad S, Wang Y, Galy B, Korf-Klingebiel M, Hirsch V, Baru AM, et al. Iron-regulatory proteins secure iron availability in cardiomyocytes to prevent heart failure. Eur Heart J. 2017;38:362–72.PubMed
    69. 69.
      Anker SD, Kirwan BA, van Veldhuisen DJ, Filippatos G, Comin-Colet J, Ruschitzka F, et al. Effects of ferric carboxymaltose on hospitalisations and mortality rates in iron-deficient heart failure patients: an individual patient data meta-analysis. Eur J Heart Fail. 2018 Jan;20(1):125–33.DOI
    70. 70.
      Lewis GD, Malhotra R, Hernandez AF, McNulty SE, Smith A, Felker GM, 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;317:1958–66.DOI
    71. 71.
      Packer M, Holcomb R, Abraham WT, Anker S, Dickstein K, Filippatos G, et al. Rationale for and design of the TRUE-AHF trial: the effects of ularitide on the short-term clinical course and long-term mortality of patients with acute heart failure. Eur J Heart Fail. 2017;19:673–81.DOI
    72. 72.
      Packer M, O’Connor C, McMurray JJV, Wittes J, Abraham WT, Anker SD, et al. TRUE-AHF Investigators. Effect of ularitide on cardiovascular mortality in acute heart failure. N Engl J Med. 2017;376:1956–64.DOI
    73. 73.
      Teerlink JR, Voors AA, Ponikowski P, Pang PS, Greenberg BH, Filippatos G, et al. Serelaxin in addition to standard therapy in acute heart failure: rationale and design of the RELAX-AHF-2 study. Eur J Heart Fail. 2017;19:800–9.DOI
    74. 74.
      Matsue Y, Damman K, Voors AA, Kagiyama N, Yamaguchi T, Kuroda S, et al. Time-to-furosemide treatment and mortality in patients hospitalized with acute heart failure. J Am Coll Cardiol. 2017;69:3042–51.DOI
    75. 75.
      Pang PS, Butler J, Collins SP, Cotter G, Davison BA, Ezekowitz JA, et al. Biased ligand of the angiotensin II type 1 receptor in patients with acute heart failure: a randomized, double-blind, placebo-controlled, phase IIB, dose ranging trial (BLAST-AHF). Eur Heart J. 2017;38:2364–73.DOI
    76. 76.
      Butler J, Anstrom KJ, Felker GM, Givertz MM, Kalogeropoulos AP, Konstam MA, et al. Efficacy and safety of spironolactone in acute heart failure: the ATHENA-HF randomized clinical trial. JAMA Cardiol. 2017 Sep 1;2(9):950–8.DOI
    77. 77.
      Lund LH, Khush KK, Cherikh WS, Goldfarb S, Kucheryavaya AY, Levvey BJ, et al. The Registry of the International Society for Heart and Lung Transplantation: Thirty-fourth Adult Heart Transplantation Report-2017; focus theme: allograft ischemic time. J Heart Lung Transplant. 2017;36:1037–46.DOI
    78. 78.
      Kirklin JK, Cantor R, Mohacsi P, Gummert J, De By T, Hannan MM, et al. First Annual IMACS Report: a global International Society for Heart and Lung Transplantation Registry for mechanical circulatory support. J Heart Lung Transplant. 2016;35:407–12.DOI
    79. 79.
      Wever-Pinzon O, Edwards LB, Taylor DO, Kfoury AG, Drakos SG, Selzman CH, et al. Association of recipient age and causes of heart transplant mortality: implications for personalization of post-transplant management-An analysis of the International Society for Heart and Lung Transplantation Registry. J Heart Lung Transplant. 2017;36:407–17.DOI
    80. 80.
      Mehra MR, Naka Y, Uriel N, Goldstein DJ, Cleveland JC, Colombo PC, et al. MOMENTUM 3 Investigators. A fully magnetically levitated circulatory pump for advanced heart failure. N Engl J Med. 2017;376:440–50.DOI
    81. 81.
      Rogers JG, Patel CB, Mentz RJ, Granger BB, Steinhauser KE, Fiuzat M, et al. Palliative care in heart failure: the PAL-HF randomized, controlled clinical trial. J Am Coll Cardiol. 2017;70:331–41.DOI
    82. 82.
      Teerlink JR, Felker GM, McMurray JJ, Solomon SD, Adams KF, Cleland JG, et al. COSMIC-HF Investigators. Chronic Oral Study of Myosin Activation to Increase Contractility in Heart Failure (COSMIC-HF): a phase 2, pharmacokinetic, randomised, placebo-controlled trial. Lancet. 2016;388:2895–903.DOI
    83. 83.
      Choudhury T, Mozid A, Hamshere S, Yeo C, Pellaton C, Arnous S, et al. An exploratory randomized control study of combination cytokine and adult autologous bone marrow progenitor cell administration in patients with ischaemic cardiomyopathy: the REGENERATE-IHD clinical trial. Eur J Heart Fail. 2017;19:138–47.DOI
    84. 84.
      Bartunek J, Terzic A, Davison BA, Filippatos GS, Radovanovic S, Beleslin B, et al. CHART-1 Program. Cardiopoietic cell therapy for advanced ischaemic heart failure: results at 39 weeks of the prospective, randomized, double blind, sham-controlled CHART-1 clinical trial. Eur Heart J. 2017;38:648–60.PubMed
    85. 85.
      Teerlink JR, Metra M, Filippatos GS, Davison BA, Bartunek J, Terzic A, et al. CHART-1 Investigators. Benefit of cardiopoietic mesenchymal stem cell therapy on left ventricular remodelling: results from the Congestive Heart Failure Cardiopoietic Regenerative Therapy (CHART-1) study. Eur J Heart Fail. 2017;19:1520–9.DOI
    86. 86.
      Lázár E, Sadek HA, Bergmann O. Cardiomyocyte renewal in the human heart: insights from the fall-out. Eur Heart J. 2017;38:2333–42.DOI
    87. 87.
      Mathur A, Fernandez-Aviles F, Dimmeler S, Hauskeller C, Janssens S, Menasche P, et al. BAMI Investigators. The consensus of the Task Force of the European Society of Cardiology concerning the clinical investigation of the use of autologous adult stem cells for the treatment of acute myocardial infarction and heart failure: update 2016. Eur Heart J. 2017;38:2930–5.DOI
    88. 88.
      Fernández-Avilés F, Sanz-Ruiz R, Climent AM, Badimon L, Bolli R, Charron D, et al. TACTICS (Transnational Alliance for Regenerative Therapies in Cardiovascular Syndromes) Writing Group; Authors/Task Force Members. Chairpersons; Basic Research Subcommittee; Translational Research Subcommittee; Challenges of Cardiovascular Regenerative Medicine Subcommittee; Tissue Engineering Subcommittee; Delivery, Navigation, Tracking and Assessment Subcommittee; Clinical Trials Subcommittee; Regulatory and funding strategies subcommittee; Delivery, Navigation, Tracking and Assessment Subcommittee. Global position paper on cardiovascular regenerative medicine. Eur Heart J. 2017 Sep 1;38(33):2532–46.DOI
    89. 89.
      Ma H, Marti-Gutierrez N, Park SW, Wu J, Lee Y, Suzuki K, et al. Correction of a pathogenic gene mutation in human embryos. Nature. 2017;548:413–9.DOI