ISSUE @ A GLANCE
European Heart Journal (2015) 36, 699–701 doi:10.1093/eurheartj/ehv040
Novel prognostic markers and treatment options in heart failure: from palliative to regenerative medicine Thomas F. Lu¨scher, MD, FESC Editor-in-Chief, Zurich Heart House, Careum Campus, Moussonstrasse 4, 8091 Zurich, Switzerland
entitled ‘Left atrial function measured by cardiac magnetic resonance imaging in patients with heart failure: clinical associations and prognostic value’,10 Pierpaolo Pellicori et al. from Hull and East Yorkshire Medical Research and Teaching Centre in Kingston upon Hull, UK carefully studied left atrial emptying function using cardiac magnetic resonance imaging (MRI) in 664 outpatients referred with heart failure with reduced left ventricular function and elevated N-terminal pro brain natriuretic peptide (NT-proBNP). The paper is accompanied by an Editorial by Carolyn S.P. Lam from the Mayo Clinic and National University Health System, Singapore.11 Left atrial emptying function was 42% and 55% in patients with and without heart failure, respectively. Patients with heart failure in the lowest quartile of left atrial emptying function had a lower left and right ventricular ejection fraction, and greater ventricular mass and higher plasma NT-proBNP than those in the highest quartile. Log left atrial emptying function and log NT-proBNP were inversely correlated. During a median follow-up of .2 years, 59% of patients died or were admitted with heart failure and 15% developed atrial fibrillation. In a multivariable Cox model, increasing left atrial emptying function, but not left ventricular ejection fraction, was associated with survival. On the other hand, increasing age and decreasing left atrial emptying function predicted atrial fibrillation. Thus, in heart failure, left atrial emptying function predicts adverse outcome independently of other measures of cardiac dysfunction. Left atrial function should, therefore, be considered routinely in the assessment and risk stratification of patients with heart failure. The third paper, by Philippe Menasche´ from the Hoˆpital Europe´en Georges Pompidou in Paris, France, focuses on a truly experimental approach. Although stem cell therapy has received a lot of attention in recent years, its effectiveness in patients after infarction,12,13,14 as well as in those with heart failure remains controversial.15 There is, however, evidence that precursor cells committed to a cardiac lineage might effectively improve the function of infarcted hearts.16. This has been established by the author’s preclinical studies entailing transplantation of human embryonic stem cell-derived cardiac progenitors in rat and non-human primate models of myocardial infarction. In this third paper, ‘Towards a clinical use of human embryonic stem cell-derived cardiac progenitors: a translational experience’,17 Menasche´ et al. present their translational
Published on behalf of the European Society of Cardiology. All rights reserved. & The Author 2015. For permissions please email: [email protected].
Downloaded from by guest on April 7, 2015
In spite of impressive progress in the last decades, the management of heart failure remains essentially palliative in nature.1,2 Rates of rehospitalizations and death remain high even in patients on optimal therapy, according to current guidelines.3,4 Thus, ongoing research at the basic and clinical levels is urgently needed to address this unmet clinical need. This issue of the European Heart Journal is devoted to novel insights into the mechanisms, outcomes, and treatment options in chronic and acute heart failure at the basic and clinical level. Although interfering with neurohumoral activation was most successful so far therapeutically,5,6 it is obvious that the primary problem, particularly in dilated cardiomyopathy, is due to altered cardiac muscular function. The first paper, entitled ‘Ultrastructural features of cardiomyocytes in dilated cardiomyopathy with initially decompensated heart failure as a predictor of prognosis’7 by Tsunenori Saito from the Department of Cardiovascular Medicine of the Nippon Medical School in Tokyo, Japan, which is accompanied by an excellent Editorial by Carsten Tscho¨pe from the Charite´ University in Berlin, Germany,8 attempted to characterize myocardial ultrastructural changes by electron microscopy in endomyocardial biopsy specimens of the left ventricle obtained from 250 patients with dilated cardiomyopathy presenting with decompensated heart failure. During a follow-up period of 5 years, 10% died and 27% were readmitted with heart failure. Myofilament changes, classified as either focal derangement of myofilaments (sarcomere damage) or diffuse myofilament lysis (disappearance of most sarcomeres in cardiomyocytes), were found in 66% of the patients. Multivariate analysis identified that a family history of dilated cardiomyopathy; atrial fibrillation, haemoglobin level, and diffuse myofilament lysis were independent predictors of mortality. A family history, haemoglobin, focal derangement of myofilaments, and diffuse myofilament lysis were also predictors of readmission for heart failure. This study shows for the first time that in patients with dilated cardiomyopathy and a first episode of decompensated heart failure, myofilament changes are strongly associated with mortality and recurrence. As a next step, it appears mandatory to understand the molecular mechanisms of such structural changes to define novel therapeutic targets. Although left ventricular and right ventricular function are well recognized determinants of outcome in patients with heart failure,9 atrial function has not been studied in detail. In the second paper,
700
discussed. Ularitide, a synthetic form of the human natriuretic peptide urodilatin produced in distal renal tubule cells involved in sodium homeostasis, is currently in clinical testing in a phase III trial. Ularitide exerts its pharmacological actions, i.e. vasodilation, diuresis, and natriuresis, through the natriuretic peptide receptor and activation of particulate guanylate cyclase, and in turn a reduction in intracellular calcium. In animal models as well as Phase I and II clinical studies in patients with heart failure, ularitide exerted beneficial effects such as symptom relief and vasodilation, while preserving renal function. The pivotal acute decompensated heart failure Phase III study, the TRUE-AHF trial, is currently under way and has recruited .2000 patients. This trial will confirm or refute whether in patients presenting with acute heart fialure an infusion of ularitide will improve the clinical status and mortality. The editors sincerely hope that this issue of the European Heart Journal will be received with interest by its readers.
References 1. Stewart S, Demers C, Murdoch DR, McIntyre K, MacLeod ME, Kendrick S, Capewell S, McMurray JJ. Substantial between-hospital variation in outcome following first emergency admission for heart failure. Eur Heart J 2002;23:650 –657. 2. van Bommel RJ, Borleffs CJ, Ypenburg C, Marsan NA, Delgado V, Bertini M, van der Wall EE, Schalij MJ, Bax JJ. Morbidity and mortality in heart failure patients treated with cardiac resynchronization therapy: influence of pre-implantation characteristics on long-term outcome. Eur Heart J 2010;31:2783 –2790. 3. McMurray JJ, Adamopoulos S, Anker SD, Auricchio A, Bohm M, Dickstein K, Falk V, Filippatos G, Fonseca C, Gomez-Sanchez MA, Jaarsma T, Kober L, Lip GY, Maggioni AP, Parkhomenko A, Pieske BM, Popescu BA, Ronnevik PK, Rutten FH, Schwitter J, Seferovic P, Stepinska J, Trindade PT, Voors AA, Zannad F, Zeiher A, ESC Committee for Practice Guidelines. ESC Guidelines for the diagnosis and treatment of acute and chronic heart failure 2012: the Task Force for the Diagnosis and Treatment of Acute and Chronic Heart Failure 2012 of the European Society of Cardiology. Developed in collaboration with the Heart Failure Association (HFA) of the ESC. Eur Heart J 2012;33:1787 – 1847. 4. Brignole M, Auricchio A, Baron-Esquivias G, Bordachar P, Boriani G, Breithardt OA, Cleland J, Deharo JC, Delgado V, Elliott PM, Gorenek B, Israel CW, Leclercq C, Linde C, Mont L, Padeletti L, Sutton R, Vardas PE; ESC Committee for Practice Guidelines (CPG), Zamorano JL, Achenbach S, Baumgartner H, Bax JJ, Bueno H, Dean V, Deaton C, Erol C, Fagard R, Ferrari R, Hasdai D, Hoes AW, Kirchhof P, Knuuti J, Kolh P, Lancellotti P, Linhart A, Nihoyannopoulos P, Piepoli MF, Ponikowski P, Sirnes PA, Tamargo JL, Tendera M, Torbicki A, Wijns W, Windecker S; Document Reviewers, Kirchhof P, Blomstrom-Lundqvist C, Badano LP, Aliyev F, Ba¨nsch D, Baumgartner H, Bsata W, Buser P, Charron P, Daubert JC, Dobreanu D, Faerestrand S, Hasdai D, Hoes AW, Le Heuzey JY, Mavrakis H, McDonagh T, Merino JL, Nawar MM, Nielsen JC, Pieske B, Poposka L, Ruschitzka F, Tendera M, Van Gelder IC, Wilson CM. 2013 ESC Guidelines on cardiac pacing and cardiac resynchronization therapy: the Task Force on cardiac pacing and resynchronization therapy of the European Society of Cardiology (ESC). Developed in collaboration with the European Heart Rhythm Association (EHRA). Eur Heart J 2013;34:2281 –2329. 5. Verdecchia P, Angeli F, Cavallini C, Gattobigio R, Gentile G, Staessen JA, Reboldi G. Blood pressure reduction and renin –angiotensin system inhibition for prevention of congestive heart failure: a meta-analysis. Eur Heart J 2009;30:679–688. 6. Zannad F, Gattis Stough W, Rossignol P, Bauersachs J, McMurray JJ, Swedberg K, Struthers AD, Voors AA, Ruilope LM, Bakris GL, O’Connor CM, Gheorghiade M, Mentz RJ, Cohen-Solal A, Maggioni AP, Beygui F, Filippatos GS, Massy ZA, Pathak A, Pin˜a IL, Sabbah HN, Sica DA, Tavazzi L, Pitt B. Mineralocorticoid receptor antagonists for heart failure with reduced ejection fraction: integrating evidence into clinical practice. Eur Heart J 2012;33:2782 –2795. 7. Saito T, Asai K, Sato S, Takano H, Mizuno K, Shimizu W. Ultrastructural features of cardiomyocytes in dilated cardiomyopathy with initially decompensated heart failure as a predictor of prognosis. Eur Heart J 2015;36:724 –732. 8. Savvatis K, Schultheiss H-P, Tscho¨pe C. Endomyocardial biopsy and ultrastructural changes in dilated cardiomyopathy: taking a ‘deeper’ look into patients’ prognosis. Eur Heart J 2015;36:708 –710. 9. Ho JE, Gona P, Pencina MJ, Tu JV, Austin PC, Vasan RS, Kannel WB, D’Agostino RB, Lee DS, Levy D. Discriminating clinical features of heart failure with preserved vs. reduced ejection fraction in the community. Eur Heart J 2012;33:1734 –1741. 10. Pellicori P, Zhang J, Lukaschuk E, Joseph AC, Bourantas CV, Loh H, Bragadeesh T, Clark AL, Cleland JGF. Left atrial function measured by cardiac magnetic resonance
Downloaded from by guest on April 7, 2015
programme aimed at a phase I clinical trial. The main steps of this programme have included (i) the expansion of a clone of pluripotent human embryonic stem cell-derived cardiac progenitors to generate a master cell bank under Good Manufacturing Practice (GMP) conditions; (ii) a growth factor-induced cardiac specification; (iii) the purification of committed cells by immunomagnetic sorting to yield an SSEA-1-positive cell population strongly expressing the early cardiac transcription factor Isl-1; (iv) the incorporation of these cells into a fibrin scaffold; (v) a safety assessment focused on the loss of teratoma-forming cells by in vitro (transcriptomics) and in vivo (cell injections in immunodeficient mice) measurements; (vi) an extensive cytogenetic and viral testing; and (vii) the characterization of the final cell product and its release criteria. These data have led to the approval by the French regulatory authorities for a first-in-man clinical trial of transplantation of such SSEA-1-positive progenitors in patients with severely impaired cardiac function. Although we are aware of the fact that the road to evidence is a bumpy one,18 and several aspects of this manufacturing process still need to be improved, this approach may prove a useful platform for the production of human embryonic stem cell-derived cardiac progenitors under safe and cost-effective GMP conditions, and certainly is a first step towards the development of a regenerative therapy of heart failure. The fourth paper, by Eduardo Marban from the Cedars-Sinai Medical Center in Los Angeles, USA entitled ‘Therapeutic efficacy of cardiosphere-derived cells in a transgenic mouse model of non-ischaemic dilated cardiomyopathy’,19 pursues a similar strategy by testing the effects of transplantation of cardiospherederived cells in mice with cardiac-specific Gaq overexpression, which predictably develop cardiac dilation, heart failure, and accelerated mortality. Indeed, it has been shown that cardiosphere-derived cells exhibit regenerative effects in the post-infarct setting, while it remains unknown whether such cells are beneficial in dilated cardiomyopathy. Wild-type mouse cardiosphere-derived cells or vehicle were injected intramyocardially in 6-, 8-, and 11-week old Gaq mice. Over 3 months, cardiac function deteriorated in vehicle-treated mice accompanied by oxidative stress, inflammation, and ventricular remodelling. In contrast, cardiosphere-derived cells preserved cardiac function and volumes, improved survival, and promoted cardiomyogenesis, while blunting Gaq-induced oxidative stress and inflammation in the heart. The mechanism of benefit is indirect, as long-term engraftment of transplanted cells is vanishingly low. The authors conclude that cardiosphere-derived cells reverse fundamental abnormalities in cell signalling, prevent adverse remodelling, and improve survival in a mouse model of dilated cardiomyopathy. The ability to impact favourably on disease progression in non-ischaemic heart failure heralds new potential therapeutic applications of cardiosphere-derived cells. This issue ends with a review on a potentially novel treatment of acute heart failure. The short- and long-term morbidity and mortality of acute heart failure is still unacceptably high. The use of vasodilator drugs in acute heart failure has received a lot of attention after the potentially life-saving effects of seralaxin in this patient population became public.20,21,22 In the review article by Stefan D. Anker from the University of Go¨ttingen in Germany, the current evidence supporting the future use of the novel vasodilator and natriuretic peptide ‘Ularitide for the treatment of acute decompensated heart failure: from pre-clinical to clinical studies’23 is
Issue @ a Glance
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Issue @ a Glance
11. 12.
13.
14.
15.
16.
imaging in patients with heart failure: clinical associations and prognostic value. Eur Heart J 2015;36:733 –742. Shah AM, Lam CSP. Function over form? Assessing the left atrium in heart failure. Eur Heart J 2015;36:711 –714. Kang HJ, Kim MK, Lee HY, Park KW, Lee W, Cho YS, Koo BK, Choi DJ, Park YB, Kim HS. Five-year results of intracoronary infusion of the mobilized peripheral blood stem cells by granulocyte colony-stimulating factor in patients with myocardial infarction. Eur Heart J 2012;33:3062 –3069. Su¨rder D, Manka R, Lo Cicero V, Moccetti T, Rufibach K, Soncin S, Turchetto L, Radrizzani M, Astori G, Schwitter J, Erne P, Zuber M, Auf der Maur C, Jamshidi P, Gaemperli O, Windecker S, Moschovitis A, Wahl A, Bu¨hler I, Wyss C, Kozerke S, Landmesser U, Lu¨scher TF, Corti R. Intracoronary injection of bone marrowderived mononuclear cells early or late after acute myocardial infarction: effects on global left ventricular function. Circulation 2013;127:1968 –1979. Cogle CR, Wise E, Meacham AM, Zierold C, Traverse JH, Henry TD, Perin EC, Willerson JT, Ellis SG, Carlson M, Zhao DX, Bolli R, Cooke JP, Anwaruddin S, Bhatnagar A, da Graca Cabreira-Hansen M, Grant MB, Lai D, Moye´ L, Ebert RF, Olson RE, Sayre SL, Schulman IH, Bosse RC, Scott EW, Simari RD, Pepine CJ, Taylor DA; Cardiovascular Cell Therapy Research Network (CCTRN). Detailed analysis of bone marrow from patients with ischemic heart disease and left ventricular dysfunction: BM CD34, CD11b, and clonogenic capacity as biomarkers for clinical outcomes. Circ Res 2014;115:867 –874. Tongers J, Losordo DW, Landmesser U. Stem and progenitor cell-based therapy in ischaemic heart disease: promise, uncertainties, and challenges. Eur Heart J 2011;32: 1197– 1206. Mauritz C, Martens A, Rojas SV, Schnick T, Rathert C, Schecker N, Menke S, Glage S, Zweigerdt R, Haverich A, Martin U, Kutschka I. Induced pluripotent stem cell (iPSC)-derived Flk-1 progenitor cells engraft, differentiate, and improve heart
17.
18. 19.
20.
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function in a mouse model of acute myocardial infarction. Eur Heart J 2011;32: 2634 –2641. Menasche P, Vanneaux V, Fabreguettes J-R, Bel A, Tosca L, Garcia S, Bellamy V, Farouz Y, Pouly J, Damour O, Pe´rier M-C, Desnos M, Hage`ge A, Agbulut O, Bruneval P, Tachdjian G, Trouvin J-H, Larghero J. Towards a clinical use of human embryonic stem cell-derived cardiac progenitors: a translational experience. Eur Heart J 2015;36:743 –750. Luscher TF. The bumpy road to evidence: why many research findings are lost in translation. Eur Heart J 2013;34:3329 –3335. Aminzadeh MA, Tseliou E, Sun B, Cheng K, Malliaras K, Makkar RR, Marba´n E. Therapeutic efficacy of cardiosphere-derived cells in a transgenic mouse model of nonischaemic dilated cardiomyopathy. Eur Heart J 2015;36:751 –762. Metra M, Ponikowski P, Cotter G, Davison BA, Felker GM, Filippatos G, Greenberg BH, Hua TA, Severin T, Unemori E, Voors AA, Teerlink JR. Effects of serelaxin in subgroups of patients with acute heart failure: results from RELAX-AHF. Eur Heart J 2013;34:3128 –3136. Filippatos G, Teerlink JR, Farmakis D, Cotter G, Davison BA, Felker GM, Greenberg BH, Hua T, Ponikowski P, Severin T, Unemori E, Voors AA, Metra M. Serelaxin in acute heart failure patients with preserved left ventricular ejection fraction: results from the RELAX-AHF trial. Eur Heart J 2014;35:1041 –1050. Ponikowski P, Mitrovic V, Ruda M, Fernandez A, Voors AA, Vishnevsky A, Cotter G, Milo O, Laessing U, Zhang Y, Dahlke M, Zymlinski R, Metra M. A randomized, doubleblind, placebo-controlled, multicentre study to assess haemodynamic effects of serelaxin in patients with acute heart failure. Eur Heart J 2014;35:431 –441. Anker SD, Ponikowski P, Mitrovic V, Peacock WF, Filippatos G. Ularitide for the treatment of acute decompensation heart failure: from pre-clinical to clinical studies. Eur Heart J 2015;36:715 –723.
Downloaded from by guest on April 7, 2015
European Heart Journal (2015) 36, 699–701 doi:10.1093/eurheartj/ehv040
Novel prognostic markers and treatment options in heart failure: from palliative to regenerative medicine Thomas F. Lu¨scher, MD, FESC Editor-in-Chief, Zurich Heart House, Careum Campus, Moussonstrasse 4, 8091 Zurich, Switzerland
entitled ‘Left atrial function measured by cardiac magnetic resonance imaging in patients with heart failure: clinical associations and prognostic value’,10 Pierpaolo Pellicori et al. from Hull and East Yorkshire Medical Research and Teaching Centre in Kingston upon Hull, UK carefully studied left atrial emptying function using cardiac magnetic resonance imaging (MRI) in 664 outpatients referred with heart failure with reduced left ventricular function and elevated N-terminal pro brain natriuretic peptide (NT-proBNP). The paper is accompanied by an Editorial by Carolyn S.P. Lam from the Mayo Clinic and National University Health System, Singapore.11 Left atrial emptying function was 42% and 55% in patients with and without heart failure, respectively. Patients with heart failure in the lowest quartile of left atrial emptying function had a lower left and right ventricular ejection fraction, and greater ventricular mass and higher plasma NT-proBNP than those in the highest quartile. Log left atrial emptying function and log NT-proBNP were inversely correlated. During a median follow-up of .2 years, 59% of patients died or were admitted with heart failure and 15% developed atrial fibrillation. In a multivariable Cox model, increasing left atrial emptying function, but not left ventricular ejection fraction, was associated with survival. On the other hand, increasing age and decreasing left atrial emptying function predicted atrial fibrillation. Thus, in heart failure, left atrial emptying function predicts adverse outcome independently of other measures of cardiac dysfunction. Left atrial function should, therefore, be considered routinely in the assessment and risk stratification of patients with heart failure. The third paper, by Philippe Menasche´ from the Hoˆpital Europe´en Georges Pompidou in Paris, France, focuses on a truly experimental approach. Although stem cell therapy has received a lot of attention in recent years, its effectiveness in patients after infarction,12,13,14 as well as in those with heart failure remains controversial.15 There is, however, evidence that precursor cells committed to a cardiac lineage might effectively improve the function of infarcted hearts.16. This has been established by the author’s preclinical studies entailing transplantation of human embryonic stem cell-derived cardiac progenitors in rat and non-human primate models of myocardial infarction. In this third paper, ‘Towards a clinical use of human embryonic stem cell-derived cardiac progenitors: a translational experience’,17 Menasche´ et al. present their translational
Published on behalf of the European Society of Cardiology. All rights reserved. & The Author 2015. For permissions please email: [email protected].
Downloaded from by guest on April 7, 2015
In spite of impressive progress in the last decades, the management of heart failure remains essentially palliative in nature.1,2 Rates of rehospitalizations and death remain high even in patients on optimal therapy, according to current guidelines.3,4 Thus, ongoing research at the basic and clinical levels is urgently needed to address this unmet clinical need. This issue of the European Heart Journal is devoted to novel insights into the mechanisms, outcomes, and treatment options in chronic and acute heart failure at the basic and clinical level. Although interfering with neurohumoral activation was most successful so far therapeutically,5,6 it is obvious that the primary problem, particularly in dilated cardiomyopathy, is due to altered cardiac muscular function. The first paper, entitled ‘Ultrastructural features of cardiomyocytes in dilated cardiomyopathy with initially decompensated heart failure as a predictor of prognosis’7 by Tsunenori Saito from the Department of Cardiovascular Medicine of the Nippon Medical School in Tokyo, Japan, which is accompanied by an excellent Editorial by Carsten Tscho¨pe from the Charite´ University in Berlin, Germany,8 attempted to characterize myocardial ultrastructural changes by electron microscopy in endomyocardial biopsy specimens of the left ventricle obtained from 250 patients with dilated cardiomyopathy presenting with decompensated heart failure. During a follow-up period of 5 years, 10% died and 27% were readmitted with heart failure. Myofilament changes, classified as either focal derangement of myofilaments (sarcomere damage) or diffuse myofilament lysis (disappearance of most sarcomeres in cardiomyocytes), were found in 66% of the patients. Multivariate analysis identified that a family history of dilated cardiomyopathy; atrial fibrillation, haemoglobin level, and diffuse myofilament lysis were independent predictors of mortality. A family history, haemoglobin, focal derangement of myofilaments, and diffuse myofilament lysis were also predictors of readmission for heart failure. This study shows for the first time that in patients with dilated cardiomyopathy and a first episode of decompensated heart failure, myofilament changes are strongly associated with mortality and recurrence. As a next step, it appears mandatory to understand the molecular mechanisms of such structural changes to define novel therapeutic targets. Although left ventricular and right ventricular function are well recognized determinants of outcome in patients with heart failure,9 atrial function has not been studied in detail. In the second paper,
700
discussed. Ularitide, a synthetic form of the human natriuretic peptide urodilatin produced in distal renal tubule cells involved in sodium homeostasis, is currently in clinical testing in a phase III trial. Ularitide exerts its pharmacological actions, i.e. vasodilation, diuresis, and natriuresis, through the natriuretic peptide receptor and activation of particulate guanylate cyclase, and in turn a reduction in intracellular calcium. In animal models as well as Phase I and II clinical studies in patients with heart failure, ularitide exerted beneficial effects such as symptom relief and vasodilation, while preserving renal function. The pivotal acute decompensated heart failure Phase III study, the TRUE-AHF trial, is currently under way and has recruited .2000 patients. This trial will confirm or refute whether in patients presenting with acute heart fialure an infusion of ularitide will improve the clinical status and mortality. The editors sincerely hope that this issue of the European Heart Journal will be received with interest by its readers.
References 1. Stewart S, Demers C, Murdoch DR, McIntyre K, MacLeod ME, Kendrick S, Capewell S, McMurray JJ. Substantial between-hospital variation in outcome following first emergency admission for heart failure. Eur Heart J 2002;23:650 –657. 2. van Bommel RJ, Borleffs CJ, Ypenburg C, Marsan NA, Delgado V, Bertini M, van der Wall EE, Schalij MJ, Bax JJ. Morbidity and mortality in heart failure patients treated with cardiac resynchronization therapy: influence of pre-implantation characteristics on long-term outcome. Eur Heart J 2010;31:2783 –2790. 3. McMurray JJ, Adamopoulos S, Anker SD, Auricchio A, Bohm M, Dickstein K, Falk V, Filippatos G, Fonseca C, Gomez-Sanchez MA, Jaarsma T, Kober L, Lip GY, Maggioni AP, Parkhomenko A, Pieske BM, Popescu BA, Ronnevik PK, Rutten FH, Schwitter J, Seferovic P, Stepinska J, Trindade PT, Voors AA, Zannad F, Zeiher A, ESC Committee for Practice Guidelines. ESC Guidelines for the diagnosis and treatment of acute and chronic heart failure 2012: the Task Force for the Diagnosis and Treatment of Acute and Chronic Heart Failure 2012 of the European Society of Cardiology. Developed in collaboration with the Heart Failure Association (HFA) of the ESC. Eur Heart J 2012;33:1787 – 1847. 4. Brignole M, Auricchio A, Baron-Esquivias G, Bordachar P, Boriani G, Breithardt OA, Cleland J, Deharo JC, Delgado V, Elliott PM, Gorenek B, Israel CW, Leclercq C, Linde C, Mont L, Padeletti L, Sutton R, Vardas PE; ESC Committee for Practice Guidelines (CPG), Zamorano JL, Achenbach S, Baumgartner H, Bax JJ, Bueno H, Dean V, Deaton C, Erol C, Fagard R, Ferrari R, Hasdai D, Hoes AW, Kirchhof P, Knuuti J, Kolh P, Lancellotti P, Linhart A, Nihoyannopoulos P, Piepoli MF, Ponikowski P, Sirnes PA, Tamargo JL, Tendera M, Torbicki A, Wijns W, Windecker S; Document Reviewers, Kirchhof P, Blomstrom-Lundqvist C, Badano LP, Aliyev F, Ba¨nsch D, Baumgartner H, Bsata W, Buser P, Charron P, Daubert JC, Dobreanu D, Faerestrand S, Hasdai D, Hoes AW, Le Heuzey JY, Mavrakis H, McDonagh T, Merino JL, Nawar MM, Nielsen JC, Pieske B, Poposka L, Ruschitzka F, Tendera M, Van Gelder IC, Wilson CM. 2013 ESC Guidelines on cardiac pacing and cardiac resynchronization therapy: the Task Force on cardiac pacing and resynchronization therapy of the European Society of Cardiology (ESC). Developed in collaboration with the European Heart Rhythm Association (EHRA). Eur Heart J 2013;34:2281 –2329. 5. Verdecchia P, Angeli F, Cavallini C, Gattobigio R, Gentile G, Staessen JA, Reboldi G. Blood pressure reduction and renin –angiotensin system inhibition for prevention of congestive heart failure: a meta-analysis. Eur Heart J 2009;30:679–688. 6. Zannad F, Gattis Stough W, Rossignol P, Bauersachs J, McMurray JJ, Swedberg K, Struthers AD, Voors AA, Ruilope LM, Bakris GL, O’Connor CM, Gheorghiade M, Mentz RJ, Cohen-Solal A, Maggioni AP, Beygui F, Filippatos GS, Massy ZA, Pathak A, Pin˜a IL, Sabbah HN, Sica DA, Tavazzi L, Pitt B. Mineralocorticoid receptor antagonists for heart failure with reduced ejection fraction: integrating evidence into clinical practice. Eur Heart J 2012;33:2782 –2795. 7. Saito T, Asai K, Sato S, Takano H, Mizuno K, Shimizu W. Ultrastructural features of cardiomyocytes in dilated cardiomyopathy with initially decompensated heart failure as a predictor of prognosis. Eur Heart J 2015;36:724 –732. 8. Savvatis K, Schultheiss H-P, Tscho¨pe C. Endomyocardial biopsy and ultrastructural changes in dilated cardiomyopathy: taking a ‘deeper’ look into patients’ prognosis. Eur Heart J 2015;36:708 –710. 9. Ho JE, Gona P, Pencina MJ, Tu JV, Austin PC, Vasan RS, Kannel WB, D’Agostino RB, Lee DS, Levy D. Discriminating clinical features of heart failure with preserved vs. reduced ejection fraction in the community. Eur Heart J 2012;33:1734 –1741. 10. Pellicori P, Zhang J, Lukaschuk E, Joseph AC, Bourantas CV, Loh H, Bragadeesh T, Clark AL, Cleland JGF. Left atrial function measured by cardiac magnetic resonance
Downloaded from by guest on April 7, 2015
programme aimed at a phase I clinical trial. The main steps of this programme have included (i) the expansion of a clone of pluripotent human embryonic stem cell-derived cardiac progenitors to generate a master cell bank under Good Manufacturing Practice (GMP) conditions; (ii) a growth factor-induced cardiac specification; (iii) the purification of committed cells by immunomagnetic sorting to yield an SSEA-1-positive cell population strongly expressing the early cardiac transcription factor Isl-1; (iv) the incorporation of these cells into a fibrin scaffold; (v) a safety assessment focused on the loss of teratoma-forming cells by in vitro (transcriptomics) and in vivo (cell injections in immunodeficient mice) measurements; (vi) an extensive cytogenetic and viral testing; and (vii) the characterization of the final cell product and its release criteria. These data have led to the approval by the French regulatory authorities for a first-in-man clinical trial of transplantation of such SSEA-1-positive progenitors in patients with severely impaired cardiac function. Although we are aware of the fact that the road to evidence is a bumpy one,18 and several aspects of this manufacturing process still need to be improved, this approach may prove a useful platform for the production of human embryonic stem cell-derived cardiac progenitors under safe and cost-effective GMP conditions, and certainly is a first step towards the development of a regenerative therapy of heart failure. The fourth paper, by Eduardo Marban from the Cedars-Sinai Medical Center in Los Angeles, USA entitled ‘Therapeutic efficacy of cardiosphere-derived cells in a transgenic mouse model of non-ischaemic dilated cardiomyopathy’,19 pursues a similar strategy by testing the effects of transplantation of cardiospherederived cells in mice with cardiac-specific Gaq overexpression, which predictably develop cardiac dilation, heart failure, and accelerated mortality. Indeed, it has been shown that cardiosphere-derived cells exhibit regenerative effects in the post-infarct setting, while it remains unknown whether such cells are beneficial in dilated cardiomyopathy. Wild-type mouse cardiosphere-derived cells or vehicle were injected intramyocardially in 6-, 8-, and 11-week old Gaq mice. Over 3 months, cardiac function deteriorated in vehicle-treated mice accompanied by oxidative stress, inflammation, and ventricular remodelling. In contrast, cardiosphere-derived cells preserved cardiac function and volumes, improved survival, and promoted cardiomyogenesis, while blunting Gaq-induced oxidative stress and inflammation in the heart. The mechanism of benefit is indirect, as long-term engraftment of transplanted cells is vanishingly low. The authors conclude that cardiosphere-derived cells reverse fundamental abnormalities in cell signalling, prevent adverse remodelling, and improve survival in a mouse model of dilated cardiomyopathy. The ability to impact favourably on disease progression in non-ischaemic heart failure heralds new potential therapeutic applications of cardiosphere-derived cells. This issue ends with a review on a potentially novel treatment of acute heart failure. The short- and long-term morbidity and mortality of acute heart failure is still unacceptably high. The use of vasodilator drugs in acute heart failure has received a lot of attention after the potentially life-saving effects of seralaxin in this patient population became public.20,21,22 In the review article by Stefan D. Anker from the University of Go¨ttingen in Germany, the current evidence supporting the future use of the novel vasodilator and natriuretic peptide ‘Ularitide for the treatment of acute decompensated heart failure: from pre-clinical to clinical studies’23 is
Issue @ a Glance
701
Issue @ a Glance
11. 12.
13.
14.
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