Challenges and Opportunities in Pediatric Heart Failure and Transplantation Introduction to the Series Challenges and Opportunities in Pediatric Heart Failure and Transplantation Daniel Bernstein, MD
O
ver the past 2 decades, there have been major advances in understanding the mechanisms by which the heart responds to stress, a process now referred to as either adaptive or maladaptive remodeling.1–5 Whereas cardiomyopathies were previously described predominantly by their physiological consequences, such as systolic dysfunction, diastolic dysfunction, dilation, or hypertrophy, we have now developed a detailed understanding of the alterations in cell signaling and cell and tissue remodeling underlying these basic physiological phenotypes.6–9 Powerful tools, such as whole genome sequencing and targeted genetic manipulation in the mouse, are rapidly advancing our understanding of the underlying genetic basis of these cellular events and provide further insight into the complex cross-talk between different signaling pathways regulating cardiac function and remodeling.10–14 However, even as we solve 1 layer of cellular regulation, new levels of complexity are being uncovered, eg, regulation of gene expression by noncoding RNAs and histone modification.15–19 In a similar time frame, we have seen major advances in the clinical treatment of heart failure. Pharmacological therapies, in particular, the use of β-blockers and a ngiotensin-converting enzyme inhibitors, have revolutionized the care of adult patients with dilated cardiomyopathy.20–23 The addition of resynchronization pacing and the implantable cardioverter defibrillator have further improved transplant-free survival.24–26 And for those adult patients with intractable heart failure, the field has seen the equally rapid development of safer and more effective left ventricular assist devices and a total artificial heart, as well, either as a bridge to transplant or as destination therapy.27 However, the cardiovascular challenges faced by infants and children with heart failure are substantially different from those in adults. Whereas ischemic cardiomyopathy comprises the majority of cases of adult heart failure,28 ischemia is a rare cause of heart failure in children, where cardiomyopathy is more likely to be of genetic or viral origin, or to develop as a consequence of repaired or palliated congenital heart disease.29,30 Over the same 2 decades, there have been equally dramatic advances in the diagnosis and surgical treatment of congenital heart diseases. Children with even the most severe cardiac malformations, eg, hypoplastic left or right heart syndromes
or tetralogy of Fallot with pulmonary atresia,31,32 now have an excellent chance of survival following staged palliative surgical procedures. However, despite these surgical successes, many patients with severe cardiac malformations eventually develop either ventricular failure (systolic or diastolic dysfunction) or circulatory failure (eg, complications related to the Fontan circulation)33,34 and will require some form of heart failure therapy and eventually cardiac transplantation.35 In infants, congenital heart disease currently represents 63% of transplants, whereas among adolescents this percentage drops to 25%, and is only 3% in adults.36,37 However, as children with palliated complex congenital heart disease grow into adulthood, the number of older patients with congenital heart disease requiring transplantation will continue to grow. The unique aspects of transplantation in this patient population represent a major challenge to both the pediatric and the adult transplant community.35,38 Unfortunately, research on the mechanisms and therapies for the types of heart failure experienced by children has lagged behind that of adults. Many of the models used to study cardiac failure, particularly ischemia, do not accurately recapitulate the cardiac stresses experienced by children with genetic cardiomyopathies or in patients with congenital heart disease.39 The signaling events regulating cardiac remodeling in ischemia may be quite different from those regulating a genetic dilated cardiomyopathy. One example has particular clinical relevance, given the widespread use of β-blocker therapy: whereas β2-adrenergic receptor signaling has been shown to be cardioprotective in ischemic cardiomyopathy, leading to the suggestion that a combination of a β1-blocker with a β2-agonist would be more efficacious than a nonspecific β-blocker alone,40 β2-adrenergic receptor signaling turns out to be detrimental in at least 1 form of genetic cardiomyopathy and also in pressure overload, both conditions more likely to be experienced in the pediatric population.41 There has also been a very left ventricular-centric bias in heart failure research,39 whereas many patients who have congenital heart disease experience failure of their right ventricle, either in a normal pulmonary position (eg, tetralogy of Fallot) or in a systemic position (eg, l-transposition of the great arteries, hypoplastic left heart syndrome). Developing a better understanding
From the Department of Pediatrics and the Stanford Cardiovascular Institute, Stanford University, Stanford, CA. Guest Editor for this article was Jane Newburger, MD, MPH. Correspondence to Daniel Bernstein, MD, Department of Pediatrics, Stanford University, 750 Welch Rd, Suite 325, Palo Alto, CA 94304. E-mail [email protected] (Circulation. 2014;129:112-114.) © 2014 American Heart Association, Inc. Circulation is available at http://circ.ahajournals.org
DOI: 10.1161/CIRCULATIONAHA.113.006102
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Bernstein Pediatric Heart Failure and Transplantation 113 of the similarities and differences between left and right ventricular remodeling and failure is critically important. This point is emphasized by clinical studies that show that many standard left ventricular heart failure therapies (β-blockers, angiotensinconverting enzyme inhibitors, angiotensin II receptor blockers) fail to improve exercise capacity or cardiac function in right ventricular (RV) failure.42,43 In the largest pediatric clinical trial of a heart failure drug to date, Shaddy et al44 actually found a possible detrimental effect of the β-blocker carvedilol when used in patients with systemic RVs in comparison with those with systemic left ventricles. In another study, the angiotensin-converting enzyme inhibitor enalapril failed to improve ventricular function or somatic growth (a sign of heart failure in children) in patients with single ventricles, the majority of whom had a single RV.45 Thus, the characterization of models of RV failure that more accurately recapitulate the ventricular stresses experienced in patients with congenital heart disease46,47 will be important to advance our understanding of the molecular mechanisms unique to RV remodeling, as similar models have done for the left ventricle. The results of these studies will hopefully lead to new therapies for patients with a vulnerable RV. The development of nonpharmacological treatments for heart failure in children has also shown unique challenges in comparison with adults. Resynchronization pacing, most useful in adults with left ventricular dysfunction and left bundle-branch block, may have different indications in children, where left bundle-branch block is rare and right or single ventricular dysfunction may be more attractive targets.48,49 Finally, perhaps nowhere else are the challenges of treating children versus adults more evident than in the field of ventricular assist devices. One of the largest challenges to device development for children is the size constraint inherent in using a mechanical device in a small infant. However, the solution to these problems is not limited to just building a smaller version of adult devices, because the risks for complications like thrombosis and stroke appear to increase with miniaturization.50,51 For those patients with a univentricular heart, the complications associated with mechanical assist support are even more daunting. Even if all of these challenges are overcome, implantation of a destination device that can provide an extra 5 to 10 years of quality life for a 65-year-old adult is, at best, a temporizing option for the pediatric population. The articles making up this series will address, in 3 major areas, several pressing challenges and opportunities facing pediatric cardiologists who care for children with heart failure and after transplantation. Focusing on mechanisms of heart failure, Drs Mark Friedberg and Andrew Reddington will review the physiology of right versus left ventricular failure, suggesting that not all ventricles are built the same. Dr Sushma Reddy will detail several novel models of right ventricular failure that are uncovering differences in gene and microRNA expression and cell signaling between the stressed right and left ventricles. Dr Jeff Towbin will then provide a guide to the testing for genetic cardiomyopathies in the age of rapid and increasingly inexpensive genome sequencing. Focusing on therapeutics, Drs Joseph Rossano and Robert Shaddy will provide an update on pharmacological heart failure therapies in children, reviewing whether adult medications work in the pediatric population and the potential mechanisms
for any differences. Drs Charles Canter and Kathleen Simpson will review the current status of diagnosis and treatment of myocarditis in children. Drs Kara Motonaga and Anne Dubin will summarize the outcomes of cardiac resynchronization therapy for pediatric heart failure and congenital heart disease patients. Finally, Dr Betsy Blume will summarize the experience with pediatric mechanical support devices and review the engineering and regulatory challenges of developing these orphan devices. A third focus of this series is on transplantation, where Dr Daphne Hsu will review the changing indications for pediatric heart transplantation with a particular emphasis on complex congenital heart disease. Dr Clifford Chin will review transplantation in the highly sensitized pediatric patient, Dr Lori West will review her pioneering work with transplantation across the ABO barrier, and Dr Steven Webber will provide insight into a pharmacogenomic approach to personalized health care for the pediatric patient undergoing heart transplant. Finally, the series will conclude with my review of the current status of stem cell–induced cardiomyocytes and their potential as both diagnostic and therapeutic tools in pediatric cardiology.
Sources of Funding Dr Bernstein is supported by grants from the National Institutes of Health (HL061535, HL117083), the Oak Foundation, and the Children’s Heart Foundation.
Disclosures None.
References 1. Koitabashi N, Kass DA. Reverse remodeling in heart failure–mechanisms and therapeutic opportunities. Nat Rev Cardiol. 2012;9:147–157. 2. Hill JA, Olson EN. Cardiac plasticity. N Engl J Med. 2008;358:1370–1380. 3. Fedak PW, Verma S, Weisel RD, Li RK. Cardiac remodeling and failure: from molecules to man (Part I). Cardiovasc Pathol. 2005;14:1–11. 4. Cohn JN, Ferrari R, Sharpe N. Cardiac remodeling–concepts and clinical implications: a consensus paper from an international forum on cardiac remodeling. Behalf of an International Forum on Cardiac Remodeling. J Am Coll Cardiol. 2000;35:569–582. 5. Gajarsa JJ, Kloner RA. Left ventricular remodeling in the post-infarction heart: a review of cellular, molecular mechanisms, and therapeutic modalities. Heart Fail Rev. 2011;16:13–21. 6. van Berlo JH, Maillet M, Molkentin JD. Signaling effectors underlying pathologic growth and remodeling of the heart. J Clin Invest. 2013;123:37–45. 7. Heineke J, Molkentin JD. Regulation of cardiac hypertrophy by intracellular signalling pathways. Nat Rev Mol Cell Biol. 2006;7:589–600. 8. Perrino C, Rockman HA. Reversal of cardiac remodeling by modulation of adrenergic receptors: a new frontier in heart failure. Curr Opin Cardiol. 2007;22:443–449. 9. Kho C, Lee A, Hajjar RJ. Altered sarcoplasmic reticulum calcium cycling– targets for heart failure therapy. Nat Rev Cardiol. 2012;9:717–733. 10. Cordero P, Ashley EA. Whole-genome sequencing in personalized therapeutics. Clin Pharmacol Ther. 2012;91:1001–1009. 11. Seidman CE, Seidman JG. Identifying sarcomere gene mutations in hypertrophic cardiomyopathy: a personal history. Circ Res. 2011;108:743–750. 12. Houser SR, Margulies KB, Murphy AM, Spinale FG, Francis GS, Prabhu SD, Rockman HA, Kass DA, Molkentin JD, Sussman MA, Koch WJ, Koch W; American Heart Association Council on Basic Cardiovascular Sciences, Council on Clinical Cardiology, and Council on Functional Genomics and Translational Biology. Animal models of heart failure: a scientific statement from the American Heart Association. Circ Res. 2012;111:131–150. 13. Ahmad F, Seidman JG, Seidman CE. The genetic basis for cardiac remodeling. Annu Rev Genomics Hum Genet. 2005;6:185–216.
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114 Circulation January 7, 2014 14. Dorn GW 2nd. Mitochondrial dynamics in heart disease. Biochim Biophys Acta. 2013;1833:233–241. 15. Han P, Hang CT, Yang J, Chang CP. Chromatin remodeling in cardiovascular development and physiology. Circ Res. 2011;108:378–396. 16. van Rooij E. Introduction to the series on microRNAs in the cardiovascular system. Circ Res. 2012;110:481–482. 17. Topkara VK, Mann DL. Role of microRNAs in cardiac remodeling and heart failure. Cardiovasc Drugs Ther. 2011;25:171–182. 18. McKinsey TA. Isoform-selective HDAC inhibitors: closing in on translational medicine for the heart. J Mol Cell Cardiol. 2011;51:491–496. 19. Haberland M, Montgomery RL, Olson EN. The many roles of histone deacetylases in development and physiology: implications for disease and therapy. Nat Rev Genet. 2009;10:32–42. 20. Packer M, Fowler MB, Roecker EB, Coats AJ, Katus HA, Krum H, Mohacsi P, Rouleau JL, Tendera M, Staiger C, Holcslaw TL, Amann-Zalan I, DeMets DL; Carvedilol Prospective Randomized Cumulative Survival (COPERNICUS) Study Group. Effect of carvedilol on the morbidity of patients with severe chronic heart failure: results of the carvedilol prospective randomized cumulative survival (COPERNICUS) study. Circulation. 2002;106:2194–2199. 21. Jessup M, Abraham WT, Casey DE, Feldman AM, Francis GS, Ganiats TG, Konstam MA, Mancini DM, Rahko PS, Silver MA, Stevenson LW, Yancy CW. 2009 focused update: ACCF/AHA Guidelines for the Diagnosis and Management of Heart Failure in Adults: a report of the American College of Cardiology Foundation/American Heart Association Task Force on Practice Guidelines: developed in collaboration with the International Society for Heart and Lung Transplantation. Circulation. 2009;119:1977–2016. 22. Nair AP, Timoh T, Fuster V. Contemporary medical management of systolic heart failure. Circ J. 2012;76:268–277. 23. Trupp RJ, Abraham WT. American College of Cardiology/American Heart Association 2009 clinical guidelines for the diagnosis and management of heart failure in adults: update and clinical implications. Pol Arch Med Wewn. 2009;119:436–438. 24. Young JB, Abraham WT, Smith AL, Leon AR, Lieberman R, Wilkoff B, Canby RC, Schroeder JS, Liem LB, Hall S, Wheelan K; Multicenter InSync ICD Randomized Clinical Evaluation (MIRACLE ICD) Trial Investigators. Combined cardiac resynchronization and implantable cardioversion defibrillation in advanced chronic heart failure: the MIRACLE ICD Trial. JAMA. 2003;289:2685–2694. 25. Maron BJ, Spirito P. Implantable defibrillators and prevention of sudden death in hypertrophic cardiomyopathy. J Cardiovasc Electrophysiol. 2008;19:1118–1126. 26. Rossi A, Rossi G, Piacenti M, Startari U, Panchetti L, Morales MA. The current role of cardiac resynchronization therapy in reducing mortality and hospitalization in heart failure patients: a meta-analysis from clinical trials. Heart Vessels. 2008;23:217–223. 27. Caccamo M, Eckman P, John R. Current state of ventricular assist devices. Curr Heart Fail Rep. 2011;8:91–98. 28. He J, Ogden LG, Bazzano LA, Vupputuri S, Loria C, Whelton PK. Risk factors for congestive heart failure in US men and women: NHANES I epidemiologic follow-up study. Arch Intern Med. 2001;161:996–1002. 29. Towbin JA, Lowe AM, Colan SD, Sleeper LA, Orav EJ, Clunie S, Messere J, Cox GF, Lurie PR, Hsu D, Canter C, Wilkinson JD, Lipshultz SE. Incidence, causes, and outcomes of dilated cardiomyopathy in children. JAMA. 2006;296:1867–1876. 30. Kindel SJ, Miller EM, Gupta R, Cripe LH, Hinton RB, Spicer RL, Towbin JA, Ware SM. Pediatric cardiomyopathy: importance of genetic and metabolic evaluation. J Card Fail. 2012;18:396–403. 31. Czosek RJ, Anderson JB, Heaton PC, Cassedy A, Schnell B, Cnota JF. Staged palliation of hypoplastic left heart syndrome: trends in mortality, cost, and length of stay using a national database from 2000 through 2009. Am J Cardiol. 2013;111:1792–1799. 32. Malhotra SP, Hanley FL. Surgical management of pulmonary atresia with ventricular septal defect and major aortopulmonary collaterals: a protocol-based approach. Semin Thorac Cardiovasc Surg Pediatr Card Surg Annu. 2009:145–151. 33. Atz AM, Travison TG, McCrindle BW, Mahony L, Glatz AC, Kaza AK, Breitbart RE, Colan SD, Kaltman JR, Margossian R, Pasquali SK, Wang Y, Gersony WM; Pediatric Heart Network Investigators. Cardiac performance and quality of life in patients who have undergone the Fontan procedure with and without prior superior cavopulmonary connection. Cardiol Young. 2013;23:335–343. 34. Ohuchi H, Yasuda K, Miyazaki A, Kitano M, Sakaguchi H, Yazaki S, Tsuda E, Yamada O. Haemodynamic characteristics before and after the
onset of protein losing enteropathy in patients after the Fontan operation. Eur J Cardiothorac Surg. 2013;43:e49–e57. 35. Bernstein D, Naftel D, Chin C, Addonizio LJ, Gamberg P, Blume ED, Hsu D, Canter CE, Kirklin JK, Morrow WR; Pediatric Heart Transplant Study. Outcome of listing for cardiac transplantation for failed Fontan: a multi-institutional study. Circulation. 2006;114:273–280. 36. Kirk R, Edwards LB, Kucheryavaya AY, Aurora P, Christie JD, Dobbels F, Rahmel AO, Stehlik J, Hertz MI. The Registry of the International Society for Heart and Lung Transplantation: thirteenth official pediatric heart transplantation report–2010. J Heart Lung Transplant. 2010;29:1119–1128. 37. Stehlik J, Edwards LB, Kucheryavaya AY, Aurora P, Christie JD, Kirk R, Dobbels F, Rahmel AO, Hertz MI. The Registry of the International Society for Heart and Lung Transplantation: twenty-seventh official adult heart transplant report–2010. J Heart Lung Transplant. 2010;29:1089–1103. 38. Lamour JM, Kanter KR, Naftel DC, Chrisant MR, Morrow WR, Clemson BS, Kirklin JK; Cardiac Transplant Registry Database; Pediatric Heart Transplant Study. The effect of age, diagnosis, and previous surgery in children and adults undergoing heart transplantation for congenital heart disease. J Am Coll Cardiol. 2009;54:160–165. 39. Bernstein D, Webber S. New directions in basic research in hypertrophy and heart failure: relevance for pediatric cardiology. Prog Pediatr Cardiol. 2011;32:5–9. 40. Talan MI, Ahmet I, Xiao RP, Lakatta EG. Β2 AR agonists in treatment of chronic heart failure: long path to translation. J Mol Cell Cardiol. 2011;51:529–533. 41. Fajardo G, Zhao M, Urashima T, Farahani S, Hu DQ, Reddy S, Bernstein D. Deletion of the β2-adrenergic receptor prevents the development of cardiomyopathy in mice. J Mol Cell Cardiol. 2013;63:155–164. 42. Winter MM, Bouma BJ, Groenink M, Konings TC, Tijssen JG, van Veldhuisen DJ, Mulder BJ. Latest insights in therapeutic options for systemic right ventricular failure: a comparison with left ventricular failure. Heart. 2009;95:960–963. 43. Szymañski P, Klisiewicz A, Hoffman P. Therapeutic options for systemic right ventricular failure. Heart. 2009;95:1950–1951; author reply 1951. 44. Shaddy RE, Boucek MM, Hsu DT, Boucek RJ, Canter CE, Mahony L, Ross RD, Pahl E, Blume ED, Dodd DA, Rosenthal DN, Burr J, LaSalle B, Holubkov R, Lukas MA, Tani LY; Pediatric Carvedilol Study Group. Carvedilol for children and adolescents with heart failure: a randomized controlled trial. JAMA. 2007;298:1171–1179. 45. Hsu DT, Zak V, Mahony L, Sleeper LA, Atz AM, Levine JC, Barker PC, Ravishankar C, McCrindle BW, Williams RV, Altmann K, Ghanayem NS, Margossian R, Chung WK, Border WL, Pearson GD, Stylianou MP, Mital S; Pediatric Heart Network Investigators. Enalapril in infants with single ventricle: results of a multicenter randomized trial. Circulation. 2010;122:333–340. 46. Reddy S, Zhao M, Hu DQ, Fajardo G, Katznelson E, Punn R, Spin JM, Chan FP, Bernstein D. Physiologic and molecular characterization of a murine model of right ventricular volume overload. Am J Physiol Heart Circ Physiol. 2013;304:H1314–H1327. 47. Reddy S, Zhao M, Hu DQ, Fajardo G, Hu S, Ghosh Z, Rajagopalan V, Wu JC, Bernstein D. Dynamic microRNA expression during the transition from right ventricular hypertrophy to failure. Physiol Genomics. 2012;44:562–575. 48. Dubin AM, Janousek J, Rhee E, Strieper MJ, Cecchin F, Law IH, Shannon KM, Temple J, Rosenthal E, Zimmerman FJ, Davis A, Karpawich PP, Al Ahmad A, Vetter VL, Kertesz NJ, Shah M, Snyder C, Stephenson E, Emmel M, Sanatani S, Kanter R, Batra A, Collins KK. Resynchronization therapy in pediatric and congenital heart disease patients: an international multicenter study. J Am Coll Cardiol. 2005;46:2277–2283. 49. Motonaga KS, Miyake CY, Punn R, Rosenthal DN, Dubin AM. Insights into dyssynchrony in hypoplastic left heart syndrome. Heart Rhythm. 2012;9:2010–2015. 50. Stein ML, Robbins R, Sabati AA, Reinhartz O, Chin C, Liu E, Bernstein D, Roth S, Wright G, Reitz B, Rosenthal D. Interagency Registry for Mechanically Assisted Circulatory Support (INTERMACS)-defined morbidity and mortality associated with pediatric ventricular assist device support at a single US center: the Stanford experience. Circ Heart Fail. 2010;3:682–688. 51. Almond CS, Buchholz H, Massicotte P, Ichord R, Rosenthal DN, Uzark K, Jaquiss RD, Kroslowitz R, Kepler MB, Lobbestael A, Bellinger D, Blume ED, Fraser CD Jr, Bartlett RH, Thiagarajan R, Jenkins K. Berlin Heart EXCOR Pediatric ventricular assist device Investigational Device Exemption study: study design and rationale. Am Heart J. 2011;162:425–35.e6. Key Words: heart failure ◼ heart transplantation ◼ pediatrics
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Introduction to the Series: Challenges and Opportunities in Pediatric Heart Failure and Transplantation Daniel Bernstein Circulation. 2014;129:112-114 doi: 10.1161/CIRCULATIONAHA.113.006102 Circulation is published by the American Heart Association, 7272 Greenville Avenue, Dallas, TX 75231 Copyright © 2014 American Heart Association, Inc. All rights reserved. Print ISSN: 0009-7322. Online ISSN: 1524-4539
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O
ver the past 2 decades, there have been major advances in understanding the mechanisms by which the heart responds to stress, a process now referred to as either adaptive or maladaptive remodeling.1–5 Whereas cardiomyopathies were previously described predominantly by their physiological consequences, such as systolic dysfunction, diastolic dysfunction, dilation, or hypertrophy, we have now developed a detailed understanding of the alterations in cell signaling and cell and tissue remodeling underlying these basic physiological phenotypes.6–9 Powerful tools, such as whole genome sequencing and targeted genetic manipulation in the mouse, are rapidly advancing our understanding of the underlying genetic basis of these cellular events and provide further insight into the complex cross-talk between different signaling pathways regulating cardiac function and remodeling.10–14 However, even as we solve 1 layer of cellular regulation, new levels of complexity are being uncovered, eg, regulation of gene expression by noncoding RNAs and histone modification.15–19 In a similar time frame, we have seen major advances in the clinical treatment of heart failure. Pharmacological therapies, in particular, the use of β-blockers and a ngiotensin-converting enzyme inhibitors, have revolutionized the care of adult patients with dilated cardiomyopathy.20–23 The addition of resynchronization pacing and the implantable cardioverter defibrillator have further improved transplant-free survival.24–26 And for those adult patients with intractable heart failure, the field has seen the equally rapid development of safer and more effective left ventricular assist devices and a total artificial heart, as well, either as a bridge to transplant or as destination therapy.27 However, the cardiovascular challenges faced by infants and children with heart failure are substantially different from those in adults. Whereas ischemic cardiomyopathy comprises the majority of cases of adult heart failure,28 ischemia is a rare cause of heart failure in children, where cardiomyopathy is more likely to be of genetic or viral origin, or to develop as a consequence of repaired or palliated congenital heart disease.29,30 Over the same 2 decades, there have been equally dramatic advances in the diagnosis and surgical treatment of congenital heart diseases. Children with even the most severe cardiac malformations, eg, hypoplastic left or right heart syndromes
or tetralogy of Fallot with pulmonary atresia,31,32 now have an excellent chance of survival following staged palliative surgical procedures. However, despite these surgical successes, many patients with severe cardiac malformations eventually develop either ventricular failure (systolic or diastolic dysfunction) or circulatory failure (eg, complications related to the Fontan circulation)33,34 and will require some form of heart failure therapy and eventually cardiac transplantation.35 In infants, congenital heart disease currently represents 63% of transplants, whereas among adolescents this percentage drops to 25%, and is only 3% in adults.36,37 However, as children with palliated complex congenital heart disease grow into adulthood, the number of older patients with congenital heart disease requiring transplantation will continue to grow. The unique aspects of transplantation in this patient population represent a major challenge to both the pediatric and the adult transplant community.35,38 Unfortunately, research on the mechanisms and therapies for the types of heart failure experienced by children has lagged behind that of adults. Many of the models used to study cardiac failure, particularly ischemia, do not accurately recapitulate the cardiac stresses experienced by children with genetic cardiomyopathies or in patients with congenital heart disease.39 The signaling events regulating cardiac remodeling in ischemia may be quite different from those regulating a genetic dilated cardiomyopathy. One example has particular clinical relevance, given the widespread use of β-blocker therapy: whereas β2-adrenergic receptor signaling has been shown to be cardioprotective in ischemic cardiomyopathy, leading to the suggestion that a combination of a β1-blocker with a β2-agonist would be more efficacious than a nonspecific β-blocker alone,40 β2-adrenergic receptor signaling turns out to be detrimental in at least 1 form of genetic cardiomyopathy and also in pressure overload, both conditions more likely to be experienced in the pediatric population.41 There has also been a very left ventricular-centric bias in heart failure research,39 whereas many patients who have congenital heart disease experience failure of their right ventricle, either in a normal pulmonary position (eg, tetralogy of Fallot) or in a systemic position (eg, l-transposition of the great arteries, hypoplastic left heart syndrome). Developing a better understanding
From the Department of Pediatrics and the Stanford Cardiovascular Institute, Stanford University, Stanford, CA. Guest Editor for this article was Jane Newburger, MD, MPH. Correspondence to Daniel Bernstein, MD, Department of Pediatrics, Stanford University, 750 Welch Rd, Suite 325, Palo Alto, CA 94304. E-mail [email protected] (Circulation. 2014;129:112-114.) © 2014 American Heart Association, Inc. Circulation is available at http://circ.ahajournals.org
DOI: 10.1161/CIRCULATIONAHA.113.006102
Downloaded from http://circ.ahajournals.org/ at CONS 112 CALIFORNIA DIG LIB on December 16, 2014
Bernstein Pediatric Heart Failure and Transplantation 113 of the similarities and differences between left and right ventricular remodeling and failure is critically important. This point is emphasized by clinical studies that show that many standard left ventricular heart failure therapies (β-blockers, angiotensinconverting enzyme inhibitors, angiotensin II receptor blockers) fail to improve exercise capacity or cardiac function in right ventricular (RV) failure.42,43 In the largest pediatric clinical trial of a heart failure drug to date, Shaddy et al44 actually found a possible detrimental effect of the β-blocker carvedilol when used in patients with systemic RVs in comparison with those with systemic left ventricles. In another study, the angiotensin-converting enzyme inhibitor enalapril failed to improve ventricular function or somatic growth (a sign of heart failure in children) in patients with single ventricles, the majority of whom had a single RV.45 Thus, the characterization of models of RV failure that more accurately recapitulate the ventricular stresses experienced in patients with congenital heart disease46,47 will be important to advance our understanding of the molecular mechanisms unique to RV remodeling, as similar models have done for the left ventricle. The results of these studies will hopefully lead to new therapies for patients with a vulnerable RV. The development of nonpharmacological treatments for heart failure in children has also shown unique challenges in comparison with adults. Resynchronization pacing, most useful in adults with left ventricular dysfunction and left bundle-branch block, may have different indications in children, where left bundle-branch block is rare and right or single ventricular dysfunction may be more attractive targets.48,49 Finally, perhaps nowhere else are the challenges of treating children versus adults more evident than in the field of ventricular assist devices. One of the largest challenges to device development for children is the size constraint inherent in using a mechanical device in a small infant. However, the solution to these problems is not limited to just building a smaller version of adult devices, because the risks for complications like thrombosis and stroke appear to increase with miniaturization.50,51 For those patients with a univentricular heart, the complications associated with mechanical assist support are even more daunting. Even if all of these challenges are overcome, implantation of a destination device that can provide an extra 5 to 10 years of quality life for a 65-year-old adult is, at best, a temporizing option for the pediatric population. The articles making up this series will address, in 3 major areas, several pressing challenges and opportunities facing pediatric cardiologists who care for children with heart failure and after transplantation. Focusing on mechanisms of heart failure, Drs Mark Friedberg and Andrew Reddington will review the physiology of right versus left ventricular failure, suggesting that not all ventricles are built the same. Dr Sushma Reddy will detail several novel models of right ventricular failure that are uncovering differences in gene and microRNA expression and cell signaling between the stressed right and left ventricles. Dr Jeff Towbin will then provide a guide to the testing for genetic cardiomyopathies in the age of rapid and increasingly inexpensive genome sequencing. Focusing on therapeutics, Drs Joseph Rossano and Robert Shaddy will provide an update on pharmacological heart failure therapies in children, reviewing whether adult medications work in the pediatric population and the potential mechanisms
for any differences. Drs Charles Canter and Kathleen Simpson will review the current status of diagnosis and treatment of myocarditis in children. Drs Kara Motonaga and Anne Dubin will summarize the outcomes of cardiac resynchronization therapy for pediatric heart failure and congenital heart disease patients. Finally, Dr Betsy Blume will summarize the experience with pediatric mechanical support devices and review the engineering and regulatory challenges of developing these orphan devices. A third focus of this series is on transplantation, where Dr Daphne Hsu will review the changing indications for pediatric heart transplantation with a particular emphasis on complex congenital heart disease. Dr Clifford Chin will review transplantation in the highly sensitized pediatric patient, Dr Lori West will review her pioneering work with transplantation across the ABO barrier, and Dr Steven Webber will provide insight into a pharmacogenomic approach to personalized health care for the pediatric patient undergoing heart transplant. Finally, the series will conclude with my review of the current status of stem cell–induced cardiomyocytes and their potential as both diagnostic and therapeutic tools in pediatric cardiology.
Sources of Funding Dr Bernstein is supported by grants from the National Institutes of Health (HL061535, HL117083), the Oak Foundation, and the Children’s Heart Foundation.
Disclosures None.
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Introduction to the Series: Challenges and Opportunities in Pediatric Heart Failure and Transplantation Daniel Bernstein Circulation. 2014;129:112-114 doi: 10.1161/CIRCULATIONAHA.113.006102 Circulation is published by the American Heart Association, 7272 Greenville Avenue, Dallas, TX 75231 Copyright © 2014 American Heart Association, Inc. All rights reserved. Print ISSN: 0009-7322. Online ISSN: 1524-4539
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