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Differential Response to Medications between Children and Adults with Heart Failure


Shelley D. Miyamoto, MD
Brian L. Stauffer, MD
Carmen C. Sucharov, PhD

University of Colorado Denver School of Medicine
Children's Hospital Colorado
Aurora, CO, USA
shelley.miyamoto@childrenscolorado.org



Although the pathophysiology and treatment of adult heart failure (HF) is well studied, HF in children remains poorly understood with most clinical treatment paradigms based solely on experience in adults. Emerging experimental evidence and epidemiologic data confirm that the pediatric HF population distinctly differs from adult HF patients. The heterogeneous nature of pediatric HF and the lack of associated co-morbidities in children (eg diabetes, hypertension) prevent direct extrapolation of adult-based therapies [1,2]. The most common cause of end-stage HF and indication for heart transplantation in infants is congenital heart disease, while dilated cardiomyopathy is the most common indication for transplant in children over the age of 1 year [3]. The combination of age, heart failure etiology and differences in medication pharmacokinetics and metabolism in children complicates the ability to identify the most efficacious therapies [4]. In addition, while adult HF survival has improved with the advancement of medical and surgical HF therapies, the outcome for children with HF has remained largely unchanged, which also suggests dissimilar pathophysiology [2,5].

Prospective medication trials in pediatric HF are scarce due to the rarity and diversity of the disease process as well as funding challenges. While the vast majority of adult HF clinical trials that inform clinical practice are industry-sponsored, the cost-effectiveness of supporting pediatric-specific HF drug development cannot be demonstrated due to the small population size. In the few pediatric clinical HF studies that have been performed, the results speak against the assumption that children will respond in the same way to HF medications as adults. The industry-supported pediatric carvedilol study is the largest randomized, controlled prospective HF drug study in children to date [6]. This study took over 5 years to enroll 161 children with symptomatic HF and there were no differences in the outcome measures studied. The results of this study have been widely challenged primarily due to study design, which included children with complex single ventricle forms of congenital heart disease as well as cardiomyopathies, and the higher than expected spontaneous improvement of enrolled patients. There have been a few small placebo-controlled, prospective studies of ACE-inhibitors and angiotensin receptor blockade in those with a single ventricle or a systemic right ventricle and results again have been negative or equivocal [7-10]. In many of these studies, the patients enrolled were considered to be at risk for HF given underlying anatomy, but did not have the clinical syndrome of HF, making these findings difficult to interpret.

There is an evolving body of evidence demonstrating important underlying age- and disease-related differences in myocardial HF pathophysiology. For example, there is a differential pattern of β-receptor down-regulation and microRNA expression in explanted end-stage failing left ventricles from children compared to adults with non-ischemic dilated cardiomyopathy [11,12]. Failure of the right ventricle is an important and increasingly common clinical problem, as children with severe forms of congenital heart disease are surviving into adulthood. There are no proven therapies for right ventricular failure and data from human and animal studies suggest that the right ventricle has a distinct response to pressure and volume overload with a unique pattern of gene expression, ?-receptor regulation and signaling and microRNA expression compared to the failing left ventricle [13,14].

When considering all of the above, perhaps the most important conclusions from the current body of literature on pediatric HF therapy should be: (1) we cannot assume that children with HF will respond in the same way as adults to medical therapies, (2) ventricular morphology is an important consideration for HF therapy, (3) performing appropriately powered prospective clinical trials in pediatric HF may not be practical and (4) novel approaches to the identification of efficacious therapies for children with HF are needed. In the field of adult HF a significant body of evidence is needed before a change in clinical practice is accepted. This body of evidence often starts at the bench with human tissue, molecular and animal model investigations followed by drug development, pre-clinical and then multiple clinical trials demonstrating efficacy in large populations of patients. Because it is not practical to employ this adult paradigm to children, innovative approaches that minimize risk to children and combine findings from molecular studies (utilizing biorepositories, cell and animal models), genetic and biomarker investigations, longitudinal data obtained from large registries, computer modeling and worldwide collaborations are necessary. Increased awareness of the differences in children and adults with HF must lead to a renewed push for investment by government and foundation funding agencies in pediatric HF research and drug development if outcomes are to improve. ■

Disclosure Statement: Shelley Miyamoto has no conflicts of interest to disclose. Carmen Sucharov has equity in miRagen, Inc. Brian Stauffer has research support from Forest Laboratories, Inc.


References:

  1. Krum H, Gilbert RE. Demographics and concomitant disorders in heart failure. Lancet. 2003;362(9378):147-58.
  2. Towbin JA, Lowe AM, Colan SD, et al. Incidence, causes, and outcomes of dilated cardiomyopathy in children. Jama. 2006;296(15):1867-76.
  3. Dipchand AI, Kirk R, Edwards LB, et al. The Registry of the International Society for Heart and Lung Transplantation: Sixteenth Official Pediatric Heart Transplantation Report--2013; focus theme: age. J Heart Lung Transplant. 2013;32(10):979-88.
  4. Kirk R, Dipchand AI, Rosenthal DN, et al. The International Society of Heart and Lung Transplantation Guidelines for the management of pediatric heart failure: executive summary. J Heart Lung Transplant. 2014;33(9):888-909.
  5. Kantor PF, Abraham JR, Dipchand AI, et al. The impact of changing medical therapy on transplantation-free survival in pediatric dilated cardiomyopathy. J Am Coll Cardiol. 2010;55(13):1377-84.
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  9. Dore A, Houde C, Chan KL, et al. Angiotensin receptor blockade and exercise capacity in adults with systemic right ventricles: a multicenter, randomized, placebo-controlled clinical trial. Circulation. 2005;112(16):2411-6.
  10. van der Bom T, Winter MM, Bouma BJ, et al. Effect of valsartan on systemic right ventricular function: a double-blind, randomized, placebo-controlled pilot trial. Circulation. 2013;127(3):322-30.
  11. Miyamoto SD, Stauffer BL, Nakano S, et al. Beta-adrenergic adaptation in paediatric idiopathic dilated cardiomyopathy. European heart journal. 2014;35(1):33-41. PMCID: 3877432.
  12. Stauffer BL, Russell G, Nunley K, et al. miRNA expression in pediatric failing human heart. Journal of molecular and cellular cardiology. 2013;57:43-6. PMCID: 3694420.
  13. Miyamoto SD, Stauffer BL, Polk J, et al. Gene expression and beta-adrenergic signaling are altered in hypoplastic left heart syndrome. J Heart Lung Transplant. 2014;33(8):785-93. PMCID: 4111994.
  14. Reddy S, Zhao M, Hu DQ, et al. Dynamic microRNA expression during the transition from right ventricular hypertrophy to failure. Physiological genomics. 2012;44(10):562-75. PMCID: 3426410.



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