Personalizing Medicine for the Child With Heart Disease: A Path Forward

“We worry about what a child will become tomorrow, yet we forget that he is someone today”—Stacia Tauscher. Genomic and stem-cell technologies are revolutionizing the way we practice medicine. Molecular maps of human disease generated by high-resolution genomic and biomarker discoveries are being used to develop new diagnostics and feed a pipeline for new drug discovery. The rare and neglected diseases program harbors hope for new genetically guided therapies for rare genetic disorders. However, these approaches are yet to be applied to common childhood diseases, including congenital heart disease and pediatric heart failure. Over 50% of commonly used cardiovascular drugs in children remain off-label uses. Angiotensin-converting enzyme inhibitors, β-blockers and angiotensin-receptor blockers have altered the natural history of heart failure in adults but have yet to show benefit in infants and children.1,2 In the absence of more effective alternatives, physicians continue empiric use of these drugs despite the lack of reported benefit. Although the lack of demonstrable efficacy may be related to inadequate power of pediatric clinical trials, there are also important biologic differences between children and adults, including immaturity of drug receptors and drug metabolizing enzymes, that may limit the efficacy of these drugs in the young. In this review series titled “New Pharmacologic Approaches for Childhood Heart Disease,” we provide a comprehensive review of the current evidence base for cardiovascular drug use in infants and children with heart disease and strategies for improving the availability of newer, more effective and safer drugs in this hitherto underrepresented cohort. In part 1 of the series, Li et al3 discuss the challenges in conducting pediatric cardiovascular drug trials and the design factors that contribute to the failure of trials. It is hoped that the lessons learned to date will help inform future pediatric clinical trial design. In this regard, a recent Food and Drug Administration workshop provided new insights into pediatric trial designs that are particularly well suited to clinical trials in small populations and to relatively rare diseases.4 Buijs et al5 discuss biologic differences that contribute to age-related differences in drug response. For example, catecholamine receptor distribution and function mature with age, and this can influence the hemodynamic effects of cardiotonic drugs in children. The article discusses how new, receptor subtype-selective agents are required to increase the therapeutic effectiveness of cardiotonic drugs in newborns and children with cardiac disease.5 A very important concern related to cardiac immaturity is the potential for cardiotoxicity during embryonic cardiogenesis. Several drugs are known to be teratogenic in the developing fetus, most likely reflecting a complex interplay between genetic susceptibility and environmental toxin exposure in utero. In this issue, Matok et al6 critically evaluate the drugs believed to be teratogenic to the developing heart, highlighting the debate and the practical implications of such associations, and the need for rigor in developing studies to evaluate these associations. Assessing for true cause and effect will require moving beyond population-association studies. In this regard, the availability of human embryonic stem cells (hESCs) provides a potential platform to screen for developmental toxicity of drugs and chemicals. West et al7 identified a unique biochemical signature associated with teratogenic drug exposure in hESCs, which can be used to screen new and existing drugs for teratogenicity. In addition, pharmacogenetic studies may help us to ascertain if maternal and fetal genetic factors increase the susceptibility to drug teratogenicity. Goldmuntz et al8 reported that the developmental toxicity associated with folate deficiency in pregnancy was enhanced in mothers and fetuses with susceptible genotypes. Together, these studies will provide important insights into the mechanisms of cardiac teratogenicity, drugs to avoid during pregnancy, women who are at the highest risk, help the development of drugs that are safe during pregnancy and, it is hoped, the development of the “next folic acid” to protect against the injurious effects of inadvertent exposure to offending drugs and chemicals. In part 2 of the series, the articles discuss emerging therapies for pediatric heart failure and hypertension and some of the challenges related to choice and dosing of drugs for these common conditions. Drug therapies for systemic hypertension have a stronger evidence base as compared with that of other pediatric heart diseases. The acceptance of systemic blood pressure as a surrogate outcome in pediatric hypertension has allowed clinical trials to be successfully performed despite relatively small sample sizes. A comprehensive review in this series by Flynn9 of new antihypertensive agents that are approved for use in children highlights the importance of further research in this area in light of the increase in risk factors such as childhood obesity. In the article by Hoffman,10 the role of newer inotropes in the treatment of acute heart failure in children is reviewed as is the need for a pipeline to develop and market newer inotropes with fewer side effects in the future. A particularly unique and challenging patient cohort comprises infants and children with end-stage heart failure, who are supported by extracorporeal circulatory support, that is, extracorporeal membrane oxygenation. Watt et al.11 discuss the unique challenges of drug dosing because these systems can dramatically alter drug pharmacokinetics and cause therapeutic failure or unnecessary toxicities. They emphasize the need for pharmacodynamic/pharmacokinetic trials and modeling of high-impact drug classes, to provide a safer and evidence-based approach to pediatric dosing in this high risk cohort. In the final part of this series, we discuss some new and exciting approaches to pharmaceutical applications in a young population. In the first article, Laer12 describes the use of cutting-edge technology that includes computer modeling and simulation of “in silico” pediatric populations, to allow the integration of data from previous trials and experiments in the design of future clinical trials. In particular, this modeling allows the selection of optimized drug doses that may enhance the success of clinical trials in children. In the next article, Visscher et al. discuss the application of another new approach, that is, pharmacogenetics to pediatric cardiovascular drug studies. Over a dozen drugs now have altered drug labeling to include genetic testing to guide the choice or dose of drug. The majority of these labeling changes involve genetic variants in absorption-distribution-metabolism-excretion genes. These genotype-guided dosing algorithms unfortunately cannot be easily extrapolated to children due to the immaturity of drug metabolizing enzymes and the ontogenic variations that significantly influence drug pharmacokinetics. Visscher et al13 discuss the developmental changes in body size and organ function that may affect drug pharmacokinetics and pharmacodynamics and point out the importance and need for pediatric-focused pharmacogenomic and pharmacogenetic studies. Our recent study highlights the fact that pharmacogenetics can be successfully applied to a pediatric population. In a trial from the National Heart, Lung, and Blood Institute-funded Pediatric Heart Network, we performed a prospective pharmacogenetic study of enalapril in infants with single ventricles to assess the influence of renin-angiotensin-aldosterone genotypes on the response to enalapril.14 Enalapril did not improve somatic growth in the overall cohort.2 However, enalapril was associated with greater impairment in height but only in the subset of patients with renin-angiotensin-aldosterone-upregulation genotypes, suggesting that enalapril response is influenced by underlying genotype. This represents the first prospective cardiovascular pharmacogenetic study in a pediatric population.14 More recently, in a study in pediatric heart transplant recipients, we found significant pharmacogenetic interactions between age, variants in CYP3A5 genotype and tacrolimus dose requirements. Younger patients with a CYP3A5 expressor genotype had significantly higher tacrolimus dosing requirements with the attainment of lower drug levels in the first 14 days after transplantation.15 These studies are paving the way for the application of genotype-guided therapies in children with heart disease. There are still no comprehensive commercially available single nucleotide polymorphism arrays that capture all common and rare variants in absorption-distribution-metabolism-excretion and other genes involved in the pharmacokinetics and pharmacodynamics of commonly used cardiovascular drugs. The use of next-generation sequencing will likely plug these gaps in the landscape of the cardiac pharmacogenome. The final article in this series discusses the use of cardiomyocytes derived from hESCs and/or human-induced pluripotent stem cells to test for toxicity and efficacy of cardioactive drugs. In this article, Laposa16 concludes that “the ability to test candidate drugs on a cardiomyocyte library containing a spectrum of representative human genetic variation should improve the predictive capacity of cell-based drug testing for clinical efficacy and toxicity.” These new platforms coupled with rapid high-throughput screening assays will accelerate the speed of drug discovery and assessment of drug safety. Overall, these novel technologies provide exciting possibilities for the future of pharmaceutical research in children. As we move forward, it is important to remember that most adult cardiovascular diseases have their onset in childhood, sometimes as early as fetal life. To impact disease early in its course requires an investment in pediatric-focused clinical and pharmacogenetic drug trials and the use of novel approaches that incorporate clinical and biologic knowledge to improve drug safety and efficacy and guide new drug discovery. Optimizing interventions early in the course of disease can significantly reduce the burden of both pediatric and adult cardiovascular disease. As Frederick Douglass, a 19th century American social reformer, said: “It is easier to build strong children than to repair broken men.”