Congenital Heart Defects (CHD) and Angiotensin Converting Enzyme (ACE) Inhibitors


Congenital Heart Defects (CHD) and Angiotensin Converting Enzyme (ACE) Inhibitors

Congenital Heart Defects (CHD) are abnormalities that occur during the development of a fetus’s heart during gestation (Children’s Hospital of Philadelphia, 2019a; Ni, Lv, Ding & Yao, 2019).  Because of the advances in medical technology, individuals with CHD are surviving into adulthood at larger rates (Centers for Disease Control and Prevention, 2018a; Lantin-Hermoso et al., 2017).  The Centers for Disease Control and Prevention (2018a) reported that as of the 2010 census, about 2 million infants, children, adolescents, and adults in the United States were living with CHD.  Of those 2 million, about 1 million of those were children and 1.4 million were adults; moreover, as these children age, they need more coordinated and specialized medical care (Centers for Disease Control and Prevention, 2018a; Lantin-Hermoso et al., 2017).  After life-saving surgical interventions are utilized, medications like ACE inhibitors may be needed (Feinstein et al., 2012; Wilson et al., 2016; Yimgang, Sorkin, Evans, Abraham, & Rosenthal, 2018).


Congenital Heart Defects (CHD)

Congenital Heart Defects are the leading birth defect, affecting about 1 in 120 babies born every year in the United States (Children’s Hospital of Philadelphia, 2019a; Lantin-Hermoso et al., 2017).  Although CHD is prevalent, the causes are relatively unknown. According the Children’s Hospital of Philadelphia (2019a), there are certain steps that are taken during gestation that cause the heart to form correctly.  Unfortunately, in someone with CHD, there is some misstep that causes an abnormality of the heart.  Research has tried to ascertain the why, with limited success.  Sometimes, links can be drawn between CHD and genetics or the utilization of certain medications while pregnant, but most of the time there is no distinguishable cause (Centers for Disease Control and Prevention, 2018b; Children’s Hospital of Philadelphia, 2019a).

These abnormalities are usually detected by a Fetal Echocardiogram that is performed between 18-22 weeks’ gestation (Lantin-Hermoso et al., 2017).  The survival rates of individuals with CHD improve when these abnormalities are found earlier, allowing for definitive plans and steps to be created for treatment (Centers for Disease Control and Prevention, 2018b; Pace et al., 2018).  That being said, some defects evade basic screening measures or develop later in gestational age (Lantin-Hermoso et al., 2017); moreover, understanding the severity index of Congenital Heart Defects is integral for understanding utilized treatments.

CHD vary in severity from mild to severe (Centers for Disease Control and Prevention, 2018b; Pace et al., 2018).  The Children’s Hospital of Philadelphia (2019a) outline the different abnormalities into three different areas: 1. Problems that cause too much blood to pass through the lungs (Patent Ductus Arteriosus (PDA), Atrial Septal Defect (ASD), Ventricular Septal Defect (VSD), Atrioventricular Canal (AVC or AV Canal)), 2. Problems that cause too little blood to pass through the lungs (Tricuspid Atresia, Pulmonary Atresia, Transposition of the Great Arteries (TGA), Tetralogy of Fallot (TOF), Double Outlet Right Ventricle (DORV), and Truncus Arteriosus) and 3. Problems that cause too little blood to travel to the body (Coarctation of the Aorta (CoA), Aortic Stenosis (AS) and Hypoplastic Left Heart Syndrome (HLHS)).  These qualitative categorizations allow for the person to understand the severity of each malformation based on its end result and the necessary treatment.

Treatment changes based on the severity of the defect.  Simple CHD may be able to be managed with medication and the child may even outgrow the defect (Children’s Hospital of Philadelphia, 2019a).  On the other end of the spectrum, more complex CHD may require surgery and ongoing care throughout the life span (Centers for Disease Control and Prevention, 2018b; Children’s Hospital of Philadelphia, 2019a; Pace et al., 2018).  These surgeries are utilized to extend the first year of life and are needed, but also can cause residual effects on the heart and other body systems; moreover, continued cardiac care will be needed through coordination between both a pediatric cardiologist and the child’s primary care physician (Pace et al., 2018).  One of the most severe CHD is Hypoplastic Left Heart Syndrome (HLHS).  HLHS requires rapid surgical intervention after birth and continued care throughout the lifespan (Yimgang, et al., 2018).


Hypoplastic Left Heart Syndrome (HLHS)

Focusing on one type of severe heart defect can be helpful in understanding treatment and mechanisms of action for drugs.  Hypoplastic Left Heart Syndrome is a congenital heart defect where the left side of the heart is underdeveloped (Children’s Hospital of Philadelphia, 2019a; Children’s Hospital of Philadelphia, 2019b).  This causes issues with systemic blood flow, since the responsibility of the left side of the heart is to pump oxygen-rich blood to the rest of the body (Children’s Hospital of Philadelphia, 2019b; Yimgang et al., 2018).  As compared to 25 years ago, there has been many advancements in the identification and treatment of HLHS (Feinstein et al., 2012).

Similar to other congenital heart defects, HLHS is most likely diagnosed with a Fetal Echocardiogram (Children’s Hospital of Philadelphia, 2019b).  It is integral that that diagnosis is made prior to birth so that surgical plans can be made because, with the absence of any surgical interventions, HLHS is lethal to the neonate (Children’s Hospital of Philadelphia, 2019b; Yimgang et al., 2018).  With the influx of modern technology and research on HLHS, a 3-stage model of surgical interventions is the most widely accepted route for palliation and care (Children’s Hospital of Philadelphia, 2019b; Feinstein et al., 2012; Yimgang et al., 2018).  These procedures are called the Norwood Procedure, the Glenn (or Hemi-Fontan) Procedure and the Fontan Procedure (Children’s Hospital of Philadelphia, 2019b; Feinstein et al., 2012).  The goal of all of these procedures, called “Staged Reconstruction” is to re-route the right side of the heart to perform the function of the left: pumping oxygen-rich blood to the body (Children’s Hospital of Philadelphia, 2019b).  Therefore, the Norwood procedure, performed at about one-week old, starts the process by creating a viable source of oxygen-rich blood to the body (Yimgang et al., 2018).  The Glenn or Hemi-Fontan procedure, performed between 4-6 months old, reduces stress on the heart and improve circulatory system efficiency (Yimgang et al., 2018).  The final step is the Fontan Procedure, which is performed between 3 years and 5 years old, and results in the child having “Fontan Circulation,” where the blood from the lower extremities goes directly to the lungs where it picks up oxygen (Bingler, 2018; Children’s Hospital of Philadelphia, 2019b; Yimgang et al., 2018).  This results in less strain on the heart (Bingler, 2018).  Although these procedures are a life-saving necessity, there are some effects on the heart as well as other organ systems; moreover, continued cardiac care and the utilization of medications, like ACE inhibitors, may be needed (Feinstein et al., 2012; Wilson et al., 2016; Yimgang et al., 2018).


Angiotensin Converting Enzyme (ACE) Inhibitors

Studies have documented the use of Angiotensin Converting Enzyme (ACE) Inhibitors since the late 1980s and early 1990s (Casas, Álvarez & Lucero, 2015; Frishman, 1992; McMurray et al., 2014; SOLVD Investigators, 1991).  ACE inhibitors can be prescribed for a variety of issues including diabetic nephropathy, heart failure, hypertension, nondiabetic kidney disease, left ventricular dysfunction and myocardial infarction (Bowling et al., 2011; British Heart Foundation, 2018; DynaMed, 2018; Kechagia, Kalantzi & Dokoumetzidis, 2015; Ku et al., 2017; Mayo Clinic Staff, 2019; Stage et al., 2017; Thabet, Walsh & Breitkreutz, 2018).


Types

There are also a variety of different types of ACE inhibitors (Casas et al., 2015; DynaMed, 2018; Mayo Clinic Staff, 2019).  The first ACE inhibitor to be discovered was captopril (Casas et al., 2015).  From there a variety of different ACE Inhibitors were synthesized such as benazepril, enalapril, fosinopril, lisinopril, moexipril, perindopril, quinapril, ramipril and trandolapril (Frishman, 1992; Mayo Clinic Staff, 2019).  These ACE inhibitors are taken by mouth, with the exception of enalapril, which also has the option of being  given intravenously (Herman & Bashir, 2019).  Depending on the type of ACE inhibitor and the route of administration, the dosing may change, but the overall mechanism of action within the body stays constant


Mechanisms of Action

The exact mechanism of action of ACE inhibitors has evaded researchers throughout the years (Herman & Bashir, 2019; Mayo Clinic Staff, 2019).  What is known is that ACE inhibitors work within the renin-angiotensin-aldosterone system (RAAS) within the body (Herman & Bashir, 2019; Mayo Clinic Staff, 2019).  This system resides within the endocrine system and helps to regulate long-term blood pressure and extracellular volume within the body (Mechanisms in Medicine, 2012).  There are many different facets within this system that require further description in order to understand the entirety of the known mechanisms of action of ACE inhibitors.

The key components include Angiotensinogen, renin, Angiotensin I, Angiotensin Converting Enzyme (ACE) and Angiotensin II.  Angiotensinogen is released in response to low-blood pressure and interacts with renin, which is secreted by the kidneys (Mechanisms of Medicine, 2012).  This interaction causes the production of Angiotensin I (Mechanisms of Medicine, 2012).  Angiotensin I is a relatively inactive enzyme in the blood stream, until it interacts with the Angiotensin Converting Enzyme (ACE) (British Heart Foundation, 2018; Herman & Bashir, 2019; Mechanisms of Medicine, 2012).  ACE can be found in a multitude of areas within the body including the pulmonary circulation (lungs) and the vascular endothelium of many tissues like the kidney, adrenal glands, brain and heart (Mechanisms of Medicine, 2012).  ACE converts Angiotensin I into the very active enzyme Angiotensin II (British Heart Foundation, 2018; Casas et al., 2015; Herman & Bashir, 2019; Kechagia et al., 2015; Mayo Clinic Staff, 2019; Mechanisms of Medicine, 2012).  Angiotensin II causes a multitude of effects within the body.  Angiotensin II is a vasoconstrictor, meaning it narrows the blood vessels (British Heart Foundation, 2018; Frishman, 1992; Herman & Bashir, 2019).  It also is responsible for inhibiting the reuptake of norepinephrine, stimulating the release of catecholamines from the adrenal medulla, reducing the urinary excretion of sodium and water, stimulating the synthesis and release of aldosterone (which results in sodium retention) and stimulating hypertrophy (enlargement) of both vascular and smooth muscle cells and cardiac myocytes (Herman & Bashir, 2019).  Between its vasoconstrictive and sodium retention effects, Angiotensin II raises the blood pressure of the individual (Mechanisms of Medicine, 2012).  The creation of ACE inhibitors allow for pharmacological control of this system because they interrupt this process (British Heart Foundation, 2018; Ferreira, 2000; Frishman, 1992; Herman & Bashir, 2019; Mayo Clinic Staff, 2019). Analyzing a specific ACE inhibitor, enalapril, can provide further details about the mechanism of action of ACE inhibitors.


Enalapril.

Enalapril is an ACE inhibitor that is commonly used because of its effectiveness in in treating hypertension and reducing hospitalizations of individuals with congestive heart failure (Bowling et al., 2011).  Enalapril also has been preferred over other ACE inhibitors because of the research supporting its use in pediatric settings and the capability for once-daily dosing, which improves patient compliance (Casas et al., 2015).

Enalapril works by interrupting the Angiotensin Converting Enzyme (ACE) (British Heart Foundation, 2018; Casas et al., 2015; Frishman, 1992; Herman & Bashir, 2019).  When this enzyme is inhibited, angiotensin I cannot be transformed into angiotensin II (British Heart Foundation, 2018; Herman & Bashir, 2019).  As a result, less angiotensin II is available in the body, which leads to a relaxation of the blood vessels (British Heart Foundation, 2018).  Since angiotensin II also stimulates the synthesis and release of aldosterone the decrease of angiotensin II means that more sodium and water are filtered through the kidneys, which increases their excretion through the urine and decreases the amount of fluids in a person’s body (British Heart Foundation, 2018; DynaMed, 2018).  The combination of a relaxation of the blood vessels and less fluid retention leads to a decrease in blood pressure (British Heart Foundation, 2018; DynaMed, 2018).  When an individual’s blood pressure is low, there is less strain on the heart because there is less volume of blood that the heart needs to pump (British Heart Foundation, 2018).

Enalapril can be taken by mouth or administered intravenously (Herman & Bashir, 2019).  All ACE inhibitors share a number of pharmacokinetic properties and enalapril is no different.  For example, these medications are rapidly absorbed from the gastrointestinal traction, show a wide distribution in most tissues in the body and are excreted through the kidneys (Frishman, 1992).  For an oral dose of enalapril, absorption is about 60-70% and the presence of food does not complicate the absorption (DynaMed, 2018; Frishman, 1992; Moffett, DiSanto, Espinosa, Hou & Colabuono, 2014).  Once enalapril is absorbed, it is metabolized into its active form enalaprilat (Frishman, 1992).  The conversion of enalapril into enalaprilat occurs in the liver via carboxylesterase 1 (CES1) (Frishman, 1992; Stage et al., 2017).  It is in this active form of enalaprilat that the mechanism of inhibiting ACE occurs.  Once the enalaprilat has completed its job, it is excreted through the kidneys (Frishman, 1992).  Understanding the mechanism of action is important when doctors are contemplating the varying doses that can be given.


Dosing.

Dosing requires intimate knowledge of the mechanisms of action and the pharmacokinetics of enalapril and the other ACE inhibitors.  When discussing appropriate dosages, one area to consider is the root of administration of the drug.  For example, enalapril can be offered by mouth as a tablet (either a solid capsule or an orodispersible minitablet (ODMT)), liquid formula (Epaned) or intravenously (Faisal, Cawello, Burckhardt & Laer, 2019; Herman & Bashir, 2019; Moffett et al., 2014; Thabet et al., 2018).  The absorption of these modes of administration vary and needs to be taken into account when prescribing.  For example, Faisal and colleagues (2019) assessed the pharmacokinetic properties of the ODMT form of enalapril versus the capsules.  These researchers found that the OMDT appeared in systemic circulation four minutes faster than the capsules, possibly because of their faster disintegration and dissolution upon entrance to the gastrointestinal tract (Faisal et al., 2019).  The route of administration is not the only area which effects the pharmacokinetics of enalapril.  Another area to be considered is the research about pediatric versus adult dosages.

The pharmacokinetics and pharmacodynamics are different in children than in adults; moreover, dosing regimens for ACE inhibitors are different for children (Faisal et al., 2019). Although ACE inhibitors have the largest amount of evidence to support their use in a pediatric population, dosages for children are also renegotiated based on body weight (Casas et al., 2015).  Therefore, size of the child must be taken into account when making decisions on the use of enalapril and other ACE inhibitors.  ACE inhibitors like enalapril are a treatment regimen that can be utilized in response to medical complications with CHD, like HLHS.


HLHS and ACE Inhibitors

HLHS is one of the most severe congenital heart anomalies and needs lifelong cardiac care (Children’s Hospital of Philadelphia, 2019b).  The surgical interventions that are utilized as a treatment for HLHS are necessary, but they also cause different pressure and circulation issues and different hemodynamics (Heusch, Kahl, Hensel & Calaminus, 2017).  Moreover, ACE inhibitors may be utilized as a treatment to release pressure on the heart (Wilson et al., 2016; Yimgang et al., 2018).

The use of ACE inhibitors for individuals with HLHS is not wholly accepted and seems to be decided on a case-by-case basis (Wilson et al., 2016).  There has been documentation of the use of ACE inhibitors after the Norwood Procedure (Yimgang et al., 2018).  Since the Norwood Procedure is utilized for increased blood flow, the prescription of ACE inhibitors during this period helps to reduce the cardiac afterload, or the tension that the heart must work against in order to pump blood to the body, increasing cardiac output (Yimgang et al., 2018).  There has also been evidence to support their use in individuals with Fontan circulation (Feinstein et al., 2012; Wilson et al., 2016).  Since individuals with Fontan circulation are in a state of heart failure and ACE inhibitors are used to treat heart failure in individuals with two ventricles, their use is hypothesized for individuals with a single ventricle or Fontan circulation (Wilson et al., 2016).  As seen in their use between the Norwood and Glenn procedures, ACE inhibitors may decrease the individual’s cardiac afterload, allowing for better contraction of the heart for those with Fontan Circulation (Feinstein et al., 2012).  As stated previously, Fontan circulation has effects on other organ systems; moreover, the use of ACE inhibitors with HLHS has shown better neurodevelopmental outcomes, improved endothelial function and reduced renal injury (Feinstein et al., 2012).  There is still more research to be done in order to help the increase of individuals that are living with a CHD, particularly those with Fontan circulation (Feinstein et al., 2012; Wilson et al., 2016).


Conclusion

The survival rate of individuals with CHD is growing (Centers for Disease Control and Prevention, 2018a; Lantin-Hermoso et al., 2017).  Therefore, these individuals need continued cardiac care throughout the lifespan (Children’s Hospital of Philadelphia, 2019a).  The surgical interventions utilized for individuals with CHD cause varying effects on the heart and other organ systems; moreover, medications, like ACE inhibitors, may be utilized to assist in long-term care (Feinstein et al., 2012; Heusch et al., 2017; Wilson et al., 2016; Yimgang et al., 2018).  Since ACE inhibitors are utilized in the treatment of heart failure, it can be hypothesized that their use would show benefits in treating individuals with CHD, specifically those with HLHS (Feinstein et al., 2012; Wilson et al., 2016; Yimgang et al., 2018)


References

  • Bingler, M. A. (2018). Hypoplastic left heart syndrome surgery: The fontan procedure. Retrieved from

    https://kidshealth.org/en/parents/fontan.html
  • Bowling, C. B., Sanders, P. W., Allman, R. M., Rogers, W. J., Patel, K., Aban, I. B., . . . Ahmed, A. (2011). Effects of enalapril in systolic heart failure patients with and without chronic kidney disease: Insights from the SOLVD treatment trial.

    International Journal of Cardiology,


    167

    (1), 151-156. doi:10.1016/j.ijcard.2011.12.056
  • British Heart Foundation. (2018). How do ACE inhibitors work? Retrieved from

  • Casas, M., Álvarez, J., & Lucero, M. J. (2015). Physicochemical stability of captopril and enalapril extemporaneous formulations for pediatric patients.

    Pharmaceutical Development and Technology,


    20

    (3), 271-278. doi:10.3109/10837450.2013.860552
  • Centers for Disease Control and Prevention. (2018a). Data and statistics on congenital heart defects  Retrieved from

    https://www.cdc.gov/ncbddd/heartdefects/data.html
  • Centers for Disease Control and Prevention. (2018b). What are congenital heart defects? Retrieved from

    https://www.cdc.gov/ncbddd/heartdefects/facts.html
  • Children’s Hospital of Philadelphia (2019a). Congenital heart disease. Retrieved from

    https://www.chop.edu/conditions-diseases/congenital-heart-disease
  • Children’s Hospital of Philadelphia. (2019b). Hypoplastic left heart syndrome. Retrieved from

    https://www.chop.edu/conditions-diseases/hypoplastic-left-heart-syndrome-hlhs
  • DynaMed. (2018).

    Enalapril;

    . Ipswich, MA: EBSCO Information Services.
  • Faisal, M., Cawello, W., Burckhardt, B. B., & Laer, S. (2019). Model-dependent pharmacokinetic analysis of enalapril administered to healthy adult volunteers using orodispersible minitablets for use in pediatrics.

    Drug Design, Development and Therapy,


    13

    , 481-490. doi:10.2147/DDDT.S188417
  • Feinstein, J. A., Benson, D. W., Dubin, A. M., Cohen, M. S., Maxey, D. M., Mahle, W. T., . . . Martin, G. R. (2012). Hypoplastic left heart syndrome: Current considerations and expectations.

    Journal of the American College of Cardiology,


    59

    (1 Suppl), 1. doi:10.1016/j.jacc.2011.09.022
  • Ferreira, S. H. (2000). Angiotensin converting enzyme: History and relevance.

    Seminars in Perinatology,


    24

    (1), 7-10. doi:10.1016/S0146-0005(00)80046-4
  • Frishman, W. H. (1992). Comparative pharmacokinetic and clinical profiles of angiotensin-converting enzyme inhibitors and calcium antagonists in systemic hypertension.

    The American Journal of Cardiology,


    69

    (10), C17-C25. doi:10.1016/0002-9149(92)90277-6
  • Herman, L. L., & Bashir, K. (2019).

    Angiotensin converting enzyme inhibitors (ACEI)

    . Treasure Island, Florida: StatPearls Publishing LLC.
  • Heusch, A., Kahl, H. J., Hensel, K. O., & Calaminus, G. (2017). Health-related quality of life in paediatric patients with congenital heart defects: Associated with type of heart defect and the surgical technique.

    Qual Life Res,


    26

    , 3111-3117.
  • Kechagia, I., Kalantzi, L., & Dokoumetzidis, A. (2015). Extrapolation of enalapril efficacy from adults to children using pharmacokinetic/pharmacodynamic modelling.

    Journal of Pharmacy and Pharmacology,


    67

    (11), 1537-1545. doi:10.1111/jphp.12471
  • Ku, L., Zimmerman, K., Benjamin, D., Clark, R., Hornik, C., & Smith, P. (2017). Safety of enalapril in infants admitted to the neonatal intensive care unit.

    Pediatric Cardiology,


    38

    (1), 155-161. doi:10.1007/s00246-016-1496-2
  • Lantin-Hermoso, M. R., Berger, S., Bhatt, A. B., Richerson, J. E., Morrow, R., Freed, M. D., & Beekman, R. H. (2017). The care of children with congenital heart disease in their primary medical home.

    American Academy of Pediatrics,


    140

    (2)
  • Mayo Clinic Staff. (2019). Angiotensin-converting enzyme (ACE) inhibitors. Retrieved from

    https://www.mayoclinic.org/diseases-conditions/high-blood-pressure/in-depth/ace-inhibitors/art-20047480
  • McMurray, J. J. V., Packer, M., Desai, A. S., Gong, J., Lefkowitz, M. P., Rizkala, A. R., . . . Zile, M. R. (2014). Angiotensin–Neprilysin inhibition versus enalapril in heart failure.

    The New England Journal of Medicine,


    371

    (11), 993-1004. doi:10.1056/NEJMoa1409077
  • Mechanisms in Medicine. (2012). Renin angiotensin aldosterone system. Retrieved from


  • Moffett, B. S., DiSanto, A. R., Espinosa, O., Hou, J., & Colabuono, P. (2014). Bioequivalence of enalapril oral solution for treatment of pediatric hypertension and enalapril tablets.

    Clinical Pharmacology in Drug Development,


    3

    (6), 493-498. doi:10.1002/cpdd.129
  • Ni, Z. H., Lv, H. T., Ding, S., & Yao, W. Y. (2019). Home care experience and nursing needs of caregivers of children undergoing congenital heart disease operations: A qualitative descriptive study.

    PloS One,


    14

    (3), e0213154. doi:10.1371/journal.pone.0213154
  • Pace, N. D., Oster, M. E., Forestieri, N. E., Enright, D., Knight, J., & Meyer, R. E. (2018). Sociodemographic factors and survival of infants with congenital heart defects.

    American Academy of Pediatrics,


    142

    (3) doi:10.1542/peds.2018-0302
  • SOLVD Investigators. (1991). Effect of enalapril on survival in patients with reduced ventricular ejection fractions and congestive heart failure.

    The New England Journal of Medicine,


    325

    (5), 293-302.
  • Stage, C., Jürgens, G., Guski, L. S., Thomsen, R., Bjerre, D., Ferrero‐Miliani, L., . . . Dalhoff, K. (2017). The pharmacokinetics of enalapril in relation to CES1 genotype in healthy danish volunteers.

    Basic & Clinical Pharmacology & Toxicology,


    121

    (6), 487-492. doi:10.1111/bcpt.12835
  • Thabet, Y., Walsh, J., & Breitkreutz, J. (2018). Flexible and precise dosing of enalapril maleate for all paediatric age groups utilizing orodispersible minitablets.

    International Journal of Pharmaceutics,


    541

    (1-2), 136-142. doi:10.1016/j.ijpharm.2018.02.037
  • Wilson, T. G., Iyengar, A. J., Winlaw, D. S., Weintraub, R. G., Wheaton, G. R., Gentles, T. L., . . . d’Udekem, Y. (2015). Use of ACE inhibitors in fontan: Rational or irrational?

    International Journal of Cardiology,


    210

    , 95-99. doi:10.1016/j.ijcard.2016.02.089
  • Yimgang, D. P., Sorkin, J. D., Evans, C. F., Abraham, D. S., & Rosenthal, G. L. (2018). Angiotensin converting enzyme inhibitors and interstage failure in infants with hypoplastic left heart syndrome.

    Congenital heart disease

    ,

    13

    (4), 533–540. doi:10.1111/chd.12622

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