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Neurohormonal targets in the treatment of pediatric heart failure
Accepted Manuscript Neurohormonal targets in the treatment of pediatric heart failure
Jonathan Edelson, Joseph W. Rossano PII: DOI: Reference:
S1058-9813(17)30057-7 doi:10.1016/j.ppedcard.2017.10.004 PPC 1024
To appear in:
Progress in Pediatric Cardiology
Received date: Accepted date:
18 September 2017 3 October 2017
Please cite this article as: Jonathan Edelson, Joseph W. Rossano , Neurohormonal targets in the treatment of pediatric heart failure. The address for the corresponding author was captured as affiliation for all authors. Please check if appropriate. Ppc(2017), doi:10.1016/ j.ppedcard.2017.10.004
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ACCEPTED MANUSCRIPT Neurohormonal Targets in the Treatment of Pediatric Heart Failure Jonathan Edelson, MD, Joseph W. Rossano, MD, MS
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The Cardiac Center, Children’s Hospital of Philadelphia Department of Pediatrics, Perelman School of Medicine at the University of Pennsylvania
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Word Count: 2,224
Address for Correspondence:
Jonathan Edelson, MD Children’s Hospital of Philadelphia 34th Street & Civic Center Boulevard Philadelphia, PA 19104 Phone: 215-590-4040 Email: [email protected]
ACCEPTED MANUSCRIPT Abstract The history of the clinical approach to heart failure has been notable for a series of evolving conceptual paradigms, each in an effort to explain the clinical syndrome that presents. With the recent emphasis on a neurohormonal model of heart failure,
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we have seen the development of new therapeutic options that target biologically
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active molecules to preserve myocardial function. Sacubtril-valsartan, a combined
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angiotensin-neprilysin inhibitor shows the greatest clinical promise, while there is
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less evidence to support the use of recombinant relaxin-2 or vasopressin antagonists. This article will review the history of posited mechanisms of heart
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failure and the impact on treatment, novel therapeutic options with neurohormonal targets, and the challenges of developing therapies for the pediatric heart failure
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population.
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Keywords: heart failure, neurohormonal, medical therapy
ACCEPTED MANUSCRIPT Introduction While the field of pediatric cardiology has historically focused on the treatment and palliation of congenital heart disease, there is a growing awareness of the importance of heart failure in pediatric health. In 2006, there were nearly 14,000
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hospitalizations related to heart failure in pediatric patients, and those children with
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heart failure had a 20-fold increase in mortality compared to children without heart
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failure. The cost of pediatric heart failure is not limited to mortality; there are also
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increased morbidities and significant costs with respect to resource utilization [1]. It is in this setting that the diagnosis and treatment of pediatric heart failure has
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emerged as a subspecialty. With that emergence has come the challenge of developing a paradigm suitable for the population and effective evidence based
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medical therapies. This review will focus on the history of posited mechanisms of
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heart failure and the impact on treatment, novel therapeutic options with
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neurohormonal targets, and the challenges of developing therapies for the pediatric
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heart failure population.
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Mechanisms of Heart Failure The history of the clinical approach to heart failure has been characterized by a series of changing conceptual paradigms, each in an effort to explain the clinical syndrome that presents [2]. The first part of the 20th century saw the development of the “cardiorenal model”, in which heart failure was seen as the result of disordered regulation of salt and water retention, caused by abnormalities in
ACCEPTED MANUSCRIPT perfusion to the kidneys (Figure 1). This framework provided the initial justification for the use of diuretics to regulate the volume status of patients in heart failure. [3]
In time, clinicians began to see that the pathology of salt and water retention did not
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fully account for the symptomatology of heart failure including the impaired
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pumping capacity of the heart, and pathologic peripheral vasoconstriction. The
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subsequent “hemodynamic model” provides the basis for the use of inotropes and
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vasodilators to augment cardiac output (Figure 2). While these models have had significant impact on our understanding of heart failure, and on medical therapy,
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they have not been able to explain or mitigate the disease progression seen in the clinical syndrome, nor been effective at prolonging life in those with moderate to
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severe heart failure. Indeed, the use of inotropes are associated with increased
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adverse events and mortality in adult heart failure patients [4–8].
Heart Failure as a Progressive Process: a Neurohormonal Model
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Over the last 35 years, there has been an increased emphasis on viewing heart
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failure as a progressive process, and with this viewpoint has come a shift towards a neurohormonal model of heart failure. In this model, heart failure can be understood as an evolving disorder that takes place after an index event. That initial insult can be something acute, like a myocardial infarction, or hereditary, like genetic cardiomyopathies [9,10]. Regardless of the event itself, there is a shared common pathway in which myocytes are damaged, the ability of the myocardium to generate force is disrupted, and there is an ensuing decline in pump function.
ACCEPTED MANUSCRIPT While patients will generally remain either asymptomatic, or minimally symptomatic in the time period immediately following the index event, that is in part because of a series of compensatory mechanisms employed by the body, aimed at preserving left ventricular function. These mechanisms are thought to include
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“early activation of the adrenergic nervous system” to preserve cardiac output and
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“activation of a family of vasodilatory molecules, including natriuretic peptides,
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prostaglandins, and nitric oxide” to counteract the vasoconstriction promoted by
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excessive activation of the adrenergic system and the renin-angiotensin-aldosterone system (RAAS) (Figure 3).This neurohormonal model of heart failure postulates that
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even before the clinical syndrome of heart failure is phenotypically present, there is a series of abnormally expressed biologically active molecules, some of which in
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time have a profoundly negative impact on the heart and circulation, and are
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therefore potentially promising areas for targeted medical therapies (Figure 4)
Targeting Biologically Active Molecules to Preserve Myocardial Function
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It is within the neurohormonal context of heart failure that the current successful
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medical therapies were developed. Rather than focusing on medications that exclusively target the symptoms of heart failure (e.g. congestion), there were a series of successful clinical trials which showed the value of targeting biologically active molecules from the adrenergic and RAAS systems to slow the progression of heart failure.
ACCEPTED MANUSCRIPT In 1991, the SOLVD trial demonstrated that the addition of enalapril to conventional medical therapies reduced the 4 yr mortality by 16% and reduced heart failure related hospitalizations[11]. The data from the randomized study was robust, with an estimated prevention of 50 premature deaths, and 350 hospitalizations for every
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1,000 CHF patients treated with enalapril for 3 years. Subsequently, in 1999, the
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RALES trial demonstrated that in patients with symptomatic heart failure and an
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ejection fraction of less than 35%, the addition of spironolactone led to a 30%
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reduction in all-cause mortality, without a significant increase in the risk of serious
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hyperkalemia or renal failure [12].
Another landmark prospective randomized trial in 1991, COPERNICUS, revealed
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that the addition of carvedilol to a medical heart failure regimen reduced the risk of
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death or heart failure hospitalization by 31% compared to placebo in those adults[13]. Remarkably, in the span of less than 5 years, three separate classes of
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drugs were shown to confer significant morbidity and mortality benefit, and it has
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become the standard of care for all adults with heart failure to be on a medication regimen that includes an angiogensin converting enzyme (ACE) inhibitor (or
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angiotensin receptor blocker [ARB]), aldosterone antagonist, and a beta-blocker.
Use of Adult Heart Failure Medications in the Pediatric Population While the treatment of children with heart failure has also come include the use of ACE inhibitors, aldosterone antagonist, and beta-blockers, studies have failed to demonstrate the robust morbidity and mortality benefit that was seen in adults.
ACCEPTED MANUSCRIPT There have been some small studies in children that support the use of beta blockers[14–19] and ACE inhibitors [20–22] in pediatric patients with ventricular dysfunction. However, the findings from these limited studies were not observed in larger trials. In 2007, a randomized double blind control trial of the use of carvedilol
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in pediatric and adolescents with symptomatic heart failure did not demonstrate
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improved clinical outcomes (Figure 5) [23]. Additionally in 2010, a multi-center
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randomized trial evaluating the use of enalapril in the single ventricle population
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also demonstrated no benefit to growth, ventricular function, or heart failure severity when compared with placebo (Figure 6) [24]. Furthermore, a retrospective
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evaluation of the impact of the introduction of ACE inhibition and beta blockade on patients with dilated cardiomyopathy did not demonstrate a long-term survival
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benefit [25].
Neprilysin Inhibition
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Novel Therapeutic Options
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Some of the pathologic fluid overload seen in heart failure is thought to occur
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secondary to the body’s inability to naturally increase natriuretic peptides to the degree that is needed to maintain a normal fluid status. The importance of the natriuretic system has been emphasized by the observation that those with genetic variants of the ANP and BNP genes which “increase circulating levels” are protected “against hypertension, structural remodeling of the heart, and metabolic disease”. As such, attempts to increase the amount of circulating natriuretic peptides in the body has been an attempted treatment strategy through a variety of mechanisms,
ACCEPTED MANUSCRIPT with the intention of promoting natriuresis, vasodilatation, suppression of hypertrophy and fibrosis, and inhibition of RAAS. In the Vasodilation in the Management of Acute Congestive Heart Failure (VMAC) trial, intravenous nesiritide was compared to intravenous nitroglycerin and placebo in patients with acute
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congestive heart failure [26]. Initial results showed promise, with the alleviation of
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dyspnea within 3 hours of administration and lower pulmonary capillary wedge
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pressures. There were, however, significant issues with hypotension, and the
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subsequent Acute Study of Clinical Effectiveness of Nesiritide in Decompensated Heart Failure (ASCEND) trial was unable to show a reduction in
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death or heart failure related hospitalization at 30 days [27,28].
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More recent efforts have eschewed the use of exogenous natriuretic peptide for
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drugs which act to inhibit the body’s breakdown of endogenous natriuretic peptides.
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Neprilysin is a naturally occurring enzyme whose biologic role is to breakdown biologically active natriuretic peptides and a variety of other vasoactive compounds
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whose absence is implicated in pathologic cardiac remodeling and vasoconstriction,
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thus its inhibition seems a natural target for heart failure therapies. Initial therapies of isolated neprilysin inhibition were not effective, in part because inhibition alone leads to an up-regulation of the renin-angiotensin system. However, significant promise has been shown when combining a neprylisin inhibitor with an ARB (Figure 7) [29].
ACCEPTED MANUSCRIPT Sacubritil/valsartan (LCZ696) is a combined agent whose use was studied in the PARADIGM-HF trial. This study demonstrated a significant reduction in cardiovascular mortality and heart failure related hospitalization when compared to enalapril (21.8% vs. 26.5%; number needed to treat 21) and a significant reduction
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in all-cause mortality (17.0% vs. 19.8%; number needed to treat 36). The trial was
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stopped early following a positive interval efficacy analysis, and the FDA fast
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tracked the sacubritil/valsartan combination for approval. At this point,
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sacubritil/valsartan appears to be an important advance in the treatment of heart failure, and the prevention of clinical deterioration in adults [30,31]. Given the
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promising results seen in the adult population, a current double-blinded study is underway to assess the results of LCZ696 vs. enalapril in the pediatric population,
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the results of which are not yet available (Figure 8) [32].
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Relaxin
Relaxin is a naturally occurring peptide hormone that is present in all people, but is
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up-regulated in pregnant women to help govern the hemodynamic changes that
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take place in a women’s body during pregnancy. In particular, it is thought to increase cardiac output, decrease systemic vascular resistance, and improve blood flow to the kidneys [33](Figure 9). Given that all those effects would be potentially helpful in a patient with a heart failure, there have been recent studies which focused on the administration of a recombinant version of relaxin-2 (Serelaxin) to patients with heart failure[34]
ACCEPTED MANUSCRIPT The RELAX-AHF was an international, multi-center, double blinded study, which compared the administration of Serelaxin to placebo in patients admitted to the hospital with acute heart failure. The study did demonstrate a reduction in both cardiovascular and all-cause mortality, in addition to acute improvement in
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worsening heart failure and concurrent reduction of dyspnea[34,35]. Given the
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impressive study results, the medication was granted breakthrough. However, the
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follow-up study with a much larger enrollment population, RELAX-AHF-2, did not
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show a difference in cardiovascular mortality at 180 days, nor was the reduction of worsening heart failure at day 5 statistically significant [36]. Given those somewhat
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Vasopressin Receptor Antagonists
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disappointing results, a trial in the pediatric population was discontinued.
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Volume overload is a major cause of hospitalization and morbidity among patients
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hospitalized with acute heart failure, as elevated levels of circulating vasopressin lead to water retention and the resultant congestive symptoms. The abnormal
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hormone levels also cause electrolyte disturbances, and hyponatremia is present in
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20% of heart failure patients on presentation [37]. The use of diuretics to relieve congestive symptoms is a mainstay of treatment, but can be complicated renal injury and electrolyte derangement. The availability of vasopressin receptor blockers has offered new possible treatment options.
Tolvaptan is a vasopressin receptor (V2) antagonist that promotes the secretion of free water and theoretically could restore a normal fluid balance without injuring
ACCEPTED MANUSCRIPT the kidney or further altering electrolytes. It is also thought that the V2 receptor is associated with abnormal and pathologic hormonal pathways, and so antagonism of that receptor is hypothesized to not only improve symptoms but potentially to
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prevent progression of the disease.
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The use of Tolvaptan was studied in the 2007 EVEREST trials that randomized
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about 4000 patients admitted with acute heart failure to tolvaptan or placebo for 60
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days. At 10 months, there was no difference in all-cause mortality, cardiovascular mortality, or heart failure rehospitalization. There was shown to be some benefits
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with respect to short term heart failure symptoms, raising the possibility that vasopressin antagonism may have a role in the symptomatic treatment of acute
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heart failure [38]. There was a pediatric trial of tolvaptan for persistent
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hyponatremia, though the study was recently stopped due to poor enrollment.
Conclusions
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The neurohormonal model of heart failure that emphasizes targeting the adrenergic
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and RAAS to slow the progression of disease is well established. Yet, it is difficult to determine the proper use of adult heart failure medications in the pediatric population. As was noted, the therapies which have been shown to be efficacious in adults do not have great evidence supporting their use in children. There are certainly several reasons this may be the case. Negative studies do not necessarily mean that the drugs do not work, but may in fact be explained by the challenges of study design and implementation. Prospective pediatric trials are nearly universally
ACCEPTED MANUSCRIPT underpowered to detect survival differences in pediatric heart failure. Additional challenges exist with the lack of pharmacokinetic and pharmacodynamic data for many medications. However, it is also worth considering whether the neurohormonal model is applicable to children with heart failure in the same
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manner as adults with heart failure. The pediatric and adult heart failure
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populations are in fact quite different with respect to underlying diseases and
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demonstrate different gene expression [39]and molecular characteristics [40].
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Perhaps, improved understanding of a pediatric specific model of heart failure
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would lead to new targets of therapy.
ACCEPTED MANUSCRIPT References:
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Infants With Single Ventricle: Results of a Multicenter Randomized Trial. Circulation 2010;122:333–40. doi:10.1161/CIRCULATIONAHA.109.927988.
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Changing Medical Therapy on Transplantation-Free Survival in Pediatric Dilated Cardiomyopathy n.d. doi:10.1016/j.jacc.2009.11.059. [26] McKie PM, Burnett JC. NT-proBNP: The Gold Standard Biomarker in Heart Failure. J Am Coll Cardiol 2016;68:2437–9. doi:10.1016/j.jacc.2016.10.001. [27] Intravenous Nesiritide vs Nitroglycerin for Treatment of Decompensated Congestive Heart Failure: A Randomized Controlled Trial. JAMA 2002;287. doi:10.1001/jama.287.12.1531.
ACCEPTED MANUSCRIPT [28] O’Connor CM, Starling RC, Hernandez AF, Armstrong PW, Dickstein K, Hasselblad V, et al. Effect of Nesiritide in Patients with Acute Decompensated Heart Failure. N Engl J Med 2011;365:32–43. doi:10.1056/NEJMoa1100171. [29] Braunwald E. The path to an angiotensin receptor antagonist-neprilysin
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Zhao Z., Kantor P., Burch M. CF. Design for the sacubitril/valsartan (LCZ 696) compared with enalapril study of pediatric patients with heart failure due to
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systemic left ventricular systolic dysfunction (PANORAMA-HF study). Am
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[33] Dschietzig T. Relaxin, a Pregnancy Hormone, Is a Functional Endothelin-1 Antagonist: Attenuation of Endothelin-1-Mediated Vasoconstriction by Stimulation of Endothelin Type-B Receptor Expression via ERK-1/2 and Nuclear Factor-kappaB. Circ Res 2003;92:32–40. doi:10.1161/01.RES.0000051884.27117.7E. [34] Teerlink JR, Cotter G, Davison BA, Felker GM, Filippatos G, Greenberg BH, et al.
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TRIAL. 2017.
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[37] Verbrugge FH, Steels P, Grieten L, Nijst P, Tang WHW, Mullens W. Hyponatremia in acute decompensated heart failure: Depletion versus
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dilution. J Am Coll Cardiol 2015;65:480–92. doi:10.1016/j.jacc.2014.12.010. [38] Konstam MA, Gheorghiade M, Burnett JC, Grinfeld L, Maggioni AP, Swedberg
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K, et al. Effects of oral tolvaptan in patients hospitalized for worsening heart
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failure: the EVEREST Outcome Trial. JAMA 2007;297:1319–31.
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doi:10.1001/jama.297.12.1319. [39] Reddy S. Failure of Right Ventricular Adaptation in Children With Tetralogy of
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Fallot. Circulation 2006;114:I-37-I-42.
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doi:10.1161/CIRCULATIONAHA.105.001248. [40] Miyamoto SD, Stauffer BL, Nakano S, Sobus R, Nunley K, Nelson P, et al. Betaadrenergic adaptation in paediatric idiopathic dilated cardiomyopathy. Eur Heart J 2014;35:33–41. doi:10.1093/eurheartj/ehs229.
ACCEPTED MANUSCRIPT Figure Legend Figure 1[3] The kidney’s role in causing fluid overload has been proposed since the 16th century, but became clinically relevant in the 1920’s with Saxl and Helling’s discovery of the
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diuretic properties of organic mercurials and the ensuing development of thiazide
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and loop diuretics. In the coming years, Wigger’s work on hemodynamics in animal
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models was incorporated into clinical practice through the development of cardiac
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catheterization and cardiac surgery. Myocardiality contractility was first described by Sarnoff in 1955, and in 1967 Braunwald recognized how its depression was
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implicated in heart failure.
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Figure 2 [3]
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As evidence mounted that impaired myocardial contractility played an important
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role in the development of heart failure, emphasis shifted to the use of inotropes and vasodilators. While initial short term clinical trials seemed to show an improvement
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in both hemodynamics and symptoms, the use of inotropes was ultimately shown to
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worsen prognosis. In the early 1990’s, the emphasis shifted to the maladaptive process of the hypertrophic response, and the role of angiotensin II and myosin mutations in stimulating hypertrophy was shown.
Figure 3 [10] In this model an initial index event provokes impaired pumping function of the heart. This decline in function prompts changes in the RAAS, adrenergic nervous
ACCEPTED MANUSCRIPT system and cytokine systems, which upregulate in order to restore function and keep patients asymptomatic. However, these compensatory mechanisms also have negative impacts on cardiac remodeling and offer areas to target therapeutically.
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Figure 4 [3]
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In the 1990’s evidence mounted that vasodilators worsened prognosis, and beta
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blockers were shown to improve survival despite their negative inotropic action,
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both likely through their mediation of neurohormonal pathways.
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Figure 5 [23]
A double blind randomized control trial comparing carvedilol to placebo in pediatric
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in mortality of hospitalization.
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patients with symptomatic heart failure did not show clinically significant difference
Figure 6 [24]
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A multi-center randomized control trial evaluating the use of enalapril in the single
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ventricle population demonstrated no difference in LOWESS (locally weighted scatterplot smoothing) curves of weight-for age z score in children treated with enalapril vs. those without.
Figure 7 [30] LCZ 696 is comprised of two molecular components; the angiotensin receptor blocker valsartan and the neprilysin inhibitor prodrug sacubitril. Valsartan inhibits
ACCEPTED MANUSCRIPT the RAAS system by blocking AT1 while sacubtril is enzymatically converted to an active neprilysin inhibitor to prevent the breakdown of natriuretic peptides.
Figure 8 [32]
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Shown is the study design of a double-blinded trial to assess the results of LCZ696
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vs. enalapril in the pediatric population.
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Figure 9 [35]
The potential benefits of increasing the concentration of circulating relaxin in
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patients with heart failure include improved renal function and lower SVR, reduced
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Figure 1: The Role of the Kidney [3]
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diuretic properties of organic mercurials and the ensuing development of thiazide and loop diuretics. In the coming years, Wigger’s work on hemodynamics in animal models was incorporated into clinical practice through the development of cardiac catheterization and cardiac surgery. Myocardiality contractility was first described by Sarnoff in 1955, and in 1967 Braunwald recognized how its depression was implicated in heart failure.
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Figure 2: The Rise and Fall of Inotropic Therapy [3]
As evidence mounted that impaired myocardial contractility played an important
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role in the development of heart failure, emphasis shifted to the use of inotropes and vasodilators. While initial short term clinical trials seemed to show an improvement in both hemodynamics and symptoms, the use of inotropes was ultimately shown to worsen prognosis. In the early 1990’s, the emphasis shifted to the maladaptive process of the hypertrophic response, and the role of angiotensin II and myosin mutations in stimulating hypertrophy was shown.
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Figure 3: The Body’s Response to Myocardial Injury [10]
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In this model an initial index event provokes impaired pumping function of the heart. This decline in function prompts changes in the RAAS, adrenergic nervous system and cytokine systems, which upregulate in order to restore function and keep patients asymptomatic. However, these compensatory mechanisms also have negative impacts on cardiac remodeling and offer areas to target therapeutically.
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Figure 4: A Growing Awareness of Neurohormonal Pathways [3]
In the 1990’s evidence mounted that vasodilators worsened prognosis, and beta blockers were shown to improve survival despite their negative inotropic action, both likely through their mediation of neurohormonal pathways.
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Figure 5: The Pediatric Randomized Carvedilol Trial [23]
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in mortality of hospitalization.
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Figure 6: The Use of Enalapril in the Single Ventricle Population [24]
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ventricle population demonstrated no difference in LOWESS (locally weighted scatterplot smoothing) curves of weight-for age z score in children treated with enalapril vs. those without.
ACCEPTED MANUSCRIPT Figure 7: Targets of a Combined Angiotensin Receptor Blocker Valsartan and the
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Neprilysin Inhibitor [30]
LCZ 696 is comprised of two molecular components; the angiotensin receptor blocker valsartan and the neprilysin inhibitor prodrug sacubitril. Valsartan inhibits the RAAS system by blocking AT1 while sacubtril is enzymatically converted to an active neprilysin inhibitor to prevent the breakdown of natriuretic peptides.
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Figure 8: A Pediatric Trial of LCZ696 [32]
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vs. enalapril in the pediatric population.
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Figure 9: Targets of Serelaxin [35]
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patients with heart failure include improved renal function and lower SVR, reduced inflammation, oxidative stress and apoptosis, and decreased fibrosis.
ACCEPTED MANUSCRIPT [1]
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ACCEPTED MANUSCRIPT children: a multi-institutional experience. J Hear Lung Transplant 1999;18:269–74. doi:10.1016/S1053-2498(98)00030-8. [15] Bruns LA, Chrisant MK, Lamour JM, Shaddy RE, Pahl E, Blume ED, et al. Carvedilol as therapy in pediatric heart failure: An initial multicenter
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[16] Rusconi P, Gómez-Marín O, Rossique-González M, Redha E, Marín JR, Lon-
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[17] Azeka E, Antonio Franchini Ramires J, Valler C, Alcides Bocchi E, Paulo S. Delisting of Infants and Children From the Heart Transplantation Waiting List
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[18] Blume ED, Canter CE, Spicer R, Gauvreau K, Colan S, Jenkins KJ. Prospective Single-Arm Protocol of Carvedilol in Children with Ventricular Dysfunction.
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Pediatr Cardiol 2006;27:336–42. doi:10.1007/s00246-005-1159-1.
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[19] Bajcetic M, Samardzic R. Effects of Carvedilol on Left Ventricular Function and Oxidative Stress in Infants and Children with Idiopathic Dilated Cardiomyopathy: A 12-Month, Two-Center, Open-Label Study. Clin Ther Ther 2008;30:702–14. [20] Stern H, Weil J, Genz T, Vogt W, Bühlmeyer K. Captopril in children with dilated cardiomyopathy: Acute and long-term effects in a prospective study of hemodynamic and hormonal effects. Pediatr Cardiol 1990;11:22–8.
ACCEPTED MANUSCRIPT doi:10.1007/BF02239543. [21] Eronen M, Pesonen E, Wallgren EI, Tikkanen I, Fyhrquist F, Andersson S. Enalapril in children with congestive heart failure. Acta Paediatr Scand 1991;80:555–8.
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[22] Lewis AB, Chabot M. The effect of treatment with angiotensin-converting
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cardiomyopathy. Pediatr Cardiol 1993;14:9–12. doi:10.1007/BF00794837.
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[23] Shaddy RE, Boucek MM, Hsu DT, Boucek RJ, Canter CE, Mahony L, et al. Carvedilol for Children and Adolescents With Heart Failure: A Randomized
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Controlled Trial. JAMA 2007;298:1171. doi:10.1001/jama.298.10.1171. [24] Hsu DT, Zak V, Mahony L, Sleeper LA, Atz AM, Levine JC, et al. Enalapril in
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[25] Kantor PF, Abraham JR, Dipchand AI, Benson LN, Redington AN. The Impact of Changing Medical Therapy on Transplantation-Free Survival in Pediatric
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Dilated Cardiomyopathy n.d. doi:10.1016/j.jacc.2009.11.059.
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[26] McKie PM, Burnett JC. NT-proBNP: The Gold Standard Biomarker in Heart Failure. J Am Coll Cardiol 2016;68:2437–9. doi:10.1016/j.jacc.2016.10.001. [27] Intravenous Nesiritide vs Nitroglycerin for Treatment of Decompensated Congestive Heart Failure: A Randomized Controlled Trial. JAMA 2002;287. doi:10.1001/jama.287.12.1531. [28] O’Connor CM, Starling RC, Hernandez AF, Armstrong PW, Dickstein K, Hasselblad V, et al. Effect of Nesiritide in Patients with Acute Decompensated
ACCEPTED MANUSCRIPT Heart Failure. N Engl J Med 2011;365:32–43. doi:10.1056/NEJMoa1100171. [29] Braunwald E. The path to an angiotensin receptor antagonist-neprilysin inhibitor in the treatment of heart failure. J Am Coll Cardiol 2015;65:1029–41. doi:10.1016/j.jacc.2015.01.033.
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[30] Vardeny O, Miller R, Solomon SD. Combined neprilysin and renin-angiotensin
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2014;2:663–70. doi:10.1016/j.jchf.2014.09.001.
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system inhibition for the treatment of heart failure. JACC Hear Fail
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[31] McMurray JJV, Packer M, Desai AS, Gong J, Lefkowitz MP, Rizkala AR, et al. Angiotensin–Neprilysin Inhibition versus Enalapril in Heart Failure. N Engl J
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Zhao Z., Kantor P., Burch M. CF. Design for the sacubitril/valsartan (LCZ 696)
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[33] Dschietzig T. Relaxin, a Pregnancy Hormone, Is a Functional Endothelin-1
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ACCEPTED MANUSCRIPT England) 2013;381:29–39. doi:10.1016/S0140-6736(12)61855-8. [35] Tietjens J, Teerlink JR. Serelaxin and acute heart failure. Heart 2016;102:95–9. doi:10.1136/heartjnl-2014-306786. [36] SERELAXIN FAILS TO MEET PRIMARY ENDPOINTS IN PHASE 3 RELAX-AHF-2
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TRIAL. 2017.
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dilution. J Am Coll Cardiol 2015;65:480–92. doi:10.1016/j.jacc.2014.12.010. [38] Konstam MA, Gheorghiade M, Burnett JC, Grinfeld L, Maggioni AP, Swedberg
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K, et al. Effects of oral tolvaptan in patients hospitalized for worsening heart failure: the EVEREST Outcome Trial. JAMA 2007;297:1319–31.
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[39] Reddy S. Failure of Right Ventricular Adaptation in Children With Tetralogy of
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Fallot. Circulation 2006;114:I-37-I-42. doi:10.1161/CIRCULATIONAHA.105.001248.
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[40] Miyamoto SD, Stauffer BL, Nakano S, Sobus R, Nunley K, Nelson P, et al. Beta-
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adrenergic adaptation in paediatric idiopathic dilated cardiomyopathy. Eur Heart J 2014;35:33–41. doi:10.1093/eurheartj/ehs229.
ACCEPTED MANUSCRIPT Highlights The review will highlight new medicaitons including Sacubtril-valsartan, a combined angiotensin-neprilysin inhibitor shows great clinical promise, and others including recombinant relaxin-2 and vasopressin antagonists. This article will
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review the history of posited mechanisms of heart failure and the impact on
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treatment, novel therapeutic options with neurohormonal targets, and the
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challenges of developing therapies for the pediatric heart failure population.
Jonathan Edelson, Joseph W. Rossano PII: DOI: Reference:
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To appear in:
Progress in Pediatric Cardiology
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Please cite this article as: Jonathan Edelson, Joseph W. Rossano , Neurohormonal targets in the treatment of pediatric heart failure. The address for the corresponding author was captured as affiliation for all authors. Please check if appropriate. Ppc(2017), doi:10.1016/ j.ppedcard.2017.10.004
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ACCEPTED MANUSCRIPT Neurohormonal Targets in the Treatment of Pediatric Heart Failure Jonathan Edelson, MD, Joseph W. Rossano, MD, MS
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The Cardiac Center, Children’s Hospital of Philadelphia Department of Pediatrics, Perelman School of Medicine at the University of Pennsylvania
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Word Count: 2,224
Address for Correspondence:
Jonathan Edelson, MD Children’s Hospital of Philadelphia 34th Street & Civic Center Boulevard Philadelphia, PA 19104 Phone: 215-590-4040 Email: [email protected]
ACCEPTED MANUSCRIPT Abstract The history of the clinical approach to heart failure has been notable for a series of evolving conceptual paradigms, each in an effort to explain the clinical syndrome that presents. With the recent emphasis on a neurohormonal model of heart failure,
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we have seen the development of new therapeutic options that target biologically
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active molecules to preserve myocardial function. Sacubtril-valsartan, a combined
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angiotensin-neprilysin inhibitor shows the greatest clinical promise, while there is
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less evidence to support the use of recombinant relaxin-2 or vasopressin antagonists. This article will review the history of posited mechanisms of heart
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failure and the impact on treatment, novel therapeutic options with neurohormonal targets, and the challenges of developing therapies for the pediatric heart failure
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population.
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Keywords: heart failure, neurohormonal, medical therapy
ACCEPTED MANUSCRIPT Introduction While the field of pediatric cardiology has historically focused on the treatment and palliation of congenital heart disease, there is a growing awareness of the importance of heart failure in pediatric health. In 2006, there were nearly 14,000
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hospitalizations related to heart failure in pediatric patients, and those children with
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heart failure had a 20-fold increase in mortality compared to children without heart
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failure. The cost of pediatric heart failure is not limited to mortality; there are also
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increased morbidities and significant costs with respect to resource utilization [1]. It is in this setting that the diagnosis and treatment of pediatric heart failure has
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emerged as a subspecialty. With that emergence has come the challenge of developing a paradigm suitable for the population and effective evidence based
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medical therapies. This review will focus on the history of posited mechanisms of
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heart failure and the impact on treatment, novel therapeutic options with
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neurohormonal targets, and the challenges of developing therapies for the pediatric
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heart failure population.
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Mechanisms of Heart Failure The history of the clinical approach to heart failure has been characterized by a series of changing conceptual paradigms, each in an effort to explain the clinical syndrome that presents [2]. The first part of the 20th century saw the development of the “cardiorenal model”, in which heart failure was seen as the result of disordered regulation of salt and water retention, caused by abnormalities in
ACCEPTED MANUSCRIPT perfusion to the kidneys (Figure 1). This framework provided the initial justification for the use of diuretics to regulate the volume status of patients in heart failure. [3]
In time, clinicians began to see that the pathology of salt and water retention did not
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fully account for the symptomatology of heart failure including the impaired
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pumping capacity of the heart, and pathologic peripheral vasoconstriction. The
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subsequent “hemodynamic model” provides the basis for the use of inotropes and
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vasodilators to augment cardiac output (Figure 2). While these models have had significant impact on our understanding of heart failure, and on medical therapy,
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they have not been able to explain or mitigate the disease progression seen in the clinical syndrome, nor been effective at prolonging life in those with moderate to
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severe heart failure. Indeed, the use of inotropes are associated with increased
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adverse events and mortality in adult heart failure patients [4–8].
Heart Failure as a Progressive Process: a Neurohormonal Model
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Over the last 35 years, there has been an increased emphasis on viewing heart
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failure as a progressive process, and with this viewpoint has come a shift towards a neurohormonal model of heart failure. In this model, heart failure can be understood as an evolving disorder that takes place after an index event. That initial insult can be something acute, like a myocardial infarction, or hereditary, like genetic cardiomyopathies [9,10]. Regardless of the event itself, there is a shared common pathway in which myocytes are damaged, the ability of the myocardium to generate force is disrupted, and there is an ensuing decline in pump function.
ACCEPTED MANUSCRIPT While patients will generally remain either asymptomatic, or minimally symptomatic in the time period immediately following the index event, that is in part because of a series of compensatory mechanisms employed by the body, aimed at preserving left ventricular function. These mechanisms are thought to include
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“early activation of the adrenergic nervous system” to preserve cardiac output and
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“activation of a family of vasodilatory molecules, including natriuretic peptides,
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prostaglandins, and nitric oxide” to counteract the vasoconstriction promoted by
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excessive activation of the adrenergic system and the renin-angiotensin-aldosterone system (RAAS) (Figure 3).This neurohormonal model of heart failure postulates that
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even before the clinical syndrome of heart failure is phenotypically present, there is a series of abnormally expressed biologically active molecules, some of which in
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time have a profoundly negative impact on the heart and circulation, and are
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therefore potentially promising areas for targeted medical therapies (Figure 4)
Targeting Biologically Active Molecules to Preserve Myocardial Function
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It is within the neurohormonal context of heart failure that the current successful
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medical therapies were developed. Rather than focusing on medications that exclusively target the symptoms of heart failure (e.g. congestion), there were a series of successful clinical trials which showed the value of targeting biologically active molecules from the adrenergic and RAAS systems to slow the progression of heart failure.
ACCEPTED MANUSCRIPT In 1991, the SOLVD trial demonstrated that the addition of enalapril to conventional medical therapies reduced the 4 yr mortality by 16% and reduced heart failure related hospitalizations[11]. The data from the randomized study was robust, with an estimated prevention of 50 premature deaths, and 350 hospitalizations for every
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1,000 CHF patients treated with enalapril for 3 years. Subsequently, in 1999, the
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RALES trial demonstrated that in patients with symptomatic heart failure and an
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ejection fraction of less than 35%, the addition of spironolactone led to a 30%
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reduction in all-cause mortality, without a significant increase in the risk of serious
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hyperkalemia or renal failure [12].
Another landmark prospective randomized trial in 1991, COPERNICUS, revealed
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that the addition of carvedilol to a medical heart failure regimen reduced the risk of
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death or heart failure hospitalization by 31% compared to placebo in those adults[13]. Remarkably, in the span of less than 5 years, three separate classes of
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drugs were shown to confer significant morbidity and mortality benefit, and it has
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become the standard of care for all adults with heart failure to be on a medication regimen that includes an angiogensin converting enzyme (ACE) inhibitor (or
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angiotensin receptor blocker [ARB]), aldosterone antagonist, and a beta-blocker.
Use of Adult Heart Failure Medications in the Pediatric Population While the treatment of children with heart failure has also come include the use of ACE inhibitors, aldosterone antagonist, and beta-blockers, studies have failed to demonstrate the robust morbidity and mortality benefit that was seen in adults.
ACCEPTED MANUSCRIPT There have been some small studies in children that support the use of beta blockers[14–19] and ACE inhibitors [20–22] in pediatric patients with ventricular dysfunction. However, the findings from these limited studies were not observed in larger trials. In 2007, a randomized double blind control trial of the use of carvedilol
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in pediatric and adolescents with symptomatic heart failure did not demonstrate
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improved clinical outcomes (Figure 5) [23]. Additionally in 2010, a multi-center
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randomized trial evaluating the use of enalapril in the single ventricle population
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also demonstrated no benefit to growth, ventricular function, or heart failure severity when compared with placebo (Figure 6) [24]. Furthermore, a retrospective
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evaluation of the impact of the introduction of ACE inhibition and beta blockade on patients with dilated cardiomyopathy did not demonstrate a long-term survival
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benefit [25].
Neprilysin Inhibition
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Novel Therapeutic Options
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Some of the pathologic fluid overload seen in heart failure is thought to occur
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secondary to the body’s inability to naturally increase natriuretic peptides to the degree that is needed to maintain a normal fluid status. The importance of the natriuretic system has been emphasized by the observation that those with genetic variants of the ANP and BNP genes which “increase circulating levels” are protected “against hypertension, structural remodeling of the heart, and metabolic disease”. As such, attempts to increase the amount of circulating natriuretic peptides in the body has been an attempted treatment strategy through a variety of mechanisms,
ACCEPTED MANUSCRIPT with the intention of promoting natriuresis, vasodilatation, suppression of hypertrophy and fibrosis, and inhibition of RAAS. In the Vasodilation in the Management of Acute Congestive Heart Failure (VMAC) trial, intravenous nesiritide was compared to intravenous nitroglycerin and placebo in patients with acute
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congestive heart failure [26]. Initial results showed promise, with the alleviation of
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dyspnea within 3 hours of administration and lower pulmonary capillary wedge
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pressures. There were, however, significant issues with hypotension, and the
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subsequent Acute Study of Clinical Effectiveness of Nesiritide in Decompensated Heart Failure (ASCEND) trial was unable to show a reduction in
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death or heart failure related hospitalization at 30 days [27,28].
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More recent efforts have eschewed the use of exogenous natriuretic peptide for
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drugs which act to inhibit the body’s breakdown of endogenous natriuretic peptides.
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Neprilysin is a naturally occurring enzyme whose biologic role is to breakdown biologically active natriuretic peptides and a variety of other vasoactive compounds
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whose absence is implicated in pathologic cardiac remodeling and vasoconstriction,
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thus its inhibition seems a natural target for heart failure therapies. Initial therapies of isolated neprilysin inhibition were not effective, in part because inhibition alone leads to an up-regulation of the renin-angiotensin system. However, significant promise has been shown when combining a neprylisin inhibitor with an ARB (Figure 7) [29].
ACCEPTED MANUSCRIPT Sacubritil/valsartan (LCZ696) is a combined agent whose use was studied in the PARADIGM-HF trial. This study demonstrated a significant reduction in cardiovascular mortality and heart failure related hospitalization when compared to enalapril (21.8% vs. 26.5%; number needed to treat 21) and a significant reduction
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in all-cause mortality (17.0% vs. 19.8%; number needed to treat 36). The trial was
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stopped early following a positive interval efficacy analysis, and the FDA fast
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tracked the sacubritil/valsartan combination for approval. At this point,
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sacubritil/valsartan appears to be an important advance in the treatment of heart failure, and the prevention of clinical deterioration in adults [30,31]. Given the
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promising results seen in the adult population, a current double-blinded study is underway to assess the results of LCZ696 vs. enalapril in the pediatric population,
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the results of which are not yet available (Figure 8) [32].
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Relaxin
Relaxin is a naturally occurring peptide hormone that is present in all people, but is
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up-regulated in pregnant women to help govern the hemodynamic changes that
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take place in a women’s body during pregnancy. In particular, it is thought to increase cardiac output, decrease systemic vascular resistance, and improve blood flow to the kidneys [33](Figure 9). Given that all those effects would be potentially helpful in a patient with a heart failure, there have been recent studies which focused on the administration of a recombinant version of relaxin-2 (Serelaxin) to patients with heart failure[34]
ACCEPTED MANUSCRIPT The RELAX-AHF was an international, multi-center, double blinded study, which compared the administration of Serelaxin to placebo in patients admitted to the hospital with acute heart failure. The study did demonstrate a reduction in both cardiovascular and all-cause mortality, in addition to acute improvement in
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worsening heart failure and concurrent reduction of dyspnea[34,35]. Given the
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impressive study results, the medication was granted breakthrough. However, the
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follow-up study with a much larger enrollment population, RELAX-AHF-2, did not
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show a difference in cardiovascular mortality at 180 days, nor was the reduction of worsening heart failure at day 5 statistically significant [36]. Given those somewhat
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Vasopressin Receptor Antagonists
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disappointing results, a trial in the pediatric population was discontinued.
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Volume overload is a major cause of hospitalization and morbidity among patients
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hospitalized with acute heart failure, as elevated levels of circulating vasopressin lead to water retention and the resultant congestive symptoms. The abnormal
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hormone levels also cause electrolyte disturbances, and hyponatremia is present in
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20% of heart failure patients on presentation [37]. The use of diuretics to relieve congestive symptoms is a mainstay of treatment, but can be complicated renal injury and electrolyte derangement. The availability of vasopressin receptor blockers has offered new possible treatment options.
Tolvaptan is a vasopressin receptor (V2) antagonist that promotes the secretion of free water and theoretically could restore a normal fluid balance without injuring
ACCEPTED MANUSCRIPT the kidney or further altering electrolytes. It is also thought that the V2 receptor is associated with abnormal and pathologic hormonal pathways, and so antagonism of that receptor is hypothesized to not only improve symptoms but potentially to
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prevent progression of the disease.
IP
The use of Tolvaptan was studied in the 2007 EVEREST trials that randomized
CR
about 4000 patients admitted with acute heart failure to tolvaptan or placebo for 60
US
days. At 10 months, there was no difference in all-cause mortality, cardiovascular mortality, or heart failure rehospitalization. There was shown to be some benefits
AN
with respect to short term heart failure symptoms, raising the possibility that vasopressin antagonism may have a role in the symptomatic treatment of acute
M
heart failure [38]. There was a pediatric trial of tolvaptan for persistent
PT
ED
hyponatremia, though the study was recently stopped due to poor enrollment.
Conclusions
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The neurohormonal model of heart failure that emphasizes targeting the adrenergic
AC
and RAAS to slow the progression of disease is well established. Yet, it is difficult to determine the proper use of adult heart failure medications in the pediatric population. As was noted, the therapies which have been shown to be efficacious in adults do not have great evidence supporting their use in children. There are certainly several reasons this may be the case. Negative studies do not necessarily mean that the drugs do not work, but may in fact be explained by the challenges of study design and implementation. Prospective pediatric trials are nearly universally
ACCEPTED MANUSCRIPT underpowered to detect survival differences in pediatric heart failure. Additional challenges exist with the lack of pharmacokinetic and pharmacodynamic data for many medications. However, it is also worth considering whether the neurohormonal model is applicable to children with heart failure in the same
T
manner as adults with heart failure. The pediatric and adult heart failure
IP
populations are in fact quite different with respect to underlying diseases and
CR
demonstrate different gene expression [39]and molecular characteristics [40].
US
Perhaps, improved understanding of a pediatric specific model of heart failure
AC
CE
PT
ED
M
AN
would lead to new targets of therapy.
ACCEPTED MANUSCRIPT References:
[1]
Rossano JW, Shaddy RE. Heart Failure in Children: Etiology and Treatment. J Pediatr 2014;165:228–33. doi:10.1016/j.jpeds.2014.04.055. Rossano JW, Shaddy RE. Update on Pharmacological Heart Failure Therapies
T
[2]
IP
in Children: Do Adult Medications Work in Children and if Not, Why Not?
Yellon L, Opie D, editors. Cardiology At the Limits IV. London: University of
US
[3]
CR
Circulation 2014;129:607–12. doi:10.1161/CIRCULATIONAHA.113.003615.
Cape Town and University College, London; 2001. Packer M, Carver JR, Rodeheffer RJ, Ivanhoe RJ, DiBianco R, Zeldis SM, et al.
AN
[4]
Effect of Oral Milrinone on Mortality in Severe Chronic Heart Failure. N Engl J
Cuffe MS, Califf RM, Kirkwood F. Adams J, Benza R, Bourge R, Colucci WS, et al.
ED
[5]
M
Med 1991;325:1468–75. doi:10.1056/NEJM199111213252103.
PT
Short-term Intravenous Milrinone for Acute Exacerbation of Chronic Heart Failure
Felker GM, Benza RL, Chandler AB, Leimberger JD, Cuffe MS, Califf RM, et al.
AC
[6]
CE
JAMA 2002;287:1541. doi:10.1001/jama.287.12.1541.
Heart failure etiology and response tomilrinone in decompensated heart failure. J Am Coll Cardiol 2003;41:997–1003. doi:10.1016/S07351097(02)02968-6. [7]
Abraham WT, Adams KF, Fonarow GC, Costanzo MR, Berkowitz RL, LeJemtel TH, et al. In-Hospital Mortality in Patients With Acute Decompensated Heart Failure Requiring Intravenous Vasoactive Medications. J Am Coll Cardiol
ACCEPTED MANUSCRIPT 2005;46:57–64. doi:10.1016/j.jacc.2005.03.051. [8]
Costanzo MR, Johannes RS, Pine M, Gupta V, Saltzberg M, Hay J, et al. The safety of intravenous diuretics alone versus diuretics plus parenteral vasoactive therapies in hospitalized patients with acutely decompensated
T
heart failure: A propensity score and instrumental variable analysis using the
IP
Acutely Decompensated Heart Failure National Registry (ADHERE) database.
Katz AM, Konstam MA. Heart failure: pathophysiology, molecular biology, and
US
[9]
CR
Am Heart J 2007;154:267–77. doi:10.1016/j.ahj.2007.04.033.
clinical management. 2nd ed. Philadelphia: Wolters Kluwer Health/Lippincott
AN
Williams & Wilkins; 2009.
[10] Mann DL. Mechanisms and Models in Heart Failure: The Biomechanical Model
M
and Beyond. Circulation 2005;111:2837–49.
ED
doi:10.1161/CIRCULATIONAHA.104.500546.
PT
[11] Effect of Enalapril on Survival in Patients with Reduced Left Ventricular Ejection Fractions and Congestive Heart Failure. N Engl J Med 1991;325:293–
CE
302. doi:10.1056/NEJM199108013250501.
AC
[12] Pitt B, Zannad F, Remme WJ, Cody R, Castaigne A, Perez A, et al. The Effect of Spironolactone on Morbidity and Mortality in Patients with Severe Heart Failure. N Engl J Med 1999;341:709–17. doi:10.1056/NEJM199909023411001. [13] Packer M, Fowler MB, Roecker EB, Coats AJS, Katus HA, Krum H, et al. Effect of Carvedilol on the Morbidity of Patients With Severe Chronic Heart Failure. Circulation 2002;106.
ACCEPTED MANUSCRIPT [14] Shaddy RE, Tani LY, Gidding SS, Pahl E, Orsmond GS, Gilbert EM, et al. Betablocker treatment of dilated cardiomyopathy with congestive heart failure in children: a multi-institutional experience. J Hear Lung Transplant 1999;18:269–74. doi:10.1016/S1053-2498(98)00030-8.
T
[15] Bruns LA, Chrisant MK, Lamour JM, Shaddy RE, Pahl E, Blume ED, et al.
IP
Carvedilol as therapy in pediatric heart failure: An initial multicenter
CR
experience. J Pediatr 2001;138:505–11. doi:10.1067/mpd.2001.113045.
US
[16] Rusconi P, Gómez-Marín O, Rossique-González M, Redha E, Marín JR, LonYoung M, et al. Carvedilol in children with cardiomyopathy: 3-year experience
AN
at a single institution. J Hear Lung Transplant 2004;23:832–8. doi:10.1016/j.healun.2003.07.025.
M
[17] Azeka E, Antonio Franchini Ramires J, Valler C, Alcides Bocchi E, Paulo S.
ED
Delisting of Infants and Children From the Heart Transplantation Waiting List
PT
After Carvedilol Treatment. J Am Coll Cardiol 2002;40:2034–8. doi:10.1016/S0735-1097(02)02570-6.
CE
[18] Blume ED, Canter CE, Spicer R, Gauvreau K, Colan S, Jenkins KJ. Prospective
AC
Single-Arm Protocol of Carvedilol in Children with Ventricular Dysfunction. Pediatr Cardiol 2006;27:336–42. doi:10.1007/s00246-005-1159-1. [19] Bajcetic M, Samardzic R. Effects of Carvedilol on Left Ventricular Function and Oxidative Stress in Infants and Children with Idiopathic Dilated Cardiomyopathy: A 12-Month, Two-Center, Open-Label Study. Clin Ther Ther 2008;30:702–14. [20] Stern H, Weil J, Genz T, Vogt W, Bühlmeyer K. Captopril in children with
ACCEPTED MANUSCRIPT dilated cardiomyopathy: Acute and long-term effects in a prospective study of hemodynamic and hormonal effects. Pediatr Cardiol 1990;11:22–8. doi:10.1007/BF02239543. [21] Eronen M, Pesonen E, Wallgren EI, Tikkanen I, Fyhrquist F, Andersson S.
T
Enalapril in children with congestive heart failure. Acta Paediatr Scand
IP
1991;80:555–8.
CR
[22] Lewis AB, Chabot M. The effect of treatment with angiotensin-converting
US
enzyme inhibitors on survival of pediatric patients with dilated cardiomyopathy. Pediatr Cardiol 1993;14:9–12. doi:10.1007/BF00794837.
AN
[23] Shaddy RE, Boucek MM, Hsu DT, Boucek RJ, Canter CE, Mahony L, et al. Carvedilol for Children and Adolescents With Heart Failure: A Randomized
M
Controlled Trial. JAMA 2007;298:1171. doi:10.1001/jama.298.10.1171.
ED
[24] Hsu DT, Zak V, Mahony L, Sleeper LA, Atz AM, Levine JC, et al. Enalapril in
PT
Infants With Single Ventricle: Results of a Multicenter Randomized Trial. Circulation 2010;122:333–40. doi:10.1161/CIRCULATIONAHA.109.927988.
CE
[25] Kantor PF, Abraham JR, Dipchand AI, Benson LN, Redington AN. The Impact of
AC
Changing Medical Therapy on Transplantation-Free Survival in Pediatric Dilated Cardiomyopathy n.d. doi:10.1016/j.jacc.2009.11.059. [26] McKie PM, Burnett JC. NT-proBNP: The Gold Standard Biomarker in Heart Failure. J Am Coll Cardiol 2016;68:2437–9. doi:10.1016/j.jacc.2016.10.001. [27] Intravenous Nesiritide vs Nitroglycerin for Treatment of Decompensated Congestive Heart Failure: A Randomized Controlled Trial. JAMA 2002;287. doi:10.1001/jama.287.12.1531.
ACCEPTED MANUSCRIPT [28] O’Connor CM, Starling RC, Hernandez AF, Armstrong PW, Dickstein K, Hasselblad V, et al. Effect of Nesiritide in Patients with Acute Decompensated Heart Failure. N Engl J Med 2011;365:32–43. doi:10.1056/NEJMoa1100171. [29] Braunwald E. The path to an angiotensin receptor antagonist-neprilysin
T
inhibitor in the treatment of heart failure. J Am Coll Cardiol 2015;65:1029–41.
IP
doi:10.1016/j.jacc.2015.01.033.
CR
[30] Vardeny O, Miller R, Solomon SD. Combined neprilysin and renin-angiotensin
US
system inhibition for the treatment of heart failure. JACC Hear Fail 2014;2:663–70. doi:10.1016/j.jchf.2014.09.001.
AN
[31] McMurray JJV, Packer M, Desai AS, Gong J, Lefkowitz MP, Rizkala AR, et al. Angiotensin–Neprilysin Inhibition versus Enalapril in Heart Failure. N Engl J
M
Med 2014;371:993–1004. doi:10.1056/NEJMoa1409077.
ED
[32] Shaddy R., Canter C., Halnon N., Kochilas L., Rossano J., Bonnet D., Brush C.,
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Zhao Z., Kantor P., Burch M. CF. Design for the sacubitril/valsartan (LCZ 696) compared with enalapril study of pediatric patients with heart failure due to
CE
systemic left ventricular systolic dysfunction (PANORAMA-HF study). Am
AC
Heart J n.d.
[33] Dschietzig T. Relaxin, a Pregnancy Hormone, Is a Functional Endothelin-1 Antagonist: Attenuation of Endothelin-1-Mediated Vasoconstriction by Stimulation of Endothelin Type-B Receptor Expression via ERK-1/2 and Nuclear Factor-kappaB. Circ Res 2003;92:32–40. doi:10.1161/01.RES.0000051884.27117.7E. [34] Teerlink JR, Cotter G, Davison BA, Felker GM, Filippatos G, Greenberg BH, et al.
ACCEPTED MANUSCRIPT Serelaxin, recombinant human relaxin-2, for treatment of acute heart failure (RELAX-AHF): a randomised, placebo-controlled trial. Lancet (London, England) 2013;381:29–39. doi:10.1016/S0140-6736(12)61855-8. [35] Tietjens J, Teerlink JR. Serelaxin and acute heart failure. Heart 2016;102:95–9.
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doi:10.1136/heartjnl-2014-306786.
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[36] SERELAXIN FAILS TO MEET PRIMARY ENDPOINTS IN PHASE 3 RELAX-AHF-2
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TRIAL. 2017.
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[37] Verbrugge FH, Steels P, Grieten L, Nijst P, Tang WHW, Mullens W. Hyponatremia in acute decompensated heart failure: Depletion versus
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dilution. J Am Coll Cardiol 2015;65:480–92. doi:10.1016/j.jacc.2014.12.010. [38] Konstam MA, Gheorghiade M, Burnett JC, Grinfeld L, Maggioni AP, Swedberg
M
K, et al. Effects of oral tolvaptan in patients hospitalized for worsening heart
ED
failure: the EVEREST Outcome Trial. JAMA 2007;297:1319–31.
PT
doi:10.1001/jama.297.12.1319. [39] Reddy S. Failure of Right Ventricular Adaptation in Children With Tetralogy of
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Fallot. Circulation 2006;114:I-37-I-42.
AC
doi:10.1161/CIRCULATIONAHA.105.001248. [40] Miyamoto SD, Stauffer BL, Nakano S, Sobus R, Nunley K, Nelson P, et al. Betaadrenergic adaptation in paediatric idiopathic dilated cardiomyopathy. Eur Heart J 2014;35:33–41. doi:10.1093/eurheartj/ehs229.
ACCEPTED MANUSCRIPT Figure Legend Figure 1[3] The kidney’s role in causing fluid overload has been proposed since the 16th century, but became clinically relevant in the 1920’s with Saxl and Helling’s discovery of the
T
diuretic properties of organic mercurials and the ensuing development of thiazide
IP
and loop diuretics. In the coming years, Wigger’s work on hemodynamics in animal
CR
models was incorporated into clinical practice through the development of cardiac
US
catheterization and cardiac surgery. Myocardiality contractility was first described by Sarnoff in 1955, and in 1967 Braunwald recognized how its depression was
AN
implicated in heart failure.
M
Figure 2 [3]
ED
As evidence mounted that impaired myocardial contractility played an important
PT
role in the development of heart failure, emphasis shifted to the use of inotropes and vasodilators. While initial short term clinical trials seemed to show an improvement
CE
in both hemodynamics and symptoms, the use of inotropes was ultimately shown to
AC
worsen prognosis. In the early 1990’s, the emphasis shifted to the maladaptive process of the hypertrophic response, and the role of angiotensin II and myosin mutations in stimulating hypertrophy was shown.
Figure 3 [10] In this model an initial index event provokes impaired pumping function of the heart. This decline in function prompts changes in the RAAS, adrenergic nervous
ACCEPTED MANUSCRIPT system and cytokine systems, which upregulate in order to restore function and keep patients asymptomatic. However, these compensatory mechanisms also have negative impacts on cardiac remodeling and offer areas to target therapeutically.
T
Figure 4 [3]
IP
In the 1990’s evidence mounted that vasodilators worsened prognosis, and beta
CR
blockers were shown to improve survival despite their negative inotropic action,
US
both likely through their mediation of neurohormonal pathways.
AN
Figure 5 [23]
A double blind randomized control trial comparing carvedilol to placebo in pediatric
PT
ED
in mortality of hospitalization.
M
patients with symptomatic heart failure did not show clinically significant difference
Figure 6 [24]
CE
A multi-center randomized control trial evaluating the use of enalapril in the single
AC
ventricle population demonstrated no difference in LOWESS (locally weighted scatterplot smoothing) curves of weight-for age z score in children treated with enalapril vs. those without.
Figure 7 [30] LCZ 696 is comprised of two molecular components; the angiotensin receptor blocker valsartan and the neprilysin inhibitor prodrug sacubitril. Valsartan inhibits
ACCEPTED MANUSCRIPT the RAAS system by blocking AT1 while sacubtril is enzymatically converted to an active neprilysin inhibitor to prevent the breakdown of natriuretic peptides.
Figure 8 [32]
T
Shown is the study design of a double-blinded trial to assess the results of LCZ696
CR
IP
vs. enalapril in the pediatric population.
US
Figure 9 [35]
The potential benefits of increasing the concentration of circulating relaxin in
AN
patients with heart failure include improved renal function and lower SVR, reduced
AC
CE
PT
ED
M
inflammation, oxidative stress and apoptosis, and decreased fibrosis.
ACCEPTED MANUSCRIPT
PT
ED
M
AN
US
CR
IP
T
Figure 1: The Role of the Kidney [3]
CE
The kidney’s role in causing fluid overload has been proposed since the 16th century, but became clinically relevant in the 1920’s with Saxl and Helling’s discovery of the
AC
diuretic properties of organic mercurials and the ensuing development of thiazide and loop diuretics. In the coming years, Wigger’s work on hemodynamics in animal models was incorporated into clinical practice through the development of cardiac catheterization and cardiac surgery. Myocardiality contractility was first described by Sarnoff in 1955, and in 1967 Braunwald recognized how its depression was implicated in heart failure.
ACCEPTED MANUSCRIPT
CE
PT
ED
M
AN
US
CR
IP
T
Figure 2: The Rise and Fall of Inotropic Therapy [3]
As evidence mounted that impaired myocardial contractility played an important
AC
role in the development of heart failure, emphasis shifted to the use of inotropes and vasodilators. While initial short term clinical trials seemed to show an improvement in both hemodynamics and symptoms, the use of inotropes was ultimately shown to worsen prognosis. In the early 1990’s, the emphasis shifted to the maladaptive process of the hypertrophic response, and the role of angiotensin II and myosin mutations in stimulating hypertrophy was shown.
ACCEPTED MANUSCRIPT
CE
PT
ED
M
AN
US
CR
IP
T
Figure 3: The Body’s Response to Myocardial Injury [10]
AC
In this model an initial index event provokes impaired pumping function of the heart. This decline in function prompts changes in the RAAS, adrenergic nervous system and cytokine systems, which upregulate in order to restore function and keep patients asymptomatic. However, these compensatory mechanisms also have negative impacts on cardiac remodeling and offer areas to target therapeutically.
ACCEPTED MANUSCRIPT
AC
CE
PT
ED
M
AN
US
CR
IP
T
Figure 4: A Growing Awareness of Neurohormonal Pathways [3]
In the 1990’s evidence mounted that vasodilators worsened prognosis, and beta blockers were shown to improve survival despite their negative inotropic action, both likely through their mediation of neurohormonal pathways.
ACCEPTED MANUSCRIPT
M
AN
US
CR
IP
T
Figure 5: The Pediatric Randomized Carvedilol Trial [23]
ED
A double blind randomized control trial comparing carvedilol to placebo in pediatric patients with symptomatic heart failure did not show clinically significant difference
AC
CE
PT
in mortality of hospitalization.
ACCEPTED MANUSCRIPT
PT
ED
M
AN
US
CR
IP
T
Figure 6: The Use of Enalapril in the Single Ventricle Population [24]
CE
A multi-center randomized control trial evaluating the use of enalapril in the single
AC
ventricle population demonstrated no difference in LOWESS (locally weighted scatterplot smoothing) curves of weight-for age z score in children treated with enalapril vs. those without.
ACCEPTED MANUSCRIPT Figure 7: Targets of a Combined Angiotensin Receptor Blocker Valsartan and the
AC
CE
PT
ED
M
AN
US
CR
IP
T
Neprilysin Inhibitor [30]
LCZ 696 is comprised of two molecular components; the angiotensin receptor blocker valsartan and the neprilysin inhibitor prodrug sacubitril. Valsartan inhibits the RAAS system by blocking AT1 while sacubtril is enzymatically converted to an active neprilysin inhibitor to prevent the breakdown of natriuretic peptides.
ACCEPTED MANUSCRIPT
ED
M
AN
US
CR
IP
T
Figure 8: A Pediatric Trial of LCZ696 [32]
PT
Shown is the study design of a double-blinded trial to assess the results of LCZ696
AC
CE
vs. enalapril in the pediatric population.
ACCEPTED MANUSCRIPT
PT
ED
M
AN
US
CR
IP
T
Figure 9: Targets of Serelaxin [35]
CE
The potential benefits of increasing the concentration of circulating relaxin in
AC
patients with heart failure include improved renal function and lower SVR, reduced inflammation, oxidative stress and apoptosis, and decreased fibrosis.
ACCEPTED MANUSCRIPT [1]
Rossano JW, Shaddy RE. Heart Failure in Children: Etiology and Treatment. J Pediatr 2014;165:228–33. doi:10.1016/j.jpeds.2014.04.055.
[2]
Rossano JW, Shaddy RE. Update on Pharmacological Heart Failure Therapies in Children: Do Adult Medications Work in Children and if Not, Why Not?
Yellon L, Opie D, editors. Cardiology At the Limits IV. London: University of
Packer M, Carver JR, Rodeheffer RJ, Ivanhoe RJ, DiBianco R, Zeldis SM, et al.
US
[4]
CR
Cape Town and University College, London; 2001.
IP
[3]
T
Circulation 2014;129:607–12. doi:10.1161/CIRCULATIONAHA.113.003615.
Effect of Oral Milrinone on Mortality in Severe Chronic Heart Failure. N Engl J
[5]
AN
Med 1991;325:1468–75. doi:10.1056/NEJM199111213252103. Cuffe MS, Califf RM, Kirkwood F. Adams J, Benza R, Bourge R, Colucci WS, et al.
M
Short-term Intravenous Milrinone for Acute Exacerbation of Chronic Heart
ED
Failure
[6]
PT
JAMA 2002;287:1541. doi:10.1001/jama.287.12.1541. Felker GM, Benza RL, Chandler AB, Leimberger JD, Cuffe MS, Califf RM, et al.
CE
Heart failure etiology and response tomilrinone in decompensated heart
AC
failure. J Am Coll Cardiol 2003;41:997–1003. doi:10.1016/S07351097(02)02968-6. [7]
Abraham WT, Adams KF, Fonarow GC, Costanzo MR, Berkowitz RL, LeJemtel TH, et al. In-Hospital Mortality in Patients With Acute Decompensated Heart Failure Requiring Intravenous Vasoactive Medications. J Am Coll Cardiol 2005;46:57–64. doi:10.1016/j.jacc.2005.03.051.
[8]
Costanzo MR, Johannes RS, Pine M, Gupta V, Saltzberg M, Hay J, et al. The
ACCEPTED MANUSCRIPT safety of intravenous diuretics alone versus diuretics plus parenteral vasoactive therapies in hospitalized patients with acutely decompensated heart failure: A propensity score and instrumental variable analysis using the Acutely Decompensated Heart Failure National Registry (ADHERE) database.
Katz AM, Konstam MA. Heart failure: pathophysiology, molecular biology, and
IP
[9]
T
Am Heart J 2007;154:267–77. doi:10.1016/j.ahj.2007.04.033.
CR
clinical management. 2nd ed. Philadelphia: Wolters Kluwer Health/Lippincott
US
Williams & Wilkins; 2009.
[10] Mann DL. Mechanisms and Models in Heart Failure: The Biomechanical Model
AN
and Beyond. Circulation 2005;111:2837–49.
doi:10.1161/CIRCULATIONAHA.104.500546.
M
[11] Effect of Enalapril on Survival in Patients with Reduced Left Ventricular
ED
Ejection Fractions and Congestive Heart Failure. N Engl J Med 1991;325:293–
PT
302. doi:10.1056/NEJM199108013250501. [12] Pitt B, Zannad F, Remme WJ, Cody R, Castaigne A, Perez A, et al. The Effect of
CE
Spironolactone on Morbidity and Mortality in Patients with Severe Heart
AC
Failure. N Engl J Med 1999;341:709–17. doi:10.1056/NEJM199909023411001. [13] Packer M, Fowler MB, Roecker EB, Coats AJS, Katus HA, Krum H, et al. Effect of Carvedilol on the Morbidity of Patients With Severe Chronic Heart Failure. Circulation 2002;106. [14] Shaddy RE, Tani LY, Gidding SS, Pahl E, Orsmond GS, Gilbert EM, et al. Betablocker treatment of dilated cardiomyopathy with congestive heart failure in
ACCEPTED MANUSCRIPT children: a multi-institutional experience. J Hear Lung Transplant 1999;18:269–74. doi:10.1016/S1053-2498(98)00030-8. [15] Bruns LA, Chrisant MK, Lamour JM, Shaddy RE, Pahl E, Blume ED, et al. Carvedilol as therapy in pediatric heart failure: An initial multicenter
T
experience. J Pediatr 2001;138:505–11. doi:10.1067/mpd.2001.113045.
IP
[16] Rusconi P, Gómez-Marín O, Rossique-González M, Redha E, Marín JR, Lon-
CR
Young M, et al. Carvedilol in children with cardiomyopathy: 3-year experience
doi:10.1016/j.healun.2003.07.025.
US
at a single institution. J Hear Lung Transplant 2004;23:832–8.
AN
[17] Azeka E, Antonio Franchini Ramires J, Valler C, Alcides Bocchi E, Paulo S. Delisting of Infants and Children From the Heart Transplantation Waiting List
M
After Carvedilol Treatment. J Am Coll Cardiol 2002;40:2034–8.
ED
doi:10.1016/S0735-1097(02)02570-6.
PT
[18] Blume ED, Canter CE, Spicer R, Gauvreau K, Colan S, Jenkins KJ. Prospective Single-Arm Protocol of Carvedilol in Children with Ventricular Dysfunction.
CE
Pediatr Cardiol 2006;27:336–42. doi:10.1007/s00246-005-1159-1.
AC
[19] Bajcetic M, Samardzic R. Effects of Carvedilol on Left Ventricular Function and Oxidative Stress in Infants and Children with Idiopathic Dilated Cardiomyopathy: A 12-Month, Two-Center, Open-Label Study. Clin Ther Ther 2008;30:702–14. [20] Stern H, Weil J, Genz T, Vogt W, Bühlmeyer K. Captopril in children with dilated cardiomyopathy: Acute and long-term effects in a prospective study of hemodynamic and hormonal effects. Pediatr Cardiol 1990;11:22–8.
ACCEPTED MANUSCRIPT doi:10.1007/BF02239543. [21] Eronen M, Pesonen E, Wallgren EI, Tikkanen I, Fyhrquist F, Andersson S. Enalapril in children with congestive heart failure. Acta Paediatr Scand 1991;80:555–8.
T
[22] Lewis AB, Chabot M. The effect of treatment with angiotensin-converting
IP
enzyme inhibitors on survival of pediatric patients with dilated
CR
cardiomyopathy. Pediatr Cardiol 1993;14:9–12. doi:10.1007/BF00794837.
US
[23] Shaddy RE, Boucek MM, Hsu DT, Boucek RJ, Canter CE, Mahony L, et al. Carvedilol for Children and Adolescents With Heart Failure: A Randomized
AN
Controlled Trial. JAMA 2007;298:1171. doi:10.1001/jama.298.10.1171. [24] Hsu DT, Zak V, Mahony L, Sleeper LA, Atz AM, Levine JC, et al. Enalapril in
M
Infants With Single Ventricle: Results of a Multicenter Randomized Trial.
ED
Circulation 2010;122:333–40. doi:10.1161/CIRCULATIONAHA.109.927988.
PT
[25] Kantor PF, Abraham JR, Dipchand AI, Benson LN, Redington AN. The Impact of Changing Medical Therapy on Transplantation-Free Survival in Pediatric
CE
Dilated Cardiomyopathy n.d. doi:10.1016/j.jacc.2009.11.059.
AC
[26] McKie PM, Burnett JC. NT-proBNP: The Gold Standard Biomarker in Heart Failure. J Am Coll Cardiol 2016;68:2437–9. doi:10.1016/j.jacc.2016.10.001. [27] Intravenous Nesiritide vs Nitroglycerin for Treatment of Decompensated Congestive Heart Failure: A Randomized Controlled Trial. JAMA 2002;287. doi:10.1001/jama.287.12.1531. [28] O’Connor CM, Starling RC, Hernandez AF, Armstrong PW, Dickstein K, Hasselblad V, et al. Effect of Nesiritide in Patients with Acute Decompensated
ACCEPTED MANUSCRIPT Heart Failure. N Engl J Med 2011;365:32–43. doi:10.1056/NEJMoa1100171. [29] Braunwald E. The path to an angiotensin receptor antagonist-neprilysin inhibitor in the treatment of heart failure. J Am Coll Cardiol 2015;65:1029–41. doi:10.1016/j.jacc.2015.01.033.
T
[30] Vardeny O, Miller R, Solomon SD. Combined neprilysin and renin-angiotensin
CR
2014;2:663–70. doi:10.1016/j.jchf.2014.09.001.
IP
system inhibition for the treatment of heart failure. JACC Hear Fail
US
[31] McMurray JJV, Packer M, Desai AS, Gong J, Lefkowitz MP, Rizkala AR, et al. Angiotensin–Neprilysin Inhibition versus Enalapril in Heart Failure. N Engl J
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ACCEPTED MANUSCRIPT Highlights The review will highlight new medicaitons including Sacubtril-valsartan, a combined angiotensin-neprilysin inhibitor shows great clinical promise, and others including recombinant relaxin-2 and vasopressin antagonists. This article will
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review the history of posited mechanisms of heart failure and the impact on
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treatment, novel therapeutic options with neurohormonal targets, and the
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challenges of developing therapies for the pediatric heart failure population.