Update on Pharmacological Heart Failure Therapies in Children

Rossano, Joseph W.; Shaddy, Robert E.

doi:10.1161/circulationaha.113.003615

Cited by 34 publications

(14 citation statements)

References 68 publications

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“…In the presence of such abnormal loading conditions, the RV undergoes a maladaptive remodeling process characterized by chamber dilatation, hypertrophy, myocardial fibrosis, and ultimately failure (18). Existing medical therapies have been extrapolated from experience in adult patients and have not been shown to halt the ventricular remodeling process or promote systolic and diastolic functional recovery (31). In the event of progression to overt RV failure, heart transplantation remains the only definitive treatment.…”

Section: We Demonstrate For the First Time That Intramyocardial Injecmentioning

confidence: 99%

Mesenchymal stem cells preserve neonatal right ventricular function in a porcine model of pressure overload

Wehman

Sharma

Pietris

et al. 2016

American Journal of Physiology-Heart and Circulatory Physiology

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(MSCs) have not been evaluated in a preclinical model of pressure overload, which simulates the pathophysiology relevant to many forms of CHD. A neonatal swine model of RV pressure overload was utilized to test the hypothesis that MSCs preserve RV function and attenuate ventricular remodeling. Immunosuppressed Yorkshire swine underwent pulmonary artery banding to induce RV dysfunction. After 30 min, human MSCs (1 million cells, n ϭ 5) or placebo (n ϭ 5) were injected intramyocardially into the RV free wall. Serial transthoracic echocardiography monitored RV functional indices including 2D myocardial strain analysis. Four weeks postinjection, the MSC-treated myocardium had a smaller increase in RV end-diastolic area, end-systolic area, and tricuspid vena contracta width (P Ͻ 0.01), increased RV fractional area of change, and improved myocardial strain mechanics relative to placebo (P Ͻ 0.01). The MSC-treated myocardium demonstrated enhanced neovessel formation (P Ͻ 0.0001), superior recruitment of endogenous c-kitϩ cardiac stem cells to the RV (P Ͻ 0.0001) and increased proliferation of cardiomyocytes (P ϭ 0.0009) and endothelial cells (P Ͻ 0.0001). Hypertrophic changes in the RV were more pronounced in the placebo group, as evidenced by greater wall thickness by echocardiography (P ϭ 0.008), increased cardiomyocyte cross-sectional area (P ϭ 0.001), and increased expression of hypertrophy-related genes, including brain natriuretic peptide, ␤-myosin heavy chain and myosin light chain. Additionally, MSC-treated myocardium demonstrated increased expression of the antihypertrophy secreted factor, growth differentiation factor 15 (GDF15), and its downstream effector, SMAD 2/3, in cultured neonatal rat cardiomyocytes and in the porcine RV myocardium. This is the first report of the use of MSCs as a therapeutic strategy to preserve RV function and attenuate remodeling in the setting of pressure overload. Mechanistically, transplanted MSCs possibly stimulated GDF15 and its downstream SMAD proteins to antagonize the hypertrophy response of pressure overload. These encouraging results have implications in congenital cardiac pressure overload lesions. stem cell therapy; congenital heart disease; right ventricle; pressure overload CONGENITAL HEART DISEASE (CHD) is the leading cause of morbidity and mortality in children with birth defects. While surgical interventions have dramatically improved outcomes and longevity in patients with CHD, many patients still progress to heart failure, a population that has grown significantly over the last decade (30). In contrast to adult patients, in whom ischemic heart disease is the predominant etiology of heart failure, children with CHD are frequently exposed to acute or chronic ventricular pressure and volume overload, which if untreated can progress to ventricular dysfunction and ultimately to heart failure. Further, patients with CHD who develop right ventricular (RV) dysfunction have the poorest outcomes (23, 26), particularly in those patients with univentricular heart disease i...

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Section: We Demonstrate For the First Time That Intramyocardial Injecmentioning

confidence: 99%

Mesenchymal stem cells preserve neonatal right ventricular function in a porcine model of pressure overload

Wehman

Sharma

Pietris

et al. 2016

American Journal of Physiology-Heart and Circulatory Physiology

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“…It has been recognised that large observational studies, databases, and registries, when well designed, could represent an alternative means by which to generate the muchneeded clinical evidence. 7,40 The agreement on the veracity of these statements might also contribute to the efficient dissemination of relevant paediatric research to the physicians for whom this information is important, which has been found to be an area that needs to be improved. 41,42 Three of these statements considered the role of angiotensin-converting-enzyme-inhibitors in the context of…”

Section: Discussionmentioning

confidence: 99%

“…4,5 It is well known that conducting randomised clinical trials in the paediatric heart failure population poses many challenges and is often not possible. 6,7 Hence it is vital to consider alternative approaches to achieve safe and effective therapy. In this regard, the potential of qualified opinion has been underused, with few structured debates and expert consensus documents having been published.…”

mentioning

confidence: 99%

Pharmacotherapy in paediatric heart failure: a Delphi process

et al. 2019

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Background:Little evidence exists to support pharmacotherapeutic strategies for heart failure management in paediatrics. A recent Europe-wide survey suggests that this translates into substantial variability in clinical practice.Objective:To conduct a formal discussion among an expert group of paediatric cardiology physicians on controversial aspects regarding the pharmacotherapy of children heart failure, facilitate consensus, and highlight areas of agreement and disagreement.Methods:A two-round modified Delphi process was conducted between July and August 2015. Topics addressed were predominantly selected from the results of a previous Europe-wide survey. Fourteen statements were presented for discussion grouped under three categories; Angiotensin-converting-enzyme-inhibitors: Considerations for optimal dosage; Angiotensin-converting-enzyme-inhibitors for the management of CHDs; Neurohumoral antagonists for the management of dilated cardiomyopathy-related heart failure.Results:A total of 13 paediatricians dedicated to cardiology from across Europe and the United States of America completed the study; of them, 92% had a working experience in the field of more than 10 years and were working in a specific paediatric cardiology unit. Agreement on the acceptance/rejection of 11 statements was achieved. Results show agreement on the importance of a set of topics relevant to the standardisation of the therapy as well as consensus upon specific therapeutic attitudes.Conclusions:We have found areas of common thinking and motivation, which can provide a means of triggering scientific collaboration. Our results might also contribute to disseminate available paediatric evidence and promote reducing unjustified variability in everyday practice. Until solid evidence is available, other research methods can contribute to advancing the goal of safe and effective paediatric heart failure pharmacotherapy.

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“…Pharmacotherapy to prevent or treat myocardial failure in patients with single-ventricle physiology does not exist, underscoring the need for research to define the molecular mechanisms of this complex congenital heart lesion( 4 ). Treatment of adult heart failure (HF) has dramatically advanced over the past several decades, yet many of the drugs used to treat adult HF have not been proven to be beneficial in treating pediatric HF( 21 ). Part of the challenge lies in the fact that pediatric HF is a much more heterogeneous disease than in adults, with a low incidence of ischemic disease.…”

Section: Discussionmentioning

confidence: 99%

Histone deacetylase adaptation in single ventricle heart disease and a young animal model of right ventricular hypertrophy

et al. 2017

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BackgroundHistone deacetylase (HDAC) inhibitors are promising therapeutics for various forms of cardiac disease. The purpose of this study was to assess cardiac HDAC catalytic activity and expression in children with single ventricle heart disease of right ventricular morphology (SV), as well as in a rodent model of right ventricular hypertrophy (RVH).MethodsHomogenates of RV explants from non-failing controls and SV children were assayed for HDAC catalytic activity and HDAC isoform expression. Postnatal 1-day old rat pups were placed in hypoxic conditions and echocardiographic analysis, gene expression, HDAC catalytic activity and isoform expression studies of the RV were performed.ResultsClass I, IIa, and IIb HDAC catalytic activity and protein expression were elevated in hearts of SV children. Hypoxic neonatal rats demonstrated RVH, abnormal gene expression and elevated class I and class IIb HDAC catalytic activity and protein expression in the RV compared to control.ConclusionsThese data suggest that myocardial HDAC adaptations occur in the SV heart and could represent a novel therapeutic target. While further characterization of the hypoxic neonatal rat is needed, this animal model may be suitable for pre-clinical investigations of pediatric RV disease and could serve as a useful model for future mechanistic studies.

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Update on Pharmacological Heart Failure Therapies in Children

Cited by 34 publications

References 68 publications

Mesenchymal stem cells preserve neonatal right ventricular function in a porcine model of pressure overload

Mesenchymal stem cells preserve neonatal right ventricular function in a porcine model of pressure overload

Pharmacotherapy in paediatric heart failure: a Delphi process

Histone deacetylase adaptation in single ventricle heart disease and a young animal model of right ventricular hypertrophy

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