The Left Ventricle in Congenital Diaphragmatic Hernia: Implications for the Management of Pulmonary Hypertension

Kinsella, John P.; Steinhorn, Robin H.; Mullen, Mary P.; Hopper, Rachel K.; Keller, Roberta L.; Ivy, D. Dunbar; Austin, Eric D.; Krishnan, Usha; Rosenzweig, Erika B.; Fineman, Jeffrey R.; Everett, Allen D.; Hanna, Brian D.; Humpl, Tilman; Raj, J. Usha; Abman, Steven H.

doi:10.1016/j.jpeds.2018.02.040

Cited by 94 publications

(56 citation statements)

References 53 publications

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“…Collaboration across national and international clinical PH sites will be necessary to yield sufficient sample sizes due to the extremely small number of pediatric PAH patients at single PH sites, heterogeneity of risk genes for PAH, and need for ancestral diversity. PPHNet is an example of a pediatric-specific PAH consortium with ongoing recruitment across 13 North American clinical sites [ 74 , 75 , 76 , 77 , 78 ]. PVDomics [ 79 ], a US multicenter study launched in 2014, and PAH-ICON (pahicon.com), a new international effort, represent additional large-scale PAH cohorts.…”

Section: A Genomics First Approach Towards Better Understanding Ofmentioning

confidence: 99%

Genetics and Genomics of Pediatric Pulmonary Arterial Hypertension

Welch

Chung

2020

Genes

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Pulmonary arterial hypertension (PAH) is a rare disease with high mortality despite recent therapeutic advances. The disease is caused by both genetic and environmental factors and likely gene–environment interactions. While PAH can manifest across the lifespan, pediatric-onset disease is particularly challenging because it is frequently associated with a more severe clinical course and comorbidities including lung/heart developmental anomalies. In light of these differences, it is perhaps not surprising that emerging data from genetic studies of pediatric-onset PAH indicate that the genetic basis is different than that of adults. There is a greater genetic burden in children, with rare genetic factors contributing to ~42% of pediatric-onset PAH compared to ~12.5% of adult-onset PAH. De novo variants are frequently associated with PAH in children and contribute to at least 15% of all pediatric cases. The standard of medical care for pediatric PAH patients is based on extrapolations from adult data. However, increased etiologic heterogeneity, poorer prognosis, and increased genetic burden for pediatric-onset PAH calls for a dedicated pediatric research agenda to improve molecular diagnosis and clinical management. A genomics-first approach will improve the understanding of pediatric PAH and how it is related to other rare pediatric genetic disorders.

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Section: A Genomics First Approach Towards Better Understanding Ofmentioning

confidence: 99%

Genetics and Genomics of Pediatric Pulmonary Arterial Hypertension

Welch

Chung

2020

Genes

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“…Pulmonary hypoplasia and pulmonary hypertension, secondary to abnormal pulmonary vascular development, are key pathological findings. There is growing appreciation that cardiac dysfunction may also play an important role in CDH [2]. …”

Section: Introductionmentioning

confidence: 99%

Ventricular Dysfunction, Interdependence, and Mechanical Dispersion in Newborn Infants with Congenital Diaphragmatic Hernia

et al. 2019

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Background: Congenital diaphragmatic hernia (CDH) is an important cause of mortality and morbidity in the neonatal period. Pulmonary hypertension and pulmonary hypoplasia are key pathological findings. Cardiac function may also be an important determinant of disease severity, prognostic indicator, and therapeutic target in CDH. Objective: The aim of this study was to assess ventricular mechanics and synchrony in infants with CDH and controls using speckle tracking echocardiography (STE). Methods: Retrospective analysis was performed of echocardiograms obtained in the first 48 h of life in 27 infants with CDH and 20 controls. STE-derived longitudinal strain (LS) was measured in the right and left ventricles (RV, LV). Circumferential strain (CS) and radial strain (RS) were additionally measured in the LV. Mechanical dispersion (MD), a measure of synchrony, was assessed by calculation of the standard deviation of time to peak systolic strain in six ventricular segments. Results: RV LS and LV LS, LV CS, and LV RS were significantly reduced in CDH compared to controls. In the LV free wall, LS and RS were significantly reduced in CDH. LV LS correlated significantly with RV LS in CDH cases (r² = 0.37, p = 0.002), but not controls (r² = 0.19, p = 0.06). LV LS also correlated with LV MD in CDH (r² = 0.25, p = 0.01) but not controls (r² = 0.02, p = 0.54). Conclusions: Global impairment of RV and LV systolic function are present in newborn infants with CDH and are associated with primary left ventricular dysfunction, ventricular interdependence, and MD.

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“…This latter finding is in agreement with prior reports regarding impaired growth of the left ventricle with CDH. 4 Of all the markers evaluated, the LVIDd z-score showed the largest relative improvement from baseline. In the absence of an untreated comparison group, this improvement might be attributed as a potential benefit from the lusitropic effect of milrinone.…”

Section: Discussionmentioning

confidence: 93%

Is Milrinone Effective for Infants with Mild-to-Moderate Congenital Diaphragmatic Hernia?

2019

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Objective Pulmonary hypertension with left ventricular dysfunction commonly occurs in congenital diaphragmatic hernia (CDH). Milrinone, a phosphodiesterase-III inhibitor with lusitropic and vasodilator effects, is used in up to 30% of CDH infants across the United States. No randomized trials have tested the efficacy or safety of milrinone in CDH neonates. Study Design We performed a paired retrospective analysis of CDH infants to assess the efficacy of milrinone treatment (N = 24 pairs). Efficacy was assessed by change in oxygenation index (OI) and calculated pulmonary artery pressure (PAP). We evaluated safety on the basis of risks factors such as nonoperative bleeding, dysrhythmia, hypokalemia, and thrombocytopenia. Results The median age of milrinone initiation was 18 hours (interquartile range [IQR]: 9–38) and the median duration was 127 hours (IQR: 95–194). PAP did not change from the baseline of 49 ± 11 mm Hg (milrinone) and 53 ± 11 mm Hg (no milrinone; p = 0.327). Baseline OI was 9.6 ± 6.5. There was a similar decrease in OI (median [IQR]; milrinone: 58% [16–74]; vs. no milrinone: 65% [50–71]; p = 0.221 between groups; p < 0.005 within groups). Baseline left ventricle measurements were similar. Both groups showed significant improvement over time. No adverse events were noted. Conclusion In OI-matched untreated neonates with mild-to-moderate CDH, milrinone use was associated with neither improved OI, PAP, or left ventricular measurements, nor adverse events. Study limitations warrant prospective randomized controlled trials.

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The Left Ventricle in Congenital Diaphragmatic Hernia: Implications for the Management of Pulmonary Hypertension

Cited by 94 publications

References 53 publications

Genetics and Genomics of Pediatric Pulmonary Arterial Hypertension

Genetics and Genomics of Pediatric Pulmonary Arterial Hypertension

Ventricular Dysfunction, Interdependence, and Mechanical Dispersion in Newborn Infants with Congenital Diaphragmatic Hernia

Is Milrinone Effective for Infants with Mild-to-Moderate Congenital Diaphragmatic Hernia?

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