The Genetics of Pulmonary Arterial Hypertension Austin, Eric D; Loyd, James E
Circulation research,
2014-June-20, 2014-Jun-20, 2014-06-20, 20140620, Letnik:
115, Številka:
1
Journal Article
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Pulmonary arterial hypertension (PAH) is a progressive and fatal disease for which there is an ever-expanding body of genetic and related pathophysiological information on disease pathogenesis. Many ...germline gene mutations have now been described, including mutations in the gene coding bone morphogenic protein receptor type 2 (BMPR2) and related genes. Recent advanced gene-sequencing methods have facilitated the discovery of additional genes with mutations among those with and those without familial forms of PAH (CAV1, KCNK3, EIF2AK4). The reduced penetrance, variable expressivity, and female predominance of PAH suggest that genetic, genomic, and other factors modify disease expression. These multi-faceted variations are an active area of investigation in the field, including but not limited to common genetic variants and epigenetic processes, and may provide novel opportunities for pharmacological intervention in the near future. They also highlight the need for a systems-oriented multi-level approach to incorporate the multitude of biological variations now associated with PAH. Ultimately, an in-depth understanding of the genetic factors relevant to PAH provides the opportunity for improved patient and family counseling about this devastating disease.
Bronchopulmonary dysplasia (BPD) is a major complication in prematurely born infants. Pulmonary hypertension (PH) associated with BPD (BPD-PH) is characterized by alveolar diffusion impairment, ...abnormal vascular remodeling, and rarefication of pulmonary vessels (vascular growth arrest), which lead to increased pulmonary vascular resistance and right heart failure. About 25% of infants with moderate to severe BPD develop BPD-PH that is associated with high morbidity and mortality. The recent evolution of broader PH-targeted pharmacotherapy in adults has opened up new treatment options for infants with BPD-PH. Sildenafil became the mainstay of contemporary BPD-PH therapy. Additional medications, such as endothelin receptor antagonists and prostacyclin analogs/mimetics, are increasingly being investigated in infants with PH. However, pediatric data from prospective or randomized controlled trials are still sparse. We discuss comprehensive diagnostic and therapeutic strategies for BPD-PH and briefly review the relevant differential diagnoses of parenchymal and interstitial developmental lung diseases. In addition, we provide a practical framework for the management of children with BPD-PH, incorporating the modified definition and classification of pediatric PH from the 2018 World Symposium on Pulmonary Hypertension, and the 2019 EPPVDN consensus recommendations on established and newly developed therapeutic strategies. Finally, current gaps of knowledge and future research directions are discussed. IMPACT: PH in BPD substantially increases mortality. Treatment of BPD-PH should be conducted by an interdisciplinary team and follow our new treatment algorithm while still kept tailored to the individual patient. We discuss recent developments in BPD-PH, make recommendations on diagnosis, monitoring and treatment of PH in BPD, and address current gaps of knowledge and potential research directions. We provide a practical framework, including a new treatment algorithm, for the management of children with BPD-PH, incorporating the modified definition and classification of pediatric PH (2018 WSPH) and the 2019 EPPVDN consensus recommendations on established and newly developed therapeutic strategies for BPD-PH.
Pulmonary arterial hypertension (PAH) is a disease characterized by progressive loss and remodeling of the pulmonary arteries, resulting in right heart failure and death. Until recently, PAH was seen ...as a disease restricted to the pulmonary circulation. However, there is growing evidence that patients with PAH also exhibit systemic vascular dysfunction, as evidenced by impaired brachial artery flow-mediated dilation, abnormal cerebral blood flow, skeletal myopathy, and intrinsic kidney disease. Although some of these anomalies are partially due to right ventricular insufficiency, recent data support a mechanistic link to the genetic and molecular events behind PAH pathogenesis. This review serves as an introduction to the major systemic findings in PAH and the evidence that supports a common mechanistic link with PAH pathophysiology. In addition, it discusses recent studies describing morphological changes in systemic vessels and the possible role of bronchopulmonary anastomoses in the development of plexogenic arteriopathy. On the basis of available evidence, we propose a paradigm in which metabolic abnormalities, genetic injury, and systemic vascular dysfunction contribute to systemic manifestations in PAH. This concept not only opens exciting research possibilities but also encourages clinicians to consider extrapulmonary manifestations in their management of patients with PAH.
In this scientific statement from the American Heart Association, experts in the field of cardiomyopathy (heart muscle disease) in children address 2 issuesthe most current understanding of the ...causes of cardiomyopathy in children and the optimal approaches to diagnosis cardiomyopathy in children. Cardiomyopathies result in some of the worst pediatric cardiology outcomes; nearly 40% of children who present with symptomatic cardiomyopathy undergo a heart transplantation or die within the first 2 years after diagnosis. The percentage of children with cardiomyopathy who underwent a heart transplantation has not declined over the past 10 years, and cardiomyopathy remains the leading cause of transplantation for children >1 year of age. Studies from the National Heart, Lung, and Blood Institute–funded Pediatric Cardiomyopathy Registry have shown that causes are established in very few children with cardiomyopathy, yet genetic causes are likely to be present in most. The incidence of pediatric cardiomyopathy is ≈1 per 100 000 children. This is comparable to the incidence of such childhood cancers as lymphoma, Wilms tumor, and neuroblastoma. However, the published research and scientific conferences focused on pediatric cardiomyopathy are sparcer than for those cancers. The aim of the statement is to focus on the diagnosis and classification of cardiomyopathy. We anticipate that this report will help shape the future research priorities in this set of diseases to achieve earlier diagnosis, improved clinical outcomes, and better quality of life for these children and their families.
The European Pediatric Pulmonary Vascular Disease Network is a registered, non-profit organization that strives to define and develop effective, innovative diagnostic methods and treatment options in ...all forms of pediatric pulmonary hypertensive vascular disease, including pulmonary hypertension (PH) associated with bronchopulmonary dysplasia, PH associated with congenital heart disease (CHD), persistent PH of the newborn, and related cardiac dysfunction. The executive writing group members conducted searches of the PubMed/MEDLINE bibliographic database (1990-2018) and held face-to-face and web-based meetings. Ten section task forces voted on the updated recommendations, based on the 2016 executive summary. Clinical trials, meta-analyses, guidelines, and other articles that include pediatric data were searched using the term "pulmonary hypertension" and other keywords. Class of recommendation (COR) and level of evidence (LOE) were assigned based on European Society of Cardiology/American Heart Association definitions and on pediatric data only, or on adult studies that included >10% children or studies that enrolled adults with CHD. New definitions by the World Symposium on Pulmonary Hypertension 2018 were included. We generated 10 tables with graded recommendations (COR/LOE). The topics include diagnosis/monitoring, genetics/biomarkers, cardiac catheterization, echocardiography, cardiac magnetic resonance/chest computed tomography, associated forms of PH, intensive care unit/lung transplantation, and treatment of pediatric PH. For the first time, a set of specific recommendations on the management of PH in middle- and low-income regions was developed. Taken together, these executive, up-to-date guidelines provide a specific, comprehensive, detailed but practical framework for the optimal clinical care of children and young adults with PH.
The authors looks on the study of Hirsch and colleagues who provide additional preclinical evidence underscoring the therapeutic efficacy of HIF stabilization in attenuation and prevention of BPD. By ...combining intraamniotic injection of Escherichia coli endotoxin (mimicking human chorioamnionitis) and preterm delivery, the authors sought to determine whether prenatal stressors are sufficient to compromise alveolar development in the offspring and whether this anticipated defect could be rescue by activation of HIFs. As the authors anticipated, reduced expression of HIF-1 and HIF-2 and their target genes (VEGF and endothelial nitric oxide synthase) decreased pulmonary vascular density, increased airspace enlargement, and increased right ventricular hypertrophy (RVH) were noticed in 14-day-old pups maternally exposed to endotoxin. Remarkably, all of these abnormalities were partially or completely cancelled on antenatal or postnatal inhibition of PHDs with dimethyloxalylglycine or GSK360A. The group demonstrated that postnatal supplementation in IGF-1 (insulin-like growth factor 1) and its binding protein IGFBP-3, a PHD-independent positive regulator of HIF-1 expression, significantly preserves lung structure and function and prevents RVH in three different animal models of BPD, including intraamniotic injection of endotoxin. Furthermore, the authors emphasized that the findings validate promising results of a phase 2 randomized controlled trial (NCT 01096784) reporting a decrease in the occurrence of severe BPD in extremely preterm infants receiving continuous intravenous infusion of IGF-1/IGFBP-3.
Bronchopulmonary dysplasia (BPD) is the most common chronic lung disease of prematurity resulting from complex interactions of perinatal factors that often lead to prolonged respiratory support and ...increased pulmonary morbidity. There is also growing appreciation for the dysmorphic pulmonary bed characterized by vascular growth arrest and remodeling, resulting in pulmonary vascular disease and its most severe form, pulmonary hypertension (PH) in children with BPD. In this review, we comprehensively discuss the pathophysiology of PH in children with BPD, evaluate the current recommendations for screening and diagnosis of PH, discern associated comorbid conditions, and outline the current treatment options.
Pulmonary arterial hypertension (PAH) is a disease that is typically fatal within 5-7 years of diagnosis for most subjects and occurs in all ancestral populations. The paper by Karnes et al. explore ...the role of race and ethnicity in PAH. They determined ancestry in patients with PAH using genetic markers by incorporating information contained in several large US datasets. Intriguingly, in survival analyses, self-reported Hispanic status in both the PAH Biobank and Allegheny Health Network cohorts was associated with a statistically significantly improved transplant-free survival. It does not appear that survival was modified by genetic ancestry according to the a priori level of statistical significance.
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