619CHAPTER 53 Diseases of the Pulmonary Circulation RVH and lowering right ventricular systolic pressure (RVSP) in experimental RVH 112,113 Neurohormonal activation is also evi dent in adults with CHD[.]
CHAPTER 53 Diseases of the Pulmonary Circulation RVH and lowering right ventricular systolic pressure (RVSP) in experimental RVH.112,113 Neurohormonal activation is also evident in adults with CHD.114 There are no randomized studies of adrenergic blockage in children with PAH or CHD Right Ventricle Ischemia Ischemic signs and symptoms are not uncommon in patients with PH and severe RVH In adults with PAH and RVF, angina-like chest pain, increased levels of BNP and even troponin indicate poor prognosis.115 An emerging theory in adult PAH is that some of the RV dysfunction may be due to myocardial hibernation (i.e., chronic reduction in RV perfusion leading to impaired function of viable myocardium).103 Supporting this, there is increased RV uptake of 18FDG (fluorodeoxyglucose) on PET scans in humans102,116 and rodents103 with PAH There is little direct evidence of ischemia in the pediatric PAH patient population; however, impaired myocardial flow reserve, consistent with an inadequate coronary blood supply relative to increased oxygen demand, often accompanies failure of the systemic RV (post– Mustard procedure).117–119 Moreover, there is a high prevalence (.50%) of both reversible and fixed perfusion defects with concordant regional wall motion abnormalities in the right (systemic) ventricle to decades post–Mustard repair of transposition of the great arteries, as detected by Sestamibi single-photon emission computerized tomography (SPECT).117 This suggests that late RV dysfunction may reflect RV ischemia,117 at least in this unusual patient population It has been suggested that impaired systolic filling of the right coronary artery (RCA) due to elevated RVSP is the predominant cause of RV ischemia.120,121 The potential contribution of epicardial coronary artery-induced RV ischemia has been demonstrated in acute PA banding models121 and humans with PAH.120 However, autoregulation of RCA likely means that this mechanism is relevant only at the extremes RV contractile function remains constant until perfusion pressures fall below 50 mm Hg.122 Moreover, the RCA perfuses the RV in both systole and diastole, and only the systolic phase is sensitive to elevated RVSP Arguing against impaired coronary perfusion pressure as the major cause of RV failure, pulmonary artery banding (PAB) rats and rats with monocrotaline-induced PH have similar RVH and similar elevation of RVSP, but PAB induces an adaptive RVH while monocrotaline causes a maladaptive RVH Thus, the maladaptive nature of monocrotaline-induced RVH cannot be explained by diminished coronary perfusion pressure.103 Microvascular rarefaction (attenuation of small vessel density in the RV) might contribute to the maladaptive RVH.104,123 If microvascular ischemia could be demonstrated in pediatric PAH, therapeutic strategies such as modulating metabolism to “do more with less”103 or promoting angiogenesis might be efficacious Studies using improved or more sensitive approaches (PET, MRI) are necessary to understand the RV microcirculation in pediatric PAH Metabolism in Right Ventricular Hypertrophy The predominant sources of adenosine triphosphate (ATP) production in the fetal heart are glycolysis and glucose oxidation In contrast, circulating fatty acid levels are low in the fetus.124 This metabolic fingerprint differs from the adult, where fatty acid oxidation accounts for most of the cardiac ATP (60%–90%) with glucose metabolism contributing (10%–40%).125 Interestingly, fatty acid oxidation comes at some cost For the same ATP 619 production, fatty acid oxidation requires roughly 12% more oxygen consumption/mol ATP than does glucose oxidation The normal RV can vary its substrate use from fatty acids to glucose as needed However, in RVH, there appears to be more reliance on glucose metabolism.126 In experimental RVH, the metabolic fate of glucose is altered with a shift away from glucose oxidation to glycolysis.103,125 Glycolysis begins with glucose uptake via its transporters (glut) Glycolytically derived nicotinamide adenine dinucleotide (NADH) serves as a substrate for the electron transport chain; pyruvate is transferred to the mitochondria, where it serves as a substrate for pyruvate dehydrogenase (PDH).127 Pyruvate is converted to acetyl CoA, which fuels the Krebs cycle In RVH, pyruvate dehydrogenase kinase (PDK) is activated,103 which phosphorylates and inhibits PDH, blocking the entry of pyruvate into the mitochondria This slows the Krebs cycle and reduces oxygen consumption/g tissue and reduces energy production.128 Consequently, only ATP molecules/glucose are obtained (vs 32 ATP, the end product of glucose oxidation) New evidence suggests that the hypertrophied RV behaves as hibernating myocardium (i.e., that the reduced ejection fraction relates to an ischemia-induced metabolic shift to glycolysis, causing RV hypokinesis).103 The PDK inhibitor, dichloroacetate, restores oxidative glucose metabolism and RV contractility in experimental RVH.103 However, it is not clear whether specific metabolic therapy is required to achieve benefit In a series of adult PAH patients studied with FDG-PET, increased RV uptake of FDG was reduced by epoprostenol (a nonmetabolic but hemodynamically effective PH therapy).102 However, RV function in experimental models can be improved by metabolically targeted therapies that restore glucose oxidation—either directly, using dichloroacetate,103 or indirectly, by inhibition of fatty acid oxidation, which activates glucose oxidation via Randle cycle.129 While there are no metabolic therapies approved for PH or RVH, there are drugs that are approved by the FDA or European Regulatory Agency for adult patients with ischemic heart disease who might be considered for study in pediatric PAH These include drugs that inhibit fatty acid oxidation, such as trimetazidine and ranolazine.129 The PDK inhibitor dichloroacetate is not approved by the FDA for cardiac indications, although it has been used extensively (and safely) as a therapy for children with lactic acidosis.130 The first-in-human trial of dichloroacetate as a mitochondrial-targeting drug in iPAH demonstrates that dichloroacetate offers hemodynamic improvement in genetically susceptible patients However, the effect was not the same across all patients Those with variants in SIRT3 (result in a deficiency of pyruvate transportation from the cytoplasm to mitochondria) and UCP2 genes, which code for proteins that work to suppress mitochondrial function but are independent of PDK, did not respond.131 Another important metabolic pathway in hypertrophy involves AMP-activated protein kinase (AMPK) AMPK activation in ventricular hypertrophy132–134 preserves ATP levels by increasing glucose transport, accelerating glycolysis, and inhibiting acetyl CoA carboxylase.135 These drugs (and therapeutic strategies) should be used only if carefully designed clinical trials demonstrate safety and efficiency in children Right Ventricle Inflammation and Fibrosis An additional feature of the decompensated pressure-overloaded RV is the consistent appearance of inflammatory cells in and around pulmonary arteries and in the RV, which suggests an underlying inflammatory component to RV dysfunction.136–138 Histologic evidence of chamber-specific inflammation and mononuclear 620 S E C T I O N V Pediatric Critical Care: Pulmonary cell infiltration and the appearance of fibrocytes is common in experimental models of RV dysfunction, including hypoxia, monocrotaline, and SU5416-induced PAH This suggests complex interactions between resident cardiac myocytes and fibroblasts and circulating inflammatory/fibrotic precursor cells in remodeling of the pressure-overloaded RV.139,140 This relationship between inflammation and RV decompensation is underscored by the striking degree of decompensated RV function in patients with autoimmune diseases, such as scleroderma, that is disproportionate to the pulmonary artery pressures seen In addition, inflammatory vascular remodeling in systemic hypertension is hypothesized to contribute to altered vascular impedance exacerbating the effects of resistive overload on the ventricle.141 In a rat model of pulmonary embolism, increases in chamber-specific expression of cytokine-induced neutrophil chemoattractant (CINC1), CINC2, macrophage inflammatory protein (MIP2), monocyte chemoattractant protein-1 (MCP-1), and MIP1a correlate with the severity of RV dysfunction.142 These data suggest that therapeutic strategies targeting inflammation should be tested, examining their effects on both the pulmonary vasculature and the RV Such studies could be achieved using MRI, which requires minimal sedation143 and which permits assessment of fibrosis and inflammation through quantification of gadolinium enhancement Should fibrosis and inflammation prove to be important, therapeutic agents could be tested to address these abnormalities, including class-specific histone deacetylase (HDAC) inhibitors (which reduce pulmonary artery pressures) and to reverse the pathologic fetal gene expression in experimental RVH144 or aldosterone antagonists, such as spironolactone, which are beneficial in LV failure in adults, presumably due to antifibrotic properties.145 It is reported that spironolactone or eplerenone prevented or reversed pulmonary vascular remodeling and improved cardiopulmonary hemodynamics in two animal models (MCT rat model and SU-5416/hypoxia-induced rat Mechanical strain Inflammation model) of PAH.146 Spironolactone has been used safely in children to treat heart failure, hypertension, and edema However, it is untested in children with PH or RVH Recent Advances in Molecular Mechanisms and Novel Therapeutic Targets in Pulmonary Hypertension The use of approved vasodilator drugs, either alone or in combination, has led to an improvement in the quality of life and clinical outcomes in pediatric patients with PAH However, PH remains a progressive disease without a cure and mortality, despite contemporary therapies, remains high From 1997 to 2012, there has been an increase of 55,900 hospitalizations annually for children with PH and a corresponding increase in hospital charges ($926 million in 1997 to $3.12 billion in 2012).147 There is a pressing need to develop new pharmacologic therapies targeting the fundamental origins and characteristics of PH, that is, vascular remodeling.8,148 This section summarizes recent advances in molecular mechanisms and emerging therapies targeting vascular remodeling in PH An overview is presented in Fig 53.8 Genetic Predisposition For more than half a century, IPAH—originally called primary pulmonary hypertension—has been recognized as a lethal pulmonary vascular disease of mysterious origin However, around 1998, a new understanding was developed regarding the specific genetic predisposition in families with PAH That information led to a revision of the classification of PAH into idiopathic as well as familial forms of PAH (see Box 53.1) Technological advances in Hypoxia Genetic predisposition Nutrients Growth factors Ion channels Metabolic state Cofactor/ substrate Transcription factors/ coregulators Antiproliferative, antiinflammatory gene expression Chromatin/ epigenetic modulators Gene expression Proproliferative, proinflammatory metabolic gene expression Vascular remodelling • Fig 53.8 Advances in molecular mechanisms and emerging therapies targeting vascular remodeling Cross-talk between transcription factors, epigenetics, and metabolism in pulmonary hypertension Growth factors, ion channels, hormones, and cytokines activate the classical signaling pathways and downstream transcriptional factors, which will recruit chromatin-modifying enzymes to local chromatin On the other hand, nutrient levels and cell metabolism will affect levels of the metabolites, which are required substrates of chromatin-modifying enzymes that use these metabolites to modify both histones and DNA Variations in these inputs will determine epigenome remodeling and transcription and, subsequently, vascular remodeling CHAPTER 53 Diseases of the Pulmonary Circulation genetic sequencing have enabled inexpensive and rapid sequencing of the coding regions of the genome using either whole exome sequencing or whole-genome sequencing in families as well as large cohorts of patients In 2000, investigators in two separate institutions identified heterozygous germ line mutations in BMPR2, the gene encoding bone morphogenetic type 2, a member of the transforming growth factor-b (TGFb) superfamily.149,150 Later, investigators also identified similar mutations in IPAH patients.151 It is now well established that around 70% to 80% of families with PAH and 10% to 20% of IPAH cases are caused by mutations in BMPR2 In adults, a recent large survey in a collaborative European cohort of adult-onset patients with IPAH, familial PAH, and anorexigen-associated PAH established the presence of several causal mutations contributing to familial PAH, including BMPR2 (15.3%), TBX4 (1.3%), ACVRL1 (0.9%), ENG (0.6%), Smad9 (0.4%), and KCNK3 (0.4%) Further, mutations in new PAH genes were identified, including ATP13A3, XOX17, AQP1, and GDF2 Mutations in all of these genes are autosomal dominantly inherited and exhibit reduced penetrance, meaning that some individuals who carry a mutation not manifest PAH Interestingly, recent studies using exome sequencing in children with PAH demonstrate differences in genes associated with pulmonary hypertension compared with adults Although the contribution of BMPR2 mutations was similar between adults and children, mutations in TBX4 made a significantly greater contribution to pediatric- versus adult-onset PAH patients The observations of high rates of mutation in TBX4 in children compared with adults support the idea that PAH is at least in part a developmental lung disease when it presents early in life152 (Fig 53.9) Because of the increasing data showing that identification of gene variance has the ability to help physicians counsel patients regarding disease course and potential therapies, many now believe that there is a medicolegal duty to inform all patients in these FPAH groups about the possibility of a genetic condition and that family members could carry a mutation that increases the risk of PAH, allowing for screening and potentially early diagnosis Genetic testing can help to explain the etiology of disease and risk for other family members and future children Because the number of genes associated with PAH is constantly increasing, it has become difficult to test for each of these genes individually, and there are often high costs associated with whole-genome or whole-exome sequencing With the advent of next-generation sequencing (NGS) and the development of gene panels, we can interrogate numerous genes simultaneously Recently, this NGS panel approach was used in patients referred to a reference laboratory for PAH or PVOD in France.153 The panel of genes used included genes established in previous publications and research genes based on physiologic functions Using this NGS-targeted capture approach, diverse types of mutations could be detected by a single technique, allowing savings in cost and time Pathogenic mutations were identified in 19.5% of sporadic PAH patients, 55% of familial PAH patients, and 13.3% of PVOD patients using this approach The data confirmed that BMPR2 was the most frequently mutated gene followed by TBX4 in both pediatric and adult PAH Data confirmed a significant increase in BMP9 mutations, which is consistent with whole-genome sequencing Importantly, it was noted that EIF2AK4 biallelic mutations were restricted to those with PVOD and pulmonary capillary hemangiomatosis.153 This type of approach will allow many patients to be analyzed in a cost-efficient manner and provide important information to the patient, families, and caregivers Growth Factors and Apoptosis Resistance PH is consistently associated with early and persistent perivascular proliferative changes Growth factors—including platelet-derived IPAH 0.8% 7.7% 12% 24% 0.8% 9.2% 0.8% 8% 6.2% Pediatric 56% 74.6% ENG ACVRL1 TBX4 KCNK3 N = 25 N = 130 1.3% 6.3% 1.3% 1.1% 9% BMPR2 CAV1 0.6% SMAD9 38% EIF2AK4 Adult 89.3% 49.4% De novo candidate unknown 2.5% 1.3% N = 79 N = 178 • Fig 53.9 Genetics of pulmonary arterial hypertension FPAH, Familial pulmonary arterial hypertension; IPAH, idiopathic pulmonary arterial hypertension 621 622 S E C T I O N V Pediatric Critical Care: Pulmonary growth factor (PDGF)-BB, FGF2 (previously known as basic fibroblast growth factor, bFGF), epidermal growth factor (EGF), and vascular endothelial growth factor (VEGF)—have been implicated in the abnormal proliferation and migration of pulmonary vascular cells in PH.154–157 These growth factors, produced by cells in the vessel wall, can act as potent mitogens for smooth muscle cells (SMCs), fibroblasts, and endothelial cells They stimulate cell surface receptors, which activate tyrosine kinase signaling Of specific relevance to pediatric PH are observations of upregulation of PDGFRa and PDGFRb protein levels in an ovine model of chronic intrauterine pulmonary hypertension.158 In another model of severe neonatal PH, PDGF-mediated signaling in the adventitial fibroblast mediated through JNK-1 was increased, resulting in a hyperproliferative fibroblast/myofibroblast.159,160 Insulin-like growth factor (IGF-1) signaling, implicated in cell proliferation in systemic vascular diseases and cancer, is also increased in neonatal models of severe PH.161–163 Several studies have led to the use of receptor tyrosine kinase inhibitors to target the “hyperproliferative” cell phenotype, which seems to characterize at least certain stages of pulmonary hypertension.164 A Phase trial investigating imatinib, a small molecule tyrosine kinase inhibitor, in adults showed tolerability with some efficacy in specific PAH subsets (notably those with the highest PVR).165 Resistance to programmed cell death (apoptosis) is another emerging characteristic of PH,166–169 a feature shared with cancer Tumor cells evolve a variety of strategies to limit or circumvent apoptosis Most common is the loss of TP53 tumor suppressor function, which eliminates this critical damage sensor from the apoptosis-inducing circuitry A study has demonstrated that p53 gene deficiency also promotes hypoxia-induced pulmonary hypertension in vascular remodeling in mice.170 Upregulation of the antiapoptotic/prosurvival factors BCL2 and survivin are observed in models of PH, and increases in survivin protein expression have been confirmed in human PH Future studies will be necessary to determine the exact mechanisms leading to the emergence of these cells and to determine whether strategies targeted at reducing this escape from cell death signals will be effective in the treatment of PH A recent study demonstrated that a selective, orally available apoptosis signal-regulating kinase (ASK1) inhibitor halts disease progression in two preclinical rat models of PAH (monocrotaline and Sugen/hypoxia), a murine model of RV pressure overload induced by PAB, and cellular models.171 However, the promise of these preclinical data is significantly tempered by the results of the recent Gilead Sciences clinical phase study of the inhibitor in PAH (NCT02234141) That study did not achieve its primary end point, as no significant change in pulmonary vascular resistance from baseline was observed after 24 weeks of treatment with selonsertib (an investigational small molecule inhibitor of ASK1), indicating that translation of preclinical findings to the clinical arena is challenging and will require additional studies to ensure that the appropriate population is targeted and that the mechanism is more fully elucidated.172,173 Inflammation Mounting evidence suggests a link between the immune system and inflammatory mechanisms in the development of PH In addition, there is strong evidence that this chronic inflammation is not simply a bystander but an active participant in the progression of vascular abnormalities in PH,174–176 consistent with the findings that (1) pathologic specimens from patients with PAH reveal an accumulation of perivascular inflammatory cells, including macrophages, dendritic cells, T and B lymphocytes, and mast cells; and (2) elevated levels of inflammatory cytokines, including IL-1b and IL-6, have been shown to predict poor survival in idiopathic and familial PAH.175–178 Additional inflammatory conditions, such as connective tissue diseases, are associated with an increased incidence of PAH; treatment of the underlying inflammatory condition may alleviate the associated PAH.179 Circulating autoantibodies have been detected in pediatric and adult patients.180–184 A role for inflammation in the development and perpetuation of PAH is further supported by enhanced pulmonary expression of various cytokines and chemokines, such as fractalkine, IL-6, C-C Motif Chemokine Ligand (CCL5) and CCL2 (MCP-1) and their association with inflammatory cell infiltrates in severe PAH.181,185–187 Importantly, a marked increase in secondary lymphoid tissue (BALT) has been observed in the lung of patients with PAH.188–190 Nearly every animal model of PH manifests a striking perivascular accumulation of inflammatory cells (macrophages and dendritic cells) An inverse correlation between PH and the number of macrophages relative to T-regulatory cells has been reported.191 Noncalcium Ion Channels The identification of heterozygous loss-of-function mutations in the KCNK3 (potassium channel subfamily K member 3) gene that encodes TWIK-related acid-sensitive potassium channel (TASK1) as a cause for PAH has revived interest in the concept of channelopathy.192 The dysregulation of potassium channels could have a central role in the immediate and long-term regulation of pulmonary vascular function in PAH.193,194 Pharmacologic activation of KCNK3 has beneficial effects in monocrotaline-induced PH.193 Interestingly, endothelin, serotonin (5-HT), oxidative stress, BMPR2, docosahexaenoic acid, and growth factors such as PDGF are known modulators of potassium channel activities.195 Furthermore, inhibition of voltage-gated potassium channels could represent one potential mechanism involved in some druginduced PH.196,197 The current challenge is to identify small molecules or specific strategies to restore the expression and/or activity of these ion channels in PAH dysfunctional pulmonary vasculature Transcription Factors and Transcriptional Coregulators PH is a complex and multifactorial disease involving genetic, epigenetic, and environmental factors Numerous stimuli and pathologic conditions (shear stress, hypoxia, oxidative stress, infection, HIV, and others) can result in PH by activating a complex cascade of signaling pathways.176,198 Ultimately, different signaling cascades converge on a common program targeting the activity of certain sequence-specific DNA-binding transcription factors (TFs) and coregulators.199 This leads to activation of a vascular gene program in the nucleus that is manifested finally as the PH vascular phenotype.200 Epigenetic regulation of chromatin structure is also recognized to influence gene expression in development or disease states There are numerous TFs and transcriptional coactivators that have been implicated in PH and RV dysfunction Therefore, a complete understanding of the mechanisms involved in altered gene expression in diseased cells is vital for the design of novel therapeutic strategies Recent technological advances in DNA sequencing will provide a comprehensive improvement in our understanding of mechanisms involved in the CHAPTER 53 Diseases of the Pulmonary Circulation development of PH and possibilities in employing potential epigenetic or TF-based therapies for achieving complete reversal of PH Metabolic Reprogramming and Mitochondrial Dysfunction Another characteristic contributing to PH phenotype is a dysregulation of the cellular energetics Metabolic and mitochondrial reprogramming have been increasingly recognized as hallmarks of pulmonary hypertension, serving as a central driver of PH pathogenesis of pulmonary vascular cell overgrowth.178,201–204 These changes have been described to occur in several pulmonary vascular cell types, including endothelial cells,163 SMCs,205 and fibroblasts202–204,206 and circulating blood outgrowth endothelial cells (BOECs).207 These observations have led to a “metabolic theory” of PH whereby mitochondrial and cytosolic defects drive a “Warburg-like” cell phenotype (described originally for cancer cells, which reprogram metabolic pathways toward aerobic glycolysis to support high proliferation) that can explain the molecular and functional abnormalities seen in PH cells, including excessive proliferation, apoptosis resistance, and inflammation.202–205,208 As will be discussed later, similar glycolytic changes in metabolism occur in parallel in the myocardium during RVH The metabolic phenotype of PAH can be targeted with experimental drugs such as dichloroacetate, which have demonstrated hemodynamic improvement in preclinical rodent models209–211 and a clinical trial in humans (in genetically susceptible patients).131 In addition, there is a growing awareness that central components of intermediary metabolism are cofactors or substrates of chromatin-modifying enzymes.212–214 As such, their concentrations constitute a potential regulatory interface between the metabolic and chromatin states Ongoing research focusing on different metabolic modulators will pave the way for novel precision medicine approaches in this disease Epigenetic Modifications Recent findings of alterations in the DNA methylation state of superoxide dismutase 2215 and granulysin gene loci216; histone H1 levels217; aberrant expression levels of histone deacetylases 218,219 and histone acetylation readers, bromodomains (BRDs)220,221 and dysregulated microRNA networks222 together suggest the involvement of epigenetics in PAH pathogenesis Thus, PAH pathogenesis involves the interplay of a predisposed genetic background, epigenetic state, and injurious events.223 Profiling the genomewide alterations in the epigenetic mechanisms, such as DNA methylation or histone modification pattern in PAH vascular cells, may explain the great variability in susceptibility and disease severity that is frequently associated with pronounced remodeling and worse clinical outcome Therapies aimed at correcting epigenetic alterations in vascular cells such as inhibitors of DNA methyltransferases, histone deacetylase inhibitors (HDACi), histone acetylation readers (BRDs) inhibitors and microRNAs are being investigated.144,215,219–222 Apabetalone is a first-in-class orally active inhibitor of BRD, and extraterminal domain (BET) transcriptional regulators, including BRD4, are in a phase clinical trial of major adverse cardiovascular event outcomes in cardiovascular disease.224 However, virtually all of this testing is in adult humans or animals, and pediatric-specific studies are required, particularly in light of the unique complexity of modulating proliferation and apoptosis in the developing lung In summary, genetic, epigenetic, and environmental factors lead to deregulation of gene expression, including growth factors, 623 ion channels, hormones, and cytokines that subsequently activate a complex cascade of signaling pathways causing abnormalities in vascular cell phenotype, including proliferation, differentiation/dedifferentiation, and inflammation This suggests that transcriptional dysregulation in the pulmonary vasculature can be an early event and perpetuate PH development that shapes the pulmonary vascular transcriptome, causing both depletion and ectopic activation of gene products that eventually lead to aberrant cellular processes and, consequently, adverse vascular remodeling (see Fig 53.8).8,95 Long-Term Outcomes of Patients With Pulmonary Vascular Disease PVD encompasses a heterogeneous patient population with varying rates of survival and insufficiently measured functional morbidities Short- and long-term outcome measures are inconsistently evaluated in clinical studies Additionally, the outcome measures available lack objectivity and sensitivity to subtle functional limitations One subset of children with PVD in whom long-term outcomes have been well studied are children with BPD The long-term outcomes in this population are characterized by persistent respiratory disease that can result in frequent hospitalizations, emergency department visits, and the need for prolonged respiratory support, including oxygen supplementation and pharmacologic pulmonary vasodilator therapies.225,226 However, long-term pulmonary deficits were not predicted by the clinical diagnosis of BPD In fact, long-term respiratory morbidity was more accurately predicted by mechanical ventilation and evidence of PVD at days of life This suggests that premature infants at the highest risk of long-term morbidities may be identifiable early in life and, importantly, that PVD may have significant implications on long-term pulmonary outcomes The current literature also shows that exercise intolerance, a reduction in peak lung function early in the third decade of life followed by a hastening of the expected decline, an increased risk of chronic obstructive pulmonary disease, and cardiovascular dysfunction, including PH and RV dysfunction can occur in adults born prematurely.227–230 BPD as a form of early, severe injury to the immature pulmonary system may offer important insights into lung injury incurred at later stages of pulmonary development The pulmonary system continues to develop throughout childhood and into early adulthood, with some of the most active development occurring in infancy and early childhood.230 Severe lung injury can occur at any point along this developmental spectrum; the impact it has on the underdeveloped lungs and pulmonary vasculature is poorly understood The improved survival rates of infants born prematurely are associated with advancements in therapeutic interventions, including methods of delivering respiratory support during the neonatal period Optimizing ventilator support provided to children who suffer severe lung injury such as ARDS during later stages of pulmonary development (e.g., in childhood) may have important implications on the developing pulmonary vasculature and subsequent long-term pulmonary morbidities To adequately test therapeutic strategies, it is imperative to develop a better understanding of the long-term implications of both congenital and acquired severe lung injury and the associated PVD, particularly as it relates to the immature lung Our ability to improve outcomes after acquired PVD (in perinatal and/or childhood time periods) relies on two critical areas of investigation: (1) adequate screening for and detection of ... experimental models of RV dysfunction, including hypoxia, monocrotaline, and SU5416-induced PAH This suggests complex interactions between resident cardiac myocytes and fibroblasts and circulating... circulating inflammatory/fibrotic precursor cells in remodeling of the pressure-overloaded RV.139,140 This relationship between inflammation and RV decompensation is underscored by the striking degree... targeting the fundamental origins and characteristics of PH, that is, vascular remodeling.8,148 This section summarizes recent advances in molecular mechanisms and emerging therapies targeting