Pulmonary hypertension (PH) is a relatively misunderstood disease, partly related to the fact that many perceive PH to be a singular diagnosis. An unintended consequence of this is the misapplication of the role of the Doppler-Echocardiographic (DE) examination, as well as an underappreciation for its ability to help discern PH pathophysiology prior to right heart catheterization. Since DE often serves as the "gatekeeper" to invasive right heart catheterization, misinterpretation of the DE can lead to missed or delayed diagnosis with devastating consequences. Too often, the primary or nearly exclusive focus of the DE examination is placed on the pulmonary artery pressure estimation. Two main issues with this approach are that Doppler pressure estimations can be inaccurate and even when accurate, without integration of additional 2-D and Doppler information, the clinician will often still not appreciate the pathophysiology of the PH nor its clinical significance. This review will focus on the 2-D and Doppler features necessary to assess pulmonary vascular disease (PVD), discern the salient differences between PVD and pulmonary venous hypertension (PVH), and how to integrate these key DE parameters such that PH pathophysiology can be determined noninvasively and early in the patient workup. Overreliance on any single DE metric, and especially PA pressure estimation, detracts from the overall diagnostic potential of the DE examination. Integrating the relative balance of right and left heart findings, along with proper Doppler interpretation provides a wealth of clinical and pathophysiologic insight prior to invasive hemodynamic assessment. The end results are heightened awareness and improved identification of which patients should be referred for further invasive testing, as well the use of the DE information to compliment the findings from invasive testing.

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Pulmonary hypertension (PH), a progressive disorder associated with significant morbidity and mortality, is caused by complex pathways that culminate in structural and functional alterations of the pulmonary circulation and increases in pulmonary vascular resistance and pressure. Diverse genetic, pathological, or environmental triggers stimulate PH pathogenesis culminating in vasoconstriction, cell proliferation, vascular remodeling, and thrombosis. We conducted a thorough literature review by performing MEDLINE searches via PubMed to identify articles pertaining to PPARγ as a therapeutic target for the treatment of PH. This review examines basic and preclinical studies that explore PPARγ and its ability to regulate PH pathogenesis. Despite the current therapies that target specific pathways in PH pathogenesis, including prostacyclin derivatives, endothelin-receptor antagonists, and phosphodiesterase type 5 inhibitors, morbidity and mortality related to PH remain unacceptably high, indicating the need for novel therapeutic approaches. Consequently, therapeutic targets that simultaneously regulate multiple pathways involved in PH pathogenesis have gained attention. This review focuses on peroxisome proliferator-activated receptor gamma (PPARγ), a member of the nuclear hormone receptor superfamily of ligand-activated transcription factors. While the PPARγ receptor is best known as a master regulator of lipid and glucose metabolism, a growing body of literature demonstrates that activation of PPARγ exerts antiproliferative, antithrombotic, and vasodilatory effects on the vasculature, suggesting its potential efficacy as a PH therapeutic target.

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The acute respiratory distress syndrome (ARDS) is a complex disorder of heterogeneous etiologies characterized by a consistent, recognizable pattern of lung injury. Extensive epidemiologic studies and clinical intervention trials have been conducted to address the high mortality of this disorder and have provided significant insight into the complexity of studying new therapies for this condition. The existing clinical investigations in ARDS will be highlighted in this review. The limitations to current definitions, patient selection, and outcome assessment will be considered. While significant attention has been focused on the parenchymal injury that characterizes this disorder and the clinical support of gas exchange function, relatively limited focus has been directed to hemodynamic and pulmonary vascular dysfunction equally prominent in the disease. The limited available clinical information in this area will also be reviewed. The current standards for cardiopulmonary management of the condition will be outlined. Current gaps in our understanding of the clinical condition will be highlighted with the expectation that continued progress will contribute to a decline in disease mortality.

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Pulmonary hypertension is characterized by cellular and structural changes in the walls of pulmonary arteries. Intimal thickening and fibrosis, medial hypertrophy and fibroproliferative changes in the adventitia are commonly observed, as is the extension of smooth muscle into the previously non-muscularized vessels. A majority of these changes are associated with the enhanced presence of α-SM-actin+ cells and inflammatory cells. Atypical abundances of functionally distinct endothelial cells, particularly in the intima (plexiform lesions), and also in the perivascular regions, are also described. At present, neither the origin(s) of these cells nor the molecular mechanisms responsible for their accumulation, in any of the three compartments of the vessel wall, have been fully elucidated. The possibility that they arise from either resident vascular progenitors or bone marrow-derived progenitor cells is now well established. Resident vascular progenitor cells have been demonstrated to exist within the vessel wall, and in response to certain stimuli, to expand and express myofibroblastic, endothelial or even hematopoietic markers. Bone marrow-derived or circulating progenitor cells have also been shown to be recruited to sites of vascular injury and to assume both endothelial and SM-like phenotypes. Here, we review the data supporting the contributory role of vascular progenitors (including endothelial progenitor cells, smooth muscle progenitor cells, pericytes, and fibrocytes) in vascular remodeling. A more complete understanding of the processes by which progenitor cells modulate pulmonary vascular remodeling will undoubtedly herald a renaissance of therapies extending beyond the control of vascular tonicity and reduction of pulmonary artery pressure.

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The activity of voltage-gated ion channels is critical for the maintenance of cellular membrane potential and generation of action potentials. In turn, membrane potential regulates cellular ion homeostasis, triggering the opening and closing of ion channels in the plasma membrane and, thus, enabling ion transport across the membrane. Such transmembrane ion fluxes are important for excitation-contraction coupling in pulmonary artery smooth muscle cells (PASMC). Families of voltage-dependent cation channels known to be present in PASMC include voltage-gated K ⁺ (Kv) channels, voltage-dependent Ca ²⁺ -activated K ⁺ (Kca) channels, L- and T- type voltage-dependent Ca ²⁺ channels, voltage-gated Na ⁺ channels and voltage-gated proton channels. When cells are dialyzed with Ca ²⁺ -free K ⁺ - solutions, depolarization elicits four components of 4-aminopyridine (4-AP)-sensitive Kvcurrents based on the kinetics of current activation and inactivation. In cell-attached membrane patches, depolarization elicits a wide range of single-channel K ⁺ currents, with conductances ranging between 6 and 290 pS. Macroscopic 4-AP-sensitive Kv currents and iberiotoxin-sensitive Kca currents are also observed. Transcripts of (a) two Na ⁺ channel α-subunit genes (SCN5A and SCN6A), (b) six Ca²⁺ channel α−subunit genes (α_1A, α _1Β , α _1Χ , α_1D, α_1E and α_1G) and many regulatory subunits (α₂δ₁, β_1-4, and γ₆), (c) 22 Kv channel α−subunit genes (Kv1.1 - Kv1.7, Kv1.10, Kv2.1, Kv3.1, Kv3.3, Kv3.4, Kv4.1, Kv4.2, Kv5.1, Kv 6.1-Kv6.3, Kv9.1, Kv9.3, Kv10.1 and Kv11.1) and three Kv channel β-subunit genes (Kvβ1-3) and (d) four Kca channel α−subunit genes (Sloα1 and SK2-SK4) and four Kca channel β-subunit genes (Kcaβ1-4) have been detected in PASMC. Tetrodotoxin-sensitive and rapidly inactivating Na ⁺ currents have been recorded with properties similar to those in cardiac myocytes. In the presence of 20 mM external Ca ²⁺ , membrane depolarization from a holding potential of -100 mV elicits a rapidly inactivating T-type Ca ²⁺ current, while depolarization from a holding potential of -70 mV elicits a slowly inactivating dihydropyridine-sensitive L-type Ca ²⁺ current. This review will focus on describing the electrophysiological properties and molecular identities of these voltage-dependent cation channels in PASMC and their contribution to the regulation of pulmonary vascular function and its potential role in the pathogenesis of pulmonary vascular disease.

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Earlier electron microscopic data had shown that a hallmark of the vascular remodeling in pulmonary arterial hypertension (PAH) in man and experimental models includes enlarged vacuolated endothelial and smooth muscle cells with increased endoplasmic reticulum and Golgi stacks in pulmonary arterial lesions. In cell culture and in vivo experiments in the monocrotaline model, we observed disruption of Golgi function and intracellular trafficking with trapping of diverse vesicle tethers, SNAREs and SNAPs in the Golgi membranes of enlarged pulmonary arterial endothelial cells (PAECs) and pulmonary arterial smooth muscle cells (PASMCs). Consequences included the loss of cell surface caveolin-1, hyperactivation of STAT3, mislocalization of eNOS with reduced cell surface/caveolar NO and hypo-S-nitrosylation of trafficking-relevant proteins. Similar Golgi tether, SNARE and SNAP dysfunctions were also observed in hypoxic PAECs in culture and in PAECs subjected to NO scavenging. Strikingly, a hypo-NO state promoted PAEC mitosis and cell proliferation. Golgi dysfunction was also observed in pulmonary vascular cells in idiopathic PAH (IPAH) in terms of a marked cytoplasmic dispersal and increased cellular content of the Golgi tethers, giantin and p115, in cells in the proliferative, obliterative and plexiform lesions in IPAH. The question of whether there might be a causal relationship between trafficking dysfunction and vasculopathies of PAH was approached by genetic means using HIV-nef, a protein that disrupts endocytic and trans-Golgi trafficking. Macaques infected with a chimeric simian immunodeficiency virus (SIV) containing the HIV-nef gene (SHIV-nef), but not the non-chimeric SIV virus containing the endogenous SIV-nef gene, displayed pulmonary arterial vasculopathies similar to those in human IPAH. Only macaques infected with chimeric SHIV-nef showed pulmonary vascular lesions containing cells with dramatic cytoplasmic dispersal and increase in giantin and p115. Specifically, it was the HIV-nef-positive cells that showed increased giantin. Elucidating how each of these changes fits into the multifactorial context of hypoxia, reduced NO bioavailability, mutations in BMPR II, modulation of disease penetrance and gender effects in disease occurrence in the pathogenesis of PAH is part of the road ahead.

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Epigenetics refers to changes in phenotype and gene expression that occur without alterations in DNA sequence. Epigenetic modifications of the genome can be acquired de novo and are potentially heritable. This review focuses on the emerging recognition of a role for epigenetics in the development of pulmonary arterial hypertension (PAH). Lessons learned from the epigenetics in cancer and neurodevelopmental diseases, such as Prader-Willi syndrome, can be applied to PAH. These syndromes suggest that there is substantial genetic and epigenetic cross-talk such that a single phenotype can result from a genetic cause, an epigenetic cause, or a combined abnormality. There are three major mechanisms of epigenetic regulation, including methylation of CpG islands, mediated by DNA methyltransferases, modification of histone proteins, and microRNAs. There is substantial interaction between these epigenetic mechanisms. Recently, it was discovered that there may be an epigenetic component to PAH. In PAH there is downregulation of superoxide dismutase 2 (SOD2) and normoxic activation of hypoxia inducible factor (HIF-1α). This decrease in SOD2 results from methylation of CpG islands in SOD2 by lung DNA methyltransferases. The partial silencing of SOD2 alters redox signaling, activates HIF-1α) and leads to excessive cell proliferation. The same hyperproliferative epigenetic abnormality occurs in cancer. These epigenetic abnormalities can be therapeutically reversed. Epigenetic mechanisms may mediate gene-environment interactions in PAH and explain the great variability in susceptibility to stimuli such as anorexigens, virus, and shunts. Epigenetics may be relevant to the female predisposition to PAH and the incomplete penetrance of BMPR2 mutations in familial PAH.

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During normal lung development and in lung diseases structural cells in the lungs adapt to permit changes in lung function. Fibroblasts, myofibroblasts, smooth muscle, epithelial cells, and various progenitor cells can all undergo phenotypic modulation. In the pulmonary vasculature occlusive vascular lesions that occur in severe pulmonary arterial hypertension are multifocal, polyclonal lesions containing cells presumed to have undergone phenotypic transition resulting in altered proliferation, cell lifespan or contractility. Dynamic changes in gene expression and protein composition that underlie processes responsible for such cellular plasticity are not fully defined. Advances in molecular biology have shown that multiple classes of ribonucleic acid (RNA) collaborate to establish the set of proteins expressed in a cell. Both coding Messenger Ribonucleic acid (mRNA) and small noncoding RNAs (miRNA) act via multiple parallel signaling pathways to regulate transcription, mRNA processing, mRNA stability, translation and possibly protein lifespan. Rapid progress has been made in describing dynamic features of miRNA expression and miRNA function in some vascular tissues. However posttranscriptional gene silencing by microRNA-mediated mRNA degradation and translational blockade is not as well defined in the pulmonary vasculature. Recent progress in defining miRNAs that modulate vascular cell phenotypes is reviewed to illustrate both functional and therapeutic significance of small noncoding RNAs in pulmonary arterial hypertension.

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There have been tremendous strides in the management of pulmonary hypertension over the past 20 years with the introduction of targeted medical therapies and overall improvements in surgical treatment options and general supportive care. Furthermore, recent data shows that the survival of those with pulmonary arterial hypertension is improving. While there has been tremendous progress, much work remains to be done in improving the care of those with secondary forms of pulmonary hypertension, who constitute the majority of patients with this disorder, and in the optimal treatment approach in those with pulmonary arterial hypertension. This article will review general and targeted medical treatment, along with surgical interventions, of those with pulmonary hypertension.

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Biophysically-based computational models provide a tool for integrating and explaining experimental data, observations, and hypotheses. Computational models of the pulmonary circulation have evolved from minimal and efficient constructs that have been used to study individual mechanisms that contribute to lung perfusion, to sophisticated multi-scale and -physics structure-based models that predict integrated structure-function relationships within a heterogeneous organ. This review considers the utility of computational models in providing new insights into the function of the pulmonary circulation, and their application in clinically motivated studies. We review mathematical and computational models of the pulmonary circulation based on their application; we begin with models that seek to answer questions in basic science and physiology and progress to models that aim to have clinical application. In looking forward, we discuss the relative merits and clinical relevance of computational models: what important features are still lacking; and how these models may ultimately be applied to further increasing our understanding of the mechanisms occurring in disease of the pulmonary circulation.

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Pulmonary arterial hypertension (PAH) is a rapidly progressive and fatal disease for which there is an ever-expanding body of genetic and related pathophysiological information on disease pathogenesis. The most common single culprit gene known is BMPR2, and animal models of the disease in several forms exist. There is a wealth of genetic data regarding modifiers of disease expression, penetrance, and severity. Despite the rapid accumulation of data in the last decade, a complete picture of the molecular pathogenesis of PAH leading to novel therapies is lacking. In this review, we attempt to summarize the current understanding of PAH from the genetic perspective. The most recent PAH demographics are discussed. Heritable PAH in the post-BMPR2 era is examined in detail as the most robust model of PAH genetics in both animal models and human pedigrees. Important downstream molecular pathways and modifiers of disease expression are reviewed in light of what is known about PAH pathogenesis. Current and emerging therapies are examined in light of genetic data. The role of genetic testing in PAH in the post-BMPR2 era is discussed. Finally, directions for future investigations that ideally will fulfill the promise of novel therapeutic or preventive strategies are discussed.

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Current classifications of pulmonary hypertension have contributed a great deal to our understanding of pulmonary vascular disease, facilitated drug trials, and improved our understanding of congenital heart disease in adult survivors. However, these classifications are not applicable readily to pediatric disease. The classification system that we propose is based firmly in clinical practice. The specific aims of this new system are to improve diagnostic strategies, to promote appropriate clinical investigation, to improve our understanding of disease pathogenesis, physiology and epidemiology, and to guide the development of human disease models in laboratory and animal studies. It should be also an educational resource. We emphasize the concepts of perinatal maladaptation, maldevelopment and pulmonary hypoplasia as causative factors in pediatric pulmonary hypertension. We highlight the importance of genetic, chromosomal and multiple congenital malformation syndromes in the presentation of pediatric pulmonary hypertension. We divide pediatric pulmonary hypertensive vascular disease into 10 broad categories.

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Although mild increase in pulmonary vascular resistance following intracardiac repair of tetralogy of Fallot is often seen in the early postoperative period, it usually subsides without any sequel. Persistent severe pulmonary artery hypertension after total correction is rare. We report a child with tetralogy of Fallot and Down's syndrome, who developed severe pulmonary hypertension and low cardiac output syndrome following an intracardiac repair, which was resistant to specific pulmonary vasodilators and increasing ionotropes. The post correction echocardiogram suggested an intact ventricular septal defect patch, no residual gradient across the right ventricular outflow tract, with free pulmonary regurgitation. The child had a poor outcome. A postmortem biopsy revealed histopathological signs of pulmonary hypertension.

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Platelet-derived growth factor (PDGF) has been implicated in the pathobiology of vascular remodeling. The multikinase inhibitor imatinib that targets PDGF receptor (PDGFR), c-kit and Abl kinases, shows therapeutic efficacy against experimental pulmonary hypertension (PH); however, the role of PDGFR-b in experimental PH has not been examined by genetic approach. We investigated the chronic hypoxia-induced PH in mice carrying an activating point mutation of PDGFR-b (D849N) and evaluated the therapeutic efficacy of imatinib. In addition, we studied pulmonary global gene expression and confirmed the expression of identified genes by immunohistochemistry. Chronically hypoxic D849N mice developed PH and strong pulmonary vascular remodeling that was improved by imatinib (100 mg/kg/day) as evident from the significantly reduced right ventricular systolic pressure, right ventricular hypertrophy and muscularization of peripheral pulmonary arteries. Global gene expression analysis revealed that stromal cell derived factor SDF)-1α was significantly upregulated, which was confirmed by immunohistochemistry. Moreover, an enhanced immunoreactivity for SDF-1α, PDGFR-β and CXCR4, the receptor for SDF-1α was localized to the α-smooth muscle cell (SMC) actin positive pulmonary vascular cells in hypoxic mice and patients with idiopathic pulmonary arterial hypertension (IPAH). In conclusion, our findings substantiate the major role of PDGFR activation in pulmonary vascular remodeling by a genetic approach. Immunohistochemistry findings suggest a role for SDF-1α/CXCR4 axis in pulmonary vascular remodeling and point to a potential interaction between the chemokine SDF-1 and the growth factor PDGF signaling. Future studies designed to elucidate an interaction between the chemokine SDF-1 and the PDGF system may uncover novel therapeutic targets.

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In this perspective, we review published data which support the concept that many or most chronic and progressive lung diseases also involve the lung vessels and that microvascular abnormalities and endothelial cell death contribute to the pathobiology of emphysema. Lung vessel maintenance depends on Vascular Endothelial Growth Factor signaling and both are compromised in the emphysematous lung tissue. Although hypoxic pulmonary vasoconstriction has been considered as an important factor contributing to the vascular remodeling in chronic obstructive pulmonary disease (COPD) (COPD/emphysema, it is now clear that inhaled cigarette smoke can damage the lung vessels independent of the lung vascular tone. We propose that a "sick lung circulation" rather than the right heart afterload may better explain the cardiac abnormalities in COPD patients which are usually summarized with the term "cor pulmonale." The mechanisms and causes of pulmonary hypertension are likely complex and include vessel loss, in situ thrombosis, and endothelial cell dysfunction. Assessment of the functional importance of pulmonary hypertension in COPD requires hemodynamic measurements during exercise.

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Hereditary pulmonary arterial hypertension (PAH) is usually caused by mutations in BMPR2. Mutations are found throughout the gene, and common molecular consequences of different types of mutation are not known. Knowledge of common molecular consequences would provide insight into the molecular etiology of the disease. The objective of this study was to determine the common molecular consequences across classes of BMPR2 mutation. Increased superoxide and peroxide production and alterations in genes associated with oxidative stress were a common consequence of stable transfection of the vascular smooth muscle cells, with three distinct classes of BMPR2 mutation, in the ligand binding domain, the kinase domain and the cytoplasmic tail domain. Measurement of oxidized lipids in whole lung from transgenic mice expressing a mutation in the BMPR2 cytoplasmic tail showed a 50% increase in isoprostanes and a two-fold increase in isofurans, suggesting increased reactive oxygen species (ROS) of mitochondrial origin. Immunohistochemistry on BMPR2 transgenic mouse lung showed that oxidative stress was vascular-specific. Electron microscopy showed decreased mitochondrial size and variability in the pulmonary vessels from BMPR2-mutant mice. Measurement of oxidized lipids in urine from humans with BMPR2 mutations demonstrated increased ROS, regardless of disease status. Immunohistochemistry on hereditary PAH patient lung confirmed oxidative stress specific to the vasculature. Increased oxidative stress, likely of mitochondrial origin, is a common consequence of BMPR2 mutation across mutation types in cell culture, mice and humans.

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Pulmonary hypertension (PH) is associated with structural and mechanical changes in the pulmonary vascular bed that increase right ventricular (RV) afterload. These changes, characterized by narrowing and stiffening, occur in both proximal and distal pulmonary arteries (PAs). An important consequence of arterial narrowing is increased pulmonary vascular resistance (PVR). Arterial stiffening, which can occur in both the proximal and distal pulmonary arteries, is an important index of disease progression and is a significant contributor to increased RV afterload in PH. In particular, arterial narrowing and stiffening increase the RV afterload by increasing steady and oscillatory RV work, respectively. Here we review the current state of knowledge of the causes and consequences of pulmonary arterial stiffening in PH and its impact on RV function. We review direct and indirect techniques for measuring proximal and distal pulmonary arterial stiffness, measures of arterial stiffness including elastic modulus, incremental elastic modulus, stiffness coefficient b and others, the changes in cellular function and the extracellular matrix proteins that contribute to pulmonary arterial stiffening, the consequences of PA stiffening for RV function and the clinical implications of pulmonary vascular stiffening for PH progression. Future investigation of the relationship between PA stiffening and RV dysfunction may facilitate new therapies aimed at improving RV function and thus ultimately reducing mortality in PH.

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Although hypoxic pulmonary vasoconstriction is a well-recognized physiological phenomenon it is unusual to observe and assess its efficiency in clinical practice. Here, we report the case of a 50-year-old female who presented with unilateral incomplete bronchial occlusion due to a carcinoid tumor involving the left main bronchus in the absence of atelectasis. Ventilation-perfusion imaging revealed absent ventilation and perfusion to the left lung. She underwent bronchotomy and removal of the tumor. One month after the operation a further ventilation-perfusion lung scan revealed complete restoration of ventilation to the left lung and almost complete recovery of the perfusion. This unusual case demonstrates the marked efficiency of hypoxic pulmonary vasoconstriction at the level of a single lung and its reversible nature following relief of regional hypoxia.

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Pulmonary arterial hypertension (PAH) is a devastating disease characterized by pulmonary vasoconstriction, pulmonary arterial remodeling, abnormal angiogenesis and impaired right ventricular function. Despite progress in pharmacological therapy, there is still no cure for PAH. The peptide apelin and the G-protein coupled apelin receptor (APLNR) are expressed in several tissues throughout the organism. Apelin is localized in vascular endothelial cells while the APLNR is localized in both endothelial and smooth muscle cells in vessels and in the heart. Apelin is regulated by hypoxia inducible factor -1α and bone morphogenetic protein receptor-2. Patients with PAH have lower levels of plasma-apelin, and decreased apelin expression in pulmonary endothelial cells. Apelin has therefore been proposed as a potential biomarker for PAH. Furthermore, apelin plays a role in angiogenesis and regulates endothelial and smooth muscle cell apoptosis and proliferation complementary and opposite to vascular endothelial growth factor. In the systemic circulation, apelin modulates endothelial nitric oxide synthase (eNOS) expression, induces eNOS-dependent vasodilatation, counteracts angiotensin-II mediated vasoconstriction, and has positive inotropic and cardioprotective effects. Apelin attenuates vasoconstriction in isolated rat pulmonary arteries, and chronic treatment with apelin attenuates the development of pulmonary hypertension in animal models. The existing literature thus renders APLNR an interesting potential new therapeutic target for PH.

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Mutations in the bone morphogenetic protein type II receptor gene (BMPR-II) are the major cause of heritable pulmonary arterial hypertension (PAH). Although both endothelial and smooth muscle cell BMPR-II dysfunction have been seen to contribute to pulmonary hypertension in vivo, little is known about the impact of BMPR-II mutation on the interaction between these two important cell types. We employed adenoviral vectors to overexpress wild type or mutant (kinase-deficient mutation, D485G) BMPR-II in human pulmonary arterial endothelial cells (PAECs). PAECs transfected with mutant BMPR-II demonstrated increased susceptibility to apoptosis. Conditioned media from PAECs transfected with mutant BMPR-II increased the proliferation of pulmonary arterial smooth muscle cells (PASMCs), when compared with conditioned media from PAECs transfected with wild-type BMPR-II. PAECs transfected with mutant BMPR-II released higher levels of TGF-β₁ and FGF2 into the conditioned media than the wild-type BMPR-II-transfected cells. Conditioned media from PAECs expressing mutant BMPR-II also showed increased activation of luciferase activity in a TGF-β bioassay. The increased proliferation observed in PASMCs exposed to conditioned media from PAECs expressing mutant BMPR-II was inhibited by neutralizing the antibodies to TGF-β1, or small molecule inhibitors of ALK-5 (SD208) or FGFR1 (SU5402). We conclude that mutation in BMPR-II increases susceptibility to apoptosis of PAECs and leads to secretion of growth factors that stimulate the proliferation of PASMCs. These processes may contribute to the remodeling of pulmonary arteries observed in patients with familial or heritable PAH.

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Although medical therapies for pulmonary arterial hypertension have greatly improved, it remains a chronic and fatal disease. For patients who are refractory to medical therapy, lung transplantation is an important treatment option. This review discusses issues pertaining to indications for transplant, preparation for transplant and listing, operative issues, and outcomes for patients with pulmonary arterial hypertension.

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Acute pulmonary embolism causes redistribution of blood in the lung, which impairs ventilation/perfusion matching and gas exchange and can elevate pulmonary arterial pressure (PAP) by increasing pulmonary vascular resistance (PVR). An anatomically-based multi-scale model of the human pulmonary circulation was used to simulate pre- and post-occlusion flow, to study blood flow redistribution in the presence of an embolus, and to evaluate whether reduction in perfused vascular bed is sufficient to increase PAP to hypertensive levels, or whether other vasoconstrictive mechanisms are necessary. A model of oxygen transfer from air to blood was included to assess the impact of vascular occlusion on oxygen exchange. Emboli of 5, 7, and 10 mm radius were introduced to occlude increasing proportions of the vasculature. Blood flow redistribution was calculated after arterial occlusion, giving predictions of PAP, PVR, flow redistribution, and micro-circulatory flow dynamics. Because of the large flow reserve capacity (via both capillary recruitment and distension), approximately 55% of the vasculature was occluded before PAP reached clinically significant levels indicative of hypertension. In contrast, model predictions showed that even relatively low levels of occlusion could cause localized oxygen deficit. Flow preferentially redistributed to gravitationally non-dependent regions regardless of occlusion location, due to the greater potential for capillary recruitment in this region. Red blood cell transit times decreased below the minimum time for oxygen saturation (<0.25 s) and capillary pressures became high enough to initiate cell damage (which may result in edema) only after ~80% of the lung was occluded.

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