Pulmonary arterial hypertension

Pulmonary arterial hypertension is a disease of the small pulmonary arteries characterized by vascular narrowing and increased pulmonary vascular resistance, which eventually leads to right ventricular failure. Vasoconstriction, vascular proliferation, remodeling of the pulmonary vessels, and thrombosis are all contributing factors to the increased vascular resistance seen in this disease. Pulmonary arterial hypertension develops as a sporadic disease (idiopathic), as an inherited disorder (familial), or in association with certain conditions (collagen vascular diseases, portal hypertension, human immunodeficiency virus infection, congenital systemic-to-pulmonary shunts, ingestion of drugs or dietary products, or persistent fetal circulation). The pathogenesis of pulmonary arterial hypertension is a complicated, multifactorial process. It seems doubtful that any one factor alone is sufficient to activate the necessary pathways leading to the development of this disease. Rather, clinically apparent pulmonary arterial hypertension most likely develops after a second insult occurs in an individual who is already susceptible owing to genetic factors, environmental exposures, or acquired disorders. Currently, there is no cure for pulmonary arterial hypertension but several novel therapeutic options are now available that can improve symptoms and increase survival.     

Longitudinal distribution of pulmonary vascular resistance after endotoxin administration in sheep.

BACKGROUND AND METHODS: Pulmonary hypertension may increase pulmonary capillary pressure and exacerbate pulmonary edema in acute respiratory failure. The effects of pulmonary hypertension on pulmonary capillary pressure depend on the longitudinal distribution of pulmonary vascular resistance. Since pulmonary hypertension occurs during acute respiratory failure, we hypothesized that acute respiratory failure may produce time-dependent changes in the longitudinal distribution of pulmonary vascular resistance. Therefore, we measured pulmonary capillary pressure and the longitudinal distribution of pulmonary vascular resistance in an animal model of acute respiratory failure. Escherichia coli endotoxin (2.5 to 5.0 micrograms/kg) was administered over a 1-hr period in eight anesthetized sheep. Pulmonary and systemic hemodynamics, including pulmonary artery occlusion pressure (PAOP), pulmonary capillary pressure, and the longitudinal distribution of pulmonary vascular resistance, were measured over the next 5 hrs. Pulmonary capillary pressure was estimated by analysis of the pressure decay following pulmonary artery balloon inflation. RESULTS: Endotoxin administration resulted in sustained pulmonary hypertension for the subsequent 5 hrs of the study. Pulmonary capillary pressure was increased 7 mm Hg above baseline at 0.5 and 0.75 hrs during the infusion of endotoxin but returned to baseline values at 1.5 hrs. Despite sustained pulmonary hypertension, pulmonary capillary pressure remained at baseline values for the duration of the study. Similar to pulmonary capillary pressure, pulmonary venous (or postcapillary) resistance was increased approximately four-fold over baseline at 0.5 and 0.75 hrs after initiating endotoxin administration, but returned to baseline values by the end of endotoxin administration and remained at baseline values throughout the remainder of the study. In contrast, pulmonary arterial (or precapillary) resistance remained at values approximately three times baseline during the infusion and throughout the duration of the study. CONCLUSIONS: In this experimental model of acute respiratory failure, the effects of endotoxin on the longitudinal distribution of pulmonary vascular resistance are time-dependent. If these data from animals can be extrapolated to humans, we speculate that the importance of pulmonary venoconstriction in exacerbating pulmonary edema may vary over time in patients with acute respiratory failure.     

肺动脉高压动物模型与分子机制的研究进展

肺动脉高压（PAH）是一种以肺末梢小动脉增生重构促进肺动脉压力和阻力进行性增加为特征的严重疾病。其发病机制十分复杂,多种致病因子参与其发生发展过程。本文探讨肺动脉的离子稳态、骨形成蛋白、血管活性物质等细胞信号因子在PAH中的致病机制,为PAH分子水平干预和早期临床康复介入提供新的治疗靶点。因此,本文就目前PAH的动物造模的研究方法以及与PAH血管重构关键信号通路进行综述。     

Pulmonary Hypertension: Evaluation and Management

Pulmonary hypertension (PH) is a hemodynamic state characterized by elevation in the mean pulmonary arterial pressure and pulmonary vascular resistance leading to right ventricular failure and premature death. PH can be the result of a variety of diseases of different etiologies. Pulmonary arterial hypertension (PAH) should be distinctly differentiated from pulmonary venous hypertension (PVH) as a result of left heart disease. PAH is commonly caused by or associated with an underlying pulmonary, cardiac, or systemic disease (APAH). In the absence of an identifiable etiology or associated underlying disease, PAH is referred to as idiopathic (IPAH). IPAH, formerly known as primary pulmonary hypertension (PPH), is a rare disease most commonly seen in women of childbearing age. Presenting symptoms and signs are nonspecific and include dyspnea on exertion, fatigue, and a loud pulmonary component of the second heart sound. Transthoracic Doppler echocardiography is an excellent noninvasive test to detect the presence of pulmonary hypertension, although every patient should receive a right heart catheterization to confirm the diagnosis. A detailed work up, including laboratory tests and imaging studies, is also indicated to rule out known causes of pulmonary hypertension. Several targeted treatment options have become available in recent years and include parenteral and inhaled prostanoids, oral endothelin receptor antagonists, and oral phosphodiesterase type-5 inhibitors. As a result of their complex care, patients should be referred to centers with expertise in pulmonary hypertension.     

肺动脉高压药物靶向治疗的展望

肺动脉高压是一种以肺血管重构为特征,以肺血管阻力病理性增高为主要表现的临床综合征。肺动脉高压患者病情常呈进行性发展,最终导致右心衰竭和死亡。肺动脉高压现有的药物治疗在一定程度上改善了患者的症状,提高了生存率,但不能阻止病情的恶化,肺动脉高压患者的长期预后仍不尽人意。近年来,基于对肺动脉高压病理生理机制的深入认识,肺动脉高压的靶向治疗药物也不断涌现,为肺动脉高压的治疗带来了新的希望。现将肺动脉高压靶向治疗药物的研究进展进行综述。     

Calpain mediates pulmonary vascular remodeling in rodent models of pulmonary hypertension, and its inhibition attenuates pathologic features of disease

Pulmonary hypertension is a severe and progressive disease, a key feature of which is pulmonary vascular remodeling. Several growth factors, including EGF, PDGF, and TGF-β1, are involved in pulmonary vascular remodeling during pulmonary hypertension. However, increased knowledge of the downstream signaling cascades is needed if effective clinical interventions are to be developed. In this context, calpain provides an interesting candidate therapeutic target, since it is activated by EGF and PDGF and has been reported to activate TGF-β1. Thus, in this study, we examined the role of calpain in pulmonary vascular remodeling in two rodent models of pulmonary hypertension. These data showed that attenuated calpain activity in calpain-knockout mice or rats treated with a calpain inhibitor resulted in prevention of increased right ventricular systolic pressure, right ventricular hypertrophy, as well as collagen deposition and thickening of pulmonary arterioles in models of hypoxia- and monocrotaline-induced pulmonary hypertension. Additionally, inhibition of calpain in vitro blocked intracellular activation of TGF-β1, which led to attenuated Smad2/3 phosphorylation and collagen synthesis. Finally, smooth muscle cells of pulmonary arterioles from patients with pulmonary arterial hypertension showed higher levels of calpain activation and intracellular active TGF-β. Our data provide evidence that calpain mediates EGF- and PDGF-induced collagen synthesis and proliferation of pulmonary artery smooth muscle cells via an intracrine TGF-β1 pathway in pulmonary hypertension.     

Primary pulmonary hypertension: an overview of epidemiology and pathogenesis

Pulmonary arterial hypertension (PAH) refers to a group of diseases characterized by high pulmonary artery pressure of unknown mechanism. Primary pulmonary hypertension (PPH) is the idiopathic subset of PAH that affects a mostly young population and is more common in females than in males. A familial form of PPH accounts for about 6% of cases, and its autosomal dominant gene was recently identified. Pulmonary arterial hypertension is histologically characterized by endothelial and smooth muscle cell proliferation, medial hypertrophy, and thrombosis in situ. The pathogenesis of PAH remains unclear. Elevated pulmonary vascular resistance seems to result from an imbalance between locally produced vasodilators and vasoconstrictors, in addition to vascular wall remodeling. Nitric oxide, a locally produced selective pulmonary vasodilator, appears to play a central role in the pathobiology of PAH.     

Advances in the management of pediatric pulmonary hypertension

Pulmonary hypertension is a rare disease in neonates, infants, and children, and is associated with substantial morbidity and mortality. An adequate understanding of the controlling pathophysiologic mechanisms is lacking. Moreover, a minority of research is focused specifically on neonatal and pediatric populations. Although therapeutic options have increased over the past several decades, they remain limited. In advanced pulmonary hypertension, progressive pulmonary vascular functional and structural changes ultimately cause increased pulmonary vascular impedance, right-ventricular failure, and death. Management includes the prevention and/or treatment of active pulmonary vasoconstriction, the support of right-ventricle function, treatment of the underlying disease (if possible), and the promotion of regressive remodeling of structural pulmonary vascular changes. Most currently available therapies augment or inhibit factors, or mediators of their downstream signaling cascades, that originate in the pulmonary vascular endothelium. These pathways include nitric-oxide/cyclic guanosine monophosphate (cGMP), prostacyclin, and endothelin-1. The ability to reverse advanced structural changes remains an as yet unattained goal. This paper reviews the epidemiology, pathophysiology, current treatments, and emerging therapies related to neonatal and pediatric pulmonary hypertension.     

Prise en charge diagnostique et thérapeutique de l'hypertension artérielle pulmonaire

Pulmonary hypertension is a rare disease related to increased resistance in the pulmonary vascular bed. The disease leads spontaneously to right heart failure and death. A pathophysiological classification taking into account possible causal factors is available. Diagnosis rests on right heart catheterisation when clinical and paraclinical data suggest the diagnosis. To date, guidelines are available for severe forms of the disease. ICU management may be required for right heart failure. Despite the lack of consensus, management of patients with pulmonary hypertension resembles to this of patients with severe pulmonary embolism with right heart failure and the need for inotropic support.     

Effects of bosentan on cellular processes involved in pulmonary arterial hypertension: do they explain the long‐term benefit?

Pulmonary arterial hypertension is a rapidly progressing disease characterized by an over‐ expression of endothelin. In addition to its potent pulmonary vasoconstrictor effects, endothelin has been shown to produce many of the aberrant changes, such as hypertrophy, fibrosis, inflammation, and neurohormonal activation that underlie the shortened life span in pulmonary arterial hypertensive patients. The fact that endothelin expression correlates significantly with disease severity and outcome in these patients suggests that endothelin, through binding to both ET _A and ET _B receptor subtypes, is a key causative agent in the pathophysiology of pulmonary arterial hypertension. The orally active dual endothelin receptor antagonist bosentan ¹ competitively antagonizes the binding of endothelin to both endothelin receptor subtypes with high affinity and specificity. In animal models relevant for the pathophysiology of pulmonary hypertension, bosentan not only causes selective pulmonary vasodilation, but also prevents vascular hypertrophy and cardiac remodeling, attenuates pulmonary fibrosis, decreases vascular inflammation, and blunts neuro‐hormonal activation. These experimental data may explain the effects on disease progression and the long‐term benefit observed with bosentan in pulmonary arterial hypertension.     

Neither nitroglycerin nor nitroprusside selectively reduces sepsis-induced pulmonary hypertension in piglets

No therapeutic agent consistently decreases pulmonary arterial pressure (PAP) more than aortic pressure in neonates with persistent pulmonary hypertension of the newborn. We have investigated whether nitroglycerin (NG) or nitroprusside (NP) selectively decreases PAP in an animal model of sepsis-induced pulmonary hypertension. Piglets were anesthetized, intubated, and ventilated. Pulmonary hypertension was induced by an iv infusion of group B Streptococci. Piglets were then divided into three groups with group B Streptococci infusion ongoing. Neither PAP nor the pulmonary vascular resistance index was decreased significantly by either NP or NG. NP decreased significantly both mean aortic pressure and the systemic vascular resistance index. Cardiac index decreased significantly during both NG and placebo infusion. These data suggest that neither NP nor NG is likely to be beneficial in sepsis-induced pulmonary hypertension in newborns.     

Inhaled treprostinil for the treatment of pulmonary arterial hypertension

Pulmonary arterial hypertension is a progressive disease characterized by vascular proliferation and vasoconstriction of the small pulmonary arteries that eventually leads to right-sided heart failure and death. Patients often initially have symptoms such as shortness of breath, fatigue, and edema; later in the disease, presyncope and syncope are common. Patients with progressive pulmonary arterial hypertension despite oral therapy and/or with severe disease typically require treatment with a prostanoid. Inhaled treprostinil (Tyvaso) is a prostacyclin analog indicated for the treatment of pulmonary arterial hypertension to increase walk distance in patients with symptoms classified as New York Heart Association functional class III. Inhaled treprostinil was approved by the Food and Drug Administration in July 2009. This article provides a brief overview of the pathophysiology of pulmonary arterial hypertension and reviews the mechanism of action, key clinical data, and the practical management of inhaled treprostinil in patients with pulmonary arterial hypertension.     

Pulmonary arterial hypertension: evaluation and management

Pulmonary arterial hypertension (PAH), a rare disease involving the pulmonary vascular circuit, is defined as an elevation in pulmonary arterial pressures and is characterized by symptoms of dyspnea, chest pain, and syncope. If left untreated, the disease carries a high mortality rate, with the most common cause of death being decompensated right heart failure. Over the past 5 years, there have been significant advances in this field in regards to understanding the pathogenesis, diagnosis, and classification of PAH. The availability of newer drugs has resulted in a radical change in the management of this disease with significant improvement in both quality of life and mortality. Ongoing research promises to lead to a more comprehensive understanding of the genetics, etiology, and pathogenesis of pulmonary arterial hypertension, which may ultimately translate into more effective therapeutic options.     

Pulmonary capillary pressure: a review.

OBJECTIVES: To demonstrate the importance of a) measuring effective pulmonary capillary pressure and b) evaluating the longitudinal distribution of pulmonary vascular resistance relative to pre- and postcapillary resistances. To review the development of methods used to determine pulmonary capillary pressure in experimental animal and clinical studies. DATA SOURCES: Human, animal, and modeling studies published since 1966 identified through MEDLINE and a review of bibliographies of relevant articles. STUDY SELECTION AND DATA EXTRACTION: All studies identified were reviewed with an emphasis on recent studies and those studies identifying various methodologies used to determine capillary pressure. Experimental studies were selected for their historical value and applicability to the clinical setting. DATA SYNTHESIS: Different models of the pulmonary circulation have been proposed. The electrical circuit model, which incorporated capacitance elements and two or four resistive elements, has been the basis for the determination of pulmonary capillary pressure in isolated lungs and in situ lungs in animals and patients. Methods used to determine pulmonary capillary pressure from a pulmonary arterial pressure tracing after balloon occlusion are: a) division of waveform into two components and logarithmic extrapolation of the slow component to occlusion time; b) visual determination of the pressure inflection point of the pulmonary arterial pressure tracing; and c) computer processing of the total arterial pressure transient. Both ease of calculations and difficulties can arise when each method is used. CONCLUSIONS: Pulmonary capillary hydrostatic pressure is an important determinant of pulmonary edema especially in the setting of pulmonary hypertension and adult respiratory distress syndrome. Hypoxia, sepsis, cardiac valvular disease, and inflammatory mediators produce variable changes in the longitudinal distribution of pulmonary vascular resistance so that an increased capillary pressure cannot be predicted by the pulmonary arterial or occlusion pressure. For proper therapy aimed at decreasing pulmonary vascular resistance, it is important to determine whether or not the particular therapy increases capillary pressure. Pulmonary capillary pressure is the most important determinant of lung fluid balance and is the major physiologic parameter that should be measured when various forms of plasma volume expansion and pulmonary vasodilators are used in the critically ill patient.     

Pulmonary Vasodilator Responses to Nitroprusside and Nitroglycerin in the Dog

The objective of this study was to determine the direct actions of nitroprusside and nitroglycerin on the pulmonary vascular bed in the intactchest dog. These widely used nitrogen oxide-containing vasodilator agents decreased pulmonary arterial pressure and increased cardiac output without altering left atrial pressure. Reductions in pulmonary arterial pressure and pulmonary vascular resistance were small under resting conditions, but were enhanced when pulmonary vascular tone was elevated by infusion of a stable prostaglandin analog that increases pulmonary vascular resistance by constricting intrapulmonary veins and upstream segments. In studies in which pulmonary blood flow to the left lower lobe was maintained constant, nitroprusside and nitroglycerin caused small but significant reductions in lobar arterial and small-vein pressures without significantly affecting left atrial pressure. With constant blood flow, lobar vascular pressures that were reduced in response to the vasodilators were more greatly reduced when lobar vascular resistance was increased by infusion of the prostaglandin analog or serotonin. However, when lobar vascular pressures were elevated by passive obstruction of lobar venous outflow, vasodilator responses to nitroprusside and nitroglycerin were not enhanced. These data suggest that nitroprusside and nitroglycerin decrease pulmonary vascular resistance by dilating intrapulmonary veins and upstream segments. These responses were minimal under control conditions but were enhanced when vascular tone was increased. This vasodilator action is independent of passive factors such as changes in pulmonary blood flow or left atrial pressure and is not secondary to an effect of these agents on the systemic circulation. Pulmonary vasodilator responses to nitroprusside and nitroglycerin were, however, found to be dependent on the existing level of vasomotor tone in the pulmonary vascular bed.     

Pulmonary hemodynamics in systemic hypertension

We reviewed cardiac catheterization data and the medical records of 30 patients with systemic hypertension to establish their pulmonary hemodynamic profiles and the relationship between certain clinical and demographic variables and increased pulmonary vascular resistance. Mean systemic arterial pressure ranged from 110 to 210 mm Hg, and systemic vascular resistance ranged from 17.6 to 47.0 units. Seven patients had normal pulmonary wedge pressure and normal pulmonary vascular resistance, one had elevated pulmonary wedge pressure and normal pulmonary vascular resistance, five had elevated pulmonary wedge pressure and increased pulmonary vascular resistance, and 17 had normal pulmonary wedge pressure and increased pulmonary vascular resistance. There were significant positive correlations between systemic vascular resistance and pulmonary vascular resistance and between mean systemic arterial pressure and mean pulmonary artery pressure, but there was no correlation between mean pulmonary wedge pressure and pulmonary vascular resistance. Of the 17 patients with normal pulmonary wedge pressure and increased pulmonary vascular resistance, seven had clinical or radiologic evidence of prior left ventricular failure. We conclude that increased pulmonary vascular resistance occurs commonly in patients with systemic hypertension. Although some cases of increased pulmonary vascular resistance relate to active or preexistent left ventricular failure, the majority remain unexplained, suggesting that neurohumoral or other factors may produce a hypertensive response in both the systemic and pulmonary arterial circuit.     

Pulmonary arterial remodeling induced by a Th2 immune response

Pulmonary arterial remodeling characterized by increased vascular smooth muscle density is a common lesion seen in pulmonary arterial hypertension (PAH), a deadly condition. Clinical correlation studies have suggested an immune pathogenesis of pulmonary arterial remodeling, but experimental proof has been lacking. We show that immunization and prolonged intermittent challenge via the airways with either of two different soluble antigens induced severe muscularization in small- to medium-sized pulmonary arteries. Depletion of CD4(+) T cells, antigen-specific T helper type 2 (Th2) response, or the pathogenic Th2 cytokine interleukin 13 significantly ameliorated pulmonary arterial muscularization. The severity of pulmonary arterial muscularization was associated with increased numbers of epithelial cells and macrophages that expressed a smooth muscle cell mitogen, resistin-like molecule alpha, but surprisingly, there was no correlation with pulmonary hypertension. Our data are the first to provide experimental proof that the adaptive immune response to a soluble antigen is sufficient to cause severe pulmonary arterial muscularization, and support the clinical observations in pediatric patients and in companion animals that muscularization represents one of several injurious events to the pulmonary artery that may collectively contribute to PAH.     

Pulmonary hypertension and cor pulmonale in COPD

The prevalence and natural history of cor pulmonale in COPD are not yet clear. Factors that are known to contribute to the development of pulmonary hypertension in COPD include hypoxic pulmonary vasoconstriction(HPV), remodeling of pulmonary arteries, destruction of the pulmonary capillary bed and polycythemia. In addition, impaired mechanisms of endothelium-dependent vasodilation such as reduced NO synthesis or release, and abnormal secretion of vasoconstrictor peptides play an important role in the development of pulmonary hypertension. These factors can lead to right ventricular hypertrophy and right heart failure. Pulmonary hypertension develops late in the course of COPD (stage III) usually after the development of severe hypoxemia and is associated with a poor prognosis of the disease.     

Nitric oxide and other novel therapies for pulmonary hypertension

Pulmonary hypertension is an uncommon, yet devastating, syndrome with a complex underlying pathobiology. Hypoxia, inflammation, and increased shear stress appear to be the primary pathogenic events; however, mechanisms by which these processes lead to pulmonary hypertension remain incompletely understood. The ultimate increase in pulmonary vascular resistance is attributed to remodelling of the walls of resistance vessels, which can lead to encroachment on and reduction of the vascular lumen. The number of blood vessels per unit of cross-sectional area in the hypertensive lung is also reduced, which can contribute to increased vascular resistance. Regardless of its etiology, endothelial dysfunction underlies pulmonary hypertension, one manifestation of which is the attenuated production of bioactive nitric oxide. Nitric oxide administration can exert beneficial effects at various stages of the disease. Here we review the known pathobiology of pulmonary hypertension, with a principal focus on endothelial nitric oxide, and also summarize the data on nitric oxide replacement therapy and other novel therapies that relate to nitric oxide as one approach to treatment.     

Endotoxemic pulmonary hypertension is largely mediated by endothelin-induced venous constriction

Objective To analyze the effect of endothelin-1 on pulmonary arterial and venous contractile force in vitro and on up- and downstream pulmonary vascular resistance in vivo under sham and endotoxemic conditions in pigs. Materials and methods In vitro: paired preparations of pulmonary arteries and veins were mounted in a myograph (n = 13) for measurements of contractile responses to increasing concentrations of phenylephrine, endothelin-1, and sarafotoxin (endothelin receptor type B agonist). In vivo: 20 pigs were anesthetized, mechanically ventilated, and subjected to phenylephrine (reference substance), endothelin-1, sarafotoxin, endotoxin, and tezosentan (dual endothelin receptor antagonist). Hemodynamic and gas-exchange variables were monitored. Pulmonary capillary pressure, used for calculation of upstream and downstream vascular resistance, was assessed by the pulmonary vascular occlusion technique. Measurements and results Pulmonary veins were more sensitive than arteries to endothelin-1 both in vitro and in vivo. This difference was more pronounced with sarafotoxin, where almost no arterial effects were noted. In vivo and in vitro exposure to phenylephrine resulted in selective arterial constriction. Endotoxin infusion resulted in pulmonary hypertension with a clear downstream dominance. The latter changes including the increase in capillary pressure were totally abolished by intervention with the dual endothelin receptor antagonist tezosentan. Conclusions The endothelin system is extensively involved in endotoxemic pulmonary venous hypertension, an effect possibly mediated by the endothelin B receptor. Electronic supplementary material The online version of this article (doi:) contains supplementary material, which is available to authorized users. This study was supported by the Swedish Research Council, the Swedish Heart-Lung Foundation, and funds from the Karolinska Institute and Swedish Society of Medicine.