Pathophysiology Of Pulmonary Arterial Hypertension Research Articles

Tezosentan Decreases Pulmonary Artery Pressure and Improves Survival Rate in an Animal Model of Meconium Aspiration

Acute pulmonary arterial hypertension in acute lung injury aggravates the clinical course and complicates treatment. Increased release and turnover of endogenous endothelin-1 is known to be a major determinant in the pathophysiology of pulmonary arterial hypertension of various etiologies. We tested whether intravenous tezosentan, a dual endothelin receptor antagonist, reduced pulmonary artery pressure in a pig model of acute lung injury induced by meconium aspiration. Acute pulmonary arterial hypertension was induced in 12 anesthetized and instrumented pigs by instillation of human pooled meconium in a 20% solution. Hemodynamic and gas exchange parameters were recorded every 30 min. Six animals received tezosentan 5 mg/kg after 0 and 90 min; six animals served as controls. Tezosentan led to a decrease of mean pulmonary artery pressure (PAP) from 33.4 +/- 4.0 mm Hg to 24.7 +/- 2.1 mm Hg and pulmonary vascular resistance (PVR) from 7.8 +/- 1.4 mm Hg.L(-1).min.m2 to 5.2 +/- 0.7 mm Hg.L(-1).min.m2. All animals treated with tezosentan survived, whereas in the control group four out of six animals died. Tezosentan improved survival and decreased pulmonary artery pressure in a porcine model of acute pulmonary arterial hypertension after meconium aspiration. Tezosentan has the potential for effective pharmacological treatment of pulmonary arterial hypertension following acute lung injury.

Pulmonary arterial hypertension: an autoimmune disease?

Pulmonary arterial hypertension (PAH) is a rare condition that occurs as a consequence of chronic obstruction of small pulmonary arteries due to endothelial cell, vascular smooth muscle cell and fibroblast dysfunction and proliferation 1. In recent years, major advances have been achieved in the understanding of PAH pathophysiology 1–7. It has been firmly demonstrated that pulmonary artery endothelial dysfunction leads to chronically impaired production of vasodilators, such as nitric oxide and prostacyclin, along with overexpression of vasoconstrictors such as endothelin-1 8–10. Moreover, genetic studies have shown that germline mutations in the gene coding for bone morphogenetic protein receptor type II (BMPR2) certainly play a critical role in a proportion of patients with familial and idiopathic PAH 2, 3. Immune disturbances are also believed to contribute to PAH 5. This is particularly clear in PAH related to connective tissue diseases 5, 11. In addition, there is a long standing association between autoimmunity and PAH of various origins including idiopathic PAH. However, it remains uncertain how autoimmune mechanisms contribute to the pathogenesis of PAH. In the current issue of the European Respiratory Journal , Nicolls et al. 7 review available data documenting the association of autoimmunity and PAH and speculate on the possible role of autoimmune injury in the pathogenesis of the disease. PAH is a common …

Pro: Inhaled Prostaglandin as a Pulmonary Vasodilator Instead of Nitric Oxide

PERIOPERATIVE MANAGEMENT of pulmonary hypertension (PHTN) is important because it significantly affects perioperative outcome. Perioperative PHTN and accompanying right ventricular (RV) failure are major predictors for mortality after coronary artery bypass grafting, left ventricular assist-device placement, and heart transplantation. 1 Maslow A. Regan M. Panzica P. et al. Precardiopulmonary bypass right ventricular function is associated with poor outcome after coronary artery bypass grafting in patients with severe left ventricular systolic dysfunction. Anesth Analg. 2002; 95: 1507-1518 Crossref PubMed Scopus (159) Google Scholar , 2 Fukamachi K. McCarthy P.M. Smedira N. et al. Preoperative risk factors for right ventricular failure after implantable left ventricular assist device insertion. Ann Thor Surg. 1999; 68: 2181-2184 Abstract Full Text Full Text PDF PubMed Scopus (208) Google Scholar , 3 Augoustides J.G. Ochroch E.A. Perioperative use of nitric oxide in cardiothoracic anesthesia and intensive care. Prog Anesth. 2001; 15: 115-124 Google Scholar Inhaled nitric oxide (iNO) was the first selective pulmonary vasodilator that allowed selective pulmonary vasodilation with no systemic vasodilation. This pharmacologic breakthrough represented a significant advance in the perioperative management of PHTN and RV dysfunction. 3 Augoustides J.G. Ochroch E.A. Perioperative use of nitric oxide in cardiothoracic anesthesia and intensive care. Prog Anesth. 2001; 15: 115-124 Google Scholar , 4 Augoustides J.G. Mancini D.J. Postoperative care of the adult cardiac surgical patient. Prog Anesth. 2002; 16: 99-112 Google Scholar , 5 Steudel W. Hurford W. Zapol W. Inhaled nitric oxide Basic biology and clinical applications. Anesthesiology. 1999; 91: 1090-1121 Crossref PubMed Scopus (133) Google Scholar , 6 Blaise G. Langleben D. Hubert B. Pulmonary arterial hypertension Pathophysiology and anesthetic approach. Anesthesiology. 2003; 99: 1415-1432 Crossref PubMed Scopus (153) Google Scholar , 7 Fischer L.G. Van Atken H. Burkle H. Management of pulmonary hypertension and pharmacological considerations for anesthesiologists. Anesth Analg. 2003; 96: 1603-1616 Crossref PubMed Scopus (156) Google Scholar

When cure is care: Diagnosis and management of pulmonary arterial hypertension

PurposeThe purpose of this article is to provide nurse practitioners with an understanding of the pathophysiology of pulmonary arterial hypertension (PAH) disease, clinical manifestations, diagnostic evaluation, drug therapy, strategies for health promotion, and relevant care issues for patients and families.Data sourcesSelected clinical and research articles, as well as current government guidelines.ConclusionsSymptoms expressed are more apparent as PAH disease progresses, leaving fewer treatment options in advanced disease stages. New drugs are currently being tested for the treatment of PAH; however, the costs of many of the currently approved treatments may be prohibitive.Implications for practiceEarlier recognition of disease symptoms leads to prompt initiation of diagnostic evaluation and referral to specializing medical centers. Upon referral, specialty centers may begin appropriate treatment regimens earlier in the disease process, which could improve clinical outcomes and quality of life.

Red Blood Cell S-Nitrosohemoglobin Deficiency in Pulmonary Arterial Hypertension.

Recent studies have suggested that binding of oxygen to hemoglobin (Hb) facilitates reactions of nitric oxide (NO) that lead to production of S-nitrosohemoglobin (SNO-Hb), and that vasodilator S-nitrosthiol (SNO) is dispensed by red blood cells (RBCs) at low oxygen tension (pO2) to dilate blood vessels. In human lungs, NO bioactivity serves to attenuate hypoxic pulmonary vasoconstriction (HPV). We therefore considered the possibility that RBC-SNO may oppose HPV and that defective vasodilation by RBCs may contribute to the pathophysiology of pulmonary arterial hypertension (PAH). Here we report that RBCs from patients with PAH exhibit substantial depletion of SNO-Hb and consequent impairment in hypoxia-mediated vasodilation. Furthermore, levels of RBC-NO correlated inversely with pulmonary artery pressures. A SNO-Hb deficiency characteristic of PAH was reproduced in control RBCs by hypoxia: loss of SNO-Hb was accompanied by a buildup of heme-NO species that are deficient in the pO2-governed intramolecular transfer of NO to cysteine thiol, yielding RBCs deficient in NO bioactivity. SNO-deficient RBCs produced exaggerated HPV responses as compared to SNO-replete RBCs. In PAH patients, SNO-Hb repletion fully restored the hypoxic vasodilator activity of RBCs. Our results suggest that a deficiency in RBC-SNO contributes to pulmonary hypertension and hypoxemia, and that repletion of RBC-SNO represents a rational strategy for treating PAH patients.

Increased arginase II and decreased NO synthesis in endothelial cells of patients with pulmonary arterial hypertension.

Pulmonary arterial hypertension (PAH), a fatal disease of unknown etiology characterized by impaired regulation of pulmonary hemodynamics and vascular growth, is associated with low levels of pulmonary nitric oxide (NO). Based upon its critical role in mediating vasodilation and cell growth, decrease of NO has been implicated in the pathogenesis of PAH. We evaluated mechanisms for low NO and pulmonary hypertension, including NO synthases (NOS) and factors regulating NOS activity, i.e. the substrate arginine, arginase expression and activity, and endogenous inhibitors of NOS in patients with PAH and healthy controls. PAH lungs had normal NOS I-III expression, but substrate arginine levels were inversely related to pulmonary artery pressures. Activity of arginase, an enzyme that regulates NO biosynthesis through effects on arginine, was higher in PAH serum than in controls, with high-level arginase expression localized by immunostaining to pulmonary endothelial cells. Further, pulmonary artery endothelial cells derived from PAH lung had higher arginase II expression and produced lower NO than control cells in vitro. Thus, substrate availability affects NOS activity and vasodilation, implicating arginase II and alterations in arginine metabolic pathways in the pathophysiology of PAH.

Pharmacogenomics in pulmonary arterial hypertension (PAH): the relationship between an ET-1 gene polymorphism (PM) and efficacy of bosentan (BO)

Purpose: ET-1 plays a key role in the pathophysiology of PAH. Levels of ET-1 correlate with the severity of PAH and may be influenced by the presence of certain PMs in the ET-1 gene. BO is an nonselective ET receptor antagonist used to treat PAH. Therefore a pharmacogenetic interaction may occur in patients (pts) with specific ET-1 PMs treated with BO. We investigated whether this interactions exists for the G/T ET-1 PM where the T allele appears to be associated with higher ET-1 levels.

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 ETAand ETBreceptor subtypes, is a key causative agent in the pathophysiology of pulmonary arterial hypertension. The orally active dual endothelin receptor antagonist bosentan1competitively 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.

High Prevalence of Autoimmune Thyroid Disease in Pulmonary Arterial Hypertension

An association between thyroid disease and pulmonary arterial hypertension (PAH) has been reported, yet the pathogenetic relationship between these conditions remains unclear. Because immune system dysfunction may underlie this association, we sought to determine the prevalence of autoimmune thyroid disease (AITD) in patients with PAH. Prospective observational study at a single academic institution. Sixty-three consecutive adults with PAH (ie, sustained pulmonary artery systolic pressure, > 25 mm Hg) were evaluated for clinical, biochemical, and serologic features of AITD. Thyroid gland dysfunction was determined by clinical examination for goiter, and by biochemical measurements of thyrotropin and free thyroxine. Immune system dysfunction was determined by serologic measurements of antibodies to thyroglobulin and thyroid peroxidase. First-degree family history of AITD also was ascertained in order to investigate for genetic clustering of autoimmunity. Thirty-one patients (49%; 95% confidence interval [CI], 37 to 62%) received diagnoses of AITD. Eighteen patients were newly diagnosed, and 9 patients required the initiation of pharmacologic treatment. There was no chronologic relationship between the diagnosis or treatment of PAH and that of AITD. Sixteen patients (25%; 95% CI, 15 to 36%) had 24 first-degree family members with AITD. Approximately half of the patients with PAH have concomitant AITD. These two conditions may be linked by a common immunogenetic susceptibility, and the elucidation of this association may advance the understanding of the pathophysiology and treatment of PAH. Systematic surveillance for occult thyroid dysfunction in patients with PAH may prevent the hemodynamic exacerbation of right heart failure.

Pulmonary arterial hypertension in congenital heart disease

Pulmonary arterial hypertension (PAH) is a recognized complication of congenital systemic to pulmonary arterial cardiac shunts. The prognosis of PAH in this situation is better than primary or other secondary forms of PAH. Our knowledge of the pathophysiology of PAH complicating congenital heart disease has evolved over the past decade. Despite differences in etiology and pathobiology, therapies that have proven successful for primary PAH may benefit this group of patients.