Biventricular diastolic dysfunction, thrombocytopenia, and red blood cell macrocytosis in experimental pulmonary arterial hypertension.

Pulmonary arterial hypertension is a fatal disease, where death is associated with right heart failure and reduced cardiorespiratory reserve. The Sugen 5416, hypoxia and normoxia Fischer rat model mimics human pulmonary arterial hypertension, although the cause(s) of death remains incompletely understood. Here, we hypothesized that these animals develop biventricular diastolic dysfunction that contributes to tissue hypoperfusion coincident with severe pulmonary arterial hypertension.

The changing face of pulmonary hypertension diagnosis: a historical perspective on the influence of diagnostics and biomarkers.

Pulmonary hypertension is a complex, multifactorial disease that results in right heart failure and premature death. Since the initial reports of pulmonary hypertension in the late 1800s, the diagnosis of pulmonary hypertension has evolved with respect to its definition, screening tools, and diagnostic techniques. This historical perspective traces the earliest roots of pulmonary hypertension detection and diagnosis through to the current recommendations for classification.

Therapy for Pulmonary Arterial Hypertension in Adults: Update of the CHEST Guideline and Expert Panel Report.

Background: Pulmonary arterial hypertension (PAH) carries a poor prognosis if not promptly diagnosed and appropriately treated. The development and approval of 14 medications over the last several decades have led to a rapidly evolving approach to therapy, and have necessitated periodic updating of evidence-based treatment guidelines. This guideline statement, which now includes a visual algorithm to enhance its clinical utility, represents the fourth iteration of the American College of Chest Physicians Guideline and Expert Panel Report on Pharmacotherapy for PAH.

Health Disparities in Patients with Pulmonary Arterial Hypertension: A Blueprint for Action. An Official American Thoracic Society Statement.

Background: Health disparities have a major impact in the quality of life and clinical care received by minorities in the United States. Pulmonary arterial hypertension (PAH) is a rare cardiopulmonary disorder that affects children and adults and that, if untreated, results in premature death. The impact of health disparities in the diagnosis, treatment, and clinical outcome of patients with PAH has not been systematically investigated.

Clinical characteristics and survival of systemic sclerosis patients with pulmonary hypertension and elevated wedge pressure: Observations from the PHAROS cohort.

Background And Objective: Systemic sclerosis (SSc) is a complex autoimmune disease commonly associated with pulmonary hypertension (PH). When associated with elevated pulmonary artery wedge pressure (PAWP), pulmonary artery pressure (PAP) is either in-proportion (post-capillary PH) or higher than expected (combined PH) relative to the increased PAWP.

Methods: Patients from the PHAROS registry (a prospective observational cohort of SSc-PH patients) who had mean PAP ≥ 25 and PAWP > 15 on right heart catheterization were stratified based on diastolic pressure gradient (DPG).

Sphingosine-1-phosphate is involved in the occlusive arteriopathy of pulmonary arterial hypertension.

Despite several advances in the pathobiology of pulmonary arterial hypertension (PAH), its pathogenesis is not completely understood. Current therapy improves symptoms but has disappointing effects on survival. Sphingosine-1-phosphate (S1P) is a lysophospholipid synthesized by sphingosine kinase 1 (SphK1) and SphK2.

Participant expectations in pulmonary hypertension-related research studies.

The Pulmonary Hypertension Association (PHA) is a patient advocacy organization seeking to find ways to prevent, improve treatment for, and cure pulmonary hypertension (PH) and to provide hope for the PH community through support, education, research, advocacy, and awareness. Many patients involved with PHA are also involved in various PH-specific research studies; however, the patient expectations and priorities for PH-specific research are currently unknown or not well examined. Our objective was to identify the current modes of study entry, priorities within research, and expectations over the course of study involvement for patient constituents of PHA.

An official American Thoracic Society Statement: pulmonary hypertension phenotypes.

Background: Current classification of pulmonary hypertension (PH) is based on a relatively simple combination of patient characteristics and hemodynamics. This limits customization of treatment, and lacks the clarity of a more granular identification based on individual patient phenotypes. Rapid advances in mechanistic understanding of the disease, improved imaging methods, and innovative biomarkers now provide an opportunity to define PH phenotypes on the basis of biomarkers, advanced imaging, and pathobiology.

Dehydroepiandrosterone restores right ventricular structure and function in rats with severe pulmonary arterial hypertension.

Current therapy of pulmonary arterial hypertension (PAH) is inadequate. Dehydroepiandrosterone (DHEA) effectively treats experimental pulmonary hypertension in chronically hypoxic and monocrotaline-injected rats. Contrary to these animal models, SU5416/hypoxia/normoxia-exposed rats develop a more severe form of occlusive pulmonary arteriopathy and right ventricular (RV) dysfunction that is indistinguishable from the human disorder.

Alveolar hypoxia promotes murine lung tumor growth through a VEGFR-2/EGFR-dependent mechanism.

Patients with chronic obstructive pulmonary disease (COPD) are at an increased risk for the development of lung cancer, the mechanisms for which are incompletely understood. We hypothesized that the hypoxic pulmonary microenvironment present in COPD would augment lung carcinogenesis. Mice were subjected to chemical carcinogenesis protocols and placed in either hypoxia or normoxia.

Misclassification of pulmonary hypertension in adults with sickle hemoglobinopathies using Doppler echocardiography.

Objective: To compare the diagnostic utility of Doppler echocardiography-derived tricuspid regurgitant jet velocity (TRV) ≥ 2.5 m/s to right heart catheterization (RHC) in defining pulmonary hypertension (PH) in adult patients with sickle cell disease (SCD).

Methods: This is a retrospective chart review of adults with SCD who had a TRV ≥ 2.

Cytoskeletal defects in Bmpr2-associated pulmonary arterial hypertension.

The heritable form of pulmonary arterial hypertension (PAH) is typically caused by a mutation in bone morphogenic protein receptor type 2 (BMPR2), and mice expressing Bmpr2 mutations develop PAH with features similar to human disease. BMPR2 is known to interact with the cytoskeleton, and human array studies in PAH patients confirm alterations in cytoskeletal pathways. The goal of this study was to evaluate cytoskeletal defects in BMPR2-associated PAH.

Tyrosine kinase inhibitors are potent acute pulmonary vasodilators in rats.

Tyrosine kinase inhibitors are promising for the treatment of severe pulmonary hypertension. Their therapeutic effects are postulated to be due to inhibition of cell growth-related kinases and attenuation of vascular remodeling. Their potential vasodilatory activities have not been explored.

Strategic plan for lung vascular research: An NHLBI-ORDR Workshop Report.

The Division of Lung Diseases of the National Heart, Lung, and Blood Institute, with the Office of Rare Diseases Research, held a workshop to identify priority areas and strategic goals to enhance and accelerate research that will result in improved understanding of the lung vasculature, translational research needs, and ultimately the care of patients with pulmonary vascular diseases. Multidisciplinary experts with diverse experience in laboratory, translational, and clinical studies identified seven priority areas and discussed limitations in our current knowledge, technologies, and approaches. The focus for future research efforts include the following: (1) better characterizing vascular genotype-phenotype relationships and incorporating systems biology approaches when appropriate; (2) advancing our understanding of pulmonary vascular metabolic regulatory signaling in health and disease; (3) expanding our knowledge of the biologic relationships between the lung circulation and circulating elements, systemic vascular function, and right heart function and disease; (4) improving translational research for identifying disease-modifying therapies for the pulmonary hypertensive diseases; (5) establishing an appropriate and effective platform for advancing translational findings into clinical studies testing; and (6) developing the specific technologies and tools that will be enabling for these goals, such as question-guided imaging techniques and lung vascular investigator training programs.

Formation of plexiform lesions in experimental severe pulmonary arterial hypertension.

Background: The plexiform lesion is the hallmark of severe pulmonary arterial hypertension. However, its genesis and hemodynamic effects are largely unknown because of the limited availability of lung tissue samples from patients with pulmonary arterial hypertension and the lack of appropriate animal models. This study investigated whether rats with severe progressive pulmonary hypertension developed plexiform lesions.

Rho kinase-mediated vasoconstriction in pulmonary hypertension.

Rho kinase-mediated vasoconstriction rather than fixed arterial wall thickening is responsible for increased pulmonary vascular resistance and pulmonary hypertension in chronically hypoxic and monocrotaline-injected rats. In the absence of vascular tone, the medial and adventitial thickening in these models has only minimal impact on the cross-sectional area of the pulmonary arterial bed. In contrast, increased pulmonary vascular resistance in left-pneumonectomized plus monocrotaline-injected rats and VEGF receptor blocker-injected plus chronic hypoxia rats is attributable to both Rho kinase-mediated vasoconstriction and formation of lumen obliterating lesions in small pulmonary arteries.

Use of fat-fed rats to study the metabolic and vascular sequelae of obesity and beta-adrenergic antagonism.

Obesity-associated cardiovascular disease exerts profound human and monetary costs, creating a mounting need for cost-effective and relevant in vivo models of the complex metabolic and vascular interrelationships of obesity. Obesity is associated with endothelial dysfunction and inflammation. Free fatty acids (FFA), generated partly through beta-adrenergic receptor-mediated lipolysis, may impair endothelium-dependent vasodilation (EDV) by proinflammatory mechanisms.

Future perspectives for the treatment of pulmonary arterial hypertension.

Over the past 2 decades, pulmonary arterial hypertension has evolved from a uniformly fatal condition to a chronic, manageable disease in many cases, the result of unparalleled development of new therapies and advances in early diagnosis. However, none of the currently available therapies is curative, so the search for new treatment strategies continues. With a deeper understanding of the genetics and the molecular mechanisms of pulmonary vascular disorders, we are now at the threshold of entering a new therapeutic era.

Neprilysin null mice develop exaggerated pulmonary vascular remodeling in response to chronic hypoxia.

Neprilysin is a transmembrane metalloendopeptidase that degrades neuropeptides that are important for both growth and contraction. In addition to promoting carcinogenesis, decreased levels of neprilysin increases inflammation and neuroendocrine cell hyperplasia, which may predispose to vascular remodeling. Early pharmacological studies showed a decrease in chronic hypoxic pulmonary hypertension with neprilysin inhibition.

Mice expressing BMPR2R899X transgene in smooth muscle develop pulmonary vascular lesions.

Familial pulmonary arterial hypertension (PAH) is associated with mutations in bone morphogenetic protein type II receptor (BMPR2). Many of these mutations occur in the BMPR2 tail domain, leaving the SMAD functions intact. To determine the in vivo consequences of BMPR2 tail domain mutation, we created a smooth muscle-specific doxycycline-inducible BMPR2 mutation with an arginine to termination mutation at amino acid 899.

Vascular dysfunction in a murine model of severe hemolysis.

Spectrin is the backbone of the erythroid cytoskeleton; sph/sph mice have severe hereditary spherocytosis (HS) because of a mutation in the murine erythroid alpha-spectrin gene. sph/sph mice have a high incidence of thrombosis and infarction in multiple tissues, suggesting significant vascular dysfunction. In the current study, we provide evidence for both pulmonary and systemic vascular dysfunction in sph/sph mice.