Structural and functional changes of the pulmonary vasculature after hypoxia exposure in the neonatal period - a new swine model of pulmonary vascular disease

Introduction: Hypertension and hyperperfusion of the pulmonary vascular bed in the setting of congenital cardiac malformations may lead to progressive pulmonary vascular disease. To improve the understanding of the basic mechanisms of this disease, there is a need for clinically relevant animal models which reflect the disease process. Material and Results: We randomly allocated 45 newborn pigs, at the age of 48 hrs, to groups in which there was either construction of a 3 mm central aorto-pulmonary shunt, undertaken in 9, or ligation of the left pulmonary artery, achieved in 13. Controls included sham operations in 13, or no operations in 10 pigs. Follow-up was continued for three months. The interventions were compatible with survival in most pigs. The shunts resulted in an acute 85% increase in systolic pulmonary arterial pressure, and a more than twofold increase in pulmonary blood flow. By three months of age, nearly all shunts had closed spontaneously, and haemodynamics were normal. Ligation of the left pulmonary artery resulted in a normal total pulmonary blood flow, despite only the right lung being perfused, and a 33% increase in systolic pulmonary arterial pressure. These haemodynamic changes were maintained throughout the period of study. In both groups, histomorphometry revealed markedly increased muscularity of the intra-acinar pulmonary arteries. Circulating levels of endothelin were normal in the shunted animals, and elevated in those with ligation of the left pulmonary artery. Conclusion: In neonatal porcine models of pulmonary vascular disease, created by construction of 3 mm central aorto-pulmonary shunts and ligation of one pulmonary artery, we observed histopathological changes of the pulmonary vasculature similar to early hypertensive pulmonary vascular disease in humans. Elevated circulating levels of endothelin were associated with abnormal haemodynamics rather than abnormal pathology. These findings could be valuable for future studies on the pathogenesis of hypertensive pulmonary vascular disease associated with congenital cardiac malformations.

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Mechanics and Function of the Pulmonary Vasculature: Implications for Pulmonary Vascular Disease and Right Ventricular Function

Comprehensive Physiology ◽

10.1002/cphy.c100070 ◽

2012 ◽

Cited By ~ 3

Author(s):

Steven Lammers ◽

Devon Scott ◽

Kendall Hunter ◽

Wei Tan ◽

Robin Shandas ◽

...

Keyword(s):

Right Ventricular ◽

Vascular Disease ◽

Ventricular Function ◽

Right Ventricular Function ◽

Pulmonary Vasculature ◽

Pulmonary Vascular Disease ◽

And Function

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Impact of human immunodeficiency virus on pulmonary vascular disease

Global Cardiology Science and Practice ◽

10.21542/gcsp.2021.12 ◽

2021 ◽

Vol 2021 (2) ◽

Author(s):

Ashok Kumar ◽

Aatish Mahajan ◽

Ethan A Salazar ◽

Kevin Pruitt ◽

Christian Arce Guzman ◽

...

Keyword(s):

Vascular Disease ◽

Clinical Manifestations ◽

Pulmonary Vasculature ◽

Pulmonary Vascular Disease ◽

Chronic Obstructive ◽

People Living With Hiv ◽

Obstructive Pulmonary Disease ◽

Advantages And Disadvantages ◽

Complex Interactions ◽

Living With Hiv

With the advent of anti-retroviral therapy, non-AIDS-related comorbidities have increased in people living with HIV. Among these comorbidities, pulmonary hypertension (PH) is one of the most common causes of morbidity and mortality. Although chronic HIV-1 infection is independently associated with the development of pulmonary arterial hypertension, PH in people living with HIV may also be the outcome of various co-morbidities commonly observed in these individuals including chronic obstructive pulmonary disease, left heart disease and co-infections. In addition, the association of these co-morbidities and other risk factors, such as illicit drug use, can exacerbate the development of pulmonary vascular disease. This review will focus on these complex interactions contributing to PH development and exacerbation in HIV patients. We also examine the interactions of HIV proteins, including Nef, Tat, and gp120 in the pulmonary vasculature and how these proteins alter the endothelial and smooth muscle function by transforming them into susceptible PH phenotype. The review also discusses the available infectious and non-infectious animal models to study HIV- associated PAH, highlighting the advantages and disadvantages of each model, along with their ability to mimic the clinical manifestations of HIV-PAH.

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DIAGNOSIS AND TREATMENT: MANAGEMENT OF VENTRICULAR SEPTAL DEFECT

PEDIATRICS ◽

10.1542/peds.34.2.271 ◽

1964 ◽

Vol 34 (2) ◽

pp. 271-273

Author(s):

Alexander S. Nadas

Keyword(s):

Blood Flow ◽

Ventricular Septal Defect ◽

Vascular Disease ◽

Pulmonary Blood Flow ◽

Septal Defect ◽

Pulmonary Vasculature ◽

Pulmonary Vascular Disease ◽

The Status ◽

Full Analysis ◽

Intelligent Management

Intelligent management of a ventricular septal defect necessitates full analysis of the size of the defect, the shunt across it and the status of the pulmonary vasculature. Only patients with moderate or large defects with appreciably increased pulmonary blood flow deserve surgery. Those with small left-to-right shunts, with or without pulmonary vascular disease, should be managed medically.

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Abstract 13549: GP130 Signaling Promotes Right Ventricular Dysfunction in Pulmonary Arterial Hypertension via Microtubules

Circulation ◽

10.1161/circ.142.suppl_3.13549 ◽

2020 ◽

Vol 142 (Suppl_3) ◽

Author(s):

Sasha Z Prisco ◽

Lynn Hartweck ◽

Lauren Rose ◽

Thenappan Thenappan ◽

Kurt W Prins

Keyword(s):

Mass Spectrometry ◽

Pulmonary Arterial Hypertension ◽

Arterial Hypertension ◽

Vascular Disease ◽

Pulmonary Vasculature ◽

Pulmonary Vascular Disease ◽

Heart Catheterization ◽

Pulmonary Arterial ◽

The Relationship ◽

Rv Function

Introduction: Pulmonary arterial hypertension (PAH) is a lethal pulmonary arterial vasculopathy that results in right ventricle dysfunction (RVD). We showed that microtubule-mediated junctophilin-2 (MT-JPH2 pathway) downregulation promotes t-tubule disruption and RVD; however, the upstream regulators of this pathway are unknown. GP130 signaling via its downstream mediator, STAT3 promotes microtubule remodeling in neonatal cardiomyocytes. However, the relationship between GP130 signaling and the MT-JPH2 pathway in RVD are unknown. Methods: Immunoblots of RV extracts were probed for the GP130 and the MT-JPH2 pathways in MCT rats treated with a GP130 antagonist (2 weeks after MCT injection). Quantitative mass spectrometry analyzed the microtubule associated protein (MAP) fraction of RV extracts. Echocardiography and invasive closed-chest right heart catheterization quantified RV function and pulmonary vascular disease. Pulmonary vasculature remodeling was assessed by H&E histology. Finally, the relationship between the GP130 agonist, interleukin (IL)-6, and RVD in PAH patients was examined. Results: GP130 antagonist treatment blunted RV STAT3 activation, normalized the MT-JPH2 pathway, and restored t-tubule architecture. Hierarchical cluster analysis and principal component analysis of 2842 proteins identified using mass spectrometry revealed normalization of the MAP-fraction with GP130 antagonist treatment. These molecular changes manifested as improved RV function, improved RV-pulmonary artery coupling, blunted RV hypertrophy, and improved survival despite no differences in pulmonary vascular disease severity. In PAH patients, higher IL-6 levels were associated with higher N-terminal pro-brain natriuretic peptide and lower RV fractional area change despite no differences in pulmonary vascular disease burden. Conclusions: Small molecular inhibition of GP130 enhances RV function, and improves survival in MCT PAH via modulation of the MT-JPH2 pathway.

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