Left main bronchus compression due to main pulmonary artery dilatation in pulmonary hypertension: two case reports

Abstract. Pulmonary arterial dilatation associated with pulmonary hypertension may result in significant compression of local structures. Left main coronary artery and left recurrent laryngeal nerve compression have been described. Tracheobronchial compression from pulmonary arterial dilatation is rare in adults, and there are no reports in the literature of its occurrence in idiopathic pulmonary arterial hypertension. Compression in infants with congenital heart disease has been well described. We report 2 cases of tracheobronchial compression: first, an adult patient with idiopathic pulmonary arterial hypertension who presents with symptomatic left main bronchus compression, and second, an adult patient with Eisenmenger ventricular septal defect and right-sided aortic arch, with progressive intermedius and right middle lobe bronchi compression in association with enlarged pulmonary arteries

Pathogenic Role of mTORC1 and mTORC2 in Pulmonary Hypertension.

Concentric lung vascular wall thickening due to enhanced proliferation of pulmonary arterial smooth muscle cells is an important pathological cause for the elevated pulmonary vascular resistance reported in patients with pulmonary arterial hypertension. We identified a differential role of mammalian target of rapamycin (mTOR) complex 1 and complex 2, two functionally distinct mTOR complexes, in the development of pulmonary hypertension (PH). Inhibition of mTOR complex 1 attenuated the development of PH; however, inhibition of mTOR complex 2 caused spontaneous PH, potentially due to up-regulation of platelet-derived growth factor receptors in pulmonary arterial smooth muscle cells, and compromised the therapeutic effect of the mTOR inhibitors on PH. In addition, we describe a promising therapeutic strategy using combination treatment with the mTOR inhibitors and the platelet-derived growth factor receptor inhibitors on PH and right ventricular hypertrophy. The data from this study provide an important mechanism-based perspective for developing novel therapies for patients with pulmonary arterial hypertension and right heart failure

Vascular fibrosis in aging and hypertension: molecular mechanisms and clinical implications

Aging is the primary risk factor underlying hypertension and incident cardiovascular disease. With aging, the vasculature undergoes structural and functional changes characterized by endothelial dysfunction, wall thickening, reduced distensibility, and arterial stiffening. Vascular stiffness results from fibrosis and extracellular matrix (ECM) remodelling, processes that are associated with aging and are amplified by hypertension. Some recently characterized molecular mechanisms underlying these processes include increased expression and activation of matrix metalloproteinases, activation of transforming growth factor-β1/SMAD signalling, upregulation of galectin-3, and activation of proinflammatory and profibrotic signalling pathways. These events can be induced by vasoactive agents, such as angiotensin II, endothelin-1, and aldosterone, which are increased in the vasculature during aging and hypertension. Complex interplay between the “aging process” and prohypertensive factors results in accelerated vascular remodelling and fibrosis and increased arterial stiffness, which is typically observed in hypertension. Because the vascular phenotype in a young hypertensive individual resembles that of an elderly otherwise healthy individual, the notion of “early” or “premature” vascular aging is now often used to describe hypertension-associated vascular disease. We review the vascular phenotype in aging and hypertension, focusing on arterial stiffness and vascular remodelling. We also highlight the clinical implications of these processes and discuss some novel molecular mechanisms of fibrosis and ECM reorganization

Clinical trials with endothelin receptor antagonists: What went wrong and where can we improve?

In the early 1990s, within three years of cloning of endothelin receptors, orally active endothelin receptor antagonists (ERAs) were tested in humans and the first clinical trial of ERA therapy in humans was published in 1995. ERAs were subsequently tested in clinical trials involving heart failure, pulmonary arterial hypertension, resistant arterial hypertension, stroke/subarachnoid hemorrhage and various forms of cancer. The results of most of these trials – except those for pulmonary arterial hypertension and scleroderma-related digital ulcers – were either negative or neutral. Problems with study design, patient selection, drug toxicity, and drug dosing have been used to explain or excuse failures. Currently, a number of pharmaceutical companies who had developed ERAs as drug candidates have discontinued clinical trials or further drug development. Given the problems with using ERAs in clinical medicine, at the Twelfth International Conference on Endothelin in Cambridge, UK, a panel discussion was held by clinicians actively involved in clinical development of ERA therapy in renal disease, systemic and pulmonary arterial hypertension, heart failure, and cancer. This article provides summaries from the panel discussion as well as personal perspectives of the panelists on how to proceed with further clinical testing of ERAs and guidance for researchers and decision makers in clinical drug development on where future research efforts might best be focused

Metformin reverses development of pulmonary hypertension via aromatase inhibition

Females are more susceptible to pulmonary arterial hypertension than males, although the reasons remain unclear. The hypoglycemic drug, metformin, is reported to have multiple actions, including the inhibition of aromatase and stimulation of AMP-activated protein kinase. Inhibition of aromatase using anastrazole is protective in experimental pulmonary hypertension but whether metformin attenuates pulmonary hypertension through this mechanism remains unknown. We investigated whether metformin affected aromatase activity and if it could reduce the development of pulmonary hypertension in the sugen 5416/hypoxic rat model. We also investigated its influence on proliferation in human pulmonary arterial smooth muscle cells. Metformin reversed right ventricular systolic pressure, right ventricular hypertrophy, and decreased pulmonary vascular remodeling in the rat. Furthermore, metformin increased rat lung AMP-activated protein kinase signaling, decreased lung and circulating estrogen levels, levels of aromatase, the estrogen metabolizing enzyme; cytochrome P450 1B1 and its transcription factor; the aryl hydrocarbon receptor. In human pulmonary arterial smooth muscle cells, metformin decreased proliferation and decreased estrogen synthesis by decreasing aromatase activity through the PII promoter site of Cyp19a1. Thus, we report for the first time that metformin can reverse pulmonary hypertension through inhibition of aromatase and estrogen synthesis in a manner likely to be mediated by AMP-activated protein kinase

Transient but not genetic loss of miR-451 attenuates the development of pulmonary arterial hypertension

<b>Rationale:</b> MicroRNAs are small non-coding RNAs involved in the regulation of gene expression and have recently been implicated in the development of pulmonary arterial hypertension (PAH). Previous work established that miR-451 is up-regulated in rodent models of PAH.<p></p> <b>Objectives:</b> The role of miR-451 in the pulmonary circulation is unknown. We therefore sought to assess the involvement of miR-451 in the development of pulmonary arterial hypertension.<p></p> <b>Methods:</b> Silencing of miR-451 was performed in vivo using miR-451 knockout mice and an antimiR targeting mature miR-451 in rats. Coupled with exposure to hypoxia, indices of pulmonary arterial hypertension were assessed. The effect of modulating miR-451 on human pulmonary artery smooth muscle cell proliferation and migration was analysed.<p></p> <b>Measurements and Main Results:</b> We observed a reduction in systolic right ventricular pressure in hypoxic rats pre-treated with antimiR-451 compared to hypoxia alone (47.7 ± 1.36mmHg and 56.0 ± 2.03mmHg respectively, p<0.01). In miR-451 knockout mice following exposure to chronic hypoxia, no significant differences were observed compared to wild type hypoxic mice. In vitro analysis demonstrated that over-expression of miR-451 in human pulmonary artery smooth muscle cells promoted migration under serum-free conditions. No effect on cellular proliferation was observed.<p></p> <b>Conclusions:</b> Transient inhibition of miR-451 attenuated the development of pulmonary arterial hypertension in hypoxia exposed rats. Genetic deletion of miR-451 had no beneficial effect on indices of pulmonary arterial hypertension, potentially due to pathway redundancy compensating for the loss of miR-451.<p></p&gt

Computational modeling of hypertensive growth in the human carotid artery

The final publication is available at Springer via http://dx.doi.org/10.1007/s00466-013-0959-zArterial hypertension is a chronic medical condition associated with an elevated blood pressure. Chronic arterial hypertension initiates a series of events, which are known to collectively initiate arterial wall thickening. However, the correlation between macrostructural mechanical loading, microstructural cellular changes, and macrostructural adaptation remains unclear. Here, we present a microstructurally motivated computational model for chronic arterial hypertension through smooth muscle cell growth. To model growth, we adopt a classical concept based on the multiplicative decomposition of the deformation gradient into an elastic part and a growth part. Motivated by clinical observations, we assume that the driving force for growth is the stretch sensed by the smooth muscle cells. We embed our model into a finite element framework, where growth is stored locally as an internal variable. First, to demonstrate the features of our model, we investigate the effects of hypertensive growth in a real human carotid artery. Our results agree nicely with experimental data reported in the literature both qualitatively and quantitatively.Peer ReviewedPostprint (author's final draft

Role of prostacyclin in pulmonary hypertension

Date of Acceptance: 11/12/2014 This is an open access article distributed under the terms of the Creative Commons Attribution license CC BY-4.0, which permits unrestricted use, distribution and reproduction in any medium, provided the original work is properly cited.Prostacyclin is a powerful cardioprotective hormone released by the endothelium of all blood vessels. Prostacyclin exists in equilibrium with other vasoactive hormones and a disturbance in the balance of these factors leads to cardiovascular disease including pulmonary arterial hypertension. Since it’s discovery in the 1980s concerted efforts have been made to make the best therapeutic utility of prostacyclin, particularly in the treatment of pulmonary arterial hypertension. This has centred on working out the detailed pharmacology of prostacyclin and then synthesising new molecules based on its structure that are more stable or more easily tolerated. In addition, newer molecules have been developed that are not analogues of prostacyclin but that target the receptors that prostacyclin activates. Prostacyclin and related drugs have without doubt revolutionised the treatment and management of pulmonary arterial hypertension but are seriously limited by side effects within the systemic circulation. With the dawn of nanomedicine and targeted drug or stem cell delivery systems it will, in the very near future, be possible to make new formulations of prostacyclin that can evade the systemic circulation allowing for safe delivery to the pulmonary vessels. In this way, the full therapeutic potential of prostacyclin can be realised opening the possibility that pulmonary arterial hypertension will become, if not curable, a chronic manageable disease that is no longer fatal. This review discusses these and other issues relating to prostacyclin and its use in pulmonary arterial hypertensionPeer reviewedFinal Published versio

Care of patients with pulmonary arterial hypertension during the coronavirus (COVID-19) pandemic

The COVID-19 pandemic presents many unique challenges when caring for patients with pulmonary hypertension. The COVID-19 pandemic has altered routine standard of care practice and the acute management particularly for those patients with pulmonary arterial hypertension, where pulmonary arterial hypertension-specific treatments are used. It is important to balance the ongoing care and evaluation of pulmonary arterial hypertension patients with exposure risk to COVID-19 for patients coming to clinic or the hospital. If there is a morbidity and mortality benefit from starting pulmonary arterial hypertension therapies, for example in a patient with high-likelihood of pulmonary arterial hypertension, then it remains important to complete the thorough evaluation. However, the COVID-19 outbreak may also represent a unique time when pulmonary hypertension experts have to weigh the risks and benefits of the diagnostic work-up including potential exposure to COVID-19 versus initiating targeted pulmonary arterial hypertension therapy in a select high-risk, high likelihood World Symposium Pulmonary Hypertension Group 1 pulmonary arterial hypertension patients. This document will highlight some of the issues facing providers, patients, and the pulmonary arterial hypertension community in real-time as the COVID-19 pandemic is evolving and is intended to share expected common clinical scenarios and best clinical practices to help the community at-large

Micro-CT Image-Derived Metrics Quantify Arterial Wall Distensibility Reduction in a Rat Model of Pulmonary Hypertension

We developed methods to quantify arterial structural and mechanical properties in excised rat lungs and applied them to investigate the distensibility decrease accompanying chronic hypoxia-induced pulmonary hypertension. Lungs of control and hypertensive (three weeks 11% O2) animals were excised and a contrast agent introduced before micro-CT imaging with a special purpose scanner. For each lung, four 3D image data sets were obtained, each at a different intra-arterial contrast agent pressure. Vessel segment diameters and lengths were measured at all levels in the arterial tree hierarchy, and these data used to generate features sensitive to distensibility changes. Results indicate that measurements obtained from 3D micro-CT images can be used to quantify vessel biomechanical properties in this rat model of pulmonary hypertension and that distensibility is reduced by exposure to chronic hypoxia. Mechanical properties can be assessed in a localized fashion and quantified in a spatially-resolved way or as a single parameter describing the tree as a whole. Micro-CT is a nondestructive way to rapidly assess structural and mechanical properties of arteries in small animal organs maintained in a physiological state. Quantitative features measured by this method may provide valuable insights into the mechanisms causing the elevated pressures in pulmonary hypertension of differing etiologies and should become increasingly valuable tools in the study of complex phenotypes in small-animal models of important diseases such as hypertension