S. John Wort

Nuclear Factor κ-B Is Activated in the Pulmonary Vessels of Patients with End-Stage Idiopathic Pulmonary Arterial Hypertension

Objectives To assess activation of the inflammatory transcription factor NF-kappa B (NF-κB) in human idiopathic pulmonary arterial hypertension (PAH). Background Idiopathic PAH is a severe progressive disease characterized by pulmonary vascular remodeling and excessive proliferation of vascular cells. Increasing evidence indicates that inflammation is important in disease pathophysiology. Methods NF-κB-p65 and CD68, CD20 and CD45 were measured by immunohistochemistry and confocal microscopy on lung specimens from patients with idiopathic PAH (n = 12) and controls undergoing lung surgery (n = 14). Clinical data were recorded for all patients including invasive pulmonary hemodynamics for the PAH patients. Immunohistochemical images were analyzed by blinded observers to include standard pulmonary vascular morphometry; absolute macrophage counts/mm2 and p65-positivity (p65+) using composite images and image-analysis software; and cytoplasmic:nuclear p65+ of individual pulmonary arterial endothelial and smooth muscle cells (PASMC) in 10–20 pulmonary arteries or arterioles per subject. The expression of ET-1 and CCL5 (RANTES) in whole lung was determined by RT-qPCR. Results Macrophage numbers were increased in idiopathic PAH versus controls (49.0±4.5 vs. 7.95±1.9 macrophages/100 mm2, p<0.0001): these macrophages demonstrated more nuclear p65+ than in macrophages from controls (16.9±2.49 vs. 3.5±1.25%, p<0.001). An increase in p65+ was also seen in perivascular lymphocytes in patients with PAH. Furthermore, NF-κB activation was increased in pulmonary arterial endothelial cells (62.3±2.9 vs. 14.4±3.8, p<0.0001) and PASMC (22.6±2.3 vs. 11.2±2.0, p<0.001) in patients with PAH versus controls, with similar findings in arterioles. Gene expression of both ET-1 mRNA ((0.213±0.069 vs. 1.06±0.23, p<0.01) and CCL5 (RANTES) (0.16±0.045 vs. 0.26±0.039, p<0.05) was increased in whole lung homogenates from patients with PAH. Conclusions NF-κB is activated in pulmonary macrophages, lymphocytes, endothelial and PASMC in patients with end-stage idiopathic PAH. Future research should determine whether NF-κB activation is a driver or bystander of pulmonary vascular inflammation and if the former, its potential role as a therapeutic target.

Sustained Elevation of Circulating Growth and Differentiation Factor-15 and a Dynamic Imbalance in Mediators of Muscle Homeostasis Are Associated With the Development of Acute Muscle Wasting Following Cardiac Surgery*

Objectives:Acute muscle wasting in the critically ill is common and causes significant morbidity. In a novel human model of acute muscle wasting following cardiac surgery, known or potential circulating modulators of muscle mass—insulin-like growth factor-1, myostatin, and growth and differentiation factor-15—were measured over a week. It was hypothesized that patients who developed acute muscle wasting would show distinct patterns of change in these mediators. Design:A prospective longitudinal observational study of high-risk elective cardiac surgical patients identifying, by ultrasound, those developing muscle wasting. Setting:Tertiary cardiothoracic referral center: Royal Brompton Hospital, London, UK. Patients:Forty-two patients undergoing elective high-risk cardiothoracic surgery. Interventions:Circulating insulin-like growth factor-1, myostatin, and growth and differentiation factor-15 were assayed preoperatively and over the first week postoperatively. The ability of growth and differentiation factor-15 to cause muscle wasting in vitro was determined in C2C12 myotubes. Measurements and Main Results:Of the 42 patients, 23 (55%) developed quadriceps atrophy. There was an acute decrease in insulin-like growth factor-1 and unexpectedly myostatin, known mediators of muscle hypertrophy and atrophy, respectively. By contrast, plasma growth and differentiation factor-15 concentrations increased in all patients. This increase in growth and differentiation factor-15 was sustained at day 7 in those who developed muscle wasting (day 7 compared with baseline, p < 0.01), but recovered in the nonwasting group (p > 0.05). Insulin-like growth factor-1 did not recover in those who developed muscle wasting (day 7 compared with baseline, p < 0.01) but did in the nonwasting group (p > 0.05). Finally, we demonstrated that growth and differentiation factor-15 caused atrophy of myotubes in vitro. Conclusion:These data support the hypothesis that acute muscle loss occurs as a result of an imbalance between drivers of muscle atrophy and hypertrophy. Growth and differentiation factor-15 is a potential novel factor associated with muscle atrophy, which may become a therapeutic target in patients with ICU acquired paresis and other forms of acute muscle wasting.

The use of sildenafil to treat pulmonary hypertension associated with interstitial lung disease.

Background and objective:  Limited data suggest a benefit following sildenafil treatment in patients with pulmonary hypertension (PH) and interstitial lung disease (ILD). The role of sildenafil in the management of PH in ILD is not clear. We report our experience of ILD patients with PH after 6‐month sildenafil therapy.

Plasma Metabolomics Implicates Modified Transfer RNAs and Altered Bioenergetics in the Outcomes of Pulmonary Arterial Hypertension.

Background: Pulmonary arterial hypertension (PAH) is a heterogeneous disorder with high mortality. Methods: We conducted a comprehensive study of plasma metabolites using ultraperformance liquid chromatography mass spectrometry to identify patients at high risk of early death, to identify patients who respond well to treatment, and to provide novel molecular insights into disease pathogenesis. Results: Fifty-three circulating metabolites distinguished well-phenotyped patients with idiopathic or heritable PAH (n=365) from healthy control subjects (n=121) after correction for multiple testing (P<7.3e-5) and confounding factors, including drug therapy, and renal and hepatic impairment. A subset of 20 of 53 metabolites also discriminated patients with PAH from disease control subjects (symptomatic patients without pulmonary hypertension, n=139). Sixty-two metabolites were prognostic in PAH, with 36 of 62 independent of established prognostic markers. Increased levels of tRNA-specific modified nucleosides (N2,N2-dimethylguanosine, N1-methylinosine), tricarboxylic acid cycle intermediates (malate, fumarate), glutamate, fatty acid acylcarnitines, tryptophan, and polyamine metabolites and decreased levels of steroids, sphingomyelins, and phosphatidylcholines distinguished patients from control subjects. The largest differences correlated with increased risk of death, and correction of several metabolites over time was associated with a better outcome. Patients who responded to calcium channel blocker therapy had metabolic profiles similar to those of healthy control subjects. Conclusions: Metabolic profiles in PAH are strongly related to survival and should be considered part of the deep phenotypic characterization of this disease. Our results support the investigation of targeted therapeutic strategies that seek to address the alterations in translational regulation and energy metabolism that characterize these patients.

Histopathology of the great vessels in patients with pulmonary arterial hypertension in association with congenital heart disease: Large pulmonary arteries matter too

BACKGROUND Pulmonary arterial hypertension (PAH) is considered primarily a disease of the distal pulmonary arteries whereas little is known on the effect of long-standing pulmonary hypertension on the larger proximal pulmonary arteries. This study aims to investigate the structural changes in the great arteries of adults who developed PAH in association with congenital heart disease (CHD), with severe cases termed Eisenmenger syndrome. METHODS We performed macroscopic and light microscopy analyses on the great arteries of 10 formalin-fixed human hearts from patients with PAH/CHD and compared them to age-matched healthy controls. A detailed histology grading score was used to assess the severity of medial wall abnormalities. RESULTS Severe atherosclerotic lesions were found macroscopically in the elastic pulmonary arteries of 4 PAH/CHD specimens and organised thrombi in 3; none were present in the controls. Significant medial wall abnormalities were present in the pulmonary trunk (PT), including fibrosis (80%), and atypical elastic pattern (80%). Cyst-like formations were present in less than one third of patients and were severe in a single case leading to wall rupture. The cumulative PT histology grading score was significantly higher in PAH/CHD cases compared to controls (p<0.0001) and correlated positively with larger PT diameters (ρ=0.812, p<0.0001) and the degree of medial wall hypertrophy (ρ=0.749, p<0.0001). CONCLUSIONS Chronic PAH in association with CHD results in marked macroscopic and histological abnormalities in the large pulmonary arteries. These abnormalities are likely to affect haemodynamics and contribute to morbidity and mortality in this cohort.

Topics in acute respiratory distress syndrome: the patient needs our tender loving and care

This editorial introduces a four-part series on acute respiratory distress syndrome (ARDS) that will cover a wide range of related topics in reviews written by internationally renowned experts. The first part of this series will be published in this issue of the European Respiratory Review by Guerin [1] on the role of prone positioning. This will be followed by articles on the topics of: 1) the role of imaging in the diagnosis and management of ARDS; 2) the novel ventilatory aspects involved in managing patients with ARDS; and 3) how to manage a patient failing conventional ventilation with extracorporeal support, in particular, extracorporeal membrane oxygenation (ECMO). It is nearly 50 years since the first report of “acute respiratory distress in adults” by Ashbaugh et al. [2]. This later became known as ARDS and acute lung injury (ALI). This group of conditions was characterised by acute onset of hypoxaemia associated with the presence of bilateral infiltrates on chest radiography, poor lung compliance and the exclusion of cardiogenic pulmonary oedema [3]. ARDS may develop after a diverse spectrum of causes. These associated conditions may be categorised according to the nature of the insult with, for example, pulmonary sepsis causing a “direct” insult whilst pancreatitis and non-pulmonary sepsis cause an “indirect” insult resulting in ARDS often as part of multi-organ dysfunction syndrome. Despite some evidence of improvements in mortality in selected centres over recent decades, ARDS remains a major public health problem with a 28-day mortality in the region of 25–35%, and a corresponding large fiscal burden to national health services [4]. In 1994, an American–European Consensus Conference (AECC) formalised the criteria for the diagnosis of ARDS and ALI. Thus, ARDS was defined by an arterial oxygen tension ( P aO2)/inspiratory oxygen fraction …

Pulmonary hypertension in interstitial lung disease: Limitations of echocardiography compared to cardiac catheterization: Pulmonary hypertension in ILD

In interstitial lung disease (ILD), pulmonary hypertension (PH) is a major adverse prognostic determinant. Transthoracic echocardiography (TTE) is the most widely used tool when screening for PH, although discordance between TTE and right heart catheter (RHC) measured pulmonary haemodynamics is increasingly recognized. We evaluated the predictive utility of the updated European Society of Cardiology/European Respiratory Society (ESC/ERS) TTE screening recommendations against RHC testing in a large, well‐characterized ILD cohort.

The Hepcidin/Ferroportin axis modulates proliferation of pulmonary artery smooth muscle cells

Studies were undertaken to examine any role for the hepcidin/ferroportin axis in proliferative responses of human pulmonary artery smooth muscle cells (hPASMCs). Entirely novel findings have demonstrated the presence of ferroportin in hPASMCs. Hepcidin treatment caused increased proliferation of these cells most likely by binding ferroportin resulting in internalisation and cellular iron retention. Cellular iron content increased with hepcidin treatment. Stabilisation of ferroportin expression and activity via intervention with the therapeutic monoclonal antibody LY2928057 reversed proliferation and cellular iron accumulation. Additionally, IL-6 treatment was found to enhance proliferation and iron accumulation in hPASMCs; intervention with LY2928057 prevented this response. IL-6 was also found to increase hepcidin transcription and release from hPASMCs suggesting a potential autocrine response. Hepcidin or IL-6 mediated iron accumulation contributes to proliferation in hPASMCs; ferroportin mediated cellular iron excretion limits proliferation. Haemoglobin also caused proliferation of hPASMCs; in other novel findings, CD163, the haemoglobin/haptoglobin receptor, was found on these cells and offers a means for cellular uptake of iron via haemoglobin. Il-6 was also found to modulate CD163 on these cells. These data contribute to a better understanding of how disrupted iron homeostasis may induce vascular remodelling, such as in pulmonary arterial hypertension.

Pulmonary hypertension in ARDS: inflammation matters!

The recognition of pulmonary vascular complications in acute respiratory distress syndrome (ARDS) spans more than 40 years. Pulmonary hypertension (PH) is defined as a mean pulmonary artery pressure of ≥25 mm Hg at right heart catheterisation. PH is a recognised consequence of ARDS, with a high prevalence in early studies. The pathogenesis of PH in ARDS is likely to be multifactorial and disease stage-dependent. Further to the modifiable effects of positive pressure ventilation,1 potential underlying mechanisms of PH in ARDS include vessel obliteration, microthrombosis and pulmonary vasoconstriction due to hypoxia, hypercapnia and vasoactive mediator imbalance. Pulmonary vascular remodelling occurs later.2 Sepsis-related right-sided and also left-sided ventricular myocardial dysfunction may also contribute. Whatever the cause of PH, the resulting right ventricular (RV) dysfunction is associated with increased morbidity and mortality,3 ,4 although it is not actually proven that RV failure is a mode of death in ARDS. Trials of pulmonary vasodilators, such as inhaled nitric oxide and prostacyclin, have met with disappointment in terms of outcomes, although there is fair criticism of the design of the studies and the heterogeneity of the populations involved. Notably, these studies targeted oxygenation rather than pulmonary haemodynamics; so, any potential contribution of improved RV function to better outcomes is untested. What is clear is that outcome has improved in ARDS with a parallel apparent reduction in prevalence of PH and RV dysfunction. Both may be due to changes in ventilation practice following the landmark protective ventilation studies, as limiting ventilator airway pressures directly reduces RV dysfunction through physiological mechanisms.5 However, even with the use of ‘modern era’ lower airway pressures, RV dysfunction remains in the region of 20%–25%3 ,4 and interestingly appears to be associated with sepsis.3 So, what is the role of sepsis and, …

Conservative Management and Recommendations for Pulmonary Arterial Hypertension Related to Congenital Heart Disease

Pulmonary arterial hypertension (PAH) in congenital heart disease (PAH–CHD) is the result of numerous pathomechanistic pathways affecting the pulmonary vascular bed and leading to a rise in pulmonary vascular resistance (PVR), right heart failure and premature death. Depending on the type of underlying defect or previous repair (timing and method used), patients can present with diverse anatomy and pathophysiology. At the extreme end of the spectrum is Eisenmenger syndrome (ES), which is characterized by pulmonary arterial pressure elevated to near-systemic levels with shunt reversal and cyanosis. It is a multisystem disorder driven by slow progressive chronic hypoxemia and the persistence of a shunt, resulting in coagulation disorders, iron deficiency anaemia, renal dysfunction, hypertrophic osteoarthropathy, paradoxical emboli and heart failure. Differences between various types of PAH–CHD are not purely academic, but significantly impact on presentation, treatment and outcome. This chapter covers the conservative management of PAH–CHD, with a specific focus on Eisenmenger syndrome.