Incidence and risk factors of chronic thromboembolic pulmonary hypertension following venous thromboembolism, a population-based cohort study in England.

Chronic thromboembolic pulmonary hypertension (CTEPH) is a complication of unresolved organised pulmonary emboli/thrombi obstructing the major pulmonary arteries. The aim of this study was to estimate the incidence and risk factors of CTEPH in a cohort with first venous thromboembolism (VTE). This was a population-based cohort study of patients with first VTE and no active cancer in England between 2001 and 2012. CTEPH was assessed using a rigorous case-ascertainment algorithm. Risk factors for CTEPH were studied using a nested case-control approach by matching CTEPH cases to VTE patients without CTEPH. Adjusted odds ratios (OR) of comorbidities were estimated from conditional logistic regression. During 81,413 person-years of follow-up among 23,329 patients with first VTE (mean follow-up 3.5 years; maximum 11.0 years) 283 patients were diagnosed with CTEPH (incidence rate 3.5 per 1000 person-years); cumulative incidence was 1.3% and 3.3% at 2 and 10 years after pulmonary embolism, and 0.3% and 1.3% following deep vein thrombosis (DVT), respectively. Risk factors for CTEPH included age over 70, OR 2.04 (95% CI 1.23 to 3.38), female gender, 1.44 (1.06 to 1.94), pulmonary embolism at first VTE, 3.11 (2.23 to 4.35), subsequent pulmonary embolism and DVT, 3.17 (2.02 to 4.96) and 2.46 (1.34 to 4.51) respectively, chronic obstructive pulmonary disease 3.17 (2.13 to 4.73), heart failure 2.52 (1.76 to 3.63) and atrial fibrillation, 2.42 (1.71 to 3.42). CTEPH develops most commonly after pulmonary embolism and less frequently after DVT. Awareness of risk factors may increase referrals to specialised centres for confirmation of CTEPH and initiation of specific treatment.

Hypoxaemia in patients with pulmonary arterial hypertension during simulated air travel.

BACKGROUND: Recent air travel recommendations suggest patients with precapillary pulmonary hypertension (PCPH) in New York Heart Association (NYHA) functional class 3 and 4 should have in-flight oxygen without the need for pre-flight testing. However it remains unclear as to how best to determine patients fitness to fly. METHODS: This study (i) investigates the effect of hypoxic challenge testing (HCT) on the arterial oxygen levels in a cohort of 36 patients with PCPH and (ii) compares the relative frequency with which FC and HCT predict the requirement for in-flight oxygen. RESULTS: The degree of arterial hypoxaemia induced by HCT (fall in partial pressure of oxygen in arterial blood (PaO(2)) 2.36 kPa, 95% CI 2.06-2.66 kPa) was similar to the drop observed in other published studies of chronic respiratory diseases. Following current air travel recommendations based on FC, 25 patients of the cohort would require in-flight oxygen whilst 10 subjects failed the HCT. Fourteen subjects had flown post-diagnosis. Of these, nine subjects should have had in-flight oxygen based on FC but were asymptomatic without. Also one who passed the HCT had developed symptoms during the flight whilst three who failed the HCT were asymptomatic flying without in-flight oxygen. CONCLUSIONS: Hypoxaemia induced by simulated air travel in patients with PCPH is similar to that seen in published studies of patients with other chronic respiratory diseases. HCT failed to predict correctly who had developed symptoms during an aircraft flight in a significant minority of the study subjects. Similarly guidelines based on functional class result in a major increase in the proportion of patients being advised to use oxygen, many of whom had been asymptomatic on previous flights without it. More work is required to improve prediction of need for in-flight oxygen in patients with PCPH.

The role of per cent predicted 6-min walk distance in pulmonary arterial hypertension.

Absolute 6-min walk distance (6MWD) predicts mortality in pulmonary arterial hypertension (PAH), but varies greatly between normal individuals due to physiological factors such as age, sex, height and weight. The % predicted 6MWD adjusts for these factors and may predict mortality more reliably. The aim of the study was to compare the strength of mortality prediction by absolute and % predicted 6MWD in PAH at baseline and on treatment. % predicted 6MWD was calculated using four different reference equations in 137 PAH patients (idiopathic and connective tissue disease associated) diagnosed between November 2000 and November 2009. Cox proportional hazards and receiver-operating characteristic (ROC) analyses were used to compare the prognostic strength of absolute and % predicted 6MWD. % predicted 6MWD was predictive of all-cause mortality at baseline (hazard ratio 0.74-0.83 per 10% increase; p<0.05) and on treatment (0.67-0.75 per 10% increase; p<0.01), but each respective area under the ROC curve was not different from that of absolute 6MWD for predicting 2-yr mortality at baseline (absolute versus % predicted: 0.74 versus 0.71-0.75) or on treatment (0.77 versus 0.72-0.78). In conclusion, % predicted 6MWD may help clinicians interpret the 6-min walk test, but its prognostic value is not superior to that of absolute 6MWD.

End-points and clinical trial design in pulmonary arterial hypertension: have we made progress?

There is enormous interest in the treatment of pulmonary arterial hypertension (PAH), so it is appropriate to consider the design of trials of new therapies and the end-points to be measured when trying to decide whether or not a therapy is effective. In May 2003, the first meeting devoted solely to the discussion of end-points and trial design in PAH was held in Gleneagles, UK. At that time, most of the randomised controlled trials in PAH had used 6-min walking distance and/or resting haemodynamics as their primary end-points. The present article considers the progress that has been made since 2003. It deals with aspects of clinical trial design (such as noninferiority, superiority and withdrawal trials), considers end-points used in previous and current studies (such as 6-min walking distance, time to clinical worsening, haemodynamics, imaging and plasma brain natriuretic peptide), and considers what end-points might be used in the future. The second end-points meeting was held in Turnberry, UK, in June 2007. It had a similar format to the first meeting. Much of what is presented here is a summary of the workshops from that meeting. An attempt has been made to both summarise the current state of end-points and trial design and suggest new ways in which they could be improved. The present article forms one of a series being published in the European Respiratory Journal on pulmonary hypertension.

Cardiac magnetic resonance imaging for the assessment of the heart and pulmonary circulation in pulmonary hypertension.

Pulmonary hypertension is a disease of the pulmonary arteries resulting in a progressive increase in pulmonary vascular resistance, ultimately leading to right ventricular failure and death. The functional capacity of the right ventricle is a major prognostic determinant. Our understanding of right ventricle performance in pulmonary hypertension has been hindered by the lack of techniques that give a reliable picture of right ventricle morphology and function. Cardiac magnetic resonance (CMR) imaging enables a unique combination of morphological and functional assessment of the right ventricle and pulmonary circulation. In this review article, we introduce the technique of CMR imaging, review its use in imaging of the heart and pulmonary circulation and discuss its current and future application to the management of patients with pulmonary hypertension. There have been recent major advances in our understanding of the mechanism of disease development, in the diagnostic process, and in the treatment of pulmonary hypertension. Therapeutic advances in the management have reinforced the requirement for noninvasive, accurate and reproducible methods of assessment to act as "end-points" to measure the effects of treatment. We anticipate CMR imaging will increasingly be utilised as the primary modality for combined anatomic and functional assessments that enable more complete and efficient evaluation of pulmonary hypertension patients.

Prognostic and aetiological factors in chronic thromboembolic pulmonary hypertension.

Several prognostic variables have previously been identified in patients with chronic thromboembolic pulmonary hypertension (CTEPH). Specific medical conditions have also been associated with the development and prognosis of CTEPH. Using a national registry, the current authors have assessed the prognostic value of a larger number of variables and have also attempted to validate the clinical importance of previously identified aetiological factors. Baseline information for all 469 CTEPH patients diagnosed in the UK pulmonary hypertension service between January 2001 and June 2006 was collected from hospital records. Although univariate analysis confirmed the prognostic importance of pulmonary resistance, in multivariate analysis gas transfer and exercise capacity predicted pulmonary endarterectomy perioperative mortality. Cardiac index and exercise capacity independently predicted outcome in patients with nonoperable disease. Previous splenectomy was noted in 6.7% of patients, being significantly more common in patients with nonoperable than operable disease (13.7 versus 3.6%). Medical risk factors were not found to predict mortality. In a large national cohort, predictors of outcome in patients with both operable and nonoperable chronic thromboembolic pulmonary hypertension have been identified. These may be useful in planning treatment. The aetiological importance of previously identified medical risk factors has been confirmed, although the current authors were unable to validate their prognostic strength.

Imaging of the heart in pulmonary hypertension.

Pulmonary hypertension (PH) is a disease of the pulmonary arteries resulting in a progressive increase in pulmonary vascular resistance, ultimately leading to right ventricular failure and death. It is a rare disease with a poor prognosis. The functional capacity of the right ventricle (RV) is a major prognostic determinant in PH. Our understanding of RV performance in PH has been hindered by the lack of techniques that give a reliable picture of right ventricular morphology and function. There have been recent major advances in our understanding of the mechanism of disease development, in the diagnostic process and in the treatment of PH. There are now three classes of medications that are effective in the treatment of PH: prostanoids, endothelin receptor antagonists and phosphodiesterase-5 inhibitors. Therapeutic advances in the management of PH have reinforced the requirement for non-invasive, accurate and reproducible methods of assessment to act as 'end-points' to measure the effects of treatment. It is our opinion that the most useful 'end-point' would be one that evaluates right heart morphology and function. We introduce and discuss the techniques currently used to image the heart in patients with PH. Imaging modalities discussed include echocardiography, radionuclide ventriculography, cardiac computed tomography and cardiac magnetic resonance (CMR) imaging focusing on the rapidly evolving technique of CMR imaging.

An epidemiological study of pulmonary arterial hypertension.

All hospitalisations for pulmonary arterial hypertension (PAH) in the Scottish population were examined to determine the epidemiological features of PAH. These data were compared with expert data from the Scottish Pulmonary Vascular Unit (SPVU). Using the linked Scottish Morbidity Record scheme, data from all adults aged 16-65 yrs admitted with PAH (idiopathic PAH, pulmonary hypertension associated with congenital heart abnormalities and pulmonary hypertension associated with connective tissue disorders) during the period 1986-2001 were identified. These data were compared with the most recent data in the SPVU database (2005). Overall, 374 Scottish males and females aged 16-65 yrs were hospitalised with incident PAH during 1986-2001. The annual incidence of PAH was 7.1 cases per million population. On December 31, 2002, there were 165 surviving cases, giving a prevalence of PAH of 52 cases per million population. Data from the SPVU were available for 1997-2006. In 2005, the last year with a complete data set, the incidence of PAH was 7.6 cases per million population and the corresponding prevalence was 26 cases per million population. Hospitalisation data from the Scottish Morbidity Record scheme gave higher prevalences of pulmonary arterial hypertension than data from the expert centres (Scotland and France). The hospitalisation data may overestimate the true frequency of pulmonary arterial hypertension in the population, but it is also possible that the expert centres underestimate the true frequency.

NT-proBNP can be used to detect right ventricular systolic dysfunction in pulmonary hypertension.

Right ventricular systolic dysfunction (RVSD) at baseline (pre-treatment) predicts early death in patients with pulmonary hypertension (PH). However, RVSD can only be detected reliably by prohibitively invasive or expensive techniques. N-terminal B-type natriuretic peptide concentration ([NT-proBNP]) correlates with RV function in PH; however, an [NT-proBNP] threshold that indicates RVSD in individual patients has not previously been determined. Twenty-five patients with PH (pulmonary arterial hypertension (n = 19) or chronic thromboembolic PH (n = 6)) underwent cardiovascular magnetic resonance (CMR) imaging and NT-proBNP measurement at baseline. [NT-proBNP] was correlated against RV dimensions and ejection fraction (RVEF) measured directly by CMR imaging. The ability of NT-proBNP to detect RVSD (defined as a CMR-derived RVEF >2 SDS below control values) was tested and predictors of [NT-proBNP] identified. [NT-proBNP] correlated negatively with RVEF. RVSD was present in nine out of 25 patients. An [NT-proBNP] threshold of 1,685 pg.mL(-1) was sensitive (100%) and specific (94%) in detecting RVSD. RVEF and RV mass index independently predicted [NT-proBNP]. In pulmonary hypertension, a baseline N-terminal B-type natriuretic peptide concentration of >1,685 ng.L(-1) suggests right ventricular systolic dysfunction, and thus an increased risk of early death. N-terminal B-type natriuretic peptide could prove useful as an objective, noninvasive means of identifying patients with pulmonary hypertension who have right ventricular systolic dysfunction at presentation.

Noninvasive assessment and monitoring of the pulmonary circulation.

In pulmonary vascular disease, changes in the pulmonary vascular bed will lead to altered pulmonary haemodynamics. This review describes the application of several physiological principles to measure these changes noninvasively by means of novel techniques. Flow characteristics of blood through the pulmonary vascular bed alter in pulmonary vascular disease. Recent developments in magnetic resonance imaging and computed tomography make it possible to visualise and quantify these abnormal flow patterns. Information regarding pulmonary perfusion can also be obtained by measuring the electrical impedance changes in the lung by electrical impedance tomography. A more indirect approach to measure the pulmonary blood flow is the measurement of the absorption of acetylene, a perfusion limited gas. Information on the pulmonary vascular bed can also be obtained by the measurement of exhaled products of the pulmonary vascular endothelium, such as nitric oxide. Although all the techniques described offer new ways to diagnose or monitor pulmonary vascular disease, clinical data on these techniques are limited. Further improvement and evaluation of the clinical value of these techniques are therefore obligatory before they can be used in clinical practice.

Angiotensin-converting enzyme genotype and the ventilatory response to exertional hypoxia.

The "insertion" (I) rather than "deletion" (D) variant of the human angiotensin-converting enzyme (ACE) gene is associated with both lower tissue ACE activity and elite performance at high altitude. Three genotypes, II, ID and DD, are thus represented in the population. The authors examined whether an improved ventilatory response to hypoxic exercise may contribute to this effect. Subjects (n=60; 37 male, mean+/-SEM age 23.6+/-0.6 yrs, 14 II, 30 ID, 16 DD) underwent incremental cardiopulmonary exercise testing to establish maximal oxygen uptake and ventilatory threshold (VT). Four hours later, subjects exercised for 6 mins at 50% of the workload at VT. The protocol was repeated 15 mins later while breathing 12.5+/-0.5% oxygen in nitrogen. All subject characteristics were independent of genotype, as were data during normoxic exercise. However, the hypoxia-induced rise in minute ventilation was significantly greater among those of II genotype (39.6+/-4.1% versus 27.9+/-2.0% versus 28.4+/-2.2% for II versus ID versus DD, respectively). These data are supported by a significantly greater decrease in end tidal carbon dioxide (consistent with an increase in alveolar ventilation) among those homozygous for the I allele (II -18.7+/-1.3%, ID -15.7+/-0.4%, DD -15.1%+/-1.1). The ventilatory response to hypoxic exercise is influenced by angiotensin-converting enzyme genotype. Potential implications concern high altitude performance and the pathogenesis and management of hypoxic lung disease.

Ventricular mass index using magnetic resonance imaging accurately estimates pulmonary artery pressure.

Magnetic resonance imaging (MRI) can provide accurate anatomical measurements of the cardiac ventricles. This study investigated whether a calculated ventricular mass index (VMI) would provide an accurate means of estimating pulmonary artery pressure noninvasively, and compared the results with conventional Doppler echocardiography and invasive measurement. A total of 26 subjects referred for investigation of pulmonary hypertension were studied by MRI and echocardiography within 2 weeks of cardiac catheterisation. The correlations for mean pulmonary artery pressure were as follows: VMI (ratio of right ventricular mass over left ventricular mass) r=0.81; pulmonary artery systolic pressure (echocardiography) r=0.77. The confidence intervals for the VMI were narrower than for echocardiography. Sensitivity and specificity for pulmonary hypertension were 84 and 71% respectively for the VMI compared with 89 and 57% for echocardiography. The calculated ventricular mass index provides an accurate and practical means of estimating pulmonary artery pressure noninvasively in pulmonary hypertension and may provide a more accurate estimate than Doppler echocardiography. This may be because it reflects the right ventricular response to sustained pulmonary hypertension over a long period and is not influenced by short-term physiological variables affecting echocardiography, such as heart rate, posture, hydration status and oxygen supplementation.

Ambulatory pulmonary artery pressure monitoring during sleep and exercise in normal individuals and patients with COPD.

BACKGROUND: Pulmonary hypertension is a common complication of chronic obstructive airways disease (COPD) and its presence implies a poor prognosis. However, it is difficult to measure and its specific contribution to symptoms is difficult to quantify. A micromanometer tipped pulmonary artery catheter was used to measure pulmonary artery pressure (PAP) during sleep and on exercise. METHODS: Ten patients (five with COPD receiving long term oxygen therapy and five normal individuals) were studied. Pulmonary artery pressure was recorded continuously during two periods of sleep (breathing oxygen followed by air for the COPD group) and during exercise. RESULTS: In the COPD group PAP during sleep on oxygen was significantly lower than PAP during sleep breathing air (mean (SD) difference 9.6 (5.3) mm Hg, 95% CI 4.9 to 14.3, p= 0.016). PAP during exercise was not significantly different from PAP during sleep breathing air (mean (SD) difference 0.8 (8.9) mm Hg, 95% CI -7.0 to 8.6, p= 0.851). In normal individuals the group mean (SD) PAP was 15 (5.9) mm Hg for the first nocturnal period and 15 (5.7) mm Hg for the second nocturnal period. PAP during exercise was not significantly different from PAP during sleep breathing air (mean (SD) difference 3.3 (2.2) mm Hg, 95% CI 1.1 to 5.5, p= 0.061). CONCLUSION: In patients with COPD, PAP rose significantly during sleep to levels similar to those measured during exercise, but this could be reversed with oxygen.

Build your own infection control link nurse: an innovative study day.

Infection control is everyone's business and it is important that all members of staff observe good infection control practice. An effective infection control link nurse system has been shown to support and develop this approach. The strength of ward-based infection control link nurses depends upon their effectiveness as role models and their ability to influence practice on their wards and beyond. In addition, the degree of respect they command from their peers and colleagues and the amount and quality of knowledge they possess is crucial. This paper describes an innovative approach taken in Mid-Essex, which allowed infection control link nurses to assess their capabilities and limitations in communicating with and influencing colleagues. In addition, we show how quantitative measures may be made available by this approach. Such measures may be used to explain to management how particular areas of infection control practice (e.g. the need for infection control link nurses to have more authority and more 'muscle') may be important.

Chronic hypoxia induces constitutive p38 mitogen-activated protein kinase activity that correlates with enhanced cellular proliferation in fibroblasts from rat pulmonary but not systemic arteries.

Pulmonary hypertension occurs commonly in patients with chronic hypoxic lung disease and is characterized by the remodeling of the pulmonary artery walls. The molecular mechanisms underlying such remodeling are unknown but we have recently shown that the stress-activated (Jnk and p38) mitogen-activated protein (MAP) kinases are activated in pulmonary artery fibroblasts following acute hypoxia. We now show that Erk and p38 MAP kinases are constitutively activated in fibroblasts derived from the remodeled pulmonary, but not the systemic circulation from rats exposed to chronically hypoxic conditions. Moreover, we find that such fibroblasts show sustained enhanced proliferative capacities relative to pulmonary artery fibroblasts derived from normoxic rats or to aortic fibroblasts from either normoxic or hypoxic rats. Finally, abrogation of p38, but not Erk MAP kinase activity by use of specific inhibitors, prevents the enhanced proliferative capacity exhibited by pulmonary artery fibroblasts. Taken together, these data suggest that enhanced p38 MAP kinase activity provides a molecular mechanism to explain the proliferation of pulmonary artery fibroblasts required for remodeling of the pulmonary vasculature.

Pulmonary artery pressure measurement during exercise testing in patients with suspected pulmonary hypertension.

It is recognized that exercise produces abnormally large increases in pulmonary artery pressure in patients with pulmonary vascular disease as a consequence of a variety of disorders, but the relationship between pressure and cardiopulmonary exercise performance is poorly understood. This lack of understanding is due (in part) to difficulty making measurements of pulmonary haemodynamics using conventional fluid filled catheters. This article seeks to improve understanding by comparing variables measured during formal exercise testing with simultaneous measurements of pulmonary artery pressure using a micro-manometer tipped catheter. Ten patients with suspected pulmonary hypertension were studied using a micromanometer tipped pulmonary artery catheter, during cardiopulmonary exercise testing. Ventilatory equivalents for oxygen and carbon dioxide correlated with the pulmonary artery pressure measured on exercise, but oxygen pulse and oxygen uptake did not. Ventilatory equivalents, noninvasively measured during exercise, may merit further study as potential surrogates of pulmonary artery pressure and hence be useful in identifying individuals at risk of developing pulmonary hypertension.