Jaquelina Sonoe Ota-Arakaki

Optimizing the evaluation of excess exercise ventilation for prognosis assessment in pulmonary arterial hypertension.

Background Increased ventilatory ( V · E) response to carbon dioxide output ( V · CO2) is a key finding of incremental cardiopulmonary exercise testing in both heart failure and pulmonary arterial hypertension (PAH). As with heart failure, measures of excessive exercise ventilation considering high-to-peak exercise V · E– V · CO2 might have higher prognostic relevance than those restrained to sub-maximal exercise in PAH. Design Cross-sectional and observational study on a tertiary center. Methods Eighty-four patients (36 idiopathic and 48 with associated conditions) were followed up for up to five years. Excessive exercise ventilation was calculated as a slope (Δ V · E/Δ V · CO2 to the respiratory compensation point (RCP) and to exercise cessation (PEAK)) and as a ratio ( V · E/ V · CO2 at the anaerobic threshold (AT) and at PEAK). Results Thirteen patients died and three had atrial septostomy. Multivariable regression analyses revealed that Δ V · E/Δ V · CO2(PEAK) <55 and V · E/ V · CO2(PEAK) <57 were better related to prognosis than Δ V · E/Δ V · CO2(RCP) and V · E/ V · CO2(AT) (p < 0.01). Δ oxygen uptake ( V · O2)/Δ work rate >5.5 ml/min per W was the only other independent prognostic index. According to a Kaplan–Meier survival analysis, 96.9% (90.8% to 100%) of patients showing Δ V · E/Δ V · CO2(PEAK) <55 and Δ V · O2/Δ work rate >5.5 ml/min per W were free from a PAH-related event. In contrast, 74.7% (70.1% to 78.2%) with both parameters outside these ranges had a negative outcome. Conclusion Measurements of excessive exercise ventilation which consider all data points maximize the usefulness of incremental cardiopulmonary exercise testing in the prognosis evaluation of PAH.

A haemodynamic study of pulmonary hypertension in chronic hypersensitivity pneumonitis

Chronic hypersensitivity pneumonitis is a common fibrotic interstitial lung disease. The prevalence of pulmonary hypertension diagnosed by right heart catheterisation and its cardiopulmonary function findings in patients with chronic hypersensitivity pneumonitis are unknown. Consecutive symptomatic patients with chronic hypersensitivity pneumonitis were prospectively evaluated. All patients were submitted to right heart catheterisation, pulmonary function testing, a 6-min walk test, echocardiography, blood gas determination and N-terminal pro-brain natriuretic peptide analyses. Nonhypoxaemic patients also underwent incremental cardiopulmonary exercise testing. 50 patients underwent right heart catheterisation; 25 (50%) of these had pulmonary hypertension and 22 (44%) had a pre-capillary haemodynamic pattern. The patients with pre-capillary pulmonary hypertension had lower forced vital capacity (mean±sd 50±17% versus 69±22% predicted, p<0.01), carbon monoxide diffusing capacity (37±12% versus 47±14% predicted, p<0.01), arterial oxygen tension (median (interquartile range) 59.0 (47.8–69.3) versus 73.0 (62.2–78.5) mmHg, p<0.01) and saturation after the 6-min walk test (78±8% versus 86±7%, p<0.01). In pre-capillary pulmonary hypertension, oxygen uptake was also lower at the anaerobic threshold (41±11% versus 50±8% predicted, p=0.04) and at peak exercise (12.8±1.6 versus 15.0±2.5 mL·kg−1·min−1, p=0.02). Pre-capillary pulmonary hypertension is common in symptomatic chronic hypersensitivity pneumonitis and is related to interstitial lung disease severity. Additionally, pulmonary hypertension is more prevalent in hypoxaemic patients with impaired lung function and exercise capacity. PH is common in chronic hypersensitivity pneumonitis and is related to interstitial lung disease severity http://ow.ly/uTXXx

Usefulness of pulmonary capillary wedge pressure as a correlate of left ventricular filling pressures in pulmonary arterial hypertension

BACKGROUND Pulmonary arterial hypertension (PAH) is characterized by a pulmonary capillary wedge pressure (PCWP) of ≤15 mm Hg, given a normal left ventricular filling pressure (LVFP). However, recent studies have shown that, in PAH patients, diagnosis based on PCWP can erroneously classify a significant number of patients compared with diagnosis based on left ventricular end-diastolic pressure (LVEDP). Therefore, we sought to compare the diagnostic accuracy of end-expiratory PCWP and LVEDP measurements in patients suspected of having pulmonary hypertension (PH). METHODS We reviewed the hemodynamic data from 122 patients suspected of having PH who underwent simultaneous right- and left-side heart catheterizations at a PH referral center from 2006 to 2011. RESULTS PH was diagnosed in 105 patients, 79% of whom (n = 83) showed a pre-capillary pattern according to the LVEDP measurement. Ninety percent of patients with PCWP ≤15 mm Hg were correctly classified as having pre-capillary PH. However, 39% of patients with a PCWP >15 mm Hg had LVEDP ≤15 mm Hg and would have been erroneously diagnosed with pulmonary venous hypertension based on their PCWP measurements alone. The sensitivity and specificity was 0.89 and 0.64, respectively. A Bland-Altman analysis of the PCWP and LVEDP measurements revealed a mean bias of 0.3 mm Hg with 95% limits of agreement of -7.2 to 7.8 mm Hg. CONCLUSIONS A PCWP ≤15 mm Hg was found to be a reliable indicator of normal LVFP in pre-capillary PH patients. When measured properly and analyzed in the clinical context, PCWP is a valuable tool for accurate diagnosis of PAH.

Exercise oxygen uptake efficiency slope independently predicts poor outcome in pulmonary arterial hypertension.

To the Editor: Pulmonary arterial hypertension (PAH) remains a disabling and frequently lethal disease despite remarkable advances in treatment. Cardiopulmonary exercise testing (CPET) has proved a valuable tool to objectively quantify disease severity and estimate prognosis in these patients [1–3]. Exercise intolerance is characteristically multifactorial in PAH. Among its potential contributing mechanisms, increased ventilatory response, deranged pulmonary mechanics, peripheral muscle impairment and reduced oxygen delivery have been more widely investigated [1–5]. In this context, a CPET-derived variable that conflates the effects of increased ventilation and poor O2 transfer and/or peripheral O2 utilisation is the O2 uptake efficiency slope (OUES) [6]. OUES is the slope of the linear relationship between O2 uptake ( V ′O2) and the logarithmic transformation of minute ventilation ( V ′E) during rapidly incremental exercise, i.e. it aims to reflect how effectively O2 is extracted from the atmosphere and taken into the body as exercise progresses. We recently found that a combination of increased sub-maximal exercise V ′E as a function of carbon dioxide output ( V ′CO2) and reduced O2 delivery/utilisation (as suggested by shallow V ′O2–work rate relationship) were independent predictors of negative outcome in PAH of mixed aetiology [7]. These findings prompted the hypothesis that OUES would combine the prognostic information provided separately by those variables, thereby being the single predictor of poor outcome in our cohort. In order to address this question, we revisited our dataset and contrasted OUES prognostic relevance with that of a range of resting and cardiopulmonary exercise responses to ramp-incremental cycle ergometry. In the previous report [7], we described results from a group of 84 patients in whom 16 PAH-related deaths and two …

Contrasting Cardiopulmonary Responses to Incremental Exercise in Patients with Schistosomiasis-Associated and Idiopathic Pulmonary Arterial Hypertension with Similar Resting Hemodynamic Impairment

It has been reported that schistosomiasis-associated PAH (Sch-PAH) has a more benign clinical course compared with idiopathic PAH (IPAH). We therefore hypothesized that Sch-PAH subjects would present with less impaired cardiopulmonary and metabolic responses to exercise than IPAH patients, even with similar resting pulmonary hemodynamic abnormalities. The aim of this study was to contrast physiologic responses to incremental exercise on cycle ergometer between subjects with Sch-PAH and IPAH. We performed incremental cardiopulmonary exercise tests (CPET) in subjects newly diagnosed with IPAH (n = 9) and Sch-PAH (n = 8), within 1 month of the hemodynamic study and before the initiation of specific therapy for PAH. There were no significant between-group differences in cardiac index, pulmonary vascular resistance or mean pulmonary artery pressure. However, mean peak oxygen uptake (VO2) was greater in Sch-PAH than IPAH patients (75.5±21.4 vs 54.1±16.1% predicted, p = 0.016), as well as the ratio of increase in VO2 to work rate (8.2±1.0 vs 6.8±1.8 mL/min/W, p = 0.03). Additionally, the slope of the ventilatory response as a function of CO2 output was lower in Sch-PAH (40.3±3.9 vs 55.6±19.8; p = 0.04), and the heart rate response for a given change in VO2 was also diminished in Sch-PAH compared to IPAH (80.1±20.6 vs 123.0±39.2 beats/L/min; p = 0.02). In conclusion, Sch-PAH patients had less impaired physiological responses to exercise than IPAH subjects with similar resting hemodynamic dysfunction. Our data suggest a more preserved cardiopulmonary response to exercise in Sch-PAH which might be related to its better clinical course compared to IPAH.

Clinical usefulness of end-tidal CO2 profiles during incremental exercise in patients with chronic thromboembolic pulmonary hypertension

INTRODUCTION Great ventilation to carbon dioxide output (ΔV˙E/ΔV˙CO2) and reduced end-tidal partial pressures for CO2 (PetCO2) during incremental exercise are hallmarks of chronic thromboembolic pulmonary hypertension (CTEPH) and idiopathic pulmonary arterial hypertension (IPAH). However, CTEPH is more likely to involve proximal arteries, which may lead to poorer right ventricle-pulmonary vascular coupling and worse gas exchange abnormalities. Therefore, abnormal PetCO2 profiles during exercise may be more prominent in patients with CTEPH and could be helpful to indicate disease severity. METHODS Seventy patients with CTEPH and 34 with IPAH underwent right heart catheterization and cardiopulmonary exercise testing. According to PetCO2 pattern during exercise, patients were classified as having an increase or stabilization in PetCO2 up to the gas exchange threshold (GET), an abrupt decrease in the rest-exercise transition or a progressive and slow decrease throughout exercise. A subgroup of patients with CTEPH underwent a constant work rate exercise test to obtain arterial blood samples during steady-state exercise. RESULTS Multivariate logistic regression analyses showed that progressive decreases in PetCO2 and SpO2 were better discriminative parameters than ΔV˙E/ΔV˙CO2 to distinguish CTEPH from IPAH. This pattern of PetCO2 was associated with worse functional impairment and greater reduction in PaCO2 during exercise. CONCLUSION Compared to patients with IPAH, patients with CTEPH present more impaired gas exchange during exercise, and PetCO2 abnormalities may be used to identify more clinically and hemodynamically severe cases.

Pulmonary artery wedge pressure and exercise oscillatory ventilation in pre-capillary pulmonary hypertension.

a Pulmonary Function and Clinical Exercise Physiology Unit (SEFICE), Respiratory Division, Department ofMedicine, School ofMedicine, Federal University of Sao Paulo (UNIFESP), Sao Paulo, Brazil b Pulmonary Vascular Group, Respiratory Division, Department of Medicine, School of Medicine, Federal University of Sao Paulo (UNIFESP), Sao Paulo, Brazil c Laboratory of Clinical Exercise Physiology (LACEP), Division of Respiratory and Critical Care Medicine, Department of Medicine, Queens University, Kingston, Canada d Respiratory Investigation Unit (RIU), Division of Respiratory and Critical Care Medicine, Department of Medicine, Queens University, Kingston, Canada

Pulmonary haemodynamics and mortality in chronic hypersensitivity pneumonitis

Chronic hypersensitivity pneumonitis (CHP) is a common interstitial lung disease (ILD) frequently associated with lung fibrosis [1]. Among patients with CHP, the degree of pulmonary function impairment and the extent of fibrosis are known predictors of mortality [2, 3]. In other forms of ILD, such as idiopathic pulmonary fibrosis (IPF) and sarcoidosis, abnormal pulmonary haemodynamics measured during resting supine right heart catheterisation (RHC) are additionally associated with poor prognosis [4–7]. In CHP, however, the prognostic value of RHC is unknown. Indices of pulmonary vascular dysfunction are associated with mortality in chronic hypersensitivity pneumonitis http://ow.ly/1nwG30jwTSm

Intrapulmonary vascular dilatations are common in portopulmonary hypertension and may be associated with decreased survival.

We read with interest the recently published article by Fussner et al. in Liver Transplantation. The authors showed that intrapulmonary vascular dilatations (IPVDs), detected by agitated saline contrast-enhanced transthoracic echocardiography (cTTE), were common in patients with portopulmonary hypertension (POPH)—59% of patients. Moreover, this finding was associated with decreased survival, and the authors suggest the possibility of a pathophysiological overlap between POPH and hepatopulmonary syndrome in patients with end-stage liver disease. Interestingly, this feature was previously described in patients with schistosomiasis. Early reports of the disease identified a unique pattern of pulmonary involvement in patients with schistosomiasis: pulmonary hypertension with central cyanosis in the absence of intracardiac shunt. In 1 study, IPVD was found in 20% of patients with schistosomiasis cor pulmonale. According to necroscopic studies, cyanosis was associated with arteriovenous fistulae, possibly due to bypass of Schistosoma eggs in pulmonary circulation. Furthermore, other investigators confirm this finding and hypothesized that it could be related to repeated worm infestation, common in endemic areas. The pathophysiology of schistosomiasis-associated pulmonary arterial hypertension (Sch-PAH) is not completely understood, but it probably shares some similarities with POPH, in a model without liver cirrhosis. Sch-PAH is potentially the most common cause of pulmonary hypertension worldwide and is associated with higher survival rates compared to IPAH. Our group recently published an article contrasting physiological responses to incremental exercise in cardiopulmonary exercise tests (CPETs) between naive patients with Sch-PAH (n 5 8) and with idiopathic pulmonary arterial hypertension (IPAH) (n 5 9) with similar resting hemodynamics. Interestingly, Sch-PAH showed less impaired physiological responses to incremental exercise than IPAH patients, suggesting a more preserved cardiopulmonary response to exercise in Sch-PAH, which could be related to its better clinical course compared to IPAH. However, at that time, the mechanisms involved were not identified. Even though none of the patients with Sch-PAH had cyanosis or hypoxemia (only 3 had SpO2 90% at the end of the incremental CPET), cTTE was performed after the publication, and IPVD was detected in 6/8 (75%) Sch-PAH patients (data not published). It is noteworthy that despite the high prevalence of IVPD in this study, only 2 patients died to date (1 of them was without IPVD), which contrasts with the poor prognosis of the presence of IPVD in patients with cirrhosis described by Fussner et al. The clinical relevance of the presence of IPVD in patients with Sch-PAH is not clear, but it is possible to hypothesize that IPVD could attenuate right ventricular stress during exercise. Further studies are needed in order to obtain a better understanding of the natural history of IPVD associated with schistosomiasis as well as to assess the impact of this finding on the exercise capacity and survival of affected patients. Fussner et al. suggested that patients with POPH should be evaluated for IPVD with cTTE, until the relevance of IPVD in this population is clarified. At this time, we believe that it is reasonable to also recommend cTTE in patients with Sch-PAH, which could lead to a better understanding of pulmonary vascular diseases associated with liver dysfunction. Address reprint requests to Fabricio M. Valois, M.D., Ph.D., Division of Respiratory Diseases, Department of Medicine, Universidade Federal de Sao Paulo, Sao Paulo, Brazil. E-mail: fabriciomv@globo.com

Inspiratory muscle weakness contributes to exertional dyspnea in chronic thromboembolic pulmonary hypertension

Determination of potentially-reversible factors contributing to exertional dyspnea remains an unmet clinical need in chronic thromboembolic pulmonary hypertension (CTEPH). Therefore, we aimed to evaluate the influence of inspiratory muscle weakness (IMW) on exercise capacity and dyspnea during effort in patients with CTEPH. We performed a prospective cross-sectional study that included thirty-nine consecutive patients with CTEPH (48 ± 15 yrs, 61% female) confirmed by right heart catheterization that underwent an incremental cardiopulmonary exercise test, 6-minute walk test and maximum inspiratory pressure (MIP) measurement. MIP < 70%pred was found in 46% of patients. On a multiple linear regression analysis, MIP was independently associated with 6MWD and V˙O2PEAK. Patients with MIP < 70% presented greater ΔV˙E/ΔV˙CO2 than those with MIP ≥ 70%. Additionally, they also presented stronger sensations of dyspnea throughout exercise, even when adjusted for ventilation. At rest and at different levels of exercise, mean inspiratory flow (VT/TI) was significantly higher in patients with MIP < 70%. In conclusion, IMW is associated with a rapid increase of dyspnea, higher inspiratory load and poor exercise capacity in patients with CTEPH.