There is growing recognition of the clinical importance of pulmonary haemodynamics during exercise, but several questions remain to be elucidated. The goal of this statement is to assess the ...scientific evidence in this field in order to provide a basis for future recommendations.Right heart catheterisation is the gold standard method to assess pulmonary haemodynamics at rest and during exercise. Exercise echocardiography and cardiopulmonary exercise testing represent non-invasive tools with evolving clinical applications. The term "exercise pulmonary hypertension" may be the most adequate to describe an abnormal pulmonary haemodynamic response characterised by an excessive pulmonary arterial pressure (PAP) increase in relation to flow during exercise. Exercise pulmonary hypertension may be defined as the presence of resting mean PAP <25 mmHg and mean PAP >30 mmHg during exercise with total pulmonary resistance >3 Wood units. Exercise pulmonary hypertension represents the haemodynamic appearance of early pulmonary vascular disease, left heart disease, lung disease or a combination of these conditions. Exercise pulmonary hypertension is associated with the presence of a modest elevation of resting mean PAP and requires clinical follow-up, particularly if risk factors for pulmonary hypertension are present. There is a lack of robust clinical evidence on targeted medical therapy for exercise pulmonary hypertension.
Current European guidelines recommend periodic risk assessment for patients with pulmonary arterial hypertension (PAH). The aim of our study was to determine the association between the number of ...low-risk criteria achieved within 1 year of diagnosis and long-term prognosis.Incident patients with idiopathic, heritable and drug-induced PAH between 2006 and 2016 were analysed. The number of low-risk criteria present at diagnosis and at first re-evaluation were assessed: World Health Organization (WHO)/New York Heart Association (NYHA) functional class I or II, 6-min walking distance (6MWD) >440 m, right atrial pressure <8 mmHg and cardiac index ≥2.5 L·min
·m
1017 patients were included (mean age 57 years, 59% female, 75% idiopathic PAH). After a median follow-up of 34 months, 238 (23%) patients had died. Each of the four low-risk criteria independently predicted transplant-free survival at first re-evaluation. The number of low-risk criteria present at diagnosis (p<0.001) and at first re-evaluation (p<0.001) discriminated the risk of death or lung transplantation. In addition, in a subgroup of 603 patients with brain natriuretic peptide (BNP) or N-terminal pro-brain natriuretic peptide (NT-proBNP) measurements, the number of three noninvasive criteria (WHO/NYHA functional class, 6MWD and BNP/NT-proBNP) present at first re-evaluation discriminated prognostic groups (p<0.001).A simplified risk assessment tool that quantifies the number of low-risk criteria present accurately predicted transplant-free survival in PAH.
Introduction
Contemporary risk assessment tools categorise patients with pulmonary arterial hypertension (PAH) as low, intermediate or high risk. A minority of patients achieve low risk status with ...most remaining intermediate risk. Our aim was to validate a four-stratum risk assessment approach categorising patients as low, intermediate-low, intermediate-high or high risk, as proposed by the Comparative, Prospective Registry of Newly Initiated Therapies for Pulmonary Hypertension (COMPERA) investigators.
Methods
We evaluated incident patients from the French PAH Registry and applied a four-stratum risk method at baseline and at first reassessment. We applied refined cut-points for three variables: World Health Organization functional class, 6-min walk distance and N-terminal pro-brain natriuretic peptide. We used Kaplan–Meier survival analyses and Cox proportional hazards regression to assess survival according to three-stratum and four-stratum risk approaches.
Results
At baseline (n=2879), the four-stratum approach identified four distinct risk groups and performed slightly better than a three-stratum method for predicting mortality. Four-stratum model discrimination was significantly higher than the three-stratum method when applied during follow-up and refined risk categories among subgroups with idiopathic PAH, connective tissue disease-associated PAH, congenital heart disease and portopulmonary hypertension. Using the four-stratum approach, 53% of patients changed risk category from baseline compared to 39% of patients when applying the three-stratum approach. Those who achieved or maintained a low risk status had the best survival, whereas there were more nuanced differences in survival for patients who were intermediate-low and intermediate-high risk.
Conclusions
The four-stratum risk assessment method refined risk prediction, especially within the intermediate risk category of patients, performed better at predicting survival and was more sensitive to change than the three-stratum approach.
The relationship between the initial treatment strategy and survival in pulmonary arterial hypertension (PAH) remains uncertain.
To evaluate the long-term survival of patients with PAH categorized ...according to the initial treatment strategy.
A retrospective analysis of incident patients with idiopathic, heritable, or anorexigen-induced PAH enrolled in the French Pulmonary Hypertension Registry (January 2006 to December 2018) was conducted. Survival was assessed according to the initial strategy: monotherapy, dual therapy, or triple-combination therapy (two oral medications and a parenteral prostacyclin).
Among 1,611 enrolled patients, 984 were initiated on monotherapy, 551 were initiated on dual therapy, and 76 were initiated on triple therapy. The triple-combination group was younger and had fewer comorbidities but had a higher mortality risk. The survival rate was higher with the use of triple therapy (91% at 5 yr) as compared with dual therapy or monotherapy (both 61% at 5 yr) (
< 0.001). Propensity score matching of age, sex, and pulmonary vascular resistance also showed significant differences between triple therapy and dual therapy (10-yr survival, 85% vs. 65%). In high-risk patients (
= 243), the survival rate was higher with triple therapy than with monotherapy or dual therapy, whereas there was no difference between monotherapy and double therapy. In intermediate-risk patients (
= 1,134), survival improved with an increasing number of therapies. In multivariable Cox regression, triple therapy was independently associated with a lower risk of death (hazard ratio, 0.29; 95% confidence interval, 0.11-0.80;
= 0.017). Among the 148 patients initiated on a parenteral prostacyclin, those on triple therapy had a higher survival rate than those on monotherapy or dual therapy.
Initial triple-combination therapy that includes parenteral prostacyclin seems to be associated with a higher survival rate in PAH, particularly in the youngest high-risk patients.
Treatment for pulmonary arterial hypertension (PAH) has been underpinned by single-agent therapy to which concomitant drugs are added sequentially when pre-defined treatment goals are not met.This ...retrospective analysis of real-world clinical data in 97 patients with newly diagnosed PAH (86% in New York Heart Association functional class III-IV) explored initial dual oral combination treatment with bosentan plus sildenafil (n=61), bosentan plus tadalafil (n=17), ambrisentan plus tadalafil (n=11) or ambrisentan plus sildenafil (n=8).All regimens were associated with significant improvements in functional class, exercise capacity, dyspnoea and haemodynamic indices after 4 months of therapy. Over a median follow-up period of 30 months, 75 (82%) patients were still alive, 53 (71%) of whom received only dual oral combination therapy. Overall survival rates were 97%, 94% and 83% at 1, 2 and 3 years, respectively, and 96%, 94% and 84%, respectively, for the patients with idiopathic PAH, heritable PAH and anorexigen-induced PAH. Expected survival rates calculated from the French equation for the latter were 86%, 75% and 66% at 1, 2 and 3 years, respectively.Initial combination of oral PAH-targeted medications may offer clinical benefits, especially in PAH patients with severe haemodynamic impairment.
Earlier studies have suggested an association between uric acid (UA) and pulmonary arterial hypertension (PAH) severity, but it remains unknown whether UA contributes to the disease pathogenesis.
To ...study the prognostic values of circulating UA at era of current management of PAH and
the role of UA in the pulmonary vascular remodelling.
Serum UA levels were determined in idiopathic, heritable, or anorexigen PAH at baseline and first re-evaluation in the French PAH registry. We studied protein levels of xanthine oxidase (XO) and the URATv1 transporter in lungs of control and PAH patients and of monocrotaline (MCT) and sugen/hypoxia (SuHx) rats. Functional studies were performed using human pulmonary artery smooth muscle cells (PA-SMCs) and two animal models of pulmonary hypertension (PH).
High serum UA levels are associated with a poor prognosis at first follow-up, but not at baseline. Both the generating enzyme XO and URATv1 are upregulated in the wall of remodelled pulmonary arteries in iPAH patients and MCT and SuHx rats. High UA concentrations promote a mild increase in cell growth in iPAH PA-SMCs, but not in control PA-SMCs. Consistent with these observations, we demonstrate that oxonic acid-induced hyperuricemia did not aggravate MCT-induced PH in rats. Finally, we show that chronic treatments of MCT and SuHx rats with benzbromarone mildly attenuate pulmonary vascular remodelling.
UA levels in iPAH patients is associated with impaired clinical and hemodynamic profile and might be used as a noninvasive indicator of clinical prognostic during follow-up. Our findings also indicate that metabolism of UA is disturbed in remodelled pulmonary vascular walls in both experimental and human PAH.
Pulmonary hypertension is an heterogeneous group of diseases characterised by increased pulmonary arterial pressures which impact on the upstream right ventricle. Pulmonary hypertension can be ...challenging to diagnose, classify and monitor when specific therapies are applicable. Cardiac magnetic resonance (CMR) imaging has greatly evolved in the last decades and is a promising tool to non-invasively follow pulmonary hypertension patients. CMR provides a comprehensive evaluation of the heart and is therefore the gold standard for quantification of right ventricular volumes, mass and function, which are critical for pulmonary hypertension prognosis. In addition, innovative MR techniques allow an increasingly precise evaluation of pulmonary haemodynamics and lung perfusion. This review highlights the main advantages offered by CMR in pulmonary hypertension and gives an overview of putative future applications. Although right heart catheterisation remains mandatory in the diagnostic algorithm, CMR could play an increasingly important role in the coming years in monitoring pulmonary hypertension patients.
mutation causes small patella syndrome (SPS) and/or pulmonary arterial hypertension (PAH). The characteristics and outcomes of PAH associated with
mutations are largely unknown.
We report the ...clinical, functional, radiologic, histologic and haemodynamic characteristics and outcomes of heritable PAH patients carrying a
mutation from the French pulmonary hypertension (PH) network.
20 patients were identified in 17 families. They were characterised by a median age at diagnosis of 29 years (0-76 years) and a female to male ratio of three. Most of the patients (70%) were in New York Heart Association (NYHA) functional class III or IV with a severe haemodynamic impairment (median pulmonary vascular resistance (PVR) of 13.6 (6.2-41.8) Wood units). Skeletal signs of SPS were present in 80% of cases. Half of the patients had mild restrictive or obstructive limitation and diffusing capacity of the lung for carbon monoxide (
) was decreased in all patients. High-resolution computed tomography (HRCT) showed bronchial abnormalities, peri-bronchial cysts, mosaic distribution and mediastinal lymphadenopathies. PAH therapy was associated with significant clinical improvement. At follow-up (median 76 months), two patients had died and two had undergone lung transplantation. One-year, three-year and five-year event-free survival rates were 100%, 94% and 83%, respectively. Histologic examination of explanted lungs revealed alveolar growth abnormalities, major pulmonary vascular remodelling similar to that observed in idiopathic pulmonary arterial hypertension (IPAH) and accumulation of cholesterol crystals within the lung parenchyma.
PAH due to
mutations may occur with or without skeletal abnormalities across a broad age range from birth to late adulthood. PAH is usually severe and associated with bronchial and parenchymal abnormalities.
RATIONALE:Senescence of pulmonary artery smooth muscle cells (PA-SMCs) caused by telomere shortening or oxidative stress may contribute to pulmonary hypertension associated with chronic lung ...diseases.
OBJECTIVE:To investigate whether cell senescence contributes to pulmonary vessel remodeling and pulmonary hypertension in chronic obstructive pulmonary disease (COPD).
METHODS AND RESULTS:In 124 patients with COPD investigated by right heart catheterization, we found a negative correlation between leukocyte telomere length and pulmonary hypertension severity. In-depth investigations of lung vessels and derived cultured PA-SMCs showed greater severity of remodeling and increases in senescent p16-positive and p21-positive PA-SMCs and proliferating Ki67-stained cells in 14 patients with COPD compared to 13 age-matched and sex-matched control subjects who smoke. Cultured PA-SMCs from COPD patients displayed accelerated senescence, with fewer cell population doublings, an increased percentage of β-galactosidase–positive cells, shorter telomeres, and higher p16 protein levels at an early cell passage compared to PA-SMCs from controls. Both in situ and in vitro PA-SMC senescence criteria correlated closely with the degree of pulmonary vessel wall hypertrophy. Because senescent PA-SMCs stained for p16 and p21 were virtually confined to the media near the Ki67-positive cells, which predominated in the neointima and hypertrophied media, we evaluated whether senescent cells affected normal PA-SMC functions. We found that senescent PA-SMCs stimulated the growth and migration of normal target PA-SMCs through the production and release of paracrine soluble and insoluble factors.
CONCLUSION:PA-SMC senescence is an important contributor to the process of pulmonary vascular remodeling that underlies pulmonary hypertension in chronic lung disease.
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