To assess the survival and prognostic factors in patients with newly diagnosed incident systemic sclerosis (SSc)-associated pulmonary arterial hypertension (PAH) in the modern management era.
...Prospectively enrolled SSc patients in the French PAH Network between January 2006 and November 2009, with newly diagnosed PAH and no interstitial lung disease, were analysed (85 patients, mean age 64.9±12.2 years). Median follow-up after PAH diagnosis was 2.32 years.
A majority of patients were in NYHA functional class III-IV (79%). Overall survival was 90% (95% CI 81% to 95%), 78% (95% CI 67% to 86%) and 56% (95% CI 42% to 68%) at 1, 2 and 3 years from PAH diagnosis, respectively. Age (HR: 1.05, 95% CI 1.01 to 1.09, p=0.012) and cardiac index (HR: 0.49, 95% CI 0.27 to 0.89, p=0.019) were significant predictors in the univariate analysis. We also observed strong trends for gender, SSc subtypes, New York Heart Association functional class, pulmonary vascular resistance and capacitance to be significant predictors in the univariate analysis. Conversely, six-min walk distance, mean pulmonary arterial and right atrial pressures were not significant predictors. In the multivariate model, gender was the only independent factor associated with survival (HR: 4.76, 95% CI 1.35 to 16.66, p=0.015 for male gender).
Incident SSc-associated PAH remains a devastating disease even in the modern management era. Age, male gender and cardiac index were the main prognosis factors in this cohort of patients. Early detection of less severe patients should be a priority.
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.
Background Exercise can distend the normally compliant, thin-walled pulmonary vessels. Loss of distensibility has been suggested as an early marker of pulmonary vascular remodeling. We hypothesized ...that in mild pulmonary vascular disease (PVD), a reduction in vascular distensibility during exercise occurs prior to the development of overt resting pulmonary hypertension (PH). Methods Distensibility α during exercise (percentage change in vessel diameter per mm Hg increase in transmural pressure) was estimated in 90 subjects using a model of the pulmonary circulation and invasive hemodynamic data. Distensible properties in mild PVD without resting PH (PVD-noPH) (n = 33) were compared with control subjects (n = 26) and PVD with overt resting PH (PVD-PH) (n = 31). Results Resting mean pulmonary artery pressure (mPpa) levels were 14 ± 4, 20 ± 3, and 34 ± 10 mm Hg with corresponding exercise mPpa-cardiac output slopes of 1.5 ± 0.6, 3.5 ± 0.9, and 5.7 ± 3.2 mm Hg/L/min for control subjects and the PVD-noPH and PVD-PH groups, respectively. The distensible model produced high accuracy and precision with no mean bias and 95% limits of agreement of −4.5 to 4.5 mm Hg between calculated and measured mPpa. Distensibility α was lowest in the PVD-PH group, intermediate in the PVD-noPH group, and highest in control subjects (0.25 ± 0.14%/mm Hg vs 0.45 ± 0.24%/mm Hg vs 1.40 ± 0.45%/mm Hg, P < .0001). Distensibility α discriminated PVD-noPH from control subjects with a sensitivity of 88% and a specificity of 100%. The discriminatory performance of α was similar for the subgroup of PVD-noPH, with a strictly normal resting mPpa ≤ 20 mm Hg. Conclusions Loss of pulmonary vascular distensibility during exercise occurs prior to resting PH in PVD. The usefulness of α as a novel vascular index for the early detection of PVD warrants further validation.
Uncontrolled and controlled clinical trials with different compounds and procedures are reviewed to define the risk-benefit profiles for therapeutic options in pulmonary arterial hypertension (PAH). ...A grading system for the level of evidence of treatments based on the controlled clinical trials performed with each compound is used to propose an evidence-based treatment algorithm. The algorithm includes drugs approved by regulatory agencies for the treatment of PAH and/or drugs available for other indications. The different treatments have been evaluated mainly in idiopathic PAH, heritable PAH, and in PAH associated with the scleroderma spectrum of diseases or with anorexigen use. Extrapolation of these recommendations to other PAH subgroups should be done with caution. Oral anticoagulation is proposed for most patients; diuretic treatment and supplemental oxygen are indicated in cases of fluid retention and hypoxemia, respectively. High doses of calcium-channel blockers are indicated only in the minority of patients who respond to acute vasoreactivity testing. Nonresponders to acute vasoreactivity testing or responders who remain in World Health Organization (WHO) functional class III, should be considered candidates for treatment with either an oral phosphodiesterase-5 inhibitor or an oral endothelin-receptor antagonist. Continuous intravenous administration of epoprostenol remains the treatment of choice in WHO functional class IV patients. Combination therapy is recommended for patients treated with PAH monotherapy who remain in WHO functional class III. Atrial septostomy and lung transplantation are indicated for refractory patients or where medical treatment is unavailable.
Registry data suggest that disease progression in pulmonary arterial hypertension (PAH) is indicative of poor prognosis. However, the prognostic relevance of PAH-related morbidity has not been ...formally evaluated in randomized controlled trials.
The purpose of these analyses was to assess the impact of morbidity events on the risk of subsequent mortality using the landmark method and data from the SERAPHIN and GRIPHON studies.
For each study, the risk of all-cause death up to the end of the study was assessed from the landmark time point (months 3, 6, and 12) according to whether a patient had experienced a primary endpoint morbidity event before the landmark. Each analysis was conducted using data from all patients who were available for survival follow-up at the landmark.
In the SERAPHIN study, on the basis of the 3-month landmark time point, patients who experienced a morbidity event before month 3 had an increased risk of death compared with patients who did not (hazard ratio HR: 3.39; 95% confidence interval CI: 1.94 to 5.92). In the GRIPHON study, on the basis of the 3-month landmark time point, there was also an increased risk with a HR of 4.48; (95% CI: 2.98 to 6.73). Analyses based on 6-month and 12-month landmarks also showed increased risk in patients who experienced morbidity events, albeit with a reduced HR.
These results demonstrate the prognostic relevance of PAH-related morbidity as defined in the SERAPHIN and GRIPHON studies, highlighting the importance of preventing disease progression in patients with PAH and supporting the clinical relevance of SERAPHIN and GRIPHON morbidity events. (Study of Macitentan ACT-064992 on Morbidity and Mortality in Patients With Symptomatic Pulmonary Arterial Hypertension SERAPHIN; NCT00660179; Selexipag ACT-293987 in Pulmonary Arterial Hypertension GRIPHON; NCT01106014)
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Characteristics of patients with idiopathic pulmonary arterial hypertension (IPAH) who benefit from long-term calcium channel blockers (CCB) are unknown.
Acute pulmonary vasodilator testing with ...epoprostenol or nitric oxide was performed in 557 IPAH patients. Acute responders, defined by a fall in both mean pulmonary artery pressure (PAP) and pulmonary vascular resistance (PVR) >20%, received long-term oral CCB. Patients who benefit from long-term CCB were defined as those being in New York Heart Association (NYHA) functional class I or II after at least 1 year on CCB monotherapy. Among the 70 patients who displayed acute pulmonary vasoreactivity (12.6%; 95% CI, 9.8% to 15.3%) and received CCB therapy, only 38 showed long-term improvement (6.8%; 95% CI, 4.7% to 8.9%). Long-term CCB responders had less severe disease at baseline than patients who failed. During acute vasodilator testing, long-term CCB responders displayed a more pronounced fall in mean PAP (-39+/-11% versus -26+/-7%; P<0.0001), reaching an absolute value of mean PAP lower than that measured in patients who failed (33+/-8 versus 46+/-10 mm Hg; P<0.0001). After 7.0+/-4.1 years, all but 1 long-term CCB responders were alive in NYHA class I or II, with a sustained hemodynamic improvement. In the group of patients who failed on CCB, the 5-year survival rate was 48%.
Long-term CCB responders represent <10% of IPAH patients evaluated in a pulmonary vascular referral center. During acute vasodilator testing, these patients showed significantly lower levels of both mean PAP and PVR, which reached near-normal values.
The prevalence of HIV-associated pulmonary arterial hypertension (PAH) has not been evaluated since introduction of combined, highly active antiretroviral treatments.
To establish the current ...prevalence of PAH in a large HIV-positive population.
Prospective study conducted in 7,648 consecutive HIV-positive adults in 14 HIV clinics in France. PAH was identified through screening with a predefined algorithm. Patients with dyspnea unexplained by other causes underwent transthoracic Doppler echocardiography. PAH was suspected if peak velocity of tricuspid regurgitation was greater than 2.5 m/second and was confirmed by right heart catheterization.
PAH was diagnosed if mean pulmonary arterial pressure at rest was 25 mm Hg or greater (with pulmonary capillary wedge pressure < or = 15 mm Hg) or 30 mm Hg or greater on exercise. A total of 739 patients had dyspnea, of which 312 met exclusion criteria and 150 refused to participate. Among the remaining 277, 30 had known PAH and 247 had unexplained dyspnea and underwent echocardiography; PAH was suspected in 18 and confirmed in 5, to give a total of 35 cases. The prevalence was thus 0.46% (95% confidence interval, 0.32-0.64%). All new cases had relatively milder PAH.
The prevalence of HIV-associated PAH is about the same as it was in the early 1990s. Given the current good long-term prognosis of patients with HIV, the severity of PAH in HIV-infected patients, and the absence of predictive factors, careful screening for PAH is warranted for patients with unexplained dyspnea.
Pulmonary arterial hypertension (PAH) is diagnosed by various investigations that are essential for making the diagnosis, and by additional tests to clarify the category of pulmonary hypertension ...(PH). A diagnostic algorithm can guide the evaluation of PH, but like all guidelines the algorithm can be modified according to specific clinical circumstances. Most patients are diagnosed as the result of an evaluation of symptoms, whereas others are diagnosed during screening of asymptomatic populations at risk. Right heart catheterization (RHC) must be performed in patients with suspected PH to establish the diagnosis and document pulmonary hemodynamics. Before initiation of medical therapy, assessment of acute vasoreactivity (during catheterization) is necessary to determine the appropriate therapy for an individual patient. An acute response is generally defined as a decrease in mean pulmonary arterial pressure of at least 10 mm Hg with the mean pulmonary arterial pressure decreasing to 40 mm Hg or below, accompanied by a normal or high cardiac output. After PAH is diagnosed, disease severity should be assessed in order to accurately determine risk:benefit profiles for various therapeutic options. Useful tools to predict outcome include functional class, exercise capacity, pulmonary hemodynamics, acute vasoreactivity, right ventricular function, as well as brain natriuretic peptide, endothelin-1, uric acid, and troponin levels. Repeating these tests serially on treatment is useful for monitoring the response to a given therapy. Close follow-up at a center specializing in management of PH is recommended, with careful periodic reassessment and adjustment of therapy.
We read with interest the correspondence by M.M. Hoeper and colleagues regarding risk assessment in pulmonary arterial hypertension (PAH). This follows the three manuscripts on the topic published in ...2017 in the European Respiratory Journal 1, 2 and in the European Heart Journal 3. All utilised a risk-assessment method derived from the risk-stratification table proposed by the 2015 European Society of Cardiology/European Respiratory Society Guidelines for the diagnosis and treatment of pulmonary hypertension 4, 5.
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