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1.
Lancet Respir Med ; 7(7): 594-604, 2019 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-31178422

RESUMO

BACKGROUND: No dedicated randomised clinical trials have evaluated therapies for pulmonary arterial hypertension in patients with portopulmonary hypertension. The endothelin receptor antagonist macitentan has demonstrated long-term efficacy in pulmonary arterial hypertension with a good hepatic safety profile. We aimed to evaluate efficacy and safety of macitentan in patients with portopulmonary hypertension. METHODS: PORTICO was a phase 4 study done in 36 centres in seven countries, consisting of a 12-week double-blind period (randomly assigned 1:1 to macitentan 10 mg or placebo once daily) followed by a 12-week open-label period. Adults (≥18 years) with portopulmonary hypertension, a 6-minute walk distance of 50 m or more, and with pulmonary vascular resistance of 320 dyn·s·cm-5 or more without severe hepatic impairment (Child-Pugh class C or model for end-stage liver disease score ≥19) were eligible. The primary endpoint was pulmonary vascular resistance at week 12, expressed as ratio of baseline in the full analysis set. Safety was assessed throughout. This trial is registered at ClinicalTrials.gov, number NCT02382016. FINDINGS: Between June 23, 2015, and July 28, 2017, 85 patients were randomly assigned to macitentan (n=43) or placebo (n=42). At baseline, 54 (64%) were receiving background therapy for pulmonary arterial hypertension. Most patients were WHO functional class II (50, 59%) or III (33, 39%) with a mean 6-minute walk distance of 384·5 m (SD 103·9). At week 12, the geometric mean ratio of baseline pulmonary vascular resistance was 0·63 (95% CI 0·58-0·67) in the macitentan group and 0·98 (95% CI 0·91-1·05) in the placebo group, corresponding to a ratio of geometric mean for pulmonary vascular resistance of 0·65 (95% CI 0·59-0·72, p<0·0001), which in turn represented a 35% (95% CI 28-41) reduction in pulmonary vascular resistance with macitentan versus placebo. During the double-blind period, 36 (84%) macitentan-treated and 33 (79%) placebo-treated patients had adverse events, and nine (21%) and six (14%), had serious adverse events. Four (9%) macitentan-treated patients had an adverse event leading to discontinuation versus none in the placebo group. The most frequent adverse event during the double-blind period was peripheral oedema (11 [26%] in the macitentan group and five [12%] in the placebo group). INTERPRETATION: Macitentan significantly improved pulmonary vascular resistance in portopulmonary hypertension patients, with no hepatic safety concerns. FUNDING: Actelion Pharmaceuticals Ltd.

2.
Circ Cardiovasc Qual Outcomes ; 12(5): e005095, 2019 May.
Artigo em Inglês | MEDLINE | ID: mdl-31109190

RESUMO

Background Conducting randomized controlled trials to investigate survival in a rare disease like pulmonary arterial hypertension has considerable ethical and logistical constraints. In many studies, such as the Study with an Endothelin Receptor Antagonist in Pulmonary Arterial Hypertension to Improve Clinical Outcome (SERAPHIN) randomized controlled trial, evaluating survival is further complicated by bias introduced by allowing active therapy among placebo-treated patients who clinically deteriorate. Methods and Results SERAPHIN enrolled and followed patients in the same time frame as the US Registry to Evaluate Early And Long-term PAH Disease Management, providing an opportunity to compare observed survival for SERAPHIN patients with predicted survival had they received real-world treatment as in the Registry to Evaluate Early And Long-term PAH Disease Management. From the Registry to Evaluate Early And Long-term PAH Disease Management (N=3515), 734 patients who met SERAPHIN eligibility criteria were selected and their data used to build a prediction model for time to death up to 3 years based on 10 baseline prognostic variables. The model was used to predict a survival curve for each of the 742 SERAPHIN patients via their baseline variables. The average of these predicted survival curves was compared with observed survival of the placebo (n=250) and macitentan 10 mg (n=242) groups using a log-rank test and Cox proportional hazard model. Observed mortality risk for patients randomized to placebo, 62% of whom were taking background pulmonary arterial hypertension therapy, tended to be lower than that predicted for all SERAPHIN patients (16% lower; P=0.259). The observed placebo survival curve closely approximated the predicted survival curve for the first 15 months. Beyond that time, observed risk of mortality decreased compared with predicted mortality, potentially reflecting the impact of crossover of patients in the placebo group to active therapy. Over 3 years, risk of mortality observed with macitentan 10 mg was 35% lower than predicted mortality ( P=0.010). Conclusions These analyses show that, in a rare disease, real-world observational data can complement randomized controlled trial data to overcome some challenges associated with assessing survival in the setting of a randomized controlled trial. Clinical Trial Registration https://www.clinicaltrials.gov . Unique identifiers: NCT00660179 and NCT00370214.

3.
J Heart Lung Transplant ; 38(8): 833-842, 2019 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-31103383

RESUMO

BACKGROUND: Treatment options for inoperable chronic thromboembolic pulmonary hypertension (CTEPH) have recently evolved with the availability of balloon pulmonary angioplasty (BPA) and pulmonary vasodilators. Our aim was to analyze the prognostic variables associated with long-term outcome in a cohort of patients with not-operated CTEPH. METHODS: From January 2006 to December 2016, 343 newly diagnosed consecutive patients with not-operated CTEPH were diagnosed and followed up in the French Reference Center for Pulmonary Hypertension. Overall long-term survival and prognostic factors according to the diagnosis period (early period, 2006-2012, vs recent period, since 2013, i.e., one year before availability of BPA) were analyzed. RESULTS: In the overall population, baseline New York Heart Association functional class, right atrial pressure, 6-minute walk distance (6MWD), and diagnosis period were independent predictors of survival. The 1- and 3-year survival rates of patients diagnosed in the recent period (n = 170) were 91.6% and 85.0%, compared with 89.0% and 74.3% in patients diagnosed in the early period (n = 173), respectively (p = 0.030). Multivariate analysis from patients diagnosed in the recent period found that baseline 6MWD (per 20 m increase in distance) (hazard ratio [HR], 0.879; 95% confidence interval [CI], 0.832-0.928, p < 0.001) and BPA (HR, 0.307; 95% CI, 0.099-0.957; p = 0.042) were independently associated with survival. CONCLUSIONS: Survival of not-operated patients with CTEPH has significantly improved in the recent management era. New treatment options, including BPA, might have the potential to improve the prognosis of patients with inoperable CTEPH.

4.
Eur Respir J ; 53(5)2019 May.
Artigo em Inglês | MEDLINE | ID: mdl-31023842

RESUMO

AIMS: To evaluate safety and efficacy of balloon pulmonary angioplasty (BPA) in a large cohort of patients with chronic thromboembolic pulmonary hypertension (CTEPH). METHODS: From 2014 to 2017, 184 inoperable CTEPH patients underwent 1006 BPA sessions. Safety and efficacy during the first 21 months (initial period) were compared with those of the last 21 months (recent period). A total of 154 patients had a full evaluation after a median duration of 6.1 months. RESULTS: Overall, there was a significant improvement in New York Heart Association functional class, 6-min walk distance (mean change +45 m), and a significant decrease in mean pulmonary artery pressure (PAP) and in pulmonary vascular resistance (PVR) by 26% and 43%, respectively. The percentage decreases of mean PAP and PVR were 22% and 37% in the initial period versus 30% and 49% in the recent period, respectively (p<0.05). The main complications included lung injury, which occurred in 9.1% of 1006 sessions (13.3% in the initial period versus 5.9% in the recent period; p<0.001). Per-patient multivariate analysis revealed that baseline mean PAP and the period during which BPA procedure was performed (recent versus initial period) were the strongest factors related to the occurrence of lung injury. 3-year survival was 95.1%. CONCLUSION: This study confirms that a refined BPA strategy improves short-term symptoms, exercise capacity and haemodynamics in inoperable CTEPH patients with an acceptable risk-benefit ratio. Safety and efficacy improve over time, underscoring the unavoidable learning curve for this procedure.

5.
Circulation ; 139(21): 2440-2450, 2019 May 21.
Artigo em Inglês | MEDLINE | ID: mdl-30982349

RESUMO

BACKGROUND: NT-proBNP (N-terminal pro brain natriuretic peptide) levels are included in the multiparametric risk assessment approach for pulmonary arterial hypertension (PAH) outlined in PAH guidelines. However, data supporting the use of NT-proBNP risk thresholds in assessing prognosis in PAH are limited. The GRIPHON trial (Prostacyclin [PGI2] Receptor Agonist In Pulmonary Arterial Hypertension) provides an opportunity to assess the prognostic value of NT-proBNP thresholds in a controlled clinical trial and to evaluate the response to selexipag according to these thresholds. METHODS: The event-driven GRIPHON trial randomly assigned patients to selexipag or placebo. NT-proBNP was measured at regular intervals in GRIPHON. Here, patients were categorized post hoc into low, medium, and high NT-proBNP subgroups according to 2 independent sets of thresholds: (1) baseline tertiles: <271 ng/L; 271 to 1165 ng/L; >1165 ng/L; and (2) 2015 European Society of Cardiology/European Respiratory Society guidelines cutoffs: <300 ng/L; 300 to 1400 ng/L; >1400 ng/L. Hazard ratios (selexipag versus placebo) with 95% CIs were calculated for the primary end point (composite morbidity/mortality events) by NT-proBNP category at baseline using Cox proportional-hazards models, and at any time during the exposure period using a time-dependent Cox model. RESULTS: With both thresholds, baseline and follow-up NT-proBNP categories were highly prognostic for future morbidity/mortality events during the study ( P<0.0001). In the time-dependent analysis, the risk of experiencing a morbidity/mortality event was 92% and 83% lower in selexipag-treated patients with a low and medium NT-proBNP level, and 90% and 56% lower in placebo-treated patients with a low and medium NT-proBNP level, in comparison with patients with a high NT-proBNP level. Selexipag reduced the risk of morbidity/mortality events across all 3 NT-proBNP categories in both the baseline and time-dependent analyses, with a more pronounced treatment benefit of selexipag seen in the medium and low NT-proBNP subgroups (interaction P values 0.20 and 0.007 in the baseline and time-dependent analyses). CONCLUSIONS: These analyses further establish the prognostic relevance of NT-proBNP levels in PAH and provide first evidence for the association of NT-proBNP level and treatment response. Using 2 similar sets of thresholds, these analyses support the relevance of the low, medium, and high NT-proBNP categories as part of the multiparametric risk assessment approach outlined in the European Society of Cardiology/European Respiratory Society guidelines for the management of PAH patients. CLINICAL TRIAL REGISTRATION: URL: https://www.clinicaltrials.gov . Unique identifier: NCT01106014.

6.
Am J Pathol ; 189(6): 1159-1175, 2019 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-30926335

RESUMO

Hepatic veno-occlusive disease (HVOD), alias sinusoidal obstruction syndrome, may develop as a complication of chemotherapy in the setting of hematopoietic stem cell transplantation. HVOD is less frequently described after exposure to chemotherapy in the nontransplant setting and can also be a complication after ingestion of toxins, such as pyrrolizidine alkaloids. Veno-occlusive disease may also affect the lungs, and it is therefore termed pulmonary veno-occlusive disease (PVOD). Similarly, PVOD can develop after exposure to chemotherapeutic agents in the treatment of solid and hematological malignancies. In addition, PVOD has also been linked to autoimmune disorders and occupational solvent exposure. Finally, the heritable form of PVOD is due to biallelic mutations of the EIF2AK4 gene. Both HVOD and PVOD share common histopathological features and pathophysiologic mechanisms. Both clinical disorders are rare complications that can appear after exposure to the common inciting trigger of chemotherapeutic agents. The present review aims to summarize the current knowledge of HVOD and PVOD and to describe both similarities as well as differences regarding both conditions.

7.
Eur J Heart Fail ; 21(3): 352-359, 2019 03.
Artigo em Inglês | MEDLINE | ID: mdl-30632656

RESUMO

AIMS: Patients with pulmonary arterial hypertension associated with congenital heart disease (CHD-PAH) after defect correction have a poor prognosis compared with other CHD-PAH patients. Therefore, it is important that these patients are treated as early and effectively as possible. Evidence supporting the use of PAH therapies in patients with corrected CHD-PAH from randomised controlled trials is limited. The purpose of these analyses was to characterise the corrected CHD-PAH patients from the GRIPHON study and examine the response to selexipag. METHODS AND RESULTS: Out of the 110 patients diagnosed with corrected CHD-PAH, 55 had atrial septal defects, 38 had ventricular septal defects, 14 had persistent ducti arteriosus, and 3 had defects not further specified. Hazard ratios (HR) and 95% confidence intervals (CI) for the primary composite endpoint were calculated using Cox proportional hazard models. Compared with the non-CHD patients from GRIPHON, patients with corrected CHD-PAH were slightly younger, with a greater proportion being treatment-naive and in World Health Organization functional class I/II. The rate of the primary composite endpoint of morbidity/mortality was lower in patients with corrected CHD-PAH who were treated with selexipag compared with those treated with placebo (HR 0.58; 95% CI 0.25, 1.37). The most common adverse events were those known to be related to selexipag. CONCLUSIONS: These post-hoc analyses of GRIPHON provide valuable information about a large population of patients with corrected CHD-PAH, and suggest that selexipag may delay disease progression and was well-tolerated in patients with corrected CHD-PAH.

8.
Chest ; 155(5): 991-998, 2019 May.
Artigo em Inglês | MEDLINE | ID: mdl-30594558

RESUMO

BACKGROUND: The golden ratio (phi, Φ = 1.618) is a proportion that has been found in many phenomena in nature, including the cardiovascular field. We tested the hypothesis that the systolic over mean pulmonary artery pressure ratio (sPAP/mPAP) and the mean over diastolic pressure ratio (mPAP/dPAP) may match Φ in patients with pulmonary arterial hypertension (PAH) and in control patients. METHODS: In the first, theoretical part of the study, we discuss why our hypothesis is consistent with three known hemodynamic features of the pulmonary circulation: (1) the 0.61 slope of the mPAP vs sPAP relationship, (2) pulmonary artery pulse pressure and mPAP have an almost 1:1 ratio, and (3) the proportional relationship among sPAP, mPAP, and dPAP. In the second part of the study, fluid-filled pressures were analyzed in 981 incident, untreated PAH and high-fidelity pressures were also analyzed in 44 historical control patients (mPAP range, 9-113 mm Hg). RESULTS: In PAH (non-normal distribution), median values of sPAP/mPAP and mPAP/dPAP were 1.591 (98%Φ) and 1.559 (96%Φ), respectively. In control patients (normal distribution), mean sPAP/mPAP and mPAP/dPAP were 1.572 (97%Φ) and 1.470 (91%Φ), respectively. In both PAH and control patients, this was consistent with the Φ hypothesis, assuming < 1 mm Hg error in estimation of sPAP, mPAP, and dPAP on average. CONCLUSIONS: In PAH and in control patients, the fluctuations in sPAP and dPAP around mPAP exhibited a constant scaling factor matched to Φ. This remarkable property allows linkage of various empirical observations on pulmonary hemodynamics that were hitherto apparently unrelated. These findings warrant further confirmation in other types of pulmonary hypertension and warrant explanation.

9.
Eur Respir J ; 53(1)2019 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-30545975

RESUMO

Until 20 years ago the treatment of pulmonary arterial hypertension (PAH) was based on case reports and small series, and was largely ineffectual. As a deeper understanding of the pathogenesis and pathophysiology of PAH evolved over the subsequent two decades, coupled with epidemiological studies defining the clinical and demographic characteristics of the condition, a renewed interest in treatment development emerged through collaborations between international experts, industry and regulatory agencies. These efforts led to the performance of robust, high-quality clinical trials of novel therapies that targeted putative pathogenic pathways, leading to the approval of more than 10 novel therapies that have beneficially impacted both the quality and duration of life. However, our understanding of PAH remains incomplete and there is no cure. Accordingly, efforts are now focused on identifying novel pathogenic pathways that may be targeted, and applying more rigorous clinical trial designs to better define the efficacy of these new potential treatments and their role in the management scheme. This article, prepared by a Task Force comprised of expert clinicians, trialists and regulators, summarises the current state of the art, and provides insight into the opportunities and challenges for identifying and assessing the efficacy and safety of new treatments for this challenging condition.

10.
Eur Respir J ; 52(4)2018 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-30305330

RESUMO

The long-term effects of chronic blood exchange transfusions (BETs) on pre-capillary pulmonary hypertension complicating sickle cell disease (SCD) are unknown.13 homozygous SS SCD patients suffering from pre-capillary pulmonary hypertension and treated by chronic BETs were evaluated retrospectively. Assessments included haemodynamics, New York Heart Association Functional Class (NYHA FC), 6-min walk distance (6MWD) and blood tests.Before initiating BETs, all patients were NYHA FC III or IV, median (range) 6MWD was 223 (0-501) m and median (range) pulmonary vascular resistance (PVR) was 3.7 (2-12.5) Wood Units. After a median number of 4 BET sessions, all patients had improved to NYHA FC II or III. Significant improvements in haemodynamics were observed, including a decrease in PVR (p=0.01). There was a trend to higher 6MWD (p=0.09). Median (range) follow-up time after initiation of BETs was 25 (6-53) months. During this period, two patients decided to stop BETs. One of them died from acute right heart failure and the other experienced worsening pulmonary hypertension. Two other patients died during follow-up at 25 and 54 months after BET initiation.Chronic BETs may be a potential therapeutic option in pre-capillary pulmonary hypertension complicating SCD, leading to significant clinical and haemodynamic improvements. These data must be confirmed in a prospective study.

11.
Eur Respir J ; 52(4)2018 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-30209196

RESUMO

The prognostic importance of follow-up haemodynamics and the validity of multidimensional risk assessment are not well established for systemic sclerosis (SSc)-associated pulmonary arterial hypertension (PAH).We assessed incident SSc-PAH patients to determine the association between clinical and haemodynamic variables at baseline and first follow-up right heart catheterisation (RHC) with transplant-free survival. RHC variables included cardiac index, stroke volume index (SVI), pulmonary arterial compliance and pulmonary vascular resistance. Risk assessment was performed according to the number of low-risk criteria: functional class I or II, 6-min walking distance (6MWD) >440 m, right atrial pressure <8 mmHg and cardiac index ≥2.5 L·min-1·m-2Transplant-free survival from diagnosis (n=513) was 87%, 55% and 35% at 1, 3 and 5 years, respectively. At baseline, 6MWD was the only independent predictor. A follow-up RHC was available for 353 patients (median interval 4.6 months, interquartile range 3.9-6.4 months). The 6MWD, functional class, cardiac index, SVI, pulmonary arterial compliance and pulmonary vascular resistance were independently associated with transplant-free survival at follow-up, with SVI performing better than other haemodynamic variables. 1-year outcomes were better with increasing number of low-risk criteria at baseline (area under the curve (AUC) 0.63, 95% CI 0.56-0.69) and at first follow-up (AUC 0.71, 95% CI 0.64-0.78).Follow-up haemodynamics and multidimensional risk assessment had greater prognostic significance than at baseline in SSc-PAH.

12.
Eur Respir Rev ; 27(149)2018 Sep 30.
Artigo em Inglês | MEDLINE | ID: mdl-30158278

RESUMO

Neurofibromatosis type 1 (NF1), also known as von Recklinghausen disease, is a frequent autosomal dominant genetic disorder with a prevalence of 1 in 3000. Pulmonary hypertension (PH) associated with NF1 (PH-NF1) is a rare but severe complication of NF1 and is classified as Group 5 PH, defined as "PH with unclear and/or multifactorial mechanisms". A literature review in PubMed on the association between NF1 and PH identified 18 articles describing 31 cases. PH-NF1 was characterised by a female predominance, an advanced age at diagnosis, an association with parenchymal lung disease in two out of three cases and poor long-term prognosis. NF1 is generally associated with interstitial lung disease but some cases of severe PH without parenchymal lung disease suggest that there could be a specific pulmonary vascular disease. There is no data available on the efficacy of specific pulmonary arterial hypertension treatment in PH-NF1. Therefore, these patients should be evaluated in expert PH centres and referred for lung transplantation at an early stage. As these patients have an increased risk of malignancy, careful assessment of the post-transplant malignancy risk prior to listing for transplantation is necessary. Clinical trials are needed to evaluate promising treatments targeting the RAS-downstream signalling pathways.

13.
Int J Clin Pharm ; 40(4): 790-794, 2018 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-30101375

RESUMO

Spontaneous reporting is the primary method used in pharmacovigilance (PV) to detect drug safety signal. Specific criteria used in pharmacovigilance to prove accountability of a drug are rarely present in rare disease. The low number of alerts also makes it challenging. The aim of this commentary is to raise awareness among pharmacists on issues and opportunities for pharmacovigilance in rare diseases, taking pulmonary arterial hypertension (PAH) as example, from which a subset of cases are drug-induced. It is demonstrated how a dedicated program named VIGIAPATH created to reinforce pharmacovigilance of drug-induced pulmonary arterial hypertension at a national level, led to increase self-reporting and confirm safety signals. Thanks to a specific program such as VIGIAPATH, pharmacists can play an important role in communication with clinicians, patients and regulatory agencies, facilitating the detection of potential safety signals at an early stage in rare disease.

14.
J Heart Lung Transplant ; 37(9): 1102-1110, 2018 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-30037729

RESUMO

BACKGROUND: Balloon pulmonary angioplasty (BPA) is a technique proposed for inoperable patients with chronic thromboembolic pulmonary hypertension (CTEPH). In this study we aimed to determine whether initiation of the BPA program has modified the characteristics and outcome of patients undergoing pulmonary endarterectomy (PEA), and compared the characteristics of patients undergoing one or the other procedure. METHODS: This prospective registry study included all patients with CTEPH who underwent PEA in the French National Reference Center before (2012 to 2013) and after (2015 to 2016) BPA program initiation (February 2014). Pre-operative clinical and hemodynamics profiles, peri-operative (Jamieson classification, surgery duration, need of assistance) characteristics of both groups, and all-cause mortality were compared using the t-test or chi-square test. Characteristics of patients subjected to surgery or BPA since February 2014 were also compared. RESULTS: The total number of patients referred to the CTEPH team increased in the BPA era (n = 291 vs n = 484). The pre-operative characteristics of patients from the pre-BPA era (n = 240) were similar to those from the BPA era (n = 246). Despite more Jamieson Type 3 cases (29%) in the second period, 30- and 90-day mortality remained stable (both p > 0.30). Patients subjected to BPA (n = 177) were older than those subjected to PEA (n = 364) (64 ± 14 vs 60 ± 14 years, respe`ctively), and had higher rates of splenectomy (10% vs 1%) or implantable port (9% vs 3%), lower total pulmonary resistance, better cardiac index, and better renal function (all p < 0.01). CONCLUSIONS: This study shows the influence of the initiation of the BPA program on the profile of patients with CTEPH undergoing PEA.

15.
Curr Opin Pulm Med ; 24(5): 407-415, 2018 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-30004992

RESUMO

PURPOSE OF REVIEW: Periodic risk stratification is recommended for patients with pulmonary arterial hypertension (PAH). The purpose of this article is to review the available risk stratification tools in PAH. RECENT FINDINGS: Validated tools, such as the REVEAL (Registry to Evaluate Early And Long-term PAH Disease Management) score or European Society of Cardiology/European Respiratory Society (ESC/ERS) risk assessment table incorporate clinical, exercise, imaging, and hemodynamic variables to obtain a multidimensional estimate of prognosis. Recent studies from REVEAL and European registries have further validated these tools and improved our understanding of prognostic factors in PAH. Serial risk assessment over time, especially after treatment initiation or modification, provides more useful information than at a single time point, with changes in risk profiles being particularly informative. A brief, simplified approach includes counting the number of ESC/ERS low-risk criteria achieved, with 3 or 4 low-risk criteria associated with an excellent prognosis. When a more precise estimation of risk is desired, the REVEAL score can delineate five risk groups with 1-year survival rates between 97.3% (low risk) and 50.2% (very high risk). SUMMARY: The REVEAL and ESC/ERS risk table are useful, validated, multidimensional risk stratification tools that should be periodically applied to patients with PAH in practice.

16.
Chest ; 154(4): 882-892, 2018 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-29940163

RESUMO

BACKGROUND: The role of decreased pulmonary arterial (PA) compliance (C), equivalent to increased PA stiffness (1/C), as a critical determinant of right ventricular dysfunction and prognosis has been emphasized in pulmonary arterial hypertension (PAH). METHODS: This study retrospectively reviewed all incident patients diagnosed with idiopathic PAH according to right heart catheterization who were enrolled in the French Pulmonary Arterial Hypertension Network registry between 2006 and 2016 and who had complete baseline data allowing calculation of stiffness (PA pulse pressure/stroke volume index). RESULTS: In the 719 patients included (median age: 66 years; 53.7% female), PA stiffness was 1.49 mm Hg × m2/mL (interquartile ratio: 1.08-2.04 mm Hg × m2/mL). Stiffness was related to mean pulmonary artery pressure (mPAP) (r2 = 0.33) and heart rate (r2 = 0.15) but not to age or sex. Higher PA stiffness and higher pulmonary vascular resistance (PVR) were documented in high-risk vs low-risk patients, as defined according to the European Society of Cardiology/European Respiratory Society guidelines. The dispersion of the PVR × C product was as variable as patient age and mPAP, and C could not be estimated on the basis of PVR alone (95% limits of agreement of the bias: -50% to 54%). Although transplant-free survival differed across PA stiffness quartiles (P = .04), stiffness was not an independent predictor of long-term outcome (median follow-up duration: 2.43 years). CONCLUSIONS: In incident idiopathic PAH, PA stiffness was related to mPAP and heart rate, and this finding outperformed the potential influences of age and sex. Baseline PA stiffness did not independently predict outcome. The great dispersion of the PVR × C product implied that PVR and PA stiffness were differently affected by the disease process.

17.
PLoS One ; 13(6): e0198198, 2018.
Artigo em Inglês | MEDLINE | ID: mdl-29927944

RESUMO

OBJECTIVE: Few studies have reported predictive factors of outcome after pulmonary endarterectomy (PEA) in chronic thromboembolic pulmonary hypertension. The purpose of this study was to determine factors influencing mortality and predictors of hemodynamic improvement after PEA. METHODS: A total of 383 consecutive patients who underwent PEA between January 2005 and December 2009 were retrospectively reviewed. Among them, 150 were fully reevaluated 7.5±1 months after PEA by NYHA class, 6-minute walk distance (6MWD), percentage of predicted carbon monoxide transfer factor (TLCO) and right heart catheterisation. RESULTS: Mortality rates at 1 month, 1 year and 3 years were 2.8%, 6.9% and 7.5%, respectively. Preoperative pulmonary vascular resistance (PVR) independently predicted 1-month, 1- and 3-year mortality and age predicted mortality at 1 year and 3 years. Significant improvement in NYHA class and 6MWD were observed and PVR decreased from 773±353 to 307±221 dyn.sec.cm-5 (p<0.001). In 96 patients (64%), PVR decreased by at least 50% and/or was reduced to lower than 250 dyn.sec.cm-5. Preoperative cardiac output (CO) and TLCO predicted hemodynamic improvement. CONCLUSION: PEA is associated with an excellent long-term survival and a marked improvement in clinical status and hemodynamics. Some preoperative factors including PVR, CO and TLCO can predict postoperative outcomes.

19.
PLoS One ; 13(5): e0197112, 2018.
Artigo em Inglês | MEDLINE | ID: mdl-29763468

RESUMO

Pre-capillary pulmonary hypertension (PH) in systemic sclerosis (SSc) is a heterogeneous condition with an overall bad prognosis. The objective of this study was to identify and characterize homogeneous phenotypes by a cluster analysis in SSc patients with PH. Patients were identified from two prospective cohorts from the US and France. Clinical, pulmonary function, high-resolution chest tomography, hemodynamic and survival data were extracted. We performed cluster analysis using the k-means method and compared survival between clusters using Cox regression analysis. Cluster analysis of 200 patients identified four homogenous phenotypes. Cluster C1 included patients with mild to moderate risk pulmonary arterial hypertension (PAH) with limited or no interstitial lung disease (ILD) and low DLCO with a 3-year survival of 81.5% (95% CI: 71.4-88.2). C2 had pre-capillary PH due to extensive ILD and worse 3-year survival compared to C1 (adjusted hazard ratio [HR] 3.14; 95% CI 1.66-5.94; p = 0.0004). C3 had severe PAH and a trend towards worse survival (HR 2.53; 95% CI 0.99-6.49; p = 0.052). Cluster C4 and C1 were similar with no difference in survival (HR 0.65; 95% CI 0.19-2.27, p = 0.507) but with a higher DLCO in C4. PH in SSc can be characterized into distinct clusters that differ in prognosis.


Assuntos
Hemodinâmica , Hipertensão Pulmonar , Fenótipo , Escleroderma Sistêmico , Idoso , Humanos , Hipertensão Pulmonar/diagnóstico por imagem , Hipertensão Pulmonar/etiologia , Hipertensão Pulmonar/mortalidade , Hipertensão Pulmonar/fisiopatologia , Masculino , Pessoa de Meia-Idade , Estudos Retrospectivos , Fatores de Risco , Escleroderma Sistêmico/complicações , Escleroderma Sistêmico/diagnóstico por imagem , Escleroderma Sistêmico/mortalidade , Escleroderma Sistêmico/fisiopatologia , Taxa de Sobrevida
20.
Chest ; 154(4): 872-881, 2018 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-29800550

RESUMO

BACKGROUND: An obesity paradox, wherein patients who are obese have lower mortality, has been described in cardiopulmonary diseases, including pulmonary arterial hypertension (PAH). Our objective was to determine whether obesity and BMI are associated with mortality in patients with PAH. METHODS: We assessed incident patients with idiopathic, drug-induced, and heritable PAH from the French Pulmonary Hypertension Network registry. Cox regression and Kaplan-Meier analysis were used to assess the association between BMI and obesity with all-cause mortality. RESULTS: Of 1,255 patients included, 30% were obese. A higher proportion of women (65.1% vs 53.4%, P < .01), drug-induced PAH (28.9% vs 9.2%, P < .01), systemic hypertension, diabetes, and hypothyroidism were present in the obese group. More obese patients were in New York Heart Association class III (66.4% vs 57.1%), fewer were class IV (11.8% vs 16.9%, P < .01), and 6-min walk distance was lower (276 ± 121 vs 324 ± 146, P < .01). Right atrial pressure, pulmonary wedge pressure, and cardiac index were higher, whereas pulmonary vascular resistance was lower in patients who were obese. Neither BMI (hazard ratio [HR], 0.99; 95% CI, 0.97-1.01; P = .41) nor obesity (HR, 1.0; 95% CI, 0.99-1.01; P = .46) were associated with mortality in multivariable analyses. There was a significant interaction between age and obesity such that mortality increased among patients < 65 years of age who were morbidly obese (HR, 3.01; 95% CI, 1.56-5.79; P = .001). CONCLUSIONS: Obesity was not associated with mortality in the overall population, but there was an age-obesity interaction with increased mortality among young patients who were morbidly obese. These results have implications for active weight management in younger patients who are morbidly obese who are otherwise candidates for lung transplantation.

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