Long-term survival in pulmonary arterial hypertension and chronic thromboembolic pulmonary hypertension: Insights from a referral center in Portugal

Objectives

This study aims to assess the long-term survival of pulmonary arterial hypertension (PAH) and chronic thromboembolic pulmonary hypertension (CTEPH) patients followed in a Portuguese pulmonary hypertension (PH) referral center.

Pulmonary arterial hypertension in connective tissue diseases

Pulmonary arterial hypertension (PAH) may complicate diverse connective tissue diseases (CTDs). Approximately 10% of patients with systemic sclerosis develop PAH, the prevalence being much lower in other CTDs. However, PAH is an important contributor to morbidity and mortality in all forms of CTD. Despite similarities in presentation, hemodynamic perturbations, and pathogenesis, patients with CTD-associated PAH (CTD-PAH) usually have a poorer response to PAH-specific medications and poorer prognosis than patients with idiopathic PAH (IPAH). Select patients with CTD-PAH may be candidates for lung transplantation, but results are less favorable than for IPAH because of comorbidities and complications specifically associated with CTD.     

2009 ESC/ERS pulmonary hypertension guidelines and connective tissue disease

Pulmonary hypertension was defined as mean pulmonary artery pressure ≥ 25 mmHg at the 4th World Symposium on Pulmonary Hypertension. In 2009, the European Society of Cardiology and European Respiratory Society jointly created guidelines for practical pulmonary hypertension classifications and treatments based on the discussions at the 4th World Symposium. This classification is characterized by division into five groups: Pulmonary arterial hypertension (PAH); Pulmonary hypertension due to left heart disease; Pulmonary hypertension due to lung disease and/or hypoxia; Chronic thromboembolic pulmonary hypertension; and Pulmonary hypertension with unclear and/or multifactorial mechanisms. PAH is a common and fatal complication of connective tissue disease (CTD), but pulmonary hypertension in CTD consists of PAH, pulmonary hypertension caused by myocardial involvement, pulmonary veno-occlusive disorder, pulmonary hypertension due to interstitial lung disease. PAH has been studied widely in SSc and the estimated prevalence of 7-12%. Treatment of CTD associated PAH (CTD-PAH) consists of general therapeutic options and specific treatment. Specific treatment of CTD-PAH patients is targeted to produce vasodilatation. Calcium channel blockers (CCBs) are indicated in cases where a sufficient decrease in pulmonary arterial pressure is seen in vasoreactivity testing. If vasoreactivity is absent in CTD-PAH patients, the treatment consists of the endothelin receptor antagonists, the prostacyclin analogues and phosphodiesterase-type 5 inhibitors. Few data are available to support the use of immunosuppression in CTD-PAH. However, some case reports suggested that a minority of CTD-PAH patients could benefit from immunosuppressive therapy. The treatment of CTD-PAH patients may differ from the treatment of idiopathic PAH.     

Pulmonary endarterectomy in chronic thromboembolic pulmonary hypertension: How can patients be better selected?

Chronic thromboembolic pulmonary hypertension (CTEPH) comprises organizing thrombotic obstructions in the pulmonary arteries by nonresolving thromboemboli, formation of fibrosis and remodeling of pulmonary blood vessels. Surgical pulmonary endarterectomy (PEA) is the therapy of choice for patients with surgically accessible CTEPH, which leads to a profound improvement in hemodynamics, functional class and survival. Select- ing the candidates that will benefit from surgery is still a challenging task. Criteria for surgical suitability have been described but the decision-making for or against surgical intervention remains still subjective. The optimal characterization of the reciprocal contribution of large vessel and small vessel disease in the elevation of pulmonary vascular resistance is crucial for the indication and outcome of PEA. Recently, Toshner et al intended to validate the partition resistance into small and large vessels compartments (upstream resistance:Rup) by the occlusion technique in the preoperative assessment of PEA. We discuss the advantages and disadvantages of Rup and compare it with other hemodynamic predictor to evaluate operative risk in CTEPH patients.     

Is methamphetamine use associated with idiopathic pulmonary arterial hypertension?

BACKGROUND: Amphetamine, methamphetamine, and cocaine are suspected of being pulmonary hypertension risk factors based on a small number of case reports along with pharmacologic similarities to fenfluramine, a diet drug associated with pulmonary arterial hypertension (PAH). We sought to determine whether rates of stimulant use are increased in patients believed to have idiopathic PAH compared with patients with PAH and known risk factors and patients with chronic thromboembolic pulmonary hypertension (CTEPH). METHODS: In this retrospective study, rates of stimulant use were determined for 340 patients with idiopathic PAH, PAH and known risk factors, or CTEPH seen between November 2002 and April 2004. "Stimulant" use was defined as any reported use of amphetamine, methamphetamine, or cocaine. Odds of stimulant use were calculated using a polychotomous logistic regression model. RESULTS: A history of stimulant use was found in 28.9% of patients with a diagnosis of idiopathic PAH, compared with 3.8% of patients with PAH and a known risk factor, and 4.3% of patients with CTEPH. After adjustment for differences in age, patients with idiopathic PAH were 10.14 times (95% confidence interval, 3.39 to 30.3; p < 0.0001) more likely to have used stimulants than patients with PAH and known risk factors, and 7.63 times (95% confidence interval, 2.99 to 19.5; p < 0.0001) more likely to have used stimulants than patients with CTEPH. CONCLUSIONS: Patients with idiopathic PAH are significantly more likely to have used stimulants than patients with other forms of pulmonary hypertension.     

结缔组织病相关肺动脉高压抗内皮细胞抗体检测及其靶抗原研究

目的 检测抗内皮细胞抗体(AECA)在结缔组织病(CTD)相关肺动脉高压(PAH)患者中的阳性率,探讨其可能的致病机制.方法 试验组选取68例CTD相关PAH患者,对照组为12例特发性肺动脉高压患者、61例CTD无PAH的患者、20例慢性阻塞性肺疾病合并肺源性心脏病患者及20名健康人.提取EA.hy926内皮细胞株的膜蛋白质,免疫印迹法检测以上各组患者血清中AECA阳性率,采用X2检验确定特异性的条带.进而应用液相色谱-电喷雾离子阱质谱分析,分离和鉴定AECA特定的靶抗原.结果免疫印迹法检测结果显示,AECA-78 000条带的阳性率在CTD相关PAH患者79%(54/68)和CTD合并肾小球病变的患者71%(15/21),明显高于特发性PAH患者8%(1/12)、CTD无内脏受累患者50%(10/20)、CTD单纯合并肺间质纤维化患者15%(3/20)和健康对照组(P<0.05或P<0.01).经蛋白质组学方法 分离鉴定,AECA-78 000的靶抗原成分为膜突蛋白.结论 CTD不同靶器官受累的患者AECA78 000条带的阳性率不同,CTD合并PAH患者和CTD合并肾小球病变的患者可能存在有共同的靶抗原(78 000内皮细胞蛋白质),其成分为膜突蛋白.     

Pulmonary hypertension in Switzerland: treatment and clinical course

BACKGROUND: The prognosis of pulmonary hypertension (PH), especially idiopathic pulmonary arterial hypertension (IPAH), has improved during the recent years. The Swiss Registry for PH represents the collaboration of the various centres in Switzerland dealing with PH and serves as an important tool in quality control. The objective of the study was to describe the treatment and clinical course of this orphan disease in Switzerland. METHODS: We analyzed data from 222 of 252 adult patients, who were included in the registry between January 1999 and December 2004 and suffered from either PAH, PH associated with lung diseases or chronic thromboembolic PH (CTEPH) with respect to the following data: NYHA class, six-minute walking distance (6-MWD), haemodynamics, treatments and survival. RESULTS: If compared with the calculated expected figures the one, two and three year mean survivals in IPAH increased from 67% to 89%, from 55% to 78% and from 46% to 73%, respectively. Most patients (90%) were on oral or inhaled therapy and only 10 patients necessitated lung transplantation. Even though pulmonary endarterectomy (PEA) was performed in only 7 patients during this time, the survival in our CTEPH cohort improved compared with literature data and seems to approach outcomes usually seen after PEA. The 6-MWD increased maximally by 52 m and 59 m in IPAH and CTEPH, respectively, but in the long term returned to or below baseline values, despite the increasing use of multiple specific drugs (overall in 51% of IPAH and 29% of CTEPH). CONCLUSION: Our national registry data indicate that the overall survival of IPAH and presumably CTEPH seems to have improved in Switzerland. Although the 6-MWD improved transiently, it decreased in the long term despite specific and increasingly combined drug treatment. Our findings herewith underscore the progressive nature of the diseases and the need for further intense research in the field.     

结缔组织病合并肺动脉高压及肺间质病变的肺功能分析

目的 比较和分析不同结缔组织病(CTD)相关肺部病变患者组间各项肺功能指标的差异.探讨肺功能检查对于评价CTD肺部病变性质和程度的临床意义.方法 前瞻性纳入CTD肺脏受累患者,根据肺部病变性质分为3组:CTD合并肺动脉高压组(CTD-PAH)29例、合并肺间质病变组(CTD-ILD))35例、合并PAH及ILD组(CTD-PAH+ILD)16例;另纳入无肺部病变的CTD患者34例作为对照组.比较各组间肺总量占预计值百分比(TLC%)、用力肺活量占预计值百分比(FVC%)、第1秒用力呼气量占预计值百分比(FEV_(1.0)%)、FEV_(1.0)/FVC、一氧化碳弥散量占预计值百分比(DLco%)、弥散率(DLco/VA)等主要肺功能指标的差异.结果 共114例患者纳入本研究,以女性多见,平均年龄35～39岁,易合并肺部病变的CTD依次为:混合性结缔组织病(MCTD)、系统性硬化症(SSc)、系统性红斑狼疮(SLE)和原发性干燥综合征(pSS).CTD-PAH组、CTD-ILD组和CTD-PAH+ILD组分别有10%、29%和46%的患者出现TLC下降;分别有50%、36%和71%的患者出现FVC%下降;分别有54%、47%和71%的患者出现FEV_(1.0)%下降;分别有100%、82%和100%的患者出现DLco%下降.多组间样本比较分析发现TLC%、FVC%、FEV_(1.0)%、DLco%在CTD对照组与CTD合并各肺部病变组之间的差异均有统计学意义(P＜0.05),而在CTD-ILD组与CTD-PAH组间差异均无统计学意义.TLC%在CTD-PAH组大于CTD-PAH+ILD组[(89±15)%与(79±12)%,P＜0.05)];FVC%在CTD-PAH组或CTD-ILD组均大于CTD-PAH+ILD组[(81±13)%、(80±16)%与(65±22)%,P＜0.05)].结论 肺功能检查对于筛查CTD合并的各种肺部病变具有临床应用价值,常表现为限制性通气功能障碍和弥散功能障碍,但从单次数值上无法鉴别CTD肺部病变种类(PAH与ILD).     

Mid-term efficacy of beraprost, an oral prostacyclin analog, in the treatment of distal CTEPH: a case control study

BACKGROUND: Prostanoids are a well-established therapy for pulmonary arterial hypertension (PAH), and observational studies suggest their efficacy even in chronic thromboembolic pulmonary hypertension (CTEPH) patients. OBJECTIVE: To compare the effects of 6 months of treatment with beraprost, an orally-active prostacyclin analog, in patients with distal CTEPH and PAH. DESIGN: Case-control study. POPULATION: Sixteen patients with severe pulmonary hypertension (NYHA II-IV), eight with distal CTEPH matched with eight patients with idiopathic PAH for similar effort tolerance. METHODS: All patients were in stable clinical and hemodynamic condition for 3 months with maximal standard therapy. During the titration phase (4 weeks) beraprost was increased to maximal tolerated dose (mean daily dosage: CTEPH 275 +/- 47 microg, PAH 277 +/- 47 microg) in adjunction of standard therapy, patients were followed-up for 6 months. MAIN OUTCOME MEASURES: World Heart Organization (WHO) functional class, exercise capacity measured by distance walked in 6 min, and systolic pulmonary pressure (echocardiography), were evaluated at baseline, and at 1-, 3- and 6-month interval. RESULTS: At 6 months WHO class decreased significantly in both groups (CTEPH from 2.7 +/- 0.6 to 2.0 +/- 0.24, p < 0.05; PAH from 3.0 +/- 0.26 to 2.1 +/- 0.25, p < 0.05), similarly the 6-min walk distance increased significantly from baseline (CTEPH from 312 +/- 31 to 373 +/- 29 m, p < 0.003; PAH from 303 +/- 31 to 347 +/- 29, p < 0.0003). Systolic pulmonary artery pressure showed a trend toward lower value (CTEPH from 85 +/- 7 m to 81 +/- 6 mm Hg, p = NS; PAH from 89 +/- 7 to 82 +/- 5, p = NS). During the observation period we did not have any death. The drug was well-tolerated with minor side-effects. CONCLUSION: In patients with CTEPH beraprost had similar mid-term clinical and hemodynamic improvements than in patients with PAH.     

Etiology-specific endothelin-1 clearance in human precapillary pulmonary hypertension

STUDY OBJECTIVES: Endothelin (ET)-1 is a mediator of vascular remodeling seen in human pulmonary hypertension (PH), and it is normally cleared via endothelial ET-B receptors. Increased levels of ET-1 are found in precapillary PH, partly from increased synthesis. We hypothesized that the endothelial dysfunction and vascular remodeling seen in human precapillary PH would also reduce ET-1 clearance. DESIGN AND SETTING: Case series from a single institutional PH center. PATIENTS: Thirty-four patients with pulmonary arterial hypertension (PAH; idiopathic [IPAH], n = 19; connective tissue disease [CTD], n = 15) and 11 patients with chronic thromboembolic PH were studied. MEASUREMENTS AND RESULTS: Using indicator dilution methods, the first-pass extraction of radiolabeled ET-1 through the pulmonary circulation, and permeability surface (PS) area, an index of functional microvascular surface available for ET-1 clearance, were determined. Mean extraction for IPAH and thromboembolic PH groups was normal, but it was reduced in PAH from CTD; 69% of all patients studied had normal extraction. The mean PS product was reduced significantly for all three etiologies as compared to normal, but 58% of IPAH patients and 40% of CTD-related PAH patients had normal PS products. CONCLUSIONS: Receptor-mediated ET-1 extraction and functional vascular surface area for clearance vary between etiologies of PAH. However, contrary to our hypothesis, endothelial ET-B receptor-mediated extraction is preserved in many patients. The scientifically significant finding of our study is that high ET-1 levels seen in patients with PAH must be predominantly due to excess synthesis rather than reduced clearance. The finding that endothelial ET-B receptors are still present and functional in PAH may also be of relevance to the choice of selective vs nonselective ET receptor antagonists.     

Efficacy of long-term subcutaneous treprostinil sodium therapy in pulmonary hypertension

STUDY OBJECTIVES: The aim of this long-term multicenter analysis was to investigate whether subcutaneously infused treprostinil could provide sustained improvements of exercise capacity and survival benefits in patients with pulmonary arterial hypertension (PAH) and inoperable chronic thromboembolic pulmonary hypertension (CTEPH). Subcutaneous administration of the prostacyclin analog treprostinil is an effective treatment for PAH that, unlike epoprostenol, does not require the insertion of a permanent central venous catheter. DESIGN: Multicenter retrospective study. SETTING: Three European university hospitals. METHODS: Ninety-nine patients with PAH and 23 patients with CTEPH in New York Heart Association (NYHA) classes II-IV were followed up for a mean of 26.2 +/- 17.2 months (+/- SE) [range, 3 to 57 months]. Long-term efficacy was assessed by 6-min walking distance (SMWD), Borg dyspnea score, and NYHA class. Clinical events were monitored to assess survival and event-free survival. RESULTS: At 3 years, significant improvements from baseline were observed in mean SMWD (305 +/- 11 to 445 +/- 12 m, p = 0.0001), Borg dyspnea score (5.7 +/- 0.2 to 4.5 +/- 1, p = 0.0006), and NYHA class (3.20 +/- 0.04 to 2.1 +/- 0.1, p = 0.0001). These changes were observed under a mean dose of subcutaneously infused treprostinil at 40 +/- 2.6 ng/kg/min (range, 16 to 84 ng/kg/min). Subcutaneously infused treprostinil was well tolerated, and local pain at the subcutaneous site accounted for treatment interruption in only 5% of the cases. Survival was 88.6% and 70.6% at 1 year and 3 years, respectively. At the same time points, the event-free survival rates, defined as survival without hospitalization for clinical worsening, transition to IV epoprostenol, and need for combination therapy or atrial septostomy, were 83.2% and 69%, respectively. CONCLUSIONS: Long-term subcutaneous therapy with treprostinil appears to continuously improve exercise tolerance and symptoms in patients with PAH and inoperable CTEPH. Moreover, treatment may provide a significant survival benefit.     

Atorvastatin in pulmonary arterial hypertension (APATH) study

Statins have been shown to both prevent and attenuate pulmonary hypertension in animal models. This study investigates the potential therapeutic benefits of atorvastatin as an affordable treatment for pulmonary hypertension patients. 220 patients with pulmonary arterial hypertension (PAH) or chronic thromboembolic pulmonary hypertension (CTEPH) were randomised, double-blind, to receive atrovastatin 10 mg daily or matching placebo in addition to supportive care. At 6 months, 6-min walk distance decreased by 16.6 m in the atorvastatin group and 14.1 m in the placebo group. The mean placebo-corrected treatment effect was -2.5 m (95% CI: -38-33; p=0.96), based on intention to treat. A small nonsignificant increase in pulmonary vascular resistance and fall in cardiac output was seen in both treatment groups. There was no significant difference in the proportion of patients who improved, remained stable or showed a deterioration in World Health Organization functional class between atorvastatin and placebo treatments. Nine patients died in the atorvastatin group and 11 in the placebo group. Serum cholesterol levels fell significantly on atorvastatin treatment. Discontinuation rates were 23.2% and 26.9% on atorvastatin and placebo, respectively. Atorvastatin 10 mg daily has no beneficial effect on the natural history of PAH or CTEPH over 6 months.     

Pulmonale Hypertonie und rheumatische Erkrankungen

After idiopathic pulmonary arterial hypertension (IPAH), connective tissue disease (CTD)-associated PAH represents the largest subgroup within the PAH group of diseases. Systemic sclerosis (SSc) and mixed connective tissue diseases are at the highest risk of PAH; however, systemic lupus erythematosus (SLE), dermatomyositis, Sjögren’s syndrome, antisynthetase syndrome and rheumatoid arthritis also show an increased risk for PAH. The pulmonary symptoms and treatment are similar to those for IPAH. For SSc a yearly echocardiographic screening for PAH is recommended. In the other CTDs this diagnostic measure is recommended only if signs and symptoms of PAH occur, particularly dyspnea on exertion, fatigue or fainting/syncope. An early therapy with targeted PAH medication is recommended, as the prognosis of CTD-associated PAH is much worse compared to IPAH. A CTD-associated pulmonary veno-occlusive disease (PVOD) must be considered as a differential diagnosis, because this disease is particularly prone to treatment-associated side effects. Approved for targeted collagen-associated PAH are endothelin receptor antagonists (ERA), phosphodiesterase 5 inhibitors (PDE5i), IP receptor agonists (IPA) and stimulators of soluble guanylate cyclase (sGCS). When combined with immunosuppressants and because of the special properties of the underlying diseases, targeted PAH medications are associated with higher risks of severe side effects compared to IPAH patients.     

Chronic thromboembolic and pulmonary arterial hypertension share acute vasoreactivity properties

BACKGROUND: Pulmonary arterial hypertension (PAH) and chronic thromboembolic pulmonary hypertension (CTEPH) are the major classes of pulmonary hypertensive disorders according to the World Health Organization; both lead to right heart failure and death. A better understanding of disease mechanisms has led to the suggestion that the thromboembolic and nonthromboembolic types of pulmonary hypertension may share pathophysiologic features. We therefore compared acute vasoreactivity and proximal pulmonary artery compliance in patients with PAH and CTEPH during the initial diagnostic heart catheterization. METHODS: Right heart catheterization using a flow-directed Swan-Ganz catheter was performed in patients with CTEPH (n = 22) and PAH (n = 35). Pulmonary hemodynamics were assessed at baseline, during the inhalation of 40 ppm of nitric oxide, and 30 min after the inhalation of 10 mug of iloprost. To assess the proximal pulmonary artery compliance, the pulse pressure (PP) [systolic-diastolic pressure] and the fractional PP (PPf) [divided by the mean pressure] were calculated. RESULTS: Both vasodilators produced similar hemodynamic improvement, and the difference between CTEPH and PAH was not significant. The baseline PP and PPf did not vary between the two groups. CONCLUSION: Patients with PAH and CTEPH show similar acute vasoreactivity to inhaled nitric oxide and iloprost, and have similar pulmonary artery compliance. These findings support the presence of some shared pathophysiologic pathways in both disorders and may lead to therapeutic implications in patients with inoperable CTEPH.     

Assessment of the pulmonary volume pulse in idiopathic pulmonary arterial hypertension by means of electrical impedance tomography

BACKGROUND: Electrical impedance tomography (EIT) is a non-invasive imaging technique which can be used to measure the blood volume changes in the pulmonary vascular bed during the cardiac cycle. STUDY OBJECTIVES: This study was performed to evaluate the differences in the EIT signal of the pulmonary vascular bed between healthy subjects and patients with idiopathic pulmonary arterial hypertension (IPAH), who are known to have a remodelled pulmonary vascular bed. PATIENTS AND METHODS: Twenty-one patients (17 females, 4 males) with IPAH and 30 healthy controls (5 females, 25 males) were measured. EIT measurements were performed in duplicate, on the same day as right heart catheterization to obtain haemodynamic data. The maximal impedance change during systole (Delta Z(sys)) was used as a measure of the pulmonary volume pulse and expressed in arbitrary units (AU). Total lung capacity, spirometric values and diffusion capacity for carbon monoxide were measured as well. RESULTS: Mean Delta Z(sys) was 215 +/- 58 x 10(-2) AU (95% CI 193 x 10(-2) to 236 x 10(-2)) in the healthy subjects and 78 +/- 27 x 10(-2) AU (95% CI 66 x 10(-2) to 91 x 10(-2)) in the IPAH patient group (p < 0.0001). No significant correlation was found between Delta Z(sys) and any of the haemodynamic or lung function data. CONCLUSION: The impedance pulsation of the pulmonary vascular bed is reduced in IPAH in comparison with controls, indicating a reduced volume pulse. This might represent the reduced cross section area, as well as the reduced compliance and number of the pulmonary vessels in these patients.     

Pulmonary capillary endothelial metabolic dysfunction: severity in pulmonary arterial hypertension related to connective tissue disease versus idiopathic pulmonary arterial hypertension

OBJECTIVE: Pulmonary endothelial dysfunction is intertwined with the development and progression of pulmonary arterial hypertension (PAH). Pulmonary endothelium is an active metabolic tissue in healthy human subjects. This study was undertaken to determine the effects of PAH on pulmonary endothelial angiotensin-converting enzyme (ACE) activity and to identify differences between common PAH types, i.e., PAH related to connective tissue disease (PAH-CTD) versus idiopathic PAH (IPAH). METHODS: Nineteen patients with PAH-CTD, 25 patients with IPAH, and 23 control subjects were evaluated. The single-pass transpulmonary percent metabolism (%M) and hydrolysis (both reflecting enzyme activity per capillary) of an ACE synthetic substrate were determined. In addition, the calculated functional capillary surface area (FCSA), normalized to body surface area (BSA), was determined. RESULTS: The %M values in patients with PAH-CTD (mean+/-SEM 53.6+/-3.6%) were significantly reduced compared with those in control subjects (P<0.01) and those in patients with IPAH (P<0.03), but were similar between the IPAH and control groups (mean+/-SEM 66.2+/-3.6% and 74.7+/-2.7%, respectively). Substrate hydrolysis was also significantly reduced in patients with PAH-CTD. The FCSA/BSA was significantly reduced in patients with PAH-CTD (mean+/-SEM 1,068+/-118 ml/minute/m2) and in patients with IPAH (1,443+/-186 ml/minute/m2) compared with that in controls (2,948+/-245 ml/minute/m2; P<0.01 for both). At a given cardiac index, the FCSA/BSA tended to be lower in the PAH-CTD group than in the IPAH group. Moreover, unlike in IPAH, a linear relationship between the FCSA/BSA and the diffusing capacity for carbon monoxide (DLCO) was observed in PAH-CTD (r=0.54, P<0.03). CONCLUSION: The metabolically functional pulmonary capillary bed appears to be reduced to an equal extent in PAH-CTD and IPAH. However, %M and hydrolysis appear to be reduced in PAH-CTD but not in IPAH, reflecting relatively diminished ACE activity on the pulmonary capillary endothelial cells of patients with PAH-CTD, and showing that pulmonary endothelial metabolic function differs between PAH types. This study also provides the first functional evidence that a reduced DLCO value in patients with PAH-CTD is related to the degree of FCSA loss.     

Portopulmonary hypertension: hemodynamics, pulmonary angiography, and configuration of the heart.

BACKGROUND: The goal of the present study was to examine the cardiac configuration and pulmonary vascular changes in patients with portopulmonary hypertension (PPHTN) and compare them with those of idiopathic pulmonary arterial hypertension (IPAH). METHODS AND RESULTS: The subjects were 10 patients with PPHTN and 18 with IPAH. In PPHTN, the increases in the right ventricular end-diastolic volume index (89+/-19 vs 128+/-50 ml/m2; p=0.04), right end-systolic volume index (50+/-19 vs 95+/-47 ml/m 2; p=0.02) and right ventricular mass index (47+/-18 g/m2 vs 79+/-31; p=0.04) were low compared with IPAH. The decrease in the right ventricular ejection fraction was also low in PPHTN (45+/-10 vs 28+/-13%; p=0.01). The degree of sparse arborization and abrupt narrowing on wedged pulmonary angiography was moderate in PPHTN compared with IPAH. In PPHTN, the proximal pulmonary arteries were dilated near the segmental arteries, which were narrow in IPAH. CONCLUSION: Changes in the configuration of the heart were moderate in PPHTN compared with those in IPAH. The degree of sparse arborization and abrupt narrowing were also moderate in PPHTN.     

COPD a social disease: inappropriateness and pharmaco-economics. The role of the specialist: present and future

Despite the development of specific therapies for pulmonary arterial hypertension (PAH) some patients fail to respond to such treatment. One of the potential reasons for the unresponsiveness to targeted therapies may be the presence of fibrous occlusion of small pulmonary veins that accompanies pre-capillary arteriopathy. This type of pathologic change is called pulmonary veno-occlusive disease (PVOD). Underdiagnosed PVOD occurs probably in 5-10% of idiopathic pulmonary hypertension (IPAH) and in a substantial proportion of PAH related to connective tissue diseases (mainly in scleroderma). A definite diagnosis of PVOD requires histological examination of lung sample, but surgical lung biopsy in pulmonary hypertension is combined with high risk of bleeding. Thus major interest is focused on a non-invasive diagnostic approach enabling early recognition of PVOD and referral for lung transplantation. The present review is focused on the radiological features suggestive of PVOD-like vasculopathy in PAH.     

肿瘤坏死因子-α拮抗剂用于结缔组织病相关肺动脉高压的治疗

肺动脉高压（pulmonary arterial hypertension，PAH）是结缔组织病（connec tivetissue disease，CTD）常见且严重的并发症之一，与特发性肺动脉高压相比较，其生存率更低。目前PAH的发病机制尚不明确，但有证据显示肿瘤坏死因子-α（TNF-α）在结缔组织病和肺动脉高压发病过程中起重要作用，并且血清TNF-α升高与CTD-PAH的疾病进展相关。新开发的生物制剂（infliximab，etanercept，adalimumab）能够选择性阻断TNF-α，从而为PAH的治疗提供了新的机会。     

Acute effects of the combination of sildenafil and inhaled treprostinil on haemodynamics and gas exchange in pulmonary hypertension

BACKGROUND: Inhaled treprostinil was recently developed for the treatment of pulmonary arterial hypertension (PAH). We investigated the safety and acute haemodynamic effects of the combination oral sildenafil and inhaled treprostinil in an open label study in patients with precapillary pulmonary hypertension. METHODS AND PATIENTS: Inhaled nitric oxide (20ppm; n=50), sildenafil (50mg; n=50) and inhaled treprostinil (15mug; n=25 or 30mug; n=25) were applied in subsequent order during right heart catheter investigation to consecutive patients with pulmonary arterial hypertension (PAH; n=28), non-operable chronic thromboembolic pulmonary hypertension (CTEPH; n=17) and pulmonary fibrosis associated pulmonary hypertension (n=5). RESULTS: Inhaled nitric oxide reduced pulmonary vascular resistance (PVR) to 87.3+/-5.1% of baseline values, reduced mean pulmonary arterial pressure (PAP) to 89.7+/-3.5% and increased cardiac output (CO) to 102.4+/-2.9%. Sildenafil reduced PVR to 80.1+/-5.0%, mPAP to 86.5+/-2.9% and increased CO to 103.8+/-3.2%. Treprostinil, inhaled 1h after sildenafil, reduced PVR to 66.3+/-3.8%, mPAP to 77.8+/-3.3%, and increased CO to 107.1+/-3.3% (mean+/-95% confidence interval). Subgroup analysis showed similar acute haemodynamic effects in PAH and CTEPH patients. Ventilation/perfusion distribution measurement in six patients with pre-existing gas exchange limitations was not changed by sildenafil and treprostinil. Relevant side effects were not observed. CONCLUSION: The combination of sildenafil and inhaled treprostinil was well tolerated and induced additive, pulmonary selective vasodilatation in pulmonary hypertension patients. This could be of relevance also for long-term treatment of PAH and CTEPH patients.