Pulmonary capillary endothelial dysfunction in early systemic sclerosis

OBJECTIVE: Pulmonary capillary endothelium-bound angiotensin-converting enzyme (PCEB-ACE) activity is a sensitive and quantifiable index of endothelial function in vivo. Systemic sclerosis (SSc) is characterized by endothelial damage and excess collagen formation, causing mainly pulmonary hypertension (PH) in the limited cutaneous SSc (lcSSc) subset and interstitial lung disease with pulmonary interstitial fibrosis (PIF) in the diffuse cutaneous SSc (dcSSc) subset. This study was undertaken to investigate the hypothesis that PCEB-ACE activity is reduced early in SSc, in the absence of PH or PIF. METHODS: Applying indicator-dilution techniques, we measured single-pass transpulmonary hydrolysis and percent metabolism (%M) of a synthetic ACE substrate and calculated functional capillary surface area (FCSA) in 25 SSc patients and 11 controls. Substrate hydrolysis and %M reflect ACE activity per capillary; FCSA reflects ACE activity per vascular bed. RESULTS: PCEB-ACE activity was decreased in both SSc subsets. Among patients without PH, substrate hydrolysis and %M were decreased in patients with lcSSc and more profoundly in those with dcSSc; loss of FCSA normalized to body surface area (FCSA/BSA) was observed in dcSSc, but not in lcSSc. High-resolution computed tomography of the lung, performed in all SSc patients, revealed no correlation between substrate %M, hydrolysis, or FCSA/BSA and the degree of PIF; 5 dcSSc and 5 lcSSc patients with no detectable PIF exhibited decreases in hydrolysis and %M, while FCSA/BSA was decreased only in dcSSc. CONCLUSION: Depression of PCEB-ACE activity, indicating pulmonary endothelial dysfunction, occurs early in SSc, in the absence of PH or PIF, and is more pronounced, at this early pulmonary disease stage, in dcSSc than in lcSSc.     

Addition of sildenafil to bosentan monotherapy in pulmonary arterial hypertension.

Combination therapy has been recommended for the treatment of pulmonary arterial hypertension (PAH). However, there is scant information on combination therapy after failure of monotherapy, particularly in patients with scleroderma-associated PAH (PAH-SSD). From a group of 82 consecutive patients with PAH who received initial bosentan monotherapy, a total of 13 idiopathic PAH (IPAH) and 12 PAH-SSD patients requiring additional therapy with sildenafil were studied. Sildenafil was added for clinical deterioration based upon symptoms, New York Heart Association (NYHA) classification or 6-min walk distance (6MWD). Clinical data and haemodynamics were collected at baseline. Assessments were made at 1-3-month intervals. At baseline, there were no differences in demographics, NYHA classification, haemodynamics or 6MWD between the two groups. After initiation of bosentan, both groups experienced clinical improvement but ultimately deteriorated (median time to monotherapy failure 792 versus 458 days for IPAH and PAH-SSD patients, respectively). After addition of sildenafil, more IPAH patients tended to improve in NYHA class (five out of 13 versus two out of 12) and walked further (mean difference in 6MWD 47+/-77 m versus -7+/-40 m) compared with PAH-SSD patients. In conclusion, addition of sildenafil after bosentan monotherapy failure improved New York Heart Association class and 6-min walk distance in idiopathic pulmonary arterial hypertension patients but failed to improve either parameter in scleroderma-associated pulmonary arterial hypertension patients. Additional studies are needed to assess the tolerability and efficacy of this combination in patients with scleroderma-associated pulmonary arterial hypertension.     

Additional effects of bosentan in patients with idiopathic pulmonary arterial hypertension already treated with high-dose epoprostenol.

BACKGROUND: Combination therapy has been proposed in treatment algorithms for idiopathic pulmonary arterial hypertension (IPAH), so the additional effects of bosentan in IPAH patients already treated with high-dose epoprostenol (EPO) was evaluated in the present study. METHODS AND RESULTS: Bosentan (62.5 mg twice daily) was administered to 8 IPAH patients already being treated with high-dose EPO (average dose 99.6+/-43.4 ng . kg(-1) . min(-1)). Hemodynamics were assessed at baseline and at 2 days and then 1 year after the initiation of bosentan. Because a remarkable elevation of mixed venous oxygen saturation was observed at the initiation of bosentan, the dosage of EPO was reduced in 7 patients (from 99.6+/-43.4 to 82.8+/-31.3 ng . kg(-1) . min(-1), p<0.05). There was a significant decrease from the baseline value for systolic pulmonary artery pressure (80.1+/-19.3 to 66.8+/-16.5 mmHg, p<0.05). These effects were maintained for 1 year without progression of PAH in 6 patients whose condition had been stabilized at baseline. CONCLUSIONS: The additional use of bosentan for IPAH patients whose condition has been stabilized by high-dose EPO is safe and effective.     

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.     

Heart rate responses during the 6-minute walk test in pulmonary arterial hypertension.

Patients with pulmonary arterial hypertension (PAH) exhibit a limited increase in stroke volume on exercise, and the heart rate (HR) increases may reflect the main mechanism that allows cardiac output to increase. The current prospective study documented the contribution of HR to the 6-min walking distance (6MWD) in idiopathic (IPAH) and nonidiopathic PAH. Eighty-three patients (46 IPAH and 37 nonidiopathic PAH) underwent haemodynamic evaluation and a 6MWD test. Chronotropic response (peak walking HR minus resting HR) and peripheral oxygen saturation were monitored. Fifty-seven patients were also assessed after 5+/-2 months of treatment (bosentan n = 38, epoprostenol n = 14, bosentan-epoprostenol n = 3, iloprost n = 2). Before treatment, the 6MWD was related to numerous demographic, haemodynamic and walking test characteristics. Stepwise regression analysis indicated that the only factors significantly associated with the 6MWD were stroke volume and chronotropic response in both IPAH and nonidiopathic PAH patients. Following treatment, changes in 6MWD were significantly related to changes in chronotropic response in both IPAH and nonidiopathic PAH. In conclusion, baseline stroke volume and chronotropic response were independently associated with the 6-min walking distance in pulmonary arterial hypertension. The lack of chronotropic response may reflect the loss in normal physiological reserve in more unwell patients.     

Asymmetrical dimethylarginine in idiopathic pulmonary arterial hypertension

OBJECTIVE: We explored the potential role of the endogenous NO synthase inhibitor asymmetrical dimethylarginine (ADMA) in patients with idiopathic pulmonary arterial hypertension (IPAH). Method and Results- We correlated plasma ADMA levels and cardiovascular indices from right heart catheterization in 57 patients with IPAH. Predictors of survival in patients with IPAH were studied. Furthermore, the effect of systemic ADMA infusion on pulmonary ventricular resistance and stroke volume was investigated in healthy volunteers using right heart catheterization. Mean plasma ADMA concentrations were significantly higher in patients with IPAH than in control subjects (0.53+/-0.15 versus 0.36+/-0.05 micromol/L; P<0.001). ADMA plasma concentrations correlated significantly with indices of right ventricular function, such as mixed-venous oxygen saturation (r=-0.49; P<0.0001), right atrial pressure (r=0.39; P<0.003), cardiac index (r=-0.35; P<0.008), as well as survival (r=-0.47; P<0.0001). Multiple regression analysis revealed that right atrial pressure (r=0.31; P<0.026) and ADMA (r=0.29; P<0.039) were independent predictors of mortality. Moreover, patients with supra-median plasma ADMA levels had significantly (P<0.021) worse survival than patients with infra-median ADMA values. ADMA infusion in healthy volunteers increased pulmonary vascular resistance (68.9+/-7.6 versus 95.6+/-6.3 dyne x s x cm(-5); P<0.05) and decreased stroke volume (101.1+/-6.7 mL versus 95.6+/-6.3 mL; P<0.05). CONCLUSIONS: Increased ADMA plasma levels are associated with unfavorable pulmonary hemodynamics and worse outcome in patients with IPAH.     

Leptin and regulatory T-lymphocytes in idiopathic pulmonary arterial hypertension

Immune mechanisms and autoimmunity seem to play a significant role in idiopathic pulmonary arterial hypertension (IPAH) pathogenesis and/or progression, but the pathophysiology is still unclear. Recent evidence has demonstrated a detrimental involvement of leptin in promoting various autoimmune diseases by controlling regulatory T-lymphocytes. Despite this knowledge, the role of leptin in IPAH is currently unknown. We hypothesised that leptin, synthesised by dysfunctional pulmonary endothelium, might play a role in the immunopathogenesis of IPAH by regulating circulating regulatory T-lymphocytes function. First, we collected serum and regulatory T-lymphocytes from controls, and IPAH and scleroderma-associated pulmonary arterial hypertension (SSc-PAH) patients; secondly, we recovered tissue samples and cultured endothelial cells after either surgery or transplantation in controls and IPAH patients, respectively. Our findings indicate that serum leptin was higher in IPAH and SSc-PAH patients than controls. Circulating regulatory T-lymphocyte numbers were comparable in all groups, and the percentage of those expressing leptin receptor was higher in IPAH and SSc-PAH compared with controls, whereas their function was reduced in IPAH and SSc-PAH patients compared with controls, in a leptin-dependent manner. Furthermore, endothelial cells from IPAH patients synthesised more leptin than controls. Our data suggest that endothelial-derived leptin may play a role in the immunopathogenesis of IPAH.     

Underrated value of repeated right heart catheterization in pulmonary hypertension with heart failure—a case of persisted pulmonary arterial hypertension after treatment for biventricular failure

Pulmonary hypertension (PH) is a common complication of left heart disease and its presence in patients with heart failure predicts worse clinical outcomes. Specific agents targeting pulmonary arterial hypertension (PAH) have been developed over the last few years, but the efficacy of these agents in pulmonary hypertension due to left heart disease (PH-LHD) is uncertain. We report a case of idiopathic pulmonary arterial hypertension (IPAH) initially presented with biventricular failure, which was misdiagnosed as PH-LHD. A 31-year-old man who had a history of recurrent hemoptysis was referred to our center with biventricular failure. Right heart catheterization (RHC) showed elevated mean pulmonary arterial pressure (mPAP) and pulmonary capillary wedge pressure (PCWP). He was diagnosed as having PH-LHD, specifically combined post-capillary and precapillary PH (CpcPH). We treated him for 2 years with diuretics, a beta blocker, an angiotensin-converting enzyme (ACE) inhibitor, and sildenafil, which was added to treat CpcPH. A follow-up echocardiography showed that biventricular function had improved, but not PH. A second RHC revealed elevated mPAP and normal PCWP, which made us change the diagnosis to IPAH. In conclusion, it is important to perform repeated RHC in CpcPH patients after the improvement of left heart dysfunction to distinguish CpcPH from IPAH.     

Diffusing capacity for nitric oxide and carbon monoxide in patients with diffuse parenchymal lung disease and pulmonary arterial hypertension

BACKGROUND: The passage of carbon monoxide (CO) through the alveolocapillary membrane and into the plasma and intraerythrocytic compartments determines the diffusing capacity of the lung for CO (DLCO) as defined by the Roughton and Forster equation. On the other hand, the single-breath diffusing capacity of the lung for nitric oxide (DLNO) is thought to represent the true membrane diffusing capacity because of its very high affinity for hemoglobin (Hb) and its independence from pulmonary capillary blood volume. Therefore, the DLNO/DLCO ratio can be used to differentiate between thickened alveolocapillary membranes (both DLNO and DLCO are decreased, and the DLNO/DLCO ratio is normal) and decreased perfusion of ventilated alveoli (the DLNO less decreased than the DLCO; therefore, the DLNO/DLCO ratio is high) in patients with pulmonary disease. STUDY DESIGN: We measured the combined values of DLCO and DLNO in 41 patients with diffuse parenchymal lung disease (DPLD), 26 patients with pulmonary arterial hypertension (PAH), and 71 healthy subjects. RESULTS: The DLCO (corrected to the standard Hb value) was lowered in the DPLD group (64% of predicted) and in the PAH group (64% of predicted), and was normal in the control group (105% of predicted). The DLNO/DLCO ratio in patients with PAH (4.98) was significantly higher than that in patients with DPLD (4.56) and in healthy subjects (4.36). CONCLUSION: The DLNO/DLCO ratio is significantly higher in patients with PAH than in healthy subjects, although this ratio cannot be applied as a screening test to discriminate between patients with DPLD and PAH as the overlap between these groups is too large.     

Correlation of pulmonary function variables with hemodynamic measurements in patients with pulmonary arterial hypertension

Introduction: A reduced diffusing capacity of the lung for carbon monoxide (DLCO) measured during a pulmonary function test can suggest pulmonary arterial hypertension (PAH). The DLCO has been reported to weakly correlate with pulmonary hemodynamics. Objective: To determine whether the relationship between the DLCO and pulmonary arterial pressures can be strengthened by normalizing the DLCO to spirometric variables. Patient and Methods: Patients were seen at a tertiary care referral center. Consecutive subjects who underwent right heart catheterization (RHC) for the evaluation of suspected PAH from 01 January 1991 through 01 October 2006 were identified. Pulmonary function testing (PFT) data performed within 60 days of the RHC was collected. Spearman rank correlation between PFT and RHC variables was calculated. Results: One hundred thirty‐eight patients who had an RHC performed had complete PFTs available. No significant correlation was identified between the mean pulmonary artery pressure and the pulmonary vascular resistance against the DLCO, nor the DLCO when normalized to: forced expiratory volume in 1 s, forced vital capacity, total lung capacity or alveolar volume. Spirometric subgroups were identified by standard definitions of restrictive and/or obstructive ventilatory defects. Clinical subgroups were classified based on the clinically diagnosed cause of the patient's PAH. Again, no significant correlation was identified between the PFT variables and RHC measurements in these stratified subgroups. Conclusion: In patients with suspected PAH, invasive hemodynamic measurements of PAH do not correlate with PFT variables, even when corrected for spirometric volumes, and regardless of the subgroup of ventilatory physiology or clinical diagnosis. Please cite this paper as: Arunthari V, Burger CD and Lee AS. Correlation of pulmonary function variables with hemodynamic measurements in patients with pulmonary arterial hypertension. Clin Respir J 2011; 5: 35–43.     

Reduced number and activity of circulating endothelial progenitor cells in patients with idiopathic pulmonary arterial hypertension

BACKGROUND: Endothelial dysfunction plays a central and critical role in the initiation and development of idiopathic pulmonary arterial hypertension (IPAH), and a variety of evidence suggests that endothelial progenitor cells (EPCs) constitute one aspect of endothelium repair. In addition, transplantation of EPCs could attenuate pulmonary hypertension induced by monocrotaline in rats. However, it has not been examined and reported whether circulating EPCs from patients with IPAH are damaged. METHODS: EPCs were isolated and cultured from patients with IPAH (n=20) and matched healthy volunteers (n=20). Circulating EPC numbers (enumerated as AC133+KDR+ cells) as well as migratory and adhesive activity were assessed. Blood levels of vascular endothelial growth factor (VEGF), homocysteine (Hcy), B-type natriuretic peptide (BNP), von Willebrand Factor (vWF) and interleukin-6 (IL-6) were also measured. RESULTS: A significant decrease was observed in circulating EPC (AC133+KDR+ cells, 86.6+/-20.7cells/ml blood vs. 119.6+/-25.4cells/ml blood, P<0.001) numbers and the cell numbers expanded in vitro (47.2+/-14.5 vs. 70.7+/-15.2EPCs/x200 field; P<0.001) in patients with IPAH. EPCs from patients with IPAH were significantly impaired in their migratory capacity and ability to adhere to fibronectin. Blood levels of VEGF, Hcy, BNP, vWF and IL-6 were elevated in patients with IPAH. EPC numbers and activity were inversely related to Hcy, IL-6, BNP and vWF. CONCLUSIONS: Our observations indicated that EPC numbers and functional capacity were impaired in patients with IPAH, which might not only give potential insight into the pathophysiological mechanisms but also might be useful for identifying suitable therapeutic targets in these patients.     

The short-term role of corticosteroid therapy for pulmonary arterial hypertension associated with connective tissue diseases: report of five cases and a literature review

Pulmonary arterial hypertension (PAH) is a life-threatening complication in connective tissue diseases (CTD). It remains controversial whether immunosuppressive therapy is useful for PAH associated with CTD (PAH-CTD). The Dana Point algorithm does not refer such treatments in patients with PAH-CTD due to the lack of evidence. However, some case reports have shown the potential efficacy of immunosuppression for PAH-CTD. Here we report five cases of PAH-CTD treated with corticosteroids and discuss the current management of PAH-CTD with immunosuppressive agents. Our cases consisted of three active systemic lupus erythematosus (SLE), a quiescent SLE and an active polymyositis. WHO functional classes at baseline were class III in three cases and class II in two. Median follow-up period was 44 (28-92) weeks. PAH was diagnosed by right heart catheterization in all cases (median pulmonary arterial pressure was 45 (29-49) mmHg). All patients received 1?mg/kg of prednisolone (PSL) for 2-4?weeks, followed by appropriate dose reduction. Methylprednisolone pulse therapy was performed in patients resistant to the high dosage of PSL. Four patients received vasodilators in combination. The therapy as above improved WHO functional class 4?weeks after the initiation of PSL in all the patients. Two patients required dose increase or additional administration of vasodilators due to the dose reduction of PSL. Corticosteroid therapy may be effective for PAH-CTD at least in the short term, even in low general activity of CTD or moderate PAH. Our experience suggests that corticosteroid therapy, by itself or in conjunction with standard vasodilators, is effective for PAH-CTD patients.     

Respiratory muscle dysfunction in idiopathic pulmonary arterial hypertension.

Idiopathic pulmonary arterial hypertension (IPAH) is a pulmonary vasculopathy of unknown aetiology. Dyspnoea, peripheral airway obstruction and inefficient ventilation are common in IPAH. Data on respiratory muscle function are lacking. This prospective single-centre study included 26 female and 11 male patients with IPAH in World Health Organization functional classes II-IV. Mean+/-SD pulmonary artery pressure was 48.6+/-16.9 in females and 53.1+/-22.9 mmHg in males; cardiac output was 3.7+/-1.3 and 4.2+/-1.7 L x min(-1). Maximal inspiratory pressure (PI,max) was lower in the female patients than in 20 controls (5.3+/-2.0 versus 8.2+/-2.0 kPa). In the male patients, PI,max was lower than in 25 controls (6.8+/-2.2 versus 10.5+/-3.7 kPa). Maximal expiratory pressure (PE,max) was lower in the female patients than in controls (6.2+/-2.6 versus 9.5+/-2.1 kPa), and in male patients as compared to controls (7.1+/-1.6 versus 10.3+/-3.9 kPa). There was no correlation between PI,max or PE,max and parameters of pulmonary haemodynamics or exercise testing. The ratio of mouth occlusion pressure within the first 0.1 s of inspiration and PI,max was higher in IPAH than in controls (females 0.067+/-0.066 versus 0.021+/-0.008; males 0.047+/-0.061 versus 0.023+/-0.016). In conclusion, this study provides the first evidence of inspiratory and expiratory muscle weakness in idiopathic pulmonary arterial hypertension. The pathomechanisms and the prognostic significance should be further investigated.     

Genetics and mediators in pulmonary arterial hypertension

Pulmonary arterial hypertension (PAH) is an uncommon disorder of the pulmonary vasculature characterized by remodeling of the smallest pulmonary arteries, leading to a progressive increase in pulmonary vascular resistance. Various forms of PAH exist, including familial (FPAH) and idiopathic (IPAH) forms and associated conditions. FPAH transmits as an autosomal dominant trait that exhibits genetic anticipation but also markedly reduced penetrance (20%). The primary genetic defect of FPAH, identifiable in more than 70% of cases of FPAH, is a mutation in the gene encoding bone morphogenetic protein receptor type 2 (BMPR2), a member of the transforming growth factor beta superfamily. The true prevalence of BMPR2 mutations in IPAH is unknown, with reports ranging from 10% to 40% of patients. The cause of the variable phenotypic expression of PAH among carriers of mutated BMPR2 genes and patients is unclear, and likely related to environmental and genetic modifiers of disease not yet fully elucidated. Although BMPR2-related pathways seem to be pivotal, many other mediator pathways participate in the pathogenesis of different forms of PAH and are being actively investigated, both independently and in combination. As understanding of the molecular basis of this devastating disease improves, opportunities for earlier diagnosis, additional therapeutic regimens, and perhaps disease prevention will emerge.     

Dendritic cell recruitment in lesions of human and experimental pulmonary hypertension.

In the present study, the hypothesis that dendritic cells (DCs), key players in immunity and tolerance, might be involved in the immunopathology of idiopathic pulmonary arterial hypertension (IPAH) was tested. The phenotype and localisation of DCs were characterised by immunohistochemistry and double-labelling immunofluorescence in lung samples from controls, human IPAH patients and an experimental pulmonary hypertension model (monocrotaline-exposed rats). As compared with controls, morphometric analysis demonstrated increased numbers of dendritic cell-specific intercellular adhesion molecule-grabbing nonintegrin (DC-SIGN)-positive cells in muscular pulmonary arteries in IPAH and OX-62-positive DCs in monocrotaline-induced pulmonary hypertension. In human samples, the mean+/-SEM number of DC-SIGN-positive cells.artery(-1) of 100-300 microm diameter was 1.4+/-0.4 in controls versus 26.4+/-2.7 in IPAH. In rats, the number of OX-62-positive cells.artery(-1) of 50-150 microm diameter was 0.5+/-0.2 in controls, and 0.7+/-0.5, 3.1+/-0.5 and 8.4+/-0.6 at day 7, 14 and 28 after monocrotaline exposure, respectively. Human complex lesions of muscular pulmonary arteries showed transmural DC infiltration. Phenotyping revealed an immature DC profile in human and experimental pulmonary hypertension. The results support the concept that immature dendritic cells accumulate in remodelled pulmonary vessels and hence could be involved in the immunopathology of pulmonary hypertension.     

Smooth muscle cell matrix metalloproteinases in idiopathic pulmonary arterial hypertension.

Pulmonary arterial hypertension (PAH) results from persistent vasoconstriction, smooth muscle growth and extracellular matrix (ECM) remodelling of pulmonary arteries (PAs). Matrix metalloproteinases (MMPs) are matrix-degrading enzymes involved in ECM turnover, and in smooth muscle cell (SMC) and endothelial cell migration and proliferation. MMP expression and activity are increased in experimental PAH. Therefore, this study investigated whether similar changes occur in idiopathic PAH (IPAH; formerly known as primary pulmonary hypertension). Both in situ and in vitro studies were performed on PAs from patients undergoing lung transplantation for IPAH and from patients treated by lobectomy for localised lung cancer, who served as controls. In IPAH, MMP-tissue inhibitor of metalloproteinase (TIMP) imbalance was found in cultured PA-SMCs, with increased TIMP-1 and decreased MMP-3. MMP-2 activity was markedly elevated as a result of increases in both total MMP-2 and proportion of active MMP-2. In situ zymography and immunolocalisation showed that MMP-2 was associated with SMCs and elastic fibres, and also confirmed the MMP-3-TIMP-1 imbalance. In conclusion, the findings of this study were consistent with a role for the matrix metalloproteinase-tissue inhibitor of metalloproteinase system in pulmonary vascular remodelling in idiopathic pulmonary arterial hypertension. The matrix metalloproteinase-tissue inhibitor of metalloproteinase imbalance may lead to matrix accumulation, and increased matrix metalloproteinase-2 activity may contribute to smooth muscle cell migration and proliferation. Whether these abnormalities are potential therapeutic targets deserves further investigation.     

Unexplained pulmonary hypertension in elderly patients

BACKGROUND: Idiopathic pulmonary arterial hypertension (IPAH) preferentially affects young women. However, a subset of patients with IPAH is elderly. Our objective was to compare elderly (age >/= 65 years) vs younger persons with unexplained pulmonary hypertension (PH) and a presumptive diagnosis of IPAH. METHODS: Clinical, echocardiographic, hemodynamic, and survival data were collected on consecutive patients with suspected IPAH after evaluation in a large tertiary center PH clinic. RESULTS: Of 197 patients (mean age +/- SD, 52 +/- 16 years; 80% female), 48 patients (24%) were elderly. Elderly and younger patients had similar symptom severity, systolic pulmonary artery (PA) pressure (82.7 +/- 20.3 mm Hg vs 86.9 +/- 18.8 mm Hg, respectively; p = 0.21), and severity of right ventricular enlargement and dysfunction. Elderly patients had higher pulmonary capillary wedge pressure (PCWP) [15.3 +/- 7.3 mm Hg vs 11.1 +/- 5.3 mm Hg; p < 0.0001] and more frequently failed (56%) to meet hemodynamic criteria for IPAH (PH with PCWP < 15 mm Hg) than did younger patients (19%). Elderly patients also had higher systemic systolic (p < 0.0001) and pulse (p < 0.0001) pressures and more cardiovascular disease. Among those patients with normal PCWP, elderly patients had worse survival than young patients (p = 0.007). Among those patients with elevated PCWP, elderly patients had lower PA pressures (p = 0.04) and better survival (p = 0.02). CONCLUSIONS: Elderly patients with clinically suspected IPAH often fail to meet hemodynamic criteria for IPAH due to elevated PCWP. Studies to define the proper diagnostic strategy and the safety and efficacy of pulmonary vasodilators in elderly patients with unexplained PH are needed.     

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.     

Prevalence of exercise pulmonary arterial hypertension in scleroderma

Pulmonary arterial hypertension (PAH) is a complication of scleroderma (systemic sclerosis, SSc); as soon as PAH develops, the patient's prognosis deteriorates rapidly. Early detection of PAH ensures timely treatment. We investigated the prevalence of exercise-induced PAH in a cohort of patients with SSc, and examined the relation between exercise-induced PAH and clinical characteristics and biochemical markers. METHODS: Patients with SSc and normal resting systolic pulmonary arterial pressure (sPAP) were studied. Eligible patients were asked to perform cycloergometer exercise until exhaustion, and exercise sPAP was measured. All patients had their pulmonary function tested and underwent echocardiography at rest. Brain natriuretic peptide (BNP) was also determined. RESULTS: Forty-one patients with SSc were studied. Mean sPAP at rest was 29.7 mm Hg, rising to a mean of 41.4 mm Hg on exercise. Eleven of 41 patients (26.8%) had sPAP post-exercise > 50 mm Hg and 8/41 (19.5%) > 55 mm Hg. A significant correlation was found between exercise sPAP and DLCO (p = 0.008) and between sPAP and BNP levels (p = 0.04). Pre-existing severe Raynaud's phenomenon was more prevalent (50% vs 20%), DLCO levels lower (78.9 vs 92.7 % predicted), and BNP levels higher (72.6 vs 42.1 pmol/ml) in patients with exercise sPAP > 55 mm Hg. CONCLUSION: The prevalence of exercise-induced PAH in patients with scleroderma is high. Patients with lower DLCO and higher levels of BNP are at higher risk of developing higher sPAP. Studies with longterm followup are required to evaluate the risk of developing resting PAH in these patients.