Successful treatment with sildenafil in systemic sclerosis patients with isolated pulmonary arterial hypertension: two case reports

We describe two systemic sclerosis (SSc) patients with isolated pulmonary arterial hypertension (PAH) who were given treatment with 50 mg oral sildenafil per day. We evaluated the efficacy of oral sildenafil for isolated PAH in SSc patients by direct assessment with cardiac catheterization before and 6 months after the initiation of sildenafil. Right-heart catheterization demonstrated decreased mean pulmonary artery pressure, decreased pulmonary vascular resistance, and increased cardiac output after treatment with sildenafil. Brain natriuretic peptide levels were gradually decreased. The 6-min walking distance was greatly extended. Moreover, the physical conditions of both patients were much improved. We recognized no adverse events. We propose that oral sildenafil may be beneficial as a selective pulmonary vasodilator and as long-term treatment in SSc patients with isolated PAH.     

Pulmonary arterial hypertension associated with systemic sclerosis: Current diagnostic approach and therapeutic strategies

Pulmonary arterial hypertension(PAH) represents a devastating vascular complication of systemic sclerosis(SSc) and is found in 10%-15% of cases carrying a severe prognosis. PAH has a dramatic impact on the clinical course and overall survival, being the single most common cause of death in patients with this entity. The clinical course and aggressive progression of PAH has led clinicians to perform annual screening for it, since early detection and diagnosis are the cornerstone of a prompt therapeutic intervention. The diagnosis of PAH can be challenging to clinicians, particularly in its early stages, since in the context of SSc, the multiple causes of dyspnea need to be assessed. Doppler echocardiography represents the best initial screening tool, however, right heart catheterization remains the gold standard and definitive diagnostic means. Remarkable advances have been achieved in elucidating the pathogenesis of PAH in the past two decades, leading to the development of disease-specific targeted therapies: prostacyclin analogues, endothelin receptor antagonists and inhibitors of five phosphodiesterase pathways. However, the clinical response to these therapies in SSc-associated PAH has not been as great as the one seen with idiopathic PAH. This review also focuses on the diagnosis and novel therapies that are currently available for PAH, as well as potential future therapeutic developments based on newly acquired knowledge of diverse pathogenic mechanisms.     

Bi-ventricular interplay in patients with systemic sclerosis-associated pulmonary arterial hypertension: Detection by cardiac magnetic resonance

Objectives: Pulmonary arterial hypertension (PAH) associated with systemic sclerosis (SSc) has a poor prognosis compared to PAH associated with other connective tissue diseases (CTD). The objective of this study was to examine the difference in hemodynamic state between SSc-PAH and other CTD-PAH by performing cardiac magnetic resonance (CMR) imaging.

Methods: A single center retrospective analysis was conducted comprising 40 consecutive CTD patients who underwent right heart catheterization and CMR at the same period from January 2010 to October 2015.

Results: Thirty-two patients had pre-capillary pulmonary hypertension. Of these, 15 had SSc and 17 had other CTD. CMR measurements, particularly the ratio of right to left end-diastolic volume (RVEDV/LVEDV), correlated well with mean pulmonary arterial pressure (mPAP). Conversely, RVEDV/LVEDV and mPAP correlated differently in SSc and non-SSc patients. In SSc patients, the ratio of RVEDV/LVEDV to mPAP was significantly higher compared to non-SSc patients. In the follow-up study, 2 SSc patients exhibited increased RVEDV/LVEDV in spite of decreased mPAP following treatment. Kaplan–Meier analysis revealed poor prognosis of patients with increased RVEDV/LVEDV following treatment.

Conclusions: Our data indicated that altered bi-ventricular interplay detected at CMR may represent SSc-related cardiac involvement and reflect poor prognosis of SSc-PAH.     

系统性红斑狼疮合并肺动脉高压的临床相关因素分析

目的探讨系统性红斑狼疮（SLE）患者易合并肺动脉高压的相关临床因素。方法37例SLE合并肺动脉高压的患者作为病例组,78例诊断为SLE而无合并肺动脉高压的患者为对照组。采用病例1对照研究的方法,对各个研究因素采用逐步引入一剔除法,建立Logistic回归模型。结果多因素Lo—gistic回归分析显示,SLE患者易发生肺动脉高压的独立危险因素包括雷诺现象、疾病活动、心悸气促症状、心包积液。结论雷诺现象、疾病活动、心悸气促症状、心包积液是SLE患者易并发肺动脉高压的独立危险因素,对于这4个指标阳性的患者要尽早进行心脏彩色多普勒检查,以进行早期诊断。     

Clinical aspects of pulmonary hypertension in patients with systemic lupus erythematosus and in patients with idiopathic pulmonary arterial hypertension

Clinical aspects and pathology of pulmonary hypertension (PH) in patients with systemic lupus erythematosus (SLE) have been reported to be similar to those in patients with idiopathic pulmonary arterial hypertension (IPAH). To determine whether PH in these patients is similar, we compared the clinical characteristics, hemodynamics at diagnosis, and survival in groups of patients with SLE–PH and IPAH. We reviewed the case records of 20 patients with SLE–PH and 34 patients with IPAH, who had been assessed by echocardiography or right cardiac catheterization at Asan Medical Center, Seoul, Korea, from January 1995 to October 2003. Clinical features, laboratory data, chest X-rays, electrocardiogram results, pulmonary function tests, pulmonary perfusion scans, echocardiographic findings, serologic profiles, and survival were compared in the two groups of patients. The mean follow-up period was 18.1±20.6 months for patients with SLE–PH and 33.0±23.4 months for patients with IPAH. During follow-up, 12 SLE–PH (60%) and 11 IPAH (32%) patients died. For SLE–PH, the 3-year survival rate was 44.9% and the 5-year survival rate was 16.8%. For IPAH, the 3-year survival rate was 73.4% and the 5-year survival rate was 68.2% (p=0.02). There were no other significant differences in clinical characteristics and laboratory data between the two groups. In contrast to previous reports that the prognosis of patients with pulmonary arterial hypertension associated with collagen vascular disease was better than that of patients with IPAH, we found that the prognosis of patients with SLE–PH was much worse than that of patients with IPAH.     

Clinical correlation of brachial artery flow-mediated dilation in patients with systemic sclerosis

Abstract

Objective To investigate the clinical significance of flow-mediated dilation (FMD) in systemic sclerosis (SSc).

Methods Thirty-three SSc patients and 12 healthy controls were studied. Ultrasound assessment of the brachial artery FMD was performed on all subjects. The results were expressed as the percentage of increase in brachial artery diameter following hyperemia.

Results Limited cutaneous SSc (lcSSc) patients had significantly lower FMD values than healthy controls (5.3 ± 2.7 versus 7.7 ± 2.0 %, p < 0.05), while the values in diffuse cutaneous SSc (dcSSc) patients (6.7 ± 4.0 %) were comparable to those in lcSSc patients and healthy controls. Although FMD values did not correlate with any clinical features in dcSSc patients, there was an inverse correlation between FMD values and disease duration in lcSSc patients (r = ?0.64, p < 0.05). Furthermore, lcSSc patients with decreased FMD values showed significantly higher prevalence of digital ulcers and elevated right ventricular systolic pressure than those with normal values (for each; 75 versus 10 %, p < 0.05).

Conclusion The FMD values represent the severity of vascular damages, which progress along with disease duration and lead to digital ulcers and pulmonary arterial hypertension, in lcSSc patients.     

Systemic sclerosis complicated by arrhythmogenic right ventricular dysplasia that was misinterpreted as pulmonary arterial hypertension

Abstract

A 58-year old Japanese woman who had been diagnosed with and managed for systemic sclerosis (SSc) with pulmonary arterial hypertension died suddenly. However, the autopsy revealed marked right ventricular dilatation, and the myocardium had been replaced by fatty tissue. These findings were consistent with arrhythmogenic right ventricular dysplasia (ARVD). A literature search identified nine cases of SSc with ARVD in Japan, including this case; this number is significantly higher than the value estimated from the prevalences of ARVD and SSc in Japan, suggesting an association between these two rare diseases.     

系统性硬化症相关性肺动脉高压的临床特点

目的 探讨系统性硬化症（SSc）合并肺动脉高压（PAH）的发病率、临床特点及评估指标.方法 分析本院确诊的18例系统性硬化症合并肺动脉高压的患者临床资料和诊治过程,并以同期确诊的系统性硬化症（未合并肺动脉高压）患者作为对照.结果 两组患者在性别比和年龄上并无统计学差异.但SSc合并PAH组（SSc-PAH）患者在肺动脉收缩压（sPAP）、雷诺现象发生率、肺间质性改变发生率等方面明显高于SSc组.此外,SSc-PAH组患者的RNP抗体阳性率、IgG水平显著高于对照组.结论 雷诺现象、肺间质性改变、RNP抗体、血清IgG水平与SSc患者合并PAH密切相关.这类患者应及早行心超检查,以求早期诊治,改善预后.     

Connective tissue disease-related pulmonary arterial hypertension

Over the past two decades, there have been several advances in the assessment and management of connective tissue disease-related pulmonary arterial hypertension (CTD-PAH) that improved outcomes of the treatment of this lethal disease, and this will be the focus of this study. Systemic sclerosis is the leading cause of CTD-PAH, followed by systemic lupus erythematosus, mixed connective tissue disease, idiopathic inflammatory myositis, rheumatoid arthritis, and Sjogren's syndrome. Clinical registries have been invaluable in informing about the burden of disease, risk and prognostic factors, and temporal trends with respect to treatment and outcome in CTD-PAH. The major advances have centered on improved disease classification and diagnostic criteria, screening and early diagnosis, the emergence of evidence-based therapies including combination goal-orientated treatment strategies, and the establishment of centers with expertise in PAH.     

Pulmonary hypertension in systemic lupus erythematosus

Systemic lupus erythematosus is associated with several forms of pulmonary hypertension. It can cause pulmonary hypertension through pulmonary thromboembolic disease, left heart disease and lung disease as well as causing an isolated pulmonary vasculopathy called pulmonary arterial hypertension. The true prevalence of pulmonary arterial hypertension in patients with lupus is not known but probably is no more than 1%. Currently, treatment for lupus-associated pulmonary arterial hypertension is with pulmonary vasodilators including phosphodiesterase-5 inhibitors, endothelin receptor antagonists and prostacyclin analogues, as it is for other causes of pulmonary arterial hypertension. Case series suggest there may be a special role for immunosuppression in this rare group of patients. We present two brief case histories and summarise our experience over 15 years. Prognosis is better in lupus-associated pulmonary arterial hypertension than in systemic sclerosis-associated pulmonary arterial hypertension, but unfortunately it remains a fatal condition in most patients.     

特发性肺动脉高压一例临床分析

特发性肺动脉高压（idiopathic pulmonary arterial hypertension,IPAH）是一种罕见的、进行性加重、原因不明的肺动脉血管硬化病变,诊断往往比较困难,预后险恶。至今全世界约有1000多例报道,我国尚无精确统计,但也有散在报道。2010年我院收治1名患者,现将其临床资料进行回顾性分析。     

Determinants of exercise-induced pulmonary arterial hypertension in systemic sclerosis

Background

Exercise-induced pulmonary arterial hypertension (EIPH) in systemic sclerosis (SSc) has already been observed but its determinants remain unclear. The aim of this study was to determine the incidence and the determinants of EIPH in SSc.

Methods and results

We prospectively enrolled 63 patients with SSc (age 54 ± 3 years, 76% female) followed in CHU Sart-Tilman in Liège. All patients underwent graded semi-supine exercise echocardiography. Systolic pulmonary arterial pressure (sPAP) was derived from the peak velocity of the tricuspid regurgitation jet and adding the estimation of right atrial pressure, both at rest and during exercise. Resting pulmonary arterial hypertension (PH) was defined as sPAP > 35 mm Hg and EIPH as sPAP > 50 mm Hg during exercise. The following formulas were used: mean PAP (mPAP) = 0.61 × sPAP + 2, left atrial pressure (LAP) = 1.9 + 1.24 × left ventricular (LV) E/e′ and pulmonary vascular resistance (PVR) = (mPAP–LAP) / LV cardiac output (CO) and slope of mPAP–LVCO relationship = changes in mPAP / changes in LVCO. Resting PH was present in 3 patients (7%) and 21 patients developed EIPH (47%). Patients with EIPH had higher resting LAP (10.3 ± 2.2 versus 8.8 ± 2.3 mm Hg; p = 0.03), resting PVR (2.6 ± 0.8 vs. 1.4 ± 1.1 Woods units; p = 0.004), exercise LAP (13.3 ± 2.3 vs. 9 ± 1.7 mm Hg; p < 0.0001), exercise PVR (3.6 ± 0.7 vs. 2.1 ± 0.9 Woods units; p = 0.02) and slope of mPAP–LVCO (5.8 ± 2.4 vs. 2.9 ± 2.1 mm Hg/L/min; p < 0.0001). After adjustment for age and gender, exercise LAP (β = 3.1 ± 0.8; p = 0.001) and exercise PVR (β = 7.9 ± 1.7; p = 0.0001) were independent determinants of exercise sPAP.

Conclusion

EIPH is frequent in SSc patients and is mainly related to both increased exercise LV filling pressure and exercise PVR.     

心率恢复评估系统性红斑狼疮相关肺动脉高压女性患者疾病严重程度的价值

目的 探讨心率恢复评估系统性红斑狼疮相关肺动脉高压(SLE-PAH)女性患者疾病严重程度的价值.方法 回顾性纳入2009年11月到2015年9月在同济大学附属上海市肺科医院住院治疗的21例SLE-PAH女性患者,对所有患者进行右心导管检查、肺功能测试及心肺运动试验,并以同期年龄、性别、体质量指数上匹配的32名女性健康志愿者为正常对照组进行对比分析.结果 与正常组相比,SLE-PAH患者的峰值公斤摄氧量(Peak VO2/kg)、峰值摄氧量占预计值百分比(PeakVO2％ pred)、峰值心率(Peak HR)、摄氧效率平台(OUEP)及OUEP％ pred显著下降(t=-8.59～-2.49,P＜0.05),最低通气效率(Lowest VE/VCO2)及Lowest VE/VCO2％ pred明显升高(t=4.85、5.48,P＜0.01),2组间基础心率差异无统计学意义(t=0.34,P＞0.05),而SLE-PAH患者的HRR1、HRR2[(19.1±7.4)次/min、(34.7±11.1)次/min]却显著低于正常对照组[(28.0±6.3)次/min、(42.0±8.3)次/min](t=-4.73、-2.73,P＜0.05).Pearson相关性分析发现SLE-PAH患者HRR1及HRR2与Peak VO2％ pred、OUEP％ pred、心输出量(CO)、心指数(CI)均呈中度正相关(r =0.47～0.69,P＜0.05),与Lowest VE/VCO2％ pred呈中度负相关(r=-0.62、-0.55,P＜0.05),与mPAP无相关性(r=-0.35、-0.11,P＞0.05).此外,HRR1还与肺血管阻力(PVR)呈弱正相关(r=-0.45,P＜0.05),而PVR与HRR2无相关性(r=-0.31,P＞0.05).ROC曲线显示HRR1及HRR2曲线下面积分别为0.807(敏感度84.4％,特异度71.4％)及0.676(敏感度68.8％,特异度71.4％)(P＜0.05),HRR1及HRR2在ROC曲线上的分界点分别为23次/min及40次/min.结论 HRR1及HRR2均可以用来评估SLE-PAH女性患者疾病严重程度.因此,我们可以把HRR作为早期发现SLE-PAH的一个重要参数,并对疾病严重程度进行评估从而判断预后.     

N-Terminal probrain natriuretic peptide as a biochemical marker in the evaluation of bosentan treatment in systemic-sclerosis-related pulmonary arterial hypertension

The purpose of our study was to investigate the effect of bosentan treatment on surrogate markers in patients with systemic-sclerosis-related pulmonary arterial hypertension (SScPAH). We studied ten SScPAH patients (nine female, median age 58 years, median duration of disease 9 years). Six-minute walk test (SMWT) and plasma N-terminal probrain natriuretic peptide (NT-proBNP) levels were recorded from patients at baseline and after 20 weeks under bosentan treatment. Wilcoxon paired signed rank test was applied in order to compare NT-proBNP levels and SMWT at baseline and week 20. At week 20, NT-proBNP levels were decreased from a median of 474 fmol/ml (range, 212–1407 fmol/ml) at baseline to 238 fmol/ml (range, 198–335 fmol/ml; p = 0.002). Mean SMWT distance increased from a baseline median value of 323 m (range, 224–368 m) to 372 m (range, 232–530 m), representing a nonsignificant increase. Our results suggest that NT-proBNP is a biochemical surrogate marker, which could be used to evaluate the effects of bosentan or other vasodilation therapy in SScPAH.     

Reversible pulmonary arterial hypertension associated with interferon-beta treatment for multiple sclerosis

Interferon (IFN) therapy has an important role in the treatment of multiple sclerosis and chronic hepatitis C infection. A few case reports have described an association between IFN therapy and the development of irreversible pulmonary arterial hypertension (PAH), and it is currently listed as a possible drug-induced cause of PAH in the most recent classification of pulmonary hypertension. A causal link between IFN use and PAH remains to be elucidated; many reports of PAH resulting from IFN occur in individuals with some other risk factor for PAH. The authors present a case involving a patient with multiple sclerosis with no known risk factors for PAH, who developed severe PAH after exposure to IFN therapy. The patient experienced significant clinical and hemodynamic improvement, with normalization of her pulmonary pressures after the initiation of combination therapy for PAH. At 28 months after diagnosis, she remains asymptomatic with no hemodynamic evidence of PAH and has been off all PAH therapy for 10 months.     

Right ventricle Tei-index: a tool to increase the accuracy of non-invasive detection of pulmonary arterial hypertension in connective tissue diseases.

OBJECTIVE: To assess the accuracy of echocardiography for predicting pulmonary arterial hypertension (PAH) in a cohort of patients with systemic sclerosis and other connective tissue diseases, and to evaluate whether addition of the right ventricular (RV) Tei-index contributes to the non-invasive diagnosis of PAH in this patient group. PATIENTS AND METHODS: Ninety-eight patients with systemic sclerosis and other connective tissue diseases in whom an echocardiography was performed in the period from January 1st 2004 to July 1st 2005 were included. Echocardiographic systolic pulmonary arterial pressure (PAP), end-diastolic PAP and RV Tei-index were calculated. In cases with a high suspicion of PAH right heart catheterization was performed and systolic, diastolic and mean PAP as well as pulmonary wedge pressure, cardiac output and pulmonary vascular resistance were obtained. These results were compared to the echocardiographic measurements. RESULTS: The average RV Tei-index of our patients was substantially above normal values. In 35 (36%) patients a right heart catheterization was performed and PAH was confirmed in 28 patients. In 6 of 7 patients without PAH, the RV Tei-index was below the upper limit of normal. A significant correlation was found between the RV Tei-index and the catheterization parameters such as systolic PAP, diastolic PAP and mean PAP. CONCLUSION: The accuracy of echocardiography for the detection of PAH increases when the echocardiographic systolic PAP is combined with an elevated RV Tei-index. As a result, by applying the Tei-index, the number of negative catheterizations can be minimized.     

提高对肺动脉高压的诊断意识

肺动脉高压（PAH）是一种预后极差的进展性疾病,由于病因多而复杂,症状体征不典型,常规检查敏感性低,PAH常常被延误诊断,而且当患者确立PAH诊断时,多数已经处于NYHA功能分级Ⅲ-Ⅳ级。最重要提高临床诊断水平的手段是提高对PAH的认识和诊断意识。临床医生只有全面理解WHO肺高压分类标准,掌握并合理使用各种诊断方法和措施,仔细筛查,确诊PAH并明确病因,评估病情,才能尽早采取具有循证医学证据的规范化治疗,提高患者的生活质量和预后。     

结缔组织病并发肺动脉高压110例临床分析

目的：评估结缔组织病并发肺动脉高压的发生率、临床特点、诊断及治疗方法。方法：1278例结缔组织病患者中110例伴有肺动脉高压,对其进行回顾性分析。结果：结缔组织病合并肺动脉高压的发生率约为8.6%（110/1278）。110例患者中,女性95例,男性15例,年龄11～79岁,平均（46±17）岁;病程0.5～20年,平均（7±6）年。系统性硬化症（SSc）和混合性结缔组织病（MCTD）合并肺动脉高压发生率最高,分别为40.0%和25.0%,显著高于其他结缔组织病（P〈0.01）。有雷诺现象或雷诺现象合并肺间质病变者肺动脉压力显著升高（P〈0.01和P〈0.05）。且雷诺现象与肺动脉压力呈正相关（r=0.531,P〈0.01）。肺功能异常发生率较高,以弥散量降低最为多见。轻度肺动脉高压患者临床表现少,治疗可逆转;重度肺动脉高压治疗反应差,病死率高。结论：结缔组织病合并肺动脉高压较为常见,其中以SSc和MCTD合并肺动脉高压发生率最高。雷诺现象与肺动脉压力呈正相关,是预测肺动脉高压的良好指标。早期诊断和治疗,可以改善患者预后。