Abstract
血小板源生长因子受体inhibitor imatinib has demonstrated clinical and haemodynamical improvement in both animal models of pulmonary hypertension (PH) and patients with PH. It has been suggested that anti-proliferative effects on pulmonary vascular smooth muscle cells are responsible for these beneficial effects.
The current study describes a patient with pulmonary arterial hypertension associated with a suspected pulmonary veno-occlusive disease.
用伊马替尼治疗可在高分辨率计算机断层扫描中快速改善临床改善和降低地面玻璃渗透率和小叶间隔增厚。
基于这些发现和体外伊马替尼对内皮渗透性的影响,作者假设快速临床结果部分是由于伊马替尼对血管完整性的影响。
案例报告
一名56岁的女性被转诊至VU大学医学中心(荷兰阿姆斯特丹),以评估肺动脉高压。该患者的病史包括在12岁时结核病,并接受了氨基氨基水杨酸酯,甲状腺功能减退症和7种包装的吸烟史。转诊之前,该患者在其他地方住院并被诊断出患有肺炎。由于她对进行性呼吸困难的抱怨15个月,并且在诊断出特发性肺动脉高压(PAH)之后,她的姐姐早1年就进行了超声心动图,表明肺动脉收缩压升高为50 mmMHg。
The patient was in functional New York Heart Association (NYHA) class 4. Physical examination revealed a blood pressure of 150/110 mmHg, a tachycardia of 110 beats·min-1,,,,a tachypnea of 30 breaths·min-1,以及15 L·min的97%的脉搏氧气表上的周围饱和度-1o2delivered by oxygen mask. Laboratory testing demonstrated an arterial oxygen tension (pa,o2)6.52 kPa(49 mmHg)。N末端促脑纳地钠肽(NT-Probnp)为588 ng·L-1(normal range 0–301 ng·L-1)。自身免疫性血清学表现出较弱的阳性抗核抗体。可萃取的核抗原和抗肿瘤的细胞质抗体为阴性。肺功能测试显示,碳一氧化碳肺的扩散能力降低(dl,co) of 37%, and a reduceddl,co/alveolar volume of 40%. A high-resolution computed tomography (HRCT) scan revealed thickened septal lines and mosaic ground-glass opacities. There were no signs of pulmonary embolism. An echocardiogram showed normal left ventricular (LV) function.
pulmonary hypertension (PH) was confirmed by right heart catheterisation, revealing a pulmonary arterial systolic pressure of 102 mmHg, a pulmonary arterial diastolic pressure of 40 mmHg and a mean pulmonary arterial pressure of 69 mmHg. The mean right atrial pressure was 9 mmHg. The pulmonary capillary wedge pressure (PCWP) was 12 mmHg. There was a mixed venous saturation of 59%, a cardiac output of 3.0 L·min-1和a pulmonary vascular resistance of 1,497 dynes·s-1·cm-5。Systemic blood pressure during right heart catheterisation was 102/40 mmHg. No testing on acute vasodilator response was performed.
HRCT的发现以及低dl,co氧含量和正常的PCWP与肺静脉牙菌性疾病(PVOD)兼容,PVOD是PAH的罕见变体。这种模式与患者的姐姐相似,因此怀疑家族性PVOD,这种现象在文献中几乎没有报道1,,,,2。该患者的病情被认为是进行开放肺活检以进行诊断确认的禁忌症。在外显子和侧翼内含子区域上的基因筛查显示没有骨形态发生蛋白受体(BMPR)2基因突变。
用前列环素类似物卵丙烯醇以13 ng·kg的剂量开始治疗-1·min-1,,,,loop diuretics and anticoagulation. No clinical improvement was observed and the epoprostenol dose was increased gradually to 23 ng·kg-1·min-1在4个月的时间内,导致适度的临床改善。诊断后8个月的患者恶化,报告了进行性呼吸困难,食欲不振,过去4个月的体重减轻23公斤,以及无法进行最小的体育活动,例如梳理头发。嗜积烯醇增加到25 ng·kg-1·min-1利尿剂治疗加强了200 mg速尿的总剂量。没有临床改善,在增量嗜积烯醇后2周,该患者再次住院。那时,患者再次进入NYHA 4类,需要高剂量的氧气。外围饱和度为87%,7 l·min-1o2。There was a renal insufficiency with a glomerular filtration rate of 30 mg·min-1。NT-ProBNP增加到4,443 ng·L-1。重复的HRCT扫描显示出间隔增厚和地面玻璃的不透明性(图1A)×)。前三天从25 ng·kg降低了嗜oprostenol剂量-1·min-1至22 ng·公斤-1·min-1。Again there was no clinical improvement. Although additional effects of sildenafil and/or bosentan to epoprostenol could not be excluded, it was not expected that these drugs would result in a prompt, timely reversal of the devastating clinical condition of the patient. Therefore, it was decided that the patient should be treated experimentally with imatinib (Gleevec®; Novartis Pharma, Arnhem, the Netherlands), a tyrosine kinase inhibitor directed against the platelet-derived growth factor receptor (PDGFR). The decision was also based on an avialable case report of imatinib treatment of PH3和data concerning upregulation of PDGFR genes in pulmonary capillary haemangiomatosis (PCH)4。伊马替尼的治疗以每天200毫克的剂量开始,在住院的第三天开始。在24小时内,患者报告了呼吸困难的改善。外围饱和度为94%,7 l·min-1o2。pa,o2从6.52 kPa(49 mmHg)增加到8.25 kPa(62 mmHg)。该患者恢复了自己的胃口,并能够独立进行轻度的日常活动。外周饱和度为100%,5 l·min-1o2,,,,3 days after initiation of imatinib.
![Fig. 1—](http://www.qdcxjkg.com/content/erj/32/1/232/F1.medium.gif)
肺的高分辨率计算机断层扫描,表明A)a)在用伊马替尼和b)持续的地面玻璃渗透率治疗前的叶片增厚叶片和斑块的镶嵌玻璃玻璃渗透不相差,但在开始伊马替尼后持续降低了小叶隔膜增厚。
1个月后的第三次HRCT扫描显示了地面玻璃泥浆率和间隔增厚的部分分辨率(图1B⇑)。Meanwhile, the NT-proBNP level had fallen to 886 ng·L-1。during a 6-min walking distance test she was able to walk 346 m.
该患者在22 ng·kg的卵巢烯醇上仍在临床上稳定-1·min-1和imatinib at 200 mg投标。12 months after initiation of imatinib. Haemodynamic evaluation was refused by the patient. However, she reported symptomatic improvement and was in NYHA class 3 and was able to perform light activities without oxygen supplementation.pa,o2remained stable at 9.18 kPa (69 mmHg) and 8.51 kPa (64 mmHg), after 1 and 7 months of imatinib treatment, respectively. Besides alopecia the patient has not reported side effects that could be ascribed to the use of imatinib.
dISCUSSION
据目前的作者所知,这是第一项显示伊马替尼在具有PVOD特征特征的患者中的有益作用的研究。PVOD是一种罕见的PAH形式,它通过纤维组织遮挡肺静脉和静脉,以及通过肌肉化的肌肉培养基的发展来影响毛细血管血管。5-7。An important histopathological feature is interstitial oedema, radiographically represented by the patchy ground-glass opacities and the thickened septal lines on HRCT scans, especially in the lobular septa.
The diagnosis of PVOD could not be proven histologically in this patient. However, there are several arguments for this diagnosis, such as the normal PCWP, the characteristic radiological features, the lowdl,co/肺泡体积和疾病表现的家族方面6;而家族性PAH的论点被负BMPR2基因筛选削弱了。根据临床发现,不能排除PCH的诊断。但是,是否应将两种疾病视为不同的疾病还是作为单一疾病的组织学变异,仍然值得怀疑8。底层LV病理学似乎不太可能的缺点idering the normal PCWP, the normal LV function on echocardiogram and the familial occurrence of PH. Sarcoid vasculopathy should be considered in the differential diagnosis, as similar radiological features and diffusion abnormalities may occur9;however, in this case the familial occurrence and the absence of extrapulmonary sarcoidosis make this diagnosis less likely.
伊马替尼still has an experimental status in the treatment of PH and should not be used outside reference centres for PH treatment. Several examples of imatinib treatment of PH in exceptional cases have now been published, in which improvement of clinical status, exercise capacity and haemodynamics resulted3,,,,10,,,,11。在本研究患者中,临床状况和运动能力也得到了改善。无法进行右心导管插入术,以支持血流动力学数据的观察到的伊马替尼的作用。然而,NT-proBNP水平在伊马替尼治疗开始后显示出明显降低。这表明血流动力学参数的改善,因为最近的一些研究表明,NT-螺旋水平与PAH患者的右心室功能之间的关系12-14。
伊马替尼是一种针对多种受体酪氨酸激酶的酪氨酸激酶抑制剂,包括PDGFR,PDGFR,酪氨酸激酶C-KIT和断点簇区域(BCR)/Abelson Murine Murine Leukemia(ABL)融合蛋白的酪氨酸激酶C-KIT和酪氨酸激酶结构域。尚未研究C-KIT和BCR/ABL在pH发病机理中的作用,但已提出PDGFR在pH中的作用in vivo由Schermuly等15。在具有既定pH的大鼠和慢性低氧小鼠中单蛋白诱导的pH值的动物模型中,伊马替尼的给药导致肺血管重塑,pH和右侧心肥大的逆转。有趣的是,PDGFB和pdGFR-ß genes have been demonstrated to be upregulated in the nodules of proliferating capillaries of PCH lesions, which could occur secondarily to PVOD4,,,,8。
The mechanism of action of imatinib in the present patient is merely speculative. Besides the previously described antiproliferative effects, which might have caused the long-term clinical improvement, vasodilation might have played a role as well, although such an effect of imatinib on the pulmonary vasculature has not been described.
of particular interest in the present case is that treatment with imatinib led not only to immediate clinical improvement, but also to a decrease in septal thickening on the HRCT scan. It is tempting to speculate that the rapid improvement was caused by some other process, such as resolution of pulmonary oedema. This might be partially explained by an effect of the integrity of the endothelial layer, as there are indications from体外研究血小板衍生的生长因子和/或伊马替尼对内皮血管完整性的影响16,,,,17。水肿的快速分辨率是出乎意料的,因为肿瘤患者抑制PDGFR信号传导抑制的副作用是由于间隙液压升高而增加的流体保留率18,,,,19。
总之,本研究表明,一名患有疑似,严重恶化的肺静脉疾病的患者,他们在将伊马替尼添加到proprostenol治疗后表现出快速的临床改善和稳定。作者推测,除了伊马替尼的抗增殖作用外,伊马替尼还通过改善内皮衬里的完整性或降低静液压毛细管压力,从而减少了肺水肿的形成,从而有助于患者的快速临床和射线照相改善。
支持声明
G.P. van Nieuw Amerongen was supported by a grant from the Netherlands Heart Foundation (T2003-0032).
利益声明
None declared.
- 已收到May 6, 2007.
- 公认december 10, 2007.
- © ERS Journals Ltd