1、临床医师如何处理肺动脉高压中国医学科学院中国协和医科大学阜外心血管病医院 程显声2009年10月11日（长城会 ）,一、目的1.如何学习和掌握肺动脉高压的快速进展与变 化，如定义、分类、诊断、治疗及指南等； 2.如何执行肺动脉高压指南；3.如何参加“肺动脉高压多中心临床试验”；4.如何做好日常工作。,二、肺动脉高压的定义与术语中文译名（一）定义肺动脉高压是血流动力学和病理生理学紊乱（condition） ，静息下右心导管术检查mPAP25mm Hg（适用全部PH）；毛细血 管前PH: PWP15mm Hg, CO正常或减少；毛细血管后PH :PWP 15mm Hg, CO正常或减少（被动性TP
2、G12mm Hg，反应性TPG12mm Hg）。新的PH的阈值mPAP21mm Hg, 21-25mm Hg为临界PH, 25mm Hg为表现型PH。（二）术语译名Pulmonary hypertension, PH, PHT（肺动脉高压 Pulmonary arterial hypertension, PAH 动脉型（性）肺动脉高压、肺高血压（肺高压） Unexplained pulmonary hypertension, UPH（不能解释的肺 动脉高压）,三、肺动脉高压临床分类的变化1975 WHO（PPH专家委员会）日内瓦1998 WHO 法国依云2003 WHO 意大利威尼斯2008
3、肺动脉高压学会 美国Dana Point意义：1. 对肺动脉高压的本质及其发病机制认识的深入2. 对继发性肺动脉高压与基础疾病间关系认识的深入3. 从动脉型肺动脉高压向其他型肺动脉高压扩展，更趋全面4. 更加符合实用，便于临床诊断与治疗,表2 1998年与2003年肺动脉高压的分类1998（埃维安） 2003（威尼斯）1.动脉型（性）PAH 1.PPH不再应用PPH散发性 特发性 PAH家族性 家族性 PAH相关与： 相关与：结缔组织病 结缔组织病 HIV HIV 药物和毒素门脉高压 门脉高压节食药 节食药艾森曼格综合征 先心病 新生儿持续性 PH 新生儿持续性 PH 明显的肺静脉和/或肺毛细
4、血管受累 ,其他类型PH2.肺静脉高压性 2.左心疾病性PH （如继发左心疾病）3.呼吸系统相关性PH 3.肺疾病和/或低氧血症性PH 4.慢性血栓拴塞性PH 4.慢性血栓形成和/或拴塞疾病性PH5.影响肺血管结构的杂类PH 5.影响肺血管结构的杂类PH （如结节病） （如结节病）,肺动脉高压的最新临床分类（Dana Point 2008）1.动脉型（性）肺动脉高压（PAH）（1）特发性（2）遗传性1）BAPR22）ALKI,内皮连蛋白（有或无遗传性出血性毛细血管扩张症）3）原因不明的（3）药物和毒素引起的（4）相关性的（APAH）1）血吸虫病2）慢性溶血性贫血（5）新生儿持续性肺动脉高压1.
5、肺静脉堵塞病和/或肺毛细血管瘤样扩张症,2.左心疾病引起的肺动脉高压1）收缩功能不全2）舒张功能不全3）瓣膜性3.肺疾病和/或低氧血症性肺动脉高压1）COPD2）间质性肺病3）伴混合限制性和阻塞性其他肺疾病4）睡眠呼吸紊乱性5）肺泡低通气紊乱6）慢性高原暴露7）发育异常4.慢性血栓栓塞性肺动脉高压,5.原因不清和/或多因素机制的肺动脉高压1）血液学紊乱：骨髓组织增殖紊乱、脾切除术2）全身性疾病、结节病、肺朗罕细胞组织细胞增生病、淋巴血管平滑肌瘤病、神经纤维瘤病、血管炎3）代谢紊乱：糖原积蓄病、Gaucher 病、甲状腺疾病4）其他：肿瘤堵塞、纤维化性纵膈炎、慢性肾功能衰竭透析,四、肺动脉高压的
6、诊断有无肺动脉高压；肺动脉高压的原因与类型；肺动脉高压的严重程度（NYHA功能分级、WHO PHA功能分 级、6MWT及血流动力学检查等）；肺动脉高压的可逆性（ 急性血管扩张药物试验）；右心功能状态；肺动脉高压患者的预后。,（一）肺高压有创和无创性检查有创性： 无创性：- 右或左心导管术 - 胸部X线平片、心电图、- 肺动脉造影 超声/多普勒、CT、MRI、- 肺活检 - 肺功能- 生物标记物 - 功能测定（6MWT等）,（二）无创性（超声/多普勒）血流动力学检测1. 估测：- 肺动脉收缩压- 右心室收缩压- 肺动脉平均压- 肺动脉舒张压- 肺血管容量- 每搏量(SV)/搏动压(PP)- RV
7、dp/dt- 肺血管阻力,2. 超声心动图诊断肺高压的限制15%的患者测不到三尖瓣返流束-盐水对比剂可提高三尖瓣返流束的检出率不是所有的先心病都能检出左室充盈压或心排出量（CO）的测定方法不可靠三尖瓣返流速率测量的微小误差可明显改变结果三尖瓣返流速率可以低估或高估右心室收缩压,3. 超声心导管术右室收缩压不相关的原因低估三尖瓣返流速率- 取不到峰值信号,线性不满意高估三尖瓣返流速率- 取到过多的模糊信号右心房压估计不准确 条件改变压力改变心导管检查不准确,（三）肺高压心导管检查1.为何要进行血流动力学评估（1）定义（诊断标准）（2）肺高压是血流动力学紊乱(disorder)-为准确诊断-为确定
8、病因-为选择治疗-为评估预后-可估测病情进展- 确定肺移植时间-可预测钙拮抗剂反应,2. 有创性血流动力学评估(右和左心导管术)测量：- 所有上述内容- 左室充盈压- 肺毛细血管楔压- 左房压- 左室舒张终末压- 肺血流量- 平均右房压- 急性血管扩张药物试验,4.有创或无创血流动力学评估比较“准确性”的意义其他问题：- 单一时间点的信息代表性- 随诊的可行性- 信息量- 信息的有用性预后,1985,2009,5. 基于静息三尖瓣反流峰速率，Doppler估测SPAP（RAP=5mm Hg）及其他提示PH的超声变量提示存在PH的规定标准： 超声诊断PH不可能：三尖瓣反流速率2.8m/sec,
9、SPAP36mm Hg, 无其他提示PH的超声变量； 超声诊断PH可能：三尖瓣反流速率2.8m/sec, SPAP36mm Hg, 但有提示PH的其他超声变量； 三尖瓣反流速率2.9-3.4m/sec, SPAP37-50mm Hg, 有或无提示PH的其他超声变量； 超声诊断PH很可能：三尖瓣反流速率 3.4m/sec, SPAP 50mm Hg, 有或无提示PH的其他超声变量； 不推荐运动超声Doppler筛查PH。,五、与心脏科密切的两种情况（一）先心病PAH的分类：1. 艾森门格综合征：因大的缺损引起的体-肺分流导致的严重PVR增加，变成肺-体或双向分流、紫绀、红细胞增多及存在多器官受累
10、，能否靶向治疗手术；2. 体-肺分流并发的PAH：中到大的缺损，PVR轻到中度增加，体-肺分流仍大量存在，静息无紫绀；3. 小缺损肺动脉高压（通常VSD1cm; ASD2cm）：临床表现非常类似IPAH。4. 心外科矫治后PAH：先心病已矫治，术后即刻或数月、数年后PAH复发，且无新的或残留缺损(ASD12%，VSD13%），靶向治疗疗效？。,（二）左心疾病性PH患病率高，占人群筛查肺动脉高压的第一位，约78.8%以上。1. 收缩性心功能不全；2. 舒张性心功能不全：LVEF正常（45%），舒张功能不全（约占心衰的50%）肺动脉高压和肺血管病变很常见，早期的临床表现为肺淤血，易被临床忽视，常发
11、生于糖尿病、高血压及冠心病患者。3. 瓣膜病性。,患者，男性，51岁。1985年体检发现心脏杂音，诊断“风心病，二尖瓣狭窄”。1988年在北京安贞医院行二尖瓣置换术，术后症状消失，活动耐力正常。规律服用华法林抗凝，美托洛尔及地高辛控制房颤心室率。于2005年患者再次出现活动后气短，双下肢水肿，症状加重，就诊于安贞医院，给予利尿、控制心率等治疗，症状好转。本次因入院前3天出现咯血，伴有气短，不能平卧。查体：T 36。C， P 97次/分，R 20次/分，Bp140/100mmHg。端坐位，双肺大量湿罗音，为大水泡音，心率130次/分，律不齐，S1强弱不等，三尖瓣听诊区可闻及2/6级收缩期杂音。腹
12、软，双下肢不肿，利尿药治疗后症状好转。辅助检查：超声心动图估测肺动脉收缩压102mmHg,ECG和 胸片见后。,治疗前,治疗后,ECG:电轴右偏，RVH?,问题:1. 肺动脉高压的发生机制是什么？2. 肺动脉高压病变如何评估？3. 肺动脉高压对患者预后有何影响？4. 如何预防和治疗本型肺动脉高压？可否使用靶向治疗药物？,六、现行肺动脉高压的治疗指南 WHO威尼斯会议纪要- 指南(病理学、基因学、终点、诊断、治疗）；（ JACC 2004） 美国胸科医师学会共识指南：- 筛查、早期检测、诊断；Chest 2004- 治疗；（ Chest 2004, 2007）欧洲心脏学会（Eu）共识指南：- 诊
13、断与治疗；（Eur Heart J 2004） 美国Dana Point 肺动脉高压研讨会（2008.09.21）ACCF（美国心脏学会基金会）/AHA（美国心脏学会）（-1st JACC 2009 ， March）,联合治疗? 前列环素波生坦 西地那非,持续有效,一般治疗措施,急性血管反应性试验特发性（A）其他（E/C）,阳性,阴性,口服CCB IPAH（A） PAH（E/B）其他,功能级,功能级,功能级,西地那非（A） 曲前列环素皮下（C） 依前列醇（A） 曲前列环素静脉（C）,波生坦（A） 西地那非（A） 依前列醇（A） 吸入依洛前列素（A） 曲前列环素皮下（B） 曲前列环素静脉（C）,
14、依前列醇静滴（A） 波生坦（B） 吸入依洛前列素（B） 西地那非（C） 曲前列环素皮下（C） 曲前列环素静滴脉（C）,（一）症状性肺动脉高压,不改善或恶化,安贝生坦 他达拉非,否,是,房间隔造口术肺移植,继续CCB,（二）肺动脉高压内科治疗流程,一般治疗 口服抗凝药利尿药氧疗地高辛,急性血管反应性试验,阳性,阴性,口服CCB,低危,高危,持续好转,内皮素受体拮抗剂 磷酸二酯酶-5抑制剂 （口服）；依前列 醇 或曲前列环素（静脉） 依洛前列素（吸入） 曲前列环素（皮下）,依前列醇 或曲前列环素（静脉） 依洛前列素（吸入） 内皮素受体拮抗剂或 磷酸二酯酶-5抑制剂（口服） 曲前列环素（皮下）,检查
15、方案 联合治疗,房间隔造口术 肺移植,临床再评估，如治疗指南 不满足，考虑附加治疗,是,否,继续CCB,（三） 肺动脉高压内科治疗流程（危险度）危险因素 低 危 高危右心衰临床证据 无 有进展 逐渐 迅速WHO功能分级 、 6分钟步行距离 较长（400m） 较短（300m）心肺运动试验 10.4ml/kg/min 10.4ml/kg/min （pkVO2)B型利钠肽 轻度升高 非常高超声心动图 轻度右心功能不全 心包积液、明显右心功能不全血流动力学 正常/接近正常右房压 右房压高心脏指数 心脏指数低,（四）长期钙拮抗剂有效（95%CI）特发性PAH 7.5%节食性PAH 7.9%结缔组织相关性
16、PAH 1.2%HIVPAH 1.6%门脉性PH 0.7%,七、QuERI注册登记PAH的治疗按ACCP推荐的PAH处理：52名美国专科医生，517例PAH患者。特发性：37%；家族性:3%；相关性:50%。治疗：依前列醇/吸入依洛前列素/曲前列环素（PGI)：33.7%; 西地那非(SID): 37.3%; 波生但(BOS):53.1%; 联合治疗：PGI+SID:16.9%; BOS+SID:18.2%; PGI+BOS:15.6%; PGI+BOS+SID:6.7%; 未治疗：19.8%。96例服CCB, 27例做过急性药物试验（占总数的6.3%），其中仅6例有ACCP推荐的明确血管反应
17、性。抗凝治疗：44%；利尿药：功能分级、级分别为：40%、53%及72%；抗醛固酮药：21%；地高辛16%。,八、肺动脉高压的随诊（一）症状：疲乏、气短，运动耐受力（6分钟步行距离）等；（二）体征：心衰征象外，脉搏及血压的数量和质量变化，P2响度及三尖瓣杂音强度变化等；（三）实验室检查：X线胸片、心电图、超声/多普勒、MR、核素造影等；（四）肺动脉压力的评估：PAP=CO(肺血流量） PVRPAP、PAP、PAP的解释，综合判断，包括肺循环血流动力学和右心功能的参数变化。,九、总结1. 了解有关肺动脉高压的发展与变化；2. 研究者必须严格执行研究方案；3. 临床医师应尽可能参照指南施治；4.
18、基于“个体化”原则处理肺高压患者；5. 临床医师的行医宗旨是利用肺高压的现代知识最好的服务于患者,（如老年人的不能解释的肺高压）。,谢谢！,A clinician how to manage pulmonary hypertension Xiansheng Cheng MDDiagnosis and Treatment Centerof Pulmonary Vascular DiseaseFuwai Cardiovascular Hospital CAMS & PUMC Oct 11. 2009 (Great Wall),1. Aim:(1) How to learn and apply th
19、e recentadvance and changes in PAH: definition, classification, diagnosis, treatment and “ guideline”?(2) How to carry out the ?(3) How to join the multicenter clinical trials?(4) How to do everyday practice ?,2. Definition and Chinese translation of the term “pulmonary hypertension”(1) DefinitionPH
20、 is an haemodynamic and pathophysiological condition defined as an increase in mPAP25mm Hg at rest as assessed by RHC. Pre-capillary PH:PWP15mm Hg; Post- capillary PH15mm Hg, CO normal or reduced (Passive TPG12mm Hg, Reactive TPG12mm Hg). New PH thresholds for mPAP21mm Hg(normal);21-25mm Hg(borderli
21、ne); 25mm Hg(manifest PH).(2) How to translate PH (or PAH) to Chinese (debate) ：1) PH, 2) PAH, 3) UPH,3. Changes in clinical classification of PH1975 WHO (PPH expert committee) Geneva1998 WHO France Evan2003 WHO Italy Venice 2008 PH Association US Dana PointSignificance:1. Recognition enhancement of
22、 the nature and pathogenesis of PH.2. Recognition improvement of relationship between PH and underlying disease3. Alone PAH expand to some type of PH, more perfect4. To facilitate clinical practice,(1) Evan criteria(1998) (2) Venice(2003)1. PPH 1. PPH no longer used Sporadic Idiopathic PAH Familial
23、Familial PAHRelated to Related to CTD CTD HIV HIV drugs and toxins Portal hypertension Portal hypertension Anorexigens Anorexigens Eisenmengers S CHD Persistent PH of the newborn Persistent PH of the newborn Significant venous and/or capillary involvement,(1)WHO criteria(1998) (2)Venice(2003)Other f
24、orms of PH2. PVH 2. PH with left heart disease3. PH related to disorders 3. PH with lung disease and/or of the respiratory system hypoxemia4. CTEPH 4. PH due to chronic thrombotic and/or embolic disease5. Miscellaneous disorders 5. Miscellaneous disorders affecting pulmonary affecting pulmonary vasc
25、ulaturevasculature,(3) Updated clinical classification of PH(Dana Point)1.PAH1.1 Idiopathic1.2 Heritable1.2.1 BMPR21.2.2 ALKI, endoglin ( with or without hereditary haemorrhagic telangiectasia )1.3 Drug and toxins induced1.4 Associated with (APAH)1.4.1 Connective tissue diseases1.4.2 HIV infection 1
26、.4.3 Portal hypertension1.4.4 Congenital heart disease 1.4.5 Schistosomiasis1.4.6 Chronic haemolytic anaemia,1.5 Persistent pulmonary hypertension of the newborn1. Pulmonary veno-occlusive disease and/or pulmonary capillary haemangiomatosis2. Pulmonary hypertension due to left heart disease2.1 Systo
27、lic dysfunction2.2 Diastolic dysfunction2.3 Valvular disease3. Pulmonary hypertension due to lung diseases and/or hypoxemia3.1 COPD3.2 Interstitial lung disease3.3 Other pulmonary diseases with mixed restrictive and obstructive pattern3.4 Sleep disordered breathing3.5 Alveolar hypoventilation disord
28、ers3.6 Chronic exposure to high altitude,3.7 Developmental abnormalities4. Chronic thromboembolic pulmonary hypertension5. PH with unclear and/or multifactorial mechanisms5.1 Haemotological disorders: myeloproliferative disorders, splenectomy5.2 Systemic disorders, sarcoidosis, pulmonary Langerhans
29、cell histocytosis, lymphagioleiomyomatosis, neurofibromatosis, vasculitis5.3 Matabolic disorders: glycogen storage disease, Gaucher disease, thyroid disorders5.4 Others: tumoral obstruction, fibrosing mediastinitis, chronic renal failure on dialysisALKI = actvin receptor-like kinase 1 gene,4. Diagno
30、sis of PH(1) Presence or absence of PH?(2) Cause and pattern of PH?(3) Severity of PH (6MWT, hemodynamics, etc.)? (4) Right ventricular function(5) Reversibility of PH (acute vasodilator testing)?(6) Prognosis of patient with PH,(1) Invasive vs Noninvasive Modalities (PAH) Diagnosis:Invasive: Noninv
31、asive: R & L Heart Cath CXR, ECG pulmonary Echo/Doppler, Angiography CT, MRI Lung Biopsy PFTs Biomarkers Functional Tests,(2) Noninvasive (Echo/Doppler)Hemodynamic Assessment1) Estimates:- Systolic PA pressure- right ventricular systolic pressure- Mean PA pressure- Diastolic PA pressure - Pulmonary
32、vascular capacitance- SV/PP- RV dp/dt- Pulmonary vascular resistance,2) Echocardiography in Diagnosing PH Limitations. 15% of patients will not display TR jets- Saline contrast can enhance TR jet. Not all congenital heart lesions will be obvious. Poor method to measure LV filling pressure or cardiac
33、 output (CO). Small errors in TR velocity (TRV) measuremendscan significantly alter results. TRV can underestimate RVSP or overestimateRVSP,3) Reasons for failure of echo-cath RVSP correlation. Underestimating TR velocity -not getting peak signal, poor alignment. Overestimating TR velocity-taking ov
34、er-gained shaggy signals. Failing to adequately assess right atrialpressure. Changing conditions-changing pressures. Cath inaccuracies,(3)Cardiac Catheterization in PAH:1) WHY PERRFORM HEMODYNAMIC EVALUATION?By definition,Pulmonary Hypertension is a Hemodynamic Disorder. For accurate diagnosis. For
35、establishing etiology . For treatment selection. Permits estimation of prognosis. Permits assessment of progression. Timing of transplantation. Permits prediction of response to chronic calcium blocker Rx,2) Invasive (R & L Heart Cath)Hemodynamic Assessment Measures:- All of the previous- Left heart
36、 filling pressure- PCWP- Left atrial pressure- LV end- diastolic pressure- Pulmonary blood flow- Mean right atrial pressure- Acute response to vasodilators,4) Invasive vs NoninvasiveHemodynamic Assessment. Is comparing “Accuracy” meaningful?. Other issues:. Representativeness of informationat single
37、 point in time. Feasibility for follow-up. Breadth of information. Usefulness of information. Prognosis,1985,2009,5. Arbitrary criteria for the presence of PH based on TR peak velocity Doppler-estimated SPAP at rest (assuming a normal RAP=5mm Hg) and on additional echo variables suggestive of PHEcho
38、 diagnosis: PH unlikelyTRV2.8m/sec, SPAP36mm Hg and no echo variables of PHEcho diagnosis: PH possible TRV2.8m/sec, SPAP36mm Hg but presence of echo variables of PH, or TRV 2.9-3.4m/sec, SPAP 37-50mm Hg with/without echo variables of PHEcho diagnosis: PH likelyTVR 3.4m/sec, SPAP 50mm Hg, with/withou
39、t echo variables of PHExercise Doppler / Echo is not recommended for screening of PH,6. Two conditions closely rerated to Cardiology(1) The classification of CHD associated with PAH1) Eisenmengers syndrome-target therapy-bridge-operation?2) PAH (moderate to large defects) associated with large S-to-
40、P shunts3) PAH with small defects(VSD1cm,ASD2cm)4) PAH after corrective cardiac surgery-how to prevent and treat it?,(2) PH due to left heart diseasePrevalence of 78.8%, it is important clinical issue 1) Systolic dysfunction2) Diastolic dysfunction (LVEF45%),approximately 50%3) Valvular disease,Case
41、 reportPatient male 51 years old, was found cardiac murmur in1985. He underwent mitral valve replacement in 1988, in post-operation his symptoms disappeared and excise tolerance was normal. He regularly took warfarin, metoprolol and digoxin . In 2005 the patient recurred exertional dyspnea, extremit
42、as edema, that were alleviative after treatment. He was admitted to hospital with hemoptysis and nocturnal dyspnea for three days.Physical exam: T36, P97bpm, Bp140/100mm Hg. Sitting position, numerous rales in lungs, HR130bpm, irregular rhythm, 2/6SM in TV area, heptomegaly, no edema in low extremit
43、y. Echocardiography estimated SPAP=102mm Hg, ECG and chest X-ray film see next slide. Diagnosis: chronic rheumatic heart disease, post-MV replacement, heart failure, secondary PH.,Pre-treatment,Post-treatment,ECG: E-axis to right，RVH?,Questions:1. What is the pathogenesis of the PH?2. How to evaluat
44、e the pulmonary vascular lesion?3. What is the impact of the secondary PH on prognosis of the patient?4. How to prevent and treat the pattern of PH? Whether to can use target therapy?,7.Current PAH Treatment GuidelinesWHO-Venice Proceedings:- A - to Z ( Pathobiology, Genetics, EndpointsDiagnosis, Tr
45、eatment ); (JACC 2004)ACCP(US) Consensus Guidelines:- Screening, Early Detection, Diagnosis; (CHEST 2004)- Treatments; CHEST 2004, 200ESC(EU) Consensus Guidelines: - Diagnosis and Treatment; (Eur Heart J 2004 )ACCF/AHA ( 1st Presented at JACC; March, 2009),(1)Symptomatic PAH,Combination Therapy? Pro
46、stanoidBosentan Sildenafil,General Treatment Measure,Acute Vasoreactivity Testing (A IPAH,E/C for other PAH),Positive,Negative,Oral CCB B for IPAH, E/B for other PAH,Sustained Response?,yes,No,FC,FC,FC,Sildenafil A Treprostinii SC C Treprostinii IV C,Bosentan A Sildenafil A Epoprostenol A Iloprost inh A Treprostinii SC B Treprostinii IV C,Epoprostenol IV A Bosentan B Iloprost inh B Sildenafil C Treprostinii SC C Treprostinii IV C,ambrientan tadalafil,No Improvement or deterioration,
