Zhi-Cheng JING, M.D; FCCP. Professor of Cardiology Pulmonary Circulation Center Tongji University School of Medicine Shanghai, China Pulmonary Arterial Hypertension: New insights into 2010

Patho-Anatomy of AMI

In 1891, the German pathologist Romberg observed that the heart of an individual, suffering from a stricture of the pulmonary arteries due to severe sclerosis, was double the size of a man´s fist. He again named this disease sclerosis of the pulmonary arteries.

原发性肺高血压 – 发病率 : 1-2/ 百万人口 – 成人女男比 1.7:1 – 平均发病年龄 36±15 岁 –1 年、 3 年和 5 年的生存 率分别为 68%, 48% 和 34% D‘ Alonzo GE, et al. Ann Intern med.1991;115: Rich S, et al. Ann Intern med. 1987;107:216-23

Long-term response with CCBs in IPAH First study to demonstrate 95% 5-year survival in a very select group of patients with IPAH who exhibited an acute vasodilator response to CCBs Rich S,et al.N Engl J Med. 1992;327:76-81.

Survival in IPAH Long-term CCB responders Rich et al. N Engl J Med 1992

经左前臂静脉漂浮导管检查

急性肺血管扩张试验 Rubin LJ et al. Ann Intern Med 2005; 143:

急性肺血管扩张试验 - 阳性标准 阳性 肺动脉平均压 降至 40 mm Hg 以下 肺动脉平均压 下降幅度超过 10 mm Hg 心输出量 增加或不变 IPAH 患者阳 性率仅为 10% 左右 其他类型肺动 脉高压患者阳 性率更低

阳性患者 PAP 92/34/59 mm Hg PAP 36/11/20 mm Hg CO 3.5 3L/minCO 2.94 L/min

急性肺血管扩张试验 - 药物的选择 吸入装置和浓度检测 装置复杂 吸入给药 安全耐受性好 需要配合 滴定静脉泵入 不良反应多 静脉泵入 国内未上市 NO 依前 列醇 腺苷 伊洛前列 环素 指南公认

Long-term response with CCBs in IPAH Sitbon O, et al.Circulation. 2005;111;

John R. Vane And Flolan ■ ■ 1927 年 3 月 29 日出生 ■ ■ 1953 年，获得牛津大学医学博士学位； ■ ■ 20 世纪 60 年代中期，发现了阿司匹林与前列腺素的联系； ■ ■ 1976 年，发现前列环素，并在体外成功合成前列环素 epoprostenol ■ 1982 年，同另外两位科学家获得诺贝尔医学奖； ■ 1982 年，同另外两位科学家获得诺贝尔医学奖； ■ ■ 2004 年 11 月 19 日因病去世。

Flolan monotherapy era

improvements in Survival – IV Epoprostenol Barst R,et al.NEJM.1996;334: N=81

Long-term survival with epoprostenol in IPAH McLaughlin VV. Circulation.2002;106: N=162

Sitbon O, et al. JACC. 2002;40:780-8 N=178 Long-term survival with epoprostenol in IPAH

PAH 患者肺部肌性小动脉 ET-1 表达 Giaid et al. NEJM. 1993; 326:1732. 内皮素 ET-1 在最明显受累的病变部位出现最 大量的表达  肺部肌性小动脉和弹性动脉 PAH 患者中 PVR 和 ET-1 的表达相关， 但在其他类型的肺高血压（ WHO 诊断 分类第 2 类或第 3 类）中未观察到这种 现象  支持了 ET-1 至少与 PAH 中血管病 变相关的理论 ET-1 在最明显受累的病变部位出现最 大量的表达  肺部肌性小动脉和弹性动脉 PAH 患者中 PVR 和 ET-1 的表达相关， 但在其他类型的肺高血压（ WHO 诊断 分类第 2 类或第 3 类）中未观察到这种 现象  支持了 ET-1 至少与 PAH 中血管病 变相关的理论 肺动脉高压治疗 1998 年进入 内皮素受体拮抗剂波生坦治疗时代 肺动脉高压治疗 1998 年进入 内皮素受体拮抗剂波生坦治疗时代

Bosentan Observed and predicted survival months 169Patients at risk Event Rate / year (exponential): 5.5% % of event-free patients Predicted (NIH 2 ) Observed 1 1 Mc Laughlin, et al. Eur Resp J 2005; 25: D’Alonzo, et al. Ann Intern Med 1991;115:343 96% 69% Kaplan-Meier survival estimates with 99% CI

Survival of Patients with PAHypertension (PAH) Diagnosed at 3 Different Time Periods Zhi-Cheng JING, O Sitbon, M Humbert, G Simonneau et al. Oral presentation, accepted by ATS 2006

AIR 研究 : 标志肺动脉高压治疗进入 Mordern therapy era Death until day 90: Iloprost: n=1 Placebo: n=4

Inhaled Iloprost– Long term efficacy Hoeper,MM, et al.NEJM.2000;342:

曲前列素改善患者的预后 Barst RJ, et al.Eur Respir J 2006; 28: PAH 90%82%79% Obaerved survival Predicted survival IPAH 76%82%91%72%

Sildenafil-SUPER 2 Study No. at risk: (Data on file. Pfizer Inc, New York, NY.) 88% All patients up titrated to 80mgs TID

Sildenafil long-term open-label study from China P=0.03 X-Q XU, Z-C JING, et al. Hypertension Research. 2009;32:911-5

Vardenafil long-term open-label study from China No patients dead during obversational period Z-C JING, et al. HEART.2009;95:1531-6

Humbert et al. Circulation in press 1 年 83% 2 年 67% 3 年 58%

REVEAL study- 评分系统 One-year survival from enrollment in newly diagnosed patients with PAH ATS 2010

Diagnostic classification of Pulmonary Hypertension (updated 4th World Symposium on PAH, Dana Point 2008)

BAS (E/B) and/or lung transplant (E/B) Inadequate clinical response Combination therapy PDE-5 I Prostanoids ERA+ (E/B) + (B) Inadequate clinical response Continue CCB Yes Vasoreactive WHO Class I-III Oral CCB (B) Sustained response (WHO I-II) WHO Class III ERA (A) or PDE-5 I (A) Inhaled iloprost (A) SC treprostinil (B) IV epoprostenol (A) IV iloprost (C) IV treprostinil (C) Beraprost (C) WHO Class IV IV epoprostenol (A) IV iloprost (C) IV treprostinil (C) Inhaled iloprost (B) SC treprostinil (B) ERA (B) PDE-5 I (B) WHO Class II ERA (A) or PDE-5 I (A) Non-vasoreactive No PAH Evidence-based Treatment Algorithm Acute vasoreactivity test (A for iPAH) (E/C for APAH) Expert referral (E/A) Supportive therapy and general measures Avoid excessive physical exertion (E/A) Birth control (E/A) Psycho-social support (E/C) Infection prevention (E/A) Oral anticoagulants (E/B) - IPAH Diuretics (E/A) Oxygen* (E/A) Digoxin (E/C) Supervised rehabilitation (E/B) *To maintain O 2 at 92%

Survival data for PAH patients in China-from The data was from Shanghai Pulmonary Hospital, Tongji University --- CDHPAH --- IPAH --- CTDPAH

WHO FC ⅠⅡ WHO FC ⅢⅣ WHO FC Ⅰ and Ⅱ WHO FC Ⅲ and Ⅳ 1 year99.1%86.3% 2 year97.2%70.7% 3 year94.8%67.3% What we should do in 2010? Earlier detection should be important data of Shanghai Pulmonary hospital

Right heart remodeling and ischemia Right coronary artery flow will be decreased or stopped during the systol- period PA-RV-LV interaction NF. Voelkel, et al. Circulation, 2006; 114: HC. Champion, et al. Circulation, 2009; 120:992.

PAH is all about the RV Time PAP PVR CO Pre-symptomatic/ Compensated Symptomatic/ Decompensating Symptom Threshold RV Failure Declining/ Decompensated

Future: what we should do? To set up the truly therapy goal : pulmonary artery remodeling—occlusion---hemodynamic worse—heart remodeling—heart failure ( not only right heart failure, the wholely cardivascular system collapse ) To reverse the right heart pathological remodeling : stronger combination therapy to 1 ） control the pulmonary arerial spasm and contraction ； 2 ） stop and reverse the pulmonary vascular remodeling; 3 ） resolve the ischemia of myocardium To investigate who is the murderer to initiate the pulmonary arterial disease : not BMPRII mutation, maybe Virus infection on the pulmonary vascular bed?

Acknowledgment , our team only based in Beijing From April 2008, our team actived in Beijing and Shanghai From April 2008, our lab research team was founded in Shanghai