臨床医学群・循環器「肺高血圧症」（2013 年 12 月 2 日）

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肺 高 血 圧 症

附属心臓血管研究施設 分子細胞情報学部門 平野勝也

講義資料ダウンロード → http://www.molcar.med.kyushu-u.ac.jp

1. 肺高血圧の定義

平均肺動脈圧 (mPAP) ≥25 mmHg

（安静時）

心臓カテーテル検査

肺高血圧： ≥25 mmHg

境界： 21 ～ 24 mmHg

正常肺動脈圧：≤ 20 mmHg (14.3 ± 3 mmHg)

運動負荷 mPAP >30 mmHg （古い定義）

Pre-capillary vs. post-capillary PH

PWP (pulmonary wedge pressure)

≤15 mmHg --- Pre-capillary

>15 mmHg --- Post-capillary

2. 臨床分類（2008 年 Dana Point 分類）

臨床医学群・循環器「肺高血圧症」（2013 年 12 月 2 日）

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病型別有病率

Echocardiographic survey

10.5% (483 cases) of 4579 patients

systolic PAP ≥40 mmHg

Group 1 4.2%

Group 2 78.7%

Group 3 9.7%

Group 4 0.6%

Group 5 6.8%

Gabbay, Am J Resp Crit Care Med 2007; 175:A713

Group 1

French National Registry (2006)

Scottish Registry (2007)

有病率 15–50 cases/million

IPAH 5.9 cases/million adult

発症率 2.4 cases/million/year

Am J Respir Crit Care Med 173:1023–1030, 2006

Eur Respir J 30:104–109, 2007

サブ分類 (% of total PAH)

Registry 1 Registry 2

1.1 IPAH 39.3% 46.0%

1.2 HPAH 3.9% 2.7%

1.3 Drug 9.5% 5.4%

1.4 APAH ~50% 51.0%

1 CTD 15.3% 25.4%

2 HIV 6.2% 2.0%

3 Portal 10.4% 5.4%

4 CHD 11.3% 9.9%

1.5 PPHN 0.0%

1’ PVOD - 0.4%

1’ PCH - <0.1%

Registry 1: French National Registry

Am J Respir Crit Care Med 173:1023–1030, 2006

Registry 2: REVEAL study (U.S. Registry)

Chest 137:376–387, 2010

Female:male in IPAH (% of total)

F:M = 936:230 = 4.1 : 1.0 (F: 80.3%) /REVEAL

F:M = 109:66 = 1.7 : 1.0 (F: 62.3%) /Scottish registry

病型別予後

McLaughlin et al., Chest 126:78S–92S, 2004

3. 病理

mPAP = CO x PVR + mPAWP

PVR = TPG/CO = (mPAP-mPAWP)/CO

PAP: pulmonary arterial pressure CO: cardiac output PVR: Pulmonary vascular resistance PAWP: pulmonary artery wedge pressure TPG: Trans-pulmonary pressure gradient

PVR (Pulmonary vascular resistance) の調節

1. 肺血流量による調節

2. 肺気量による調節

3. 血管作動物質による調節（血管収縮・弛緩）

4. 血管リモデリング（病態）

主要病理所見 ↑PVR ↑PAP

Vasoconstriction

Vascular remodeling

Thrombosis

Vasoconstriction

Endothelial dysfunction

Reduced vasodilators (NO, PGI2)

Increased vasoconstrictors (ET1, TXA2)

Increased smooth muscle tone

Increased Ca2+

handling (Impaired Kv1.5)

Increased myofilament Ca2+

sensitivity

Vascular remodeling

Constrictive lesions

Medial hypertrophy

Intimal thickening; cellular/fibrotic

Adventitial thickening

Complex lesions

Plexiform lesions

Dilation lesions Arteritis

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※ 2004 年病理分類 (J. Am. Coll. Cardiol. 43:25S-32S, 2004) 1. Pulmonary arteriopathy (Pre- and intra-acinar arteries)

With isolated medial hypertrophy With medial hypertrophy and intimal thickening

(cellular, fibrotic) Concentric laminar Eccentric, concentric non-laminar

With plexiform and/or dilation lesions or arteritis With isolated arteritis

The presence of the following changes should be noted: Adventitial thickening Thrombotic lesions (fresh, organized, re-canalized,

colander lesion) Necrotizing or lympho-monocytic arteritis Elastic artery changes (fibrotic or atheromatous intimal

plaques, elastic laminae degeneration) Bronchial vessel changes Ferruginous incrustation Calcifications Foreign body emboli Organized infact Perivascular lymphocytic infiltrates

※ Heath-Edwards 分類 (Circulation 18:533-547, 1958)

Grade 1 2 3 4 5 6

内膜

反応

none

Cellular

Fibrous/fibroelastic

Plexiform

中膜

病変

Hypertrophy

Some generalized dilatation

Local dilation lesions

Pulmonary hemosiderosis

Necrotizing arteritis

肺動脈血管床減少の程度と肺動脈圧の関連

肺血管抵抗上昇における血管収縮と血管リモデリングの

相対的関与

Goupr 1: PAH

Pre-capillary --- distal pulmonary artery (<500m)

除外診断：その他の PAH の原因の除外

機序 (Frumkin. Pharmacol Rev 64:583–620, 2012)

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BMPR2 and ALK1/Endoglin

Endothelial cells: Anti-apoptosis

Smooth muscle cells: Anti-proliferation

Drugs and toxins-induced PAH

Group 2: PH due to left heart disease

Post-capillary --- increase in PAWP

（左房圧上昇の伝搬による PAP 上昇）

Passive vs. Reactive

Passive mPAP ≥25mmHg

PAWP ≥15mmHg

TPG ≤12mmHg

肺血管抵抗正常

Reactive

(out of proportion)

TPG >12mmHg

肺血管抵抗上昇

TPG (transpulmonary pressure gradient)

= mPAP – mPWP

PVR (Pulmonary vascular resistance)

= TPG/CO

Guazzi, Borlaug. Circulation 126:975-990, 2012

Group 3: PH due to lung disease and/or hypoxia

Pre-capillary (distal pulmonary artery)

機序

Hypoxic pulmonary vasoconstriction

Mechanical stress by hyperinflated lung

Destruction of vascular beds

Inflammation

Toxic effect of smoking

Chaouat et al., Eur Respir J 32:1371–1385, 2008

Hypoxic pulmonary vasoconstriction

Sylvester et al., Physiol Rev 92: 367–520, 2012

Group 4: CTEPH

Pre-capillary

Proximal (～区域動脈, elastic artery)

Distal (亜区域動脈～)

器質化血栓

Pulmonary arteriopathy

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機序 遺伝的素因 (-)

急性肺動脈血栓塞栓の既往

血栓治癒線維化, 中膜付着, 内腔狭窄

症例の 0.5-2%が CTEPH 発症

CTEPH の 50%に既往なし

凝固系・血小板・内皮機能異常

向血栓性因子

Lupus anti-coagulant

Anti-phospholipid antibody

Distal lesions --- Pulmonary arteriopathy similar to

PAH

4. 診断

症状・所見

症状 所見

労作時息切れ

易疲労感／虚脱感

失神

胸痛

腹部膨満

Left sternal lift

心音：↑IIP音、SIII音/SIV音、

汎収縮期雑音

頸静脈怒張

肝腫大

腹水

下腿浮腫

心電図

右室肥大

右房拡大

胸部 X 線写真

肺動脈拡張

右房・右室拡大

心臓超音波検査

Systolic PAP 推定

Systolic PAP = Systolic RVP = 4xTRV2+RA (mmHg)

Rudski et al., J Am Soc Echocardiogr 23:685-713, 2010

RV 拡大 PAP 推定

楕円 半円 三日月

核医学検査

肺換気シンチグラフィ― (左図)

肺血流シンチグラフィ― (右図)

6 分間歩行テスト

6MWD > 400 m --- low risk

< 300 m --- high risk

右心カテーテル検査

Hemodynamics

mPAP, PAWP, PTG, CO

血管反応性検査（Vaso-reactivity test）

Acute vasodilator challenge

血管造影

CTEPH の確定診断、手術適応性の検討

診断フローチャート

臨床医学群・循環器「肺高血圧症」（2013 年 12 月 2 日）

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WHO-functional class

4. 治療

General measures 運動療法・リハビリテーション 受胎調節・避妊 旅行 精神的支援 感染予防 待機的手術

Supportive therapy Oral anti-coagulation therapy（抗凝固療法） Diuretics（利尿剤） Oxygen therapy（酸素療法） Digoxin（強心剤）

Specific drug therapy

Approved drug

PGI2 pathway: Epoprostenol, Treprostinil, Iloprost, Beraprost

NO pathway: Sildenafil, Tadalafil, NO

ET-1 pathway: Bosentan, Ambrisentan

Ca2+

channel blockers

Drugs in late-development stage

PGI2, NO, ET-1 pathways New pathways:

Tyrosine kinase inhibitor 5HTT inhibitor 5HT antagonist

Drugs in the preclinical stage

Rho kinase VIP Statins

Interventional/surgical therapy

Targeting RVF Atrial septostomy Transplantation

Lung (single, bilateral) Heart-lung

Specific treatment for CTEPH

Pulmonary endarterectomy (PEA) --- proximal Balloon pulmonary angioplasty (BPA) --- distal

PEA

参考文献 1. The Task Force for the Diagnosis and Treatment of Pulmonary

Hypertension of the European Society of Cardiology (ESC) and the European Respiratory Society (ERS), endorsed by the International Society of Heart and Lung Transplantation (ISHLT). Guidelines for the diagnosis and treatment of pulmonary hypertension. Eur Heart J 30: 2493–2537, 2009（現在の肺高血圧診療指針）

2. Gabbay et al., Pulmonary arterial hypertension (PAH) is an uncommon cause of pulmonary Hhypertension (PH) in an unselected population: the Armadale echocardiography study. Am J Resp Crit Care Med 175:A713, 2007.

3. Humbert et al., Pulmonary arterial hypertension in France: results from a national registry. Am J Respir Crit Care Med 173:1023–1030, 2006

4. Badesch et al., Pulmonary arterial hypertension: baseline characteristics from the REVEAL Registry. Chest 137:376–387, 2010

5. McLaughlin et al., Prognosis of pulmonary arterial hypertension: ACCP evidence-based clinical practice guidelines. Chest 126:78S–92S, 2004

6. Pietra et al., Pathologic assessment of vasculopathies in pulmonary hypertension. J. Am. Coll. Cardiol. 43:25S-32S, 2004

7. Heath, Edwards. The pathology of hypertensive pulmonary vascular disease; a description of six grades of structural changes in the pulmonary arteries with special reference to congenital cardiac septal defects. Circulation 18:533-547, 1958

8. Frumkin. The pharmacological treatment of pulmonary arterial hypertension. Pharmacol Rev 64:583–620, 2012

9. Guazzi, Borlaug. Pulmonary hypertension due to left heart disease. Circulation 126:975-990, 2012

10. Chaouat et al., Pulmonary hypertension in COPD Eur Respir J 32:1371–1385, 2008

11. Sylvester et al., Hypoxic pulmonary vasoconstriction. Physiol Rev 92: 367–520, 2012

12. Rudski et al., Guidelines for the Echocardiographic Assessment of the Right Heart in Adults: A Report from the American Society of Echocardiography. J Am Soc Echocardiogr 23:685-713, 2010

History of specific drug treatment (Frumkin. Pharmacol Rev 64:583–620, 2012-一部改訂)

Development situation

in USA, Europe