病型別有病率 Echocardiographic survey 10.5% (483 cases) of 4579 patients systolic PAP 40 mmhg Group 1 4.2% Group % Group 3 9.7% Group 4 0.6% Group 5 6

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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

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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

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 病型別有病率



Echocardiographic survey



10.5% (483 cases) of 4579 patients

 systolic PAP ≥40 mmHg

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%) /

 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

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

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 (<500m)



除外診断：その他の PAH の原因の除外

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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

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

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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：↑II

音、S

音/S

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 = 4xTRV

+RA (mmHg)

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

 RV 拡大  PAP 推定

 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

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 WHO-functional class

4. 治療

 General measures

 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

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 (

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