1. 肺高血圧の定義 2. 臨床分類(2008 年Dana Point …...
Transcript of 1. 肺高血圧の定義 2. 臨床分類(2008 年Dana Point …...
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)
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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
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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