Chronic Thromboembolic Pulmonary Hypertension

ABSTRACT

The last 4 decades have witnessed dramatic changes in the treatment of patients with pulmonary hypertension. And with the advances in cardiothoracic surgical techniques, selected patients with chronic thromboembolic pulmonary hypertension (CTEPH) are afforded a surgical remedy for their disease. In the vast majority of these patients, surgical endarterectomy of chronic thromboemboli from the pulmonary vascular bed effectively treats even severe pulmonary hypertension, and as a result, the debilitating symptoms of right heart dysfunction. This article reviews the natural history of chronic thromboembolic disease and outline a suggested diagnostic approach to determine whether a patient with chronic thromboembolic disease might be an appropriate surgical candidate. Pulmonary thromboendarterectomy surgery, and the growing information on the use of pharmacotherapy in inoperable CTEPH, are also reviewed.

KEYWORDS

Pulmonary hypertension - chronic thromboemboli - pulmonary thromboendarterectomy - pulmonary vasodilator therapy

REFERENCES

• 1 Nijkeuter M, Hovens MMC, Davidson B L, Huisman M V. Resolution of thromboemboli in patients with acute pulmonary embolism: a systematic review.  Chest. 2006;  129 192-197
• 2 Miniati M, Monti S, Bottai M et al.. Survival and restoration of pulmonary perfusion in a long-term follow-up of patients after acute pulmonary embolism.  Medicine (Baltimore). 2006;  85 253-262
• 3 Rosenhek R, Korschineck I, Gharehbaghi-Schnell E et al.. Fibrinolytic balance of the arterial wall: pulmonary artery displays increased fibrinolytic potential compared with aorta.  Lab Invest. 2003;  83 871-876
• 4 Lang I M, Marsh J J, Olman M A, Moser K M, Schleef R R. Parallel analysis of tissue-type plasminogen activator and type 1 plasminogen activator inhibitor in plasma and endothelial cells derived from patients with chronic pulmonary thromboemboli.  Circulation. 1994;  90 706-712
• 5 Morris T A, Marsh J J, Chiles P G et al.. Abnormally sialylated fibrinogen gamma-chains in a patient with chronic thromboembolic pulmonary hypertension.  Thromb Res. 2007;  119 257-259
• 6 Morris T A, Marsh J J, Chiles P G, Auger W R, Fedullo P F, Woods Jr V L. Fibrin derived from patients with chronic thromboembolic pulmonary hypertension is resistant to lysis.  Am J Respir Crit Care Med. 2006;  173 1270-1275
• 7 Wolf M, Boyer-Neumann C, Parent F et al.. Thrombotic risk factors in pulmonary hypertension.  Eur Respir J. 2000;  15 395-399
• 8 Bonderman D, Turecek P L, Jakowitsch J et al.. High prevalence of elevated clotting factor VIII in chronic thromboembolic pulmonary hypertension.  Thromb Haemost. 2003;  90 372-376
• 9 Pengo V, Lensing AWA, Prins M H Thromboembolic Pulmonary Hypertension Study Group et al. Incidence of chronic thromboembolic pulmonary hypertension after pulmonary embolism.  N Engl J Med. 2004;  350 2257-2264
• 10 Liu P, Meneveau N, Schiele F, Bassan J P. Predictors of long-term clinical outcome of patients with acute massive pulmonary embolism after thrombolytic therapy.  Chin Med J (Engl). 2003;  116 503-509
• 11 Ribeiro A, Lindmarker P, Johnsson H, Juhlin-Dannfelt A, Jorfeldt L. Pulmonary embolism: one-year follow-up with echocardiography Doppler and five-year survival analysis.  Circulation. 1999;  99 1325-1330
• 12 Moser K M, Bloor C M. Pulmonary vascular lesions occurring in patients with chronic major vessel thromboembolic pulmonary hypertension.  Chest. 1993;  103 685-692
• 13 Ryan K L, Fedullo P F, Davis G B, Vasquez T E, Moser K M. Perfusion scan findings understate the severity of angiographic and hemodynamic compromise in chronic thromboembolic pulmonary hypertension.  Chest. 1988;  93 1180-1185
• 14 Azarian R, Wartski M, Collignon M A et al.. Lung perfusion scans and hemodynamics in acute and chronic pulmonary embolism.  J Nucl Med. 1997;  38 980-983
• 15 Suntharalingam J, Treacy C M, Doughty N J et al.. Long-term use of sildenafil in inoperable chronic thromboembolic pulmonary hypertension.  Chest. 2008;  134 229-236
• 16 Ulrich S, Speich R, Domenighetti G et al.. Bosentan therapy for chronic thromboembolic pulmonary hypertension: a national open label study assessing the effect of bosentan on haemodynamics, exercise capacity, quality of life, safety and tolerability in patients with chronic thromboembolic pulmonary hypertension (BOCTEPH-Study).  Swiss Med Wkly. 2007;  137 573-580
• 17 Du L, Sullivan C C, Chu D et al.. Signaling molecules in nonfamilial pulmonary hypertension.  N Engl J Med. 2003;  348 500-509
• 18 Kim H, Yung G L, Marsh J J et al.. Endothelin mediates pulmonary vascular remodelling in a canine model of chronic embolic pulmonary hypertension.  Eur Respir J. 2000;  15 640-648
• 19 Bauer M, Wilkens H, Langer F, Schneider S O, Lausberg H, Schäfers H J. Selective upregulation of endothelin B receptor gene expression in severe pulmonary hypertension.  Circulation. 2002;  105 1034-1036
• 20 Thistlethwaite P A, Lee S H, Du L L et al.. Human angiopoietin gene expression is a marker for severity of pulmonary hypertension in patients undergoing pulmonary thromboendarterectomy.  J Thorac Cardiovasc Surg. 2001;  122 65-73
• 21 Fedullo P F, Auger W R, Kerr K M, Kim N H. Chronic thromboembolic pulmonary hypertension.  Semin Respir Crit Care Med. 2003;  24 273-286
• 22 Becattini C, Agnelli G, Pesavento R et al.. Incidence of chronic thromboembolic pulmonary hypertension after a first episode of pulmonary embolism.  Chest. 2006;  130 172-175
• 23 Silverstein M D, Heit J A, Mohr D N, Petterson T M, O'Fallon W M, Melton III L J. Trends in the incidence of deep vein thrombosis and pulmonary embolism: a 25-year population-based study.  Arch Intern Med. 1998;  158 585-593
• 24 Riedel M, Stanek V, Widimsky J, Prerovsky I. Long-term follow-up of patients with pulmonary thromboembolism: late prognosis and evolution of hemodynamic and respiratory data.  Chest. 1982;  81 151-158
• 25 Lewczuk J, Piszko P, Jagas J et al.. Prognostic factors in medically treated patients with chronic pulmonary embolism.  Chest. 2001;  119 818-823
• 26 Auger W R, Moser K M. Pulmonary flow murmurs: a distinctive physical sign found in chronic pulmonary thromboembolic disease [abstract].  Clin Res. 1989;  37 145A
• 27 Simonneau G, Azarian R, Brenot F, Dartevelle P G, Musset D, Duroux P. Surgical management of unresolved pulmonary embolism: a personal series of 72 patients.  Chest. 1995;  107(1, Suppl) 52S-55S
• 28 Fedullo P F, Auger W R, Kerr K M, Rubin L J. Chronic thromboembolic pulmonary hypertension.  N Engl J Med. 2001;  345 1465-1472
• 29 Bonderman D, Jakowitsch J, Adlbrecht C et al.. Medical conditions increasing the risk of chronic thromboembolic pulmonary hypertension.  Thromb Haemost. 2005;  93 512-516
• 30 Dittrich H C, McCann H A, Blanchard D G. Cardiac structure and function in chronic thromboembolic pulmonary hypertension.  Am J Card Imaging. 1994;  8 18-27
• 31 Mahmud E, Raisinghani A, Hassankhani A et al.. Correlation of left ventricular diastolic filling characteristics with right ventricular overload and pulmonary artery pressure in chronic thromboembolic pulmonary hypertension.  J Am Coll Cardiol. 2002;  40 318-324
• 32 Lisbona R, Kreisman H, Novales-Diaz J, Derbekyan V. Perfusion lung scanning: differentiation of primary from thromboembolic pulmonary hypertension.  AJR Am J Roentgenol. 1985;  144 27-30
• 33 Bailey C L, Channick R N, Auger W R et al.. “High probability” perfusion lung scans in pulmonary venoocclusive disease.  Am J Respir Crit Care Med. 2000;  162 1974-1978
• 34 King M A, Bergin C J, Yeung D W et al.. Chronic pulmonary thromboembolism: detection of regional hypoperfusion with CT.  Radiology. 1994;  191 359-363
• 35 Schwickert H C, Schweden F, Schild H H et al.. Pulmonary arteries and lung parenchyma in chronic pulmonary embolism: preoperative and postoperative CT findings.  Radiology. 1994;  191 351-357
• 36 Tunariu N, Gibbs SJR, Win Z et al.. Ventilation-perfusion scintigraphy is more sensitive than multidetector CTPA in detecting chronic thromboembolic pulmonary disease as a treatable cause of pulmonary hypertension.  J Nucl Med. 2007;  48 680-684
• 37 Moser K M, Fedullo P F, Finkbeiner W E, Golden J. Do patients with primary pulmonary hypertension develop extensive central thrombi?.  Circulation. 1995;  91 741-745
• 38 Silversides C K, Granton J T, Konen E, Hart M A, Webb G D, Therrien J. Pulmonary thrombosis in adults with Eisenmenger syndrome.  J Am Coll Cardiol. 2003;  42 1982-1987
• 39 Russo A, De Luca M, Vigna C et al.. Central pulmonary artery lesions in chronic obstructive pulmonary disease: a transesophageal echocardiography study.  Circulation. 1999;  100 1808-1815
• 40 Heinrich M, Uder M, Tscholl D, Grgic A, Kramann B, Schäfers H J. CT scan findings in chronic thromboembolic pulmonary hypertension: predictors of hemodynamic improvement after pulmonary thromboendarterectomy.  Chest. 2005;  127 1606-1613
• 41 Pitton M B, Kemmerich G, Herber S et al.. Chronic thromboembolic pulmonary hypertension: diagnostic impact of multislice CT and selective pulmonary DSA.  Rofo. 2002;  174 474-479
• 42 Reichelt A, Hoeper M M, Galanski M, Keberle M. Chronic thromboembolic pulmonary hypertension: evaluation with 64-detector row CT versus digital subtraction angiography.  Eur J Radiol. 2008;  , In press
• 43 Suntharalingam J, Hughes R J, Goldsmith K et al.. Acute haemodynamic responses to inhaled nitric oxide and intravenous sildenafil in distal chronic thromboembolic pulmonary hypertension (CTEPH).  Vascul Pharmacol. 2007;  46 449-455
• 44 Auger W R, Fedullo P F, Moser K M, Buchbinder M, Peterson K L. Chronic major-vessel chronic thromboembolic pulmonary artery obstruction: appearance at angiography.  Radiology. 1992;  182 393-398
• 45 Pitton M B, Düber C, Mayer E, Thelen M. Hemodynamic effects of nonionic contrast bolus injection and oxygen inhalation during pulmonary angiography in patients with chronic major-vessel thromboembolic pulmonary hypertension.  Circulation. 1996;  94 2485-2491
• 46 Kreitner K-F, Kunz R P, Ley S et al.. Chronic thromboembolic pulmonary hypertension: assessment by magnetic resonance imaging.  Eur Radiol. 2007;  17 11-21
• 47 Nikolaou K, Schoenberg S O, Attenberger U et al.. Pulmonary arterial hypertension: diagnosis with fast perfusion MR imaging and high-spatial-resolution MR angiography—preliminary experience.  Radiology. 2005;  236 694-703
• 48 Yi C A, Lee K S, Choe Y H, Han D, Kwon O J, Kim S. Computed tomography in pulmonary artery sarcoma: distinguishing features from pulmonary embolic disease.  J Comput Assist Tomogr. 2004;  28 34-39
• 49 Kacl G M, Bruder E, Pfammatter T, Follath F, Salomon F, Debatin J F. Primary angiosarcoma of the pulmonary arteries: dynamic contrast-enhanced MRI.  J Comput Assist Tomogr. 1998;  22 687-691
• 50 Kerr K M, Auger W R, Fedullo P F, Channick R H, Yi E S, Moser K M. Large vessel pulmonary arteritis mimicking chronic thromboembolic disease.  Am J Respir Crit Care Med. 1995;  152 367-373
• 51 Packer D L, Keelan P, Munger T M et al.. Clinical presentation, investigation, and management of pulmonary vein stenosis complicating ablation for atrial fibrillation.  Circulation. 2005;  111 546-554
• 52 Berry D F, Buccigrossi D, Peabody J, Peterson K L, Moser K M. Pulmonary vascular occlusion and fibrosing mediastinitis.  Chest. 1986;  89 296-301
• 53 Thistlethwaite P A, Auger W R, Madani M M, Pradhan S, Kapelanski D P, Jamieson S W. Pulmonary thromboendarterectomy combined with other cardiac operations: indications, surgical approach, and outcome.  Ann Thorac Surg. 2001;  72 13-17 discussion 17-19
• 54 Dartevelle P, Fadel E, Mussot S et al.. Chronic thromboembolic pulmonary hypertension.  Eur Respir J. 2004;  23 637-648
• 55 Thistlethwaite P A, Kemp A, Du L, Madani M M, Jamieson S W. Outcomes of pulmonary endarterectomy for treatment of extreme thromboembolic pulmonary hypertension.  J Thorac Cardiovasc Surg. 2006;  131 307-313
• 56 Jamieson S W, Kapelanski D P, Sakakibara N et al.. Pulmonary endarterectomy: experience and lessons learned in 1,500 cases.  Ann Thorac Surg. 2003;  76 1457-1462 discussion 1462-1464
• 57 Kim N H, Fesler P, Channick R N et al.. Preoperative partitioning of pulmonary vascular resistance correlates with early outcome after thromboendarterectomy for chronic thromboembolic pulmonary hypertension.  Circulation. 2004;  109 18-22
• 58 Masuda M, Nakajima N. Our experience of surgical treatment for chronic pulmonary thromboembolism.  Ann Thorac Cardiovasc Surg. 2001;  7 261-265
• 59 Mayer E, Kramm T, Dahm M et al.. Early results of pulmonary thromboendarterectomy in chronic thromboembolic pulmonary hypertension [in German].  Z Kardiol. 1997;  86 920-927
• 60 Gilbert T B, Gaine S P, Rubin L J, Sequeira A J. Short-term outcome and predictors of adverse events following pulmonary thromboendarterectomy.  World J Surg. 1998;  22 1029-1032, discussion 1033
• 61 Dartevelle P, Fadel E, Chapelier A et al.. Angioscopic video-assisted pulmonary endarterectomy for post-embolic pulmonary hypertension.  Eur J Cardiothorac Surg. 1999;  16 38-43
• 62 Ando M, Okita Y, Tagusari O, Kitamura S, Nakanishi N, Kyotani S. Surgical treatment for chronic thromboembolic pulmonary hypertension under profound hypothermia and circulatory arrest in 24 patients.  J Card Surg. 1999;  14 377-385
• 63 Rubens F D, Bourke M, Hynes M et al.. Surgery for chronic thromboembolic pulmonary hypertension—inclusive experience from a national referral center.  Ann Thorac Surg. 2007;  83 1075-1081
• 64 Mares P, Gilbert T B, Tschernko E M et al.. Pulmonary artery thromboendarterectomy: a comparison of two different postoperative treatment strategies.  Anesth Analg. 2000;  90 267-273
• 65 D'Armini A M, Cattadori B, Monterosso C et al.. Pulmonary thromboendarterectomy in patients with chronic thromboembolic pulmonary hypertension: hemodynamic characteristics and changes.  Eur J Cardiothorac Surg. 2000;  18 696-701 discussion 701-702
• 66 Tscholl D, Langer F, Wendler O, Wilkens H, Georg T, Schäfers H J. Pulmonary thromboendarterectomy—risk factors for early survival and hemodynamic improvement.  Eur J Cardiothorac Surg. 2001;  19 771-776
• 67 Masuda M, Nakajima N. Our experience of surgical treatment for chronic pulmonary thromboembolism.  Ann Thorac Cardiovasc Surg. 2001;  7 261-265
• 68 Piovella F, D'Armini A M, Barone M, Tapson V F. Chronic thromboembolic pulmonary hypertension.  Semin Thromb Hemost. 2006;  32 848-855
• 69 Mellemkjaer S, Ilkjaer L B, Klaaborg K E et al.. Pulmonary endarterectomy for chronic thromboembolic pulmonary hypertension: ten years experience in Denmark.  Scand Cardiovasc J. 2006;  40 49-53
• 70 Madani M M, Jamieson S W. Technical advances of pulmonary endarterectomy for chronic thromboembolic pulmonary hypertension.  Seminar Thorac Cardiovasc Surg. 2006;  18 243-249
• 71 Mayer E, Klepetko W. Techniques and outcomes of pulmonary endarterectomy for chronic thromboembolic pulmonary hypertension.  Proc Am Thorac Soc. 2006;  3 589-593
• 72 Zund G, Prêtre R, Niederhäuser U, Vogt P R, Turina M I. Improved exposure of the pulmonary arteries for thromboendarterectomy.  Ann Thorac Surg. 1998;  66 1821-1823
• 73 Hagl C, Khaladj N, Peters T et al.. Technical advances of pulmonary thromboendarterectomy for chronic thromboembolic pulmonary hypertension.  Eur J Cardiothorac Surg. 2003;  23 776-781, discussion 781
• 74 Thomson B, Tsui SSL, Dunning J et al.. Pulmonary endarterectomy is possible and effective without the use of complete circulatory arrest—the UK experience in over 150 patients.  Eur J Cardiothorac Surg. 2008;  33 157-163
• 75 Mikus P M, Mikus E, Martìn-Suàrez S et al.. Pulmonary endarterectomy: an alternative to circulatory arrest and deep hypothermia: mid-term results.  Eur J Cardiothorac Surg. 2008;  34 159-163
• 76 Sabiston Jr D C, Wolfe W G, Oldham Jr H N et al.. Surgical management of chronic pulmonary embolism.  Ann Surg. 1977;  185 699-712
• 77 Cabrol C, Cabrol A, Acar J et al.. Surgical correction of chronic postembolic obstructions of the pulmonary arteries.  J Thorac Cardiovasc Surg. 1978;  76 620-628
• 78 Daily P O, Johnston G G, Simmons C J, Moser K M. Surgical management of chronic pulmonary embolism: surgical treatment and late results.  J Thorac Cardiovasc Surg. 1980;  79 523-531
• 79 Menzel T, Wagner S, Mohr-Kahaly S et al.. [Reversibility of changes in left and right ventricular geometry and hemodynamics in pulmonary hypertension: echocardiographic characteristics before and after pulmonary thromboendarterectomy].  Z Kardiol. 1997;  86(11) 928-935
• 80 Blanchard D G, Malouf P J, Gurudevan S V et al.. Utility of right ventricular Tei index in the noninvasive evaluation of chronic thromboembolic pulmonary hypertension before and after pulmonary thromboendarterectomy.  JACC Cardiovasc Imaging. 2009;  2 143-149
• 81 Mayer E, Dahm M, Hake U et al.. Mid-term results of pulmonary thromboendarterectomy for chronic thromboembolic pulmonary hypertension.  Ann Thorac Surg. 1996;  61 1788-1792
• 82 Corsico A G, D'Armini A M, Cerveri I et al.. Long-term outcome after pulmonary endarterectomy.  Am J Respir Crit Care Med. 2008;  178 419-424
• 83 Archibald C J, Auger W R, Fedullo P F et al.. Long-term outcome after pulmonary thromboendarterectomy.  Am J Respir Crit Care Med. 1999;  160 523-528
• 84 Zoia M C, D'Armini A M, Beccaria M Pavia Thromboendarterectomy Group et al. Mid term effects of pulmonary thromboendarterectomy on clinical and cardiopulmonary function status.  Thorax. 2002;  57 608-612
• 85 Tanabe N, Okada O, Nakagawa Y et al.. The efficacy of pulmonary thromboendarterectomy on long-term gas exchange.  Eur Respir J. 1997;  10 2066-2072
• 86 Auger W R, Kim N H, Kerr K M, Test V J, Fedullo P F. Chronic thromboembolic pulmonary hypertension.  Clin Chest Med. 2007;  28 255-269, x
• 87 Hartz R S, Byrne J G, Levitsky S, Park J, Rich S. Predictors of mortality in pulmonary thromboendarterectomy.  Ann Thorac Surg. 1996;  62 1255-1259 discussion 1259-1260
• 88 Manecke Jr G R, Kotzur A, Atkins G et al.. Massive pulmonary hemorrhage after pulmonary thromboendarterectomy.  Anesth Analg. 2004;  99 672-675
• 89 Levinson R M, Shure D, Moser K M. Reperfusion pulmonary edema after pulmonary artery thromboendarterectomy.  Am Rev Respir Dis. 1986;  134 1241-1245
• 90 Miller Jr W T, Osiason A W, Langlotz C P, Palevsky H I. Reperfusion edema after thromboendarterectomy: radiographic patterns of disease.  J Thorac Imaging. 1998;  13 178-183
• 91 Mo M, Kapelanski D P, Mitruka S N et al.. Reoperative pulmonary thromboendarterectomy.  Ann Thorac Surg. 1999;  68 1770-1776 discussion 1776-1777
• 92 Bresser P, Pepke-Zaba J, Jaïs X, Humbert M, Hoeper M M. Medical therapies for chronic thromboembolic pulmonary hypertension: an evolving treatment paradigm.  Proc Am Thorac Soc. 2006;  3 594-600
• 93 Jensen K W, Kerr K M, Fedullo P F et al.. Prevalence of medical therapy for pulmonary arterial hypertension (PAH) in chronic thromboembolic pulmonary hypertension (CTEPH) prior to referral for pulmonary thromboendarterectomy (PTE) [abstract].  Am J Respir Crit Care Med. 2008;  177 A181
• 94 Reichenberger F, Voswinckel R, Enke B et al.. Long-term treatment with sildenafil in chronic thromboembolic pulmonary hypertension.  Eur Respir J. 2007;  30 922-927
• 95 Hughes R J, Jais X, Bonderman D et al.. Bosentan in inoperable chronic thromboembolic pulmonary hypertension: a 1-year follow-up study.  Eur Respir J. 2006;  28 138-143
• 96 Jaïs X, D'Armini A M, Jansa P Bosentan Effects in iNopErable Forms of chronIc Thromboembolic pulmonary hypertension Study Group et al. Bosentan for treatment of inoperable chronic thromboembolic pulmonary hypertension: BENEFiT (bosentan effects in inoperable forms of chronic thromboembolic pulmonary hypertension), a randomized, placebo-controlled trial.  J Am Coll Cardiol. 2008;  52 2127-2134
• 97 Cabrol S, Souza R, Jais X et al.. Intravenous epoprostenol in inoperable chronic thromboembolic pulmonary hypertension.  J Heart Lung Transplant. 2007;  26 357-362
• 98 Skoro-Sajer N, Bonderman D, Wiesbauer F et al.. Treprostinil for severe inoperable chronic thromboembolic pulmonary hypertension.  J Thromb Haemost. 2007;  5 483-489
• 99 Nagaya N, Sasaki N, Ando M et al.. Prostacyclin therapy before pulmonary thromboendarterectomy in patients with chronic thromboembolic pulmonary hypertension.  Chest. 2003;  123 338-343
• 100 Bresser P, Fedullo P F, Auger W R et al.. Continuous intravenous epoprostenol for chronic thromboembolic pulmonary hypertension.  Eur Respir J. 2004;  23 595-600