REVIEW ARTICLE

Cronic tromboemboic pulmonary hypertension

H.J. Reesink, J.J. Kloek, P. Bresser

Chronic thromboembolic pulmonary hypertension (CTEPH) is a rapidly progressive and deadly disease, resulting from incomplete resolution of acute pulmonary embolism. Historically, the incidence of CTEPH was significantly underestimated but it may be as high as 3.8% following acute pulmonary embolism. Although the medical management of CTEPH may be supportive, the only curative treatment is pulmonary endarterectomy (PEA). However, a careful screening programme is mandatory to select CTEPH patients who are likely to benefit from PEA. In this review we discuss the pathophysiology, clinical and diagnostic pitfills, surgical treatment, outcome after surgery, and the potential benefit of medical treatment in inoperable CTEPH patients. (Neth HeartJ2006;14:219-24.)

Keywords: chronic thromboembolic pulmonary hypertension, diagnosis, pathophysiology, pulmonary endarterectomy, treatment

Chronic thromboembolic pulmonary hypertension 0(CTEPH) results from incomplete resolution of pulmonary embolism (PE).' CTEPH is a life-threatening, but potentially correctable cause of pulmonary hypertension which has been neglected in the past.2 CTEPH was considered to develop in less than 0.5% HJ. Rees P. B_ssr

Departnent of Pulmonology, Academic Medical Centre, University ofAmsterdam, Amsterdam, the Netherlands JJ. Kiosk Cardiothoracic Surgery, Academic Medical Centre, University of Amsterdam, Amsterdam, the Netherlands

Correspondence to: P. Bresser Department of Pulmonology, F5444, Academic Medical Centre, University of Amsterdam, PO Box 22700, 1100 DE Amsterdam, the Netherlands E-mail: [email protected]

'C

Nahedands Heart JournA Volume 14, Number 6, June 2006

of all patients who survived an acute pulmonary embolism.1 Recently, however, Pengo et al. conducted a prospective, long-term, follow-up study to assess the incidence of symptomatic CTEPH in consecutive patients after an acute first episode of PE. The cumulative incidence was 3.8% after two years of follow-up.3 In view of the fact that in most patients presenting with CTEPH the initial thromboembolic event is asymptomatic,' the true incidence of CTEPH may be even higher. The incidence of acute PE is approximately 1:1000,4 and in the Netherlands, it is diagnosed in about 16,000 patients a year. Although the incidence of CTEPH in the Netherlands is as yet unknown, taken together, these data indicate that annually up to 600 patients may be at risk of developing CTEPH. If left untreated, the prognosis in patients with CTEPH is poor. Survival is proportional to the degree of pulmonary hypertension. Riedel and co-workers reported that in CTEPH patients with a mean pulmonary artery pressure (mPAP) >30 mmHg at the time ofdiagnosis, five-year survival was 30%, whereas in patients with an mPAP >50 mmHg the five-year survival was only 10%.5 This observation was confirmed more recently by others.6 Pulmonary endarterectomy (PEA) represents the therapy ofchoice for patients with CTEPH.' After surgery, most patients experience a substantial haemodynamic improvement, which is associated with improvements in functional status and long-term survival.' 7-9 PEA, however, does not come without potential risk' and careful selection ofCTEPH patients in specialised centres is, therefore, warranted.

Pathophyslology Although the pulmonary hypertension is a consequence ofthe anatomic loss ofpulmonary vascular bed due to chronic thromboembolic obstruction, the pathophysiology of CTEPH appears far more complex. Pneumonectomy, for instance, is associated with little, if any increase in pulmonary artery pressure, even with follow-up to 11 years.'0 Experimental studies have even indicated that up to a 75% reduction in lung volumes does not cause pulmonary hypertension." 219

Chronic thromboembolic pulmonary hypertension

Nevertheless significant pulmonary hypertension at rest can be observed in CTEPH patients with relatively minor (50 years, a coronary angiography and left heart catheterisation provide additional preoperative information in those at risk for coronary artery or valvular disease.36 Surgical treatment Pulmonary endarterectomy (PEA), first reported in 1958 by Hurwitt and co-workers,4' represents the therapy of choice for patients with CTEPH.1212,42 However, only some ofthe patients with CTEPH filfil the criteria for surgical intervention. The decision to perform pulmonary endarterectomy is based on several objective and subjective factors which are carefully defined during the preoperative evaluation." 2"12 42 The pulmonary vascular obstruction results in haemodynamic and ventilatory impairment at rest or during exercise.' In general, patients undergoing PEA exhibit a preoperative pulmonary vascular resistance (PVR) of

Figure 2. (A) Right and leftpul-

mowary angiogram from th patient in figure 1, demonstrating absent igh and lft middle and Ilwer lobe flow as a result of organised iobeblcmaterial

as pochbes (avws). m_anijistngand

(B) Right kft pulmonaty anIgiogram (oblique position)

J+wmanotbrpatien

........

emostrt-

~ingapouechin txihetloft wer lobe*

subewgmental webs in the *bt middle and lftupper lobes anda band in de keftlower lobe (arrows).

#c

Netherlands Heart Journal, Volume 14, Number 6, June 2006

221

Chronic thromboembolic pulmonary hypertension

Figure 3. (A) Pulmonatyendartrectomy (PEA) specimenfrom the patient demonstrated infigures I and 2A. (B) PEA specimenfrom the patient demonstrated in figure 2B. Note the organised thrombotic material involving multiple branches beyond the proimal area of obstruction. Careful removal of distal obstuction is crucialfor an optimal haemodynamic outcome. more than 300 dynes.s.cm-5, typically in the range of 800 to 1200 dynes.s.cm-5.-6 Operability depends on localisation of the chronic emboli. Proximal disease is confined to the main and lobar arteries. Chronic thromboembolic occlusions of segmental or even subsegmental arteries are more difficult to treat surgically, but may be operable in highly experienced centres." 2,12,42 The PEA procedure is performed via median sternotomy. The right pulmonary artery is incited where it passes the aorta to the division of the lower lobe arteries. On the left, the incision extends from the main pulmonary artery to the origin ofthe left upperlobe branch."'2 PEA is a true endarterectomy, and differs substantially from (acute) pulmonary embolectomy. The organised thromboembolic material is fibrotic and adherent to the vessel wall (figures 3A and 3B). An endarterectomy plane is established between the intima and the fibrotic thromboembolic material. Subsequently, the obstructing material is grasped with a forceps and distally circumferential dissection is performed with an aspirating dissector.

Outcome after pulmonary endarterectomy Since the preoperative work-up and the postoperative management are highly complex, a multidisciplinary approach with participation of pulmonary medicine, cardiothoracic surgery, cardiology, radiology, anaesthesiology and critical care is an absolute prerequisite to perform PEA with an acceptable mortality risk.' Operative mortality figures have ranged from 4 to 25%.1 Perioperative mortality risk is markedly increased in patients with preoperative signs of right heart failure,'8 and is associated with the haemodynamic severity ofthe disease. In patients with a preoperative PVR >1000 dynes.s.cm5, the most experienced centre in the world, the University of California San Diego (UCSD), reported a mortality rate of -10%. In contrast, mortality rate was only 1.3% in patients with a preoperative PVR 1100 dynes.s.cm-5 compared with patients with a PVR50 mmHg. Dartevelle and co-workers draw similar conclusions from their experience in 275 cases. Overall postoperative mortality was 11%; however, in CTEPH patients with a PVR >1200 dynes.s.cm-5 mortality was 20%.2 The major causes of death are attributable to reperfusion lung injury and, in particular, persistent pulmonary hypertension associated with right ventricular failure.1242 In our centre, between 2002 and 2006, PEA was performed in 68 CTEPH patients with a perioperative mortality of 8.8% (6/68). Pulmonary endarterectomy is curative in many patients and, with few exceptions,44 may be regarded as permanent.42 Successful PEA is associated with dramatic improvements in exercise tolerance and life expectancy.745 Postoperatively, most patients can be classified as New York Heart Association functional class I or II.7,45 Six years' survival after PEA is 75%.7 After PEA, pulmonary artery pressures will (near) normalise in most cases. As a consequence, there is a normalisation in the preoperative severely impaired (right) heart function after PEA (figures 4A and 4B ) 46,47 Medical treatment PEA represents the therapy ofchoice in patients with CTEPH; however, only patients with chronic thromboembolic disease confined to the central and proximal segmental arteries will be candidates for surgery. In addition, about 5% of operated patients will suffer from residual pulmonary hypertension. In view of the similarities in histopathology in CTEPH and idiopathic pulmonary arterial hypertension (iPAH), there is rationale to extend the use of medications that have demonstrated an effect in iPAH patients.48-50 Indeed, uncontrolled studies in patients with distal CTEPH who are not suitable for surgical treatment suggest that these patients might benefit from medical treatment.5' In two open-label studies in patients with inoperable CTEPH, treatment with the dual endothelin-l receptor antagonist bosentan for three months was associated with a significant haemodynamic improvement, as well as an increase in the distance walked in the six-minute walk test (6-MWT).'25 Also, treatment with the phosphodiesterase type 5 inhibitor sildenafil was shown to improve haemodynamics and exercise capacity in patients with progressive distal CTEPH.54 Sildenafil may even be of use in CTEPH patients with coexisting left ventricular dysfunction.55 Although these observations support the notion that treatments focusing on the secondary arteriopathy might be of benefit in CTEPH, they still need confirmation from randomised placebo-controlled trials. Although, in general, pretreatment of CTEPH prior to PEA is not indicated, selected patients who have a high mortality risk might benefit from preoperative medical therapy, that is patients with severely increased pulmonary vascular resistance and signs of

Netherlands Heart Jounal Volume 14, Number 6, June 2006

right heart failure.'8'42 In two reported case series, preoperatively administered continuous intravenous epoprostenol was demonstrated to be beneficial in selected (high-risk) patients with proximal CTEPH.'6,57 Conclusion Chronic thromboembolic pulmonary hypertension is a life-threatening, but by means of pulmonary endarterectomy, potentially correctable form ofpulmonary hypertension. In an experienced centre, PEA can be curative with acceptable perioperative mortality. Moreover, CTEPH patients with inoperable, distal disease and patients with residual pulmonary hypertension after PEA might benefit from medical therapy. U References 1 2

3

4

5

6

7

8

9

10 11

12

13

14

15

16

Fedullo PF, Auger WR, Kerr KM, Rubin LJ. Chronic thromboembolicpulmonaryhypertension. NEngIJMed2001;345:1465-72. Dartevelle P, Fadel E, Mussot S, Chapelier A, Herve P, de Perrot M, et al. Chronic thromboembolic pulmonary hypertension. Eur RespirJ2004;23:637-48. Pengo V, Lensing AW, Prins MH, Marchiori A, Davidson BL, Tiozzo F, et al. Incidence ofchronic thromboembolic pulmonary hypertension after pulmonary embolism. NEnglJMed2004;350: 2257-64. Horlander KT, Mannino DM, Leeper KV. Pulmonary embolism mortality in the United States, 1979-1998: an analysis using multiple-cause mortality data. Arch Intern Med 2003;163:1711-7. Riedel M, Stanek V, Widimsky J, Prerovsky I. Longterm follow-up ofpatients with pulmonary thromboembolism. Late prognosis and evolution of hemodynamic and respiratory data. Chest 1982;81: 151-8. Lewczuk J, Piszko P; Jagas J, Porada A, Wojciak S, Sobkowicz B, et al. Prognostic factors in medically treated patients with chronic pulmonary embolism. Chest 2001;119:818-23. Archibald CJ, Auger WR, Fedullo PF, Channick RN, Kerr KM, Jamieson SW, et al. Long-term outcome after pulmonary thrombo-

endarterectomy. AmJRespir Crit Care Med 1999;160:523-8. Mayer E, Dahm M, Hake U, Schmid FX, Pitton M, Kupferwasser I, et al. Mid-term results ofpulmonary thromboendarterectomy for chronic thromboembolic pulmonary hypertension. Ann Thorac Surg 1996;61:1788-92. Moser KM, Daily PO, Peterson K, Dembitsky W, Vapnek JM, Shure D, et al. Thromboendarterectomy for chronic, major-vessel thromboembolic pulmonary hypertension. Immediate and longterm results in 42 patients. Ann Intern Med 1987;107:560-5. Coumand A, Riley RL. Pulmonary circulation and alveolar ventilation perfusion relationships after pneumonectomy. J Thorac Surg 1950;19:80-116. Harrison RW, Buehler W, Thomson RG, Long ET, Carlson R, Charbon B, et al. Cardiopulmonary reserve five to fifteen years following fifty per cent or more reduction of lung volume. Surg Forum 1957;7:209-13. Jamieson SW, Kapelanski DP. Pulmonary endarterectomy. Curr Probl Surg 2000;37:165-252. AugerWR, Permpikul P, Moser KM. Lupus anticoagulant, heparin use, and thrombocytopenia in patients with chronic thromboembolic pulmonary hypertension: a preliminary report. AmJMed 1995;99:392-6. Wolf M, Boyer-Neumann C, Parent F, Eschwege V, Jaillet H, Meyer D, et al. Thrombotic risk factors in pulmonary hypertension. Eur RespirJ2000;15:395-9. Bonderman D, Turecek PL, Jakowitsch J, Weltermann A, Adlbrecht C, Schneider B, et al. High prevalence of elevated clotting factor VIII in chronic thromboembolic pulmonary hypertension. Thromb Haemost2003;90:372-6. O'Donnell J, Tuddenham EG, Manning R, Kemball-Cook G, Johnson D, Laffan M. High prevalence of elevated factor VIII levels in patients referred for thrombophilia screening: role of increased synthesis and relationship to the acute phase reaction. Thromb Haemost 1997;77:825-8.

223

Chronic thromboembolic pulmonary hypertension

17 Kyrle PA, Minar E, Hirschl M, Bialonczyk C, Stain M, Schneider B, et al. High plasma levels offactor VIII and the risk of recurrent venous thromboembolism. N EngljMed 2000;343:457-62. 18 Moser KM, Auger WR, Fedullo PF. Chronic major-vessel thromboembolic pulmonary hypertension. Circulation 1990;81: 1735-43. 19 Colorio CC, Martinuzzo ME, Forastiero RR, Pombo G, Adamczuk Y, Carreras LO. Thrombophilic factors in chronic thromboembolic pulmonary hypertension. Blood CoagulFibrinolysis2001;12:42732. 20 Bonderman D, Jakowitsch J, Adlbrecht C, Schemper M, Kyrle PA, Schonauer V, et al. Medical conditions increasing the risk ofchronic thromboembolic pulmonary hypertension. Thromb Haemost 2005;93:512-6. 21 Jais X, loos V, Jardim C, Sitbon 0, Parent F, Hamid A, et al. Splenectomy and chronic thromboembolic pulmonary hypertension. Thorax2005;60:1031-4. 22 Fedullo PF, Auger WR, Channick RN, Kerr KM, Rubin LJ. Chronic thromboembolic pulmonary hypertension. Clin Chest Med 2001;22:561-81. 23 Kim H, Yung GL, Marsh JJ, Konopka RG, Pedersen CA, Chiles PG, et al. Pulmonaryvascular remodeling distal to pulmonary artery ligation is accompanied by upregulation of endothelin receptors and nitric oxide synthase. Exp Lung Res 2000;26:287-301. 24 Moser KM, Bloor CM. Pulmonary vascular lesions occurring in patients with chronic major vessel thromboembolic pulmonary hypertension. Chest 1993;103:685-92. 25 Lewczuk J, Piszko P, Jagas J, Porada A, Wojciak S, Sobkowicz B, et al. Prognostic factors in medically treated patients with chronic pulmonary embolism. Chest2001;119:818-23. 26 Goto K Basic and therapeutic relevance of endothelin-mediated regulation. Biol Pharm Bull 2001;24:1219-30. 27 Stewart DJ, Levy RD, Cemacek P, Langleben D. Increased plasma endothelin-1 in pulmonary hypertension: marker or mediator of disease? Ann Intern Med 1991;114:464-9. 28 Bauer M, Wilkens H, Langer F, Schneider SO, Lausberg H, Schafers HJ. Selective upregulation of endothelin B receptor gene expression in severe pulmonary hypertension. Circulation 2002; 105:1034-6. 29 McCulloch KM, Docherty CC, Morecroft I, MacLean MR. EndothelinB receptor-mediated contraction in human pulmonary resistance arteries. BrJPharmacol 1996;119:1125-30. 30 Davie N, Haleen SJ, Upton PD, Polak JM, Yacoub MH, Morrell NW, et al. ET(A) and ET(B) receptors modulate the proliferation of human pulmonary artery smooth muscle cells. AmJRespir Crit Care Med 2002;165:398-405. 31 Thistlethwaite PA, Lee SH, Du LL, Wolf PL, Sullivan C, Pradhan S, et al. Human angiopoietin gene expression is a marker for severity of pulmonary hypertension in patients undergoing pulmonary thromboendarterectomy. J Thorac Cardiovasc Surg2001; 122:65-73. 32 Lewczuk J, Ajlan AW, Piszko P, Jagas J, Mikulewicz M, Wrabec K Electrocardiographic signs of right ventricular overload in patients who underwent pulmonary embolism event(s). Are they useful in diagnosis of chronic thromboembolic pulmonary hypertension? J Electrocardiol 2004;37:219-25. 33 McGoon M, Gutterman D, Steen V, Barst R, McCrory DC, Fortin TA, et al. Screening, early detection, and diagnosis of pulmonary arterial hypertension: ACCP evidence-based clinical practice guidelines. Chest2004;126:14S-34S. 34 Lisbona R, Kreisman H, Novales-Diaz J, Derbekyan V. Perfusion lung scanning: differentiation of primary from thromboembolic pulmonary hypertension. AJR AmJRoentgenol 1985;144:27-30. 35 Ryan KL, Fedullo PF, Davis GB, Vasquez TE, Moser KM. Perfusion scan findings understate the severity of angiographic and hemodynamic compromise in chronic thromboembolic pulmonary hypertension. Chest 1988;93:1180-5. 36 Thistlethwaite PA, Madani M, Jamieson SW. Pulmonary thromboendarterectomy surgery. Cardiol Clin 2004;22:467-78, vii. 37 Pitton MB, Duber 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:

2485-91.

224

38 King MA, Ysrael M, Bergin CJ. Chronic thromboembolic pulmonary hypertension: CT findings. AJR Am JRoentgenol 1998;

170:955-60. 39 Kreitner KFJ, Ley S, Kauczor HU, Mayer E, Kramm T, Pitton MB, et al. Chronic Thromboembolic Pulmonary Hypertension: Preand Postoperative Assessment with Breath-hold MR Imaging Techniques. Radiology 2004;232:535-43. 40 Nikolaou K, Schoenberg SO, Attenberger U, Scheidler J, Dietrich 0, Kuehn B, et al. Pulmonary Arterial Hypertension: Diagnosis with Fast Perfusion MRImaging and High-Spatial-Resolution MR Angiography-Preliminary Experience. Radiology 2005;236:694703. 41 Hurwitt ES, Schein CJ, Rifkin H, Lebendiger A. A surgical approach to the problem of chronic pulmonary artery obstruction due to thrombosis or stenosis. Ann Surg 1958;147:157-65. 42 Jamieson SW, Kapelanski DP, Sakakibara N, Manecke GR, Thistlethwaite PA, Kerr KM, et al. Pulmonary endarterectomy: experience and lessons learned in 1,500 cases. Ann Thorac Surg 2003;76:1457-62. 43 Hartz RS, Byrne JG, Levitsky S, Park J, Rich S. Predictors of mortality in pulmonary thromboendarterectomy. Ann Thorac Surg 1996;62:1255-9. 44 Mo M, Kapelanski DP, Mitruka SN, Auger WR, Fedullo PF, Channick RN, et al. Reoperative pulmonary thromboendarterectomy. Ann Thorac Surg 1999;68:1770-6. 45 Masuda M, Nakajima N. Our experience ofsurgical treatment for chronic pulmonary thromboembolism. Ann Thorac Cardiovasc Surg2001;7:261-5. 46 Kreitner KF, Ley S, Kauczor HU, Mayer E, Kramm T, Pitton MB, et al. Chronic thromboembolic pulmonary hypertension: pre- and postoperative assessment with breath-hold MR imaging techniques. Radiology 2004;232:535-43. 47 Tulevski II, Bresser P, Hirsch A, Groenink M, Channick RN, Jamieson SW, et al. Decreased plasma neurohormones and improved cardiac performance after surgical treatment ofchronic pulmonary embolism. Ann Thorac Surg 2003;76:287-90. 48 Channick RN, Simonneau G, Sitbon 0, Robbins IM, Frost A, Tapson VF, et al. Effects ofthe dual endothelin-receptor antagonist bosentan in patients with pulmonary hypertension: a randomised placebo-controlled study. Lancet 2001;358:1119-23. 49 Galie N, Humbert M, Vachiery JL, Vizza CD, Kneussl M, Manes A, et al. Effects of beraprost sodium, an oral prostacyclin analogue, in patients with pulmonary arterial hypertension: a randomized, double-blind, placebo-controlled trial. JAm Coll Cardiol 2002;39: 1496-502. 50 Rubin LJ, Badesch DB, Barst RJ, Galie N, Black CM, Keogh A, et al. Bosentan therapy for pulmonary arterial hypertension. NEngl JMed 2002;346:896-903. 51 Ono F, Nagaya N, Okumura H, Shimizu Y, Kyotani S, Nakanishi N, et al. Effect of orally active prostacyclin analogue on survival in patients with chronic thromboembolic pulmonary hypertension without major vessel obstruction. Chest 2003;123:1583-8. 52 Hoeper MM, Kramm T, Wilkens H, Schulze C, Schafers HJ, Welte T, et al. Bosentan Therapy for Inoperable Chronic Thromboembolic Pulmonary Hypertension. Chest 2005;128:2363-7. 53 Hughes R, George P, Parameshwar J, Cafferty F, Dunning J, Morrell NW, et al. Bosentan in inoperable chronic thromboembolic pulmonary hypertension. Thorax 2005;60:707. 54 Ghofrani HA, Schermuly RT, Rose F, Wiedemann R, Kohstall MG, Kreckel A, et al. Sildenafil for long-term treatment of nonoperable chronic thromboembolic pulmonary hypertension. Am JRespir Crit Care Med 2003;167:1139-41. 55 Sheth A, Park JES, Ong YE, Ho TB, Madden BP. Early haemodynamic benefit of sildenafil in patients with coexisting chronic thromboembolic pulmonary hypertension and left ventricular dysfunction. VasculPharmacol2005;42:41-5. 56 Bresser P, Fedullo PF, Auger WR, Channick RN, Robbins IM, Kerr KM, et al. Continuous intravenous epoprostenol for chronic thromboembolic pulmonary hypertension. Eur RespirJ2004;23: 595-600. 57 Nagaya N, Sasaki N, Ando M, Ogino H, Sakamaki F, Kyotani S, et al. Prostacyclin therapy before pulmonary thromboendarterectomy in patients with chronic thromboembolic pulmonary

hypertension. Chest2003;123:338-43

Netherlands Heart Journal, Volume 14, Number 6, June 2006

q

Chronic thromboembolic pulmonary hypertension.

Chronic thromboembolic pulmonary hypertension (CTEPH) is a rapidly progressive and deadly disease, resulting from incomplete resolution of acute pulmo...
2MB Sizes 1 Downloads 40 Views