Thromb Haemost
DOI: 10.1055/a-2418-7895

Filippo Biondi

1   Cardiology Division, Department of Surgical, Medical and Molecular Pathology and Critical Area, University of Pisa, Pisa, Italy

,

Mattia Alberti

1   Cardiology Division, Department of Surgical, Medical and Molecular Pathology and Critical Area, University of Pisa, Pisa, Italy

,

Elisa Montemaggi

1   Cardiology Division, Department of Surgical, Medical and Molecular Pathology and Critical Area, University of Pisa, Pisa, Italy

,

Alberto D'Alleva

2   Cardiac Intensive Care and Interventional Cardiology Unit, Santo Spirito Hospital, Pescara, Italy

,

Rosalinda Madonna

1   Cardiology Division, Department of Surgical, Medical and Molecular Pathology and Critical Area, University of Pisa, Pisa, Italy

› Author Affiliations Funding This work was supported by the Italian Ministry of University and Research to R.M. (PRIN-2022 Prot. 2022S74XWB; 549901_2023_Madonna_Ateneo - Fondi di Ateneo 2023), and by the European Union—Next-Generation EU through the Italian Ministry of University and Research under PNRR—M4C2-I1.3 Project PE_00000019 “HEAL ITALIA,” CUP I53C22001440006 to R.M.
› Further Information Also available at    Buy Article Permissions and Reprints Abstract

Three mutually exclusive entities can underlie a postpulmonary embolism syndrome (PPES): not obstructed postpulmonary embolism syndrome (post-PE dyspnea), chronic thromboembolic pulmonary disease (CTEPD), and chronic thromboembolic pulmonary hypertension (CTEPH). Cardiorespiratory impairment in CTEPH and CTEPD underlies respiratory and hemodynamic mechanisms, either at rest or at exercise. Gas exchange is affected by the space effect, the increased blood velocity, and, possibly, intracardiac right to left shunts. As for hemodynamic effects, after a period of compensation, the right ventricle dilates and fails, which results in retrograde and anterograde right heart failure. Little is known on the pathophysiology of post-PE dyspnea, which has been reported in highly comorbid with lung and heart diseases, so that a “two-hit” hypothesis can be put forward: it might be caused by the acute myocardial damage caused by pulmonary embolism in the context of preexisting cardiac and/or respiratory diseases. More than one-third of PE survivors develops PPES, with only a small fraction (3–4%) represented by CTEPH. A value of ≈3% is a plausible estimate for the incidence of CTEPD. Growing evidence supports the role of CTEPD as a hemodynamic phenotype intermediate between post-PE dyspnea and CTEPH, but it still remains to be ascertained whether it constantly underlies exercise-induced pulmonary hypertension and if it is a precursor of CTEPH. Further research is needed to improve the understanding and the management of CTEPD and post-PE dyspnea.

Keywords venous thromboembolism - chronic thromboembolic pulmonary disease - chronic thromboembolic pulmonary hypertension - exercise-induced pulmonary hypertension Authors' Contribution

F.B. and R.M. contributed to the conception of the manuscript; R.M., F.B., M.A., A.D., and E.M. drafted the manuscript; R.M. critically reviewed and contributed to the final draft.

Publication History

Received: 13 June 2024

Accepted: 18 September 2024

Accepted Manuscript online:
19 September 2024

Article published online:
04 October 2024

© 2024. Thieme. All rights reserved.

Georg Thieme Verlag KG
Stuttgart · New York

  References 1 Delcroix M, Torbicki A, Gopalan D. et al. ERS statement on chronic thromboembolic pulmonary hypertension. Eur Respir J 2021; 57 (06) 2002828 2 Humbert M, Kovacs G, Hoeper MM. et al; ESC/ERS Scientific Document Group. 2022 ESC/ERS Guidelines for the diagnosis and treatment of pulmonary hypertension. Eur Heart J 2022; 43 (38) 3618-3731 3 Abel P. Pulmonary hypertension. In: xPharm: The Comprehensive Pharmacology Reference. London, UK: Elsevier. 2007: 1-8 4 Naeije R. Physiology of the pulmonary circulation and the right heart. Curr Hypertens Rep 2013; 15 (06) 623-631 5 Norton JM. Toward consistent definitions for preload and afterload. Adv Physiol Educ 2001; 25 (1–4): 53-61 6 Monge García MI, Santos A. Understanding ventriculo-arterial coupling. Ann Transl Med 2020; 8 (12) 795-795 7 Rako ZA, Kremer N, Yogeswaran A, Richter MJ, Tello K. Adaptive versus maladaptive right ventricular remodelling. ESC Heart Fail 2023; 10 (02) 762-775 8 Vanderpool RR, Rischard F, Naeije R, Hunter K, Simon MA. Simple functional imaging of the right ventricle in pulmonary hypertension: can right ventricular ejection fraction be improved?. Int J Cardiol 2016; 223: 93-94 9 Sharan L, Stackhouse K, Awerbach JD, Bashore TM, Krasuski RA. Effect of patent foramen ovale in patients with pulmonary hypertension. Am J Cardiol 2018; 122 (03) 505-510 10 Homma S, Messé SR, Rundek T. et al. Patent foramen ovale. Nat Rev Dis Primers 2016; 2: 15086 11 Sietsema KE, Sue DY, Stringer WW, Ward SA. “Wasserman & Whipp's principles of exercise testing and interpretation,”. p. 586, Accessed April 27, 2024 at: https://www.wolterskluwer.com/en/solutions/ovid/wasserman–whipps-principles-of-exercise-testing-and-interpretation-5305 12 Wendelboe AM, Raskob GE. Global burden of thrombosis: epidemiologic aspects. Circ Res 2016; 118 (09) 1340-1347 13 White RH. The epidemiology of venous thromboembolism. Circulation 2003; 107 (23, Suppl 1): I4-I8 14 Kearon C. Natural history of venous thromboembolism. Circulation 2003; 107 (23, Suppl 1): I22-I30 15 Lang IM. Campean IA, Sadushi-Kolici R, Badr-Eslam R, Gerges C, Skoro-Sajer N. Chronic thromboembolic disease and chronic thromboembolic pulmonary hypertension. 2021; 42 (Suppl. 01) 81-90 16 Taboada D, Pepke-Zaba J, Jenkins DP. et al. Outcome of pulmonary endarterectomy in symptomatic chronic thromboembolic disease. Eur Respir J 2014; 44 (06) 1635-1645 17 Dzikowska-Diduch O, Kostrubiec M, Kurnicka K. et al. “The post-pulmonary syndrome - results of echocardiographic driven follow up after acute pulmonary embolism”. Thromb Res 2020; 186: 30-35 18 Pugliese SC, Kawut SM. The post-pulmonary embolism syndrome: real or ruse?. Ann Am Thorac Soc 2019; 16 (07) 811-814 19 Barco S, Russo M, Vicaut E. et al. Incomplete echocardiographic recovery at 6 months predicts long-term sequelae after intermediate-risk pulmonary embolism. A post-hoc analysis of the Pulmonary Embolism Thrombolysis (PEITHO) trial. Clin Res Cardiol 2019; 108 (07) 772-778 20 Kahn SR, Hirsch AM, Akaberi A. et al. Functional and exercise limitations after a first episode of pulmonary embolism: results of the ELOPE prospective cohort study. Chest 2017; 151 (05) 1058-1068 21 Milne KM, James MD, Smyth RM. et al. Neurophysiological mechanisms of exertional dyspnea in post-pulmonary embolism syndrome. J Appl Physiol 2023; 134 (03) 667-677 22 Nilsson LT, Andersson T, Carlberg B, Johansson LÅ, Söderberg S. Electrocardiographic abnormalities and NT-proBNP levels at long-term follow-up of patients with dyspnea after pulmonary embolism. Scand Cardiovasc J 2024; 58 (01) 2373090 23 Jervan Ø, Haukeland-Parker S, Gleditsch J. et al. The effects of exercise training in patients with persistent dyspnea following pulmonary embolism: a randomized controlled trial. Chest 2023; 164 (04) 981-991 24 Humbert M, Kovacs G, Hoeper MM. et al. 2022 ESC/ERS Guidelines for the diagnosis and treatment of pulmonary hypertension. 2022; 43 (38) 3618-3731 25 Claeys M, Claessen G, La Gerche A. et al. Impaired cardiac reserve and abnormal vascular load limit exercise capacity in chronic thromboembolic disease. JACC Cardiovasc Imaging 2019; 12 (8, Pt 1): 1444-1456 26 Slegg OG, Willis JA, Wilkinson F. et al. IMproving PULmonary hypertension Screening by Echocardiography: IMPULSE. Echo Res Pract 2022; 9 (01) 9 27 Claessen G, La Gerche A, Voigt JU. et al. Accuracy of echocardiography to evaluate pulmonary vascular and RV function during exercise. JACC Cardiovasc Imaging 2016; 9 (05) 532-543 28 Madonna R, Fabiani S, Morganti R. et al. Exercise-induced pulmonary hypertension is associated with high cardiovascular risk in patients with HIV. J Clin Med 2022; 11 (09) 2447 29 Madonna R, Morganti R, Radico F. et al. Isolated exercise-induced pulmonary hypertension associates with higher cardiovascular risk in scleroderma patients. J Clin Med 2020; 9 (06) 1910 30 Madonna R, Ridolfi L, Morganti R. et al. Impact of exercise-induced pulmonary hypertension on right ventricular function and on worsening of cardiovascular risk in HIV patients. J Clin Med 2022; 11 (24) 7349 31 Madonna R, Alberti M, Biondi F. et al. Chronic thromboembolic pulmonary disease: association with exercise-induced pulmonary hypertension and right ventricle adaptation over time. Eur J Intern Med 2024; 123: 120-126 32 Rosenkranz S, Lang IM, Blindt R. et al. Pulmonary hypertension associated with left heart disease: updated recommendations of the Cologne Consensus Conference 2018. Int J Cardiol 2018; 272S: 53-62 33 Kovacs G, Zeder K, Rosenstock P. et al. Clinical impact of the new definition of precapillary pulmonary hypertension. Chest 2021; 159 (05) 1995-1997 34 Galiè N, Humbert M, Vachiery JL. et al; ESC Scientific Document Group. 2015 ESC/ERS Guidelines for the diagnosis and treatment of pulmonary hypertension. Eur Heart J 2016; 37 (01) 67-119 35 Newnham M, South K, Bleda M. et al. The ADAMTS13-VWF axis is dysregulated in chronic thromboembolic pulmonary hypertension. Eur Respir J 2019; 53 (03) 1801805 36 Natali D. Jais X, Abraham M. et al. Chronic thromboembolic pulmonary hypertension associated with indwelling Port-A-Cath® central venous access systems. Am J Respir Crit Care Med 2011; 183: A2409 37 Bonderman D, Jakowitsch J, Adlbrecht C. et al. Medical conditions increasing the risk of chronic thromboembolic pulmonary hypertension. Thromb Haemost 2005; 93 (03) 512-516 38 Tuder RM, Marecki JC, Richter A, Fijalkowska I, Flores S. Pathology of pulmonary hypertension. Clin Chest Med 2007; 28 (01) 23-42 , vii 39 Lang IM, Dorfmüller P, Vonk Noordegraaf A. The pathobiology of chronic thromboembolic pulmonary hypertension. Ann Am Thorac Soc 2016; 13 (Suppl. 03) S215-S221 40 Delcroix M, Lang I, Pepke-Zaba J. et al. Long-term outcome of patients with chronic thromboembolic pulmonary hypertension: results from an international prospective registry. Circulation 2016; 133 (09) 859-871 41 Dhont S, Derom E, Van Braeckel E, Depuydt P, Lambrecht BN. The pathophysiology of 'happy' hypoxemia in COVID-19. Respir Res 2020; 21 (01) 198 42 Miniati M, Pistolesi M, Marini C. et al. Value of perfusion lung scan in the diagnosis of pulmonary embolism: results of the Prospective Investigative Study of Acute Pulmonary Embolism Diagnosis (PISA-PED). Am J Respir Crit Care Med 1996; 154 (05) 1387-1393 43 van Es J, Douma RA, Hezemans RE. et al. Accuracy of X-ray with perfusion scan in young patients with suspected pulmonary embolism. Thromb Res 2015; 136 (02) 221-224 44 Cengiz TB, Abdelrahman A, Rohren SA, Doucette J, Ghesani M. The diagnostic accuracy of perfusion-only scan in the diagnosis of pulmonary embolism in the era of COVID-19: a single-center study of 434 patients. Ann Thorac Med 2023; 18 (04) 199-205 45 Kearon C, Akl EA, Comerota AJ. et al. Antithrombotic therapy for VTE disease: Antithrombotic Therapy and Prevention of Thrombosis, 9th ed: American College of Chest Physicians Evidence-Based Clinical Practice Guidelines. Chest 2012; 141 (2 Suppl): e149S-e496S 46 Jeong I, Alotaibi M, Fernandes TM. et al. Direct oral anticoagulants in patients with chronic thromboembolic pulmonary hypertension and the presence of recent thrombus during pulmonary endarterectomy. Pulm Circ 2022; 12 (03) e12110 47 Cohen AT, Hamilton M, Bird A. et al. Comparison of the non-VKA oral anticoagulants apixaban, dabigatran, and rivaroxaban in the extended treatment and prevention of venous thromboembolism: systematic review and network meta-analysis. PLoS One 2016; 11 (08) e0160064 48 Barnard PJ. Pulmonary arteriosclerosis and cor pulmonale due to recurrent thromboembolism. Circulation 1954; 10 (03) 343-361 49 Olgun Yıldızeli Ş, Kepez A, Taş S. et al. Pulmonary endarterectomy for patients with chronic thromboembolic disease. Anatol J Cardiol 2018; 19 (04) 273-278 50 Guth S, Wiedenroth CB, Rieth A. et al. Exercise right heart catheterisation before and after pulmonary endarterectomy in patients with chronic thromboembolic disease. Eur Respir J 2018; 52 (03) 1800458 51 Jenkins DP. Pulmonary thromboendarterectomy in chronic pulmonary disease—the Royal Papworth Hospital experience. Ann Cardiothorac Surg 2022; 11 (02) 128-132 52 Pin M. et al. Pulmonary endarterectomy in CTED: the pavia experience. J Heart Lung Transplant 2019; 38 (04) S130 53 Dumitrescu D, Gerhardt F, Viethen T, Schmidt M, Mayer E, Rosenkranz S. Case report: subjective loss of performance after pulmonary embolism in an athlete- beyond normal values. BMC Pulm Med 2016; 16 (01) 21 54 Guth S, Mayer E, Prüfer D, Wiedenroth CB. Pulmonary endarterectomy: technique and pitfalls. Ann Cardiothorac Surg 2022; 11 (02) 180-188 55 Mizoguchi H, Ogawa A, Munemasa M, Mikouchi H, Ito H, Matsubara H. Refined balloon pulmonary angioplasty for inoperable patients with chronic thromboembolic pulmonary hypertension. Circ Cardiovasc Interv 2012; 5 (06) 748-755 56 Zhang L, Bai Y, Yan P. et al. Balloon pulmonary angioplasty vs. pulmonary endarterectomy in patients with chronic thromboembolic pulmonary hypertension: a systematic review and meta-analysis. Heart Fail Rev 2021; 26 (04) 897-917 57 Cao Y, Singh V, Jiang N, Wei R, Jiang K, Wang H. Stenting for pulmonary artery stenosis resistant to balloon pulmonary angioplasty in chronic thrombo-embolic pulmonary hypertension: a bail out strategy. Eur Heart J Case Rep 2021; 5 (03) ytab071