Clinical Cases in Chronic Thromboembolic Pulmonary Hypertension [1st ed. 2020] 978-3-030-17365-4, 978-3-030-17366-1

Table of contents :
Front Matter ....Pages i-xvii
Case 1: The Evaluation of Chronic Thromboembolic Pulmonary Hypertension (Manreet Kanwar, Deepa Gopalan, William R. Auger)....Pages 1-10
Case 2: There’s No Perfusion to that Lung! An Unusual Presentation for CTEPH (Mona Alotaibi, Victor Pretorius, Deepa Gopalan, William R. Auger)....Pages 11-20
Case 3: Distal Chronic Thromboembolic Disease—Is Surgery an Option? (Anjali Vaidya, Deepa Gopalan, William R. Auger)....Pages 21-31
Case 4: The Case for Balloon Pulmonary Angioplasty (David S. Poch, Deepa Gopalan, William R. Auger)....Pages 33-40
Case 5: Operable CTEPH …but Is PTE the Best Option? (Sonja Bartolome, Deepa Gopalan, William R. Auger)....Pages 41-50
Case 6: Distal Vessel Thromboendarterectomy— How Far Can We Go? (Angela Bautista, Michael M. Madani, Deepa Gopalan, William R. Auger)....Pages 51-59
Case 7: It’s Not CTEPH, but It Is Chronic Thromboembolic Disease (CTED) (Paul R. Forfia, Deepa Gopalan, William R. Auger)....Pages 61-70
Case 8: Another Case of CTED: Is Surgery the Way? (Colleen McEvoy, Deepa Gopalan, William R. Auger)....Pages 71-80
Case 9: Pulmonary Artery Sarcoma Mimicking Massive Thromboembolic Disease (Demosthenes G. Papamatheakis, Deepa Gopalan, William R. Auger)....Pages 81-89
Case 10: Chronic Thrombus and Metastatic Cancer—An Unexpected CTEPH Mimic (Alison S. Witkin, William R. Auger)....Pages 91-97
Case 11: Don’t Forget About the Pulmonary Veins! (Terence K. Trow, Deepa Gopalan, William R. Auger)....Pages 99-107
Case 12: Pulmonary Veno-Occlusive Disease …but It Started Out as CTEPH (Rana Awdish, Sara Hegab, Deepa Gopalan, William R. Auger)....Pages 109-119
Case 13: Pulmonary Arteritis… The Great CTEPH Mimic (Kim M. Kerr, Albert Hsiao, William R. Auger)....Pages 121-131
Case 14: Sarcoidosis and Large Vessel Pulmonary Vascular Disease—Another CTEPH Mimic (Robert Schilz, Deepa Gopalan, William R. Auger)....Pages 133-140
Case 15: CTEPH? But the Lung Scan Is Normal! (Victor J. Test, Deepa Gopalan, William R. Auger)....Pages 141-146
Case 16: Acute Versus Chronic Thromboembolic Disease—Beware! (Dianne L. Zwicke, Sara Paulus, Deepa Gopalan, William R. Auger)....Pages 147-156
Case 17: Can Severe Pulmonary Arterial Pulmonary Hypertension Mimic CTEPH? (Jean M. Elwing, Deepa Gopalan, William R. Auger)....Pages 157-165
Case 18: Atrial Septal Defect with Chronic Thrombus Mimicking CTEPH (Timothy M. Fernandes, Deepa Gopalan, William R. Auger)....Pages 167-176
Case 19: Parenchymal Lung Disease and Chronic Thromboemboli (Lynette Brown, Deepa Gopalan, William R. Auger)....Pages 177-184
Back Matter ....Pages 185-194

Citation preview

Clinical Cases in Cardiology Series Editors: Ravi V. Shah · Siddique A. Abbasi · James L. Januzzi

William R. Auger Deepa Gopalan Editors

Clinical Cases in Chronic Thromboembolic Pulmonary Hypertension

Clinical Cases in Cardiology Series Editors: Ravi V. Shah Boston, MA, USA Siddique A. Abbasi Providence, Rhode Island, USA James L. Januzzi Boston, MA, USA

Clinical cases are a key component in modern medical education, assisting the trainee or recertifying clinician to work through unusual cases using best practice techniques. Cardiology is a key discipline in this regard and is a highly visual subject requiring the reader to describe often very subtle differences in the presentation of patients and define accurately the diagnostic and management criteria on which to base their clinical decision-making. This series of concise practical guides is designed to facilitate the clinical decision-making process by reviewing a number of cases and defining the various diagnostic and management decisions open to clinicians. Each title will be illustrated and diverse in scope, enabling the reader to obtain relevant clinical information regarding both standard and unusual cases in a rapid, easy to digest format. More information about this series at http://www.springer.com/series/14348

William R. Auger  •  Deepa Gopalan Editors

Clinical Cases in Chronic Thromboembolic Pulmonary Hypertension

Editors

William R. Auger Lewis Katz School of Medicine Temple University Philadelphia, PA USA

Deepa Gopalan Department of Radiology Imperial College Hospitals London UK

ISSN 2523-3009     ISSN 2523-3017 (electronic) Clinical Cases in Cardiology ISBN 978-3-030-17365-4    ISBN 978-3-030-17366-1 (eBook) https://doi.org/10.1007/978-3-030-17366-1 © Springer Nature Switzerland AG 2020 This work is subject to copyright. All rights are reserved by the Publisher, whether the whole or part of the material is concerned, specifically the rights of translation, reprinting, reuse of illustrations, recitation, broadcasting, reproduction on microfilms or in any other physical way, and transmission or information storage and retrieval, electronic adaptation, computer software, or by similar or dissimilar methodology now known or hereafter developed. The use of general descriptive names, registered names, trademarks, service marks, etc. in this publication does not imply, even in the absence of a specific statement, that such names are exempt from the relevant protective laws and regulations and therefore free for general use. The publisher, the authors, and the editors are safe to assume that the advice and information in this book are believed to be true and accurate at the date of publication. Neither the publisher nor the authors or the editors give a warranty, expressed or implied, with respect to the material contained herein or for any errors or omissions that may have been made. The publisher remains neutral with regard to jurisdictional claims in published maps and institutional affiliations. This Springer imprint is published by the registered company Springer Nature Switzerland AG. The registered company address is: Gewerbestrasse 11, 6330 Cham, Switzerland

Preface

It might be best to first acknowledge the origins of Clinical Cases in Chronic Thromboembolic Pulmonary Hypertension. Having seen thousands of chronic thromboembolic disease cases over the years, it has always been instructive as to the diagnostic challenges presented by these patients. The questions that remain in our understanding of the natural history of this disease, the non-specific nature of the clinical presentation, and the often indistinguishable exam findings between CTEPH and other forms of pulmonary hypertension make an understanding of the evaluation algorithm and the reliance on diagnostic studies a critically important element in ultimately establishing the diagnosis of chronic thromboembolic disease or CTEPH. Consequently, this book focuses not on an overall review of CTEPH as a discipline but rather provides a number of case vignettes, each illustrating an important teaching point that a clinician might find helpful when evaluating a patient suspected of having CTEPH.  Each case is an actual patient presentation referred for endarterectomy surgery; the book is proportioned to present patients who actually exhibited “typical” cases of chronic thromboembolic disease, those with clinically challenging cases, as well as several examples of CTEPH mimics. It is our hope that this book will provide a helpful diagnostic road map for the clinician. Chronic thromboembolic pulmonary hypertension (CTEPH) is a form of pulmonary hypertension that results from incomplete or non-resolution of a pulmonary embolic burden within the proximal pulmonary arterial bed. Though the initial embolic event can be relatively “silent” in some v

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patients who will ultimately develop CTEPH, many patients progress to established disease despite the acute event being recognized and despite an appropriate course of antithrombotic therapy having been prescribed. The mechanism of transition between acute and chronic thrombosis is incompletely understood, as are the risk factors in any one individual [1]. Complicating matters is that the “obstructive” component due to organized thrombus is but a piece of the entire clinical picture. The development of a precapillary vasculopathy and the establishment of systemic collateral circulation “feeding” the pulmonary vasculature are also considered operative in the establishment of the pulmonary hypertension one sees in this disease [2, 3]. This complex interplay contributes not only to the variability in clinical presentation but also to a range of radiographic presentations dependent on where any individual is in the course of their chronic thromboembolic disease. The “pathology drives the radiology,” and an understanding of this is critically important to the diagnostician. Considered to be a rare disease, the actual prevalence of CTEPH worldwide has been difficult to determine [4]. Even less is known when considering chronic thromboembolic disease (CTED), which is the presence of persistent, unresolved thrombus in the absence of pulmonary hypertension or right heart compromise [5]. The non-specificity of presenting cardiopulmonary complaints, the variability in time course for disease development, and the wide range of patient populations that can be affected account for some of the gaps in our understanding of the epidemiology. But equally as important, if not more so, are the difficulties with disease recognition radiographically. Confusion as to the utility of ventilation-­­ perfusion scintigraphy, unappreciated pulmonary vascular and parenchymal perfusion findings by CT, and poorly understood pulmonary angiographic patterns in patients with established CTEPH contribute to the underdiagnosis of this disease. Difficulties with the distinction between acute, acute-­­ on-­­ chronic, and chronic thromboembolic disease and the misinformation about CTEPH “mimics” further lend to the confusion.

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CTEPH is unique among other causes of pulmonary hypertension as it is potentially possible to obtain a complete cure in selected patients, particularly with early intervention. Imaging is pivotal for ensuring that the appropriate diagnosis is made at an opportune time [6]. The primary goal of imaging is to confirm the presence of CTEPH and evaluate right heart function, while the secondary goal is to delineate the distribution of the disease as a means to determine the most appropriate therapeutic option. A single imaging technique is unlikely to provide all the requisite information, and therefore, multimodality imaging is widely used in clinical practice. Transthoracic echocardiography is a simple but indispensable noninvasive tool that is routinely employed as the first step in the diagnostic pathway. There are several publications detailing the various echocardiographic parameters that are useful in PH evaluation. However, it is well recognized that echocardiography relying predominantly on Doppler pressure estimates can miss PH in as many as 10–30%, particularly in the early stages of the disease. Technical advances such as three-dimensional (3D) echocardiography can overcome the challenges presented by the complex RV geometry, while RV strain imaging can potentially detect subclinical pulmonary hypertension. In a patient with known or suspected pulmonary hypertension, it is necessary to confirm or exclude CTEPH earlier on in the diagnostic pathway. Ventilation-perfusion (VQ) scintigraphy is the most sensitive test in the diagnostic algorithm for excluding CTEPH.  A normal perfusion scan carries a high negative predictive valve, and hence, VQ is invaluable as a simple but effective screening tool. However, its high sensitivity is unfortunately not matched by high specificity, and there are various conditions in addition to CTEPH that are associated with mismatched perfusion defects. Examples of these CTEPH mimics are illustrated in this atlas. Any patient with a mismatched perfusion defect will require downstream anatomical testing. The vascular abnormalities of CTEPH have been extensively described in the

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literature and include eccentric thrombus that may or may not be calcified, intravascular webs, and stenosis with or without post-stenotic dilatation and pouch defects. The vessel may be completely occluded or show abrupt truncation with attenuated segmental branches. Systemic collateral vessels (bronchial and non-bronchial) are a feature of chronicity. All these features can be delineated using noninvasive techniques such as computed tomography pulmonary angiography (CTPA) and magnetic resonance pulmonary angiography (MRPA) or by the more conventional catheter pulmonary angiography. While CTPA is now considered as the standard of care for acute PE, its role in the diagnosis of CTEPH is tinged with controversy. There is a well-recognized variability in the diagnostic performance of CTPA in CTEPH that can be partially attributed to relative rarity of the disease and the lack of awareness among the imaging community. The lower CT temporal resolution compared to catheter angiography contributes to the suboptimal delineation of the distal pulmonary vasculature. This can be circumvented by employing contemporary techniques such as dual-energy CT (DECT) that allow for simultaneous evaluation of pulmonary vascular morphology and lung perfusion abnormalities, but as of now, this lacks prospective validation and hence cannot be mandated for incorporation into routine clinical practice. Although CT, MR, and catheter angiography are often considered to be complementary, corroborative information such as mosaic attenuation, another useful discriminator for chronicity in patients with suspected acute or acute-on-­ chronic disease, can be depicted using CTPA, while the bronchopulmonary shunt fraction can be calculated using MR. Cardiac MR is also the reference standard for evaluation of ventricular function. There is a growing body of evidence demonstrating the value of multiparametric MR techniques for characterization of RV structure and ­physiology, but their clinical utility in CTEPH is yet to be proven. Multidirectional 4D phase-contrast MR is a compelling evolving tool for evaluation of the complex flow patterns within the RV and pulmonary circula-

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tion and could potentially be useful as a screening tool in identifying subclinical PH in the future. A few high-volume clinical centers with experience in noninvasive imaging routinely use the road maps of the pulmonary vasculature obtained from CT and MR for operability assessment, but most institutions still resort to catheter angiography for this evaluation. Conventional angiography can be tagged to a right heart catheter examination, eliminating the need for a separate puncture. While proven to be a safe technique in accomplished hands, it is not without complications. Considerable technical expertise is required to ensure that appropriate views are undertaken without excessive exposure to radiation and iodinated contrast medium. This involves a fine balance between acquiring orthogonal views following selective or super selective engagement of the catheter into the vessel under consideration and observing the capillary phase for perfusion defects. The advent of balloon pulmonary angioplasty has led to further refinement of this technique. Rotational angiography and cone-beam CT are used in conjunction with the catheter angiography to get exquisite images of the pulmonary arterial tree to the subsegmental level. That multimodality imaging contributes vital information for CTEPH diagnosis as well as to the decision-making process for disease management is incontrovertible. Some physicians and surgeons are accustomed to interpreting the imaging data without active input from radiologists. While there is no doubt that some clinicians are seasoned veterans with years of experience in dealing with CTEPH, they may still fail to understand the nuances of the different imaging modalities and miss subtle but crucial findings. It is best to involve a pulmonary vascular imaging specialist who is conversant with the contemporary techniques and understands the subtleties involved. Most international guidelines and scientific statements emphasize the need for suspected or confirmed CTEPH cases to be referred to an expert center for discussion by a multidisciplinary team in which a radiologist performs an essential role.

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References 1. Fernandes T, Planquette B, Sanchez O, Morris T.  From acute to chronic thromboembolic disease. Ann Am Thorac Soc. 2016;13(Suppl 3):S207–14. 2. Moser KM, Bloor CM. Pulmonary vascular lesions occurring in patients with chronic major vessel thromboembolic pulmonary hypertension. Chest. 1993;103: 685–92. 3. Dorfmüller P, Günther S, Ghigna M-R, Thomas de Montpréville V, et  al. Microvascular disease in chronic thromboembolic pulmonary hypertension: a role for pulmonary veins and systemic vasculature. Eur Respir J. 2014;44(5):1275–88. 4. Ende-Verhaar YM, Cannegieter SC, Vonk Noordegraaf A, et  al. Incidence of chronic thromboembolic pulmonary hypertension after acute pulmonary embolism: a contemporary view of the published literature. Eur Resp J. 2017;49:1601792. 5. Klok FA, van der Hulle T, den Exter PL, Lankeit M, Huisman MV, Konstantinides S. The post-PE syndrome: a new concept for chronic complications of pulmonary embolism. Blood Rev. 2014;28:221–6. 6. Gopalan D, Blanchard D, Auger WR.  Diagnostic evaluation of chronic thromboembolic pulmonary hypertension. Ann Am Thorac Soc. 2016;13(Suppl 3):S222–39. Philadelphia, PA London, UK 

William R. Auger Deepa Gopalan

Contents

1 Case 1: The Evaluation of Chronic Thromboembolic Pulmonary Hypertension . . . . . . . . . . . . . . . . . . . . . . . .   1 Manreet Kanwar, Deepa Gopalan, and William R. Auger 2 Case 2: There’s No Perfusion to that Lung! An Unusual Presentation for CTEPH. . . . . . . . . . . . . .  11 Mona Alotaibi, Victor Pretorius, Deepa Gopalan, and William R. Auger 3 Case 3: Distal Chronic Thromboembolic Disease— Is Surgery an Option?. . . . . . . . . . . . . . . . . . . . . . . . . . .  21 Anjali Vaidya, Deepa Gopalan, and William R. Auger 4 Case 4: The Case for Balloon Pulmonary Angioplasty. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .  33 David S. Poch, Deepa Gopalan, and William R. Auger 5 Case 5: Operable CTEPH …but Is PTE the Best Option?. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .  41 Sonja Bartolome, Deepa Gopalan, and William R. Auger 6 Case 6: Distal Vessel Thromboendarterectomy— How Far Can We Go?. . . . . . . . . . . . . . . . . . . . . . . . . . .  51 Angela Bautista, Michael M. Madani, Deepa Gopalan, and William R. Auger

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7 Case 7: It’s Not CTEPH, but It Is Chronic Thromboembolic Disease (CTED). . . . . . . . . . . . . . . . .  61 Paul R. Forfia, Deepa Gopalan, and William R. Auger 8 Case 8: Another Case of CTED: Is Surgery the Way?. . . . . . . . . . . . . . . . . . . . . . . . . . . . .  71 Colleen McEvoy, Deepa Gopalan, and William R. Auger 9 Case 9: Pulmonary Artery Sarcoma Mimicking Massive Thromboembolic Disease. . . . . . . . . . . . . . . . .  81 Demosthenes G. Papamatheakis, Deepa Gopalan, and William R. Auger 10 Case 10: Chronic Thrombus and Metastatic Cancer—An Unexpected CTEPH Mimic. . . . . . . . . . .  91 Alison S. Witkin and William R. Auger 11 Case 11: Don’t Forget About the Pulmonary Veins!. . .  99 Terence K. Trow, Deepa Gopalan, and William R. Auger 12 Case 12: Pulmonary Veno-Occlusive Disease … but It Started Out as CTEPH. . . . . . . . . . . . . . . . . . . . . 109 Rana Awdish, Sara Hegab, Deepa Gopalan, and William R. Auger 13 Case 13: Pulmonary Arteritis… The Great CTEPH Mimic. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 121 Kim M. Kerr, Albert Hsiao, and William R. Auger 14 Case 14: Sarcoidosis and Large Vessel Pulmonary Vascular Disease—Another CTEPH Mimic. . . . . . . . . 133 Robert Schilz, Deepa Gopalan, and William R. Auger 15 Case 15: CTEPH? But the Lung Scan Is Normal!. . . . 141 Victor J. Test, Deepa Gopalan, and William R. Auger

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16 Case 16: Acute Versus Chronic Thromboembolic Disease—Beware!. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .147 Dianne L. Zwicke, Sara Paulus, Deepa Gopalan, and William R. Auger 17 Case 17: Can Severe Pulmonary Arterial Pulmonary Hypertension Mimic CTEPH?. . . . . . . . . . 157 Jean M. Elwing, Deepa Gopalan, and William R. Auger 18 Case 18: Atrial Septal Defect with Chronic Thrombus Mimicking CTEPH. . . . . . . . . . . . . . . . . . . . 167 Timothy M. Fernandes, Deepa Gopalan, and William R. Auger 19 Case 19: Parenchymal Lung Disease and Chronic Thromboemboli. . . . . . . . . . . . . . . . . . . . . 177 Lynette Brown, Deepa Gopalan, and William R. Auger Index. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 185

Contributors

Mona  Alotaibi Pulmonary Fellow, Division of Pulmonary and Critical Care Medicine, University of California, San Diego, San Diego, CA, USA William  R.  Auger Lewis Katz School of Medicine, Temple University, Philadelphia, PA, USA Rana  Awdish Pulmonary Hypertension Program, Division of Pulmonary and Critical Care Medicine, Henry Ford Hospital, Detroit, MI, USA Pulmonary Hypertension Program, Heart and Vascular Institute, St. John Providence Ascension Health, Southfield, MI, USA School of Medicine, Wayne State University, Detroit, MI, USA Sonja  Bartolome CTEPH Program, UT Southwestern Medical Center, Dallas, TX, USA Pulmonary and Critical Care Medicine, UT Southwestern Medical Center, Dallas, TX, USA Angela Bautista  CTEPH Program, University of California, San Diego, San Diego, CA, USA Lynette Brown  Asssociate Professor (Clinical), University of Utah, Salt Lake, UT, USA Pulmonary Hypertension Program, Intermountain Medical Center, Murray, UT, USA

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Jean M. Elwing  Pulmonary Hypertension Program, Division of Pulmonary Critical Care Medicine, University of Cincinnati College of Medicine, Cincinnati, OH, USA Timothy  M.  Fernandes  Division of Pulmonary and Critical Care Medicine, University of California, San Diego, San Diego, CA, USA Paul R. Forfia  Pulmonary Hypertension, Right Heart Failure and CTEPH Program, Temple University Hospital, Philadelphia, PA, USA Deepa Gopalan  Department of Radiology, Imperial College Hospitals, London, UK Sara  Hegab  Pulmonary Hypertension Program, Division of Pulmonary and Critical Care Medicine, Henry Ford Hospital, Detroit, MI, USA Pulmonary Hypertension Program, Heart and Vascular Institute, St. John Providence Ascension Health, Southfield, MI, USA School of Medicine, Wayne State University, Detroit, MI, USA Albert Hsiao  Asssociate Professor in Residence, Department of Radiology, University of California, San Diego, San Diego, CA, USA Manreet  Kanwar Cardiovascular Institute at Allegheny Health Network, Pittsburgh, PA, USA Kim  M.  Kerr Division of Pulmonary and Critical Care Medicine, University of California, San Diego, San Diego, CA, USA Michael M. Madani  University of California, San Diego, San Diego, CA, USA Colleen  McEvoy Division of Pulmonary and Critical Care Medicine, Washington University in St. Louis, St. Louis, MO, USA Demosthenes  G.  Papamatheakis Pulmonary, Critical Care and Sleep Medicine, University of California, San Diego, La Jolla, CA, USA

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Sara  Paulus Pulmonary Hypertension Clinic, Aurora St. Luke’s Medical Center, Milwaukee, WI, USA David S. Poch  University of California, San Diego, La Jolla, CA, USA Victor  Pretorius Division of Cardiovascular and Thoracic Surgery, University of California, San Diego, San Diego, CA, USA Heart Transplant and MCS Program, University of California, San Diego, San Diego, CA, USA Robert  Schilz CWRU School of Medicine, Cleveland, OH, USA Lung Transplantation and Pulmonary Vascular Disease, University Hospitals of Cleveland, Cleveland, OH, USA Victor J. Test  Division of Pulmonary Medicine and Critical Care, Texas Tech University School of Medicine, Lubbock, TX, USA Terence  K.  Trow Pulmonary, Critical Care, and Sleep Medicine, DynaMed Plus, EBSCO Health Information Services, Ipswich, MA, USA Yale Pulmonary Vascular Disease Program, Yale School of Medicine, New Haven, CT, USA Anjali  Vaidya Pulmonary Hypertension, Right Heart Failure, and CTEPH Program, Advanced Heart Failure and Cardiac Transplant, Lewis Katz School of Medicine, Temple University, Philadelphia, PA, USA Pulmonary Hypertension, Right Heart Failure, and CTEPH Program, Lewis Katz School of Medicine, Temple University, Philadelphia, PA, USA Alison  S.  Witkin Division of Pulmonary and Critical Care Medicine, Massachusetts General Hospital, Harvard Medical School, Boston, MA, USA Dianne  L.  Zwicke  Pulmonary Hypertension Clinic, Aurora St. Luke’s Medical Center, Milwaukee, WI, USA

Chapter 1 Case 1: The Evaluation of Chronic Thromboembolic Pulmonary Hypertension Manreet Kanwar, Deepa Gopalan, and William R. Auger

Case Presentation Patient is a 68-year-old African American male who was referred to us for evaluation of worsening shortness of breath in the setting of previous history of pulmonary emboli (PE) and recently diagnosed pulmonary hypertension (PH).

M. Kanwar (*) Cardiovascular Institute at Allegheny Health Network, Pittsburgh, PA, USA e-mail: [email protected] D. Gopalan Department of Radiology, Imperial College Hospitals, London, UK e-mail: [email protected] W. R. Auger Lewis Katz School of Medicine, Temple University, Philadelphia, PA, USA e-mail: [email protected] © Springer Nature Switzerland AG 2020 W. R. Auger, D. Gopalan (eds.), Clinical Cases in Chronic Thromboembolic Pulmonary Hypertension, Clinical Cases in Cardiology, https://doi.org/10.1007/978-3-030-17366-1_1

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He was initially diagnosed with unprovoked bilateral deep venous thrombi (DVT) and PE in 2013. Hypercoagulability work-up was negative. He was started on warfarin for anticoagulation which was subsequently discontinued after a year. He again presented in June 2016 with worsening shortness of breath from a recurrent PE.  Anticoagulation was resumed with apixaban with some initial improvement in his symptoms. An IVC filter was placed (although there was no documented recurrent DVT). The patient reported increasing shortness of breath over the following months, with associated lower extremity swelling and abdominal distention. He was evaluated as an outpatient and started on diuretics and treated for bronchitis for several weeks. His symptoms eventually started affecting his activities of daily living when he presented to an outside hospital for evaluation in September 2016, after an event of near syncope following moderate exertion. His initial chest radiograph (Fig.  1.1) and lab work were unremarkable for any “acute findings”. An echocardiogram showed severe right ventricular dilatation (RVEDD 57 mm) with moderately reduced right ventricular global systolic function (TAPSE 11  mm) and mild hypertrophy (Fig.  1.2). His left ventricular ejection fraction was preserved at 65% and his calculated pulmonary artery

Figure 1.1  Chest radiograph upon presentation

Chapter 1.  Case 1: The Evaluation of Chronic…

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Figure 1.2 TTE pre-op (parasternal long-axis view, four-chamber view; TR jet). The right ventricle is severely dilated with moderately to severely reduced systolic function. There is moderate hypertrophy of the right ventricle. The right ventricular systolic pressure is 101 mmHg

Figure 1.3  CT angiography of the chest with findings diagnostic of CTEPH. Enlarged bronchial collateral artery: solid white arrow

systolic pressure (PASP) was about 105 mmHg, with a small, circumferential pericardial effusion. Given his previous history of PEs, he underwent a repeat CT angiogram of his chest which showed chronic pulmonary emboli bilaterally (Fig. 1.3). The largest thrombus burden was at the distal portion of the right pulmonary artery with extension and occlusion of the right lower lobe interlobar pulmonary artery as well as the proximal right middle lobe pulmonary artery. At that point he was started on diuretics,

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placed on 5 L oxygen via nasal cannula and transferred to our institution for further management. His past medical history was also significant for ongoing smoking with over 20 pack year history of tobacco abuse. He denied any history suggestive of connective tissue disease, liver or kidney disease, malignancy, thyroid or hematological disorders, or other risk factors for pulmonary hypertension. His EKG showed right axis deviation with borderline right ventricular hypertrophy in a sinus rhythm. V/Q perfusion images revealed large mismatched defects bilaterally (Fig. 1.4). Right heart catheterization showed significantly elevated right-sided filling pressures with a right atrial (RA) pressure of 20 mmHg, a PAP of 71/33 mmHg (mean 45) and a pulmonary capillary wedge pressure of 11 mmHg. His cardiac index was marginal at 2.2  L/min/m2 and his calculated pulmonary vascular resistance (PVR) was 9.1  Wood Units. Pulmonary angiogram showed lack of perfusion in his right lower and middle lobes with multiple other findings consistent with CTEPH (Fig. 1.5a, b). Coronary angiogram revealed no significant obstructive disease. His pulmonary function tests showed moderate obstructive lung disease with an FEV1 of 2.1 L.

RT ANTERIOR LT

LT POSTERIOR RT

RT RAO LT

LT LPO RT

RT LATERAL

LT LATERAL

LT RPO RT

RT LAO LT

Figure 1.4  Preoperative lung perfusion scintigraphy

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Figure 1.5  (a, b) Catheter-based pulmonary angiography illustrating features of chronic thromboembolic disease. Angiographic web depicted by solid white arrow

He was admitted for aggressive diuresis, and given his hemodynamic presentation we used inotropic support with IV milrinone for 72 h prior to surgery for volume and right ventricular optimization. After obtaining informed consent, he underwent pulmonary thromboendarterectomy (PTE) surgery with the right side circulatory arrest time of 32 and 16 min on the left side (Fig. 1.6). He was extubated the following morning and weaned off of his inotropic support over the next 3 days. Off support, his postoperative PA pressures were RA 6 mmHg, PA 33/9 mmHg (mean 19), PCWP 7 mmHg, CI 2.7 L/min/m2, PVR 2.7 Wood Units, BP 107/82. He was discharged home 7 days later and had a follow-up right heart catheterization 6  months later,

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Figure 1.6  Clot specimen removed at the time of pulmonary thromboendarterectomy

which demonstrated a mean PAP of 23 and a PVR of 2.8  Wood Units. He continues to do well at his 1  year follow-up.

Radiological Interpretation A more detailed interpretation of the radiographic studies reveals that the chest radiograph in Fig. 1.1 is remarkable for cardiomegaly and asymmetric dilatation of the proximal ­pulmonary arteries (right is larger than the left) with reduced pulmonary vascular markings in the periphery. VQ scintigraphy (Fig. 1.4) reveals lobar perfusion defects present in the right lower lobe and lingula, with wedge shaped segmental perfusion defect in the left lower lobe. Ventilation was homogenous in both lungs. Computerized Tomography Pulmonary Angiography (CTPA) (Fig. 1.3) shows intimal thrombus in the distal right

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main pulmonary artery with occlusion of the right lower lobe. On the left, there is eccentric intimal thrombus around the distal left main pulmonary artery with proximal occlusion of the lingula. There is attenuation of the segmental branches of the left lower lobe with loss of peripheral arcades. Right atrium and right ventricle are markedly dilated with flattening of the interventricular septum. There is enlargement of the bronchial arteries (solid white arrow) and small pericardial and pleural effusions. Catheter pulmonary angiography (Fig.  1.5a, b) demonstrates intimal irregularity of the distal right main pulmonary artery and proximal right lower lobe vessel with a proximal web (solid white arrow) followed by a pouch defect with a thin trickle of contrast medium. The right middle lobe vessel is occluded. There is a proximal stenosis in the origin of the posterior segment of the right upper lobe with post-stenotic dilatation. On the left, intimal thrombus is present in the distal left main pulmonary artery with segmental occlusion of the lingula, and abrupt truncation of the anterior basal branch of the left lower lobe with mid segmental attenuations of the posterior and lateral basal segments. Note that in the capillary phase there is good perfusion in the left upper lobe and lack of perfusion in the lingula and left lower lobe.

Clinical Comments This case is an illustration of a “typical” approach to the evaluation of CTEPH, though it did not follow the diagnostic guidelines that have been promoted over the past years (Fig. 1.7). With the background history of pulmonary embolic events, and his presentation showing volume overload, screening for the presence of pulmonary hypertension and right heart disease with echocardiography was in line with the recommendations as depicted in Fig. 1.7. However, it can be argued that obtaining CT angiography of the chest to investigate the possibility of recurrent pulmonary emboli was completely appropriate. The fact that the diagnosis of chronic

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M. Kanwar et al. Symptoms, signs, history suggestive of CTEPH Echocardiographic probability of PH (Table 8)

High or intermediate probability of PH Yes

CTEPH possible

Refer to PH/CTEPH expert centre

V/Q scana Mismatched perfusion defects?

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CT pulmonary angiography Right heart catheterization +/- Pulmonary angiography CT = computed thomography;CTEPH = chronic thromboembolic pulmonary hypertension; PAH = pulmonary arterial hypertension;PH = pulmonary hypertension; V/Q = ventilation/perfusion. aCT pulmonary angiography alone may miss diagnosis of chronic thromboembolic pulmonary hypertension.

Figure 1.7 CTEPH diagnostic algorithm. Galiè et  al. 2015 ESC/ ERS guidelines for the diagnosis and treatment of pulmonary hypertension. Eur Respir J 2015; 46:903

thromboembolic disease was established with this study can be attributed to an appropriate radiographic interpretation, and when all the data were considered, the clinical picture was that of operable CTEPH. The additional benefit of CT was its effectiveness in ruling out coexisting mediastinal or parenchymal lung disease, along with competing diagnoses involving the pulmonary vessels such as a sarcoma (Chap. 12). In order to completely delineate or “map-out” this patient’s chronic thromboembolic disease, lung scintigraphy and catheter-­based pulmonary angiography were performed. To better establish surgical risk, pulmonary function studies (to rule out co-existing airways disease) and right heart catheter-

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ization were obtained to complete the evaluation. In many centers performing PTE surgery, coronary angiography is additionally obtained in certain age groups or in patients with CAD risk factors as it is prudent to surgically address significant coronary vascular disease when present. The recommended diagnostic guidelines have been promoted to emphasize a number of key points. It has been asserted that lung scintigraphy is the screening study of choice for CTEPH.  To a large extent this is based on a study by Tunariu and colleagues (2007) which demonstrated a greater sensitivity of lung scintigraphy in the detection of CTEPH compared to CT angiography. Though subsequent investigations performed at CTEPH experienced centers have challenged these findings (see He et  al. 2012) it has been consistently observed that distal vessel chronic thromboembolic disease can be difficult to detect with CT by inexperienced diagnosticians. Consequently, the finding of an abnormal lung perfusion study even with a “negative for PE” CTA warrants further evaluation for chronic thromboembolic disease and CTEPH. And although lung scintigraphy lacks specificity for CTEPH, a “negative study” showing a normal perfusion pattern effectively rules out operable CTEPH. The algorithm in Fig.  1.7 further suggests that in the setting of suspected CTEPH, seeking the advice of a group with experience in the diagnosis and management of this disease can be helpful. Confirming the diagnosis, establishing surgical candidacy, and sorting through optimal treatment options can be challenging.

Points of Emphasis For an at-risk patient and for those with unexplained exertional dyspnea and exercise intolerance…no matter what age….pulmonary vascular disease and/or CTEPH should be explored. The establishment of CTEPH as a diagnosis can lead to a potential cure with a surgical endarterectomy.

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Diagnosis 1. Operable chronic thromboembolic pulmonary hypertension.

Further Reading Galiè N, Humbert M, Vachiery JL, Gibbs S, Lang I, et al. 2015 ESC/ ERS guidelines for the diagnosis and treatment of pulmonary hypertension. The joint task force for the diagnosis and treatment of pulmonary hypertension of the European Society of Cardiology (ESC) and the European Respiratory Society (ERS). Eur Respir J. 2015;46:903–75. Gopalan D, Blanchard D, Auger WR.  Diagnostic evaluation of chronic thromboembolic pulmonary hypertension. Ann Am Thorac Soc. 2016;13(Suppl 3):S222–39. He J, Fang W, Lv B, He JG, Xiong CM, Liu ZH, He ZX. Diagnosis of chronic thromboembolic pulmonary hypertension: comparison of ventilation/perfusion scanning and multidetector computed tomography pulmonary angiography with pulmonary angiography. Nucl Med Commun. 2012;33(5):459–63. Renapurkar RD, Shrikanthan S, Heresi GA, Lau CT, Gopalan D. Imaging in chronic thromboembolic pulmonary hypertension. J Thorac Imaging. 2017;32(2):71–88. Tunariu N, Gibbs SJR, Win Z, Gin-Sing W, Graham A, Gishen P, AL-Nahhas A.  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;48:680–4.

Chapter 2 Case 2: There’s No Perfusion to that Lung! An Unusual Presentation for CTEPH Mona Alotaibi, Victor Pretorius, Deepa Gopalan, and William R. Auger

M. Alotaibi Pulmonary Fellow, Division of Pulmonary and Critical Care Medicine, University of California, San Diego, San Diego, CA, USA V. Pretorius (*) Division of Cardiovascular and Thoracic Surgery, University of California, San Diego, San Diego, CA, USA Heart Transplant and MCS Program, University of California, San Diego, San Diego, CA, USA e-mail: [email protected] D. Gopalan Department of Radiology, Imperial College Hospitals, London, UK e-mail: [email protected] W. R. Auger Lewis Katz School of Medicine, Temple University, Philadelphia, PA, USA e-mail: [email protected] © Springer Nature Switzerland AG 2020 W. R. Auger, D. Gopalan (eds.), Clinical Cases in Chronic Thromboembolic Pulmonary Hypertension, Clinical Cases in Cardiology, https://doi.org/10.1007/978-3-030-17366-1_2

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Case Presentation A 56-year-old white female presented with bilateral humeral fractures after a mechanical fall and worsening exertional dyspnea. She was hypoxemic in the emergency department with oxygen saturations of 84% on room air normalizing with 2 L nasal cannula O2 supplementation. Vital signs showed a pulse of 82, BP of 147/95, respiratory rate of 18, and a temperature of 98.6 °F. Physical exam was notable for normal first heart sound, loud P component of second heart sound and grade I/VI holosystolic murmur at the left lower sternal boarder. No dullness to percussion of the lungs was appreciated. No pulmonary bruit was auscultated. Lower extremities showed bilateral pitting edema, without clubbing or cyanosis. An initial troponin was 0.01  μg/L.  N-Terminal proBrain natriuretic peptide (NT-proBNP) was 467  pg/mL.  An electrocardiogram (ECG) revealed a normal sinus rhythm. A chest x-ray (Fig.  2.1) was

Figure 2.1  Frontal and lateral chest radiographs show asymmetrically enlarged left pulmonary artery, small right pulmonary artery; a hypovascular right lung with a relatively smaller right hemithorax

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read as showing an enlarged left pulmonary artery with diffuse bronchovascular markings; in addition, there was right lung volume loss with a reduction in vascular markings. Past medical history included left leg DVT and pulmonary embolism in 1987 with a placement of IVC filter and has been on anticoagulation with warfarin ever since. Her breathing never returned to baseline since. She has history of heparin induced thrombocytopenia (HIT), anti-thrombin 3 deficiency, and hypertension. Social history was notable for no alcohol, illicit drug use or tobacco use. An initial echocardiogram revealed mild right atrial dilation, mild right ventricular dilation and dysfunction with mild tricuspid regurgitation and a pulmonary artery systolic pressure (PASP) estimate of 32 mmHg. The left atrium was mildly dilated. The left ventricle was normal in size and systolic ­function. No pericardial effusion was present. Bubble contrast administration revealed no evidence of shunting. Serologies for connective tissue disease and human immunodeficiency virus were negative. Spirometry tests revealed a forced expiratory volume of 1.96 L (84% of predicted), forced vital capacity of 2.37  L (76% of predicted), with a ratio of 80%. A ventilation-perfusion scan was performed and revealed non-­perfusion of the entire right lung (Fig. 2.2). A computerized tomography pulmonary angiogram revealed abrupt termination of the distal right main pulmonary artery with unopacification of more distal right pulmonary arteries suggestive of chronic thromboembolism (Fig. 2.3). Right heart catheterization revealed a right atrial mean pressure (RAP) of 12  mmHg, pulmonary artery pressure (PAP) of 70/31 with a mean of 47 mmHg, a pulmonary wedge pressure (PAWP) of 21 mmHg, left ventricular end diastolic pressure (LVEDP) of 11  mmHg, cardiac output (CO) of 7.20  L/min, cardiac index (CI) of 3.32  L/min, resulting in a pulmonary vascular resistance (PVR) of 3.6 Wood units. Consultation with the pulmonary hypertension specialist resulted in a diagnosis of WHO group 4 chronic thromboembolic pulmonary hypertension (CTEPH).

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Figure 2.2  Lung scintigraphy showing absence of perfusion to the right lung; Xenon ventilation documenting a smaller right lung with resultant hemidiaphragm elevation, correlating with chest radiograph findings

Figure 2.3  CT angiography demonstrated complete obstruction of the distal right main PA.  There was no evidence for a mediastinal mass or adenopathy. Bronchial collaterals are indicated by the arrow

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Figure 2.4  Catheter based pulmonary angiogram shows complete occlusion of the right main pulmonary artery; on the left side there’s segmental vessel tortuosity without angiographic features for chronic thromboembolic disease. Poor opacification of the left sided vessels was due to a high output state

Pulmonary angiography revealed complete proximal occlusion of main right pulmonary artery without major vessel chronic thromboembolic disease in the left lung (Fig. 2.4). Referral to CTEPH center experienced with pulmonary thromboendarterectomy surgery was requested. Pulmonary thromboendarterectomy was ultimately performed with the removal of chronic thrombotic material as pictured in Fig. 2.5. Considerable “back-bleeding” in the right pulmonary arteries was observed during cardiopulmonary bypass. This resulted in a significant improvement in pulmonary hemodynamics with the following postoperative values: CVP 7, PAp 40/16 (25 mean), a thermodilution CO 4.9 L/min,

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Figure 2.5  Organized thrombus removed at time of PTE

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Figure 2.6 Lung scintigraphy after PTE surgery showing partial reperfusion of the right lung

a cardiac index of 2.3 L/min/m2. The only postoperative complication was a transient episode of atrial fibrillation. Early postoperative lung scintigraphy revealed partial reperfusion of her right lung (Fig. 2.6).

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Radiographic Interpretation Selected images from computerized tomography pulmonary angiography demonstrate a pouch defect in the distal right main pulmonary artery with complete occlusion of the lobar, segmental and subsegmental arteries in the right lung (Fig.  2.3). There are multiple enlarged bronchial collaterals, seen best on the coronal view (Fig. 2.7, open arrow).

Clinical Comments The first observation relevant to this case is that there are a number of clinical entities that are more commonly associated with non-perfusion of an entire lung than occlusion of a main pulmonary with organized, chronic thrombus. Extrinsic compression of the pulmonary artery from a mediastinal or hilar mass (adenopathy or neoplasm) or intrinsic disease of the artery as seen in vasculitis (e.g., Takayasu’s

Figure 2.7 Coronal view of CT angiography pictured in Fig.  2.3. Very large bronchial collateral vessel going to right lung (arrow)

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vasculitis, see Chap. 17) or a tumor (e.g. angiosarcoma, see Chap. 12) are in the diagnostic differential. In an adult, rarely is this finding due to pulmonary artery agenesis, especially in the absence of ipsilateral airway or parenchymal lung disease. This serves as the basis for the recommendation that a patient displaying such significant compromise in lung perfusion requires computed tomography or magnetic resonance imaging of the chest to assist the clinician in making the correct diagnosis. For those patients with chronic thromboembolic obstruction, and who are candidates for thromboendarterectomy surgery, there are numerous challenges to confront. Experience has shown that approximately 30% of patients with complete occlusion of a main pulmonary artery will not reperfused that lung even with a complete endarterectomy of the clot. And in another third of patients, incomplete reperfusion can be expected. Which outcome a patient will experience following a thromboendarterectomy is difficult to predict, though an extended period of occlusion seems to decrease the chance of reperfusion. This is especially the case if there is accompanying lung volume loss and scarring. A poor outcome is obviously more problematic if a patient presents with pulmonary hypertension and right heart dysfunction making it imperative that reperfusion and pulmonary hemodynamic benefit are achieved with endarterectomy surgery. In addition, the reasons for suboptimal re-perfusion are unclear. The development of a distal arteriopathy with extended proximal occlusion of a main pulmonary artery has been suggested as a potential mechanism for this outcome. “Competitive blood flow” from systemic collateral vessels has also been proposed. As seen in many CTEPH patients, and illustrated in this case presentation, obstruction of major pulmonary arteries promotes the compensatory development of an extensive collateral systemic circulation, which is important to maintain tissue viability. Whether this collateral circulation is an essential factor in the development of a distal arteriopathy or is responsible for the inhibition of pulmonary

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arterial blood flow after endarterectomy remain areas of ongoing research. In the presented case, what occurred was partial reperfusion of the right lung with recruitment of enough of the pulmonary vascular bed to result in significant pulmonary hemodynamic and symptomatic improvement. Whether or not this incomplete re-perfusion relates to the extensive collateral systemic blood flow is not known. However, as has been the case in similar patients, subsequent improvement in perfusion of the endarterectomized lung tends to occur over time as long as anticoagulation is maintained.

Points of Emphasis Complete scintigraphic absence of perfusion to an entire lung requires cross sectional diagnostic imaging to ascertain the cause. For those patients with chronic thrombotic occlusion, pulmonary thromboendarterectomy can be an effective intervention to re-establish blood flow, though may be best performed early in the course of the disease.

Diagnoses 1. Complete occlusion of a main pulmonary artery with chronic thromboembolus. 2. WHO group IV pulmonary hypertension.

Further Reading Cho S-R, Tisnado J, Cockrell CH, et  al. Angiographic evaluation of patients with unilateral massive perfusion defects in the lung scan. Radiographics. 1987;7(4):729–45. Dorfmüller P, Günther S, Ghigna MR, et al. Microvascular disease in chronic thromboembolic pulmonary hypertension: a role for pulmonary veins and systemic vasculature. Eur Respir J. 2014;44:1275–88.

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Hirsch AJ, Moser KM, Auger WR, Channick RN, Fedullo PF.  Unilateral pulmonary artery thrombotic occlusion: is distal arteriopathy a consequence? Am J Respir Crit Care Med. 1996;154(2):491–6. Kitcher A, Pretorius V, Kerr K, Fedullo P, Kim NH, Poch D, Madani M, Jamieson S, Auger W.  Complete pulmonary artery occlusion from chronic thromboembolic disease: outcomes following pulmonary thromboendarterectomy surgery. J Heart Lung Transplant. 2014;32(4S):S54. Laczika K, Lang IM, Quehenberger P, et  al. Unilateral chronic thromboembolic pulmonary disease associated with combined inherited thrombophilia. Chest. 2002;121:286–9. Madani M, Mayer E, Fadel E, Jenkins DP.  Pulmonary endarterectomy: patient selection, technical challenges, and outcomes. Ann Am Thorac Soc. 2016;13(Suppl 3):S240–7. Moser KM, Olson LK, Schlusselberg M, Dembitsky WP.  Chronic thromboembolic occlusion in the adult can mimic pulmonary artery agenesis. Chest. 1989;95:503–8.

Chapter 3 Case 3: Distal Chronic Thromboembolic Disease—Is Surgery an Option? Anjali Vaidya, Deepa Gopalan, and William R. Auger

Case Presentation A 63 year old white male with a history of hyperlipidemia and sick sinus syndrome requiring placement of a permanent pacemaker presented with dyspnea on exertion. A CT angiogram

A. Vaidya (*) Pulmonary Hypertension, Right Heart Failure, and CTEPH Program, Advanced Heart Failure and Cardiac Transplant, Lewis Katz School of Medicine, Temple University, Philadelphia, PA, USA Pulmonary Hypertension, Right Heart Failure, and CTEPH Program, Lewis Katz School of Medicine, Temple University, Philadelphia, PA, USA e-mail: [email protected] D. Gopalan Department of Radiology, Imperial College Hospitals, London, UK e-mail: [email protected] W. R. Auger Lewis Katz School of Medicine, Temple University, Philadelphia, PA, USA e-mail: [email protected] © Springer Nature Switzerland AG 2020 W. R. Auger, D. Gopalan (eds.), Clinical Cases in Chronic Thromboembolic Pulmonary Hypertension, Clinical Cases in Cardiology, https://doi.org/10.1007/978-3-030-17366-1_3

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of the chest at the time of presentation was read as showing no pulmonary embolus. Right heart catheterization revealed pre-capillary pulmonary hypertension, and he was started on bosentan for idiopathic pulmonary arterial hypertension (iPAH). After 9 months, this was discontinued due to elevated liver activity enzymes, and he was transitioned to sildenafil. One year later, for progressive dyspnea and right heart failure related to pulmonary hypertension, he was initiated on inhaled treprostinil. Subsequently, ambrisentan was added to his regimen. Two years thereafter, on this combination regimen, a repeat right heart catheterization was performed: mean PA pressure (mPAP) of 84 mmHg, cardiac output (CO) 5.2  L/min, pulmonary capillary wedge pressure (PCWP) of 10  mmHg, and pulmonary vascular resistance (PVR) of 14.2  Wood Units. Another CT angiogram of the chest was performed, again showing no evidence for acute pulmonary emboli. He remained on this regimen for 2 years, and after an episode of syncope, was transitioned from inhaled treprostinil to intravenous epoprostenol during a local hospital admission. Five years after his initial presentation, he was referred to a Pulmonary Hypertension Cardiologist for further evaluation. He reported exertional dyspnea and syncope with symptoms limiting his activities of daily living and World Health Organization functional class III. Physical exam was notable for BP 124/56, pulse 89, respiratory rate 14, and oxygen saturation of 95% on room air. His jugular venous pressure was 8 cm of water with ‘v’ waves to 12 cm of water, with positive abdominojugular reflux. An accentuated P2 and a III/VI holosystolic tricuspid regurgitation murmur that augmented with inspiration at the left lower sternal border were heard. No pulmonary bruits were heard. There were sharp contour arterial pulses without peripheral edema. An electrocardiogram (ECG) revealed sinus rhythm with an incomplete right bundle branch block, right ventricular hypertrophy, and evidence of right heart strain with right sided precordial and inferior T wave inversions. His 6  min walk distance (6 MW) was 331 m with oxygen desaturation to

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91%. N-terminal proBrain natriuretic peptide (NT-ProBNP) was 1178, Cr 0.96, and Na 138. ANA and HIV were negative. Review of his transthoracic echocardiogram revealed a small pericardial effusion, small and underfilled left ventricle with hyperdynamic function (LVEF 75%), severe tricuspid regurgitation, transmitral and tissue Doppler pattern consistent with normal left heart filling pressures, severe systolic interventricular septal flattening, mid-systolic notching of the right ventricular outflow tract pulse wave Doppler profile with a severely reduced acceleration time, severe RV enlargement (RV:LV ratio 1.8), RVSP estimated at 100 mmHg, and tricuspid annular plane systolic excursion (TAPSE) of 2.3 cm (Fig. 3.1). Social history was notable for no alcohol or drug use, and no history of anorexigen, methamphetamine, or other illicit drug use. There was no family history of pulmonary hypertension, autoimmune disease, or thrombophilia. His sildenafil dose was escalated, epoprostenol dose up-­ titrated, and an initial ventilation perfusion (V/Q) scan was performed, which revealed multiple unmatched perfusion defects in the bilateral upper and lower lobes (Fig. 3.2).

a

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Figure 3.1 (a, b) Preoperative echocardiogram showing enlargement of the right atrium (RA) and right ventricle (RV) with flattening of the interventricular septum (arrow)

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Figure 3.2 VQ scan shows bilateral mismatched segmental and subsegmental perfusion defects

A repeat CT angiography of the chest was performed and directly reviewed. Although no acute pulmonary emboli were seen, there was peripheral lining clot seen in the bilateral lower lobes and right upper lobe, suggestive of chronic thromboembolic disease. As his suspected underlying diagnosis shifted from iPAH to chronic thromboembolic pulmonary hypertension (CTEPH), he underwent pulmonary angiography with repeat right heart catheterization. Hemodynamics on triple PH directed medical therapy included a right atrial pressure (RAP) of 14 mmHg, PAP 98/26 (50) mmHg, PCWP 10 mmHg, CO 4.1 L/min, and PVR 10.5 Wood Units. Pulmonary angiography revealed evidence of bilateral multiple vascular narrowings and obstructive lesions in the distal vessels, with significantly reduced vascular markings in the right upper, right middle, and left lower lobes (Fig. 3.3). Taken together, his hemodynamics, VQ scan, direct review of his CT angiography, and pulmonary angiography con-

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Figure 3.3 Pulmonary angiogram demonstrating scattered distal arterial narrowings (“webs”) and vessel attenuation particularly in the right upper, right middle and left lower lobes

firmed his diagnosis of CTEPH.  Given the distal nature of his thromboembolic disease, consultation with an experienced PTE center performing distal endarterectomies was requested. Over the course of his initial evaluation with our Pulmonary Hypertension Cardiology program, the patient continued to deteriorate with worsening severe right heart failure. He lost 22 lb of weight, pulse increased to 110 and blood pressure fell to 101/50  mmHg. His jugular venous pressure was greater than 20 cm of water with abdominal ascites, pitting peripheral edema, and he was admitted for IV diuresis and further titration of IV epoprostenol. His NTProBNP increased to 2147, and creatinine increased to 1.45 mg/dL. His 6 min walk distance fell to 247 m. He was urgently evaluated at the referral PTE center, where he underwent IVC filter placement followed by bilateral pulmonary thromboendarterectomy (Fig. 3.4).

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Figure 3.4  Chronic thrombotic material removed at thromboendarterectomy. Ruler = 15 cm

Post-operatively, his hemodynamics (off PH-directed medical therapy) revealed RAP of 12 mmHg, PA 58/12 (25) mmHg, CO 5.3 L/min, and PVR 2.3 Wood Units. He was treated for reperfusion lung injury with mechanical ventilator support and diuresis, and ultimately discharged on post-­operative day #13. His post-operative V/Q scan revealed increased perfusion to posterior and superior RLL, RML, LLL, and lingular territories, with ‘perfusion steal’ from the LUL, superior segment of the LLL, and persistent defects RUL. Six months post-operatively, off all PH specific medical therapy and oxygen supplementation, he had regained 28 lb of flesh weight, had WHO Functional Class I, pulse reduced to 71, BP increased to 134/70, 6 min walk distance increased to 567  m without significant desaturation. NT ProBNP had fallen to 847, and creatinine had fallen to 0.69  mg/dL.  His echocardiogram revealed no interventricular systolic septal flattening, only mild RV enlargement, normal RV function, and estimated PASP 30 mmHg. His pulmonary hypertension has been cured, managed solely with warfarin for anticoagulation. His recovery and excellent clinical status has persisted to 2 years post-operatively (Fig. 3.5).

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Figure 3.5  Echocardiogram 6 months after pulmonary thromboendarterectomy showing a significant reduction in right atrial and right ventricular size with improved RV function

Radiographic Interpretation To better assess this patient’s candidacy for PTE surgery, selective pulmonary angiography with AP and lateral views was performed to “map out” the extent and localization of disease. This study demonstrates numerous features of chronic thromboembolic disease. On the right side (Fig. 3.6a), there were several “pouch” defects involving the segmental anterior and posterior right upper lobe and basal lateral right lower lobe arteries (solid arrows). A segmental web is present in the apical branch of the right upper lobe artery (open arrow). There is abrupt calibre change with diffuse irregularity in a predominant distal distribution in the lower lobe vessels. On the left (Fig. 3.6b), “pouch” defects are present in the anterior segment of the left upper lobe and medial basal left lower lobe arteries and at the subsegmental level in the apical branch of the left upper lobe vessel (solid arrows). There is a web in the distal lingula and stenosis in the posterior basal left lower lobe artery (open arrows). These findings are best depicted on lateral views, and were not evident on the prior AP pulmonary angiographic studies.

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Clinical Comments This case provides a number of important lessons in the diagnosis and treatment of patients with CTEPH, especially for those with disease primarily in the segmental and subsegmental vessels. The initial point of discussion, however, is that the evaluation of a patient with pulmonary hypertension should include a V/Q scan to screen for chronic thromboembolic pulmonary hypertension. Observations from Tunariu and colleagues have demonstrated that the V/Q scan has a sensitivity of greater than 96% for detecting CTEPH, better than the 51% sensitivity of CT angiography of the chest. Although with contemporary CT capabilities and expert interpretation the value of CT in screening for this disease has been shown to be nearly comparable to lung scintigraphy, “missing” CTEPH by CT… as was the issue in the above case… can result in considerable delay in diagnosis, and as a result, a missed opportunity to offer the most appropriate and effective intervention. The essential lesson from this case comes from what occurred once the patient was referred to a center experienced in the evaluation and treatment of CTEPH. Once the perfusion scan revealed unmatched defects, the diagnostic approach was appropriately directed to establishing the basis for these defects. A review of the CT angiogram raised suspicions for the presence of organized thrombi in the distal vascular bed, but the lack of certainty prompted what many feel to be the “gold standard” procedure for the diagnosis of chronic thromboembolic disease….catheter based p ­ ulmonary angiography. And in fact, at the segmental and subsegmental level, a properly performed pulmonary angiogram has been shown to be of greater sensitivity for the detection of chronic thromboembolic lesions compared to CT angiography (see Suguira et al. 2013). This approach in this case led to the correct diagnosis, ultimately prompting a referral to a center with surgical experience in the removal of distal vessel chronic thromboembolic disease.

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The task for the expert surgical center than becomes one of not only confirming the diagnosis, but adequately defining the extent of disease and localizing or “mapping out” the lesions. An assessment of surgical candidacy is dependent on the quality of pre-operative imaging and, most importantly, the capabilities of the surgical team. A significant prognostic factor for successful outcomes following PTE surgery relates to the experience of the CTEPH physicians and institution, and this is especially the case with segmental (Level III) and subsegmental (Level IV) resection. Selective pulmonary angiography including lateral views in this patient more clearly defined the extent and localization of the chronic thromboembolic disease present, thereby allowing the surgical team to assess whether or not endarterectomy was feasible within their capabilities. Finally, the importance of recognizing distal vessel CTEPH as potentially amenable to thromboendarterectomy is underscored by the observation that significant pulmonary hemodynamic benefit, and in most instances, resolution of a patient’s pulmonary hypertension and RV failure can be achieved with surgery (see D’Armini et al. 2014). This case is also an example of a known risk factor for developing distal vessel CTEPH.  The presence of chronic indwelling catheters, pacemaker wires, or ventriculoatrial shunts are far more prevalent in patients with Level III and Level IV disease than in proximal vessel CTEPH. Given the relatively small thrombus formation associated with such devices, it is not surprising that the chronic thromboembolic disease in this patient’s case was distal, as opposed to the more proximal disease associated with known lower e­ xtremity deep vein thrombosis (DVT) or a history of a massive or submassive pulmonary embolus.

Points of Emphasis In experienced CTEPH centers, resection of distal vessel chronic thromboembolic disease is technically feasible and can result in meaningful improvement in pulmonary hemodynamics and clinical status.

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Diagnosis 1. Distal vessel hypertension.

chronic

thromboembolic

pulmonary

Further Reading Bonderman D, Wilkens H, Wakounig S, et  al. Risk factors for chronic thromboembolic pulmonary hypertension. Eur Respir J. 2009;33:325–31. D’Armini AM, Morsolini M, Mattiucci G, et al. Pulmonary endarterectomy for distal chronic thromboembolic pulmonary hypertension. J Thorac Cardiovasc Surg. 2014;148:1005–12. He J, Fang W, Lv B, et  al. Diagnosis of chronic thromboembolic pulmonary hypertension: comparison of ventilation/perfusion scanning and multidetector computed tomography pulmonary angiography with pulmonary angiography. Nucl Med Commun. 2012;33:459–63. Madani MM, Jamieson SW. Technical advances of pulmonary endarterectomy for chronic thromboembolic pulmonary hypertension. Semin Thorac Cardiovasc Surg. 2006;18:243–9. Madani M, Mayer E, Fadel E, Jenkins DP.  Pulmonary endarterectomy: patient selection, technical challenges, and outcomes. Ann Am Thorac Soc. 2016;13(Suppl 3):S240–7. Mayer E, Jenkins D, Lindner J, et  al. Surgical management and outcomes of patients with chronic thromboembolic pulmonary hypertension: results from an international prospective registry. J Thorac Cardiovasc Surg. 2011;141:702. 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;48:680–4. Sugiura T, Tanabe N, Matsuura Y, et al. Role of 320-slice CT imaging in the diagnostic workup of patients with chronic thromboembolic pulmonary hypertension. Chest. 2013;143:1070–7.

Chapter 4 Case 4: The Case for Balloon Pulmonary Angioplasty David S. Poch, Deepa Gopalan, and William R. Auger

Case Presentation A 27-year-old female with no significant past medical history developed dyspnea and a mild non-productive cough 2  years prior to presentation. She was evaluated by her internist at that time and placed on a proton pump inhibitor and an inhaled corticosteroid with some improvement. Approximately 1 year later she developed sudden onset of left arm discomfort, swelling and “purplish” discoloration. An ultrasound showed a left arm DVT,

D. S. Poch (*) University of California, San Diego, La Jolla, CA, USA e-mail: [email protected] D. Gopalan Department of Radiology, Imperial College Hospitals, London, UK e-mail: [email protected] W. R. Auger Lewis Katz School of Medicine, Temple University, Philadelphia, PA, USA e-mail: [email protected] © Springer Nature Switzerland AG 2020 W. R. Auger, D. Gopalan (eds.), Clinical Cases in Chronic Thromboembolic Pulmonary Hypertension, Clinical Cases in Cardiology, https://doi.org/10.1007/978-3-030-17366-1_4

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and a CT angiogram of her chest showed segmental and subsegmental pulmonary emboli. An echocardiogram at that time showed RV dilatation and an estimated RVSP of 46  mmHg. Lower extremity duplex showed no evidence of DVT. She was started on rivaroxaban with improvement in her left upper extremity but only modest improvement in her dyspnea. Three months after starting rivaroxaban her symptoms of dyspnea persisted and a follow up echocardiogram demonstrated RV enlargement and worsening pulmonary hypertension. V/Q scan was performed and demonstrated large, bilateral perfusion defects. The patient was told she had thoracic outlet syndrome, although she had no history of repetitive upper extremity motions that might provoke this syndrome (such as those occurring in sports like volleyball or swimming). Additionally, she never experienced an accident or trauma to her thoracic cavity. Based on the suspicion for chronic thromboembolic pulmonary hypertension (CTEPH) she was referred to a specialized CTEPH center with expertise in pulmonary thromboendarterectomy (PTE) surgery. At the time of evaluation for PTE she was NYHA functional class III.  She had difficulty climbing stairs and could walk less than 300  ft on flat ground without becoming winded. She also noted right-sided chest pain and intermittent right arm numbness with exertion. She reported frequent palpitations and a persistent non-productive cough. She had no episodes of syncope, no edema or abdominal distention. Review of symptoms revealed a history of Raynaud’s phenomenon but no other stigmata of connective tissue disease. She had no other identifiable risk factors for WHO Group I pulmonary arterial hypertension and no signs or symptoms consistent with systemic vasculitis. She had no history of tobacco use, alcohol consumption or illicit drug use. Physical examination revealed a tall (6  ft), 54  kg female with a systemic blood pressure of 112/72, pulse rate of 76 BPM, respiratory rate of 16 BPM and saturation of 99% on room air. Cardiac exam was notable for a loud S2, a tricuspid regurgitant murmur, soft RV heave, but no S3 gallop. Lung exam revealed clear lung fields and no pulmonary flow murmurs. There was

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Figure 4.1 Lung scintigraphy demonstrating multiple unmatched perfusion defects in both lungs

no edema, clubbing or cyanosis of her extremities and peripheral pulses were intact without bruits. Laboratory findings were notable for an NT-pro BNP of 2793 pg/mL, Hgb of 15.3 g/dL and serum creatinine of 1.0 mg/ dL. Hypercoagulable work up was negative. Ventilation perfusion imaging (Fig. 4.1) demonstrated normal ventilation with multiple, large perfusion defects in the bilateral lung fields. Echocardiogram revealed an RVSP of 82 mmHg, a severely enlarged right ventricle, a trivial pericardial effusion and a TAPSE of 1.3  cm. Hemodynamics obtained during right heart catheterization were: mean RA pressure 12  mmHg, PAP 83/34  mmHg, mean PA pressure 52  mmHg, PCWP 10  mmHg. Fick CO 2.63  L/min (CI 1.54  L/min/m2), thermodilution CO 2.77 L/min (CI 1.62 L/min/m2) and PVR 16.2 Wood Units. Testing with inhaled nitric oxide was negative for vasoreactivity. A non-selective digital subtraction angiogram was performed (Fig. 4.2) to evaluate her lung scan findings and demonstrated features atypical for CTEPH.

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Figure 4.2  Pre-intervention pulmonary digital subtraction pulmonary arteriogram

While there were several features suggestive of chronic thromboembolic disease on her pulmonary angiogram, the small vessel caliber size throughout, along with a discordance between the degree of pulmonary hypertension and her “thrombus burden” suggested an atypical presentation for a pulmonary vasculitis. (see Case) However, an MR angiogram of the systemic great vessels was obtained and showed no evidence for vasculitis in the aorta, mesenteric, renal, subclavian or carotid arteries. Even with vasculitis ruled out, the atypical and discordant angiographic features were to such a degree that it was assessed endarterectomy surgery might offer little benefit and, with her degree of right heart compromise, carry a high procedural mortality. The decision was made to start combination oral pulmonary hypertension targeted therapy with riociguat and macitentan followed by balloon pulmonary angioplasty (BPA). Approximately 3  weeks after initiating macitentan and riociguat the patient returned for the first session of balloon pulmonary angioplasty. Her dyspnea on exertion was modestly improved but she remained NYHA functional class III. NT-pro BNP had improved to 1022 pg/mL and she walked 360 m on 6 min walk testing. Repeat right heart catheterization immediately prior to the first BPA session demonstrated the benefits of her PAH targeted medical therapy. Her mean PA pressure had decreased to 45 mmHg and her Fick CO had increased to 4.26  L/min (CI 2.52  L/min/m2) and thermodilu-

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tion CO 3.77 L/min (CI 2.22 L/min/m2), resulting in a reduction of PVR from 16 to 9–10 Wood Units. Selective angiography revealed very small caliber vessels in every lung segment. Most of her lower lobe segmental vessels were no more than 2  mm in diameter prior to BPA (Fig.  4.3). The approach to initial BPA sessions was necessarily cautious given her severe pulmonary hypertension and small caliber of her vessels. After eight sessions of balloon pulmonary angioplasty, all PH targeted therapies had been discontinued and the patient was NYHA Functional Class II. Right heart catheterization prior to her ninth and final session of BPA revealed PA 49/16 mmHg, mean PA pressure 30 mmHg Fick CO 5.81 L/ min (CI 3.28  L/min/m2), thermodilution CO 4.73  L/min (CI 2.67 L/min/m2) and a PVR of 3.4–4.2 Wood Units. Follow-up lung scintigraphy (Fig. 4.4) revealed areas of improved perfusion, particularly in her lower lobes.

Radiographic Interpretation Frontal and lateral views of the selective pulmonary angiogram demonstrated that the segmental branches bilaterally were of generally small caliber with attenuation as the vessels reach the mid third of the lungs. There was a generalized paucity of vasculature in the peripheral third of the lungs with lack of sub-pleural perfusion in the parenchymal phase, this slightly more prominent on the right. A “pouch lesion” was present in the right middle lobe with a thin trickle of contrast medium extending from the convexity. There were segmental stenoses in the medial, anterior and lateral basal right lower lobe and anterior branch of the left lower lobe (Fig. 4.2). The right lower lobe stenoses were much better delineated on the dedicated super-selective angiogram performed prior to balloon pulmonary angioplasty. Post-angioplasty, there was angiographic improvement, with restoration of flow beyond the diseased segments (Fig. 4.3). This improvement was mirrored on the perfusion scintigraphy with resolution of some of the perfusion defects when compared to the pre-treatment scintigram (Fig. 4.4).

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Figure 4.3  Immediate increase in vessel density to right lower lobe after BPA session

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Clinical Comments Published guidelines, and clinical practice at most expert CTEPH centers have advocated that balloon pulmonary angioplasty should be reserved for those CTEPH patients with lesions felt to be inoperable, or in those patients with co-morbidities that preclude surgical consideration. It was only after discussion with a multidisciplinary team of experts skilled in the surgical approach to CTEPH that this patient was excluded from PTE surgery. Even after MRI made the diagnosis of vasculitis less likely, the unusual pulmonary angiographic features raised significant concern that PTE would be technically challenging given the small caliber of vessels and offer limited hemodynamic benefit. There is clearly some subjectivity that led to this decision. Challenging cases such as this emphasize that PTE operability decisions are best handled by multidisciplinary teams, experienced in the evaluation and management of the CTEPH patient. This case further stresses the step-wise approach to angioplasty in establishing meaningful endpoints. Though there remained numerous…and large …perfusion defects on lung scintigraphy, the patient achieved significant hemodynamic improvement off all PH targeted medical therapy, improvement in Nt Pro BNP, improvement in 6 min walk testing and dramatic improvement in functional status.

Point of Emphasis For those patients with inoperable chronic thromboembolic pulmonary hypertension, balloon pulmonary angioplasty can be a viable option to provide a clinically meaningful improvement in pulmonary hemodynamics and functional status.

Diagnosis 1. Inoperable chronic hypertension.

thromboembolic

pulmonary

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Further Reading Mahmud E, Madani MM, Kim NH, et  al. Chronic thromboembolic pulmonary hypertension: evolving therapeutic approaches for operable and inoperable disease. J Am Coll Cardiol. 2018;71(21):2468–86. Ogawa A, Satoh T, Fukuda T, Sugimura K, Fukumoto Y, et al. Balloon pulmonary angioplasty for chronic thromboembolic pulmonary hypertension: results of a multicenter registry. Circ Cardiovasc Qual Outcomes. 2017;10(11):pii:e004029. Ogo T.  Balloon pulmonary angioplasty for inoperable chronic thromboembolic pulmonary hypertension. Curr Opin Pulm Med. 2015;21(5):425–31.

Chapter 5 Case 5: Operable CTEPH … but Is PTE the Best Option? Sonja Bartolome, Deepa Gopalan, and William R. Auger

Case Presentation A 66-year old male presents to the hospital with increased dyspnea and was admitted to the hospital with acute on chronic hypoxemic respiratory failure. He had been on his usual 3–4 L/ min of oxygen by nasal cannula but just could not catch his breath. He denied fever, wheezing or a productive cough.

S. Bartolome (*) CTEPH Program, UT Southwestern Medical Center, Dallas, TX, USA Pulmonary and Critical Care Medicine, UT Southwestern Medical Center, Dallas, TX, USA e-mail: [email protected] D. Gopalan Department of Radiology, Imperial College Hospitals, London, UK e-mail: [email protected] W. R. Auger Lewis Katz School of Medicine, Temple University, Philadelphia, PA, USA e-mail: [email protected] © Springer Nature Switzerland AG 2020 W. R. Auger, D. Gopalan (eds.), Clinical Cases in Chronic Thromboembolic Pulmonary Hypertension, Clinical Cases in Cardiology, https://doi.org/10.1007/978-3-030-17366-1_5

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In the emergency department a 100% oxygen nonrebreather mask was required to maintain oxygen saturations >90%. On physical exam he had a pulse of 112, was tachypneic at 22 breaths per minute, blood pressure was 118/73 and he was afebrile. His lung exam revealed no wheezing but a few rales in the right base and a pulmonary flow murmur on the right. His cardiac exam revealed a markedly increased pulmonic component of the second heart sound, a grade 2/6 systolic murmur at the right upper sternal border, a right ventricular S3, and a right ventricular heave. He had JVD to the jaw and 2+ lower extremity pitting edema to the knees. He had a normal white blood cell count, his hemoglobin was elevated at 17.6 mg/dL, platelet count was normal, electrolytes and renal function were normal and an N-terminal proBrain natriuretic peptide was 5354  pg/mL.  A portable chest X-ray was performed (Fig.  5.1) which revealed marked cardiomegaly and large pulmonary arteries. Lasix was administered and he was admitted to the intensive care unit. Prior to presentation, he was unable to walk through large grocery stores without stopping. However, he drives, cares for himself, and does his other activities of daily living. He is

Figure 5.1 Admission chest radiograph demonstrating cardiomegaly and massively enlarged central pulmonary arteries

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using 3 L oxygen by nasal cannula at all times but his oxygen saturations drop to the 70s when walking short distances. Recently in clinic his 6-min walk test showed a distance of 134  m with oxygen saturations 80–86% on 25  L per nasal cannula. His pulmonary function testing reveals an FEV1 of 1.89 L (54% of predicted), FVC of 3.66 L (78% predicted), and an FEV1/FVC ratio of 51%. The patient was unable to perform the lung volume or DLCO maneuver due to dyspnea and hypoxemia. By provided history, at age 19 he was diagnosed with a pulmonary embolism after presenting with hemoptysis and was anticoagulated for several months but then enlisted in the United States Army and stopped his warfarin. He stayed off of the warfarin until 1990 when he presented with dyspnea and was found to have an “acute PE in the main pulmonary artery.” He again was treated with warfarin but only took it for 1–2  years and then was lost to follow-up. He presented to a health care provider for routine care and was restarted on anticoagulation in 2000 and has been on it ever since. He has been a heavy smoker for the past 30 years and was diagnosed with chronic obstructive pulmonary disease (COPD) a decade ago by pulmonary function testing. He started using oxygen about 8 years ago. The patient has had frequent admissions for COPD exacerbation characterized by productive cough, dyspnea, wheezing and an increased oxygen requirement. At the time of each episode he is treated with antibiotics and steroids and improves. His pulmonologist noted he had pulmonary hypertension, and recognized that it might be related to chronic thromboembolic disease after a ventilation/perfusion scan and computed tomography of the chest were obtained. He was started him on an oral prostacyclin approximately 8 months prior to presentation. The patient felt much worse on this and his oxygen requirement had been increasing. Other past medical history included a gastric ulcer, chronic atrial fibrillation, gout, a chainsaw accident with a hand injury and squamous cell skin cancer. He has been evaluated for a thrombophilia but none was found.

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Social History is notable for smoking 3/4 pack per day for 30 years. Upon presentation he was smoking e-cigarettes. He has a significant alcohol history and consumed at least 20 cans of beer per week for 30 years. He now drinks 1–2 beers per week. He worked in oil field, drilling. In the Army, he was a transportation security gunner. Family history was significant for coronary artery disease but no clotting disorders, pulmonary emboli or deep vein thrombosis. A ventilation perfusion scan was performed. There were segmental V/Q mismatches in the anterior left upper lobe, the lingula, and to a lesser extent, in the LLL. Overall perfusion to the right lung was reduced sparing a small region of the anterior right lower lobe (Fig. 5.2). A CT angiogram was performed revealing large pulmonary arteries with lining, calcified clot in the main pulmonary arteries and bilateral segmental branches, and an enlarged right atrium and ventricle (Fig. 5.3). High resolution computed tomography of the chest was then obtained due to his history of parenchymal lung disease. This revealed centriacinar and paraseptal emphysema, ­dilation of the main pulmonary artery with calcification along

Figure 5.2  Abnormal perfusion scintigraphy with distinct segmental defects involving primarily the left lung

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Figure 5.3  Calcified thrombus lining the central pulmonary vessels. (Panels a–c) Proximal vessel narrowing of the lingula (Panel b, arrow) from chronic thromboembolic disease, along with reduction in vascularity of the RML (Panel c, open arrow) and vessel attenuation (Panel d, arrow) due to involvement of the central vessels with calcified thrombus. Panel d also showing right atrial enlargement and hypertrophy of the RV free wall

its walls and the right and left segmental pulmonary arteries (Fig. 5.4). Pulmonary angiography was performed suggesting central chronic thromboembolic disease with web defects and discrete vessel narrowing in the RUL, RLL, and LUL, absent perfusion to the RML, a “pouch defect” in the RUL, occluded segmental vessels in the LLL and lingula, with turbulent contrast filling in both main pulmonary arteries (Fig. 5.5).

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Figure 5.4  (a–c) Extensive parenchymal lung disease demonstrated on high resolution computed tomography

Figure 5.5  Frontal views of the pulmonary arteriogram demonstrating changes consistent with chronic thromboembolic disease

Right and left heart catheterization revealed a right atrial pressure of 12  mmHg, pulmonary artery pressure of 103/42 (63) mmHg, a left ventricular end diastolic pressure of 5  mmHg, and a cardiac output of 6.43  L/min with a cardiac index of 2.95 L/min/m2 while on inotropic support. Coronary angiography revealed no significant coronary disease.

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During this evaluation, the patient was in the ICU on a high flow nasal cannula. The oral prostacyclin therapy was titrated to off because of concerns that it may be worsening ventilation/perfusion mismatching and an oral phosphodiesterase type-5 inhibitor was titrated up to a high dosage. He was diuresed aggressively and his decompensated right ventricular failure was treated with a dopamine infusion to decrease right ventricular pressure/volume overload. The patient tolerated this well and after approximately 2.5 weeks in the ICU and another 1.5 weeks on the hospital floor he was transferred to home on 6 L per nasal cannula. He was evaluated for pulmonary thromboendarterectomy including a ­second review by an experienced center and it was determined he was a poor candidate due to his degree of pulmonary parenchymal disease. A transplant evaluation was pursued and completed while the patient was an inpatient and he was listed for transplant shortly thereafter. He underwent successful lung transplantation approximately 1 month later. He is doing well at home and is no longer needing oxygen.

Radiographic Interpretation Chest radiograph shows cardiomegaly with marked proximal pulmonary artery dilatation. There is calcification, seen most prominently in the main PA. Subsegmental atelectasis is present in the right lower lobe. There is a small left pleural ­effusion. Overall, the appearances are that of long standing PH with likely pulmonary congestion. The findings on perfusion scan with the presence of large bilateral segmental perfusion defects is highly suspicious for thromboembolic disease rather than PAH as the underlying aetiology. CTPA shows dilated and hypertrophied right ventricle with reversal of septal curvature and an enlarged right atrium with compression of the under-filled left atrium. There is eccentric thrombus with peripheral calcification in the dilated right and left main pulmonary arteries. Associated with this

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finding is proximal vessel narrowing of the lingula, a reduction in vascularity of the RML, and vessel attenuation of the medial left lower lobe artery. Eccentric lining thrombus is also evident in one of the right lower lobe segmental vessels. The lung windows demonstrate paraseptal and centrilobular emphysema with upper lobe predominance. Selected views from a catheter pulmonary angiogram shows eccentric intimal thrombus in the right main PA, extending in to the right lower lobe. There is a pouch defect with complete occlusion of the middle lobe. Proximal webs are present in segmental right upper lobe. The anterior, posterior and lateral basal segments of the right lower lobe are occluded. There is stenosis with post stenotic dilatation of medial branch of the right lower lobe. On the left, there is intimal thrombus in main PA and left lower lobe vessel where there is a proximal stenosis followed by post stenotic dilatation. The superior segment of the lower lobe is occluded and anterior and lateral segments are truncated. There is segmental web disease in the left upper lobe and truncated appearance to the lingular branches. A salient feature seen bilaterally is the extreme tortuosity of the vessels in general. This is seen in very longstanding PH. The known PA wall calcification is difficult to appreciate on the angiogram although there is excellent depiction of the vessel lumen, this is a well-­recognized limitation of catheter angiography.

Clinical Comments This case has features of severe pulmonary hypertensions secondary to very long standing chronic thromboembolic disease. Disease distribution is proximal and radiologically amenable to surgery but an important co-morbidity in the form of emphysema has been revealed on the thoracic CT. Patients with significant parenchymal lung disease derive little benefit from pulmonary endarterectomy, as revascularization of regions affected with either significant emphysema or interstitial lung disease can cause profound refractory hypoxemia and respiratory failure post-surgery (see Madani et  al. 2016). This observation has resulted in one of the

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­ axims of PTE surgery… “never attempt to reperfuse bad m lung” (also see Chap. 19). An exception to this rule is when the emphysema is limited to the upper lobes and chronic thromboembolic disease involves vessels supplying preserved lung parenchyma. Surgery in this situation has the potential to be beneficial as there will be improvement in matching ventilation and perfusion. One should however be very careful when assessing the emphysema severity. CT has been extensively validated as a tool for assessment of the presence, pattern, and severity of emphysema. But it should be remembered that visual quantification of emphysema burden on CT scan is a weak predictor of lung function and individuals with similar levels of physiological impairment may have very different CT appearances. Hence, it is important to complement the CT changes with objectives measures of lung function. Consequently, though this patient’s history was compelling for recurrent pulmonary embolic events, and his radiographic studies showed evidence for operable chronic thromboembolic disease, the extent of his air flow obstruction, his parenchymal lung disease, and other comorbidities made it unlikely thromboendarterectomy alone would result in meaningful clinical improvement.

Point of Emphasis The presence of operable chronic thromboembolic disease does not by itself establish the surgical candidacy of a patient for pulmonary thromboendarterectomy. A consideration of comorbidities and an assessment that there’s a high likelihood of achieving a favorable outcome need to factored in the decision to proceed with PTE surgery.

Diagnosis 1. Chronic thromboembolic pulmonary hypertension with decompensated right heart failure. 2. Centriacinar and paraseptal COPD—BODE index of 6.

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Further Reading Auger W, Kerr K, Kim N, Fedullo P.  Evaluation of patients with chronic thromboembolic pulmonary hypertension for pulmonary thromboendarterectomy. Pulm Circ. 2012;2(2):155–62. Madani M, Eckhard M, Fadel E, Jenkins P. Pulmonary endarterectomy: patient selection, technical challenges and outcomes. Ann Am Thorac Soc. 2016;13(S3):S240–7.

Chapter 6 Case 6: Distal Vessel Thromboendarterectomy— How Far Can We Go? Angela Bautista, Michael M. Madani, Deepa Gopalan, and William R. Auger

Case Presentation Fifteen-year-old female who had been previously healthy, playing competitive volleyball all of her life. In March 2014, during softball tryouts, she noted chest pain and dyspnea with A. Bautista (*) CTEPH Program, University of California, San Diego, San Diego, CA, USA e-mail: [email protected] M. M. Madani University of California, San Diego, San Diego, CA, USA e-mail: [email protected] D. Gopalan Department of Radiology, Imperial College Hospitals, London, UK e-mail: [email protected] W. R. Auger Lewis Katz School of Medicine, Temple University, Philadelphia, PA, USA e-mail: [email protected] © Springer Nature Switzerland AG 2020 W. R. Auger, D. Gopalan (eds.), Clinical Cases in Chronic Thromboembolic Pulmonary Hypertension, Clinical Cases in Cardiology, https://doi.org/10.1007/978-3-030-17366-1_6

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running. She was seen by her primary care physician and diagnosed with musculoskeletal pain, pleurisy and exercise-­ induced asthma. By October of 2014, she could not walk up one flight of stairs. Further workup revealed a pulmonary embolus and a right subclavian DVT. She was initially placed on warfarin, however, she developed a right hemothorax in the area of the right lower lobe infarct, which required chest tube placement and had approximately 1.5 L drained. During the same hospitalization, a right subclavian venogram showed a nonocclusive thrombus directly adjacent to the first rib consistent with Paget-Schroetter syndrome. On right heart catheterization, her pulmonary pressures were 70/20 with a mean of 40 with an echocardiogram revealing right atrial and right ventricular enlargement along with RVH.  She also developed an occlusive thrombus involving her left basilic vein at a previous IV site despite having therapeutic INRs and was deemed a “coumadin failure”. She was eventually discharged home on Eliquis. At the time of her evaluation 2 months later at a specialized center for CTEPH patients, she was experiencing WHO functional class III symptoms. She could walk for approximately 25 ft and not quite half a flight of stairs before experiencing dyspnea. She complained of chest pain with overexertion and had some lightheadedness when bending forward. She denied syncope, cough, hemoptysis, lower extremity edema. She was started on diuretics due to liver congestion and was also placed on supplemental oxygen at 2 L during sleep and with exertion. No family history of blood clots or bleeding disorders. She denies tobacco use, alcohol and illicit drug use. Her chest radiograph revealed blunting of the right costophrenic angle with peripheral scarring of the right upper lobe. The right atrium was enlarged and the central pulmonary arteries were prominent (Fig. 6.1). Ventilation perfusion scan showed perfusion defects to the apical posterior segments of the left upper lobe, superior lingula, and the anterobasal and lateral basal segments of the left lower lobe. In the right lung there are defects in the right upper lobe, right middle lobe and basal segments of the right lower lobe (Fig. 6.2).

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Figure 6.1 Preoperative chest radiograph showing a prominent right atrial shadow, with central PA enlargement

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An echocardiogram revealed RA and RV severely enlarged with depressed RV systolic function. LV size is small, with normal systolic function, TR velocity 4.5 m/s with PA systolic pressure 82 mmHg plus CVP, cardiac output 4.4 L/min, mild tricuspid regurgitation, absent pericardial effusion. Laboratory data was as follows: Sodium 142, potassium 4.0, chloride 103, bicarbonate 24, BUN 15, creatinine 1.14, blood glucose 99. Liver function tests within normal limits except total bilirubin mildly up at 1.54. Urinalysis was negative for protein. White blood cell count 6.9, hemoglobin 13.6, hematocrit 41.5, platelets 259,000. INR 1.3, PTT 39.6. Right heart catheterization showed right atrial mean pressure 10 mmHg, PA pressure 101/28 with a mean of 58 mmHg, Pulmonary capillary wedge pressure 13 mmHg, Cardiac output 3.30 L/min, cardiac index 1.95 L/min/m2, Pulmonary vascular resistance 1091 dynes/sec/cm-5. Pulmonary angiogram on the right side demonstrated a “pouch defect” in the right lower lobe; webs in the right upper lobe apical and anterior vessels. On the left side, the anterior medial vessels to the lower lobe were narrowed at the distal segmental and subsegmental level with a reduction in vascularity to the posterior LLL.  Otherwise, there was a “pouch defect” in the superior segment, proximal occlusion of the lingula and a web in posterior left upper lobe (Fig. 6.3). She was ultimately determined to have operable CTEPH and underwent pulmonary thromboendarterectomy with a total circulatory arrest time of 67 min; 35 min for the right side and 32  min for the left. Postoperative hemodynamics were CVP 12, PAP 47/18 (28), mean 19 mmHg, CO 5.30 L/min, CI 3.2 L/min/m2 and estimated PVR 256 dynes/s/cm-5 (Fig. 6.4). In the absence of major postoperative difficulties, this patient was discharged from hospital on postoperative day 9, with the recommendation for lifelong anticoagulation. Subsequent hematologic evaluation showed her to have “elevated PAI-1 levels”. Over the 3  years following her surgery, she has returned to a normal functional status (high school activities, lifting weights, running), and able to engage in her first year of university studies.

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Figure 6.3  (a–d) Frontal (panel a) and lateral (panel b) views of the left pulmonary artery. Frontal (panel c) and lateral (panel d) views of the right pulmonary artery

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Figure 6.4 Organized thrombus removed at endarterectomy, primarily from the subsegmental vessels (Level IV resection)

Radiographic Interpretation A more detailed interpretation of the studies presented reveals that the chest radiograph demonstrates a dilated right atrium and enlargement of proximal pulmonary arteries with peripheral pruning. There is parenchymal scarring in the right mid zone. The blunted costophrenic angle could be due to chronic right basal pleural reaction secondary to the previous documented episode of right haemothorax with a small effusive component. VQ scintigraphy shows normal ventilation and multiple mismatched bilateral perfusion defects, the location of which are as described in the text. Of note, the majority of defects are segmental in size. The frontal and lateral views of selective pulmonary angiograms of the right and left pulmonary arteries are presented

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in Fig. 6.3. On the right, in the upper lobe, there is segmental web in the apical branch and proximal stenosis with post stenotic dilatation in the anterior branch, proximal pouch in the lower lobe with segmental web in the lateral branch and proximal irregular stenosis in the medial branch. Overall, there is paucity of vessels in the mid to distal third of the lungs, particularly in the upper and mid zones. On the left, in the lower lobe, the posterior and lateral segmental vessels are attenuated, there was a truncated apical segment, and distal vessel narrowing of the anterior segmental branch. There are segmental webs in the apico-posterior branch of the upper lobe and lobar occlusion of the lingula. There is severe reduction in perfusion in the lower lobe as evidenced by the lack of parenchymal blush in the capillary phase. Overall, this is a case of chronic thromboembolic disease with mixed disease distribution. Although there is disease in the lobar and segmental vessels, on balance, the extent of demonstrable disease is out of proportion to the markedly elevated pulmonary vascular resistance of 1091 dynes/s/cm-5. This implies there is significant small vessel component. Whilst it is the accepted norm that there should be concordance between the extent of disease seen on imaging and the pulmonary hemodynamics, there is no exact formula linking the two parameters. It is more of an art rather than an exact science and therefore, decision regarding operability should not be based purely on the basis of uni-modality imaging.

Clinical Comments There are several points of interest illustrated by this case. The first comes from the observation that significant chronic thromboembolic disease was diagnosed in this 15-year-old girl, emphasizing that CTEPH can occur even in pediatric patients. As is often the case in this age group, a prothrombotic state was demonstrated (see Madani et  al. 2011). However, an additional risk factor for the development of thromboembolic disease was likely related to repetitive

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injury of her subclavian vein with her athletic activities, ultimately leading to the diagnosis of Paget-Schroetter syndrome. The initial diagnosis of pleurisy and exercise-induced asthma was also not surprising, given the absence of specific symptoms to suggest thromboembolic disease and the relative rarity of CTEPH, especially in pediatric patients. However, that’s one of the reasons behind presenting this case, to acknowledge that in the absence of an evident cause for the new onset of exertional dyspnea…regardless of age group…pulmonary vascular disease needs to be considered. And given the degree of pulmonary hypertension discovered during her initial hospitalization, it was evident that CTEPH was already present. The other point to be made is that the evaluation for surgery was somewhat misleading. The size of the perfusion abnormalities by lung scintigraphy, and the pulmonary angiographic findings which suggested lobar disease on the right (in the descending PA), and segmental disease in the right upper lobe and throughout the pulmonary vascular bed on the left, correctly created the impression that these lesions were accessible to endarterectomy. However, the actual organized thrombi removed were primarily from the distal segmental and subsegmental arteries, which would be consistent with what one would expect given the source of clot was from the upper extremities veins. This emphasizes the importance of having the surgical expertise to perform distal vessel endarterectomies, especially in those clinical scenarios where distal disease is likely. This case also illustrates the discrepancy that occasionally occurs between the preoperative assessment and what is discovered at surgery. But most importantly, this presentation highlights the significant pulmonary hemodynamic and clinical benefits that can be achieved with a properly performed distal vessel thromboendarterectomy. As available information has documented that the best chance for a cure comes with PTE surgery, every patient with CTEPH…regardless of chronic thrombus location within the pulmonary vessels…should have a complete surgical assessment by experienced CTEPH diagnosticians and surgeons.

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Point of Emphasis Though technically a more difficult surgery requiring considerable expertise, a properly performed thromboendarterectomy in patients with distal vessel CTEPH can lead to significant improvements in pulmonary hemodynamics, functional status and quality of life. Careful patient selection is critical to a successful outcome.

Diagnosis 1. Distal vessel hypertension.

chronic

thromboembolic

pulmonary

Further Reading Auger WR, Kim NK, Fernandes T, et  al. Distal vessel endarterectomy: results from a single institution. J Thorac Cardiovasc Surg. D’Armini AM, Morsolini M, Mattiucci G, et al. Pulmonary endarterectomy for distal chronic thromboembolic pulmonary hypertension. J Thorac Cardiovasc Surg. 2014;148:1005–12. Madani M, Mayer E, Fadel E, Jenkins DP.  Pulmonary endarterectomy: patient selection, technical challenges, and outcomes. Ann Am Thorac Soc. 2016;13(Suppl 3):S240–7. Madani MM, Wittine LM, Auger WR, et  al. Chronic thromboembolic pulmonary hypertension in pediatric patients. J Thorac Cardiovasc Surg. 2011;141:624–30.

Chapter 7 Case 7: It’s Not CTEPH, but It Is Chronic Thromboembolic Disease (CTED) Paul R. Forfia, Deepa Gopalan, and William R. Auger

Case Presentation Twenty-eight-year-old male without significant past medical history who was very physically active until 2015 when he was diagnosed with essential hypertension. He noted heart rates in the 90s when he normally had been running in the low 50s. He was a competitive rower in college and cycled long distance, performing at least 20 century rides and mul-

P. R. Forfia (*) Pulmonary Hypertension, Right Heart Failure and CTEPH Program, Temple University Hospital, Philadelphia, PA, USA e-mail: [email protected] D. Gopalan Department of Radiology, Imperial College Hospitals, London, UK e-mail: [email protected] W. R. Auger Lewis Katz School of Medicine, Temple University, Philadelphia, PA, USA e-mail: [email protected] © Springer Nature Switzerland AG 2020 W. R. Auger, D. Gopalan (eds.), Clinical Cases in Chronic Thromboembolic Pulmonary Hypertension, Clinical Cases in Cardiology, https://doi.org/10.1007/978-3-030-17366-1_7

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tiple 200  miles rides. By September 2015, he noted more labored breathing with exertion but he was still able to cycle. He stopped his beta blocker due to insomnia side effect. He vacationed in a remote country in October 2015 and noted much worsening symptoms of shortness of breath. He was diagnosed with pulmonary embolism and was given tPA after echocardiogram showed PASP of 109 mmHg, (though CTA and VQ were not performed). He was hospitalized for 1 month and was ultimately anticoagulated with Eliquis. Although his symptoms improved, he was not able to resume previous activities at the desired level. He still worked out 3 h a week for 25–30 min using the elliptical machine. On infrequent occasions when he did cycle, he could cover 2  h before experiencing fatigue. He did not note dyspnea. He coached his kid’s rugby and noticed that he can no longer sprint. He was felt to be WHO functional class I. He denied chest pain, lightheadedness, syncope, hemoptysis, lower extremity edema. He did note oxygen desaturation during exercise, going down to 89%. V/Q scan from July 5, 2016 and January 9, 2017 were essentially unchanged showing right upper lobe, lingula, questionable left lower lobe perfusion defects. Echocardiogram from August 12, 2016. showed normal RA, RV size and RV systolic function, normal LV size and systolic function, no evidence of pulmonary hypertension. His past medical history was notable only for his pulmonary embolism as above and essential hypertension. There was a questionable history of left popliteal DVT (the patient reported pain and swelling in 2003) for which he was treated for a short period with aspirin. Prior surgeries included a septoplasty (2011), left ACL reconstruction (2000), bilateral varicocelectomy (2007) and a dermoid cyst removal as a child. On review of systems, the patient denied constitutional symptoms of fevers, chills, malaise, weight loss, weight gain, a known coagulopathy, connective tissue disease, Raynaud’s phenomena, previous exposure to stimulants, anorexiants, trauma. Family history was remarkable for venous thromboembolism experienced by his father (PE), uncle, grand aunt (DVT). With concerns over the persistent perfusion defects on VQ scan, and his dissatisfaction with his functional limitations, a

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referral was initiated to a CTEPH center specializing in thromboendarterectomy. On exam, the patient was a muscular, well developed male, BP 131/89, HR 72 and room air O2 saturation of 99%. HEENT exam was unremarkable; there was no thyromegaly or jugular venous distension. Lung fields were clear with normal diaphragmatic excursion; no pulmonary flow murmurs. No palpable RV lift; S2 splitting with inspiration and no murmur or S3 gallop. No hepatomegaly. No lower extremity edema or venous stasis skin changes. Laboratory data included a BUN 14, creatinine 1.40, liver transaminase levels within normal limits. ProBNP 13. Urinalysis negative for protein. White blood cell count 6.1, hemoglobin 15.2, hematocrit 45.7. Platelets 311,000. INR 1.0. PTT 38.2. EKG: normal sinus rhythm, 83 beats per minute. Normal QRS axis and R wave progression across the precordium. His echocardiogram (June 2017) demonstrated normal LV size and function (estimated EF 69%); right atrium and right ventricular size were normal with normal RV systolic function, no tricuspid regurgitation, and no pericardial effusion. On chest radiograph (Fig. 7.1) there was no cardiomegaly or central PA enlargement. Lungs were well expanded without infiltrates.

Figure 7.1  Chest radiograph at time of evaluation for thromboendarterectomy

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WASH IN

EQUIL

WASHOUT1

WASHOUT2

ANT Q

POST Q

LPO Q

RPO Q

LLAT Q

RLAT Q

LAO Q

RAO Q

Figure 7.2  Lung scintigraphy demonstrating unmatched perfusion defects in both lungs

Lung scintigraphy (Fig. 7.2) demonstrated large right upper lobe and lingular perfusion defects, with a smaller unmatched defect in the anterior right lower lobe. Results of the right heart catheterization showed pulmonary hemodynamics at rest of right atrial mean of 6 mmHg, PA pressure 31/13  mmHg (20 mean), PAOP 10  mmHg, ­thermodilution cardiac output of 7.2  L/min (cardiac index 3.17 L/min/m2) and calculated PVR 112 dyn s/cm5. Exertion of his upper extremities resulted in a PA pressure of 46/12  mmHg (28 mean), a pulmonary capillary wedge pressure of 12  mmHg, and a thermodilution cardiac output 13.6  L/min (cardiac index 5.99  L/min/m2); calculated PVR was 94 dyn s/cm5. Pulmonary angiography revealed evidence for chronic thromboembolic disease at the lobar level of a right upper lobe vessel and lingula (Fig. 7.3). Though there was radiographic evidence for operable chronic thromboembolic disease, in the absence of significant

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Figure 7.3 Digital subtraction pulmonary arteriogram: “pouch defect” proximal right upper lobe (open arrow), and occluded lingula (closed arrow)

exercise limitation and with essentially normal pulmonary hemodynamics at rest and during modest exertion, it was assessed that the risk of a surgical thromboendarterectomy was unwarranted and unlikely to result in a noticeable clinical benefit. However, to provide a more complete physiologic evaluation at higher levels of exercise, a cardiopulmonary exercise test (CPET) was requested. The patient exercised up to 271 W for a total exercise time of 11 min 1 s and was reported stopping because of dyspnea (3 out of 10) At rest, minute ventilation (VE) at rest was 13.5  L/min, maximum voluntary ventilation was 194  L/min, and resting oxygen saturation was 99% (pulse oximetry). The patient’s physiological dead space proportion (VD/VT) at rest, estimated from the transcutaneous PCO2 (PtcCO2) and exhaled PCO2 (PexCO2), was 0.31. Anaerobic threshold, based on the rates of change in VE/VO2, VE/VCO2 and R was reached at a VO2 of 1.692 L/min (16.6 mL/kg/min), 59% of predicted peak VO2. At the point of AT, the VE/VCO2 ratio was 28, the RQ was 0.95 and the heart rate was 139 BPM (81% of the predicted max). At peak exercise, VO2 (3.505 L/ min, 34.4  mL/kg/min) was 123% of the predicted peak

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(2.856 L/min). The RQ was 1.15. The anaerobic reserve (peak­AT VO2) was 1.81, which was 63% of the predicted peak VO2. VE peak (100.8 L/min) reached 52% of the MVV measured just prior to exercise (194 L/min). The oxygen saturation during peak exercise was 92%, physiological VD/VT was 0.27, heart rate (179 BPM) was 104% of the predicted maximum heart rate and the BP was 144  mmHg/90  mmHg. The O2 pulse at peak exercise was 19.6 mL/beat mL/beat (438% of the O2 pulse at rest and 109% of the predicted maximum of 17.9  mL/beat). The O2 pulse increased continuously throughout the point when the patient reached anaerobic threshold and continued to increase even after the VO2 exceeded the predicted peak VO2. Summary of the CPET results: • This was a maximal exercise test. • The patient reached >100% of maximal predicted oxygen consumption, consistent with supra-normal aerobic exercise capacity. • Normal cardiac response to exercise, with no evidence of impairment of heart rate or stroke volume reserve. • There was no evidence of a ventilatory limitation. • There was modest oxygen desaturation (nadir 92%), however, the SpO2 did not fall below 95% until a VO2 was twofold the value at the onset of anaerobic threshold and >100% of the maximal predicted VO2. • The absence of significant ventilatory inefficiency at peak workload as well as the absolute fall in the VE/VCO2 throughout exercise is consistent with relatively normal pulmonary vascular recruitment with exertion. Overall interpretation: The presence of a greater than normal aerobic exercise capacity, normal cardiac response to exercise, and absence of significant ventilatory inefficiency did not support the presence of objective exercise physiologic limitation on the basis of chronic thromboembolic disease. Follow-up 12  months after the initial surgical evaluation revealed that the patient was engaged in high intensity exercise programs, experiencing an overall improvement in his athletic

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capabilities. His echocardiogram showed a normal sized right atrium and right ventricle, with normal RV wall thickness and normal RV systolic function; only trace tricuspid regurgitation. The findings on lung scintigraphy were unchanged.

Radiographic Interpretation The chest radiograph does not show any generic features of pulmonary hypertension such as cardiomegaly or proximal pulmonary artery dilatation. Allowing for the mild rotation, the lungs and pleural spaces are clear. There are bilateral segmental mismatched perfusion defects on VQ scintigraphy with no significant change in the appearances over a 6-month period after commencement of anticoagulation. It is not surprising to see persistent scintigraphic perfusion defects following acute PE. Complete resolution may not be achieved for almost up to a year after the initial diagnosis. The reported residual obstruction rate on VQ after institution of anticoagulation is variable. A systemic analysis showed residual defects in more than 65% of patients at 3 months and 50% at 6 months after which thrombus resolution reaches a plateau phase (Nijkeuter et  al.). A more recent study showed persistent defects in 30% of cases after 6  months of anticoagulation and was associated with higher incidence of symptoms, shorter distances covered in the 6MWT and higher systolic pulmonary artery pressure (Sanchez et al.). Since VQ cannot readily distinguish between acute PE and CTEPH, it is necessary to perform another test, usually CTPA to look for features of chronic thromboembolic disease. Another VQ pitfall is that the radiolabeled particles can potentially pass through partially obstructed vessels and hence perfusion defects can underestimate the severity of vascular obstruction and may not correlate with pulmonary vascular resistance or mean pulmonary artery pressure (Ryan et al.). Therefore, VQ cannot be relied upon in the evaluation of disease morphology and operability assessment.

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Catheter pulmonary angiography shows limited proximal thromboembolic disease with a pouch defect in the origin of the right upper lobe branch and lobar lingular occlusion. There is also attenuation of anterior basal branch of the left lower lobe from mid segmental level. The remaining vessels are smooth with no intimal irregularity.

Clinical Comments As noted by Dr. Gopalan, the presence of residual perfusion defects following an acute pulmonary embolic event, despite appropriate antithrombotic therapy, can be found in a considerable number of patients. If these perfusion defects are in the region of a previous acute thromboembolism, it likely reflects organized thrombotic residua, or in more contemporary terms, chronic thromboembolic disease (CTED). Recognized within the spectrum of the “Post PE Syndrome”, clinically relevant questions then need to address the extent of CTED present and whether it is accompanied by cardiopulmonary symptoms, or associated with pulmonary hemodynamic compromise (Fig. 7.4).

All patients after PE

All patients after PE

Reported symptoms of reduced functional status Persistent thrombi Measurable limitations in cardiopulmonary function CTEPH Post-PE syndrome CTEPH

Figure 7.4 Post PE Syndrome: Klok et  al. Blood Reviews 2014; 28:221

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It is also speculated that the presence of chronic thrombotic residua represents a precursor to CTEPH.  There are several unresolved issues, however, including whether there’s a certain amount of CTED that will trigger the development of the secondary small vessel (see Introduction), the pathophysiologic mechanism responsible for this transition, and the time course for these changes to occur. As a result, the clinician is then faced with the difficult task of recommending a treatment plan for patients such as presented here. Though there was clearly operable chronic thromboembolic disease in this case, this was not enough to proceed with a thromboendarterectomy acknowledging that surgery is not risk free (Chap. 11 and Taboada et  al.). And the “prevention of CTEPH” by removing the CTE lesions is speculative at best in the absence of a well-defined natural history of this problem. Typically, surgery has been advocated in this particular patient group if (1) they are symptomatic and are impaired from a functional status perspective, or (2) if significant physiologic derangement, such as elevated dead space ventilation or ventilatory inefficiency, can be documented. Essentially, if there a problem that can be fixed and result in a demonstrable improvement if a patient’s quality of life, an endarterectomy or perhaps balloon pulmonary angioplasty should be considered.

Point of Emphasis The presence of chronic thromboembolic disease by itself does not necessarily warrant invasive intervention. The decision to proceed with surgery or balloon pulmonary angioplasty requires a careful assessment of the risks and anticipated benefits for the patient undergoing such aggressive treatment.

Diagnosis 1. Chronic thromboembolic disease without pulmonary hypertension at rest.

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Further Reading Held M, Grün M, Holl R, et  al. Cardiopulmonary exercise testing to detect chronic thromboembolic pulmonary hypertension in patients with normal echocardiography. Respiration. 2014;87(5):379–87. Klok FA, van der Hulle T, den Exter PL, Lankeit M, Huisman MV, Konstantinides S.  The post-PE syndrome: a new concept for chronic complications of pulmonary embolism. Blood Rev. 2014;28:221–6. Nijkeuter M, Hovens MM, Davidson BL, Huisman MV. Resolution of thromboemboli in patients with acute pulmonary embolism: a systematic review. Chest. 2006;129:192–7. 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. Sanchez O, Helley D, Couchon S, et al. Perfusion defects after pulmonary embolism: risk factors and clinical significance. J Thromb Haemost. 2010;8(6):1248–55. Taboada D, Pepke-Zaba J, Jenkins DP, Berman M, et al. Outcome of pulmonary endarterectomy in symptomatic chronic thromboembolic disease. Eur Respir J. 2014;44(6):1635–45.

Chapter 8 Case 8: Another Case of CTED: Is Surgery the Way? Colleen McEvoy, Deepa Gopalan, and William R. Auger

Case Presentation A 33 year-old female with a limited past medical history presented to the Pulmonary Vascular clinic with complaint of dyspnea on exertion 2 months after a diagnosis of large bilateral pulmonary embolisms (PE) in the central pulmonary arteries (Fig. 8.1).

C. McEvoy (*) Division of Pulmonary and Critical Care Medicine, Washington University in St. Louis, St. Louis, MO, USA e-mail: [email protected] D. Gopalan Department of Radiology, Imperial College Hospitals, London, UK e-mail: [email protected] W. R. Auger Lewis Katz School of Medicine, Temple University, Philadelphia, PA, USA e-mail: [email protected] © Springer Nature Switzerland AG 2020 W. R. Auger, D. Gopalan (eds.), Clinical Cases in Chronic Thromboembolic Pulmonary Hypertension, Clinical Cases in Cardiology, https://doi.org/10.1007/978-3-030-17366-1_8

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Figure 8.1  Selected images from computed tomography pulmonary angiography at time of diagnosis of pulmonary embolism

At the time of her acute pulmonary embolism, the echocardiogram revealed LVEF 50%, RV hypokinesis, RV pressure overload with PASP 40–45 mmHg. She did not require thrombolytic therapy. Troponins were negative. Lower extremity duplex dopplers were negative for acute deep vein thrombosis. She was placed on anticoagulation with enoxaparin and bridged to rivaroxaban. The PE was thought to be provoked from a long car trip. She complained of shortness of breath carrying her children and groceries. She had difficulty climbing stairs, though denied chest pain, lower extremity edema and presyncope. During her initial clinic evaluation, vital signs showed BP 115/82, heart rate 103, respiratory rate of 24, oxygen saturation 96% on room air. Physical examination was unremarkable. Laboratories were notable for BNP 5 pg/mL, complete blood count and comprehensive metabolic panel were within normal limits. Imaging was significant for a V/Q scan (Fig. 8.2) with perfusion defects in left lower lobe, lingula and right upper lobe. Her echocardiogram showed normal LV and RV size and systolic function, TAPSE 1.8 cm. PASP 35 mmHg, saline contrast study mildly positive for right to left shunt most consistent with a patent foramen ovale (PFO). Six minute walk test revealed a distance of 1050  ft and no desaturations with concluding Borg Score of 2. Pulmonary function testing was

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Figure 8.2 Ventilation perfusion scintigraphy 2 months post-acute pulmonary embolism

significant for reduced DLCO 44% predicted. Given that the acute pulmonary embolism was only 2 months prior and the echocardiogram did not show features of pulmonary hypertension or right heart enlargement, the perfusion defects seen on V/Q scan were felt to be due to her acute PE. Therefore, the decision was made to continue anticoagulation and repeat imaging 6  months after her acute pulmonary embolism. At the follow up appointment, 6  months after acute PE, the patient continued to complain of dyspnea on exertion and impaired exercise tolerance. No signs of right heart failure. Repeat VQ scan (Fig.  8.3) demonstrated multiple ­ perfusion defects, unchanged from prior scintigraphy. CT angiogram of the chest (Fig. 8.4) showed resolution of larger more central filling defects within the pulmonary arteries, now with residual linear appearing peripheral filling defects consistent with pulmonary artery webs at the segmental level, particularly in the right lower lobe and left lower lobe pulmonary arteries, mosaic attenuation and mild enlargement of the right ventricle. Repeat echocardiogram showed

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Figure 8.3 Ventilation perfusion scintigraphy 6  months post-acute pulmonary embolism

upper normal RV size and mild RV hypokinesis (RV global longitudinal strain −13.7%), PASP 25  mmHg, normal IVC size. Due to her young age, persistence of symptoms 6 months post acute PE, with chronic changes consistent with chronic thromboembolic disease on CTA chest and V/Q scan, she was referred to CTEPH Center for evaluation and consideration of pulmonary thromboendarterectomy (PTE). A right heart catheterization was performed to evaluate for chronic thromboembolic pulmonary hypertension (CTEPH). Resting pulmonary hemodynamics: RA 10, PA 42/19 (mean 29), PCWP 14, thermodilution cardiac output 5.4  L/min, cardiac index 2.5 L/min/m2, PVR 2.8 Wood Unit, PA saturation 64%. Using weights, her upper extremities were exercised resulting in an increase in her thermodilution cardiac output to 8.1 L/min, PA pressure was 72/30 (mean 49), PCWP 17. She was diagnosed with chronic thromboembolic disease (CTED), characterized by persistent pulmonary thromboembolic occlusion with mild

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a

b

Figure 8.4  (a–d) Selected images from computed tomography pulmonary angiography 6 months post-acute pulmonary embolism

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Figure 8.4  (continued)

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Figure 8.5  Organized thrombus endarterectomized at surgery

pulmonary hypertension at rest and significant rise in pulmonary artery pressures with a modest increase in cardiac output. As a result of her dissatisfaction with her functional status, and with her exercised induced pulmonary hypertension, she elected to proceed with surgery. She underwent pulmonary thromboendarterectomy 1 year after diagnosis of her acute pulmonary embolism. She was found to have level 1 disease on the right and level 2 disease on the left (Fig.  8.5). Her post-operative hemodynamics off vasopressors showed a mean PA pressure 19  mmHg with cardiac index 3.1 L/min/m2 and PVR 1.0 (not shown). There is a small amount of fluid in the superior pericardial recess. These findings are in keeping with acute pulmonary embolism with CT features of right heart strain. On the 2 month follow-up VQ scintigraphy, there are mismatched segmental perfusion defect in the right upper lobe and large lobar defect in the lingula and left lower lobe (Fig. 8.2). There is no interval change in the size and distribution of the defects on the 6  month VQ (Fig.  8.3). Selected images from the repeat CT pulmonary angiography shows complete occlusion of the lingula and left lower lobe with recanalized clot. There is a proximal web in the right proximal descending PA (best visualized with changing the window to “lighten” the contrast, Fig.  8.4b) and tight trifurcation stenosis in the right lower

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lobe. Following successful pulmonary endarterectomy, there is complete resolution of the perfusion defects with normal tracer distribution in both lungs (Fig. 8.6).

Clinical Commentary This case is an extension of observations made in Case 10 (Chap. 10). Even after an appropriate period of anticoagulation, there was failure to resolve her thromboembolic burden, with progression to occlusive organized chronic thromboembolic disease. Despite relatively normal echocardiographic findings and pulmonary hemodynamics at rest, a more detailed assessment with exercise right heart catheterization revealed considerable exertion related pulmonary hypertension. Her symptoms were therefore felt to be related to pulmonary hypertension with exercise and/or maladaptation of the right ventricle with a decrease in RV compliance. In addition, studies in patients with symptomatic thromboembolic disease have demonstrated abnormal dead space ventilation as contributing to their exertional dyspnea. Whether or not this was an issue with this patient would have required a carefully performed cardiopulmonary exercise test. The decision to proceed with surgery necessitated an understanding on the patient’s part that the desired surgical outcomes included the prevention of pulmonary hypertension with exertion, a reduction in dead space ventilation and a return of pulmonary vascular reserve. These goals are clearly different than that seen in CTEPH where the reversal of pulmonary hypertension and RV dysfunction are the desired primary outcomes. Debate continues as to whether PTE should be performed in patients with chronic thromboembolic disease in the absence of pulmonary hemodynamic compromise. The natural history of this problem is poorly characterized and as Taboada and colleagues have demonstrated (see reference below), the surgery carries significant risk. Though in their series there was no perioperative mortality, complications occurred in 40% of patients. Consequently, the assessment of risks and anticipated benefits of surgery in

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this patient subgroup needs to be individualized. In this case, at least from a functional standpoint, and with normalization of her echocardiogram and perfusion scan, a favorable surgical outcome was obtained.

Points of Emphasis Pulmonary thromboendarterectomy surgery can benefit symptomatic patients with chronic thromboembolic disease, though an understanding of surgical goals and attendant risks with this approach are essential.

Diagnosis 1. Chronic thromboembolic disease (CTED).

Further Reading Held M, Kolb P, Grün M, Jany B, Hübner G, Grgic A, et al. Functional characterization of patients with chronic thromboembolic disease. Respiration. 2016;91:503–9. McCabe C, Preston SD, Gopalan D, Dunning J, Pepke-Zaba J.  Cardiopulmonary exercise testing suggests a beneficial response to pulmonary endarterectomy in a patient with chronic thromboembolic obstruction and normal preoperative pulmonary hemodynamics. Pulm Circ. 2014;4:137–41. McCabe C, White PA, Hoole SP, Axell RG, Priest AN, Gopalan D, et  al. Right ventricular dysfunction in chronic thromboembolic obstruction of the pulmonary artery: a pressure-volume study using the conductance catheter. J Appl Physiol (1985). 2014;116:355–63. Taboada D, Pepke-Zaba J, Jenkins DP, Berman M, et al. Outcome of pulmonary endarterectomy in symptomatic chronic thromboembolic disease. Eur Respir J. 2014;44(6):1635–45. van Kan C, van der Plas MN, Reesink HJ, van Steenwijk RP, Kloek JJ, Tepaske R, et al. Hemodynamic and ventilatory responses during exercise in chronic thromboembolic disease. J Thorac Cardiovasc Surg. 2016;152:763–71.

Chapter 9 Case 9: Pulmonary Artery Sarcoma Mimicking Massive Thromboembolic Disease Demosthenes G. Papamatheakis, Deepa Gopalan, and William R. Auger

Case Presentation A 68  year old woman started experiencing progressively worsening shortness of breath during her walks over the course of a year, more pronounced during inclines. She could initially walk for 2–3  miles without any symptoms, but she had to gradually decrease this distance due to dyspnea and fatigue. Her symptoms were initially attributed to her aging D. G. Papamatheakis (*) Pulmonary, Critical Care and Sleep Medicine, University of California, San Diego, La Jolla, CA, USA e-mail: [email protected] D. Gopalan Department of Radiology, Imperial College Hospitals, London, UK e-mail: [email protected] W. R. Auger Lewis Katz School of Medicine, Temple University, Philadelphia, PA, USA e-mail: [email protected] © Springer Nature Switzerland AG 2020 W. R. Auger, D. Gopalan (eds.), Clinical Cases in Chronic Thromboembolic Pulmonary Hypertension, Clinical Cases in Cardiology, https://doi.org/10.1007/978-3-030-17366-1_9

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Figure 9.1  Selected images from computed tomography pulmonary angiography (see “Radiographic Interpretation” section for arrow explanations)

and she did not seek further attention, however they continued to worsen. She eventually started feeling lightheaded and having chest pressure with exertion, at which point she went to the emergency department. A computed tomogram (CT) pulmonary angiography was performed showing large central pulmonary artery filling defects (Fig. 9.1). Based on this she was diagnosed with an acute pulmonary embolus for which she was treated with catheter directed thrombolysis using tPA.  Based on hospital reports, pulmonary artery pressures and angiographic imaging did not improve significantly after this procedure. Although lower extremity ultrasound did not exhibit any evidence of deep vein thrombosis, due to the size of the filling defects within the pulmonary vasculature on CT it was decided to proceed with an inferior vena cava (IVC) filter placement. During placement, venography revealed a duplicated IVC, therefore dual IVC filters were deployed. She was started on a heparin drip after conclusion of the above procedures, switched to rivaroxaban, and eventually discharged home. Past medical history included osteopenia, systemic hypertension, anxiety, gastro-esophageal reflux disease, and cataracts for which she had right eye surgery a few years prior. Her only other surgery was a total abdominal hysterectomy and oophorectomy more than 15  years before her current presentation. She had no known allergies, and no history of prior deep vein thrombosis, or pulmonary emboli. She also denied any prior estrogen use.

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Social history disclosed no alcohol, tobacco, diet pill or illicit drug use. She worked as a flight attendant prior to retiring and was widowed. Her family history did not include any clotting disorder or any relatives with prior blood clots. She noted a rash with penicillin and some pruritus with enoxaparin and with clindamycin. A few weeks after her discharge, she followed up as an outpatient with a pulmonologist due to continued shortness of breath and decreased exercise tolerance. Not only had she not returned to her baseline, but she occasionally experienced exertional chest tightness and palpitations that were alleviated with rest. On one occasion, after pushing herself to walk approximately 200  ft at a brisk pace, she felt dizzy and presyncopal. Her pulmonologist ordered an echocardiogram that showed a normal left ventricular size and systolic function, with mild diastolic dysfunction. Abnormal ventricular septal motion and position were noted, suggesting the presence or right ventricular pressure overload. The right ventricle was moderately enlarged and hypertrophied with reduced systolic function and the right ventricular systolic pressure was reported at 67 mmHg with a TAPSE measured at 1.32 cm. The left atrium was normal, the right atrium was moderately dilated and a trivial pericardial effusion was noted in addition to some moderate tricuspid regurgitation. The main pulmonary artery was enlarged and a large mass was seen within it. Based on these findings and in the context of her more chronic and progressive symptoms with poor response to anticoagulation, chronic thromboembolic pulmonary hypertension was suspected and she was referred to a CTEPH center for pulmonary thromboendarterectomy (PTE) surgery evaluation. During her evaluation for PTE surgery her vital signs were notable for elevated systemic blood pressure at 150/73, a temperature of 97 °F, a respiratory rate of 16, and a SpO2 of 98% on room air. Her height was 5′ 4″ and her weight was 60.5 kg. On exam, she had mild JVD and an accentuated P2 heart sound. Although her lungs were clear to auscultation bilaterally, a loud flow murmur was heard over her right lung zones during breath hold. Her only other finding were some lower extremity varicose veins.

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Figure 9.2  Chest radiograph

At that time a chest x-ray showed two IVC filters in place, some blunting of the left costophrenic angle, enlarged pulmonary arteries, and a prominent right ventricle (Fig. 9.2). Moreover a ventilation perfusion lung scintigraphy scan showed lack of perfusion to the entire left lung and a wedge defect of the superior segment of the right middle lobe (selected views in Fig. 9.3). After the above preliminary testing she underwent a left heart catheterization to rule out any coronary artery disease prior to possible PTE surgery that was unremarkable. Based on her imaging findings and her clinical history it was suspected that CTEPH was a less likely diagnosis. Therefore, right heart catheterization and digital subtraction pulmonary angiography were deferred and felt to be of excessive risk given the degree of proximal vessel occlusion by CT. As part of her evaluation, she did however undergo a positron

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Figure 9.3  Ventilation perfusion scintigraphy (RAO: right anterior oblique, Lat: lateral)

e­ mission tomography scan with fusion computed tomography images (Fig. 9.4). Following these studies she was admitted to the hospital, and placed on continuous intravenous heparin drip in anticipation of endarterectomy surgery. This was performed a few days later including pulmonary valve repair and PFO closure. The surgery was complicated by left lower lobe airway bleeding requiring a bronchial blocker that resolved within a few days (specimen shown in Fig. 9.5). Although her post-operative course was complicated by airway bleeding, an episode of aspiration and retained secretions, a small posterior cerebral artery stroke, and persisting

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Figure 9.4  Fusion PET CT images of the chest (see “Radiographic Interpretation” section for image explanation)

Figure 9.5  Surgical specimen removed at time of endarterectomy

dysphagia requiring a gastric tube placement, she was eventually discharged home approximately 4 weeks after her operation. Her final pathology noted high grade intimal sarcoma with PD-L1 positive staining. She is now being followed by radiation oncology and medical oncology and undergoing treatment for residual/metastatic pulmonary artery sarcoma.

Radiographic Interpretation From the outset, CT images in this case were very suggestive of a vascular tumor. The selected images from CT pulmonary angiography (Fig. 9.1) demonstrated an expansile mass within the main and left pulmonary artery (block arrow). The lesion extends to the level of the pulmonary valve and is of uni-

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formly low attenuation with no calcification. Careful review reveals breach of the pulmonary artery wall (thin arrow) with extension of soft tissue in to the mediastinum. The loss of the integrity of the vascular wall is highly suspicious for an aggressive lesion such as a sarcoma. Chronic thromboembolic disease can involve the main pulmonary arteries, but the CT features were not typical of thrombus. The chest radiograph (Fig. 9.2) demonstrated enlargement of the main pulmonary artery with reduced vascular markings in the left lung with few tiny foci of parenchymal scarring. On VQ scintigraphy (Fig. 9.3) there was complete absence of perfusion to the left lung. Surprisingly, there was also a segmental wedge shaped mismatched perfusion defect in the right lung; this could be due to tumor “thrombus” or vascular metastases. The positron emission tomography (PET) CT (Fig.  9.4) confirmed high FDG uptake in the soft tissue within the pulmonary arteries in keeping with a metabolically active intra-­ vascular malignancy.

Clinical Comments This case is a dramatic illustration that proximal pulmonary intra-arterial filling defects are not universally thromboembolic in nature. In fact, there are a number of historical and radiographic hints, particularly on CT, that push the differential away from this being a large proximal vessel thromboembolus. That this patient experienced a decline in exercise capabilities over the months prior to presentation suggests a more chronic and progressive process. An acute saddle embolus of this size would not typically present in this manner. Additionally, a thromboembolus would not be expected to simply “halt” in the proximal main pulmonary artery, with contrast seen to completely opacify a normal sized vessel beyond the globular shaped lesion (Fig. 9.1). Other features that might suggest a pulmonary vascular tumor include

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“eclipsing” or “breach” of the pulmonary arterial wall from the mass like lesion (see Gan et  al. 2013), extension of the mass involving the right ventricular outflow tract and pulmonic valve, size progression of the mass despite anticoagulation, and the presence of nodular lesions “within the parenchyma” following the course of the pulmonary arteries. Moreover, the presence of radiographic and/or echocardiographic signs of pulmonary hypertension with such a large burden of occlusive vascular disease would not be anticipated with an acute massive pulmonary embolus, where cardiogenic shock might be expected at the time of presentation. An appreciation of some of the clinical and radiographic aspects of pulmonary vascular tumors can reduce the time interval to appropriate therapeutic intervention, including surgical endarterectomy and adjuvant modalities appropriate to the patient’s tumor type and clinical condition. A clinical suspicion of this unusual tumor might also prevent ineffectual and potentially life threatening attempts at reperfusion therapy.

Points of Emphasis The differential for major pulmonary arterial mass lesions includes vascular neoplasm. The clinical history and distinctive radiographic findings, particularly with CT and metabolic imaging, can be helpful in making this important distinction from acute or chronic thromboembolic disease.

Diagnosis 1. Pulmonary artery sarcoma.

Further Reading Gan H-L, Zhang J-Q, Huang X-Y, Yu W. The wall eclipsing sign on pulmonary artery computed tomography is pathognomonic for pulmonary artery sarcoma. PLoS One. 2013;8(12):e83200.

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Grazioli V, Vistarini N, Morsolini M, et  al. Surgical treatment of primary pulmonary artery sarcoma. J Thorac Cardiovasc Surg. 2014;148:113–8. Mussot S, Ghigna MR, Mercier O, et al. Retrospective institutional study of 31 patients, treated for pulmonary artery sarcoma. Eur J Cardiothorac Surg. 2013;43:787–93. Papamatheakis DG, Kerr KM.  Pulmonary vascular tumors. In: Peacock AJ, Naeije R, Rubin LJ, editors. Pulmonary circulation. Diseases and their treatment. Boca Raton, FL: CRC Press (Taylor & Francis group; 2016. p. 736–42. von Falck C, Meyer B, Fegbeutel C, et al. Imaging features of primary sarcomas of the great vessels in CT, MRI and PET/CT: a single center experience. BMC Med Imaging. 2013;13:25.

Chapter 10 Case 10: Chronic Thrombus and Metastatic Cancer—An Unexpected CTEPH Mimic Alison S. Witkin and William R. Auger

Case Presentation A 65-year-old Caucasian female presented for evaluation of one and a half years of progressive shortness of breath. One year prior to presentation she was diagnosed with a right sided pulmonary embolism (PE) in the setting of an acute increase in symptoms and was started on warfarin for anticoagulation. She experienced a mild, temporary improvement but within 3 months again experienced dyspnea with ambulation. The dyspnea was associated with leg swelling but no chest pain, syncope or pre-syncope.

A. S. Witkin (*) Division of Pulmonary and Critical Care Medicine, Massachusetts General Hospital, Harvard Medical School, Boston, MA, USA e-mail: [email protected] W. R. Auger Lewis Katz School of Medicine, Temple University, Philadelphia, PA, USA e-mail: [email protected] © Springer Nature Switzerland AG 2020 W. R. Auger, D. Gopalan (eds.), Clinical Cases in Chronic Thromboembolic Pulmonary Hypertension, Clinical Cases in Cardiology, https://doi.org/10.1007/978-3-030-17366-1_10

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In addition to the above, past medical history was notable for a history of mild asthma and osteoporosis. She was up to date on her age appropriate cancer screening. She was a former smoker, with a 55 pack-year history and quit 5 years prior to presentation. There was no family history of venous thromboembolism. On exam, she was afebrile. Blood pressure was 137/75 mmHg, pulse was 96 beats per minute, respiratory rate was 18 and her oxygen saturation was 92% on room air. She was well-appearing and able to speak in full sentences without accessory muscle use at rest but became dyspneic with one flight of stairs. Heart rate and rhythm were regular with a 2/6 systolic murmur. Her lungs were clear and a pulmonary artery bruit was audible over the left upper posterior lung field. There was no palpable cervical, supraclavicular, or axillary lymphadenopathy. She had no palpable hepatosplenomegaly and her extremities were warm with trace edema. A CT scan of the chest was available for review and showed significant thickening of the blood vessel wall of the left pulmonary artery, and occlusive thrombus in the right interlobar pulmonary artery (Fig. 10.1).

Figure 10.1 Computed tomography of the chest demonstrating thickening of the wall of the left pulmonary artery (blue arrow), occlusive thrombus in the proximal right PA (solid white arrow) and vessel attenuation of the right lower lobe arteries (open white arrow)

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Pulmonary function testing revealed an FEV1 of 81% predicted, and FVC of 94% predicted with an FEV1/FVC of 62%. The DLCO was decreased at 45% predicted. A TTE showed a left ventricular ejection fraction of 60–65%. The right ventricle was dilated with right ventricular hypertrophy and a moderate decrease in systolic function. The estimated pulmonary artery systolic pressure was 75–80 mmHg. A recent right heart catheterization demonstrated pulmonary hypertension. The right atrial pressure was 27 mmHg, the pulmonary artery pressure was 91/23(46)  mmHg and the pulmonary capillary wedge pressure was 10  mmHg. The cardiac output by ­thermodilution was 4.2 L/min and the pulmonary vascular resistance was 8.5 Woods units. A ventilation perfusion scan showed multiple mismatched perfusion abnormalities (Fig. 10.2). The patient was diagnosed with chronic thromboembolic pulmonary hypertension and admitted to the hospital for further management. The patient was admitted to the hospital and treated with intravenous diuretics. Supplemental oxygen was used to maintain an oxygen saturation >95%. On day 4 of hospitalization she underwent pulmonary thromboendarterectomy (Fig. 10.3).

Figure 10.2  The ventilation-perfusion scan. The ventilation images were normal. The perfusion scan demonstrated multiple defects consistent with acute or chronic pulmonary embolism

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Figure 10.3  The endarterectomy specimen from the patient

She had an excellent hemodynamic result with improvement in her systolic pulmonary artery pressure from 85 mmHg at the start of the case to 45  mmHg at the completion. The post-operative course was uneventful. She was extubated and weaned of vasopressors on the first post-operative day (POD). On POD 5, the surgical specimen pathology resulted with islands of malignant cells within the endarterectomy specimen (Fig. 10.4a). These cells stained positive for keratin and p-40 and were negative for CD34, consistent with squamous cell carcinoma (Fig. 10.4b). A PET-CT was done which showed intense uptake in the region of the right pulmonary artery and paratracheal lymph nodes as well as in the left eighth rib and right iliac crest. No primary source was identified and the patient was diagnosed with metastatic squamous cell carcinoma of known primary. The patient had an uneventful recovery from her surgery with significant improvement in her functional capacity. After 3 months of recovery, she was started on chemotherapy with an excellent radiographic response to treatment.

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a

b

Figure 10.4  (a) Islands of malignancy cells (arrow) within endarterectomy specimen. (b) The malignant cells stain strongly positive for keratin. A p-40 stain was positive as well (not shown)

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Clinical Comments Pulmonary tumor emboli can present in a manner similar to thromboembolic disease, with some of the more common primary tissue types include breast, stomach, lung, liver, prostate and pancreas. Tumor cell emboli in the pulmonary vascular bed can involve the proximal vessels and present acutely, or can primarily involve the microvasculature with a more sub-acute, progressive clinical course. This case is of interest in that the presentation was entirely consistent with CTEPH, and the tumor cells were found embedded in the organized thrombus removed at the time of surgery—emphasizing the importance of a pathologic examination of endarterectomized material. Unclear is the mechanism by which the tumor cells became incorporated within the clot— whether there was an initial tumor embolus leading to an in-situ thrombus, or the pulmonary thromboembolism was somehow “seeded” by circulating tumor cells.

Points of Emphasis Metastatic neoplasm involving the pulmonary vessels can present in various ways, this case illustrating an unusual involvement with organized thrombus. It is essential that material endarterectomized from the pulmonary vessels undergo complete examination to ensure that coexisting pathology is not present.

Diagnosis 1. Chronic thromboembolic pulmonary hypertension. 2 . Metastatic squamous cell carcinoma, unknown origin.

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Further Reading Kane RD, Hawkins HK, Miller JA, Noce PS.  Microscopic pulmonary tumor emboli associated with dyspnea. Cancer. 1975;36(4):1473–82. Miyoshi S, Hamada H, Katayama H, Hamaguchi N, et al. Pulmonary tumor thrombotic microangiopathy associated with lung cancer. J Cardiol Cases. 2010;1:e120–3. Roberts KE, Hamele-Bena D, Saqi A, Stein CA, Cole RP. Pulmonary tumor embolism: a review of the literature. Am J Med. 2003;115:228–32.

Chapter 11 Case 11: Don’t Forget About the Pulmonary Veins! Terence K. Trow, Deepa Gopalan, and William R. Auger

Case Presentation A 50 year old white female presented with complaints of gripping, squeezing substernal chest pain awakening her from sleep at 1  A.M. The pain spontaneously resolved after 10  min. Evaluation in the emergency department revealed hypoxemia

T. K. Trow (*) Pulmonary, Critical Care, and Sleep Medicine, DynaMed Plus, EBSCO Health Information Services, Ipswich, MA, USA Yale Pulmonary Vascular Disease Program, Yale School of Medicine, New Haven, CT, USA e-mail: [email protected] D. Gopalan Department of Radiology, Imperial College Hospitals, London, UK e-mail: [email protected] W. R. Auger Lewis Katz School of Medicine, Temple University, Philadelphia, PA, USA e-mail: [email protected] © Springer Nature Switzerland AG 2020 W. R. Auger, D. Gopalan (eds.), Clinical Cases in Chronic Thromboembolic Pulmonary Hypertension, Clinical Cases in Cardiology, https://doi.org/10.1007/978-3-030-17366-1_11

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with oxygen saturations of 82% on room air normalizing with three liters nasal cannula (LNC) supplementation. Vital signs showed a pulse of 54, BP of 156/87, respiratory rate of 24, and a temperature of 98.2. Physical exam was notable for some reproducible chest wall tenderness that was not relieved by leaning forward, a grade 1/6 holosystolic murmur heard best at left upper sternal border as well as a grade 1/6 diastolic murmur, and rales at both lung bases. No dullness to percussion of the lungs was appreciated. No pulmonary bruit was heard between the scapulas. The lower extremities showed no clubbing, cyanosis, or edema. An initial troponin was 0.03 μg/L. N-Terminal proBrain natriuretic peptide (NT-proBNP) was 5330  pg/ml. An electrocardiogram (ECG) revealed a right bundle branch block with left posterior fascicular block and T wave inversions in V1-V4 with some ectopic atrial beats. A chest X-ray (Fig. 11.1) revealed enlarged pulmonary arteries with perihilar pulmonary vascular congestion and some alveolar opacities suggestive of pulmonary edema. A dose of 40 mg of furosemide was administered. She was admitted for further evaluation and treatment.

Figure 11.1  PA and lateral chest radiograph showing cardiomegaly and enlarged central pulmonary arteries

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Past medical history included hypertension, gastroesophageal reflux disease, depression, and a history of congenital atrial septal defect with repair at age 10 in 1975 followed by mitral valve repair with 28 mm Physio II annuloplasty ring as well as closure of A2 plus A3 and release of P3 chordae in 2010. A tricuspid valve annuloplasty and patch reconstruction of the right superior pulmonary vein were also performed at that time. Social history was notable for no alcohol or illicit drug use but ongoing tobacco abuse with a 20 pack-year history. Hospital Course: The patient was diuresed with gradual improvement in dyspnea and oxygen requirement. Nonsteroidal anti-inflammatory therapy improved her musculoskeletal chest wall pain. An initial echocardiogram revealed severe pulmonic regurgitation with severe pulmonary hypertension with a pulmonary artery systolic pressure (PASP) estimate of 72, moderate right ventricular dysfunction and dilatation, with mild tricuspid regurgitation. Her left atrium was severely dilated and moderate diastolic relaxation impairment was noted. Mild mitral regurgitation was noted. No pericardial effusion was present. She was diuresed further and symptomatically improved with a repeat echocardiogram showing a PAPs estimate of 42. Bubble contrast administration revealed no evidence of shunting. Consultation with the pulmonary hypertension and cardiology service resulted in a differential diagnosis of WHO group 2 pulmonary venous hypertension, WHO group 4 chronic thromboembolic pulmonary hypertension (CTEPH), or chronic obstructive pulmonary disease (COPD) associated WHO group 3 pulmonary hypertension. Congenital heart disease associated pulmonary hypertension (PH) was deemed unlikely due to previous echocardiograms showing no PH as recently as 2010. Serologies for connective tissue disease, inherited or acquired hypercoagulability and human immunodeficiency virus were negative. Pulmonary function tests revealed a forced expiratory volume of 1.67  L (52% of predicted), forced vital capacity of 2.08  L (51% of predicted), a ratio between them of 80, total lung capacity of 3.66 L (52% of predicted), and a diffusion capacity

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Figure 11.2 Lung scintigraphy. Perfusion to right upper lobe is decreased (arrow) with intact ventilation

adjusted for hemoglobin of 19.28 (72% of predicted) consistent with a moderate restrictive ventilatory defect with mildly impaired diffusion but no COPD.  A ventilation-perfusion scan was performed (Fig. 11.2) and revealed unmatched perfusion defects to the entire right upper lobe (blue arrow). A computerized tomography pulmonary angiogram revealed no filling defects to suggest acute pulmonary emboli, with linear densities in the lower lobes and RUL suggestive of atelectasis. Concern over CTEPH prompted a combined right heart catheterization with pulmonary angiography. This revealed a right atrial pressure (RAP) of 10, pulmonary artery pressure (PAP) of 45/25 with a mean of 31, a pulmonary wedge pressure (PAWP) of 12, cardiac output (CO) of 4.61 L/min, cardiac index (CI) of 2.14  L/min, resulting in a pulmonary vascular resistance (PVR) of 4.12  Wood units. A saturation run revealed a high superior vena cava saturation of 66%, RA sat of 65.9 %, PA sat of 68.1%, with a systemic saturation of 95.5%. Inhaled nitric oxide at 40 ppm resulted in PAP of 50/23; mean of 32. A 500  cc rapid fluid bolus resulted in a doubling of the PAWP to 24. Pulmonary angiography (Fig.  11.3) revealed markedly decreased right upper lobe (RUL) perfusion with smooth stenosis of the truncus anterior.

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Figure 11.3  Right pulmonary arteriogram: intact right upper lobe vessels with distal pruning and absent venous return (arrow)

Taken together this was interpreted as PH from heart failure with preserved ejection fraction (HFpEF) and possibly CTEPH.  Consultation with a CTEPH center experienced with pulmonary thromboendarterectomy surgery was requested. A review of the chest CT angiogram in this patient confirmed the reduction in RUL arterial density relative to the left upper lobe (LUL), as well as, the absence of intra-arterial organized thrombus. However, with the history of a previous cardiac surgical procedure which included reconstruction of the right superior pulmonary vein, assessment of the mediastinum in the region of the pulmonary veins (Fig.  11.4) revealed complete obstruction of the right superior pulmonary vein near the juncture with the left atrium (open arrow).

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Figure 11.4 CT angiogram demonstrating occlusion of the right superior pulmonary vein

Radiographic Interpretation The chest radiograph also demonstrates evidence for a previous sternotomy, tricuspid valve annuloplasty, and mitral valve repair (best viewed on lateral film). In addition to generalized “haziness” over the lower zones, the cardiac silhouette is enlarged and the vascular markings in the right upper lobe appear less prominent relative to the left upper lobe. The anterior view of the V/Q scintigraphy shows overall poor perfusion to the right upper lobe (blue arrow) as the only significant unmatched defect. Notable is the “type” of perfusion abnormality, a graded reduction without definitive segmental or subsegmental defects. The pulmonary angiogram is remarkable for the early opacification of the right upper lobe vessels, and distal vessel “pruning” as contrast fails to opacify the most distal vasculature on sequential cuts. As the venous phase appears, there is no drainage of contrast from the upper lobe of the right lung. Important to note is the absence of angiographic irregulari-

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Figure 11.5 Coronal view of the CT angiogram demonstrated thrombus in the right superior pulmonary vein (block arrow, left panel). Note the contrast filled patent left superior pulmonary vein (block arrow, right panel) for comparison (LA: Left atrium; RPA: right pulmonary artery)

ties to suggest chronic thromboembolic disease; the overall architecture of the right upper lobe vessels is basically normal. The white arrow points to some reflux of contrast into the right superior pulmonary vein from the left atrium. A coronal view of the same CT angiogram better demonstrates the obstructed pulmonary vein (Fig. 11.5).

Clinical Comments This case illustrates that impedance of outflow from a lung region due to obstruction or narrowing of a large pulmonary vein may result in perfusion defects on lung scintigraphy. As

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seen in this patient, arterial “pruning” may result from diminished perfusion of the distal vessels, and should not be interpreted as an angiographic feature of chronic thromboembolic disease. In the example above, the basis for the poor perfusion of the right upper lobe was occlusion of the right superior pulmonary vein, likely chronically thrombosed following surgical reconstruction of this vessel several years previously. By itself, it is unlikely this finding contributes significantly to her symptoms, or plays a major role in her pulmonary hypertension. Impressive was the considerable rise in pulmonary arterial wedge pressure with a fluid challenge, in keeping with her diagnosis of WHO group II pulmonary hypertension. There are also other disease states that may compromise the pulmonary veins as they enter the mediastinal space and drain into the left atrium. Mediastinal fibrosis, adenopathy and/or neoplasms that can compress the major pulmonary veins and pulmonary vein stenosis post atrial fibrillation ablation procedures are among the more common considerations.

Points of Emphasis Not all perfusion defects are due to pulmonary arterial disease. Large vessel pulmonary venous narrowing or occlusion can similarly cause perfusion defects seen on lung scintigraphy and CT.

Diagnoses 1. Right upper lobe perfusion defect due to occlusion of the right superior pulmonary vein (post-surgical). 2. WHO group II pulmonary hypertension.

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Further Reading McNeeley MF, Chung JH, Bhalla S, Godwin JD.  Imaging of granulomatous fibrosing mediastinitis. AJR Am J Roentgenol. 2012;199(2):319–27. Packer DL, Keelan P, Munger TM, Breen JF, Asirvatham S, Peterson LA, Monahan KH, Hauser MF, Chandrasekaran K, Sinak LJ, Holmes DR.  Clinical presentation, investigation, and management of pulmonary vein stenosis complicating ablation for atrial fibrillation. Circulation. 2005;111:546–54. Toonkel RL, Borczuk AC, Pearson GD, Horn EM, Thomashow BM. Sarcoidosis-associated fibrosing mediastinitis with resultant pulmonary hypertension: a case report and review of the literature. Respiration. 2010;79(4):341–5.

Chapter 12 Case 12: Pulmonary VenoOcclusive Disease …but It Started Out as CTEPH Rana Awdish, Sara Hegab, Deepa Gopalan, and William R. Auger

Case Presentation A 23  year old male with no significant past medical history was transferred from a small community based intensive care unit (ICU) to a tertiary care referral center for evaluation of R. Awdish (*) · S. Hegab Pulmonary Hypertension Program, Division of Pulmonary and Critical Care Medicine, Henry Ford Hospital, Detroit, MI, USA Pulmonary Hypertension Program, Heart and Vascular Institute, St. John Providence Ascension Health, Southfield, MI, USA School of Medicine, Wayne State University, Detroit, MI, USA e-mail: [email protected] D. Gopalan Department of Radiology, Imperial College Hospitals, London, UK e-mail: [email protected] W. R. Auger Lewis Katz School of Medicine, Temple University, Philadelphia, PA, USA e-mail: [email protected] © Springer Nature Switzerland AG 2020 W. R. Auger, D. Gopalan (eds.), Clinical Cases in Chronic Thromboembolic Pulmonary Hypertension, Clinical Cases in Cardiology, https://doi.org/10.1007/978-3-030-17366-1_12

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pulmonary hypertension. The patient had a 3 month history of gradually progressive exertional dyspnea where activities such as rising from seated position or taking a few steps resulted in severe shortness of breath. He endorsed dizziness and lightheadedness with exertion as well as pre-syncope, though he denied any syncopal episodes or lower extremity edema. The patient was a lifelong nonsmoker with no history of alcohol use. He reported traveling on several long car and airplane trips in the few months prior to presentation. Evaluation in the ICU showed blood pressure of 139/79, pulse of 79 beats per minute, respiratory rate of 20 breaths per minute, and oxygen saturation of 93% on room air. Physical examination showed a well-developed, age appropriate male in mild respiratory distress. Cardiac auscultation was significant for S1 and S2 with accentuated pulmonary component of S2 audible at the apex, grade 1/6 holosystolic murmur audible at left lower sternal border. There was no JVD or lower extremity edema noted. 2-dimensional (2D) echocardiography showed a mildly reduced left ventricular ejection fraction of 54% without significant abnormalities in diastolic parameters, an estimated right ventricular systolic pressure (RVSP) of 63  mmHg with severe enlargement of the right ventricle, tricuspid annular plane systolic excursion (TAPSE) 2.04  cm, right ventricular fractional area change of 29.4% and flattening of the interventricular septum in diastole and systole. Saline contrast bubble study was negative for evidence of intra-cardiac shunting. Due to concern for acute pulmonary embolism given recent travel history, the patient had a computerized ­tomography angiogram (CTA) of the chest. (Fig.  12.1) This was negative for acute pulmonary embolism but did show right and left lower lobe ground glass opacities with diffuse lymphadenopathy most pronounced in the mediastinal and subcarinal areas. The patient underwent bronchoscopy with transbronchial needle aspiration (TBNA) of lymph node stations 11R, 7 and 4R with no evidence of malignancy. An evaluation for pulmonary arterial hypertension was initiated given history and echocardiographic findings. Serological screening for connective tissue disease in the form of antinuclear antibody (ANA) and rheumatoid factor (RF)

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Figure 12.1 CT angiography shows prominent perivascular and subcarinal tissue

were negative. Human immunodeficiency virus (HIV) testing was negative. Pulmonary function testing was consistent with a restrictive pattern as evidenced by FVC 60% predicted, FEV1 57% of predicted, FEV1/FVC 77, TLC 63% of predicted and DLCO was significantly reduced at 38% of predicted. A ventilation perfusion (VQ) scan (Fig. 12.2) to screen for chronic thromboembolic disease revealed numerous segmental and subsegmental mismatched perfusion defects ­bilaterally with modestly decreased perfusion noted to the entire right lung relative to the left. Right cardiac catheterization showed, in mmHg, right atrial pressure (RAP) 8/5/2, right ventricular pressure (RVP) 72/0/2, pulmonary artery pressure (PAP) 73/37/46, pulmonary capillary wedge pressure (PCWP) 5. Pulmonary arterial oxygen saturation was measured at 62% with a cardiac output and cardiac index obtained by Fick method of 6.42 L/min and 2.69  L/min/m2 respectively. Pulmonary angiogram was also performed showing multiple cut-off’s in the right upper, middle, and lower lobes that was interpreted to be due to a large burden of chronic thrombus in the entire right lung. Small cut-off also noted in the left upper anterior artery consistent with chronic thrombus (Fig. 12.3).

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Figure 12.2  Lung scintigraphy shows R > L bilateral segmental and subsegmental unmatched defects

A multi-disciplinary meeting was held including the Pulmonary Hypertension Team, Interventional Cardiology who had performed angiography, the Chest Radiologist and CT Surgery. In light of the V/Q scan findings and the interpretation of the PA gram, despite the absence of evident thromboembolic disease by CTA, CTEPH was entertained as the probable diagnosis. There was further concern for the possibility of large pulmonary venous thrombosis on CTA (Fig. 12.4). The patient was started on unfractionated heparin while inpatient and discharged home on long term anticoagulation for chronic thromboembolic disease. His diagnostic testing was sent to the University of California in San Diego for an assessment of operability.

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Figure 12.3 Pulmonary arteriogram shows a reduction in peripheral perfusion or “pruning” in the left lower lobe (arrows)

Figure 12.4  CT angiogram of the chest show a flow disturbance in the right inferior pulmonary vein (block arrow)

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Figure 12.5 CT angiogram shows bilateral diffuse ground glass opacities (thin arrow), smooth interlobular septal thickening (notched arrow), pronounced mediastinal and hilar lymphadenopathy (chevron) with a small left pleural effusion(black star)

The patient presented to the hospital one month later with worsening dyspnea, now occurring at rest. Physical examination was significant for normal S1 and S2 with prominent P2, grade 2/6 holosystolic murmur heard best a left upper sternal border, JVD of 8 cmH2O, and 2+ lower extremity edema. There was significant progression of CT imaging findings (as below), with increase in interlobular septal thickening and areas of ground glass opacities with stable lymphadenopathy (Fig. 12.5). Due to the very rapid progression of disease, and the constellation of CT findings in conjunction with the hemodynamic data, pulmonary veno-occlusive disease was favored. Pulmonary transplant team was consulted and patient underwent expedited workup and was listed for lung transplant. As a bridge to transplant, the patient was started on low dose parenteral epoprostenol at 2 ng/kg/min. His right ventricular failure progressed despite this, as did his hypoxemic respiratory failure. A second multi-disciplinary meeting was held, including CT Surgery, Pulmonary Hypertension and Pulmonary Transplant and it was agreed to proceed with veno-arterial (VA) extracorporeal membrane oxygenation (ECMO) for hemodynamic support as a bridge to lung transplantation. The patient required support of VA ECMO for two days prior to undergoing bilateral lung transplantation. He was discharged to rehab, and subsequently home.

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Figure 12.6  Gross specimen explanted lung. Scale represented by ruler. Thickened interlobular septa (thick arrow). Evidence of diffuse alveolar damage in intervening tissue (circle). Accentuated branch points (thin arrow)

Figure 12.7 Verhoeff stain demonstrating thickened interlobar septa; Magnification ×4. Thickened vein (thin arrow) within fibrotic interlobar septae (thick arrow)

Histopathology of the explanted lungs was consistent with pulmonary veno-occlusive disease, arterial intimal fibrosis, diffuse alveolar damage/acute interstitial pneumonitis. The patient is alive ten months post-transplant and continues to do well (Figs. 12.6, 12.7, 12.8, and 12.9).

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Figure 12.8  Verhoeff stain magnification ×4 demonstrating arterial intimal hyperplasia (arrow)

Figure 12.9  H and E stain. Magnification ×4 demonstrating septal thickening (thick arrow) and thickened venules (thin arrow)

Radiographic Interpretation Review of the imaging studies in this case warrants several comments.

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Ventilation-Perfusion scintigraphy demonstrates numerous segmental and sub segmental perfusion defects without corresponding ventilation defect. The perfusion throughout the entire right lung is also decreased relative to left. Ventilation is homogenous in both lungs. Computerized tomography pulmonary angiogram (CTPA) shows generic features of pulmonary hypertension such as dilatation of the right atrium and right ventricle with flattening of the interventricular septum. There are bilateral diffuse ground glass opacities (thin arrow) smooth interlobular septal thickening (notched arrow), pronounced mediastinal and hilar lymphadenopathy (chevron) with a small left pleural effusion (black star). There is no evidence of acute or proximal chronic thromboembolic disease. Flow disturbance is noted within the inferior pulmonary veins with no evidence of any extrinsic compressive lesion (block arrow); this was initially interpreted as a large pulmonary venous thrombus. On catheter pulmonary angiography, there is smooth change in the calibre of the pulmonary arteries from proximal to distal bed with no intimal thrombus, pouch defect, intravascular webs or stenosis. During the capillary phase, there is heterogeneous reduction of perfusion in the left upper zone with reduced peripheral perfusion in the mid and lower zones. These findings are consistent with the presence of extensive small vessel disease, and are not a feature associated with chronic thromboemboli. Similar findings were felt to be present throughout the right, though the quality of the study limits interpretation.

Clinical Comments The principal lesson in this case centers on the radiographic miscues that occasionally occur when dealing with pulmonary veno-occlusive disease (PVOD). Given the rarity of PVOD, it is difficult to describe what typical patterns manifest in perfusion scans, but the largest series available described normal perfusion scans as the predominate pattern.

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(see Seferian and colleagues) That lung perfusion scintigraphy can be abnormal in PVOD is not often recognized. In the presented case, despite an initial CT of the chest and pulmonary angiogram without evidence for either acute or chronic thromboembolic disease, the abnormal perfusion scan briefly deviated diagnostic focus toward the possibility of CTEPH.  Although the VQ scintigraphy might have been “high-probability” for thromboembolic disease, the patient’s clinical course, degree of hypoxemia, very low DLCO, and CT findings—such as his diffuse adenopathy—ultimately were highly suspicious for, and led to the diagnosis of, pulmonary veno-occlusive disease. One of the best reviews of this subject is provided by Seferian and colleagues. In both PVOD and idiopathic or inheritable PAH, the majority of patients will have normal or essentially normal ventilation-perfusion scintigraphy. However, unmatched perfusion defects were described in 7% of cases with PVOD, likely a result of focal “downstream” increase in resistance caused by the narrowing and obliteration of pulmonary veins and venules. Also of interest in this same study was that 10% of patients with idiopathic PAH demonstrated abnormal perfusion scans.

Points of Emphasis Mismatched perfusion defects on scintigraphy in a patient with pulmonary hypertension does not always indicate a pulmonary arterial occlusive process. Pulmonary veno-occlusive disease should be considered when a positive scintigraphy is coupled with an angiogram showing no arterial obstruction. The conglomeration of CT findings can be very helpful in making the correct diagnosis.

Diagnosis 1. Pulmonary veno-occlusive disease.

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Further Reading Bailey CL, Channick RM, Auger WR, Fedullo PF, Kerr KM, Yung GL, Rubin LJ. “High probability” perfusion lung scans in pulmonary veno-occlusive disease. Am J Resp Crit Care Med. 2000;162:1974–8. Balke L, Both M, Winkler C, Schreiber T, Röcken C, Koch K, Bewig B.  Scintigraphy leading to the misdiagnosis of chronic ­thromboembolic disease in a patient with pulmonary veno-occlusive disease. Circulation. 2016;133(16):1627–8. Montani D, Girerd B, Jais X, Levy M, Amar D, Savale L, Dorfmuller P, Seferian A, Lau EM, Eyries M, Le Pavec J, Parent F, Bonnet D, Soubrier F, Fadel E, Sitbon O, Simonneau G, Humbert M. Clinical phenotypes and outcomes of heritable and sporadic pulmonary veno-occlusive disease: a population-based study. Lancet Respir Med. 2017;5(2):125–34. Seferian A, Helal B, Jaïs X, Girerd B, Price LC, Günther S, Savale L, Dorfmüller P, Parent F, Sitbon O, Humbert M, Simonneau G, Montani D. Ventilation/perfusion lung scan in pulmonary veno-­ occlusive disease. Eur Respir J. 2012;40:75–83.

Chapter 13 Case 13: Pulmonary Arteritis… The Great CTEPH Mimic Kim M. Kerr, Albert Hsiao, and William R. Auger

Case Presentation A 30 year old male presented with a 2 year history of progressive dyspnea, chest pain and fatigue. His past medical history was notable for a heart murmur since childhood and a subjective reduced exercise tolerance compared to his contemporaries. An echocardiogram was performed as K. M. Kerr (*) Division of Pulmonary and Critical Care Medicine, University of California, San Diego, San Diego, CA, USA e-mail: [email protected] A. Hsiao Asssociate Professor in Residence, Department of Radiology, University of California, San Diego, San Diego, CA, USA W. R. Auger Lewis Katz School of Medicine, Temple University, Philadelphia, PA, USA e-mail: [email protected] © Springer Nature Switzerland AG 2020 W. R. Auger, D. Gopalan (eds.), Clinical Cases in Chronic Thromboembolic Pulmonary Hypertension, Clinical Cases in Cardiology, https://doi.org/10.1007/978-3-030-17366-1_13

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part of his chest pain and dyspnea evaluation and revealed a mild to moderately dilated right ventricle and pulmonary hypertension. Right heart catheterization showed RA 8, PA 90/13 (mean 35), PAOP 8, thermodilution cardiac output 3.1  L/min (cardiac index 1.6  L/min/m2), PVR 697 dyn s cm−5. However, a repeat echocardiogram performed 2 months later demonstrated only a mildly enlarged right atrium with a normal size right ventricle that appeared severely hypokinetic. This prompted a cardiac MR which showed normal cardiac chamber sizes with the exception of a right atrium at the upper limits of normal and mild right ventricular hypertrophy with some flattening of the interventricular septum without evidence of intra-cardiac shunting. Soon after this evaluation the patient developed acute respiratory failure while travelling to altitude requiring mechanical ventilation and hospitalization for two weeks. He was diagnosed with pneumonia and pulmonary embolism by chest CT and placed on warfarin anticoagulation. Upon returning home to lower altitude he remained symptomatic and tadalafil was added to his regimen to treat his pulmonary hypertension. A VQ scan demonstrated unmatched perfusion defects (Fig.  13.1) and his CT angiogram (Fig. 13.2) was felt to be compatible for chronic thromboembolic disease. He was referred for possible pulmonary thromboendarterectomy. On initial evaluation at a CTEPH center he reported some improvement in exercise tolerance, but remained WHO functional class III with one block DOE and exertional lightheadedness. Additional PMH included left spontaneous pneumothorax treated with VATS (report of evaluation for Marfan’s negative at that time), chronic hoarseness, mild thrombocytopenia, questionable Protein S deficiency in the setting of warfarin therapy, and abnormal LFTs with a liver ultrasound demonstrating early cirrhotic changes. His family history was remarkable for a sister who required surgery as a child for a “hole in her heart”. He previously drank 6–12 beers daily, but had decreased his alcohol intake substantially and continued to smoke marijuana.

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Figure 13.1 Lung scintigraphy demonstrating a number of unmatched perfusion defects, predominantly involving the upper lobes, lingula and right middle lobe

Physical exam revealed a very tall and thin Hispanic male comfortable at rest. HR 65, BP 136/67, RR 16, SpO2 96% on room air. There was no JVD, but a carotid bruit vs. a transmitted murmur over his left carotid artery was auscultated. Lung fields were clear with loud pulmonary flow murmurs noted anteriorly and posteriorly in both lungs. There was no RV lift, S1 was normal with a loud second heart sound and a soft systolic murmur without gallop. Abdominal exam was normal without evidence of bruits. Extremities revealed no edema, no bruits over proximal arteries, and pulses were all strong and symmetric except for a diminished right dorsalis pedis and posterior tibialis pulses. Laboratories were notable for elevated alkaline phosphatase (251 U/L) and ALT/AST (72/46 U/L) that were improved from prior labs, BNPP was normal. CBC was normal. A chest X-ray (Fig. 13.3) showed no cardiomegaly or central pulmonary artery enlargement, but blunting of the costophrenic angle with some diaphragmatic tenting was noted on the left.

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a

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Figure 13.2 (a) Right main pulmonary artery narrowing (white arrow) throughout its course with marked vessel narrowing of the left descending PA (chevron). Bronchial arterial collateral vessels also noted. (open arrow). (b) Proximal to distal (left to right) axial images of the CT angiogram shown in (a). Small right descending PA to attenuated proximal RLL segmental vessels to dilatation of the more distal segmental vessels of the right lower lobe. No CT evidence for chronic thrombus

An echocardiogram showed normal right and left sided chamber size and function, normal valvular function and estimated RV systolic pressure of 121 mmHg. Repeat right heart catheterization was performed: RA 5, RV 110/6, PA 110/16 (mean 43), PAOP 7, cardiac output 4.25 L/min, cardiac index 2.19 L/min/m2, PVR 678 dynes s cm−5, PA saturation 70%.

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Figure 13.3 PA chest radiograph: no central pulmonary artery enlargement despite the severe pulmonary hypertension documented by right heart catheterization

To better define pulmonary vessel anatomy, digital subtraction pulmonary angiography (Fig.  13.4a, b) was performed. On the right, a small main pulmonary artery was noted with absent perfusion to the posterior RUL, post-­ stenotic dilation of the apical RUL, proximal segmental obstruction of the RML, irregularity and narrowing of the RLL arteries with absent flow to the superior segment. The left main pulmonary artery was also small with marked narrowing of the descending PA, absent perfusion to the m ­ ajority of the LUL and lingula and flow to the LLL confined to the posterior basal artery. These arteriographic findings were felt to be atypical for CTEPH and more compatible with large vessel arteritis. An MR angiogram (MRA) was performed of the neck, chest, and abdomen revealing marked diffuse narrowing of the distal descending thoracic and upper abdominal aorta with occlusion of the celiac origin and moderate stenosis of the superior mesenteric artery, compatible with the diagnosis of

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Figure 13.5  Chest MRA depicting small caliber left central PA with segments of irregular narrowing (open arrow)

large vessel arteritis. There was also moderate narrowing of the renal artery origins, along with extensive collateralization of the hepatic artery territory via the splenic artery, likely through gastric and gastroepiploic collaterals. The pulmonary arteries were also noted to be diminished in caliber (Fig. 13.5), particularly centrally with occlusion of some vessels as seen on the digital subtraction angiogram. The finding of arteritis in the systemic vessels (Fig. 13.6) on CTA and MRA further substantiated the diagnosis of large vessel arteritis of the pulmonary arteries resulting in pulmonary hypertension.

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Figure 13.6  3D reconstructions from a CTA of the abdominal vessels, with the notable occlusion of the celiac axis and irregular narrowing of the superior mesenteric artery (white arrow)

Clinical Comments This case is in many ways atypical for the presentation of major vessel pulmonary arteritis—one etiology of which is Takayasu arteritis—though compelling from the perspective of when to suspect an alternative diagnosis to CTEPH. The length of time this patient was experiencing cardiopulmonary symptoms (dating back to childhood), and the severity of pulmonary hypertension documented by right heart catheterization should have immediately raised concerns that the initial acute deterioration at altitude may have been an exacerbation of right heart failure with the presence of pulmonary embolism perhaps a “secondary” event. The subsequent assessment led to a more appropriate consideration of CTEPH given the sub-acute symptoms, the severity of pulmonary hypertension, the abnormal VQ, and CT findings which could easily be misinterpreted as chronic

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t­hromboembolic disease such as segments of vessel narrowing and attenuation and even the post-stenotic dilatation occasionally observed in CTEPH. There was even the presence of bronchial arterial collateral vessels. The detection of pulmonary artery bruits or flow murmurs could be indicative of CTEPH as well, an auscultatory finding in approximately 30% of patients with proximal vessel, chronic thrombotic lesions. However, the findings that might suggest an alternate diagnosis are the longstanding presence of cardiopulmonary difficulties, the extraordinary pulmonary arterial pulse pressure noted on his initial right heart catheterization—a sign of noncompliant proximal pulmonary vessels—and the appearance of the proximal arteries by CT and on his routine chest radiograph. With this degree of pulmonary hypertension, there’s typically significant enlargement of the proximal pulmonary arteries. But based on historical features alone, pulmonary arteritis was not an obvious diagnosis. His gender was an issue; Takayasu arteritis usually affects young females, reports indicating a rate ten times greater than males. Furthermore, the problems during childhood raised concerns that congenital pulmonary vascular disease should be considered, such as pulmonary artery stenosis which may have similar abnormalities on CT and VQ.  However, pulmonary artery stenosis is typically associated with congenital heart defects such as Tetralogy of Fallot, pulmonary arterial stenosis of Williams syndrome, patent ductus arteriosus, or pulmonary valve stenosis. Such lesions are usually detected during childhood (and none present on this patient’s cardiac MR). The absence of systemic arterial events was also puzzling, though in retrospect, his chronically elevated liver-related enzymes may have been a manifestation of compromised hepatic vascular supply. Though pulmonary artery involvement can be the initial presentation of Takayasu arteritis, this is not the typical course. Ultimately, the digital subtraction pulmonary arteriogram was the study to raise the greatest doubts about chronic thromboembolic disease as the cause of this patient’s

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­ ulmonary hypertension. The marked proximal vessel narp rowing and the diminutive vessels at every level, associated with discrete narrowings and post-stenotic dilatation are not angiographic features commonly associated with chronic thromboembolic disease (Case 1, Chap. 1). This is especially the case when eccentric lining thrombus and intravascular, recanalized clot are not evident on CT. Proceeding with confirmatory imaging of the aorta and the major vessels, even without historical or exam evidence for vascular compromise was appropriate and confirmed the diagnosis of major vessel arteritis.

Points of Emphasis Historical evidence for peripheral arterial events, the presence of arterial bruits or diminished pulses, and atypical CT or catheter-based angiographic findings, especially in young female patients with pulmonary hypertension, should alert the clinician to the possibility of pulmonary arteritis.

Diagnoses 1. Pulmonary arteritis and aorto-arteritis arteritis). 2. WHO group V pulmonary hypertension.

(Takayasu

Further Reading Hayashi K, Nagasaki M, Matsunaga N, Hombo Z, Imamura T. Initial pulmonary involvement in Takayasu arteritis. Radiology. 1986;159:401–3. Kerr KM, Auger WR, Fedullo PF, Channick RN, Yi ES, Moser KM. Large vessel pulmonary arteritis mimicking chronic thromboembolic disease. Am J Respir Crit Care Med. 1995;152:367–73. Marten K, Schnyder P, Schirg E, Prokop M, Rummeny EJ, Engelke C.  Pattern-based differential diagnosis in pulmonary vasculitis using volumetric CT. AJR Am J Roentgenol. 2005;184:720–33.

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Matsunaga N, Hayashi K, Sakamoto I, Ogawa Y, Matsumoto T. Takayasu arteritis: protean radiologic manifestations and diagnosis. Radiographics. 1997;17(3):579–94. Sekiguchi M, Suzuki J.  An overview on Takayasu arteritis. Heart Vessels Suppl. 1992;7:6–10.

Chapter 14 Case 14: Sarcoidosis and Large Vessel Pulmonary Vascular Disease—Another CTEPH Mimic Robert Schilz, Deepa Gopalan, and William R. Auger

Case Presentation Fifty-two-year-old female with a vague medical history of a nonspecific mixed connective tissue disease, and poorly characterized lung nodules, experiencing years of exertional dyspnea. Progressing more rapidly over 6  months, she was

R. Schilz (*) CWRU School of Medicine, Cleveland, OH, USA Lung Transplantation and Pulmonary Vascular Disease, University Hospitals of Cleveland, Cleveland, OH, USA e-mail: [email protected] D. Gopalan Department of Radiology, Imperial College Hospitals, London, UK e-mail: [email protected] W. R. Auger Lewis Katz School of Medicine, Temple University, Philadelphia, PA, USA e-mail: [email protected] © Springer Nature Switzerland AG 2020 W. R. Auger, D. Gopalan (eds.), Clinical Cases in Chronic Thromboembolic Pulmonary Hypertension, Clinical Cases in Cardiology, https://doi.org/10.1007/978-3-030-17366-1_14

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hospitalized for the treatment of a pericarditis and pleural effusions. A month later, an echocardiogram revealed normal left ventricular size and function; right ventricular size and function were also assessed as normal, with an RV systolic pressure estimated at 24 mmHg. The pericardial effusion had resolved. With the development of sharp chest wall pains and persistent dyspnea 4 months later, a follow up chest radiograph was obtained (Fig.  14.1) and was without demonstrable cardiomegaly, parenchymal infiltrates or pleural effusions.

Figure 14.1  PA chest radiograph demonstrating normal heart size, symmetric hilar fullness, in the absence of significant parenchymal abnormalities

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Figure 14.2  Extensive soft tissue in the subcarinal space and surrounding the proximal pulmonary vessels

CT angiogram of chest was then requested demonstrating diffuse mediastinal and hilar “soft tissue fullness” consistent with matted adenopathy was described; multifocal parenchymal opacities were again demonstrated and there was no evidence for acute pulmonary emboli (Fig. 14.2). Pulmonary function tests in April 2018: FVC 2.65 L (78%), FEV-1 2.20  L (81%), FEV-1/FVC ratio 83% with DLCO 18.65 (82% predicted). Ongoing investigation of the patient’s symptoms prompted a right heart catheterization in May 2018. Resting pulmonary hemodynamics showed RA mean 3, PAp 39/12 mmHg with a mean pressure of 22  mmHg. Fick cardiac output 5.2  L/min with a cardiac index 3.0 L/min/m2; PVR was 3.25 Wood units. A level 3 cardiopulmonary stress test later that same month included rest and exercise pulmonary hemodynamics and full gas exchange. A borderline elevated PA pressure at rest (40/18  mmHg, mean pressure of 25  mmHg) showing a dramatic rise with exertion to 90/35  mmHg, 53  mmHg mean (Table 14.1). In further evaluation of the abnormal pulmonary vascular response to exercise, lung perfusion imaging was obtained (Figs. 14.3 and 14.4).

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Table 14.1  Summary of level 3 cardiopulmonary exercise testing Rest Peak VO2 RAP 3 8 PAP (systolic/diastolic/mean)

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Given the concern for the possibility of chronic thromboembolic disease, catheter-based pulmonary angiography was obtained (Fig. 14.5). With concerns over the persistent perfusion defects on VQ scan, significant functional limitations, and the atypical presentation, a referral was initiated for a second opinion.

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Figure 14.4 Spectral imaging demonstrating the relationship between compressive adenopathy and perfusion defects

Figure 14.5  Web-like narrowing of a right upper lobe artery (open arrow), with an vessel narrowing over a considerable length of the proximal descending pulmonary arteries, bilaterally (closed arrows)

Given the extent of mediastinal and hilar tissue, and the absence of definable pulmonary intravascular findings to suggest organized thrombus, biopsy of the subcarinal/mediastinal tissue was recommended. This yielded non-caseating

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granulomas; all microbiologic stains and titers were negative consistent with the diagnosis of sarcoid.

Radiographic Interpretation Chest radiograph demonstrates bilateral symmetrical hilar enlargement with lobulated outline that favors lymph-nodal enlargement as opposed to vascular dilatation. The lung volumes are preserved. There is no cardiomegaly. CTPA confirms mediastinal and hilar lymphadenopathy with some nodes exhibiting calcification. There is extrinsic compression of the pulmonary vasculature (for example, the right lower lobe artery in the Fig.  14.2, far right mediastinal widow) with lobar stenoses. The resultant perfusion abnormalities are elegantly demonstrated on the Spectral CT (Fig. 14.4). The main pulmonary artery is of normal dimension. The right ventricle is not dilated or hypertrophied. The nature and distribution of the lymph nodes are highly suspicious for sarcoidosis although the lung windows did not reveal any bronchocentric nodules, fissural nodularity or interstitial fibrosis. There are matched and mismatched perfusion defects bilaterally on VQ scintigraphy. Catheter angiography elegantly depicts the proximal smooth stenoses in the right upper and both lower lobe pulmonary arteries with mild post-stenotic dilatation. The segmental vessels are preserved with gradual tapering. There is no evidence of eccentric thrombus, pouch defects or intravascular webs. Taken in conjunction with the CT findings, the location of the stenoses would be in keeping with fibrosing mediastinitis and extrinsic compression by the mediastinal nodes. Multifactorial causes contribute to pulmonary hypertension in sarcoidosis. VQ appearances can be confusing as the perfusion defects may be matched, mismatched or reverse mismatched (ventilation worse than perfusion). CT is extremely useful to delineate the extent and severity of the lung fibrosis, mediastinal lymphadenopathy and extrinsic

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compression of the pulmonary arteries and veins. Sarcoid vasculopathy is however difficult to evaluate on CT and is an important factor to remember if imaging features are underwhelming in the presence of significant pulmonary hypertension in a patient with known sarcoidosis.

Clinical Comments The presented case represents a reminder to the diagnostician that perfusion abnormalities on lung scintigraphy can be caused by a wide variety of disease states. Therefore, an abnormal lung scan is insufficient to establish the diagnosis of chronic thromboembolic disease. This is especially the case when it comes to main PA and lobar level perfusion defects. In these settings, it is imperative to rule out mediastinal and hilar pathology that might be extrinsically compressing or obstructing the pulmonary vessels. Though sarcoidosis was the culprit in this case, mediastinal fibrosis such as from histoplasmosis, or mediastinal neoplasm can present with similar radiographic findings on screening studies. And finally, when digital subtraction angiography demonstrates vascular findings atypical for chronic thromboembolic disease—especially in the proximal vessels—more advanced thoracic imaging needs to be considered to better define mediastinal anatomy.

Point of Emphasis There are several mimics of chronic thromboembolic disease that the astute clinician needs to differentiate. Persistent perfusion defects on lung scintigraphy, and the pulmonary vascular irregularities on catheter-based pulmonary angiography, while suggestive of chronic thromboembolic disease, may also result from intrinsic pulmonary vascular disease (as in large vessel pulmonary arteritis) or from extrinsic c­ ompression from mediastinal or hilar adenopathy as seen in this presented case of pulmonary sarcoidosis.

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Diagnosis 1. Pulmonary sarcoidosis.

Further Reading Bazmpani MA, Arsos G, Zarogoulidis P, Doumas A, Dimitroulas T, Sianos G, Hadjimiltiades S, Kouskouras K, Mayer E, Karvounis H, Giannakoulas G. A case of sarcoidosis-associated pulmonary hypertension masquerading as chronic thromboembolic pulmonary hypertension. Pulm Circ. 2018;8(3):2045894018768289. https://doi.org/10.1177/2045894018768289. Damuth TE, Bower JS, Cho K, Dantzker DR.  Major pulmonary artery stenosis causing pulmonary hypertension in sarcoidosis. Chest. 1980;78(6):888–91. McNeeley MF, Chung JH, Bhalla S, Godwin JD.  Imaging of granulomatous fibrosing mediastinitis. AJR Am J Roentgenol. 2012;199:319–27. Toonkel RL, Borczuk AC, Pearson GD, Horn EM, Thomashow BM. Sarcoidosis-associated fibrosing mediastinitis with resultant pulmonary hypertension: a case report and review of the literature. Respiration. 2010;79:341–5. Wijesuriya S, Chandratreya L, Medford AR.  Chronic pulmonary emboli and radiologic mimics on CT pulmonary angiography: a diagnostic challenge. Chest. 2013;143:1460–71.

Chapter 15 Case 15: CTEPH? But the Lung Scan Is Normal! Victor J. Test, Deepa Gopalan, and William R. Auger

Case Presentation Fifty-five-year-old male with a medical history significant for tobacco abuse (>35 pack-years), prior heavy alcohol use, mild cirrhosis (Child-Pugh class A), hypertension and ­hyperlipidemia. There was also the history of right ventricular dysfunction diagnosed in 2000. In July 2014, the patient’s exertional dyspnea and functional disability had progressed to WHO functional class III. His exam notable for a holosystolic murmur, a soft early V. J. Test (*) Division of Pulmonary Medicine and Critical Care, Texas Tech University School of Medicine, Lubbock, TX, USA e-mail: [email protected] D. Gopalan Department of Radiology, Imperial College Hospitals, London, UK e-mail: [email protected] W. R. Auger Lewis Katz School of Medicine, Temple University, Philadelphia, PA, USA e-mail: [email protected] © Springer Nature Switzerland AG 2020 W. R. Auger, D. Gopalan (eds.), Clinical Cases in Chronic Thromboembolic Pulmonary Hypertension, Clinical Cases in Cardiology, https://doi.org/10.1007/978-3-030-17366-1_15

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diastolic murmur, P2 accentuation, jugular venous distension and ankle edema. Lung exam was unremarkable. An echocardiogram revealed normal left ventricular function, severe right ventricular dilatation, RVH and severe RV dysfunction, moderate tricuspid regurgitation, an RV systolic pressure estimated at 85 mmHg, mild to moderate pulmonic regurgitation, and severe pulmonary artery dilatation (4.7 cm). Left and right heart catheterization were subsequently performed. There was no atherosclerotic coronary vascular disease, though his LVEDP was elevated at 22  mmHg. His pulmonary artery pressure was measured at 100/40 with a PVR of 9.7  Wood units. There was no significant PVR response to inhaled nitric oxide. CT angiography of the chest showed “chronic pulmonary embolism” with an extensive clot burden involving several lobar and segmental vessels. The central pulmonary arteries were severely dilated and the RV was enlarged with thickening of the RV wall. No lung parenchymal abnormalities were observed (Fig. 15.1a–d).

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Figure 15.1  CT angiogram imaging the proximal pulmonary vessels (a), progressing down to the lower lobe arteries (b–d). Lining thrombus is noted throughout the proximal vessels, which does not extend into the enlarged segmental lower lobe arteries. There was no evidence for vessel obstruction or narrowing of the pulmonary vessels with organized clot

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Figure 15.1  (continued)

A lung perfusion scan was recommended given the CT findings, and was assessed as “fairly unremarkable” and “low probability for acute PE” (Fig. 15.2). Lower extremity dopplers were negative and a hypercoagulable workup was positive for a heterozygous Factor V Leiden abnormality. The patient was ultimately place on diuretics and a soluble guanylate cyclase stimulator in treatment of his pulmonary hypertension. This resulted in an improvement in his overall functional status.

Radiographic Interpretation CTPA demonstrates features of significant pulmonary hypertension as evidenced by aneurysmal dilation of main pulmonary artery, markedly enlarged right sided cardiac ­ chambers and severe right ventricular hypertrophy. There is reversal of septal curvature with small under-filled left ventricle. There is eccentric non-occlusive clot lining the distal right and left main pulmonary arteries. The segmental pulmonary artery branches are also dilated with thin rim of clot in

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Figure 15.2 Perfusion scan of the same patient at the same time that the CT angiogram in Fig.  15.1 was obtained. Other than an “imprint” of the enlarged central PAs, the perfusion pattern in both lungs is essentially normal

multiple vessels. No intravascular webs, stenosis or pouch defects were present. Lung windows did not reveal mosaic attenuation. There was no evidence of intracardiac shunt and the pulmonary venous anatomy was normal. Scintigraphy shows mottled perfusion but there are no segmental mismatched perfusion defects that is typical of CTEPH. The overall appearances are that of PAH with in-situ thrombosis (IST). Lining clot is a well known complication of long standing PAH (Moser et  al.). Proposed mechanism for IST includes wall shear stress from turbulent flow, vascular dilatation leading to stasis and endothelial injury creating a procoagulant

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environment (Chaouat et  al., Archer et  al.). Like CTEPH, these clots can also exhibit calcification. Differentiation between the two conditions is crucial as they have entirely different therapeutic options. In CTEPH, the segmental vessels tend to be attenuated whilst PAH is associated with enlarged proximal vessels and peripheral pruning. Other angiographic features of CTEPH such as truncation of segmental arteries, variation in size of segmental vessels, webs, stenosis and pouch defects are absent in PAH. Congenital heart disease can also be associated with IST and is seen in about one-fifth of the patients with Eisenmenger's syndrome. Hence, it is important to make a thorough search for the presence of intracardiac shunts.

Clinical Comments Though CTEPH has been defined as pulmonary hypertension in the presence of radiographic evidence for chronic thromboembolic disease, the case presented here is an example of how that definition can sometimes be misconstrued. What is present in this patient is organized thrombus lining enlarged central pulmonary vessels—in-situ and non-embolic. It is a consequence of longstanding pulmonary hypertension and not the cause of it. Most often this is seen in congenital heart disease with Eisenmenger’s physiology that has resulted in massively enlarged proximal pulmonary arteries (see Case 19, Chap. 19). How this develops is not completely understood. As pointed out by Dr. Gopalan, it is possible that the blood flow juxtaposed to the enlarged vessel is “stagnant” enough to allow thrombosis to occur; or possibly there’s an endothelial injury of the proximal vasculature which promotes clot formation. Either consideration is speculative. Though the extent of thrombus visualized by CT can be impressive, as the vessels are examined distally, most often the lining thrombus disappears leaving the vessels intact and unobstructed. As blood flow through these vessels is unimpeded, the relatively normal perfusion pattern seen on lung

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scintigraphy is not surprising. Consequently, logic dictates and previous experience has demonstrated that surgical endarterectomy of this lining thrombus provides no pulmonary hemodynamic benefit and should be considered contraindicated.

Point of Emphasis Lining thrombus within enlarged central pulmonary vessels is typically unobstructive and is not the basis for a patient’s pulmonary hypertension, but a consequence of it.

Diagnosis 1. Lining thrombus within enlarged central pulmonary arteries. 2. Pulmonary arterial hypertension.

Further Reading Archer S, Rich S. Primary pulmonary hypertension: a vascular biology and translational research “work in progress”. Circulation. 2000;02:2781–91. Chaouat A, Weitzenblum E, Higenbottam T. The role of thrombosis in severe pulmonary hypertension. Eur Respir J. 1996;9:356–63. Gopalan D, Blanchard D, Auger WR.  Evaluation of chronic thromboembolic pulmonary hypertension. Ann Thorac Soc. 2016;13(Suppl 3):S222–39. Moser KM, Fedullo PF, Finkbeiner WE, Golden I. Do patients with pulmonary hypertension develop extensive central thrombus? Circulation. 1995;91(3):741–5. Perloff JK, Hart EM, Greaves SM, Miner PD, Child JS.  Proximal pulmonary arterial and intrapulmonary radiologic features of Eisenmenger syndrome and primary pulmonary hypertension. Am J Cardiol. 2003;92:182–7.

Chapter 16 Case 16: Acute Versus Chronic Thromboembolic Disease—Beware! Dianne L. Zwicke, Sara Paulus, Deepa Gopalan, and William R. Auger

Case Presentation This patient is an 18-year-old, female, college freshman, and ROTC student. She presented to the student health service with a chief complaint of SOB, left-sided chest pain, and exertion-related episodes of presyncope, with one episode of frank syncope, promptly regaining consciousness after becoming supine on the ground. She was referred to an electrophysiologist at a nearby hospital for a same day evaluation of

D. L. Zwicke (*) · S. Paulus Pulmonary Hypertension Clinic, Aurora St. Luke’s Medical Center, Milwaukee, WI, USA D. Gopalan Department of Radiology, Imperial College Hospitals, London, UK e-mail: [email protected] W. R. Auger Lewis Katz School of Medicine, Temple University, Philadelphia, PA, USA e-mail: [email protected] © Springer Nature Switzerland AG 2020 W. R. Auger, D. Gopalan (eds.), Clinical Cases in Chronic Thromboembolic Pulmonary Hypertension, Clinical Cases in Cardiology, https://doi.org/10.1007/978-3-030-17366-1_16

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the syncopal episode and persistent tachycardia at 100 bpm (usual heart rate 60 bpm). Her detailed clinical history included the onset of symptoms 6 weeks prior to presentation for medical evaluation. Although she was in a good state of physical fitness, she was unable to walk more than one block and developed lightheadedness and presyncope with stair climbing and with any of her ROTC activities. The syncopal episode occurred during ROTC exercises, two weeks before her clinic presentation, and she was suspended from any further military training until cleared medically. She denied any history of similar symptoms, surgical procedures, pregnancy, history of DVT/PE, chronic lower extremity edema, or injury. She did take a plane flight and went on a cruise 6 weeks before the onset of her symptoms. She did report starting estrogen-­ containing oral contraceptives 17 months before the onset of her first clinical symptoms, for the purpose of birth control and premenstrual dysphoric syndrome. She had an unremarkable past medical history. Her family history was notable for her father having experienced a deep venous thrombosis (DVT) without a known clotting disorder. The physical examination was unremarkable, except for a resting heart rate of 120 bpm and respiratory rate of 20 per minute. The blood pressure was 100/70  mmHg. The resting pulse oximetry showed an O2 saturation of 99% on room air. A 12-lead electrocardiogram demonstrated normal findings with a sinus tachycardia. Laboratory studies were normal except for a mild elevation of the ALT at 50 U (normal range 5–35 U). A urine pregnancy test was negative. Initial assessment included an echocardiogram which demonstrated a low normal LV ejection fraction at 50%, a severely increased RV size with severely decreased function, significant shift of the intraventricular septum into the LV cavity, a severely enlarged right atrium, mild tricuspid regurgitation with a RVSP estimated at 68  mmHg, and a small pericardial effusion. Injected agitated saline did show evidence of an intra-atrial right-to-left shunt at rest (Fig. 16.1).

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Figure 16.1 Transthoracic echocardiogram showing signs of right ventricular strain

This was followed by the acquisition of a CT angiogram of the chest. This revealed bilateral pulmonary emboli affecting the proximal lobar vessels of the right upper and bilateral lower lobes, extending into the segmental branches. Partially occluding thrombi are seen within the segmental left upper lobe branches and a large thrombus is visible in the left lower lobe pulmonary artery extending into the segmental branches. There was a small infiltrate versus atelectasis in the anterior left lung base, and a small amount of anterior pericardial fluid (Fig. 16.2). A duplex venous ultrasound of both lower extremities disclosed the deep veins to be widely patent with normal flow and no evidence of thrombus. She was admitted to the Intensive Care Unit, after initiating intravenous heparin, with the intention of proceeding with lytic therapy utilizing tissue plasminogen activator (TPA). The clinical history related was consistent with a possible pulmonary embolic event as long as 6 weeks prior; however her presentation was prompted by worsening symptoms that were hemodynamically significant. She was transferred to a tertiary hospital as the patient and parents requested additional consults prior to moving forward with thrombolysis given lack of consensus in the treatment plan. Hematology and Pulmonary Hypertension/ Cardiology consults were obtained and achieved consensus was to withhold lytic therapy for concern that she had acute on chronic pulmonary emboli.

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a

b

c

Figure 16.2  Axial (a) and coronal views (b, c) of the CT angiogram demonstrating extensive proximal vessel intraluminal defects in both lungs consistent with acute pulmonary emboli. There is modest central PA enlargement and RV enlargement, though no significant RV hypertrophy

A lung ventilation-perfusion scan was recommended. (Hospital Day # 3) This showed extensive modest to large sized peripherally located wedge shaped perfusion defects bilaterally throughout the lungs, consistent with findings of pulmonary emboli by CT (Fig. 16.3). On hospital day 6, a right heart catheterization was performed: BP 99/66  mmHg, mean arterial pressure 79  mmHg, HR 77  bpm, pulse oximetry on room air 99%. RA mean 6 mmHg, RV 40/6 mmHg, PA pressure 40/17 (25 mean) mmHg,

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Figure 16.3  Several unmatched, large perfusion defects, particularly apparent throughout the right lung and medial left lower lobe (posterior view)

PCWP 6 mmHg; PA saturation 67.3%; cardiac output 4.5 L/ min with a cardiac index 2.43 L/min/m2; transpulmonary gradient was 19 mmHg. Concurrent with her catheterization, pulmonary angiography was obtained. This demonstrated pronounced filling defects in the left lower pulmonary arteries and smaller filling defects in the segmental and subsegmental levels; there were filling defects in the right upper, middle, and lower lobe pulmonary arteries at the lobar and segmental levels (Fig. 16.4). By hospital day 12, she was discharged in stable condition. She was at a therapeutic level on warfarin therapy (patient refused Eliquis). She was hemodynamically stable and ambulatory. Thrombolytic therapy was never given, as the consensus of opinions was that she had acute pulmonary emboli on top of significant chronic thrombi. The oral contraceptive (OCP) drugs were discontinued on admission.

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Figure 16.4  Intraluminal filling defects apparent (arrows) in both descending pulmonary arteries, as well as in the segmental vessels of the right upper lobe, right lower lobe and lingula

Six weeks after hospital discharge the patient was working full-time in a restaurant in her hometown, was increasing her activities and doing well. She was stable on 8 mg of warfarin daily. By eleven weeks after hospital discharge, the patient was feeling fine with no complaints. She was participating in a yoga class and sailing. She also underwent a HAST study for a planned vacation trip to San Diego and did not require oxygen for the flight. She denied dyspnea with her activities, though still had not regained her usual physical activity level yet. Her physical examination was unremarkable. Hypercoagulable lab studies all came back negative. A limited echocardiogram showed normal RV size, with mildly decreased systolic function (40%), and a PA systolic pressure estimated at 23 mmHg, Chest radiograph findings were “normal” and a lung ventilation-perfusion scan documented resolution of the previously observed perfusion defects (Fig. 16.5). At the time of her six month follow up, the patient was clinically doing well and had resumed all prior activities including the exercise required by ROTC training. She discontinued her warfarin without recurrence of any concerning symptoms (WHO Functional Class I). Echocardiogram findings: normal RV size and function; PASP 21 mmHg, TAPSE 26 mm, normal IVC, and no effusion.

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Figure 16.5 Return of an essentially normal perfusion pattern in both lungs

Radiographic Interpretation CTPA demonstrates acute and subacute pulmonary embolism. There are central filling defects surrounded by rim of contrast medium in multiple segmental pulmonary artery branches, characteristic of acute emboli. Clot retraction to the periphery of the vessel in the distal right main pulmonary artery is likely due to clot reorganisation and recanalization and is indicative of the subacute nature of the process. There is near complete occlusion of left lower lobe and right upper lobe arteries. Whilst this can be seen with both acute and chronic thromboembolic disease, the vessel is typically distended in acute PE and becomes fibrosed and attenuated with progression to CTEPH.  Other angiographic features of CTEPH include pouch defects, intravascular webs and stenosis with or without post-stenotic dilatation (Castañer et  al.).

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Systemic collaterals also take time to develop and are therefore not a feature of acute PE.  Another useful clue to the chronicity of the disease on CT is the presence of geographical variation in lung parenchymal attenuation, termed as ‘mosaic attenuation’. It is possible to evaluate the cardiac chambers even on a non-ECG gated CTPA.  The diameter ratio of right to left ventricle on transverse CT sections has the strongest predictive value and most robust evidence base for adverse clinical outcomes in acute PE. A RV/LV ratio ≥1.0 has been shown to have a 2.5-fold risk for all-cause mortality and a fivefold risk for PE–related mortality (Meinel at al.). On this study, there is dilatation of the right ventricle, under-filled small left ventricular cavity size (RV:LV > 1.5) with flattening of interventricular septum. The appearances of catheter pulmonary angiography mirror that of CTPA with multifocal, predominantly central filling defects bilaterally associated with large wedge shaped perfusion defects. Similar bilateral wedge shaped segmental mismatched perfusion defects are also seen on the VQ scintigraphy. Unlike CTPA, it is difficult to differentiate acute and chronic thromboembolic disease solely using ­scintigraphy as both can produce similar defects. A baseline VQ at presentation can be very useful to follow the temporal evolution of the disease but perfusion deficits can be persistent for up to 12 months after the initial event and do not necessarily equate to CTEPH (Nijkeuter et al.). Happily in this case, the follow-up VQ shows complete resolution of the perfusion defects, effectively excluding progression to CTEPH. A small proportion of patients labelled as acute PE at the time of initial presentation actually have acute on chronic thromboembolic disease (Guérin et al.). This is an important distinction to make as they have very different therapeutic options. Of the various imaging modalities, CTPA is the non-­ invasive method of choice for differentiating the two conditions, particularly in an emergency setting.

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Clinical Comments Though this patient was initially referred for pulmonary thromboendarterectomy surgery, there were a number of considerations that supported a more conservative approach. Available information does suggest that when cardiopulmonary symptoms are presented for greater than 2 weeks at the time of initial presentation, that there’s a higher likelihood that some component of chronic thromboembolic disease may be present. Though the presence of RV enlargement and strain are concerning, this in itself is not a distinguishing feature between an acute pulmonary embolic event versus the presence of chronic thromboembolic disease. The absence of RVH, the CT appearance of the thrombus, the absence of pulmonary vascular changes that are associated with organized, recanalized thrombus as described by Dr. Gopalan, and the absence of other findings that might suggest long-­ time pulmonary arterial obstruction, such as bronchial arterial collateral blood vessels—as was the situation in this case—makes acute or subacute pulmonary emboli the most likely diagnosis. The pulmonary hemodynamic profile as well supported the diagnosis of a more acute pulmonary embolic event. The classic findings of Sutton and colleagues in the 1970s established that with an acute PE, a modest rise in pulmonary pressures are to be expected given the limitations of a “unconditioned” RV presented with an abrupt rise in vascular resistance. For those with chronic thromboembolic disease, however, the right ventricle has been able to compensate for the longstanding elevation in RV afterload, and pulmonary pressures at presentation can be significantly elevated.

Points of Emphasis With the availability of numerous interventional modalities to treat acute and chronic thromboembolic disease, especially for clinically decompensating patients, it becomes increasingly important to be able to distinguish between clinical entities.

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Diagnosis 1. Acute pulmonary emboli with right heart strain.

Further Reading Castañer E, Gallardo X, Ballesteros E, et al. CT diagnosis of chronic pulmonary thromboembolism. Radiographics. 2009;29(1):31–50. Eischer L, Eichinger S, Kyrle PA. The risk of recurrence in women with venous thromboembolism while using estrogens: a prospective cohort study. J Thromb Haemost. 2014;12(5):635–40. Guérin L, Couturaud F, Parent F, et al. Prevalence of chronic thromboembolic pulmonary hypertension after acute pulmonary embolism. Prevalence of CTEPH after pulmonary embolism. Thromb Haemost. 2014;112(3):598–605. Meinel FG, Nance JW Jr, Schoepf UJ, Hoffmann VS, Thierfelder KM, Costello P, Goldhaber SZ, Bamberg F.  Predictive value of computed tomography in acute pulmonary embolism: systematic review and meta-analysis. Am J Med. 2015;128(7):747–59. Nijkeuter M, Hovens MM, Davidson BL, Huisman MV. Resolution of thromboemboli in patients with acute pulmonary embolism: a systematic review. Chest. 2006;129:192–7. Sutton GC, Hall RJC, Kerr IH. Clinical course and late prognosis of treated subacute massive, acute minor, and chronic thromboembolic disease. Br Heart J. 1977;39:1135–42. Vinogradova Y, Coupland C, Hippisley-Cox J.  Use of combined oral contraceptives and risk of venous thromboembolism: nested case-control studies using the QResearch and CPRD databases. BMJ. 2015;350:h2135.

Chapter 17 Case 17: Can Severe Pulmonary Arterial Pulmonary Hypertension Mimic CTEPH? Jean M. Elwing, Deepa Gopalan, and William R. Auger

Case Presentation A 58  year-old Caucasian male with a history of DVT presented for evaluation of shortness of breath. At his initial assessment, he reported a 2 year history of progressive symptoms. He endorsed exertional dyspnea with walking more than ¼ mile and noted shortness of breath when climbing one

J. M. Elwing (*) Pulmonary Hypertension Program, Division of Pulmonary Critical Care Medicine, University of Cincinnati College of Medicine, Cincinnati, OH, USA e-mail: [email protected] D. Gopalan Department of Radiology, Imperial College Hospitals, London, UK e-mail: [email protected] W. R. Auger Lewis Katz School of Medicine, Temple University, Philadelphia, PA, USA e-mail: [email protected] © Springer Nature Switzerland AG 2020 W. R. Auger, D. Gopalan (eds.), Clinical Cases in Chronic Thromboembolic Pulmonary Hypertension, Clinical Cases in Cardiology, https://doi.org/10.1007/978-3-030-17366-1_17

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flight of stairs. He denied associated chest pain but did experience lightheadedness, dizziness and presyncope with activity. He also noted recent onset of lower extremity edema. His past medical history was notable for controlled GERD, anxiety, a DVT in 2010 on full dose anticoagulation, recurrent superficial venous thrombosis, homozygous MTHFR C677T mutation, OSA, controlled asthma, splenectomy after an automobile accident in 1968 and remote tobacco abuse. He denied a history of connective tissue disease. He did not have known prior pulmonary emboli or a family history of pulmonary hypertension. Social history was notable for tobacco abuse, quitting more than a decade prior to presentation. He denied any previous stimulant or anorexigen use. He had no history of illegal substance or alcohol abuse. Examination was notable for blood pressure of 120/90 mmHg, pulse of 72, and saturations of 98% on room air. He was in no acute distress. Cardiopulmonary exam revealed hepatojugular reflux without JVD at 45°. Cardiac auscultation was notable for regular rate and rhythm with an accentuated P2 but no appreciable murmurs. Lungs were clear to auscultation without bruits over posterior lung fields. 1+ bilateral lower extremity edema was appreciated on extremity exam. Laboratory and routine testing revealed hemoglobin of 15.2 g/dL. Creatinine was mildly elevated at 1.26 mg/dL with a sodium level in the normal range at 142  mmol/L.  BNP was within acceptable limits at 84 pg/mL. Liver functions were normal. EKG revealed sinus rhythm with septal T-wave changes but no other significant abnormality. Radiographic evaluation revealed a chest X-ray (Fig. 17.1) with clear lung fields. Because of significant symptoms, further assessment was pursued. Echocardiogram was notable for normal systolic left ventricular (LV) function with ejection fraction of 55%. Right ventricle was mild to moderately dilated. Tricuspid valve was moderate to severely regurgitant and pulmonary pressures were estimated at 78 mmHg. His abnormal echocardiogram prompted further evaluation of the etiology and severity of his elevated pulmonary pressures. Additional laboratory assessment revealed normal thyroid function and no significant abnormalities on autoimmune workup. Pulmonary function testing (Table  17.1) did

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Figure 17.1  Chest X-ray with normal heart size and no significant parenchymal abnormalities

Table 17.1 Pulmonary function test without significant obstruction or restriction. Diffusing capacity was mildly decreased

FEV1 (L)

2.96

FEV1%

89

FVC (L)

4.31

FVC%

92

FEV1/FVC (%)

69

TLC (L)

6.56

TLC%

98

RV

1.52

RV%

65

VC

5.04

VC%

1.08

DLCO (mL/ mmHg s)

19.5

DLCO %

78

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not reveal significant changes that could account for severity of elevated pulmonary pressures. Additional imaging was performed to assess for possibility of pulmonary embolism as etiology of his progressive shortness of breath and echocardiographic findings. Ventilation (Fig.  17.2)/perfusion (Fig.  17.3) scanning was performed and revealed bilateral patchy perfusion defects without significant ventilation abnormalities. Based on V/Q, there was concern for chronic thromboembolic pulmonary hypertension (CTEPH). A more definitive evaluation with CT pulmonary angiogram (CTPA) (Fig. 17.4) was therefore requested. CTPA revealed enlarged pulmonary arteries but no evidence of significant parenchymal lung disease or pulmonary emboli. Patient then proceeded to further assessment with right heart catheterization (RHC) (Table  17.2) and pulmonary angiogram (Fig.  17.5). RHC revealed moderately elevated pulmonary pressures in a precapillary pattern without evidence of acute or chronic thromboembolic disease on angiography. After completion of his assessment, he was reevaluated and data reviewed. His workup was consistent with symptomatic precapillary pulmonary hypertension. Initial testing with

Figure 17.2  Xenon ventilation scanning with symmetric ventilation and mild bilateral retention

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Figure 17.3  Ventilation/perfusion scanning with significant bilateral patchy perfusion defects

Figure 17.4 CT chest with pulmonary angiography revealed enlarged pulmonary arteries (arrow) without evidence of acute or chronic pulmonary emboli

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Table 17.2 Right heart catheterization hemodynamics revealing significant precapillary pulmonary hypertension with elevated pulmonary vascular resistance Hemodynamic findings Right atrial (RA) 4 mmHg Right ventricular (RV)

65/4 mmHg

Pulmonary artery (PA)

64/25 (38) mmHg

Pulmonary artery wedge (PAWP)

4 mmHg

Inferior vena cava (IVC)

Saturation 67%, Hgb 12.9 g/dL

Right atrium (RA)

Saturation 69%, Hgb 12.9 g/dL

Pulmonary artery (PA)

Saturation 66%, Hgb 12.9 g/dL

Systemic saturations

Saturation 90%

Thermodilution cardiac output (CO)

4.5 L/min

Thermodilution cardiac index (CI)

2.2 L/min/m2

Thermodilution systemic vascular resistance (SVR)

1529 dyn-s/cm5

Thermodilution pulmonary vascular resistance (PVR)

7.6 WU, 604 dyn-s/cm5

V/Q was concerning for chronic thromboembolic pulmonary hypertension (CTEPH); however, after consultation with an expert CTEPH Center and detailed review of imaging, it was determined that V/Q changes were attributable to his pulmonary arterial hypertension and there was no radiographic evidence of significant chronic thromboembolic disease. He was diagnosed with WHO Group I pulmonary arterial hypertension. He was initiated on oral pulmonary vasodilator therapy with significant symptomatic improvement. His exercise tolerance increased and presyncope with exertion resolved. He remains active with NHYA functional class II symptoms.

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Figure 17.5  Pulmonary angiography with bilateral equal perfusion without evidence of luminal narrowing or vascular obstruction

Radiographic Interpretation The frontal and lateral chest radiographs demonstrate normal cardiac silhouette with clear lungs. VQ scintigraphy shows mottled perfusion bilaterally with small mismatched perfusion defects. There are generic features of pulmonary hypertension on the CT pulmonary angiography such as mildly dilated and hypertrophied right ventricle and flattening of interventricular septum. The left atrium and left ventricle are not enlarged and there’s no evident intracardiac shunt. There is no evidence of acute or chronic thromboembolic disease. The lungs are unremarkable. Catheter ­pulmonary angiography shows good opacification of pulmonary vasculature with smooth vessels that demonstrate areas of abnormal tapering to the periphery (“pruning”). There are no specific features of thromboembolic disease. Abnormal perfusion on scintigraphy is a well-recognized feature of non-thrombotic PAH and is most likely a reflection of underlying pulmonary vasculopathy (Fishman et  al.). Whilst the perfusion defects in PAH typically tends to be mostly patchy and in a non-anatomical distribution, occasionally segmental defects have also been described. A recent study using SPECT VQ found perfusion abnormalities with no demonstrable thromboembolic disease on corroborative pulmonary angiography in as many as 43% of cases with

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PAH with worse hemodynamics and clinical outcome in patients with global perfusion defects (Chan et al.). Pulmonary veno-occlusive disease (PVOD) is another important differential to consider in the setting of pulmonary hypertension and false positive VQ (Bailey et al.; see Case 13, Chap. 13). CTPA is a useful discriminator as the triad of interlobular septal thickening, diffuse ground glass opacification and mediastinal lymphadenopathy are hallmarks of PVOD rather than PAH. These features were not present on the CT in the current case. As Group 2, 3 and 4 were also excluded by imaging, the diagnosis is WHO Group 1 disease.

Clinical Comments The presented case provides a “textbook” illustration of a logical progression in the evaluation of a patient’s dyspnea. The absence of an obvious basis for this complaint accompanied by an unremarkable physical exam, routine laboratory studies, electrocardiography, chest radiograph and PFTs, led to an investigation for pulmonary vascular disease. With the echocardiogram then suggestive of pulmonary hypertension, screening for CTEPH with lung scintigraphy is the appropriate next step. This possible diagnosis was further enhanced given the pro-thrombotic risk factor of a previous ­splenectomy and the prior DVT history (the methylenetetrahydrofolate reductase polymorphism is not a significant risk factor for thrombosis). Despite the abnormal perfusion scan, the pattern of perfusion abnormality was very suggestive of distal vessel disease. CT angiography of chest as a diagnostic tool was entirely appropriate to further define the VQ findings. Without CT evidence for chronic thromboembolic lesions, the question might be raised as to the rationale for further diagnostic testing. As CTA has been shown to underestimate CTEPH within the segmental and subsegmental vessels (Sugiura et  al.), it was appropriate to proceed with digital subtraction pulmonary angiography to complete the evaluation. This ultimately ruled out chronic thromboembolic disease as the basis for this patient’s pulmonary hypertension.

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Finally, confirmatory right heart catheterization was essential to document the degree of pulmonary hypertension and right heart dysfunction to guide therapy.

Point of Emphasis Ventilation perfusion scanning is an essential part of the evaluation of patients with pulmonary hypertension. The absence of perfusion defects reliably rules out chronic thromboembolic disease. However, patchy perfusion can be seen in the setting of pulmonary arterial hypertension and can mimic CTEPH.  This often requires assessment with pulmonary angiography to confirm the presence of chronic thromboembolic disease.

Diagnosis 1. WHO group I pulmonary arterial hypertension (precapillary pulmonary hypertension).

Further Reading Bailey CL, Channick RN, Auger WR, et al. High probability perfusion lung scans in pulmonary venoocclusive disease. Am J Respir Crit Care Med. 2000;162(5):1974–8. Chan K, Ioannidis S, Coghlan JG, et  al. Pulmonary arterial hypertension with abnormal V/Q single-photon emission computed tomography. JACC Cardiovasc Imaging. 2018;11(10):1487–93. Fishman AJ, Moser KM, Fedullo PF. Perfusion lung scans vs pulmonary angiography in evaluation of suspected primary pulmonary hypertension. Chest. 1983;84(6):679–83. Suigura T, Tanabe N, Matsuura Y, et al. Role of 320-slice CT imaging in the diagnostic workup of patients with chronic thromboembolic pulmonary hypertension. Chest. 2013;143:1070–7. Worsley DF, Palevsky HI, Alavi A. Ventilation-perfusion lung scanning in the evaluation of pulmonary hypertension. J Nucl Med. 1994;35(5):793–6.

Chapter 18 Case 18: Atrial Septal Defect with Chronic Thrombus Mimicking CTEPH Timothy M. Fernandes, Deepa Gopalan, and William R. Auger

Case Presentation A 31 year old Filipino male with no significant past medical history presented with complaints of two years of progressively worsening dyspnea on exertion with associated weight loss of 20 lb. He had an acute deterioration after a trip to visit family in the Philippines. Upon landing back in the United States, he was found to be profoundly hypoxemic and cyanotic.

T. M. Fernandes (*) Division of Pulmonary and Critical Care Medicine, University of California, San Diego, San Diego, CA, USA e-mail: [email protected] D. Gopalan Department of Radiology, Imperial College Hospitals, London, UK e-mail: [email protected] W. R. Auger Lewis Katz School of Medicine, Temple University, Philadelphia, PA, USA e-mail: [email protected] © Springer Nature Switzerland AG 2020 W. R. Auger, D. Gopalan (eds.), Clinical Cases in Chronic Thromboembolic Pulmonary Hypertension, Clinical Cases in Cardiology, https://doi.org/10.1007/978-3-030-17366-1_18

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He has transferred to the local Emergency room and found to have SpO2 in the low 80s % with only a modest improvement in oxygenation with supplemental oxygen. On exam, he was tachycardic with a prominent P2 component of the second heart sound. There was no S3. He had jugular venous distention to the jaw and pretibial edema. There was prominent clubbing of the digits of the hands and feet. Upon further questioning, it was unclear as to the length of time the patient exhibited clubbing and nailbed cyanosis. His feeling was that this was how “fingers should look”. Given his travel history, there was concern for acute pulmonary embolism so the patient was sent for a CT pulmonary angiogram (Fig. 18.1a–c). The CT demonstrated a severely enlarged main pulmonary artery consistent with pulmonary hypertension and “severe bilateral pulmonary emboli”. He underwent a transthoracic echocardiogram which revealed severe tricuspid regurgitation with and right ventricular systolic pressure estimated at 112 mmHg. The patient was then transferred to a pulmonary thromboendarterectomy center for evaluation of potential chronic thromboembolic pulmonary hypertension. Hospital Course: A chest radiograph (Fig. 18.2) and ventilation- perfusion scan (Fig.  18.3a, b) were performed. The perfusion scan revealed multiple unmatched perfusion defects in the anterior left upper lobe, lateral basal left lower lobe and lateral segment of the right middle lobe. There was uptake of technetium macro aggregated albumin seen in the brain and kidneys consistent with a right-to-left shunt. A repeat transthoracic echocardiogram with agitated saline was ordered and demonstrated a severely enlarged right atrium with early positive bubble study, concerning for an atrial septal defect. The patient underwent right heart catheterization with shunt run with results as follows: • Saturation Run: Systemic pulse oximetry 82–84%, high SVC saturation 45%, low SVC saturation 44%, mid RA saturation 62%, IVC saturation 46%, right ventricle saturation 61%, PA saturation 59%. • Baseline hemodynamics: • Mean right atrial pressure of 2.

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a

b

Figure 18.1  CTA of the chest showing occlusive thrombus in a left upper lobe (panel b, blue arrow) and right middle lobe pulmonary artery (panel c, open blue artery). Eccentric lining thrombus in a markedly enlarged right main PA, and in dilated left upper lobe, right lower lobe segmental vessels also noted (panels a, c, white arrows)

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c

Figure 18.1  (continued)

Figure 18.2 Chest radiography (AP view) demonstrates cardiomegaly with aneurysmal dilatation of the proximal pulmonary arteries. There is no obvious pulmonary artery calcification

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a WASH IN

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b EQUIL

ANT Q

POST Q

LLAT Q

RLAT Q

WASHOUT1

LPO Q

LAO Q

WASHOUT2

RPO Q

POST KIDNEY

RAO Q

Figure 18.3 Lung scintigraphy showing unmatched perfusion defects (panel a) as described in the text, with uptake evident in the kidneys suggesting a right to left shunt (panel b)

• Right ventricular systolic pressure of 88, right ventricular end-diastolic pressure of 4. • Pulmonary artery pressure 92/51, mean pulmonary artery pressure 64. • Pulmonary capillary wedge pressure 4. • Cardiac output calculations: Qs was equal to 2.17  L/min with cardiac index of 1.4  m−2. Qp was calculated using a few assumed pulmonary venous saturations. Assuming a pulmonary venous saturation of 95%, Qp was equal to 2.36 L/min, 1.5 m−2. Given the step-up in saturation seen in the right atrium, a cardiac MR was ordered to further assess cardiac anatomy. This revealed total right-sided anomalous pulmonary venous drainage with both the upper and lobe right-sided pulmonary veins draining back into the right atrium (Fig. 18.4). This was associated with mixed atrial septal defects including a sinus venosus defect (Fig. 18.4) and an ostium secundum ASD. For management of his pulmonary hypertension due to Eisenmenger’s syndrome (an atrial septal defect with right-­ to-­left shunt, cyanosis, pulmonary hypertension) and total right-sided anomalous pulmonary venous drainage, the decision was made for medical management. The patient was started on intravenous epoprostenol, bosentan (an endothe-

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Figure 18.4 Cardiac magnetic resonance imaging (axial view) depicting right superior (solid blue arrow) and right inferior (open blue arrow) pulmonary veins draining into the right atrium. Sinus venosus defect: white arrow

lin receptor antagonist) and sildenafil with improvement in oxygenation, functional class and pulmonary hemodynamics. For the lining thrombus and pulmonary hypertension, the decision was made for anticoagulation with warfarin.

Radiographic Interpretation There are multiple mismatched perfusion defects on VQ scintigraphy (Fig. 18.3) but the salient feature is the extra pulmonary uptake in the kidneys. Free Tc-99m-pertechnetate in the radiopharmaceutical can give rise to this appearance but there is no activity in thyroid, salivary glands, or the stomach to support a fault in the radiopharmaceutical. The other possibility is the Tc-99m-macroaggregate of albumin (MAA) bypassing the lungs due to a right to left shunt. These two conditions can be differentiated by imaging the brain as free Tc-99m-pertechnetate and other radio contaminants do not cross the blood brain barrier whilst shunted Tc-99m-MAA will lodge in the cerebral circulation. On selected images from CT pulmonary angiography (Fig. 18.1), there is marked dilatation of the main pulmonary artery with a ratio of MPA: ascending aorta (AA) greater than 1.0. In addition to the eccentric filling defect in the distal

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right PA, there are multiple occlusive and partially occlusive filling defects in the segmental vessels in both lungs. An important observation is the dilatation of these segmental pulmonary arteries, a feature that is not seen in chronic thromboembolic disease where the segmental vessels become attenuated with abrupt change in the vessel calibre. There is mild distortion of the cardiac silhouette due to a pectus excavatum, with dilatation of the right atrium and right ventricle, right ventricular hypertrophy and flattening of the interventricular septum. Careful analysis of the CT and gradient echo sequence Cardiac Magnetic Resonance image (Fig.  18.4) reveals a sinus venosus type atrial septal defect. The right superior pulmonary vein drains in to the superior vena cava whilst the middle and inferior pulmonary veins drains in to the atrium at the level of the ASD. There is normal drainage of the left inferior pulmonary veins in to the left atrium. Sinus venosus atrial septal defect (SV-ASD) is an inter-­ atrial communication caused by the deficiency of the common wall between the superior or inferior vena cava and the right-sided pulmonary veins. It represents 4–11% of atrial septum defects and is typically associated with partial anomalous right pulmonary venous drainage (PAPVD). This case illustrates the need for methodical review of the various imaging modalities. Although pulmonary artery dilatation on radiography is not a specific marker of a particular type of disease, the presence of aneurysmal dilatation should raise the suspicion of a congenital heart disease. The visualization of kidneys on a VQ scintigram is highly suspicious for a intracardiac or intrapulmonary shunting but it is important to image the brain to exclude the possibility of free Tc-99m-­ pertechnetate. While it is not customary to use CT for the visualization of intracardiac shunts, even nonelectrocardiogram (ECG)-triggered CT can frequently demonstrate large shunts. However, it is not common clinical practice to look for the shunts on CT as traditionally it is the preserve of echocardiography and more recently magnetic resonance imaging to identify and clarify the functional consequences of the underlying shunt.

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Multiplanar CT reconstructions are particularly useful in the assessment of the complex anatomy of this type of ASD.  Transthoracic echocardiography can easily miss the PAPVD.  Given that CTPA is a very commonly performed examination, it is important to remember to look for structural heart defects. Knowledge of the different types of the shunts is the key to detection. The cardiac MR can then be performed as a targeted imaging to quantify the magnitude of the shunt.

Clinical Comments Upon presentation, there were several historical and radiographic aspects of this case that raised suspicions that acute thromboembolic disease was not the primary diagnosis. The length of time he had been experiencing exertional dyspnea, the cardiomegaly and massively enlarged central pulmonary arteries noted on chest radiograph, the degree of pulmonary hypertension as evidenced by echocardiography, and the eccentric thrombus noted in several of his enlarged segmental pulmonary vessels—CT findings that are not seen in acute thromboembolic disease—were all suggestive of a more chronic process. And although not well depicted in Fig. 18.1, the vessels beyond the lining thrombus returned to a normal configuration without the narrowing or vessel attenuation that one observes in more proximal obstruction with chronic thromboembolic disease. Even with the knowledge that the patient had severe pulmonary hypertension, the historical clue that this patient did not have CTEPH was the presence of clubbing—the physiologic mechanisms by which someone develops clubbing are simply not operative in CTEPH. The development of pulmonary hypertension in patients with congenital cardiac defects and left-to-right shunting is not the reason to present this case. The pulmonary vascular changes that arise as a result, particularly the marked enlarge-

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ment of the central PAs, and the “lining thrombus” that can be observed in these dilated vessels—and mistaken as “CTEPH”—is the principal lesson to be learned. In the vast majority of cases like this, the perfusion scintigram shows little in the way of perfusion defects, as the organized thrombus within the vessel is non occlusive (see Case 19, Chap. 19). However, this patient did exhibit some occlusive clot resulting in segmental perfusion defects. Theoretically, in situ clot may have resulted from a low flow state within these vessels. This assumption and the basis for the development of lining thrombus are areas of ongoing investigation.

Points of Emphasis • An abnormal VQ scan and angiographic evidence of thrombus in the pulmonary arteries are necessary to diagnose chronic thromboembolic pulmonary hypertension. However, an atrial septal defect with Eisenmenger’s syndrome and the resultant massive central PA enlargement may • A perfusion scan with uptake of technetium macro aggregated albumin in the brain and kidneys may be seen with significant right-to-left shunting. • Digital clubbing is common in congenital heart disease but is exceeding rare in chronic thromboembolic pulmonary hypertension. Clubbing should raise suspicion for alternative diagnoses in patients being evaluated for CTEPH.

Diagnosis 1. Atrial septal defect with Eisenmenger’s syndrome and pulmonary hypertension. 2. Partial anomalous pulmonary venous return (right upper and lower pulmonary veins drain into right atrium). 3. In situ thrombosis of the pulmonary arteries.

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Further Reading Bradlow WM, Babu-Narayan SV, Mohiaddin RH. Pulmonary hypertension in congenital heart disease. In: Cardiac CT and MR for adult congenital heart disease. New  York, NY: Springer; 2014. p. 553–72. Webb G, Gatzoulis MA. Atrial septal defects in the adult. Circulation. 2006;114(15):1645–53.

Chapter 19 Case 19: Parenchymal Lung Disease and Chronic Thromboemboli Lynette Brown, Deepa Gopalan, and William R. Auger

Case Presentation A 60 year old man with a history of emphysema who resides in a rural environment. He considered himself relatively healthy until 9 months prior to his initial presentation. At that time, he began to experience dyspnea with exertion when throwing hay to his cattle. He attributed the breathlessness to L. Brown (*) Asssociate Professor (Clinical), University of Utah, Salt Lake, UT, USA Pulmonary Hypertension Program, Intermountain Medical Center, Murray, UT, USA e-mail: [email protected] D. Gopalan Department of Radiology, Imperial College Hospitals, London, UK e-mail: [email protected] W. R. Auger Lewis Katz School of Medicine, Temple University, Philadelphia, PA, USA e-mail: [email protected] © Springer Nature Switzerland AG 2020 W. R. Auger, D. Gopalan (eds.), Clinical Cases in Chronic Thromboembolic Pulmonary Hypertension, Clinical Cases in Cardiology, https://doi.org/10.1007/978-3-030-17366-1_19

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his known diagnosis of emphysema; however, he ultimately developed acute shortness of breath at rest. Imaging demonstrated bilateral consolidation, a left-sided pneumothorax, bilateral pulmonary emboli (Fig. 19.1) and a chronic appearing right popliteal thrombus. A chest tube was placed and he was treated with heparin and antibiotics. He was ultimately discharged home on oxygen and warfarin. He received a total of 12 months of anticoagulation. The patient presented again 7 years later with dyspnea. He noted initial improvement in his respiratory symptoms after his discharge from the previous hospitalization; however, the improvement was short-lived. He was now limited to climbing less than a flight of stairs without stopping and he was sharing farm chores with his sons due to his limitations. His 6 min walk distance at that time was 209 m with a BORG dyspnea score of 10. He denied chest pain, lightheadedness and near syncope. He had lower extremity edema (right leg  >  left leg). Vital signs upon consultation demonstrated a blood pressure of 122/70 mmHg and a SaO2 of 93% on 4 L/min. His BMI was 26  kg/m2. His chest exam was notable for end-expiratory

Figure 19.1  CT angiogram of the chest obtained at initial presentation

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wheezes bilaterally. His cardiovascular exam noted a jugular venous pressure of 8 cm, a normal S1 and S2 and no appreciable murmurs. Pulmonary function tests revealed severe obstruction with a forced expiratory volume (FEV1)  =  1.1  L (35%) and a diffuse capacity adjusted for hemoglobin (DLCO) of 10.3 mL/mmHg/min (33% predicted). Forced vital capacity was 3.76  L (92%). His echocardiogram showed a mildly dilated right ventricle and an insufficient tricuspid regurgitant jet to estimate a right ventricular systolic pressure (RVSP) estimate. Laboratory assessment showed normal α-1 antitrypsin levels, a non-reactive antinuclear antibody, normal thyroid stimulating hormone and no evidence of hepatitis C virus or human immunodeficiency virus. Chest x-ray (Fig. 19.2) demonstrated flat hemidiaphragms, increased lung volumes and dilated intralobar pulmonary arteries: Past medical history was notable for emphysema and systemic hypertension. On social history, the patient has 5 healthy children. He worked as a welder and in the oil fields. He currently runs a small farm with horses and cows only. He has a 12 pack-year tobacco history and quit 20 years ago. He does not drink alcohol. There is no history of methamphetamine, cocaine or fenfluramine exposures. Family history was notable for a father and brother with emphysema.

Figure 19.2  PA and lateral chest radiograph

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Figure 19.3  Lung scintigraphy showing both ventilation and perfusion abnormalities

Figure 19.4 Follow up CT angiogram of the chest reveals lining thrombus involving the central pulmonary arteries

Given the previous history of pulmonary embolism, a ventilation-perfusion scan was obtained. The study showed multiple moderate or large segmental perfusion defects throughout both lungs. Ventilation images showed xenon retention (Fig. 19.3). Further assessment was obtained via CT pulmonary angiogram (Figs. 19.4 and 19.5). Due to concern for chronic thromboembolic pulmonary hypertension, a right heart catheterization was ultimately performed. The hemodynamic measurements showed a right

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Figure 19.5 Lung windows of the same CT image displayed in Figure 19.4

atrial pressure of 9  mmHg, pulmonary artery pressure of 84/28 mmHg with a mean of 47 mmHg, pulmonary capillary wedge pressure of 12  mmHg, cardiac output of 5.52  L/min and pulmonary vascular resistance of 6.3 Woods unit. Expert opinion regarding the patient was subsequently pursued.

Radiographic Interpretation The series of images in the case exhibit a number of interesting findings. Figure 19.1 is a single image from a CT pulmonary angiography demonstrating a lobar filling defect in the lingula (block arrow) in keeping with acute pulmonary embolism. There is evidence for a pneumomediastinum and subcutaneous air (arrow heads) and a collapsed lung (thin arrow) with a chest drain that has been inserted for a large pneumothorax (not visible on this mediastinal window). The chest radiograph obtained during a subsequent evaluation reveals severe emphysema on the frontal and lateral chest radiograph (Fig. 19.2) as evidenced by hyperexpanded lungs and flattened hemi-diaphragms with disorganization of bronchovascular markings. The heart is not enlarged, though there is dilatation of the proximal pulmonary arteries.

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Accompanying VQ scintigraphy appears abnormal in both the ventilation and perfusion components. There are multiple segmental and subsegmental mismatched perfusion defects, but in a pattern atypical for that seen in pulmonary embolic disease. Ventilation is diffusely abnormal on both sides. The follow up CTPA (Figs. 19.4 and 19.5) shows eccentric clot lining the right main pulmonary artery and “straddling” across the main and left pulmonary artery. No clot was present in the segmental and subsegmental vasculature. There is mild dilatation of the main pulmonary artery compared to the adjacent ascending aorta. Lung windows show severe centrilobular emphysema involving both lungs with large areas of lung destruction, this worse in the right lung. These proximal vessel findings are most likely secondary to in-situ thrombus that has developed as a result of altered blood flow in areas of destroyed lung as a consequence of gross emphysema. The presence of central of central clot with normal or even large segmental vessels should raise the suspicion of in-situ thrombus.

Clinical Comments The possibility that this patient’s pulmonary hypertension was secondary to chronic thromboembolic disease was rooted in his initial presentation of acute dyspnea. Though his symptoms to a large extent were attributable to his infiltrates and pneumothorax—there was also a documented DVT and radiographic evidence for acute pulmonary emboli. And despite appropriate treatment of these entities, including a 12 month course of anticoagulants, he failed to return to his prior clinical status. The discovery of pulmonary hypertension by echo, and confirmed by right heart catheterization to be beyond what might be expected from COPD alone, raised concerns that another problem might be contributing to his clinical decline. And with unmatched perfusion defects by lung scintigraphy, and the finding of eccentric lining thrombus on CT, considering chronic thromboembolic disease as a factor in his ongoing difficulties was reasonable.

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But despite what might be interpreted as a significant thrombus burden in the proximal pulmonary vessels, the assessment as to whether or not thromboendarterectomy surgery is appropriate should follow consideration of two observations—that the lining thrombus may not be the principal problem, and there may be no clinical value in attempting to re-perfuse severely damaged lung parenchyma. As has been discussed with other cases in this book (see Chaps. 19 and 23), the presence of central lining thrombus is not the reason for pulmonary hypertension in most cases. As Dr. Gopalan has suggested, the mechanism behind the development of lining thrombus is not entirely understood, but is likely a result of an aberrant flow pattern along the vessel wall. In particular, this is the probable mechanism in extremely dilated proximal pulmonary arteries. And not only can it occur in the context of chronic lung destruction as in this case, but can also be seen in dilated central vessels associated with congenital heart disease such as atrial or ventricular defects. Most notable is the concept that attempted re-perfusion of damage lung parenchyma—be it emphysema or fibrosis—is never a clinically sound decision. Though some of the CT and VQ abnormalities in this case might have been on the basis of segmental level chronic thromboembolic disease, an endarterectomy of the vessels supplying lung regions with extensive emphysema would not have provided clinical benefit and would have only added risk to an already risky operation. Having said this, however, on occasion there are patients with primarily upper lobe emphysema who present with chronic thromboembolic disease involving vessels supplying r­ elatively “preserved” lung parenchyma. An endarterectomy of these vessels can restore perfusion-ventilation “matching” and prove to be clinically beneficial.

Points of Emphasis Thrombendarterectomy in a patient with extensive parenchymal lung disease requires careful assessment of the limited pulmonary hemodynamic and clinical benefits that can be

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achieved with this approach. Lining thrombus in the central pulmonary arteries can be observed in such patients.

Diagnoses 1. Emphysema. 2 . Lining thrombus involving the proximal pulmonary arteries.

Further Reading Moser KM, Fedullo PF, Finkbeiner WE, Golden J. Do patients with primary pulmonary hypertension develop extensive central thrombi? Circulation. 1995;91:741–5. Perloff JK, Hart EM, Greaves SM, et al. Proximal pulmonary arterial and intrapulmonary radiologic features of Eisenmenger syndrome and primary pulmonary hypertension. Am J Cardiol. 2003;92:182–7.

Index

A Acute respiratory failure, 122 Atrial septal defect cardiac magnetic resonance imaging, 171, 172 chest radiograph, 168, 170 CTA, 168, 169, 172 diagnosis, 175 historical and radiographic aspects, 174 lung scintigraphy, 168, 171 multiplanar CT reconstructions, 174 perfusion scintigram, 175 pulmonary hypertension development, 174 SV-ASD, 173 VQ scintigraphy, 172 B Balloon pulmonary angioplasty diagnosis, 39 guidelines and clinical practice, 39 lung scintigraphy, 38 post-angioplasty, 37 pulmonary angiogram, 37 pulmonary digital subtraction pulmonary arteriogram, 36 Raynaud’s phenomenon, 34

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186 Index Balloon pulmonary angioplasty (cont.) ventilation perfusion imaging, 35 vessel density, 38 Bilateral unmatched perfusion defects, 136 C Catheter pulmonary angiography, 48, 138 acute versus chronic thromboembolic disease, 154 CTED, 68 CTEPH, 5, 7, 15 Central pulmonary arteries, 42 Chest CT angiogram, 103, 104 Chest radiograph, 12 atrial septal defect, 168, 170 CTED, 63, 67 CTEPH, 2, 47 distal vessel thromboendarterectomy, 52, 53, 56 parenchymal lung disease and chronic thromboemboli, 179, 181 pulmonary arteritis, 125 pulmonary veins, 100, 104 sarcoidosis and large vessel pulmonary vascular disease, 134, 138 Chest x-ray pulmonary arterial pulmonary hypertension mimic CTEPH, 158, 159 pulmonary artery sarcoma, 84, 87 Chronic obstructive pulmonary disease (COPD), 43, 101, 182 Chronic pulmonary embolism, 142 Chronic thromboembolic disease (CTED) acute vs. catheter pulmonary angiography, 154 clinical history, 148 CT angiogram, 149, 150 CTPA, 153 diagnoses, 156 duplex venous ultrasound, 149 echocardiogram, 148 family history, 148 intraluminal filling defects, 151, 152 lung ventilation-perfusion scan, 150, 151 perfusion pattern, return of, 152, 153 physical examination, 148 pulmonary hemodynamic profile, 155 transthoracic echocardiogram, 148, 149 cardiovascular exam, 179 catheter pulmonary angiography, 68 chest radiograph, 63, 67, 179, 181 clinic evaluation, vital signs, 72

Index 187 computed tomography pulmonary angiography, 72 CT angiogram, 73, 75, 178, 180, 181 CT pulmonary angiography, 78 diagnosis, 69, 80, 184 digital subtraction pulmonary arteriogram, 64, 65 distal vessel thromboendarterectomy, 57 family history, 62 laboratory assessment, 179 laboratory data, 63 lung scintigraphy, 64, 180 medical history, 61, 62, 71 minute ventilation, 65 organized thrombus endarterectomized at surgery, 77 pulmonary thromboendarterectomy, 77 residual perfusion defects, 68 surgery, 69 surgical outcomes, 79 ventilation perfusion scintigraphy, 73, 74, 78 VQ scintigraphy, 67, 78 Chronic thromboembolic pulmonary hypertension (CTEPH) calcified thrombus lining, central pulmonary vessels, 45 catheter pulmonary angiography, 5, 7, 48 calcified thrombus lining, central pulmonary vessels, 45 chest radiograph, 2, 42, 47 chronic thromboembolic disease, radiographic evidence for, 145 clot specimen removing, 5, 6 COPD, 43 CT angiography, 3, 7, 142 CT scan, 49 CTPA, 7, 47 diagnosis, 10, 49, 146 diagnostic algorithm, 7, 8 diagnostic guidelines, 9 disease distribution, 48 dyspnea, 41 echocardiogram, 2, 142 exertional dyspnea and functional disability, 141 extensive parenchymal lung disease, 44, 46 features of, 143 lining clot, 144 lining thrombus within enlarged central pulmonary vessels, 146 lung perfusion scan, 143, 144 lung scintigraphy, 145–146 medical history, 43 negative study, 9 oral prostacyclin therapy, 47 PAH with IST, 144

188 Index Chronic thromboembolic pulmonary hypertension (CTEPH) (cont.) physical exam, 42 preoperative lung perfusion scintigraphy, 4 pulmonary arteriogram, 46 pulmonary embolism, 43 transplant evaluation, 47 TTE, 2, 3 unusual presentation for catheter based pulmonary angiogram, 15 computerized tomography pulmonary angiogram, 13 CT angiography, 14, 17 diagnosis, 19 distal arteriopathy, 18 frontal and lateral chest radiographs, 12 lung scintigraphy, 14, 16 organized thrombus removing, 16 pulmonary angiography, 15 ventilation perfusion scan, 44 VQ scintigraphy, 6 Chronic thrombus and metastatic cancer CT scan, 92 diagnosis, 96 endarterectomy specimen, 93, 94 islands of malignancy cells, 94, 95 medical history, 92 PET-CT, 94 pulmonary function testing, 93 pulmonary tumor emboli, 96 ventilation-perfusion scan, 93 Computerized tomography (CT), 92 Computerized tomography angiogram acute versus chronic thromboembolic disease, 149, 150 atrial septal defect, 168, 169, 172 CTED, 73, 75 CTEPH, 14, 17, 142 parenchymal lung disease and chronic thromboemboli, 178, 180, 181 pulmonary artery sarcoma, 82, 86, 87 pulmonary veins, 105 pulmonary veno-occlusive disease, 110, 111, 113, 114 Computerized tomography pulmonary angiogram (CTPA), 47 CTED, 72 CTEPH, 6 pulmonary arterial pulmonary hypertension mimic CTEPH, 164 pulmonary veno-occlusive disease, 117 Congenital heart disease, 145

Index 189 D Deep venous thrombi (DVT), 2 Distal arteriopathy, 18 Digital subtraction pulmonary angiogram CTED, 64, 65 distal chronic thromboembolic disease, 27, 28 pulmonary arteritis, 129 Distal chronic thromboembolic disease chronic thrombotic material removing, 26 diagnosis, 31 ECG, 22 echocardiogram, 23, 27 PA and lateral digital subtraction pulmonary angiogram, 27, 28 perfusion scan, 29 prognostic factor, 30 pulmonary angiogram, 24, 25 risk factor, 30 transthoracic echocardiogram, 23 VQ scan, 23, 24, 29 Distal vessel thromboendarterectomy chest radiograph, 52, 53, 56 chronic thromboembolic disease, 57 diagnosis, 59 endarterectomy, organized thrombus removed at, 56 pulmonary angiogram, 54 pulmonary artery, 55, 56 right heart catheterization, 54 subclavian venogram, 52 surgery evaluation, 58 ventilation perfusion scan, 52, 53 VQ scintigraphy, 56 E Echocardiogram acute versus chronic thromboembolic disease, 148 distal chronic thromboembolic disease, 23, 27 Eisenmenger’s syndrome, 145 Emphysema, 179, 182 Endarterectomy, organized thrombus removed at, 56 Extensive parenchymal lung disease, 44, 46 H Hypoxemia, 99

190 Index I Intraluminal filling defects, 151, 152 L Large vessel pulmonary vascular disease bilateral unmatched perfusion defects, 136 cardiopulmonary exercise testing, 136 catheter angiography, 138 chest radiograph, 134, 138 chronic thromboembolic disease catheter-based pulmonary angiography, 136 mimics of, 139 compressive adenopathy and perfusion defects, 137, 138 CT angiogram, 135 CTPA, 138 diagnosis, 140 echocardiogram, 134 extensive soft tissue, 135, 138 nultifactorial causes, 138 perfusion abnormalities, 139 Lung perfusion scan, 143, 144 Lung scintigraphy atrial septal defect, 168, 171 balloon pulmonary angioplasty, 38 CTED, 64 CTEPH, 14, 16, 146 parenchymal lung disease and chronic thromboemboli, 179, 180 pulmonary arteritis, 122, 123 pulmonary veins, 102 Lung ventilation-perfusion scan, 150, 151 M MR angiogram (MRA), 125, 127 N Nonsteroidal therapy, 101 O Oral prostacyclin therapy, 47

Index 191 P Paget-Schroetter syndrome, 52 Parenchymal lung disease cardiovascular exam, 179 chest radiograph, 179, 181 CT angiogram, 178, 180, 181 diagnoses, 184 laboratory assessment, 179 lung scintigraphy, 180 re-perfusion of, 183 PET CT chronic thrombus and metastatic cancer, 94 pulmonary artery sarcoma, 85–87 Post PE syndrome, 68 Pulmonary angiogram distal chronic thromboembolic disease, 24, 25 distal vessel thromboendarterectomy, 54 pulmonary veins, 104 Pulmonary arterial pulmonary hypertension mimic CTEPH chest x-ray, 158, 159, 163 CT chest with pulmonary angiography, 161 CTPA, 160, 164 diagnosis, 165 echocardiogram, 158, 164 laboratory and routine testing, 158 medical history, 158 pulmonary angiography, 163 pulmonary function test, 158, 159 PVOD, 164 right heart catheterization hemodynamics, 162 ventilation perfusion scanning, 161, 165 xenon ventilation scanning, 160 Pulmonary arteriogram pulmonary veins, 102, 103 pulmonary veno-occlusive disease, 113 Pulmonary arteritis acute respiratory failure, 122 chest radiograph, 125 diagnoses, 130 digital subtraction pulmonary arteriogram, 129 echocardiogram, 121 initial evaluation, 122 lung scintigraphy, 122, 123

192 Index Pulmonary arteritis (cont.) MRA, 125, 127 physical exam, 123 pulmonary artery stenosis, 129 pulmonary vessel anatomy and digital subtraction pulmonary angiography, 125, 126 right main pulmonary artery, 122, 124 subsequent assessment, 128 VQ scan, 122 Pulmonary artery sarcoma chest x-ray, 84, 87 chronic and progressive symptoms, 83 CT pulmonary angiography, 82, 86, 87 diagnosis, 88 fusion PET CT, 85–87 PTE surgery, 83 pulmonary intra-arterial filling defects, 87 pulmonary vascular tumors, 88 social history, 83 surgical specimen removing, 85, 86 ventilation perfusion lung scintigraphy scan, 84 VQ scintigraphy, 87 Pulmonary artery stenosis, 129 Pulmonary digital subtraction pulmonary arteriogram, 36 Pulmonary emboli (PE), 1 Pulmonary veins chest CT angiogram, 103, 104 chest radiograph, 100, 104 computerized tomography, 102 CT angiogram, 105 diagnoses, 106 heart catheterization with pulmonary angiography, 102 hypoxemia, 99 lung scintigraphy, 102 medical history, 101 nonsteroidal therapy, 101 outflow impedance, 105 pulmonary angiogram, 104 pulmonary arteriogram, 102, 103 social history, 101 V/Q scintigraphy, 104 Pulmonary veno-occlusive disease, 109 2D echocardiography, 110 abnormal in, 118 catheter pulmonary angiography, 117 CT angiography, 110, 111, 113, 114

Index 193 CTPA, 117 diagnosis, 118 H and E stain, 116 histopathology, 115 mismatched perfusion defects, 118 multi-disciplinary meeting, 112 pulmonary arteriogram, 113 right cardiac catheterization, 111 ventilation perfusion, 111, 112 ventilation-perfusion scintigraphy, 117 Verhoff stain, 115 Pulmonary veno-occlusive disease (PVOD), 164 R Right heart catheterization, 54 Rivaroxaban, 34 S Sarcoidosis bilateral unmatched perfusion defects, 136 cardiopulmonary exercise testing, 136 catheter angiography, 138 chest radiograph, 134, 138 chronic thromboembolic disease, catheter-based pulmonary angiography, 136 chronic thromboembolic disease, mimics of, 139 compressive adenopathy and perfusion defects, 137, 138 CT angiogram, 135 CTPA, 138 diagnosis, 140 echocardiogram, 134 extensive soft tissue, 135, 138 nultifactorial causes, 138 perfusion abnormalities, 139 Sinus venosus atrial septal defect (SV-ASD), 173 Subclavian venogram, 52 Systemic hypertension, 179 T Takayasu arteritis, 128 Transthoracic echocardiogram (TTE) acute versus chronic thromboembolic disease, 148, 149 CTEPH, 2, 3

194 Index Thromboembolic disease, acute vs. chronic catheter pulmonary angiography, 154 clinical history, 148 CT angiogram, 149, 150 CTPA, 153 diagnoses, 156 duplex venous ultrasound, 149 echocardiogram, 148 family history, 148 intraluminal filling defects, 151, 152 lung ventilation-perfusion scan, 150, 151 perfusion pattern, return of, 152, 153 physical examination, 148 pulmonary hemodynamic profile, 155 transthoracic echocardiogram, 148, 149 V Ventilation perfusion imaging balloon pulmonary angioplasty, 35 chronic thrombus and metastatic cancer, 93 CTPEH, 44 distal vessel thromboendarterectomy, 52, 53 pulmonary arterial pulmonary hypertension mimic CTEPH, 161 pulmonary veno-occlusive disease, 111, 112 Ventilation perfusion scintigraphy, 73, 74, 78, 84, 117 VQ scintigraphy, 104 atrial septal defect, 172 CTED, 67, 78 CTEPH, 6 distal chronic thromboembolic disease, 23, 24 distal vessel thromboendarterectomy, 56 parenchymal lung disease and chronic thromboemboli, 182 pulmonary arteritis, 122 pulmonary artery sarcoma, 87 W Williams syndrome, 129 X Xenon ventilation scanning, 160