Pulmonary Hypertension: Controversial and Emerging Topics 9783030527860

Table of contents :
Contents
Contributors
Chapter 1: Exercise Pulmonary Hypertension
Introduction
Normal Resting and Exercise Pulmonary Hemodynamics
What Is the Normal Pulmonary Vascular Response to Exercise?
Exercise Pulmonary Hypertension
What Are the Hemodynamic Criteria to Define ePH?
Should Age Be Considered in the Definition of ePH?
Is There Any Benefit to Performing Confrontational Exercise Testing in Patients with an mPAP 21–24 mmHg?
What About the Wedge?
The Clinical Impact of ePH
Exercise Pulmonary Hypertension, Who Cares?
Is There Evidence of Pulmonary Vasculature Pathology in ePH?
Is There Evidence of Molecular Alterations in ePH That May Drive Disease?
Unresolved Questions and Controversies Regarding Exercise Hemodynamics to Define ePH
Is ePH a Distinct Clinical Entity?
How Should the Cardiac Output Be Measured to Define ePH?
What Do Novel Hemodynamic Measures Add to Our Understanding of ePH?
Alpha
Can ePH Be Predicted?
Can ePH Be Treated?
Methods to Assess Invasive Exercise Hemodynamics
What Methodologies Are Available to Assess Exercise Pulmonary Hypertension?
Conclusion
References
Chapter 2: Advanced Right Ventricular Assessment: Pulmonary Artery Compliance and RV-PA Coupling
Introduction
The Pulmonary Vascular System as Right Ventricular Load: Resistance vs. Compliance
Anatomy
Components of Right Ventricular Afterload
Relationship Between Resistance and Compliance
Effect of Pulmonary Artery Wedge Pressure on the Resistance-Compliance Relationship
Right Ventricular Function: Determinants, Assessment, and Pathophysiology
Determinants of Right Ventricular Function
Heart Rate and Rhythm
Preload, Afterload, and Interventricular Dependence
Contractility
Pathophysiology of Right Ventricular Dysfunction and Failure
Assessment of Right Ventricular Function
Ventricular-Vascular Coupling: The Right Ventricular-Pulmonary Arterial Unit
Pressure-Volume Loops of the Normal Left Ventricle
Effects of Ventricular Determinants on Pressure-Volume Loops of the Left Ventricle
Pressure-Volume Loops of the Right Ventricle
The Concept of Ventricular-Vascular Coupling
Clinical Applications of Ventricular-Vascular Coupling
Noninvasive Methods to Estimate Ventricular-Vascular Coupling
Diastolic Function of the Right Ventricle
Diastolic Stiffness in Patients with Pulmonary Hypertension
Glossary
References
Chapter 3: Beyond Scleroderma: Pulmonary Arterial Hypertension in Patients with Other Connective Tissue Diseases
Introduction
Epidemiology of CTD-PAH
Scleroderma
Mixed Connective Tissue Disease
Other Connective Tissue Diseases
Screening and Early Detection of CTD-PAH
Scleroderma Spectrum Diseases
SLE-PAH
Other CTDs
Treatment of CTD-PAH
Selexipag
Riociguat
Immunosuppression
Conclusion and Future Directions
Bibliography
Chapter 4: Isolated Postcapillary and Combined Pre- and Postcapillary Pulmonary Hypertension
Introduction
Do We Need Invasive Hemodynamics to Diagnose Postcapillary PH and to Differentiate Pulmonary Hypertension Due to Left Heart Disease (PH-LHD) Subsets With or Without Pulmonary Vascular Disease or Can We Substitute Right Heart Catheterization with Al
Hemodynamic Variables to Dissect Pulmonary Hypertension Due to Left Heart Disease (PH-LHD) Subsets: With or Without Pulmonary Vascular Disease (Table 4.1)
Definition and Classification of PH-LHD
Isolated Postcapillary and Combined Pre- and Postcapillary Pulmonary Hypertension: Are They Clinical Phenotypes?
Do We Need to Differentiate Isolated Postcapillary (Ipc-PH) from Combined Pre- and Postcapillary Pulmonary Hypertension (Cpc-PH)?
Conclusion
References
Chapter 5: Current Approach to Chronic Thromboembolic Disease Without Pulmonary Hypertension
Background
Pathogenesis and Epidemiology
Pathophysiology
Clinical Presentation
Diagnostic Evaluation
Treatment
Conclusion
References
Chapter 6: Pulmonary Veno-occlusive Disease and Pulmonary Capillary Hemangiomatosis
Introduction
Pathology
Clinical Classification
Epidemiology
Genetics
Nongenetic Risk Factors
Clinical Features and Diagnosis
Presenting Signs and Symptoms
Echocardiography and Hemodynamics
Radiology
Pulmonary Function Studies
Bronchoalveolar Lavage
Response to Therapy
Noninvasive Diagnosis of PVOD/PCH
Prognosis
Management
Lung Transplantation
Supportive Care
PAH-Specific Therapy
Immunosuppression
Other Therapies
Conclusion
References
Chapter 7: Controversies in the Management of Pulmonary Hypertension in the Setting of Lung Disease
Introduction
Pathogenesis
Diagnosis
What to Do with PH in the Context of Lung Disease Once It Is Detected?
Treat PH Complicating Lung Disease: Yes!
Treat PH Complicating Lung Disease: No!
Treat PH Complicating Lung Disease: Taking the Middle Road
Where to from Here for CLD-PH?
What to Do Now with CLD-PH?
Glossary
References
Chapter 8: Pulmonary Hypertension in Sickle Cell Disease: Current Controversies and Clinical Practices
Introduction
How Should PH of SCD Be Classified?
Diagnosis of PH in SCD
When Should One Perform a Right Heart Catheterization in Patients with SCD?
How Does One Diagnose PH of SCD Hemodynamically?
Which Investigations Should Be Performed in Patients with RHC-Confirmed PH?
How Should One Treat PH of SCD?
Which Patients with PH of SCD Should Be Treated with Anticoagulation?
Do Patients with PH of SCD Respond to PAH Therapy?
Conclusion
References
Chapter 9: Sarcoidosis-Associated Pulmonary Hypertension
Introduction
Pathophysiology
Diagnosis
Prevalence
History and Physical Exam
Pulmonary Function Testing
Serum Biomarkers
Six-Minute Walk Test
Echocardiography
Right Heart Catheterization
Treatment
Outcomes
Future Directions/Prognosis
References
Chapter 10: Parenteral Prostacyclin Use in Pulmonary Arterial Hypertension
Physiologic Effects of Prostacyclin
The Parenteral Prostacyclins
Epoprostenol
Practical Use and Side Effects
Treprostinil
Practical Use and Side Effects
Controversies in Prostacyclin Therapeutic Trials
Endpoints in Prostacyclin Trials
Study Duration
Patient Selection and Inclusion
WHO Group 1
Idiopathic and Heritable PAH
Connective Tissue Disease-Associated PAH
Congenital Heart Disease
Portopulmonary Hypertension
Drug and Toxin Associated
Human Immunodeficiency Virus (HIV)
Pulmonary Veno-occlusive Disease (PVOD)
Schistosomiasis
WHO Group 4
Chronic Thromboembolic Pulmonary Hypertension (CTEPH)
WHO Group 5
Sarcoidosis
Implementation into Clinical Practice
Timing of Parenteral Therapy
Patient-Related Features
Psychosocial Components to Parenteral Therapy
Summary
References
Chapter 11: Pulmonary Hypertension in Chronic Kidney Disease and End-Stage Renal Disease
Introduction, Definitions, and Terminology
Epidemiology of Pulmonary Hypertension in CKD and ESRD Populations
Clinical Significance of PHTN and Kidney Disease Together
Etiology of Pulmonary HTN in CKD and ESRD
A) Comorbidities Connecting PH and CKD-ESRD (“Explained PH”)
B) Possible Causes of the “Unexplained” PH
Screening and Diagnosis
Treatment
Conclusion
Bibliography
Chapter 12: Gender and Race Disparities in Pulmonary Hypertension Diagnosis and Treatment
Introduction
Race/Ethnicity and PAH
Socioeconomic Status and PAH
Gender, Age, and PAH
Genetic Contributors to Healthcare Disparities in PAH
Future Directions in Healthcare Disparities in PAH
References
Index

Citation preview

Respiratory Medicine Series Editors: Sharon I.S. Rounds · Anne Dixon · Lynn M. Schnapp

H. James Ford Gustavo A. Heresi Michael G. Risbano   Editors

Pulmonary Hypertension Controversial and Emerging Topics

Respiratory Medicine Series Editors Sharon I. S. Rounds Alpert Medical School of Brown University Providence, RI, USA Anne Dixon University of Vermont, Larner College of Medicine Burlington, VT, USA Lynn M. Schnapp University of Wisconsin - Madison Madison, WI, USA

More information about this series at http://www.springer.com/series/7665

H. James Ford  •  Gustavo A. Heresi Michael G. Risbano Editors

Pulmonary Hypertension Controversial and Emerging Topics

Editors H. James Ford Division of Pulmonary and Critical Care Medicine, Department of Medicine Pulmonary Hypertension Program University of North Carolina at Chapel Hill Chapel Hill, NC USA

Gustavo A. Heresi Department of Pulmonary, and Critical Care Medicine, Respiratory Institute Cleveland Clinic Cleveland, OH USA

Michael G. Risbano Division of Pulmonary Allergy and Critical Care Medicine, Pittsburgh Heart, Lung Blood and Vascular Medicine Institute University of Pittsburgh Medical Center Pittsburgh, PA USA

ISSN 2197-7372     ISSN 2197-7380 (electronic) Respiratory Medicine ISBN 978-3-030-52786-0    ISBN 978-3-030-52787-7 (eBook) https://doi.org/10.1007/978-3-030-52787-7 © 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 Humana imprint is published by the registered company Springer Nature Switzerland AG The registered company address is: Gewerbestrasse 11, 6330 Cham, Switzerland

Contents

1 Exercise Pulmonary Hypertension ��������������������������������������������������������    1 Michael G. Risbano 2 Advanced Right Ventricular Assessment: Pulmonary Artery Compliance and RV-PA Coupling����������������������������������������������   29 Michael J. Bashline and Marc A. Simon 3 Beyond Scleroderma: Pulmonary Arterial Hypertension in Patients with Other Connective Tissue Diseases������������������������������   51 Scott Visovatti, Christopher Lewis, Ryan Sanderson, Nektarios Vasilottos, and Alexander Zheutlin 4 Isolated Postcapillary and Combined Pre- and Postcapillary Pulmonary Hypertension ������������������������������������������������   61 Irene M. Lang 5 Current Approach to Chronic Thromboembolic Disease Without Pulmonary Hypertension ��������������������������������������������������������   71 Gustavo A. Heresi and Batool Jamal AbuHalimeh 6 Pulmonary Veno-occlusive Disease and Pulmonary Capillary Hemangiomatosis��������������������������������������������������������������������   89 Barbara L. LeVarge, David Montani, and Marc Humbert 7 Controversies in the Management of Pulmonary Hypertension in the Setting of Lung Disease����������������������������������������  109 Steven D. Nathan and Joan Albert Barberà 8 Pulmonary Hypertension in Sickle Cell Disease: Current Controversies and Clinical Practices��������������������������������������  123 Laurent Savale, Marc Humbert, and Elizabeth S. Klings 9 Sarcoidosis-Associated Pulmonary Hypertension��������������������������������  135 H. James Ford, Ahmed Sesay, Elizabeth Sonntag, and Sheila Krishnan v

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Contents

10 Parenteral Prostacyclin Use in Pulmonary Arterial Hypertension ����  147 Jessica H. Huston and Anna R. Hemnes 11 Pulmonary Hypertension in Chronic Kidney Disease and End-Stage Renal Disease������������������������������������������������������������������  173 Veeranna Maddipati and Murali Chakinala 12 Gender and Race Disparities in Pulmonary Hypertension Diagnosis and Treatment������������������������������������������������������������������������  195 Karla Cruz Morel, Vinicio De Jesus Perez, and Arunabh Talwar Index������������������������������������������������������������������������������������������������������������������  203

Contributors

Batool Jamal AbuHalimeh, MD  Internal Medicine Resident, Internal Medicine Department, Cleveland Clinic Akron General, Akron, OH, USA Joan  Albert  Barberà, MD  Department of Pulmonary Medicine and Allergy, Hospital Clínic  – Biomedical Research Institute August Pi i Sunyer (IDIBAPS), University of Barcelona, Barcelona, Spain Biomedical Research Networking Center on Respiratory Diseases (CIBERES), Madrid, Spain Michael  J.  Bashline, MD  Division of Cardiology, Department of Medicine, University of Pittsburgh and UPMC, Pittsburgh, PA, USA Murali  Chakinala, MD, FCCP  Washington University School of Medicine, WUSM & BJH Pulmonary HTN Care Center, St. Louis, MO, USA H.  James  Ford, MD  Division of Pulmonary and Critical Care Medicine, Department of Medicine, Pulmonary Hypertension Program, University of North Carolina at Chapel Hill, Chapel Hill, NC, USA Anna R. Hemnes, MD  Division of Allergy, Pulmonary, and Critical Care Medicine, Vanderbilt University Medical Center, Nashville, TN, USA Gustavo  A.  Heresi, MD, MS  Department of Pulmonary, and Critical Care Medicine, Respiratory Institute, Cleveland Clinic, Cleveland, OH, USA Marc  Humbert, MD, PhD  Université Paris-Saclay, School of Medicine, Le Kremlin-­Bicêtre, France INSERM UMR_S 999 “Pulmonary Hypertension: Pathophysiology and Novel Therapies”, Hôpital Marie Lannelongue, Le Plessis-Robinson, France Assistance Publique - Hôpitaux de Paris (AP-HP), Department of Respiratory and Intensive Care Medicine, Pulmonary Hypertension National Referral Center, Hôpital Bicêtre, Le Kremlin-Bicêtre, France

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Contributors

Jessica  H.  Huston, MD  Division of Cardiovascular Medicine, Vanderbilt University Medical Center, Nashville, TN, USA Elizabeth  S.  Klings, MD  The Pulmonary Center, Boston University School of Medicine, Boston, MA, USA Sheila  Krishnan, DO  Division of Pulmonary and Critical Care Medicine, Department of Medicine, Pulmonary Hypertension Program, University of North Carolina at Chapel Hill, Chapel Hill, NC, USA Irene M. Lang, MD  Department of Internal Medicine II, Division of Cardiology, Vienna General Hospital, Medical University of Vienna, Vienna, Austria Barbara L. LeVarge, MD  Pulmonary Critical Care Medicine, University of North Carolina at Chapel Hill, Chapel Hill, NC, USA Christopher  Lewis, MD  Department of Internal Medicine, University of Michigan, Ann Arbor, MI, USA Veeranna Maddipati, MD  Brody School of Medicine, East Carolina University, Greenville, NC, USA David Montani, MD, PhD  Service de Pneumologie et Soins Intensifs Thoraciques, Centre de Référence de l’Hypertension Pulmonaire, INSERM U999 “Pulmonary hypertension: Pathophysiology and Novel Therapies”, Hôpital de Bicêtre, Assistance Publique Hôpitaux de Paris, Le Kremlin-Bicêtre, France Karla  Cruz Morel, MD  Pulmonary and Critical Care Medicine, Prisma Health University of South Carolina Medical Group, Columbia, SC, USA Steven D. Nathan, MD  Inova Heart and Vascular Institute, Inova Fairfax Hospital, Falls Church, VA, USA Vinicio  De Jesus Perez, MD  Pulmonary and Critical Care Medicine, Stanford University Hospital, Stanford, CA, USA Michael G. Risbano, MD, MA  Division of Pulmonary Allergy and Critical Care Medicine, Pittsburgh Heart, Lung, Blood and Vascular Medicine Institute, University of Pittsburgh Medical Center, Pittsburgh, PA, USA Ryan Sanderson, MD  Department of Internal Medicine, University of Michigan, Ann Arbor, MI, USA Laurent  Savale, MD, PhD  Université Paris-Saclay, School of Medicine, Le Kremlin-­Bicêtre, France INSERM UMR_S 999 “Pulmonary Hypertension: Pathophysiology and Novel Therapies”, Hôpital Marie Lannelongue, Le Plessis-Robinson, France Assistance Publique - Hôpitaux de Paris (AP-HP), Department of Respiratory and Intensive Care Medicine, Pulmonary Hypertension National Referral Center, Hôpital Bicêtre, Le Kremlin-Bicêtre, France

Contributors

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Ahmed Sesay, MD  Division of Pulmonary and Critical Care Medicine, Department of Medicine, Pulmonary Hypertension Program, University of North Carolina at Chapel Hill, Chapel Hill, NC, USA Marc A. Simon, MD  Division of Cardiology, Department of Medicine, University of Pittsburgh and UPMC, Pittsburgh, PA, USA Pittsburgh Heart, Lung, Blood and Vascular Medicine Institute, Pittsburgh, PA, USA Department of Bioengineering, University of Pittsburgh and UPMC, Pittsburgh, PA, USA Elizabeth  Sonntag, MD  Division of Pulmonary and Critical Care Medicine, Department of Medicine, Pulmonary Hypertension Program, University of North Carolina at Chapel Hill, Chapel Hill, NC, USA Arunabh Talwar, MD  Pulmonary and Critical Care Medicine, Northwell Health, New Hyde Park, NY, USA Nektarios  Vasilottos, MD  Department of Internal Medicine, University of Michigan, Ann Arbor, MI, USA Scott  Visovatti, MD  University of Michigan, Department of Internal Medicine, Division of Cardiovascular Medicine, Ann Arbor, MI, USA Alexander  Zheutlin, MD, MS  Department of Internal Medicine, University of Michigan, Ann Arbor, MI, USA

Chapter 1

Exercise Pulmonary Hypertension Michael G. Risbano

Introduction Exercise pulmonary hypertension (ePH) is an underappreciated form of exertional limitation that results in symptoms with physical activity and a reduction in aerobic exercise capacity [1–4]. ePH is a clinical syndrome that may reside on a continuum between normal resting hemodynamics and manifest pulmonary arterial hypertension (PAH). An abnormal pulmonary vascular response during exercise delineates ePH from normal resting hemodynamics. At the present time there are no uniformly established definitions of ePH; however, there has been a recent interest in reviving a definition of ePH. At the fourth World Symposium on Pulmonary Hypertension in Dana Point (CA, USA) in 2008 the definition of “exercise-induced pulmonary hypertension” of mean pulmonary artery pressure (mPAP) >30 mmHg was abandoned due to the lack of a unified diagnostic approach, concerns pertaining to normal aging and changes in hemodynamics, as well as the need for more precise hemodynamic cutoffs [5, 6]. The subsequent fifth and sixth World Symposium on Pulmonary Hypertension both held in Nice, France, in 2013 and 2018 did not provide a working definition of ePH. The task force concluded that exercise challenge is beneficial methodology to unmask pulmonary vascular disease in patients with normal resting hemodynamics that are early in the disease state or well-compensated. They recommended that additional studies be performed to further refine the clinical syndrome of ePH [7, 8]. Exercise pulmonary hypertension (ePH) describes elevated right-sided filling pressures during exertion and is preferred to the older terminology “exercise-­ induced pulmonary hypertension.” The latter has implications that exercise has a causative role in the pulmonary vascular disease [9]. It may make sense to use the M. G. Risbano (*) Division of Pulmonary Allergy and Critical Care Medicine Pittsburgh Heart, Lung, Blood and Vascular Medicine Institute, University of Pittsburgh Medical Center, Pittsburgh, PA, USA e-mail: [email protected] © Springer Nature Switzerland AG 2020 H. J. Ford et al. (eds.), Pulmonary Hypertension, Respiratory Medicine, https://doi.org/10.1007/978-3-030-52787-7_1

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M. G. Risbano

term exercise pulmonary arterial hypertension (ePAH) to primarily distinguish abnormally elevated right-sided filling pressures during exercise from exercise pulmonary venous hypertension (ePVH); however, this terminology has not been widely adopted in recent statement on pulmonary hemodynamics during exercise [9]. Patients at risk for developing ePH include systemic sclerosis [10, 11], chronic PE [12, 13], parenchymal lung disease (including ILD [3] and COPD [14, 15]), HFpEF [16, 17], HFrEF [18, 19], atrial septal defects [20], valve disease [21, 22], family members of patients with iPAH [17], and asymptomatic carriers of the BMPR2 gene mutation [23]. These groups are representative of the types of patients that may benefit from confrontational exercise testing, especially when resting supine invasive hemodynamics are either normal or borderline elevated. There is irony that the workup of patients with symptomatic exertion includes a majority of procedures performed at rest. It is therefore intuitive that the workup of symptomatic dyspnea may include exercise stress testing. Our preference is to perform invasive cardiopulmonary exercise testing (iCPET), which in the vast majority of cases provides real pathophysiological insight into the condition contributing to patient’s symptoms and helps make a diagnosis. There have been significant scientific contributions in the literature that have helped define normal and abnormal values in ePH to help move the field of invasive exercise testing forward [1, 3, 12, 18, 24–26]. Ongoing work in the field may ultimately result in the restitution of a definition of ePH. This chapter will focus on the controversial topic of exercise pulmonary hypertension, in particular the precapillary (arterial) syndrome measured by invasive cardiopulmonary hemodynamics. Normal resting hemodynamic values and borderline pressures will be addressed. The specifics of ePH and the clinical impact of ePH will be discussed. Unresolved questions and controversies regarding ePH will be covered. The evidence for treatment of ePH will be presented. Finally, methods to assess invasive exercise hemodynamics will be discussed. Topics of exercise pulmonary hypertension in the setting of specific disease states such as parenchymal lung disease, parenchymal lung disease, and left heart disease will be touched upon in this chapter but will not be completely addressed.

Normal Resting and Exercise Pulmonary Hemodynamics What Is the Normal Pulmonary Vascular Response to Exercise? One of the initial impediments to defining ePH was the lack of consensus for a normal resting pulmonary artery pressure. This concern has since been reconciled. At rest under normal conditions the pulmonary vasculature is a low-pressure high capacitance system. A landmark systematic review of the available literature by Kovacs et al. included 1187 healthy individuals with invasively measured

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hemodynamics and showed that normal resting mPAP ± SD is 14 ± 3.3 mmHg in the supine position and 13.6 ± 3.1 mmHg in the upright position [6]. In the supine position the upper limit of normal was 20.6 mmHg and 19.8 mmHg in the upright position. Resting mPAP was independent of gender. Based upon these findings, the sixth World Symposium on Pulmonary Hypertension redefined resting pulmonary arterial hypertension as mPAP >20 mmHg, PVR >3 WU with a pulmonary artery wedge pressure (PAWP) ≤15 mmHg [8]. The same review by Kovacs and colleagues showed that the upper limit of normal during exercise stress testing was dependent on the intensity of exercise with mPAP of 28.8 mmHg in the upright position with slight exercise and 36.8 mmHg at maximal exercise [6]. This amounted to 47% of the 91 normal subjects aged >50 years with an mPAP >30 mmHg in the “slight” exercise category. Of the 193 subjects with more than one level of exercise performed the mPAP was >30 mmHg in 21% of subjects aged 30 mmHg was not valid and there was no established upper limit of normal mPAP during exercise. As a result, the fifth World Symposium on Pulmonary Hypertension in 2013 removed the definition of ePH as an mPAP >30 mmHg, which had been in place for over 30 years [7].

Exercise Pulmonary Hypertension What Are the Hemodynamic Criteria to Define ePH? Other impediments to defining ePH have included the lack of a unified diagnostic approach, concerns regarding age-related changes in hemodynamics, and the need for more precise hemodynamic cutoffs [5, 6]. A variety of hemodynamic thresholds have been proposed to describe an abnormal pulmonary vascular response to exercise [9, 12, 18, 25–29]. These methods emphasize the pressureflow relationship of mPAP to CO to delineate normal from abnormal exercise hemodynamics, underscoring mPAP as a flow-dependent variable. For example, highly trained athletes can generate an mPAP that may exceed 30 mmHg at peak exercise. The elevated mPAP is largely due to a conditioned increase in CO and stroke volume (SV) [30] rather than pulmonary vascular disease or diastolic dysfunction, for example, in an exceptionally healthy individual. Therefore, it is reasonable that ePH is not defined by mPAP alone. The conceptual basis of the mPAP-CO relationship is that disproportionate increases in mPAP are related to either remodeling of the pulmonary vasculature or transmission of the left atrial pressure to the pulmonary vasculature due to left heart disease as CO increases during exercise [25]. This pressure-flow approach alleviates some of the difficulties ascribed to the former ePH definition that solely employed mPAP >30  mmHg. Healthy individuals should not have an mPAP exceed 30  mmHg when CO is 30  mmHg and TPRmax >3.0 WU at maximum exercise [12] 2. Multipoint measurement where multiple mPAP and CO (4–5 data points are needed) are measured from start of exercise to peak exercise and the mPAP-­ COslope is defined as ≥3 WU [18] 3. Two-point measurement of the mPAP-CO slope that includes the difference in maximal and resting ∆mPAP/∆CO >3.0 WU [28, 29] 4. An age-based definition with age ≤50 years mPAPmax >30 mmHg, PVRmax >1.34 WU, or age >50 years mPAPmax >33 mmHg, PVRmax >2.11 WU [27] The European Respiratory Society issued a statement on exercise hemodynamics in 2018 and although no official definition of ePH was recognized the single-point criteria seem to have been favored based upon previously reported findings [9, 12]. Herve and colleagues compared patients with an mPAPmax >30 mmHg to those with an mPAPmax  >30  mmHg and TPRmax  >3.0 WU to evaluate whether measuring mPAPmax  >30  mmHg alone at maximum exercise overdiagnosed ePH [12]. The authors found that the addition of TPR to the ePH definition improved the specificity without significantly compromising sensitivity. They demonstrated that mPAPmax alone had lower specificity (0.77) and higher sensitivity (0.98) when compared to mPAPmax >30 and TPRmax >3.0 WU which had a specificity (1.0) and sensitivity (0.93). The single-point method may outperform mPAP >30 mmHg threshold; however, how do the individual ePH definitions compare? A small trial by Godinas and colleagues compared the single-point, multipoint, and two-point measurements in 49 patients with pulmonary vascular disease with non-PH controls demonstrated diagnostic concordance of 78% among the three criteria [26]. The sensitivity and specificity of the single-point definition mPAPmax >30 mmHg and TPRmax >3.0 WU for ePH were reported as 0.94 and 1.0, respectively. This outperformed the sensitivity and specificity of the mPAP-COslope of 0.67 and 0.88 and ∆mPAP/∆CO >3.0 WU of 0.88 and 0.87, respectively. Additionally, the single-point definition reduced the misclassification of healthy controls diagnosed with ePH compared to mPAP >30 mmHg alone [31]. The value of an age-driven definition of ePH is unclear as the sensitivity and specificity has not been compared to the other three ePH definitions.

Should Age Be Considered in the Definition of ePH? As the pulmonary vasculature ages, there is deterioration of the vascular structure and function due to remodeling with increases in pulmonary vascular stiffness that cause increases in pulmonary artery pressures and resistance [32]. The intrinsic pulmonary vascular changes of normal aging result in lower pulmonary artery compliance (PAC) and reduced pulmonary vascular reserve in humans aged >50  years

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[33]. In addition, alpha (𝛼), a mechanical descriptor of the pulmonary vasculature and a measure of vascular distensibility, is reduced in older patients [34–36]. The exact cause of the vascular stiffness in senescence remains unclear. Although age-­ related pulmonary vascular changes do not limit exercise in the majority of older healthy patients, identifying the limits of normal in aging is important when defining an abnormal pulmonary vascular response to exercise. Kovacs and colleagues have shown mPAP increased with age with individuals aged >50 years with significantly higher mPAP compared to younger subjects; the mean mPAP ± SD in individuals ≥50 years was 14.7 ± 4.0 mmHg, 30–50 years was 12.9  ±  3.0  mmHg, and  50 had similar mPAP (mean ± SD 22 ± 4 vs. 23 ± 5 mmHg; p = 0.22) with an upper limit of normal of 30 and 33 mmHg, respectively [27]. The CO was reduced in subjects aged ≤50 compared to >50 16.2 vs. 12.1  L/min (p 33 mmHg with a PVR >2.10 for age >50 years and have utilized these cutoffs in subsequent publications [2, 37]. Given the available data an age-driven definition of ePH may be useful to identify patients with ePH due to a pathologic state rather than normal aging. It is unclear if PVR is superior to TPR to define ePH as a direct comparison has not been performed. The European Respiratory Society position paper did not address these controversies, but future studies may provide clarification on the issue [9].

I s There Any Benefit to Performing Confrontational Exercise Testing in Patients with an mPAP 21–24 mmHg? Resting mPAP between 21 and 24 mmHg formerly represented borderline pulmonary artery pressures. As a result of the sixth World Symposium on Pulmonary Hypertension in 2018 the working definition of PAH was changed to include mPAP >20  mmHg as long as pulmonary vascular resistance (PVR) is greater than 3.0 Wood units (WU) [8]. Not all at-risk patients with an mPAP between 21

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and 24 mmHg will meet the strict definition of resting PAH, as many patients will have a normal PVR. The clinical characteristics of patients with borderline pulmonary hypertension was not well understood until recently [2, 4, 11, 28, 38]. In a study of 141 patients with resting and exercise hemodynamics, 32 patients had borderline pulmonary artery pressures [28]. These patients were older and had a history of cardiac and lung disease. Exercise capacity in borderline mPAP compared to normal patients is limited with shorter 6-minute walk distance (6MWD) (383  ±  120 vs. 448  ±  92 meters; p = 0.001) and a trend toward a reduced ⩒O2peak (16.9 ± 4.6 vs. 20.9 ± 4.7 mL/ min/kg; p = 0.09) [28]. Max hemodynamic response during exercise was higher in the borderline group. In particular the pressure-flow relationship measured as the slope of the mPAP-cardiac output (defined as the change in mPAP divided by change in CO from rest to 50 Watts) was higher in the borderline compared to normal group (5.2 vs. 3.2 mmHg/L/min; p 30 mmHg and TPRmax >3.0 WU. Patients with mPAP 21–24  mmHg had peak exercise values mPAP, TPR, and PVR that were higher and CO lower compared to subjects with mPAP ≤20  mmHg. The mPAP 21–24 mmHg group had reduced peak exercise workload as well as reduced functional capacity with 6MWD (423 ± 110 vs 471 ± 109 meters; p = 0.002) and significantly worse New York Heart Association (NYHA) Functional Class compared to controls. With resting mPAP stratified into ranges 25 mmHg at maximum exercise may identify heart failure with preserved ejection fraction (HFpEF) [44]; however, some experts have identified 20 mmHg as the upper limit of normal [2, 45]. We utilize a lower limit of normal of PAWP >25 mmHg in the supine position [46] and PAWP >20 mmHg during iCPET studies in the upright position. Oliveira et al. showed that the peak PAWP during exercise in healthy adults aged >50 is similar to those aged ≤50 using a cutoff of 20 mmHg [27], though other authors have shown that PAWP may rely on age and exercise training in healthy controls [47]. The so-called left ventricular filling resistance represented by the PAWP/CO relationship has been proposed by Kovacs and colleagues [48]. This ratio may discriminate the pathologic from physiologic during exercise. Lewis and colleagues identified that a PAWP/CO slope >2 WU predicted reduced peak exercise capacity (⩒O2peak) and adverse composite cardiac outcomes such as cardiac death, incident resting PAWP elevation, or heart failure hospitalization at a mean of 5.3-year follow-up [49]. Borlaug and colleagues showed that patients with HFpEF had a significant elevation in PAWP during passive leg elevation compared to patients without cardiac disease (+7 ± 3 vs. +2 ± 3 mmHg; p 30 mmHg and TPR >3.0 WU does not discriminate patients with pulmonary vascular disease (PVD) from those with left heart disease (LHD). (This figure has been used with permission from reference [12])

early increase (1.5 min into low-level exercise at 20 W); the PAWP increased from baseline value in the HFpEF group to +16  ±  6  mmHg [80% of peak value] vs. noncardiac dyspnea patients to +5  ±  3  mmHg [80% of peak value], p  30  mmHg, which was primarily due to elevations in PAWP; PVR decreased in this group indicating ability to recruit pulmonary vasculature during exercise. Interestingly Borlaug and colleagues evaluated 61 compensated HFpEF patients that performed iCPET testing at rest and submaximal exercise [50]. Using high-­ fidelity micromanometers with simultaneous lung ultrasound and echocardiography the group found that during exercise 54% of patients developed extravascular lung water associated with higher PAWP and a higher incidence of RV dysfunction by echocardiogram. The authors concluded that even at submaximal exercise the acute accumulation of extravascular lung water is related to elevations in central venous pressures secondary to RV abnormalities and RV-PA coupling. The mPAP, RAP, and

1  Exercise Pulmonary Hypertension 40

*†

pt(p.Pro1115Leu) in the EIF2KA4 gene in iberian romani patients with pulmonary veno-occlusive disease: a warning for our daily practice. Arch Bronconeumol. 2016;52(8):444–5. 38. Hadinnapola C, Bleda M, Haimel M, et al. Phenotypic characterization of EIF2AK4 mutation carriers in a large cohort of patients diagnosed clinically with pulmonary arterial hypertension. Circulation. 2017;136(21):2022–33. 39. Eichstaedt CA, Song J, Benjamin N, et al. EIF2AK4 mutation as "second hit" in hereditary pulmonary arterial hypertension. Respir Res. 2016;17(1):141. 40. Nossent EJ, Antigny F, Montani D, et al. Pulmonary vascular remodeling patterns and expression of general control nonderepressible 2 (GCN2) in pulmonary veno-occlusive disease. J Heart Lung Transplant. 2018;37(5):647–55. 41. Ravishankar B, Liu H, Shinde R, et al. The amino acid sensor GCN2 inhibits inflammatory responses to apoptotic cells promoting tolerance and suppressing systemic autoimmunity. Proc Natl Acad Sci U S A. 2015;112(34):10774–9. 42. Montani D, Achouh L, Dorfmuller P, et al. Pulmonary veno-occlusive disease: clinical, functional, radiologic, and hemodynamic characteristics and outcome of 24 cases confirmed by histology. Medicine (Baltimore). 2008;87(4):220–33. 43. Lombard CM, Churg A, Winokur S. Pulmonary veno-occlusive disease following therapy for malignant neoplasms. Chest. 1987;92(5):871–6. 44. Perros F, Gunther S, Ranchoux B, et al. Mitomycin-induced pulmonary Veno-occlusive disease: evidence from human disease and animal models. Circulation. 2015;132(9):834–47. 45. Swift GL, Gibbs A, Campbell IA, Wagenvoort CA, Tuthill D. Pulmonary veno-occlusive disease and Hodgkin's lymphoma. Eur Respir J. 1993;6(4):596–8. 46. Knight BK, Rose AG.  Pulmonary veno-occlusive disease after chemotherapy. Thorax. 1985;40(11):874–5. 47. Joselson R, Warnock M. Pulmonary veno-occlusive disease after chemotherapy. Hum Pathol. 1983;14(1):88–91. 48. Williams LM, Fussell S, Veith RW, Nelson S, Mason CM. Pulmonary veno-occlusive disease in an adult following bone marrow transplantation. Case report and review of the literature. Chest. 1996;109(5):1388–91. 49. Hackman RC, Madtes DK, Petersen FB, Clark JG. Pulmonary venoocclusive disease following bone marrow transplantation. Transplantation. 1989;47(6):989–92. 50. Seguchi M, Hirabayashi N, Fujii Y, et  al. Pulmonary hypertension associated with pulmonary occlusive vasculopathy after allogeneic bone marrow transplantation. Transplantation. 2000;69(1):177–9. 51. Salzman D, Adkins DR, Craig F, Freytes C, LeMaistre CF. Malignancy-associated pulmonary veno-occlusive disease: report of a case following autologous bone marrow transplantation and review. Bone Marrow Transplant. 1996;18(4):755–60. 52. Gazourian L, Spring L, Meserve E, et  al. Pulmonary Clinicopathological correlation after allogeneic hematopoietic stem cell transplantation: an autopsy series. Biol Blood Marrow Transplant. 2017;23(10):1767–72.

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53. Pradere P, Tudorache I, Magnusson J, et al. Lung transplantation for scleroderma lung disease: an international, multicenter, observational cohort study. J Heart Lung Transplant. 2018;37(7):903–11. 54. Gupta S, Gupta A, Rehman S, et al. Pulmonary veno-occlusive disease is highly prevalent in scleroderma patients undergoing lung transplantation. ERJ Open Res. 2019;5(1). 55. Dorfmuller P, Humbert M, Perros F, et al. Fibrous remodeling of the pulmonary venous system in pulmonary arterial hypertension associated with connective tissue diseases. Hum Pathol. 2007;38(6):893–902. 56. Gunther S, Jais X, Maitre S, et al. Computed tomography findings of pulmonary venoocclusive disease in scleroderma patients presenting with precapillary pulmonary hypertension. Arthritis Rheum. 2012;64(9):2995–3005. 57. Connolly MJ, Abdullah S, Ridout DA, Schreiber BE, Haddock JA, Coghlan JG. Prognostic significance of computed tomography criteria for pulmonary veno-occlusive disease in systemic sclerosis-pulmonary arterial hypertension. Rheumatology (Oxford). 2017;56(12):2197–203. 58. Holcomb BW Jr, Loyd JE, Ely EW, Johnson J, Robbins IM. Pulmonary veno-occlusive disease: a case series and new observations. Chest. 2000;118(6):1671–9. 59. Montani D, Savale L, Natali D, et al. Long-term response to calcium-channel blockers in non-­ idiopathic pulmonary arterial hypertension. Eur Heart J. 2010;31(15):1898–907. 60. Creagh-Brown BC, Nicholson AG, Showkathali R, Gibbs JS, Howard LS. Pulmonary veno-­ occlusive disease presenting with recurrent pulmonary oedema and the use of nitric oxide to predict response to sildenafil. Thorax. 2008;63(10):933–4. 61. Hoeper MM, Eschenbruch C, Zink-Wohlfart C, et al. Effects of inhaled nitric oxide and aerosolized iloprost in pulmonary veno-occlusive disease. Respir Med. 1999;93(1):62–4. 62. Resten A, Maitre S, Humbert M, et al. Pulmonary hypertension: CT of the chest in pulmonary venoocclusive disease. AJR Am J Roentgenol. 2004;183(1):65–70. 63. 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. 64. Seferian A, Helal B, Jais X, et al. Ventilation/perfusion lung scan in pulmonary veno-occlusive disease. Eur Respir J. 2012;40(1):75–83. 65. Rabiller A, Jais X, Hamid A, et al. Occult alveolar haemorrhage in pulmonary veno-occlusive disease. Eur Respir J. 2006;27(1):108–13. 66. Laveneziana P, Montani D, Dorfmuller P, et al. Mechanisms of exertional dyspnoea in pulmonary veno-occlusive disease with EIF2AK4 mutations. Eur Respir J. 2014;44(4):1069–72. 67. Lederer H, Muggli B, Speich R, et al. Haemosiderin-laden sputum macrophages for diagnosis in pulmonary veno-occlusive disease. PLoS One. 2014;9(12):e115219. 68. Resten A, Maitre S, Humbert M, et al. Pulmonary arterial hypertension: thin-section CT predictors of epoprostenol therapy failure. Radiology. 2002;222(3):782–8. 69. Galie N, Manes A, Negro L, Palazzini M, Bacchi-Reggiani ML, Branzi A.  A meta-­ analysis of randomized controlled trials in pulmonary arterial hypertension. Eur Heart J. 2009;30(4):394–403. 70. Liu HL, Chen XY, Li JR, et al. Efficacy and safety of pulmonary arterial hypertension-specific therapy in pulmonary arterial hypertension: a meta-analysis of randomized controlled trials. Chest. 2016;150(2):353–66. 71. Wille KM, Sharma NS, Kulkarni T, et al. Characteristics of patients with pulmonary venoocclusive disease awaiting transplantation. Ann Am Thorac Soc. 2014;11(9):1411–8. 72. Quezada-Loaiza CA, de Pablo GA, Perez V, et  al. Lung transplantation in pulmo nary hypertension: a multidisciplinary Unit's management experience. Transplant Proc. 2018;50(5):1496–503. 73. Galie N, Humbert M, Vachiery JL, 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): endorsed by: Association for European Paediatric and Congenital

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Cardiology (AEPC), International Society for Heart and Lung Transplantation (ISHLT). Eur Respir J. 2015;46(4):903–75. 74. Davies P, Reid L. Pulmonary veno-occlusive disease in siblings: case reports and morphometric study. Hum Pathol. 1982;13(10):911–5. 75. Montani D, Jais X, Price LC, et  al. Cautious epoprostenol therapy is a safe bridge to lung transplantation in pulmonary veno-occlusive disease. Eur Respir J. 2009;34(6):1348–56. 76. Ogawa A, Miyaji K, Yamadori I, et al. Safety and efficacy of epoprostenol therapy in pulmonary veno-occlusive disease and pulmonary capillary hemangiomatosis. Circ J. 2012;76(7):1729–36. 77. Palazzini M, Manes A. Pulmonary veno-occlusive disease misdiagnosed as idiopathic pulmonary arterial hypertension. Eur Respir Rev. 2009;18(113):177–80. 78. Barreto AC, Franchi SM, Castro CR, Lopes AA. One-year follow-up of the effects of sildenafil on pulmonary arterial hypertension and veno-occlusive disease. Braz J Med Biol Res. 2005;38(2):185–95. 79. Ogawa A, Sakao S, Tanabe N, Matsubara H, Tatsumi K. Use of vasodilators for the treatment of pulmonary veno-occlusive disease and pulmonary capillary hemangiomatosis: a systematic review. Respir Investig. 2019;57(2):183–90. 80. Koyama M, Yano T, Kikuchi K, et al. Favorable response to an endothelin receptor antagonist in mitomycin-induced pulmonary veno-occlusive disease with pulmonary capillary hemangiomatosis. Int J Cardiol. 2016;212:245–7. 81. Sourla E, Paspala A, Boutou A, Kontou P, Stanopoulos I, Pitsiou G.  A case of pulmonary veno-occlusive disease: diagnostic dilemmas and therapeutic challenges. Ther Adv Respir Dis. 2013;7(2):119–23. 82. Ye XQ, Yan CS, Zhang XY, Cai Y, Guo F, Kuang JL. Lengthy diagnostic challenge in a rare case of pulmonary veno-occlusive disease: case report and review of the literature. Intern Med. 2011;50(12):1323–7. 83. Naniwa T, Takeda Y.  Long-term remission of pulmonary veno-occlusive disease associated with primary Sjogren's syndrome following immunosuppressive therapy. Mod Rheumatol. 2011;21(6):637–40. 84. Gilroy RJ Jr, Teague MW, Loyd JE. Pulmonary veno-occlusive disease. Fatal progression of pulmonary hypertension despite steroid-induced remission of interstitial pneumonitis. Am Rev Respir Dis. 1991;143(5 Pt 1):1130–3. 85. Saito A, Takizawa H, Ito K, Yamamoto K, Oka T. A case of pulmonary veno-occlusive disease associated with systemic sclerosis. Respirology. 2003;8(3):383–5. 86. Sanderson JE, Spiro SG, Hendry AT, Turner-Warwick M. A case of pulmonary veno-occlusive disease responding to treatment with azathioprine. Thorax. 1977;32(2):140–8. 87. Diao XL, Mu XD, Jin ML. Pulmonary capillary Hemangiomatosis associated with CREST syndrome: a challenge of diagnosis and treatment. Chin Med J. 2017;130(21):2645–6. 88. Hoeper MM, Barst RJ, Bourge RC, et  al. Imatinib mesylate as add-on therapy for pulmonary arterial hypertension: results of the randomized IMPRES study. Circulation. 2013;127(10):1128–38. 89. Frost AE, Barst RJ, Hoeper MM, et al. Long-term safety and efficacy of imatinib in pulmonary arterial hypertension. J Heart Lung Transplant. 2015;34(11):1366–75. 90. Ogawa A, Miyaji K, Matsubara H.  Efficacy and safety of long-term imatinib therapy for patients with pulmonary veno-occlusive disease and pulmonary capillary hemangiomatosis. Respir Med. 2017;131:215–9.

Chapter 7

Controversies in the Management of Pulmonary Hypertension in the Setting of Lung Disease Steven D. Nathan and Joan Albert Barberà

Introduction It has been well established for many years that pulmonary hypertension (PH) commonly complicates the course of most forms of chronic lung diseases. The majority of the data attesting to this emanates from the chronic obstructive pulmonary disease (COPD), idiopathic pulmonary fibrosis (IPF), and sarcoidosis literature [1–3]. PH complicating chronic lung disease (CLD-PH) has been shown to be associated with worse functional status, lower arterial oxygenation, and poorer outcomes including mortality and possibly acute exacerbations [4, 5]. The severity of CLD-PH is generally mild to moderate with a small minority of patients developing severe PH (mPAP ≥35 mmHg). Nonetheless, the presence of PH has a significant effect on outcomes.

Pathogenesis The pathogenesis of PH in these various entities is likely multifactorial. Certainly hypoxemia (resting, exercise-induced, or nocturnal) plays a role, as might vascular ablation from the underlying parenchymal process. Comorbid conditions could also contribute to the development of PH.  These include obstructive sleep apnea; heart S. D. Nathan (*) Inova Heart and Vascular Institute, Inova Fairfax Hospital, Falls Church, VA, USA e-mail: [email protected] J. A. Barberà Department of Pulmonary Medicine and Allergy, Hospital Clínic – Biomedical Research Institute August Pi i Sunyer (IDIBAPS), University of Barcelona, Barcelona, Spain Biomedical Research Networking Center on Respiratory Diseases (CIBERES), Madrid, Spain e-mail: [email protected] © Springer Nature Switzerland AG 2020 H. J. Ford et al. (eds.), Pulmonary Hypertension, Respiratory Medicine, https://doi.org/10.1007/978-3-030-52787-7_7

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failure, especially occult heart failure with preserved ejection fraction; and, rarely, thromboembolic disease. These should therefore be appropriately sought and aggressively managed if present. Another potential factor might be cytokine “cross-­talk,” since many of the same cytokines that perpetuate the primary disease may also affect the pulmonary vasculature (e.g., TGF-B, platelet-derived growth factor, endothelin-1).

Diagnosis Suspicion for PH should be raised in those patients who are more short of breath and more functionally impaired or desaturate to a greater extent than their lung function, and chest computed tomography (CT chest) appearance might suggest. A low single-­ breath diffusing capacity for carbon monoxide (DLCO) might also be a harbinger of underlying PH. A pulmonary artery segment to ascending aorta ratio of >1 on chest CT has similar predictive accuracy for underlying PH [6]. An elevated BNP or NT-proBNP might also be a marker of underlying PH but could also be due to comorbid left heart failure, especially in more elderly individuals. Echocardiography is the best screening tool, where an elevated estimated right ventricular systolic pressure (RVSP) (≥35 mmHg) might suggest underlying PH [7]. The sensitivity of this threshold is relatively good for underlying PH, but the specificity is quite poor at this low cut point, particularly in patients with chronic lung disease [8, 9]. The specificity increases with higher thresholds, but this is at the expense of a reduced sensitivity. Measurement of the RVSP is dependent on a detectable tricuspid regurgitant jet and in some cases this might not be obtained. Evidence of right ventricular dysfunction might also indicate underlying PH. The gold standard for the diagnosis of PH complicating lung disease remains right heart catheterization. A flow diagram depicting clues to the presence of PH and a suggested diagnostic algorithm is shown in Fig. 7.1. Of note, there was a proposed change to the definition of PH at the 2018 World Pulmonary Hypertension Symposium. The old definition relied on the mean pulmonary artery pressure (mPAP) alone with a cut point of 25 mmHg or greater defining the presence of PH.  The proposed new definition includes patients with mPAPs 21–24 mmHg if their pulmonary vascular resistance is 3 or more Wood units [10]. How this new definition performs in discerning outcomes and identifying a specific vascular phenotype in the context of lung disease remains to be determined.

 hat to Do with PH in the Context of Lung Disease W Once It Is Detected? This is the 64 million dollar question which remains to be answered and is the subject of this debate. There are numerous medications approved for the treatment of group 1 PH; three of these target the endothelin pathway (bosentan, ambrisentan,

7  Controversies in the Management of Pulmonary Hypertension in the Setting of Lung… 111 Dyspnea/SOB out of proportion

Loud P2, evidence of RHF Right axis deviation in ECG Elevated NT-pro BNP/BNP levels

CT: - Enlarged PA segment - PA:A ratio > 1

PFT: - DLco35 mmHg (FEV1 30 mmHg

Echo: sPAP >40 mmHg

RHC

Echo

Diagnosis of PH RHC: mPAP ≥25 mmHg

12 weeks

16 weeks

Sildenafil 20 mg tid

mPAP 39 mmHg FEV1 CI 2.4 L/min/m2 54% DLCO PVR 7 WU 33%

3 months

Tadalafil 10 mg qd

Sildenafil

FEV1 32%

sPAP 42 ± 10 mmHg mPAP 31 ± 5 mmHg Echo: sPAP 42 mmHg

12 weeks

18 months

12 weeks

Time 3 months

FEV1 41%

Sildenafil 20 mg tid

Bosentan

Bosentan

Therapy “Pulsed” nitric oxide

FEV1 32.5%

PFTs FEV1 1.09 FEV1/ FVC 44.5% Not reported FEV1 37%

sPAP 52.7 mmHg

sPAP 32 mmHg (29–38) mPAP 37 ± 5 mmHg

Hemodynamics mPAP 27.6 mmHg CI 2.7

PVR, decreased 1.4 WU

6MWD, increased 190 m Exercise endurance time, no change 6MWD, no change

6MWD, no change No defined primary

Primary endpoint PVRi, improved

Decreased sPAP – 12 mmHg. No difference in QOL, BNP, or SaO2 Improved cardiac index, BODE scores, QOL. No effect on gas exchange

No change in 6MWD, peak VO2, QOL, or oxygenation

Worsened hypoxemia and QOL mPAP, PVR, BODE index, and 6MWD (64 m) improved Decrease in sPAP

Other outcomes Improved hemodynamics. No worsened hypoxemia

112 S. D. Nathan and J. A. Barberà

RHC

RCT

147 IIP, FVC >45%, mPAP >25 mmHg

Nathan (2017)** [21]

FVC 67% DLCO 39% FVC 76.3 +/− 19 DLCO 32 +/− 12

RHC

RCT 2:1

68 IPF with group 2 PH (14% of the whole cohort)

Raghu (2015) [20] mPAP 33.2 +/− 8.2 CI 2.6 +/− 0/7

mPAP 30 mmHg

RHC: mPAP mPAP ≥25 mmHg 37 mmHg CI 2.2

RCT 2:1

60 IPF or idiopathic fibrotic NSIP

N Inclusion criteria 119 IPF with echo available

Baseline PFTs FVC 57% pred DLCO 26% pred FVC 56% Kco 45%

Study Diagnosis of Baseline design PH hemodynamics NA RCT Echo: RV systolic dysfunction

Corte (2014) [19]

Author (year) Han (2013) [18]

Table 7.2  ILD studies

16 weeks

Bosentan

Riociguat 2.5 mg tid

26 weeks

Ambrisentan Study 10 mg/day terminated early

Duration 12 weeks

Therapy Sildenafil 20 mg tid

Other outcomes Improvement in QOL in patients with RVSD

All secondary PVRi endpoints negative decrease of 20%, negative No change in functional capacity or symptoms More Disease progression, hospitalizations with ambrisentan arm unfavorable trend Study stopped early 6MWD, no difference at for increased harm to riociguat arm study halt (death and hospitalization)

Primary endpoint, result 6MWD, less decline

7  Controversies in the Management of Pulmonary Hypertension in the Setting of Lung… 113

Retrospective RHC case series

Bonham 26 Any treated SAPH, Retrospective RHC case series (2015) [27] no left-sided disease

Keir 33 Any SAPH (2014) [26]

mPAP 44 mmHg PVR 10 CI 2.1 mPAP 46 CI 2.1 PVR 8.3

FEV1 51.8% FVC 64.8% FEV1 48% FVC 48% DLCO 29%

Diagnosis Study design of PH Hemodynamics PFTs Retrospective RHC mPAP 46.1 FVC case series CO 4.2 L/min 53.6% FEV1 51.2% FVC 50% Baughman 22 Any SAPH Prospective RHC mPAP FEV1/FVC (2009) [23] open label 33 mmHg 73% Co 5.9 PVR 5.1 FEV1 59 RHC mPAP 32.7 Judson 25 mPAP >25 mmHg, Prospective open label CO 4.45 L/min (+/−21) (2011) [24] PVR >3 FVC 61.5 PVR 5.86 FVC >40% (+/−16.5) 6MWD 150–450 m FVC Baughman 39 mPAP ≥25 mmHg RCT 2:1 RHC mPAP 36 60+/16.6% (2014) [25] NYHA FC2 or 3 +/− 7 mmHg CI 2.6 +/− 0.7 L/min

Author (year) N Inclusion criteria Barnett 22 Any SAPH (2009) [22]

Table 7.3  Sarcoidosis studies

4 months

16 weeks

Epo 7, Tre 6, Variable ERA 12, PDE5i 20

Sildenafil or 6 months bosentan

Bosentan

Other outcomes NYHA FC improvement in nine patients

None identified

Increased CI/CO, decreased PVR Improved NT-proBNP

Six patients with ≥20% ↓in PVR;↑ in 6MWD of ≥30 m in 3 of 15 No change 10/21 who in 6MWD completed had improvements in FC and QOL Decrease in No change in 6MWD mPAP (to 32 mmHg) PVR decreased from 6.1 to 4.4 WU None 6MWD improved identified 14 m, BNP and TAPSE improved

6MWD unchanged

Primary Duration endpoint Median 6MWD ↑ 11 months by 59 m

Ambrisentan 24 weeks 10 mg daily

Inhaled iloprost

Therapy Bosentan, sildenafil

114 S. D. Nathan and J. A. Barberà

7  Controversies in the Management of Pulmonary Hypertension in the Setting of Lung… 115

Pathologically, patients with CLD have been shown to have vasculopathic lesions that are similar to PAH, including the presence of plexiform lesions [29]. On a molecular level, some of the same vasoactive mediators that are dysregulated in PAH are similarly dysregulated in CLD-PH, attesting to other commonalities between these two forms of PH [30]. This provides biologic plausibility to treat CLD-PH patients with PAH medications. Some of the vascular changes can occur in geographically disparate regions of the lung that are seemingly unaffected by the diffuse parenchymal disease process (Fig. 7.2). The analogy can perhaps be drawn between PH-CLD and chronic thromboembolic PH, where it is not the vessels that are directly affected by the primary disease, but rather the other “innocent bystander” vessels that are targeted with therapy. Why do we not as yet have any randomized controlled trials (RCTs) attesting to the efficacy of PAH therapies for CLD-PH? One only needs to be reminded of the many negative studies, some of them harmful studies that were orchestrated prior to the development and approval of the two antifibrotic therapies that are now available to treat patients with IPF.  Therefore, despite the negative results from the RISE-IIP study [31], as well as some other smaller clinical trials, the jury is still very much out as to the role of PAH therapy in patients with lung disease. Indeed, there have been numerous other small case series, open-label studies, and registry reports attesting to the potential efficacy of therapy in patients with lung disease complicated by PH.  One can make the case that because of the generally poor Medial hypertrophy

Areas of well-preserved lung

Fibrotic changes

Medial hypertrophy in a medium sized pulmonary artery

Fig. 7.2  Vasculopathic changes with medial hypertrophy in arterioles seen in regions of the lung that are relatively well preserved in a patient with pulmonary fibrosis

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prognosis associated with PH-CLD, the burden of proof and threshold to treat CLD-PH should be lowered and can occur outside the context of RCTs. Indeed, such studies have been notoriously difficult to recruit with most of the patients randomized having mild to moderate PH. This has been predicated by the notion that it is unethical to withhold PH therapy in those with more severe PH.  This bias to patients with less severe PH might impact the ability for any RCT to demonstrate a difference in outcomes.

Treat PH Complicating Lung Disease: No! Because of the association between PH and outcomes in patients with lung disease, it becomes tantalizing to employ any of the agents approved for PAH when PH supervenes in patients with underlying lung disease. However, as mentioned in the pro-treatment section above, association does not infer causation, and PH might just be a surrogate for the severity of the underlying lung disease. Therefore just because we can treat does not mean we should treat. There are many instances in the history of medicine where interventions that make intuitive, physiologic, and biologic sense simply do not pan out when put to the test in clinical trials. On the extreme end of this spectrum, there is the risk of doing harm in our zest and quest to help patients. A good example of this is treating heart failure with inotropic agents, where studies have shown that we can make patients feel better and walk further, but at the expense of an increased mortality rate [32]. This also raises the question of what endpoints to look at in the context of clinical trials [33]. A number of agents have shown acute hemodynamic improvements in patients with CLD-PH, but does this translate to a clinically meaningful benefit? And if there is short-term or intermediate improvement (e.g., in the 6-minute walk test), what of the long-term consequences? Tables 7.1, 7.2, and 7.3 shows published randomized controlled trials conducted in patients with CLD-PH. The largest randomized controlled clinical trial to date has been the RISE-IIP study which evaluated riociguat as a therapy for PH complicating any of the idiopathic interstitial pneumonias (Table 7.2) [31]. Unfortunately, this study was stopped early at the recommendation of the Data Safety Monitoring Board (DSMB) based on increased serious adverse events including death in the treatment arm [31]. The ARTEMIS-IPF trial evaluated ambrisentan for its potential antifibrotic properties in a broad population of IPF patients with mild to moderate disease [34]. All patients had right heart catheterizations to qualify for study entry [34]. This study was also stopped early by the DSMB for increased hospitalizations and death in the treatment arm. A subsequent subgroup analysis of those subjects with PH did not show a difference in these outcomes [20]. The BPHIT study was one of a very few randomized, prospective double-blind placebo-controlled studies that examined the use of bosentan in patients with various forms of idiopathic interstitial pneumonia [19]. While this study did not demonstrate harm, it was decidedly negative with not even one of many secondary endpoints suggesting any element of efficacy. A meta-analysis of the RCTs conducted in patients with interstitial lung disease-associated PH assessing the effect of targeted PAH therapy failed to show any effect on 6-min walk distance or symptomatic burden [35].

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In COPD, despite some studies having shown improvement in pulmonary hemodynamics [17, 35, 36], the impact on exercise tolerance or symptomatic burden is questionable, as the majority of RCTs have failed to show any benefit in cases with moderate PH [35, 37] (Table 7.1). The effect of targeted therapy on symptomatic burden in COPD-PH is also disappointing when evaluated in RCTs [35, 36]. Neither dyspnea [13] nor SGRQ [13, 15, 16] improved significantly with targeted therapy compared with placebo or usual care. Furthermore, there is evidence that targeted PAH vasodilators worsen gas exchange in COPD due to the inhibition of hypoxic pulmonary vasoconstriction [38]. However, the jury is still very much out in this large group of patients as to which phenotype might benefit from therapy. There does appear to be a vascular phenotype of COPD patients who have more moderate obstructive disease and markedly reduced DLCO’s [39]. In one study, this represented about 7% of patients with advanced COPD [40]. PH therapy in these patients might appear to make sense but remains to be validated in appropriate prospective clinical trials. Sarcoidosis-PH remains in group 5 due to the multifactorial nature of its etiology. While the majority of cases are due to parenchymal lung disease, there are a minority that may be due to other reasons, including sarcoidosis vasculitis that may potentially be steroid responsive, mechanical compression of the vasculature by mediastinal lymphadenopathy, or fibrosing mediastinitis. Of all the lung diseases, sarcoidosis represents the group of patients who tend to have a greater incidence of moderate to severe PH, therefore a group most primed to demonstrate a treatment benefit. While there is data to support the use of PAH medications in these patients (Table 7.3), there has also been at least one prospective study (of ambrisentan) that failed to show any benefit [24]. There are a few notable differences in the demographics of CLD-PH patients. Specifically, these are generally more elderly patients who might be prone to more comorbidities which themselves might contribute to the development of PH, for example, heart failure both with reduced and preserved ejection fraction. These patients might be at higher risk of adverse events from PH therapy where the right ventricle is unloaded resulting in increased preload presented to a compromised left ventricle placing the patient at risk of pulmonary edema and an untoward outcome. Pulmonary veno-occlusive disease is a well-accepted contraindication to PH therapy. In patients with lung fibrosis, the scarring might be centered around veins and venules, thereby mimicking veno-occlusive physiology and imparting a similar risk of a deleterious outcome. Veno-occlusive type lesions have been described in 65% of IPF patients in one explant/autopsy series [41].

 reat PH Complicating Lung Disease: Taking T the Middle Road The question looms of whether or when PH complicating lung disease is an adaptive phenomenon or maladaptive event. If the former, then perhaps we run the risk of doing more harm than good by alleviating the PH. If the latter, then there might be opportunity to help patients. Arguably, it is likely that there is a spectrum, where

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some patients might be helped by treating their PH and others might not. However, the group that is most likely to benefit is yet to be determined among the various forms of CLD-PH.

Where to from Here for CLD-PH? What emerges from the two sides of the argument to treat or not to treat CLD-PH is the clear need for further clinical trials to address this issue in this severely afflicted patient population. The key is picking the right patient phenotype to prime any future studies for success. What this phenotype is remains elusive. Specifically, how to balance the hemodynamic profile with parenchymal disease severity is integral to the success of any future clinical trials. How best to assess both of these elements also remains uncertain. The hemodynamic criteria for inclusion in PH clinical trials have been anchored to the mean pulmonary artery pressure (mPAP), with an inclusion cut point of 25 mmHg typically utilized. Arguments can be made to both lower and raise this threshold, while a case can be made for using other modalities and parameters as inclusionary criteria, for example, echo evidence of right ventricular dysfunction or CT evidence of pulmonary artery segment enlargement. The parenchymal disease component has usually been evaluated based on PFTs. However, PFTs can both over- and underestimate the extent of disease. Therefore direct visualization and scoring of lung morphology through CT scanning or other imaging is likely key to patient selection for future clinical trials. Figure 7.3 provides a cartoon depiction of this theoretic concept.

Theoretic CT/Score

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Patient A: mPAP=48 mmHg FVC=90% and CT Score=35

30 Patient C: mPAP=35 mmHg FVC=50% and CT Score=20

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Patient B: mPAP=45 mmHg FVC=100% and CT Score=22

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90% 80% 70% 60% 50% 40%

15 10 25

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45

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mPAP (mmHg) Fig. 7.3  Concept plot incorporating the interaction between lung volumes (FVC) in interstitial lung disease, hemodynamics (mPAP), and theoretic CT fibrosis score

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Aside from the hemodynamic and lung morphologic criteria, there are other elements that are essential for a positive study including the correct clinical trial endpoint(s) and a trial period sufficiently long to meet the endpoint. Endpoints in these studies can vary from short-term physiologic biomarkers, including the tried and tested 6-minute walk test. However, there is data to suggest that short-term changes in the 6MWT are not a good surrogate for longer-term outcomes. What is generally more desirable are longer-term clinical meaningful and patient-centric endpoints including quality of life measurements, functional measurements (including the 6MWT and patient activity monitoring), hospitalizations, and mortality itself. These are all probably best employed in concert as a composite endpoint (of all or some of these).

What to Do Now with CLD-PH? What is one to do in the absence of such clinical trials when faced with these patients in the clinical trenches? While PAH therapies cannot be universally endorsed for PH complicating lung disease, there are situations where the patients hemodynamic profile appears similar to patients with group 1 PAH.  Arguably, some of these patients could have two conditions, and it becomes a philosophical argument if group 1 PAH can be diagnosed in the presence of any lung disease. Recently, the term pulmonary vascular phenotype has been proposed to describe these patients [42]. In any event, for those patients with severe PH, especially if there is evidence of RV failure (high right atrial pressure, low cardiac index), treating them as group 1 PAH is not unreasonable. However, this is best accomplished at PH Centers of Excellence where they can also be vetted for enrollment in any available clinical trials.

Glossary 6MWT  Six-minute walk test COPD  Chronic obstructive pulmonary disease CT  Computed tomography DLCO  Single-breath diffusing capacity for carbon monoxide FVC  Forced vital capacity IPF  Idiopathic pulmonary fibrosis mPAP  Mean pulmonary artery pressure PAH  Pulmonary arterial hypertension PFTs  Pulmonary function tests PH  Pulmonary hypertension RCT  Randomized controlled trials

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RISE-IIP  A randomized, double-blind, placebo-controlled phase II study to investigate the efficacy and safety of riociguat in patients with symptomatic pulmonary hypertension associated with idiopathic interstitial pneumonias

References 1. Barbera JA, Blanco I. Management of pulmonary hypertension in patients with chronic lung disease. Curr Hypertens Rep. 2015;17:62. 2. Blanco I, Piccari L, Barbera JA.  Pulmonary vasculature in COPD: the silent component. Respirology. 2016;21:984–94. 3. Barbera JA, Blanco I. Pulmonary hypertension in patients with chronic obstructive pulmonary disease: advances in pathophysiology and management. Drugs. 2009;69:1153–71. 4. Kessler R, Faller M, Fourgaut G, Mennecier B, Weitzenblum E. Predictive factors of hospitalization for acute exacerbation in a series of 64 patients with chronic obstructive pulmonary disease. Am J Respir Crit Care Med. 1999;159:158–64. 5. Wells JM, Washko GR, Han MK, et al. Pulmonary arterial enlargement and acute exacerbations of COPD. N Engl J Med. 2012;367:913–21. 6. Iyer AS, Wells JM, Vishin S, Bhatt SP, Wille KM, Dransfield MT. CT scan-measured pulmonary artery to aorta ratio and echocardiography for detecting pulmonary hypertension in severe COPD. Chest. 2014;145:824–32. 7. Galie N, Humbert M, Vachiery JL, 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): Endorsed by: Association for European Paediatric and Congenital Cardiology (AEPC), International Society for Heart and Lung Transplantation (ISHLT). Eur Respir J. 2015;46:903–75. 8. Arcasoy SM, Christie JD, Ferrari VA, et al. Echocardiographic assessment of pulmonary hypertension in patients with advanced lung disease. Am J Respir Crit Care Med. 2003;167:735–40. 9. Fisher MR, Criner GJ, Fishman AP, et al. Estimating pulmonary artery pressures by echocardiography in patients with emphysema. Eur Respir J. 2007;30:914–21. 10. Simonneau G, Montani D, Celermajer DS, et al. Haemodynamic definitions and updated clinical classification of pulmonary hypertension. Eur Respir J. 2019;53. 11. Vonbank K, Ziesche R, Higenbottam TW, et al. Controlled prospective randomised trial on the effects on pulmonary haemodynamics of the ambulatory long term use of nitric oxide and oxygen in patients with severe COPD. Thorax. 2003;58:289–93. 12. Stolz D, Rasch H, Linka A, et  al. A randomized, controlled trial of bosentan in severe COPD. Eur Respir J. 2008;32:619–28. 13. Valerio G, Bracciale P, Grazia DA. Effect of bosentan upon pulmonary hypertension in chronic obstructive pulmonary disease. Ther Adv Respir Dis. 2009;3:15–21. 14. Rao RS, Singh S, Sharma BB, Agarwal VV, Singh V.  Sildenafil improves six-minute walk distance in chronic obstructive pulmonary disease: a randomised, double-blind, placebo-­ controlled trial. Indian J Chest Dis Allied Sci. 2011;53:81–5. 15. Blanco I, Santos S, Gea J, et al. Sildenafil to improve respiratory rehabilitation outcomes in COPD: a controlled trial. Eur Respir J. 2013;42:982–92. 16. Goudie AR, Lipworth BJ, Hopkinson PJ, Wei L, Struthers AD.  Tadalafil in patients with chronic obstructive pulmonary disease: a randomised, double-blind, parallel-group, placebo-­ controlled trial. Lancet Respir Med. 2014;2:293–300. 17. Vitulo P, Stanziola A, Confalonieri M, et al. Sildenafil in severe pulmonary hypertension associated with chronic obstructive pulmonary disease: a randomized controlled multicenter clinical trial. J Heart Lung Transplant. 2017;36:166–74.

7  Controversies in the Management of Pulmonary Hypertension in the Setting of Lung… 121 18. Han MK, Bach DS, Hagan PG, et al. Sildenafil preserves exercise capacity in patients with idiopathic pulmonary fibrosis and right-sided ventricular dysfunction. Chest. 2013;143:1699–708. 19. Corte TJ, Keir GJ, Dimopoulos K, et al. Bosentan in pulmonary hypertension associated with fibrotic idiopathic interstitial pneumonia. Am J Respir Crit Care Med. 2014;190:208–17. 20. Raghu G, Nathan SD, Behr J, et al. Pulmonary hypertension in idiopathic pulmonary fibrosis with mild-to-moderate restriction. Eur Respir J. 2015;46:1370–7. 21. Nathan SD, Behr J, Collard HR, et  al. RISE-IIP: riociguat for the treatment of pulmonary hypertension associated with idiopathic interstitial pneumonia (abstr). Eur Respir J. 2017;50:OA1985. 22. Barnett CF, Bonura EJ, Nathan SD, et  al. Treatment of sarcoidosis-associated pulmonary hypertension. A two-center experience. Chest. 2009;135:1455–61. 23. Baughman RP, Judson MA, Lower EE, et al. Inhaled iloprost for sarcoidosis associated pulmonary hypertension. Sarcoidosis Vasc Diffuse Lung Dis. 2009;26:110–20. 24. Judson MA, Highland KB, Kwon S, et al. Ambrisentan for sarcoidosis associated pulmonary hypertension. Sarcoidosis Vasc Diffuse Lung Dis. 2011;28:139–45. 25. Baughman RP, Culver DA, Cordova FC, et al. Bosentan for sarcoidosis-associated pulmonary hypertension: a double-blind placebo controlled randomized trial. Chest. 2014;145:810–7. 26. Keir GJ, Walsh SL, Gatzoulis MA, et  al. Treatment of sarcoidosis-associated pulmonary hypertension: a single centre retrospective experience using targeted therapies. Sarcoidosis Vasc Diffuse Lung Dis. 2014;31:82–90. 27. Bonham CA, Oldham JM, Gomberg-Maitland M, Vij R.  Prostacyclin and oral vasodilator therapy in sarcoidosis-associated pulmonary hypertension: a retrospective case series. Chest. 2015;148:1055–62. 28. Badesch DB, Raskob GE, Elliott CG, et al. Pulmonary arterial hypertension: baseline characteristics from the REVEAL Registry. Chest. 2010;137:376–87. 29. Carlsen J, Hasseriis AK, Boesgaard S, Iversen M, Steinbruchel D, Bogelund AC. Pulmonary arterial lesions in explanted lungs after transplantation correlate with severity of pulmonary hypertension in chronic obstructive pulmonary disease. J Heart Lung Transplant. 2013;32:347–54. 30. Peinado VI, Pizarro S, Barbera JA.  Pulmonary vascular involvement in COPD.  Chest. 2008;134:808–14. 31. Nathan SD, Behr J, Collard HR, et al. Riociguat for idiopathic interstitial pneumonia-­associated pulmonary hypertension: the randomized RISE-IIP study. Lancet RespirMed. 2019; Ref Type: In Press. 32. O'Connor CM, Gattis WA, Uretsky BF, et al. Continuous intravenous dobutamine is associated with an increased risk of death in patients with advanced heart failure: insights from the Flolan International Randomized Survival Trial (FIRST). Am Heart J. 1999;138:78–86. 33. Barbera JA, Blanco I. Gaining insights into pulmonary hypertension in respiratory diseases. Eur Respir J. 2015;46:1247–50. 34. Raghu G, Behr J, Brown KK, et al. Treatment of idiopathic pulmonary fibrosis with ambrisentan: a parallel, randomized trial. Ann Intern Med. 2013;158:641–9. 35. Prins KW, Duval S, Markowitz J, Pritzker M, Thenappan T.  Chronic use of PAH-specific therapy in World Health Organization Group III Pulmonary Hypertension: a systematic review and meta-analysis. Pulm Circ. 2017;7:145–55. 36. Chen X, Tang S, Liu K, et  al. Therapy in stable chronic obstructive pulmonary disease patients with pulmonary hypertension: a systematic review and meta-analysis. J Thorac Dis. 2015;7:309–19. 37. Park J, Song JH, Park DA, Lee JS, Lee SD, Oh YM. Systematic review and meta-analysis of pulmonary hypertension specific therapy for exercise capacity in chronic obstructive pulmonary disease. J Korean Med Sci. 2013;28:1200–6. 38. Blanco I, Gimeno E, Munoz PA, et al. Hemodynamic and gas exchange effects of sildenafil in patients with chronic obstructive pulmonary disease and pulmonary hypertension. Am J Respir Crit Care Med. 2010;181:270–8.

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39. Boerrigter BG, Bogaard HJ, Trip P, et al. Ventilatory and cardiocirculatory exercise profiles in COPD: the role of pulmonary hypertension. Chest. 2012;142:1166–74. 40. Thabut G, Dauriat G, Stern JB, et al. Pulmonary hemodynamics in advanced COPD candidates for lung volume reduction surgery or lung transplantation. Chest. 2005;127:1531–6. 41. Colombat M, Mal H, Groussard O, et al. Pulmonary vascular lesions in end-stage idiopathic pulmonary fibrosis: histopathologic study on lung explant specimens and correlations with pulmonary hemodynamics. Hum Pathol. 2007;38:60–5. 42. Kovacs G, Agusti A, Barbera JA, et al. Pulmonary vascular involvement in chronic obstructive pulmonary disease. is there a pulmonary vascular phenotype? Am J Respir Crit Care Med. 2018;198:1000–11.

Chapter 8

Pulmonary Hypertension in Sickle Cell Disease: Current Controversies and Clinical Practices Laurent Savale, Marc Humbert, and Elizabeth S. Klings

Introduction Sickle cell disease (SCD), the most common genetic disorder worldwide, affects up to 100,000 people living in the United States and accounts for up to 300,000 births annually worldwide. SCD is a hemoglobinopathy characterized by recurrent episodes of hemolysis and vaso-occlusion affecting nearly every vascular bed of the systemic and pulmonary vasculature. The two primary pathogenic mechanisms of SCD are vaso-occlusion and hemolysis, with downstream effects on inflammation, redox biology, nitric oxide (NO) metabolism, and coagulation. The hallmark of vaso-occlusion in SCD is abnormal interactions between erythrocytes, leukocytes, platelets, and the vascular endothelium leading to promotion of inflammation, thrombosis, and oxidative stress [1, 2]. Pulmonary hypertension (PH) occurs in 6–10.5% of HbSS adults and is associated with a 40% six-year mortality [3–5]. Similar to other forms of PH, mortality risk increases with worsening hemodynamics and increased right ventricular dysfunction [3, 6]. PH in SCD is heterogenous both in etiology and hemodynamics [7]. In prevalence studies with invasive hemodynamic assessment, approximately 40% of SCD patients with PH have precapillary PH, defined by a mean pulmonary artery

L. Savale · M. Humbert Université Paris-Saclay, School of Medicine, Le Kremlin-Bicêtre, France INSERM UMR_S 999 “Pulmonary Hypertension: Pathophysiology and Novel Therapies”, Hôpital Marie Lannelongue, Le Plessis-Robinson, France Assistance Publique - Hôpitaux de Paris (AP-HP), Department of Respiratory and Intensive Care Medicine, Pulmonary Hypertension National Referral Center, Hôpital Bicêtre, Le Kremlin-Bicêtre, France E. S. Klings (*) The Pulmonary Center, Boston University School of Medicine, Boston, MA, USA e-mail: [email protected] © Springer Nature Switzerland AG 2020 H. J. Ford et al. (eds.), Pulmonary Hypertension, Respiratory Medicine, https://doi.org/10.1007/978-3-030-52787-7_8

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pressure (mPAP)  ≥25  mmHg and a pulmonary artery wedge pressure (PAWP) 3 Woods units (>240  dyn·s·cm−5); and (3) a well-documented response to PAH-specific therapies [11]. PH of SCD was thought to be not consistent with this definition of group 1 PAH for the following reasons. Precapillary PH due to SCD has a distinct hemodynamic profile, characterized by a less marked increase in mPAP, a higher cardiac output, and lower PVR than patients with idiopathic PAH. Specific therapies approved for the treatment of PAH include prostacyclin derivatives, endothelin receptor antagonists, soluble guanylyl cyclase stimulators, and phosphodiesterase-5 inhibitors. However, none of these agents are currently approved for the treatment of PH associated with sickle cell disease due to the lack of data in this specific population. Indeed, response to specific PAH therapies may be different in these patients. For example, the placebo-controlled randomized clinical trial of sildenafil in SCD patients with echocardiographic evidence of elevated pulmonary pressures was terminated early because of an increased rate of hospitalizations primarily for vaso-occlusive events (VOEs) in those receiving sildenafil [12]. In addition, the ASSET 1 and 2 studies failed to demonstrate effect of bosentan, an endothelin receptor antagonist, in this specific indication due to a

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lack of termination of the study by the sponsor before the powered sample size was achieved [13]. The histopathological characterization of pulmonary vascular lesions in PH due to SCD is limited and observations are controversial. The identification of plexiform lesions was reported in 12 of 20 autopsy cases by Haque et al. [14]. However, the presence of coexistent hepatic cirrhosis in many of them suggests another possible etiology of PAH. More recently, a Brazilian study of 30 autopsies revealed recent thrombosis in 80% and old thrombosis in 43% [15]. Many, if not all, of these patients did not have PH diagnosed premortem. As 60% of patients with PH of SCD have postcapillary PH, it is possible that chronically elevated left-sided pressures contribute to the observed pulmonary vascular remodeling [15] . The contribution of thrombosis, particularly in situ thrombosis of the smaller pulmonary arterioles, is highlighted in a larger autopsy study of 306 cases of SCD patients with a clinical suspicion of PH [16]. Based upon the complex and multifactorial physiological mechanisms implicated in PH of SCD, it appears most appropriate to place this disorder within group 5 PH reflective of its unclear and/or multifactorial mechanisms.

Diagnosis of PH in SCD Is Screening Echocardiography Useful in the Diagnosis of PH in SCD? While an elevated (tricuspid regurgitant jet velocity) TRV in adults with sickle cell disease (SCD) is common and predicts pulmonary hypertension (PH) and mortality risk, it is not diagnostic of PH. The TRV and other indirect features suggestive of PH, such as right atrial and ventricular enlargement, are used to assess the probability of PH [17, 18]. But TTE alone is not sufficient for PH diagnosis and right heart catheterization (RHC) is required to confirm a PH diagnosis. A meta-analysis of four studies which included data from 173 patients who underwent transthoracic echocardiography (TTE) and right heart catheterization demonstrated a positive predictive value of TTE for PH of only 31% [6]. The use of screening echocardiography was proposed as part of the American Thoracic Society (ATS) Clinical Guidelines for Diagnosis and Treatment of PH in SCD as a means for early identification of these patients. Screening for an elevated TRV was proposed to identify high-risk patients for intensification of hematological therapy with hydroxyurea or chronic transfusions and consideration of right heart catheterization for PH diagnosis. Patients with an elevated TRV should also be evaluated for other comorbidities which can play a role in the development of PH, such as sleep-disordered breathing and venous thromboembolism. However, it is unclear whether interventions in response to abnormal echocardiograms in asymptomatic individuals impact clinical outcomes [19, 20]. Echocardiography is, however, widely accepted in the evaluation of dyspnea, a commonly reported symptom in adults with SCD [19–21]. Whether increased mortality can be ameliorated with early intervention is unclear, because randomized trials have not been completed. Reflective of this controversy, three recent guideline documents offer conflicting recommendations [19, 20]. The

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ATS guidelines recommend screening all patients 18 years and older, while the National Heart, Lung, and Blood Institute (NHLBI) and more recently published American Society of Hematology (ASH) guidelines for the care of patients with SCD do not. Optimal PH screening tests and frequency of testing have not been determined. Elevated TRV is not associated with mortality among children and adolescents, weakening the argument for screening pediatric age groups [19, 22, 23]. However, the association with progressive exercise limitation in children with higher TRVs suggests that studies may be needed to evaluate screening in children for cardiopulmonary complications with longitudinal follow-up into adulthood to identify higher-risk groups for intervention. It is unknown whether newer modalities such as cardiac MRI could be more informative than echocardiography [24].

 hen Should One Perform a Right Heart Catheterization W in Patients with SCD? While TTE is the noninvasive procedure of choice for detecting PH in high-risk patients, the question of who to refer for an invasive RHC is important for primary care physicians and hematologists to understand. An elevated TRV higher than 2.5  m.s−1 is observed in approximately 30% of adult patients with SCD and this predicts increased mortality risk [4, 5, 25]. However, the high false-positive rate for PH argues against performing a RHC in all patients. Recent long-term outcome data from patients included in the ETENDARD study (Evaluation of the Prevalence of Pulmonary Hypertension in Adult Patients with Sickle Cell Disease) demonstrated that 10-year survival is similar between patients with TRV  40 years old) who often have comorbidities including renal disease, relative systemic h­ ypertension, leg ulcers, and ischemic strokes. This suggests that therapies targeting the hemoglobinopathy may be beneficial in these patients. Hydroxyurea is effective in reducing the number of vaso-occlusive crises, acute chest syndrome (ACS), hospitalizations, transfusions, and improving survival in patients with HbSS disease [37, 38]. The potential benefits for prevention and evolution of the chronic end-organ damage, other than cerebral vasculopathy, are not established. However, as ACS can precipitate acute right-sided congestive heart failure and death in patients with PH of SCD, it makes sense to utilize this medication. The 2014 ATS guidelines gave a strong recommendation for hydroxyurea use in the management of PH due to SCD, but further studies to investigate the potential benefits are likely warranted [19].

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An alternative to hydroxyurea in PH of SCD patients is chronic red blood cell exchange transfusion. This is an interesting therapeutic option which decreases the HbS fraction, optimizes the hemoglobin concentration, and limits the impact of chronic hemolysis on pulmonary endothelial function. This therapeutic approach benefits other complications of SCD, particularly ischemic stroke [38]. A report of two patients with PH of SCD demonstrated a beneficial effect of chronic transfusions but invasive hemodynamic data were lacking [39]. The ATS guidelines suggested consideration of chronic transfusion in the management of precapillary PH in SCD patients who have an increased risk for mortality (i.e., PH confirmed by right heart catheterization) and who are not responsive to or are not candidates for hydroxyurea, but this was admittedly based upon low-quality evidence [19]. More recently, a retrospective study reported the short- and long-term clinical and hemodynamic effects of chronic exchange transfusion in a cohort of 13 SCD patients with precapillary PH, demonstrating improved NYHA functional class and a 25% reduction in PVR in the majority of patients [40]. This is being studied more comprehensively in the recently funded prospective Sickle Cell Disease and CardiovAscular Risk—Red cell Exchange Trial (SCD-CARRE) to be conducted in the United States, the United Kingdom, and France.

 hich Patients with PH of SCD Should Be Treated W with Anticoagulation? SCD is a hypercoagulable state [41], yet our understanding of the role of venous thromboembolism (VTE) in the modulation of PH in SCD remains rudimentary. By the age of 40, 11–12% of SCD patients will have experienced a VTE; in those with severe disease (defined by three or more hospitalizations in the past year), this increased to 17% [28, 29]. Historically, a first time VTE in patients with SCD was treated with 3 to 6 months of anticoagulation in accordance with the American College of Chest Physicians guidelines. More recently, a VTE recurrence rate of 31% (and 36.8% in those with severe disease) [29] has supported a shift in practice toward lifelong anticoagulation after a first VTE [42, 43]. The ATS Clinical Guidelines for Diagnosis and Treatment of PH in SCD addressed the issue of thrombosis as a potential pulmonary vascular modulator in patients with PH of SCD by recommending consideration of lifelong anticoagulation for those with PH and a VTE and no increased bleeding risk (weak recommendation, low-quality evidence) even though this predated our current understanding of the epidemiology of VTE. We advocate for an assessment of chronic VTE in all PH of SCD patients and lifelong anticoagulation for those with either acute or chronic pulmonary embolism.

Do Patients with PH of SCD Respond to PAH Therapy? PH in SCD represents a spectrum of hemodynamic and clinical findings; those with precapillary PH similar to pulmonary arterial hypertension (PAH) are most appropriate to study for efficacy of PAH therapy. The use of FDA-approved PAH

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medications for SCD-PAH is controversial as no randomized trials in SCD have been completed [12, 13]. In SCD-PAH, the strongest support for PAH-targeted therapy comes from seven case series in which 53 patients with SCD and precapillary PH hemodynamics (six with chronic thromboembolic PH) who received targeted PAH therapies had improved 6MWD [44–48]. Improvements in mean PAP, PVR, and cardiac index occurred, but were only assessed in a subset of patient [45]. Three randomized trials of bosentan or sildenafil in SCD were stopped early and were underpowered to address efficacy. Two of the clinical trials, evaluating bosentan for pre- and postcapillary PH (ASSET 1 and 2), were terminated by the sponsor due to under enrollment [13]. The trial of sildenafil for the treatment of PH in SCD enrolled patients on the basis of an elevated TRV and not by right heart catheterization proven PAH [12]. The sildenafil trial was stopped after enrollment of 72 subjects due to an increased rate of hospitalizations, particularly for vaso-occlusive crises in the sildenafil-treated group. PAH therapy may be most appropriate in those with precapillary hemodynamics, similar to group 1 PAH [19]. Despite similarities in hemodynamics, hemoglobinopathy-related complications in these patients emphasize the importance of clinical trials in SCD [49]. In our practice, we utilize PAH therapy solely for those with precapillary PH by hemodynamics and NYHA class II–IV dyspnea. We favor the use of endothelin receptor antagonists and prostacyclins over phosphodiesterase-5 inhibitors and have observed clinical benefits from these agents but advocate for future clinical trials focused on this patient group to better assess the response to therapy.

Conclusion While PH is a common complication of SCD, the diverse hemodynamics and pathophysiology coupled with the lack of understanding of disease natural history has made it difficult to approach clinically. Many important questions relating to PH of SCD remain unanswered, and this chapter combines the published literature with the experience of the authors to try to address them. Patient registries are critical to study the natural history of this disease, and barriers to characterizing PH of SCD include a lack of multicenter prospective studies, inadequate research funding, and inconsistent phenotyping strategies. We advocate for high-quality, multicenter, longitudinal cohort studies and randomized clinical trials designed and implemented by multidisciplinary teams to move this field forward in the next decade.

References 1. Moerdler S, Manwani D. New insights into the pathophysiology and development of novel therapies for sickle cell disease. Hematol Am Soc Hematol Educ Program. 2018;2018(1):493–506. 2. Telen MJ, Malik P, Vercellotti GM. Therapeutic strategies for sickle cell disease: towards a multi-agent approach. Nat Rev Drug Discov. 2019;18(2):139–58. 3. Mehari A, Alam S, Tian X, Cuttica MJ, Barnett CF, Miles G, et al. Hemodynamic predictors of mortality in adults with sickle cell disease. Am J Respir Crit Care Med. 2013;187(8):840–7.

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4. Parent F, Bachir D, Inamo J, Lionnet F, Driss F, Loko G, et al. A hemodynamic study of pulmonary hypertension in sickle cell disease. N Engl J Med. 2011;365(1):44–53. 5. Fonseca GHH, Souza R, Salemi VMC, Jardim CVP, Gualandro SFM. Pulmonary hypertension diagnosed by right heart catheterisation in sickle cell disease. Eur Respir J. 2012;39(1):112–8. 6. Niss O, Quinn CT, Lane A, Daily J, Khoury PR, Bakeer N, et al. Cardiomyopathy with restrictive physiology in sickle cell disease. JACC Cardiovasc Imaging. 2016;9(3):243–52. 7. Savale L, Habibi A, Lionnet F, Maitre B, Cottin V, Jais X, et al. Clinical phenotypes and outcomes of precapillary pulmonary hypertension of sickle cell disease. Eur Respir J. 2019;19. 8. Galiè N, McLaughlin VV, Rubin LJ, Simonneau G. An overview of the 6th World Symposium on Pulmonary Hypertension. Eur Respir J. 2019;53(1). 9. Simonneau G, Galiè N, Rubin LJ, Langleben D, Seeger W, Domenighetti G, et al. Clinical classification of pulmonary hypertension. J Am Coll Cardiol. 2004;43(12 Suppl S):5S–12S. 10. Simonneau G, Robbins IM, Beghetti M, Channick RN, Delcroix M, Denton CP, et  al. Updated clinical classification of pulmonary hypertension. J Am Coll Cardiol. 2009;54(1 Suppl):S43–54. 11. Simonneau G, Gatzoulis MA, Adatia I, Celermajer D, Denton C, Ghofrani A, et  al. Updated clinical classification of pulmonary hypertension. J Am Coll Cardiol. 2013;62(25 Suppl):D34–41. 12. Machado RF, Barst RJ, Yovetich NA, Hassell KL, Kato GJ, Gordeuk VR, et al. Hospitalization for pain in patients with sickle cell disease treated with sildenafil for elevated TRV and low exercise capacity. Blood. 2011;118(4):855–64. 13. Barst RJ, Mubarak KK, Machado RF, Ataga KI, Benza RL, Castro O, et al. Exercise capacity and haemodynamics in patients with sickle cell disease with pulmonary hypertension treated with bosentan: results of the ASSET studies. Br J Haematol. 2010;149(3):426–35. 14. Haque AK, Gokhale S, Rampy BA, Adegboyega P, Duarte A, Saldana MJ. Pulmonary hypertension in sickle cell hemoglobinopathy: a clinicopathologic study of 20 cases. Hum Pathol. 2002;33(10):1037–43. 15. Carstens GR, Paulino BBA, Katayama EH, Amato-Lourenço LF, Fonseca GH, Souza R, et al. Clinical relevance of pulmonary vasculature involvement in sickle cell disease. Br J Haematol. 2019;185(2):317–26. 16. Manci EA, Culberson DE, Yang Y-M, Gardner TM, Powell R, Haynes J, et al. Causes of death in sickle cell disease: an autopsy study. Br J Haematol. 2003;123(2):359–65. 17. Galiè N, Humbert M, Vachiery J-L, Gibbs S, Lang I, Torbicki A, 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): Endorsed by: Association for European Paediatric and Congenital Cardiology (AEPC), International Society for Heart and Lung Transplantation (ISHLT). Eur Heart J. 2016;37(1):67–119. 18. Galiè N, Humbert M, Vachiery J-L, Gibbs S, Lang I, Torbicki A, 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): Endorsed by: Association for European Paediatric and Congenital Cardiology (AEPC), International Society for Heart and Lung Transplantation (ISHLT). Eur Respir J. 2015;46(4):903–75. 19. Klings ES, Machado RF, Barst RJ, Morris CR, Mubarak KK, Gordeuk VR, et  al. An official American Thoracic Society clinical practice guideline: diagnosis, risk stratification, and management of pulmonary hypertension of sickle cell disease. Am J Respir Crit Care Med. 2014;189(6):727–40. 20. Yawn BP, Buchanan GR, Afenyi-Annan AN, Ballas SK, Hassell KL, James AH, et  al. Management of sickle cell disease: summary of the 2014 evidence-based report by expert panel members. JAMA. 2014;312(10):1033–48.

8  Pulmonary Hypertension in Sickle Cell Disease: Current Controversies and Clinical… 133 21. Klings ES, Anton Bland D, Rosenman D, Princeton S, Odhiambo A, Li G, et al. Pulmonary arterial hypertension and left-sided heart disease in sickle cell disease: clinical characteristics and association with soluble adhesion molecule expression. Am J Hematol. 2008;83(7):547–53. 22. Gordeuk VR, Campbell A, Rana S, Nouraie M, Niu X, Minniti CP, et al. Relationship of erythropoietin, fetal hemoglobin, and hydroxyurea treatment to tricuspid regurgitation velocity in children with sickle cell disease. Blood. 2009;114(21):4639–44. 23. Sokunbi OJ, Ekure EN, Temiye EO, Anyanwu R, Okoromah CAN.  Pulmonary hyper tension among 5 to 18 year old children with sickle cell anaemia in Nigeria. PLoS One. 2017;12(9):e0184287. 24. Nguyen K-L, Tian X, Alam S, Mehari A, Leung SW, Seamon C, et al. Elevated transpulmonary gradient and cardiac magnetic resonance-derived right ventricular remodeling predict poor outcomes in sickle cell disease. Haematologica. 2016;101(2):e40–3. 25. Gladwin MT, Sachdev V, Jison ML, Shizukuda Y, Plehn JF, Minter K, et  al. Pulmonary hypertension as a risk factor for death in patients with sickle cell disease. N Engl J Med. 2004;350(9):886–95. 26. Kovacs G, Berghold A, Scheidl S, Olschewski H. Pulmonary arterial pressure during rest and exercise in healthy subjects: a systematic review. Eur Respir J. 2009;34(4):888–94. 27. Simonneau G, Montani D, Celermajer DS, Denton CP, Gatzoulis MA, Krowka M, et  al. Haemodynamic definitions and updated clinical classification of pulmonary hypertension. Eur Respir J. 2018. 28. Naik RP, Streiff MB, Haywood C, Segal JB, Lanzkron S. Venous thromboembolism incidence in the cooperative study of sickle cell disease. J Thromb Haemost JTH. 2014;12(12):2010–6. 29. Brunson A, Lei A, Rosenberg AS, White RH, Keegan T, Wun T. Increased incidence of VTE in sickle cell disease patients: risk factors, recurrence and impact on mortality. Br J Haematol. 2017;178(2):319–26. 30. Brunson A, Keegan T, Mahajan A, White R, Wun T. High incidence of venous thromboembolism recurrence in patients with sickle cell disease. Am J Hematol. 2019;94(8):862–70. 31. Kim NH, Delcroix M, Jais X, Madani MM, Matsubara H, Mayer E, et al. Chronic thromboembolic pulmonary hypertension. Eur Respir J. 2018. 32. Mahesh B, Besser M, Ravaglioli A, Pepke-Zaba J, Martinez G, Klein A, et al. Pulmonary endarterectomy is effective and safe in patients with haemoglobinopathies and abnormal red blood cells: the Papworth experience. Eur J Cardio-Thorac Surg Off J Eur Assoc Cardio-Thorac Surg. 2016;50(3):537–41. 33. Freeman AT, Ataga KI. Pulmonary endarterectomy as treatment for chronic thromboembolic pulmonary hypertension in sickle cell disease. Am J Hematol. 2015;90(12):E223–4. 34. Marques MB, Wille KM, Ren Z, Sheth M, McGiffin DC. Successful pulmonary thromboendarterectomy in a patient with sickle cell disease treated with a single preoperative red blood cell exchange. Transfusion (Paris). 2014;54(7):1901–2. 35. Whitesell PL, Owoyemi O, Oneal P, Nouraie M, Klings ES, Rock A, et al. Sleep-disordered breathing and nocturnal hypoxemia in young adults with sickle cell disease. Sleep Med. 2016;22:47–9. 36. Worsham CM, Martin ST, Nouraie S-M, Cohen RT, Klings ES.  Clinical and laboratory findings associated with sleep disordered breathing in sickle cell disease. Am J Hematol. 2017;92(12):E649–51. 37. Charache S, Terrin ML, Moore RD, Dover GJ, Barton FB, Eckert SV, et al. Effect of hydroxyurea on the frequency of painful crises in sickle cell anemia. Investigators of the multicenter study of hydroxyurea in sickle cell Anemia. N Engl J Med. 1995;332(20):1317–22. 38. Voskaridou E, Christoulas D, Bilalis A, Plata E, Varvagiannis K, Stamatopoulos G, et  al. The effect of prolonged administration of hydroxyurea on morbidity and mortality in adult patients with sickle cell syndromes: results of a 17-year, single-center trial (LaSHS). Blood. 2010;115(12):2354–63.

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39. Tsitsikas DA, Seligman H, Sirigireddy B, Odeh L, Nzouakou R, Amos RJ. Regular automated red cell exchange transfusion in the management of pulmonary hypertension in sickle cell disease. Br J Haematol. 2014;167(5):707–10. 40. Turpin M, Chantalat-Auger C, Parent F, Driss F, Lionnet F, Habibi A, et al. Chronic blood exchange transfusions in the management of pre-capillary pulmonary hypertension complicating sickle cell disease. Eur Respir J. 2018;52(4). 41. Ataga KI, Moore CG, Hillery CA, Jones S, Whinna HC, Strayhorn D, et  al. Coagulation activation and inflammation in sickle cell disease-associated pulmonary hypertension. Haematologica. 2008;93(1):20–6. 42. Shet AS, Wun T. How I diagnose and treat venous thromboembolism in sickle cell disease. Blood. 2018;132(17):1761–9. 43. Liem RI, Lanzkron SD, Coates T, Decastro L, Desai AA, Ataga KI, et al. American Society of Hematology 2019 guidelines for sickle cell disease: cardiopulmonary and kidney disease. Blood Adv. 2019;3(23):3867–97. 44. Derchi G, Forni GL, Formisano F, Cappellini MD, Galanello R, D’Ascola G, et al. Efficacy and safety of sildenafil in the treatment of severe pulmonary hypertension in patients with hemoglobinopathies. Haematologica. 2005;90(4):452–8. 45. Minniti CP, Machado RF, Coles WA, Sachdev V, Gladwin MT, Kato GJ. Endothelin receptor antagonists for pulmonary hypertension in adult patients with sickle cell disease. Br J Haematol. 2009;147(5):737–43. 46. Weir NA, Conrey A, Lewis D, Mehari A. Riociguat use in sickle cell related chronic thromboembolic pulmonary hypertension: a case series. Pulm Circ. 2018;8(4):2045894018791802. 47. Weir NA, Saiyed R, Alam S, Conrey A, Desai HD, George MP, et  al. Prostacyclin-analog therapy in sickle cell pulmonary hypertension. Haematologica. 2017;102(5):e163–5. 48. Machado RF, Martyr S, Kato GJ, Barst RJ, Anthi A, Robinson MR, et  al. Sildenafil therapy in patients with sickle cell disease and pulmonary hypertension. Br J Haematol. 2005;130(3):445–53. 49. Weatherald J, Savale L, Humbert M. Medical Management of Pulmonary Hypertension with unclear and/or multifactorial mechanisms (group 5): is there a role for pulmonary arterial hypertension medications? Curr Hypertens Rep. 2017;19(11):86.

Chapter 9

Sarcoidosis-Associated Pulmonary Hypertension H. James Ford, Ahmed Sesay, Elizabeth Sonntag, and Sheila Krishnan

Introduction Sarcoidosis is an idiopathic systemic inflammatory disease characterized by the presence of epithelioid cells and noncaseating granulomas. Generally, it is more likely to affect young adults, especially African American women and individuals of Scandinavian descent [1]. The current estimated incidence of this disease within the United States is 10–40 per 100,000, with a higher incidence and prevalence in African American women compared to Caucasian women [1]. Despite vast knowledge about mechanisms of disease, the etiology is still unclear. Various etiologic theories have been researched and proposed, ranging from microorganisms to environmental factors such as pine tree pollen, but none have been proven definitively. A current favored hypothesis is that it is a complex mix between environmental, infectious, and genetic factors, the contribution from which each of these may vary from one individual to another. Sarcoidosis can affect all organ systems, but the pulmonary and lymphatic systems are the most commonly affected. The incidence of lung involvement in sarcoidosis patients is greater than 90% with significant variation in clinical presentation, radiographic findings, and pulmonary function compromise [1, 2]. Within the lungs, sarcoidosis can affect the large and small airways, lymph nodes, lung parenchyma, pleural space, and pulmonary arteries and veins. Historically, the Scadding criteria (Fig. 9.1), which rely on chest radiograph findings, have been used to stage patients. The stages range from 0 to IV. Patients with stage 0 have a normal lung architecture. Those with stage I disease have bilateral hilar lymphadenopathy. Stage II patients have bilateral hilar lymphadenopathy with parenchymal

H. J. Ford (*) · A. Sesay · E. Sonntag · S. Krishnan Division of Pulmonary and Critical Care Medicine, Department of Medicine, Pulmonary Hypertension Program, University of North Carolina at Chapel Hill, Chapel Hill, NC, USA e-mail: [email protected] © Springer Nature Switzerland AG 2020 H. J. Ford et al. (eds.), Pulmonary Hypertension, Respiratory Medicine, https://doi.org/10.1007/978-3-030-52787-7_9

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Stage I

Stage III

Stage II

Stage IV

Fig. 9.1  The Scadding stages of sarcoidosis. Stage 0: no evidence of disease on thoracic imaging. (Images for stages I, II, and IV are reprinted with permission from [38]. Farver 2008. Image for stage III is reprinted from the open-access chapter [39]. Shulimzon and Koslow (2011)). Stage I: hilar or mediastinal nodal enlargement only. Stage II: nodal enlargement and parenchymal disease. Stage III: parenchymal disease only. Stage IV: end-stage lung (pulmonary fibrosis)

involvement. Stage III patients have only parenchymal infiltration without hilar adenopathy. Stage IV patients have fibrocystic disease and distortion of lung architecture [1]. While the Scadding criteria provide general information on prognosis, it does not correlate well with an individual patient’s clinical state. As a result, the Scadding criteria are generally not used in assessment or treatment decisions. Sarcoidosis-associated pulmonary hypertension (SAPH) was initially thought of as an uncommon complication of radiographically advanced sarcoidosis with prevalence estimated at 1–5% [1]. Presently, the prevalence of SAPH is estimated to range between 5.7% and 74% with the highest prevalence seen in patients referred for lung transplant evaluation due to advanced disease [2, 3]. SAPH is associated with significant mortality and morbidity, with an estimated 5-year survival reported at 50–60% [2–4]. Moreover, sarcoidosis patients with pulmonary hypertension tend to have a greater need for supplemental oxygen, reduced exercise capacity, and greater caregiver dependence. They are also more likely to be listed for lung transplantation and are more likely to die while waiting for lung transplant. Patients with radiographically advanced sarcoidosis (stages III and IV) are more likely to develop pulmonary hypertension [2, 3, 5]. Nevertheless, SAPH can also present in patients with normal lung parenchyma and pulmonary function. In a prospective, observational study of 246 Japanese patients by Handa and colleagues, the incidence of SAPH by echocardiographic criteria was 5.7%. Among these patients, 42% had a Scadding classification of stage 0 or I disease [6]. Therefore, pulmonary hypertension should be considered in all sarcoidosis patients despite their Scadding classification. There should be a higher pretest probability for sarcoidosis patients with decreased force vital capacity (FVC) or total lung capacity (TLC), ambulatory oxygen desaturation, and disproportionate decrease in diffusion capacity.

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Pathophysiology According to the 6th World Symposium on Pulmonary Hypertension, SAPH is classified as World Health Organization (WHO) group 5 [3]. Its classification in this group reflects its complex and multifaceted pathophysiology. Arguably, sarcoidosis patients with pulmonary hypertension can present with elements from all five WHO groups. WHO group 1 patients include idiopathic pulmonary arterial disease and other forms of pulmonary arterial hypertension, while groups 2, 3, and 4 are driven by increased LV filling pressures, structural and hypoxic lung disorders, and chronic thromboembolic disease, respectively. Patients with unclear and/or multiple mechanisms of PH are relegated to WHO group 5 [7]. There are various proposed mechanisms of action by which sarcoidosis may induce pulmonary hypertension. This includes hypoxic vasoconstriction and destruction of capillary bed, cytokine derangements, extrinsic compression of the pulmonary vasculature by lymph nodes and mediastinal fibrosis, granulomatous infiltration of pulmonary vessels, left ventricular dysfunction, portopulmonary hypertension, and pulmonary veno-occlusive disease [2, 3, 5, 8]. 1. Hypoxic Vasoconstriction and Destruction of Capillary Bed SAPH is more common in patients with Scadding stage IV disease. The hallmark of this stage is fibrosis, lung parenchymal remodeling, and destruction of capillary bed. The subsequent hypoxemia is typically thought to play a vital role in causing pulmonary hypertension. Pulmonary hypertension (PH) from hypoxemia is governed by vasoconstriction, vascular remodeling, proliferation of vascular smooth muscle cells, increased extracellular matrix deposition, and endothelial dysfunction [2, 3, 8, 9]. Fibrosis in the absence of hypoxemia is also implicated in causing PH due to the associated vessel tortuosity, turbulent flow, and shear stresses on pulmonary vasculature [8]. Moreover, fibrosis in the proximity of the pulmonary vasculature can also exacerbate the effect of PH by decreasing vascular capacitance. A low vascular capacitance has been linked to poorer outcomes in patients with PAH [8, 10]. Nevertheless, given the often observed incongruence between PH severity and lung parenchymal disease, other mechanisms have been suggested to play a primary or contributory role in causing SAPH. 2. Cytokine Derangement Endothelin-1 (ET-1) is an isopeptide whose transcription is upregulated and released by endothelial cells, smooth muscle cells, and airway epithelial cells in response to hypoxia and mechanical force on the vasculature [2, 11]. ET-1 is a potent vasoconstrictor of pulmonary arteries and veins. It also has mitogenic effects on vascular smooth muscle cells and stimulates matrix production by the vessel wall. Increased expression of ET-1 is well correlated with increase in pulmonary vascular resistance (PVR) and the severity of structural abnormalities in the pulmonary arteries [11]. In a study conducted by Terashita et al., bronchoalveolar lavage fluid from 22 nonsmoking sarcoidosis patients showed significant elevation in ET-1 levels compared to control subjects [12].

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Another cytokine implicated in causing PH in sarcoidosis patients is tumor necrosis factor alpha (TNF-α). TNF-α is known to play a significant role in the pathophysiology of sarcoidosis and functions in regulating the bone morphogenetic protein (BMP) signaling pathway, leading to the proliferation of pulmonary artery smooth muscle cells [2, 3, 5]. 3. Extrinsic Compression Another cause of PH in patients with sarcoidosis is extrinsic compression of the large pulmonary vessels. Extrinsic compression may arise secondary to enlarged mediastinal/hilar lymph nodes or as a result of interstitial or mediastinal fibrosis. In a retrospective series by Nunes and colleagues of 22 patients with sarcoidosis, approximately 21% of the patients with PH had evidence of extrinsic compression [2, 3, 13]. 4 . Intrinsic Vascular Disease Pulmonary vascular invasion by granulomas is common in sarcoidosis because of the peribronchovascular distribution of pulmonary disease, and this is a major cause of SAPH.  Presently, vascular infiltration is estimated at 69 to 100% with a large proportion occurring in the veins/venules [2, 3, 5]. When this invasion occurs, it may cause necrosis and destruction of vessels as well as endothelial proliferation and disruption of the basal lamina [10]. The end result is an occlusive vasculopathy in small arterioles and venules. When this process is localized to the veins, it can lead to pulmonary veno-occlusive disease (PVOD) [2, 3]. Overall, the end result of these processes can vary in terms of how they ultimately manifest from a histopathologic standpoint and how they impact clinical presentation. Figure 9.2 summarizes and provides representative images of the different vascular manifestations of pulmonary vasculopathy in sarcoidosis. 5. Miscellaneous Portopulmonary hypertension has been noted in sarcoidosis patients with granulomatous hepatic invasion and cirrhosis. PH in this patient is partly due to the hyperdynamic circulatory state of cirrhosis leading to mechanical stress on pulmonary vasculature and remodeling [2, 5, 13]. SAPH can also be caused by left ventricular dysfunction, which in turn causes passive retrograde pressure elevation within the pulmonary circulation (akin to group 2 PH). This was highlighted by Baughman and colleagues in a study that evaluated 130 sarcoidosis patients with dyspnea refractory to immunosuppressive therapy that underwent right heart catheterization. In that study 29% of subjects had elevated pulmonary capillary wedge pressures [4].

Diagnosis Prevalence The presence and severity of sarcoidosis-associated pulmonary hypertension (SAPH) varies depending on the main drivers of the pulmonary hypertension (which can also be variable as noted above) and the degree of parenchymal lung disease.

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(b)

A.Pulmonary arterial granuloma

B. Venous fibrosis/obliteration

(c)

(d)

C and D. Non-granulomatous arteriopathy Fig. 9.2  Various types of pulmonary vascular lesions observed in sarcoidosis-associated pulmonary hypertension. Panel a is representative of granulomatous vascular disease. Panel b shows venous fibrosis, much like seen in pulmonary venooclusive disease. Panels c and d demonstrate non-granulomatous pulmonary arteriopathy, like that seen in traditional group 1 pulmonary arterial hypertension. (a and b are reprinted with permission from [40]. Rosen 1994. c and d are reprinted with permission from [41]. Pietra 2004)

Older studies have reported a frequency of PH in sarcoidosis patients between 4% and 28% [14, 15], but more recent studies have reported much higher prevalence between 40% and 50% [6, 16]. This number increases further when looking at patients awaiting lung transplantation. In a study evaluating sarcoidosis patients who were listed for lung transplantation, Arcasoy and colleagues determined that almost 74% of them had PH, the majority of these having advanced parenchymal lung disease [3]. Many studies have reported that SAPH is most commonly associated with advanced radiographic stages of sarcoidosis [3, 16, 17]. Therefore, clinical suspicion of PH in these patients is challenging as dyspnea may be a result of parenchymal lung destruction yet is also the most common symptom of pulmonary vascular involvement. Sarcoidosis patients with pulmonary fibrosis, bulky lymphadenopathy, and mediastinal fibrosis may be at higher risk of PH [18]. Regardless of the

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extent of parenchymal lung involvement or other radiographic findings, PH should be suspected, and diagnostic workup should be pursued, in any patient with sarcoidosis who presents with concerning history and physical exam findings.

History and Physical Exam The most common reported symptoms of SAPH are dyspnea on exertion, chest pain, and cough [16]. Most patients present with functional class III or IV symptoms [17]. Physical examination findings are similar to those found in other etiologies of PH. Patients may exhibit a loud P2 heart sound, lower extremity edema, and jugular venous distension. Other signs of right heart failure, including a right ventricular heave, are unusual and typically seen only with severe cases.

Pulmonary Function Testing Of all pulmonary function testing parameters, a reduced diffusion capacity for carbon monoxide (DLCO) correlates the most with pulmonary vascular involvement in SAPH patients [19]. Spirometry and lung volume testing is useful to assess the relative physiologic severity of parenchymal lung disease compared to the severity of pulmonary hypertension.

Serum Biomarkers N-terminal pro-brain natriuretic peptide (NT-pro-BNP) is the only biomarker that is helpful for predicting PH in patients with parenchymal lung disease, as it is elevated in response to right heart volume and pressure overload seen with pulmonary vascular disease. Other biomarkers of sarcoidosis such as angiotensin-converting enzyme level, serum calcium, or lymphocyte counts are not known to correlate with SAPH presence or severity.

Six-Minute Walk Test Heart rate recovery is calculated by the difference in heart rate at the end of the 6-minute walk test and after 1-minute recovery and has been found to be associated with underlying PH in patients with idiopathic pulmonary fibrosis. This may be a helpful tool in evaluating patients with stage IV sarcoid who might have associated PH.

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Echocardiography Echocardiography remains the screening tool of choice for evaluating patients with suspected PH. Helpful measurements include estimated right ventricular systolic pressure, tricuspid regurgitant jet velocity, tricuspid annular plane systolic excursion (TAPSE), and right ventricular size and systolic function. It is also useful for evaluating for left-sided heart disease, including assessment of diastolic dysfunction and left atrial size. Clinicians must keep in mind that it is not a perfect test for confirming or disproving PH and it can be inaccurate in patients with advanced lung disease due to poor ultrasonographic windows. If clinical suspicion for PH is high and echocardiography does not show evidence of PH, right heart catheterization should still be pursued.

Right Heart Catheterization SAPH is confirmed when right heart catheterization is performed and reveals a mean pulmonary arterial pressure (mPAP) greater than or equal to 25 mmHg (previous definition–now greater than or equal to 20 mmHg based on the new 6th World Symposium definition) with a pulmonary artery occlusion pressure (PAOP) less than 15  mmHg and a pulmonary vascular resistance (PVR) greater than 3 Wood units. Given that sarcoidosis patients are also at risk for pulmonary venous hypertension from left-sided heart disease, a fluid challenge during catheterization may be helpful to determine the existence of diastolic dysfunction, particularly if the PAOP is in the upper limits of normal at baseline.

Treatment There is no FDA-approved treatment for management of SAPH.  Like all other forms of non-group 1 PH, management is primarily aimed at control of the underlying disease process. In the case of sarcoidosis, immunosuppressant therapy targeting inflammatory alveolitis (depending on the stage of disease) and supplemental oxygen when needed to eliminate hypoxic pulmonary vasoconstriction are imperative. These interventions should ideally be instituted before performing an invasive assessment of pulmonary hemodynamics. The decision of whether to further escalate immunosuppressive therapy at the time of diagnosis of PH in these patients or to solely add vasodilator therapy is challenging. It is unclear from the limited existing literature whether or not additional anti-inflammatory or immunosuppressive therapy improves pulmonary hypertension. In Boucly’s analysis of SAPH patients from the French Pulmonary Hypertension Registry, 11 SAPH patients were treated with anti-inflammatory therapy alone. Only four of these patients had improvement in their hemodynamics at follow-up [20].

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There have been studies evaluating the use of pulmonary arterial hypertension-­ specific therapy in patients with SAPH; however, the results are mixed. Table 9.1 is adapted from a recent paper by Shlobin and colleagues [21] and summarizes the existing studies and treatment results in SAPH. The multifactorial nature of SAPH Table 9.1  Existing published studies evaluating treatment of sarcoid-associated pulmonary hypertension Publication Preston et al., 2001 [26]

Study design (number of subjects) Prospective observational (8)

Culver et al., 2005 [27] Fisher et al., 2006 [28] Milman et al., 2008 [29]

Retrospective chart review (7) Retrospective case series (7) Retrospective chart review (12)

Barnett et al., 2009 [30]

Retrospective case series (22)

Prospective open Baughman et al., 2009 [31] label 16 weeks (15) Baughman et al., 2010 [4] Judson et al., 2011 [32]

Retrospective chart review (5) Prospective open label 12 weeks (25)

Dobarro et al., 2013 [33]

Retrospective chart review (8)

Baughman Prospective et al., 2014 [34] placebo-controlled 16 weeks (35) Keir et al., 2014 Retrospective (33) [35] Bonham et al., 2015 [36]

Retrospective case series (26)

Ford et al., 2016 Prospective open [37] label 24 weeks (12)

Treatment (# of patients) Inh NO (5), inh NO with IV epo (1), CCB (2) Bosentan (3), bosentan and IV epo (4) IV epo (6), subcut trep (1) Sildenafil (12)

Outcome Short-term 20% decreased PVR and mPAP; long-term increased 6MWT Decreased mPAP at 6–18 mo in about 50% patients Improved functional class

Decreased mPAP and PVR, increased CO, no change 6MWT IV epo (1), bosentan Increased 6MWT and (12), sildenafil (9) functional class, decreased mPAP and PVR Inh iloprost (15) Decreased mPAP and PVR in 6–15 and increased 6MWT in 3–15 patients Bosentan (5) Decreased mPAP in three to five patients at 4 mo Ambrisentan (21) No change 6MWT; 11 patients discontinued drug at 12 weeks Sildenafil (9), bosentan Increased 6MWT and decreased NT-pro-BNP; (2); only eight nonstatistically significant followed up with increase in CO/CI and repeat RHC decreased PVR Bosentan (23), placebo Decreased mPAP and PVR; (12) no change in 6MWT Sildenafil (29), bosentan (3)

Increased 6MWT, decreased NT-pro-BNP, improved TAPSE Parenteral prostacyclin Increased CI/CO, decreased PVR, improved functional with epo (7) and trep class, decreased NT-pro-BNP (6), ERAs (12), PDE5-I (20), CCB (1) Tadalafil (12) No change 6MWT at 24 weeks

Inh inhaled, NO nitric oxide, IV intravenous, epo epoprostenol, CCB calcium channel blocker, mPAP mean pulmonary arterial pressure, PVR pulmonary vascular resistance, 6MWT 6-minute walk test, CO cardiac output, CI cardiac index, mo months, NT-pro-BNP N-terminal pro-brain natriuretic peptide, TAPSE tricuspid annular plane systolic excursion

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has made it very difficult to identify any signal of efficacy from PAH therapies in general. Isolated, intrinsic pulmonary vasculopathy may be seen in some SAPH patients. However, the majority of SAPH patients have left heart dysfunction (WHO group 2 PH) and/or restrictive lung disease related to parenchymal fibrosis (WHO group 3 PH). Most trials of PAH therapy for SAPH have had small sample sizes and were not placebo-controlled. Furthermore, many have been retrospective and/or observational studies. Overall, the body of literature looking at PAH therapies to treat SAPH has not shown benefit in traditional PAH trial endpoints. One exception to this is a study by Baughman et al. looking at the efficacy of bosentan for SAPH in a 16-week, double-blind, placebo-controlled trial [16]. In this study, no difference was observed in distance during the 6-minute walk test, but significant improvements were seen in mean PAP and PVR at week 16.

Outcomes There are limited studies evaluating prognosis in SAPH patients, but overall, they demonstrate that similar to other diseases, once sarcoidosis patients develop pulmonary hypertension, they have increased morbidity and mortality. There are a few notable studies that report hemodynamic data of SAPH patients and their long-term outcomes. Patients with pulmonary hypertension without left heart dysfunction seem to represent a distinct phenotype of patients for whom the prognosis is most grim. Baughman and colleagues stratified patients into three groups based on right heart catheterization findings: those without PH (mPAP 25, PAOP 25, PAOP >15). They found that patients with PH without LVD had the worst outcomes. When compared to sarcoid patients without PH, patients with PH without LVD had a hazard ratio for death of 10.36, and when compared to sarcoid patients with PH due to LVD, patients with PH without LVD had a hazard ratio for dying of 3.14 [4]. Boucly et al. compiled the treatment results of 126 severe SAPH patients from the French Pulmonary Hypertension Registry and found that despite treatment with pulmonary arterial hypertension-specific therapy and an improvement in hemodynamics, these patients did not have a functional class improvement or an improvement in their 6-minute walk test [20]. Overall survival rates were 93%, 74%, and 55% at 1, 3, and 5 years, respectively. The median survival time was 6.8 years. In addition, external pulmonary vascular compression by mediastinal lymph nodes can result in SAPH. Boucly et al. showed that patients with increased uptake of 18F-FDG on PET scan showed improved hemodynamics with immunosuppressive therapy alone [20]. If the pulmonary vascular compression was secondary to fibrosing mediastinitis, this was not the case. Furthermore, case studies have shown improvement of SAPH in patients with lymphadenopathy and mediastinal fibrosis after balloon angioplasty, pulmonary artery or vein angioplasty, or stenting [22–24]. PH secondary to active inflammation of mediastinal lymph nodes leading to pulmonary vascular compression may be reversible with

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Chest HRCT+V/Q lung scan ±pulmonary angiogram

Pulmonary hypertension by vascular compression?

Yes

mPAP >24 mmHg or 25-35 mmHg –1 –2 with CI 20 mm Hg during right heart catheterization (RHC) [2]. Systolic pulmonary artery pressure can be estimated noninvasively by echocardiography using the modified Bernoulli equation: RVSP = 4 × TR2 + RAP where RVSP is right ventricular systolic pressure, TR is tricuspid valve regurgitant jet velocity, and RAP is estimated right atrial pressure. Although echocardiography is widely available and used as a screening method, it has limitations. The gold standard test for diagnosis, quantification, and classification of PH is right heart catheterization, RHC (as reviewed in Chap. 4), and the data obtained helps characterize PH into either precapillary PH, postcapillary PH, or combined post- and precapillary PH [2]. The World Health Organization (WHO) classification of PH categorizes PH into groups which share similar pathological and hemodynamic characteristics. Group I PH (pulmonary arterial hypertension (PAH)) includes disorders with proliferative

V. Maddipati (*) Brody School of Medicine, East Carolina University, Greenville, NC, USA e-mail: [email protected] M. Chakinala Washington University School of Medicine, WUSM & BJH Pulmonary HTN Care Center, St. Louis, MO, USA e-mail: [email protected] © Springer Nature Switzerland AG 2020 H. J. Ford et al. (eds.), Pulmonary Hypertension, Respiratory Medicine, https://doi.org/10.1007/978-3-030-52787-7_11

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Table 11.1  CKD stages based on the KIDGO 2012 recommendations for glomerular filtration rate and albuminuria level GFR category 1 2 3a 3b 4 5 Albuminuria category A1 A1 A3

GFR ml/min/1.73 m2 ≥90 60–89 45–59 30–44 15–29 3 months, with implications for health. CKD is classified based on cause, GFR (glomerular filtration rate), and albuminuria stage (Table 11.1) [3]. End-stage renal disease (ESRD) is renal failure with need for a regular course of long-term dialysis or a kidney transplant to maintain life.

 pidemiology of Pulmonary Hypertension in CKD E and ESRD Populations Prevalence  Since its early recognition three decades ago, there have been several echocardiogram-based studies looking at the prevalence of PH in the renal disease population. However, the true epidemiology of PH in CKD and ESRD population is unknown as most of these studies are limited by retrospective nature, referral bias,

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small samples, varying definitions of PH, and most importantly lack of invasive hemodynamic measurement to confirm presence and measure severity of PH.  A recent meta-analysis by Shang et al. looked at the prevalence of PH in CKD without hemodialysis [4]. Although limited by presence of heterogeneity, the overall prevalence of PH was a staggering 32%. Prevalence of PH in different stages of CKD was stage 1 (10%), 2 (13%), 3 (28%), 4 (30%), and stage 5 (30%). Similarly Tang et al. report another meta-analysis with an overall prevalence of 21–27% in CKD patients [5]. There is higher prevalence of PH in dialysis patients especially as age and duration on dialysis increase. Several studies estimate the prevalence of PH between 19% and 56% [6–15] and have been summarized in a meta-analysis by Tang et al. [5], again limited by lack of hemodynamic data and varying threshold of PASP to define PH. In patients undergoing peritoneal dialysis the epidemiologic data is further limited, but the reported prevalence of PH in patients on PD is 12–58% [9, 11, 16–20]. There may be higher rates of PH in patients on continuous cycling PD when compared to those of continuous ambulatory PD [18]. One has to be cautious when comparing the prevalence of PH in patients undergoing HD vs. PD as they are both different subsets of ESRD differing in age and other comorbidities as well as the intervention itself. O’Leary et al. reported findings from retrospective study looking at presence of pulmonary hypertension in patients with CKD who underwent RHC [21]. Although the high prevalence could be explained by referral bias (i.e., sicker patients or patients suspected of PH were referred to RHC) it is a pivotal study that sheds light on the nature of PH in CKD-ESRD patients. Postcapillary PH was the predominant phenotype (76%) vs. precapillary PH (24%). Remarkably, 58% of the CKD patients with precapillary PH had no other established risk factors for pulmonary hypertension, qualifying for “unexplained PH” [21]. Incidence  In a study by Yigla et al. that screened a cohort of ESRD with echocardiography before starting HD, 13% had PH before starting HD, while 18% developed PH after starting HD, mostly within 1 year [22]. In an echocardiogram-based study from China, where 180 patients on maintenance PD were followed prospectively for 3 years or until PH developed, the incidence of pulmonary hypertension was 33% [16]. Extrapolating from these two limited experiences, PH can manifest soon after initiating dialysis and the risk appears to continue overtime.

Clinical Significance of PHTN and Kidney Disease Together CKD and ESRD are associated with increased mortality, morbidity, and healthcare costs when compared with the general population. Over a 5-year period, the 1-, 3-, and 5-year survival rates of patients with and without PH are 78.6%, 42.9%, 25.2% vs. 96.5%, 78.8%, and 66.4%, respectively [13]. Similarly, in a large study with 4-year follow-up by Navaneethan et al., the presence of PH was independently associated with a 38% increased risk for all-cause mortality [23]. CKD and PH individually have a nearly identical impact on mortality and when both CKD and PH coexist, the mortality is higher (Fig.  11.1) [21]. Interestingly there is no difference in

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Fig. 11.1  Survival according to CKD and PH status. (a) Kaplan–Meyer curves of unadjusted mortality in years based on the presence or absence of PH and any degree of CKD. The number at risk is displayed beneath the curves. (b) Kaplan–Meyer curves of unadjusted mortality in years among PH patients based on the presence or absence of CKD III or CKD IV/V. The number at risk is displayed beneath the curves. Adjusted HRs and 95% CIs for CKD stages III–V are shown in the box. (Reproduced from O’Leary et al. [21])

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mortality between pre- and postcapillary PH patients within a given CKD stage [21]. In a large meta-analysis, presence of PH in patient with renal failure was associated with increased all-cause mortality as well as increased cardiovascular mortality [5]. Presence of PH in patients having concomitant CKD and heart failure is associated with an increased all-cause mortality and cardiovascular events (HR of 3.1) [24]. In spite of these associations, a causal link between PH and mortality cannot be established as PH could represent a marker of more significant cardiac, pulmonary, and/or vascular pathology. CKD is by itself associated with decreased quality of life [25] and presence of PH can have detrimental effects. In the Jackson Heart study, presence of PH is associated with increased risk of hospitalization due to heart failure 27% with PH vs. 10% without PH [26]. Even more importantly, acute worsening of renal function in hospitalized patients with PH and right sided heart failure predicts an increased morbidity and mortality (OR of 13.3) [27]. When eGFR was examined as a continuous measure, a 5  ml/min/1.73  m2 lower eGFR was associated with a 5% higher hazard for death [28]. Presence of PH has practical implications in the care of these patients as well. As PH advances, patients become less tolerant to fluid shifts and hence interfering with effective dialysis. As heart failure ensues they might transition from having h­ ypertension to hypotension. Development of pericardial effusion also might also limit the degree of fluid removal during dialysis. Similarly presence of PH has significant impact on allograft function and posttransplant outcomes (see treatment considerations).

Etiology of Pulmonary HTN in CKD and ESRD PH in the context of CKD-ESRD is a very complex entity. From a descriptive and practical standpoint we will approach this section in following categories. First, we will review the “explained PH,” that is, PH explainable or attributable to WHO groups I–IV that are commonly encountered in CKD and ESRD. We will then delve into the more unique aspects that might be contributing to the group V PH: CKD-­ ESRD-­PH (“unexplained PH”).

 ) Comorbidities Connecting PH and CKD-ESRD A (“Explained PH”) Patients with PAH (WHO group I) may have a significant coexisting CKD, which could be further compounded by episodes of AKI, especially during bouts of decompensated right-sided heart failure. Patients with connective tissue diseases, liver disease, and HIV that cause associated PAH can also have kidney disease either concomitantly or because of the underlying disease or treatments. Impaired

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renal function can develop in approximately 50% of patients with systemic lupus erythematosus and in up to 5% patients with systemic sclerosis scleroderma renal crisis may develop [29, 30]. As referred to above, in the section on “Introduction, Definitions, and Terminology,” if no other factors or comorbidities are present, these patients should be treated as WHO group I PH/PAH. WHO group II PH is the most prevalent subgroup of PH in general and the same is true in patients with renal failure and PH whence they are described as cardiorenal syndromes. In the study by O’Leary et al., majority (two-thirds) of the PH is postcapillary or WHO group II disease [21]. This is partly explained by the high prevalence of hypertension, left ventricular hypertrophy, impaired diastolic function, impaired systolic function, functional mitral regurgitation, and pulmonary venous congestion which usually worsen during exercise [31–33]. In patients with advanced kidney disease, presence of volume overload and higher cardiac output because of a fistula and or anemia also become significant contributors [34]. Although initially it is merely a passive transmission of pressure, prolonged backward pressure from the left atrium to the pulmonary vasculature can cause remodeling of the right heart [31]. In the PEPPER study investigating unexplained dyspnea in CKD-ESRD patients, postcapillary PH was still the most common form in ESRD patients, but precapillary PH was unmasked in some patients only by RHC after dialysis [35]. Systolic LV and RV function, as reflected by LV longitudinal strain and RV free wall strain, is worse in HFpEF patients with concomitant CKD and predicts worse outcomes [36]. Another large study reported higher mortality in cardiorenal syndrome type IV (chronic kidney disease causing heart failure) compared with the rest of the cardiorenal syndromes [37]. WHO group III PH (due to lung disease) is very common subgroup of PH in the general population with COPD, OSA, and hypoxia being important contributors. Smoking is an important risk factor for both COPD [38] and kidney disease [7, 39]. There is high prevalence of CKD in patients with COPD [40, 41] and higher prevalence of lung disease in patients with CKD [42]. Similarly, sleep apnea is very common in renal disease and the prevalence is between 50% and 60%, about ten times higher than general population [43]. Hypoxemia is a common occurrence in lung diseases and could potentially explain the endothelial damage, proteinuria, and progression of kidney disease [44] and is also a cause of PH [45]. In general PH associated with lung disease is mild and presence of severe PH should prompt search for other etiology. Finally, venous thromboembolism (VTE) can lead to chronic thromboembolic PH (group IV PH) in CKD-ESRD patients, including contribution to increased mortality [32, 33, 46]. Having AV access fistula/graft intervened upon frequently or long-standing central venous catheters are risk factors for VTE.

B) Possible Causes of the “Unexplained” PH Several pathophysiologic mechanisms may adversely affect the pulmonary circulation and impair its adaptive mechanisms in renal failure, thus causing an increase in pulmonary vascular resistance (PVR). These are either (i) studied in CKD-ESRD

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patients who have PH or (ii) they have been implicated in the pathobiology of both PAH and CKD-ESRD and an extrapolation is being made for etiological plausibility for PH in the setting of CKD-ESRD. a) Uremic Toxins  Impaired renal function is accompanied by the accumulation of toxins either due to decreased clearance or sometimes due to increased production. Pertinent molecules that are felt relevant in the CKD-ESRD-PH realm will be discussed in the following section. Guanidine uremic toxins likely play a key role in decreased nitric oxide (NO) and endothelial dysfunction in the setting of renal failure. Methylation and subsequent proteolysis of certain arginine-containing proteins yields monomethyl-L-­ arginine (MMA), symmetric dimethyl arginine (SDMA), and asymmetric dimethyl arginine (ADMA). MMA > ADMA ≫ SDMA are all inhibitors of NO synthase (which cleaves L-arginine to citrulline + NO which is a potent vasodilator). The guanidine uremic toxins have also been associated with endothelial dysfunction, inflammation, oxidative stress, and increased cardiovascular death and mortality [47–50]. HD patients without PH and controls subjects had a higher basal NO levels compared to HD patients with PH. HD therapy caused a significant increase in NO levels again higher in the former than the later [12]. In addition, the vasculature of patients with ESRD may be less sensitive to effects of NO [51]. b) Molecular Pathways Implicated in Renal Failure and PH Endothelin and its G-protein-coupled receptors ETRA and ETRB play an important role for vascular tone, especially in the kidneys and lungs. Type A receptor (ET-A) is preferentially expressed on smooth muscle cells (SMCs) and promotes vasoconstriction and cellular proliferation while the type B receptor (ET-­B) is expressed on ECs and promotes vasodilation. ET-1 promotes cell proliferation, hypertrophy, inflammation, and extracellular matrix accumulation, all of which are important factors in progression of CKD [52]. ET-1 levels are significantly elevated in CKD patients and also in HD patients, levels of which are not influenced by dialysis [12]. In patients with PH, endothelin receptors are overexpressed in the pulmonary circulation as well as there are increased levels of circulating ETs. Coupled together, these have been implicated in smooth muscle cell proliferation and vasoconstriction in the pulmonary circulation [53]. Anemia is very common in kidney disease and numerous epidemiological studies have reported an association with PH in these patients [19, 23, 54, 55]. Anemia in this setting is usually iron deficiency or anemia of chronic disease. In the small bowel enterocytes, hepcidin binds to a cellular iron exporter ferroportin (which then undergoes endocytosis and proteolysis), thereby interfering with iron absorption as well as delivery of cellular iron into plasma. Increased hepcidin has been reported in both PH [56] and kidney disease [57] which suppresses iron absorption leading to iron deficiency anemia. At the cellular level, oxygen is sensed by prolyl hydroxylases 1 to 3, which are oxygen and iron-dependent enzymes that hydroxylate the hypoxia-inducible factors (HIFs)1α or 2α, hence targeting them for degradation. Therefore, either hypoxia or iron deficiency can cause decreased degradation of

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HIFs which then leads to an increase in the transcription of many hypoxia-inducible genes, prominently including erythropoietin and vascular endothelial factor [56, 57]. Endothelial prolyl hydroxylase and HIF 2 have also been implicated as the core mediator of pulmonary vascular muscular hypertrophy and increased endothelin activity leading to PH in mice [58]. HIF 1 α is known to switch the metabolic profile of the right ventricle when it undergoes ischemia from a glucose oxidation pathway to a glycolytic pathway by inhibition of pyruvate dehydrogenase. These changes shift toward an inefficient fuel use from glucose to fatty acid, thus making the RV vulnerable to fail during stress [59]. Inflammation Both CKD and PH are known to have inflammation at the cellular level and the same could be true when both diseases coexist in the host. Alpha-1-­ acid glycoprotein levels were present in higher levels in patients with echocardiogram-­based ESRD-PH than those without ESRD-PH [34]. In addition, high serum level of acute phase c-reactive protein and cytokines, including IL-1β, TNF-α, and IL-6, has been demonstrated in this population suggesting that chronic inflammation might have some role in the pathogenesis of PH in patients undergoing hemodialysis [60]. TNF-α is a potent pro-inflammatory cytokine which plays a strong role in progressive renal injury especially in the setting of HTN and angiotensin II activation. This potent inflammatory cytokine has deleterious effects on the right ventricular myocardium as well. It promotes the activation of MED13/ NCoR1 complex that facilitates transition from compensated to decompensated right heart failure [59]. Transforming growth factor (TGF) super family consists of two functional groups of signaling molecules, the TGF β group and the BMP (bone morphogenetic protein) group. Through their downstream regulatory proteins known as “Smads,” they play a crucial role in gene transcription. They are responsible for tissue homeostasis such as cell proliferation, differentiation, apoptosis, migration, adhesion, cytoskeletal organization, and extracellular matrix production [61]. In both the chronic kidney disease and PAH the TGF-β/BMP pathway is skewed toward a pro-­ inflammatory, pro-fibrotic state with vascular smooth muscle proliferation through myofibroblasts. One of the key steps in such transition is a process referred to as endothelial to mesenchymal transition (EndoMT) known to happen both in renal disease and PAH [61, 62]. Angiopoietins (Ang) Ang-1 and Ang-2 factors regulate vascular development and homeostasis through TIE 1 and 2 receptor (on endothelial cells). Disrupted balance is associated with vascular smooth muscle cell proliferation and has been implicated in both renal failure and PAH [63]. Thromboxane Thromboxane A 2 (TXA2) is a vasoconstrictor in the pulmonary circulation and is implicated in the pathogenesis of PH. Elevated levels TXA2 and its metabolite thromboxane B2 (TXB2) are elevated in patients with PH [64]. In ESRD patients, TXB2 levels were higher in the dialysis group than in the non-­ dialysis group and also in those with PH vs. those who didn’t have PH [65]. A potential cause elevated TXB2 in the HD group may be related to the process of HD which induces a detectable extracorporeal increase of TXB 2 through

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blood-membrane interaction causing degranulation of platelets and monocytes [66]. Kiykim et al. dialyzed 74 patients via a central venous catheter using a cellulose acetate membrane and a high flux polysulfone membranes 1  week apart, estimating PASP with echocardiogram. Relative to the pre-HD PASP, post-HD PASP significantly decreased with the polysulfone membrane but not with the cellulose membrane again possibly secondary to thromboxane release with the latter filter [67]. Microangiopathy In a mouse model of chronic kidney disease, serum urea level was associated with a distinct microangiopathy. There was a heterogeneous pattern of focal microvascular rarefication with loss of coherent microvascular networks and dysfunctional angiogenesis. Also notable was microvascular dysfunction by significantly diminished blood flow velocity and consequently increased oxygen uptake. Chronic kidney disease induces a systemic microangiopathy, tissue hypoxia, and dysfunctional angiogenesis including in the myocardium [68]. While similar findings in humans with CKD PH need to be corroborated, PAH is in general characterized by loss of small precapillary arterioles through obliteration, abnormal muscularization, and perivascular inflammation in the pulmonary circulation. This is an example of the two-hit theory of PH where a genetically susceptible host has a second hit of renal failure to develop PH [69]. Calcium, Phosphate, and the Parathyroid Hormone (PTH) Metastatic or extraosseous calcification is common in renal failure and is attributed to hyperparathyroidism. It usually involves the alveolar septa and is often associated with significant restrictive defects as well as diffusion abnormalities on pulmonary function studies. Metastatic pulmonary artery calcifications are also common as has been reported in autopsy studies [70, 71]. Increased calcium–phosphorus product and elevated PTH levels have been associated with PH in some studies [9, 10, 54, 55, 72] while others did not find an association [19, 23, 65]. Calcium-sensing receptor (CaSR) upregulation in the pulmonary artery smooth muscle cells (PASMCs) could lead to vasoconstriction and proliferation, thus contributing to PH as shown in human PASMC and animal studies [73, 74]. c) Dialysis Access and Dialysis-Related Factors  Patients on hemodialysis have an increased risk of pulmonary vascular complications due to the following mechanisms: (i) microemboli involving air or clot [75, 76], (ii) blood-membrane interactions (see section on “Thromboxane” above) [65, 67, 77], and (iii) significant left to right shunt. The influence of AVF on pulmonary hemodynamics is very ­complex and is challenging to tease out its exact contribution to PH.  This is because most patients with ESRD already have issues with volume overload, reduced ­compliance of left-sided cardiac chambers, and increased cardiac output (see ­ section on “Etiology of Pulmonary HTN in CKD and ESRD” above). Forbearing these ­limitations, there is some evidence available to guide the clinician as reviewed below. The “Fistula First” initiative by CMS (Centers for Medicare & Medicaid Services) in 2003 has revolutionized the care of patients needing hemodialysis

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[78]. AV access (both natural fistula and synthetic graft) have been implicated in the pathogenesis of significant cardiovascular complications [79] as well as RV dysfunction and or development of overt PH [8, 80–86]. Although both graft and fistula can cause cardiovascular complications, fistulae tend to grow over time transforming into mega fistulae causing significant shunt. Creation of an AVF causes increased LV end-diastolic dimension (LVEDD), contractility, stroke volume, and cardiac output leading to cardiovascular complications [79]. Brachial location of the AV access tends to have a higher blood flow and is more often associated with PH (vs. radial or anatomical snuff box site). Interestingly, Al-Ghonaim et al. did not find an increased risk of death at higher levels of fistula flow over a 28-month follow-up [87]. While most patients tolerate hemodynamic consequences of an AVF well (because the pulmonary circuit is very compliant), some develop PH after AVF creation. This is either due to due a baseline pulmonary vascular dysfunction (due to mechanisms discussed above) or inability of the left heart to accommodate the AVF-­mediated elevated CO. Therefore it is important to consider alternative modes of dialysis, modify mega shunts, and use novel vascular accesses for dialysis [88] or early referral for transplant in those at high risk for decompensation with an AVF [79]. Additionally when contemplating to declot a thrombosed access, presence of severe PH or a right to left intracardiac shunt is an absolute contraindication while a mega fistula is a relative contraindication [75].

Screening and Diagnosis Symptoms and signs of PH are usually nonspecific including dyspnea, fatigue, chest pain, palpitations, and in advanced disease, edema, and other signs of heart failure. In CKD-ESRD patients, recognition of PH is more likely to be delayed as these symptoms often attributed to uremia, azotemia, renal failure, and other comorbidities. Usually syncope or pre-syncope indicates a falling cardiac output. Volatile blood pressure and hypotension during hemodialysis is an important clue for heart failure, including right-sided failure from severe PH.  Physical exam findings of CKD-ESRD-PH are nonspecific as well. Jugular venous distension may be challenging especially in advanced CKD because of fluid overload, heart failure, and vascular complications such as stenosis due to prior instrumentation. A loud S2, flow murmur, or precordial heave may be present. Pulmonary exam may reveal effusions and crackles. Special attention should be paid to number and nature of vascular access. A high index of suspicion and early screening is prudent and should be advocated among primary providers and nephrologists. Laboratory tests that have been associated with PH include anemia, increased CRP, disturbances in calcium-phosphate-parathyroid axis, hypoalbuminemia, as

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well as elevated liver enzymes alkaline phosphatase (ALP) and γ-glutamyl transpeptidase (GGT) [89]. BNP and NT-proBNP (brain natriuretic peptide and its N-terminal pro-peptide) are effected by declining renal function [90] but elevated levels are helpful in predicting fluid overload and also major adverse cardiovascular events [91]. Although the NT-proBNP and BNP tend to vary by dialysis modality, increasing levels of these peptides are associated with increased mortality [92, 93]. Pulmonary function studies, chest imaging, assessment for sleep apnea, and ambulatory oxygen saturations should be obtained in all patients to evaluate for ruling out lung disease (group III PH). VQ scan should be performed to rule out group IV PH. Echocardiogram is easily available and noninvasive and yields vital information and hence serves as a screening tool. Cardiac MRI is also emerging as modality of imaging for the right ventricle PH [94]. For patients on dialysis, echocardiogram should be done soon after dialysis (at dry weight) given significant differences preand post-dialysis measurements [67]. Presence of tricuspid regurgitation, PASP  >40  mm Hg, and right-sided chamber enlargements predict PH.  Tricuspid annular plane systolic excursion (TAPSE) is a marker of right ventricular function [95]. Tissue Doppler imaging study might also pick up disease before overt PH develops [82, 96]. Importantly, echocardiogram can identify mitral valve disease, aortic valve disease, left atrial enlargement, LV enlargement or hypertrophy, impaired diastolic or systolic function, as well as high output situation, all of which can lead to group II PH. Echocardiogram has limitations including poor windows, erroneous estimation of PASP, as well as being operator dependent [97]. A more thorough overview of cardiac imaging in CKD has been reviewed elsewhere [94, 98]. As already highlighted, RHC is of paramount importance in diagnosing and characterizing PH.  As noted in the PEPPER study, for dialysis-dependent patients RHC should be done following dialysis because PH can resolve in some individuals after fluid removal while in others precapillary PH is unmasked only after dialysis [35]. In patients with AV access, attention should be paid to the fistula flows, cardiac output, and ratio of fistula flow as a percentage of the cardiac output. Fistula flow estimates and shunt fraction quantification have been discussed in detail in recent guidelines [99, 100]. During RHC if the CO is elevated, a temporary occlusion of the AV access (3–5 min) will uncover its contribution to the elevated CO and PH, providing important information about the short- and long-term effects of fistula flow reduction [84]. Usually a fistula flow (Qa) >2 l/min is considered high flow by most authors. Qa/CO of 20% should increase vigilance and a shunt fraction ~30% is predictive of transition to high output HF [99–101]. RHC should ideally be performed by providers with experience in evaluating patients with PH as misclassification could have detrimental effects [102–104]. After a thorough evaluation and workup by providers with expertise in PH, a diagnosis of CKD-ESRD-PH can be made (Figs.  11.2 and 11.3).

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ECHO, PFT, CXR/CT Chest polysomnography, lab studies and ambulatory oxygen assessment

Comprehensive history and physical exam

Does patient meet any of the following? - Risk factors for Group I PH or PAH (or) - No obvious risk factors "unexplained PH" (or) - Signs of heart failure (or) - Moderate or severe RV dysfunction on echo

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Treat contributing conditions and further work up For example: HTN control, afterload reduction optimizing fluid status, treating OSA, oxygen supplimentation, fistula flow evaluation # VQ scan& cardiology/pulmonology evlauation Symptoms persist (or) >PASP 50 mm Hg on repeat Echo (3–6 months) (or) moderate or severe RV dysfunction on Echo RHC ± LHC$ Done at a state of euvolemia/ "dry weight"/post dialysis

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Evaluate for: Anemia Valvular pathology HD access - high output%

Fig. 11.3  Approach to diagnosis of PH in patients with CKD-ESRD. PH, pulmonary hypertension; PAH, pulmonary arterial hypertension; mPAP, mean pulmonary artery pressure; LHD, left heart disease associated with PH; PAWP, pulmonary artery wedge pressure; LVEDP, left ventricular end diastolic pressure; PVR, pulmonary vascular resistance. # Fistula flow can be assessed at any stage. In addition to flow, its fraction as a percent of cardiac output is also important. Please see text for details. % as discussed in the section on “Screening and Diagnosis.” * Group 1 PH or PAH if risk factor or underlying disorder (e.g., scleroderma) is uncovered

Treatment (a) General measures: Counseling and education should be directed toward salt, fluid restriction, and smoking cessation. Ambulatory oxygen saturation should be checked and oxygen supplementation to keep saturations >90% with activity and rest [105, 106]. Diuretics and antihypertensive medications should be tailored to address optimization of the preload, afterload, heart rate, and rhythm.

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Adjusting dialysis prescription optimization of volume status is paramount to minimizing PH [107]. Supervised physical exercise and rehabilitation should be recommended. (b) Targeted interventions: Patients with connective tissue disease should be treated with immunomodulatory medications and that might help both PH and renal disease. Sleep apnea and nocturnal hypoxia should be addressed. Patients with thromboembolic disease should be on anticoagulation and should be evaluated at centers capable of pulmonary endarterectomy. Fistulae in the presence of a high output or a working renal transplant should be surgically addressed, either by ligation or banding [84, 108, 109]. Pericardial effusion is common in the setting of advanced renal disease and connective tissue disease and is a poor prognostic factor in PH. However draining the fluid especially with a window has been associated with high mortality and should be addressed with thought and caution in the setting of severe RV dilation or dysfunction [110, 111]. (c) Renal transplant: In the presence of PH, renal transplant (RTx) has both pros and cons. Renal transplant is associated with improvement of LV and RV parameters and should definitely be considered early on especially if they have risk factors for PH [112–114]. In contradistinction, presence of PH prior to renal transplantation appears to be an independent predictor of early graft dysfunction among those patients who receive a deceased donor kidney [115]. PH before renal transplantation carries a threefold increased risk of death-censored allograft failure [116] and a PASP >50 mm Hg is associated with increased mortality [117] with the caveat being these as echocardiogram-based studies. One study noted reduced survival after RTx with an mPAP >25 mm Hg coupled with an increased PVR >3 WU [118]. Unlike in liver transplantation, specific recommendations for safely performing RTx in the setting of ESRD-PH are not available due to the lack of evidence [119]. The decision to perform RTx in the setting of ESRD-PH needs to be handled carefully and only after multidisciplinary evaluation with discussion between PH experts and transplant physicians. (d) Use of selective pulmonary vasodilators: Consensus recommendations are against the use of pulmonary vasodilators in non-group I PH and the same holds true for CKD-ESRD-PH. In most cases of CKD-ESRD-PH, pulmonary vasodilator is not indicated nor should be used, as controlling underlying causes of PH is the mainstay of treatment. In a very selective group of patients with significant PH that is leading to attributable symptoms or RV dysfunction, pulmonary vasodilator therapy may be considered, possibly to optimize one’s chances of undergoing RTx. Currently approved medications for PAH can be grouped into three categories based on their mechanism of action: (i) prostacyclin receptor agonists and prostaglandin analogues, (ii) endothelin receptor antagonists (ETRA), and (iii) phosphodiesterase 5 inhibitors/soluble guanylate cyclase stimulators. They are to be used only under close supervision by clinicians with expertise in PH as they can be associated with serious adverse effects including VQ mismatch, systemic hypotension, pulmonary edema, or other adverse effects. None have been approved in ESRD. Riociguat and Tadalafil are contraindicated and others need dose adjustment with renal disease.

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Similarly, choice of monitoring parameters is hindered by lack of robust data in this context but general guides [120] can be used until more specific data is available.

Conclusion PH in the setting of CKD-ESRD is often unrecognized and has significant impact on morbidity and mortality. Primary care providers and nephrologists play key roles in screening and early identification. Echocardiogram is a good screening tool and RHC is needed for definitive diagnosis and characterizing PH. A careful and through evaluation of the “known causes” of PH should be performed as treating them would address PH in most individuals. If there are multiple causes of PH or PH is severe despite mild comorbidities or there are no known causes, then a form of group V PH should be considered. Renal transplant improves PH in general; however, severe disease could cause graft issues or decreased survival. Role of pulmonary vasodilators for group V PH remains largely unknown but may have a role in a select group of patients, but should be managed by someone with expertise in the management of PH.

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83. Beigi AA, Sadeghi AMM, Khosravi AR, Karami M, Masoudpour H. Effects of the arteriovenous fistula on pulmonary artery pressure and cardiac output in patients with chronic renal failure. J Vasc Access. 2009;10(3):160–6. 84. Raza F, Alkhouli M, Rogers F, Vaidya A, Forfia P. Case series of 5 patients with end-stage renal disease with reversible dyspnea, heart failure, and pulmonary hypertension related to arteriovenous dialysis access. Pulm Circ. 2015;5(2):398–406. 85. Yilmaz S, Yetim M, Yilmaz B, Dogan T, Aksoy E, Yuksel N, et al. High hemodialysis vascular access flow and impaired right ventricular function in chronic hemodialysis patients. Indian J Nephrol. 2016;26(5):352. 86. Narechania S, Tonelli AR. Hemodynamic consequences of a surgical arteriovenous fistula. Ann Am Thorac Soc. 2016;13(2):288–91. 87. Al-Ghonaim M, Manns BJ, Hirsch DJ, Gao Z, Tonelli M. Relation between access blood flow and mortality in chronic hemodialysis patients. Clin J Am Soc Nephrol. 2008;3(2):387–91. 88. Caversaccio M, Wimmer W, Widmer M, Bachtler M, Kalicki R, Uehlinger D, et al. A novel retroauricular fixed port for hemodialysis: surgical procedure and preliminary results of the clinical investigation. Acta Otolaryngol [Internet]. 2019;139(2):129–34. Available from: https://doi.org/10.1080/00016489.2018.1562217. 89. Ortega O, Rodriguez I, Hinostroza J, Laso N, Callejas R, Gallar P, et al. Serum alkaline phosphatase levels and left ventricular diastolic dysfunction in patients with advanced chronic kidney disease. Nephron Extra. 2012;1(1):283–91. 90. Takase H, Dohi Y.  Kidney function crucially affects B-type natriuretic peptide (BNP), N-terminal proBNP and their relationship. Eur J Clin Investig. 2014;44(3):303–8. 91. Tsai Y-C, Lee C-S, Chiu Y-W, Kuo H-T, Lee S-C, Kuo M-C, et al. The interaction between N-terminal pro-brain natriuretic peptide and fluid status in adverse clinical outcomes of late stages of chronic kidney disease. PLoS One. 2018;13(8):1–16. 92. Paniagua R, Ventura MDJ, Ávila-Díaz M, Hinojosa-Heredia H, Méndez-Durán A, Cueto-­ Manzano A, et al. NT-proBNP, fluid volume overload and dialysis modality are independent predictors of mortality in ESRD patients. Nephrol Dial Transplant. 2010;25(2):551–7. 93. Roberts MA, Hare DL, Sikaris K, Ierino FL. Temporal trajectory of b-type natriuretic peptide in patients with ckd stages 3 and 4, dialysis, and kidney transplant. Clin J Am Soc Nephrol. 2014;9(6):1024–32. 94. Ureche C, Sascău R, Țăpoi L, Covic A, Moroșanu C, Voroneanu L, et  al. Multi-modality cardiac imaging in advanced chronic kidney disease. Echocardiography. 2019;36:1372–80. 95. Grabysa R, Wańkowicz Z. Can echocardiography, especially tricuspid annular plane systolic excursion measurement, predict pulmonary hypertension and improve prognosis in patients on long-term dialysis? Med Sci Monit. 2015;21:4015–22. 96. Said K, Hassan M, Baligh E, Zayed B, Sorour K. Ventricular function in patients with end-­ stage renal disease starting dialysis therapy: a tissue doppler imaging study. Echocardiography. 2012;29(9):1054–9. 97. Fisher MR, Forfia PR, Chamera E, Housten-Harris T, Champion HC, Girgis RE, et  al. Accuracy of doppler echocardiography in the hemodynamic assessment of pulmonary hypertension. Am J Respir Crit Care Med. 2009;175:619. 98. Dubin RF.  Application of echocardiographic data in patients with chronic kidney disease. Curr Opin Nephrol Hypertens. 2018;27(4):283–8. 99. Kukita K, Ohira S, Amano I, Naito H, Azuma N, Ikeda K, et al. 2011 update Japanese Society for Dialysis Therapy Guidelines of vascular access construction and repair for chronic hemodialysis. Ther Apher Dial. 2015;19(S1):1–39. 100. Ibeas J, Roca-Tey R, Vallespín J, Moreno T, Moñux G, Martí-Monrós A, et al. Erratum to “Spanish Clinical Guidelines on Vascular Access for Haemodialysis.”. Nefrol (English Ed). 2019;39(1):1–2. 101. Saleh MA, El Kilany WM, Keddis VW, El Said TW. Effect of high flow arteriovenous fistula on cardiac function in hemodialysis patients. Egypt Heart J [Internet]. 2018;70(4):337–41. Available from: https://doi.org/10.1016/j.ehj.2018.10.007.

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102. Thenappan T. Pulmonary hypertension in chronic kidney disease: a hemodynamic characterization. Pulm Circ. 2017;7(3):567–8. 103. LeVarge BL, Pomerantsev E, Channick RN.  Reliance on end-expiratory wedge pressure leads to misclassification of pulmonary hypertension. Eur Respir J. 2014;44(2):425–34. 104. Halpern SD, Taichman DB.  Misclassification of pulmonary hypertension due to reliance on pulmonary capillary wedge pressure rather than left ventricular end-diastolic pressure. Chest [Internet]. 2009;136(1):37–43. Available from:. https://doi.org/10.1378/chest. 08-2784. 105. Continuious or nocturnal oxygen therapy in hypoxemic chronic obstructive lung disease. Ann Intern Med. 1980;93(3):391–8. 106. Centers for Medicare and Medicaid Services. Home oxygen therapy. Medicare Learn Netw [Internet]. 2017;(October):1–35. Available from: https://www.cms.gov/Outreach-andEducation/Medicare-Learning-Network-MLN/MLNProducts/Downloads/Home-OxygenTherapy-Text-Only.pdf. 107. Tsilonis K, Sarafidis PA, Kamperidis V, Loutradis C, Georgianos PI, Imprialos K, et  al. Echocardiographic parameters during long and short interdialytic intervals in hemodialysis patients. Am J Kidney Dis [Internet]. 2019;68(5):772–81. Available from:. https://doi. org/10.1053/j.ajkd.2016.06.017. 108. Vaes RHD, Wouda R, Van Loon M, Van Hoek F, Tordoir JH, Scheltinga MR. Effectiveness of surgical banding for high flow in brachial artery-based hemodialysis vascular access. J Vasc Surg. 2015;61(3):762–6. 109. Rao NN, Stokes MB, Rajwani A, Ullah S, Williams K, King D, et al. Effects of arteriovenous fistula ligation on cardiac structure and function in kidney transplant recipients. Circulation. 2019;139(25):2809–18. 110. Hemnes AR, Gaine SP, Wiener CM. Poor outcomes associated with drainage of pericardial effusions in patients with pulmonary arterial hypertension. South Med J. 2008;101:490. 111. Fenstad ER, Le RJ, Sinak LJ, Maradit-Kremers H, Ammash NM, Ayalew AM, et  al. Pericardial effusions in pulmonary arterial hypertension: characteristics, prognosis, and role of drainage. Chest [Internet]. 2013;144(5):1530–8. Available from:. https://doi.org/10.1378/ chest.12-3033. 112. Reddy YNV, Lunawat D, Abraham G, Matthew M, Mullasari A, Nagarajan P, et  al. Progressive pulmonary hypertension: another criterion for expeditious renal transplantation. Saudi J Kidney Dis Transpl. 2013;24(5):925–9. 113. Pirat B, Bozbas H, Demirtas S, Simsek V, Sayin B, Colak T, et  al. Comparison of tissue Doppler echocardiography parameters in patients with end-stage renal disease and renal transplant recipients. Transplant Proc. 2008;40(1):107–10. 114. Casas-Aparicio G, Castillo-Martínez L, Orea-Tejeda A, Abasta-Jiménez M, Keirns-Davies C, Rebollar-González V. The effect of successful kidney transplantation on ventricular dysfunction and pulmonary hypertension. Transplant Proc [Internet]. 2010;42(9):3524–8. Available from:. https://doi.org/10.1016/j.transproceed.2010.06.026. 115. Zlotnick DM, Axelrod DA, Chobanian MC, Friedman S, Brown J, Catherwood E, et al. Non-­ invasive detection of pulmonary hypertension prior to renal transplantation is a predictor of increased risk for early graft dysfunction. Nephrol Dial Transplant. 2010;25(9):3090–6. 116. Foderaro AE, Baird GL, Bazargan-Lari A, Morrissey PE, Gohh RY, Poppas A, et  al. Echocardiographic pulmonary hypertension predicts post-transplantation renal allograft failure. Transplant Proc [Internet]. 2017;49(6):1256–61. Available from:. https://doi. org/10.1016/j.transproceed.2017.01.085. 117. Issa N, Krowka MJ, Griffin MD, Hickson LJ, Stegall MD, Cosio FG. Pulmonary hypertension is associated with reduced patient survival after kidney transplantation. Transplantation. 2008;86(10):1384–8. 118. Wolfe JD, Hickey GW, Althouse AD, Sharbaugh MS, Kliner DE, Mathier MA, et  al. Pulmonary vascular resistance determines mortality in end-stage renal disease patients with pulmonary hypertension. Clin Transplant. 2018;32(6):e13270.

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119. Lentine KL, Villines TC, Axelrod D, Kaviratne S, Weir MR, Costa SP. Evaluation and management of pulmonary hypertension in kidney transplant candidates and recipients: concepts and controversies. Transplantation. 2017;101(1):166–81. 120. Galiè N, Humbert M, Vachiéry J-L, Gibbs S, Lang I, Torbicki A, et al. 2015 ESC/ERS guidelines for the diagnosis and treatment of pulmonary hypertension. Eur Heart J [Internet]. 2015;37(1):67–119. Available from: http://eurheartj.oxfordjournals.org/lookup/doi/10.1093/ eurheartj/ehv317%5Cnpapers3://publication/doi/10.1093/eurheartj/ehv317.

Chapter 12

Gender and Race Disparities in Pulmonary Hypertension Diagnosis and Treatment Karla Cruz Morel, Vinicio De Jesus Perez, and Arunabh Talwar

Introduction Health disparities between population groups are defined as significant differences in healthcare that are closely linked to racial ancestry, social, economic, and/or environmental differences [1]. Health disparities have a major impact in the quality of life and clinical care received by minorities in the United States. Approximately 36% of the population belong to a racial or ethnic minority group, and these numbers will likely increase over the next decade. Minorities, compared with the rest of the US population, experience reduced quality of life as a result of health-related problems predominantly due to lack of timely access to healthcare [2]. Pulmonary arterial hypertension (PAH) stands out as a rare disease that affects predominantly women, with an estimated median survival of 2.8  years without treatment [3]. The prevalence of PAH is estimated to be 15–50 cases per million and survival depends on early diagnosis and institution of therapy. In the United States, most efforts have been focusing on tackling diseases with the highest rates of morbidity and mortality, such as cardiovascular disease, cancer, and chronic obstructive pulmonary disease. However, less attention has been given to PAH [4]. Minorities affected with PAH are probably at higher risk for worse outcomes than nonminorities due to healthcare disparities including lack of insurance, access K. Cruz Morel Pulmonary and Critical Care Medicine, Prisma Health University of South Carolina Medical Group, Columbia, SC, USA e-mail: [email protected] V. De Jesus Perez (*) Pulmonary and Critical Care Medicine, Stanford University Hospital, Stanford, CA, USA e-mail: [email protected] A. Talwar Pulmonary and Critical Care Medicine, Northwell Health, New Hyde Park, NY, USA e-mail: [email protected] © Springer Nature Switzerland AG 2020 H. J. Ford et al. (eds.), Pulmonary Hypertension, Respiratory Medicine, https://doi.org/10.1007/978-3-030-52787-7_12

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to care, and affordability of medical treatment. The extent of how health disparity impacts patients with PAH is not well known, as there has been limited research in this area. Different registries have shown that age, gender, race/ethnicity, country of origin, medical treatments, and socioeconomic status (SES) have been linked with types of PAH, response to therapy, and outcome. Some of these findings are likely inherently explained by genetic and biological differences but also by environmental exposures and affordability of medical treatment. However, patient registries have historically lacked adequate representation of racial and ethnic minorities, which limits our capacity to determine whether there are differences in clinical phenotypes and implementation of therapies [4].

Race/Ethnicity and PAH Few studies have addressed the difference in prevalence and etiology of PH between races. Historically, PH registries have lacked a good representation of different races/ethnicities. The NIH registry reported the distribution of its patients as 85.4% white, 12.3% African-American, and 2.3% Hispanic. More recently, the REVEAL registry [registry to evaluate early and long-term PAH disease management] found similar patterns of distribution. REVEAL was a multicenter observational US-based registry designed to characterize the contemporary US PAH population. The REVEAL registry used a multicenter prospective cohort design involving 54 centers in the United States. Between March 2006 and September 2007, 3052 patients with clinically suspected WHO group I PAH were screened. Patients were prospectively tracked through December 2012, with a minimum follow-up of 5 years. One analysis of REVEAL compared the demographics of the registry to the concurrent general population. Results showed that blacks were relatively overrepresented in the registry compared with the general population, with a prevalence of 12.2% and an expected prevalence of 10.9%. There was underrepresentation of Hispanic patients, with a prevalence of 8.9% compared to the expected prevalence of 11.5%. There was also a relative underrepresentation of the Asian/Pacific Islander population [5]. It is known that an elevated PASP on echocardiogram is associated with increased risk for hospitalization for heart failure [6]. Brittain et al., in the CARDIA cohort study, found that PASP was higher among black individuals, accounting for 63% of the highest PASP quartile [7]. A recent study by Yang et al. included 4576 patients with PAH, of which 3990 (87%) were Caucasians and 586 (13%) were African-­ Americans. The study showed that African-American race was associated with a 41% increased risk for PH compared to Caucasians after adjusting for age, gender, heart failure, hypertension, diabetes, COPD, interstitial lung disease, BMI, creatinine, left ventricular ejection fraction, and left ventricular hypertrophy. In addition, the study found that African-American patients with PAH were younger and had a higher rate of heart failure, more severe pulmonary hemodynamics (higher right

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atrial pressure, mean pulmonary artery pressure [mPAP], mean pulmonary arterial wedge pressure [PAWP], pulmonary vascular resistance [PVR], and lower cardiac index), more prevalent cardio-metabolic and renal disease, and increased mortality compared to Caucasians [8]. The prevalence of scleroderma-associated PAH (SSc-PAH) in large cohorts ranges from 5% to 12% [9]. SSc-PAH patients tend to be less responsive to therapy than patients with other types of PAH and have a worse prognosis [10]. A retrospective study comparing African-American and non-African-American scleroderma patients by Moore et  al. found that African-American scleroderma patients have more severe pulmonary hypertension and more severe cardiac involvement [11]. In this study, African-Americans had lower measures of socioeconomic status as measured by marital status, employment, and household income. After adjustment for these factors, however, African-American race was not a significant risk factor for mortality, but lower household income by zip code was an independent risk factor for increased mortality. Although there are known risk factors for cardiovascular diseases inherent to race, it is also proven that the gaps in healthcare access contribute to a difference in mortality between races. A recent study by Parikh examined the association between health insurance and racial disparities. Among 250 patients referred to two large pulmonary hypertension referral centers in the United States, blacks had worse survival from time of evaluation. However, additional adjustment for insurance status attenuated the association of race with outcomes, suggesting that insurance status plays an important role in pulmonary hypertension outcomes [12]. Al-Naamani et al. explored the racial and ethnic differences in presentation, severity, and treatment of patients with PAH in a large registry. A total of 1837 patients were included in the analysis, 79% were non-Hispanic white (NHWs), 11% were African-­ American, and 10% were Hispanic. African-American patients were more likely to have CTD-PAH, Hispanics were more likely to have congenital heart disease-­ associated PAH, and NHWs had more familial PAH and PAH associated with drug use. Furthermore, the study found that Hispanic patients were less commonly treated with PAH-specific medications compared to NHWs [13]. In contrast, Valverde et al. analyzed local epidemiological data of PAH in Latin America and found that the percentage of idiopathic PAH patients in Latin America is higher compared to European studies and the REVEAL registry.

Socioeconomic Status and PAH Socioeconomic status (SES) is a combination of sociological and economic factors that combines a family’s work experience, income, and social status in relation to others in the same economy. In the United States, persons with a lower SES suffer disproportionately from many diseases and show a higher rate of mortality than those with a higher SES. Talwar et al. found that a lower SES is associated with more clinically advanced pulmonary hypertensive disease at first presentation,

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based on WHO-FC and worse outcomes [14]. In this study, 116 PAH patients (32 males and 84 females) were evaluated. There was negative correlation between median household income and functional class at initial presentation [Spearman r  =  − 0.308, p  30 years ago that healthy black patients had increased circulating levels of endothelin-1 compared with white patients [4].

Future Directions in Healthcare Disparities in PAH It is evident that healthcare disparities contribute to delays in PAH diagnosis, lack of appropriate management, worse prognosis, and underrepresentation of minorities in innovative research that aims to advance personalized and precision medicine. An

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effort must be made to include gender, age, race/ethnicity, and socioeconomic status as a major variable in research studies. Education of physicians and other healthcare providers facilitating PAH awareness, increased cross-cultural training, and recognizing the risk factors associated with race, gender, SES, age, etc., are crucial to closing the gaps in healthcare disparities. Legislation that advocates for minority healthcare access is also key. The following recommendations were published as an official American Thoracic Society Statement [4] and serve to summarize the relevant future directions in this area: 1.

PAH registries must be organized to reliably capture information concerning race/ethnicity and SES of patients. 2. Genetic screening of large populations should include patients with PAH belonging to minority groups and address the existence of unique genetic determinants. 3. SES should be included in the risk stratification to help identify patients with PAH who may be at greatest risk for noncompliance. 4. Hospitals, health insurers, and providers should be educated on the importance of data on key determinants of health and encouraged to increase their efforts to collect data such as SES as well as race/ethnicity. 5. Partnership with public health divisions, community-based health centers, and existing heart failure outreach programs should be encouraged to collect relevant data concerning adverse environmental exposures and clinical outcomes on vulnerable PAH populations. 6. A cross-cultural curriculum should be mandatory and implemented early in medical training. The PHA and other patient-centered organizations, with the help of specialists in the field, should develop more educational resources for patients and providers in minority communities. 7. Cross-cultural competence needs to be framed as a skill set—similar to a review of systems or checklist—that can help providers manage challenging cross-cultural cases. It must be seen as (a) practical, actionable, and time efficient, (b) should be taught in a case-based fashion that creates clinical challenges, (c) must be linked to evidence-based guidelines and the peer-reviewed literature, and (d) must leave students with a concrete set of tools and skills. 8. Formal training courses should be developed that address health disparities and cross-­ cultural competency through online training/modules for accreditation. An ideal educational program would target both providers and patients and would need to be tailored for PAH-specific needs. 9. Increase awareness among physicians regarding the impact of implicit or unconscious bias toward particular population groups in the setting of PAH. 10. Increase the amount of racial and ethnic minority physicians in the healthcare provider workforce to promote race- and language-concordant patient–physician interactions. 11. Legislate governmental standards regarding access to cultural- and language-appropriate services across all healthcare organizations.

The prognosis of patients with PAH has improved in the last two decades, with significant advances in pharmacologic therapies. Further research is still needed into the factors that result in delay in diagnosis and lack of access to healthcare, particularly for minority populations, to further improve the outcome of this disease in the most comprehensive way.

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References 1. Celedón JC, Roman J, Schraufnagel DE, Thomas A, Samet J.  Respiratory health equality in the United States: the American Thoracic Society perspective. Ann Am Thorac Soc. 2014;11:473–9. 2. Galiè N, Humbert M, Vachièry J-L, Gibbs S, Lang I, Torbicki A, Simonneau G, Peacock A, Vonk-Noordegraaf A, Beghetti M, Joint Task Force for the Diagnosis and Treatment of Pulmonary Hypertension of the European Society of Cardiology (ESC), European Respiratory Society (ERS), et al. 2015 ESC/ERS guidelines for the diagnosis and treatment of pulmonary hypertension. Eur Respir J. 2015;46:903–75. 3. Wu W-H, Yang L, Peng F-H, Yao J, Zou L-L, Liu D, Jiang X, Li J, Gao L, Qu J-M, et al. Lower socioeconomic status is associated with worse outcomes in pulmonary arterial hypertension. Am J Respir Crit Care Med. 2013;187:303–10. 4. Talwar A, Garcia JGN, Tsai H, Moreno M, Lahm T, Zamanian RT, Machado R, Kawut SM, et  al. Health disparities in patients with pulmonary arterial hypertension: a blueprint for action. An official American Thoracic Society statement. Am J Respir Crit Care Med. 2017;196(8):e32–47. 5. Frost AE, Badesch DB, Barst RJ, et al. The changing picture of patients with pulmonary arterial hypertension in the United States: how REVEAL differs from historic and non-US contemporary registries. Chest. 2011;139(1):128–37. 6. Choudhary G, Jankowich M, Wu W-C.  Elevated pulmonary artery systolic pressure predicts heart failure admissions in African Americans: Jackson Heart Study. Circ Heart Fail. 2014;7:558–64. 7. Brittain EL, Nwabuo C, Xu M, et al. Echocardiographic pulmonary artery systolic pressure in the coronary artery risk development in young adults (CARDIA) study: associations with race and metabolic dysregulation. J Am Heart Assoc. 2017;6(4):e005111. Published 30 Mar 2017. https://doi.org/10.1161/JAHA.116.005111. 8. Yang BQ, Assad T, O’Leary JM, Xu M, et al. Racial differences in patients referred for right heart catheterization and risk of pulmonary hypertension. Pulm Circ. 2018;8(2):1–9. 9. Avouac J, Airo P, Meune C, et  al. Prevalence of pulmonary hypertension in systemic sclerosis in European Caucasians and meta-analysis of 5 studies. J Rheumatol. 2010;37: 2290–8. 10. Lefevre G, Dauchet L, Hachulla E, et al. Survival and prognostic factors in systemic sclerosis-­ associated pulmonary hypertension: a systematic review and meta-analysis. Arthritis Rheum. 2013;65:2412–23. 11. Moore DF, Kramer E, Eltaraboulsi R, Steen VD.  Increased morbidity and mortality of scleroderma in African Americans compared to Non-African Americans. Arthritis Care Res. 2019;71(9):1154. https://doi.org/10.1002/acr.23861. 12. Parikh K, Stackhouse K, Hart S, Bashore T, Krasuski R. Health insurance and racial disparities in pulmonary hypertension outcomes. Am J Manag Care. 2017;23(8):474–80. 13. Al-Naamani N, Paulus JK, Roberts KE, et  al. Racial and ethnic differences in pulmonary arterial hypertension. Pulm Circ. 2017;7(4):793–6. https://doi.org/10.1177/2045893217 732213. 14. Talwar A, Sahni S, Talwar A, Kohn N, Klinger JR. Socioeconomic status affects pulmonary hypertension disease severity at time of first evaluation. Pulm Circ. 2016;6(2):191–5. https:// doi.org/10.1086/686489. 15. Jin H, Granton JT, Thenganatt J, Moric J, Gupta A, Kron AT, Chau C, Johnson SR. Impact of socioeconomic status on survival in connective tissue disease associated and idiopathic pulmonary arterial hypertension [abstract]. Arthritis Rheumatol. 2015;67(suppl 10). 16. Carnes M, Johnson P, Klein W, Jenkins M, Bairey Merz CN. Advancing women’s health and women’s leadership with endowed chairs in women’s health. Acad Med. 2017;92(2):167–74. https://doi.org/10.1097/ACM.0000000000001423.

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17. Ginoux M, Turquier S, Chebib N, et  al. Impact of comorbidities and delay in diagnosis in elderly patients with pulmonary hypertension. ERJ Open Res. 2018;4:00100–2018. https://doi. org/10.1183/23120541.00100-2018. 18. Personalized Medicine Coalition. The case for personalized medicine. 2009 May. Available at: http://www.personalizedmedicinecoalition.org/Resources. Accessed 30 June 2015. 19. Deng Z, Morse JH, Slager SL, Cuervo N, Moore KJ, Venetos G, Kalachikov S, Cayanis E, Fischer SG, Barst RJ, et  al. Familial primary pulmonary hypertension (gene PPH1) is caused by mutations in the bone morphogenetic protein receptor-II gene. Am J Hum Genet. 2000;67:737–44. 20. Nichols WC, Koller DL, Slovis B, Foroud T, Terry VH, Arnold ND, Siemieniak DR, Wheeler L, Phillips JA III, Newman JH, et al. Localization of the gene for familial primary pulmonary hypertension to chromosome 2q31-32. Nat Genet. 1997;15:277–80. 21. Marchuk DA.  Genetic abnormalities in hereditary hemorrhagic telangiectasia. Curr Opin Hematol. 1998;5:332–8. 22. Austin ED, Ma L, LeDuc C, Berman Rosenzweig E, Borczuk A, Phillips JA III, Palomero T, Sumazin P, Kim HR, Talati MH, et al. Whole exome sequencing to identify a novel gene (caveolin-1) associated with human pulmonary arterial hypertension. Circ Cardiovasc Genet. 2012;5:336–43. 23. Ma L, Roman-Campos D, Austin ED, Eyries M, Sampson KS, Soubrier F, Germain M, Trégouët D-A, Borczuk A, Rosenzweig EB, et al. A novel channelopathy in pulmonary arterial hypertension. N Engl J Med. 2013;369:351–61. 24. Eyries M, Montani D, Girerd B, Perret C, Leroy A, Lonjou C, Chelghoum N, Coulet F, Bonnet D, Dorfmüller P, et al. EIF2AK4 mutations cause pulmonary veno-occlusive disease, a recessive form of pulmonary hypertension. Nat Genet. 2014;46:65–9. 25. Vadapalli S, Rani HS, Sastry B, Nallari P.  Endothelin-1 and endothelial nitric oxide polymorphisms in idiopathic pulmonary arterial hypertension. Int J Mol Epidemiol Genet. 2010;1:208–13. 26. Calabrò P, Limongelli G, Maddaloni V, Vizza CD, D’Alto M, D’Alessandro R, Poscia R, Argiento P, Ziello B, Badagliacca R, et al. Analysis of endothelin-1 and endothelin-1 receptor A gene polymorphisms in patients with pulmonary arterial hypertension. Intern Emerg Med. 2012;7:425–30. 27. Yu Y, Keller SH, Remillard CV, Safrina O, Nicholson A, Zhang SL, Jiang W, Vangala N, Landsberg JW, Wang J-Y, et al. A functional single-nucleotide polymorphism in the TRPC6 gene promoter associated with idiopathic pulmonary arterial hypertension. Circulation. 2009;119:2313–22. 28. Austin ED, Cogan JD, West JD, Hedges LK, Hamid R, Dawson EP, Wheeler LA, Parl FF, Loyd JE, Phillips JA III.  Alterations in oestrogen metabolism: implications for higher penetrance of familial pulmonary arterial hypertension in females. Eur Respir J. 2009;34:1093–9. 29. Damico R, Kolb TM, Valera L, Wang L, Housten T, Tedford RJ, Kass DA, Rafaels N, Gao L, Barnes KC, et al. Serum endostatin is a genetically determined predictor of survival in pulmonary arterial hypertension. Am J Respir Crit Care Med. 2015;191:208–18.

Index

C Chronic kidney disease (CKD) comorbidities, 177, 178 definition, 174 incidence, 175 molecular pathways anemia, 179, 180 calcium, phosphate and parathyroid harmone (PTH), 181 dialysis, 181, 182 inflammation, 180, 181 microangiopathy, 181 mortality, morbidity and healthcare costs, 175 pathophysiologic mechanisms, 178 prevalence, 174 screening and diagnosis, 182, 183 treatment, 185–187 uremic toxins, 179 Chronic lung disease with pulmonary hypertension (CLD-PH) Artemis-IPF trial, 116 BPHIT study, 116 clinical trials, 118 contraindications, 117 diagnosis, 110, 111 hemodynamic profile, 118, 119 inotropic agents, 116 medications, 110, 117 PAH vasodilators, 117 pathogenesis, 109 randomized controlled trials, 112, 115, 116 RISE-IIP study, 116 targeted therapy, 117 treatment, 111

Chronic thromboembolic disease clinical presentation, 77 complications, 74 definition, 72 diagnosis, 77, 78, 80, 81 ELOPE study, 74 incidence, 72, 74 management, 81–83 pathogenesis, 72 pathophysiology, 74–77 post-PE syndrome, 73 pulmonary endarterectomy (PEA), 72 residual perfusion defects, 74 Chronic thromboembolic pulmonary hypertension (CTEPH), 159–160 Combined post- and pre-capillary PH (Cpc-PH), 61, 62, 66, 67 Connective tissue disease with pulmonary arterial hypertension (CTD-PAH) complications, 51 epidemiology of, 52–54 prevalence, 52 screening guidelines, 54 routine programs, 56 scleroderma spectrum diseases, 54, 55 SLE-PAH, 55, 56 treatment follow-up and multidisciplinary management, 56 immunosuppression, 57 PAH-specific medications, 56 Riociguat, 57 selexipag, 56

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Index

204 E End stage renal disease (ESRD) comorbidities, 177, 178 incidence, 175 molecular pathways anemia, 179, 180 calcium, phosphate and parathyroid harmone (PTH), 181 dialysis, 181, 182 inflammation, 180, 181 microangiopathy, 181 mortality, morbidity and healthcare costs, 175 pathophysiologic mechanisms, 178 prevalence, 174 screening and diagnosis, 182, 183 treatment, 185–187 uremic toxins, 179 Epoprostenol, 150–152 Exercise pulmonary hypertension (ePH) age-related pulmonary vascular changes, 4, 5 alpha (α), 15, 16 cardiac output measurement, 14, 15 confrontational exercise testing, 5–7 definition, 1 exercise hemodynamics, 11–13 extravascular lung water, 9 follow-up intervals, 13 heart failure with preserved ejection fraction (HFpEF), 7, 8 hemodynamic changes, 13 hemodynamic criteria, 3, 4 iCPET study hemodynamic pressure measurements, 8, 22 invasive cardiopulmonary exercise testing (iCPET), 2, 10 invasive exercise hemodynamics, 20, 21 left ventricular filling resistance, 7 metabolomic signatures, 13 molecular alterations, 11 normal resting and exercise pulmonary hemodynamics, 2–3 pulmonary artery wedge pressure (PAWP), 7, 9 pulmonary microvasculopathy, 16, 17 pulmonary vasculature pathology, 10, 11 pulmonary vasodilators, 14 resting PAH, 14 RHC-confirmed PAH, 13 risk factors, 2 treatment, 17, 20 Exercise pulmonary venous hypertension (ePVH), 2

G Gender and race disparities age, 198, 199 American Thoracic Society Statement recommendations, 200 CARDIA cohort study, 196 cardiovascular diseases, 197 definition, 195 etiology, 196 genetic contributors, 199 NIH registry, 196 patient registries, 196 prevalence, 195, 196 REVEAL registry, 196 scleroderma associated PAH (SSc-­ PAH), 197 socioeconomic status (SES), 197, 198 I Invasive cardiopulmonary exercise testing (iCPET), 2, 10 Isolated post-capillary PH (Ipc-PH), 61, 62, 66, 67 J Jackson Heart study, 177 M Mixed connective tissue disease, 53 P Parenteral prostacyclin therapy ACC/AHA guidelines, 149 clinical practice, 149 epoprostenol, 150–152 parenteral therapies, 161–163 patient-related features, 163, 164 physiologic effects, 147–149 psychological components, 164 therapeutic trials demographic factors, 154 exercise limitations, 154 FDA-approved therapies, 153 patient selection and inclusion, 155 placebo-controlled trials, 154 six-minute walk distance (6MWD), 154 study duration, 155 treprostinil, 152, 153 WHO group 1 connective heart disease, 157, 158

Index connective tissue disease, 156, 157 drug and toxins, 158, 159 human immunodeficiency virus (HIV), 159 idiopathic and heritable PAH, 155, 156 portopulmonary hypertension, 158 pulmonary veno-occlusive disease (PVOD), 159 schistosomiasis-associated PAH, 159 WHO group 4, 159, 160 WHO group 5, 160 PH in heart failure with preserved ejection fraction (PH-HFpEF), 61 Pulmonary endarterectomy (PEA), 72 Pulmonary hypertension (PH) Group I PH, 173 Group II PH, 174 Group III PH, 174 Group IV PH, 174 Group V PH, 174 PH-HFpEF, see PH in heart failure with preserved ejection fraction (PH-HFpEF), 61 Pulmonary hypertension due to left heart disease (PH-LHD) combined post- and pre-capillary PH (Cpc-PH), 61, 62, 66, 67 definition, 66 diagnostic investigation, 62 echocardiographic score, 62 hemodynamic variables, 63–66 invasive hemodynamics, 62 isolated post-capillary PH (Ipc-PH), 61, 62, 66, 67 pre- and postcapillary PH, 62 prognostic power of the diastolic pulmonary vascular gradient (DPG), 65 Pulmonary veno-occlusive disease and pulmonary capillary hemangiomatosis (PVOD-PCH) autopsy features, 90 bronchoalveolar lavage, 99, 100 clinical and pathologic evidence, 89, 91 clinical classification system, 90–93 clinical features and diagnosis, 90, 95 echocardiography and hemodynamics, 96, 97 epidemiology, 93 genetics, 93, 94 management imatinib, 104 immunosuppression, 103 lung transplantation, 102

205 PAH-specific therapy, 101–103 supportive care, 102 medications, 100 nongenetic risk factors, 94, 95 noninvasive diagnosis, 100 pathology, 90 prognosis, 101 pulmonary function studies, 99 radiology, 97, 99 symptoms and signs, 96 R Right ventricular assessment anatomy, 30 determinants, 33 diastolic stiffness, 43 heart rate and rhythm, 34 preload, afterload and interventricular dependence, 34–37 pressure-volume loops of normal left ventricle, 37, 38 of right ventricle, 39–41 ventricular determinants, 39, 40 pulmonary artery wedge pressure (PAWP), 33 pulmonary vascular impedance, 31 pulmonary vascular resistance (PVR), 30 resistance (R) and compliance (C), 31, 32 right heart catherization (RHC), 36, 37 ventricular-vascular coupling clinical applications, 42, 43 definition, 41 Ees/Ea ratio, 41, 42 noninvasive methods, 43 Windkessel model, 31 Riociguat, 57 S Sarcoidosis-associated pulmonary hypertension (SAPH) cytokine derangement, 137, 138 echocardiographic criteria, 136, 141 extrinsic compression, 138 history and physical examination, 140 hypoxic vasoconstriction and destruction of capillary bed, 137 immunosuppressive therapy, 144 incidence, 135 intrinsic vascular disease, 138, 139 morbidity and mortality, 144 PAH-specific therapy, 144 pathophysiology, 137

Index

206 Sarcoidosis-associated pulmonary hypertension (SAPH) (cont.) prevalence, 136, 138, 140 pulmonary function testing, 140 right heart catheterization, 141 Scadding Criteria, 135, 136 serum biomarkers, 140 six minute walk test, 140 treatment, 141–144 Sarcoplasmic endoplasmic reticulum calcium-ATPase (SERCA), 34 Scadding Criteria, 135, 136 Scleroderma, 52 Selexipag, 56 Sickle cell disease (SCD) autopsy studies, 128 cardiovascular risk - red cell exchange trial, 130 chronic thromboembolic PH (CTEPH), 129 classification, 124 diagnosis, 125, 126 echocardiographic measures, 127 histopathological characterization, 125 hydroxyurea and chronic exchange transfusions, 129, 130 mortality risk, 123

mPAP and PVR elevation, 128 pathogenic mechanisms, 123 placebo-controlled randomized clinical trial, 124 post-capillary PH, 124, 125 pre-capillary PH, 123 pulmonary arterial hypertension (PAH) therapy, 130, 131 pulmonary endarterectomy, 129 pulmonary hemodynamic derangement, 129 right heart catheterization, 126, 128 vasoocclusion, 123 venous thromboembolism (VTE), 130 ventilation perfusion (V/Q) scintigraphy, 129 Sjögren’s syndrome, 53 T Treprostinil, 152, 153 W Windkessel model, 31 World Symposia on Pulmonary Hypertension (WSPH), 124