Somatic Mutations in Pulmonary Arterial Hypertension - ATS Journals

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physiology of disease in those with and without BMPR2 muta- tions. While rare somatic mutations of the BMPR2 gene within pulmonary vasculature cells could ...



antiproliferative agents, or even fibrinolytics could yield better outcomes, and it is conceivable that the survival benefit of drotrecogin a in sepsis-related ARDS (14) is at least partly related to amelioration of the pulmonary vasculopathy, but these hypotheses and others remain to be tested. Nevertheless, there seems little doubt that agents capable of attenuating the initial endothelial injury and/or interrupting the subsequent cascade of events that produce the acute lung (and other organ) injury would also prevent the pulmonary vasculopathy. Despite the many studies that have provided insights into the mechanisms of injury leading to ARDS, finding such agents remains a daunting challenge in ARDS therapy. The concluding statement made by Tomashefsky and coworkers (3) nearly 30 years ago—that ‘‘an understanding of the basic mechanisms of lung injury in ARDS may eventually lead to the development of specific pharmacologic agents to protect the vascular endothelium’’ and prevent the development of seemingly irreversible pulmonary vascular changes—rings as true today as it did then. Author Disclosure: N.S.H. has received industy-sponsored grants from United Therapeutics, Actelion, Pfizer, Gilead, and Bayer (each $10,001–$50,000). He has received royalties from Humana Publishers ($1,001–$5,000). He has received a research grant from Genzyme ($10,001–$50,000). K.R. has no financial relationship with a commercial entity that has an interest in the subject of this manuscript. I.R.P. has received advisory board fees from Actelion ($5,001– $10,000), Bayer (up to $1,000), Gilead ($5,001–$10,000), and United Therapeutics ($1,001–$5,000). She has received industry-sponsored grants from Actelion, Gilead, Novartis, and GeNo (each $10,001–$50,000).

Nicholas S. Hill, M.D. Kari Roberts, M.D. Ioana Preston, M.D. Division of Pulmonary Critical Care and Sleep Medicine Tufts Medical Center Boston, Massachusetts

References 1. Blaisdell FW. Pathophysiology of the respiratory distress syndrome. Arch Surg 1974;108:44–49. 2. Zapol WM, Snider MT. Pulmonary hypertension in severe acute respiratory failure. N Engl J Med 1977;296:476–480.

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3. Tomashefski JF Jr, Davies P, Boggis C, Greene R, Zapol WM, Reid LM. The pulmonary vascular lesions of the adult respiratory distress syndrome. Am J Pathol 1983;112:112–126. 4. Tomashefski JF Jr. Pulmonary pathology of the acute respiratory (diffuse alveolar damage). New York: Marcel Dekker; 2003. 5. Greene R, Lind S, Jantsch H, Wilson R, Lynch K, Jones R, Carvalho A, Reid L, Waltman AC, Zapol W. Pulmonary vascular obstruction in severe ARDS: angiographic alterations after V. Fibrinolytic therapy. AJR Am J Roentgenol 1987;148:501–508. 6. Zapol WM, Kobayashi K, Snider MT, Greene R, Laver MB. Vascular obstruction causes pulmonary hypertension in severe acute respiratory failure. Chest 1977;71:306–307. 7. Hill NS, Rounds S. Vascular reactivity is increased in rat lungs injured with a-naphthyl-thiourea. J Appl Physiol 1983;54:1693–1701. 8. Rossaint R, Falke KJ, Lopez F, Slama K, Pison U, Zapol WM. Inhaled nitric oxide for the adult respiratory distress syndrome. N Engl J Med 1993;328:399–405. 9. Adhikari NK, Burns KE, Friedrich JO, Granton JT, Cook DJ, Meade MO. Effect of nitric oxide on oxygenation and mortality in acute lung injury: Systematic review and meta-analysis. BMJ 2007;334: 779–786. 10. Bull TM, Clark B, McFann K, Moss M; NIH NHLBI ARDS Network. Pulmonary vascular dysfunction is associated with poor outcomes in patients with acute lung injury. Am J Respir Crit Care Med 2010;182: 1123–1128. 11. The National Heart, Lung, and Blood Institute Acute Respiratory Distress Syndrome (ARDS) Clinical Trials Network. Pulmonaryartery versus central venous catheter to guide treatment of acute lung injury. N Engl J Med 2006;354:2213–2224. 12. Vieillard-Baron A, Schmitt JM, Augarde R, Fellahi JL, Prin S, Page B, Beauchet A, Jardin F. Acute cor pulmonale in acute respiratory distress syndrome submitted to protective ventilation: incidence, clinical implications, and prognosis. Crit Care Med 2001;29:1551– 1555. 13. Cornet AD, Hofstra JJ, Swart EL, Girbes AR, Juffermans NP. Sildenafil attenuates pulmonary arterial pressure but does not improve oxygenation during ARDS. Intensive Care Med 2010;36: 758–764. 14. Bernard GR, Vincent JL, Laterre PF, LaRosa SP, Dhainaut JF, LopezRodriguez A, Steingrub JS, Garber GE, Helterbrand JE, Wesley EW, et al.; Recombinant Human Activated Protein C Worldwide Evaluation in Severe Sepsis (PROWESS) Study Group. Efficacy and safety of recombinant human activated protein C for severe sepsis. N Engl J Med 2001;344:699–709.

DOI: 10.1164/rccm.201007-1116ED

Somatic Mutations in Pulmonary Arterial Hypertension Primary or Secondary Events? Pulmonary arterial hypertension (PAH) is a devastating pulmonary vascular disease characterized by pulmonary arterial obstruction that causes a progressive increase in pulmonary vascular resistance, ultimately leading to right ventricular failure and death (1). While persistent vasoconstriction contributes to the pathophysiology of disease, the predominant histopathologic finding in PAH is a profound remodeling of the pulmonary arterioles, characterized by intimal hyperplasia, medial hypertrophy, proliferation and fibrosis of the adventitial layer, and infiltration by circulating cells (2). The cellular and molecular processes involved are an area of intense investigation, and involve proliferation and dysfunction of both endothelial and Supported by National Institutes of Health funding HL098743 (E.D.A), RR1 7697 (E.D.A.), HL095401 (F.A.), and HL089903 (R.H.). Also supported by a Doris Duke Charitable Foundation Clinical Scientist Development Grant (F.A.), an American Heart Association Scientist Development Grant 053531N (F.A.), and the American Respiratory Alliance of Western Pennsylvania (F.A.).

smooth muscle cells, as well as fibroblast activation and the recruitment of circulating cells (3). Luminal obliteration due to cellular proliferation, as well as prior evidence of endothelial cell monoclonality and somatic endothelial cell gene mutations, highlight the features which suggest that PAH may be more of an angioproliferative disorder with neoplastic features than previously believed (4–7). In this issue of the Journal, Aldred and colleagues (pp. 1153–1160) advance the hypothesis that the acquisition of somatic mutations within the lung promotes the development of complex vascular lesions with neoplastic features (8). While the most severe lesions characteristic of PAH are not truly cancer, the histologic features of abnormal and uncontrolled cell growth do suggest a process ‘‘akin to neoplasia’’ (6, 9). The association of germline mutations in bone morphogenetic protein receptor type II (BMPR2) (a type of transforming growth factor [TGF]-b receptor) with familial and idiopathic PAH suggests that BMPR2 may be a key player in this process in all forms of PAH,


perhaps as the ‘‘brake on proliferation’’ akin to a tumor suppressor gene. Mutations in BMPR2 associate with the majority of familial PAH cases, as well as approximately 15% of idiopathic PAH (IPAH) cases, while BMPR2 gene expression is reduced in the lungs of patients with multiple forms of PAH (7, 10–13). However, the low penetrance of disease among BMPR2 mutation carriers suggests that additional factors contribute to the pathophysiology of disease in those with and without BMPR2 mutations. While rare somatic mutations of the BMPR2 gene within pulmonary vasculature cells could cause or aggravate BMPR2 haploinsufficiency, previous work has failed to find this to be true among those with a germline BMPR2 mutation (14). In contrast, the current study by Aldred and colleagues demonstrates somatic changes in a BMPR2 mutation carrier with PAH at a locus on chromosome 13 which contains additional genes relevant to BMP signaling (SMAD9 gene) as well as control of cell growth (RB1 and BRCA2 genes). While this is particularly interesting given the importance of SMADs to BMP signaling and experimental PAH as well as the association of a SMAD9 mutation with IPAH, only one of the two BMPR2 mutation carriers studied had detectable somatic mutations (15). Further investigation is warranted before somatic changes can be confidently labeled a definitive ‘‘second hit’’ among BMPR2 mutation carriers. The finding of the same chromosomal abnormality at multiple discrete locations in the lungs by Aldred and colleagues may suggest that somatic changes occur irrespective of plexiform lesion development, but this too requires further investigation. Interestingly, somatic mutations have now been identified within other complex vascular lesions such as cerebral cavernous malformations, both as a ‘‘second hit’’ phenomenon in familial patients, as well as among patients with idiopathic vascular anomalies (16). This creates an interesting parallel with the endothelial cells of BMPR2-associated PAH and perhaps other forms of PAH. However, further studies are required to determine whether the reduced penetrance, variable expressivity, and multifocality of lesions in inherited vascular anomalies is associated with a progressive accumulation of somatic mutations. Interestingly, hereditary hemorrhagic telangiectasia is a familial disorder of complex vascular lesions that is associated with TGFb receptor mutations (ALK1 and endoglin), as well as reduced penetrance and variable expressivity of PAH (17, 18). The pulmonary vascular bed has a tremendous reserve to accept gradual reductions in surface area prior to the development of detectable pulmonary hypertension, such that by the time of diagnosis tremendous destruction is globally evident by angiography (19, 20). Although the plexiform lesion is a hallmark of severe PAH, it remains unclear whether the lesion is present throughout the lung in early stage disease, and whether it is a cause or effect of severe pulmonary hypertension (21). In addition, the true cellular composition of the plexiform lesion is probably as dynamic as it is mysterious, likely at least composed of proliferative endothelial cells with an uncertain contribution of smooth muscle cells, myofibroblasts, and other cell types (22). Given the intimate association of endothelial cell changes and the plexiform lesion, this work by Aldred and colleagues is provocative as the first study to document somatic mutations in the endothelial cells of end-stage PAH lungs. Furthermore, the finding of differential changes between endothelial and smooth muscle cells would be consistent with the perceived central role of endothelial cells in the pathogenesis of disease (3). However, as the authors state, it is difficult to discern whether the plexiform lesion represents a primary or secondary phenomenon with regard to the underlying pulmonary vasculopathy. Furthermore, more advanced studies will be necessary to evaluate whether the somatic mutations impair the signaling or function of involved cells, as well as if possession of a small


percentage of mutated cells is even relevant to the vascular bed. To determine that somatic mutations are the primary cause of PAH would require evidence that such mutations occur prior to any detectable disease. Given the limitations of available tissue at early stages of disease, such a study will be very difficult. The development of methods to detect pulmonary vascular changes earlier, particularly among susceptible individuals, would be highly valuable. For now, experimental models of PAH may provide a productive resource to examine the lung tissue at different time points in disease pathogenesis to answer some of the questions that arise as a result of the interesting findings reported by Aldred and colleagues. Author Disclosure: E.D.A. has received industry-sponsored grants from Actelion Pharmaceuticals US, Inc. ($50,001–$100,000); he has received sponsored grants from the National Institutes of Health (NIH) National Heart, Lung, and Blood Institute (NHLBI) (over $100,000), and three sponsored grants from Vanderbilt University (two over $100,000, and one $10,001–$50,000). F.A. has received sponsored grants from the NIH (over $100,000) and the American Respiratory Alliance ($5001–$10,000). R.H. has received sponsored grants from the NHLBI and ACS (each over $100,000).

Eric D. Austin, M.D., M.S.C.I. Rizwan Hamid, M.D., Ph.D Department of Pediatrics Vanderbilt University Medical Center Nashville, Tennessee Ferhaan Ahmad, M.D., Ph.D Cardiovascular Institute, Departments of Medicine and Human Genetics University of Pittsburgh Pittsburgh, Pennsylvania The authors contributed equally to this editorial.

References 1. Archer SL, Weir EK, Wilkins MR. Basic science of pulmonary arterial hypertension for clinicians: new concepts and experimental therapies. Circulation 2010;121:2045–2066. 2. Tuder RM, Abman SH, Braun T, Capron F, Stevens T, Thistlethwaite PA, Haworth SG. Development and pathology of pulmonary hypertension. J Am Coll Cardiol 2009;54:S3–S9. 3. Morrell NW, Adnot S, Archer SL, Dupuis J, Jones PL, MacLean MR, McMurtry IF, Stenmark KR, Thistlethwaite PA, Weissmann N, et al. Cellular and molecular basis of pulmonary arterial hypertension. J Am Coll Cardiol 2009;54:S20–S31. 4. Tuder RM, Groves B, Badesch DB, Voelkel NF. Exuberant endothelial cell growth and elements of inflammation are present in plexiform lesions of pulmonary hypertension. Am J Pathol 1994;144:275–285. 5. Yeager ME, Golpon HA, Voelkel NF, Tuder RM. Microsatellite mutational analysis of endothelial cells within plexiform lesions from patients with familial, pediatric, and sporadic pulmonary hypertension. Chest 2002;121:61S. 6. Rai PR, Cool CD, King JA, Stevens T, Burns N, Winn RA, Kasper M, Voelkel NF. The cancer paradigm of severe pulmonary arterial hypertension. Am J Respir Crit Care Med 2008;178:558–564. 7. Lee SD, Shroyer KR, Markham NE, Cool CD, Voelkel NF, Tuder RM. Monoclonal endothelial cell proliferation is present in primary but not secondary pulmonary hypertension. J Clin Invest 1998;101:927– 934. 8. Aldred MA, Comhair SA, Varella-Garcia M, Asosingh K, Xu W, Noon GP, Thistlethwaite PA, Tuder RM, Erzurum SC, Geraci MW, et al. Somatic chromosome abnormalities in the lungs of patients with pulmonary arterial hypertension. Am J Respir Crit Care Med 2010; 182:1153–1160. 9. Humbert M, Hoeper MM. Severe pulmonary arterial hypertension: a forme fruste of cancer? Am J Respir Crit Care Med 2008;178:551– 552. 10. 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; 67:737–744. Aldred MA, Vijayakrishnan J, James V, Soubrier F, Gomez-Sanchez MA, Martensson G, Galie N, Manes A, Corris P, Simonneau G, et al. BMPR2 gene rearrangements account for a significant proportion of mutations in familial and idiopathic pulmonary arterial hypertension. Hum Mutat 2006;27:212–213. Thomson JR, Machado RD, Pauciulo MW, Morgan NV, Humbert M, Elliott GC, Ward K, Yacoub M, Mikhail G, Rogers P, et al. Sporadic primary pulmonary hypertension is associated with germline mutations of the gene encoding BMPR-II, a receptor member of the TGFbeta family. J Med Genet 2000;37:741–745. Atkinson C, Stewart S, Upton PD, Machado R, Thomson JR, Trembath RC, Morrell NW. Primary pulmonary hypertension is associated with reduced pulmonary vascular expression of type II bone morphogenetic protein receptor. Circulation 2002;105:1672–1678. Machado RD, James V, Southwood M, Harrison RE, Atkinson C, Stewart S, Morrell NW, Trembath RC, Aldred MA. Investigation of second genetic hits at the BMPR2 locus as a modulator of disease progression in familial pulmonary arterial hypertension. Circulation 2005;111:607–613. Shintani M, Yagi H, Nakayama T, Saji T, Matsuoka R. A new nonsense mutation of SMAD8 associated with pulmonary arterial hypertension. J Med Genet 2009;46:331–337.

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16. Brouillard P, Vikkula M. Genetic causes of vascular malformations. Hum Mol Genet 2007;16:R140–R149. 17. Trembath RC, Thomson JR, Machado RD, Morgan NV, Atkinson C, Winship I, Simonneau G, Galie N, Loyd JE, Humbert M, et al. Clinical and molecular genetic features of pulmonary hypertension in patients with hereditary hemorrhagic telangiectasia. N Engl J Med 2001;345:325–334. 18. Lebrin F, Mummery CL. Endoglin-mediated vascular remodeling: mechanisms underlying hereditary hemorrhagic telangiectasia. Trends Cardiovasc Med 2008;18:25–32. 19. Dexter L. Pulmonary vascular disease in acquired and congenital heart disease. Arch Intern Med 1979;139:922–928. 20. Ilsar R, Chawantanpipat C, Chan KH, Dobbins TA, Waugh R, Hennessy A, Celermajer DS, Ng MK. Measurement of pulmonary flow reserve and pulmonary index of microcirculatory resistance for detection of pulmonary microvascular obstruction. PLoS ONE 2010;5:e9601. 21. Fishman AP. Changing concepts of the pulmonary plexiform lesion. Physiol Res 2000;49:485–492. 22. Abe K, Toba M, Alzoubi A, Ito M, Fagan KA, Cool CD, Voelkel NF, McMurtry IF, Oka M. Formation of plexiform lesions in experimental severe pulmonary arterial hypertension. Circulation 2010;121:2747– 2754.

DOI: 10.1164/rccm.201007-1147ED

Prognostication of Pulmonary Embolism Not Just a Matter of the Heart Hemodynamic status has significant prognostic implications for patients diagnosed with acute pulmonary embolism (PE). Massive PE, defined by the presence of arterial hypotension or shock, accounts for 5% of all cases of PE and has a short-term mortality of at least 15% (1). In the subgroup of normotensive patients with acute PE, rapid and accurate prognostication and risk stratification have focused mainly on right ventricular (RV) dysfunction and/or injury to the myocardium as a result of acute pressure overload. Accordingly, the guidelines by the European Society of Cardiology recommended that clinicians use markers of RV dysfunction (i.e., echocardiography, spiral computed tomography, or brain natriuretic peptide testing) and markers of myocardial injury (i.e., cardiac troponin T or I testing) to assess the severity of PE (2). Some meta-analyses and registries supported the notion that markers of RV dysfunction or myocardial injury may predict adverse outcomes (3, 4). However, conflicting conclusions about the prognostic ability of such markers from a recently published meta-analysis (5) and a large cohort study (6) have prompted further debate. Some recent studies assessed the prognostic validity of tests that assess thrombus burden (i.e., D-dimer, complete lower limb compression ultrasound) or severity of illness based on variables collected during the evaluation for suspected PE (i.e., Pulmonary Embolism Severity Index [PESI]). A prospective cohort study demonstrated that concomitant deep vein thrombosis (DVT) diagnosed by lower extremity compression ultrasonography independently predicted adverse outcomes among patients presenting with acute symptomatic PE (7); patients with DVT had a twofold increase in short-term mortality compared with those without DVT. Studies have also validated the PESI for predicting short-term all-cause and PE-specific mortality in patients diagnosed with acute PE. Aujesky and colleagues derived the PESI from 10,354 inpatients with a hospital discharge diagnosis of PE from 186 Pennsylvania hospitals in the United States (8). One study compared the usefulness of the PESI and troponin testing for the identification of low-risk patients with acute symptomatic PE

(9). Compared with cardiac troponin I testing, PESI classification more accurately identified patients with PE who had a low risk of all-cause death within 30 days of presentation. Although abnormal cardiac tests may function as markers of decreased cardiorespiratory reserve in patients with PE, they may not capture the prognostic significance of other important clinical factors such as age, cancer, or previous lung or cardiac disease. In this issue of the Journal (pp. 1178–1183), Scherz and colleagues demonstrate the prognostic significance of hyponatremia in patients with acute symptomatic PE (10). In a retrospective cohort study, they studied 13,728 patients diagnosed with acute PE, of whom 9% died within 30 days. Hyponatremia, defined as a baseline serum sodium level of 135 mmol/L or less, had a prevalence of 21%. The presence and the severity of the hyponatremia predicted adverse outcome. Compared with patients without hyponatremia, those with hyponatremia had a significantly greater risk of death in the 30 days after diagnosis of PE (for those with sodium 130–135 mmol/L: adjusted odds ratio [OR], 1.53; 95% confidence interval [CI], 1.33–1.76; for those with sodium ,130 mmol/L: adjusted OR, 3.26; 95% CI, 2.48–4.29). Patients with hyponatremia also had a higher risk of readmission than those without hyponatremia (for those with sodium 130–135 mmol/L: adjusted OR, 1.28; 95% CI, 1.12–1.46; for those with sodium ,130 mmol/L: adjusted OR, 1.44; 95% CI, 1.02–2.02). Interestingly, when the investigators excluded 5,951 patients with a history of cancer, chronic lung disease, or heart failure from the analyses, the study had similar findings. Limitations of the study included its retrospective design. Also, the study could not assess the prognostic implications of transient versus persistent hyponatremia because it did not assess sodium levels after hospital discharge. Hyponatremia serves as a marker of neurohormonal activation in patients with left ventricular heart failure. Heart failure results in marked activation of the renin–angiotensin system and increases catecholamine production. These events promote renal vasoconstriction and lead to diminished glomerular filtration. Subsequent delivery of tubular fluid to the diluting segment of the

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