Epidemiology of Pulmonary Arterial Hypertension Darren B. Taichman, MD, PhD a,b, *, Jess Mandel, MD c INTRODUCTION The last 2 decades have seen an expansion of in- terest in pulmonary arterial hypertension (PAH) as new treatments have been introduced and new in- sights into pulmonary vascular biology obtained. Over this period the epidemiology of PAH has evolved as echocardiography became ubiquitous, the availability of treatments promoted clinicians to pursue the diagnosis of PAH with greater vigor, and the classification of PAH underwent several revisions. Changes in the Classification of the Pulmonary Hypertensive Diseases An unexplained sclerosis of the pulmonary arteries was first documented in 1891 by Ernst von Rom- berg, 1 and again described as cardiacos negros in 1901 by Abel Ayerza because of the degree of cyanosis that patients could develop. Thereafter, his colleagues referred to the entity as Ayerza disease, and thought it was a consequence of luetic (syphilitic) vasculitis, although some cases were described in patients with advanced lung dis- ease. Little more was understood until the 1940s when Oscar Brenner reported the histopathologic changes in the arteries of 100 patients with pulmo- nary hypertension (PH), notably lacking findings that suggested syphilis as a cause. In the 1950s, when the advent of cardiac catheterization al- lowed an investigation of the disease’s hemody- namic abnormalities, 2 Dresdale and colleagues 3 performed cardiac catheterization and described a hypertensive vasculopathy of the pulmonary cir- culation. It was characterized by vasoconstriction, an increase in pulmonary arterial pressures, and a measurable response to the injection of tolazoline, a vasodilator with both pulmonary and systemic effects. When no cause such as mitral stenosis or emphysema could be identified in these pa- tients, the entity was termed primary PH. Cases of PH for which a cause could be established a Annals of Internal Medicine, American College of Physicians; b Penn Presbyterian Medical Center, University of Pennsylvania Perelman School of Medicine, 190 North Independence Mall West, Philadelphia, PA 19104, USA; c University of California, San Diego School of Medicine, 9500 Gilman Drive #0606, La Jolla, CA 92093-0606, USA * Corresponding author. Penn Presbyterian Medical Center, University of Pennsylvania Perelman School of Medicine, 190 North Independence Mall West, Philadelphia, PA 19104. E-mail address: [email protected]KEYWORDS Pulmonary arterial hypertension Idiopathic pulmonary arterial hypertension HIV infection Portopulmonary hypertension Systemic sclerosis Hemolytic anemia Pulmonary veno-occlusive disease Anorectic drugs KEY POINTS Changes in the epidemiology of pulmonary arterial hypertension (PAH) have resulted in changes in classification schemes and an increased emphasis on diagnosis because of the availability of effec- tive therapies. The terms primary pulmonary hypertension and secondary pulmonary hypertension are considered inappropriate, confusing, and should not be used. Recent registries of patients with PAH have provided improved data regarding prognosis in the era of advanced therapies. Clin Chest Med 34 (2013) 619–637 http://dx.doi.org/10.1016/j.ccm.2013.08.010 0272-5231/13/$ – see front matter Ó 2013 Elsevier Inc. All rights reserved. chestmed.theclinics.com
Transcript
Epidemiology of PulmonaryArterial Hypertension
Darren B. Taichman, MD, PhDa,b,*, Jess Mandel, MDc
� Changes in the epidemiology of pulmonary arterial hypertension (PAH) have resulted in changes inclassification schemes and an increased emphasis on diagnosis because of the availability of effec-tive therapies.
� The terms primary pulmonary hypertension and secondary pulmonary hypertension are consideredinappropriate, confusing, and should not be used.
� Recent registries of patients with PAH have provided improved data regarding prognosis in the eraof advanced therapies.
INTRODUCTION
The last 2 decades have seen an expansion of in-terest in pulmonary arterial hypertension (PAH) asnew treatments have been introduced and new in-sights into pulmonary vascular biology obtained.Over this period the epidemiology of PAH hasevolved as echocardiography became ubiquitous,the availability of treatments promoted cliniciansto pursue the diagnosis of PAH with greater vigor,and the classification of PAH underwent severalrevisions.
Changes in the Classification of thePulmonary Hypertensive Diseases
An unexplained sclerosis of the pulmonary arterieswas first documented in 1891 by Ernst von Rom-berg,1 and again described as cardiacos negrosin 1901 by Abel Ayerza because of the degree ofcyanosis that patients could develop. Thereafter,his colleagues referred to the entity as Ayerza
a Annals of Internal Medicine, American College of Physiof Pennsylvania Perelman School of Medicine, 19019104, USA; c University of California, San Diego School92093-0606, USA* Corresponding author. Penn Presbyterian Medical CeMedicine, 190 North Independence Mall West, PhiladelpE-mail address: [email protected]
Clin Chest Med 34 (2013) 619–637http://dx.doi.org/10.1016/j.ccm.2013.08.0100272-5231/13/$ – see front matter � 2013 Elsevier Inc. All
disease, and thought it was a consequence ofluetic (syphilitic) vasculitis, although some caseswere described in patients with advanced lung dis-ease. Little more was understood until the 1940swhen Oscar Brenner reported the histopathologicchanges in the arteries of 100 patients with pulmo-nary hypertension (PH), notably lacking findingsthat suggested syphilis as a cause. In the 1950s,when the advent of cardiac catheterization al-lowed an investigation of the disease’s hemody-namic abnormalities,2 Dresdale and colleagues3
performed cardiac catheterization and describeda hypertensive vasculopathy of the pulmonary cir-culation. It was characterized by vasoconstriction,an increase in pulmonary arterial pressures, and ameasurable response to the injection of tolazoline,a vasodilator with both pulmonary and systemiceffects. When no cause such as mitral stenosisor emphysema could be identified in these pa-tients, the entity was termed primary PH. Casesof PH for which a cause could be established
cians; b Penn Presbyterian Medical Center, UniversityNorth Independence Mall West, Philadelphia, PAof Medicine, 9500 Gilman Drive #0606, La Jolla, CA
nter, University of Pennsylvania Perelman School ofhia, PA 19104.
Adapted from Simonneau G, Robbins IM, Beghetti M,et al. Updated clinical classification of pulmonaryhypertension. J Am Coll Cardiol 2009;54(1 Suppl):S43–54; with permission.
Taichman & Mandel620
were thereafter labeled secondary PH (eg, PH sec-ondary to left ventricular failure, chronic pulmonarydiseases, hypoxemia).4 Later, using acetylcholine,a vasodilator that was cleared exclusively withinthe pulmonary circulation, Paul Wood showed apulmonary-specific hemodynamic improvementin patients with primary PH.2 Intense pathologicevaluation in a series of 156 patients permittedWagenvoort and Wagenvoort5 to describe ex-tensive vascular injury and remodeling, whichthey termed plexogenic pulmonary arteriopathy,thought to be the pathognomonic hallmark of thedisease.Although the terms primary, secondary, and
plexogenic PH were used for many years, anappreciation of important similarities and differ-ences in the histopathologic and clinical charac-teristics of varying patient groups has promptedthe adoption of more precise terminology. In partto reach consensus on clinically useful classifica-tion schemes for the pulmonary hypertensive dis-orders, there have been several internationalworking groups under the sponsorship of theWorld Health Organization (WHO) since 1973.These classification schemes have evolved asnew information has emerged regarding bothpathophysiologic mechanisms and clinical char-acteristics. Histologic findings are no longer thecornerstone of clinical classification because fewof the pathologic patterns observed are diseasespecific, biopsies are now rarely performed, andpostmortem diagnoses are, by definition, notclinically useful. The current approach to classifi-cation (Box 1) is based on a hemodynamic defini-tion of PH, coupled with clinical and associatedcharacteristics.PH is deemed present when the mean pulmo-
nary artery pressure exceeds 25 mm Hg at rest.The presence of PAH further requires normal leftheart filling pressures (ie, a normal left ventricularend diastolic pressure directly measured, or indi-rectly approximated by a pulmonary artery wedgepressure less than or equal to 15 mm Hg). Classi-fication as PAH further requires the absence ofsignificant chronic respiratory disease or thrombo-embolic disease.The distinction between the entities classified
as PAH and the other known causes of PH (eg,
Box 2Risk factors for the development of PAH
A. Drugs and toxins
1. Definite
� Aminorex
� Fenfluramine
� Dexfenfluramine
� Toxic rapeseed oil
� Dasatinib
2. Very likely
� Amphetamines
� L-Tryptophan
� Interferon
3. Possible
� Meta-amphetamines
� Cocaine
� Chemotherapeutic agents
� Antidepressants
4. Unlikely
� Oral contraceptives
� Estrogen therapy
� Cigarette smoking
B. Demographic and medical conditions
1. Definite
� Female gender
2. Possible
� Pregnancy
� Systemic hypertension
3. Unlikely
� Obesity
C. Diseases
1. Definite
� HIV infection
2. Very likely
� Portal hypertension/liver disease
� Collagen vascular diseases
� Congenital systemic-pulmonary-cardiacshunts
� Splenectomy
3. Possible
� Thyroid disorders
Adapted and updated from the assessment of riskfactors evaluated at the 1998 World Symposium onPulmonary Hypertension in Evian. France; and
Simonneau G, Galie N, Rubin LJ, et al. Clinical classifi-cation of pulmonary hypertension. J Am Coll Cardiol2004;43(12 Suppl S):5S–12S; with permission.
Epidemiology of Pulmonary Arterial Hypertension 621
chronic left heart or chronic respiratory disease) isimportant because therapy is different. From sim-ilarities in histologic and clinical features of pa-tients with various forms of PAH, entities aregrouped as WHO group 1 diseases; this includespatients with identifiable genetic causes of PAH(ie, those with heritable PAH) and those withcollagen vascular diseases or other conditionsknown to be associated with PAH (associatedPAH). Patients with PAH in whom no known asso-ciated disease entity or genetic cause can befound are classified as having idiopathic PAH(IPAH), rather than the previously used term pri-mary PH.
Abandonment of the name primary PH is im-portant as a means of discouraging the confusingand clinically inappropriate term secondary PH.Use of such primary and secondary groupingsinappropriately suggests similarities in the patho-physiology and treatment of patients with manydifferent diseases. As an example, patients withchronic obstructive pulmonary disease, chronicthromboembolic disease, and those with congen-ital heart disease might each be loosely labeled ashaving secondary PH, although the pathogenesisis distinct in each category and the appropriatetherapy is different. Conceptualizing patients ashaving either primary or secondary disease mayalso obscure important clinical similarities(including appropriate treatment) between whatwas previously called primary PH and other en-tities labeled secondary (eg, patients with congen-ital heart disease or human immunodeficiencyvirus [HIV] infection).
Although understanding of the cellular and mo-lecular mechanisms that produce PH remainsincomplete, several clearly identifiable risk factorsfor the development of PAH are recognized. Thecausal relationship of some risk factors has beenfirmly established by controlled epidemiologicstudies (eg, exposure to fenfluramine-derivedanorectic agents), whereas others (eg, thyroiddisease) are less well established (Box 2).6–8
IDIOPATHIC PAH
IPAH is a rare disease with an estimated incidenceof 1 to 2 cases per million in industrialized coun-tries.9–12 The paucity of patients with IPAH andthe likelihood that diverse causes might producesimilar clinical syndromes have complicated de-scriptions of the natural history of the disease. To
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overcome the limitations of sporadic reports, theNational Institutes of Health (NIH) established theprospective National Registry for the Character-ization of Primary Pulmonary Hypertension in theearly 1980s, enrolling 187 patients from 32 centersbetween 1981 and 1985.13 The disease affected allages, both men and women, and many differentethnic groups. Themean age of patients in the reg-istry was 36.4 years and was similar for womenand men. However, women were affected morefrequently, with a female/male ratio of 1.7:1(Fig. 1). Nine percent of patients were older than60 years. The race and ethnicity of the cohortwere similar to the general population. Similar de-mographic trends have been reported in seriesfrom France, Israel, Japan, Mexico, andChina.11,14–17 Dyspnea was the most commonpresenting symptom, and the mean time fromthe onset of symptoms to diagnosis among pa-tients in the NIH registry was approximately2 years.In a more recent series, 674 patients referred for
treatment of PAH were enrolled in a French na-tional registry over a 1-year period during 2002and 2003.12 Both prevalent and incident patientswere evaluated, making up 18% and 82% of thestudy population, respectively. Patients withIPAH accounted for 39% of the registry and, asin prior studies, disease was seen more commonly
Fig. 1. Distribution of patients with idiopathic PAHentered into the NIH registry. Patients entered intothe Registry of the Characterization of Primary Pulmo-nary Hypertension were most often in their third andfourth decades of life, with a similar ratio of womento men (1.7:1) in all decades. Open bars representwomen; shaded bars represent men.
in women, with a ratio to men of 1.6:1. The meanage of patients with IPAH was 52 years, olderthan that seen in prior series. Although data spe-cific to IPAH were not available, one-quarter ofpatients with PAH of any form were older than60 years, and some patients were diagnosed intheir 80s. However, despite the significant ad-vances in therapy that had occurred in the 20 yearssince the NIH registry, a significant delay in thediagnosis of IPAH continued; 80% of patientswith IPAH hadWHO functional class III or IV symp-toms (Box 3) at the time of diagnosis, which issimilar to what was reported in the National Regis-try for the Characterization of Primary PulmonaryHypertension in the early 1980s.13 Exercise ca-pacity was severely impaired in these patients,with a mean 6-minute walk distance of only328m, and hemodynamic values were nearly iden-tical to those of the NIH registry population.
Prognostic Factors in IPAH
Although a diagnosis of IPAH has been associatedwith an invariably dismal prognosis, therapiesdeveloped in the last two decades have signifi-cantly improved the prognosis of the conditionand yielded many long-term survivors. However,no currently available medical treatment is consid-ered curative and lung transplantation continues tobe an important therapeutic consideration.
Box 3WHO functional classification
Class I: patients with PH but without resultinglimitation of physical activity. Ordinary physicalactivity does not cause undue dyspnea or fa-tigue, chest pain, or near syncope.
Class II: patients with PH resulting in slight lim-itation of physical activity. They are comfortableat rest. Ordinary physical activity causes unduedyspnea or fatigue, chest pain, or near syncope.
Class III: patients with PH resulting in markedlimitation of physical activity. They are comfort-able at rest. Less than ordinary activity causesundue dyspnea or fatigue, chest pain, or nearsyncope.
Class IV: patients with PH with inability toperform any physical activity without symp-toms. These patients manifest signs of rightheart failure. Dyspnea and/or fatigue mayeven be present at rest. Discomfort is increasedby any physical activity.
Adapted from Rubin LJ. Diagnosis and managementof pulmonary arterial hypertension: ACCP Evidence-Based Clinical Practice Guidelines. Introduction. Chest2004;126:7S–10S.
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The prognosis of IPAH is poor in the absence ofeffective therapy. The median survival of patientsin the NIH registry was 2.8 years, with estimatedsurvival rates of 68% at 1 year, 48% at 3 years,and 34% at 5 years.13 Similar outcomes havebeen reported in other series from various coun-tries,18,19 with most patients dying of right heartfailure.
Although multiple studies have evaluated theoutcome of patients with IPAH treated with newtherapies and studies have frequently includedpatients with PAH with the scleroderma spectrumof collagen vascular disease, information on pa-tients with other forms of PAH is sparse. Mostsubjects in controlled clinical trials of treatmentwith calcium channel antagonists, prostanoids,endothelin receptor antagonists, or phosphodies-terase inhibitors have had IPAH. Fewer patientswith either hereditary or various forms of associ-ated PAH have been studied. It is important tobear in mind this paucity of data when informingpatients with some forms of PAH about the ex-pected outcomes of treatment. It is also importantto acknowledge the limits in understanding therelative efficacy of available agents. Data fromhead-to-head comparisons are minimal. Mostoften, patients treated with intravenous prosta-noids have been sicker than those treated withoral therapies, making comparisons betweenstudies problematic.
In the French national registry population from2002 to 2003, after advanced therapies hadbecome available, the 1-year survival of patientswith PAH with either IPAH, familial, or anorexi-gen-associated PAH was 89.3%. Although infor-mation regarding specific treatments involvedwas not reported, the expected survival from theNIH registry equation was 71.8%.12
The multicenter observational Registry to Eval-uate Early and Long-Term Pulmonary ArterialHypertension Disease Management (REVEAL reg-istry) is the largest registry of patients with PAH inthe era of advanced PAH therapies.20 Based ondata from 2716 patients, a risk score calculatorfor newly diagnosed patients with PAH has beendeveloped and validated and is shown in Fig. 2and Table 1. As can be seen, the strongest con-tributors to a poor prognosis were a diagnosis ofportopulmonary hypertension or heritable PAH,male sex combined with age greater than 60 years,New York Heart Association/WHO functionalclass IV, and pulmonary vascular resistance(PVR) greater than 32 Wood units.
Objective measurements of exercise capacityalso predict survival. Among 43 patients treatedpredominantly with infused or oral prostanoids,the pretreatment 6-minute walk distance was
independently associated with survival, whichwas significantly better for those who could walkfarther than 332 m (Fig. 3).21 In randomized trialsof epoprostenol therapy, patients with a lowerbaseline 6-minute walk distance similarly hadpoorer survival.22,23 Maximal oxygen consumptionduring cardiopulmonary exercise testing alsocorrelates with survival.24
Findings on echocardiography, including rightatrial enlargement or the presence and size of apericardial effusion, can be useful in assessingprognosis.25–27 An index of right ventricular func-tion derived by dividing the combined isovolumet-ric contraction and relaxation times by the rightventricular ejection time (Tei index) also predictssurvival, with a higher index associated with apoorer prognosis.28 The degree of tricuspidannular displacement during systole was associ-ated with right ventricular function, hemodynamicmeasurements, as well as survival in a cohort ofpatients with various forms of PAH, as well asothers with PH associated with chronic respiratoryor thromboembolic disease (Fig. 4).29 The rightventricular diameter and some measures of rightventricular free wall strain also can also provideprognostic information.30,31
Hemodynamic measurements have been pre-dictors of survival in numerous studies, includingboth observational and clinical trials. Despite iso-lated differences, overall these studies indicatethat values reflecting a declining right ventricularfunction (eg, an increased right atrial pressureand a decreased cardiac index) are associatedwith poorer survival.11,15,16,32,33 Survival is lessconsistently linked with mean pulmonary arterypressures (mPAPs), and both increasing anddecreasing values have been associated withworsened outcomes. This finding reflects the nat-ural history of right heart failure in PAH: mPAPincreases progressively as the vascular derange-ments worsen, only to decrease later as the rightheart progressively fails and is no longer able togenerate increased pressures (Fig. 5).
Many serum markers are increased in patientswith IPAH and are associated with a worse prog-nosis. Uric acid levels are increased in hypoxicstates, and the degree of increase correlates withhemodynamic and functional decline in patientswith IPAH.34,35 Levels of B-natriuretic peptide arealso increased in patients with IPAH, reflecting rightheart failure analogous to that seen in patients withleft-sided heart dysfunction. In one series of 60 pa-tients with IPAH, serum brain natriuretic peptide(BNP) concentrations were increased versus con-trol, and inversely correlated with both functionalstatus and survival.36 BNP levels declined as hemo-dynamic measures improved with therapy, and a
Fig. 2. REVEAL Registry PAH risk score calculator. Calculated risk scores can range from 0 (lowest risk) to 22 (high-est risk). If N-terminal proBNP is available and BNP is not, listed cut points are replaced with less than 300 pg/mLand more than 1500 pg/mL. APAH, associated pulmonary arterial hypertension; BNP, brain natriuretic peptide;BPM, beats per minute; CTD, connective tissue disease; DLco, diffusing capacity of lung for carbon monoxide;FPAH, familial PAH; HR, heart rate; mRAP, mean right atrial pressure; NYHA, New York Heart Association;POPH, portopulmonary hypertension; PVR, pulmonary vascular resistance; SBP, systolic blood pressure. (FromBenza RL, Gomberg-Maitland M, Miller DP, et al. The REVEAL Registry risk score calculator in patients newlydiagnosed with pulmonary arterial hypertension. Chest 2012;141(2):354–62; with permission.)
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persistently increased BNP (>180 pg/mL) despitetherapy predicted a poorer prognosis.Serum concentrations of endothelin-1,37 cate-
cholamines,38 and atrial natriuretic peptide39 inserum have also been correlated with diseaseseverity. Increases in von Willebrand factor,D-dimer, and troponin-T, or a decrease in theserum albumin level have been individually associ-ated with poorer survival in patients with
IPAH.35,39,40 However, none of these putativeprognostic markers are routinely incorporatedinto clinical decision making.The prognosis of patients with IPAH who have
had cardiac arrest is dismal even when resuscita-tive efforts are initiated promptly. In one retrospec-tive review of records from more than 3000patients, 132 episodes of attempted cardiopulmo-nary resuscitation (CPR) following cardiac arrest
Table 1Predicted 12-month survival based upon thecalculated REVEAL risk score
Score Risk GroupPredicted 12-moSurvival (%)
0–7 Low 95–100
8 Average 90–<95
9 Moderately high 85–<90
10–11 High 70–<85
>12 Very high <70
Epidemiology of Pulmonary Arterial Hypertension 625
were identified. Survival at 90 days following CPRwas only 6%.41
The long-term prognosis is good for the smallgroup of patients with IPAH who respond acutelyto the administration of short-acting pulmonary va-sodilators. Testing is performed at the time of rightheart catheterization.42–48 Although the definitionof an acutely responsive patient has varied, adecrease in the mPAP of at least 10 mm Hg to afinal value less than 40 mm Hg, with either anincreased or unchanged cardiac output, is nowgenerally considered a positive response.49,50 Inone study performed before the availability ofother effective treatments, the survival rate ofacutely responsive patients treated chronicallywith oral calcium channel antagonists was 94%at 5 years compared with only 38% among nonre-sponders.51 However, only approximately 12% ofpatients in a 2005 series showed acute vasoreac-tivity, and of these only about half experienced asustained clinical response to high-dose oral cal-cium channel antagonist therapy.52 For the fewacutely vasoreactive patients who do experience
Long distance group (≥ 332 m)
Short distance group (< 332 m)
0
0
20
40
60
80
100
10 20 30 40 50 60
Time (months)
Su
rvival rate (%
)
Fig. 3. Survival in IPAH according to 6-minute walktest distance. Kaplan-Meier survival curves accordingto the median value of distance walked in meters dur-ing a 6-minute walk test. Patients unable to walkmore than 332 m had a lower survival (P<.001).
a sustained response to high-dose oral calciumchannel antagonists therapy, the prognosis isexcellent. In one retrospective study, Sitbon andcolleagues52 found that, among 38 patients withsustained clinical response (defined as being inWHO functional class I or II after 1 year of treat-ment), survival was 97% in up to 7 years offollow-up. However, oral calcium channel antago-nists are of no benefit and can cause considerableharm when administered to patients who do notdisplay acute pulmonary vasoreactivity. Empiricuse of high-dose calcium channel antagonists inPAH is never appropriate.
The prognostic significance of acute pulmo-nary vasoreactivity is less clear in patientstreated with therapies other than oral calciumchannel antagonists. The magnitude of improve-ments in mPAP and cardiac index at the time ofacute vasodilator testing correlated with survivalin one series of patients treated with long-termepoprostenol infusion; such a correlation wasnot seen in another group of similarly treated pa-tients.22,53 A retrospective evaluation of survivalin patients treated with calcium channel antago-nists, prostanoid therapies, bosentan, warfarin,or a combination of these agents found no corre-lation between survival and acute vasoreactivityat baseline.40
Heritable PAH
A genetic basis for the development of PAH hasbeen suspected since a family of patients withIPAH was described by Dresdale and colleagues3
in 1951. In the NIH registry, 6% of patients re-ported one or more affected family members.13
Loyd and colleagues54 showed that familial PAHhas an autosomal dominant pattern of inheritance,an increased tendency for female carriers to man-ifest clinical disease, and an earlier onset in suc-cessive generations (a phenomenon known asgenetic anticipation), although more recent datasuggest that genetic anticipation may representan artifact.55,56 Mutations in the gene for amemberof the transforming growth factor beta (TGF-b) su-perfamily of receptors, the bone morphogeneticprotein receptor type II (BMP-RII), have been iden-tified as the major cause of familial PAH.57–60 Morethan 140 distinct BMP-RII mutations have beenidentified to date, and disease is thought to occurwhen haploinsufficiency results in inadequatequantities of protein being produced for normalfunction.61 The low penetrance of diseaseobserved in familial PAH suggests that environ-mental factors or other genetic loci likelycontribute to disease development in geneticallysusceptible individuals.62
Fig. 4. Survival according to an echocardiographic assessment right ventricular function. The displacementfrom end diastole to end systole of the lateral tricuspid annulus (tricuspid annular plane excursion [TAPSE])is shown in M-mode views from 2 patients, one with preserved tricuspid excursion (and right ventricular func-tion) (A) compared with a patient with greater impairment (B). Kaplan-Meier estimates of survival in a cohortof patients with either PAH (idiopathic or associated with collagen vascular disease) or chronic respiratory orthromboembolic PH (C and D). (Adapted from Forfia P, Fisher MR, Mathei SC, et al. Tricuspid annular displace-ment predicts survival in pulmonary hypertension. Am J Respir Crit Care Med 2006;174(9):1034–41; withpermission.)
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Mutations in another member of the TGF-b su-perfamily, activin receptor-like kinase 1 (ALK1),predisposes patients with hereditary hemorrhagictelangiectasia to develop PAH.63–66
In 2013, a genomewide association study of 625individuals with heritable PAH without the BMP-RIIor ALK1mutations and 1525 healthy controls sug-gested a significant association at the cerebellin 2(CBLN2) locus at 18q22.3, with the risk alleleconferring an odds ratio for PAH of 1.97.67
CBLN2 codes for a glycoprotein expressed in thelung; its expression is higher in individuals withPAH. New genetic abnormalities specific to PAHhave recently been reported at the Fifth WorldSymposium on Pulmonary Hypertension in Nice,France (see the discussion on the genetics of PHelsewhere in this issue).Germline mutations in a BMP-RII have been
identified in up to 80% of patients with heritablePAH.67,68 Approximately 20% of patients with
idiopathic (nonfamilial) and other associated formsof PAH also have BMPR-IImutations59,60,69–73 andcommon ancestries have been identified in somepatients with PAH previously assumed to be spo-radic. Mutations in other genes, such as ACVRL1(ALK1) and SMAD8, have also been identified butaccount for fewer cases of heritable PAH thanBMPR-II mutations.74,75
Heritable cases of PAH might not be recognizedon account of incomplete family history taking orreporting, as well as low disease penetrance insmall families.76,77 Carriers of gene mutationsmay be asymptomatic despite mild PH docu-mented by echocardiography.78
Genetic testing of family members can assessthe risk of developing PAH. There is a roughly 1in 5 chance of PAH developing in a first-order rela-tive who carries a disease-causing BMP-RIImuta-tion. In the absence of genetic testing results, therisk of disease developing in the first-order relative
Fig. 5. Hemodynamic changes with progression ofPAH. The changes in cardiac output (CO), mean pul-monary artery pressure (PAP), and PVR in the absenceof effective therapy. PVR increases progressively as thevascular derangements progress, eventually leadingto the development of right heart dysfunction. PAPsinitially increase because the right ventricle remainscapable of generating the increased pressuresrequired to maintain a given degree of CO. However,with more advanced disease, CO decreases and thePAP decreases because of the inability of the failingright ventricle to generate increased pressures.(From Friedman E, Palevsky HI, Taichman DB. Classifi-cation and prognosis of pulmonary arterial hyperten-sion. In: Mandel J, Taichman DB, editors. Pulmonaryvascular disease. Philadelphia: Elsevier Science; 2006.p. 66–82; with permission.)
Epidemiology of Pulmonary Arterial Hypertension 627
of a patient with known familial PAH can beapproximated as 1 in 10. When testing shows anabsence of disease-causing BMP-RII mutations,the risk is the same as in the general population(estimated at 1 in 1 million).62 Genetic testingshould only be performed in conjunction with pro-fessional genetic counseling because of the poten-tial interpersonal, psychological, and economicimplications of identifying an at-risk genotype.
PAH Associated with Specific Conditions
Collagen vascular diseasesAmong the identifiable risk factors for the devel-opment of PAH, the presence of systemic scle-rosis is the most commonly reported. In theFrench national registry, 76% of patients withPAH with collagen vascular disease had systemicsclerosis, accounting for 11.6% of all patientsenrolled.12 PAH occurs most often in patientswith limited disease or the CREST (calcinosis,Raynaud phenomenon, esophageal dysmotility,sclerodactyly, telangiectasia) syndrome. Esti-mates vary significantly but, when assessed byright heart catheterization, PAH has been foundin between 7% and 29% of patients.79,80 Whenscreening of symptomatic patients is performedby echocardiogram, approximately 13% of pa-tients with systemic sclerosis had PH in each of2 large series.81,82
The prognosis of patients with systemic scle-rosis and PAH is even worse than that of patientswith systemic sclerosis who develop severe pul-monary fibrosis. Median survival of patients withsystemic sclerosis and PAH is approximately 1 to3 years, versus 3 years among those with sclero-derma and pulmonary fibrosis alone.83–85 Evenwhen similar therapies are used (including epo-prostenol, endothelin receptor antagonists, cal-cium channel antagonists, and warfarin), survivalof patients with PAH associated with systemicsclerosis is generally less favorable than for pa-tients with IPAH (Fig. 6).83 As an example,although hemodynamic values and exercise ca-pacity improve when patients with IPAH aretreated with bosentan, the benefit observedamong similarly treated patients with systemicsclerosis seems to be primarily a slowing in therate of deterioration.86
PAH also occurs in patients with other forms ofcollagen vascular disease, including systemic
Fig. 6. Survival in PAH associatedwith systemic sclerosis comparedwith idiopathic PAH. Kaplan-Meierestimates of survival in patients withPAH associated with the systemicsclerosis (SS) spectrum of diseases(SS-PAH) and IPAH. (From Kawut SM,Taichman DB, Archer-Chicko CL,et al. Hemodynamics and survival inpatients with pulmonary arterial hy-pertension related to systemic scle-rosis. Chest 2003;123(2):344–50; withpermission.)
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lupus erythematosis (SLE), rheumatoid arthritis,and Sjogren syndrome. In most studies, pulmo-nary artery pressures have been estimated byechocardiogram, and thus the prevalence of PAHin these connective tissue disorders is not known.PH has been identified by echocardiogram inapproximately 10% of patients with SLE, and upto 43% of patients who are followed prospec-tively.87–91 Estimates are similarly broad amongpatients with mixed connective tissue disease,and again lack confirmation by catheterization inmost studies. Regardless of the exact frequencythe presence of PH seems to be a significantcause of death in these patients.89 The possibilityof PH patients should therefore be considered inall patients with collagen vascular disease with ex-ertional dyspnea or other symptoms, and earlyevaluation is warranted.
HIVPatients infected with HIV are at increased riskfor PAH. The mechanisms by which HIV infectionleads to PAH are not known. Although directinfection of pulmonary endothelial cells doesnot seem be involved, indirect mechanismsinvolving alterations in cytokines, growth factors,and vasoconstrictors have been implicated.92
Estimates of the incidence of PAH among HIV-infected patients have varied, and although ithas been hypothesized that a decrease in inci-dence followed the introduction of highly activeantiretroviral therapy this has not been seenconsistently and variation in estimates may becaused by differences in the definitions andmodes of evaluation.93–95 The estimated preva-lence of PAH confirmed by right heart catheteri-zation among dyspneic HIV-infected patientssince the availability of highly active antiretroviraltherapies is 0.5%.94
The symptoms, hemodynamic findings, and sur-vival of PAH associated with HIV are similar tothose of IPAH.96 Like IPAH, the prognosis of pa-tients with PAH associated with HIV infection isworse when symptoms are more advanced (eg,WHO functional class III or IV compared witheither class I or II) or when cardiac function isdepressed.97 CD4 lymphocyte counts more thanapproximately 200/mm3 are associated with a bet-ter prognosis.95,98 Mortality is more often directlyattributable to PAH and right heart failure than toinfectious complications.96,98 Survival from thetime of diagnostic right heart catheterization eval-uated in 48 patients with HIV-associated PAHenrolled in the US-based REVEAL cohort was93.3% � 6.2%, 75.1% � 8.8%, 63.8% � 9.5%,and 63.8% � 9.5% at 1, 3, 5, and 7 years,respectively.99
Portal hypertensionPatients with chronic liver disease are at risk forthe development of pulmonary complications.When portal hypertension and PAH are present,the combination is referred to as portopulmonaryhypertension (POPH).100,101 POPH involvesvascular derangements that increase PVR toproduce an increased mPAP, as opposed toincreased pulmonary pressures caused solely bythe increased cardiac output and the volume over-loaded state that frequently accompanies chronicliver disease. The cause of PH in these patientsmay be difficult to identify because the high car-diac output state may precede, or accompany,the development of POPH. Despite similar de-grees of clinical impairment, patients with POPHmay manifest numerically smaller increases inPVR or smaller decreases in cardiac output thanthose with IPAH.The histopathologic changes in patients with
POPH are similar to those described in otherforms of PAH including both plexiform and throm-botic lesions.102,103 The pathogenesis is not wellunderstood but seems to involve abnormal prolif-erative (or other) vascular responses. The incitingcauses remain unknown. Portal hypertensionmight alter the vasoactive mediators to whichthe pulmonary circulation is exposed because ofblood bypassing the liver via portosystemicshunts and returning to the systemic circula-tion.104 Alterations in levels of various vasodilatorsand vasoconstrictors have been observed in pa-tients with POPH as in other forms of PAH.105,106
Women with portal hypertension seem to be atgreater risk for the development of POPH thanmen, as do patients with autoimmune hepatitis.107
The severity of portal hypertension does not seemto influence the risk of POPH.107,108 Predisposing,likely genetic, factors are also thought to deter-mine why only some patients with liver diseasedevelop POPH.109
The frequency of PAH in patients with liver dis-ease has not been firmly established. Estimateshave ranged from 0.73% in 1241 autopsies frompatients with cirrhosis to 16% of 62 patients un-dergoing catheterization during evaluation fortransjugular intrahepatic portosystemic shunt-ing.105,110 In a prospective study of more than1200 patients undergoing evaluation for livertransplantation (and thus with advanced liver dis-ease and symptoms) the prevalence of POPHwas 5%.111 Among 2525 patients with PAHenrolled into the US-based REVEAL study cohortof patients with PAH, 136 (5.4%) were categorizedas having disease associated with portal hyperten-sion; the mean age at diagnosis was 51 years, withan equal number of men and women.112
Epidemiology of Pulmonary Arterial Hypertension 629
The prognosis of POPH is poor in the absence ofeffective treatment. Retrospective series have re-ported 1-year survival rates less than 50% in theabsence of treatment.113–115 Survival is worseamong patients with POPH than IPAH even whenavailable treatments are used.115 In a large UScohort (REVEAL), the 5-year survival of 174 pa-tients with POPH was significantly worse thanthat of 1478 patients with idiopathic or heritablePAH (40% vs 64%, respectively), despite less se-vere hemodynamic derangements among the pa-tients with POPH at the time of enrollment intothe study (Fig. 7).116
Although patients with POPH and advancedhepatic dysfunction often require liver transplanta-tion, the presence of PAH increases the perioper-ative mortality, and an mPAP more than 35 mm Hggenerally is considered a contraindication to livertransplantation.117,118 Although therapy to lowermPAP has permitted successful orthotopic livertransplantation in some patients,119–124 the pulmo-nary vascular abnormalities of PAH are not consis-tently reversed by liver transplantation. Althoughsome instances of reversal have been reported,in other patients POPH has progressed despitetransplantation.125
Anorectic agentsThe ingestion of certain anorexigens can lead tothe development of PAH, possibly by increasingblood levels of the vasoconstrictor serotonin. Anepidemic of PAH occurred in Switzerland, Austria,and Germany between 1966 and 1968 whenthe incidence increased 20-fold following the intro-duction in those countries of the appetite-depressant, aminorex fumarate.126 Although only2% of those exposed to the drug developedPAH, the relative risk compared with unexposedindividuals was 52:1.127 The use of fenfluraminederivatives was similarly associated with thedevelopment of PAH both in Europe and NorthAmerica.128 In a registry of 95 patients with PAHin Europe, the odds ratio of developing PAH was
6.3 after any anorectic agent use, and 23.8 whenanorectic agents were taken for longer than3 months.9 Likewise, a North American registryof 579 patients reported that the use of fenflur-amine was strongly associated with the develop-ment of PAH (odds ratio of 7.5 when taken formore than 6 months). The study also identified ahigh frequency of anorectic agent use among pa-tients with other associated forms of PAH (eg,collagen vascular disease), suggesting that thesedrugs might precipitate disease when combinedwith other risk factors.129
In a series of 62 patients evaluated over a10-year period at a single center in France, the in-terval between the initial exposure to fenfluramineand the development of dyspnea was approxi-mately 4 years.130 In the multicenter Frenchnational registry from 2002 to 2003, anorexigen-associated PAH was diagnosed within 2 years ofdrug exposure in 24% of cases, between 2 and5 years in 32% and after more than 5 yearsfollowing drug exposure in 44%.12 In both series,the baseline hemodynamic values were similar tothose of patients with IPAH, although patientsexposed to anorectic agents were even less likelyto show acute vasoreactivity. Among 2525 pa-tients with PAH enrolled into a US-based registryof patients with PAH (REVEAL), 131 (5.3%) had ahistory of using fenfluramine or fenfluramine deriv-atives; the mean age at diagnosis was 46 years,and 84% were women.112
The prognosis of anorectic agent–associatedPAH has not been well established. Datacomparing survival with patients with IPAH areconflicting. Survival of patients with aminorex-associated PAH was better than that of patientswith IPAH in a retrospective study of 104 patientstreated with anticoagulation.131 With additionaltherapies, including epoprostenol, survival infenfluramine-exposed patients with PAH seemedto be similar to that of patients with IPAH in onestudy130 but poorer in another series in which pa-tients were matched according to treatments and
Fig. 7. Survival of patients with IPAH/FPAH compared with POPH from thetime of enrollment in a US-based reg-istry. (From Krowka MJ, Miller DP,Barst RJ, et al. Portopulmonary hyper-tension: a report from the US-basedREVEAL Registry. Chest 2012;141:4;with permission.)
Taichman & Mandel630
disease severity.132 In a cohort of 674 patients withPAH enrolled in a French registry between 2002and 2003, 9.5% had anorexigen-associated dis-ease; reported survival for this group was similarto that of patients with idiopathic or familialPAH.133
HemoglobinopathiesThe risk of developing PH is increased in patientswith certain chronic hemolytic disorders.134 PH inpatients with hemolytic anemia in the past hasbeen categorized as group I (PAH); the 2013Nice Conference reclassified it as group 5 (miscel-laneous.) PH caused by difficulty distinguishingbetween intrinsic pulmonary vascular derange-ments and increased pulmonary pressurescaused by left heart dysfunction in many patients.Hemolytic states might lead to pulmonaryvascular derangements by releasing both free he-moglobin and arginase into the plasma where theycan reduce the bioavailability of both NO and itssubstrate, L-arginine.134–136 Histologic findingsconsistent with PAH were noted in 15 of 20 au-topsies performed on patients with sickle cellanemia.137
Prevalence estimates of PH in patients witheither sickle cell anemia or thalassemia haveranged significantly, according to the age of thepopulation studied, the severity of symptoms,and the method of pulmonary artery pressure(PAP) assessment used.138–141 Isolated cases ofPH with other chronic hemolytic disorders havebeen reported, including patients with hereditaryspherocytosis and paroxysmal nocturnalhemoglobinuria.142,143
Patients with PAH associated with sickle cellanemia tend to have lower mean PAPs and highercardiac outputs than patients with idiopathic orother forms of associated PAH. Furthermore, pa-tients with PAH associated with hemoglobinopa-thies also have hemodynamic findings consistentwith both intrinsic pulmonary vascular disease(ie, an increased PVR) and increased pulmonarycapillary wedge pressures (PCWPs), suggestingthe possibility that left ventricular diastolicdysfunction also plays a role. In one study of 20patients with PAH associated with sickle cell ane-mia, the mean PAP was 36 mm Hg, cardiac output8.6 L/min, and PCWP 16 mm Hg; one-half of thepatients had PCWP values greater than 15 mmHg and most had PVR less than 3 Wood units.144
In another study of 25 adult French patients withsickle cell anemia and a tricuspid regurgitant ve-locity of greater than or equal to 2.5 m/s suggest-ing PH, right heart catheterization found 33% tohave PAH, whereas 66% had an increased pulmo-nary artery wedge pressure and pulmonary venous
hypertension.145 In a prospective study of 398 pa-tients with sickle cell disease, although the preva-lence of PH (defined by a tricuspid regurgitantvelocity of �2.0 m/s) was 27%, the prevalence ofPH confirmed by right heart catheterization(defined as a mean PAH �25 mm Hg) was only6%.146,147 Similar findings were reported in a pro-spective study of 80 Brazilian patients with sicklecell anemia.148
The presence of PH portends a worse prognosisin patients with sickle cell anemia. Mortality within2 to 2.5 years of almost 50% of patients with sicklecell with PH has been reported in several se-ries.144,149,150 In a prospective NIH registry of195 adult patients with sickle cell anemia followedfor a mean of 18 months, Gladwin and col-leagues151 found that mortality increased whenthe tricuspid regurgitant velocity was greaterthan 2.5 m/s (relative risk 10.1), compared withdeath in 2% when the pressures were lower.Markers of hemolysis, such as plasma arginase,correlate not only with the presence of PH butalso with an increased risk of death.135 Whethertherapy for PH alters the survival of patients withsickle cell (or other forms of hemolytic anemia) re-mains incompletely understood. One randomizedcontrolled trial of sildenafil in patients with sicklecell anemia with a tricuspid regurgitant velocitygreater than or equal to 2.7 m/s and a 6-minutewalk distance between 150 and 500 m was termi-nated early because of a higher rate of seriousadverse events in the active treatment arm (pri-marily an increased rate of hospitalization forpain).152
Pulmonary veno-occlusive diseasePulmonary veno-occlusive disease (PVOD) is arare form of PH that is characterized by extensiveand diffuse obliteration of small pulmonary veins orvenules by cellular proliferation, in situ thrombosis,and fibrous tissue.153,154 In most patients, pulmo-nary arteriolar changes accompany the venouschanges, although it is unclear whether arteriolarremodeling develops simultaneously with or as aconsequence of progressive venous destruc-tion.155 PVOD usually presents with dyspnea onexertion and findings of right ventricular failure ina manner similar to IPAH, although subtle differ-ences from IPAH may be present, such as digitalclubbing, basilar rales, pleural effusions, andradiographic evidence of pulmonary lymphaticengorgement (eg, Kerley B lines visible on chestradiographs and septal thickening on chestcomputed tomography).153,156,157
Differentiation from other forms of PAH is impor-tant because treatment with prostanoids or otheragents that are effective for IPAH may produce
Epidemiology of Pulmonary Arterial Hypertension 631
pulmonary edema by increasing cardiac output topostcapillary vessels with obstructing lesions anddeath in a subset of patients with PVOD.158 Inpart because of these difficulties in treatment,the prognosis of PVOD is poor, with most patientsdying within 2 years of diagnosis unless long-termtreatment with prostanoids is tolerated.154,156,159
Immediate consideration of lung transplantationis thus encouraged when the diagnosis of PVODis established, although recurrence of the condi-tion after transplantation has been reported.160
The epidemiology of PVOD is not clearlydefined. Unlike IPAH, men and women seemequally at risk for PVOD, and the age at diagnosishas ranged from the first weeks through theseventh decade of life.154,161,162 Because PVODseems approximately one-tenth as common asIPAH, the annual incidence of PVOD in the generalpopulation has been estimated at 0.1 to 0.2 casesper million persons per year.153 However, this mayrepresent an underestimate because many casesare probably misclassified as IPAH, heart failure,or interstitial lung disease. No well-designedstudies have adequately examined the magnitudeof this likely misclassification phenomenon. Of2525 patients with PAH in a multicenter US regis-try, 0.4% were classified as having PVOD.112
The cause of PVOD remains unknown and likelyrepresents a common clinicopathologic pathwaythat develops in a susceptible host following expo-sure to one of several different triggers. BMP-RIImutation has been reported in patients withPVOD,73,163 as have epigenetic abnormalities inan effector protein active in the control of specificinflammatory cell populations.164
Several factors associated with PVOD havebeen proposed but none of these epidemiologichypotheses have been tested by rigorousmethods. Conditions theorized to be associatedwith an increased risk of PVOD include the devel-opment of the condition in a sibling, exposure toantineoplastic chemotherapy, infection with HIVor other agents, or the presence of thrombophiliaor autoimmune diseases.153,165–173 Small autopsyseries have suggested a high prevalence of PVOD-type pathologic lesions among patients withsystemic sclerosis, suggesting that the conditionmay frequently go unrecognized in patients withPH from this connective tissue disease.174–176
SUMMARY
The epidemiology of PAH has changed. Classifica-tion schemes have evolved from a focus on histo-patholgy to systems grouping patients accordingto similarities in hemodynamic and other clinicalcharacteristics. Beyond helping to guide further
research and understanding of the causes of PH,study of the epidemiology of PH will inform furtherrefinements in disease classification, the enroll-ment of patients within clinical trials, and ultimatelythe care of patients. An accurate understanding ofdisease epidemiology and classification informsaccurate diagnosis, a prerequisite to guidingappropriate therapy.
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