Journal of the American College of Cardiology
`© 2013 by the American College J Cardiology Foundation
`Published by Elsevier Inc.
`
`Vol. 62, No. 25, Suppl D, 2013
`ISSN 0735 1097/8600
`htt'pJ/clV.doi.org/10.li)l(>lj.jacc.2()l(i.lU.U32
`
`Definitions and Diagnosis of Pulmonary Hypertension
`
`Marius M. Hoeper, MD,* Harm Jan Bogaard, MD,i Robin Condliffc, MD,i§2 Robert Frantz, MD,ij;
`
`Dinesh Khanna, MD, Marcin Kurzyna, MD,'[ David Langleben, MD,# Alessandra Manes, MD,**
`
`Toru Satoh, MD,TT Fernando Torres, MD,:§ZZ§: Martin R. Wilkins, MD,i;?; David B. Badesch, MD
`
`Hannover, Germany; Amsterdam, t/.re Netlterlands; Slrefield and London, United Kingdom;
`
`Rocbester, Minnesota; Ann Arbor, Micbigan; Warsaw, Poland; Montreal, Quebec, Canada; Bologna, Italy;
`
`Tokyo, japan; Dallas, Texas; and Denver, Colorado
`
`Pulmonary hypertension (PH) is defined by a mean pulmonary artery pressure 225 mm Hg at rest, measured
`during right heart catheterlzatlon. There is still insufficient evidence to add an exercise criterion to this definition.
`The term pulmonary arterial hypertension (PAH) describes a subpopulation of patients with PH characterized
`hemodynamicaiiy by the presence of pre capillary PH including an end expiratory pulmonary artery wedge pressure
`(PAWP) 515 mm Hg and a pulmonary vascular resistance >3 Wood units. Right heart catheterlzatlon remains
`essential for a diagnosis of PH or PAH. This procedure requires further standardization, including uniformity of the
`pressure transducer zero level at the midthoracic line, which is at the level of the left atrium. One of the most
`common problems in the diagnostic workup of patients with PH is the distinction between PAH and PH due to left
`heart failure with preserved ejection fraction (HFpEF). A normal PAWP does not rule out the presence of HFpEF.
`Volume or exercise challenge during right heart catheterlzatlon may be useful to unmask the presence of left heart
`disease, but both tools require further evaluation before their use in general practice can be recommended. Early
`diagnosis of PAH remains difficult, and screening programs in asymptomatic patients are feasible only in high risk
`populations. particularly in patients with systemic sclerosis, for whom recent data suggest that a combination of
`clinical assessment and pulmonary function testing including diffusion capacity for carbon monoxide, biomarkers,
`(J Am Coll Cardiol 2013,62:
`and echocardiography has a higher predictive value than echocardiography alone.
`D42 50) © 2013 by the American College of Cardiology Foundation
`
`Diagnosis and assessment of patients with pulmonary arte-
`rial hypertension (PAH) have been major topics at all
`previous world meetings on pulmonary hypertension (PH),
`with the last update coming from the 4th World Symposium
`
`on Pulmonary Hypertension (WSPH) held in 2008 in Dana
`Point, California (1). The recommendations from that
`conference were incorporated into the most recent interna-
`tional guidelines (2 4). During the 5th WSPH in 2013 in
`
`From the ‘Department of Respiratory Medicine and German Center for Lung
`Research, Hannover Medical School, Hannover, Germany; ’[Departmcnt of Pulmo
`nary Medicine, VU University Medical Center. Amsterdam,
`the Nethedands;
`tPulmonary Vascular Disease Unit, Rcyal Hallamshire Hospital, Shefiicld, United
`Kingdom; §College of Medicine, Mayo Clinic, Rochester. Minnesota; ||University J
`Michigan Scleroderma Program, Ann Arbor, Michigan; {Department of Pulmonary
`Circulation and Thromboembolic Diseases, Medical Centre J Postgraduate Medi
`cation, Warsaw, Poland; #Center for Pulmonary Vascular Disease, Division J
`Cardiology, Jewish General Hospital, McGill University, Montreal. Qiebx, Canada;
`"Department of Experimental, Diagnostic and Specialty Medicine DINIES,
`Bologna University Hospital. Bologna,
`Italy. HDivision of Cardiology, Kyorin
`University School of Medicine, Tokyo, Japan; Itpulmonary Hypertension Program,
`University of Texas Southwestern Medical Center, Dallas, Texas: §§Experimental
`Medicine, Imperial College London, London, United Kingdom; and the ||]|Division
`of Pulmonary Sciences and Critical Care Medicine and Cardioloy, University J
`Colorado, Denvu, Colorado. Dr. Hoeper has received speaka and/or consulting fees
`from Actelion, Bayer, Gilead, GlaxoSmi1hKline, Eli Lilly, Lung Rx, Pfizer, and
`Novarfs. Dr. Bogaard has received speaker fees from and sened on advisory boards for
`Pfizer and United Therapeutics. Dr. Condliffe has received speaker and/or conference
`travel fees from and/or served on adv'sory boards for Actelion, Bayu, Pfner, Glaxo
`SmithKline, and Eli Lilly. Dr. Frantz has recdved consrlting fees from Pfizer, and has
`received research fiinding from United Therapeutic. Dr. Khanna has received speaker
`and/or conference travel fees from and/or served on advisory boards for Audion, Bayer,
`Bristol Myers Squibb, Digna, Interrnone, Cvilad, Pfiza, Roche, Sanofi Avenfs, and
`
`United Therapeutics; and has received research funding from the National Institutes of
`Health and the Scleroderma Foundation. Dr. Kurzyna has received gimker and/or
`conference travel fees from and/or served on advisory boards for Bayu, AOP Orphan,
`Acrelion, Pfizer, and Gla.xoSmit:hKline. Dr. Langleben his received qimker and/or
`consultingfeesfrom, has served on advisoryboards for, and/orhas been an investigatorin
`clinical trials for Actelion, Bayer, GlaxoSmithKline, Eli Lilly, Myogcn, Northern
`Therapeutics, Novartis, Pfizer, and United Therapeutics. Dr. Manes has received speaker
`few from Actelion, Bayer, and GlaxoSrnit:hKline. Dr. Satoh has received speaker fees
`from Adelion. Dr. Torres has received grant funding from GENO, Medtronic, Acre
`lion/CoTherix, Gilead, Pfizer, United 'Il’ierapeuIics/Lung Rx, Eli Lilly/ICOS, Bayer,
`Nov-artis, Akaria, and ARIES; has served as a consultant (often in the role of steering
`committee or advisory board member) for Actelion/CoTh<:'ix, Gilead, Novarfs, Pfizer,
`United Therapeutics/Lung Rx, GlaxoSmithKline, and Bayer, and is a speaker/advisory
`board member of Gilead, Actclion, United Tliempeudcs, Bayu, and Novartis. Dr.
`Wilkins has received spealcer and/or consulting fees from Bayer, GlaxoSmithKline,
`Pfizer, and Novarfs; a.nd has received research firnding from the British Heart Foun
`dation, Wellcome Trust, and the National Institutes ofHealth. Dr. Badcsch has received
`grant funding from Actelion/Co'Il’icrix, Gilead, Pfizer, United Therapeutics/Lung Rx,
`Eli Lilly/ICOS, Bayer, Novartis, Ikaria, and ARIES; has sened is a consultant (often in
`the role of steering committee or advkory board member) for Actelion/CoTherix,
`Gilead. Pfizer, Mondo Biotech/Mondogen, United Therapeutics/Lung Rx, Glax
`oSmithKline, Eli Lilly/ICOS, Bayer, Ikaria, Reatta, and Arena; and has provided advice
`in a legal matter to Actelion.
`Manuscript received October 11, 2013; accepted October 22, 2013.
`
`042
`
`PRAXAIR ET AL. 1012
`
`

`
`JAOC Vol. 62, No. 25, Slml D, 2013
`Deoermer 24, 20131042 50
`
`Hooper et at
`Defnition md Dhgnosis of PH
`
`D43
`
`Nice, France, the working group on diagnosis and assess-
`ment did not attempt to fully revise previous recommen-
`dations but proposed changes only where strong new
`evidence has been generated to support new proposals.
`
`manifest PAH (9). The thera-
`
`such
`consequences of
`peutic
`findings, however, are unknown.
`
`RECOMMENDATIONS.
`
`Definitions, Limitations, Uncertainties,
`and controversies
`
`Some aspects of the definitions and recommendations
`derived from the 4th WSPH have remained controversial.
`
`Debates are still ongoing, especially regarding the following
`questions. 1) Should PH be defined by a resting mean
`pulmonary artery pressure (PAPm) 225 mm Hg as is
`currently the case or by a resting PAPm >20 mm Hg and
`should the term “borderline PH” be introduced for patients
`with a PAPm between 21 and 24 mm Hg? 2) Should
`exercise—induced PH be reintroduced as part of the PH
`definition? 3) Should pulmonary vascular resistance (PVR)
`be included in the PH/PAH definition? 4) Is pulmonary
`artery wedge pressure (PAVVP) of 15 mm Hg appropriate to
`distinguish between pre—capillary and post-capillary PH and
`how should PAVVP be measured? 5) Should fluid or exercise
`
`challenge be used to distinguish patients with PAH from
`patients with PH due to left ventricular (LV) dysfirnction?
`Should PH be defined by a resting PAPm 225 mm Hg as
`is currently the case or by a resting PAPm >20 mm Hg
`and should the term “borderline PH” be introduced for
`
`patients with a PAPm between 21 and 24 mm Hg? A
`resting PAPm >25 mm Hg has been the cutofl value for
`a diagnosis of manifest PH since the 1st WSPH. However,
`the upper level of normal for resting PAPm is 20 mm Hg (5),
`and it is unclear how to classify and manage patients with
`PAPm levels between 21 and 24 mm Hg. Most of the
`relevant epidemiological and therapeutic studies in the field
`of PAH have used the 25 mm Hg threshold, and little is
`known about patients with PAPm levels between 21 and
`24 mm Hg.
`Several studies have suggested that even mildly elevated
`PA pressures may be of prognostic significance, particularly
`in patients with lung disease or connective tissue disease
`(CTD) (6,7). Introduction of the term “borderline PH” for
`patients with a PAPm ranging from 21 to 24 mm Hg was
`discussed in Dana Point and in Nice (8). This term could be
`
`used to avoid labeling patients with PAPm values between
`21 and 24 mm Hg as manifest PH/PAH but at the same
`time would ensure that such values are not labeled “healthy.”
`In some circumstances, “borderline” PH might indicate early
`pulmonary vascular disease, especially when PAVVP is low
`and transpulmonary gradient and PVR are
`elevated.
`However, the term “borderline PH” would not be usefirl in
`
`patients with left heart disease and elevated PAWP levels.
`The natural history of patients with PAPm values between
`21 and 24 mm Hg has not been widely studied. One
`exception are patients with the scleroderma spectrum of
`disease,
`in whom the presence of “borderline” pressures
`is associated with a high risk of future development of
`
`Abbreviations
`and Acronyms
`
`C0=ca¢Incou1put
`CTD = connective tissue
`tissue
`
`DLCO = diffusion capacttyla
`carbon monoxide
`
`HFpEF= heutlnlun with
`pleoervodeiootionlrnotion
`
`HPAH = Inevitable putnonary
`arterial hypertension
`
`",AH=“w.mcwmmuy
`313,“ hypenengon
`LVEDP = left ventricular end-
`tlntolc pressure
`NT-pvoBNP = N-temiml pm-
`
`B-tyne natfluntic peptide
`pm = pqfinotgy gtgflfl
`WWW“
`PAPm = mean pulmonary
`
`‘''’'V P'’‘’“'‘
`PAWP = pulmonary artery
`“'m° "'“"°
`P" = P“""“'“'Y
`mwumb"
`resistance
`PVR = "“""'°'“"V "”°““"
`
`RHC = rlgrt heat
`catheterlntion
`Ssc = sdevotbnna
`WU=woodunlts
`
`0 The general definition of
`PH should
`remain
`un-
`
`changed. PH is defined by
`PAPm 225 mm Hg at rest
`measured by right heart
`catheterization (RHC).
`0 There are still insufficient
`data I0 lI'ltl'0dllCC tl'lC term
`“borderline PH” for patients
`with PAPm levels between
`
`21 and 24 mm Hg, espe-
`cially because the prognostic
`and therapeutic
`implica-
`tions remain unknown.
`0 Patients with PAPm values
`
`between 21 and 24 mm Hg
`should be
`carefirlly fol—
`lowed,
`in particular when
`they are at risk for devel—
`oping PAH (e.g., patients
`with CTD,
`family mem-
`bers of patients with idio-
`pathic pulmonary arterial
`hypertension [IPAH] or
`heritable pulmonary arterial
`hypertension [HPAH]).
`
`Should exercise-induced PH be reintroduced as part of
`the PH definition? Before the 4th WSPH, PH was defined
`by resting PAPm >25 mm Hg or PAPm with exercise
`>30 mm
`Potential weaknesses ofthat definition included
`the fact that the level, type, and posture of exercise had not
`been specified. Furthermore, the normal exercise PAP varies
`with age. In a systematic review of the available literature (5),
`there were no significant differences in PAP at rest according
`to age groups; however, during exercise, PAPm was signifi-
`cantly higher in older patients (>50 years of age). Based on
`these data, a task force at the 4th WSPH concluded that it was
`
`impossible to define a cutofl' value for exercise-induced PH
`and recommended eliminating this criterion ( 1).
`Since 2008, several studies have shed more light on
`exercise-induced PH (10,11), but there is still uncertainty
`about the most suitable exercise protocol and cutoff levels. In
`addition, prognostic value and therapeutic consequences of
`exercise-induced PH in the setting of normal
`resting
`hemodynarnics have not been elucidated.
`
`RECOMMENDATIONS ON EXERCISE INDUCED PH.
`
`0 Because of the lack of a suitable definition, an exercise
`criterion for PH should not be reintroduced at the
`
`present time.
`
`043
`
`

`
`D44
`
`Hoeper et al.
`Definition and Diagnosis of PH
`
` Further studies are needed to define which levels of
`exercise-induced elevations in PAPm and PVR have
`prognostic and therapeutic implications.
`
`Should PVR be included in the definition of PH/PAH?
`HARMONIZATION OF PVR UNITS.
`Although PA is always given as mm Hg, various units
`are used for PVR, most frequently dyn∙s∙cm 5 and
`Wood units (mm Hg/l∙min). Consistency would be
`useful, and the working group suggested using Wood
`units (WU), which can be directly derived from PAP
`and cardiac output
`(CO) measurements without
`multiplication with the factor 80. The use of SI units is
`not endorsed because they are not commonly being
`used for hemodynamics in clinical practice.
`
`According to a recent analysis (12), normal PVR at rest is
`to some extent age dependent, but PVR >2 WU can be
`considered elevated in all age populations. In the current
`U.S. guidelines, PVR >3 WU is used as part of the
`hemodynamic definition of PAH (3).
`The working group members unanimously agreed that the
`general definition of PH should be kept as simple and as
`broad as possible. Some PH populations (for instance,
`patients with elevated PAWP levels or patients with high
`pulmonary blood flow) may have elevated PAP but normal
`PVR. Thus, PVR should not be part of the general defini-
`tion of PH.
`the working group members proposed to
`However,
`include PVR in the hemodynamic definition of PAH for the
`following reasons: 1) including PVR underscores the need
`to base the definition of PH on invasive measurements
`(i.e., RHC); 2) including PVR makes PAWP (or left
`ventricular end-diastolic pressure [LVEDP]) measurements
`mandatory; 3) including PVR requires measurements of
`CO, which would be a substantial advantage because it is
`current practice in many nonexpert centers to perform
`RHCs without measuring CO; 4) including PVR will
`exclude high flow conditions with normal PVR and without
`pulmonary vasculopathy from the PAH definition; and
`5) including PVR will lower the likelihood of patients with
`left heart disease of being labeled as having PAH.
`
`RECOMMENDATIONS ON PVR.
`
` To avoid the use of various units, PVR should be given
`in WU.
` PVR should not become part of the general PH
`definition.
` PVR should be included in the hemodynamic char-
`acterization of patients with PAH as follows: patients
`with PAH are characterized by pre-capillary PH (i.e.,
`PAPm 25 mm Hg, PAWP 15 mm Hg, and
`elevated PVR [>3 WU]).
` Although the upper level of normal PVR is approxi-
`mately 2 WU, the PVR cutoff value for PAH should
`be kept at 3 WU because patients with lower PVR
`levels are unlikely to have PAH (this is consistent with
`
`JACC Vol. 62, No. 25, Suppl D, 2013
`December 24, 2013:D42 50
`
`setting the cutoff for PAPm at 25 mm Hg, despite the
`upper limit of normal being 20 mm Hg).
`Is PAWP of 15 mm Hg appropriate to distinguish be-
`tween pre-capillary and post-capillary PH and how should
`PAWP be measured? PAWP/PAOP/PCWP HARMONIZTION
`OF TERMINOLOGY.
`capillary wedge pressure
`The
`term pulmonary
`(PCWP) is widely used in the medical literature. For
`measurement of this pressure, balloon occlusion occurs
`in the pulmonary arteries, and the obtained value is not
`equal to the pulmonary capillary pressure in non-
`occluded areas. Thus, the term PCWP is misleading.
`Better terms are pulmonary artery occlusion pressure
`(PAOP) and PAWP. The working group prefers the
`latter term because the short versions “wedge” and
`“wedge pressure” are well established in daily clinical
`practice, even in non English-speaking countries.
`Current guidelines
`recommend using a PAWP (or
`LVEDP) 15 mm Hg to define pre-capillary PH. Higher
`PAWP values are commonly viewed as indicators of left
`heart disease. However, patients with the diagnosis of heart
`failure with preserved ejection fraction (HFpEF) can have
`a resting PAWP <15 mm Hg and patients with features
`otherwise indicating the presence of PAH may present with
`higher PAWP values (13). In addition, PAWP measure-
`ments vary between centers, and standardization is necessary
`to ensure comparisons of patient populations.
`
`STANDARDIZATION OF PAWP MEASUREMENTS. PAWP mea-
`surements may be largely affected by swings in the intra-
`thoracic pressure, especially in patients with lung disease.
`This effect is least pronounced at the end of a normal
`expiration, which is the point at which PAWP should be
`determined. Many available devices do not provide end-
`expiratory but digitized mean PAWP and therefore tend
`to underestimate the PAWP. For standardization of PAWP
`measurements, values should be determined at the end of
`normal expiration (breath holding is not required). Ideally,
`high-fidelity tracings on paper should be used, rather than
`small moving tracings on a cardiac monitor.
`Normal PAWP values have been explored since the
`advent of cardiac catheterization and have been found to
`range from 5 to 12 mm Hg in healthy volunteers. However,
`these data were generated in younger patients, and it remains
`unclear whether there is a physiological increase in PAWP
`with aging. In a comprehensive analysis of the medical
`literature, Kovacs et al. (12) found that PAWP at rest was
`independent of age, with values of 9  2 mm Hg found in
`patients ranging from <24 to 70 years. Of note, the data
`of the oldest patient population were derived from 17
`patients only. Prasad et al. (14) performed a small but
`meticulous study comparing hemodynamics and LV func-
`tion in elderly patients with and without HFpEF, demon-
`strating that the normal PAWP slightly increased with age,
`although usually not beyond 15 mm Hg. Most importantly,
`
`044
`
`

`
`JACC Vol. 62, No. 25, Suppl D, 2013
`December 24, 2013:D42 50
`
`PAWP levels 15 mm Hg did not rule out the presence of
`HFpEF. On the basis of these and other data, it has been
`suggested to lower the PAWP cutoff for pre-capillary PH to
`12 mm Hg. Reasons to reduce the PAWP threshold to
`12 mm Hg include the notion that PAWP of 15 mm Hg is
`associated with a higher chance of misclassifying patients
`with HFpEF as PAH and that the use of 15 mm Hg has
`probably contributed to the labeling of patients with HFpEF
`as PAH with consequences for medical therapy as well as
`inclusions in clinical trials.
`On the other hand, PAWP 15 mm Hg has a high
`sensitivity to identify patients with pre-capillary PH, and
`this cutoff value has been used for decades and has been
`widely memorized among physicians. Almost all PAH trials
`have included patients with PAWP 15 mm Hg, which
`means that the safety and efficacy of PAH drugs have been
`evaluated in this patient population. Lowering the PAWP
`threshold to 12 mm Hg decreases the likelihood of falsely
`labeling patients with PH due to HFpEF as PAH but at the
`same time increases the rate at which the presence of PAH is
`mistakenly excluded.
`There is no single PAWP value that allows for correct
`classification of all patients. PAWP is not a constant number
`but a biological variable that is affected by various factors,
`including fluid balance, intrathoracic pressure, and others. In
`many patients with left heart disease, it will be possible to at
`least temporarily lower PAWP below 15 mm Hg with
`meticulous afterload reduction and diuretic medication (15).
`A comprehensive assessment of the patient’s medical history
`and risk factors together with echocardiographic assessment
`will provide a more reliable diagnosis than a single PAWP
`(or LVEDP) measurement. The presence of clinical risk
`factors (systemic hypertension, older age, obesity, diabetes
`mellitus, obstructive sleep apnea, coronary artery disease),
`atrial fibrillation, and echocardiographic findings such as left
`atrial enlargement or LV hypertrophy indicate a high like-
`lihood of HFpEF (16).
`A recent study showed that more than 50% of the patients
`with PH and PAWP 15 mm Hg had LVEDP values
`>15 mm Hg during simultaneous right and left heart
`catheterization (17). These data raised a debate as to
`whether the hemodynamic classification as pre- or post-
`capillary PH might be improved with routine LVEDP
`measurements. The additional risks and costs associated
`with routine left heart catheterizations are considerable but
`might be offset by a more accurate diagnosis and the
`avoidance of the expensive and potentially harmful use of
`PAH medications in patients with HFpEF. The working
`group felt that the current evidence does not support rec-
`ommending left heart catheterization in all patients with
`PAH, especially when neither the patient’s history nor
`clinical and echocardiographic findings suggest the presence
`of LV dysfunction. However, the threshold to perform
`left heart catheterization should be low in patients with
`echocardiographic signs of systolic and/or diastolic LV
`dysfunction as well as in patients with risk factors for
`
`Hoeper et al.
`Definition and Diagnosis of PH
`
`D45
`
`coronary heart disease or HFpEF. In addition, the finding of
`an elevated PAWP in a patient when this is unexpected
`(normal left atrial size, absence of echocardiographic markers
`of elevated LV filling pressures, absence of risk factors for
`HFpEF)
`should prompt
`the performing physician to
`measure LVEDP to avoid misclassification.
`
`RECOMMENDATIONS FOR PAWP AT REST.
`
` The working group does not recommend lowering the
`threshold to 12 mm Hg in clinical practice.
` The cutoff for pre-capillary PH should remain at
`15 mm Hg because this value has been used in
`almost all clinical trials generating evidence for the
`safety and efficacy of PAH-targeted therapies in
`patients fulfilling these criteria.
` Invasive hemodynamics need to be placed in clinical
`and echocardiographic context with regard to proba-
`bility of existence of left heart disease.
` The current evidence does not support recommending
`left heart catheterization in all patients with PAH.
`
`Should fluid or exercise challenge be used to distinguish
`patients with PAH from patients with PH due to LV
`dysfunction? SHOULD FLUID CHALLENGE BE USED TO
`UNMASK LV DIASTOLIC DYSFUNCTION? The effect of volume
`challenge on left-sided end-diastolic pressure has been
`a subject of interest for some time. Studies in healthy indi-
`viduals have shown that administration of 1 liter of saline over
`6 to 8 min raised the PAWP by a maximum of 3 mm Hg
`but not to >11 mm Hg (18). In contrast, in a population at
`high risk for diastolic dysfunction, administration of 500 ml
`of saline over 5 min was able to reveal patients in whom the
`PAWP increased to >15 mm Hg (19).
`Thus, fluid challenge may identify patients with HFpEF
`but normal PAWP at baseline and may help reduce the
`number of inappropriate diagnoses of PAH in patients
`with LV diastolic dysfunction. A fluid bolus of 500 ml
`administered over a period of 5 to 10 min appears to be
`safe and seems to discriminate patients with PAH from
`those with LV diastolic dysfunction (20). Larger volumes,
`in contrast, may cause the PAWP to rise even in healthy
`volunteers (21). The diagnostic performance (sensitivity,
`specificity, and positive and negative predictive values) of
`fluid challenge has not yet been sufficiently evaluated, and
`the same is true for the safety of fluid challenge in patients
`with severe PH as well as in patients with HFpEF. In
`addition, fluid challenge adds another layer of complexity
`to RHC.
`
`RECOMMENDATION ON FLUID CHALLENGE FOR UNMASKING
`
`HFPEF. Fluid challenge may be useful in identifying patients
`with occult HFpEF, but
`this
`technique requires
`meticulous evaluation and standardization before its use
`in clinical practice can be recommended.
` Current evidence suggests that administration of 500
`ml of fluid over 5 to 10 min is safe and may help to
`
`045
`
`

`
`D46
`
`Hoeper et al.
`Definition and Diagnosis of PH
`
`JACC Vol. 62, No. 25, Suppl D, 2013
`December 24, 2013:D42 50
`
`distinguish patients with PAH from those with occult
`LV diastolic dysfunction. The results of this test,
`however, must be interpreted with caution and should
`not be used alone to discard a diagnosis of PAH.
`
`SHOULD HEMODYNAMICS BE ASSESSED AT EXERCISE TO
`UNMASK LV DIASTOLIC DYSFUNCTION? Exercise, with wide
`swings in airway and pleural pressures, poses particular
`technical challenges in recording and interpreting cardiac
`pressures, and few studies have systematically analyzed the
`PAWP changes during exercise. In a study of healthy non-
`athletes, the mean wedge pressure rose by up to 5 mm Hg
`with exercise but did not exceed 15 mm Hg (22). In well-
`trained athletes, recumbent exercise significantly increased
`the PAWP, reaching 20 to 25 mm Hg in several individuals
`(23). In a more recent study on exercise-induced PH, Tolle
`et al. (11) found PAWP values >15 mm Hg in approxi-
`mately half of the healthy control group as well as in patients
`with exercise-induced or resting PH.
`Borlaug et al. (24) studied the effects of exercise on
`hemodynamics in patients with exertional dyspnea and
`presumed HFpEF but normal resting PAWP levels. At rest,
`patients with HFpEF had slightly higher PAWP (11  2 vs.
`9  3 mm Hg in controls without cardiac disease). During
`exercise, end-expiration PAWP rose to 32  6 mm Hg in
`patients with HFpEF compared with 13  5 mm Hg in
`controls (24). In addition, a recent study suggested that
`exercise hemodynamics may be useful
`in distinguishing
`between PAH and PH associated with LV diastolic
`dysfunction in patients with the scleroderma (SSc) spectrum
`of disease (25).
`Thus, exercise hemodynamics may identify patients with
`HFpEF with normal PAWP at
`rest. However,
`it
`is
`cumbersome and time consuming to exercise patients with
`a catheter in place, reading of the PAWP during exercise is
`difficult, and there has been no standardization on the level
`of exercise, type of exercise, position at exercise, and normal
`values for various ages.
`
`RECOMMENDATION ON EXERCISE CHALLENGE TO UNMASK
`
`HFPEF. It is likely that exercise hemodynamics will be useful in
`uncovering HFpEF. However,
`further evaluation,
`standardization, and comparison with volume chal-
`lenge are necessary before their use in clinical practice
`can be endorsed.
`
`Additional Recommendations for RHC
`
`Although current guidelines and textbooks recommend
`RHC for the diagnostic evaluation of patients with PH,
`specific recommendations on how to perform this procedure
`are rare. The following points should be noted.
` RHC in patients with PH can be technically demanding
`and has been associated with serious, sometimes fatal,
`
`this invasive diagnostic
`complications (26). Thus,
`procedure should be performed in expert centers.
` Every RHC should include a comprehensive hemo-
`dynamic
`assessment,
`including measurements of
`pressures in the right atrium, right ventricle, and PA;
`in the “wedge” position; and CO and mixed-venous
`oxygen saturation.
` The zero level of the pressure transducer varies among
`centers and should be standardized for future research
`because the level of the transducer has an important
`impact on the hemodynamic results, especially on right
`atrium pressure and PAWP (27). The working group
`recommends zeroing the pressure transducer at the
`midthoracic line in a supine patient halfway between
`the anterior sternum and the bed surface. This repre-
`sents the level of the left atrium.
` The balloon should be inflated in the right atrium
`from where the catheter should be advanced until it
`reaches the PAWP position. Repeated deflations and
`inflations of the catheter should be avoided because
`this has been associated with ruptures of PAs (26).
`The PAWP should be recorded as the mean of 3
`measurements at end-expiration.
` The gold standard for CO measurement is the direct
`Fick method, which requires direct measurement of
`the oxygen uptake, a technique that is not widely
`available. Therefore, it has become common practice in
`many centers to use the indirect Fick method, which
`uses estimated values for oxygen uptake derived from
`tables. This approach is acceptable but lacks reliability.
`Therefore, the preferred method of measuring CO is
`thermodilution, which has been shown to provide
`reliable measurements even in patients with very low
`CO and/or severe tricuspid regurgitation (28).
` Oximetry (i.e., stepwise assessment of oxygen satura-
`tion) should be performed in every patient with a PA
`oxygen saturation >75% and whenever a cardiac left-
`to-right shunt is suspected.
` Pulmonary vasoreactivity testing for identification of
`calcium channel blocker “responders” is recommended
`only for patients with IPAH. In all other forms of
`PAH or PH, pulmonary vasoreactivity testing is not
`recommended unless it is completed for scientific
`purposes because “responders” are exceedingly rare
`among these patients and the results can be misleading
`(29). Inhaled nitric oxide at 10 to 20 parts per million is
`the gold standard for pulmonary vasoreactivity testing
`(30); intravenous epoprostenol (2 to 12 ng/kg/min),
`intravenous adenosine (50 to 350 mg/min), and inhaled
`iloprost (5 mg) can be used as alternatives (31,32). The
`use of oxygen, calcium channel blockers, phosphodi-
`esterase 5 inhibitors, or other vasodilators for acute
`pulmonary vasoreactivity testing is discouraged.
` Pulmonary angiography can be part of the RHC but
`should be performed after all hemodynamic assess-
`ments have been completed.
`
`046
`
`

`
`JACC Vol. 62, No. 25, Suppl D, 2013
`December 24, 2013:D42 50
`
`Hoeper et al.
`Definition and Diagnosis of PH
`
`D47
`
`Figure 1
`
`Diagnostic Approach to Pulmonary Hypertension
`
`diffusion
`chronic thromboembolic pulmonary hypertension; DLCO
`connective tissue disease; CTEPH
`congenital heart disease; CTD
`blood gas analysis; CHD
`BGA
`capacity of the lung for carbon monoxide; ECG
`electrocardiogram; HR-CT
`high-resolution computed tomography; PA
`pulmonary angiography; PAH
`pulmonary arterial
`hypertension; PAPm mean pulmonary artery pressure; PAWP
`pulmonary arterial wedge pressure; PCH
`pulmonary capillary hemangiomatosis; PEA
`pulmonary endar-
`terectomy; PFT
`pulmonary function testing; PH
`pulmonary hypertension; PVOD
`pulmonary veno-occlusive disease; PVR
`pulmonary vascular resistance; RHC
`right
`heart catheter; RV
`right ventricle; V/Q
`ventilation/perfusion; x-ray
`chest radiograph.
`
`Diagnostic Approach in Patients With
`Clinical Suspicion of PH/PAH
`
`The most fundamental principles in the diagnostic workup
`of patients with clinical suspicion of PH/PAH remain
`unchanged. PH/PAH should be suspected in any patient
`with otherwise unexplained dyspnea on exertion, syncope,
`
`and/or signs of right ventricular dysfunction. Transthoracic
`echocardiography continues
`to be the most
`important
`noninvasive screening tool to assess the possibility of PH,
`but RHC remains mandatory to establish the diagnosis. A
`diagnosis of PAH requires the exclusion of other causes of
`PH, and the working group proposes a slightly modified
`version of the diagnostic algorithm proposed in the 2009
`
`047
`
`

`
`D48
`
`Hoeper et al.
`Definition and Diagnosis of PH
`
`JACC Vol. 62, No. 25, Suppl D, 2013
`December 24, 2013:D42 50
`
`European guidelines (2,4) as shown in Figure 1. This revised
`version has been simplified and, in some aspects, is more
`specific. The pathway leading from ventilation/perfusion
`scintigraphy to pulmonary veno-occlusive disease has been
`deleted (33), and diffusing capacity of the lung for carbon
`monoxide (DLCO) measurements have been added to the
`initial assessment because spirometry alone does not always
`reveal parenchymal lung disease, for instance, in patients
`with combined pulmonary fibrosis and emphysema (34 36).
`A comprehensive workup for PH requires expertise and
`should be performed at expert centers (2).
`
`Early Identification of Patients With PAH
`
`Sporadic cases (IPAH). Despite increasing awareness,
`there is often considerable delay between onset of symptoms
`and diagnosis of IPAH. In the recent REVEAL (Registry to
`Evaluate Early and Long-Term PAH Disease Manage-
`ment) registry, 21% of patients had symptoms for >2 years
`before diagnosis (37,38). The vast majority of patients
`diagnosed with IPAH are in World Health Organization
`functional classes III and IV (37,39 41), which have been
`shown to predict poorer survival (42,43). The nature of
`patients formally diagnosed with IPAH has also changed
`over recent years, at least in the Western world, with
`a significant increase in age and number of comorbidities
`(41,44,45). Identifying patients with IPAH earlier in the
`disease process is likely to be beneficial, allowing targeted
`therapies to be started before the d