Download - Pulmonary Hypertension - IMED 2017updateinternalmedicine.com/syllabus/Syllabus/.../68-LeVarge_new.pdf · Pulmonary Hypertension in 2016 Learning objectives Identify patients at risk

Pulmonary Hypertension in 2016

Barbara LeVarge MD

Pulmonary Hypertension Center

Beth Israel Deaconess Medical CenterCOPYRIG

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� No disclosures

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� Learning objectives◦ Identify patients at risk for development of

pulmonary arterial hypertension (PAH)

◦ Recognize key signs and symptoms of PAH

◦ Utilize data obtained from echocardiography, right heart catheterization, and additional studies in the evaluation of a patient with possible pulmonary hypertension

◦ Understand important similarities and differences between PAH and other forms of pulmonary hypertension, particularly as related to treatment

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� Pulmonary hypertension (PH) vs. pulmonary arterial hypertension (PAH)

� Pathophysiology of PAH

� Clinical manifestations and diagnosis

� Medical management

� Non-PAH pulmonary hypertensionCOPYRIG

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Definitions

� Pulmonary hypertension (PH): Mean pulmonary artery pressure (mPAP) ≥ 25 mm Hg◦ Without specification as to cause

◦ V=IR (analogous to ΔP=Q x R)

◦ In pulmonary circulation

mPAP - PAWP = CO x PVR

mPAP = PAWP + CO x PVR

◦ Therefore, mPAP can be elevated in states of:

� PAWP elevation (left sided heart failure)

� CO elevation (hyperdynamic states, exercise)

� PVR elevation

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Definitions

� Precapillary pulmonary hypertension: PH due to elevation in PVR (high resistance state)◦ Large PA to capillary level

� Pulmonary arterial hypertension (PAH): precapillary PH fitting into WHO Group 1 classification

◦ Prevalence estimates: ~15 per million adults

PrecapillaryPH

PH PAH

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WHO Group 2: left heart disease

WHO Group 4: chronic

thromboembolismWHO Group

3: lung disease

WHO Group 1: PAH

WHO Group 1’:

PVOD/PCH

WHO Group 5: unclear or variable mechanisms

WHO Classification of PH

McManus DD, De Marco T. Chapter 27. Pulmonary Hypertension. In: Crawford MH, ed. CURRENT Diagnosis & Treatment: Cardiology. 3rd ed. New York: McGraw-Hill; 2009. http://www.accessmedicine.com.ezp-prod1.hul.harvard.edu/content.aspx?aID=3649568.

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pulmonary hypertension (PH) with a median ingestionduration of 30 months and a median delay between start ofexposure and diagnosis of 108 months. One-quarter ofpatients in these series showed coexisting PH and mild tomoderate valvular heart diseases (14).

Chronicmyeloproliferative (CML)disorders are a rare causeof PH, involving various potential mechanisms (Group 5)including high cardiac output, splenectomy, direct obstruc-tion of pulmonary arteries, chronic thromboembolism,portal hypertension, and congestive heart failure. Theprognosis of CML has been transformed by tyrosine kinaseinhibitors (TKIs) such as imatinib, dasatinib, and nilotinib.Although, TKIs are usually well tolerated, these agents areassociated nevertheless with certain systemic side effects(edema, musculoskeletal pain, diarrhea, rash, pancytopenia,elevation of liver enzymes). It is also well establishedthat imatinib may induce cardiac toxicity. Pulmonarycomplications and specifically pleural effusions have beenreported more frequently with dasatinib. In addition, casereports suggested that PHmay be a potential complication ofdasatinib use (15).

Montani et al. (16) recently published incidental cases ofdasatinib-associated PAH reported in the French registry.Between November 2006 and September 2010, 9 casestreated with dasatinib at the time of PH diagnosis wereidentified. At diagnosis, patients had moderate to severe pre-capillary PH confirmed by heart right catheterization. Noother PH cases were reported with other TKIs at the timeof PH diagnosis. Interestingly, clinical, functional, andhemodynamic improvements were observed within 4 monthsof dasatinib discontinuation in all but 1 patient. However,after a median follow-up of 9 months, most patients did notdemonstrate complete recovery, and 2 patients died. Today,more than 13 cases have been observed in France among2,900 patients treated with dasatinib for CML during thesame period, giving the lowest estimate incidence ofdasatinib-associated PAH of 0.45%. Finally, notifications ofalmost 100 cases of PH have been submitted for Europeanpharmaceutical vigilance. Dasatinib is considered a likely riskfactor for PH (Table 2).

Few cases of PAH associated with the use of interferon(IFN)-a or -b (17,18) have been published so far. Recently,all cases of PAH patients with a history of IFN therapynotified in the French PH registry were analyzed (19). Fifty-three patients with PAH and a history of IFN use wereidentified between 1998 and 2012. Forty-eight patients weretreated with IFN-a for chronic hepatitis C, most of themhad an associated risk factor for PH such as humanimmunodeficiency virus (HIV) infection and/or portalhypertension. Five other cases were treated with IFNb formultiple sclerosis; those patients did not have any associatedrisks factor for PAH. The mean delay between initiation ofIFN therapy and PAH diagnosis was approximately 3 years.Sixteen additional patients with previously documentedPAH were treated with IFN-a for hepatitis C and showeda significant increase in pulmonary vascular resistance (PVR)within a few months of therapy initiation; in half of them,withdrawal of IFN resulted in a marked hemodynamic

Table 2Updated Classification for Drug- and Toxin-InducedPAH*

Definite Possible

Aminorex Cocaine

Fenfluramine Phenylpropanolamine

Dexfenfluramine St. John’s wort

Toxic rapeseed oil Chemotherapeutic agents

Benfluorex Interferon a and b

SSRIsy Amphetamine-like drugs

Likely Unlikely

Amphetamines Oral contraceptives

L-Tryptophan Estrogen

Methamphetamines Cigarette smoking

Dasatinib

*Nice 2013. ySelective serotonin reuptake inhibitor (SSRIs) have been demonstrated as a riskfactor for the development of persistent pulmonary hypertension in the newborn (PPHN) in preg-nant women exposed to SSRIs (especially after 20 weeks of gestation). PPHN does not strictlybelong to Group 1 (pulmonary arterial hypertension [PAH]) but to a separated Group 1. Mainmodification to the previous Danapoint classification are in bold.

Table 1 Updated Classification of Pulmonary Hypertension*

1. Pulmonary arterial hypertension1.1 Idiopathic PAH1.2 Heritable PAH1.2.1 BMPR21.2.2 ALK-1, ENG, SMAD9, CAV1, KCNK31.2.3 Unknown1.3 Drug and toxin induced1.4 Associated with:1.4.1 Connective tissue disease1.4.2 HIV infection1.4.3 Portal hypertension1.4.4 Congenital heart diseases1.4.5 Schistosomiasis

10 Pulmonary veno-occlusive disease and/or pulmonary capillary hemangiomatosis10 0. Persistent pulmonary hypertension of the newborn (PPHN)

2. Pulmonary hypertension due to left heart disease2.1 Left ventricular systolic dysfunction2.2 Left ventricular diastolic dysfunction2.3 Valvular disease2.4 Congenital/acquired left heart inflow/outflow tract obstruction andcongenital cardiomyopathies

3. Pulmonary hypertension due to lung diseases and/or hypoxia3.1 Chronic obstructive pulmonary disease3.2 Interstitial lung disease3.3 Other pulmonary diseases with mixed restrictive and obstructive pattern3.4 Sleep-disordered breathing3.5 Alveolar hypoventilation disorders3.6 Chronic exposure to high altitude3.7 Developmental lung diseases

4. Chronic thromboembolic pulmonary hypertension (CTEPH)

5. Pulmonary hypertension with unclear multifactorial mechanisms5.1 Hematologic disorders: chronic hemolytic anemia, myeloproliferativedisorders, splenectomy5.2 Systemic disorders: sarcoidosis, pulmonary histiocytosis,lymphangioleiomyomatosis5.3Metabolicdisorders: glycogenstoragedisease,Gaucherdisease, thyroiddisorders5.4 Others: tumoral obstruction, fibrosing mediastinitis, chronic renal failure,segmental PH

*5th WSPH Nice 2013. Main modifications to the previous Dana Point classification are in bold.BMPR ¼ bone morphogenic protein receptor type II; CAV1 ¼ caveolin-1; ENG ¼ endoglin;

HIV ¼ human immunodeficiency virus; PAH ¼ pulmonary arterial hypertension.

Simonneau et al. JACC Vol. 62, No. 25, Suppl D, 2013Classification of Pulmonary Hypertension December 24, 2013:D34–41

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pulmonary hypertension due to chronic lung disease and/orhypoxia (Group 3); chronic thromboembolic pulmonaryhypertension (Group 4); and pulmonary hypertension due tounclear multifactorial mechanisms (Group 5). During thesuccessive world meetings, a series of changes were carriedout, reflecting some progresses in the understanding of thedisease. However, the general architecture and the philosophyof the clinical classification were unchanged. The currentclinical classification of pulmonary hypertension (3) is nowwell accepted and, widely used in the daily practice ofpulmonary hypertension experts. It has been adopted by theGuidelines Committee of the Societies of Cardiology and,Pneumology (4,5). Moreover, this classification is currentlyused by the U.S. Food and Drug Administration and theEuropean Agency for Drug Evaluation for the labelling ofnew drugs approved for pulmonary hypertension.

During the Fifth World Symposium held in 2013 inNice, France, the consensus was to maintain the generaldisposition of previous clinical classification. Somemodifications and updates, especially for Group 1, wereproposed according to new data published in the lastyears. It was also decided in agreement with the TaskForce on Pediatric PH to add some specific items relatedto pediatric pulmonary hypertension in order to havea comprehensive classification common for adults andchildren (Table 1).

Group 1: Pulmonary Arterial Hypertension (PAH)

Since the second World Symposium in 1998, the nomen-clature of the different subcategories of Group 1 havemarkedly evolved and, additional modification were made inthe Nice classification.

Heritable Pulmonary Hypertension

In 80% of families with multiple cases of pulmonary arterialhypertension (PAH), mutations of the bone morphogenicprotein receptor type 2 (BMPR2), a member of the tumorgrowth factor (TGF)-beta super family, can be identified(6). In addition, 5% of patients have rare mutations in othergenes belonging to the TGFb super family: activin-likereceptor kinase-1 (ALK1) (7), endoglin (ENG) (8),and mothers against decapentaplegic 9 (Smad 9) (9).Approximately 20% of families have no detectable mutationsin currently known disease-associated genes. Recently two

new gene mutations have beenidentified: a mutation in cav-eolin-1 (CAV1) which encodesa membrane protein of caveolae,abundant in the endothelial cellsof the lung (10), and KCNK3, agene encoding potassium channelsuper family K member-3 (11).The identification of these newgenes not intimately related toTGFb signaling may provide newinsights into the pathogenesis ofPAH.

Drug- and Toxin-InducedPulmonary Hypertension

A number of drugs and toxinshave been identified as risk fac-tors for the development of PAHand were included in the previousclassification (3). Risk factorswere categorized according tothe strength of evidence, as defi-nite, likely, possible, or unlikely(Table 2).

A definite association is de-fined as an epidemic or largemulticenter epidemiologic studiesdemonstrating an association between a drug and PAH. Alikely association is defined as a single case-control studydemonstrating an association or a multiple-case series.Possible is defined as drugs with similar mechanisms of actionas those in the definite or likely category but which have notyet been studied. Last, an unlikely association is defined asone in which a drug has been studied in epidemiologic studiesand an association with PAH has not been demonstrated.

Over the last 5 years, new drugs have been identified orsuspected as potential risk factors for PAH.

Since 1976, Benfluorex (MEDIATOR, LaboratoriesServier, Neuilly-Sur-Seine, France) has been approved inEurope as a hypolipidemic and hypoglycemic drug. Thisdrug is in fact a fenfluramine derivative, and its mainmetabolite is norfenfluramine, similar to Isomeride. Ben-fluorex, due to its pharmacological properties, was with-drawn from the market in all European countries after 1998(date of the worldwide withdrawal of fenfluramine deriva-tives), except in France where the drug was marketed until2009 and was frequently used between 1998 and 2009 asa replacement for Isomeride. The first case series reportingbenfluorex-associated PAH was published in 2009. Inaddition to 5 cases of severe PAH, 1 case of valvular diseasewas also reported (12). Recently, Savale et al. (13) reported85 cases of PAH associated with benfluorex exposure,identified in the French national registry from 1999 to 2011.Of these cases, 70 patients had confirmed pre-capillary

Actelion and United Therapeutics; and has served on advisory boards of Gilead andUnited Therapeutics. Dr. Olschewski has received consultancy and lecture fees fromActelion, Bayer, Lilly, Gilead, GlaxoSmithKline, Pfizer, and Unither; and consultancyfees from NebuTec. Dr. Robbins has received honoraria from United Therapeutics,Gilead, and Actelion for attending advisory board meetings; has received honorariafrom Actelion, Gilead, United Therapeutics, and Bayer; and he has been the primaryinvestigator on industry-sponsored studies from Actelion, Gilead, United Therapeu-tics, GeNO, Novartis, and Aires in which payment was made to Vanderbilt University.Dr. Souza has received consultancy/lecture fees from Bayer. All other authors reportthat they have no relationships relevant to the contents of this paper to disclose.Manuscript received October 15, 2013; accepted October 22, 2013.

Abbreviationsand Acronyms

CHD = congenital heart

disease

HAART = highly active

antiretroviral therapy

HIV = human

immunodeficiency virus

IFN = interferon

PAH = pulmonary arterial

hypertension

PAP = pulmonary arterial

pressure

PH = pulmonary

hypertension

POPH = portopulmonary

hypertension

PPHN = persistent

pulmonary hypertension of

the newborn

PVR = pulmonary vascular

resistance

SCD = sickle cell disease

Sch-PAH = schistosomiasis-

associated PAH

TGF = tumor growth factor

TKI = tyrosine kinase

inhibitor

JACC Vol. 62, No. 25, Suppl D, 2013 Simonneau et al.December 24, 2013:D34–41 Classification of Pulmonary Hypertension

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disease



HIV = human


IFN = interferon


hypertension


pressure

PH = pulmonary

hypertension


hypertension

PPHN = persistent


the newborn


resistance



associated PAH



inhibitor


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� Idiopathic PAH (IPAH)

� Heritable PAH: BMPR2, others

� Drug/toxin related: anorectic agents, methamphetamines, others

� Connective tissue disease: scleroderma, MCTD

� Portopulmonary hypertension

� Congenital heart disease

� HIV

� Schistosomiasis� (1’ PVOD/PCH)

� (1’’ Persistent pulmonary hypertension of the newborn)

WHO Group 1 PAH

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disease



HIV = human


IFN = interferon


hypertension


pressure

PH = pulmonary

hypertension


hypertension

PPHN = persistent


the newborn


resistance



associated PAH



inhibitor


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pulmonary hypertension (PH) with a median ingestionduration of 30 months and a median delay between start ofexposure and diagnosis of 108 months. One-quarter ofpatients in these series showed coexisting PH and mild tomoderate valvular heart diseases (14).

Chronicmyeloproliferative (CML)disorders are a rare causeof PH, involving various potential mechanisms (Group 5)including high cardiac output, splenectomy, direct obstruc-tion of pulmonary arteries, chronic thromboembolism,portal hypertension, and congestive heart failure. Theprognosis of CML has been transformed by tyrosine kinaseinhibitors (TKIs) such as imatinib, dasatinib, and nilotinib.Although, TKIs are usually well tolerated, these agents areassociated nevertheless with certain systemic side effects(edema, musculoskeletal pain, diarrhea, rash, pancytopenia,elevation of liver enzymes). It is also well establishedthat imatinib may induce cardiac toxicity. Pulmonarycomplications and specifically pleural effusions have beenreported more frequently with dasatinib. In addition, casereports suggested that PHmay be a potential complication ofdasatinib use (15).

Montani et al. (16) recently published incidental cases ofdasatinib-associated PAH reported in the French registry.Between November 2006 and September 2010, 9 casestreated with dasatinib at the time of PH diagnosis wereidentified. At diagnosis, patients had moderate to severe pre-capillary PH confirmed by heart right catheterization. Noother PH cases were reported with other TKIs at the timeof PH diagnosis. Interestingly, clinical, functional, andhemodynamic improvements were observed within 4 monthsof dasatinib discontinuation in all but 1 patient. However,after a median follow-up of 9 months, most patients did notdemonstrate complete recovery, and 2 patients died. Today,more than 13 cases have been observed in France among2,900 patients treated with dasatinib for CML during thesame period, giving the lowest estimate incidence ofdasatinib-associated PAH of 0.45%. Finally, notifications ofalmost 100 cases of PH have been submitted for Europeanpharmaceutical vigilance. Dasatinib is considered a likely riskfactor for PH (Table 2).

Few cases of PAH associated with the use of interferon(IFN)-a or -b (17,18) have been published so far. Recently,all cases of PAH patients with a history of IFN therapynotified in the French PH registry were analyzed (19). Fifty-three patients with PAH and a history of IFN use wereidentified between 1998 and 2012. Forty-eight patients weretreated with IFN-a for chronic hepatitis C, most of themhad an associated risk factor for PH such as humanimmunodeficiency virus (HIV) infection and/or portalhypertension. Five other cases were treated with IFNb formultiple sclerosis; those patients did not have any associatedrisks factor for PAH. The mean delay between initiation ofIFN therapy and PAH diagnosis was approximately 3 years.Sixteen additional patients with previously documentedPAH were treated with IFN-a for hepatitis C and showeda significant increase in pulmonary vascular resistance (PVR)within a few months of therapy initiation; in half of them,withdrawal of IFN resulted in a marked hemodynamic

Table 2Updated Classification for Drug- and Toxin-InducedPAH*

Definite Possible

Aminorex Cocaine

Fenfluramine Phenylpropanolamine

Dexfenfluramine St. John’s wort

Toxic rapeseed oil Chemotherapeutic agents

Benfluorex Interferon a and b

SSRIsy Amphetamine-like drugs

Likely Unlikely

Amphetamines Oral contraceptives

L-Tryptophan Estrogen

Methamphetamines Cigarette smoking

Dasatinib

*Nice 2013. ySelective serotonin reuptake inhibitor (SSRIs) have been demonstrated as a riskfactor for the development of persistent pulmonary hypertension in the newborn (PPHN) in preg-nant women exposed to SSRIs (especially after 20 weeks of gestation). PPHN does not strictlybelong to Group 1 (pulmonary arterial hypertension [PAH]) but to a separated Group 1. Mainmodification to the previous Danapoint classification are in bold.

Table 1 Updated Classification of Pulmonary Hypertension*

1. Pulmonary arterial hypertension1.1 Idiopathic PAH1.2 Heritable PAH1.2.1 BMPR21.2.2 ALK-1, ENG, SMAD9, CAV1, KCNK31.2.3 Unknown1.3 Drug and toxin induced1.4 Associated with:1.4.1 Connective tissue disease1.4.2 HIV infection1.4.3 Portal hypertension1.4.4 Congenital heart diseases1.4.5 Schistosomiasis

10 Pulmonary veno-occlusive disease and/or pulmonary capillary hemangiomatosis10 0. Persistent pulmonary hypertension of the newborn (PPHN)

2. Pulmonary hypertension due to left heart disease2.1 Left ventricular systolic dysfunction2.2 Left ventricular diastolic dysfunction2.3 Valvular disease2.4 Congenital/acquired left heart inflow/outflow tract obstruction andcongenital cardiomyopathies

3. Pulmonary hypertension due to lung diseases and/or hypoxia3.1 Chronic obstructive pulmonary disease3.2 Interstitial lung disease3.3 Other pulmonary diseases with mixed restrictive and obstructive pattern3.4 Sleep-disordered breathing3.5 Alveolar hypoventilation disorders3.6 Chronic exposure to high altitude3.7 Developmental lung diseases

4. Chronic thromboembolic pulmonary hypertension (CTEPH)

5. Pulmonary hypertension with unclear multifactorial mechanisms5.1 Hematologic disorders: chronic hemolytic anemia, myeloproliferativedisorders, splenectomy5.2 Systemic disorders: sarcoidosis, pulmonary histiocytosis,lymphangioleiomyomatosis5.3Metabolicdisorders: glycogenstoragedisease,Gaucherdisease, thyroiddisorders5.4 Others: tumoral obstruction, fibrosing mediastinitis, chronic renal failure,segmental PH

*5th WSPH Nice 2013. Main modifications to the previous Dana Point classification are in bold.BMPR ¼ bone morphogenic protein receptor type II; CAV1 ¼ caveolin-1; ENG ¼ endoglin;

HIV ¼ human immunodeficiency virus; PAH ¼ pulmonary arterial hypertension.

Simonneau et al. JACC Vol. 62, No. 25, Suppl D, 2013Classification of Pulmonary Hypertension December 24, 2013:D34–41

D36
















disease



HIV = human


IFN = interferon


hypertension


pressure

PH = pulmonary

hypertension


hypertension

PPHN = persistent


the newborn


resistance



associated PAH



inhibitor


D35

WHO Groups 2-5

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Pathophysiology

� More than simple vasoconstriction

� Other processes◦ Endothelial dysfunction and intimal

fibrosis

◦ Vascular smooth muscle proliferation

◦ Thrombosis

◦ Inflammation

� Initiating and contributing insults

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Pathophysiology

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Pathophysiology

Molecular predisposition:

- Altered BMPR signaling- Mutations in other

pathways involved in growth, proliferation, vasculogenesis, or apoptosis PAHCOP

YRIGHT

Pathophysiology

Additional insults:

- Estrogens?- Serotonergic drugs- High flows and shear

forces (CHD-PH)- Portal

hypertension/portosystemic shunting (PoPH)

- Inflammation (CTD-PH)- Hemolysis/ROS- Hypoxia- HIV/other viruses

Molecular predisposition:

- Altered BMPR signaling- Mutations in other

pathways involved in growth, proliferation, vasculogenesis, or apoptosis PAHCOP

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Clinical manifestations

� History◦ Exertional dyspnea, lightheadedness, fatigue◦ Peripheral edema, weight gain◦ Later signs: angina, syncope

� Exam◦ Signs of PH: Loud P2, ejection murmur, TR

or PI murmur, parasternal heave

◦ Signs of RV failure: elevated JVD, edema, ascites, hepatomegaly

◦ Signs pointing towards PAH etiology

� Radiology/ECG◦ “Incidental” finding on occasion

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Diagnostic evaluation

� Diagnosis

� Etiology

� Severity

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� Diagnosis◦ Echocardiography

◦ Right heart catheterization

� Etiology

� Severity

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Echocardiography

� Estimate of pulmonary artery systolic pressure: relates to peak velocity of TR jet

(4 x TRV2 +RAP)

� Right ventricular size and function

� Septal shift or LV impingement

� RA, PA dimensions

� Flow profiles through RVOT

� Pericardial effusionCOPYRIG

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Echocardiography

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Echocardiography

� Estimate of pulmonary artery systolic pressure: relates to peak velocity of TR jet

(4 x TRV2 +RAP)

� Right ventricular size and function

� Septal shift or LV impingement

� RA, PA dimensions

� Flow profiles through RVOT

� Pericardial effusion

� Overestimates and underestimates of PH� Patient 1: normal RV, PASP 28+RAP à PA 82/33

� Patient 2: dilated RV, PASP 53+RAP à PA 32/7

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diographic estimates of the pulmonary artery pressures was20.6 mm Hg with 95% limits of agreement ranging from 138.8to 240.0 mm Hg (Figure 1). The correlation coefficient for the DEand invasive measurement of pulmonary artery systolic pressurewas 0.66 (P , 0.001). Using a definition of an accurate pulmonaryartery pressure estimate of within 10 mm Hg of the value fromcatheterization, 48% of the echocardiographic estimates wereaccurate. Six of 16 patients (38%) pressure overestimates weregreater than 20 mm Hg, whereas 12 of 15 (80%) pressureunderestimates were greater than 20 mm Hg. In keeping, themagnitude of underestimation was greater than the overestima-tion (230 6 16 vs. 119 6 11 mm Hg; P 5 0.03). Of note, 10 of 12(83%) underestimates greater than 20 mm Hg were associatedwith a fair or poor quality Doppler jet across the tricuspid valve,suggesting inadequate or incomplete resolution of the maximaljet velocity as the cause of underestimation. The TR grade wascomparatively less for subjects with ‘‘poor’’ or ‘‘fair’’ versus‘‘good’’ or ‘‘excellent’’ quality transtricuspid Doppler velocitysignals (1.3 6 0.1 vs. 2.2 6 0.1; P , 0.001).

The distribution of estimates of the right atrial pressure andthe measured pressure is shown in Figure 2. A total of 29subjects had an echo-estimated RAP of 15 mm Hg or greater,however invasive RAP measurements revealed that 11 of 20 ofthese patients had an RAP <10 mm Hg, and 4 of 20 had anRAP <5 mm Hg. In fact, half (8 of 16 subjects) of the cases ofPA systolic pressure overestimation were related solely to rightatrial pressure overestimation by echocardiography. Comparingthe transtricuspid gradient estimate from the echocardiogramsand a calculated transtricuspid gradient from the right-heartcatheterization yielded a bias of 21.8 mm Hg, with 95% limitsof agreement of 33.6 and 237.2 mm Hg.

For clinical perspective, Table 3 compares the pulmonaryartery systolic pressure (PASP) obtained by right-heart cathe-terization with the DE PASP (for under- and overestimatevalues), along with the corresponding diagnostic category ofseverity that each subject would fall into for each technique. PHwas categorized as severe if the PASP was greater than 65 mm Hg,moderate (55 to 64 mm Hg), and mild (40 to 54 mm Hg). Ofnote, 47% of patients with pressure underestimation by DE had

their PH underestimated by two or more diagnostic categories(major error); 33% of the underestimates were within onediagnostic category (minor error); and 20% of underestimateswere within the same diagnostic category. In contrast, only 13%of patients with pressure overestimates by DE had their PHoverestimated by two or more diagnostic categories (majorerror); 31% by one diagnostic category, and 56% of over-estimates were within the same diagnostic category.

Echocardiographic estimates of cardiac output were com-pared with thermodilution determinations in Figure 3. The biasof 20.1 L/min with 95% limits of agreement ranging from 2.2 to22.4 L/min fell outside the predetermined limits of clinicalacceptability (see METHODS section). The correlation coefficientfor the DE and thermodilution cardiac output was 0.74; P ,0.001. We also tested whether the velocity time integral fromthe right ventricular (RV) outflow tract (VTIRVOT ) coulddifferentiate subjects with a low or relatively preserved cardiacindex, the latter being defined as a cardiac index greater than2.2 L/min/m2. Using receiver operator curve analysis, the areaunder the curve for the VTIRVOT was 0.82 (95% confidenceinterval [CI] 0.70–0.94; P , 0.0001); the best VTIRVOT cutpointfor a reduced cardiac index was 12.2, with a sensitivity andspecificity of 85.7 and 70.8%, respectively.

DISCUSSION

This study evaluated the utility of echocardiography for theestimation of pulmonary hemodynamics and CO in a populationof patients referred for right-heart catheterization at a singlePH center. Both tests were completed sequentially and withina very short timeframe (1 hour). Despite these optimized con-ditions, echocardiographic estimates for right atrial and pulmonaryartery pressures differed significantly from those determined byinvasive measurements, as assessed by Bland-Altman analysis,with a tendency to both overestimate and underestimate thepulmonary artery systolic pressure. Underestimations were largerin magnitude and more often significantly misclassified the severityof PH. Finally, measurements of CO by DE, which has beenvalidated in other patient populations, appeared least useful.

Clinical interest in using DE to estimate right ventricularpressure arose after Berger and colleagues and Currie andcolleagues demonstrated good correlation between echocardio-graphic estimates and directly measured pressures (6, 7). How-ever, establishing good correlation does not imply that one test isan accurate substitute for another. More recent studies have

Figure 1. Bland-Altman plot of Doppler echocardiographic estimates ofpulmonary artery pressure and right-heart catheterization measure-ments. The bias was 20.6 mm Hg and the 95% limits of agreementwere 138.8 and 240.0 mm Hg. Triangles represent excellent- and good-quality Doppler signal; circles 5 fair- and poor-quality Doppler signal;dotted line 5 bias; dash/dotted line 5 upper and lower limits ofagreement. Abbreviations: DE 5 Doppler echocardiography; PASP 5pulmonary artery systolic pressure; RHC 5 right-heart catheterization.

Figure 2. Comparison of right atrial pressure as estimated by Dopplerechocardiography and right-heart catheterization. RHC 5 right-heartcatheterization.

Fisher, Forfia, Chamera, et al.: Echocardiography and Pulmonary Hypertension 617

focused on the value of echocardiography in assessing RV func-tion by various techniques, including measurement of the tricuspidannular plane systolic excursion (TAPSE), two-dimensional strain,tissue Doppler echocardiography, or the speckle tracking method(3, 17, 18). However, RV systolic pressure (RVSP) remains themost commonly emphasized echo-derived parameter in routineclinical practice, particularly as the diagnosis of PH often hingesupon its initial recognition by Doppler echocardiography. Also,direct comparisons of echocardiographic estimates (e.g., RVSP)and hemodynamic values obtained by right-heart catheterization,with the two procedures being performed within an acceptabletime frame, have been relatively lacking in PH studies.

Bland and Altman developed statistical methods to betterassess the equivalence or accuracy of one test compared withanother (14), which we used for the present study. The Bland-Altman method is arguably a more optimal way to compare twonumerical tests. Although conclusions from the present study(related to the accuracy of DE) are at odds with those reachedby Berger and colleagues and Currie and colleagues, they are inagreement with studies by Arcasoy and colleagues and Fisherand colleagues (8, 9). The former study assessed the utility ofDE in patients with advanced lung disease who had beenreferred for lung transplantation. Although DE values corre-

lated with hemodynamic measurements (the two studies wereperformed within 72 hours of each other), DE was found to befrequently inaccurate and to overestimate the degree of PH.The latter study related to patients participating in the cardio-vascular substudy of the National Emphysema Treatment Trial(NETT), using a similar Bland-Altman analysis in these patientswith end-stage chronic obstructive pulmonary disease (COPD);the authors concluded that DE estimates of pulmonary arterypressures correlated very poorly with hemodynamic measure-ments obtained by cardiac catheterization. In addition, the DEtest characteristics of sensitivity and specificity were also poor.The temporal relationship between the DE and hemodynamicmeasurements in that study was not defined. In anothercomparison of DE and right-heart catheterization limited toa population of patients with scleroderma (19), and in which themean interval between the two techniques was an average of1.8 months, Denton and colleagues found a good correlation (R 50.83, P , 0.001), however, with large discrepancies in pulmonaryartery systolic pressures (PASP), of over 20 mm Hg in approx-imately 25% of patients, between the two techniques, particu-larly with increasing PASP. Nevertheless, the authors felt thatDE was a useful technique to detect PH in this particularpopulation. In a more recent study of 42 patients with variousforms of PH in whom DE was performed simultaneously (in 22patients) or nonsimultaneously (60 patients, some with repeatedmeasurements) with cardiac catheterization (with the two pro-cedures separated by up to 48 hours), Selimovic and colleaguesfound good correlations and small absolute differences for PASPand CO between the two approaches (20). However, large discrep-ancies in individual values for CO and transpulmonary gradientwere found.

The present study extends the findings of these previousstudies to a more assorted, and clinically relevant, population ofpatients with pulmonary arterial hypertension (PAH; whichconstituted 68% of our patient sample) as well as other causesof PH. Moreover, our study addresses important limitations ofsome of these previous studies in being prospective rather thanretrospective and limiting the interval between invasive andnoninvasive measurements to 1 hour, thus obviating as much aspossible potential daily variations in hemodynamic measure-ments. Importantly, unlike the study by Selimovic and colleagues,we excluded repeated measurements in the same patients, whichhas the potential to bias results (e.g., if an individual had

TABLE 3. COMPARISON OF PH SEVERITY ACCORDING TO PASPDERIVED FROM RHC VS. PASP ESTIMATED BY DE*

RHC DE Categorycath CategoryDoppler Error

PASP Underestimates

70 48 severe mild 276 46 severe mild 265 43 severe mild 290 54 severe mild 272 51 severe mild 2118 56 severe moderate 1106 56 severe moderate 1105 94 severe severe 076 59 severe moderate 1126 74 severe severe 0119 77 severe severe 060 30 moderate none 266 33 moderate none 264 51 moderate mild 1

61 50 moderate mild 1

PASP Overestimates

113 127 severe severe 080 103 severe severe 096 108 severe severe 078 100 severe severe 080 102 severe severe 070 81 severe severe 070 89 severe severe 084 111 severe severe 065 76 severe severe 064 120 moderate severe 160 82 moderate severe 163 78 moderate severe 158 73 moderate severe 162 73 moderate severe 148 65 mild severe 254 74 mild severe 2

Definition of abbreviations: DE 5 Doppler echocardiography; PASP 5 pulmo-nary artery systolic pressure; PH 5 pulmonary hypertension; RHC 5 right-heartcatherization.

*Classification of PH severity (category) by RHC or DE: severe (> 65 mm Hg);moderate (55–64 mm Hg); mild (40–54 mm Hg). The degree of misclassification(error) of the severity of PH by DE is graded from 0–2 (0 5 same category; 1 5 1category of misclassification; 2 5 2 or more categories of misclassification).

Figure 3. Bland-Altman plot of cardiac output estimated by DE andmeasured by right-heart catheterization. The bias was 20.1 L/min andthe 95% limits of agreement were 2.2 and 22.4 L/min. Diamondsrepresent difference in CO; dotted line 5 bias; dash/dotted line 5 upperand lower limits of agreement. Abbreviations: CO 5 cardiac output;DE 5 Doppler echocardiography; RHC 5 right-heart catheterization.

618 AMERICAN JOURNAL OF RESPIRATORY AND CRITICAL CARE MEDICINE VOL 179 2009

Accuracy of Doppler Echocardiography in theHemodynamic Assessment of Pulmonary HypertensionMicah R. Fisher1*, Paul R. Forfia2†, Elzbieta Chamera2, Traci Housten-Harris1, Hunter C. Champion2,Reda E. Girgis1, Mary C. Corretti2, and Paul M. Hassoun1

1Division of Pulmonary and Critical Care Medicine; 2Division of Cardiology, Department of Medicine, Johns Hopkins University, Baltimore, Maryland

Rationale: Transthoracic Doppler echocardiography is recommen-ded for screening for the presence of pulmonary hypertension (PH).However, some recent studies have suggested that Doppler echo-cardiographic pulmonary artery pressure estimates may frequentlybe inaccurate.Objectives: Evaluate the accuracy of Doppler echocardiography forestimating pulmonary artery pressure and cardiac output.Methods: We conducted a prospective study on patients with variousforms of PH who underwent comprehensive Doppler echocardio-graphy within 1 hour of a clinically indicated right-heart catheteri-zation to compare noninvasive hemodynamic estimates with inva-sively measured values.Measurements and Main Results: A total of 65 patients completed thestudy protocol. Using Bland-Altman analytic methods, the bias forthe echocardiographic estimates of the pulmonary artery systolicpressure was 20.6 mm Hg with 95% limits of agreement rangingfrom 138.8 to 240.0 mm Hg. Doppler echocardiography was in-accurate (defined as being greater than 610 mm Hg of the invasivemeasurement) in 48% of cases. Overestimation and underestima-tion of pulmonary artery systolic pressure by Doppler echocardiog-raphy occurred with a similar frequency (16 vs. 15 instances, re-spectively). The magnitude of pressure underestimation was greaterthan overestimation (230 6 16 vs. 119 6 11 mm Hg; P 5 0.03);underestimates by Doppler also led more often to misclassificationof the severity of the PH. For cardiac output measurement, the biaswas 20.1 L/min with 95% limits of agreement ranging from 12.2 to22.4 L/min.Conclusions: Doppler echocardiography may frequently be inaccu-rate in estimating pulmonary artery pressure and cardiac output inpatients being evaluated for PH.

Keywords: echocardiography; pulmonary hypertension; pulmonarysystolic pressure; cardiac output; accuracy

Pulmonary hypertension (PH), a syndrome characterized by in-creased pulmonary vascular resistance and remodeling, is associ-ated with significant morbidity and mortality, which are directlyrelated to cardiac function (1). Although the definitive diagnosis ofPH is currently established through right-heart catheterization,accurate noninvasive assessment of pulmonary arterial pressureand cardiac output (CO) is desirable both for diagnostic purposesand to assess response to therapy.

Transthoracic Doppler echocardiography (DE) is recommen-ded as the initial noninvasive modality in the screening and

evaluation of PH (2). Echocardiography can be used to evaluateright-sided chamber size and function and the presence of pericar-dial effusion, which are known to impact survival (3–5). Fre-quently, DE is used to estimate the right ventricular systolicpressure by estimating the pressure gradient between the rightventricle and the right atrium using the modified Bernoulli equa-tion, 4v2, where v equals the velocity of the tricuspid regurgitant jet.An estimated right atrial pressure is added to this number toapproximate the right ventricular systolic pressure, which equalsthe pulmonary artery systolic pressure in the absence of pulmonicstenosis. Using this method, several investigators have demon-strated an adequate correlation between the Doppler estimatesand direct measurements with right-heart catheterization (6, 7),although the accuracy of DE has been called in to question incertain clinical settings (8, 9).

Other than measuring pulmonary pressures, DE has thepotential to provide additional information important in themanagement of patients with PH, such as assessment of CO, animportant prognostic indicator of survival in these patients (1).However, little is known about the accuracy of Doppler-estimated CO in patients with pulmonary hypertension.

The purpose of this study was to prospectively evaluate theaccuracy of DE in estimating pulmonary artery systolic pressureand CO in consecutive patients referred to a single center forevaluation or treatment of PH and in whom DE was performedwithin 1 hour of hemodynamic assessment by right-heart cathe-terization. Some of the results of the current study have beenpreviously reported in abstract form (10).

METHODS

This study was conducted by the PH Program at Johns HopkinsUniversity. The Institutional Review Board approved the conduct ofthis study, and all patients gave informed consent before enrollment.Consecutive patients referred for right-heart catheterization for thediagnosis or management of PH were asked to participate in the study.

Scientific Knowledge on the Subject

Although Doppler echocardiography (DE) is recommen-ded as a screening tool for the diagnosis of pulmonaryhypertension (PH), its accuracy in estimating pulmonaryartery systolic pressure in PH patients has been questioned.The value of DE for estimating cardiac output (CO) inthese patients has not been assessed.

What This Study Adds to the Field

This prospective study demonstrates that DE can fre-quently overestimate and underestimate pulmonary arterypressure in PH patients. This error is in part explained byinaccuracies of right atrial pressure estimation and poorDoppler imaging of the transtricuspid regurgitant jet. Theestimation of CO by DE does not appear to be reliable.

(Received in original form November 5, 2008; accepted in final form January 21, 2009)

Supported by the Johns Hopkins University General Clinical Research Center andNHLBI P50 HL084946 (P.M.H.).

Correspondence and requests for reprints should be addressed to Paul M.Hassoun, M.D., Division of Pulmonary and Critical Care Medicine, 5501 HopkinsBayview Circle, Baltimore, MD 21224. E-mail: [email protected]

* Present affiliation: Division of Pulmonary, Allergy, and Critical Care Medicine,Emory University, Atlanta, GA.

† Present affiliation: Division of Cardiology, University of Pennsylvania, Philadel-phia, Pennsylvania.

Am J Respir Crit Care Med Vol 179. pp 615–621, 2009Originally Published in Press as DOI: 10.1164/rccm.200811-1691OC on January 22, 2009Internet address: www.atsjournals.org

Study patients underwent a transthoracic DE within 1 hour of com-pleting the right-heart catheterization. A subset of patients from thiscohort was reported previously (3, 11).

Right Heart Catheterization

Right heart catheterization was performed at rest without sedation bymembers of the research team (M.F. and H.C.). Pressure measure-ments were taken from the right atrium, right ventricle, and pulmonaryartery at the end of expiration. CO was determined using the thermo-dilution method using an average of a minimum of three measurements.Left-to-right shunting was ruled out by oximetry.

Transthoracic Doppler Echocardiography

All patients had a comprehensive two-dimensional DE protocol within1 hour of right-heart catheterization, as described previously (3).Echocardiograms were performed by one technician (E.C.) usinga Philips Sonos 5500 with a 3.2 MHz transducer (Philips MedicalSystems, Andover, MA). Images were recorded in multiple views thusobtaining optimal imaging for the primary analysis. Right atrialpressure (RAP) was estimated by evaluating the inferior vena cava(IVC) size and change with respiration (12). Briefly, RAP wasestimated to be 5 mm Hg when the IVC diameter was less than20 mm and the collapsibility greater than 50%; 10 mm Hg when IVCdiameter was less than 20 mm and collapsibility less than 50%; 15 mm Hgwhen IVC diameter was greater than 20 mm and collapsibility greaterthan 50%; and 20 mm Hg when IVC diameter was greater than 20 mmand collapsibility less than 50%. Continuous wave Doppler was used tomeasure the peak velocity of the tricuspid regurgitant (TR) jet at end-expiration. The interpreting cardiologist (P.F.) also graded the qualityof the continuous wave Doppler envelope: excellent (high-intensityDoppler signal with full ‘‘spade shaped’’ Doppler envelope with clearlyvisualized peak), good (moderate- or high-intensity Doppler envelopewith mild signal dropout at the peak velocity), fair (moderate-to-lowintensity Doppler envelope with moderate-to-high signal dropout atthe peak velocity), and poor (low intensity Doppler envelope withpoorly visualized peak velocity). The degree of TR was assessed semi-quantitatively (graded 0–3), as previously reported (3). Dopplerestimated CO was derived from the Doppler-estimated stroke volumeusing the velocity time integral (VTI) of flow through the leftventricular outflow tract (LVOT), the diameter of the LVOT, andheart rate recorded during the imaging study, using the followingformula: CODoppler 5 [VTILVOT 3 (Diameter of LVOT)2 3 (0.785)] 3heart rate (13). Echocardiograms were interpreted by a single cardiol-ogist (P.F.) who was blinded to the patients’ medical history anddiagnosis and to the results of the right-heart catheterization.

Statistical Analysis

Descriptive statistics were used to describe the study population usingStata 8.0 (College Park, Texas). Pressures determined by right-heartcatheterization and DE were compared using analysis described byBland and Altman (14). Accuracy was predefined as 95% limits ofagreement within 610 mm Hg for pulmonary artery pressure estimatesand 61 L/min for cardiac output measurements.

RESULTS

Seventy-five consecutive right-heart catheterizations wereperformed between March and October 2004 on patientsreferred to the PH program. Three patients refused toparticipate in the study; two patients could not have echocar-diograms performed because of scheduling conflicts; onepatient underwent an exercise right-heart catheterization;and one patient was excluded because a left heart catheteri-zation was required at the time of the right-heart catheteriza-tion. For two patients who had a repeat right-heart catheter-ization during the study period; only the first study pairing ofDE and catheterization was used in the analysis. The echo-cardiogram on one other patient could not be adequatelyinterpreted for this study. Therefore, data from a total of65 patients were available for the final analysis.

Patient Characteristics

The baseline characteristics of the study population are presentedin Table 1. The patients tended to be white females with an averageage of 54.0 years. The majority of the patients had pulmonaryarterial hypertension (WHO Group I) as defined by the Veniceclassification system (15). Other forms of PH were related tointerstitial lung disease (5 patients), pulmonary venous hyperten-sion (4 patients), and obstructive sleep apnea (2 patients). Vaso-dilator challenges were performed when appropriate with inhalednitric oxide. Only one patient had a positive vasodilator responseas previously defined (16), and the pulmonary artery pressuresreturned to pretesting levels immediately after cessation of theagent. A minority of patients (32%) were undergoing follow-upcatheterization and were already on specific therapy for PH. Nochanges in therapy were made during the brief time between thecatheterization and the echocardiogram.

Summary statistics for hemodynamic measurementsobtained by right-heart catheterization and DE are presentedin Table 2. These values during right-heart catheterizationrevealed a wide range in right atrial and pulmonary arterypressures, from 2 to 24 mm Hg and 20 to 120 mm Hg,respectively. CO ranged from 1.6 to 11.2 L/min. Results ofDE measurements revealed a similar wide range of pressuresand outputs. Six patients were found not to have any apprecia-ble tricuspid regurgitation. However, four of these patients hadevidence of pulmonary hypertension by catheterization includ-ing one with moderate PH (defined as a mean pulmonary arterypressure greater than 35 mm Hg). No patients had evidence ofa left-to-right shunt by oximetry.

Accuracy of Echocardiographic Estimates

Fifty-nine patients had DE estimates of pulmonary arterypressure. Using Bland-Altman analysis, the bias for the echocar-

TABLE 1. PATIENT DEMOGRAPHICS

Age, yrs (SD) 54.0 (14.7)Caucasian, n (%) 49 (75.4%)Female, n (%) 55 (84.6%)PH Present, n (%) 58 (89.2%)Diagnosis

Idiopathic PAH 14PAH-CTD 23Other*, n 21

Definition of abbreviations: CTD 5 connective tissue disease; PAH 5 pulmonaryarterial hypertension; PH 5 pulmonary hypertension.

*Other patient characteristics include: chronic thromboembolic pulmonaryhypertension, 1; interstitial lung disease, 5; obstructive sleep apnea, 2; HIV-related PAH, 1; sickle cell disease, 1; diastolic dysfunction, 4; sarcoidosis, 1;exercise induced, 1; unspecified, 1; portopulmary hypertension, 2; congenitalheart disease, 1; chronic obstructive pulmonary disease, 1.

TABLE 2. HEMODYNAMIC VALUES OBTAINED BY RIGHT-HEARTCATHETERIZATION AND DOPPLER ECHOCARDIOGRAPHY

Right-Heart Catheterization n Mean SD

RAP, mm Hg 65 9.4 5.0PASP, mm Hg 65 68.5 23.9mPAP, mm Hg 65 41.4 14.6CO, L/min 65 4.4 1.7Echocardiogram

RAP, mm Hg 65 12.4 4.7RVSP, mm Hg 59 70.2 25.1CO, L/min 64 4.3 1.4

Definition of abbreviations: CO 5 cardiac output; mPAP 5 mean pulmonaryartery pressure; PASP 5 pulmonary artery systolic pressure; RAP 5 right atrialpressure; RVSP 5 right ventricular systolic pressure.

616 AMERICAN JOURNAL OF RESPIRATORY AND CRITICAL CARE MEDICINE VOL 179 2009

COPYRIG

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Right heart catheterization

http://www.nlm.nih.gov/medlineplus/ency/article/003870.htm

• Necessary for PAH diagnosis.

• Very low morbidity and mortality

• Hemodynamic pattern:

• mPAP ≥ 25 mm Hg

• PAWP ≤ 15 mm Hg

• PVR ≥ 240 dyn-s/cm5

(3 Wood Units)

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Right heart catheterization

� Acute vasodilator testing◦ Agents: inhaled nitric oxide, IV

epoprostenol, IV adenosine

◦ Definition of response: decrease in mPAPby at least 10 mm Hg, to < 40 mm Hg, without decrease in cardiac output

◦ Benefits of testing� Identification of good prognosis

� Long term response to calcium channel blockade

� Ensure no worsening in setting of pulmonary vasodilation

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� Diagnosis

� Etiology

� Severity

COPYRIG

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with greater frequency in individuals who have used intra-venous drugs, no clear etiological link has been establishedwith foreign body emboli or the portal hypertension fre-quently observed in these same individuals because ofconcomitant infection with hepatitis B or C. Because HIVdoes not directly infect vascular endothelial cells or smoothmuscle cells, the mechanism of PAH in HIV infectionremains unclear. Routine screening for PAH in HIV is notrecommended due to the relatively low disease prevalence inHIV patients.

4.6. Pulmonary Arterial Hypertension AssociatedWith Portal HypertensionIn a large autopsy series, histological changes consistentwith PAH occurred in 0.73% of individuals with cirrhosis,6 times the prevalence in all autopsies (47). Hemodynamicstudies have estimated the prevalence of PAH in theseindividuals at 2% to 6%; however, the prevalence may behigher in patients referred for liver transplantation (48). Therisk of developing PAH increases with the duration ofportal hypertension. The mechanism of this association is

Figure 1. Relevant Pathways in the Pathogenesis of Pulmonary Arterial Hypertension

Schematic depicting the potential “hits” involved in the development of PAH. A rise in [Ca2!]cyt in PASMCs (due to increased Kv channel activity ➀ and membrane depolar-ization, which opens VDCCs; upregulated TRPC channels that participate in forming receptor- and store-operated Ca2! channels ➁; and upregulated membrane receptors[e.g., serotonin, endothelin, or leukotriene receptors] ➂ and their downstream signaling cascades) causes pulmonary vasoconstriction, stimulates PASMC proliferation, andinhibits the BMP-signaling pathway that leads to antiproliferative and proapoptotic effects on PASMCs. Dysfunction of BMP signaling due to BMP-RII mutation and BMP-RII/BMP-RI downregulation ➃ and inhibition of Kv channel function and expression ➀ attenuate PASMC apoptosis and promote PASMC proliferation. Increased Ang-1 synthesisand release ➄ from PASMCs enhance 5-HT production and downregulate BMP-RIA in PAECs and further enhance PASMC contraction and proliferation, whereas inhibited nitricoxide and prostacyclin synthesis ➅ in PAECs would attenuate the endothelium-derived relaxing effect on pulmonary arteries and promote sustained vasoconstriction andPASMC proliferation. Increased activity and expression of the 5-HTT ➆ would serve as an additional pathway to stimulate PASMC growth via the MAPK pathway. In addition, avariety of splicing factors, transcription factors, protein kinases, extracellular metalloproteinases, and circulating growth factors would serve as the “hits” to mediate the phe-notypical transition of normal cells to contractive or hypertrophied cells and to maintain the progression of PAH.5-HT indicates 5-hydroxytryptamine; 5-HTT, 5-HT transporter; 5-HTR, 5-hydroxytryptophan; Ang-1, angiopoietin; AVD, apoptotic volume decrease; BMP, bone morphogeneticprotein; BMP-RI, BMP type I receptor; BMP-RII, BMP type II receptor; BMPR-IA, BMP receptor IA; Ca2!, calcium ion; Co-Smad, common smad; cyt, cytosine; DAG, diacylglyc-erol; Em, membrane potential; ET-1, endothelin-1; ET-R, endothelin receptor; GPCR, G protein-coupled receptor; IP3, inositol 1,4,5-trisphosphate; K, potassium; Kv, voltage-gated potassium channel; MAPK, mitogen-activated protein kinase; NO/PGI2, nitric oxide/prostacyclin; PAEC, pulmonary arterial endothelial cell; PAH, pulmonary arterialhypertension; PASMC, pulmonary artery smooth muscle; PDGF, platelet-derived growth factor; PIP2, phosphatidylinositol biphosphate; PLC, phospholipase C; PLC!, PLC-beta;PLC", PLC gamma; PKC, protein kinase C; ROC, receptor-operated calcium channel; R-Smad, receptor-activated smad signaling pathway; RTK, receptor tyrosine kinase; SOC,store-operated channel; SR, sarcoplasmic reticulum; TIE2, tyrosine-protein kinase receptor; TRPC, transient receptor potential channel; and VDCC, voltage-dependent calciumchannel. Reprinted from Yuan and Rubin (31a).

1581JACC Vol. 53, No. 17, 2009 McLaughlin et al.April 28, 2009:1573–619 Expert Consensus Document on Pulmonary Hypertension

Downloaded From: http://content.onlinejacc.org/ on 01/19/2013

with greater frequency in individuals who have used intra-venous drugs, no clear etiological link has been establishedwith foreign body emboli or the portal hypertension fre-quently observed in these same individuals because ofconcomitant infection with hepatitis B or C. Because HIVdoes not directly infect vascular endothelial cells or smoothmuscle cells, the mechanism of PAH in HIV infectionremains unclear. Routine screening for PAH in HIV is notrecommended due to the relatively low disease prevalence inHIV patients.

4.6. Pulmonary Arterial Hypertension AssociatedWith Portal HypertensionIn a large autopsy series, histological changes consistentwith PAH occurred in 0.73% of individuals with cirrhosis,6 times the prevalence in all autopsies (47). Hemodynamicstudies have estimated the prevalence of PAH in theseindividuals at 2% to 6%; however, the prevalence may behigher in patients referred for liver transplantation (48). Therisk of developing PAH increases with the duration ofportal hypertension. The mechanism of this association is

Figure 1. Relevant Pathways in the Pathogenesis of Pulmonary Arterial Hypertension

Schematic depicting the potential “hits” involved in the development of PAH. A rise in [Ca2!]cyt in PASMCs (due to increased Kv channel activity ➀ and membrane depolar-ization, which opens VDCCs; upregulated TRPC channels that participate in forming receptor- and store-operated Ca2! channels ➁; and upregulated membrane receptors[e.g., serotonin, endothelin, or leukotriene receptors] ➂ and their downstream signaling cascades) causes pulmonary vasoconstriction, stimulates PASMC proliferation, andinhibits the BMP-signaling pathway that leads to antiproliferative and proapoptotic effects on PASMCs. Dysfunction of BMP signaling due to BMP-RII mutation and BMP-RII/BMP-RI downregulation ➃ and inhibition of Kv channel function and expression ➀ attenuate PASMC apoptosis and promote PASMC proliferation. Increased Ang-1 synthesisand release ➄ from PASMCs enhance 5-HT production and downregulate BMP-RIA in PAECs and further enhance PASMC contraction and proliferation, whereas inhibited nitricoxide and prostacyclin synthesis ➅ in PAECs would attenuate the endothelium-derived relaxing effect on pulmonary arteries and promote sustained vasoconstriction andPASMC proliferation. Increased activity and expression of the 5-HTT ➆ would serve as an additional pathway to stimulate PASMC growth via the MAPK pathway. In addition, avariety of splicing factors, transcription factors, protein kinases, extracellular metalloproteinases, and circulating growth factors would serve as the “hits” to mediate the phe-notypical transition of normal cells to contractive or hypertrophied cells and to maintain the progression of PAH.5-HT indicates 5-hydroxytryptamine; 5-HTT, 5-HT transporter; 5-HTR, 5-hydroxytryptophan; Ang-1, angiopoietin; AVD, apoptotic volume decrease; BMP, bone morphogeneticprotein; BMP-RI, BMP type I receptor; BMP-RII, BMP type II receptor; BMPR-IA, BMP receptor IA; Ca2!, calcium ion; Co-Smad, common smad; cyt, cytosine; DAG, diacylglyc-erol; Em, membrane potential; ET-1, endothelin-1; ET-R, endothelin receptor; GPCR, G protein-coupled receptor; IP3, inositol 1,4,5-trisphosphate; K, potassium; Kv, voltage-gated potassium channel; MAPK, mitogen-activated protein kinase; NO/PGI2, nitric oxide/prostacyclin; PAEC, pulmonary arterial endothelial cell; PAH, pulmonary arterialhypertension; PASMC, pulmonary artery smooth muscle; PDGF, platelet-derived growth factor; PIP2, phosphatidylinositol biphosphate; PLC, phospholipase C; PLC!, PLC-beta;PLC", PLC gamma; PKC, protein kinase C; ROC, receptor-operated calcium channel; R-Smad, receptor-activated smad signaling pathway; RTK, receptor tyrosine kinase; SOC,store-operated channel; SR, sarcoplasmic reticulum; TIE2, tyrosine-protein kinase receptor; TRPC, transient receptor potential channel; and VDCC, voltage-dependent calciumchannel. Reprinted from Yuan and Rubin (31a).

1581JACC Vol. 53, No. 17, 2009 McLaughlin et al.April 28, 2009:1573–619 Expert Consensus Document on Pulmonary Hypertension

Downloaded From: http://content.onlinejacc.org/ on 01/19/2013

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� Diagnosis

� Etiology

� Severity◦ Echo findings and RHC hemodynamics

◦ WHO functional classification

◦ Objective exercise capacity (6MWT, CPET)COPYRIG

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WHO/NYHA functional status

Right atrial pressure, CI, and mean PAP have been incorporatedin a formula to predict prognosis.8 It is unclear whether thisformula is applicable to current clinical practice.

7.2.2 Exercise capacityFor objective assessment of exercise capacity, the 6-minute walkingtest (6MWT) and cardiopulmonary exercise testing are commonlyused in patients with PAH.

The 6MWT is technically simple, inexpensive, reproducible, andwell standardized.77 In addition to distance walked, dyspnoea onexertion (Borg scale) and finger O2 saturation are recorded.Walking distances ,332 m78 or ,250 m79 and O2 desaturation.10%80 indicate impaired prognosis in PAH. With respect totreatment effects, absolute values .380 m following 3 months ofi.v. epoprostenol correlated with improved survival in IPAHpatients while the increase from baseline did not.79 The increasein 6MWT distance has remained the primary endpoint in mostpivotal PAH RCTs. The test is not sufficiently validated in PAH sub-groups and is influenced by (but not corrected for) body weight,gender, height, age, and patient motivation.77

With cardiopulmonary exercise testing gas exchange and venti-lation are continuously recorded throughout incremental exercise.In PAH, O2 uptake at the anaerobic threshold and peak exerciseare reduced in relation to disease severity, as are peak workrate, peak heart rate, O2 pulse, and ventilatory efficiency.81 Follow-ing multivariate analysis of clinical, haemodynamic, and exerciseparameters peak O2 uptake (,10.4 ml O2/kg/min) and peak systo-lic arterial pressure during exercise (,120 mmHg) independentlypredicted a worse prognosis in IPAH patients.75

While the results of both methods do correlate in PAH, cardi-opulmonary exercise testing failed to confirm improvementsobserved with 6MWT in RCTs.82,83 Although lack of standardiz-ation and insufficient expertise in performing cardiopulmonaryexercise testing were identified as the main reasons explaining

this discrepancy,81 the 6MWT remains until now the only Foodand Drug Administration- and European Agency for the Evaluationof Medicinal Products-accepted exercise endpoint for studies eval-uating treatment effects in PAH. Despite detailed recommen-dations,84,85 a generally accepted standardization ofcardiopulmonary exercise testing with respect to data acquisitionand analysis in PAH is lacking.

7.2.3 Biochemical markersBiochemical markers emerged within the last decade as an attrac-tive non-invasive tool for assessment and monitoring of RV dys-function in patients with PH.

Serum uric acid is a marker of impaired oxidative metabolism ofischaemic peripheral tissue. High uric acid levels were found torelate to poor survival in patients with IPAH.86 However, allopur-inol is often prescribed to patients with PAH, and hyperuricaemiaand diuretics influence its plasma levels, impairing the value ofclinical monitoring based on uric acid levels.

Atrial natriuretic peptide and brain natriuretic peptide (BNP)share similar physiological properties. Both induce vasodilatationand natriuresis and are released from myocardium in response towall stress. Interest in the clinical application of natriuretic peptidesin monitoring RV failure due to chronic PH has focused on BNP.

The final step of BNP synthesis consists of a high molecularweight precursor, proBNP cleaved into biologically inactiveN-terminal segment (NT-proBNP) and the proper low molecularweight BNP. NT-proBNP has a longer half-life and a better stabilityboth in circulating blood and after sampling. RV failure is the maincause of death in PAH, and BNP/NT-proBNP levels reflect theseverity of RV dysfunction. Nagaya et al.87 showed that the baselinemedian value of BNP (150 pg/mL) distinguished patients with agood or bad prognosis. In 49 out of 60 patients, BNP measurementwas repeated after 3 months of targeted therapy and again thesupramedian level (.180 pg/mL) was related to worse long-termoutcome. Plasma BNP significantly decreased in survivors butincreased in non-survivors despite treatment. In a trial involving68 patients with PAH associated with scleroderma, NT-proBNPbelow a median of 553 pg/mL was related to better 6-monthand 1-year survival.88 Using receiver operating characteristic(ROC) analysis, an NT-proBNP cut-off point at 1400 pg/mL waspredictive of a 3-year outcome in 55 patients with severe pre-capillary PH.89 Serum NT-proBNP below 1400 pg/mL seemed par-ticularly useful for identification of patients with good prognosis,who would not need escalation of treatment in the immediatefuture, and this has been independently confirmed.90 Largeroutcome trials are still required to verify the suggested cut-offlevels for NT-proBNP.

Increases in NT-proBNP plasma levels on follow-up have beenassociated with worse prognosis.88 Several recent trials assessingnew drugs in PAH or CTEPH reported a significant decrease inNT-proBNP in the actively treated vs. placebo patients.

Elevated plasma levels of cardiac troponin T and troponin I areestablished specific markers of myocardial damage and are prog-nostic indicators in acute coronary syndromes and acute pulmon-ary embolism. Elevated cardiac troponin T was an independentpredictor of fatal outcome during 2-year follow-up in a singletrial on 51 patients with PAH and five with CTEPH.91 In some

Table 14 Functional classification of pulmonaryhypertension modified after the New York HeartAssociation functional classification according to theWHO 199876

Class I Patients with pulmonary hypertension but withoutresulting limitation of physical activity. Ordinary physicalactivity does not cause undue dyspnoea or fatigue, chestpain, or near syncope.

Class II Patients with pulmonary hypertension resulting in slightlimitation of physical activity. They are comfortable atrest. Ordinary physical activity causes undue dyspnoeaor fatigue, chest pain, or near syncope.

Class III Patients with pulmonary hypertension resulting in markedlimitation of physical activity. They are comfortable atrest. Less than ordinary activity causes undue dyspnoeaor fatigue, chest pain, or near syncope.

Class IV Patients with pulmonary hypertension with inability tocarry out any physical activity without symptoms. Thesepatients manifest signs of right heart failure. Dyspnoeaand/or fatigue may even be present at rest. Discomfortis increased by any physical activity.

ESC Guidelines2508

by guest on September 11, 2013

http://eurheartj.oxfordjournals.org/D

ownloaded from

ESC/ERS GUIDELINES

Guidelines for the diagnosis and treatmentof pulmonary hypertensionThe Task Force for the Diagnosis and Treatment of PulmonaryHypertension of the European Society of Cardiology (ESC) andthe European Respiratory Society (ERS), endorsed by theInternational Society of Heart and Lung Transplantation (ISHLT)Authors/Task Force Members: Nazzareno Galie (Chairperson) (Italy)*; Marius M. Hoeper (Germany);Marc Humbert (France); Adam Torbicki (Poland); Jean-Luc Vachiery (France); Joan Albert Barbera (Spain);Maurice Beghetti (Switzerland); Paul Corris (UK); Sean Gaine (Ireland); J. Simon Gibbs (UK);Miguel Angel Gomez-Sanchez (Spain); Guillaume Jondeau (France); Walter Klepetko (Austria)Christian Opitz (Germany); Andrew Peacock (UK); Lewis Rubin (USA); Michael Zellweger(Switzerland); Gerald Simonneau (France)

ESC Committee for Practice Guidelines (CPG): Alec Vahanian (Chairperson) (France); Angelo Auricchio(Switzerland); Jeroen Bax (The Netherlands); Claudio Ceconi (Italy); Veronica Dean (France); Gerasimos Filippatos(Greece); Christian Funck-Brentano (France); Richard Hobbs (UK); Peter Kearney (Ireland); Theresa McDonagh(UK); Keith McGregor (France); Bogdan A. Popescu (Romania); Zeljko Reiner (Croatia); Udo Sechtem (Germany);Per Anton Sirnes (Norway); Michal Tendera (Poland); Panos Vardas (Greece); Petr Widimsky (Czech Republic)

Document Reviewers: Udo Sechtem (CPG Review Coordinator) (Germany); Nawwar Al Attar (France);Felicita Andreotti (Italy); Michael Aschermann (Czech Republic); Riccardo Asteggiano (Italy); Ray Benza (USA);Rolf Berger (The Netherlands); Damien Bonnet (France); Marion Delcroix (Belgium); Luke Howard (UK);Anastasia N Kitsiou (Greece); Irene Lang (Austria); Aldo Maggioni (Italy); Jens Erik Nielsen-Kudsk (Denmark);Myung Park (USA); Pasquale Perrone-Filardi (Italy); Suzanna Price (UK); Maria Teresa Subirana Domenech (Spain);Anton Vonk-Noordegraaf (The Netherlands); Jose Luis Zamorano (Spain)

The disclosure forms of all the authors and reviewers are available on the ESC website www.escardio.org/guidelines

IMPORTANT NOTE: Since the original publication of these Guidelines, the drug sitaxentan has been withdrawn from the marketdue to liver toxicity. Sitaxentan was withdrawn in December 2010 (for further information please see Eur Heart J 2011;32:386–387and on the ESC website http://www.escardio.org/guidelines-surveys/esc-guidelines/Pages/pulmonary-arterial-hypertension.aspx).The instances where sitaxentan appears in this document have been highlighted in yellow.

Table of ContentsAbbreviations and acronyms . . . . . . . . . . . . . . . . . . . . . . . 2494Preamble . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 24951. Introduction . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 24962. Definitions . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 24973. Clinical classification of pulmonary hypertension . . . . . . . . 24984. Pathology of pulmonary hypertension . . . . . . . . . . . . . . . 24995. Pathobiology of pulmonary hypertension . . . . . . . . . . . . . 2499

6. Genetics, epidemiology, and risk factors of pulmonaryhypertension . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 25007. Pulmonary arterial hypertension (group 1) . . . . . . . . . . . . 2501

7.1 Diagnosis . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 25027.1.1 Clinical presentation . . . . . . . . . . . . . . . . . . . . 25027.1.2 Electrocardiogram . . . . . . . . . . . . . . . . . . . . . . 25027.1.3 Chest radiograph . . . . . . . . . . . . . . . . . . . . . . 2502

* Corresponding author. Institute of Cardiology, Bologna University Hospital, Via Massarenti, 9, 40138 Bologna, Italy. Tel: þ39 051 349 858, Fax: þ39 051 344 859,Email: [email protected]

The content of these European Society of Cardiology (ESC) Guidelines has been published for personal and educational use only. No commercial use is authorized. No part of theESC Guidelines may be translated or reproduced in any form without written permission from the ESC. Permission can be obtained upon submission of a written request to OxfordUniversity Press, the publisher of the European Heart Journal and the party authorized to handle such permissions on behalf of the ESC.

Disclaimer. The ESC Guidelines represent the views of the ESC and were arrived at after careful consideration of the available evidence at the time they were written. Healthprofessionals are encouraged to take them fully into account when exercising their clinical judgement. The guidelines do not, however, override the individual responsibility of healthprofessionals to make appropriate decisions in the circumstances of the individual patients, in consultation with that patient, and where appropriate and necessary the patient’sguardian or carer. It is also the health professional’s responsibility to verify the rules and regulations applicable to drugs and devices at the time of prescription.

& The European Society of Cardiology 2009. All rights reserved. For permissions please email: [email protected].

European Heart Journal (2009) 30, 2493–2537doi:10.1093/eurheartj/ehp297

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Natural history and prognosis

� Pretreatment era: median survival

◦ Symptomatic PAH: 3 years

◦ WHO functional class IV: 6 months

� Current data:

Chest. 2012;142(2):448-456. doi:10.1378/chest.11-1460

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� Goals of medical therapy:◦ Produce pulmonary arteriolar vasodilation

◦ Minimize vasodilation of systemic circulation

◦ Maximize right ventricular performance

◦ Serve anti-proliferative, anti-fibrotic, anti-inflammatory, or anti-thrombotic functions

� 13 approved therapies◦ Nitric oxide pathway (3 oral drugs)

◦ Endothelin pathway (3 oral drugs)

◦ Prostacyclin pathway (4 drugs - IV, SQ, inhaled, oral)

Management

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Yen-Chun Lai et al. Circ Res. 2014;115:115-130

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Management

� Nitric oxide pathway

◦ Phosphodiesterasetype 5 inhibitors (PDE-5Is)� Sildenafil and tadalafil

◦ Soluble guanylatecyclase agonist� Riociguat

Stasch J et al. Circulation 2011;123:2263-2273

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Management

� Endothelin pathway◦ Vasoconstrictor and

smooth muscle mitogen◦ ETA (vasoconstriction)

and ETB (mixed constriction and relaxation) receptors◦ Antagonists:

bosentan, ambrisentan (ETA), macitentan

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Management

� Prostacyclin pathway

◦ Epoprostenol (IV)

◦ Iloprost (inh)

◦ Treprostinil (IV, SQ, inh, oral)

◦ Selexipag (oral): non-prostanoidprostacyclin receptor agonist

Chest. 2008;134(4):808-814. doi:10.1378/chest.08-0820

PAH is thought to be associated with early endo-thelial apoptosis but also with the subsequent sur-vival of apoptosis-resistant clones of endothelial cells,possibly giving rise to plexiform lesions. In contrastto the effects in PASMCs, endothelial cells prolifer-ate, migrate, and form tubular structures in responseto BMP4 via a Smad 1/5-dependent mechanism.31 Inaddition, BMPs protect endothelial cells from apo-ptosis.32 These effects occur directly via BMPR-II asknocking down BMPR-II by small interfering RNAincreases the susceptibility of endothelial cells toapoptosis. Hence, the loss of BMPR-II signaling islikely to play a significant role in the early endothelialdysfunction observed in patients with PAH.

Potential Treatments Targeting theBMPR-II Signaling Pathway

Studies have demonstrated that at least somemutations in the BMPR-II lead to retention of themutant protein in the endoplasmic reticulum. Thisoccurs especially if cysteine residues are substituted.Preliminary results suggest the potential for rescueof the mutant protein and restoration of signaling bychemical chaperones. Studies in animal models21

have demonstrated that BMPR-II levels may also bereduced at the transcriptional level. Thus, restorationof BMPR-II gene expression by gene therapy is anattractive proposition. In 2006, Reynolds et al33

developed an adenoviral vector containing a BMPR2gene that was targeted to the pulmonary endothe-lium. IV administration of the adenovirus linked toan antibody targeting angiotensin-converting en-zyme was used to deliver the BMPR2 gene to thelungs. Rats injected with the BMPR2-Ad virus priorto exposure to 3 weeks of hypoxia had significantlylower pulmonary artery pressures at the end of thestudy in comparison with mock-infected controls. Afurther study,34 attempted to ameliorate monocrotaline-induced pulmonary hypertension in rats by nebu-lized delivery of an adenoviral vector containingBMPR2. Animals were given intratracheal adenovi-rus encoding BMPR2 14 days after intraperitonealinjection of monocrotaline. There was no reductionin pulmonary artery pressure in the treated animalscompared with controls, though one limitation of thisstudy would be the lack of endothelial targeting.Further studies are needed in this important area todetermine whether targeted delivery of BMPR-IIprevents the reversal of PAH in animal models.

Figure 2. Normal TGF-! superfamily signaling. A diagrammatic representation of the expression oftype I and type II TGF-! superfamily receptors on pulmonary artery smooth muscle and endothelialcells. Activation of the receptors by specific ligands leads to the phosphorylation of Smad secondmessengers. Phosphorylated receptor Smads combine with the common Smad, Smad 4, before thecomplex is translocated to the nucleus, where it leads to the transcription of multiple genes. NO "nitric oxide; eNOS " endothelial nitric oxide synthase; GTP " guanosine triphosphate; GMP "guanosine monophosphate; cGMP " cyclic guanosin monophosphate; ATP " adenosine triphosphate;AMP " adenosine monophosphate; cAMP " cyclic adenosine monophosphate; ET " endothelin;PDE " phosphodiesterase.

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PAHisthoughttobeassociatedwithearlyendo-thelialapoptosisbutalsowiththesubsequentsur-vivalofapoptosis-resistantclonesofendothelialcells,possiblygivingrisetoplexiformlesions.IncontrasttotheeffectsinPASMCs,endothelialcellsprolifer-ate,migrate,andformtubularstructuresinresponsetoBMP4viaaSmad1/5-dependentmechanism.31Inaddition,BMPsprotectendothelialcellsfromapo-ptosis.32TheseeffectsoccurdirectlyviaBMPR-IIasknockingdownBMPR-IIbysmallinterferingRNAincreasesthesusceptibilityofendothelialcellstoapoptosis.Hence,thelossofBMPR-IIsignalingislikelytoplayasignificantroleintheearlyendothelialdysfunctionobservedinpatientswithPAH.

PotentialTreatmentsTargetingtheBMPR-IISignalingPathway

StudieshavedemonstratedthatatleastsomemutationsintheBMPR-IIleadtoretentionofthemutantproteinintheendoplasmicreticulum.Thisoccursespeciallyifcysteineresiduesaresubstituted.Preliminaryresultssuggestthepotentialforrescueofthemutantproteinandrestorationofsignalingbychemicalchaperones.Studiesinanimalmodels21

havedemonstratedthatBMPR-IIlevelsmayalsobereducedatthetranscriptionallevel.Thus,restorationofBMPR-IIgeneexpressionbygenetherapyisanattractiveproposition.In2006,Reynoldsetal33

developedanadenoviralvectorcontainingaBMPR2genethatwastargetedtothepulmonaryendothe-lium.IVadministrationoftheadenoviruslinkedtoanantibodytargetingangiotensin-convertingen-zymewasusedtodelivertheBMPR2genetothelungs.RatsinjectedwiththeBMPR2-Adviruspriortoexposureto3weeksofhypoxiahadsignificantlylowerpulmonaryarterypressuresattheendofthestudyincomparisonwithmock-infectedcontrols.Afurtherstudy,34attemptedtoamelioratemonocrotaline-inducedpulmonaryhypertensioninratsbynebu-lizeddeliveryofanadenoviralvectorcontainingBMPR2.Animalsweregivenintratrachealadenovi-rusencodingBMPR214daysafterintraperitonealinjectionofmonocrotaline.Therewasnoreductioninpulmonaryarterypressureinthetreatedanimalscomparedwithcontrols,thoughonelimitationofthisstudywouldbethelackofendothelialtargeting.FurtherstudiesareneededinthisimportantareatodeterminewhethertargeteddeliveryofBMPR-IIpreventsthereversalofPAHinanimalmodels.

Figure2.NormalTGF-!superfamilysignaling.AdiagrammaticrepresentationoftheexpressionoftypeIandtypeIITGF-!superfamilyreceptorsonpulmonaryarterysmoothmuscleandendothelialcells.ActivationofthereceptorsbyspecificligandsleadstothephosphorylationofSmadsecondmessengers.PhosphorylatedreceptorSmadscombinewiththecommonSmad,Smad4,beforethecomplexistranslocatedtothenucleus,whereitleadstothetranscriptionofmultiplegenes.NO"nitricoxide;eNOS"endothelialnitricoxidesynthase;GTP"guanosinetriphosphate;GMP"guanosinemonophosphate;cGMP"cyclicguanosinmonophosphate;ATP"adenosinetriphosphate;AMP"adenosinemonophosphate;cAMP"cyclicadenosinemonophosphate;ET"endothelin;PDE"phosphodiesterase.

1274TranslatingBasicResearchIntoClinicalPractice


Molecular Mechanisms of PulmonaryArterial Hypertension*Role of Mutations in the Bone MorphogeneticProtein Type II Receptor

Rachel J. Davies, MD; and Nicholas W. Morrell, MD

Pulmonary arterial hypertension (PAH) is characterized by abnormal remodeling of small,peripheral resistance vessels in the lung involving proliferation and migration of vascular smoothmuscle, endothelial cell and fibroblasts. The increase in pulmonary vascular resistance leads toright heart failure, and, without treatment, death occurs within 3 years of diagnosis. The etiologyof PAH is multifactorial. In some patients, there is a major genetic predisposition in the form ofheterozygous germline mutations in a transforming growth factor-! superfamily receptor, thebone morphogenetic type II receptor (BMPR-II). In addition, it is likely that additional factors,such as inflammation, are important to manifest disease. The currently available treatments forPAH were developed mainly as vasodilators, and although they improve symptoms they havelimited impact on survival. This review examines the role of the BMPR-II signaling pathway in theprocess of pulmonary vascular remodeling. We discuss the ways in which manipulation ofBMPR-II signaling might be targeted with the aim of preventing or reversing vascular remod-eling and improving survival in patients with PAH. (CHEST 2008; 134:1271–1277)

Key words: bone morphogenetic type II receptor; familial pulmonary hypertension; pulmonary vascular remodeling

Abbreviations: ALK ! activin receptor-like kinase; BMP ! bone morphogenetic protein; BMPR ! bone morphoge-netic protein receptor; IPAH ! idiopathic pulmonary arterial hypertension; PAH ! pulmonary arterial hypertension;PASMC ! pulmonary artery smooth muscle cell; PDGF ! platelet-derived growth factor; TGF ! transforming growthfactor

I diopathic pulmonary arterial hypertension (IPAH)is a rare, but devastating condition. It is estimated

to affect 2 to 3 individuals per million per year1 andtypically affects young women (female/male ratio,2.3:1).2 The occlusion of small, peripheral pulmonaryarteries leads to a persistently elevated pulmonary

vascular resistance, a raised pulmonary arterialpressure, and ultimately death from right heartfailure. Before the modern treatment era, therapywas usually symptomatic and life expectancy wasshort.3

The term pulmonary arterial hypertension (PAH)4

refers to a variety of forms of precapillary pulmonaryhypertension. PAH is known to be associated withsystemic diseases such as collagen vascular disease,HIV infection, or the ingestion of drugs or toxins.It may also be found in association with congenitalheart disease. IPAH (formerly known as primarypulmonary hypertension) remains a diagnosis ofexclusion. In 6 to 10% of cases of IPAH, there ismore than one affected family member, and thecondition is referred to as familial PAH or herita-ble PAH. Despite the diverse etiology of PAH inthese subdivisions, the group may share a common

*From the Department of Medicine, University of Cambridge,Addenbrooke’s Hospital, Cambridge, UK.The authors have reported to the ACCP that no significantconflicts of interest exist with any companies/organizations whoseproducts or services may be discussed in this article.Manuscript received May 27, 2008; revision accepted July 9,2008.Reproduction of this article is prohibited without written permissionfrom the American College of Chest Physicians (www.chestjournal.org/misc/reprints.shtml).Correspondence to: Nicholas W. Morrell, MD, Department ofMedicine, University of Cambridge, Box 157, Level 5, Addenbro-oke’s Hospital, Hills Rd, Cambridge CB2 2QQ, UK; e-mail:[email protected]: 10.1378/chest.08-1341

CHEST Translating Basic Research Into Clinical Practice

www.chestjournal.org CHEST / 134 / 6 / DECEMBER, 2008 1271


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� GRIPHON: n=1156 with PAH

� Event driven; median treatment 71 weeks

� Primary outcome: time to first clinical worsening event

� Selexipag group: hazard ratio for primary outcome 0.60 (event in 27.0% treatment group, versus 41.6% in placebo group)

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� Calcium channel blockade� Combination therapy� Anticoagulation (?)� Diuretics� Oxygen� Beta blockers (?)� Primary anti-remodeling agents

(investigational)� Pulmonary rehabilitation� Avoidance of pregnancy

Management

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PAH in internal medicine

� Overall prevalence of PAH low

� Delay in diagnosis common (median 13.6 months) (Badesch et al., Chest 2010)

� Higher risk groups within every subspecialty:◦ Cardiology and pulmonary medicine◦ Endocrinology: thyroid disorders◦ Gastroenterology: cirrhosis◦ Hematology: PE/DVT, hemolysis, MPD, chemo, obstructing

tumor◦ Infectious disease: HIV, schistosomiasis, HHV8?◦ Nephrology: ESRD on HD◦ Rheumatology: SSc, SLE, MCTD, RA, sarcoid◦ Multiple: drug use, obesity, HHT, splenectomy, inborn errors

of metabolism, POEMS

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Non-PAH pulmonary hypertension

� More common than PAH

◦ Left heart disease (Group 2)

◦ Parenchymal lung disease (Group 3)

◦ OSA/OHS (mixed Group 2/3)

◦ Chronic thromboembolic pulmonary hypertension (Group 4)COPYRIG

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WHO Group 2/3 PH

� PH in left heart or lung disease àincreased mortality/morbidity

� For average patient, management with PAH-specific therapy not beneficial

� Is there misdiagnosis?

� Could there be two diagnoses?

� Severity of PH compared to severity of underlying disorder.

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WHO Group 4 PH (CTEPH)

� Chronic thromboembolic pulmonary hypertension (CTEPH) – incidence up to 4% after acute PE

� Important to recognize◦ Implications for anticoagulation

◦ Surgically curable form of precapillary PH

� Significant incidence of non-operable disease, or persistent/recurrent PH post-surgery (medical management)

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Pulmonary thromboendarterectomy

� Treatment of choice for most with CTEPH

� Sternotomy, cardiopulmonary bypass, hypothermic cardiac arrest, arterial dissection◦ Mortality range 2-5%

◦ Specialized centers only

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� Pulmonary arterial hypertension (PAH) is a rare condition, though prevalence is underestimated and delays in diagnosis are common.

� Many symptoms of PAH are nonspecific, and exam signs subtle; a high index of suspicion is necessary.

� While echocardiography is usually suggestive of PAH, right heart catheterization is necessary for diagnosis.

Summary

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� There are currently 13 approved therapies for PAH, available in oral, inhaled, and IV/SQ administration.

� The prognosis of treated PAH has markedly improved in the modern treatment era, though progressive and uncontrolled symptoms still exist for many.

� PH ≠ PAH; PAH management should not be applied to most with non-PAH PH.

Summary

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Questions?

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Download - Pulmonary Hypertension - IMED 2017updateinternalmedicine.com/syllabus/Syllabus/.../68-LeVarge_new.pdf · Pulmonary Hypertension in 2016 Learning objectives Identify patients at risk

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