overview of pulmonary hypertension: pathophysiology

Overview of Pulmonary Hypertension: Pathophysiology, Classification and DiagnosisPaul Kim, MDAssistant Clinical Professor of MedicineDivision of CardiologyUC San Diego Health

Disclosures

• None

Pulmonary Arterial Hypertension: Key Points• Symptoms often nonspecific; average 14-month

delay from initial presentation to diagnosis

• Poor prognosis without therapy and close follow-up

• Evaluation must be methodical and include right heart catheterization (RHC)

• Prognosis improves with therapy, but PAH remains a progressive fatal disease

• Therapies and management strategies continue to evolve

5th World Symposium on PH: Hemodynamic Definition of PH/PAH

PH

PAHMean PAP ≥25 mm Hg plusPAWP ≤15 mm Hg plusPVR >3 Wood units

Mean PAP ≥25 mm Hg at rest during RHC

Hoeper MM et al. J Am Coll Cardiol. 2013;62:D42-D50.

Adapted from: Sitbon O et al. J Am Coll Cardiol. 2002;40:780-788. D’Alonzo GE et al. Ann Intern Med.1991;115:343-349. McLaughlin VV et al. Chest. 2004;126:78S-91S.

Idiopathic PAH: Survival If Untreated

0 0.5 1 1.5 2 2.5 3 3.5 4 4.5 50

20

40

60

80

100

Years of follow-up

Per

cent

age

surv

ivin

g

NIH registrySitbon historical controlACCP estimate

• Incidence: 2-6 cases per million in US

• Poor prognosis in an era lacking therapy

• Therapeutic options and research efforts now offer more hope

3-yr Survival in Treatment Era: CHD, IPAH, or CTD-PAH (French Registry)

From Humbert et al. Eur Respir J. 2010;36:549-555.

0 12 24 36Time (mo)

0.0

0.2

0.4

0.6

0.8

1.0C

umul

ativ

e su

rviv

al (%

)

Subjects, n:35410376

3148673

2717170

2396264

Idiopathic PAHCTD PAHCHD PAH

CHD

IPAHCTD

p<0.05

PAH—WHO Group I: REVEAL Registry Survival Rates

2967 patients enrolled consecutively, Mar 2006 to Sept 2007; 2525 with PCWP ≤15 mm Hg.Benza RL et al. Chest. 2012;142:448-456.

Surv

ival

(%)

868 1169 1263 5751296 1146 894 309

0

70

40

60

80

10090

50

No. at Risk:Full cohort

34.7 ± 1.3%

57.0 ± 1.4%

49.0 ± 1.4%

Time From Diagnosis (years)

67.8 ± 1.4%

0 1 2 3 4 5 6 7

5th World Symposium on PH:Classification1. Pulmonary arterial hypertension

1.1 Idiopathic PAH1.2 Heritable PAH

1.2.1 BMPR21.2.2 ALK1, ENG, Smad 9, CAV1, KCNK31.2.3 Unknown

1.3 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 diseases (update)1.4.5 Schistosomiasis

1’. Pulmonary veno-occlusive disease and/orpulmonary capillary hemangiomatosis

1’’. Persistent PH of the newborn

2. PH due to left heart disease

2.1 LV systolic dysfunction2.2 LV diastolic dysfunction2.3 Valvular disease2.4 Congenital/acquired left heart inflow/outflow tract

obstruction and congenital cardiomyopathies

3. PH due to lung diseases and/or hypoxia

3.1 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 (update)

4. Chronic thromboembolic PH

5. PH with unclear multifactorial mechanisms

5.1 Hematological disorders: chronic hemolytic anemia, myeloproliferative disorders, splenectomy

5.2 Systemic disorders: sarcoidosis, pulmonary histiocytosis, lymphangioleiomyomatosis,

5.3 Metabolic disorders: glycogen storage disease, Gaucher disease, thyroid disorders

5.4 Others: tumoral obstruction, fibrosing mediastinitis, chronic renal failure, segmental PH

Simonneau G et al. J Am Coll Cardiol. 2013;62:D34-D41.

PAH Distributions in the US: REVEAL Registry

Based on Venice Clinical Classification (2003); 2967 patients.Adapted from Badesch DB et al. Chest. 2010;137:376-387.

Overall Associated

Associated(50.7%)

Idiopathic(46.2%) Connective tissue/

collagen vascular(49.9%)

Heritable (2.7%)

Pulmonaryveno-occlusive

(0.4%)

Congenitalheart disease(19.5%)

HIV (4.0%)

Other (5.5%)

Drugs/toxins (10.5%)

Portopulmonary (10.6%)

5th World Symposium on PH:Updated Risk Factors for PAHDefinite PossibleAminorex CocaineFenfluramine PhenylpropanolamineDexfenfluramine St. John’s wortToxic rapeseed oil Chemotherapeutic agentsBenfluorex Interferon α and βSSRIs (PPHN only) Amphetamine-like drugs

Likely UnlikelyAmphetamines Oral contraceptivesL-tryptophan EstrogenMethamphetamines Cigarette smokingDasatinib

.Simonneau G et al. JACC. 2013;62:D34-D41.

Methamphetamine and PAH

• Case-control analysis:

– 97 IPAH patients

– 106 PAH with other risk

factors

– 137 CTEPH patients

• Adjusted OR for prior

methamphetamine use:

– IPAH vs PAH with known

risk factors: 7.73

(2.55 – 23.5), p=0.0002

– IPAH vs CTEPH: 11.61

(3.34 – 40.3), p<0.0001

Chin K et al. Chest. 2006;130:1656-1663.

IPAH PAH

with

known

RFs

CTEPH

Pro

po

rtio

n r

ep

ortin

g s

tim

ula

nt

use

0.00

0.05

0.10

0.15

0.20

0.35

0.40

0.30

0.25

PAH Related to ConnectiveTissue Disease• Connective tissue diseases

– limited scleroderma (most common)

– diffuse scleroderma

– mixed connective tissue disease

– systemic lupus erythematosus

– rheumatoid arthritis

– Sjogren’s syndrome

• PH is one of the leading causes of death in scleroderma

• Similar to IPAH pathology

• Medical treatment same as for IPAH, but benefits less than for IPAH

Hachulla E et al. Rheumatology. 2009;48:304-308.

Prevalence of PAH in Scleroderma

• Prevalence 7.9% in large prospective study (N=599) with confirmatory catheterizations

– excluded severe PFT abnormalities– all underwent Doppler echocardiography – catheterization if VTR >3 m/sec or VTR

2.5–3 m/sec + unexplained dyspnea

• Prevalence of PAH: 47 of 599– 29 had known PAH at study entry – 18 patients were newly diagnosed with PAH

Hachulla E et al. Arthritis Rheum. 2005;52:3792-3800.

PAH Related to CongenitalHeart Disease• Incidence of PAH varies

– higher flow / pressure = higher risk (large VSD)

– ASD as a trigger?: only ~10% develop PAH

– progression may be seen even after surgery

• Common causes: VSD, ASD, AV canal defect, PDA

• Eisenmenger’s complex: reversal of L-R shunt

• Prognosis is significantly better than PAH withouta shunt

Galie N et al. Circulation. 2006;114;48-54. Oya H et al. Am Heart J. 2002;143:739-744.

PAH Related to CongenitalHeart Disease

Galie N et al. Circulation. 2006;114;48-54. Oya H et al. Am Heart J. 2002;143:739-744.

0

20

40

60

80

100

Similar to IPAH, right heart failure (low CO, high [relatively] RA pressure) is a poor prognostic marker

Systemic Cardiac Output RA Pressure

0 5 10 15 20Time (yr)

Surv

ival

rate

(%)

Systemic blood flow ≥2.9 L/min

Systemic blood flow <2.9 L/min

0 5 10 15 20Time (yr)

RAP ≤7 mm Hg

RAP >7 mm Hg

Portopulmonary Hypertension

• Prevalence overall: 2-5% by RHC; liver transplant candidate: 4% to 17%

• Dependent on portal HTN, not hepatocellular dysfunction

• Poor prognosis: higher risk of death than IPAH pts

• Liver transplant

– may improve survival with mild to moderate PAH(28-56%, 5 yr)

– significant PAH (mPAP >35 mm Hg) predicts unacceptably high perioperative mortality

Budhiraja R et al. Chest. 2003. Hadengue A et al. Gastroenterology. 1991. Castro M et al. Mayo Clin Proc. 1996. Kawut SM et al. Liver Transpl. 2005. Ramsay MA et al. Liver Transpl Surg. 1997. Krowka MJ et al. Clin Chest Med. 2005. Krowka MJ et al. Liver Transpl. 2004. Swanson KL et al. Hepatology. 2004.

Portopulmonary Hypertension: RHC to Distinguish Hemodynamic Subsets

• Normal

• Volume overload: normal PVR

– PA mean ≥25 mm Hg, PCW >15, PVR normal

• High output: normal PVR

– PA mean ≥25 mm Hg, CI >4, PVR normal

• Portopulmonary hypertension: PVR >3 WU

– PA mean ≥25 mm Hg, PCW ≤15, PVR >3

PAH Related to HIV • Prevalence

– 0.5% both before and after HAART introduced– higher among IVDU

• Occurs in early and late disease; not related to degree of immunodeficiency

• Pathology identical to IPAH

• PAH-specific therapies and antiretrovirals are most commonly used treatments

• Independent predictor of mortalityLimsukon A et al. Mt Sinai J Med. 2006;73:1037-1044.Sitbon O et al. Am J Respir Crit Care Med. 2008;177:108-113.



1.2.1 BMPR21.2.2 ALK1, ENG, SMAD9, CAV1, KCNK31.2.3 Unknown


















Most Common Cause of Elevated PAPs by Echo: Left Heart DiseaseSymptoms

– paroxysmal nocturnal dyspnea

– orthopnea

History– diabetes

– hypertension

– obesity

– coronary artery disease

– metabolic syndrome

ECG– atrial fibrillation

– absence of right axis deviation

Echo– left atrial enlargement

– left ventricular hypertrophy

– normal RA, RV

– abnormal diastolic filling

– mitral or aortic disease

100

75

50

25

0

IPAH Is Not the Most Common Cause: In Older Patients, Consider Diastolic Heart Failure• PH by echo in a community-

based sample: – heart failure with preserved EF:

83% with PH

– HTN but no CHF (control): 8% with PH

• Patients with PH:– older

– higher systolic BP

– larger LA size

– higher E/e’ ratio

Lam CS et al. J Am Coll Cardiol. 2009;53:1119-1126.

Cum

ulat

ive

(%)

10 30 50 70 90 110PASP (mm Hg)

HTNHFpEF

p<0.001

100

75

50

25

0

PH

pre

vale

nce

(%)

HTN

8

HFpEF

83

p<0.001

Pulmonary Venous Hypertension:A Simplified View• Normal, or mildly elevated transpulmonary gradient

with readily apparent cause

– treat underlying cause

• Substantially elevated transpulmonary gradient (PH out of proportion to LHD)

– treat cardiovascular risk factors (including aggressive volume control) as best you can

– improvement in PH may be slow (months)

– No FDA-approved therapies for diastolic dysfunction yet

Percentage of PAH and PVH Patients With All 4 Metabolic Syndrome Factors

*p≤0.005; **p=0.023.Robbins IM et al. Chest. 2009;136:31-36.

0

20

40

60

80

100

Percentof

patients**

*

*

*

PAHPVH

HTN13.7

(1.6-113.0)

Obesity7.1

(1.9-26.8)

DM5.7

(1.6-20.4)

HL4.2

(1.2-15.7)OR

95% CI

Distinguishing Clinical FeaturesCharacteristics HFpEF PAH PH-HFpEFAge Older Younger OlderComorbidities* Frequent Rare More frequent

RAE Absent More frequent Less frequent

LAE Frequent Absent Frequent

ASP Elevated Normal Elevated

mRAP Normal Normal-High High

mPAP Normal Markedly elevated

Moderately elevated

CO Normal Low Normal

PVR Normal Markedly elevated

Moderately elevated

*Includes hypertension, DM, obesity, and CAD.Modified From Thenappan et al. Circ Heart Fail. 2011;4:257-264.

Pulmonary Hypertension in Lung/Respiratory Disease

• May explain worsening symptoms in patient with stable PFTs

• May contribute to exercise limitation: ventilatory vs cardiovascular limitation

• Disproportionately low DLCO may suggest pulmonary vascular disease

• Correlates better with low oxygen levels than PFTs

Chronic Obstructive Pulmonary Disease (COPD) and PH• Retrospective study of 215 COPD patients• 13.5% had a PA mean >35 mm Hg• Correlated best (inversely) with PaO2

• A small number had only moderate obstruction: treatable sub-group?

Thabut G et al. Chest. 2005;127:1531-1536. FEV1 (% pred.)

mPAP (mm Hg)

10

20

30

40

60

50

0 20 40 60 80

4

12

3

0

Lettieri CJ et al. Chest. 2006;129:746-752.

PH

No PH (mPAP <25 mm Hg)

p<0.001

N=79No difference in lung volumesLower 6MWD

PH as a Predictor of Survival in Patients With IPF

1000500 1500 2000 2500Days to event

Cum

ulat

ive

prob

abili

ty o

f sur

viva

l

0.0

0.2

0.4

0.6

0.8

1.0

Sleep-disordered Breathing and PH

• Nocturnal hypoxemia results in pulmonary arterial constriction

• PH can occur with either obstructive sleep apnea (OSA) or central sleep apnea

• PH can occur with obstructive sleep apnea in the absence of intrinsic heart or lung disease

• Little correlation in severity of OSA and degree of PH

• Sleep-disordered breathing increases the risk of both PAH and PVH

Sajkov D et al. Am J Respir Crit Care Med. 1994;149:416-422.

Impact of PH on Outcomes in Obstructive Sleep Apnea

Minai O et al. Am J Cardiol. 2009;104:1300-1306.

0

No PHPH

100.0

21 4 8Time (years)

Ove

rall

surv

ival

(%)

0

20

40

60

80

100 9690

7693

86

75

43












3.1 COPD3.2 Interstitial lung disease3.3 Other pulmonary diseases with mixed restrictive









Incidence of CTEPH

• Approximately 3% to 4% 1-2 yr after acute PE

• USA: 600,000 cases of acute PE each year

• Only 40% to 50% of CTEPH patients have a history of previous episodes of acute PE

• VQ scan identifies old PE better than CTA

McLaughlin VV et al. J Am Coll Cardiol. 2009;53:1573-1619.Pengo V et al. N Engl J Med. 2004;350:2257-2264.Tapson VF, Humbert M. Proc Am Thorac Soc. 2006;3:564-567.

Years

Cu

mu

lativ

e in

cid

en

ce o

f C

TE

PH

0 1 2 3 4 7 8 9 10 115 60.00

0.01

0.02

0.03

0.04

PAH: Hemodynamic and Clinical Course

NORMAL

Time

PAP

PVR

CO

INYHA

Adventitia

Media

Intima

Adapted from Gaine S. JAMA. 2000;284:3160-3168.

NORMAL

Adventitia

Media

Intima

REVERSIBLE DISEASE

Time

PAP

PVR

CO

I II III

BNP

NYHA

Smooth Muscle Hypertrophy

Early Intimal Thickening



NORMAL

Adventitia

Media

Intima


Early Intimal Thickening

REVERSIBLE DISEASE

IRREVERSIBLE DISEASE

Plexiform Lesions

Thrombosis

Adventitial, Intimal Proliferation


Time

PAP

PVR

CO

I II III IV

BNP

NYHA



Mechanisms of Action of Approved Therapies for PH

Adapted from Humbert M et al. N Engl J Med. 2004;351:1425-1436.

cGMP

cAMP

Vasoconstriction and proliferation

Endothelinreceptor A

Endothelin-receptor

antagonists

Endothelinreceptor B

Phosphodiesterase type 5 inhibitor

Vasodilationand antiproliferation

Phosphodiesterase type 5

Vasodilationand antiproliferation

Prostacyclin derivatives

Nitric Oxide

Endothelin-1

Pre-proendothelin

L-arginine

Prostaglandin I2

L-citrulline

Nitric OxidePathway

EndothelinPathway

ProstacyclinPathway

Endothelial cells

ProendothelinEndothelial cells

Arachidonic acid

Smooth muscle cells

Prostacyclin (prostaglandin I2)

Smooth muscle cells

-Exogenous nitric oxide -sGCstimulator

Yuan JXJ, Rubin LJ. Circulation. 2005;111:534-538.

Other Potential Targets

Summary

• Classification: five major groups

• Idiopathic PAH: uncommon, but serious and progressive

• Multiple treatment options

• Prognosis is improving

• New therapies are still needed

overview of pulmonary hypertension: pathophysiology

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