Pulmonary Hypertension

How should it be evaluated? When is it important?

Murali Chakinala, MD, FCCP Washington University School of Medicine

Pulmonary Vasculature
Pulmonary venule

Pulmonary arteriole

Netter FH. Atlas of Human Anatomy

Pulmonary Circulation
High flow, low resistance
PVR ~1/15 of SVR due to large cross-sectional area

High capacitance
Accommodate CO

Arterioles offer very little resistance

Systemic arterioles supply 75% total peripheral resistance

Ohms Law Revisited

V=IxR
mPAP PAWP

TPP = CO x PVR

PVR = mPAP - PAWP / CO

Definition of Pulmonary HTN

Mean Pulmonary Artery Pressure
25 mm Hg (rest) 30 mm Hg (exercise)
pre-capillary hypertension

Pulmonary Vascular Resistance

3 Woods Units (240 dynes/sec/cm5)

Trans-pulmonary Pressure difference

12 mm Hg

Old Classification
Primary

Secondary

Left Heart Disease LV dysfunction Left atrial disease Valvular disease

Chronic thrombotic and/or embolic diseases Chronic thromboembolic disease Other emboli

Pulmonary Hypertension

Pulmonary Arterial Hypertension

Parenchymal Lung Disease and/or chronic hypoxemia COPD ILD OSA/Hypoventilation

Miscellaneous Sarcoidosis Fibrosing Mediastinitis

Pulmonary Arterial Hypertension

Idiopathic Pulmonary Arterial Hypertension (IPAH) Familial Pulmonary Arterial Hypertension (FPAH) Associated PAH (APAH) Drug & Toxins (Anorexigens)
Collagen-Vascular Disease (PSS > MCTD > SLE) Portal Hypertension HIV infection Congenital Systemic to Pulmonary Shunts Other: HHT, thyroid disorders, hemoglobinopathies

PAH in conjunction with Significant Venous or Capillary

Involvement
3rd World Symposium on PAH (Venice 2003)

Survival in PAH
100

Percent Survival

80 60 40 20 0 0 1 2 Years 3 4 5 CHD IPAH CVD HIV

Adapted from McLaughlin VV. Chest; 2004:126; 78S

Normal Pulmonary Artery

Medial Hypertrophy

Intimal Proliferation In-situ thrombosis

Plexiform Lesion

Homeostatic Imbalances
Endothelin-1 Prostacyclin Nitric Oxide

Vasoconstriction

Vasodilation

Prothrombotic

Antithrombotic

Proliferation

Apoptosis

Vascular Remodeling
Normal PAH

high flow
low resistance
Adapted from Gaine S. JAMA 2002

high resistance

low flow

Does this patient have PAH??

YES

NO
Optimize underlying condition

Treat with PAH specific therapies

30 yr. old Chinese with DOE and exertional syncope Phentermine-Fenfluramine x 3 mos. in 1996 Echo: dilated and hypokinetic RV with normal LV function

Six Minute Walk PAP Cardiac Index Right Atrial Pressure PVR Functional Class Treatment

385 meters 94 / 40 (60) 1.5 18 19

II

54 yr. old (BMI 45) with DOE & recurrent CHF HTN, DM, severe under-treated Obstructive Sleep Apnea Echo: Normal LV/RV size; diastolic dysfunction
Six Minute Walk PAP Cardiac Index PA Occlusion Pressure PVR Functional Class Treatment 90 meters 100 / 40 (60) 3.0 34 300 IV Bosentan, Sildenafil

ACCP diagnostic workup

Is there a reason to suspect PAH? clinical history, exam, CXR, ECG

Symptoms of PH Exercise intolerance

Signs of Right Heart Failure

Screening high-risk population Scleroderma Cirrhosis Congenital Heart Disease Family members with IPAH

Incidental Echo finding

McGoon M, et al. Chest 2004;126:14S-34S

Symptoms of PAH
Initial symptoms reported by patients in the NIH Registry Dyspnea in 60% Fatigue in 19% Chest pain in 7% Near syncope in 5% Palpitations in 5% Leg edema in 3% By time of diagnosis & enrollment in NIH Registry Dyspnea in 98% Fatigue in 73% Chest pain in 47% Near syncope in 41% Syncope in 36% Edema in 37% Palpitations in 33%

1Rich

S ,et al. Ann Intern Med 1987;107:216-23.

Pathophysiology
Increasing PVR Preclinical Cardiac output at peak exercise Level Cardiac output at rest

Symptomatic / stable

Progressive / declining Pulmonary pressure

Time

Physical Findings
Right Heart Failure
elevated jugular venous distention

tricuspid regurgitation
pulmonary insufficiency (Graham-Steel murmur) accentuated S2 (P2)

S3 gallop
peripheral edema hepatomegaly, pulsatile liver, ascites

Electrocardiogram
Not sensitive enough to be a screening tool Notable findings1
RVH 87% of PH cases RAD 79% of PH cases RAE P wave > 2.5 mm in II, III, aVF

1Rich

S, et al. Ann Intern Med 1987;107:216-23

Roentgenogram findings
Enlargement of central pulmonary arteries Reduced caliber of peripheral vessels (pruning)

Roentgenogram findings
Enlargement of right & left pulmonary arteries Cardiomegaly with right ventricular enlargement

ACCP diagnostic workup

Is there a reason to suspect PAH? clinical history, exam, CXR, ECG

No

No further evaluation necessary Measure RVSP, RVE, RAE, RV dysfunction

Is PAH Likely? Echocardiogram

McGoon M, et al. Chest 2004;126:14S-34S

Echocardiography
PASP (TR jet velocity) PRV PRA = 4v2 RV hypertrophy Flattened IV septum Small LV dimension Pericardial Effusion Sensitivity: 80 - 100% Specificity: 60 - 100% Correlation: 0.6 - 0.9

4 Chamber view
Right ventricle Left ventricle

Right atrium

Left atrium

Short-axis view
Right ventricle

Left ventricle

Echo Correlation to RHC

Doppler underestimation average 10 mm Hg* 20mm Hg in 1/3 of cases
100 80
Echo PASP

60 40 20 0 0 20 40 60 80 100
RHC PASP

*Hinderliter AL, et al. Circ. 1997; 95: 1479-86

Caveats of Echocardiography
Reliance on TR jet to estimate PASP
agitated saline can accentuate jet

Inaccuracy of TR jet
less trustworthy in patients with lung disease

RV morphology trumps estimated PASP RV Characterization by 2D echo less refined Challenges with LV diastolic assessment

ACCP diagnostic workup

Is there a reason to suspect PAH? clinical history, exam, CXR, ECG

No

No further evaluation necessary Measure RVSP, RVE, RAE, RV dysfunction

Is PAH Likely? Echocardiogram

Is PAH due to LH disease? Echo

Yes

Dx: LV systolic or diastolic dysfunction; valvular dysfunction appropriate treatment and further evaluation if necessary

McGoon M, et al. Chest 2004;126:14S-34S

Increasing Prevalence of DHF

Mayo Experience (1987 2001)

47% of cohort with preserved EF

Owan TE. NEJM. 2006; 355: 251-59

Phenotype of DHF
Characteristics of DHF patients versus patients with reduced EF Mayo
(Owan, TE - 2006)

Ontario
(Bhatia, RS - 2006)

Older Age Female Gender Hypertension

Atrial Fibrillation
Anemia Obesity Diabetes Hyperlipidemia CAD

Diastolic Dysfunction

Diastolic Dysfunction PH
Chronic pressure overload left-side influences pulmonary venous pressures Diastolic Dysfunction key determinant for PH in left-sided pathologies
Aortic Stenosis
1997) (Aragam JR. Am J Cardiol. 1992) (Enriquez-Sarano M. J Am Coll Cardiol.

LV Systolic Dysfunction

DHF: Mean RVSP ~47mm Hg

Cardiol. 2004)

(Klapholz M. J Am Coll

ACCP diagnostic workup

Is there a reason to suspect PAH? clinical history, exam, CXR, ECG

No

No further evaluation necessary Measure RVSP, RVE, RAE, RV dysfunction

Is PAH Likely? Echocardiogram

Is PAH due to LH disease? Echo

Yes

Dx: LV systolic or diastolic dysfunction; valvular dysfunction appropriate treatment and further evaluation if necessary

Is PAH due to CHD? Echo w/ contrast

Yes

Dx: abnormal morphology; shunt surgery, medical treatment of PAH or evaluation for further definition or contributing causes

McGoon M, et al. Chest 2004;126:14S-34S

ACCP diagnostic workup

Is PAH due to CTD, HIV? Serologies

Yes

Dx: scleroderma, SLE, other CTD; HIV medical treatment for PAH and further evaluation for contributing causes

Anti-nuclear antibodies Anti-DNA antibody Anti-centromere & Anti-Scl-70 antibodies Antibodies to Extractable nuclear antigens (ENA) Anti-phospholipid antibodies HIV serology Liver Function Tests

1McGoon

M, et al. Chest 2004;126:14S-34S

ACCP diagnostic workup

Is PAH due to CTD, HIV? Serologies

Yes

Dx: scleroderma, SLE, other CTD; HIV medical treatment for PAH and further evaluation for contributing causes

Is chronic PE suspected? V/Q scan

1McGoon

M, et al. Chest 2004;126:14S-34S

Chronic Thromboembolic Disease

Webbing Webbing

ACCP diagnostic workup

Is PAH due to CTD, HIV? Serologies

Yes

Dx: scleroderma, SLE, other CTD; HIV medical treatment for PAH and further evaluation for contributing causes

Is chronic PE suspected? V/Q scan

Yes

Is chronic PE confirmed and operable? pulmonary angiogram

1McGoon

M, et al. Chest 2004;126:14S-34S

Pulmonary Angiography
Webs Irregular lumen Truncated vessel Abnormal blush

Courtesy J. Gould

ACCP diagnostic workup

Is PAH due to CTD, HIV? Serologies

Yes

Dx: scleroderma, SLE, other CTD; HIV medical treatment for PAH and further evaluation for contributing causes

Is chronic PE suspected? V/Q scan

Yes

Is chronic PE confirmed and operable? pulmonary angiogram Yes Thromboendarterectomy if appropriate or medical treatment

1McGoon

M, et al. Chest 2004;126:14S-34S

ACCP diagnostic workup

Is PAH due to CTD, HIV? Serologies

Yes

Dx: scleroderma, SLE, other CTD; HIV medical treatment for PAH and further evaluation for contributing causes

Is chronic PE suspected? V/Q scan

Yes

Is chronic PE confirmed and operable? pulmonary angiogram

No

Yes

Thromboendarterectomy if appropriate or medical treatment

Is PAH due to lung disease or hypoxemia? PFTs, arterial saturation

Yes

Dx parenchymal lung disease, hypoxemia or sleep disorder medical treatment, oxygen, positive pressure breathing, and further evaluation for other contributing causes

1McGoon

M, et al. Chest 2004;126:14S-34S

Emphysema and PH
Cor pulmonale is a negative prognostic indicator of survival 4-fold greater mortality for every 10mm mean PAP
Cooper R. Chest. 1991;36: 752-58

Prevalence variable and biased by study design

35% with mean PAP 25.8 5.6 mm (Weitzenblum E. ARRD. 1984) 90% in severe COPD from NETT (Scharf S. AJRCCM. 2002)

25% Incidence over 6.8 years in mod-severe COPD

Kessler R. AJRCCM. 2001; 164: 219-24

PH Severity in Emphysema
Mild-moderate pressure elevations & preserved RV
mean PAP 25-40 mm (Chaouat A. AJRCCM. 2006:172;
189-94)

n=215 (mod-severe COPD) Mean PAP 26.9 8.1 mm

4% with mean PAP > 45mm

Thabut G, et al. Chest. 2005;127: 1531-36

PH Severity in Emphysema
n 30 106 63 FEV1 (%) 41.5 20.3 17.0 Mean PAP 19.0 24.5 31.3 Pa02 80.1 65.3 48.0 PaC02 39.3 43.1 51.9

PAP correlates with gas exchange

Thabut G. Chest. 2005;127: 1531-36

Hypoxic vasoconstriction and associated remodeling

PH aggravated by COPD exacerbations and common co-morbidities

Left heart disease and sleep-disordered breathing

Pulmonary Arterial Hypertension

Idiopathic Pulmonary Arterial Hypertension (IPAH) Familial Pulmonary Arterial Hypertension (FPAH) Associated PAH (APAH) Drug & Toxins (Anorexigens)
Collagen-Vascular Disease (PSS > MCTD > SLE) Portal Hypertension HIV infection Congenital Systemic to Pulmonary Shunts Other: HHT, thyroid disorders, hemoglobinopathies

PAH in conjunction with Significant Venous or Capillary

Involvement
3rd World Symposium on PAH (Venice 2003)

Right Heart Catheterization

Gold Standard
confirm diagnosis survey for left-sided disease (PAWP or LVEDP)

rule out L to R intracardiac shunt

acute vasodilator challenge prognostic information

mPAP, mRAP, CI
acute vasodilator challenge

Acute Vasodilator Challenge

ICU or Cath Lab Pulmonary Artery Catheter Adenosine, Nitric Oxide, Epoprostenol
IPAH [A] Other PAH [expert opinion/C] 10 point drop of mPAP & concluding mPAP 40 with stable or improved cardiac output
European Society of Cardiology

Goals of Therapy
Abolish Right Heart Failure Improve CO/CI, MVO2, and mean RAP Symptomatic Improvement 6MW Distance, Peak VO2, Functional Class

Reverse Vascular Remodeling Improve PAP and PVR

General Measures
maintain SaO2 > 90%, 24 hours/day
caution during air travel, high altitude routine vaccinations: FLU and Pneumovax avoid vasoconstrictors nicotine, sympathomimetics

avoid deep valsalva maneuvers

avoid pregnancy (maternal mortality 30%)

Available Therapies
Diuretics Digitalis Warfarin Oxygen Inotropes Vasoactive Agents Atrial Septostomy Transplantation Thromboendarterectomy

Vasoactive Agents
Calcium-channel blockers

Endothelial receptor antagonists (ERAs)

Phosphodiesterase-5 Inhibitors (PDE5-I) Prostanoids

Treatment Pathways
Endothelin pathway
Endothelin cells

Nitric oxide pathway

Vessel lumen

Prostacyclin pathway

Pre-proendothelin Proendothelin L-arginine L-citrulline Endothelin receptor A

Endothelin 1 Nitric oxide

Arachidonic acid Prostaglandin I2

Prostacyclin (prostaglandin I2)

cAMP

Endothelin + Exogenous receptor Endothelin cGMP nitric oxide antagonist receptor B s Vasodilation and Phosphodiesterase Vasodilation and
proliferation
type 5 antiproliferation

Prostacyclin derivatives

Vasodilation and antiproliferation

Smooth muscle cells

Phosphodiesteras e type 5 inhibitor

Humbert M. N Engl J Med 2004;351:1425-36

Simplicity

Route Bosentan, Ambrisentan Sildenafil PO PO

Indication
(WHO)

Drawback Hepatotoxicity Adequate Dosing Fluctuating levels

Cost / yr
$ thousands

II-IV I-IV

$35 $10

Iloprost

IH

III-IV

$75

Treprostinil

Efficacy

SQ IV

II-IV

Site pain Catheterrelated

Catheterrelated

$50-150

Epoprostenol

IV

III-IV

$50-100

30 yr. old Chinese with DOE and exertional syncope Phentermine-Fenfluramine x 3 mos. in 1996 Echo: dilated and hypokinetic RV with normal LV function
Six Minute Walk PAP Cardiac Index Right Atrial Pressure PVR 385 meters 94 / 40 (60) 1.5 18 19 500 meters 90 / 40 (58) 2.5 10 11

Functional Class
Treatment

II

I
Treprostinil + Bosentan

54 yr. old (BMI 45) with DOE & recurrent CHF HTN, DM, severe under-treated Obstructive Sleep Apnea Echo: Normal LV/RV size; diastolic dysfunction
Six Minute Walk
PAP Cardiac Index PA Occlusion Pressure PVR Functional Class Treatment

90 meters
100 / 40 (60) 3.0 34 300 IV Bosentan, Sildenafil

290 meters
50 /20 (32) 2.9 18 175 II ARB, diuretics, CCB oxygen, NIPPV

Conclusions
Evaluation of chronic pulmonary hypertension should focus on identifying its origin

Most common causes of PH are underlying cardiac or pulmonary conditions with treatment geared towards underlying condition PAH is a group of diverse diseases linked by pathophysiology & histopathology with a natural history of right heart failure
Existing therapies offer symptom relief and delay progression of disease but are not curative