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Pulmonary Arterial Hypertension
Xiaosong Zhao, MD, PhD
Presbyterian Hospital of Dallas
January 3, 2006
Significance of Pulmonary arterial hypertension
Pulmonary arterial hypertension is the third cause of CHF
The median survival was 2.8 years with an estimated 5-year
survival of 34%.
---NIH Registry. Ann Intern Med 1991; 115: 343-349
Annual number of hospitalizations among persons
with pulmonary hypertension, United States, 1980–
2002
CDC, National Hospital Discharge Survey.
Definitions
Pulmonary hypertension is an elevation in pulmonary
vascular pressure caused by an isolated increase in
pulmonary arterial pressure or by increase in both
pulmonary arterial and pulmonary venous pressure.
Pulmonary arterial hypertension refers to a sustained
elevation of mean pulmonary arterial pressure to greater than 25
mmHg at rest or more than 30 mmHg during exercise, with
normal pulmonary capillary wedge pressure and left ventricular
end-diastolic pressure (<15 mm Hg) .
WHO Classification of pulmonary hypertension
Group 1. Pulmonary artery hypertension (PAH)
1.1 Idiopathic (IPAH)
1.2 Familial (FPAH)
1.3 Associated with (APAH)
1.3.1 Collagen vascular disease
1.3.2 Congenital systemic-to-pulmonary shunts
1.3.3 Portal hypertension
1.3.4 HIV infection
1.3.5 Drugs and toxins
1.3.6 Other (thyroid disorders, glycogen storage disease, Gaucher disease, splenectomy, hereditary haemorrhagic telangiectasia,
haemoglobinopathy)
1.4 Associated with significant venous or capillary involvement
1.4.1 Pulmonary veno-occlusive disease
1.4.2 Pulmonary capillary haemangiomatosis
1.5 Persistent pulmonary hypertension of the newborn
Group 2. Pulmonary hypertension with left heart disease
Group 3. Pulmonary hypertension associated with lung disease and/or hypoxaemia
Group 4. Pulmonary hypertension due to chronic thrombotic and/or embolic disease
Group 5. Miscellaneous (sarcoidosis, histiocytosis X, lymphangiomyomatosis, compression of
pulmonary vessels)
(Venice 2003; revised from Evian 1998)
Histopathology
Main vascular changes
of PAH
• Vasoconstriction
• SMC and endothelialcell proliferation
• fibrosis
• thrombosis
intima
1.
2.
3.
media
Severe concentric laminar intimal fibrosis
Medial hypertrophy
in situ thrombosis of the small residual lumen
Pathophysiology
Stimuli: shear stress,
Po2, Viruses (HIV, HHV-8)
Autoimmunity (CREST,SLE), Drugs
Intrinsic
susceptibility
(PPH-1,BMPR2,Kv)
Pulmonary endothelial-cell dysfunction or injury
(Endothelin-1,Nitric Oxide and prostacyclin pathway)
Imbalance of vascular effectors
Perturbations in the normal relationships between
vasodilators and vasoconstrictors,
growth inhibitors and mitogenic factors,
antithrombotic and prothrombotic determinants.
Main vascular changes of PAH
Vasoconstriction
SMC and endothelial-cell proliferation
fibrosis
thrombosis
Regulation of pulmonary arterial tone
Clinical presentation of PAH
A 33 yo F presented to her PCP w/ a 6M h/o gradually progressive exertional dyspnea.
She had lightheadedness and near-syncope while climbing steps. She was mildly
obese but had otherwise previously been in good health. Her vital signs were normal, her
lungs were clear, and cardiac examination showed a slightly prominent second heart
sound, a systolic murmur, a heave over the left parasternal border. A initial dx of exerciseinduced asthma was made, and use of an inhaled bronchodilator was prescribed.
The pt’s symptoms did not diminish. A CXR showed mild cardiomegaly and a slightly
prominent main pulmonary artery. PFTs showed only mild reduction in DLCO, an EKG
showed right-axis deviation and possible RVH. Then, echocardiogram was done, which
showed RVH, RAE, flattening of the interventricular septum, and moderate TR with an
calculated (estimated) pulmonary artery systolic pressure of 60 mmHg.
Clinical Assessment
H&P
6MWT
History
•
•
•
•
•
Exertional dyspnea
Fatique or weakness
Peripheral edema and/or ascites
Angina
Near syncope or syncope
“An impressive feature … was the contrast between the appearance of good
health when at rest and the striking discomfort evoked by even mild exertion.”
------ original clinical description by Dr. David Dresdale, 1951
Physical Examination
•
Cardiovascular findings:
Large a wave in the jugular venous pulse;
Prominent v waves in the jugular venous pulse
Low-volume carotid arterial pulse with a normal upstroke;
Left parasternal (right ventricular) heave;
Systolic pulsation in the second left intercostal space;
Ejection click and flow murmur in the second left intercostal space;
Closely split second heart sound with a loud pulmonic component;
Fourth heart sound of right ventricular origin
Third heart sound of right ventricular origin
High-pitched early diastolic murmur of pulmonic regurgitation,
Holosystolic murmur of tricuspid regurgitation
Signs of right ventricular failure (hepatomegaly, peripheral edema, and
ascites)
Cyanosis
• Patients whose PAH is associated with another illness
often have clinical features of that disease.
CXR-PA view
Enlargement of the main pulmonary artery and its major
branches, with marked tapering of peripheral arteries .
CXR-lateral view
Encroachment of the retrosternal air space -- right ventricular
enlargement/hypertrophy
CXR-PA view
The right ventricle and atrium may also be enlarged.
ECG
•
•
•
•
•
Highly specific
but not very
sensitive.
Right axis
deviation
Right atrial and
right ventricular
enlargement.
Right bundle
branch block
ST and T wave
changes in the
anterior
precordial leads.
Echocardiography
•
Enlargement of the right atrium and ventricle with
normal or small left ventricular dimensions.
• Abnormal septal motion as a result of the right
ventricular volume and pressure overload.
• Delayed opening of the pulmonic valve, midsystolic
closure, and an increase in the ratio of right
ventricular pre-ejection time to total ejection time.
• Doppler echocardiographic quantitation of right
ventricular systolic pressure may be obtained by
measuring the velocity of the tricuspid regurgitant jet
and using the Bernoulli formula.
PAP = 4 x velocity2 + RAP
Echocardiogram
Right atrial and
ventricular enlargement
and flattening of the
intraventricular septum
-- parasternal short axis
view (a) and four
chamber view (b).
Doppler
Echocardiogram
Representation of Echocardiographic findings
Pulmonary Function Tests
• Usually completely normal for PPH
• Vital capacity may be reduced to approximately 80%
• Hyper-reactivity of the bronchial tree is common,
which can lead to a misdiagnosis of asthma
• Diffusing capacity for carbon monoxide (DLCO) is
mildly reduced to approximately 60 to 80%
• Presence of arterial hypoxemia is due to V/Q
mismatch and/or reduced mixed venous oxygen
saturations resulting from low cardiac output
Right heart Catheterization
• The diagnosis of PAH cannot be
confirmed without right heart
catheterization (gold standard)
• patients with PAH should have a low or
normal pulmonary capillary wedge
pressure
Exercise Test – 6MWT
•
The 6-minute walk test (6MWT) is
recommended as a standard exercise test
by American Thoracic Society
• Healthy subjects’ 6MWDs: 400 to 700 m
and it varies.
• It is commonly used for
1. Before-and-after treatment comparisons
2. Measuring functional status
3. Predicting hospitalization and death
Treatment
• General measures
Physical activity; Diuretics; Supplemental oxygen
Digoxin; Anticoagulation
• Specific treatment
1. Calcium channel blockers: nifedipine and diltiazem
2. Prostacylin analogues: Epoprostenol; Treprostinil; Iloprost;
3.Endothelin receptor antagonists:
Dual endothelin receptor antagonist: Bosentan
Selective ETA receptor antagonist: sitaxsentan, Ambrisentan
4. Phosphodiesterase-5 inhibitors: sildenafil
• Interventional and surgical therapy: atrial septostomy,Lung or
heart-lung transplantation
Treatment -- General measures
Physical activity and lifestyle changes
• Counseling
• Cardiopulmonary rehabilitation program
• Graded exercise activities: bike riding and swimming -- safe
• Isometric activities: lifting weights or stairclimbing – presyncope or
syncope
• Young women: birth control
Potentially Hazardous Activities for Patients with Pulmonary Arterial
Hypertension
Rubin, L. J. et. al. Ann Intern Med 2005;143:282-292
Treatment -- General measures
Diuretics: to achieve symptom relief
Loop diuretics and/or potassium-sparing aldosterone
inhibitors:
cautious vs. courage
Low salt diet
Treatment -- General measures
• Supplemental oxygen
To keep O2Sat > 90%
Nocturnal desaturation may occur in patients with pulmonary
hypertension, even in the absence of daytime hypoxemia or
sleep-disordered breathing. Some experts suggest an
assessment of noctural oximetry in patients with pulmonary
hypertension in order to determine whether nocturnal
supplemental oxygen therapy is indicated to maintain
satisfactory oxygen saturation during sleep. --- Lewis J. Rubin,
2004
Treatment -- General measures
• Digoxin
Increase in resting cardiac output of approximately 10%
Long-term benefit of digoxin administration is not clear
Treatment -- General measures
Anticoagulation– oral warfarin to achieve INR 1.5 to 2.5
Pts with PAH are likely at higher risk for thromboembolic complications:
•in situ thrombosis
•Decreased activity level
•Slower blood flow
•Dilated right-sided heart chambers
•Especially, the presence of an implanted central catheter for
administering PAH medications
The fragile hamodynamic state and limited cardiopulmonary reserve –
high risk for death even from a small thromboembolism
Treatment
• General measures
Physical activity; Diuretics; Supplemental oxygen
Digoxin; Anticoagulation
• Specific treatment of PAH
1. Calcium channel blockers: nifedipine and diltiazem
2. Prostacyclin analogues: Epoprostenol; Treprostinil; Iloprost;
3.Endothelin receptor antagonists:
Dual endothelin receptor antagonist: Bosentan
Selective ETA receptor antagonist: sitaxsentan, Ambrisentan
4. Phosphodiesterase-5 inhibitors: sildenafil
• Interventional and surgical therapy: atrial septostomy, lung or
heart-lung transplantation
Five-year survival of PPH patients who responded to calcium
channel blockers (95%) versus those that did not respond
from the same series and historical controls from the NIH
registry.
Rich S, Kaufmann E, Levy PS. N Engl J Med 1992;327:76–81.
Kaplan-Meier survival estimates in 178 patients with
PPH from the initiation of epoprostenol therapy
Survival of 162 patients with PPH treated with
epoprostenol compared to expected survival based
on the NIH registry equation
Mean ({+/-}SE) Change in Six-Minute Walking Distance from Base Line to Week 16 in the Placebo
and Bosentan Groups
Rubin, L. J. et al. N Engl J Med 2002;346:896-903
Mean Changes from Baseline, with 95 Percent Confidence Intervals, in the Six-Minute Walking
Distance at Week 12 in the Placebo and Sildenafil Groups
Galie, N. et al. N Engl J Med 2005;353:2148-2157
Treatment
• General measures
Physical activity; Diuretics; Supplemental oxygen
Cardiac glycosides; Anticoagulation
• Specific treatment of PAH
1. Calcium channel blockers: nifedipine and diltiazem
2. Prostacylin analogues: Epoprostenol; Treprostinil; Iloprost;
3.Endothelin receptor antagonists:
Dual endothelin receptor antagonist: Bosentan
Selective ETA receptor antagonist: sitaxsentan, Ambrisentan
4. Phosphodiesterase-5 inhibitors: sildenafil
• Interventional and surgical therapy: atrial septostomy, lung or
heart-lung transplantation
WHO classification of functional status of
patients with pulmonary hypertension
Description
I
Patients with pulmonary hypertension in whom there is no limitation of usual physical
activity. Ordinary physical activity does not cause increased dyspnea, fatigue, chest pain,
or syncope.
II
Patients with pulmonary hypertension who have mild limitation of usual physical activity.
There is no discomfort at rest, but normal physical activity causes increased dyspnea,
fatigue, chest pain, or presyncope.
III
Patients with pulmonary hypertension who have a marked limitation of physical activity.
There is no discomfort at rest, but less than ordinary activity causes increased dyspnea,
fatigue, chest pain, or presyncope.
IV
Patients with pulmonary hypertension who are unable to perform any physical activity at
rest and who may have signs of right ventricular failure. Dyspnoea and/or fatigue may be
present at rest and symptoms are increased by almost any physical activity.
Adapted from Rich et al. Primary pulmonary hypertension: Executive Summary. Evian,
France: World Health Organization, 1998.
Acute Vasoreactivity Test
•
The test: using right-heart catheterization to measure
pulmonary arterial pressure when challenged with
vasodilators ( adenosine IV, or Epoprostenol IV, or
NO inhale)
• A positive response is considered when there is a
greater than 10 mmHg reduction in mean pulmonary
artery pressure, to a mean pulmonary artery pressure
of less than 40 mmHg.
Treatment algorithm for
pulmonary arterial hypertension
Back to the case – pretreatment evaluation
Initial evaluation at the referral center included a 6MWT of 305 m. Right-heart catheterization showed
a pulmonary arterial pressure of 65/30 mmHg (mean 42 mmHg), RAP of 12 mmHg, pulmonary capillary
wedge pressure of 6 mmHg, and cardiac output of 3.2 L/min. The pt was thought to have idiopathic PAH,
falling into WHO pulmonary hypertension class III on the basis of her symptoms. Treatment options were
discussed with the pt, including medical therapy, diet, exercise, travel, altitude exposure, and pregnancy.
Little change was seen in hemodynamic measurements with the inhalation of NO.
Back to the case -- treatment
The pt began receiving bosentan, 62.5 mg PO Bid, and the dosage was titrated to 125 mg BID after 1
mo. 3 mo later, echo showed an estimated PASP 55 mmHg
And results of the 6MWT had increased by 35 m. the pt reported less dyspnea and greater activity
tolerance. She saw her specialist every 3 mo and F/U with her PCP regularly.
Two years later, pt reported gradually worsening fatigue, dyspnea on exertion, ankle edema, and an
episode of near-syncope. The 6MWT results were slightly worse compared with baseline, and rightheart catheterization showed PAP 75/36 mmHg (mean 48 mmHg). RAP was 13 mmHg, PCWP was 7
mmHg, and cardiac output was 2.7 L/min. An indwelling central venous catheter was placed, and
long-term intravenous epoprostenol therapy was initiated.
Although relatively little evidence supports combined use of bosentan and epoprostenol, bosentan
treatment was continued during the initiation of epoprostenol therapy. The pt also began receiving
diuretic therapy and was referred for evaluation for lung transplantation. 18 mo later, fatigue had
lessened, ankle edema had resolved, and the 6-min walking distance was 330 m. The pt decided not
to pursue lung transplantation at this time.
Rubin, L. J. et. al. Ann Intern Med 2005;143:282-292
Rubin, L. J. et. al. Ann Intern Med 2005;143:282-292
Future prospective
Stimuli: shear stress,
Po2, Viruses (HIV, HHV-8)
Autoimmunity (CREST,SLE), Drugs
Intrinsic
susceptibility
(PPH-1,BMPR2,Kv)
Pulmonary endothelial-cell dysfunction or injury
(Endothelin-1,Nitric Oxide and prostacyclin pathway)
? VEGF
Imbalance of vascular effectors
Perturbations in the normal relationships between
vasodilators and vasoconstrictors,
growth inhibitors and mitogenic factors,
antithrombotic and prothrombotic determinants.
PDGF inhibitor
Main vascular changes of PAH
Vasoconstriction
SMC and endothelial-cell proliferation
fibrosis
thrombosis
References
•
•
•
•
•
•
Rubin LJ, Rich S. Primary Pulmonary hypertension. Marcel Dekker,
Inc.,1997
Vallerie V. McLaughlin and Stuart Rich, Pulmonary Hypertension. Curr
Probl Cardiol 2004;29:575-634.
S. H. LEE & L. J. RUBIN, Current treatment strategies for pulmonary
arterial hypertension . Journal of Internal Medicine 2005; 258: 199–215
Robyn J. Barst, Michael McGoon, Adam Torbicki, Olivier Sitbon,
Michael J. Krowka, Horst Olschewski and Sean Gaine, Diagnosis and
differential assessment of pulmonary arterial hypertension. J Am Coll
Cardiol 2004;43:40S–47S
Michael McGoon, David Gutterman, Virginia Steen,Robin Barst,
Douglas C. McCrory, Terry A. Fortin,and James E. Loyd, Screening,
Early Detection, and Diagnosis of Pulmonary Arterial Hypertension.
CHEST 2004; 126:14S–34S
Lewis J. Rubin,and David B. Badesch, Evaluation and Management of
the Patient with Pulmonary Arterial Hypertension. Ann Intern Med.
2005;143:282-292.
Thank you
WT 8 months
KO 8 months
Diagram of Pulmonary and Systemic Circulation
Physiology of pulmonary arterial pressure
PR*V, R =8l/r4
1/Rtotal = 1/Ra + 1/Rb + … 1/Rn (parallel resistance)
PE, in situ thrombosis, vascular bed damage
Rtotal = Rartery + Rarterioles + Rcapillaries (series resistance)
Physiology of Pulmonary Arterial Hypertension
Rtotal = Rartery + Rarterioles + Rcapillaries (series resistance)
Regulators of pulmonary vascular tone:
adrenergic control ( and ),
hypoxia,
altitude,
aging,
Exercising
Vasodilators: PGI2, PGE1, nitric oxide (NO)
Vasoconstrictors: PGF2-, PGA2, endothelin-1,
Therapeutic Approaches to Pulmonary Hypertension
Pathophysiology of pulmonary arterial hypertension
Stimuli:
shear stress, Po2, Viruses (HIV, HHV-8)
Autoimmunity (CREST,SLE), Drugs
Platelet
PDGF, 5-HT, TXA2
Intrinsic
susceptibility
(PPH1,BMPR2,Kv)
Endothelial cells
ET-1,NO,PGI2,VIP
5-HT,TxA2,VEGF,adrenomedulin
Smooth Muscle Cells
imbalance
vasoconstriction, proliferation, fibrosis
PAH
In situ
thrombosis
Mechanistic Pathways Promoting Pulmonary
Arterial Hypertension.
History
•In 1891, Romberg reported a case of severe right heart failure and cyanosis that at
autopsy showed “unexplainable pulmonary vascular sclerosis”.
•In 1901, Abel Ayerza described a group of patients who exhibited dyspnea, cyanosis,
precordial pain and died of right heart failure. ( Ayerza’s disease)
•In 1935, Oscar Brenner: primary and secondary, “presence of pulmonary vascular
sclerosis (proliferation of the intima, hypertrophy of the media, and fibrosis of the media)
and right ventricular hypertrophy”
•In 1940s, advent of right heart catheterization
•
•1940s-50s: David Dresdale, Peter Harris and Paul Wood: pulmonary vasodilator:
Priscoline or acetylcholine
•Advent of echocardiography
•1960s-recent: Familial pulmonary hypertension: PPH-1 gene(DGB: 1381541) is mapped
to chromosome 2q31-33
•From 1967 to 1972, epidemic of pulmonary hypertension related to the anorexigen
Aminorex (2-amino-5-phenyl-2-oxaxoline)
History (continued)
•1973, World Health Organization (WHO) in Geneva: classification, pathology, etiologies,
clinical features, and epidemiology
•In 1981, National Institute of Health (NIH): National Registry for primary pulmonary
hypertension.
•In 1993, the first expert consensus statement of American College of Chest Physicians
•In 1995, epoprostenol
•In 2001, Bosentan
•In 2002, Sildenafil
•In 2003, WHO in Venice: new classification
•Today: Lewis J. Rubin and Stuart Rich
Breakdown of long-term responders to calcium channel
blocker (CCB) monotherapy amongst those who are
acutely vasoreactive
Guideline for approaching the differential diagnosis of
pulmonary hypertension
Rubin, L. J. et. al. Ann Intern Med 2005;143:282-292
Pulmonary hypertension is a condition whose management is complex and evolving rapidly. …
the diagnosis and treatment is often shared between specialists,
Including cardiologists, pulmonologists, rheumatologists, pediatricians, and surgeons. The development
of newer treatments for this condition, once considered uniformly fatal, underscores the importance of
enacting a stepwise approach to treatment based on scientific evidence.
--- Lewis J. Rubin, 2004
Chest Radiography
•
Enlargement of the main pulmonary artery and its major
branches, with marked tapering of peripheral arteries .
• The right ventricle and atrium may also be enlarged.
• In contrast to the plethoric peripheral lung fields in
patients with left-to-right shunts, oligemia is noted in
these lung regions in patients with PAH.
• Encroachment of the retrosternal air space on the lateral
film -- right ventricular enlargement/hypertrophy
ECG
• Highly specific but not very sensitive.
• Right atrial and right ventricular
enlargement.
• Right bundle branch block
• ST and T wave changes in the anterior
precordial leads.
Summary of medications approved for use in
pulmonary arterial hypertension.
Drug (class)
Route
Dose range
Major
class
Functional sideeffects
Contraindications
Regulatory
approval
(a)
Epoprostenol
(prostanoid)
i.v.
2 ng kg
up
III–IV
Flushing, headache,
nausea, diarrhoea, jaw
pain, lightheadedness,
arthralgias
None
US,
Europe,
Canada,
Australia
Iloprost
(prostanoid)
inh.
2.5–5 mcg 6–9 times
daily during waking
hours; total daily dose
usually <45 mcg
III–IV (b)
Flushing, cough,
headache, jaw pain,
insomnia, nausea,
hypotension
None
US,
Europe,
New
Zealand,
Australia
Treprostinil
(prostanoid)
s.c.
1.25 ng kg
min
and up, i.v. usually
1
1
<40 ng kg
min
(s.c. and i.v. routes are
bioequivalent)
II–IV
Infusion site pain and
reaction (i.v./s.c.),
headache, diarrhoea,
nausea, jaw pain,
flushing
None
US,
Europe,
Canada
Bosentan
(Dual ERA)
p.o.
62.5 mg q.d. ×4 weeks,
then 125 mg b.i.d.
III–IV
Hepatocellular injury,
flushing, headache,
oedema, sinus
congestion,
haemoglobin decrease
Concurrent use of cyclosporin or
glyburide; pregnancy; moderate-tosevere pre-existing liver
impairment
US,
Europe,
Canada,
Australia,
Japan
Sildenafil
(PDE-5
inhibitor)
p.o.
20 mg t.i.d.
I–IV
Headache, dyspepsia,
epistaxis, back pain,
sinus congestion
Concurrent use of organic nitrate
medication
US, under
review in
Europe
1
min
1
1
and
1