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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%.

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Pulmonary Arterial Hypertension

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Pulmonary arterial hypertension l.jpg

Pulmonary Arterial Hypertension

Xiaosong Zhao, MD, PhD

Presbyterian Hospital of Dallas

January 3, 2006


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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


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Annual number of hospitalizations among persons with pulmonary hypertension, United States, 1980–2002

CDC, National Hospital Discharge Survey.


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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) .


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WHO Classification of pulmonary hypertension

(Venice 2003; revised from Evian 1998)


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Histopathology

  • Main vascular changes of PAH

  • Vasoconstriction

  • SMC and endothelial-cell proliferation

  • fibrosis

  • thrombosis

intima

media

  • Severe concentric laminar intimal fibrosis

  • Medial hypertrophy

  • in situ thrombosis of the small residual lumen


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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

Pathophysiology


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Regulation of pulmonary arterial tone


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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 exercise-induced 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.


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Clinical Assessment

H & P

6MWT


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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


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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.


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CXR-PA view

Enlargement of the main pulmonary artery and its major branches, with marked tapering of peripheral arteries .


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CXR-lateral view

Encroachment of the retrosternal air space -- right ventricular enlargement/hypertrophy


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CXR-PA view

The right ventricle and atrium may also be enlarged.


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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.


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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


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Echocardiogram

Right atrial and ventricular enlargement and flattening of the intraventricular septum -- parasternal short axis view (a) and four chamber view (b).


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Doppler Echocardiogram


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Representation of Echocardiographic findings


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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


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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


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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

  • Before-and-after treatment comparisons

  • Measuring functional status

  • Predicting hospitalization and death


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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


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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


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Potentially Hazardous Activities for Patients with Pulmonary Arterial Hypertension

Rubin, L. J. et. al. Ann Intern Med 2005;143:282-292


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Treatment -- General measures

Diuretics: to achieve symptom relief

Loop diuretics and/or potassium-sparing aldosterone inhibitors:

cautious vs. courage

Low salt diet


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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


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Treatment -- General measures

  • Digoxin

    Increase in resting cardiac output of approximately 10%

    Long-term benefit of digoxin administration is not clear


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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


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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


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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.


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Kaplan-Meier survival estimates in 178 patients with PPH from the initiation of epoprostenol therapy


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Survival of 162 patients with PPH treated with epoprostenol compared to expected survival based on the NIH registry equation


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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


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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


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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


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WHO classification of functional status of patients with pulmonary hypertension


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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.


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Treatment algorithm for pulmonary arterial hypertension


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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.


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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 right-heart 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.


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Rubin, L. J. et. al. Ann Intern Med 2005;143:282-292


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Rubin, L. J. et. al. Ann Intern Med 2005;143:282-292


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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

Future prospective

? VEGF

PDGF inhibitor


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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.


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Thank you


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WT 8 months

KO 8 months


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Diagram of Pulmonary and Systemic Circulation


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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)


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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,


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Therapeutic Approaches to Pulmonary Hypertension


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Pathophysiology of pulmonary arterial hypertension

Stimuli: shear stress, Po2, Viruses (HIV, HHV-8)

Autoimmunity (CREST,SLE), Drugs

Platelet

PDGF, 5-HT, TXA2

Intrinsic

susceptibility

(PPH-1,BMPR2,Kv)

In situ thrombosis

Endothelial cells

ET-1,NO,PGI2,VIP

5-HT,TxA2,VEGF,adrenomedulin

Smooth Muscle Cells

imbalance

vasoconstriction, proliferation, fibrosis

PAH


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Mechanistic Pathways Promoting Pulmonary Arterial Hypertension.


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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)


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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


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Breakdown of long-term responders to calcium channel blocker (CCB) monotherapy amongst those who are acutely vasoreactive


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Guideline for approaching the differential diagnosis of pulmonary hypertension

Rubin, L. J. et. al. Ann Intern Med 2005;143:282-292


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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


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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


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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.


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Summary of medications approved for use in pulmonary arterial hypertension.


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