Listen to this patient's heart.



· Dyspnoea (60-89%).

· Fatigue (19-73%).

· Syncope, near syncope or dizziness (13-88%).

· Oedema (3-37%).

· Palpitations (5-33%).

· Determine whether the patient is on oral contraceptives, fenfiuramine or aminorex (N Engl J Med 1996;

335: 609-16).

· Determine whether the patient has habitually consumed plant products from Crotalaria species

(particularly if from the Caribbean).

· Determine whether there is a family history: the chromosome locus 2q31-q32 has been identified in

one familial cohort of primary pulmonary hypertension (Circulation 1997; 95: 2603-6).

· Determine whether there is a history of HIV (HIV-associated pulmonary hyper-tension is associated

with poor prognosis).


· Young woman.

· Loud pulmonary second sound.

· Early diastolic murmur of pulmonary regurgitation best heard on inspiration (Graham Steell murmur).

· Examine the chest for chronic lung disease.

Tell the examiner that you would like to:

· Investigate for a tight or occult mitral stenosis.

· Perform a ventilation-perfusion (V/Q) scan to exclude pulmonary emboli.


This patient has pulmonary hypertension (lesion) and should be investigated for an underlying cause;

she is in cardiac failure (functional status).


What are the signs of pulmonary hypertension ?

· Large 'a' waves in JVP.

. Left parasternal heave.

· Loud or palpable P2.

· Ejection click in the pulmonary area.

· Early diastolic murmur (Graham Steell murmur) due to pulmonary regurgitation.


How would you investigate such a patient?

· Chest radiograph: enlarged main pulmonary arteries with reduced peripheral branches, enlargement of the right ventricle.

· Pulmonary function testing, arterial blood-gas study.

· ECG: right ventricular and right atrial hypertrophy.

· V/Q scan to exclude pulmonary emboli.

· Echocardiogram, right heart catheterization and puhnonary angiography.

What are the pathological features of primary pulmonary hypertension ?

They are those of plexogenic pulmonary arteriopathy (which also occurs in post-tricuspid left-to-right atrial shunts such as VSD or PDA, and collagen vascular diseases), characterized by medial hypertrophy and concentric intimal fibrosis of the pulmonary arteries with complex plexiform lesions. Others have no plexiform lesions or concentric intimal fibrosis, but rather have recanalized thrombotic small pulmonary arteries which are said to be the result of small thrombi or recurrent emboli. The least common histological pattern is veno-occlusive disease.

What are the theories for the cause of primary pulmonary hypertension ?

· Excess endothelial production of the vasoconstrictor thromboxane relative to dilator prostaglandins

such as prostacyclin.

· Excess endothelin-I levels relative to nitric oxide. Inhaled nitric oxide and endothelin-1 antagonists

reduce pulmonary hypertension.

· Excessive thrombosis in situ due to increased platelet activation, plasminogen activator inhibitor

levels and decreased thrombomodulin.

· Increased serotonin levels.

· Inhibition or downregulation of potassium (Kv) channels in pulmonary artery smooth muscle cells and platelets.

· Activation of elastase and matrix metalloprotease enhances production of mitogens.

· Monoclonal proliferation of endothelial cells.

What is the prognosis in pulmonary hypertension?

The prognosis is poor: median survival is approximately 3 years from the time of diagnosis, with about

one third of patients surviving for 5 years. Death usually occurs suddenly, presumably from arrhythmias

or right ventricular infarction.

What are the predictors of survival?

These include indicators of severity of disease as assessed by measurement of haemodynamic

characteristics (mean pulmonary artery pressure, right atrial pressure, cardiac index and mixed venous

oxygen concentration), functional class, exercise tolerance (6-minute walk test), anticoagulant therapy

and the response to vaso-dilators. Most patients succumb to progressive right-sided failure, but sudden

death accounts for approximately 7% of deaths.

What treatment is available for primary pulmonary hypertension?

· Diuretics are useful in reducing excessive preload in patients with right heart failure, particularly when

hepatic congestion and ascites are present.

· Oral anticoagulants: warfarin is the anticoagulant of choice, in doses adjusted to achieve an INR of

approximately 2.0. Anticoagulants nearly double the 3-year survival rate (Circulation 1984; 70: 580-7).

* Calcium channel blockers: nifedipine, diltiazem. Patients who respond to calcium channel blockers

have a 5-year survival rate of 95% (N Engl J Med 1992; 327: 76-81).

· Intravenous epoprostenol (formerly prostacyclin or prostaglandin I2), which is a potent short-acting

vasodilator and inhibitor of platelet aggregation that is produced by the vascular endothelium (N Engl

J Med 1996; 334: 296-301; N Engl J Med 1998; 338: 273-7).

· Atrial septostomy: the creation of a right-to-left shunt by blade-balloon atrial septostomy has been

reported to improve forward output and alleviate right-sided heart failure by providing blood with a

low-resistance channel, thereby decompressing the right atrium and improving filling of the left side of

the heart (Circulation 1995; 91: 2028-35).

· Lung transplantation and combined heart-lung transplantation: survival rates after the two

procedures are similar. Even markedly depressed right ventricular function improves considerably

with single- or double-lung transplantation.

· Possible future drugs: (a) UT-15, a prostaglandin 12 analogue, has been shown to have sustained

and favourable effects in patients when administered sub-cutaneously (Circulation 2000; 102(18):

11-101); (b) Sitaxsentan, an oral selective endothelin-A receptor blocker, has been shown to produce

sustained improve-ments in pulmonary artery pressure (Circulation 2000; 101(25): 2922-7).

Graham Steell (1851-1942), assistant physician to the Manchester Royal Infirmary, described the murmur

in a paper titled The murmur of high pressure in the pulmonary artery (Med Chron (Manchester) 1888; 9: