Background: Normal pulmonary circulation is a high-flow, low-resistance circuit capable of accommodating the entire right ventricular output at one fifth the pressure of the systemic circulation level. The thin-walled right ventricle functions primarily as a flow-generator pump and is particularly sensitive to increases in its afterload. Increased pulmonary artery pressure and pulmonary vascular resistance characterize pulmonary hypertension.

Pulmonary hypertension may be divided into primary and secondary forms. Primary pulmonary hypertension (PPH) is a disease of unknown etiology, whereas secondary pulmonary arterial hypertension (SPAH) is due to either intrinsic parenchymal disease of the lung or disease extrinsic to the lung.

Pathophysiology: Pulmonary hypertension is conventionally categorized into primary and secondary forms. Pulmonary hypertension is present when the systolic and mean pressures in the pulmonary arteries exceed 30 and 20 mm Hg, respectively.

Causes

In PPH, the precise mechanism is unknown. Presumed mechanisms include the following:

• Endothelial dysfunction: With impaired production of both prostacyclin and nitrous oxide, endothelin is overproduced. This overproduction results in vasoconstriction and remodeling of the pulmonary vasculature.

   

• Voltage-gated K channel: A defect in this ion channel changes the resting membrane potential, increasing intracellular calcium and leading to pulmonary vasoconstriction.

   

• Thrombosis in situ: Injury to the endothelial lining of the vessel wall, abnormal fibrinolysis, and platelet abnormalities may all contribute to thrombus formation.

The etiologies of PPH include the following:

• Use of appetite suppressants such as fenfluramine and dexfenfluramine may be associated with an increased risk of PPH (odds ratio, 6.3), as shown in a recent case control study.

   

• PPH may also be inherited as an autosomal dominant trait.

   

• Cocaine or amphetamine ingestion may be another contributing factor.

In secondary hypertension, the mechanisms are often multifactorial, depending on the underlying etiology. However, 3 interactive variables exist.

• Hypoxic vasoconstriction: Chronic obstructive lung disease, sleep apnea, polio, and myasthenia gravis are some etiologies. The administration of oxygen is recommended for patients with secondary causes of SPAH due to these mechanisms.

   

• Decreased area of the pulmonary vascular bed: Collagen vascular disease, HIV infection, advanced liver disease, and toxins are various etiologies. Pulmonary embolism (PE) is the most common etiology and characterized by occlusion of the pulmonary arterial system. Although anticoagulation is the treatment of choice, most PEs are diagnosed at autopsy.

   

• Volume/pressure overload may also be a factor.

More common causes include congestive heart failure (CHF) secondary to coronary artery disease, hypertension, and valvular disease. Less commonly, atrial and ventricular septal defects are involved.

Further classification

Secondary pulmonary hypertension may be further categorized as pulmonary venous hypertension, chronic hypoxia with secondary vasoconstriction of the pulmonary vasculature, pulmonary artery obstruction, and left-to-right shunts.

Pulmonary venous hypertension is the most common form of pulmonary hypertension and usually due to left-sided heart disease. Pulmonary hypertension develops as a result of the obstruction of blood flow downstream from the pulmonary vein. Causes of pulmonary venous hypertension from distal to proximal of the pulmonary vasculature include coarctation of the aorta, aortic stenosis, aortic regurgitation, hypertrophic cardiomyopathy, constrictive pericarditis, restrictive cardiomyopathy, dilated cardiomyopathy, mitral stenosis, mitral regurgitation, and left atrial myxoma.

With chronic hypoxia with secondary vasoconstriction of the pulmonary vasculature, alveolar hypoxia induces vasoconstriction of the pulmonary vascular bed, causing high pulmonary resistance and hypertension with right ventricular failure. Causes include restrictive lung disease (obesity, pneumoconiosis, neuromuscular disorders), and obstructive lung diseases (asthma, chronic obstructive pulmonary disease [COPD], bronchiectasis).

Regarding pulmonary artery obstruction, chronic major thromboembolic vessel disease is a treatable cause of pulmonary hypertension that results in anatomical obstruction of the arteries. Thrombotic disorders include sickle cell disease and other coagulation disorder. Embolic disease includes chronic thromboemboli, connective tissue disease, lupus, and schistosomiasis.

Individuals with pulmonary hypertension due to left-to-right shunts have high blood flow to the pulmonary vessels, which leads to increased pulmonary vascular resistance over time with reversal of the shunt (Eisenmenger complex). Extracardiac shunts include patent ductus arteriosus, and intracardiac shunts include ventricular and atrial septal defects.

Frequency:

• In the US: The incidence of PPH is approximately 2 cases per million individuals in the general population. Although most cases of PPH are sporadic, approximately 10% are familial.

  The incidence of SPAH is dependent on its etiology. On the basis of the pathophysiology as described above, the most common causes include (1) Hypoxic vasoconstriction (COPD), (2) pulmonary vasculature obliteration (PE), and (3) pressure/volume overload (CHF).

  COPD is the fourth leading cause of mortality in the US. Although hospital admissions have decreased for many conditions, the number of hospital discharges for COPD in the US rose from 400,000 in 1985 to 460,000 in 1993. The annual incidence of PE is 300,000 per year, with a mortality rate of 30% without treatment. Approximately 5 million patients in the US are admitted with a diagnosis of CHF, making it the leading cause of hospitalization in the population older than 65 years. According to the Framingham data, the prevalence of CHF is 8 cases per 1000 men and 6 cases per 1000 women.

• Internationally: Frequency data are difficult to confirm, as there are no international registries tracking the incidence and prevalence of pulmonary hypertension.

Mortality/Morbidity: The natural history of PPH was evaluated in the National Institutes of Health (NIH) registry in 1981-1987. Of the 194 patients included in the study, 63% were female and 37% were male. The mean age was 36 years, with no ethnic differences. The median survival after diagnosis was 2.5 years.

Functional class is a strong predictor of PPH. Patients in classes II and III have a mean survival of 3.5 years. Conversely, those in functional class IV have a mean survival of 6 months.

The most common cause of death in patients with PPH is progressive right heart failure, followed by sudden cardiac death.

The secondary causes of PPH—chronic obstructive lung disease, thromboembolic disease, and CHF— cause significant morbidity and mortality, as described below.

• COPD is estimated to affect approximately 15 million people in the US. It is the fourth leading cause of death, as described previously, and the second leading cause of disability in the US. The prevalence and mortality rates for COPD have increased 30-40% since 1982, mainly as a result of cigarette smoking. The mortality rate 10 years after diagnosis is 50%.

• The incidence of pulmonary thromboembolism is approximately 1 case per 1000 population per year, with a higher prevalence in men. In the US, more than 250,000 patients are hospitalized with PE. In the Prospective Investigation of Pulmonary Embolism Diagnosis (PIOPED) trial, the 3-month mortality rate was approximately 15%.

• CHF is a major public issue in the industrial world. It is the most common cardiovascular condition that is increasing in both incidence and prevalence. In the US, approximately 1 million hospital admissions and 40,000 deaths due to CHF will occur.

Race: The only database registry is that of the National Institutes of Health, and the racial data are not apparent.

Sex: In PPH, the female-to-male preponderance is 1.7:1.

Age:

• Most individuals with PPH present in the third and fourth decades, with a mean patient age of 36 years.

• Exceptions do occur, and patients range from infants to the elderly.

• Most individuals with COPD, PE, and CHF present in their late 40s and early 50s.

Anatomy: The pulmonary vasculature involves a diverse system of vessels—arteries, arterioles, capillaries, venules, and veins—that are responsible for accommodating the entire cardiac output.

The pulmonary arterial system begins as the main pulmonary artery, beyond the pulmonic valve. The main pulmonary artery bifurcates into the left and right systems. The left pulmonary artery passes posteriorly above the left bronchus, whereas the right pulmonary artery passes behind the ascending aorta, anterior and inferior to the right main bronchus, toward the right hilum.

The left pulmonary artery divides into an ascending ramus supplying the upper lobe and a descending ramus supplying the lower lobe. The right pulmonary artery bifurcates into an ascending ramus supplying the upper lobe and a descending ramus supplying the middle and lower lobes.

The pulmonary venous system runs within the interlobular septa adjacent to the pulmonary arteries. The 2 superior and 2 inferior pulmonary veins empty into the left atrium. The superior pulmonary veins drain the right upper and middle lobes and the left upper lobe, whereas the inferior pulmonary veins drain the lower lobes.

Clinical Details: The interval between the onset of symptoms of PPH to diagnosis is about 2 years. The most common presenting symptoms are the following:

• Exertional dyspnea

   

• Fatigue and lethargy

   

• Angina

   

• Syncope

   

• Raynaud phenomenon

   

• Edema

Less common symptoms include cough, hemoptysis, and hoarseness.

Physical examination centers on detecting signs of right ventricular hypertrophy and right ventricular failure secondary to pulmonary hypertension.

On examination of the jugular venous pressure in the neck, the following may be observed:

• Prominent A wave with right ventricular hypertrophy

   

• Prominent V wave in acute right ventricular failure, leading to tricuspid regurgitation

   

• Low-volume carotid arterial pulse with a normal upstroke

On the precordial examination, the following may be observed:

• Palpable S2 from the increased intensity of the pulmonic component

   

• Left parasternal heaving from right ventricular hypertrophy

   

• Increased P2, narrowly split

   

• Right ventricular third heart sound

   

• Right ventricular fourth heart sound

   

• Systolic ejection murmur (a high-pitched tricuspid regurgitation murmur)

   

• A high-pitched early diastolic murmur of pulmonic regurgitation

Finally, on extracardiac physical examination, one may observe the following:

• Hepatosplenomegaly

   

• Pulsatile liver

   

• Ascites

   

• Peripheral edema

The electrocardiogram is useful for demonstrating signs of right ventricular hypertrophy and strain. These signs include the following:

• Right-axis deviation

   

• R/S ratio greater than 1 in lead V1

   

• Right atrial enlargement as indicated by an increased P-wave amplitude in lead II

   

• Right bundle branch block

In summary, pulmonary veno-occlusive disease is idiopathic, usually not diagnosed prior to death, occurs with pulmonary hypertension, and has no adequate treatment.

Preferred Examination: In an individual with suspected pulmonary hypertension, PPH is the diagnosis of exclusion. Hence, a designated algorithm should be used to exclude secondary causes of pulmonary hypertension. The following are proposed investigations:

1. Autoantibody tests, HIV test, liver function tests

    

2. Electrocardiography

    

3. Chest radiography

    

4. Pulmonary function tests

    

5. Echocardiography

    

6. Ventilation-perfusion (V/Q) scanning

    

7. Computed tomographic pulmonary angiography (CTPA)

    

8. Pulmonary angiography

    

9. Cardiac catheterization

    

10. Magnetic resonance imaging (MRI)

As a baseline, the first 5 tests are reasonable for substantiating the presence of increased pressures on the right side of the pulmonary vascular system. On the basis of the results, a more focused approach to establish the etiology of the pulmonary hypertension may then involve tests 6-9. Most patients with secondary pulmonary hypertension do not require right-heart catheterization before beginning a trial with vasodilators. However, select patients, such as those with collagen vascular disease, should undergo invasive investigations.

Imaging studies are important in individuals with pulmonary hypertension, for the following purposes:

• Detecting pulmonary hypertension (echocardiography, cardiac catheterization)

   

• Differentiating the cause (echocardiography, V/Q scanning, CTPA, cardiac catheterization, pulmonary angiography, MRI)

   

• Determining the severity (echocardiography, cardiac catheterization)

   

• Evaluating the status of the right ventricle (echocardiography, cardiac catheterization, MRI)

Various imaging modalities, including chest radiography, CT, MRI, pulmonary function tests, echocardiography, and angiography, have variable success in detecting the presence and severity of pulmonary hypertension.

PPH is diagnosed if no underlying etiology is found. See Image 1 for secondary causes of pulmonary hypertension.

DIFFERENTIALS

Pulmonary Embolism (Helical CT)

X-RAY

Findings: Chest radiographic findings of pulmonary hypertension (see Images 2-3) include the following:

• Enlarged central pulmonary arteries that taper distally may be depicted.

   

• A dilated right heart due to right ventricular enlargement is seen as a decrease in the retrosternal space on the lateral image. Right atrial enlargement may be present if significant tricuspid regurgitation is present. This finding may be recognized by the widened right heart border in the frontal projection and enlargement of the right atrial appendage in the lateral projection, which is seen as increased retrosternal opacity above the expected location of the right ventricle.

   

• Peripheral vessel opacity-oligemic lung fields may be observed. This oligemia may be asymmetric. This is also a useful finding suggestive of chronic PE.

   

• An increase in the transverse diameter of the right interlobar artery is indicative of pulmonary hypertension. The upper limit of the transverse diameter of the right interlobar artery from its lateral aspect to the intermediate bronchus is 15 mm in women and 16 mm in men.

   

• The transverse diameter of the left interlobar artery is difficult to appreciate on the posteroanterior (PA) view. Using a lateral view, one can measure from the circular lucency of the left upper lobe bronchus to the posterior margin of the vessel; the upper limit is 18 mm.

   

• Evidence of right atrial dilatation and right ventricular dilatation may be noted.

   

• Kerley B lines may be present. These indicate the presence of pulmonary venous hypertension.

Causes of SPAH and their appearances include the following:

• Atrial septal defect is characterized by cardiomegaly, enlargement of the right atrium and ventricle, and enlargement of the central pulmonary arteries. Also present is rapid tapering, with increased vascularity in the periphery of the lung.

   

• Eisenmenger syndrome is characterized by peripheral oligemia, indicating the reversal of a left-to-right shunt due to increased vascular resistance. The peripheral vasculature is diminished, and the cardiac morphology is consistent with cor pulmonale.