Pulmonary Hypertension, Cor Pulmonale, and Miscellaneous Vascular Conditions Part 1

Pulmonary hypertension is a hemodynamic abnormality that is caused by a variety of disorders. It can be classified into four broad categories: (1) pulmonary arterial hypertension; (2) pulmonary venous hypertension (e.g., left ventricular dysfunction and mitral valve disease); (3) pulmonary hypertension associated with disorders of the respiratory system, usually with hypox-emia (e.g., chronic obstructive and restrictive lung disease); and (4) pulmonary hypertension caused by chronic thrombotic or embolic disease [see Table 1].

Pulmonary Hypertension

Pulmonary hypertension is defined as a mean pulmonary arterial pressure greater than 25 mm Hg at rest or 30 mm Hg with exercise. Pulmonary hypertension may be suggested when estimated pulmonary arterial systolic pressure exceeds approximately 40 to 50 mm Hg (tricuspid regurgitation velocity of 3.0 to 3.4 m/sec), as assessed by echocardiography. The prevalence of pulmonary hypertension is difficult to measure precisely, but it is very common; most patients with heart failure have some degree of pulmonary hypertension.2

Physiology

The normal pulmonary circulation is capable of accommodating the entire cardiac output at perfusion pressures that are one fifth of those in the systemic circulation, even when cardiac output increases severalfold during exercise. The pulmonary circulation accomplishes this by dilation of the vasculature already receiving the cardiac output and recruitment of unused vascula-ture (i.e., arterioles and capillaries); by these mechanisms, the pulmonary circulation minimizes increases in perfusion pressure and maximizes gas exchange surface area. There are two unique characteristics of the pulmonary vasculature. First, the effect of gravity on blood flow through the lungs is greater than its effect on ventilation, which results in diminishing zones of per-fusion from base to apex in the upright position. Upstream pressure, such as the filling pressure from the left side of the heart, also increases pulmonary arterial pressures by distending and recruiting vasculature. Second, there are two portions of the vas-culature that are influenced in opposite directions by changes in lung gas volume. Alveolar vessels are lengthened and narrowed monotonically with increases in lung volume; this in turn produces an increase in their resistance to blood flow. In series with the alveolar vessels are the extra-alveolar vessels that are tethered by the lung parenchyma; their size increases with increases in lung gas volume. The result of this interplay of these two characteristics is a rise in pulmonary vascular resistance both when lung volume decreases below usual levels and when it increases above usual levels [see Figure 1 ].

Accordingly, the major responses of the normal pulmonary circulation to upstream and downstream vascular pressures and to changes in lung volume are generally passive responses. Neural and humoral vasomotor responses are normally modest, in keeping with the paucity of vascular smooth muscle.

Pathogenesis and pathophysiology

Pulmonary hypertension can be caused by narrowing of the precapillary vessels (arteries and arterioles), loss of vascular surface area, or passive back pressure from the postcapillary vessels [see Table 2].

Precapillary pulmonary hypertension can be produced by several mechanisms. Embolic material, such as venous thrombi, can lodge in the pulmonary artery, producing acute obstruction or, if unresolved and organized into the vessel wall, chronic obstruction. In situ thrombosis can also occur. Chronically increased blood flow, as seen in large left-to-right intracardiac shunts, is associated with remodeling of the pulmonary arterial walls to vessels that resemble systemic arteries and arterioles; this results in an increase in pulmonary vascular resistance and, ultimately, reversal of the shunt (a condition known as Eisen-menger syndrome). Remodeling of the pulmonary arterial and arteriolar walls as a result of inflammation or endothelial dysfunction can also occur, for example in idiopathic pulmonary arterial hypertension (IPAH) or pulmonary arterial hypertension (PAH) caused by connective tissue diseases.

Table 1 Revised Nomenclature and Classification of Pulmonary Hypertension (2003)1

Pulmonary arterial hypertension (PAH)

Sporadic (IPAH)

Familial (FPAH)

Conditions associated with PAH

Collagen vascular disease

Congenital systemic to pulmonary shunts (large, small, repaired or nonrepaired)

Portal hypertension

HIV infection

Drugs and toxins

Other (glycogen storage disease, Gaucher disease, hereditary hemorrhagic telangiectasia, hemoglobinopathies, myeloproliferative disorders, splenectomy)

Significant venous or capillary involvement

Pulmonary veno-occlusive disease

Pulmonary capillary hemangiomatosis

Pulmonary venous hypertension

Left-sided atrial or ventricular heart disease

Left-sided valvular heart disease Pulmonary hypertension associated with hypoxemia

Chronic obstructive pulmonary disease

Interstitial lung disease

Sleep-disordered breathing

Alveolar hypoventilation disorders

Chronic exposure to high altitude

Pulmonary hypertension due to chronic thrombotic and/or embolic disease

Thromboembolic obstruction of proximal pulmonary arteries

Thromboembolic obstruction of distal pulmonary arteries

Pulmonary embolism (tumor, parasites, foreign material)

Miscellaneous

Sarcoidosis

Histiocytosis X

Lymphangiomatosis

Compression of pulmonary vessels (adenopathy, tumor, fibrosing mediastinitis)

Figure 1 Effects of lung volume on vascular resistance in alveolar, extra-alveolar, and total pulmonary circulation. The total vascular resistance is lowest at functional residual capacity (FRC) and is higher at low lung volume (residual volume [RV]) and high lung volume (total lung capacity [TLC]).

Loss of the pulmonary vascular bed as a result of destructive processes such as emphysema or interstitial fibrotic disease will increase resistance to blood flow and produce pulmonary hypertension. Hypoxia-induced pulmonary vasoconstriction and vascular remodeling further augment the degree of pulmonary hypertension in this setting.

On rare occasions, the pulmonary veins can be obstructed by a primary process (pulmonary veno-occlusive disease) or during passage of the pulmonary veins through the mediastinum (neoplasm or mediastinal fibrosis). Any process that increases left atrial pressure (mitral stenosis or regurgitation) or increases left ventricular end-diastolic pressure (LVEDP) will also increase pulmonary arterial pressure, with less dramatic increases in intrinsic pulmonary arteriolar resistance.

Regardless of the etiology, when pulmonary hypertension occurs, the vasculature responds by undergoing changes that further increase its resistance [see Figure 2].3 The patterns of histopathologic change seen in pulmonary hypertension are medial hypertrophy, intimal thickening, plexogenic pulmonary ar-teriopathy, thrombotic pulmonary arteriopathy, and veno-occlu-sive disease.4 Historically, these patterns were felt to be specific for the different causes of pulmonary hypertension. However, more recent studies indicate that these changes likely represent a final common pathway of response to pulmonary vascular injury and persistent pulmonary hypertension.

Diagnosis

The diagnostic evaluation of pulmonary hypertension [see Figure 3] begins with a careful history and physical examination.

Many of the clinical features of pulmonary hypertension are similar regardless of the underlying cause.5 Early in the process, the symptoms of pulmonary hypertension may be minimal and nonspecific. Dyspnea, weakness, and fatigue are common; these symptoms are sometimes associated with chest pain that can mimic angina pectoris. Syncope, which is often exertional, occurs late in pulmonary hypertension; it is a sign of poor prognosis because it implies an inability to augment cardiac output during exertion. Hoarseness caused by compression of the recurrent laryngeal nerve (Ortner syndrome) and hemoptysis related to rupture of hypertensive, atherosclerotic small pulmonary vessels could occur. Signs and symptoms of right ventricular failure, such as edema and ascites, occur relatively late in the disease; as with syncope, these symptoms indicate a poor prognosis.

Physical Examination

During physical examination, the jugular veins may be distended, and there may be prominent A waves, signifying decreased right ventricular (RV) compliance. Also, increased V waves may indicate tricuspid regurgitation. Palpation of the chest may detect an RV heave in the parasternal area or, in patients with COPD, in the subxiphoid area. On auscultation of the heart, there may be an increased P2, an RV S4, an RV S3, a pul-monic ejection click, the murmur of tricuspid regurgitation at the lower right sternal border that is increased with inspiration, and, occasionally, pulmonic regurgitation (Graham Steell murmur). Hepatomegaly, ascites, and lower extremity edema are each ex-trathoracic indicators of right ventricular failure. 

Table 2 Relation between Site, Pathogenesis, and Disorders of the Pulmonary Circulation

Site	Pathogenesis	Disorders
Precapillary	Intravascular obstruction, increased blood flow, vascular remodeling or inflammation, vasospasm, increased blood viscosity	Pulmonary emboli or in situ thrombosis, left-to-right shunt, alveolar hypoxia, vasculopathy caused by collagen vascular disorder or primary pulmonary hypertension, polycythemia
Capillary	Destruction of capillary bed	Emphysema, interstitial lung disease, surgical removal
Postcapillary	Passive back pressure from pulmonary venous obstruction, high left atrial pressure, high LVEDP	Pulmonary veno-occlusive disease, pulmonary venous obstruction in the mediastinum, mitral regurgitation or stenosis, left ventricular failure

LVEDP—left ventricular end-diastolic pressure

Figure 2 Mechanisms of pulmonary hypertension. Irrespective of the initiating event or events, pulmonary hypertension worsens over time because of vascular wall injury, endothelial shear stress, and an increase in transmural wall tension. These processes result in vasoconstriction, vascular wall remodeling, and in situ thrombosis.

Initial Imaging and Physiologic Testing

Chest radiography The chest radiograph can provide clues to the diagnosis and etiology of pulmonary hypertension. Symmetrical enlargement of the pulmonary arteries, with rapid tapering of the distal vessels (pruning) and enlargement of the right ventricle, can be found but usually is not seen until later stages of the disorder. Asymmetrical enlargement of the central pulmonary arteries may be seen in patients with chronic throm-boembolic pulmonary hypertension (CTEPH). Radiographic findings that suggest the underlying cause of pulmonary hypertension include pulmonary venous congestion (e.g., LV failure), hyperinflation (COPD), and interstitial lung disease (e.g., interstitial pulmonary fibrosis).

Electrocardiography In mild cases of pulmonary hypertension, the electrocardiogram may be normal. In more severe cases, the ECG will show changes of right ventricular hypertrophy and right atrial enlargement. These changes are to be contrasted with the typical ECG findings seen in COPD, which largely reflect the hyperinflation of the lungs and low diaphragms.

Transthoracic echocardiography Transthoracic echocardio-graphy with Doppler estimation of pulmonary arterial pressure is the noninvasive method of choice in screening populations of patients with a high incidence of pulmonary hypertension; such patients include those with the scleroderma spectrum of disease, those who have a family history of pulmonary artery hypertension, patients with HIV, and patients with cirrhosis who are being evaluated for liver transplantation. Transthoracic echocar-diography is also useful in evaluating patients with symptoms suggestive of pulmonary hypertension. Findings indicative of pulmonary hypertension include hypertrophy, enlargement of the right ventricle and atrium, and abnormal motion of the septum [see Figure 4]. In some patients, transesophageal echocardio-graphy may be necessary to detect congenital defects. If hypox-emia suggestive of a right-to-left intracardiac shunt is present, injection of saline filled with air bubbles during the echocardiogram will allow detection and localization of the shunt.

Tests to Diagnose Underlying Cause of Pulmonary

Hypertension

It is often necessary to perform additional testing to determine the etiology of pulmonary hypertension. The sequence for this testing generally begins with noninvasive studies, followed by more invasive studies as needed.

Pulmonary function testing Measurements of pulmonary function can be useful in evaluating patients with pulmonary hypertension. Detection of severe obstructive or restrictive defects may indicate that all or a portion of the pulmonary hypertension is caused by intrinsic lung disease. By contrast, isolated reduction of the diffusion capacity or minimal reduction in the lung volumes can be seen in any of the causes of pulmonary vas-culopathy. Arterial blood gases at rest and pulse oximetry with exercise detect complicating resting or exercise hypoxemia that should be remedied therapeutically with supplemental oxygen. The finding of hypercapnia is most compatible with severe chronic airflow obstruction, sleep apnea, or restrictive chest wall disease.

Polysomnography Patients suspected of having a sleep disorder of breathing that may be causing or contributing to pulmonary hypertension should undergo nocturnal polysomnography.

Ventilation-perfusion lung scanning Ventilation-perfusion lung scanning is a critical test in evaluating patients with pulmonary hypertension, especially when chronic thromboembolic pulmonary hypertension is suspected. Patients with chronic thromboembolic pulmonary hypertension will have multiple, bilateral perfusion defects of different sizes (usually interpreted as indicating a high probability of pulmonary embolism), whereas patients with other causes of pulmonary hypertension will have either homogeneous or mildly mottled perfusion [see Figure 5]. The presence of radioactivity in the head or kidney suggests a right-to-left intracardiac or intrapulmonary shunt.

Computed tomography Computed tomography of the chest using spiral or helical or electron-beam techniques can visualize central pulmonary thromboemboli. High-resolution CT of the chest can detect emphysema or interstitial lung disease not seen on routine chest radiography and may also provide clues to the presence of pulmonary veno-occlusive disease.

Cardiac catheterization and pulmonary arteriography Right heart catheterization, with pulmonary arteriography and/or left heart catheterization as clinically indicated, should be performed to confirm the presence of pulmonary hypertension and determine its severity and to exclude congenital heart disease, proximal or peripheral pulmonary arterial stenosis, and valvular or ventricular left sided heart disease. Because of the increased risk of complications, experienced angiographers should perform pulmonary arteriography in this situation. In those patients who are thought to have PAH, vasodilator testing with such agents as nitrie oxide, prostacyclin, and adenosine, with monitoring of gas exchange and pulmonary hemodynamics, should be performed.5

Figure 3 Algorithm for the evaluation of pulmonary hypertension. (HRCT—high-resolution computed tomography; IPAH—idiopathic pulmonary arterial hypertension; PSG—polysomnography; RVSP—right ventricular systolic pressure; TEE—transesophageal echocardiogram; TTE—transthoracic echocardiography; V/Q scan—ventilation/perfusion lung scan)

Lung biopsy It is very uncommon that a lung biopsy is required to establish the cause of pulmonary hypertension. The only exceptions would be in patients in whom one of the interstitial lung diseases or pulmonary arteritis is suspected as a cause of pulmonary hypertension. Bronchoscopic lung biopsy is contraindicated in patients with severe pulmonary hypertension; in such cases, open or video-assisted biopsy is the technique of choice. Such a biopsy poses a greater risk for patients with pulmonary hypertension than for patients without pulmonary hypertension.

Treatment

Treatment of pulmonary hypertension depends on the underlying cause. Disorders that affect the pulmonary circulation acutely (e.g., pulmonary embolism, pulmonary edema, and the acute respiratory distress syndrome) are covered elsewhere [see 1:XVIII Venous Thromboembolism and 14:X Pulmonary Edema], as are valvular heart defects [see 1:XI Valvular Heart Disease], congenital heart defects that can cause pulmonary hypertension [see 1:XV Adult Congenital Heart Disease], and diseases that affect the lung airways and parenchyma, such as COPD and the interstitial lung diseases [see 14:III Chronic Obstructive Diseases of the Lung and 14:V Chronic Diffuse Infiltrative Lung Disease].