Any diagnosis of pulmonary hypertension requires recognition of the different types of vessels seen in the lung. This is aided by the use of elastic tissue stains, which should be a routine approach when a biopsy or larger specimen shows potential vascular disease. Knowledge of the structure of the normal pulmonary vascular bed is important in assessing biopsy material.^4,⁵ Branches of the pulmonary artery run with the bronchi and then the bronchioles. Arteries associated with the bronchi are typically larger than 1 mm in diameter and have a fairly extensive elastic fiber meshwork in their walls. Muscular pulmonary arteries (Fig. 11-1) are usually associated with bronchioles and measure between 100 and 1000 μm. They are frequently abnormal in pulmonary hypertension. Elastic stain (Fig. 11-2) shows that they have both an internal and an external elastic lamina. In the normal lung the diameter of a muscular pulmonary artery and its accompanying airway should be about the same. Below a diameter of about 100 μm, the pulmonary artery branches lose the internal elastica and are termed arterioles. Arterioles run adjacent to the alveolar ducts and can be found as a corner vessel by the alveolar saccules, but should not be found in alveolar walls. A well-defined mesh of capillaries arranged in a single layer of rings and spokes forms the gas exchange system in the alveoli⁶ (Fig. 11-3).

Figure 11-1 Normal muscular pulmonary artery branches accompanying a bronchiole.

Figure 11-2 Elastic stain of a normal small muscular pulmonary artery showing double elastic laminae surrounding a fairly thin muscular layer. The intima is unobtrusive.

Figure 11-3 Scanning electron micrograph showing a methacrylate vascular cast of an alveolus showing the mesh of capillaries.

Pulmonary Veins

Normal pulmonary veins have only a single elastica and a thin layer of muscle. Veins are best identified by anatomic location. Larger pulmonary veins run in the interlobular septa (Fig. 11-4). Smaller veins are found associated with the alveolar saccules and are indistinguishable by morphology from pulmonary arterioles; thus, the identification of a small vessel as a vein often requires tracing it back through several sections until it joins a definite vein in an interlobular septum. Of note, in pulmonary venous hypertension, the larger veins may acquire both a double elastica and additional muscle and resemble muscular arteries, but the location in the septa indicates their true nature.

Figure 11-4 Elastic stain of a normal pulmonary vein running in the interlobular septum. Note the single elastica, a characteristic finding of pulmonary veins.

Bronchial Arteries

Bronchial arteries are found in the walls of the larger bronchi. They usually are heavily muscularized and have a prominent internal elastica and a less well defined external elastica. Bronchial arteries may develop longitudinal muscle bands, a feature helpful in identification. Bronchial arteries are systemic vessels at systemic pressure, and areas where they anastomose with the pulmonary circulation (around bronchiectatic foci, in plexogenic arteriopathy) may be foci of hemorrhage.

Recognition of Right Ventricular Hypertrophy

Significant degrees of pulmonary hypertension are usually associated with right ventricular hypertrophy. A quick, but relatively inaccurate, determination of ventricular hypertrophy can be made by simple measurement of the right ventricular wall muscle thickness (Fig. 11-5). Wall thickness in the normal adult population should be approximately 2 to 3 mm, with measurements greater than 5 mm thought to represent hypertrophy.⁷

Figure 11-5 Cross section of heart at autopsy from a patient with pulmonary hypertension secondary to fenfluramine-phentermine use. Note the markedly thickened right ventricle.

Partitioning of the heart into right ventricle and left ventricle plus septum ⁸ provides a sensitive estimation of ventricular hypertrophy, with a right ventricular weight of 65 g or greater considered abnormal.⁷ Although a portion of the septum will enlarge with the right ventricle, a ratio of left ventricular weight to right ventricular weight of less than 1.9 is considered to represent right ventricular hypertrophy. Obviously, such ratios are only useful if there is no enlargement of the left ventricle.

Microscopic examination of the right ventricle does not show the generalized increase of fibrosis that can be found in left ventricular hypertrophy. Detailed measurement of the myocardiocytes will demonstrate enlarged fiber diameters,⁹ but this finding may be too subtle to recognize visually.

Classification of Pulmonary Hypertension

The normal pressure in the pulmonary artery is 20/12 mm Hg (mean, 15 mm Hg) at sea level and 38/14 mm Hg (mean, 25 mm Hg) at approximately 15,000-feet altitude. In general, a mean arterial pressure of 20 mm Hg at sea level is considered abnormal, whereas at 15,000 feet, a pressure of 25 mm Hg is considered abnormal. Pulmonary hypertension is defined clinically as a mean pulmonary artery pressure at rest of greater than 25 mm Hg, or a mean pressure greater than 30 mm Hg during exercise.¹⁰ Pulmonary hypertension may be a manifestation of a primary pulmonary vascular disease, or may be secondary to other (nonvascular) diseases in the lung, but the morphologic patterns seen in the vessels in pulmonary hypertension are fairly limited, and, thus, clinical correlation is required for a specific diagnosis.

A variety of schemes for classification of pulmonary hypertension have been proposed.^2,¹¹^–¹⁷ Box 11-1 shows a recent clinical classification, commonly called the 2003 Venice classification.¹⁷ This classification has replaced the older term primary pulmonary hypertension with the terms idiopathic and familial to recognize the occurrence of genetic mutations in the bone morphogenetic protein receptor 2 (BMPR2) gene in many cases. A problematic aspect of this classification is the inclusion of pulmonary veno-occlusive disease (PVOD) and pulmonary capillary hemangiomatosis (PCH) in the general category of pulmonary arterial hypertension on the basis of dubious claims that these entities can show all the changes of classic idiopathic pulmonary arterial hypertension, including plexiform lesions (see the sections “Pulmonary Veno-Occlusive Disease” and “Pulmonary Capillary Hemangiomatosis” later in the chapter), and on the basis of a handful of reports of cases with BMPR2 mutations.¹⁸ Since PVOD and PCH patients often develop pulmonary edema after vasodilator therapy and have a worse outcome than patients in Venice categories 1.1 to 1.3,¹⁸ we believe there is considerable logic in maintaining PVOD and PCH in a separate group (see the section “Treatment of Pulmonary Hypertension” later in the chapter).

Box 11-1 The Venice 2003 Clinical Classification of Pulmonary Hypertension

From Simonneau G, Galiè N, Rubin LJ, et al. Clinical classification of pulmonary hypertension. J Am Coll Cardiol. 2004;43(12 suppl):5S–12S.

2. Pulmonary hypertension associated with left heart disease

2.1. Left-sided atrial or ventricular disease

2.2. Left-sided valvular disease

3. Pulmonary hypertension associated with lung diseases and/or hypoexemia

3.1. Chronic obstructive pulmonary disease

3.2. Interstitial lung disease

3.3. Sleep-disordered breathing

3.4. Alveolar hypoventilation disorders

3.5. Chronic exposure to high altitude

3.6. Developmental abnormalities

4. Pulmonary hypertension due to chronic thrombotic and/or embolic disease

4.1. Thromboembolic obstruction of proximal pulmonary arteries

4.2. Thromboembolic obstruction of distal pulmonary arteries

4.3. Non-thrombotic pulmonary embolism (tumor, parasites, foreign material)

5. Miscellaneous: sarcoidosis, Langerhans cell histiocytosis, lymphangiomatosis, compression of pulmonary vessels by adenopathy, tumor, fibrosing mediastinitis

Partly for these reasons, we have not adopted the new pathologic classification of pulmonary hypertension arising from the 2003 Venice meeting,¹⁹ but prefer the older and more generally accepted scheme shown in Box 11-2. Some authors have argued that there is no real difference between thrombotic and plexogenic arteriopathy, largely because thrombotic lesions may be found in both.¹⁴ However, we believe, as Wagenvoort and Mulder²⁰ have argued, there are generally clear clinical and morphologic differences among the entities shown in Box 11-2, and that thrombosis is a secondary phenomenon in most types of pulmonary hypertension (see later on).

Box 11-2 Pathologic Classification of Pulmonary Hypertension

Associated with interstitial lung disease, emphysema, or other intrinsic lung diseases

Associated with chronic hypoxia

Pulmonary venous hypertension

Left-sided cardiac disease, especially mitral stenosis

Atrial myxomas

Sclerosing mediastinitis

Congenital cardiac malformations affecting venous outflow

Pulmonary veno-occlusive disease

Pulmonary capillary hemangiomatosis

Plexogenic Arteriopathy

Clinical Features

The features of pulmonary hypertension in general are very nonspecific. Patients typically describe progressive shortness of breath, which is particularly marked during exercise. Syncopal episodes, presumably related to cardiac arrhythmias, may occur. Chest pain is usually a sign of right-sided cardiac ischemia and is seen late in the course in those who develop cor pulmonale. Similarly, abdominal discomfort is a sign of right-sided heart failure with progressive liver congestion.

In pulmonary hypertension associated with anorectic agents, the pulmonary vascular lesions are associated with cardiac valvular lesions, predominately on the left side of the heart.^21,²² In those patients who develop their pulmonary hypertension in association with human immunodeficiency virus (HIV) disease, the majority can be directly related to HIV infection; other cofactors include liver disease and coagulation abnormalities. There is a wide age range of the affected population. The interval between HIV infection and clinical presentation of pulmonary hypertension may be up to 3 years, but after presentation the prognosis is poor.^23,²⁴