Pulmonary hypertension is classified pathologically by the site of injury into precapillary, capillary, and postcapillary hypertension (Table 63.1). “Pulmonary arterial hypertension” is a term frequently used for precapillary pulmonary hypertension. Rare idiopathic diseases of pulmonary capillaries and veins (capillary hemangiomatosis and pulmonary venoocclusive disease, respectively) are considered subcategories of pulmonary arterial hypertension (PAH) (see Chapter 62), given the clinical overlap, and are therefore considered in this chapter.

PAH is frequently idiopathic (idiopathic pulmonary arterial hypertension, or iPAH). A similar clinicopathologic syndrome is seen with chronic increased pulmonary flow, such as in untreated ventricular or atrial septal defects. There are many noncardiac conditions that impart an increased risk for PAH, by mechanisms that are incompletely understood. These include primarily autoimmune connective tissue diseases, liver disease that results in portal hypertension, and drugs and toxins.

The histologic feature that is frequently seen several types PAH is the “plexiform lesion.” Although not always present, and often only focal, this lesion is generally absent in secondary pulmonary artery hypertension.

A pathogenetic link across these disorders has been long searched for, in the hopes of developing treatment strategies that are currently ineffective. Processes that have been implicated in the pathogenesis of PAH include vasoconstriction, endothelial dysfunction, smooth muscle cell proliferation, impaired endothelial cell apoptosis, mitochondrial dysfunction, inflammation, angiogenesis, right ventricular cardiomyocyte abnormalities, and metabolic abnormalities.¹

Idiopathic PAH is rare disease, occurring at a rate of about six per million. There is a female/male ratio of 1.7:1 with a mean age at diagnosis of 37 years.² By histologic subtype, the mean age was 16 years for primary pulmonary arteritis, and 21 to 34 years for plexogenic pulmonary arteriopathy, primary medial hypertrophy, and pulmonary venoocclusive disease.³

Symptoms include shortness of breath and decreased exercise tolerance. Auscultation reveals changes of increased right heart pressures, including systolic clicks and murmurs related to turbulent flow at the pulmonary valve. Increasing right heart failure results in jugular venous distention, pulsatile liver, hepatosplenomegaly, and ascites.

Most cases of PAH are idiopathic. Approximately 10% are familial, and depending on the population studied, 10% to 20% of patients have associations including portal hypertension (“portopulmonary hypertension”), autoimmune connective tissue disorders, and HIV infection.

Chest radiography is abnormal only late in the disease course. The main pulmonary arterial segment is prominent, the central hilar vessels are dilated, and the peripheral vascularity is diminished. Echocardiography is a good noninvasive tool to measure systolic pulmonary arterial pressure using peak tricuspid regurgitant jet velocity; however, it does not perfectly correlate with the gold
standard, right heart catheterization. Mean pulmonary arterial pressures >20 mm Hg are elevated (normal 9 to 18), and values of >40 are considered severe.

Multidetector computed tomography (CT) characterizes both the cardiovascular and parenchymal changes of pulmonary hypertension, which are especially prevalent in PAH associated with connective tissue diseases. An enlarged CT-determined mean pulmonary artery diameter of ≥29 mm has a high sensitivity and specificity for pulmonary hypertension, regardless of cause.⁴

Evaluation of right ventricular function is important for prognosis. By echocardiogram, increased right ventricular volume and decreased ejection fraction are indicative of right heart failure.⁴

The evaluation and diagnosis of pulmonary hypertension is generally made clinically. Wedge biopsy may occasionally be performed in cases of chronic venous hypertension from occult mitral valve disease, because of increased interstitial lung markings (see Chapter 64). PAH is an uncommon indication for lung transplantation, in which case the diagnosis is generally made, and a spectrum of histologic findings found.⁵

Autopsies are sometimes performed on patients with known idiopathic PAH, in which cases the pathologist will encounter the spectrum of vascular changes. The pathologist may initially identify a specific secondary cause, such as tumor microembolization resulting in clinically diagnosed PAH, at autopsy.⁶ Rarely, the initial diagnosis is made at forensic autopsy in patients with the initial presentation of sudden cardiac death.³

The primary finding at autopsy or explant in cases of primary pulmonary hypertension is that of dilatation of the proximal pulmonary arteries, including the pulmonary trunk and right and left main arteries. In addition to dilatation, there may be superimposed atherosclerotic change of fibrous plaques, fatty streaks, and calcified plaques.

The pathologic findings of PAH include nonspecific features of intimal thickening, medial hypertrophy, and extension of media into acinar arterioles, all of which may be secondary reaction to localized fibrosis or inflammation of any etiology.⁷ There are several grading systems, which are seldom used today, that were initially applied to PAH secondary to cardiac right-to-left shunts (Fig. 63.1). When diffuse, or if accompanied by plexiform lesions, these changes are characteristic of PAH (Figs. 63.2, 63.3, 63.4).

Histologic studies focusing on plexiform lesions have shown that the affected arteries in idiopathic PAH are pulmonary (without contribution of bronchial arteries) and most frequently 50 to 100 µm in diameter.⁹ Plexiform lesions occur at branch points of axial arteries (so-called supernumerary arteries), interlobular arteries associated with bronchioles, or more distal intra-acinar arterioles (unassociated with airways).^7,10 Arteritis and dilatation lesions are also in the spectrum of PAH with plexiform lesions.⁷ Arteritis occurs in about 10% of plexiform arteriopathy and may be the predominant finding (Fig. 63.5).^3,11

Thrombosis is common, and can be the predominant finding in PAH. When central, thrombi in most patients can be attributed to recurrent thromboembolism (chromic thromboembolic pulmonary hypertension, CTEPH, see Chapter 67). When thrombi are in smaller muscular arteries, usually with recanalization, they are presumed caused by in situ thrombosis. The characteristic lesion of recanalized thrombus in a distal vessel has been described as a “colander lesion.”⁷ Recanalized thrombi within distal pulmonary arteries <400 µm characterize a form of PAH lacking plexiform lesions termed “primary thrombotic pulmonary hypertension.”^3,12 In the WHO classification, thrombi in distal arteries are included in secondary thromboembolic pulmonary hypertension (Chapter 67).