Pathogenesis

A number of factors contribute to the pathogenesis of PH, both acutely and chronically. First, occlusion of a sufficient cross-sectional area of the pulmonary arteries by material (e.g., pulmonary emboli) within the vessels is an important factor (discussed in Chapter 13). In acute embolism, in which massive pulmonary emboli occlude more than half to two thirds of the vasculature, pulmonary arterial pressure is elevated. The right ventricle may dilate in response to its acutely increased workload because of insufficient time for hypertrophy to occur. In contrast, in chronic embolic disease, multiple and recurrent pulmonary emboli may elevate pulmonary arterial pressures during a period sufficient for right ventricular hypertrophy to occur.

Second, remodeling of the pulmonary arterial walls causing diminution of cross-sectional area is a potential factor. Disorders acting by this mechanism are characterized by intimal and medial changes (see Pathology) that lead to thickening of the arterial and arteriolar walls and narrowing or obliteration of the lumen. This group of disorders with pulmonary arterial pathology includes idiopathic pulmonary arterial hypertension (IPAH, formerly called primary pulmonary hypertension). The familial form of this condition, called heritable pulmonary arterial hypertension, in most cases is related to mutations of the gene on chromosome 2 that encodes the bone morphogenetic protein receptor type 2 (BMPR2). Abnormalities in this receptor are believed to lead to dysregulation of proliferative responses in the endothelium and pulmonary arterial smooth muscle cells, producing the well-described pathologic changes in small pulmonary arteries and arterioles (again, see Pathology). Lesions pathologically similar to those seen in IPAH are also observed in other conditions associated with PAH (e.g., scleroderma, portal hypertension, human immunodeficiency virus [HIV] infection) or with exposure to drugs and toxins (e.g., cocaine, methamphetamine, certain diet drugs). When compromise of the pulmonary vasculature and increased resistance to flow are sufficiently pronounced in these primary disorders of the vessel wall, the level of PH can be quite severe, both at rest and with exercise.

Third, the total cross-sectional area of the pulmonary vascular bed is compromised by parenchymal lung disease, with loss of blood vessels from either a scarring or a destructive process affecting the alveolar walls. Interstitial lung disease and emphysema can affect the pulmonary vasculature via this mechanism, although the underlying disorder in the parenchyma appears quite different. Because of the large capacity of the normal pulmonary vascular bed to accept increased blood flow, a large amount of the pulmonary vascular bed must be lost before resulting in an elevation in pulmonary arterial pressure. With these diseases, pulmonary arterial pressure commonly is relatively normal at rest but mildly to moderately elevated with exercise because of insufficient recruitment or distention of vessels to handle the increase in cardiac output.

A fourth mechanism of PH is vasoconstriction in response to hypoxia and, to a lesser extent, to acidosis. The importance of this mechanism is related to its potential reversibility when normal PO₂ and pH values are restored. In several causes of cor pulmonale, particularly chronic obstructive pulmonary disease (COPD), hypoxia is the single most important factor leading to PH and is potentially the most treatable. Acidosis, either respiratory or metabolic, causes pulmonary vasoconstriction and, although it is less important than hypoxia, may augment the vasoconstrictive response to hypoxia (discussed in Chapter 12).

A fifth mechanism is chronically increased blood flow through the pulmonary vascular bed. When flow through the pulmonary vascular bed is increased, as occurs in patients with congenital intracardiac (left-to-right) shunts, the vasculature is initially able to handle the augmented flow without any anatomic changes in the arteries or arterioles. However, over a prolonged period, the pulmonary arterial walls remodel, and pulmonary arterial resistance increases. Eventually, as a result of the high pulmonary vascular resistance, right-sided cardiac pressures may become so elevated that the intracardiac shunt reverses in direction. This conversion to a right-to-left shunt, commonly called Eisenmenger syndrome, is a potentially important consequence of an atrial or ventricular septal defect or a patent ductus arteriosus. The precise mechanism by which increased pulmonary blood flow leads to remodeling is not known.

A final and especially common mechanism of PH is elevation of pressure distally due to abnormalities at the level of the left atrium or left ventricle. This leads to progressive elevation of the “back-pressure,” first in the pulmonary veins and capillaries and then in the pulmonary arterioles and arteries. As is the case with PH induced by increased flow in the pulmonary vasculature, the initial elevation in pressure is not accompanied by anatomic changes in the pulmonary arteries. However, structural changes are seen eventually, and measured pulmonary vascular resistance may be substantially increased. The major disorders that result in PH by this final mechanism are mitral stenosis and chronic left ventricular systolic or diastolic failure.

Pathology

Although PH is classified into different clinical categories (see Table 14-1), as the disease progresses and remodeling occurs, the pathologic findings in the pulmonary arteries of patients with PH are similar regardless of the underlying cause. This section focuses on these general changes, which are particularly well illustrated in the lungs of patients with IPAH.

The most prominent abnormalities are seen in pulmonary arterial tree vessels with a diameter of less than 1 mm: the small muscular arteries (0.1–1 mm) and the arterioles (<0.1 mm). The muscular arteries show hypertrophy of the media, composed of smooth muscle, and hyperplasia of the endothelial cells that make up the intimal layer lining the vessel lumen. In the arterioles, a significant muscular component to the vessel wall is not normally present, but with PH, these vessels undergo “neomuscularization” of their walls (Fig. 14-1, A). In addition, the arteriolar intima proliferates. As a result of medial hypertrophy and encroachment of proliferating endothelial cells into the vessel, the luminal diameter is significantly decreased, and the pulmonary vascular resistance is elevated. Ultimately, the lumen may be completely obliterated and the overall number of small vessels greatly diminished. In some cases of severe PH, particularly when due to IPAH or secondary to congenital intracardiac shunts, cells originating in the vessel wall (smooth muscle cells, endothelial cells, and fibroblasts) will form so-called plexiform lesions, appearing as a plexus of small, slitlike vascular channels (Fig. 14-1, B). Although the pathogenesis of these lesions is not precisely understood, disordered endothelial cell growth has been documented in patients with IPAH. It appears likely that the endothelial cells in many patients with severe PH have acquired a dysfunctional pro-proliferative phenotype that is resistant to apoptosis (cell death).

When PH becomes marked, other changes are commonly seen in the larger (elastic) pulmonary arteries (Fig. 14-1, C