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). Some degree of vasoconstriction is seen in a minority of patients with PAH and is assessed during vasodilator testing (see below), and is also typically present in patients with PH associated with longstanding left ventricular dysfunction.
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 left-to-right intracardiac shunts), the vasculature is initially able to handle the augmented flow without any anatomic changes in the arteries or arterioles. However, in most patients with a significant left-to-right shunt over a prolonged period, the pulmonary arterial walls remodel and pulmonary arterial resistance increases. The precise mechanism by which chronically increased pulmonary blood flow leads to vascular remodeling is not known. Eventually, as a result of the high PVR, 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.
A final and especially common mechanism of PH is the 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 may be accompanied by an element of vasoconstriction, but is not accompanied by anatomic changes in the pulmonary arteries. However, structural changes are eventually seen, and measured PVR may be substantially increased. The major disorders that result in PH by this final mechanism are mitral stenosis and chronic left ventricular failure, with either preserved or reduced systolic function.
Pathology
Although PH is classified into different clinical categories (see Table 14.2), as the disease progresses and remodeling occurs, many of 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.
Pathologic features of pulmonary hypertension (PH):
1.Intimal hyperplasia and medial hypertrophy of small arteries and arterioles
2.Eventual obliteration of the lumen of small arteries and arterioles
3.Thickening of the walls of larger (elastic) pulmonary arteries
4.Right ventricular hypertrophy
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
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the vessel wall is not normally present, but with PH these vessels undergo “neomuscularization” of their walls (Fig. 14.1A). In addition, cells in the arteriolar intima proliferate. As a result of medial hypertrophy and encroachment of proliferating endothelial cells into the vessel, the luminal diameter is significantly decreased and the PVR becomes elevated. Ultimately, the lumen may be completely obliterated and the overall number of patent 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, slit-like vascular channels (see Fig. 14.1B and C). 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 (programmed cell death).
FIGURE 14.1 Histologic changes in pulmonary hypertension. A, Moderate-power
photomicrograph showing the thickened wall of a pulmonary arteriole (arrow). B,
Low-power photomicrograph showing a thickened artery (large arrow) with an
adjacent plexiform lesion (small arrows). C, Elastic stain highlights thickened
vessel walls (large arrow) and adjacent plexiform lesions (small arrows).
Source: (Courtesy Dr. Lester Kobzik.)
When PH becomes marked, other changes are commonly seen in the larger (elastic) pulmonary arteries. These vessels, which normally have much thinner walls than comparably sized vessels in the systemic circulation, develop thickening of the wall, particularly in the media. They also develop the types of atherosclerotic plaques generally seen only in the higher pressure systemic circulation.
Another finding that may develop in patients with PH of any cause is in situ thrombosis in the small pulmonary arterioles. It is likely that primary endothelial cell dysfunction causing loss of normal intraluminal antithrombotic mechanisms, as well as secondary endothelial damage and sluggish blood flow, contribute to in situ thrombus formation. Development of extensive in situ thrombosis will worsen the degree of PH by further compromising the pulmonary vascular bed.
The cardiac consequences of PH are manifest pathologically as changes in the right ventricular wall.
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The magnitude of the changes depends primarily on the severity and chronicity of the PH rather than the nature of the underlying disorder. The major finding is concentric hypertrophy of the right ventricular wall. If the right ventricle fails as a result of an increase in workload, then dilation of the right ventricle is observed.
Pathophysiology
The pathophysiologic hallmark of PH is, by definition, an increase in pressure within the pulmonary circulation. If the primary component of the vascular change occurs at the precapillary level in the pulmonary arteries or arterioles, as in the case of IPAH or cor pulmonale, pulmonary arterial pressures (both systolic and diastolic) rise, but the pressure within pulmonary capillaries remains normal. On the other hand, if PH is secondary to pulmonary venous and pulmonary capillary hypertension, as in the case of mitral stenosis or left ventricular dysfunction, pulmonary capillary pressure is elevated above its normal level. Of note, fluid leaks from the pulmonary capillaries and accumulates in the interstitium or alveolar spaces when either intracapillary pressures are elevated (cardiogenic pulmonary edema) or pulmonary capillary permeability is increased (noncardiogenic pulmonary edema; see Chapter 29). In contrast, patients with precapillary PH and with normal pulmonary capillary pressures typically do not develop pulmonary edema.
As the architectural changes of PH progress, both right ventricular and pulmonary arterial pressures rise because of increased PVR. Cardiac output usually remains normal early in the course of the process. When the right ventricle begins to fail, right ventricular end-diastolic pressure rises, and cardiac output may decrease as well. Right atrial pressure also rises, which may be apparent on physical examination of the neck veins as elevation in the jugular venous pressure.
Clinical features
Although the overall constellation of symptoms in patients with PH depends on the underlying disease, certain characteristic complaints can be attributed to the PH itself. Dyspnea on exertion and fatigue are frequently observed in all forms of PH, even in the absence of any gas exchange abnormalities. The mechanism of the dyspnea is likely due to activation of stretch receptors in the pulmonary arteries and right ventricle, which are stimulated as cardiac output increases with exertion. In patients with PH related to underlying parenchymal lung disease, it is often difficult to know how much of the dyspnea is due to the PH as opposed to the underlying lung disease. Cardiopulmonary exercise testing may be useful in partitioning the relative contributions of each process to the patient’s dyspnea. Patients may have substernal chest pain that is difficult if not impossible to distinguish from classic angina pectoris, particularly because the pain is frequently precipitated by exertion. In most instances, the chest pain is presumed to be related to the increased workload of the right ventricle and to right ventricular ischemia, although, in some cases, an enlarged pulmonary artery can compress the left main coronary artery and produce true left ventricular ischemia. If PH is severe and the right ventricle cannot overcome the high PVR to increase cardiac output with exertion, patients may experience exertional lightheadedness or frank syncope. These represent very poor prognostic signs.
Clinical features of pulmonary hypertension (PH):
1.Symptoms: dyspnea, substernal chest pain, fatigue, and syncope
2.Physical signs: loud pulmonic component of the second heart sound (P2), tricuspid insufficiency
murmur, prominent parasternal (right ventricular) impulse, right-sided S4 gallop; also, right-