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). 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 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. 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 the chronic 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 failure, 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 (non-cardiogenic pulmonary edema; see Chapter 28). 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 pulmonary vascular resistance. 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 to 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. When PH is severe and the right ventricle is failing, patients are unable to increase cardiac output with exertion and may experience exertional lightheadedness or frank syncope. These are very poor prognostic signs.

Physical examination shows several features more related to the cardiac consequences of PH than to actual disease of pulmonary vessels. PH itself does not cause any changes that can be noted on examination of the lungs, although patients with underlying lung disease often have findings related to their primary disease. On cardiac examination, patients frequently exhibit an accentuation of the pulmonic component of the second heart sound (P₂) because of earlier and more forceful valve closure attributable to high pressure in the pulmonary artery. A murmur of tricuspid insufficiency is commonly heard, and a pulmonic insufficiency (Graham Steell) murmur may be appreciated. When the pulmonary artery is enlarged, a pulsation may be felt at the left upper sternal border (pulmonary artery tap). With right ventricular hypertrophy, there is often a prominent lift or heave of the region immediately to the left of the lower sternum, corresponding to a prominent right ventricular impulse during systole. As the right atrium contracts and empties its contents into the poorly compliant, hypertrophied right ventricle, a presystolic gallop (S₄) originating from the right ventricle may be heard. When the right ventricle fails, a mid-diastolic gallop (S₃) in the parasternal region is frequently heard, and the jugular veins become distended. At this stage, both lower extremity peripheral edema and ascites may develop.

Diagnostic Features

Echocardiography is usually the first test to suggest a diagnosis of PH. Key findings are right ventricular hypertrophy and elevated right ventricular systolic pressure by Doppler estimates. Detailed description of these echocardiographic techniques is beyond the scope of this chapter but can be found in standard cardiology textbooks.

Definitive diagnosis of PH and precise quantification of its hemodynamics require cardiac catheterization. Measurements of right ventricular, pulmonary arterial, and pulmonary capillary wedge pressures are important in confirming the diagnosis, determining disease severity, and assessing the response to acute vasodilator testing to guide the patient’s subsequent management (see Chapter 12 for discussion of pulmonary artery catheterization).

Clues to the status of the pulmonary vessels can be provided by chest radiography in some patients. With mild PH originating at the arterial or arteriolar level, frequently no abnormalities are seen. As PAH becomes more significant, the central (hilar) pulmonary arteries increase in size, and the vessels often rapidly taper such that the distal vasculature appears attenuated (Fig. 14-2). With hypertrophy of the right ventricle, the cardiac silhouette may enlarge. This feature is most apparent on the lateral radiograph, which shows bulging of the anterior cardiac border.

When PH is a consequence of either increased flow to the pulmonary vasculature (as in congenital heart disease with initial left-to-right shunting) or increased back pressure from the pulmonary veins and pulmonary capillaries (as in mitral stenosis or left ventricular failure), the findings are significantly different. In the case of congenital heart disease with left-to-right shunting, the pulmonary vasculature is prominent due to increased blood flow until reversal of the left-to-right shunt occurs. When there is elevation of pulmonary venous pressure from mitral stenosis or left ventricular failure, the chest radiograph often shows redistribution of blood flow from lower to upper lung zones, accompanied by evidence of interstitial or alveolar edema.

Computed tomographic angiography (CTA) or perfusion lung scanning can be valuable adjuncts in the assessment of patients with PH, primarily to look for chronic thromboembolic disease. CT scanning can also identify occult parenchymal disease not evident on chest radiograph (see Chapters 3 and 13). When CTA or perfusion scanning is positive, pulmonary angiography may be used to confirm the diagnosis and assess the surgical accessibility of the obstructing lesions.

When evaluating the patient with PH, pulmonary function tests are useful primarily for detecting underlying airflow obstruction (from COPD) or restricted lung volumes (from interstitial lung disease). As a result of the PH itself and loss of the pulmonary vascular bed, the diffusing capacity may be decreased and often may be the only other abnormality noted.

Arterial blood gas analysis is highly useful for determining whether hypoxemia or acidosis plays a role in PH pathogenesis. Arterial PO₂ may be mildly decreased as a result of pulmonary vascular disease, apparently because of nonuniform distribution of disease and ventilation-perfusion mismatch.

Specific Disorders Associated with Pulmonary Hypertension

PH is currently classified according to the scheme given in Table 14-1, which is very useful in categorizing patients based on clinical aspects of their disease. It is important to recognize, however, that there is much pathophysiologic overlap among the categories, and as we better understand the pathobiology of PH, the classification system will likely evolve.

Numerically, PH is most often related to either left heart failure or parenchymal lung disease (most commonly COPD). Whether treatment directed specifically at PH is beneficial in these disorders is an area of active research. In contrast, patients with IPAH and some other types of PAH now have a variety of medications that can be used for effective treatment.

References