sided S3 gallop, jugular venous distention, and peripheral edema in the case of right ventricular failure
Physical examination shows several features more related to the cardiac consequences of PH than to actual disease of the 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 between the ribs at the left upper sternal border (pulmonary artery tap). With right ventricular hypertrophy, there is often a prominent lift or heave in 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. Both lower extremity peripheral edema and ascites may develop.
Diagnostic features
Echocardiography is usually the first test to suggest a diagnosis of PH. When PH is present, echocardiography can also often identify if left-sided cardiac disease is responsible. Key findings of PH are right ventricular hypertrophy and elevated right ventricular and pulmonary artery systolic pressures by Doppler estimates. A detailed description of these echocardiographic techniques is beyond the scope of this chapter, but can be found in standard cardiology textbooks.
The definitive diagnosis of PH and the precise quantification of its hemodynamics require cardiac catheterization. Measurements of right ventricular, pulmonary arterial, pulmonary capillary wedge, and in some cases left ventricular end-diastolic pressures are important in confirming the diagnosis, determining the 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, abnormalities are not usually seen. As PAH becomes more significant, the central (hilar) pulmonary arteries increase in size, and the vessels often rapidly taper, so the distal vasculature appears attenuated (Fig. 14.2). With hypertrophy of the right ventricle, the cardiac silhouette may enlarge (Fig. 14.3A). This feature is most apparent on the lateral radiograph, which shows bulging of the anterior cardiac border that is formed by the right ventricle (Fig. 14.3B).
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FIGURE 14.2 Chest radiograph of a patient with pulmonary hypertension attributable to recurrent thromboemboli. Central pulmonary arteries are large bilaterally, but rapid tapering of vessels occurs distally.
FIGURE 14.3 Chest radiograph of a patient with right ventricular enlargement due
to pulmonary hypertension. A, Posteroanterior (PA) view showing cardiomegaly. B,
Lateral view demonstrating bulging of the anterior cardiac border due to an enlarged
right ventricle (arrows).
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 the 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 a redistribution of blood flow from the lower to the upper lung zones, accompanied by evidence of interstitial or alveolar edema and small pleural effusions.
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. Computed tomography scanning can also identify occult parenchymal disease that is not evident on chest radiograph (see Chapters 3 and 13). When chronic thromboembolic disease is suspected and CTA or perfusion scanning is positive, conventional pulmonary angiography may be useful 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 the reduction of the functional pulmonary vascular bed, the diffusing
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capacity is often decreased and may be the only abnormality noted.
Pulmonary function tests may demonstrate underlying restrictive or obstructive disease. Tests may also show decreased diffusing capacity due to loss of the pulmonary vascular bed.
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 the nonuniform distribution of disease and the resultant worsened ventilationperfusion matching.
Specific disorders associated with pulmonary hypertension
PH is currently classified according to the scheme given in Table 14.2, which is very useful in categorizing patients based on clinical aspects of their disease. However, it is important to recognize that there is much pathophysiologic overlap among the categories, and as we better understand the pathobiology of PH, the classification system will likely evolve.
On a population basis, PH is most commonly the result of either left heart failure or parenchymal lung disease (most commonly COPD). Treatment directed specifically at PH has not been shown to be beneficial in these disorders. In contrast, patients with IPAH and some other types of PAH now have a variety of medications that can be used for effective treatment.
Idiopathic pulmonary arterial hypertension and related disorders (group 1 PAH)
In general, diseases categorized as PAH are associated with pathology primarily in the pulmonary vasculature, without accompanying lung or left-sided cardiac abnormalities to explain the elevated PVR. Unfortunately, the nomenclature can be confusing; according to convention, only diseases in Group 1 are termed PAH.
As noted earlier, IPAH was once referred to as primary PH and is a disease of unknown cause found most commonly in women (up to 80% of patients are female), with a mean age of 50 years at diagnosis. However, IPAH also occurs in children, teens, and adults of all ages and both sexes. The diagnosis of IPAH cannot be made until other causes of PH have been excluded. Other types of PAH have a pathologic appearance and clinical presentation similar to those of IPAH, but with an accompanying process or etiologic agent known to be associated with this disease pattern. Such underlying processes or agents include connective tissue disease (particularly systemic sclerosis, also termed scleroderma), portal hypertension accompanying cirrhosis, HIV infection, and exposure to certain drugs or toxins, especially methamphetamines. In the past, several appetite suppressants were associated with PH; they include aminorex (withdrawn from the market many years ago) and the drugs fenfluramine and dexfenfluramine (withdrawn from the market in 1997).
Often, idiopathic pulmonary arterial hypertension (IPAH) occurs in women, is associated with Raynaud syndrome, and has a poor prognosis.
IPAH, by definition, occurs as a sporadic (i.e., nonfamilial) disorder. However, PAH does occur as an inherited disease in 10% or more of all cases. When the disease has a familial basis, it is termed heritable PAH. Clinically, IPAH and heritable PAH are indistinguishable. Understanding the genetic basis of heritable PAH likely has relevance to the pathogenesis of sporadic nonfamilial cases of IPAH. In approximately 80% of patients with a familial basis to the disease, a germline mutation in the BMPR2
gene can be detected. The gene product of BMPR2 is a receptor in the transforming growth factor (TGF)- β superfamily. It has been proposed that under the proper conditions, the presence of the mutant BMPR2 leads to partial loss of an inhibitory effect of BMPR2 on vascular smooth muscle cell growth. The smooth muscle cell changes may also lead indirectly to endothelial cell injury and proliferation. Importantly, up to 20% of patients who present with no family history and apparently idiopathic disease have BMPR2 mutations. Once a mutation is found, the patient is considered to have heritable disease; thus, the distinction between idiopathic and heritable PAH is also evolving. More rarely, mutations in other genes involved in the TGF-β superfamily are identified in patients with PAH. Specifically, the genes for endoglin or activin receptor-like kinase type 1 are abnormal in many patients with PAH associated with the heritable disorder hereditary hemorrhagic telangiectasia.
Without treatment, the prognosis in IPAH is poor; patients frequently die within several years of diagnosis. Treatment has focused on the use of vasoactive medications—both vasodilators and antiremodeling agents—in an attempt to reduce PVR and pulmonary arterial pressure. Typically, before a particular medication is initiated, patients undergo acute vasodilator testing (commonly with inhaled nitric oxide) in the setting of right heart catheterization to assess the resulting immediate changes in pulmonary arterial pressure, cardiac output, and systemic blood pressure in a controlled setting. Patients who have some degree of reactivity (i.e., pulmonary arterial pressure and vascular resistance fall in response to an acute pulmonary vasodilator) generally have a better prognosis.
Historically, the first vasodilator medications shown to be effective in a small subset of patients were calcium channel antagonists, such as nifedipine and diltiazem, which are administered orally. These medications are still used but are indicated only in the small subset of patients (<10%) who normalize their pulmonary arterial pressure in response to acute vasodilator testing. Currently, four other classes of drugs are available specifically to treat PAH: prostacyclin derivatives, endothelin-1 receptor antagonists, phosphodiesterase inhibitors, and guanylate cyclase stimulators. Prostacyclin derivatives administered by continuous intravenous (e.g., epoprostenol and treprostinil) or subcutaneous (treprostinil) infusion have been associated with clinical and hemodynamic improvement as well as improved survival. The longterm effect of these drugs indicates that they reverse some of the vascular remodeling and proliferative changes in the pulmonary arterial system separate from their vasodilator effects. However, these drugs are extremely expensive, and the need for continuous infusion makes them inconvenient and logistically more difficult to administer than oral agents. The prostacyclin derivatives iloprost and treprostinil also can be administered by inhalation using specialized nebulizers. Selexipag, an orally active nonprostanoid agonist of the prostacyclin receptor, has more recently been approved for use.
The endothelin-1 receptor antagonists (bosentan, ambrisentan, and macitentan), the phosphodiesterase- 5 inhibitors (sildenafil and tadalafil), and a guanylate cyclase stimulator (riociguat) are available in pill form. The oral medications are attractive therapeutic alternatives, particularly in patients with less advanced disease.
Although not based on randomized trials, patients with IPAH may be placed on long-term anticoagulation therapy. The rationale is to decrease in situ thrombosis in the pulmonary arterial system. Some, but not all, observational data suggest that anticoagulation may improve survival, especially in patients with severe disease.
For some patients with debilitating disease and a poor response to therapy, lung transplantation or combined heart-lung transplantation is indicated. However, this form of therapy has very limited availability and does not offer long-term survival for most patients. A more detailed discussion of treatment options for patients with PAH is beyond the scope of this text; the reader is referred to the excellent review articles given in the Suggested Readings at the end of this chapter.
Pulmonary hypertension due to left heart disease (group 2 PH)
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Mitral stenosis and chronic left ventricular failure are the two disorders most frequently associated with pulmonary venous, and subsequently pulmonary arterial, hypertension. The resulting right ventricular hypertrophy is not included in the category of cor pulmonale because the underlying problem resulting in PH is clearly of cardiac, not pulmonary, origin.
With pulmonary venous hypertension, the pathologic and many of the clinical and diagnostic features are different from PAH in a relatively predictable way. Pathologically, dilated and tortuous capillaries and small veins may result from high pressures in the pulmonary veins and capillaries, along with chronic extravasation of red blood cells into the pulmonary parenchyma. During the process of handling the interstitial and alveolar hemoglobin, macrophages may become loaded with hemosiderin, which is a breakdown product of hemoglobin. These macrophages can be detected by appropriate staining of sputum for iron. Often, the alveolar walls have a fibrotic response, which is presumably secondary to the longstanding extravasation of blood, so a component of interstitial lung disease with fibrosis may be seen.
Long-standing pulmonary venous hypertension is associated with the extravasation of erythrocytes into the pulmonary parenchyma, hemosiderin-laden macrophages, and a fibrotic interstitial response.
As mentioned in the discussion of radiographic abnormalities, the presence of pulmonary venous hypertension adds several features to the chest radiograph, including the redistribution of blood flow to the upper lobes and interstitial and alveolar edema. Another frequent finding is Kerley B lines, which are small, horizontal lines extending to the pleura at both lung bases that reflect the thickening of, or fluid in, lymphatic vessels in the interlobular septa, which is a consequence of interstitial edema.
Radiographic evidence of pulmonary venous hypertension includes:
1.Redistribution of blood flow to the upper zones
2.Interstitial and alveolar edema
3.Kerley B lines
Treatment of these disorders revolves around attempts to optimize therapy for the cardiac disease and to decrease pulmonary venous and capillary pressures. The potential reversibility of PH depends on disease chronicity and the degree to which venous hypertension can be alleviated. Occasionally, a patient will have a persistent elevation in PVR even after the left-sided heart disease has been treated (e.g., a patient with long-standing mitral stenosis who has had valve replacement surgery). In these patients, treatment with therapies directed specifically at PAH may be effective in treating the PH.
Pulmonary hypertension due to lung disease and/or hypoxia (group 3 PH)
The most common causes of cor pulmonale are COPD and interstitial lung disease. Hypoxia is the single most important etiologic factor in patients with COPD. Other contributory factors include respiratory acidosis, which may worsen vasoconstriction; secondary polycythemia, a consequence of chronic hypoxemia, which further increases PAPs as a result of increased blood viscosity; and reduction of the pulmonary vascular bed caused by coexistent emphysema.
Any of the interstitial lung diseases, when relatively severe, may be associated with cor pulmonale. Major contributing factors appear to be loss of the vascular bed, as a result of the scarring process in the alveolar walls, and hypoxia. However, a subset of patients develops a disproportionate degree of pulmonary vascular disease, and these patients may progress to more severe PH.