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C H A P T E R 78 Pulmonary HypertensionStuart Rich

NORMAL PULMONARY CIRCULATION, 1696Regulation of Pulmonary Vascular Tone and Blood

Flow, 1697

PATHOBIOLOGY OF PULMONARY ARTERIAL HYPERTENSION, 1697Cellular Pathology of Pulmonary Arterial

Hypertension, 1699Role of Genetics in Pulmonary Arterial

Hypertension, 1700

CLINICAL ASSESSMENT OF PATIENTS WITH SUSPECTED PULMONARY HYPERTENSION, 1701History, 1701Physical Examination, 1702Diagnostic Tests, 1702

CLASSIFICATION OF PULMONARY HYPERTENSION, 1706Pulmonary Arterial Hypertension, 1706Pulmonary Capillary Hemangiomatosis, 1711Pulmonary Venous Hypertension, 1711

Pulmonary Arterial Hypertension Associated with Hypoxic Lung Diseases, 1713

Pulmonary Hypertension Caused by Chronic Thromboembolic Disease, 1714

Pulmonary Hypertension from Conditions with Uncertain Mechanisms, 1716

FUTURE PERSPECTIVES, 1717

REFERENCES, 1717

Normal Pulmonary CirculationThe lung has a unique double arterial blood supply from the pulmo-nary and bronchial arteries, as well as double venous drainage into the pulmonary and azygos veins.1 Each pulmonary artery accompa-nies the appropriate-generation bronchus and divides with it down to the level of the respiratory bronchiole. The pulmonary arteries are classified as elastic or muscular. The elastic arteries are conducting vessels, highly distensible at low transmural pressure. As the arteries decrease in size, the number of elastic laminae decreases and smooth muscle increases. Eventually, in vessels between 100 and 500 µm, elastic tissue is lost from the media and the arteries become muscular. The intima of the pulmonary arteries consists of a single layer of endothelial cells and their basement membrane. The adventitia is com-posed of dense connective tissue in direct continuity with the peri-bronchial connective tissue sheath. The muscular arteries are 500 µm in diameter or smaller and are characterized by a muscular media bounded by internal and external elastic laminae. Arterioles are pre-capillary arteries smaller than 100 µm in outer diameter and com-posed solely of a thin intima and single elastic lamina. The alveolar capillaries are lined with a continuous layer of endothelium resting on a continuous basement membrane and focally connected to scattered pericytes located beneath the basement membrane. Within the respira-tory units, the pulmonary arteries and arterioles are centrally located and give rise to precapillary arterioles, from which a network of capil-laries radiates into the alveolar walls. The alveolar capillaries collect at the periphery of the acini and then drain into venules located in the interlobular and interlobar septa.

The bronchial circulation provides nutrition to the airways. The bronchial arteries ramify into a capillary network drained by bron-chial veins; some empty into the pulmonary veins, and the remainder empty into the systemic venous bed. The bronchial circulation there-fore constitutes a physiologic right-to-left shunt. Normally, blood flow through this system amounts to approximately 1% of the cardiac output; the resulting desaturation of left atrial blood is usually trivial. However, in some forms of pulmonary disease (e.g., severe bronchiec-tasis) and in the presence of many congenital cardiovascular malfor-mations that cause cyanosis, blood flow through the bronchial circulation can increase to as much as 30% of left ventricular output and produce a significant right-to-left shunt.

The pulmonary circulation is characterized by high flow and by low pressure and low resistance (Table 78-1) The normal pulmonary vascular bed offers less than 10% of the resistance to flow offered by the systemic bed and can be approximated as the ratio of pressure drop (ΔP, in mm Hg) to mean flow (Q, in liters per minute). The ratio can be multiplied by 80 to express the results in dyne-sec • cm−5, or

expressed in mm Hg/liter/min, which is referred to as a Wood unit. The calculated pulmonary vascular resistance in normal adults is 67 ± 23 (standard deviation, SD) dyne-sec • cm−5, or 1 Wood unit.

FETAL AND NEONATAL CIRCULATION. In the fetus, oxygenated blood enters the heart from the inferior vena cava and streams across the foramen ovale to the left atrium (see Chap. 65). Desaturated blood returns from the superior vena cava and into the right ventricle and pulmonary artery. Because the resistance of the pulmonary vascular bed in the collapsed fetal lung is extremely high, only 10% to 30% of the right ventricular output passes through the lungs, with the remain-der being shunted across the ductus arteriosus to the descending aorta and then back to the placenta. An abrupt change in the pulmo-nary circulation occurs at birth. With the first breath, expansion of the lungs and the abrupt rise in the partial pressure of oxygen (Po2) of blood lead to a reversal of pulmonary arteriolar vasoconstriction and stretching and dilation of muscular pulmonary arteries and arterioles, with a marked drop in vascular resistance. This decreased resistance facilitates a large increase in pulmonary blood flow and raises left atrial volume and pressure. The latter closes the flap valve of the foramen ovale, and interatrial right-to-left shunting ordinarily ceases within the first hour of life. Normally, the ductus arteriosus closes over the next 10 hours as a result of contraction of the thick smooth muscle bundles within its wall in response to rising arterial oxygen tension and a change in the prostaglandin milieu. Following the initial dra-matic fall in pulmonary vascular resistance at birth, a continuous decline occurs over the first few months of life, associated with thin-ning of the media of muscular pulmonary arteries and arterioles until the normal adult pattern is achieved.

AGING. In older adults, the main pulmonary artery becomes mildly dilated, and shallow atheromas may develop in the elastic pulmonary arteries. Mild medial thickening and eccentric intimal fibrosis may occur in the muscular pulmonary arteries; the capillaries become slightly thicker and the veins are frequently involved by intimal hya-linization, with mild luminal narrowing. Pulmonary artery pressure and pulmonary vascular resistance increase with advanced age. Changes in the pulmonary arteries are also affected by the reduced compliance of left ventricular filling with age that is reflected back in the pulmonary vascular bed.

EXERCISE. With moderate exercise, a large increase in pulmonary blood flow is normally accompanied by only a small increase in pulmonary artery pressure. Exercise results in an increase in left atrial pressure that is progressive with exercise intensity and accounts for most of the increase in observed pulmonary arterial pressure. This

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and development of pulmonary arterial hypertension (PAH). The response of smooth muscle cells in the pulmonary arteries to hypoxia begins within seconds. Hypoxia causes pulmonary vascular smooth muscle membrane depolarization and inhibition of potassium cur-rents (Kv 1.5 channels) as a result of changes in the membrane redox status. Increased calcium ion (Ca2+) entry into the vascular smooth muscle cells via Ca2+ (L-type) channels also mediates hypoxic pulmo-nary vasoconstriction. Within the cell, Ca2+ can be mobilized from the sarcoplasmic reticulum and mitochondrial membrane, or the inner aspect of the cell membrane. Pulmonary vascular tone is also modu-lated by the balance between local kinase and phosphatase activities.

Whereas acute hypoxia causes reversible changes in vascular tone, chronic hypoxia induces structural remodeling and is mediated by a number of growth factors. The endothelial cell manifests marked changes in permeability, coagulant, inflammatory, and protein syn-thetic capabilities in response to chronic hypoxic exposure. Distinct smooth muscle cell populations with membrane-bound receptors sen-sitive to hypoxic activation engage specific intracellular signaling pathways, conferring unique hypoxic proliferative responses. Vascu-lar endothelial growth factor (VEGF), an endothelial cell-specific mitogen, is upregulated during exposure to chronic hypoxia; this is thought to be a protective mechanism. Hypoxia-inducible factor-1α (HIF-1α) has been identified as a nuclear factor that is induced by hypoxia and bound to a site in the erythropoietin response element. HIF-1α represents a vital link between oxygen sensing, gene transcrip-tion, and the physiologic adaptation to chronic hypoxia in vivo. Expression of HIF-1α is tightly regulated by cellular oxygen tension. Acidosis increases pulmonary vascular resistance and acts synergisti-cally with hypoxia. In contrast, an increase in arterial Pco2 seems to exert no direct effect but rather operates by way of the induced increase in hydrogen ion concentration. Hypoxia and acidemia fre-quently coexist and their interaction, which is clinically important, follows a predictable pattern.

NITRIC OXIDE. Nitric oxide (NO) relaxes vascular smooth muscle by raising levels of cyclic guanosine monophosphate (cGMP).4 Endo-thelial NO synthase is found in the vascular endothelium of the normal pulmonary vasculature, where it generates NO to regulate vascular tone. Release of NO occurs in response to a multitude of physiologic stimuli, including thrombin and shear stress. In addition to its direct hemodynamic effects, NO inhibits platelet activation and confers an important antithrombotic property on the endothelial surface. NO also inhibits the growth of vascular smooth muscle cells and is probably involved in vascular remodeling in response to injury. NO is also important in the signal transduction of angiogenesis in that VEGF receptor activation results in increased NO production.

ADRENERGIC CONTROL. The pulmonary vasculature expresses both alpha and beta adrenoreceptors, which help regulate pulmonary vascular tone by producing vasoconstriction or vasodilation, respec-tively. Alpha1 adrenoreceptors in the pulmonary arteries have increased affinity and responsiveness to their agonists when com-pared with other vessels. The downstream signaling events in alpha1-adrenergic stimulation are an increase in Ca2+ levels and activation of protein kinase, which mediate vascular contractile and proliferative responses. The increased sensitivity of alpha1 adrenoreceptors to nor-epinephrine in the pulmonary arteries may facilitate local regulation of vascular tone in response to acute changes in oxygen concentra-tions, thereby adjusting regional perfusion. Excessive stimulation of alpha1-adrenergic receptors produces smooth muscle contraction, pro-liferation, and growth.

Pathobiology of Pulmonary Arterial HypertensionBy definition, the precise cause of idiopathic pulmonary arterial hypertension (IPAH) is unknown, but it likely represents the clinical expression of PAH as the final common pathway from

marked effect of downstream pressure on upstream pressure is unique to the lung circulation. Because of the high vascular compliance in the normal lung microcirculation, an increase in left atrial pressure that results from the increased flow will act to distend the small vessels, contributing to the fall in pulmonary vascular resistance during exercise.

ALTITUDE. Life at high altitudes is associated with pulmonary hyper-tension of variable severity, reflecting the range of susceptibilities of different persons to the pulmonary vasoconstrictive effect of chronic hypoxia. Altitude decreases the inspired Po2 because of a decrease in barometric pressure. At sea level, Po2 is on average 150 mm Hg. At high altitudes (3000 to 5500 m), Po2 decreases to 80 to 100 mm Hg and, and at extreme altitudes (5500 to 8840 m), Po2 decreases to 40 to 80 mm Hg. Corresponding alveolar Po2 (Pao2) and arterial Po2 (Pao2) depend on the hypoxic ventilatory response and associated respiratory alkalosis. Mild pulmonary hypertension in adults living at high altitudes occurs at rest and may increase substantially with exer-cise.2 It is not immediately reversed by breathing of oxygen, does not seem to limit exercise capacity, and is rarely the cause of right ven-tricular failure. Severe pulmonary hypertension may occur with high-altitude pulmonary edema, subacute mountain sickness, and chronic mountain sickness. Transient right ventricular dysfunction has also been described with strenuous exercise at high altitudes.

Regulation of Pulmonary Vascular Tone and Blood Flow

ALVEOLAR OXYGENATION. Changes in alveolar oxygenation affect the small pulmonary arteries and arterioles by direct gaseous diffusion from the alveoli, respiratory bronchioles, and alveolar ducts in the pulmonary arterioles, even though the latter are upstream in relation to the alveoli. This fact, taken together with evidence for a reduction in pulmonary arterial blood volume during hypoxia, sup-ports the view that the small pulmonary arteries and arterioles are the main sites of vasoconstriction and increased resistance in the pulmo-nary circulation during hypoxia. Although alveolar oxygen tension is a major physiologic determinant of pulmonary arteriolar tone, a reduction in oxygen tension in the mixed venous blood flowing through the small pulmonary arteries and arterioles may also contrib-ute to pulmonary arterial vasoconstriction.3

The effect of oxygen on the pulmonary vasculature is the most distinctive characteristic by which it differs from the systemic vascula-ture. The hypoxic pulmonary vasoconstrictor response is an important adaptive mechanism in human physiology. Alveolar hypoxia results in local vasoconstriction so that blood flow is shunted away from hypoxic regions toward better ventilated areas of the lung, improving the ventilation-perfusion matching in the lung. Although the acute effects of this response are beneficial, chronic hypoxemia can result in sus-tained elevation of pulmonary artery pressure, vascular remodeling,

TABLE 78-1  Hemodynamic Comparison of the Pulmonary and Systemic Circulations

PARAMETER

Pulmonary Circulation

Systemic Circulation

RANGE MEAN RANGE MEAN

Arterial pressure, mm Hg 25/10 15 120/80 90

Capillary pressure, mm Hg 6-9 7 10-30 17

Venous pressure, mm Hg 1-4 2 0-10 6

Arterial M/D ratio, %* 3-7 5 15-25 20

Venous M/D ratio, %* 2-5 3 3-6 5

Vascular resistance, units 1-4 3 10-25 15

Blood flow, liter/min 4-6 5 4-6 5* M/D ratio = ratio of the medial thickness to the external diameter of the vessel.

CH 78

1698VASOCONSTRICTION. The initial report of a patient with IPAH demonstrated a reversible fall in PA pressure in response to intrave-nous vasodilators. As a result, PAH has traditionally been thought of as a disease of inappropriate pulmonary vasoconstriction. However, clinical experiences from multiple registries and large referral centers have documented that reversible vasoconstriction plays an important role in less than 20% of patients with PAH.13 Although it has not been possible to relate the presence of vasoreactivity specifically to the vascular changes noted on histology, one study reported a qualitative relationship in patients, showing that those with more advanced lesions had a reduced likelihood to respond to acute vasodilator testing.

An important concept in the pathobiology of PAH is that the disease develops in patients with an underlying genetic predisposition follow-ing exposure to specific stimuli, which serve as triggers. The finding of increased pulmonary vascular reactivity and vasoconstriction in patients with IPAH suggests that a vasoconstrictive tendency under-lies the development of IPAH in predisposed individuals. Voltage-dependent and calcium-dependent potassium channels found throughout the pulmonary vascular bed (see Chap. 52) modulate pul-monary vascular tone. Inhibition of the voltage-regulated potassium channel by hypoxia or drugs can produce vasoconstriction and has been described in PASMCs harvested from patients with IPAH.14 It has been suggested that abnormalities in the potassium channel of PASMCs are involved in the initiation or progression of pulmonary hyperten-sion15 (Fig. 78-2).

VASCULAR PROLIFERATION. A striking feature of the pulmonary vasculature in patients with PAH is intimal proliferation, which in some vessels causes complete vascular occlusion. Several growth factors have been implicated in the development of this type of vascular pathology. Enhanced growth factor release, activation, and intracellular signaling may lead to PASMC proliferation and migration, as well as extracellular matrix synthesis.16 Even advanced lesions show evidence of in situ activity of ongoing synthesis of connective tissue proteins such as elastin, collagen, and fibronectin. In PAH, PASMCs have abnor-malities that favor decreased apoptosis and enhanced proliferation. The impaired apoptosis appears to be multifactorial, related to abnor-mal mitochondrial hyperpolarization, activation of transcription factors such as HIF-1α17 and the nuclear factor of activated T cells (NFAT),18 and de novo expression of the antiapoptotic protein sur-vivin.19 The PASMCs in PAH also display excessive proliferation in response to transforming growth factor-β (TGF-β), which is exacer-bated by impaired smooth muscle cell apoptosis.20 Other processes,

multiple biologic abnormalities in the pulmonary circulation.5 Our understanding of the underlying pathobiology of pulmonary hyperten-sion associated with clinical disease states has become increasingly complex as a multitude of genetic and molecular pathways have been identified.6 Overall, it appears that varying degrees of thrombosis, vaso-constriction, vascular proliferation, and inflammation underlie chronic PAH. The initiating cell line remains unclear, but abnormalities in pul-monary endothelial cell (EC) function and pulmonary artery smooth muscle cells (PASMCs) may cause or contribute to the development of pulmonary hypertension in humans.7 Disease progression is invari-ably accompanied by worsening of cellular function, which itself can further promote disease progression.

THROMBOSIS. The observation that chronic warfarin anticoagula-tion has been associated with a marked survival advantage in several longitudinal studies lends support to the important role of thrombosis in PAH.8 Several lines of evidence point to the widespread develop-ment of in situ thrombosis of the small pulmonary arteries, with intra-luminal thrombin deposition as an important causative feature of PAH. In studies of pulmonary vascular histopathology in IPAH, the preva-lence rates of thrombotic lesions were more than 50%.9 The promotion of PAH through the coagulation and fibrinolytic systems is likely a result of endothelial dysfunction. Thrombin appears to play a key role. Receptors for thrombin are present on ECs and PASMCs. Thrombin activation directly upregulates angiogenesis-related genes, including VEGF, VEGF receptors, tissue factor (TF), basic fibroblast growth factor (bFGF), and matrix metalloproteinase-2, all of which have been reported to be increased in PAH.10,11 Thrombin indirectly upregulates the transcription of VEGF by inducing the production of reactive oxygen species (ROS) and the expression of the HIF-1α transcription factor. Thrombin also activates platelets.

There is increased expression of TF in the vasculature of patients with severe PAH. TF activation leads to rapid initiation of coagulation when a vessel is damaged and is involved in the migration and prolif-eration of PASMCs (Fig. 78-1). TF can induce angiogenesis by clotting-dependent mechanisms via thrombin generation and fibrin deposition.12 Plasma levels of fibrinopeptide A, a byproduct and marker of fibrin generation, are elevated in PAH patients.

Abnormalities in platelet activation and function also occur in PAH. In addition to promoting thrombosis, platelet activation leads to the release of granules that contain mitogenic and vasoconstrictive sub-stances, including VEGF, bFGF, platelet-derived growth factor (PDGF), and serotonin, which contribute to increased endothelial cell prolifera-tion and migration.

FIGURE 78-1 Molecular mechanisms of thrombosis-mediated remodeling. Induction of tissue factor (TF) is exemplified in an endothelial cell. Various mediators induce TF expression through activation of their receptors. Induction of TF primarily occurs at the transcriptional level, resulting in an increase in TF mRNA and, eventually, in TF protein expression. TF is distributed in three cellular pools as cytoplasmic TF, surface TF, and encrypted TF. Moreover, TF-containing microparticles are released from the cell. Alternative splicing results in a soluble secreted form of TF (asTF). CD40-L = CD40-ligand; H1 = histamine H1 receptor; 5-HT2a = 5-hydroxytryptamine 2a receptor; IL-1-R = interleukin-1 receptor; KDR = VEGF receptor 2; LPS = lipopolysaccharide; PAR = protease-activated receptor; TLR-4 = Toll-like receptor 4; TNF-R = tumor necrosis factor receptor. (From Steffel J, Lüscher TF, Tanner FC: Tissue factor in cardiovascular diseases: Molecular mechanisms and clinical implications. Circulation 113:722, 2006.)

Histamine ThrombinIl-1β

Il-1-R

H1

5-HT2a

TNF-R PAR KDR

CD40-L

CD40TLR-4

Serotonin LPS VEGF TF-bearingmicroparticles

TF pool

asTF

Surface TFEncrypted TF

TNF-α

Cytoplasm Nucleus

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with connective tissue diseases (CTDs; see Chap. 89), indicate a role for vascular inflammation leading remodeling of the vessel in PAH25,26 (Fig. 78-4). Macrophages and both T and B lymphocytes are present in the vascular lesions of IPAH and PAH related to CTD and human immunodeficiency virus (HIV; see Chap. 72). Inflammatory infiltrates have been identified in plexiform lesions in the lungs of patients with severe IPAH and mononuclear inflammatory cells surround vascular sites of plexiform growth in patients with scleroderma-related PAH. Autoantibodies from patients with CTD have been shown to induce upregulation of immunoactive molecules, such as intercellular adhe-sion molecule-1, endothelial leukocyte adhesion molecule-1, and major histocompatibility complex class II, on human pulmonary ECs. The nuclear factor of activated T-cells (NFAT) increases the transcrip-tion of multiple inflammatory mediators and activating T and B cells.18 NFAT activation causes myocardial downregulation of Kv1.5, and NFATc2-activated circulating inflammatory cells are found in the blood and pulmonary arterial wall in PAH patients. Several interleukins and tumor necrosis factor-α are increased in patients with PAH,27 and many of these cytokines are regulated by NFAT.

Inflammation has been observed in affected vessels in HIV patients with PAH, although development of severe PAH seems to be unrelated to the degree of immune deficiency. HIV patients with PAH also had significantly higher autoantibody levels than a matched HIV non-PAH control group. Similarly, the presence of circulating chemokines and cytokines, viral protein components (e.g., HIV-1 Nef), and increased expression of growth factors (e.g., VEGF, PDGF) in these patients are thought to contribute directly to further recruitment of inflammatory cells.28 Many IPAH patients without immunodeficiency or other associ-ated systemic diseases have evidence of autoimmunity and/or active inflammation. These include detectable levels of antinuclear antibod-ies, elevated serum levels of the proinflammatory cytokines interleukin-1 (IL-1) and IL-6, and increased pulmonary expression of PDGF or mac-rophage inflammatory protein-1. Clinically, there is also an association of IPAH with autoimmune thyroid disease

Cellular Pathology of Pulmonary Arterial HypertensionMorphologic abnormalities in each cell line of the pulmonary vascu-lature have been described in PAH29 (Fig. 78-5). Although endothelial dysfunction has been described in PAH, it is not known at what stage during the evolution of PAH that EC proliferation occurs. It has been proposed, however, that a somatic mutation rather than nonselective cell proliferation in response to injury accounts for the growth advan-tage of ECs in patients with IPAH. Heterogeneity in the PASMC and fibroblast populations also contributes to discordance between phe-notype and function. Interconversion between cell types (fibroblast to smooth muscle cell, or endothelium to smooth muscle cell), in addi-tion to neovascularization, may occur. PASMC hypertrophy and increased connective tissue and extracellular matrix are found in the large muscular and elastic arteries. In the subendothelial layer, increased thickness may be the result of recruitment and/or prolifera-tion of smooth muscle-like cells. It is possible that precursor smooth muscle cells are in a continuous layer in the subendothelial layer along the entire pulmonary artery. These cells are similar to the pericytes responsible for the appearance of muscle in normally nonmuscular arteries and that contribute to intimal thickening in larger arteries. Alterations in the extracellular matrix secondary to proteolytic enzymes also play a role in the pathology of PAH. Matrix-degrading enzymes can release mitogenically active growth factors that stimulate PASMC proliferation. In addition, elastase and matrix metalloprotein-ases contribute to the upregulation of proliferation. Degradation of elastin has also been shown to stimulate upregulation of the glycopro-tein fibronectin, which in turn stimulates smooth muscle cell migration.

The most common vascular changes in PAH are characterized as a hypertensive pulmonary arteriopathy, which is present in 85% of cases (Table 78-2). These changes involve medial hypertrophy of the arter-ies and arterioles, often in conjunction with other vascular changes. Isolated medial hypertrophy is uncommon and, when present, has

such as mitochondrial and ion channel dysregulation, seem to convey a state of cellular resistance to apoptosis; this has recently emerged as a necessary event in the pathogenesis of pulmonary vascular remodeling.

Animal and human data point to a key role for serotonin in PAH (Fig. 78-3). Serotonin is an important constituent of platelet-dense granules and is released on activation. It is a vasoconstrictor that pro-motes smooth muscle cell hypertrophy and hyperplasia by exerting mitogenic effects on PASMCs.21 Elevated plasma levels of serotonin and reduced platelet serotonin concentration have been described in IPAH patients. One series reported increased serotonin levels in patients with PAH associated with the use of fenfluramine and with connective tissue disease. Data indicate that the serotonin transporter (SERT) in the lung is a key determinant of pulmonary vessel remodel-ing because of its effects on PASMC growth.22,23 The SERT is abundantly expressed in the lung and appears specific to PASMCs, because no similar effect has been reported with other SMC types. Mutations in the SERT and 5-hydroxytryptamine 2B receptor have now been reported in patients with IPAH.24

INFLAMMATION. The frequent association of PAH in well-defined inflammatory conditions, as well as the presence of PAH associated

FIGURE 78-2 Molecular mechanisms of vasoconstriction-mediated remodel-ing. The process may be initiated by abnormal gene transcription and expres-sion of Kv channels. Resultant reduction of Kv currents [IK(v)] causes membrane depolarization and opens voltage-gated Ca2+ channels. Increased Ca2+ influx through sarcolemmal Ca2+ channels and Ca2+-induced Ca2+ release from intra-cellular Ca2+ stores (mainly sarcoplasmic reticulum [SR]) raise cytoplasmic Ca2+ concentrations ([Ca2+]cyt), which triggers pulmonary vasoconstriction. An increase in [Ca2+]cyt would also increase nuclear Ca2+ concentration ([Ca2+]n) and stimulate cell proliferation, which causes pulmonary vascular remodeling. Endothelium-derived relaxing factors (EDRFs) may participate in regulating Em and [Ca2+]cyt through activation of K+ (KCa and Kv) channels and/or inhibition of voltage-gated Ca2+ channels in PASMCs. (+) = increase (or enhance); (−) = decrease (or inhibit). (From Yuan J, Aldinger A, Juhaszova M, et al: Dysfunctional voltage-gated K+ channels in pulmonary artery smooth muscle cells of patients with primary pulmonary hypertension. Circulation 98:1400, 1998.)

EDRF (+)

(–)

(–)

(–)

(–)

Gene expression of Kv channels ↓

Membrane depolarization

PASMC proliferation

Pulmonary vasoconstriction

PPH

Vascular remodeling

Open voltage-aged Ca2+ channels

Ca2+ influx ↑

SR Ca2+ release

[Ca2+]cyt ↑↑ [Ca2+]n

Number of functional Kv channels ↓

Function of Kv channels ↓

IK(V) ↓

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vasculature in various disease states. Examples include the consider-able variability among individuals to vasoconstrictive stimuli such as hypoxia or acidosis, which can produce marked pulmonary hypertension in one person and be essentially without effect in another. Also, the severity of pulmonary hypertension and level of pulmonary vascular resistance vary considerably among individuals with congenital heart disease and comparably sized ventricular septal defects.

Using linkage analysis, the locus designated PPH-1 on chromosome 2q33 led to the discovery of the PPH-1 gene.31 The bone morphoge-netic protein receptor type II gene (BMPR-II) codes for a receptor member of the TGF-β family (Fig. 78-7). BMPR-II modulates vascular cell growth by activating the intracellular pathways of Smad and LIM kinase. The mutations ascribed to the locus interrupt the BMP-mediated signaling pathway, resulting in a predisposition to proliferation rather than apoptosis of cells in small pulmonary arteries.32 These molecular studies have suggested that the target cells within the pulmonary arterial wall are sensitive to BMPR-II gene dosage and that the TGF-β pathway mediated through BMPR-II is critical for the mainte-nance and/or normal response to injury of the pulmonary vasculature. It is clear, however, that additional factors, environmental or genetic, are required in the pathogenesis of the disease.33 Recent data have supported the hypothesis that the dominant genetic mechanism underlying PAH is haploinsufficiency for BMPR-II.34 How defects in BMPR-II contribute to EC proliferation, PASMC hypertrophy, and fibro-blast deposition in patients with PAH remains unclear. It is interesting to note that about one in four cases of IPAH actually have germline mutations in the gene encoding the BMPR-II receptor.35 Patients with hereditary hemorrhagic telangiectasia and IPAH have been described and found to have mutations of the ALK1 gene, also within the TGF-β superfamily.

been assumed to represent an early stage of the disease. The intimal proliferation may appear as concentric laminar intimal fibrosis, eccen-tric intimal fibrosis, or concentric nonlaminar intimal fibrosis. The frequency of these findings differs from case to case and within regions of the same lung in the same patient. In addition, plexiform and dilation lesions, as well as a necrotizing arteritis, may be seen throughout the lungs. The fundamental nature of the plexiform lesion remains a mystery. Morphologically, it represents a mass of disorga-nized vessels with proliferating ECs, PASMCs, myofibroblasts, and mac-rophages. Whether the plexiform lesion represents impaired proliferation or angiogenesis remains unclear (Fig. 78-6).

The other major pattern of vascular changes in PAH is that of a thrombotic pulmonary arteriopathy. Typical features include medial hypertrophy of the arteries and arterioles, with both eccentric and concentric nonlaminar intimal fibrosis. The presence of colander lesions, which represent recanalized thrombi, is also typical. These lesions are believed to arise as a result of primary in situ thrombosis of the small vascular arteries and not from recurrent pulmonary embo-lism. Many patients have characteristics of both patterns of arteriopa-thy in varying degrees. This suggests that the vascular changes from PAH occur across a spectrum and are likely influenced by genetic and environmental factors.

Role of Genetics in Pulmonary Arterial HypertensionAn important concept in the development of PAH is that the disease develops in patients with an underlying genetic predisposition fol-lowing exposure to specific stimuli, which serve as triggers.30 Pre-disposition to the development of pulmonary hypertension has been noted by the marked heterogeneity in responses of the pulmonary

FIGURE 78-3 Molecular mechanisms of cellular proliferation–mediated remodeling. Serotonin synthesis via tryptophan hydroxylase 1 acts in a paracrine fashion on underlying PASMCs. Serotonin enters PASMC via SERT and signal transduction is initiated involving SERT-dependent generation of reactive oxygen species (ROS), rho kinase (ROCK), and mitogen-activated protein kinases (MAPK). This may contribute to contraction or, via nuclear translocation of pERK1/2, increase the expression of nuclear growth factors such as GATA 4, leading to proliferation. Serotonin may also stimulate 5-hydroxytryptamine (5-HT) 1A and 2B receptors to induce contrac-tion and ROS, ROCK, and MAPK activation. Signaling by wild-type BMPRII involves heterodimerization with the transmembrane serine-threonine kinases type I BMPR-IA and BMPR-IB receptors at the cell membrane. On ligand binding, the constitutively active BMPR-II phosphorylates the type I receptor. Activated type I receptors phosphorylate the cytoplasmic signaling proteins known as receptor-mediated Smads (R-Smads) 1, 5, and 8. These complex with Smad4 and translocate to the nucleus, where they activate downstream target genes such as the inhibitors of DNA binding 3 (Ids), which inhibit proliferation. Serotonin may antagonize the antiproliferative BMPR-II/Smad 1, 5, 8 pathway, inhibit Id3 activation, and facilitate proliferation. (−) = inhibitory effect. (From MacLean MR, Dempsie Y: Serotonin and pulmonary hypertension—from bench to bedside? Curr Opin Pharmacol 9:281, 2009.)

Serotonin

BMP

BMP

SERT

5-HT1B5-HT2A

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Activation of receptor I

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the L-allelic variant is found to be present in homozygous form in 65% of IPAH patients but in only 27% of control subjects.

Clinical Assessment of Patients with Suspected Pulmonary Hypertension

HistoryA careful and detailed history of the patient with suspected pulmo-nary hypertension is often revealing. Because the earliest symptoms in patients with pulmonary hypertension are manifest with exercise,

Other genetic factors that have been associated with PAH suggest that polymorphisms in other genes could contribute to the develop-ment of PAH. The overexpression of SERT in pulmonary arteries and platelets from patients with PAH has been reported, with the increased activity of SERT responsible for the associated PASMC hyperplasia.36 In addition, increased PASMC proliferation is related to SERT expression and activity in cultured PASMCs from patients with PAH. SERT is encoded by a single gene on chromosome 17q11.2, and a variant in the upstream promotor region of the SERT gene has been described. This polymorphism, with long (L) and short (S) forms, affects SERT expression and function, with the L allele inducing a greater rate of SERT gene transcription than the S allele. One study has shown that

FIGURE 78-4 Molecular mechanisms of inflammation-mediated remodeling. This schematic features inflammatory mediators, cells, and mechanisms involved in pulmonary vascular remodeling as well as potential therapeutic targets. Release of cytokines and chemokines in remodeled vessels (e.g., plexiform lesions) or in the circulation, from activated ECs and smooth muscle cells (SMCs), mediate the influx of inflammatory cells (e.g., monocytes, T and B lymphocytes). Cellular dysfunction (particularly involving ECs and SMCs) contributes to the release of vasomotor and growth mediators, activation of transcriptional factors (e.g., nuclear factor of activated T lymphocytes [NFAT]), influx of calcium, and mitochondrial dysfunction. The net effect is a shift of balance in favor of cell proliferation and decreased apoptosis, leading to remodeling and narrowing of the pulmonary vascular lumen. Potential therapeutic target sites include inhibition of growth factors with tyrosine kinase inhibitors, calcineurin with cyclosporine, and prevention of NFAT activation with VIVIT polypeptide, a competitive peptide that inhibits the docking of NFAT to calcineurin. Specific mechanisms are detailed further in the text. bcl2 = B-cell lymphoma 2; CCL2 = chemokine (C-C motif ) ligand 2; CCL5 = chemokine (C-C motif ) ligand 5 or RANTES (regulated upon activation, normal T cell expressed and secreted); CX3CL1 = chemokine (C-X3-C motif ) ligand 1 (fractalkine); CX3CR1 = che-mokine (C-X3-C motif ) receptor 1; DC = dendritic cells; FB = fibroblasts; FGF = fibroblast growth factor; 5-HT = serotonin; HIV-1 = human immunodeficiency virus 1; IgG = immunoglobulin G; MO = monocyte; PGI2 = prostacyclin; ROK = rho kinase. (From Hassoun PM, Mouthon L, Barbera JA, et al: Inflammation, growth factors, and pulmonary vascular remodeling. J Am Coll Cardiol 54:S10, 2009.)

↑CX3CL1 expression↑CCL5/RANTES

↑CX3CR1 expression

↑Proliferation

↓Apoptosis

↑Vasoconstrictors (ET-1, 5-HT, TXA2,)↓Vasodilators (NO, PGI2)↑ Growth factors (PDGF, VEGF, FGF)

↑Bcl-2

Hyperpolarizedmitochondria

Nucleus

↑[Ca2+]cyt

↓Kv1.5↑CX3CR1 expression (CD4+/CD8+)

↑Circulating CCL2

Release of cytokines/chemokines Proliferation of vessel wall constituents

Influx of inflammatory cells and mediators

Cellular dysfunction

Endothelial cell (EC)

Smooth muscle cell (SMC)

Apoptotic EC

EC dysfunction

SMC dysfunction

Fibroblast (FB)

Dendritic cell (DC)

Monocyte (MO) Cyclosporine

Matrix remodeling/collagen deposition

VIVIT

Tyrosine kinaseinhibitors

Calcineurinactivation

NFATNFAT-PT-lymphocyte

B-lymphocyte

IgG

Viral component (HIV-1 net)

Collagen

Normal PAH

NFAT

↑Ca2+ channel function/expression↓K+ channel function/expression↑ RhoA/ROK activity

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right ventricular failure (e.g., hepatomegaly, peripheral edema, ascites) may be present. Patients with severe pulmonary hypertension may also have prominent v waves in the jugular venous pulse as a result of tricuspid regurgitation, third heart sound of right ventricular origin, a high-pitched early diastolic murmur of pulmonic regurgita-tion, and holosystolic murmur of tricuspid regurgitation. Tricuspid regurgitation is a reflection of right ventricular dilation. Cyanosis is a late finding and, unless the patient has associated lung disease, is usually attributable to a markedly reduced cardiac output, with sys-temic vasoconstriction and ventilation-perfusion mismatch in the lung. Uncommonly, the left laryngeal nerve becomes paralyzed as a consequence of compression by a dilated pulmonary artery (Ortner syndrome).

Diagnostic TestsLABORATORY TESTS. The results of these studies (Table 78-3) are usually normal in patients with pulmonary hypertension. If chronic arterial oxygen desaturation exists, polycythemia should be present. Hypercoagulable states, abnormal platelet function, defects in fibrino-lysis, and other abnormalities of coagulation are found in some patients with PAH. Brain natriuretic peptide (BNP) levels are elevated in patients with pulmonary hypertension and correlate with the pul-monary artery pressure.38 Uric acid levels are elevated in patients with

pulmonary hypertension can have an insidious onset. With the onset of right ventricular failure, lower extremity edema from venous con-gestion is characteristic. Angina is also common, likely reflecting reduced coronary blood flow to a markedly hypertrophied right ventricle.37 As the cardiac output becomes fixed and eventually falls, patients may have episodes of syncope or near-syncope. Patients with pulmonary hypertension related to left ventricular diastolic dysfunction will characteristically have orthopnea and paroxysmal nocturnal dyspnea. Patients with underlying lung disease may also report episodes of coughing. Hemoptysis is relatively uncommon in patients with pulmonary hypertension and may be associated with underlying thromboembolism and pulmonary infarction. Some patients with advanced mitral stenosis also present with hemoptysis (see Chap. 66).

Physical ExaminationCardiovascular findings consistent with pulmonary hypertension and right ventricular pressure overload include a large a wave in the jugular venous pulse, low-volume carotid arterial pulse with a normal upstroke, left parasternal (right ventricular) heave, systolic pulsation produced by a dilated pulmonary artery in the second left interspace, ejection click and flow murmur in the same area, narrowly split second heart sound with a loud pulmonic component, and fourth heart sound of right ventricular origin. Late in the course, signs of

FIGURE  78-5 Vascular abnormalities associated with pulmonary hyperten-sion. Shown are the abnormalities throughout the pulmonary circulation, including abnormal muscularization of distal precapillary arteries (i), medial hypertrophy (thickening) of large pulmonary muscular arteries (ii), loss of pre-capillary arteries (iii), neointima formation that is particularly occlusive in vessels 100 to 500 µM in size (iv), and formation of plexiform lesions in these vessels (v). (From Rabinovitch M: Molecular pathogenesis of pulmonary arterial hyperten-sion. J Clin Invest 118:2372, 2008.)

Pulmonarycirculation

Lung

Loss ofsmallprecapillaryarteries

iii

ivNeointima formationInterrupted internal

elastic lamina

Medial hypertrophyof muscular arteries

ii

i Muscularizationof peripheral arteries

Internal elastic laminaExternal elastic lamina

SMCEC

v Plexiformlesionformation

TABLE 78-2  Histopathologic Classification of Hypertensive Pulmonary Vascular Disease

CLASSIFICATION CHARACTERISTIC FEATURES

ArteriopathyIsolated medial

hypertrophy*Medial hypertrophy—increase of medial

muscle in muscular arteries, muscularization of nonmuscularized arterioles; no appreciable intimal or luminal obstructive lesions; no plexiform lesions

Plexogenic Plexiform and dilation lesions; medial hypertrophy; pulmonary eccentric or concentric laminar and nonlaminar arteriopathy, arteriopathy, intimal thickening; fibrinoid necrosis, arteritis, and thrombotic lesions

Thrombotic Thrombi (fresh, organizing, or organized and pulmonary colander lesions); eccentric and concentric nonlaminar arteriopathy, intimal thickening, varying degrees of medial hypertrophy; no plexiform lesions

Isolated pulmonary arteritis

Active or healed arteritis, limited to pulmonary arteries; varying pulmonary degrees of medial hypertrophy, intimal fibrosis, and thrombotic arteritis lesions; no plexiform lesions; no systemic arteritis

VenopathyPulmonary venoocclusive

diseaseEccentric intimal fibrosis and recanalized

thrombi in diseased pulmonary veins and venules; arterialized veins, capillary congestion, alveolar edema and siderophages, dilated lymphatics, pleural and septal edema, and arterial medial hypertrophy; intimal thickening and thrombotic lesions

MicroangiopathyPulmonary capillary

hemangiomatosisInfiltrating thin-walled blood vessels

throughout pulmonary parenchyma, pleura, bronchi, and walls of pulmonary veins and arteries; medial hypertrophy and intimal thickening of muscular pulmonary arteries and arterioles

* Medial hypertrophy includes muscularization of arterioles.From Pietra GG: Pathology of primary pulmonary hypertension. In Rubin LJ, Rich S (eds):

Primary Pulmonary Hypertension. New York, Marcel Dekker, 1997, pp 19-61.

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CHEST RADIOGRAPHY. A chest radiograph (see Chap. 16) shows enlargement of the main pulmonary artery and its major branches, with marked tapering of peripheral arteries. The right ventricle and atrium may also be enlarged. Dilation of the right ventricle gives the heart a globular appearance, but right ventricular hypertrophy or dila-tion is not easily discernible on a plain chest radiograph. Encroach-ment of the retrosternal air space on the lateral film may be a helpful

pulmonary hypertension and correlate with hemodynamics. Although the mechanism is uncertain, it may relate to overproduction and impaired uric acid excretion caused by the low cardiac output and tissue hypoxia. There is an increased incidence of thyroid disease in patients with PAH (see Chap. 86), which can mimic the symptoms of right ventricular failure.39 Consequently, it is advised that thyroid func-tion tests be monitored serially in all patients.

FIGURE 78-6 Photomicrographs of PA histologic lesions seen in cases of clinically unexplained pulmonary hypertension. A, Medical hypertrophy with intimal proliferation. The vascular lumen is markedly reduced, contributing to the elevated resistance. B, Eccentric intimal fibrosis. These are believed to be related to local thrombin deposition. C, Plexiform lesion demonstrating obstruction in the arterial lumen, aneurysmal dilation, and proliferation of anastomosing vascular channels. Hematoxolyn and cosin stains. A and B, magnification ×20; C, magnification ×4.

A B C

FIGURE 78-7 Transforming growth factor-β (TGF-β) signaling pathway. TGF ligands bind to a range of type II receptors to form complexes that interact with type I receptors. The receptors then form heterotetramers, which result in the phosphorylation and activation of receptor-regulated SMADs (R-SMADs) that subsequently form complexes with the common SMAD (Co-SMAD) SMAD4. This complex translocates to the nucleus, where it regulates gene transcription directly or indirectly. Endoglin is a coreceptor for both TGF-1 and TGF-3. Act = activin; ActR = activin receptor; ALK = activin-like kinase; TGF-R = TGF receptor. (From Waite KA, Eng C: Developmental disorder to heritable cancer: It’s all in the BMP/TGF family. Nat Rev Genet 4:763, 2003.)

Act A/BLigands

Type IIreceptors

Type Ireceptors

R-SMADs

Co-SMAD

ActR-II/ActR-IIB

ALK-4 ALK-5 ALK-1 ALK-6BMPR1A

SMAD2 and 3 SMAD1, 5, and 8

TGF-β1, 2 and 3 BMP2, 4, 6 and 7

BMPR-II

ActR-II

Act-IIB

TGF-βRII

SMAD4

Translocation, DNA binding and gene-expression regulation

Endoglin

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1704provide an indication of right ventricular afterload. Echocardiographic findings that portend a poor prognosis include pericardial effusion and a markedly diminished left ventricular cavity. Doppler echocardio-graphic estimates of right ventricular systolic pressures can be obtained by measuring the velocity of the tricuspid regurgitant jet and by using the Bernoulli formula (see Chap. 15). Although Doppler measurements correlate with right ventricular systolic pressure, they are relatively imprecise (±20 mm Hg) and are not a substitute for catheterization if a correct measurement of pulmonary pressure is needed.41

PULMONARY FUNCTION TESTS. Although pulmonary function in patients with PAH is often completely normal, reductions in lung volumes of 20% are common, making the differentiation from intersti-tial lung disease on the basis of pulmonary function tests (PFTs) dif-ficult.40 A significant obstructive pattern is not characteristic and should suggest obstructive airways disease. In patients with PAH, the diffusing lung capacity for carbon monoxide (DLCO) is reduced to approximately 60% to 80% of that predicted. The presence of mild to moderate arterial hypoxemia is caused by ventilation-perfusion mis-match and/or reduced mixed venous oxygen saturations resulting from low cardiac output. A severe reduction of both pulmonary arte-rial and systemic arterial oxygen saturations can be caused by right-to-left intracardiac or extracardiac shunts and/or intrapulmonary shunts. Consequently, Pao2 and Sao2 may vary markedly among patients with different constellations of associated abnormalities.

LUNG SCINTIGRAPHY. Patients with PAH may reveal a relatively normal perfusion pattern or diffuse, patchy perfusion abnormalities (Fig. 78-8).The latter is associated with a variety of pulmonary vascu-lar disease causes. A perfusion lung scan will reliably distinguish patients with PAH from those who have pulmonary hypertension sec-ondary to chronic pulmonary thromboembolism

COMPUTED TOMOGRAPHY. Contrast enhanced chest computed tomography (CT) scans are helpful in diagnosing chronic thrombo-embolic pulmonary hypertension (see Chap. 19). In addition to visu-alization of thrombi in the pulmonary vasculature (see Figs. 19-23C, 77-4, and 77-7), a mosaic pattern of variable attenuation compatible with irregular pulmonary perfusion can be determined in the nonen-hanced CT scan. Marked variation in the size of segmental vessels is also a specific feature of chronic thromboembolic disease. The sen-sitivity and specificity of CT to diagnose pulmonary embolism are affected by the sophistication of the scanner. In some patients, it may be necessary to perform perfusion lung scanning along with chest CT to make a correct diagnosis.

High-resolution CT is also helpful to diagnose interstitial lung disease. It has a high degree of specificity, but its sensitivity is low. Patients with PAH without coexisting lung disease should have normal lung parenchyma. Thus, although CT tends to underrepresent the

extent of the disease, the presence of any intersti-tial abnormality should suggest that interstitial lung disease is underlying the pulmonary hyper-tension. A high-resolution CT scan of the chest is also a useful means of detecting emphysema and may demonstrate emphysema in patients with little or no abnormality detected by PFTs.

CARDIAC MAGNETIC RESONANCE IMAGING. Advances in magnetic resonance imaging technology (see Chap. 18) have led to the development of techniques for the assessment of hemodynamics in the pulmonary circulation and identification of right ventricular morphologic changes. Cardiovascular magnetic resonance (CMR) is now regarded as the reference standard for the assessment of right ventricular structure and function via the measurement of right ven-tricular volumes and ejection fraction, which makes CMR an attractive modality for serial follow-up in PAH management to determine

sign to confirm that the enlarged silhouette is a result of right ventricu-lar dilation. The lung fields should be clear and often appear darkened from the relative oligemia caused by a low cardiac output.

ELECTROCARDIOGRAPHY. The detection of right ventricular hypertrophy on the electrocardiogram (ECG) is highly specific but has a low sensitivity (see Chap. 13). The electrocardiogram in patients with PAH usually exhibits right atrial and right ventricular enlargement. T wave inversion, representing the repolarization abnormalities associ-ated with right ventricular hypertrophy, is usually seen in the anterior precordial leads and may be mistaken for anteroseptal ischemia.

ECHOCARDIOGRAPHY. Echocardiography usually demonstrates enlargement of the right atrium and ventricle, normal or small left ventricular dimensions, and a thickened interventricular septum.40 Right ventricular dysfunction is difficult to measure echocardiographi-cally, but the position and curvature of the intraventricular septum

TABLE 78-3  Clues for Interpretation of Diagnostic Tests for Pulmonary Hypertension

TEST NOTABLE FINDINGS

Chest x-ray Enlargement of central pulmonary arteries reflects level of PA pressure and duration

Electrocardiography Right axis deviation and precordial T wave abnormalities are early signs.

Pulmonary function tests Elevated pulmonary artery pressure causes restrictive physiology.

Perfusion lung scan Nonsegmental perfusion abnormalities can occur from severe pulmonary vascular disease.

Chest computed scan Minor interstitial changes may reflect diffuse disease; mosaic tomography perfusion pattern indicates thromboembolism and/or left heart failure.

Echocardiography Right ventricular enlargement will parallel the severity of the pulmonary hypertension.

Contrast echocardiography Minor right to left shunting rarely produces hypoxemia.

Doppler echocardiography This is too unreliable for following serial measurements to monitor therapy

Exercise testing This is very helpful to assess the efficacy of therapy. Severe exercise-induced hypoxemia should cause consideration of a right-to-left shunt.

FIGURE 78-8 Perfusion lung scans in patients with pulmonary hypertension. A, Patient with IPAH. B, Patient with CTEPH. Both perfusion scans are abnormal. The scan in A shows a mottled distribution in a nonsegmental nonanatomic manner. The scan in B reveals lobar, segmental, and subsegmental defects, highly suggestive of an anatomic obstruction to pulmonary blood flow.

A B

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adjusted to reflect the height of the midchest of every patient. Pressures should never be determined by the electronically integrated mean pressure from the laboratory’s computer, because these measurements ignore respiratory influences.46 Instead, measurements of all pressures are properly made at end-expiration to avoid incorporating negative intrathoracic pressures. When a reproducible wedge pressure cannot be obtained, direct measurement of left ventricular end-diastolic pres-sure is advised. If the wedge pressure is increased, it should be corre-lated with left ventricular end-diastolic pressure and not attributed to a falsely elevated reading.

It can be difficult to pass a catheter into the pulmonary artery in patients with pulmonary hypertension because of the tricuspid regur-gitation, dilated right atrium and ventricle, and low cardiac output. A specific flow-directed thermodilution balloon catheter has been developed for patients with pulmonary hypertension (American Edwards Laboratories, Irvine, Calif); it has an extra port for the place-ment of a 0.25-inch guidewire to provide better stiffness to the catheter, which greatly facilitates the procedure.

VASODILATOR TESTING. Several vasodilators are of value in the assessment of pulmonary vasoreactivity in patients with PAH (Table 78-4). All appear to have similar efficacy in identifying patients who are vasoreactive. Adenosine and epoprostenol are vasodilators at low doses but they possess potent inotropic properties which become manifest at higher doses, whereas NO has little effect on cardiac output at any dose. An increase in cardiac output with no change in pulmonary arterial pressure will result in a reduction in calculated pulmonary vascular resistance, and may be erroneously interpreted as a vasodilator response45 (Table 78-5). Changes in pulmonary capil-lary wedge pressure can also have important influences on the

TABLE 78-4  Agents Used for Determination of Acute Pulmonary Vasoreactivity

AGENTMODE OF 

ADMINISTRATION DOSAGE  ADVANTAGES DISADVANTAGES

Prostacyclin Intravenous 2 ng/kg/min (stepwise increase every 10-15 min); maximum dose, 10 ng/kg/min

Affects PA pressure, cardiac output; can be used as chronic therapy

Systemic hypotension; dramatic side effects

Adenosine Intravenous 50 µg/kg/min increased by 50 µg/kg/min every 2 min; maximum dose, 250 µg/kg/min

Affects PA pressure, cardiac output; rapid onset, rapid washout

Bradycardia

Nitric oxide Inhaled 5-80 ppm for 10 min Affects PA pressure alone; rapid onset, rapid washout

Rebound pulmonary hypertension in a few cases

Iloprost Inhaled 2.5-5.0 µg/inhaled dose Affects PA pressure selectively with minimal effects on cardiac output; can be used as chronic therapy

Potential dosing variabilities depending on investigator experience, inhalation device, and breathing pattern of patient

TABLE 78-5  Hemodynamic Assessment of Vasodilators in Pulmonary Hypertension

PARAMETER MEASURED DESIRED ACUTE CHANGES COMMENTS

Mean pulmonary artery pressure (PAP) >10-mm Hg decrease; ideally, mean PAP < 30 mm Hg

Must not be associated with significant fall in systemic blood pressure

Pulmonary vascular resistance (PVR) >33% decrease; ideally PVR < 6 units Cardiac output unchanged or increased

Pulmonary capillary wedge pressure No change Increase in wedge pressure suggests pulmonary venoocclusive disease or coexisting left ventricular dysfunction

Cardiac output Increase Increase should be from increased stroke volume rather than increased heart rate

Heart rate No significant change Chronic increased heart rate will result in RV failure; watch for bradycardia if using high doses of diltiazem

Systemic arterial oxygen saturation Increase if reduced on room air, little change if normal

Decrease in systemic arterial oxygen saturation suggests lung disease or right-to-left shunt; prohibits chronic use

Pulmonary artery (mixed venous) oxygen saturation

Increase; should parallel increase in cardiac output and reflect improved tissue oxygenation

treatment response.42 One study that used CMR to assess the response to continuous intravenous epoprostenol in IPAH patients over 1 year showed a significant increase in right ventricular stroke volume and reduction in pulmonary vascular resistance.

EXERCISE TESTING. The use of a symptom-limited exercise test (see Chap. 14) can be very helpful in the evaluation of patients with pulmonary hypertension. The 6-minute walk test is commonly used in clinical trials as an endpoint for the efficacy of therapy in patients with pulmonary hypertension.43 It has been correlated with workload, heart rate, oxygen saturation, and dyspnea response. Its drawbacks include the fact that anthropometric factors such as gait speed, age, weight, muscle mass, and length of stride can affect the test results. Treadmill testing using the Naughton-Balke protocol, which creates increases in work of 1-MET (metabolic equivalent) increments at 2-minute stages has also been used and compares with the 6-minute walk test in reflecting drug efficacy. Cardiopulmonary exercise testing using an upright bicycle and measurements of gas exchange have the potential to grade the severity of exercise limitation in patients with pulmonary hypertension noninvasively.44

CARDIAC CATHETERIZATION. In addition to confirming the diagnosis and allowing the exclusion of other causes, cardiac catheter-ization (see Chap. 20) also establishes the severity of disease and allows an assessment of prognosis. By definition, patients with PAH should have a low or normal pulmonary capillary wedge pressure. Because this is a critical measurement in distinguishing a patient with PAH from one with pulmonary venous hypertension, quality measures must be established in the catheterization laboratory to ensure that correct values are obtained.45 The transducers must be carefully

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TABLE 78-6  Clinical Classification of Pulmonary Hypertension

Category 1: Pulmonary Arterial HypertensionKey feature: Elevation in PAP with normal pulmonary capillary wedge

pressure (PCWP)Includes the following:Idiopathic (IPAH)• Sporadic• Familial• From exposure to drugs or toxins• From exposure to HIV infection• Persistent pulmonary hypertension of the newbornAssociated with other active conditions:• Congenital systemic to pulmonary shunts• Collagen vascular disease• Portal hypertensionPulmonary capillary hemangiomatosis (PCH)

Category 2: Pulmonary Venous HypertensionKey feature: Elevation in PAP with elevation in PCWPIncludes the following:• Left-sided atrial or ventricular heart disease• Left-sided valvular heart disease• Pulmonary venous obstruction• Pulmonary venoocclusive disease (PVOD)

Category 3: Pulmonary Hypertension Associated with Hypoxemic Lung DiseaseKey feature: Chronic hypoxia with mild elevation of PA pressureIncludes the following:• Chronic obstructive lung disease• Interstitial lung disease• Sleep-disordered breathing• Alveolar hypoventilation disorders• Chronic exposure to high altitude• Developmental abnormalities

Category 4: Pulmonary Hypertension Caused by Chronic Thromboembolic DiseaseKey feature: Elevation of PAP with documentation of PA obstruction for

>3 moIncludes the following:• Chronic pulmonary thromboembolism• Nonthrombotic pulmonary embolism (tumor, foreign material)

Category 5: Pulmonary Hypertension from Conditions with Uncertain MechanismsKey feature: Elevation in PAP pressure in association with systemic disease

where a causal relationship is possible but not clearly understoodIncludes the following:• Sarcoidosis• Chronic anemias• Schistosomiasis• Histiocytosis X• Lymphangiomatosis

calculation of pulmonary vascular resistance. A rising capillary wedge pressure secondary to increased cardiac output may be the first sign of impending left ventricular failure and an adverse effect of a drug, whereas the calculated pulmonary vascular resistance may be lower and suggest a beneficial effect. The resting heart rate is a physiologic parameter of marked importance in patients with congestive heart failure, and treatments that cause an increased heart rate are likely to yield deleterious long-term results. Finally, the systemic arterial oxygen content should be evaluated in patients with pulmonary hypertension. Vasodilator drugs can result in vasodilation of blood vessels supplying poorly ventilated areas of the lung and can worsen hypoxemia. This effect is particularly noticeable in patients with underlying chronic lung disease.

CLASSIFICATION OF PULMONARY HYPERTENSIONPulmonary hypertension, in its simplest sense, refers to any elevation in the pulmonary arterial pressure above normal. The presence of pulmo-nary hypertension may reflect a serious underlying pulmonary vascular disease or a manifestation of high cardiac output from thyrotoxicosis. Consequently, an accurate diagnosis of the cause of pulmonary hyper-tension in a patient is essential to establish an effective treatment plan. In addition, therapies that may be beneficial for patients with some types of pulmonary hypertension may be harmful for patients with other types.

The diagnosis of pulmonary hypertension relies on establishing an elevation in pulmonary artery pressure above normal. The upper limit of normal for pulmonary artery mean pressure is 19 mm Hg. However, this assumes that there are no abnormalities in downstream pressures of the left atrium or left ventricle, or an increased cardiac output. That is why a patient can have pulmonary hypertension from the standpoint of an elevated pulmonary artery pressure, but normal pulmonary vascular resistance. Parameters for normal pulmonary arterial systolic pressure derived by echocardiographic Doppler studies have suggested that the upper limit of normal of pulmonary arterial systolic pressure in the general population may be higher than previously appreciated.

In 1998, a new clinical classification for pulmonary hypertension was developed. This classification catalogued clinical conditions based on common causative features to serve as a guide in the clinical assessment and treatment of these patients (Table  78-6). Several modifications to this classification have since been proposed.47 In addition, a functional classification, similar to the New York Heart Association (NYHA) func-tional classification for heart disease, has been developed to allow com-parisons of patients with respect to the clinical severity of their symptoms. Because heart and lung diseases commonly coexist in these patients, a worsening functional class may not necessarily reflect worsening pulmo-nary hypertension.

PAH refers to pulmonary vascular disease originating from the arte-rioles that results in an elevation in pressure and vascular resistance and a normal pulmonary capillary wedge pressure. Although IPAH (formerly referred to as primary pulmonary hypertension, or PPH) is relatively rare, with an estimated incidence of 1 to 2/million, severe PAH associated with other conditions such as connective tissue CTDs and congenital heart defects is considerably more common. The Centers for Disease Control and Prevention has surveyed the number of hospitalizations of persons with pulmonary hypertension from any cause in the United States from 1980 to 2002 and found a dramatic increase since 1990, with 260,000 hospitalizations and 15,668 deaths reported annually since 2000.48

Pulmonary Arterial HypertensionIDIOPATHIC PULMONARY ARTERIAL HYPERTENSION. IPAH is the diagnosis given to patients with pulmonary hypertension of unexplained cause. However, the clinical features, usual age of onset, progression of the disease, and autopsy findings make IPAH a distinct clinical entity. There are sporadic and familial forms. The prevalence of familial PAH (FPAH) is uncertain, but it occurs in at least 6% of IPAH cases, and the incidence is likely higher. Many unique features are associated with the transmission and development of FPAH. The age of onset is variable and the low penetrance of the gene confers only about a 10% to 20% likelihood of development of the disease. Many individuals in families with PAH inherit the gene and have progeny in whom PAH never develops. Patients with FPAH have a similar female-to-male ratio, age of onset, and natural history of the disease as those with IPAH.

Documentation of FPAH can be difficult because remote common ancestry occurs in patients with PAH and skip generations caused by

incomplete penetrance or by variable expression can mimic sporadic disease. Vertical transmission has been demonstrated in as many as five generations in one family and is indicative of a single autosomal dominant gene for PAH. Genetic anticipation has been described in FPAH since the early reports. Most cases of FPAH can be attributed to the mutation of BMPR-2. On clinical grounds, FPAH and IPAH appear identical.

Natural History and Symptoms

The most extensive study on the natural history of IPAH was reported from the National Institutes of Health (NIH) Registry on Primary Pul-monary Hypertension from 1981 to 1987. Of the patients, 63% were female, and the mean age was 36 ± 15 years (range, 1 to 81 years) at the time of diagnosis. The mean interval from the onset of symptoms to diagnosis was 2 years, and the most common initial symptoms were dyspnea (80%), fatigue (19%), and syncope or near-syncope (13%). No ethnic or racial differentiation was observed, with 12.3% of patients being black and 2.3% being Hispanic.

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circulating procoagulant factors and the risk of pulmonary embolism from deep vein thrombosis and amniotic fluid are serious concerns. Syncope and cardiac arrest have also been reported to occur during active labor and delivery, and a syndrome of postpartum circulatory collapse has been described. For these reasons, surgical sterilization should be given strong consideration by women with PAH or their husbands, and pregnancy should be strongly discouraged.

MEDICAL THERAPY. The mainstay of therapy has focused on the use of vasodilators. However, these patients suffer from right heart failure; thus, measures that have been shown to be effective for the treatment of heart failure are often used.

DigoxinAnimal studies of right ventricular systolic overload have shown that prior administration of digoxin helps prevent the reduction in contrac-tility of the right ventricle. Clinically, digoxin can increase cardiac output by approximately 10% when given acutely to patients with right ventricular failure from pulmonary hypertension, which is similar to observations made in patients with left ventricular systolic failure. In addition, digoxin caused a reduction in circulating norepinephrine, which is markedly increased.

Diuretics

These drugs appear to be of marked benefit in symptom relief of patients with PAH. Their traditional role has been limited to patients manifesting right ventricular failure and systemic venous congestion. However, patients with advanced PAH can have increased left ven-tricular filling pressures that contribute to the symptoms of dyspnea and orthopnea, which can be relieved with diuretics. Diuretics may also serve to reduce right ventricular wall stress in patients with con-comitant tricuspid regurgitation and volume overload. The fear that diuretics will induce systemic hypotension is unfounded, because the main factor limiting cardiac output is pulmonary vascular resistance and not pulmonary blood volume. Patients with severe venous con-gestion may require high doses of loop diuretics or the use of com-bined diuretics. In these cases, electrolyte levels need to be carefully monitored to avoid hyponatremia and hypokalemia. Elevated plasma aldosterone concentrations are associated with endothelial dysfunc-tion, left ventricular hypertrophy, and cardiac death in left heart failure. Given the similarities between left and right heart failure in regard to activation of the renin-angiotensin-aldosterone system, it seems reasonable to use aldosterone antagonists in patients with PAH.

Supplemental Oxygen

Hypoxic pulmonary vasoconstriction can contribute to pulmonary vascular disease. Patients with PAH who exhibit resting hypoxemia or arterial oxygen desaturation with activity may benefit from supple-mental oxygen because increased oxygen extraction occurs with fixed oxygen delivery. Patients with severe right-sided heart failure and resting hypoxemia resulting from markedly increased oxygen extraction at rest should be treated with continuous oxygen therapy to maintain their arterial oxygen saturation above 90%. Patients with hypoxemia caused by a right-to-left shunt may not improve their level of oxygenation to an appreciable degree with supplemental oxygen.

Anticoagulants

Oral anticoagulant therapy is widely recommended for patients with PAH, supported by the numerous studies implicating thrombin as contributing to disease progression.50 A number of retrospective and prospective observational studies have shown a significant survival advantage in patients with PAH treated with warfarin. The current recommendation is to use warfarin in relatively low doses, as has been recommended for the prophylaxis of venous thromboembolism, with the international normalized ratio (INR) maintained at 2.0 to 3.0 times that of controls.

PrinciPles of Vasodilator drug treatment of Pulmonary arterial HyPertension

l Establish a correct diagnosis. The symptoms of pulmonary hypertension attributable to PAH can be indistinguishable from pulmonary hypertension of other causes. In addition, treatments

RIGHT VENTRICULAR FUNCTION. Right ventricular failure from pulmonary hypertension is a result of chronic pressure overload and associated volume overload, with the development of tricuspid regur-gitation. The mechanism of right ventricular failure in patients with pulmonary hypertension is complex. The chronic pressure overload that induces right ventricular hypertrophy and reduced contractility has been shown to cause a reduction in coronary blood flow to the right ventricular myocardium, which can produce right ventricular ischemia acutely and chronically.37 Such right ventricular dysfunction appears to be a result of a reduction in right ventricular coronary artery driving pressure. In animals, acute right ventricular failure sec-ondary to right ventricular hypertension was overcome by increasing aortic pressure, which resulted in an increase in right ventricular coro-nary driving pressure.

LEFT VENTRICULAR FUNCTION. On occasion, patients with pul-monary hypertension have a reduced left ventricular ejection fraction and even regional wall motion abnormalities of the left ventricle. These findings had been attributed to mechanisms related to inter-ventricular dependence, which suggests that in some way a dysfunc-tional right ventricle can lead to a dysfunctional left ventricle. More recently, extrinsic compression of the left main coronary artery by the pulmonary artery in patients with chronic pulmonary hypertension has been described and may be associated with classic angina-like symptoms. It is advisable to look for extrinsic compression of the left main coronary artery with coronary angiography in patients with long-standing pulmonary hypertension who have abnormal left ventricular function.

Clinical Course

The clinical course of patients with IPAH can be highly variable. The NIH registry demonstrated that the mean right atrial pressure, mean pulmonary artery pressure, and cardiac index were significantly related to mortality. The NYHA functional classification was also strongly related to survival. However, with the onset of overt right ventricular failure manifested by worsening symptoms and systemic venous congestion, patient survival is generally limited to approxi-mately 6 months. The most common cause of death in patients with IPAH in the NIH registry was progressive right-sided heart failure. Sudden cardiac death was limited to patients who were in NYHA functional Class IV, suggesting that it is a manifestation of end-stage disease rather than a phenomenon that occurs early or unpredictably in the clinical course of the disease. The remainder of the patients died of other medical complications, such as pneumonia or bleeding, which suggests that patients with IPAH do not tolerate coexistent medical conditions well.

Management

With the current classification system, patients within a category of pulmonary hypertension are commonly treated alike. Differences in the efficacy and safety of therapies for pulmonary hypertension associ-ated with other conditions are discussed later. However, the general principles surrounding the management of pulmonary hypertension patients are usually consistent.

LIFESTYLE CHANGES. The diagnosis of PAH does not necessarily imply total disability for the patient. However, marked increases in pulmonary artery have been documented to occur early in the onset of increased physical activity. For that reason, graded exercise activities, such as bicycle riding or swimming, in which patients can gradually increase their workload and easily limit the extent of their work, are thought to be safer than isometric activities. Isometric activities such as lifting weights or stair climbing can be associated with syncopal events and should be limited or avoided. One recent study has reported an improvement in exercise capacity in patients who underwent a training program that far exceeded the effects of vasodilator treatments.49

PREGNANCY. Pregnancy should be discussed with women of childbearing age. The physiologic changes that occur in pregnancy can potentially activate the disease and result in death of the mother and/or fetus. In addition to the increased circulating blood volume and oxygen consumption that will increase right ventricular work,

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1708blockers be used in vasoreactive patients, which is not an U.S. Food and Drug Administration (FDA)-approved use.8 The approved vasodila-tors are recommended for patients who are shown to be nonrespon-sive to acute vasodilator testing. Regulatory approval has been based on the demonstration that they improve exercise tolerance over 12 to 16 weeks and is not based on a fall in pulmonary artery pressure. Although there is a presumption that they also lower pulmonary arte-rial pressure, the usual decrease in pulmonary artery pressure is less than 10%.

Calcium Channel Blockers

It has been reported that up to 20% of patients with IPAH are vasoreac-tive and will respond to high doses of calcium channel blockers, with a dramatic reduction in pulmonary artery pressure and pulmonary vascular resistance; on serial catheterization, this has been main-tained for more than 20 years.52 It appears essential that high doses (e.g., amlodipine, 20 to 30 mg/day; nifedipine, 180 to 240 mg/day; diltia-zem, 720 to 960 mg/day) must be used to realize full benefit. When patients respond favorably, quality of life is restored, with improved functional class, and survival (94% at 5 years) is improved when com-pared with nonresponders and historical control subjects. This experi-ence suggests that a select subset of patients with IPAH have the ability to have their pulmonary hypertension reversed and their quality of life and length of survival enhanced. It is unknown whether the response to calcium channel blockers identifies two subsets of patients with IPAH, different stages of IPAH, or a combination of both. However, patients who do not exhibit a dramatic hemodynamic response to calcium channel blockers do not appear to benefit from their long-term administration.

Prostacyclins

Prostacyclin is produced by vascular endothelial cells and has vaso-dilatory and antiproliferative activities. It is also a potent inhibitor of platelet aggregation. Abnormalities in prostacyclin production and metabolism have been described in PAH. Continuous intravenous infusion of epoprostenol (synthetic prostacyclin) has been shown in randomized clinical trials to improve symptoms related to IPAH, exer-cise tolerance, hemodynamics, and short-term survival.53 It appears effective when given chronically, even if it does not seem effective acutely. Epoprostenol is administered through a central venous cath-eter that is surgically implanted and delivered by an ambulatory infu-sion system. The delivery system is complex and requires patients to learn the techniques of sterile drug preparation, operation of the pump, and care of the intravenous catheter. Most serious complica-tions that have occurred with epoprostenol therapy have been attrib-utable to the delivery system; these include catheter-related infections and temporary interruption of the infusion because of pump malfunc-tion. The short half-life (6 minutes) of epoprostenol is believed to contribute to the hemodynamic collapse that has occurred when the infusion is abruptly interrupted. Side effects related to epoprostenol include flushing, headache, diarrhea, and a unique type of jaw dis-comfort that occurs with eating. In most patients, these symptoms are minimal and well tolerated. Chronic foot pain and a diffuse rash develop in some patients. To date, epoprostenol has been given to patients with PAH for more than 15 years with sustained effectiveness. In some patients (NYHA Class IV) who are critically ill, it serves as a bridge to lung transplantation by stabilizing the patient to a more favorable preoperative state. Patients who are less critically ill may do so well with epoprostenol therapy that the need to consider transplan-tation may be delayed, perhaps indefinitely.

The optimal dose of epoprostenol has never been determined, but doses between 25 and 40 ng/kg/min are typical. A high cardiac output state has been reported in a series of patients with IPAH receiving chronic epoprostenol therapy and is consistent with the drug having positive inotropic effects. The development of a chronic high-output state could have long-term detrimental effects on underlying cardiac function and should be avoided. The follow-up assessment of patients receiving intravenous epoprostenol is variable among medical centers, but it does appear important to determine the cardiac output response to therapy periodically to optimize dosing. The experience

that may be helpful in PAH can often be harmful or dangerous in other conditions. For these reasons, it is essential that a correct diagnosis of the cause be made in every case. Lack of an obvious history should not be relied on as adequate, because patients with congenital heart disease may never have been told of a heart murmur, and patients with chronic thromboembolic pulmonary hypertension often have no antecedent history of pulmonary embolism. Given the poor survival of pulmonary hypertension of any cause, every patient should undergo thorough testing, including cardiac catheterization, prior to initiating therapy.

l Obtain baseline assessments of the disease. To determine whether a treatment of PAH is effective, it is important to evaluate the patient’s response objectively. Regardless of which test or tests are used (e.g., exercise testing, catheterization), an adequate baseline assessment of the patient’s disease must be obtained to monitor the patient’s response to therapy.

l Test vasoreactivity. Because of the dramatic effect that calcium blockers have on improving survival in patients who are vasoreactive, patients should be tested at the time of diagnosis so that potentially reactive patients are not missed.

l Vasoreactive patients should undergo a trial of calcium channel blockers. Calcium blockers are the drugs of choice for those patients who demonstrate vasoreactivity at the time of testing. There is no evidence to suggest that these patients would have a similarly beneficial response with other therapies. Some patients who demonstrate reactivity may not respond to calcium blockers or may respond for only a limited period. It is essential that the drugs are used in the high doses that have been described to realize full benefit for the patient.

Nonreactive patients should be offered other therapies. Currently, there are no comparative trials regarding the efficacy of the various approved therapies, so no specific treatment can or should be considered first-line treatment. However, foremost should be consideration of which treatment the physician believes will offer the patient the best chance for improved symptoms and long-term survival. This will often depend on personal opinion, because there are no long-term controlled trials of any therapies for pulmonary hypertension.

l Follow-up assessment of drug efficacy is essential. In all the clinical trials for pulmonary hypertension, the full treatment effect was reached within 1 month of the patient receiving the active drug at full dose. There are no data to suggest that patients who do not respond initially might respond over time with longer exposure. Thus, it is recommended that a repeat measure of drug efficacy be performed within 2 months of starting any new drug treatment.

l Treatments that are ineffective should be replaced. All approved therapies for PAH have inherent risks and are expensive. If a treatment is deemed ineffective by an assessment of efficacy, a different treatment should be substituted rather than added. Patients who clinically fail all treatments should be considered for lung transplantation.

l Benefits and risks of combination therapies are largely unknown. The use of these treatments in combination is becoming popular. However, the only randomized controlled trial of combination therapy demonstrating efficacy has been the addition of oral sildenafil to stable patients with PAH on intravenous epoprostenol.51 Trials evaluating the combination of bosentan with epoprostenol and bosentan with tadalafil have failed to demonstrate increased efficacy.

l Repeated measures of efficacy should be adhered to. Evidence suggests that some therapies may lose efficacy over time. Thus, even in patients in whom it has been shown that drug therapy has been helpful initially, serial assessments of drug efficacy should be performed periodically to check for loss of efficacy over time.

VASODILATOR THERAPIES. All the approved therapies for pul-monary hypertension are considered to be pulmonary vasodilators. Current practice guidelines recommend that calcium channel

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sustained for longer periods. At present, beraprost is only approved for use in Japan.

Phosphodiesterase Type 5 Inhibitors

Inhibition of the phosphodiesterase type 5 (PDE5) enzyme produces pulmonary vasodilation by promoting an enhanced and sustained level of cGMP, an identical effect to that of inhaled NO. Sildenafil is a PDE5 inhibitor that has been shown to be a selective pulmonary vasodilator with similar efficacy to that of inhaled NO in lowering pulmonary artery pressure. Sildenafil has a preferential effect on the pulmonary circulation because of the high expression of the PDE5 isoform in the lung. Recent studies have also suggested that PDE5 inhibitors may improve cardiac function by direct effects on the myocardium.55 In a large, randomized clinical trial sildenafil caused significant improvements in 6-minute walk distance and hemo-dynamics in patients with PAH.56 The recommended dosage is 20 mg three times daily, but dosages as high as 80 mg three times daily have been used safely, and in some patients may be more effective. Side effects are generally mild and mainly related to vasodilation (head-ache, flushing, and nasal congestion). Tadalafil is a long-acting selec-tive PDE5 inhibitor that has been recently approved for PAH.57 In the pivotal clinical trial, it was similarly well tolerated and improved exer-cise tolerance and quality of life measures. The effective dose was 40 mg once daily.

Endothelin Receptor Blockers

Endothelin (ET)-1 exerts vasoconstrictor and mitogenic effects and is activated in PAH. Three endothelin receptor blockers have been approved for PAH. Although there have never been direct compara-tive trials, all three appear to have similar efficacy.58 Bosentan, a nonselective ET receptor blocker, has produced an improvement in 6-minute walk distance after 16 weeks as compared with placebo in several clinical trials. It also has been shown to lengthen a composite endpoint of time to clinical worsening. The approved dosage of bosentan is 125 mg twice daily. Ambrisentan is an ETA-selective endo-thelin receptor blocker that can be given once daily at a 5-mg dose, which can be increased to 10 mg if the drug is well tolerated. Sitaxsen-tan is an ETA-selective endothelin receptor blocker that can be given once daily at a 100 mg dose. Sitaxsentan is currently approved only in the European Union, Canada, and Australia.

These drugs have similar side effects, which include peripheral edema. They also have a potential of causing liver toxicity requiring monthly monitoring of liver enzyme levels, and have interactions with warfarin that require careful monitoring of the INR and dose

with epoprostenol in patients with IPAH for more than 10 years has been reported by two large centers (Fig. 78-9). Survival rates longer than 5 years were improved compared with survival in historical control subjects and the natural history predicted by the NIH Registry. Predictors of survival included NYHA functional class, exercise toler-ance, and acute vasodilator responsiveness. Both studies provided important data for identifying patients who would do well over the long term, versus those in whom transplantation should be considered.

Treprostinil is a stable prostacyclin analogue that has pharmaco-logic actions similar to those of epoprostenol, but differs in that it is chemically stable at room temperature and has a longer half-life (4 hours). This allows it to be administered through continuous subcu-taneous infusion, although infusion site pain is common. In a large, randomized clinical trial in patients with PAH, treprostinil was effec-tive in reducing symptoms of dyspnea associated with exercise.54 Treprostinil has also been approved for intravenous administration. The optimal dose of treprostinil has never been determined, but doses of 75 to 150 ng/kg/min are typical. Because there is no difference in bioavailability between the subcutaneous and intravenous routes, patients can be transitioned from one route of administration to the other without the need for adjusting the dosage. It has been reported that the use of intravenous treprostinil is associated with a higher incidence of gram-negative sepsis than intravenous epoprostenol.

A key element of the long-term efficacy of the parenteral prostacy-clins appears to be related to the strategy of upward dose titration of the drug over time. It is important to increase the dose to tolerated side effects in patients who remain symptomatic because there is a direct relationship between the dose of drug and improvement in exercise testing and hemodynamics. Once an optimal dose has been achieved, the dose is kept constant thereafter. Patients who deterio-rate after a long period of stability usually do not respond to further dose increases.

Iloprost, an analogue of prostacyclin, has been approved for use via inhalation. Because of the short half-life of iloprost, however, it requires frequent (up to 12/day) inhalations. Iloprost is given by 2.5- or 5.0-µg ampules via a dedicated nebulizer that limits the dose of drug that can be delivered. Beraprost is an orally active prostacyclin analogue that improved exercise capacity and symptoms over a 12-week period in a European trial. A similar trial conducted in the United States, however, showed similar efficacy at 12 weeks, only to document the loss of effectiveness over 1 year. This is the only ran-domized clinical trial to follow patients for a period of 1 year and underscores how initial improvements with therapies might not be

FIGURE 78-9 Kaplan-Meier survival estimates in patients with IPAH treated with epoprostenol therapy. A, Patient survival is compared with patients with IPAH matched for NYHA functional class who never received epoprostenol therapy. B, Patient survival compared with untreated patients with IPAH from the NIH registry survival prediction equation. The observed survival with epoprostenol therapy from both studies was remarkably similar and considerably better than what would have been expected. (A from Sitbon O, Humbert M, Nunes H, et al: Long-term intravenous epoprostenol infusion in primary pulmonary hypertension. J Am Coll Cardiol 40:780, 2002; B from McLaughlin V, Shillington A, Rich S: Survival in primary pulmonary hypertension: The impact of epoprostenol therapy. Circulation 106:1477, 2002.)

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1710PULMONARY ARTERIAL HYPERTENSION FROM EXPOSURE TO HUMAN IMMUNODEFICIENCY VIRUS INFECTION. Although well documented, it remains unclear how HIV infection results in an increased incidence of PAH in HIV-infected patients (see Chap. 72). A direct pathogenic role of HIV seems unlikely inasmuch as no viral constituents have been detected in the vascular endothelium of these patients. On the other hand, reports of pulmonary arteriopathy with intimal proliferation in monkeys experimentally infected with the simian immunodeficiency virus and in a murine model of acquired immunodeficiency syndrome have suggested a pathogenetic link between infection with an immunodeficiency virus and the develop-ment of PAH, possibly mediated by the release of inflammatory media-tors or by autoimmune mechanisms.28 The Swiss HIV Cohort Study reported the cumulative incidence of HIV-associated PAH to be 1/200 patients in the HIV-infected population. PAH was diagnosed in patients in all stages of HIV infection; it was unrelated to the CD4 cell counts. The clinical and hemodynamic features of these patients were similar to those of patients with IPAH.

PERSISTENT PULMONARY HYPERTENSION OF THE NEWBORN. Three forms of persistent pulmonary hypertension of the newborn (PPHN) have been described. In the hypertrophic type, the muscular tissue of the pulmonary arteries is hypertrophied and extends peripherally to the acini, which causes narrowing of the arter-ies, an increase in pulmonary pressure, and a reduction in pulmonary blood flow. It is believed to be the result of sustained fetal hyperten-sion from vasoconstriction caused by chronic fetal distress. In the hypoplastic type, the lungs and pulmonary arteries are underdevel-oped, usually as the result of a congenital diaphragmatic hernia or prolonged leakage of amniotic fluid. The cross-sectional area of the pulmonary vascular bed is inadequate for normal neonatal pulmo-nary blood flow. In the reactive type, lung histology is presumably normal but vasoconstriction causes pulmonary hypertension. High levels of vasoconstrictive mediators such as thromboxane, norepi-nephrine, and leukotrienes may be responsible and may result from streptococcal infection or acute asphyxia at birth. Although PPHN can vary in severity, severe cases are life-threatening. It is commonly asso-ciated with severe hypoxemia and the need for mechanical ventila-tion. Right-to-left shunting at the level of the ductus arteriosus or foramen ovale is common. Inhaled nitric oxide has provided encour-aging results through improvement in oxygenation in these patients. Intravenous epoprostenol has also been used and may even have effects additive to those of inhaled NO.

Alveolar capillary dysplasia is a very rare cause of pulmonary hyper-tension in neonates and is characterized by a developmental abnor-mality in the pulmonary vasculature. The antemortem diagnosis can be made only with open lung biopsy. Despite aggressive treatment with NO, epoprostenol, and even extracorporeal membrane oxygen-ation, survival in the setting of alveolar capillary dysplasia is rare.

PULMONARY ARTERIAL HYPERTENSION ASSOCIATED WITH CONGENITAL HEART DISEASE. Pulmonary hypertension can develop from any congenital heart defect that increases pulmonary blood flow (see Chap. 65).62 If a congenital defect causes pulmonary hypertension from the time of birth, the small muscular arteries of the fetal lung may undergo delayed or only partial involution, with subse-quent persistently high levels of pulmonary vascular resistance. This is especially true in lesions in which a left-to-right shunt enters the right ventricle or pulmonary artery directly (i.e., a post-tricuspid shunt, such as ventricular septal defect or patent ductus arteriosus). These patients experience a higher incidence of severe and irreversible pulmonary vascular damage than those in whom the shunt is proximal to the tricuspid valve (pretricuspid shunts, as in atrial septal defect and partial anomalous pulmonary venous drainage). An important feature of PAH in congenital heart disease is the right ventricular adaptive response to elevated pulmonary arterial pressure. When the onset is early in life, there is marked hypertrophy and preservation of a fetal-like phenotype. As a result, these patients can sustain an increased after-load for many years or decades as compared with patients in whom the pulmonary hypertension occurs later in life.

adjustments when used together. This is particularly important with sitaxsentan. Pregnancy monitoring (when indicated), as well as quar-terly hematocrit testing, is also advised. Caution should also be used when they are coadministered with cyclosporine, strong CYP3A4 inhib-itors (ketoconazole), or CYP2C19 inhibitors (omeprazole).

Surgical TherapyAtrial Septostomy. The rationale for the creation of an atrial sep-

tostomy in patients with PAH is based on experimental and clinical observations suggesting that an intra-atrial defect allowing right-to-left shunting in the setting of severe pulmonary hypertension might be of benefit. Indications for the procedure include recurrent syncope and/or right ventricular failure despite maximum medical therapy, as a bridge to transplantation if deterioration occurs in the face of maximum medical therapy, or when no other option exists.59 The rate of procedure-related mortality with atrial septostomy in patients with PAH is high, and thus the procedure should be attempted only in centers with an established record for the treatment of advanced pulmonary hypertension and experience in performing atrial septostomy with a low rate of morbidity. The recommended technique is graded balloon dilation of the fosse ovalis, which can be achieved in stages over several weeks in unstable patients. It should not be performed in a patient with impending death and severe right ventricular failure. Predictors of procedure-related failure or death include a mean right atrial pressure higher than 20 mm Hg, a pulmonary vascular resistance index higher than 55 units/m2, or a predicted 1-year survival rate of less than 40%. The mechanisms responsible for the beneficial effects of atrial septostomy remain unclear. Possibilities include increased oxygen delivery at rest and/or with exer-cise, reduced right ventricular end-diastolic pressure or wall stress, improvement in right ventricular function, or relief of right ventricular ischemia.

Heart-Lung and Lung Transplantation. Heart-lung transplantation (see Chap. 31) has been performed successfully in patients with PAH since 1981. Currently, bilateral lung transplantation has become the pro-cedure of choice, allowing the donor heart to be given to another patient.60 Hemodynamic studies have shown an immediate reduction in pulmonary artery pressure and pulmonary vascular resistance associated with an improvement in right ventricular function. The 1-year survival rate is 70% to 75%, the 2-year survival rate is 55% to 60%, and the 5-year survival rate is between 40% to 45%. The major long-term complications in patients are the high incidence of bronchiolitis obliterans in the trans-planted lungs, acute organ rejection, and opportunistic infection.

Transplantation should be reserved for patients with pulmonary hypertension that has progressed despite optimal medical management. It is generally accepted that patients should be considered for transplan-tation when they are in NYHA functional Class III or IV despite therapy with a parenteral prostacyclin. However, the recent adoption of a lung allocation score system for candidates has made it increasingly difficult for these patients to become transplanted. The scoring system was devel-oped to reduce the mortality of patients on the waiting list, prioritize candidates on the basis of urgency, and avoid futile transplants. Because patients with pulmonary hypertension have a higher postoperative mor-tality than patients with lung disease, they receive a lower score. However, their long-term survival is comparable.

PULMONARY ARTERIAL HYPERTENSION FROM EXPOSURE TO ANOREXIGENS. Several anorexigens have been demonstrated to cause pulmonary hypertension in humans. The first observation was made in 1967, when an epidemic of PAH in Europe was associ-ated with the use of aminorex, which has similarities to adrenaline and ephedrine in its chemical structure. The clinical features of pul-monary hypertension were identical to those attributed to IPAH. The association between the use of fenfluramine appetite suppressants and the development of PAH was established in a case-control study conducted in Europe in 1992 to 1994. Anorexigens such as amphet-amines were also implicated. Ultimately, the marked increase in the number of cases of PAH and cardiac valvulopathy ascribed to the use of fenfluramine drugs in the United States led to their withdrawal in 1997. In most patients, the development of pulmonary hypertension was progressive, despite withdrawal of the anorexigen. In addition, many of the patients did not develop clinical symptoms of PAH for more than 5 years after their last ingestion. Animal models have sug-gested that the fenfluramines produce pulmonary hypertension via the SERT by allowing for serotonin to stimulate PASMC proliferation by some type of permissive effect.61

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efficacy is considerably less.64 Patients with coexisting lung disease must be watched carefully for worsening oxygenation from the vasodilators.

PULMONARY ARTERIAL HYPERTENSION ASSOCIATED WITH PORTAL HYPERTENSION. Pulmonary abnormalities are com-monly associated with the development of hepatic cirrhosis and include hepatopulmonary syndrome (HPS), and portopulmonary hypertension (POPH). HPS is characterized by vascular dilation that produces severe arterial hypoxemia from intrapulmonary shunting in the setting of normal hemodynamics. No proven medical therapy exists for HPS, except for supplemental oxygen.

POPH hypertension is progressive and is unrelated to the severity of hepatic dysfunction, with no reports of spontaneous resolution.65 There is a strong association between portal hypertension and pulmo-nary hypertension, regardless of whether liver disease is present. The prevalence of pulmonary hypertension in patients with portal hyper-tension is estimated as 2% to 6%, with an estimated 5-year survival of 10% to 30%. Patients with POPH are similar to patients with PAH without cirrhosis, with the exception that they tend to have higher cardiac output and consequently lower systemic and pulmonary vas-cular resistance, which is characteristic of the cirrhotic state. Treat-ment of POPH generally follows the guidelines developed for treating patients with IPAH, but many of these drugs pose a risk of liver toxicity and should not be used. Although severe pulmonary hypertension is considered a contraindication to liver transplantation because of the risk of irreversible right-sided heart failure, successful liver transplanta-tion has been reported in patients with mild pulmonary hypertension treated successfully with intravenous epoprostenol.

Pulmonary Capillary HemangiomatosisPulmonary capillary hemangiomatosis (PCH) was first described in 1978 as a very rare cause of pulmonary hypertension. The typical chest radio-graphic appearance is a diffuse, bilateral, reticular nodular pattern associ-ated with enlarged central pulmonary arteries. The most characteristic finding on high-resolution CT scan is diffuse bilateral thickening of the interlobular septa and small centrilobular, poorly circumscribed, nodular opacities. Diffuse ground-glass opacities have also been described. His-tologic findings often include irregular small nodular foci of thin-walled capillary-sized vessels that diffusely invade the lung parenchyma, bron-chiolar walls, and adventitia of large vessels.66 These nodular lesions are often associated with alveolar hemorrhage. Most patients appear to be young adults and present with dyspnea and/or hemoptysis. A hereditary form with probable autosomal recessive transmission has been reported. It can be difficult to distinguish PCH from IPAH clinically. The clinical course of patients with this condition is usually one of progressive dete-rioration, leading to severe pulmonary hypertension, right-sided heart failure, and death. The only definitive treatment for these patients is lung transplantation.

Pulmonary Venous HypertensionPatients with pulmonary venous hypertension have elevated pulmo-nary venous pressure (as reflected in the pulmonary capillary wedge pressure) as a consequence of left ventricular dysfunction (see Chap. 25), mitral and aortic valve disease (see Chap. 66), cardiomyopathy (see Chap. 68), cor triatriatum (see Chap. 65), and pericardial disease (see Chap. 75). Although mitral stenosis was the most common cause of this disorder decades ago, left ventricular diastolic dysfunction is the most common cause of pulmonary venous hypertension seen in the Western world today. It is presumed that the mechanism of both is similar. Specifically, a chronic elevation in the diastolic filling pressure of the left heart causes a backward transmission of the pressure to the pulmonary venous system, which appears to trigger vasoconstriction in the pulmonary arterial bed.

PATHOLOGY. Histologically, abnormal thickening of the pulmonary veins and formation of a neointima are seen. The latter can be extensive. There is medial hypertrophy and thickening of the neointima on the arterial side of the pulmonary circulation as well. Patients with chronic severe pulmonary venous hypertension may show distention of pulmonary capillaries, thickening and rupture of the

The vascular changes that occur in pulmonary hypertension associ-ated with congenital heart disease are identical to those seen in IPAH. It is believed that ECs release mediators that induce PASMC growth in response to changes in pulmonary blood flow or pressure. Experimen-tal data have suggested that medial hypertrophy can be converted to a neointimal pattern when pulmonary vascular injury is coupled with increased pulmonary blood flow. Early changes, characterized by hypertrophy of the media and intimal proliferation of the muscular pulmonary arteries and arterioles, are believed to be reversible. Advanced disease, characterized by the presence of concentric laminar fibrosis, with obliteration of many arterioles and small arter-ies, and plexiform lesions are considered irreversible.

Eisenmenger Syndrome

Eisenmenger syndrome refers to any anomalous circulatory commu-nication that leads to obliterative pulmonary vascular disease. The long-term prognosis of patients with Eisenmenger syndrome is better than that of patients with IPAH, with survival reported to be 80% at 10 years, 77% at 15 years, and 42% at 25 years. A major distinction between Eisenmenger syndrome and other forms of PAH is the pres-ence of cyanosis. Pulse oximetry at rest and with exercise is a useful way to monitor the progress of these patients and their response to therapy. Patients with bidirectional shunting may have normal resting pulse oximetry that will fall during exercise, reflecting shunt reversal. The magnitude of the fall may be helpful in deciding how to intervene. Patients with advanced pulmonary vascular disease will have hypox-emia at rest that worsens significantly with any level of exercise activ-ity. Although this can have deleterious effects on organ function, these patients commonly have significant secondary erythrocytosis, which can effectively improve tissue oxygenation. Because erythrocytosis provides an important compensatory mechanism, patients should take supplemental iron to maintain their hematocrit. The use of anti-coagulants is somewhat controversial, because these patients gener-ally have thrombosis of the pulmonary vasculature but an increased risk of hemoptysis. It is recommended that warfarin anticoagulation be prescribed unless there is a history of bleeding.

All the approved vasodilators for PAH have been used in congenital heart disease to improve exercise tolerance, but the only randomized clinical trial conducted specifically in these patients (BREATHE-5) was with bosentan.63 Intravenous epoprostenol therapy has also been reported to be effective, but the presence of an underlying right-to-left shunt presents a risk for systemic embolization from the indwelling venous catheter, which needs to be monitored closely.

PULMONARY ARTERIAL HYPERTENSION ASSOCIATED WITH CONNECTIVE TISSUE DISEASES. All the CTDs have been associ-ated with the development of PAH, which is the leading cause of death in patients with scleroderma (see Chap. 89). Advanced pulmonary hypertension has also been described in patients with systemic lupus erythematosus, mixed CTDs, polymyositis, dermatomyositis, rheuma-toid arthritis, and Sjögren syndrome. Patients with severe pulmonary hypertension usually have a pulmonary vasculature with histologic features that resemble those of IPAH, but coexisting interstitial fibrosis is extremely common and likely contributes to hypoxemia. Because CTDs may have an insidious onset and slowly progressive course, early recognition of the symptoms of pulmonary hypertension may be dif-ficult. Dyspnea is the most common initial symptom. A reduced DLCO on pulmonary function tests has been shown to be predictive of the presence of pulmonary vascular disease. Scleroderma is associated with mild pulmonary hypertension in as many as one third of patients, which would make periodic screening with echocardiography in these patients reasonable.

The prognosis for patients with CTD in whom pulmonary hyperten-sion develops is poor. Conventional therapy with digitalis, diuretics, and anticoagulation has been recommended to provide a clinical benefit similar to the practice in IPAH. Because hypoxemia is so common, patients should be tested with pulse oximetry during exer-cise, and supplemental oxygen used whenever indicated. All the approved therapies for PAH apply to the CTDs. The principles of drug selection and management for IPAH are similar, but their long-term

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suggests pulmonary venous hypertension rather than PAH. Although echocardiographic techniques for the assessment of left ventricular diastolic function are advancing, heart catheterization is required to document left heart filling pressures in those with pulmonary hypertension. To make the diagnosis of PAH, the pulmonary capillary wedge pressure or left ventricular end-diastolic pressure must be less than 16 mm Hg. If an ideal wedge pressure tracing cannot be obtained, left ventricular end diastolic pressure should be directly measured. The reduction in diastolic filling time that occurs with an increased heart rate during exercise may further increase left heart filling pressures and, as a result, pulmonary artery (PA) pressures (Fig. 78-10).

Two hemodynamic profiles have been described that are common in these patients. Some patients will have an elevation in pulmonary arterial pressure, with only a minimal increase in the transpulmonary gradient (mean PA pressure − pulmonary capillary wedge pressure), as a reflection of the passive increase in PA pressure necessary to overcome the increased downstream resistance. A preserved right ventricle must generate high systolic pressures to ensure adequate forward blood flow in these patients, and thus moderate degrees of pulmonary hypertension are not only characteristic but also favorable. Other patients will have reactive pulmonary vasoconstriction resulting in marked elevations in pulmonary arterial pressure beyond that which is necessary to maintain cardiac output. These patients are frequently distinguished by a marked elevation in PA diastolic pres-sure. This has been studied extensively in patients with mitral stenosis but is less well characterized in patients with left ventricular diastolic dysfunction.

treatment. Treatment of HFpEF is difficult (see Chap. 30). The goal is to reduce or remove the elevated pulmonary venous resistance with medications such as nitrates, diuretics, and aggressive treatment of sys-temic hypertension. When successful, the pulmonary arterial pressure will also fall and the cardiac output will increase. Comorbid diseases such as obesity, diabetes, and obstructive sleep apnea must be addressed. Atrial fibrillation is not well tolerated in these patients and every attempt should be made to maintain sinus rhythm. Pulmonary vasodilators are not indicated, because their major hemodynamic effect is to raise cardiac output, and thus will predictably cause a worsening of pulmonary edema

basement membranes of endothelial cells, and transudation of eryth-rocytes through these ruptured membranes into the alveolar spaces, which contain fragments of disintegrating erythrocytes. Pulmonary hemosiderosis is commonly observed and may progress to extensive fibrosis. In the late stages of pulmonary venous hypertension, areas of hemorrhage may be scattered throughout the lungs, edema fluid, coagulum may collect in the alveolar spaces, and widespread organi-zation and fibrosis of pulmonary alveoli may be present. Pulmonary lymphatics may become markedly distended and give the appearance of lymphangiectasis, particularly when the pulmonary venous pressure exceeds 30 mm Hg.

PATHOPHYSIOLOGY. Increased resistance to pulmonary venous drainage will force the PA pressure to increase. The severity of pulmo-nary hypertension depends, in part, on the contractility of the right ventricle. In the presence of a normal right ventricle, an increase in left atrial pressure initially results in a decrease in pulmonary vascular resistance and the pressure gradient across the lungs, reflecting disten-tion of compliant small vessels, recruitment of additional vascular channels, or both. With further increases in left atrial pressure, PA pressure rises along with pulmonary venous pressure, so that at a constant pulmonary blood flow, the pressure gradient between the pulmonary artery and veins and pulmonary vascular resistance remains constant. When pulmonary venous pressure approaches or exceeds 25 mm Hg on a chronic basis, a disproportionate elevation in pulmonary artery pressure occurs, so that the pressure gradient between the pulmonary artery and veins rises while pulmonary blood flow remains constant or falls. This is indicative of an elevation in pulmonary vascular resistance caused in part by pulmonary arterial vasoconstriction. Some patients may have a genetic predisposition, allowing the chronically elevated pulmonary venous pressures to serve as a trigger for the development of structural changes similar to those found in IPAH. Marked reactive pulmonary hypertension with PA systolic pressures in excess of 80 mm Hg occurs in less than one third of patients whose pulmonary venous pressures are elevated more than 25 mm Hg, which suggests a broad spectrum of pulmonary vascular reactivity to chronic increases in pulmonary venous pressure. The molecular mechanisms involved in elevating pulmonary vascular resistance are unclear.

CLINICAL IMPLICATIONS. Pulmonary hypertension is a common and well-recognized complication of left ventricular systolic dysfunc-tion and is an independent predictor of survival in these patients. Patients with a high pulmonary artery pressure and a low right ven-tricular ejection fraction have a sevenfold higher risk of death com-pared with heart failure patients with a normal pulmonary artery pressure and right ventricular ejection fraction. Treatment of pulmo-nary venous hypertension as caused by left ventricular systolic dys-function should include traditional therapy for the underlying disease. Both epoprostenol and endothelin receptor antagonists have been studied in these patients and have been demonstrated to increase mortality or have no benefit, respectively. Recently, sildenafil has been used with some success.

Pulmonary venous hypertension related to left ventricular diastolic dysfunction, now referred to as heart failure with preserved ejection fraction (HFpEF), is less appreciated than that related to systolic dys-function, and is commonly mistaken for IPAH (see Chap. 30). The features of pulmonary hypertension in patients with HFpEF have recently been characterized.67 Patients tend to be older than IPAH patients and often have other conditions that may contribute to pul-monary hypertension, including obesity and obstructive sleep apnea. However, important and distinctive symptoms are orthopnea and paroxysmal nocturnal dyspnea, which is not a feature of PAH. Atrial fibrillation and absence of right axis deviation on the ECG should increase the suspicion for pulmonary venous hypertension. The chest x-ray will often show pulmonary vascular congestion, pleural effusions and, on occasion, pulmonary edema. A high-resolution chest CT scan can be particularly helpful because it will often reveal ground-glass opacities consistent with chronic pulmonary edema and a mosaic perfusion pattern. Left atrial enlargement on the echocardiogram also

FIGURE  78-10 End-diastolic pressure-volume relationships from patients with heart failure with normal ejection fraction (HFNEF) and control subjects (arrows indicate curve for HFNEF and control subjects, respectively). Yellow circles indicate mean end-diastolic volume (EDV, with horizontal error bars indi-cating the standard error of the mean [SEM]) and pressure (with vertical error bars indicating SEM) during sinus rhythm (SR), during pacing with 120 bpm (beats/min), or during exercise of the HFNEF group. Blue squares indicate mean EDV and pressure (with vertical and horizontal error bars indicating SEM) of control subjects. The abnormal curve illustrates why patients with elevated left ventricular EDV or pulmonary wedge pressures experience such severe dyspnea with exercise, because any increase in stroke volume causes the pressure to rise. Conversely, a reduction in left ventricular filling pressure may relieve the symp-toms of orthopnea and dyspnea and obscure the clinical picture of heart failure with a normal ejection fraction. (From Westermann D, Kasner M, Steendijk P, et al: Role of left ventricular stiffness in heart failure with normal ejection fraction. Circula-tion 117:2051, 2008.)

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Clinically, patients with COPD present with dyspnea and signs of right heart failure, usually in the setting of marked hypoxemia. At cardiac catheterization, the level of the mean pulmonary arterial pres-sure is usually less than 30 mm Hg. The mean PA pressure typically seen in these patients is lower than the mean PA pressure in patients with IPAH who respond favorably to pulmonary vasodilator therapy. The fact that these patients are clinically failing may indicate that it is not the severity of the pulmonary hypertension but the degree of hypoxemia that is determining their clinical symptomatology. Because right ventricular failure occurs at this level of pulmonary hypertension, it is probable that the right ventricle in these patients is profoundly affected by the hypoxemia and behaves more like an ischemic right ventricle than a pressure-loaded right ventricle.

Although relatively mild, the level of the pulmonary arterial hyper-tension is predictive of prognosis in patients with COPD. Nonetheless, there has never been a clinical trial showing a beneficial effect of any pulmonary vasodilator in these patients. Concern over worsening ventilation-perfusion mismatch from vasodilators that has been dem-onstrated with acute testing is likely why these medications are not used. The only effective treatment for patients with COPD and pulmo-nary hypertension has been supplemental oxygen, with several studies showing an improvement in morbidity and mortality. Clinicians also need to follow the level of hemoglobin in these patients. Patients with hypoxemia should have reactive polycythemia as a fundamental bio-logic mechanism to compensate for their cardiopulmonary disease. A hemoglobin in the low-normal range, although well tolerated in patients with normal oxygenation, may not be tolerated in patients with hypoxemia and mild pulmonary hypertension

Patients who present with severe pulmonary hypertension should be evaluated for another disease process responsible for the high pulmonary arterial pressures before it is attributed to the COPD. However, there is a small subset of patients with COPD who do develop severe pulmonary arterial hypertension (mean PA pressure [PAP] > 45 mm Hg).70 These patients have a distinctive pattern of cardiopulmonary abnormalities with mild to moderate airway obstruc-tion, severe hypoxemia, hypocapnia, and a low DLCO. It is possible that the severe pulmonary hypertension is occurring in the presence of lung disease rather than as a result of the lung disease. Clinically, these patients have a hemodynamic profile more typical of PAH, with a marked increase in PA pressure, normal pulmonary capillary wedge pressures, and markedly elevated pulmonary vascular resistance. Pul-monary vasodilators have been associated with clinical worsening and should not be used.71

INTERSTITIAL LUNG DISEASES. Interstitial lung diseases (ILDs) represent various conditions that involve the alveolar walls, perialveo-lar tissue, and other contiguous supporting structures. Pulmonary hypertension in patients with ILD is often associated with obliteration of the pulmonary vascular bed by lung destruction and fibrosis.72 The mechanism for pulmonary hypertension may be related to hypoxemia, a loss of effective pulmonary vasculature from lung destruction, and/or by indirectly triggering a pulmonary vasculopathy. Although ILD may be caused by environmental inhalant exposures, drugs, radiation, and recurring aspiration pneumonias, a large number of patients have ILD of unknown origin, the most common being idiopathic pulmonary fibrosis. ILD associated with CTD (e.g., scleroderma), represents an additional diagnostic challenge, because these patients may have only parenchymal disease, only vascular disease, or various stages of both.

The hemodynamic profile of patients with ILD and pulmonary hypertension is distinct from that of patients with IPAH. It is uncom-mon for the mean PA pressure ever to exceed 40 mm Hg in these patients, whereas it is unusual for the mean PA pressure to be less than 40 mm Hg in patients with IPAH. Consequently the combination of an abnormality consistent with interstitial lung disease on the chest CT scan and mild pulmonary hypertension should indicate the diag-nosis of pulmonary hypertension associated with ILD and not IPAH (Fig. 78-11).

Most therapies for ILD have been directed toward halting progres-sion or inducing regression of the interstitial disease process with immunosuppressive and anti-inflammatory agents. Overall, the results

if the pulmonary venous obstruction is not being relieved. There are a number of reports of rapid deterioration and death when pulmonary vasodilators are used in the presence of pulmonary venous hypertension.

Pulmonary hypertension as a result of mitral stenosis has been well characterized, and tends to resolve with time after mitral valve repair or replacement68 (see Chap. 66). The resolution is highly variable, and can occur immediately or over more than 1 year. Although pulmonary hyper-tension is associated with an increased operative risk, it should not inter-fere with appropriate treatment, regardless of severity. Pulmonary hypertension occasionally occurs in the setting of severe aortic stenosis, and portends a worse prognosis. Although severe pulmonary hyperten-sion is an independent predictor of perioperative mortality, aortic valve replacement is associated with a reduction in pulmonary artery pres-sures and improvement in NYHA functional class. The prognosis of those with pulmonary hypertension and severe aortic stenosis who do not undergo surgery is poor, with a 20% survival after a median of 436 days.

Pulmonary VenoocclusiVe disease

Pulmonary venoocclusive disease (PVOD) is a rare form of PAH. The his-topathologic diagnosis is based on the presence of obstructive eccentric fibrous intimal pads in the pulmonary veins and venules. Arterialization of the pulmonary veins is often present and is associated with alveolar capillary congestion.66 Other changes of chronic pulmonary hyperten-sion, such as medial hypertrophy and muscularization of the arterioles with eccentric intimal fibrosis, may also be seen. The pulmonary venous obstruction explains the increased pulmonary capillary wedge pressure described in patients in the late stages of the disease and the increase in basilar bronchovascular markings noted on the chest radiograph. The chest CT scan may be helpful, revealing smooth interlobular septal thick-ening, ground-glass opacities, and a mosaic perfusion pattern. A perfu-sion lung scan showing multiple perfusion defects and a CT scan showing no evidence of pulmonary embolism are highly suggestive of the diag-nosis. The treatment of PVOD is unsatisfactory.69 Warfarin anticoagula-tion is essential. Anecdotal reports of success with calcium blockers or epoprostenol have been tempered by reports of these treatments pro-ducing fulminant pulmonary edema. Any therapy needs particularly close supervision, and early referral of the patient for lung transplanta-tion should be considered.

Pulmonary Arterial Hypertension Associated with Hypoxic Lung DiseasesDiseases of the lung parenchyma associated with hypoxia are a common cause of mild pulmonary hypertension. Hypoxia induces muscularization of distal vessels and medial hypertrophy of more proxi-mal arteries, as well as a loss of vessels, which is compounded by a loss of lung parenchyma in the setting of lung disease. Intimal thickening appears to be an early event that occurs in association with progressive air flow limitation. The development of plexiform lesions is not observed.

CHRONIC OBSTRUCTIVE PULMONARY DISEASE. Chronic obstructive pulmonary disease (COPD) refers to a heterogeneous group of diseases that share a common feature—the airways are nar-rowed, which results in an inability to exhale completely. Although there are numerous disorders that fall under the heading of COPD, the most common are emphysema and chronic bronchitis. Pulmonary hypertension in COPD has multiple causative factors, including pul-monary vasoconstriction caused by alveolar hypoxia, acidemia, and hypercarbia, compression of pulmonary vessels by the high lung volume, loss of small vessels in the vascular bed in regions of the emphysema and lung destruction, and increased cardiac output and blood viscosity from polycythemia secondary to hypoxia. Of these, hypoxia is the most important factor. Changes in airway resistance may augment pulmonary vascular resistance in patients with COPD by increasing the alveolar pressure. The effect of airway resistance on pulmonary artery pressure may be particularly important when venti-lation increases (e.g., in cases of acute exacerbation of COPD). In patients with COPD, even small increases in flow that occur during mild exercise may increase pulmonary artery pressure significantly. Alveolar hypoxia is a potent pulmonary arterial constrictor that reduces perfusion with respect to ventilation in an attempt to restore Pao2. There is also a positive correlation between the Paco2 and PA pressure in COPD.

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FIGURE  78-11 Mean PAP in patients with different causes of pulmonary hypertension (PH). The mean PAP ± 1 SDs (standard deviations) are shown from published series of patients with pulmonary hypertension from a variety of causes undergoing catheterization. From the graph, it would be difficult to determine the cause of the PH based on the mean PA pressure, with the excep-tion of those with underlying lung disease. CHD = congenital heart disease; IPF = idiopathic pulmonary fibrosis; LVDF = left ventricular diastolic failure; LVSF = left ventricular systolic failure; MS = mitral stenosis; SSD = scleroderma spectrum of diseases.

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underlying atelectasis. In patients with advanced disease, intermittent positive pressure breathing and noninvasive ventilation have been used successfully, as well as supplemental oxygen in patients who are hypoxemic. The development of right-sided heart failure is an unusual manifestation of respiratory failure caused solely by respiratory muscle weakness from neuromuscular disease. It usually develops in response to hypoxic and hypercapnic stimuli in patients with chronic forms of these disorders.

Bilateral diaphragmatic paralysis as a result of phrenic nerve injury, which can be traumatic or secondary to an underlying motor neuron disease, is an uncommon and rarely recognized cause of pulmonary hypertension. It may occur after cardiac surgery, as a manifestation of Lyme disease, after radiation therapy, or as a manifestation of other neurologic disorders. When an affected patient is upright, ventilation may be normal or almost normal, but when the patient is supine, gas exchange deteriorates. The diagnosis may be suspected in a patient with supine breathlessness, disturbed sleep pattern, paradoxical motion of the abdomen on inspiration, and low vital capacity in the upright position. Patients with nontraumatic bilateral diaphragmatic paralysis may go unrecognized until they present with respiratory failure or pulmonary hypertension. The diagnosis can be made when the vital capacity is reduced by more than 40% of predicted and para-doxical motion of the hemidiaphragms is noted with fluoroscopy. Patients can also have unilateral paralysis of the diaphragm, which is more common but is associated with fewer symptoms and physiologi-cal abnormalities. The treatment should always be directed toward correcting the underlying chronic neuromuscular disease, if present, and addressing nocturnal hypoventilation with noninvasive ventila-tory techniques.

Pulmonary Hypertension Caused by Chronic Thromboembolic DiseaseChronic thromboembolic pulmonary hypertension (CTEPH) is an underdiagnosed disorder (see Chap. 77).74 Pulmonary embolism, either as a single episode or as recurrent events, is thought to be the typical initiating process, followed by progressive vascular remod-eling and in situ propagation of the thrombus. However, more than half of patients with CTEPH may not have a history of clinically overt pulmonary embolism. Whereas the incidence was originally believed to be approximately 0.1% to 0.5% of patients who survive an acute pulmonary embolus, more recent data have suggested a higher incidence, as much as 5%. An identifiable hypercoagulable state is found in only a minority of patients. The lupus anticoagulant is present in 10% to 20% of patients with CTEPH whereas inherited deficiencies of protein C, protein S, and antithrombin III as a group can be identified in up to 5% of this population. Other risk factors for the development of chronic thromboembolic pulmonary hyper-tension have been identified, including chronic inflammatory disor-ders, myeloproliferative syndromes, presence of a ventriculoatrial shunt, and splenectomy.

Rather than having inherent fibrinolytic resolution of the thrombo-embolism with restoration of vascular patency, the thromboemboli in these patients fail to resolve adequately. They undergo organization and incomplete recanalization and become incorporated into the vascular wall. Usually, they are in the subsegmental, segmental, and lobar vessels, although it is believed that chronic thromboembolism tends to propagate in a retrograde manner, leading to slowly progres-sive vascular obstruction. The development of a pulmonary hyperten-sive arteriopathy, similar to that seen in patients with other forms of pulmonary hypertension, has been documented in nonobstructive lung regions as well as in vessels distal to partially or completely occluded proximal pulmonary arteries. These small-vessel changes therefore appear to be a significant contributor to the hemodynamic progression seen in some patients. The pathology of CTEPH has fea-tures that distinguish it from IPAH. The lesions are frequently more variable—that is, there are arterial pathways that appear relatively unaffected by vascular disease and others that typically show recana-lized vascular thromboses.

of these trials have been disappointing, which makes the treatment of any associated pulmonary hypertension an attractive therapeutic target. Although vasodilator therapy has been available for decades, there are no randomized clinical trials showing benefit of these agents in ILD. Given the expense and morbidity associated with these thera-pies, we would caution against their anecdotal use in any patient until more definitive data support their chronic use. To date, lung trans-plantation is the only intervention proven to improve survival.

SLEEP-DISORDERED BREATHING. Observational studies have demonstrated a wide variation in the incidence of pulmonary hyper-tension as a complication of obstructive sleep apnea (OSA), with a wide range of severity (see Chap. 79). OSA is associated with repetitive nocturnal arterial oxygen desaturation and hypercapnia, large intra-thoracic negative pressure swings, and acute increases in PA pressure. Mild pulmonary hypertension has been reported to occur in 20% to 40% of patients,73 although the diagnosis of pulmonary hypertension in OSA is clouded by the frequent coexistence of systemic hyperten-sion, obesity, and diastolic dysfunction. Right heart catheterization is usually necessary to make a clear diagnosis. Acute pulmonary hemo-dynamic changes during obstructive apneas have been well defined; however, the extent to which these translate into persistent daytime pulmonary hypertension remains less certain. Right ventricular failure from OSA is distinctly uncommon. Treatment with continuous positive airway pressure improves pulmonary hemodynamics in patients with OSA.

ALVEOLAR HYPOVENTILATION DISORDERS. Restrictive lung disease may result from neuromuscular diseases or other factors that affect chest wall expansion, including severe obesity. Chronic alveolar hypoventilation can lead to hypoxemia, hypercapnia, and acidosis and cause pulmonary hypertension. Thoracovertebral deformities that can result in chronic alveolar hypoventilation and pulmonary hyper-tension include idiopathic kyphoscoliosis, spinal tuberculosis, con-genital spinal developmental abnormalities, spinal cord injury, ankylosing spondylitis, or other congenital and acquired muscular skeletal conditions, such as pectus excavatum. Pulmonary hyperten-sion is related to the reduction of the vascular bed caused by hypoven-tilation and hypoxia. Usually, symptoms are slowly progressive. Hypoxemia can occur from both ventilation-perfusion mismatch and

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develops pulmonary hypertension. Whether this represents coinci-dence, a cause and effect phenomenon, or a subset of genetically susceptible individuals may be impossible to resolve.

TREATMENT. The natural history of CTEPH is poor and is related to the severity of the pulmonary hypertension. It is important to make the diagnostic distinction between patients with CTEPH and those with other forms of pulmonary hypertension because the treatments are so different. For the former group, a potentially curative therapy through pulmonary thromboendarterectomy (PTEA) is available (Fig. 78-13). In specialized centers, these patients can have a dramatic improvement in their symptoms, hemodynamics, and survival and is the treatment of choice. Because this disease is generally progressive, the hemodynamic indications for surgical intervention are an eleva-tion of PA pressure and pulmonary vascular resistance for a period of more than 3 months, despite adequate anticoagulation. Operability is determined by the location and extent of proximal thromboemboli and should involve the main, lobar, or proximal segmental arteries. It

PATIENT EVALUATION. CTEPH involving the proximal pulmo-nary arteries is a well-characterized entity. The slowly progressive nature of the course of CTEPH allows right ventricular hypertrophy to ensue, which compensates for the increased pulmonary vascular resis-tance. However, because of progressive thrombosis or vascular changes in the uninvolved vascular bed, the pulmonary hypertension becomes progressive and the patient manifests the clinical symptoms of dyspnea, fatigue, hypoxemia, and right-sided heart failure. Patients may present with progressive dyspnea on exertion and/or signs of right heart failure after a single or recurrent episode of overt pulmonary embolism. Some patients experience a reprieve between the acute event and clinical signs of CTEPH, which may last from a few months to many years. The findings on clinical examination of patients with CTEPH are similar to those of other patients with pulmonary hyperten-sion, with the exception that these patients tend to have lower cardiac outputs than patients with IPAH, which is often reflected in the reduced carotid arterial pulse volume. On occasion, bruits can be heard over areas of the lung that represent vessels with partial occlu-sions, but they must be carefully listened for. Thrombophilia screen-ing, including testing for antiphospholipid antibodies, lupus anticoagulant, and anticardiolipin antibodies, should be performed.

The perfusion lung scan has a high sensitivity for the detection of CTEPH and is an important reason why lung scans are recommended for all patients who present with pulmonary hypertension (see Fig. 78-8). However, the lung scan typically underestimates the severity of the central pulmonary arterial obstruction. Therefore, patients who present with one or more mismatched segmental or larger defects should undergo contrast-enhanced CT scanning75 (see Chaps. 19 and 77; Fig. 78-12). The contrast-enhanced CT features of CTEPH include evidence of organized thrombus lining the pulmonary vessels in an eccentric or concentric fashion, enlargement of the right ventricle and central pulmonary arteries, variation in size of segmental arteries, bron-chial artery collaterals, and parenchymal changes from pulmonary infarcts. Marked variation in the size of the segmental vessels is specific for CTEPH and is believed to represent involvement of the segmental vessels caused by thromboemboli. With nonenhanced CT, areas of increased attenuation that do not obscure the vessels and that have a ground-glass appearance have been characterized as a mosaic pattern corresponding to hypoperfusion of the lung. Although this pattern is consistent with CTEPH, it may also be seen in patients with cystic fibrosis and those with bronchiectasis, but is almost never seen in patients with IPAH.

Pulmonary angiography continues to be the standard for defining the pulmonary vascular anatomy and is performed in patients thought to be amenable to surgical intervention to determine the location and surgical accessibility of the thromboemboli and to rule out other diagnostic possibilities. Maturation and organization of clot results in vessel retraction and partial recanalization, resulting in several angio-graphic patterns suggestive of chronic thromboembolic disease–pouch defect, pulmonary webs or bands, intimal irregularities, abrupt narrowing of major pulmonary vessels, and obstruction of main, lobar, or segmental pulmonary arteries, frequently at their point of origin. Bronchial artery collaterals may be present. Because CTEPH is usually bilateral, the presence of unilateral central PA obstruction should prompt consideration of other diagnoses, such as pulmonary vascular tumors or extravascular compression from a lung carcinoma, hilar or mediastinal adenopathy, or mediastinal fibrosis.

Hemodynamically, these patients may be indistinguishable from patients with IPAH. However, it can be misleading to rely on the pul-monary capillary wedge pressure, because there is no way for the clinician to know whether the vessel that is used to obtain the wedge pressure tracing has distal thrombus. Thus, these patients need to have a direct measurement of left ventricular end-diastolic pressure when the diagnosis is made. Patients with CTEPH tend to have higher right atrial pressures and lower cardiac outputs than comparable patients with IPAH for the same level of PA pressure. Some patients will have a reactive component to their pulmonary hypertension believed to be attributable to pulmonary vasoconstriction in the vasculature that is uninvolved with pulmonary thromboemboli. One clinical dilemma is the patient with a documented solitary pulmonary embolism who

FIGURE 78-12 Chest CT scans in a patient with CTEPH. A, Helical scan with contrast medium enhancement of the pulmonary vasculature shows a marked disparity in vessel size between the involved vessels (A), which are enlarged from thrombus, and the uninvolved vessels (B). B, Noncontrast-enhanced high-resolution scan illustrates a marked mosaic pattern manifest by differences in density of regions of the lung parenchyma reflecting the perfused areas (B) and the nonperfused areas (A), also consistent with underlying thromboembolic disease.

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FIGURE  78-13 Specimen removed from a patient undergoing pulmonary thromboendarterectomy. The thrombus is highly organized and fibrous and represents a cast of the pulmonary circulation. Because the procedure is a true endarterectomy, the thrombosis can often be removed as a single unit. The more thrombus removed, the greater clinical improvement expected as a result of the surgery.

vasodilators has been tested in anecdotal short-term studies with some success.76 Both bosentan and sildenafil have been associated with an improvement in symptoms and exercise tolerance. It is assumed that the drugs affect the uninvolved pulmonary vasculature. Because there have been no prospective randomized trials of vasodilators in CTEPH, it remains unknown whether their use will translate into a clinically meaningful and sustained improvement in these patients. Nonethe-less, in patients with inoperable CTEPH a clinical trial of pulmonary vasodilator therapy may be warranted, with the goal of improving the patient’s symptomatology and quality of life.

Pulmonary Hypertension from Conditions with Uncertain MechanismsSICKLE CELL DISEASE. Cardiopulmonary complications are common in sickle cell disease. The cause of pulmonary hypertension, which has been reported in 20% to 32% of sickle cell disease patients, is multifactorial, with contributing factors that include hemolysis, impaired NO bioavailability, chronic hypoxemia, high cardiac output, thromboembolism, and parenchymal and vascular injury caused by sequestration of sickle erythrocytes, chronic liver disease, and asple-nia.77 In general, the hemodynamic profile of most patients with pul-monary hypertension in the setting of sickle cell disease is distinct from those with IPAH. It is characterized by a more modest elevation in PA pressure, an elevation in left heart filling pressures, and invari-ably a markedly elevated cardiac output. Left-sided heart disease, or pulmonary venous hypertension, is a contributing factor in most patients. Whether the pulmonary hypertension reduces survival or is simply a marker of more advanced sickle cell disease remains unclear. Intensification of sickle cell disease therapy, such as with hydroxyurea or exchange transfusions, should be the mainstay of treatment. There have been no controlled trials demonstrating benefit from pulmonary vasodilator therapy.

SCHISTOSOMIASIS. Although schistosomiasis is extremely rare in North America, hundreds of millions of people are affected world-wide, particularly in developing countries.78 The development of pul-monary hypertension almost always occurs in the setting of hepatosplenic disease. Clinical features appear when ova embolize to the lungs, where they induce formation of delayed hypersensitivity granulomas. In addition, deposition of fibrous tissue may cause nar-rowing, thickening, and occlusion of the pulmonary arterioles. Histo-logically, focal changes related directly to the presence of schistosome ova may be located in the alveolar tissue or in the pulmonary arteries. However, classic changes typical of IPAH are also found, including plexiform lesions. The clinical symptoms and radiographic findings in these patients who develop pulmonary hypertension are not distinc-tive. In developing countries, this condition can be confused with IPAH.79 The diagnosis of schistosomiasis-induced pulmonary hyperten-sion is confirmed by finding the parasite ova in the urine or stool of persons with symptoms. However, the insidious onset of pulmonary vascular disease years after infection makes finding these parasite ova difficult. Active infections are treated with praziquantel, which kills the adult worms and stops further destruction of tissue by ova deposition. However, eradication of the infection does not seem to alter the pro-gression of the pulmonary vascular disease.

SARCOIDOSIS. Sarcoidosis is a multisystemic granulomatous disease of unknown origin characterized by an enhanced cellular immune response at the sites of involvement. Although any organ can be involved, sarcoidosis most commonly affects the lungs and intra-thoracic lymph nodes. The clinical manifestation and natural history of sarcoidosis vary greatly, but the lung is involved in more than 90% of patients. The most common presenting symptoms are cough and shortness of breath, which is of a progressive nature. As the disease progresses in the lung parenchyma, extensive interstitial fibrosis is the result. In addition, obstructive airway disease, fibrocystic disease, bronchiectasis, endobronchial granulomas, and lobar atelectasis are common consequences of lung involvement. Cardiac involvement from sarcoidosis appears to be more common than previously thought

is also important to evaluate whether the amount of surgically acces-sible thrombus is compatible with a degree of hemodynamic impair-ment. Failure to reduce the pulmonary vascular resistance significantly with PTEA, usually a result of the small-vessel arteriopathy that may accompany this disease, is associated with a higher perioperative mor-tality rate and worse long-term outcome.

There is a close relationship between preoperative pulmonary vas-cular resistance and perioperative mortality. Right ventricular dysfunc-tion is not considered a contraindication to surgery because right ventricular function has been noted to improve once the obstruction of the pulmonary blood flow has been removed. The operation is a true endarterectomy, requiring establishment of a dissection plane at the level of the media. The procedure is performed on cardiopulmo-nary bypass and usually requires periods of complete circulatory arrest to allow for a bloodless field and define an adequate dissection plane.

Postoperative management can be extremely challenging. Patients in whom a large volume of central thrombus is removed (see Fig. 78-13), associated with backbleeding from the distal vascular segments and an immediate fall in the PA pressure, usually have an extremely good postoperative course and long-term follow-up. Patients in whom small amounts of thrombus can be removed, the thrombus becomes fragmented at the time of PTEA, or there is no distal backbleeding from the segment where the thrombus was removed usually have a difficult postoperative course. In addition, lack of a significant fall in PA pres-sure or increase in cardiac output portends a difficult postoperative recovery. Much of the mortality risk appears to be related to severe right ventricular dysfunction, which actually initially worsens during the surgical procedure. Reperfusion injury, manifest by profound hypoxemia and pulmonary infiltrates corresponding to the segments where thrombus was removed, occurs in approximately 15% to 20% of patients and can be extensive. The only effective management of this complication is sustained assisted ventilation and oxygen supplemen-tation. Survivors who have a good result, with a significant reduction in postoperative pulmonary vascular resistance at 48 hours, can expect to realize an improvement in functional class and exercise tolerance. Lifelong anticoagulation with a goal INR ratio of 2.5 to 3.5 is indicated postoperatively.

Some patients will have extensive disease that is inoperable or only partially amenable to surgical removal. The use of pulmonary

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11. Benisty JI, McLaughlin VV, Landzberg MJ, et al: Elevated basic fibroblast growth factor levels in patients with pulmonary arterial hypertension. Chest 126:1255, 2004.

12. White RJ, Meoli DF, Swarthout RF, et al: Plexiform-like lesions and increased tissue factor expression in a rat model of severe pulmonary arterial hypertension. Am J Physiol Lung Cell Mol Physiol 293:L583, 2007.

13. Barst RJ, McGoon M, Torbicki A, et al: Diagnosis and differential assessment of pulmonary arterial hypertension. J Am Coll Cardiol 43:40S, 2004.

14. Yu Y, Fantozzi I, Remillard CV, et al: Enhanced expression of transient receptor potential channels in idiopathic pulmonary arterial hypertension. Proc Natl Acad Sci USA 101:13861, 2004.

15. Hong Z, Smith AJ, Archer SL, et al: Pergolide is an inhibitor of voltage-gated potassium channels, including Kv1.5, and causes pulmonary vasoconstriction. Circulation 112:1494, 2005.

16. Humbert M, Morrell NW, Archer SL, et al: Cellular and molecular pathobiology of pulmonary arterial hypertension. J Am Coll Cardiol 43:13S, 2004.

17. Bonnet S, Michelakis ED, Porter CJ, et al: An abnormal mitochondrial-hypoxia inducible factor-1alpha-Kv channel pathway disrupts oxygen sensing and triggers pulmonary arterial hypertension in fawn hooded rats: Similarities to human pulmonary arterial hypertension. Circulation 113:2630, 2006.

18. Bonnet S, Rochefort G, Sutendra G, et al: The nuclear factor of activated T cells in pulmonary arterial hypertension can be therapeutically targeted. Proc Natl Acad Sci USA 104:11418, 2007.

19. McMurtry MS, Archer SL, Altieri DC, et al: Gene therapy targeting survivin selectively induces pulmonary vascular apoptosis and reverses pulmonary arterial hypertension. J Clin Invest 115:1479, 2005.

20. Richter A, Yeager ME, Zaiman A, et al: Impaired transforming growth factor-beta signaling in idiopathic pulmonary arterial hypertension. Am J Respir Crit Care Med 170:1340, 2004.

21. Marcos E, Fadel E, Sanchez O, et al: Serotonin-induced smooth muscle hyperplasia in various forms of human pulmonary hypertension. Circ Res 94:1263, 2004.

22. Eddahibi S, Guignabert C, Barlier-Mur AM, et al: Cross talk between endothelial and smooth muscle cells in pulmonary hypertension: Critical role for serotonin-induced smooth muscle hyperplasia. Circulation 113:1857, 2006.

23. de Caestecker M: Serotonin signaling in pulmonary hypertension. Circ Res 98:1229, 2006.24. Machado RD, Koehler R, Glissmeyer E, et al: Genetic association of the serotonin transporter in

pulmonary arterial hypertension. Am J Respir Crit Care Med 173:793, 2006.25. Hassoun PM, Mouthon L, Barbera JA, et al: Inflammation, growth factors, and pulmonary

vascular remodeling. J Am Coll Cardiol 54:S10, 2009.26. Hamid R, Newman JH: Evidence for inflammatory signaling in idiopathic pulmonary artery

hypertension: TRPC6 and nuclear factor-kappaB. Circulation 119:2297, 2009.27. Csiszar A, Smith KE, Koller A, et al: Regulation of bone morphogenetic protein-2 expression in

endothelial cells: Role of nuclear factor-kappaB activation by tumor necrosis factor-alpha, H2O2, and high intravascular pressure. Circulation 111:2364, 2005.

28. Marecki JC, Cool CD, Parr JE, et al: HIV-1 Nef is associated with complex pulmonary vascular lesions in SHIV-nef-infected macaques. Am J Respir Crit Care Med 174:437, 2006.

29. Tuder RM, Abman SH, Braun T, et al: Development and pathology of pulmonary hypertension. J Am Coll Cardiol 54:S3, 2009.

30. Newman JH, Trembath RC, Morse JA, et al: Genetic basis of pulmonary arterial hypertension. J Am Coll Cardiol 43:33S, 2004.

31. Cogan JD, Vnencak-Jones CL, Phillips JA 3rd, et al: Gross BMPR2 gene rearrangements constitute a new cause for primary pulmonary hypertension. Genet Med 7:169, 2005.

32. Teichert-Kuliszewska K, Kutryk MJ, Kuliszewski MA, et al: Bone morphogenetic protein receptor-2 signaling promotes pulmonary arterial endothelial cell survival: Implications for loss-of-function mutations in the pathogenesis of pulmonary hypertension. Circ Res 98:209, 2006.

33. Machado RD, James V, Southwood M, et al: Investigation of second genetic hits at the BMPR2 locus as a modulator of disease progression in familial pulmonary arterial hypertension. Circulation 111:607, 2005.

34. Machado RD, Aldred MA, James V, et al: Mutations of the TGF-beta type II receptor BMPR2 in pulmonary arterial hypertension. Hum Mutat 27:121, 2006.

35. Aldred MA, Vijayakrishnan J, James V, et al: BMPR2 gene rearrangements account for a significant proportion of mutations in familial and idiopathic pulmonary arterial hypertension. Hum Mutat 27:212, 2006.

36. Long L, MacLean MR, Jeffery TK, et al: Serotonin increases susceptibility to pulmonary hypertension in BMPR2-deficient mice. Circ Res 98:818, 2006.

Clinical Assessment of the Patient37. van Wolferen SA, Marcus JT, Westerhof N, et al: Right coronary artery flow impairment in

patients with pulmonary hypertension. Eur Heart J 29:120, 2008.38. Souza R, Bogossian HB, Humbert M, et al: N-terminal-pro-brain natriuretic peptide as a

haemodynamic marker in idiopathic pulmonary arterial hypertension. Eur Respir J 25:509, 2005.39. Li JH, Safford RE, Aduen JF, et al: Pulmonary hypertension and thyroid disease. Chest 132:793,

2007.40. McGoon M, Gutterman D, Steen V, et al: Screening, early detection, and diagnosis of pulmonary

arterial hypertension: ACCP evidence-based clinical practice guidelines. Chest 126:14S, 2004.41. Fisher MR, Forfia PR, Chamera E, et al: Accuracy of Doppler echocardiography in the

hemodynamic assessment of pulmonary hypertension. Am J Respir Crit Care Med 179:615, 2009.

42. Benza R, Biederman R, Murali S, et al: Role of cardiac magnetic resonance imaging in the management of patients with pulmonary arterial hypertension. J Am Coll Cardiol 52:1683, 2008.

43. Salzman SH: The 6-min walk test: clinical and research role, technique, coding, and reimbursement. Chest 135:1345, 2009.

44. Oudiz RJ, Barst RJ, Hansen JE, et al: Cardiopulmonary exercise testing and six-minute walk correlations in pulmonary arterial hypertension. Am J Cardiol 97:123, 2006.

45. Ghofrani HA, Wilkins MW, Rich S: Uncertainties in the diagnosis and treatment of pulmonary arterial hypertension. Circulation 118:1195, 2008.

46. Halpern SD, Taichman DB: Misclassification of pulmonary hypertension due to reliance in pulmonary capillary wedge pressure rather than left ventricular end-diastolic pressure. Chest 136:37, 2009.

and may be present in up to one third of cases.80 Consequently, patients presenting with dyspnea should undergo a thorough cardiac evaluation for the possibility of cardiac involvement. Noncaseating granulomas may infiltrate the myocardium and lead to the develop-ment of a restrictive cardiomyopathy (see Chap. 68). Patients with cardiac involvement from sarcoidosis also present with varying degrees of heart block, arrhythmias, and/or clinical features of biven-tricular diastolic heart failure. The prognosis of patients with cardiac involvement from sarcoidosis is variable but can be poor.

Pulmonary hypertension is usually the result of chronic severe fibro-cystic sarcoidosis. Patients have chronic progressive dyspnea with effort, a chest radiograph demonstrating severe diffuse interstitial fibrotic lung disease, and pulmonary function test results that reflect severe restrictive physiology and marked hypoxemia. In these cases, the resulting pulmonary hypertension is usually mild to moderate and typical of patients presenting with restrictive lung disease of any cause. Management is generally focused on reversing any acute exac-erbations of the lung disease and giving supplemental oxygen, when indicated. A subset of patients present with severe pulmonary hyper-tension thought to be caused by pulmonary vascular involvement, often in the setting of quiescent disease. It appears that these patients develop pulmonary vascular disease triggered in some way by the sarcoid disease process. The use of intravenous epoprostenol chroni-cally may reverse the right-sided heart failure and improve hemody-namics, but will not affect the underlying fibrotic lung disease, and most patients will remain symptomatic and dyspneic.81

Future PerspectivesIt has become apparent that the clinical manifestation of pulmonary hypertension is a final common pathway originating from diverse abnormalities in the pulmonary circulation associated with a number of risk factors. Animal models of pulmonary hypertension have illus-trated how changes in specific molecular pathways can produce pul-monary hypertension, and how blocking these pathways can lead to reversal of advanced disease. Whether the reversal of the disease can be achieved in patients with therapy remains unknown, but to date has never been demonstrated. As the molecular pathways involved in pulmonary hypertension are becoming elucidated and understood, drugs that block these pathways will hold promise as future treatment. Although the presence of redundant pathways and multiple abnor-malities will make clinical progress more challenging, clinical trials using growth factor inhibitors are being conducted. Many patients with long-standing pulmonary hypertension can function at a reason-able level as long as their right ventricular function remains intact. Novel therapies aimed at improving right ventricular adaptation to pulmonary hypertension with medications, or augmenting right ven-tricular function with medical devices, is another area that has great potential.

REFERENCESNormal Pulmonary Circulation

1. Kasper M: Phenotypic characterization of pulmonary arteries in normal and diseased lung. Chest 128:547S, 2005.

2. Bartsch P, Gibbs JS: Effect of altitude on the heart and the lungs. Circulation 116:2191, 2007.3. Weir EK, Lopez-Barneo J, Buckler KJ, Archer SL: Acute oxygen-sensing mechanisms. N Engl J

Med 353:2042, 2005.4. Ichinose F, Roberts JD Jr, Zapol WM: Inhaled nitric oxide: A selective pulmonary vasodilator:

Current uses and therapeutic potential. Circulation 109:3106, 2004.

Pathobiology of Pulmonary Arterial Hypertension5. Rabinovitch M: Molecular pathogenesis of pulmonary arterial hypertension. J Clin Invest

118:2372, 2008.6. Morrell NW, Adnot S, Archer SL, et al: Cellular and molecular basis of pulmonary arterial

hypertension. J Am Coll Cardiol 54:S20, 2009.7. Budhiraja R, Tuder RM, Hassoun PM: Endothelial dysfunction in pulmonary hypertension.

Circulation 109:159, 2004.8. McLaughlin VV, Archer SL, Badesch DB, et al: ACCF/AHA 2009 expert consensus document on

pulmonary hypertension. Circulation 119:2250, 2009.9. Pietra GG, Capron F, Stewart S, et al: Pathologic assessment of vasculopathies in pulmonary

hypertension. J Am Coll Cardiol 43:25S, 2004.10. Gorlach A, BelAiba RS, Hess J, Kietzmann T: Thrombin activates the p21-activated kinase in

pulmonary artery smooth muscle cells. Role in tissue factor expression. Thromb Haemost 93:1168, 2005.

CH 78

171865. Krowka MJ: Evolving dilemmas and management of portopulmonary hypertension. Semin Liver

Dis 26:265, 2006.66. Frazier AA, Franks TJ, Mohammed TL, et al: From the Archives of the AFIP: Pulmonary

veno-occlusive disease and pulmonary capillary hemangiomatosis. Radiographics 27:867, 2007.

Pulmonary Venous Hypertension67. Lam CS, Roger VL, Rodeheffer RJ, et al: Pulmonary hypertension in heart failure with preserved

ejection fraction: A community-based study. J Am Coll Cardiol 53:1119, 2009.68. Fawzy ME, Hassan W, Stefadouros M, et al: Prevalence and fate of severe pulmonary

hypertension in 559 consecutive patients with severe rheumatic mitral stenosis undergoing mitral balloon valvotomy. J Heart Valve Dis 13:942, 2004.

69. Montani D, Price LC, Dorfmuller P, et al: Pulmonary veno-occlusive disease. Eur Respir J 33:189, 2009.

Pulmonary Arterial Hypertension Associated with Hypoxic Lung Disease70. Chaouat A, Bugnet AS, Kadaoui N, et al: Severe pulmonary hypertension and chronic

obstructive pulmonary disease. Am J Respir Crit Care Med 172:189, 2005.71. Stolz D, Rasch H, Linka A, et al: A randomised, controlled trial of bosentan in severe COPD.

Eur Respir J 32:619, 2008.72. Behr J, Ryu JH: Pulmonary hypertension in interstitial lung disease. Eur Respir J 31:1357, 2008.73. Atwood CW, McCrory D, Garcia JGN, et al: Pulmonary artery hypertension and sleep-disordered

breathing: ACCP evidence-based clinical practice guidelines. Chest 126:72S, 2004.

Pulmonary Hypertension Caused by Chronic Thromboembolic Disease74. Auger WR, Fedullo PF: Chronic thromboembolic pulmonary hypertension. Semin Respir Crit

Care Med 30:471, 2009.75. Coulden R: State-of-the-art imaging techniques in chronic thromboembolic pulmonary

hypertension. Proc Am Thorac Soc 3:577, 2006.76. Condliffe R, Kiely DG, Gibbs JS, et al: Improved outcomes in medically and surgically treated

chronic thromboembolic pulmonary hypertension. Am J Respir Crit Care Med 177:1122, 2008.

Pulmonary Hypertension with Uncertain or Multifactorial Mechanisms77. Machado RF, Gladwin MT: Chronic sickle cell lung disease: New insights into the diagnosis,

pathogenesis and treatment of pulmonary hypertension. Br J Haematol 129:449, 2005.78. Butrous G, Ghofrani HA, Grimminger F: Pulmonary vascular disease in the developing world.

Circulation 118:1758, 2008.79. Lapa M, Dias B, Jardim C, et al: Cardiopulmonary manifestations of hepatosplenic

schistosomiasis. Circulation 119:1518, 2009.80. Mehta D, Lubitz SA, Frankel Z, et al: Cardiac involvement in patients with sarcoidosis: Diagnostic

and prognostic value of outpatient testing. Chest 133:1426, 2008.81. Fisher KA, Serlin DM, Wilson KC, et al: Sarcoidosis-associated pulmonary hypertension: Outcome

with long-term epoprostenol treatment. Chest 130:1481, 2006.

47. Simonneau G, Robbins IM, Beghetti M, et al: Updated clinical classification of pulmonary hypertension. J Am Coll Cardiol 54:S43, 2009.

48. Hyduk A, Croft J, Ayala C, et al: Pulmonary hypertension surveillance—United States, 1980-2002. MMRWR Surveill Summ 54:1, 2005.

Pulmonary Arterial Hypertension49. Mereles D, Ehlken N, Kreuscher S, et al: Exercise and respiratory training improve exercise

capacity and quality of life in patients with severe chronic pulmonary hypertension. Circulation 114:1482, 2006.

50. Johnson SR, Mehta S, Granton JT: Anticoagulation in pulmonary arterial hypertension: A qualitative systematic review. Eur Respir J 28:999, 2006.

51. Simonneau G, Rubin LJ, Galie N, et al: Addition of sildenafil to long-term intravenous epoprostenol therapy in patients with pulmonary arterial hypertension: A randomized trial. Ann Intern Med 149:521, 2008.

52. Sitbon O, Humbert M, Jais X, et al: Long-term response to calcium channel blockers in idiopathic pulmonary arterial hypertension. Circulation 111:3105, 2005.

53. Gomberg-Maitland M, Olschewski H: Prostacyclin therapies for the treatment of pulmonary arterial hypertension. Eur Respir J 31:891, 2008.

54. Lang I, Gomez-Sanchez M, Kneussl M, et al: Efficacy of long-term subcutaneous treprostinil sodium therapy in pulmonary hypertension. Chest 129:1636, 2006.

55. Nagendran J, Archer SL, Soliman D, et al: Phosphodiesterase type 5 is highly expressed in the hypertrophied human right ventricle, and acute inhibition of phosphodiesterase type 5 improves contractility. Circulation 116:238, 2007.

56. Galie N, Ghofrani HA, Torbicki A, et al: Sildenafil citrate therapy for pulmonary arterial hypertension. N Engl J Med 353:2148, 2005.

57. Galie N, Brundage BH, Ghofrani HA, et al: Tadalafil therapy for pulmonary arterial hypertension. Circulation 119:2894, 2009.

58. Dupuis J, Hoeper MM: Endothelin receptor antagonists in pulmonary arterial hypertension. Eur Respir J 31:407, 2008.

59. Kurzyna M, Dabrowski M, Bielecki D, et al: Atrial septostomy in treatment of end-stage right heart failure in patients with pulmonary hypertension. Chest 131:977, 2007.

60. Orens JB, Garrity ER Jr: General overview of lung transplantation and review of organ allocation. Proc Am Thorac Soc 6:13, 2009.

61. Dempsie Y, Morecroft I, Welsh DJ, et al: Converging evidence in support of the serotonin hypothesis of dexfenfluramine-induced pulmonary hypertension with novel transgenic mice. Circulation 117:2928, 2008.

62. Berger RMF: Pulmonary hypertension associated with congenital cardiac disease. Cardiol Young 19:311, 2009.

63. Galie N, Beghetti M, Gatzoulis MA, et al: Bosentan therapy in patients with Eisenmenger syndrome: A multicenter, double-blind, randomized, placebo-controlled study. Circulation 114:48, 2006.

64. Condliffe R, Kiely DG, Peacock AJ, et al: Connective tissue disease-associated pulmonary arterial hypertension in the modern treatment era. Am J Respir Crit Care Med 179:151, 2009.