The pulmonary artery (PA) functions as a low resistance conduit for blood to travel from the right heart to the systemic circulation. However, to view the PA as a passive conduit is to underestimate the complex physiologic interactions between the neurohormonal control of vascular tone, environmental factors (including infectious agents, toxins, and prolonged hypoxia), and congenital abnormalities that may occur within the PA. An understanding of the normal PA physiology is of paramount importance in understanding the clinical course of pathologic disease states. Although the acute PA response to a congenital abnormality or an environmental insult may be beneficial in the short term, prolonged response may lead to a severely debilitating and life-shortening pathologic condition. Recognition of pathologic conditions within the PA and the role of altered PA physiology is the focus of this chapter.

The following sections attempt to provide a detailed discussion of the common and rare congenital and acquired abnormalities affecting the PA. The presentation, etiology, and clinical course of pathologic PA conditions are outlined. In order to provide guidance on the delivery and timing of optimal and appropriate therapy, the diagnostic work-up and data on medical, surgical, and percutaneous treatments are presented. Also discussed are “clinical pearls” that should lead the clinician to consider a rare PA abnormality over a more common disease process.

The precursors to the adult pulmonary arterial system become recognizable by day 27 of fetal development. The main PA forms from the division of the truncus arteriosus by the aorticopulmonary septum (Figure 46-1).¹ The right and left sixth aortic arches, known as the pulmonary arches, form the proximal right and left pulmonary arteries, respectively. By day 29 of embryologic development, the sixth aortic arches are continuous with the pulmonary trunk. The distal portion of the left sixth arch forms the ductus arteriosus, and the distal part of the right sixth arch involutes.² Buds from the sixth arch arteries grow into primitive lungs and anastomose with the primitive pulmonary circulation.³

The absence of a PA (PA interruption) and anomalous left PA (pulmonary sling) are two rare conditions resulting from abnormal embryologic development of the PA.² The absence of a PA is most likely the result of involution of the proximal sixth aortic arch with a corresponding reduction in lung size on the affected side. The blood supply to the affected lung is usually supplied through collateral vessels such as the bronchial or intercostal arteries. The anomalous left PA (Figure 46-2) is because of involution of the left sixth aortic arch with the blood supply being from a vessel of the right PA coursing between the trachea and esophagus toward the left.⁴

In the adult, the main PA exits the base of the right ventricle anterior and left of the aorta. The main PA then ascends posterior and medial for 4 to 5 cm until it divides into the right and left main pulmonary arteries. The left main PA (mean diameter 26.4 mm) continues in the same posterior direction until reaching the left main bronchus at which point it arches over the left main bronchus and descends posterior to it. The right main PA (mean diameter 23.4 mm) courses in a horizontal direction posterior to the aorta, superior to the vena cava, and anterior to the right main bronchus before further subdividing. While the course of the main pulmonary arteries is predictable, the branching patterns of lobar and segmental arteries demonstrate considerable variability.⁵ After passing over the left main bronchus, the left main PA usually continues to descend posterior in a vertical direction to form the left interlobar artery, from which the segmental arteries to the upper and lower lobes arise. However, the left main PA may give off an ascending branch that divides into the segmental branches of the upper lobe after passing over the left main bronchus.⁶ The right main PA divides into the ascending and descending branches anterior to the right main bronchus. The ascending artery usually further divides into segmental branches that supply the right upper lobe, while the descending branch further subdivides into the segmental arteries of the middle and lower lobes of the right lung.⁶ Although lobar and segmental branching demonstrate considerable variability, the branching pattern is intimately related to bronchial branching; a branch always accompanies the adjacent airway down to the level of the distal respiratory bronchiole.⁷ Furthermore, multiple “supernumerary” branches outnumber conventional branches and directly penetrate the lung parenchyma.⁷

Histologically, the pulmonary arteries can be divided into elastic, muscular, and arteriolar arteries.⁷ The elastic arteries include the main PA and its branches down to the level of the bronchi–bronchiolar junction. The elastic arteries are usually greater than 1 mm and function as a reservoir for right ventricular output. The muscular arteries are 1.0 to 0.1 mm in diameter and have a well-developed medial smooth muscle layer that thins progressively until it becomes arterioles. The arteriolar arteries are less than 0.1 mm in diameter and are made up of only a thin intima and a single elastic lamina. The pulmonary vasculature has been shown to undergo age-related changes similar to the systemic circulation such as decreased distensibility of elastic arteries, development of fatty streaks and atherosclerotic plaques, and progressive intimal fibrosis.^8,9,10

The normal pulmonary vascular bed is a low-pressure system in which resistance is less than one-tenth that of the systemic bed. During exercise, the normal pulmonary bed is able to accommodate a large increase in pulmonary blood flow with minimal rise in PA pressures as a result of recruitment of under-perfused segments. Alternatively, in response to hypoxia, blood flow is reduced to under-ventilated segments in order to improve ventilation perfusion matching.

The rapid and dynamic changes in pulmonary vascular tone result from a complex interplay between the endothelium, smooth muscle, platelets, and vasoactive mediators. The endothelium plays a central role in maintaining appropriate tone via the balanced production of vasoactive mediators. Such endothelial mediators are prostacyclin (PGI₂), nitric oxide (NO), and endothelin (ET-1). PGI₂ and NO are potent vasodilators, whereas ET-1 and serotonin (produced from platelets) act as vasoconstrictors. Through complex cellular pathways, many vasoactive mediators also have mitogenic functions in which they either inhibit or promote proliferation of endothelial and smooth muscle cells, as well as activation of platelets. In general, NO and PGI₂ can be thought of as vasodilators which inhibit both platelet activation, as well as proliferation of endothelial and smooth muscle cells. ET-1 and serotonin, on the other hand, promote cellular proliferation. While the mediators of vascular tone function to preserve health in the acute setting (i.e., vasoconstriction as a response to acute hypoxia), prolonged response or imbalance can have deleterious effects.

The pulmonary artery catheter (PAC), or Swan-Ganz catheter, was introduced into clinical practice in the 1970s in order to enhance the treatment of critically ill patients. The diagnostic procedure was rapidly embraced by many clinicians because of the ability of the PAC to provide hemodynamic information that was unavailable through other clinical tools. Clinicians reasoned that better treatment would be provided through the direct measurement of right-sided pressures (Figure 46-3), estimation of cardiac index and cardiac output via thermodilution techniques, and calculation of systemic and pulmonary vascular resistances. The use of the PAC was further supported by studies demonstrating the inability of clinician to estimate reliably these hemodynamic variables on clinical examination in the intensive care unit (ICU) setting.^11,12,13

During 1980s and 1990s, in spite of the lack of data from randomized controlled trials evaluating PAC efficacy, PACs were commonly used in surgical, trauma, advanced heart failure, and acute myocardial infarction patients, as well as in patients admitted to the ICU with sepsis and/or acute respiratory distress syndrome. It was widely believed that the information obtained from PACs improved mortality. Consequently, physicians were unwilling to randomize patients in clinical trials. However, the data obtained from large observational studies suggested that PACs had either no influence or a negative impact on mortality.^{14,15,16,17,18} The SUPPORT investigators provided alarming data on the aggressive use of PACs within the first 24 hours of admission to the ICU.¹⁴ Using a propensity score, a statistical method of adjusting for treatment bias, these investigators found the 30-day mortality to be higher in patients who received a PAC than those managed without a PAC. This study raised concern over the widespread use of PACs, although the observational nature of this study was called into question because of the potential for confounding variables, lack of uniformity in treatment styles, and data interpretation. In 1997, the National Heart, Lung, and Blood Institute conducted the Pulmonary Artery Catheterization and Clinical Outcomes workshop to develop recommendations regarding actions to improve PAC utility and safety.¹⁹ The two major outcomes of this workshop were the recognition of a need for randomized clinical trials assessing the efficacy of PACs in certain high risk patient populations and a need for standardized training in obtaining and interpreting PAC-derived information.

As a result of the National Heart, Lung, and Blood Institute workshop, multiple randomized controlled trials evaluating the effect of the PAC on mortality have been conducted.^{20,21,22,23,24,25,26,27} These studies have demonstrated neither an increased mortality nor improved survival associated with PAC use in heart failure,²⁰ ICU,^21,22,23 elective vascular surgery,^24,25,26 or high risk general surgery²⁷ populations. Despite the lack of mortality benefit demonstrated in these randomized trials, proponents of the PAC do not believe sufficient evidence exists for a moratorium on the PAC.²⁸ These proponents argue that the PAC is a diagnostic, not therapeutic, modality requiring proper data interpretation. Furthermore, they claim that the lack of PAC benefit is because of the shortage of specific therapies to treat the underlying conditions.²⁹ The PAC may exhibit a benefit when coupled with a treatment plan that is known to improve outcomes.^28,30 Despite the controversy, approximately one million PACs are used annually in the United States.³¹

The indications for PAC insertion, like any diagnostic test, are difficult to define. In general, the decision to place a PAC should be based on the need for information that will guide therapy and that is not available from a noninvasive modality. Furthermore, PACs should only be used by health care providers experienced in PAC management and interpretation, because of the potential for patient harm if data is misinterpreted. In general, the physician must weigh the risks versus the benefits of the PAC prior to placement.

Pulmonary hypertension (PH) is defined as a mean PA pressure greater than 25 mm Hg at rest or 30 mm Hg with exercise. Elevations in pulmonary vascular pressure can be caused by an isolated increase in pulmonary arterial pressure or by an increase in both pulmonary arterial and pulmonary venous pressure (precapillary vs. postcapillary). Because of the diverse etiologies, the World Health Organization proposed a classification scheme in 2003 to organize PH into categories (Table 46-1) that share similarities in pathophysiologic mechanisms, clinical presentation, and therapeutic options.³²

Pulmonary arterial hypertension (PAH) is a World Health Organization classification scheme subset in which patients have PH (mean PA pressure >25 mm Hg at rest) with a normal pulmonary capillary wedge pressure (<15 mm Hg).³³ However, because patients with lung disease or embolic disease may also have PH with a normal pulmonary capillary wedge pressure, PAH should be viewed as PH that is limited predominantly to constriction, proliferation, and in situ thrombosis within the arterial component of the pulmonary vasculature.³⁴ PAH can occur in the absence of a demonstrable cause (idiopathic PAH [IPAH] or familial PAH [FPAH]) or in relation to another condition, such as collagen vascular disease, congenital systemic-to-pulmonary shunt, HIV infection, portal hypertension, or drug toxicity.

Clinical Presentation

The presence of PH can come to clinical attention as a result of symptoms, screening in an at-risk population, or as an incidental finding.³⁵ A delay in the diagnosis is not uncommon, as the nonspecific symptoms of dyspnea and fatigue in patients with PH are often attributed to normal aging or weight gain. Dyspnea, the most common symptom, first presents with exertion because of an exaggerated increase in PA pressures with exercise. With disease progression, patients may develop angina, lower extremity edema or syncope. Angina is caused by decreased coronary blood flow secondary to hypertrophy of the right ventricle. With progressive right ventricular failure, lower extremity edema from venous congestion occurs. Near-syncope and syncope result from the exercise-induced right ventricular failure that is caused by an increase in PA pressures with exercise. Patients with PAH very rarely have symptoms of hemoptysis, orthopnea, or paroxysmal nocturnal dyspnea.

Diagnostic Evaluation

The importance of a thorough and accurate diagnostic work-up can not be overemphasized, as the etiology of PH is paramount to treatment and prognosis.³⁶ The goal in evaluation of the patient with PH is to define the hemodynamic abnormality and underlying disease state, determine prognosis, and develop a therapeutic plan.³⁴ A detailed medical history and physical examination should be performed to elucidate the presence of a family history of PH or any disease states or exposures that would place the patient at risk for PH. Figure 46-4 outlines a reasonable diagnostic algorithm for PH, with an emphasis on noninvasive testing initially. The transthoracic Doppler echocardiogram is an invaluable noninvasive tool in screening for PH, because of the strong correlation with invasive assessment of PA pressures.³⁷ The echocardiogram also allows evaluation of right and left ventricular function, valvular function, and evidence of intracardiac shunting from congenital heart disease. Caution must be taken in attributing PH to a collagen vascular disease based on serologic studies alone, as up to 40% of patients with IPAH have an abnormal serologic study.³⁸ Many patients will ultimately require cardiac catheterization to confirm the presence of PH, establish the etiology, assess severity, and guide therapy.³⁹

Pathophysiology of PAH

PAH comprises a group of disorders in which the vasculature of the PA develops vascular constriction, cellular proliferation, and in situ thrombosis. Histologically, the lung tissue demonstrates intimal fibrosis, increased medial thickness, pulmonary arteriolar occlusion, and plexiform lesions.⁴⁰ The mechanism which accounts for the structural alterations in the pulmonary arterial vasculature is not known. However, evidence exists that a complex interaction between a permissive genetic substrate, environmental factors, and alterations in the production of vasoactive mediators contribute to the development of PAH.^{41,42,43,44,45,46,47,48} A multihit theory has been suggested in which an individual with a genetic predisposition encounters additional insults before the disease manifests.^42,43 Although the exact mechanism by which PAH occurs has not been elucidated, an association between certain molecular abnormalities and particular clinical types of PAH has been identified.

Genetic studies have demonstrated that mutations in two receptors of the transforming growth factor-beta (TGF-β) family⁴⁹ and a serotonin transporter⁵⁰ provide the genetic substrate for the development of PAH in certain disease states. Bone morphogenetic protein receptor II (BMPR2) is a TGF-β receptor that functions to suppress the growth of vascular cells. Mutations within the BMPR2 gene result in altered signal transduction favoring vascular cell proliferation. BMPR2 gene mutations have been most strongly associated with FPAH.^44,51,52 However, mutations have also been observed in cases of IPAH,⁵³ as well as in patients in whom PAH develops after exposure to fenfluramine.⁵⁴ Activin-like kinase type-1 receptor (ALK1) is another TGF-β receptor family member that is believed to promote vascular growth after gene mutations through a similar aberrant signaling pathway as BMPR2 mutations.⁵⁵ Mutations in ALK1 have been observed in patients with hereditary hemorrhagic telangiectasia and PAH.⁵⁶ Finally, increased expression of an allelic variant of the serotonin transporter (5-HTT) gene, a promoter of PA smooth muscle cell proliferation, has been demonstrated to be present in a greater percentage of patients with IPAH compared with controls (65% vs. 27%).⁵⁰

In addition to a permissive genetic substrate, complex interactions between the mediators of vascular tone, the PA endothelium, smooth muscle cells, and platelets manifest and contribute to the development of PAH.⁴¹ Whether the involvement of each individual factor is a cause or a consequence in the development of PAH has not been entirely elucidated. Endothelial cell dysfunction, as a result of hypoxia, shear stress, inflammation, and toxic exposures, plays a central role in the promotion of the homeostatic imbalance that occurs within the pulmonary arterial system of patients with PAH.^34,41,42 Abnormal and disorganized endothelial proliferation results in the formation of the plexiform lesion. Injury to the endothelium affects its ability to perform appropriate homeostatic functions with regard to coagulation and the production of growth factors and vasoactive agents. Endothelial dysfunction promotes platelet activation and the creation of a prothrombotic state through elevated levels of von Willebrand factor and plasminogen activator type-1. The interaction between the dysfunctional endothelium and activated platelets leads to in situ thrombosis and platelet release of procoagulant, vasoactive, and mitogenic mediators.^41,57

Multiple perturbations in the pathways which maintain appropriate pulmonary arterial tone have been discovered (Table 46-2). Nitric oxide, a potent vasodilator, is produced locally by endothelial cells within the PA. Decreased nitric oxide synthase expression leading to vasoconstriction has been demonstrated in patients with PAH.⁴⁶ The metabolism of arachidonic acid to prostacyclin (PGI₂) and thromboxane is also altered by reduced endothelial expression of prostacyclin synthase in patients with PAH.⁴⁵ Reduced prostacyclin synthase activity results in decreased prostacyclin and increased thromboxane. The net effect is a loss of prostacyclin’s vasodilatory and antiproliferative properties, with a concomitant increase in vasoconstriction and platelet activation by thromboxane. Endothelin (ET-1) is a peptide with potent vasoconstrictor and mitogenic effects via endothelin receptor A (PA smooth muscle cells) and endothelin receptor B (PA smooth muscle cells and endothelial cells). ET-1 levels are elevated in patients with PAH of various etiologies.⁴⁸ Vasoactive intestinal peptide (VIP) has been shown to be a pulmonary vasodilator and inhibitor of platelet activation and vascular smooth muscle cell proliferation.^58,59,60 VIP has been implicated as having a role in progression of PAH because of the evidence of decreased VIP levels in patients with PAH.⁶¹ Finally, serotonin (5-HT), a mediator of vasoconstriction, smooth muscle cell proliferation and platelet activation, has been suggested to have a role in the development of PAH as a result of elevated plasma levels of 5-HT and depleted platelet 5-HT in this population.⁶²

Classification of PAH

PAH has been further subclassified into the following groups of disorders.

Idiopathic Pulmonary Arterial Hypertension

IPAH, formerly called primary PAH, is a distinct form of PAH which must be distinguished from other forms of PAH because of its unique clinical features, age of onset, and clinical course. This rare disease has an incidence of 2 to 5 per million per year.^34,63 National Registry Data has shown that most patients are diagnosed in the fourth decade of life (mean age 37 years) with a female to male ratio of 1.7:1.³⁸ Other forms of PAH must be excluded in order to make the diagnosis of IPAH.

Familial Pulmonary Arterial Hypertension

FPAH is a form of IPAH in which genetic transmission of the disease state occurs. FPAH accounts for at least 6% of all cases of PAH. Mutations in the BMPR2 gene are believed to be the causative agent of FPAH.^44,52 Unique features of the transmission of FPAH include incomplete penetrance and genetic anticipation and development of a more severe phenotype at a younger age. Because the BMPR2 gene mutation has been identified in 25% of patients with IPAH and both diseases have similar clinical and pathologic features, IPAH and FPAH are thought to be related diseases.

Diseases Associated with PAH

Multiple disease processes have been associated with the development of PAH. The associated disease may be regarded as one of the “hits” leading to the development of PAH.³⁴

Collagen Vascular Disease

Collagen vascular disorders associated with the development of PAH include scleroderma, systemic lupus erythematosus (SLE), mixed connective tissue disease (MCTD), and rheumatoid arthritis. Of the collagen vascular disorders, scleroderma is the most common cause of PAH.⁶³ Autopsy studies have demonstrated evidence of PAH in up to 70% of scleroderma patients, with a higher prevalence in limited, rather than diffuse, scleroderma.^64,65 The presence of PAH portends a worse prognosis relative to scleroderma patients without PAH.⁶⁶ In multiple studies, Doppler echocardiogram has demonstrated the presence of PAH despite the lack of respiratory symptoms in a high percentage (23%–35%) of patients with scleroderma.^65,67 Thus, routine screening for PAH in the scleroderma population has been recommended. A strong association between PAH and Raynaud’s phenomenon has also been observed.⁶⁸

Congenital Systemic to Pulmonary Shunts

Congenital systemic to pulmonary shunts are a well recognized cause of PAH. Lesions with a left to right shunt (such as atrial septal defect, ventricular septal defect, patent ductus arteriosus, and truncus arteriosus) lead to chronically elevated pulmonary blood flow and mechanical stress on the pulmonary endothelium. If a significant left to right shunt (pulmonary flow/systemic flow >1.5) is not corrected, reversal of flow (Eisenmenger syndrome) may result. Children with congenital systemic to pulmonary shunts should be evaluated and followed by pediatric cardiologists experienced in the treatment of congenital heart defects. Of the conditions associated with the development of PAH, congenital heart disease has the best prognosis.

Portal Hypertension

Portopulmonary hypertension (PPHTN) is defined as PAH in the setting of underlying portal hypertension (portal pressure >10 mm Hg).⁶⁹ Of the patients diagnosed with PAH, 9% have portal hypertension.⁷⁰ Cirrhosis is not necessary for the development of PAH, as evidenced by cases of PPHTN in which portal hypertension was caused by nonhepatic causes.⁷¹ The prevalence of PAH in patients with portal hypertension is 2% to 5%.^72,73 However, the risk of developing PAH increases with the duration of portal hypertension.⁷³ On average, PPHTN is diagnosed in the fifth decade with an even male to female distribution.^69,74,75 The mean survival after diagnosis is 15 months with a median survival of 6 months.⁷⁴ The factors initiating endothelial injury and leading to the development of PAH are not known but appear to be more complicated than shear stress from increased pulmonary blood flow.⁷⁶ Finally, in patients undergoing lung transplantation, the presence of moderate or severe PAH is known to increase mortality and morbidity.^77,78

HIV Infection

HIV infection as a causative agent in the development of PAH is supported by a higher prevalence of PAH in HIV infected patients than in the general population (0.5% vs. 0.02%).⁷⁹ Direct viral action on endothelial and smooth muscle cells has been dismissed as a possible mechanism as a result of the lack of viral material in lung tissue and lack of data showing that endothelial cells are capable of supporting growth of HIV.^80,81 Furthermore, monkeys infected with the simian immunodeficiency virus developed PAH similar to that seen in humans, but viral material was not identified within the lung tissue.⁸² Alterations in pulmonary endothelial cell homeostasis or an autoimmune mechanism is now believed to be the most logical mechanism for PAH.^83,84 The development of PAH is not related to the degree of immunosuppression or the CD4 cell count.⁸⁵ PAH in patients infected with HIV portends a poor prognosis, with median survival of 6 months after diagnosis of PH.⁸⁴ Controversy exists with regard to the impact of treatment of HIV on progression of PAH.^84,86,87

Drugs and Toxins

Several appetite suppressants (anorexic drugs) are well known to increase risk for the development of PAH. Aminorex, fenfluramine, and dexfenfluramine have all been withdrawn from clinical use by the U.S. Food and Drug Administration (FDA) because of the increase risk of PAH is associated with consumption.^88,89 Fenfluramine has been shown to increase the odd of developing PAH by a factor of 6.3. The risk increases to a factor of 23.1 when exposed for greater than 3 months. The mechanism by which anorexic drugs lead to PAH is thought to be related to inhibition of voltage gated potassium channels (vasoconstriction because of the increased intracellular calcium) and depressed basal nitric oxide production.^90,91

PAH Associated with Venous or Capillary Involvement

PAH associated with venous or capillary involvement consists of two rare disorders: pulmonary veno-occlusive disease and pulmonary capillary hemangiomatosis. Histologically, these disease entities resemble other forms of PAH. However, the vasculopathy involves not only the precapillary vasculature but also the capillaries, venules, and veins. Clinically, these disease entities can be difficult to distinguish from IPAH. Development of pulmonary edema after initiation of medical therapy with calcium channel blocker and epoprostenol has been reported.^92,93 Patients should be referred promptly to a lung transplant center for evaluation early in the course of the disease.

Persistent Pulmonary Hypertension of the Newborn

Persistent pulmonary hypertension of the newborn (PPHN) exist in three forms: hypertrophic, hypoplastic, and reactive. The hypertrophic form results in hypertrophied muscular tissue of the pulmonary arteries as a result of chronic fetal distress. Hypoplastic PPHN involves underdevelopment of the pulmonary arteries because of either congenital diaphragmatic hernia or amniotic fluid leakage. The reactive form has normal lung tissue but vasoconstriction because of an imbalance of vasoactive mediators.

Prognosis

The natural history and prognostic variables in patients with PAH is best studied in the IPAH population. The National Institute of Health (NIH) registry on the natural history of IPAH has demonstrated that the median survival is 2.8 years with a 1-, 3-, and 5-year survival rates of 68%, 48%, and 34%, respectively.⁹⁴ Relative to IPAH, PAH in association with either HIV or collagen vascular disease has a worse prognosis, whereas patients with PAH in the setting of congenital heart disease fare better.⁹⁵

Clinical factors that predict a favorable outcome in patients PAH have been elucidated.⁹⁵ Functional class (Table 46-3), exercise tolerance (6-minute walk test [6MWT]), presence of a pericardial effusion, and hemodynamic variables have shown correlation with clinical outcome. Multiple studies have demonstrated that the NYHA Functional Class (NYHA-FC) is associated with improved survival and can be used as a predictor of mortality.⁹⁵ For example, the median survival of IPAH patients with NYHA- FC I or II is 6 years versus 2.5 years for patients with NYHA-FC-III and 6 months for NYHA-FC-IV.⁹⁴ Furthermore, IPAH patients with NYHA-FC IV have a significantly higher risk of death relative to patients with NYHA-FC I, II, or III when receiving similar medical therapy.^96,97 Finally, IPAH patients who are in NYHA-FC III or IV and who fail to respond after 3 months of treatment have worse survival relative to those whose symptoms improve.⁹⁸

The 6MWT is an easy, safe, and reproducible test for the assessment of exercise capacity in patients with PAH. Multiple studies have demonstrated that baseline distance during the 6MWT is predictive of survival.^99,100,101 However, comparison of different distances and treatments modalities in each study limit the ability to assign a predicted survival to a distance walked. Echocardiography studies in patient with IPAH have found that the presence and severity of a pericardial effusion is an independent predictor of poor outcome in patients with IPAH.^102,103 The negative effect of a pericardial effusion on exercise tolerance is as a result of impairment of right heart function. In individual studies, multiple different hemodynamic variables have been shown to predict outcome in IPAH patients.^{94,104,105,106} However, mean right atrial pressure (mRAP) and cardiac index have most consistently demonstrated predictive value, with mRAP being the most powerful hemodynamic predictor of survival.⁹⁵

Treatment

The leading cause of death in patients with PAH is progressive right heart failure. Thus, treatment of patients with PAH is aimed at improving or halting the progression of right heart failure, in order to improve symptoms and functional class as well as prolong life and delay the potential need for lung transplantation. A delay in the diagnosis of PAH of months to years is not uncommon as the nonspecific symptoms early in the course of the disease are often attributed to normal aging or weight gain. Unfortunately, 70% to 90% of patients have developed NYHA-FC III or IV symptoms by the time the correct diagnosis is made.³⁶ As such, most clinical trials have focused on NYHA-FC III or IV patients with little data on the benefits and risks of treating patients who are less symptomatic or have only mildly elevated PA pressures.^34,36 Patients should be referred to a specialized medical center experienced in the treatment of PAH to receive appropriate tailored therapy. Medical therapies for the treatment of patients with PAH can be divided into lifestyle alterations, conventional therapies, and vasodilator therapy. Finally, most available data is from studies of patients diagnosed with IPAH.

Lifestyle Alterations

Patients with PAH must be educated as to activities which are potentially hazardous to their well being. In general, any activity that has the potential to cause hypoxemia, pulmonary vasoconstriction, or syncope must be avoided.³⁹ In patients with PAH who have cardiac arrest, resuscitation has demonstrated limited success (6% at 90 days).¹⁰⁷ High altitude and air travel may not be well tolerated because of the potential for hypoxia, pulmonary vasoconstriction, and worsening of right-sided heart failure. Decongestants and appetite suppressants must also be avoided because of the risk of worsening PH. Also, heavy exertion increases the risk for syncope, cardiopulmonary arrest, and death. However, low-dose exercise may be beneficial to patients with PAH.¹⁰⁸ Patient should be advised to receive immunization against influenza and pneumococcal pneumonia. Pregnancy should be discouraged as the hemodynamic changes during pregnancy impose a significant stress on women with PAH, with a resultant mortality rate of 30% to 50%.¹⁰⁹ Finally, elective surgery should be approached with caution because of high risk for vasovagal events which can rapidly lead to syncope, cardiopulmonary arrest, and even death.³⁶

Conventional Therapies

Anticoagulation with warfarin for patients with IPAH has demonstrated a survival benefit in two small trials.^110,111 Based on these findings and the known role of in situ thrombosis in the pathogenesis of IPAH, warfarin therapy is generally recommended in the absence of contraindications, although the optimal INR is not known. As a result of the vasoconstrictor effects of hypoxia, oxygen supplementation is recommended to maintain oxygen saturation greater than 90%. Diuretics are indicated for the management of volume overload from right-sided heart failure. Digoxin has been used in the presence of right heart failure¹¹² and for rate control in patients with atrial fibrillation or atrial flutter. However, limited data is available on the efficacy of digoxin in PAH.

Vasodilator Therapy

Several medications with pulmonary arterial vasodilatory effects have been approved by the FDA and are available for clinical use in patients with PAH. Figure 46-5 outlines the therapeutic approach to NYHA-FC III and IV patients with PAH. The therapeutic agent to be chosen depends upon the results of acute vasodilator testing and NYHA functional class. Acute reversibility to vasodilator therapy is defined as a drop in mean PAP by at least 10 mm Hg to less than 40 mm Hg with either an increase or no change in cardiac output. Inhaled nitric oxide, intravenous epoprostenol, and intravenous adenosine are all short-acting pulmonary vasodilators which are acceptable for use in testing for reversibility. Patients with NYHA-FC IV symptoms or overt right heart failure probably should not undergo vasodilator testing, as they are not candidates for calcium channel blocker (CCB) therapy and the risks of the test outweigh the benefit.³⁴

Calcium Channel Blockers

Patient who will derive a survival benefit from long-term therapy with calcium channel blockers (CCBs) can be identified by vasodilator testing.^111,113 Unfortunately, only a small percentage of patients (12.8%) demonstrate a positive response to vasodilator testing and only half of those patients (6.8%) will have a favorable long-term response.¹¹⁴ However, because of the potential for drastic improvement in functional class (NYHA-FC I or II) over a prolonged period and the relative ease of therapy relative to other treatment regimens, nearly all patients should be evaluated for CCB therapy. After initiation of therapy with an oral CCB (nifedepine, diltiazem, or amlodopine), patients must be assessed regularly to ensure a sustained response. If the patient does not achieve NYHA-FC I or II with near normal hemodynamics during the first year of follow-up, treatment with an alternative agent should be pursued.^34,115

Prostacyclin

Prostacyclin (PGI₂) is a potent vasodilator, inhibitor of smooth muscle cell proliferation, and inhibitor of platelet activation. Prostacyclin is available in intravenous (epoprostenol, treprostinil, iloprost), subcutaneous (treprostinil), and inhaled (iloprost) forms in the United States. Beraprost, an oral prostacyclin, is available in Japan but not the United States because of the lack of data supporting long-term efficacy.¹¹⁶ All forms of PGI₂ have short half lives requiring either continuous infusion or frequent administration. Continuous epoprostenol infusion is approved by the FDA for NYHA-FC III and IV patients with IPAH because of its positive impact on exercise tolerance, hemodynamics, and long-term survival.^98,101 Epoprostenol should be considered first line therapy for patients with NYHA-FC IV symptoms as a result of the proven survival benefit.⁹⁸ Epoprostenol also has FDA approval for PAH patients with scleroderma. Because epoprostenol administration requires continuous infusion through an indwelling central venous catheter, concern over line infection, catheter associated thrombus, and rebound PH with interruption of therapy add to the complexity of epoprostenol therapy. Treprostinil (subcutaneous and intravenous) is a more stable prostacyclin which has FDA approval for NYHA-FC II, III, and IV patients because of its ability to improve 6MWD and hemodynamic parameters.^117,118 Intravenous treprostinil is only approved for patients who develop intolerable pain and erythema at the subcutaneous infusion site. Although the longer half-life of treprostinil (4 hours) relative to epoprostenol is advantageous, epoprostenol is the only vasodilator proven to prolong survival. Inhaled iloprost has demonstrated improvement with regard to 6MWD, NYHA-FC, and hemodynamic variables.^119,120 Iloprost is approved for patient with NYHA-FC III of IV symptoms. However, because of a short half-life, iloprost require six to nine inhalations per day.

Endothelin Receptor Antagonists

Endothelin-1 (ET-1) is a potent vasoconstrictor and smooth muscle mitogen. ET-1 works through endothelin receptor A (ETA), present on PA smooth muscle cells, and endothelin receptor B (ETB), present on PA smooth muscle cells and endothelial cells. Activation of ETA and ETB receptors on smooth muscle cells leads to vasoconstriction and proliferation of vascular smooth muscle, whereas endothelial ETB receptor activation leads to vasodilatation via endothelial release of nitric oxide and prostacyclin. Bosentan is a dual ETA/ETB receptor antagonist approved by the FDA for NYHA-FC III and IV patients as a result of improvement in 6MWD, NYHA-FC, and hemodynamic variables.^121,122 Because of a theoretical advantage of selective ETA receptor antagonism, selective ETA receptor agents are currently under investigation.

Phosphodiesterase-5 Inhibitors

The vasodilatory response to nitric oxide is dependent upon the presence of cyclic guanosine monophosphate (cGMP). Phosphodiesterases (PDEs) function to inactivate cGMP. Thus, inhibition of PDE-5, an isoform found in the lung, has the potential to augment the pulmonary vascular response to nitric oxide.¹²³ Sildenafil, a PDE-5 antagonist, is approved by the FDA for treatment of PAH because of the beneficial impact of sildenafil on exercise capacity, NYHA-FC, and hemodynamics.¹²⁴

Combination Therapy

The different mechanisms of action of the various drugs currently available make combination therapy an intriguing option. Studies are currently ongoing to determine if combination therapy will be of clinical benefit.

Atrial Septostomy and Lung Transplantation

In atrial septostomy, a right to left intraatrial shunt is created in order to decompress the failing right heart and increase filling of the left-sided heart chambers. Atrial septostomy has substantial risk and is offered only as palliation or as a bridge to lung transplantation. The primary indication for lung transplantation in patients with PAH is clinical deterioration despite optimal medical therapy. Survival at 1 year for PAH is approximately 70%.¹²⁵

Aneurysms of the PA have been defined pathologically as localized vascular dilatations with deterioration of one or more layers of the vessel wall.¹²⁶ Clinically, PA aneurysms (PAAs) are radiologically demonstrable blood-filled sacs formed by dilatation of the walls of the artery.¹²⁷ Dissecting aneurysm refers to blood tracking within the arterial wall as a result of a tear in the intimal layer. Pseudoaneurysms or false aneurysms result from a breach in all layers of the vessel wall but with contained blood from compression by surrounding structures and clotting.

PA aneurysms are quite rare. The largest review found only eight cases of PAA in 109 571 autopsies performed—an incidence of one in 13 696.¹²⁸ Previous classification schemes have grouped PAAs as congenital or acquired,¹²⁹ large vessel or medium/small vessel,¹³⁰ and those with and without associated arteriovenous communications.¹²⁷ These classification schemes are limited because of the diverse etiology, poor understanding of the pathophysiology, and the probable interplay of multiple factors leading to the development of PAAs. The conditions known to be associated with the development of PAAs include (Table 46-4): infection (mycotic), congenital heart disease, PH, inherent weakness in the arterial wall and trauma. The primary factor leading to the development of a PAA is often difficult to elucidate as many patients have more than one condition; that is, congenital heart disease with PH¹³¹ or congenital heart disease and endocarditis.¹³²

Infection plays a significant role in the development of PAAs. In the past, syphilis and tuberculosis (Rasmussen’s aneurysm) were the most common causative agents. Autopsy studies have demonstrated an incidence of PAAs of at least 4% in patients with untreated tuberculosis.¹³³ However, with the development of antibiotics and public health screening programs, PAAs from syphilis and tuberculosis are now rarely seen in developed countries. Pyogenic bacteria (i.e., Staphylococcus aureus, Streptococcus spp., and corynebacterium diphtheriae) and fungal species (Candida albicans and Aspergillus flavus) play a more prominent role. Whereas syphilis and tuberculosis alone can lead to the development of a PAA,¹²⁷ mycotic aneurysms associated with bacterial and fungal infections often occur in association with concomitant congenital heart disease, PH, or right-sided endocarditis.¹³⁴ Three mechanisms account for the development of mycotic aneurysms. In tuberculosis, the mechanism of aneurysm formation is caused by the external destruction of the vessel wall, replacement with granulation tissue and ultimately vessel weakness with aneurysm formation or rupture. PAAs from syphilis result in weakening of the vessel wall and atherosclerotic changes due infection of the vasa vasorum by Treponema pallidum.¹³⁵ The development of PAAs in patients with bacterial and fungal infections is from direct invasion of the intima of the pulmonary vessel at the site of septic embolism.¹³⁴

While the association of congenital heart disease with PAAs is firmly established, the pathogenesis is not clearly understood. Although structural abnormalities of the arterial wall are often observed, it is unknown if these abnormalities are inherent or acquired.¹³⁶ Acquired lesions could result from increased pulmonary blood flow resulting in the development of PH,¹²⁷ abnormal high velocity vascular jets,¹³⁷ or an association with endocarditis.¹³⁸ Patent ductus arteriosus is the most common congenital anomaly associated with PAA formation. Atrial septal defect, ventricular septal defect, tetralogy of Fallot and transposition of the great vessels have also been associated. While the above congenital conditions of PAAs often occur in patients with PH, congenital pulmonary stenosis, and congenital pulmonary regurgitation are worthy of mention because of their occurrence in patients with normal pulmonary pressures. The proximal PAA that forms in patients with pulmonary valve abnormalities probably results from abnormal valve opening and asymmetric jet of blood flow (stenosis) and abnormal stress from increased stroke volume (regurgitation) leading to weakening of the vessel wall.¹³⁹

Although case reports exist of patients with PAAs in which PH was the only identified pathogenic factor,¹⁴⁰ other factors are usually present. The role of PH in the development of PAAs is because of the presence of atheromatous disease (cystic medial necrosis) which leads to weakness within the wall of the vessel.¹⁴¹ Patients with Marfan’s syndrome are at risk for development of PAAs as a result of inherent vessel wall weakness from fibrillin deficiency and the presence of cystic medial necrosis.¹⁴² Vasculitis, most notably Bechet disease,^143,144,145 can also affect the pulmonary arteries and lead to the development of PAAs via weakness in the vessel walls. Other vasculitis associated with PAAs includes giant cell arteritis¹⁴⁶ and microscopic polyangiitis.¹⁴⁷ Hugh-Stovin syndrome (aneurysms of the PA, thrombosis of peripheral veins and dural sinuses) is thought to share a common mechanism with Bechet disease.¹⁴⁸

Trauma can lead to PAAs either from intravascular (Swan-Ganz catheter) or external (chest wall or surgical) injury. The majority of traumatic PAAs is actually pseudoaneurysms and will be discussed separately.

PAAs are often overshadowed by the underlying medical condition and often only come to medical attention because of an abnormality on a routine chest radiogram (CXR). PAAs must be considered in the work-up of a pulmonary nodule because of the potential morbidity and mortality of percutaneous needle biopsy of an aneurysm.¹⁴⁹ Symptoms of a PAA include hemoptysis, precordial pain caused by dissection, dyspnea, or cough. Of patients who present with hemoptysis, 3% to 6% is accounted for by PAAs.¹⁵⁰ The most life-threatening complications of PAAs are rupture and dissection. Other complications of PAAs are because of the compression of adjacent structures: coronary artery,¹⁵¹ pulmonary vein,¹⁵¹ and bronchus.¹⁵²

While angiography is still considered the “gold standard” for diagnosis of PAAs, invasive imaging can be reserved until intervention is planned (Figure 46-6). Computed tomography (CT), magnetic resonance imaging (MRI) and echocardiography are reasonable first-line diagnostic tests.¹³⁰

Other than treatment of the underlying etiology of the aneurysm, the optimal management strategy for PAAs is not known. Factors that are believed to increase risk of dissection or rupture are the presence of PH¹⁵³ and hemoptysis.¹²⁷ Because of the increased wall stress with any change in size (LaPlace’s law), many advocate for an aggressive approach in all patients with a PAA. Certainly, the presence or absence of PH must be assessed. Although at least one case report exists in which a patient with severe PH is alive several years after diagnosis of a “giant” (greater than 5 cm) aneurysm,¹⁵⁴ a more aggressive approach is warranted. Because of increased surgical risk in patients with PH, endovascular stenting¹⁵⁵ and embolization with coils¹⁵⁶ is an alternative that may become the preferred therapy. In patients with Behcet disease (BD), improved survival has been demonstrated in patients who received embolization therapy versus those who underwent surgery.¹⁵⁷ Patients without PH or pulmonic valve pathology can follow more conservative management as they have confirmed late survival.¹⁵⁸

Pseudoaneurysms or false aneurysms of the PA result from a breach in all layers of the vessel wall but with contained blood from compression by surrounding structures and clotting. Pseudoaneurysms may result from trauma (intravascular or extravascular), malignant lung tumors, infections, and rarely, in primary PH.¹⁵⁹ Intravascular trauma occurs mostly in association with placement of intravascular catheters (i.e., Swan-Ganz catheter). Extravascular trauma from chest tube placement,¹⁶⁰ penetrating chest wall injury, surgery in the thorax (i.e., Glenn operation),¹⁶¹ or blunt trauma¹⁶² can result in pseudoaneurysm formation. Malignant tumors that have been reported to lead to the development of pseudoaneurysms include metastatic angiosarcoma,¹⁶³ bronchial carcinoma,¹⁶⁴ squamous cell carcinoma,¹⁶⁵ and pulmonary leiomyosarcoma.¹⁶⁶

The incidence of pseudoaneurysm formation from placement of a PA catheter is 1 per 1600 cases.¹⁶⁷ While the mechanism by which the PA catheter causes pseudoaneurysm formation has not been elucidated, plausible mechanisms include pressure from the expanded balloon exceeding the tensile strength of vessel wall,¹⁶⁸ “spearing” of the vessel wall by the catheter tip,¹⁶⁹ retraction of the wedged balloon and flushing of the wedged catheter.¹⁷⁰ Risk factors for pseudoaneurysm formation include anticoagulation, older than 60 years of age, improper balloon inflation, improper catheter positioning, cardiopulmonary bypass with catheter in place,¹⁷⁰ and chronic steroid administration.¹⁷¹ Conflicting data exist over the contribution of PH to pseudoaneurysm formation.¹⁷²

Rupture of a PA with compression by lung parenchyma and clot formation is the nidus for pseudoaneurysm formation. Most pseudoaneurysms present as hemoptysis during the inciting event.¹⁷³ However, some patients remain asymptomatic and only come to clinical attention years later.¹⁷⁴ In either case, treatment is warranted as a result of the high mortality associated with an observational approach.¹⁷⁵ While spiral is a useful noninvasive modality for diagnosis of pseudoaneurysms, angiography remains the gold standard (Figure 46-7). Angiography not only allows imaging of the pseudoaneurysm but also allows for immediate treatment of the abnormality. Embolization with coils is the treatment of choice for most PA pseudoaneurysms because of high success rate and limited morbidity compared to surgical resection.¹⁷³

Pulmonary arteriovenous malformations (PAVMs) are abnormal direct communications between a branch of the PA and pulmonary vein which may be small telangiectasias or associated with an aneurysm. Because these anomalies lack an intervening capillary bed, direct communication exists between the pulmonary and systemic circulations. Hypoxemia may result (right-to-left shunt), as well as polycythemia. Fifty percent of patients remain asymptomatic,¹⁷⁶ although significant hypoxemia may be present. However, even in patients without hypoxemia or symptoms, a substantial risk for paradoxical emboli exists.¹⁷⁷

PAVMs are usually congenital but can be acquired. Congenital causes include hereditary hemorrhagic telangiectasia (HHT), that is, Osler-Weber-Rendu disease and Fanconi syndrome. The most common congenital cause of PAVMs is HHT, which accounts for more than 80% of congenital cases¹⁷⁸ and at least 60% of all cases.¹⁷⁹ Acquired causes of PAVMs include postthoracic surgery, trauma, hepatic cirrhosis, metastatic carcinoma, mitral stenosis, systemic amyloidosis, bronchiectasis, and infections (tuberculosis, actinomycosis, and schistosomiasis).^{180,181,182,183,184,185,186}

Hereditary hemorrhagic telangiectasia (HHT) consists of a classic triad of epistaxis, telangiectasias, and a family history of the disorder. Because most PAVMs occur in patients with HHT, it is important to consider this disease entity in patients with a PAVM. In order to increase diagnostic accuracy of HHT, four criteria have been developed: spontaneous recurrent nose bleeds, mucocutaneous telangiectasia, visceral involvement, and an affected first-degree relative.¹⁸⁷ Definite HHT is present when patients have three criteria, suspected HHT if two criteria are present, and unlikely HHT when only one criterion is present.