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Pulmonary Vascular Disease Suspect PH based on history and exam Perform screening echocardiography Reassess likelihood of PH lf risk of PH low consider alternate diagnosis lf advanced heart or lung disease, Exclude left heart or advanced lung disease treat underlying disease, not PH V/Q scan to exclude CTEPH lf V/O other than low probability for PE, consider CTEPH Refer to PH expert center Confirm PH diagnosis with PA catheter Confirm PH group/subgroup with ancillary studies FIGURE l6.Algorithm{ortheevaluationof pulmonaryhypertension.ClEPH=chronicthromboembolicpulmonaryhypertension; PA=pulmonaryartery; PE=pulmonary embolism; PH = pulmonary hypertension; V/0 = ventilation/perfusion. tIGURE lT.Apicalfour-chamberviewsofechocardiogramsfromapatientwithidiopathicpulmonararterial hypertension(left) andahealthyperson(right).Asseenhere, dilation of the right ventricle and right atrium is a common finding in patients with pulmonary arterial hypertension. 42

Pulmonary Vascular Disease arterioles. Imbalances in nitric oxide, prostacyclin, and I(EY POII{T endothelin affect vascular tone and endothelial and smooth r Pulmonary arterial hlpertension can occur in association muscle cellular growth and Iead to vascular narrowing. with connective tissue diseases, portal hlpertension, Accordingly, these pathways are the primary targets for congenital heart disease, HIV infection, drug use, and available therapy. toxin exposure. There are several subclassifications of group 1 PAH based on etiologz of disease (see Table 30). Idiopathic PAH (previously referred to as primary PH) is typically seen in Diagnosis middle aged adults, particularly women. Heritable forms The diagnosis of PAH requires an elevated mPAP attributa account for up to 10% of cases, with the majority attributable ble to high pulmonary vascular resistance. Cardiac output to autosomal dominant mutations in bone morphogenetic and pulmonary capillary wedge pressure should be normal protein receptor type 2 (BMPR2). PAH can also occur in asso or low and left heart or lung disease should be excluded as ciation with connective tissue diseases, portal hypertension, a potential cause. Lung biopsy poses a significant risk for congenital heart disease, HIV infection, drug use, and toxin patients with PAH and is not indicated in the diagnostic exposure. evaluation. Laboratory studies can identify potential causes Approximately 10% of patients with systemic sclerosis for PAH and should include HIV serologies, liver chemis develop PAH. In these patients, disease is often refractory to tries, thyroid function tests, and autoantibody titers includ- treatment and outcomes are worse than in PAH from other ing antinuclear antibody. Pulmonary function testing that is causes. Patients with Iimited cutaneous systemic sclerosis normal, with the exception of a marked decrease in Dlco, may be at the highest risk. PAH can rarely be seen in rheuma supports a diagnosis of PAH. Current guidelines recom toid arthritis and systemic lupus erythematosus. mend genetic screening for all patients with idiopathic PAH Portopulmonary hypertension affects some patients who or PAH associated with anorexigenic drugs (intended to have chronic liver disease (see MKSAP 19 Gastroenterologr and reduce the appetite), as well as for patients with a family Hepatologz). The mechanism remains unclear, but it may be history of PAH. related to the diseased liver's inability to metabolize vasoactive I(EY POITIT substances. . The diagnosis of pulmonary arterial hlpertension requtes PAH in patients with HIV infection is not common, but an elevated mean pulmonary artery pressure attributable HlV-infected patients have a disproportionately higher risk of to high pulmonary vascular resistance. developing PAH compared with patients without HIV infec tion. Both viral and host factors have been implicated, and disease can occur in the absence of AIDS related complica Management tions. The drugs most strongly associated with PAH are iisted Therapy fbr PAH is directed at reducing vasoconstriction and in Table 31. interrupting the pathways mediating cellular proliferation. Initial therapy should be determined on the basis of disease severity (Table 32). In most patients, a combination of TA,BLE 31. Drugs and Toxins Associated With Pulmonary PH-specific therapies targeting separate pathways within the Arterial Hypertension pulmonary circulation is associated with superior outcomes Rapeseed oil compared with single agent therapy. In a small proportion of Am in orex/dexfe nflu ra mine/benfluorex patients, high dose calcium channel blockers are effective. Hepatitis C antiviral therapies Calcium channel blockers should be reserved for "vasoreac- tive" patients who demonstrate marked improvement in mPAP lnterferon cr and B with the administration of nitric oxide, epoprostenol, or aden Dasatinib and bosutinib osine during right heart catheterization. Although survival Methamphetamines and other amphetamines among vasoreactive patients is superior to that among other Cocaine patients with PAH, close follow-up of these patients is required, Phenylpropa nola m ine as many become nonvasoreactive within a few years of diag nosis and subsequently require conventionai PAH therapy. The L-tryptophan absence of vasoreactivity during right heart catheterization St John's wort does not suggest that a patient will not benefit from appropri lndirubin ate PAH therapy. Leflunomide Additional treatments include diuretic therapy and a low Alkylating agents sodium diet to combat volume overload. Women of reproductive age who have PAH should be counseled on the risks of preg lnformation from Simonneau G, Montani D, Celermajer DS, et al- Haemodynamic definitions and updated clinical classification o{ pulmonary hypertension. Eur Respir nancy and advised against it. In patients with atrial fibrillation, J. 201 9;53. lPMl D: 305459681 doi:1 0.1 1 83/1 3993003.0 1 91 3-20 1 I attempts to restore normal sinus rhy'thm should be pursued, as

arterioles. Imbalances in nitric oxide, prostacyclin, and I(EY POII{T endothelin affect vascular tone and endothelial and smooth r Pulmonary arterial hlpertension can occur in association muscle cellular growth and Iead to vascular narrowing. with connective tissue diseases, portal hlpertension, Accordingly, these pathways are the primary targets for congenital heart disease, HIV infection, drug use, and available therapy. toxin exposure. There are several subclassifications of group 1 PAH based on etiologz of disease (see Table 30). Idiopathic PAH (previously referred to as primary PH) is typically seen in Diagnosis middle aged adults, particularly women. Heritable forms The diagnosis of PAH requires an elevated mPAP attributa account for up to 10% of cases, with the majority attributable ble to high pulmonary vascular resistance. Cardiac output to autosomal dominant mutations in bone morphogenetic and pulmonary capillary wedge pressure should be normal protein receptor type 2 (BMPR2). PAH can also occur in asso or low and left heart or lung disease should be excluded as ciation with connective tissue diseases, portal hypertension, a potential cause. Lung biopsy poses a significant risk for congenital heart disease, HIV infection, drug use, and toxin patients with PAH and is not indicated in the diagnostic exposure. evaluation. Laboratory studies can identify potential causes Approximately 10% of patients with systemic sclerosis for PAH and should include HIV serologies, liver chemis develop PAH. In these patients, disease is often refractory to tries, thyroid function tests, and autoantibody titers includ- treatment and outcomes are worse than in PAH from other ing antinuclear antibody. Pulmonary function testing that is causes. Patients with Iimited cutaneous systemic sclerosis normal, with the exception of a marked decrease in Dlco, may be at the highest risk. PAH can rarely be seen in rheuma supports a diagnosis of PAH. Current guidelines recom toid arthritis and systemic lupus erythematosus. mend genetic screening for all patients with idiopathic PAH Portopulmonary hypertension affects some patients who or PAH associated with anorexigenic drugs (intended to have chronic liver disease (see MKSAP 19 Gastroenterologr and reduce the appetite), as well as for patients with a family Hepatologz). The mechanism remains unclear, but it may be history of PAH. related to the diseased liver's inability to metabolize vasoactive I(EY POITIT substances. . The diagnosis of pulmonary arterial hlpertension requtes PAH in patients with HIV infection is not common, but an elevated mean pulmonary artery pressure attributable HlV-infected patients have a disproportionately higher risk of to high pulmonary vascular resistance. developing PAH compared with patients without HIV infec tion. Both viral and host factors have been implicated, and disease can occur in the absence of AIDS related complica Management tions. The drugs most strongly associated with PAH are iisted Therapy fbr PAH is directed at reducing vasoconstriction and in Table 31. interrupting the pathways mediating cellular proliferation. Initial therapy should be determined on the basis of disease severity (Table 32). In most patients, a combination of TA,BLE 31. Drugs and Toxins Associated With Pulmonary PH-specific therapies targeting separate pathways within the Arterial Hypertension pulmonary circulation is associated with superior outcomes Rapeseed oil compared with single agent therapy. In a small proportion of Am in orex/dexfe nflu ra mine/benfluorex patients, high dose calcium channel blockers are effective. Hepatitis C antiviral therapies Calcium channel blockers should be reserved for "vasoreac- tive" patients who demonstrate marked improvement in mPAP lnterferon cr and B with the administration of nitric oxide, epoprostenol, or aden Dasatinib and bosutinib osine during right heart catheterization. Although survival Methamphetamines and other amphetamines among vasoreactive patients is superior to that among other Cocaine patients with PAH, close follow-up of these patients is required, Phenylpropa nola m ine as many become nonvasoreactive within a few years of diag nosis and subsequently require conventionai PAH therapy. The L-tryptophan absence of vasoreactivity during right heart catheterization St John's wort does not suggest that a patient will not benefit from appropri lndirubin ate PAH therapy. Leflunomide Additional treatments include diuretic therapy and a low Alkylating agents sodium diet to combat volume overload. Women of reproductive age who have PAH should be counseled on the risks of preg lnformation from Simonneau G, Montani D, Celermajer DS, et al- Haemodynamic definitions and updated clinical classification o{ pulmonary hypertension. Eur Respir nancy and advised against it. In patients with atrial fibrillation, J. 201 9;53. lPMl D: 305459681 doi:1 0.1 1 83/1 3993003.0 1 91 3-20 1 I attempts to restore normal sinus rhy'thm should be pursued, as 43

Pulmonary Vascular Disease TABLE 32. PharmacologicTherapy for Pulmonary Arterial Hypertension Class Comments Calcium channel blockers Only {or patients with acute vasodilator response at catheterization; acute response does not ensure chronic response; adverse effects such as hypotension can occur. Prostacyclin ana logues Parenteral prostacyclin analogues such as epoprostenol, administered by a continuous central (epoprostenol, treprostinil, iloprost) venous or subcutaneous infusion, are first-line therapy for severe disease and for those in whom disease progresses despite oraltherapy; inhaled iloprost and treprostinil require frequent administration; oraltreprostinil is most effective at higher doses (>9 mg/day); prostanoids supplement endogenous levels of prostacyclin (PGl2), a vasodilator with antismooth muscle proli{erative properties. Prostacyclin receptor agonist Works as an oral prostacyclin agonist. Current guidelines do not make recommendations for or (selexipag) against the use of selexipag for mild to moderate disease.u Endothelin-'i receptor antagonists Reasonable initial oral therapies for mild to moderate disease.b Blocks action of endogenous (bosentan, am brisentan, macitentan) vasoconstrictor and smooth muscle mitogen endothelin; class-wide risk for Iiver injury and teratogenicity. Bosentan caries significant risk for liver injury and requires serial liver chemistry testing.'Continuous pregnancytesting for reproductive-aged women is required. Phosphodiesterase-5 inhibitors Reasonable initial oral therapies for mild to moderate disease.b Prolongs effect of intrinsic (sildenafil, tadalafil) vasodilator cyclic GMP by inhibiting hydrolysis by phosphodiesterase-5. Soluble cyclic GMP stimulators Reasonable initial oral therapy for mild to moderate disease. Works by directly stimulating (riociguat) guanylate cyclase receptor, independent of endogenous NO, to promote pulmonary artery vasodilation.

TABLE 32. PharmacologicTherapy for Pulmonary Arterial Hypertension Class Comments Calcium channel blockers Only {or patients with acute vasodilator response at catheterization; acute response does not ensure chronic response; adverse effects such as hypotension can occur. Prostacyclin ana logues Parenteral prostacyclin analogues such as epoprostenol, administered by a continuous central (epoprostenol, treprostinil, iloprost) venous or subcutaneous infusion, are first-line therapy for severe disease and for those in whom disease progresses despite oraltherapy; inhaled iloprost and treprostinil require frequent administration; oraltreprostinil is most effective at higher doses (>9 mg/day); prostanoids supplement endogenous levels of prostacyclin (PGl2), a vasodilator with antismooth muscle proli{erative properties. Prostacyclin receptor agonist Works as an oral prostacyclin agonist. Current guidelines do not make recommendations for or (selexipag) against the use of selexipag for mild to moderate disease.u Endothelin-'i receptor antagonists Reasonable initial oral therapies for mild to moderate disease.b Blocks action of endogenous (bosentan, am brisentan, macitentan) vasoconstrictor and smooth muscle mitogen endothelin; class-wide risk for Iiver injury and teratogenicity. Bosentan caries significant risk for liver injury and requires serial liver chemistry testing.'Continuous pregnancytesting for reproductive-aged women is required. Phosphodiesterase-5 inhibitors Reasonable initial oral therapies for mild to moderate disease.b Prolongs effect of intrinsic (sildenafil, tadalafil) vasodilator cyclic GMP by inhibiting hydrolysis by phosphodiesterase-5. Soluble cyclic GMP stimulators Reasonable initial oral therapy for mild to moderate disease. Works by directly stimulating (riociguat) guanylate cyclase receptor, independent of endogenous NO, to promote pulmonary artery vasodilation. GMP = guanosine monophosphate; NO = nitric oxide.

TABLE 32. PharmacologicTherapy for Pulmonary Arterial Hypertension Class Comments Calcium channel blockers Only {or patients with acute vasodilator response at catheterization; acute response does not ensure chronic response; adverse effects such as hypotension can occur. Prostacyclin ana logues Parenteral prostacyclin analogues such as epoprostenol, administered by a continuous central (epoprostenol, treprostinil, iloprost) venous or subcutaneous infusion, are first-line therapy for severe disease and for those in whom disease progresses despite oraltherapy; inhaled iloprost and treprostinil require frequent administration; oraltreprostinil is most effective at higher doses (>9 mg/day); prostanoids supplement endogenous levels of prostacyclin (PGl2), a vasodilator with antismooth muscle proli{erative properties. Prostacyclin receptor agonist Works as an oral prostacyclin agonist. Current guidelines do not make recommendations for or (selexipag) against the use of selexipag for mild to moderate disease.u Endothelin-'i receptor antagonists Reasonable initial oral therapies for mild to moderate disease.b Blocks action of endogenous (bosentan, am brisentan, macitentan) vasoconstrictor and smooth muscle mitogen endothelin; class-wide risk for Iiver injury and teratogenicity. Bosentan caries significant risk for liver injury and requires serial liver chemistry testing.'Continuous pregnancytesting for reproductive-aged women is required. Phosphodiesterase-5 inhibitors Reasonable initial oral therapies for mild to moderate disease.b Prolongs effect of intrinsic (sildenafil, tadalafil) vasodilator cyclic GMP by inhibiting hydrolysis by phosphodiesterase-5. Soluble cyclic GMP stimulators Reasonable initial oral therapy for mild to moderate disease. Works by directly stimulating (riociguat) guanylate cyclase receptor, independent of endogenous NO, to promote pulmonary artery vasodilation. GMP = guanosine monophosphate; NO = nitric oxide. "The 201 8 CHEST Guidelines for the treatment of pulmonary hypenension in adults made recommendations based largely on 6-minute walk test improvements in patients on various therapies. Selexipag improved other patient outcomes in a large, double blind placebo controlled randomized clinical trial (GRIPHON). The guideline commlttee acknowledged that selexipag improved outcomes in other areas than the 6 minute walk test but did not recommend for or against its use given only modest improvement of 1 2 m in the treatment group compared with placebo.

"The 201 8 CHEST Guidelines for the treatment of pulmonary hypenension in adults made recommendations based largely on 6-minute walk test improvements in patients on various therapies. Selexipag improved other patient outcomes in a large, double blind placebo controlled randomized clinical trial (GRIPHON). The guideline commlttee acknowledged that selexipag improved outcomes in other areas than the 6 minute walk test but did not recommend for or against its use given only modest improvement of 1 2 m in the treatment group compared with placebo. 6Combination therapy with ambrisentan and tadalafil is the recommended first-line therapy in if the patient is wii ing and able to tolerate it. at periodic interva ls thereafter at the discretion of the managing physician.

"The 201 8 CHEST Guidelines for the treatment of pulmonary hypenension in adults made recommendations based largely on 6-minute walk test improvements in patients on various therapies. Selexipag improved other patient outcomes in a large, double blind placebo controlled randomized clinical trial (GRIPHON). The guideline commlttee acknowledged that selexipag improved outcomes in other areas than the 6 minute walk test but did not recommend for or against its use given only modest improvement of 1 2 m in the treatment group compared with placebo. 6Combination therapy with ambrisentan and tadalafil is the recommended first-line therapy in if the patient is wii ing and able to tolerate it. at periodic interva ls thereafter at the discretion of the managing physician. persistent atrial fibrillation in patients with PAH is associated with PH. evaluation for CTEPH is warranted, even when a his with increased mortality Supervised exercise training improves tory of acute PE is absent. Current guidelines recommend a V/Q functional capacity and use of palliative care resources by scan to rule out CTEPH in all patients being evaluated for PH patients with PAH can improve patient function and quality of despite rapidly improving CT scanner technologr and imaging Iife. In patients for whom drug therapy is unsuccessful, referral techniques. A normal V/Q is sufficient to exclude CTEPH, as its for lung or heart-lung transplantation should be considered. sensitivity for detecting chronic thrombus approaches 100%. There are few data to suggest that treatment of acute PE, including thrombolytic therapy or mechanical thrombectomy, Chronic Thromboembolic reduces a patient's risk for subsequent CTEPH. Although guidelines do not recommend follow-up CTEPH screening for Pulmonary Hypertension (Group 4) all patients who present with acute PE, the diagnosis should be CTEPH is composed of organized, chronic thrombi within the considered in any patient who remains symptomatic or devel pulmonary arterial system. Patients with CTEPH demonstrate ops symptoms consistent with PH after 3 months of anticoagu both mechanical obstruction of pulmonary arteries as well as lation. In addition, current guidelines recommend that patients features of disordered pulmonary angiogenesis, fibrinollsis, and with CTEPH undergo screening for thrombophilia. This vascular remodeling. These changes manifest in increased pulmo- includes testing for anticardiolipin antibody. antiphospholipid nary r,ascular resistance and elevated mPAP Untreated, CIEPH antibody, and lupus anticoagulant. can lead to right heart failure and death. Although it is likely that When ViQ scan suggests chronic thrombus, additional fewer than 5% of patients who experience an acute pulmonary imaging to characterize vascular anatomy and to evaluate the embolism (PE) develop CTEPH, more than 1 in 5 patients diag- extent ofCTEPH is indicated. Digital subtraction angiography nosed with CTEPH do not have a documented history of PE. For has long been the gold standard for this. But recent advances further discussion of acute PE, see MKSAP 19 Hematologr in pulmonary CTA have led many experts to prefer CTA because it is less invasive than digital subtraction angiography Diagnosis and in many cases offers excellent resolution and identifica Because a history of prior PE is not always evident in patients tion of pertinent vascular anomalies such as webs, intimal diagnosed with CTEPH, it remains an underrecognized cause of irregularities, and Iuminal narrowing. CTA may be less sensi PH and requires a high index ofsuspicion. In patients diagnosed tive for more distal lesions.

persistent atrial fibrillation in patients with PAH is associated with PH. evaluation for CTEPH is warranted, even when a his with increased mortality Supervised exercise training improves tory of acute PE is absent. Current guidelines recommend a V/Q functional capacity and use of palliative care resources by scan to rule out CTEPH in all patients being evaluated for PH patients with PAH can improve patient function and quality of despite rapidly improving CT scanner technologr and imaging Iife. In patients for whom drug therapy is unsuccessful, referral techniques. A normal V/Q is sufficient to exclude CTEPH, as its for lung or heart-lung transplantation should be considered. sensitivity for detecting chronic thrombus approaches 100%. There are few data to suggest that treatment of acute PE, including thrombolytic therapy or mechanical thrombectomy, Chronic Thromboembolic reduces a patient's risk for subsequent CTEPH. Although guidelines do not recommend follow-up CTEPH screening for Pulmonary Hypertension (Group 4) all patients who present with acute PE, the diagnosis should be CTEPH is composed of organized, chronic thrombi within the considered in any patient who remains symptomatic or devel pulmonary arterial system. Patients with CTEPH demonstrate ops symptoms consistent with PH after 3 months of anticoagu both mechanical obstruction of pulmonary arteries as well as lation. In addition, current guidelines recommend that patients features of disordered pulmonary angiogenesis, fibrinollsis, and with CTEPH undergo screening for thrombophilia. This vascular remodeling. These changes manifest in increased pulmo- includes testing for anticardiolipin antibody. antiphospholipid nary r,ascular resistance and elevated mPAP Untreated, CIEPH antibody, and lupus anticoagulant. can lead to right heart failure and death. Although it is likely that When ViQ scan suggests chronic thrombus, additional fewer than 5% of patients who experience an acute pulmonary imaging to characterize vascular anatomy and to evaluate the embolism (PE) develop CTEPH, more than 1 in 5 patients diag- extent ofCTEPH is indicated. Digital subtraction angiography nosed with CTEPH do not have a documented history of PE. For has long been the gold standard for this. But recent advances further discussion of acute PE, see MKSAP 19 Hematologr in pulmonary CTA have led many experts to prefer CTA because it is less invasive than digital subtraction angiography Diagnosis and in many cases offers excellent resolution and identifica Because a history of prior PE is not always evident in patients tion of pertinent vascular anomalies such as webs, intimal diagnosed with CTEPH, it remains an underrecognized cause of irregularities, and Iuminal narrowing. CTA may be less sensi PH and requires a high index ofsuspicion. In patients diagnosed tive for more distal lesions. 44

Lung Tumors I(EY POII{T multiple myeloma, and other myeloproliferative neoplasms, complex congenital heart disease, and a variety ofother disor HVC . Patients with pulmonary hypertension should be evalu ders are included in this classification. ated lor chronic thromboembolic pulmonary hyperten- sion with a ventilation/perfusion scan. XEY POIl{I . The majority of pulmonary hypertension is attributable to Management Ieft-sided heart disease and hypoxic respiratory disorders. Anticoagulation and consideration of thromboendafierectomy are indicated for CTEPH. I-ifelong anticoagulant therapy is Diagnosis indicated in all patients to help prevent further thromboem- Not all patients with PH will fall exclusively in one category. For bolism. The only potentially curative therapy for CTEPH is example. patients with connective tissue disease-related PAH pulmonary thromboendafierectomy. Because the disease is can have concomitant heart disease that contributes to PH. \ usually progressive, surgical evaluation at an experienced Group 2 PH is often determined on the basis of abnormalities center is warranted in all patients with CTEPH regardless of identified on echocardiography and a hemodynamic profile disease severity. About half'of patients with CTEPH will be consistent with elevated left atrial pressure (measured by PA eligible fbr surgery. Pulmonary thromboendarterectomy can wedge pressure on right heart catheterization) greater than result in the normalization of pulmonary hemodynamics in 15 mm Hg. The hemodynamic profile of patients with group 3 about one third o1'patients who undergo surgery. In patients PH mirrors that of patients with PAH and CTEPH. Patient his- who are deemed inoperable by one expert center, referral fbr a tory of advanced lung disease in addition to abnormal chest second opinion is recommended by guidelines. ln inoperable imaging (radiograph or CT scan) or pulmonary function testing patients and those who have persistent PH aftcr thromboen is essential to identi$ring group 3 disease. Significant abnor darterectomy, balloon pulmonary angioplasty or medical ther malities on imaging or pulmonary function testing should apy should be considered. Riociguat, a pulmonary vasodilator prompt further attention toward treatment of the underlying that acts on the nitric oxide pathway, is currently the only lung disease, not the PH. Chronic nocturnal hypoxia associated approved PH therapy available for CTEPH treatment. Balloon with sleep disordered breathing is also associated with PH. pulmonary angioplasty has recently emerged as an alternative Studies show that the prevalence of nocturnal hypoxia in option in nonoperable patients and those with persistent PH patients with PH is as high as B9'X,. Common screening studies after thromboendarterectomy. Study results have been prom- such as the Epworth sleepiness scale do not offer reliable sensi- ising as patients show improved overall outcomes including PA tivity to exclude sleep-disordered breathing in this population. hemodynamics, RV function, and symptoms. Balloon pulmo Current guidelines suggest considering an evaluation for sleep- nary angioplasty is not recommended as an alternative to disordered breathing or nocturnal hypoxia with polysomnog thromboendarterectomy, given insufficient data to suggest raphy or home sleep study in patients with PH. equivalent outcomes between the two procedures.

I(EY POII{T multiple myeloma, and other myeloproliferative neoplasms, complex congenital heart disease, and a variety ofother disor HVC . Patients with pulmonary hypertension should be evalu ders are included in this classification. ated lor chronic thromboembolic pulmonary hyperten- sion with a ventilation/perfusion scan. XEY POIl{I . The majority of pulmonary hypertension is attributable to Management Ieft-sided heart disease and hypoxic respiratory disorders. Anticoagulation and consideration of thromboendafierectomy are indicated for CTEPH. I-ifelong anticoagulant therapy is Diagnosis indicated in all patients to help prevent further thromboem- Not all patients with PH will fall exclusively in one category. For bolism. The only potentially curative therapy for CTEPH is example. patients with connective tissue disease-related PAH pulmonary thromboendafierectomy. Because the disease is can have concomitant heart disease that contributes to PH. \ usually progressive, surgical evaluation at an experienced Group 2 PH is often determined on the basis of abnormalities center is warranted in all patients with CTEPH regardless of identified on echocardiography and a hemodynamic profile disease severity. About half'of patients with CTEPH will be consistent with elevated left atrial pressure (measured by PA eligible fbr surgery. Pulmonary thromboendarterectomy can wedge pressure on right heart catheterization) greater than result in the normalization of pulmonary hemodynamics in 15 mm Hg. The hemodynamic profile of patients with group 3 about one third o1'patients who undergo surgery. In patients PH mirrors that of patients with PAH and CTEPH. Patient his- who are deemed inoperable by one expert center, referral fbr a tory of advanced lung disease in addition to abnormal chest second opinion is recommended by guidelines. ln inoperable imaging (radiograph or CT scan) or pulmonary function testing patients and those who have persistent PH aftcr thromboen is essential to identi$ring group 3 disease. Significant abnor darterectomy, balloon pulmonary angioplasty or medical ther malities on imaging or pulmonary function testing should apy should be considered. Riociguat, a pulmonary vasodilator prompt further attention toward treatment of the underlying that acts on the nitric oxide pathway, is currently the only lung disease, not the PH. Chronic nocturnal hypoxia associated approved PH therapy available for CTEPH treatment. Balloon with sleep disordered breathing is also associated with PH. pulmonary angioplasty has recently emerged as an alternative Studies show that the prevalence of nocturnal hypoxia in option in nonoperable patients and those with persistent PH patients with PH is as high as B9'X,. Common screening studies after thromboendarterectomy. Study results have been prom- such as the Epworth sleepiness scale do not offer reliable sensi- ising as patients show improved overall outcomes including PA tivity to exclude sleep-disordered breathing in this population. hemodynamics, RV function, and symptoms. Balloon pulmo Current guidelines suggest considering an evaluation for sleep- nary angioplasty is not recommended as an alternative to disordered breathing or nocturnal hypoxia with polysomnog thromboendarterectomy, given insufficient data to suggest raphy or home sleep study in patients with PH. equivalent outcomes between the two procedures. Other Types of Pulmonary Lung Tumors Hypertension (Groups 2,3, and 5) Pulmonary Nodule Evaluation The majority of PH is attributable to left sided heart disease (group Pulmonary nodules appear on radiography as small radio 2) and hypoxic respiratory disorders (group 3). Left-sided heart graphic opacities (less than 3 cm in size) surrounded by nor disease (heart failure with reduced or preserved ejection fraction mal lung parenchyma. These nodules are asymptomatic and and mitral or aortic vah,ular disease) results in elevations in left found either incidentally or on screening. In contrast, a focal atrial and pulmonary venous pressures. Chronic hypoxia is the pulmonary opacity larger than 3 cm is considered a lung mass most likely nidus lor pulmonary vascular remodeling in PH and is presumed malignant until proved otherwise. related to advanced respiratory disorders such as COPD, intersti The finding of a pulmonary nodule is increasingly com tial lung disease, and sleep hlpoventilation syndromes. In patients mon because of the frequency of CT scans performed for other with COPD and emphysema, obliteration of the vascular bed also reasons, as well as lung cancer screening programs. Management contributes to elevated pulmonary lascular resistance; manage of these lesions can be complicated and often requires subspe- ment focuses on ensuring sufficient oxygen requirements. In cialty ref'erral. Principles of pulmonary nodule evaluation patients with left heart disease or advanced lung disease, the pres- include reviewing imaging history estimating the probability of ence of PH increases the risk for death; management tlpically malignancy, and discussing management preferences with the involves cautious diuresis and arrhyhmia treatment. patient. Guidelines recommend management based on nodule A small minorit_v of PH cases are caused by diseases that size and characteristics. When more than one nodule is present, do not share any particular clinical or pathologic similarities tbllow up is dictated by the size and characteristics ofthe largest or in which the mechanisms of pulmonary vascular disease lesion. Shared decision making is an integral part of the evalu are poorly understood (group 5). Diseases such as sarcoidosis, ation and management of pulmonary nodules.

Other Types of Pulmonary Lung Tumors Hypertension (Groups 2,3, and 5) Pulmonary Nodule Evaluation The majority of PH is attributable to left sided heart disease (group Pulmonary nodules appear on radiography as small radio 2) and hypoxic respiratory disorders (group 3). Left-sided heart graphic opacities (less than 3 cm in size) surrounded by nor disease (heart failure with reduced or preserved ejection fraction mal lung parenchyma. These nodules are asymptomatic and and mitral or aortic vah,ular disease) results in elevations in left found either incidentally or on screening. In contrast, a focal atrial and pulmonary venous pressures. Chronic hypoxia is the pulmonary opacity larger than 3 cm is considered a lung mass most likely nidus lor pulmonary vascular remodeling in PH and is presumed malignant until proved otherwise. related to advanced respiratory disorders such as COPD, intersti The finding of a pulmonary nodule is increasingly com tial lung disease, and sleep hlpoventilation syndromes. In patients mon because of the frequency of CT scans performed for other with COPD and emphysema, obliteration of the vascular bed also reasons, as well as lung cancer screening programs. Management contributes to elevated pulmonary lascular resistance; manage of these lesions can be complicated and often requires subspe- ment focuses on ensuring sufficient oxygen requirements. In cialty ref'erral. Principles of pulmonary nodule evaluation patients with left heart disease or advanced lung disease, the pres- include reviewing imaging history estimating the probability of ence of PH increases the risk for death; management tlpically malignancy, and discussing management preferences with the involves cautious diuresis and arrhyhmia treatment. patient. Guidelines recommend management based on nodule A small minorit_v of PH cases are caused by diseases that size and characteristics. When more than one nodule is present, do not share any particular clinical or pathologic similarities tbllow up is dictated by the size and characteristics ofthe largest or in which the mechanisms of pulmonary vascular disease lesion. Shared decision making is an integral part of the evalu are poorly understood (group 5). Diseases such as sarcoidosis, ation and management of pulmonary nodules. 45