Pulmonary hypertension: A clinical review

A clinical review of the condition.


Case presentation

Mrs. Y is a 44-year-old woman with a history of systemic scleroderma complicated by severe pulmonary arterial hypertension (PAH). Her current regimen includes sildenafil, bosentan, and continuous IV epoprostenol. She presented to the hospital for her second admission within a month for fever, vomiting, and diarrhea.

During her prior admission, she was managed for acutely decompensated right-heart failure thought to be progression of her underlying disease. An echocardiogram obtained 1 month before that admission demonstrated septal flattening consistent with right ventricular (RV) pressure overload, a severely dilated hypokinetic right ventricle, a moderate pericardial effusion without signs of tamponade, and an estimated RV systolic pressure of 78 mm Hg. She was diuresed 8.5 L, her continuous epoprostenol was increased, and she was discharged on 3 oral diuretics and continuation of her 2-L fluid restriction.

On current admission, she presented with nonbloody diarrhea and nonbilious, nonbloody emesis with nausea and abdominal pain. She reported temperatures at home as high as 101.4 °F. Her blood pressure and heart rate were 114/68 mm Hg and 117 beats/min, respectively, on presentation. A noncontrast CT of her abdomen performed in the ED was unremarkable. Stool studies were negative for Clostridium difficile, ova, parasites, and common bacterial pathogens. Her admission leukocyte count was 9,900 cells/mm3 (increased from 4,400 cells/mm3 at her last discharge).

Despite broad-spectrum antibiotics and judicious fluid boluses, the patient developed hypotension and oliguria, and her condition deteriorated rapidly. Notable laboratory data included an elevated serum creatinine level of 1.9 mg/dL (increased from 1.1 mg/dL), a sodium level of 131 mEq/L, a potassium level of 7 mEq/L, a lactate level of 180 mg/dL (20.0 mmol/L) and an international normalized ratio of 6.6 (increased from 3.6). Liver enzymes were markedly elevated, with an aspartate aminotransferase level greater than 2,200 U/L and an alanine aminotransferase level over 900 U/L.

The patient later developed atrial fibrillation with a rapid ventricular response and subsequent pulseless electrical activity arrest. She was pronounced dead after 35 minutes of CPR. Autopsy demonstrated no source of infection. Blood, urine, and stool cultures, including viral assays, were negative. Autopsy demonstrated microscopic evidence of changes consistent with long-standing PAH, including medial hypertrophy, intimal hyperplasia, and plexogenic pulmonary arteriopathy.

What clinicians should know about pulmonary hypertension

Pulmonary hypertension (PH) is a multifaceted disease that is the result of primary endothelial and smooth-muscle dysfunction or secondary metabolic, thrombotic, and hemodynamic derangements. PH results in severe remodeling of the distal lung vessels leading to death through RV failure. The reported prevalence and severity of PH vary widely. Understanding the pathophysiology of the various causes of PH is essential for clinicians to mitigate substantial morbidity and mortality.

Current classifications categorize PH into groups that share similar histopathologic and hemodynamic characteristics and therapeutic approaches. The latest World Health Organization (WHO) classification includes 5 broad categories (11. McLaughlin VV, Archer SL, Badesch DB, Barst RJ, Farber HW, Lindner JR, et al; American College of Cardiology Foundation Task Force on Expert Consensus Documents. ACCF/AHA 2009 expert consensus document on pulmonary hypertension a report of the American College of Cardiology Foundation Task Force on Expert Consensus Documents and the American Heart Association developed in collaboration with the American College of Chest Physicians; American Thoracic Society, Inc.; and the Pulmonary Hypertension Association. J Am Coll Cardiol. 2009;53:1573-619. [PMID: 19389575] doi:10.1016/j.jacc.2009.01.004). Pulmonary arterial hypertension (PAH) or Group 1 is composed of heritable and idiopathic pulmonary arterial hypertension; drug-induced PH; and PAH associated with connective tissue diseases (predominantly systemic sclerosis in North America), HIV, portal hypertension, congenital heart disease, and schistosomiasis. Group 1 disorders often have a poor prognosis despite optimal medical therapy. Group 2 includes pulmonary venous hypertension related to left-heart disease (one of the most common causes of PH in North America). PH in the context of significant lung diseases or hypoxemia is included in Group 3, while Group 4 is composed of chronic thromboembolic PH, and Group 5 PH includes diseases with unclear multifactorial mechanisms, such as sarcoidosis.

Diagnosis and management of clinically significant PH require a multidisciplinary approach, which may include internists, cardiologists, pulmonologists, rheumatologists, and, potentially, thoracic surgeons.

Untreated or severe refractory PH, regardless of group, is often fatal. Before contemporary therapies, D’Alonzo and colleagues (22. D’Alonzo GE, Barst RJ, Ayres SM, Bergofsky EH, Brundage BH, Detre KM, et al. Survival in patients with primary pulmonary hypertension. Results from a national prospective registry. Ann Intern Med. 1991;115:343-9. ) estimated that the median survival with symptomatic idiopathic PAH was 2.8 years from the time of diagnosis and that those with a right atrial pressure greater than 20 mm Hg usually died within 1 month. Despite multiple new therapies approved for Group 1 PAH, the median survival for idiopathic PAH and PAH associated with systemic sclerosis is 8 and 4 years, respectively. Clinicians should have a high clinical index of suspicion because clinical manifestations of PH may be masked or overlooked and the diagnosis can often be delayed because symptoms are attributed to other underlying disorders. Once PH is suspected, it is important for clinicians to appropriately screen and explore underlying causes to facilitate therapies, involve consultants and referrals to specialty centers, and treat potentially reversible causes.

This analysis, gathered from several sources including writing committees and expert opinions, discusses the pathophysiology, current definitions, classification system, clinical manifestations, diagnostic algorithm, management, and prognosis of the disease.

Definition and pathophysiology

Although echocardiography is the recommended screening tool to detect elevated right-heart pressures suggesting PH, right-heart catheterization is essential to diagnosis. PH is defined as a resting mean pulmonary artery pressure of 25 mm Hg or greater on right-heart catheterization. The diagnosis of PAH additionally includes a pulmonary capillary wedge pressure (PCWP) less than or equal to 15 mm Hg, a pulmonary vascular resistance (PVR) greater than 3 Wood units, and clinical exclusion of causes related to Groups 2 through 5.

Normally the pulmonary vascular bed has a low resistance that can dynamically distend and recruit vessels to adapt to increases in cardiac output. Moreover, hypoxic-induced vasoconstriction is a normal physiologic response to regional hypoxia within the lung to shunt blood toward oxygenated areas and optimize V/Q matching. Global, hypoxic vasoconstriction can also increase PVR. The pulmonary vasculature can undergo reactive changes in response to various chemicals that mediate vascular tone. Elevations in pulmonary artery pressure can occur at the pre- and/or post-capillary level. The right ventricle typically responds to acute increases in PVR by increasing contractility to overcome the increase in afterload. However, due to long-standing or dramatic increases in PVR, the right ventricle may become unable to generate sufficient pressure to maintain adequate cardiac output, hence right-heart failure ensues with subsequent multiorgan failure and death.

Group 1 PAH clinically manifests as the most severe form of PH in terms of hemodynamics, pathologic remodeling in the lung, and mortality. This group has been thought to be analogous to the “multiple hit” model described in malignancy (11. McLaughlin VV, Archer SL, Badesch DB, Barst RJ, Farber HW, Lindner JR, et al; American College of Cardiology Foundation Task Force on Expert Consensus Documents. ACCF/AHA 2009 expert consensus document on pulmonary hypertension a report of the American College of Cardiology Foundation Task Force on Expert Consensus Documents and the American Heart Association developed in collaboration with the American College of Chest Physicians; American Thoracic Society, Inc.; and the Pulmonary Hypertension Association. J Am Coll Cardiol. 2009;53:1573-619. [PMID: 19389575] doi:10.1016/j.jacc.2009.01.004). The “first hit” is presumed to be a genetic predisposition. The identified genetic susceptibility factors that have been identified appear to directly or indirectly alter smooth-muscle and endothelial cell function in the pulmonary vasculature. For example, up to 80% of heritable forms of PAH have a mutation on the bone morphogenetic protein receptor (BMRP), a member of the transforming growth factor (TGF)-beta receptor superfamily that regulates vascular cell growth in vitro (11. McLaughlin VV, Archer SL, Badesch DB, Barst RJ, Farber HW, Lindner JR, et al; American College of Cardiology Foundation Task Force on Expert Consensus Documents. ACCF/AHA 2009 expert consensus document on pulmonary hypertension a report of the American College of Cardiology Foundation Task Force on Expert Consensus Documents and the American Heart Association developed in collaboration with the American College of Chest Physicians; American Thoracic Society, Inc.; and the Pulmonary Hypertension Association. J Am Coll Cardiol. 2009;53:1573-619. [PMID: 19389575] doi:10.1016/j.jacc.2009.01.004). The “second hit” may be mediated through hemodynamic changes such as increased shear stress, infections, or exogenous toxins, resulting in intimal and medial hyperplasia, varying degrees of inflammation, thrombosis in situ, and plexopathy.

In Groups 2 through 5, PH is a secondary phenomenon of other diseases. It is usually less severe in these groups and has greater potential to be reversed. Left-heart diseases in Group 2 are the result of “passive” pulmonary venous hypertension that increases pressure and resistance downstream in the pulmonary arterial circuit. The lung diseases in Group 3 cause hypoxic vasoconstriction that increases PVR. Group 4 PH is the result of a fixed, organized obstruction of proximal or distal pulmonary vasculature that is caused by thromboembolism. It is critical to note that long-standing elevated pulmonary vascular pressures can also undergo vascular remodeling, leading to a more “fixed” representation of PH that may be out of proportion to the degree of underlying disease and not easily reversible.

Most of the advanced or PAH-specific therapies such as prostacyclins, phosphodiesterase inhibitors, and endothelin-receptor antagonists are targeted to promote vasodilation and restore the thromboproliferative vascular imbalances.

Classification

The classification system for PH was initially developed in 1973 and has been modified over subsequent years. It was recently updated in 2013 at the 5th World Health Symposium on PH in Nice, France. The updated classification system, which is available online (33. Simonneau G, Gatzoulis MA, Adatia I, Celermajer D, Denton C, Ghofrani A, et al. Updated clinical classification of pulmonary hypertension. J Am Coll Cardiol. 2013;62:D34-41. [PMID: 24355639] doi:10.1016/j.jacc.2013.10.029.), allows the management of PH to be directed at the underlying pathophysiologic derangements and categorizes PH into 5 groups with several subgroups. .

Group 1: PAH

PAH diseases are a group of conditions that result in genuine pulmonary arterial vasculopathy and include idiopathic and heritable causes. Drug-induced causes can be grouped as definite, possible, and likely (Table 1). The mechanisms associated with the development of PAH and HIV infection remain unclear, but this subgroup clinically mimics findings seen in idiopathic PAH. PAH associated with connective tissue disease represents a very important entity, with scleroderma the most common in North American and European registries. PAH-associated connective tissue disease occurs in the absence of lung fibrosis, reflecting the primary underlying vasculopathy. Portopulmonary hypertension is thought to be caused by the failure of the compromised liver to clear vasoactive substances involved in the development of pulmonary arterial vasculopathy. Portopulmonary hypertension is more common in women and is associated with autoimmune hepatitis. The reversal of systemic to pulmonary shunts and the subsequent vasculopathy that develops cause PAH in congenital heart disease. Previously classified in Group 4, endemic schistosomiasis has been reclassified to reflect the vascular damage and plexopathy similar to that seen in idiopathic PAH, rather than the previously thought mechanical vascular obstruction from the eggs of Schistosoma. Rarer disorders such as pulmonary venoocclusive disease and pulmonary capillary hemangiomatosis are also included in this group.

Group 2: PH due to left-heart disease

This group includes systolic and diastolic left ventricular dysfunction and left-sided valvular abnormalities of the aortic and mitral valve. Although the elevation in pulmonary artery pressure may reflect passive congestion, it is important for clinicians to be aware that patients with PH related to left-heart disease can develop elevations that are “out of proportion” to the venous pressure or a more “fixed” representation of PH (44. Park MH, Mehra MR. Pulmonary hypertension: the great leveler [Editorial]. J Am Coll Cardiol. 2012;59:232-4. [PMID: 22240127] doi:10.1016/j.jacc.2011.09.052). Out-of-proportion PH in left-heart disease is evidenced by a PCWP greater than 15 mm Hg and a transpulmonary gradient (TPG) greater than 12 mm Hg on right-heart catheterization (55. Galiè N, Hoeper MM, Humbert M, Torbicki A, Vachiery JL, Barbera JA, et al; ESC Committee for Practice Guidelines (CPG). Guidelines for the diagnosis and treatment of pulmonary hypertension: the Task Force for the Diagnosis and Treatment of Pulmonary Hypertension of the European Society of Cardiology (ESC) and the European Respiratory Society (ERS), endorsed by the International Society of Heart and Lung Transplantation (ISHLT). Eur Heart J. 2009;30:2493-537. [PMID: 19713419] doi:10.1093/eurheartj/ehp297).

Group 3: Pulmonary hypertension secondary to lung disease and/or hypoxic states

Chronic obstructive pulmonary disease (COPD), sleep-disordered breathing, interstitial lung disease, mixed obstructive and restrictive lung disease, high altitude, and developmental lung disease are included in this group. The degree of lung disease frequently parallels the degree of PH. Chaouat and colleagues (66. Chaouat A, Bugnet AS, Kadaoui N, Schott R, Enache I, Ducoloné A, et al. Severe pulmonary hypertension and chronic obstructive pulmonary disease. Am J Respir Crit Care Med. 2005;172:189-94. [PMID: 15831842]) demonstrated that only 1% of patients with COPD have severe PH. Some authors suggest that severe or out-of-proportion PH in COPD may be due to a genetic mutation and not the underlying lung disease itself (11. McLaughlin VV, Archer SL, Badesch DB, Barst RJ, Farber HW, Lindner JR, et al; American College of Cardiology Foundation Task Force on Expert Consensus Documents. ACCF/AHA 2009 expert consensus document on pulmonary hypertension a report of the American College of Cardiology Foundation Task Force on Expert Consensus Documents and the American Heart Association developed in collaboration with the American College of Chest Physicians; American Thoracic Society, Inc.; and the Pulmonary Hypertension Association. J Am Coll Cardiol. 2009;53:1573-619. [PMID: 19389575] doi:10.1016/j.jacc.2009.01.004).

Group 4: Chronic thromboembolic PH

Caused by venous thromboembolism, chronic thromboembolic PH may be fully reversible with pulmonary thromboembolectomy. Risk factors for chronic thromboembolic PH include myeloproliferative disorders, chronic inflammatory states, thrombophilia, and asplenia. The only established procoagulative condition consistently associated with chronic thromboembolic PH is the antiphospholipid syndrome. Literature suggests an annual cumulative incidence as high as 4% for chronic thromboembolic PH after pulmonary embolism (77. Fedullo P, Kerr KM, Kim NH, Auger WR. Chronic thromboembolic pulmonary hypertension. Am J Respir Crit Care Med. 2011;183:1605-13. [PMID: 21330453] doi:10.1164/rccm.201011-1854CI). This may actually be an underestimation because some patients have not had a clinical venothromboembolic event before chronic thromboembolic PH is diagnosed.

Group 5: PH with unclear or multifactorial causes

Systemic sarcoidosis, included in this group, has many proposed PH-provoking mechanisms, such as hypoxic vasoconstriction, compression of pulmonary vasculature by granulomatous lesions, and T-cell-mediated destruction of the capillary bed. Other subgroups include hematologic disorders, such as essential thrombocytosis, polycythemia vera, and chronic myelogenous leukemia, and metabolic disorders, such as glycogen and lysosomal storage diseases, glucose-6-phosphate dehydrogenase deficiency, and thyroid diseases. Chronic hemolytic anemias included in this group can also induce similar features seen in idiopathic PAH, but the true incidence is unknown. The miscellaneous subgroup includes mediastinal fibrosis, PH caused by tumor obstruction, and end-stage renal disease; patients with end-stage renal disease have been found to have a prevalence of PH as high as 40% on echocardiography (88. Yigla M, Nakhoul F, Sabag A, Tov N, Gorevich B, Abassi Z, et al. Pulmonary hypertension in patients with end-stage renal disease. Chest. 2003;123:1577-82. [PMID: 12740276]).

When to suspect PH

On the basis of history and physical examination, clinicians should be vigilant in recognizing patients who are at risk for PH. It is important to remember that other disease manifestations may mask PH symptoms. The historical clues may include a family history of PAH, presence of a connective tissue disorder, HIV infection, prior or current thromboembolic disease, congenital heart disease, sickle cell disease, and past use of anorexigenic drugs. Suspect out-of-proportion PH in Group 3 patients who have worsening symptoms despite stable pulmonary function tests, with the exception of a very low diffusion capacity (66. Chaouat A, Bugnet AS, Kadaoui N, Schott R, Enache I, Ducoloné A, et al. Severe pulmonary hypertension and chronic obstructive pulmonary disease. Am J Respir Crit Care Med. 2005;172:189-94. [PMID: 15831842]).

The most common symptoms of PH include dyspnea on exertion, fatigue, chest pain, peripheral edema, palpitations, and syncope. Orthopnea and paroxysmal nocturnal dyspnea are important symptoms that may point to pulmonary venous hypertension as seen in left-heart disease. Chest pain may be ischemic in nature as a result of the overloaded right ventricle.

Physical exam findings vary widely and may reflect resultant right-heart failure, point toward the underlying cause, or both. Signs of right-heart failure include elevated jugular venous distension, peripheral edema, ascites, a tricuspid regurgitant murmur, right-sided S3 gallop, and cool peripheral extremities. No studies to date have defined the sensitivity or specificity of the physical examination in the diagnosis of PH.

Diagnostic approach

The primary rationale for investigating causes and establishing the diagnosis of PH and PAH is to determine the degree of disease and identify appropriate treatment modalities to prevent significant morbidity and mortality. Occasionally, PH is discovered incidentally when searching for other diseases, and it is important to note that the presence of one condition does not exclude the other as a causal agent. The diagnostic sequence ultimately should be informed by the history, physical exam, and echocardiographic findings. An algorithm is provided in the Figure.

Echocardiography

After clinical suspicion of PH is established, the first screening test should be an echocardiogram. Echocardiography provides invaluable information in estimating right-heart pressure, size, and function. More important, echocardiography estimates RV systolic pressure and, in the absence of a RV outflow obstruction such as pulmonic stenosis, can estimate pulmonary artery systolic pressure (PASP). Because most patients with PH have some degree of tricuspid regurgitation (TR), measurements of the TR jet velocity are used to evaluate RV systolic pressure. The American College of Cardiology Foundation Task Force suggests that a RV systolic pressure above 40 mm Hg in a patient with unexplained dyspnea warrants further investigation (11. McLaughlin VV, Archer SL, Badesch DB, Barst RJ, Farber HW, Lindner JR, et al; American College of Cardiology Foundation Task Force on Expert Consensus Documents. ACCF/AHA 2009 expert consensus document on pulmonary hypertension a report of the American College of Cardiology Foundation Task Force on Expert Consensus Documents and the American Heart Association developed in collaboration with the American College of Chest Physicians; American Thoracic Society, Inc.; and the Pulmonary Hypertension Association. J Am Coll Cardiol. 2009;53:1573-619. [PMID: 19389575] doi:10.1016/j.jacc.2009.01.004). Echocardiography also provides information on LV size and function and valvular abnormalities associated with Group 2 diseases. Echocardiographic evidence of intra-cardiac shunting may point toward congenital heart defects. There are no definitive criteria for establishing PH via echocardiography, but signs of RV enlargement/overload, RV septal bowing, and an elevated RV systolic pressure are very suggestive. The European Task Force notes that the diagnosis of PH is very likely if echocardiographic evidence demonstrates a PASP above 50 mm Hg and a tricuspid regurgitant jet above 3.4 m·s–1 (55. Galiè N, Hoeper MM, Humbert M, Torbicki A, Vachiery JL, Barbera JA, et al; ESC Committee for Practice Guidelines (CPG). Guidelines for the diagnosis and treatment of pulmonary hypertension: the Task Force for the Diagnosis and Treatment of Pulmonary Hypertension of the European Society of Cardiology (ESC) and the European Respiratory Society (ERS), endorsed by the International Society of Heart and Lung Transplantation (ISHLT). Eur Heart J. 2009;30:2493-537. [PMID: 19713419] doi:10.1093/eurheartj/ehp297). It is also important to note that estimations of RV systolic pressure may be inaccurate by 10 to 20 mm Hg because of operator variability. Therefore, the gold standard for diagnosis of PH and PAH is right-heart catheterization.

Other diagnostic methods

Ventilation-perfusion nuclear scanning (V/Q) is the test of choice when evaluating for chronic thromboembolic PH. It is better than pulmonary embolism protocol computed tomography angiography (CTA) in diagnosing chronic thromboembolic PH, with a sensitivity of over 95% and a specificity of 90% to 95% (11. McLaughlin VV, Archer SL, Badesch DB, Barst RJ, Farber HW, Lindner JR, et al; American College of Cardiology Foundation Task Force on Expert Consensus Documents. ACCF/AHA 2009 expert consensus document on pulmonary hypertension a report of the American College of Cardiology Foundation Task Force on Expert Consensus Documents and the American Heart Association developed in collaboration with the American College of Chest Physicians; American Thoracic Society, Inc.; and the Pulmonary Hypertension Association. J Am Coll Cardiol. 2009;53:1573-619. [PMID: 19389575] doi:10.1016/j.jacc.2009.01.004, 99. Tunariu N, Gibbs SJ, Win Z, Gin-Sing W, Graham A, Gishen P, et al. Ventilation-perfusion scintigraphy is more sensitive than multidetector CTPA in detecting chronic thromboembolic pulmonary disease as a treatable cause of pulmonary hypertension. J Nucl Med. 2007;48:680-4. [PMID: 17475953]). However, V/Q may not be useful in patients with concomitant parenchymal lung disease, and CTA may be necessary. CTA may also reveal the extent and anatomic location of thromboembolic disease and help determine surgical thromboembolectomy candidacy.

Chest imaging with plain radiographs may reveal a prominent pulmonary artery suggestive of PH, interstitial or alveolar infiltrates consistent with Group 2 left-heart disease, or parenchymal lung findings consistent with Group 3 lung disease. Pulmonary function tests evaluate the presence and degree of obstructive, restrictive, or mixed lung disease. A very low diffusing lung capacity of carbon monoxide with other minimal findings or changes on pulmonary function tests is suggestive of PH. Overnight continuous oximetry and polysomnography aid in establishing sleep-disordered breathing. Electrocardiographic signs of RV overload or strain include right ventricular hypertrophy, a right bundle-branch block, or right atrial enlargement. The serologic evaluation helps identify autoimmune disease, concomitant HIV infection, thyroid or liver dysfunction, and hemolytic anemia. Serum pro-brain natriuretic peptide (BNP) is a useful marker of disease severity and prognosis in established PH.

The 6-minute walk test is useful in establishing a baseline and subsequent response to therapy. It also provides information on disease severity and prognostication and stratifies patients with PH in the appropriate WHO functional class (Table 2), which is comparable to the New York Heart Association classification for heart failure.

Right-heart catheterization

The final common pathway in the evaluation of PH is invasive hemodynamic assessment using right-heart catheterization. It is of particular importance to understand the clinical context in which pulmonary artery pressures may be elevated. An anatomically normal pulmonary vascular bed with increased pulmonary flow can be caused by high-output states such as anemia, sepsis, atrioventricular shunt, or pregnancy. These pressures may return to normal after the high-output state resolves (11. McLaughlin VV, Archer SL, Badesch DB, Barst RJ, Farber HW, Lindner JR, et al; American College of Cardiology Foundation Task Force on Expert Consensus Documents. ACCF/AHA 2009 expert consensus document on pulmonary hypertension a report of the American College of Cardiology Foundation Task Force on Expert Consensus Documents and the American Heart Association developed in collaboration with the American College of Chest Physicians; American Thoracic Society, Inc.; and the Pulmonary Hypertension Association. J Am Coll Cardiol. 2009;53:1573-619. [PMID: 19389575] doi:10.1016/j.jacc.2009.01.004). The hemodynamic definition of PH is a mean pulmonary artery pressure of 25 mm Hg or greater. PAH requires a mean pulmonary artery pressure of 25 mm Hg or greater, a PCWP of 15 mm Hg or less, a PVR greater than 3 Wood units, and exclusion of Groups 2 through 5.

Right-heart catheterization may not be required to diagnose PH if noninvasive testing reveals a cause that could potentially be reversed with treatment of the underlying condition, as in Group 2 PH. However, if the clinical suspicion for PAH or PH out of proportion to the degree of underlying left-heart disease remains high, right-heart catheterization would have utility.

The diagnosis of PAH requires the exclusion of PH secondary to left-heart disease, which will be demonstrated by an elevated PCWP. The transpulmonary pressure gradient is another useful measure of PH in Group 2 disease; it is the difference between mean pulmonary artery pressure and PCWP. Values greater than 12 mm Hg suggest PH that is out of proportion to the degree of left-heart disease. In suspected PAH, an acute vasodilator response can identify the small subset of patients who respond to oral calcium-channel blockers.

Management

The conceptual framework for the management of PH is divided into 3 categories: treating the PH itself, treating the underlying cause of PH such as in Groups 2 through 5, and treating the physiologic consequences of PH (e.g., right-heart failure) (Table 3).

General measures

General measures include providing supplemental oxygen when indicated. This has been the only treatment method proven to have mortality benefit in the Group 3 COPD subclass but can be used in all groups if there is concomitant hypoxia (11. McLaughlin VV, Archer SL, Badesch DB, Barst RJ, Farber HW, Lindner JR, et al; American College of Cardiology Foundation Task Force on Expert Consensus Documents. ACCF/AHA 2009 expert consensus document on pulmonary hypertension a report of the American College of Cardiology Foundation Task Force on Expert Consensus Documents and the American Heart Association developed in collaboration with the American College of Chest Physicians; American Thoracic Society, Inc.; and the Pulmonary Hypertension Association. J Am Coll Cardiol. 2009;53:1573-619. [PMID: 19389575] doi:10.1016/j.jacc.2009.01.004, 55. Galiè N, Hoeper MM, Humbert M, Torbicki A, Vachiery JL, Barbera JA, et al; ESC Committee for Practice Guidelines (CPG). Guidelines for the diagnosis and treatment of pulmonary hypertension: the Task Force for the Diagnosis and Treatment of Pulmonary Hypertension of the European Society of Cardiology (ESC) and the European Respiratory Society (ERS), endorsed by the International Society of Heart and Lung Transplantation (ISHLT). Eur Heart J. 2009;30:2493-537. [PMID: 19713419] doi:10.1093/eurheartj/ehp297, 1111. Barst RJ, Gibbs JS, Ghofrani HA, Hoeper MM, McLaughlin VV, Rubin LJ, et al. Updated evidence-based treatment algorithm in pulmonary arterial hypertension. J Am Coll Cardiol. 2009;54:S78-84. [PMID: 19555861] doi:10.1016/j.jacc.2009.04.017). Anticoagulation is indicated in Group 1 patients with idiopathic, heritable, and drug-induced PAH and may be used in patients with other concomitant indications such as atrial fibrillation or intracardiac thrombus (77. Fedullo P, Kerr KM, Kim NH, Auger WR. Chronic thromboembolic pulmonary hypertension. Am J Respir Crit Care Med. 2011;183:1605-13. [PMID: 21330453] doi:10.1164/rccm.201011-1854CI). Lifelong anticoagulation is indicated in chronic thromboembolic PH. Anticoagulation can help prevent a potentially life-threatening PE in PH patients who have poor cardiopulmonary reserve. Diuretics are used to treat fluid retention and offload dilated ventricles as in left- or right-heart failure but must be used with caution given that overdiuresis in patients with RV dysfunction can precipitate shock. Digoxin may be useful in slowing atrial arrhythmias and increasing RV contractility but should be used with caution as well because of the potential for toxicity.

Advanced therapies for PAH

PAH-specific or advanced therapies are for the most part directed at Group 1 patients because they have been most likely to be included in clinical trials, particularly those with scleroderma and idiopathic PAH. Therapies directed at the pathobiologic defects of PAH can cost $15,000 to over $100,000 annually (11. McLaughlin VV, Archer SL, Badesch DB, Barst RJ, Farber HW, Lindner JR, et al; American College of Cardiology Foundation Task Force on Expert Consensus Documents. ACCF/AHA 2009 expert consensus document on pulmonary hypertension a report of the American College of Cardiology Foundation Task Force on Expert Consensus Documents and the American Heart Association developed in collaboration with the American College of Chest Physicians; American Thoracic Society, Inc.; and the Pulmonary Hypertension Association. J Am Coll Cardiol. 2009;53:1573-619. [PMID: 19389575] doi:10.1016/j.jacc.2009.01.004). Advanced therapy can be cautiously considered in patients in Groups 2, 3, and 4 who have poor functional class despite maximum therapy directed at the underlying causes, but this should typically be done at specialized centers.

Prostanoids

The staple drug of this class, epoprostenol, is a prostacyclin analogue with a short half-life that mechanistically has antiproliferative, antithrombotic, and vasodilatory properties. Usually reserved for patients in WHO functional class III and IV, epoprostenol is administered only via continuous IV infusion and is effective in improving hemodynamics, functional capacity, and survival in idiopathic and hereditary forms of PAH (11. McLaughlin VV, Archer SL, Badesch DB, Barst RJ, Farber HW, Lindner JR, et al; American College of Cardiology Foundation Task Force on Expert Consensus Documents. ACCF/AHA 2009 expert consensus document on pulmonary hypertension a report of the American College of Cardiology Foundation Task Force on Expert Consensus Documents and the American Heart Association developed in collaboration with the American College of Chest Physicians; American Thoracic Society, Inc.; and the Pulmonary Hypertension Association. J Am Coll Cardiol. 2009;53:1573-619. [PMID: 19389575] doi:10.1016/j.jacc.2009.01.004). Diarrhea, arthralgia, and jaw pain are common side effects. Severe rebound PAH has been observed with abrupt cessation. Treprostinil is available in IV and subcutaneous forms. Iloprost is available in the inhaled formulation.

Endothelin-receptor antagonists

Endothelin-receptor antagonists (ERAs) are oral agents that block endothelin, a hormone that induces potent vasoconstriction and smooth-muscle proliferation. These drugs, similar to the prostanoids, improve hemodynamic parameters and functional class. Their use is limited, however, because of hepatotoxic and teratogenic effects (11. McLaughlin VV, Archer SL, Badesch DB, Barst RJ, Farber HW, Lindner JR, et al; American College of Cardiology Foundation Task Force on Expert Consensus Documents. ACCF/AHA 2009 expert consensus document on pulmonary hypertension a report of the American College of Cardiology Foundation Task Force on Expert Consensus Documents and the American Heart Association developed in collaboration with the American College of Chest Physicians; American Thoracic Society, Inc.; and the Pulmonary Hypertension Association. J Am Coll Cardiol. 2009;53:1573-619. [PMID: 19389575] doi:10.1016/j.jacc.2009.01.004).

Phosphodiesterase-5 inhibitors

These drugs exert clinical effects by increasing nitric oxide, which has vasodilatory properties. Phosphodiesterase-5 (PDE-5) inhibitors have been shown to improve functional class and hemodynamics in PAH patients (11. McLaughlin VV, Archer SL, Badesch DB, Barst RJ, Farber HW, Lindner JR, et al; American College of Cardiology Foundation Task Force on Expert Consensus Documents. ACCF/AHA 2009 expert consensus document on pulmonary hypertension a report of the American College of Cardiology Foundation Task Force on Expert Consensus Documents and the American Heart Association developed in collaboration with the American College of Chest Physicians; American Thoracic Society, Inc.; and the Pulmonary Hypertension Association. J Am Coll Cardiol. 2009;53:1573-619. [PMID: 19389575] doi:10.1016/j.jacc.2009.01.004).

Combination therapy may have synergistic effects in PAH patients whose disease progresses on monotherapy (1111. Barst RJ, Gibbs JS, Ghofrani HA, Hoeper MM, McLaughlin VV, Rubin LJ, et al. Updated evidence-based treatment algorithm in pulmonary arterial hypertension. J Am Coll Cardiol. 2009;54:S78-84. [PMID: 19555861] doi:10.1016/j.jacc.2009.04.017).

Use of advanced therapies in non-PAH conditions

Although advanced therapies can be considered in patients with Group 2 PH, several trials involving prostacyclin analogues and ERAs either demonstrated no benefit or were terminated early due to negative effects (11. McLaughlin VV, Archer SL, Badesch DB, Barst RJ, Farber HW, Lindner JR, et al; American College of Cardiology Foundation Task Force on Expert Consensus Documents. ACCF/AHA 2009 expert consensus document on pulmonary hypertension a report of the American College of Cardiology Foundation Task Force on Expert Consensus Documents and the American Heart Association developed in collaboration with the American College of Chest Physicians; American Thoracic Society, Inc.; and the Pulmonary Hypertension Association. J Am Coll Cardiol. 2009;53:1573-619. [PMID: 19389575] doi:10.1016/j.jacc.2009.01.004). Sildenafil, a PDE-5 inhibitor, has been shown to improve quality of life and exercise capacity in patients with systolic heart failure (1313. Lewis GD, Shah R, Shahzad K, Camuso JM, Pappagianopoulos PP, Hung J, et al. Sildenafil improves exercise capacity and quality of life in patients with systolic heart failure and secondary pulmonary hypertension. Circulation. 2007;116:1555-62. [PMID: 17785618]). Pulmonary vasodilators in general should be used with caution for Group 2 disorders because of the tendency to precipitate acute deterioration. The American College of Cardiology Foundation Task Force recommends advanced therapies in Group 2 under certain circumstances: 1) the pulmonary venous hypertension is optimally treated, 2) TPG and PVR are significantly elevated, and 3) advanced therapies may yield a clinical benefit. Similarly, advanced therapies can be considered for Group 3 if 1) the lung disease and hypoxemia has been optimally treated, 2) the PCWP is less than 15 mm Hg and TPG and PVR are significantly elevated, and 3) advanced therapies may yield a clinical benefit.

The unfortunate shortcoming to using PAH-specific therapies in COPD patients stems from the concern that pulmonary vasodilators may in fact increase shunting and worsen hypoxemia due to nonselective vasodilatation. Pulmonary thromboembolectomy (PTE) is an often a curative option and the treatment of choice in chronic thromboembolic PH; however, some patients are considered at high surgical risk, do not have surgically accessible distal clots, and have persistent PH after surgery.

The American College of Cardiology Foundation Task Force recommends advanced therapies in Group 4 if 1) chronic thromboembolic PH is optimally treated with anticoagulants, 2) the patient has undergone PTE and remains symptomatic from PH or PTE is contraindicated, 3) the TPG and PVR are significantly elevated, and 4) advanced therapy may yield a clinical benefit.

In general, the decision to initiate advanced therapies in non-PAH groups should be made on a case-by-case basis and in a tertiary center experienced in PH management. The Task Force for the Diagnosis and Treatment of Pulmonary Hypertension (European Society of Cardiology and European Respiratory Society) recommends against advanced therapies in all non-PAH groups besides Group 4 (55. Galiè N, Hoeper MM, Humbert M, Torbicki A, Vachiery JL, Barbera JA, et al; ESC Committee for Practice Guidelines (CPG). Guidelines for the diagnosis and treatment of pulmonary hypertension: the Task Force for the Diagnosis and Treatment of Pulmonary Hypertension of the European Society of Cardiology (ESC) and the European Respiratory Society (ERS), endorsed by the International Society of Heart and Lung Transplantation (ISHLT). Eur Heart J. 2009;30:2493-537. [PMID: 19713419] doi:10.1093/eurheartj/ehp297).

When to refer

It has been noted that there are 2 effective options for referring patients to advanced tertiary PH centers (1414. Champion HC. When to initiate intravenous therapy and/or refer. Am J Cardiol. 2013;111:21C-4C. [PMID: 23558027] doi:10.1016/j.amjcard.2013.01.321). The early option includes referral at the onset of suspected diagnosis to help facilitate proper diagnosis and management, and the later option involves referral after initial management of uncomplicated cases becomes advanced enough that continuous IV therapy or lung transplantation is being considered. In both instances, it is imperative to have experienced PH centers available for open lines of communication regarding care. Recognizing the costs associated with advanced therapy (which can approach a quarter of a million dollars a year) and the importance of adequate diagnosis and classification, we favor the early over the later approach.

Decompensated disease

The presence of clinical signs of deterioration, which may include new or increasing angina or syncope, increasing diuretic requirements, and the development of supraventricular arrhythmias, usually warrants admission to the hospital. ICU care should be sought at the outset of hospital admission, and contact with an experienced PH center for possible transfer should be considered. Once the patient is hospitalized, it is important to recognize triggers for the acute decompensation and prompt management of those triggers. Exacerbating factors often include infection, anemia, trauma, pregnancy, surgery, pulmonary embolism, medical nonadherence, hypoxemia, and tachyarrhythmias. Steadfast, frequent monitoring of renal and hepatic function, oxygen saturation, and markers of tissue perfusion (such as lactate) and neurohormones (such as BNP) should be employed early. Hoeper and colleagues (1515. Hoeper MM, Galié N, Murali S, Olschewski H, Rubenfire M, Robbins IM, et al. Outcome after cardiopulmonary resuscitation in patients with pulmonary arterial hypertension. Am J Respir Crit Care Med. 2002;165:341-4. [PMID: 11818318]) also advocate for invasive hemodynamic monitoring with Swan-Ganz catheters; however, this can be challenging without fluoroscopic guidance in the settings of high PVR. Further, there is a theoretical increased risk of pulmonary artery rupture in the context of PAH. Thus, the benefits of routine management of acute RV failure remain unclear.

The primary goal of therapy in the decompensated PH or PAH patient include maximizing cardiac output and decreasing filling pressures while avoiding end-organ failure. Fluid management is of utmost importance and can be challenging. Although acutely decompensated PH patients often require diuresis to offload the failing RV, overt cardiogenic shock can develop or worsen if these patients are overdiuresed. Inotropic agents to increase cardiac output, such as dobutamine, are often chosen but should be used with caution because of the propensity for the development of tachyarrhythmias. PDE-3 inhibitors such as milrinone are an alternative option.

Tachyarrhythmias should be managed promptly because they are poorly tolerated in patients with decompensated severe PH. In one study of 231 PH patients (1616. Tongers J, Schwerdtfeger B, Klein G, Kempf T, Schaefer A, Knapp JM, et al. Incidence and clinical relevance of supraventricular tachyarrhythmias in pulmonary hypertension. Am Heart J. 2007;153:127-32. [PMID: 17174650]), the development of SVT was associated with deterioration in 84% of the episodes. Hence, electrical cardioversion is recommended to abort supraventricular tachycardia and restore normal sinus rhythm. Invasive mechanical ventilation or intubation can be quite deleterious in PH patients given the vasodilating effects of induction and sedative agents required. Further, positive-pressure ventilation results in increased RV afterload. Thus, the potential for further decrements in cardiac output as a result of increased airway pressures also makes mechanical ventilation a unfavorable option; it should only be performed if absolutely necessary. The likelihood of successful extubation in patients with severe PH is grim.

RV offloading with reduction in PVR may be accomplished with the initiation of IV prostacyclins, especially in PAH patients who are naive to advanced therapies. The agent of choice is epoprostenol and may be limited by hypotension. Inhaled nitric oxide or the inhaled prostacyclin iloprost may be a consideration. It also may be prudent to hold PDE-5 inhibitors and ERAs in patients who were previously receiving them before decompensation in instances of hemodynamic instability.

Lung-heart or lung transplantation, atrial septostomy, and ventricular assist devices are end-stage options in patients who do not respond to the previous mentioned interventions. Extra-corporeal membrane oxygenation can be considered as a potential option as a bridge to transplantation in refractory cases (1111. Barst RJ, Gibbs JS, Ghofrani HA, Hoeper MM, McLaughlin VV, Rubin LJ, et al. Updated evidence-based treatment algorithm in pulmonary arterial hypertension. J Am Coll Cardiol. 2009;54:S78-84. [PMID: 19555861] doi:10.1016/j.jacc.2009.04.017). It is important to note that these heroic therapies pose very high risks.

Prognosis

Prognosis is influenced by type and severity of PH. Additionally, the REVEAL risk score can be used to determine 1-year mortality in patients with newly diagnosed PAH. It includes factors such as the PAH subgroup, comorbidity and demographic information, WHO functional classification, results of a 6-minute walk test, echocardiographic findings, results of pulmonary function tests, right-heart catheterization data, and BNP levels. Poor predictors in PH include the following (1717. Mathai SC, Bueso M, Hummers LK, Boyce D, Lechtzin N, Le Pavec J, et al. Disproportionate elevation of N-terminal pro-brain natriuretic peptide in scleroderma-related pulmonary hypertension. Eur Respir J. 2010;35:95-104. [PMID: 19643943] doi:10.1183/09031936.00074309, 1818. Forfia PR, Fisher MR, Mathai SC, Housten-Harris T, Hemnes AR, Borlaug BA, et al. Tricuspid annular displacement predicts survival in pulmonary hypertension. Am J Respir Crit Care Med. 2006;174:1034-41. [PMID: 16888289], 1919. Forfia PR, Mathai SC, Fisher MR, Housten-Harris T, Hemnes AR, Champion HC, et al. Hyponatremia predicts right heart failure and poor survival in pulmonary arterial hypertension. Am J Respir Crit Care Med. 2008;177:1364-9. [PMID: 18356560] doi:10.1164/rccm.200712-1876OC):

  • subtype related to connective tissue disease,
  • WHO functional class >II,
  • RV dysfunction, pericardial effusion, and tricuspid annular plane systolic excursion (TAPSE) <17 mm on echocardiography,
  • serum sodium level <136 mEq/L and elevated BNP level,
  • right-heart catheterization with a cardiac index <2 L per min/m2 and mean right atrial pressure >20 mm Hg, and
  • 6-minute walk test distance <300 m.

Right-heart failure is the most common cause of death. PAH patients who require CPR have only a 6% chance of survival at 90 days (1515. Hoeper MM, Galié N, Murali S, Olschewski H, Rubenfire M, Robbins IM, et al. Outcome after cardiopulmonary resuscitation in patients with pulmonary arterial hypertension. Am J Respir Crit Care Med. 2002;165:341-4. [PMID: 11818318]).

The American College of Cardiology Foundation Task Force and the Task Force for the Diagnosis and Treatment of Pulmonary Hypertension (European Society of Cardiology and European Respiratory Society) both recommend that pregnancy should be avoided or terminated early in patients with PAH. Mortality rates for pregnant patients are estimated to be as high as 50% (2020. Weiss BM, Zemp L, Seifert B, Hess OM. Outcome of pulmonary vascular disease in pregnancy: a systematic overview from 1978 through 1996. J Am Coll Cardiol. 1998;31:1650-7. [PMID: 9626847]).

There are no established guidelines for the preoperative management of PH patients. This population represents extremely high surgical risk and should be medically optimized in consultation with advanced tertiary PH specialty centers.

Summary

PH is a group of conditions with many causes and degrees of disease severity and is defined as a mean pulmonary artery pressure greater than 25 mm Hg. Pulmonary arterial hypertension falls under the PH umbrella and is characterized by primary vasculopathy of pulmonary vessels. In addition to a mean pulmonary artery pressure of 25 mm Hg or greater and a PCWP less than or equal to 15 mm Hg, the exclusion of Group 2 through 5 disease is required for diagnosis of PAH. PAH has a grim prognosis even when contemporary advanced therapies are available. The diagnostic approach varies and is predicated on historical clues. The screening tool of choice is echocardiography; an estimated RV systolic pressure greater than 40 mm Hg should prompt further investigation. Right-heart catheterization is the gold standard for confirmatory diagnosis. The final common pathway of severe PH regardless of cause is right-heart failure and death. Treatment is aimed at the mediators of pulmonary vascular remodeling in Group 1 disorders, the underlying cause in Groups 2 through 5, or the resultant right-heart failure in decompensated states.

The patient described in the introductory case was noted to be on optimal PAH therapies and had poor prognostic markers evidenced by a prior echocardiogram with marked RV dysfunction and a pericardial effusion, as well as low serum sodium levels and an elevated BNP level. Her course and subsequent demise illustrate the tenuous nature of patients with severe PAH. Despite advances in medical management, there remain no medical cures and the disease is universally fatal. Hence, it is important for clinicians to understand the causes, diagnostic approach, management of PH, and PAH subset, as well as when to refer to prevent significant morbidity and mortality.