Article Update

Monday, January 4, 2021




Pulmonary hypertension is an elevation in pulmonary vascular pressure that can be caused by an isolated increase in pulmonary artery pressure or by combined increases in both pulmonary artery and pulmonary venous pressures (see Plate 4-123). Normal pressures in the pulmonary vascular bed are quite low. Pulmonary arterial hypertension (PAH) refers to isolated elevation of pulmonary arterial pressure, hemodynamically defined as a resting mean pulmonary artery pressure above 25 mm Hg with a normal left atrial pressure (15 mm Hg). PAH that occurs in the absence of a demonstrable cause, formerly known as primary pulmonary hypertension (PPH), may occur sporadically (idiopathic PAH [IPAH]) or as an inherited condition (familial PAH or FPAH). Mutations in the bone morphogenetic protein receptor II (BMPR2) gene occur in 50% of families with a history of FPAH and in nearly 25% of patients thought to have sporadic IPAH. Genetic testing and counseling may be recommended for relatives of patients with FPAH. PAH occurs in association with connective tissue diseases (particularly scleroderma), HIV infection, sickle cell disease, and chronic liver disease (portopulmonary hypertension). The “Venice” classification scheme of pulmonary hypertension is shown in Plate 4-123.




Patients with significant PAH rarely undergo lung biopsy because of the surgical and anesthetic risk involved (see Plate 4-124). For this reason, much of the available pathologic information regarding the disease comes from patients with late-stage disease who die or undergo lung transplantation. In these later stages of the disease, IPAH reveals the presence of plexiform arteriopathy. The plexiform lesion is a complex tuft of proliferating intimal cells thought to be of endothelial cell or smooth muscle cell origin. Multiple small channels may remain where there was once an open arterial lumen. This obstructive, proliferative arteriopathy leads to increased resistance to pulmonary blood flow. Some patients with IPAH may demonstrate microscopic in situ thrombosis in the small pulmonary arterioles. Although IPAH is often associated with plexiform arteriopathy, some patients with underlying associated conditions such as scleroderma may demonstrate a more concentric, “onion skin” form of hypertrophy of the pulmonary vascular wall.

Obliteration of the pulmonary vascular lumen leads to an increase in pulmonary vascular resistance, ultimately placing a strain on the right ventricle. If the pulmonary vascular resistance increases slowly, as it often does in patients with PAH occurring in association with congenital heart disease, the right ventricle may adapt over time through hypertrophy, with maintenance of contractility and preservation of cardiac output. A more rapid increase in pulmonary vascular resistance, perhaps in the presence of a genetically determined less adaptive response, may lead to right ventricular dilatation, with a progressive decline in function and ultimately right ventricular failure. Right- sided heart failure is typically manifest clinically by progressive dyspnea on exertion, fatigue, fluid retention, edema, ascites, and signs of venous congestion. The most common cause of death in patients with PAH is right-sided heart failure.




Although PAH may be asymptomatic, exertional dyspnea is the most frequently encountered symptom (see Plate 4-125). Accordingly, PAH should be suspected in patients with unexplained dyspnea. Anginal chest pain or syncope is less common and portends a poor prognosis. Peripheral edema or ascites indicates right ventricular failure. The symptoms of PAH are nonspecific and are similar to those occurring in more commonly encountered diseases, such as obstructive lung disease and left-sided heart disease. A family history of pulmonary hypertension may lead to early recognition of clinical disease in other individuals. Pulmonary hypertension occurs more frequently in patients with autoimmune or connective tissue disease, especially scleroderma. Use of amphetamines or cocaine should be explored because these have been implicated in the development of PAH in some users. A history of acute pulmonary embolism requires a careful search for chronic thromboembolic pulmonary hypertension, although this condition may occur in the absence of symptomatic venous thromboembolic disease. Patients with a history of such underlying disorders or exposures who develop unexplained dyspnea should be screened for possible pulmonary hypertension.

The diagnostic strategy uses testing to determine whether PAH is the cause of symptoms and which of its causes is present (see Plate 4-125). A process of screening with less invasive and lower risk tests is followed by specific and confirmatory tests.

The electrocardiogram may provide evidence of pulmonary hypertension, such as right ventricular hypertrophy, right-axis deviation, or right atrial enlargement.

Radiographic signs of pulmonary hypertension include enlarged main and hilar pulmonary arteries (17 mm) with attenuation of peripheral pulmonary vascular markings (“pruning”). Right ventricular enlargement is evidenced by anterior displacement of the right ventricle into the retrosternal space on the lateral view (see Plate 3-9). The chest radiograph is also useful in demonstrating comorbid or causal conditions, such as pulmonary venous congestion, chronic obstructive pulmonary disease, or interstitial lung disease.

Doppler echocardiography is often the test that suggests a diagnosis of pulmonary hypertension. Echocardiography also provides information about the cause and consequences of pulmonary hypertension. Studies in patients with PAH have reported good correlations between Doppler-derived estimates of pulmonary artery systolic pressure and direct measurements obtained by right-sided heart catheterization. Echocardiography also provides evidence regarding left ventricular systolic and diastolic function and valvular function and morphology that can provide clues to causes of pulmonary hypertension stemming from elevated pulmonary venous pressures. Left atrial enlargement, even in the absence of definite left ventricular dysfunction, should raise the possibility of elevated left-sided filling pressures contributing to pulmonary hypertension.

Cardiac catheterization is ultimately required to confirm the presence of pulmonary hypertension, assess its severity, and guide therapy.

The evaluation of PAH includes assessment for an underlying cause (see Plate 4-125). Pulmonary function testing is a necessary part of the initial evaluation of patients with suspected pulmonary hypertension to exclude or characterize the contribution of underlying airways or parenchymal lung disease. In general, the degree of pulmonary hypertension seen in chronic obstructive lung disease is less severe than in PAH, and the presence and severity of pulmonary hypertension correlate with the degree of airflow obstruction and hypoxemia. Approximately 20% of IPAH patients have a mild restrictive defect. In chronic thromboembolic pulmonary hypertension (CTEPH), a mild to moderate restrictive defect is thought to be caused by parenchymal scarring from prior infarcts. In both conditions, the diffusing capacity for carbon monoxide is often mildly to moderately reduced. Mild to moderate arterial hypoxemia is caused by V/Q mismatch and reduced mixed venous oxygen saturation resulting from low cardiac output. Severe hypoxemia is caused by right- to-left intracardiac or intrapulmonary shunting. In patients with scleroderma, a decreasing diffusing capacity may indicate the development of pulmonary hypertension.

Overnight oximetry may demonstrate oxygen desaturation and might be the first clue to sleep apnea sufficient to contribute to pulmonary hypertension. Nocturnal hypoxemia can occur in patients with IPAH without sleep apnea. Because hypoxemia is a potent pulmonary vasoconstrictor, all patients with unexplained pulmonary hypertension require assessment of both sleep and exercise oxygen saturation.

It is important to screen for autoimmune and connective tissue disease, including physical examination and serologic testing for antinuclear antibodies. However, up to 40% of patients with IPAH have serologic abnormalities, usually an antinuclear antibody in a low titer and nonspecific pattern. Additional serologic studies may be indicated if initial testing suggests an underlying autoimmune disorder.

CTEPH is a potentially curable form of pulmonary hypertension and should be sought in all patients undergoing evaluation for possible pulmonary hypertension. Ventilation/perfusion (V/Q) lung scanning is the preferred test to rule out CTEPH. CTEPH is manifest by at least one segmental-sized or larger perfusion defect, which are typically mismatched and larger than ventilation abnormalities. Patchy, nonsegmental defects are less specific but may be associated with CTEPH. Although a normal perfusion scan essentially excludes surgically accessible chronic thromboembolic disease, scans suggestive of thromboembolic disease may also be seen in other conditions. Pulmonary angiography is the definitive test for diagnosing CTEPH and for determining operability and should be performed in experienced centers when this entity is a consideration.

Computed tomography (CT) scanning may suggest a cause for pulmonary hypertension, such as severe airway or parenchymal lung diseases. A spectrum of abnormalities on CT scan have been described in patients with CTEPH, including right ventricular enlargement, dilated central pulmonary arteries, chronic thromboembolic material within the central pulmonary arteries, increased bronchial artery collateral flow, variability in the size and distribution of pulmonary arteries, parenchymal abnormalities consistent with prior infarcts, and mosaic attenuation of the pulmonary parenchyma.

Open or thoracoscopic lung biopsy entails substantial risk in patients with significant pulmonary hypertension. Because of the low likelihood of altering the clinical diagnosis, routine biopsy is discouraged. Under certain circumstances, histopathologic diagnosis may be needed when vasculitis, granulomatous or interstitial lung disease, pulmonary venocclusive disease, or bronchiolitis are suggested on clinical grounds or by radiographic studies.



General Measures

There are few data on which to base recommendations regarding physical activity or cardiopulmonary rehabilitation in PAH (see Plate 4-126). Cautious, graduated physical activity is generally encouraged. Heavy physical activity can precipitate syncope. Hot baths or showers are discouraged because resultant peripheral vasodilatation can produce systemic hypotension and syncope. Excessive sodium intake can contribute to fluid retention. Exposure to high altitude (6000 ft above sea level) should generally be discouraged because it may produce hypoxic pulmonary vasoconstriction. Supplemental oxygen should be used to maintain oxygen saturations above 91%. Air travel can be problematic for patients with PAH because commercial air- craft are typically pressurized to the equivalent of approximately 8000 feet above sea level. Patients with borderline oxygen saturations at sea level may require 3 to 4 L/min of supplemental oxygen on commercial aircraft, and those already using supplemental oxygen at sea level should increase their oxygen flow rate. Because of the potential adverse effects of respiratory infections, immunization against influenza and pneumococcal pneumonia is recommended.

Pregnancy and Birth Control

The hemodynamic changes occurring in pregnancy impose significant stress in women with PAH, leading to a potential 30% to 50% mortality rate. Although there have been reports of successful treatment of pregnant IPAH patients using chronic intravenous epoprostenol, most experts recommend early termination of the pregnancy. Estrogen-containing contraceptives may increase the risk of venous thromboembolism and are not recommended for women with childbearing potential with PAH. Additionally, the endothelin receptor antagonists bosentan and ambrisentan may decrease the efficacy of hormonal contraception, and dual mechanical barrier contraceptive techniques are recommended in female patients of childbearing age taking these medications.

Concomitant Medications and Surgery

Use of vasoconstricting sinus or cold medications (e.g., pseudoephedrine) or serotonergic medications for migraine headaches may be problematic. Concomitant use of glyburide or cyclosporine with bosentan is contraindicated, and the use of azole-type antifungal agents is discouraged because of potential drug-drug interactions that may increase the risk of hepatotoxicity. Patients taking warfarin should be cautioned regarding potential drug interactions with this medication. Bosentan may decrease International Normalized Ratio (INR) levels slightly in patients taking warfarin.

Invasive procedures and surgery can be associated with an increased risk. Patients with severe PAH are particularly prone to vasovagal events leading to syncope, cardiopulmonary arrest, and death.  Cardiac output often depends on the heart rate in this situation, and the bradycardia and systemic vasodilatation accompanying a vasovagal event may result in hypotension. Heart rate should be monitored during invasive procedures, with availability of an anticholinergic agent. Oversedation may lead to ventilatory insufficiency and cause clinical deterioration. Caution should be exercised with laparoscopic procedures in which carbon dioxide is used for abdominal insufflation because absorption can produce hypercarbia, which is a pulmonary vasoconstrictor. The induction of anesthesia and intubation may be problematic because it may induce vasovagal events, hypoxemia, hypercarbia, and shifts in intrathoracic pressure.


Anticoagulation of IPAH patients with warfarin is recommended in the absence of contraindications. Although there is little evidence to guide such therapy, current consensus suggests targeting an INR of approximately 1.5 to 2.5. Anticoagulation is controversial for patients with PAH caused by other etiologies, such as scleroderma or congenital heart disease, because of a lack of evidence supporting efficacy, and the increased risk of gastrointestinal bleeding in patients with scleroderma, and hemoptysis congenital heart disease. The relative risks and benefits of anticoagulant therapy should be considered on a case-by-case basis. Patients with documented right-to-left intracardiac shunting caused by an atrial septal defect or patent foramen ovale and a history of transient ischemic attack or embolic stroke should be anticoagulated. Patients receiving treatment with chronic intravenous epoprostenol are generally anticoagulated in the absence of contraindications partly because of the additional risk of catheter- associated thrombosis.


Diuretics are indicated for volume overload or right ventricular failure. Rapid and excessive diuresis may precipitate systemic hypotension and renal insufficiency. Spironolactone, an aldosterone antagonist of benefit in patients with left-sided heart failure, is used by some experts to treat right-sided heart failure.


Although not extensively studied in PAH, digitalis is sometimes used for refractory right ventricular failure. Atrial flutter or other atrial dysrhythmias often complicate late-stage right-sided heart dysfunction, and digoxin may be useful for rate control.

Vasodilator Testing and Calcium Channel Blockers

Patients with IPAH who acutely respond to vasodilators often have improved survival with long-term use of calcium channel blockers (CCBs) (see Plate 4-126). A variety of short-acting agents have been used to test vasodilator responsiveness, including intravenous epoprostenol or adenosine and inhaled nitric oxide. The most recent consensus definition of a positive acute vasodilator response in PAH is decrease of at least 10 mm Hg in mean pulmonary artery pressure to less than or equal to 40 mm Hg with an increased or unchanged cardiac output. Most experts believe that true vasoreactivity is uncommon, occurring in 10% of patients with IPAH and rarely in those with other forms of PAH. Vasoreactivity testing should be performed in experienced centers. Only patients demonstrating a significant response to the acute administration of a short-acting vasodilator should be considered candidates for treatment with CCBs; treatment should be monitored closely because maintenance of response is not universal. Long-acting nifedipine or diltiazem or amlodipine is suggested. Agents with negative inotropic effect, such as verapamil, should be avoided.


Prostacyclin is a metabolite of arachidonic acid that is produced in vascular endothelium. It is a potent vasodilator, affecting both the pulmonary and systemic circulations, and has antiplatelet aggregatory effects. A relative deficiency of endogenous prostacyclin may contribute to the pathogenesis of PAH. In IPAH, continuously intravenously infused epoprostenol improved exercise capacity, assessed by the 6-minute walk distance (6MWD), cardiopulmonary hemodynamics, and survival compared with conventional therapy (oral vasodilators, anticoagulation). A similar study showed epoprostenol improved exercise capacity and hemodynamics in patients with PAH caused by the scleroderma spectrum of disease. Epoprostenol therapy is complicated by the need for continuous intravenous infusion. Because of its short half-life, the risk of rebound worsening with interruption of the infusion, and its irritant effects on peripheral veins, epoprostenol should be administered through an indwelling central venous catheter. Common side effects include headache, flushing, jaw pain, diarrhea, nausea, a blotchy erythematous rash, and musculoskeletal pain. Serious complications include catheter-related sepsis and thrombosis. Although epoprostenol is approved by the Food and Drug Administration for functional class III to IV patients with IPAH and PAH caused by scleroderma, it is generally reserved for patients with advanced disease refractory to oral therapies.

Other options for prostanoid therapy include subcutaneous or inhaled treprostinil, which has a longer half-life than epoprostenol, and inhaled iloprost, which must be inhaled six to nine times daily. Both drugs have demonstrated improved exercise capacity, functional class, and hemodynamics.

Endothelin Receptor Antagonists

Endothelin-1 (ET-1) is a vasoconstrictor and smooth muscle mitogen that may contribute to increased vascular tone and proliferation in PAH. Two endothelin receptor isoforms, ETA and ETB, and ET, have been identified. Controversy exists as to whether it is preferable to block block both the ETA and ETB receptors or to selectively target the ETA receptor. It has been argued that selective ETA receptor antagonism may be beneficial for the treatment of patients with PAH because of maintenance of the vasodilator and clearance functions of ETB receptors. A dual ETA/ETB receptor antagonist, bosentan, and a relatively selective ETA receptor antagonist, ambrisentan, have been approved for use in patients with PAH and moderate to severe heart failure.

Phosphodiesterase-5 Inhibitors

Sildenafil is a highly specific phosphodiesterase-5 inhibitor approved for male erectile dysfunction. Sildenafil reduces pulmonary artery pressure and increases 6MWD and confers additional benefit to background therapy with epoprostenol in patients with PAH. Sildenafil, and the longer acting tadalafil, are approved in the United States for the treatment of PAH.



Atrial septostomy involves the creation of a right-to left interatrial shunt to decompress the failing pressure/volume-overloaded right side of the heart. Where advanced medical therapies are available, atrial septostomy is seen as a largely palliative procedure or as a stabilizing bridge to lung transplantation. In areas lacking access to advanced medical therapies, atrial septostomy may be an option. Patient selection, timing, and appropriate sizing of the septostomy are critical to optimizing outcomes. Lung transplantation is particularly challenging in patients with PAH and is often reserved for those who are deteriorating despite the best available medical therapy. Survival in patients undergoing lung transplantation is approximately 66% to 75% at 1 year. Most centers prefer bilateral lung transplantation for patients with PAH.

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