Pulmonary Hypertension

Essentials of Diagnosis

• Defined as pulmonary artery (PA) systolic pressure > 30 mm Hg or mean PA pressure > 20 mm Hg

• Dyspnea, chest pain, exertional syncope

• Narrow splitting of second heart sound with loud pulmonary component; findings of right ventricular (RV) hypertrophy and cardiac failure in advanced disease

• Enlarged central pulmonary arteries on chest radiograph

• Electrocardiographic evidence of RV strain or hypertrophy and right atrial (RA) enlargement

• Two-dimensional echocardiography with Doppler flow is often diagnostic, showing elevated RV systolic pressure

• Multiple potential etiologies must be considered, including both pulmonary and cardiac

• Idiopathic (primary) pulmonary hypertension (PH) most frequently occurs in younger women

General Considerations

• The normal pulmonary circulation has low pressure and resistance, but high flow

• Normal PA systolic pressure at rest is 15 to 30 mm Hg, with a mean pressure between 10 and 18 mm Hg

• In PH, there is an increase in pulmonary vascular resistance which leads to an increase in PA systolic pressure > 30 mm Hg or mean PA pressure > 20 mm Hg

• PH is self-perpetuating, inducing changes in pulmonary vessels that further narrow the vascular bed, increasing pressure

• The World Health Organization classification of PH includes the following 5 groups:

  • Group 1 PH is PA hypertension from idiopathic (formerly primary) PA hypertension, heritable PA hypertension, HIV infection, portal hypertension, drugs and toxins, connective tissue disorders, congenital heart disease, schistosomiasis, primary veno-occlusive disease, and pulmonary capillary hemangiomatosis

  • Group 2 PH is pulmonary venous hypertension secondary to left heart disease, including left ventricular (LV) systolic or diastolic dysfunction, and valvular heart disease

  • Group 3 PH is PH secondary to lung disease or hypoxemia, caused by advanced obstructive and restrictive lung disease including chronic obstructive pulmonary disease, interstitial lung disease, pulmonary fibrosis, bronchiectasis, sleep-disordered breathing, alveolar hypoventilation syndromes, and high altitude exposure

  • Group 4 PH is PH secondary to chronic thromboembolism

  • Group 5 PH is PA hypertension secondary to hematologic disorders (eg, chronic hemolytic anemia, myeloproliferative disorders, splenectomy), systemic disorders (eg, sarcoidosis, vasculitis, pulmonary Langerhans cell histiocytosis, neurofibromatosis type 1), metabolic disorders (eg, glycogen storage disease, Gaucher disease, thyroid disease) and miscellaneous causes (tumor embolization, external compression of the pulmonary vasculature, end-stage renal disease on dialysis)

• Clinical severity of PH is classified according to the New York Heart Association classification

  • Class I: PH without limitation of physical activity. No dyspnea, fatigue, chest pain or near syncope with exertion

  • Class II: PH resulting in slight limitation of physical activity. No symptoms at rest but ordinary physical activity causes dyspnea, fatigue, chest pain or near syncope

  • Class III: PH resulting in marked limitation of physical activity. No symptoms at rest but less than ordinary activity causes dyspnea, fatigue, chest pain or near syncope

  • Class IV: PH with inability to perform any physical activity without symptoms. Evidence of right heart failure. Dyspnea and fatigue at rest and worsening of symptoms with any activity

Symptoms and Signs

• In its early stages, symptoms are due primarily to the underlying disease

• Progressive dyspnea, particularly with exertion and later, at rest

• Dull retrosternal chest pain

• Fatigue, lightheadedness, and exertional syncope

• Nonproductive cough, hemoptysis (rare)

• Malaise, fatigue

• Narrow splitting of second heart sound (S₂) with loud accentuated pulmonary component (P2); a systolic click; tricuspid and pulmonary valve regurgitation murmurs

• Signs of RV hypertrophy (RV heave), cor pulmonale and right heart failure (right-sided third heart sound, elevated JVP, abdominal distention, hepatomegaly, ascites, lower extremity edema) in advanced disease

• May be complicated by Eisenmenger physiology

  • Low cardiac output, with weakness and fatigue

  • Edema and ascites as right heart failure advances

  • Peripheral cyanosis

  • Syncope on effort when cardiac output is insufficient or there is an arrhythmia

Differential Diagnosis

• Cor pulmonale (right heart failure due to pulmonary disease)

• Heart failure

• Right-sided valvular heart disease

• Mitral stenosis

Laboratory Tests

• Polycythemia is found in cases resulting from chronic hypoxemia

• ECG findings

  • Right-axis deviation

  • RA enlargement (peaked P wave in the inferior and right-sided leads)

  • RV hypertrophy

  • RV strain

  • Incomplete right bundle branch block

• Tests to exclude secondary PH

  • HIV

  • Collagen vascular serologic studies

  • Liver chemistries

  • Surgical lung biopsy

• Tests to exclude a hypercoagulable state causing thromboembolism

  • Proteins C and S and antithrombin deficiency (serum protein C and S levels)

  • Lupus anticoagulant (eg, anticardiolipin antibodies)

  • Activated protein C resistance (factor V Leiden)

  • Hyperprothrombinemia (prothrombin gene 20210 AG mutation)

  • Nephrotic syndrome (serum albumin and creatinine, ratio of urinary protein concentration to urinary creatinine concentration)

  • Paroxysmal nocturnal hemoglobinuria (urine hemosiderin; serum LD; flow cytometry of blood leukocytes for deficiency of CD55 and CD59; FLAER [fluorescein-labeled proaerolysin] assay by flow cytometry)

  • Disseminated intravascular coagulation (D-dimers)

  • Myeloproliferative disorder, eg, polycythemia vera with hyperviscosity (hematocrit; JAK2 [V617F] mutation screening), essential thrombocytosis (platelet count)

  • Hyperhomocysteinemia (serum homocysteine level)

  • Congenital dysfibrinogenemia, abnormal plasminogen

Imaging Studies

• Chest radiographs may show

  • Enlargement of the right and left main pulmonary arteries

  • RA and RV enlargement in advanced cases

  • "Pruning" of peripheral pulmonary arteries in cases associated with COPD

  • Patchy pulmonary edema may raise suspicion of pulmonary veno-occlusive disease

• Chest CT

  • Demonstrates enlarged pulmonary arteries

  • May reveal cause in Group 3 PH due to lung disease (eg, emphysema or interstitial lung disease)

• Pulmonary angiography (or MR angiography or CT angiography)

  • Reveals loss of the smaller acinar pulmonary vessels and tapering of the larger ones

  • Can define distribution and extent of disease in PH due to chronic thromboembolism

• Ventilation-perfusion scanning, contrast spiral CT, and pulmonary angiography can diagnose recurrent or chronic pulmonary thromboembolism

Diagnostic Procedures

• Arterial blood gases in patients with idiopathic pulmonary arterial hypertension often have normal PaO₂ at rest but show evidence of hyperventilation with a decreased PaCO₂

• Pulmonary function tests: advanced emphysema and severe restrictive lung disease are associated with

  • Elevations in PA pressures

  • Reduction in the single breath diffusing capacity from diminution of the pulmonary capillary bed, suggesting chronic thromboembolic disease

• Echocardiography with Doppler

  • Echocardiography useful in the assessment of

    • Underlying cardiac disease (eg, helping to exclude an intracardiac shunt)

    • Severity of PH (based on the RV size and function)

  • Usually demonstrates an enlarged RV and RA—at times they may be huge and hypocontractile

  • Severe pulmonic or tricuspid regurgitation may be present

  • Septal flattening is consistent with PH

  • Doppler interrogation of the tricuspid regurgitation jet helps provide an estimate of RV systolic pressure and thus PA systolic pressure

• Right-heart catheterization

  • Allows for precise hemodynamic measurements of pulmonary pressures

  • Helpful in differentiating PA hypertension from pulmonary venous hypertension by assessment of the drop in pressure across the pulmonary circulation (transpulmonary gradient)

  • Identifies postcapillary disease, intracardiac shunting, or thromboembolic disease

  • Allows testing for vasoreactivity using a variety of agents, but nitric oxide is preferred due to its ease of use and short half-life

  • A significant acute vasodilator response consists of a decrease in the mean PA pressure of > 10 mm Hg to < 40 mm Hg

• Polysomnography to exclude obstructive sleep apnea

Medications

Group 1 PH

• Patients with a significant acute vasodilator response on vasoreactivity testing using an intravenous vasodilator (eg, calcium channel blocker, nitrate, or hydralazine) should first be tried on an oral calcium channel blocker

• Functional Class II

  • Patients should be given

    • Oral ambrisentan, bosentan, or macitentan (endothelin receptor antagonists)

    • Oral sildenafil, tadalafil, or vardenafil (phosphodiesterase-5 inhibitors)

    • Oral riociguat (guanylate cyclase stimulator, but potential teratogen)

• Functional Class III and IV

  • Patients not responsive to the above agents should be given

    • Intravenous epoprostenol or treprostinil (prostanoids administered continuously and long-term)

    • Intravenous epoprostenol (given continuously and long-term) has been shown to improve mortality

  • Patients unable to tolerate continuous infusions of prostanoids should be given

    • Inhaled iloprost, or

    • Oral or subcutaneous treprostinil, or

    • Oral riociguat (potential teratogen), or

    • Oral selexipag (selective prostacyclin (IP)-receptor agonist) or

    • Oral beraprost (not approved by US FDA)

• Long-term anticoagulation

  • Recommended and generally accepted, based solely on observational studies suggesting improvement in survival

  • Notably, this excludes patients with PA hypertension related to systemic sclerosis, who have an increased risk of mortality associated with anticoagulation in these observational studies

Group 2 PH

• Patients with right-sided heart failure should be given

  • Diuretics with salt restriction (< 2.4 g/day)

  • Supplemental oxygen with a goal of maintaining an oxygen saturation of > 90% for at least 15 hours per day (shown to slow the progression of PH)

  • Digoxin use in cor pulmonale is, however, controversial

Group 3 PH

• Patients should be given

  • Supplemental oxygen

  • Treatment for heart failure and volume overload

Group 4 PH

• Patients should be considered for long-term anticoagulation

  • Recommended and generally accepted, based solely on observational studies suggesting improvement in survival

  • Notably, this excludes patients with PA hypertension related to systemic sclerosis, who have an increased risk of mortality associated with anticoagulation in these observational studies

• Patients with chronic thromboembolism

  • Should be considered for operative pulmonary thromboendarterectomy

  • If deemed inoperable

    • Riociguat remains the only approved medical therapy

    • Percutaneous treatment by balloon pulmonary angioplasty may be clinically feasible

Group 5 PH

• Treatment is directed at the underlying cause of the PH

• Patients are advised against heavy physical exertion

Surgery

• Failure of medical therapies suggests that lung transplantation should be considered

• Double-lung transplantation (preferred method) or single-lung transplantation (routinely done) may be performed in patients with end-stage disease

• In some cases, simultaneous heart and double-lung transplantation is needed

• Palliation of patients who are not too cyanotic can be achieved by balloon atrial septostomy to increase cardiac output

Follow-Up

• Periodic reassessment of PA pressures to determine progression and response to therapy

Prognosis

• For Group 1 idiopathic PH patients, prognosis is poor and not affected by therapy for symptoms

• For Group 1 secondary cause and Groups 2–5 PH patients, prognosis depends on the severity of the underlying disease and its response to treatment

• Cor pulmonale (a severely dilated RV with poor contractile function) carries a poor survival outcome, regardless of underlying cause

When to Refer

• All patients with symptomatic PH should be referred to either a cardiologist or a pulmonologist who specializes in its evaluation and treatment

When to Admit

• Admit patients with PH, severe symptoms, and evidence of decompensated RV failure

  • For aggressive, carefully monitored diuresis

  • For initiation of vasodilator therapy

• Admit patients with Group 1 PH and functional Class IV symptoms to a specialized center for initiation of vasodilator therapy such as intravenous prostacyclins