Medical Update For Healthcare Professionals: Pulmonary Hypertension

By Stuart Rich, MD

Pulmonary hypertension (PH), an abnormal elevation in pulmonary artery pressure, may be the result of left heart failure, pulmonary parenchymal or vascular disease, thromboembolism, or a combination of these factors. Whether the pulmonary hypertension arises from cardiac, pulmonary, or intrinsic vascular disease, it generally is a feature of advanced disease. Because the causes of pulmonary hypertension are so diverse, it is essential that the etiology underlying the pulmonary hypertension be clearly determined before embarking on treatment.

Nomenclature and Classification

Pulmonary hypertension was traditionally divided into primary and secondary. This classification has been replaced by the one proposed by the World Health Organization in 1998. Currently PH is divided in to five major categories with further subdivisions in each category. Pulmonary arterial hypertension (PAH) refers to pulmonary vascular disease originating in the arterial side of the pulmonary circulation. PAH can be idiopathic, secondary to other medical conditions or associated with significant venous or capillary involvement. PAH can also be either sporadic or familial. Pulmonary venous hypertension is due to left heart disease with elevated pulmonary capillary artery pressure. PH associated with hypoxemia is due to lung disease and other disorders associated with hypoxemia. PH due to chronic thrombotic or embolic disease is due to prior pulmonary embolism in the majority of cases. The miscellaneous category of PH includes diverse disorders like sarcoidosis and fibrosing mediastinitis.

Pathology

The most common vascular changes in PAH can best be characterized as a hypertensive pulmonary arteriopathy, which is present in 85 percent of cases. These changes involve medial hypertrophy of the arteries and arterioles, often in conjunction with other vascular changes. Isolated medial hypertrophy is uncommon, and when present it has been assumed to represent an early stage of the disease. The intimal proliferation may appear as concentric laminar intimal fibrosis, eccentric intimal fibrosis, or concentric intimal fibrosis. The frequency of these findings differs from case to case and within regions of the same lung in the same patient. In addition, plexiform and dilation lesions, as well as a necrotizing arteritis, may be seen throughout the lungs. The fundamental nature of the plexiform lesion remains a mystery. Morphologically, they represent a mass of disorganized vessels with proliferating endothelial cells, smooth muscle cells, myofibroblasts, and macrophages. Several studies have demonstrated the involvement of growth factors that have been implicated in angiogenesis. Whether the plexiform lesion represents impaired proliferation or angiogenesis remains unclear.

Pathobiology

Pulmonary arterial hypertension (PAH) has a multifactorial pathobiology. Abnormalities in molecular pathways regulating the pulmonary vascular endothelial and smooth muscle cells have been described as underlying PAH. These include inhibition of the voltage-regulated potassium channel, mutations in the bone morphogenetic protein-2 receptor, increased serotonin uptake in the smooth muscle cells, increased angiopoetin expression in the smooth muscle cells, and excessive thrombin deposition related to a procoagulant state. As a result there appears to be loss of apoptosis of the smooth muscle cells allowing their proliferation, and the emergence of apoptosis resistant endothelial cells which can obliterate the vascular lumen. Vasoconstriction, remodeling of the pulmonary vessel wall, and thrombosis contribute to increased pulmonary vascular resistance in PAH. The process of pulmonary vascular remodeling involves all layers of the vessel wall and is complicated by cellular heterogeneity within each compartment of the pulmonary arterial wall. Each cell type (endothelial, smooth muscle, and fibroblast), as well as inflammatory cells and platelets, may play a significant role in PAH. Pulmonary vasoconstriction is believed to be an early component of the pulmonary hypertensive process. Excessive vasoconstriction has been related to abnormal function or expression of potassium channels and to endothelial dysfunction. Endothelial dysfunction leads to chronically impaired production of vasodilators such as nitric oxide and prostacyclin along with overexpression of vasoconstrictors such as endothelin. Recent genetic and pathophysiologic studies have emphasized the relevance of several mediators in this condition, including prostacyclin, nitric oxide, endothelin, angiopoietin, serotonin, and members of the transforming-growth-factor-beta superfamily. Disordered proteolysis of the extracellular matrix is also evident in PAH.

Pathophysiology

The right ventricle responds to an increase in resistance within the pulmonary circulation by increasing RV systolic pressure as necessary to preserve cardiac output. Over time, chronic changes occur in the pulmonary circulation resulting in progressive remodeling of the vasculature, which can sustain or promote pulmonary hypertension even if the initiating factor is removed. The ability of the right ventricle to adapt to increased vascular resistance is influenced by several factors including age and the rapidity of the development of pulmonary hypertension. For example, a large acute pulmonary thromboembolism can result in RV failure and shock, whereas chronic thromboembolic disease of equal severity may result in only mild exercise intolerance. Coexisting hypoxemia can impair the ability of the ventricle to compensate. Several studies support the concept that RV failure occurs in pulmonary hypertension when the RV myocardium becomes ischemic due to excessive demands and inadequate right ventricular coronary blood flow. The onset of clinical RV failure, usually manifest by peripheral edema, is associated with a poor outcome.

The anatomical disposition and geometry of the right ventricle allow it to adapt very well to wide variations in preload, but poorly to increases in afterload. In the presence of increased afterload, RV stroke volume decreases linearly with increasing resistance and the ventricle eventually dilates. This dilation is then responsible for further RV failure, due to decreased right coronary artery flow at a time when myocardial oxygen consumption is increased. Furthermore, RV dilation shifts the interventricular septum to the left, decreasing left ventricular preload and compliance and, hence, the cardiac output. An often-lethal vicious circle is induced. The main therapeutic goals aimed at breaking this circle are restoration of adequate oxygen delivery to the myocardium and diminution of RV afterload.

Diagnosis

Patients with pulmonary hypertension can present with varied cardiopulmonary symptoms. Exertional dyspnea is the most frequent symptom and unexplained dyspnea should always raise the suspicion of PH. PH may be asymptomatic in the early stages and may be an incidental finding on echocardiogram performed for other reasons. Chest pain and syncope are usually late symptoms. Patients may present with symptoms of right heart failure such as peripheral edema or ascites. A family history of PH, use of fenfluramine appetite suppressants, cocaine or amphetamines, prior history of deep vein thrombosis (DVT) or pulmonary embolism (PE),chronic liver disease or portal hypertension, risk factors for HIV, thyroid disease, splenectomy and sickle cell disease should be sought in all patients suspected to have PH.

The physical examination typically reveals increased jugular venous pressure, a reduced carotid pulse, and a palpable RV impulse. Most patients have an increased pulmonic component of the second heart sound a right-sided fourth heart sound, and tricuspid regurgitation. Peripheral cyanosis and/or edema tend to occur in later stages of the disease.

Laboratory Findings

The goals of work-up in PH include confirmation of diagnosis, establish an underlying cause, and quantifying severity with hemodynamics and functional impairment.

Electrocardiographic features of significant PH include: right axis deviation, right atrial enlargement and right ventricular hypertrophy. The Chest X-ray (CXR) may show enlarged main and branch pulmonary arteries with attenuation of peripheral vascular markings. CXR changes of obstructive or restrictive lung disease or pulmonary congestion may be helpful in elucidating the cause of PH. Echocardiography is helpful in confirming the diagnosis as well as excluding left sided cardiac lesions as the etiology of PH. A thorough study is needed to delineate cardiac anatomy and function, great arterial vessels, systemic and pulmonary veins, and to assess the severity of PH and its hemodynamic effects. Pulmonary function testing is done to evaluate for possible obstructive or restrictive lung disease. Ventilation/perfusion scan is recommended an initial investigation to evaluate for chronic thromboembolic pulmonary hypertension (CTEPH). Computed tomography (CT) scan of chest may show various abnormalities in CTEPH, including irregular pulmonary arteries, organized thrombus, webs, increased bronchial artery collateral flow, lung scars from prior infarction and mosaic perfusion pattern. CT scan may also show airway or parenchymal changes suggestive of underlying lung disease as the etiology of PH. Blood work-up should include anti-nuclear antibody tests, liver function tests, thyroid function tests and HIV testing.

Cardiac Catheterization is required to confirm the diagnosis, assess its severity, guide medical therapy and provide prognostic information. This procedure is mandatory for accurate measurement of pulmonary artery pressure, cardiac output, and LV filling pressure, as well as for exclusion of an underlying cardiac shunt. Care should be taken to measure pressures only at end-expiration. It is also recommended that patients with pulmonary arterial hypertension undergo drug testing with a short-acting pulmonary vasodilator at the time of cardiac catheterization to determine the extent of pulmonary vasodilator reactivity. Inhaled nitric oxide, intravenous adenosine, and intravenous epoprostenol appear to have comparable effects in reducing pulmonary artery pressure acutely. Nitric oxide is administered via inhalation in 10 to 20 parts per million. Adenosine is given in doses of 50 μg/kg per min and increased every 2 min until side effects develop. Epoprostenol is given in doses of 2 ng/kg per min and increased every 30 min until side effects develop. A positive vasodilator response is defined as a decrease of at least 10 mmHg in mean PAP and achieving mean PAP < 40 mmHg, and an increase or no change in cardiac output, and no significant fall in blood pressure. Patients who respond can often be treated with calcium channel blockers and have a more favorable prognosis. In some patients left heart catheterization is also performed if there is suspicion of left heart disease. All the hemodynamic data is obtained at baseline as well as after giving a short acting pulmonary vasodilator.

Idiopathic Pulmonary Arterial Hypertension

Idiopathic pulmonary arterial hypertension (IPAH), formerly referred to as primary pulmonary hypertension is uncommon, with an estimated incidence of 2 cases per million. There is a strong female predominance, with most patients presenting in the fourth and fifth decades, although the age range is from infancy to >60 years.

Familial IPAH accounts for up to 20% of cases of IPAH and is characterized by autosomal dominant inheritance, variable age of onset, and incomplete penetrance. The clinical and pathologic features of familial and sporadic IPAH are identical. Heterozygous germline mutations that involve the gene coding the type II bone morphogenetic protein receptor (BMPR II), a member of the transforming growth factor (TGF)-β superfamily, appear to account for most cases of familial IPAH. The low gene penetrance suggests that other risk factors or abnormalities are necessary to manifest clinical disease.

Natural History

The natural history of IPAH is uncertain, and because the predominant symptom is dyspnea, which can have an insidious onset, the disease is typically diagnosed late in its course. Prior to current therapies, a mean survival of 2 to 3 years from the time of diagnosis was reported.(16) Functional class remains a strong predictor of survival, with patients who are in New York Heart Association (NYHA) functional class IV having a mean survival of <6 months. The cause of death is usually RV failure, which is manifest by progressive hypoxemia, tachycardia, hypotension, and edema.

Treatment

General recommendations. Because the pulmonary artery pressure in PAH increases dramatically with exercise, patients should be cautioned against participating in activities that demand increased physical stress. Diuretic therapy relieves peripheral edema and may be useful in reducing RVEDP. Resting and exercise pulse oximetry should be obtained, as oxygen supplementation helps to alleviate dyspnea and RV ischemia in patients whose arterial oxygen saturation is reduced. Hypoxemia is a potent pulmonary vasoconstrictor and all activities leading to hypoxemia need to be avoided in such patients. Anticoagulant therapy is advocated for all patients with PAH based on retrospective and prospective studies that demonstrated that warfarin increases survival of patients with PAH. The dose of warfarin is generally titrated to achieve an INR of two to three times control. Influenza and pneumococcal vaccination is strongly recommended to prevent respiratory infections. All medication use including over the counter and herbal medications should be discussed with the physician prior to their use. All vasoconstrictor medications including pseudoephedrine containing compounds should be avoided. Appetite and diet pills should also be avoided due to their association with PH. Oxygen supplementation is recommended in patients who are hypoxemic. Patients whose SaO2 is < 89% at rest, during sleep or with ambulation, should be provided supplemental oxygen therapy to keep SpO2> 90% at all times.

Drug Treatment for Pulmonary Arterial Hypertension

Calcium Channel Blockers Patients who have substantial reductions in pulmonary arterial pressure in response to short-acting vasodilators at the time of cardiac catheterization should be treated initially with calcium channel blockers. Typically, patients require high doses (e.g., nifedipine, 240 mg/d, or amlodipine, 20 mg/d). Patients who respond favorably usually have dramatic reductions in pulmonary artery pressure and pulmonary vascular resistance associated with improved symptoms, regression of RV hypertrophy, and improved survival now documented to exceed 20 years. However, <20% of patients respond to calcium channel blockers in the long term. These drugs should not be given to patients who are unresponsive, as they can result in hypotension, hypoxemia, tachycardia, and worsening right heart failure.

Endothelin Receptor Antagonists The endothelin receptor antagonists bosentan and ambrisentan are approved treatments of PAH for patients who are NYHA functional classes III and IV. In randomized clinical trials, they improved symptoms and exercise tolerance as measured by an increase in 6 minute walk distance. Bosentan is initiated at 62.5 mg bid for the first month and then increased to 125 mg bid thereafter. Because of the high frequency of abnormal hepatic function tests associated with drug use, primarily an increase in transaminases, it is recommended that liver function be monitored monthly throughout the duration of use. Bosentan is also contraindicated in patients who are currently on cyclosporine or glyburide. Ambrisentan is used as 5mg or 10 mg doses, based on the clinical response. The safety profile of ambrisentan appears to be better than that of bosentan.

Phosphodiesterase-5 inhibitors Sildenafil, a phosphodiesterase-5 inhibitor, is approved for the treatment of PAH patients who are functional class II and III. Phosphodiesterase-5 is responsible for the hydrolysis of cyclic GMP in pulmonary vascular smooth muscle, the mediator through which nitric oxide lowers pulmonary artery pressure and inhibits pulmonary vascular growth. Randomized clinical trials have shown that sildenafil improves symptoms and exercise tolerance in PAH. The recommended dose is 20 mg T.I.D. The most common side effects are headache and stuffy nose. Sildenafil should not be given to patients who are taking nitrate compounds.

Prostacyclins Iloprost, a prostacyclin analogue, is approved for PAH patients via inhalation who are functional class III and IV. It has been shown to improve symptoms and exercise tolerance. Therapy can be given at either 2.5 or 5 mcg per inhalation treatment. The inhaler must be given by a dedicated nebulizer. The most common side effects are flushing and cough. Because of the very short half live (less than 30 minutes) it is recommended to administer treatments as often as every 2 hours. Epoprostenol is approved for the treatment of PAH patients who are NYHA functional class III or IV. Clinical trials have demonstrated an improvement in symptoms, exercise tolerance, and survival even if no acute hemodynamic response to drug challenge occurs. The drug is administered intravenously and requires placement of a permanent central venous catheter and infusion through an ambulatory infusion pump system. Side effects include flushing, jaw pain, and diarrhea, which are generally tolerated by most patients.

Treprostinil, an analogue of epoprostenol, is approved for patients with PAH who are NYHA functional classes II to IV. Treprostinil has a longer half-life than epoprostenol (4 hours), is stable at room temperature, and may be given intravenously or subcutaneously through a small infusion pump that was originally developed for insulin. Clinical trials have demonstrated an improvement in symptoms and exercise capacity. The major problem with the subcutaneous administration has been local pain at the infusion site, which has caused many patients to discontinue therapy. Side effects are similar to those seen with epoprostenol.

The intravenous prostacyclins have the greatest efficacy as treatments for PAH, and often will be effective in patients who have failed all other treatments. Favorable properties include vasodilation, platelet inhibition, inhibition of vascular smooth muscle growth and inotropic effects. It generally takes several months to titrate the dose of epoprostenol or treprostinil upwards to optimal clinical efficacy, which can be determined by symptoms, exercise testing and catheterization. The optimal doses of these drugs have not been determined, but the typical doses of epoprostenol range from 25-40 ng/kg/min, and from 75 to 150 ng/kg/min for treprostinil. The major problem with intravenous therapy is infection related to the venous catheter, which requires close monitoring and diligence on behalf of the patient.

Although most clinical trials have focused on patients with advanced symptoms, it is recommended that every patient diagnosed with PAH be treated. While no treatment has been demonstrated to be superior as first-line therapy, patients often prefer to initiate their treatment with an oral or inhaled form of therapy. In the clinical trials full clinical benefit was generally manifest within the first 2 months of therapy. Patients who fail to adequately improve should have the treatment discontinued and started on a different therapy. Equally important is that delaying a more effective treatment may allow the disease to progress and become less responsive. The use of these drugs in combination has become popular, however, the only randomized controlled trial of combination therapy demonstrating efficacy has been the addition of oral sildenafil to stable patients with PAH on intravenous epoprostenol. Patients with declining status in spite of treatment with intravenous prostanoids should be considered for lung transplantation.

Clinical Classification of Pulmonary Arterial Hypertension

1. Pulmonary arterial hypertension

1.1 Idiopathic pulmonary hypertension
Sporadic
Familial
1.2 Associated with:
Connective tissue disease
Congenital heart disease
Portal hypertension
Human immunodeficiency virus infection
Drugs/toxins

  1. Anorexigens
  2. Other

1.3 Persistent pulmonary hypertension of the newborn
1.4 Pulmonary veno-occlusive disease
1.5 Pulmonary capillary hemangiomatosis

2. Pulmonary venous hypertension

2.1 Left-sided atrial or ventricular heart disease
2.2 Left-sided valvular heart disease
2.3 Extrinsic compression of central pulmonary veins
Fibrosing mediastinitis
Adenopathy/tumors
2.4 Other

3. Pulmonary hypertension associated with disorders of the respiratory system and/or hypoxemia

3.1 Chronic obstructive pulmonary disease
3.2 Interstitial lung disease
3.3 Sleep-disordered breathing
3.4 Alveolar hypoventilation disorders
3.5 Chronic exposure to high altitude
3.6 Neonatal lung disease
3.7 Alveolar-capillary dysplasia
3.8 Other

4. Pulmonary hypertension due to chronic thrombotic and/or embolic disease

4.1 Thromboembolic obstruction of proximal pulmonary arteries
4.2 Thromboembolic obstruction of the distal pulmonary arteries
4.3 Pulmonary embolism (tumor, ova parasites, foreign material)

5. Pulmonary hypertension due to disorders directly affecting the pulmonary vasculature

5.1 Inflammatory
Schistosomiasis
Sarcoidosis
Histiocytosis X
Other

Additional Diagnostic Tests to Evaluate the Suspected Cause of Pulmonary Hypertension

Cause

Diagnostic Test

Collagen vascular disease

Serologic and immunogenetic studies

Congenital heart disease

Transesophageal echocardiography with contrast

Portal hypertension

Ultrasonography, computed tomography

Human Immunodeficiency Virus

HIV serologic test

Left ventricular diastolic dysfunction

Left ventricular end-diastolic pressure or left atrial pressure measurement

Mitral valve disease

Echocardiography with Doppler

Mediastinal fibrosis

Computed tomography, magnetic resonance imaging

Chronic obstructive lung disease

Pulmonary function tests

Obstructive sleep apnea

Sleep apnea study

Pulmonary fibrosis

High resolution chest CT

Pulmonary thromboembolitic disease

Perfusion lung scan, contrast enhanced spiral CT, pulmonary angiography

Sarcoidosis

Lung or lymph node biopsy

Bibliography

Rich S. A new classification of pulmonary hypertension. Advances in Pulmonary Hypertension 2002:1; 3-6.

Rabinovitch M. Molecular pathogenesis of pulmonary arterial hypertension. J Clin Invest 2008; 118:2372-2379.

Rich S, Dantzker R, Ayres S, et al. Primary pulmonary hypertension: a national prospective study. Ann Intern Med 1987;107:216-23.

Archer S, Rich S. Primary pulmonary hypertension: a vascular biology and translational research. Work in Progress. Circulation. 2000;102:2781-91.

Badesch DB, Abman SH, Ahearn GS, et al. Medical therapy for pulmonary arterial hypertension: ACCP evidence-based clinical practice guidelines. Chest 2004; 126:35S-62S

Rich S, Kaufmann E, Levy PS. The effect of high doses of calcium-channel blockers on survival in primary pulmonary hypertension. N Engl J Med. 1992;327:76-81.
Barst R, Rubin L, Long W, et al. A comparison of continuous intravenous epoprostenol (prostacyclin) with conventional therapy for primary pulmonary hypertension. N Engl J Med 1996;334:296-301.

McLaughlin V, Shillington A, Rich S: Survival in primary pulmonary hypertension. The impact of epoprostenol therapy. Circulation 106:1477, 2002.

McLaughlin VV, Genthner DE, Panella MM, Rich S. Reduction in pulmonary vascular resistance with long-term epoprostenol (prostacyclin) therapy in primary pulmonary hypertension. N Engl J Med. 1998;338:273-277.

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