Pulmonary Hypertension

Many conditions and drugs cause pulmonary hypertension. The most common overall causes of pulmonary hypertension are

Several other causes of pulmonary hypertension include sleep apnea Obstructive Sleep Apnea (OSA) Obstructive sleep apnea (OSA) consists of multiple episodes of partial or complete closure of the upper airway that occur during sleep and lead to breathing cessation (defined as a period of... read more , connective tissue disorders Introduction to Autoimmune Rheumatic Disorders Autoimmune rheumatic disorders include diverse syndromes such as Autoimmune myositis Eosinophilic fasciitis Mixed connective tissue disease Relapsing polychondritis read more , and recurrent pulmonary embolism Pulmonary Embolism (PE) Pulmonary embolism (PE) is the occlusion of pulmonary arteries by thrombi that originate elsewhere, typically in the large veins of the legs or pelvis. Risk factors for pulmonary embolism are... read more .

Pulmonary hypertension is currently classified into 5 groups (see table Classification of Pulmonary Hypertension Classification of Pulmonary Hypertension ) based on a number of pathologic, physiologic, and clinical factors. In the first group (pulmonary arterial hypertension [PAH]), the primary disorder affects the small pulmonary arterioles.

A small number of cases of AH occur sporadically, unrelated to any identifiable disorder; these cases are termed idiopathic PAH.

Hereditary forms of PAH (autosomal dominant with incomplete penetrance) have been identified; mutations of the following genes have been found:

Mutations in BMPR2 cause 75% of cases. The other mutations are much less common, occurring in about 1% of cases.

In about 20% of cases of hereditary PAH, the causative mutations are unidentified.

A mutation in the eukaryotic translation initiation factor 2 alpha kinase 4 gene (EIF2AK4) has been linked to pulmonary veno-occlusive disease, a form of PAH Group 1' (1, 2 Etiology references Pulmonary hypertension is increased pressure in the pulmonary circulation. It has many secondary causes; some cases are idiopathic. In pulmonary hypertension, pulmonary vessels may become constricted... read more ).

Certain drugs and toxins are risk factors for PAH. Those definitely associated with PAH are appetite suppressants (fenfluramine, dexfenfluramine, aminorex), toxic rapeseed oil, benfluorex, amphetamines, methamphetamines, and dasatinib. Similarly, other protein kinase inhibitors have also been linked to drug-induced pulmonary hypertension (3 Etiology references Pulmonary hypertension is increased pressure in the pulmonary circulation. It has many secondary causes; some cases are idiopathic. In pulmonary hypertension, pulmonary vessels may become constricted... read more ). Selective serotonin reuptake inhibitors taken by pregnant women are a risk for development of persistent pulmonary hypertension of the newborn Persistent Pulmonary Hypertension of the Newborn Persistent pulmonary hypertension of the newborn is the persistence of or reversion to pulmonary arteriolar constriction, causing a severe reduction in pulmonary blood flow and right-to-left... read more . Drugs that are likely or possibly associated with PAH are amphetamine-like drugs, cocaine, phenylpropanolamine, St. John's wort, interferon-alpha, interferon-beta, alkylating agents, bosutinib (only possibly linked to PAH), direct-acting antiviral agents against hepatitis C virus, leflunomide, indirubin, and L-tryptophan (4 Etiology references Pulmonary hypertension is increased pressure in the pulmonary circulation. It has many secondary causes; some cases are idiopathic. In pulmonary hypertension, pulmonary vessels may become constricted... read more ).

Patients with hereditary causes of hemolytic anemia Overview of Hemolytic Anemia At the end of their normal life span (about 120 days), red blood cells (RBCs) are removed from the circulation. Hemolysis is defined as premature destruction and hence a shortened RBC life span... read more , such as sickle cell disease Sickle Cell Disease Sickle cell disease (a hemoglobinopathy) causes a chronic hemolytic anemia occurring almost exclusively in people with African ancestry. It is caused by homozygous inheritance of genes for hemoglobin... read more , are at high risk of developing pulmonary hypertension (10% of cases based on right heart catheterization criteria). The mechanism is related to intravascular hemolysis and release of cell-free hemoglobin into the plasma, which scavenges nitric oxide, generates reactive oxygen species, and activates the hemostatic system. Other risk factors for pulmonary hypertension in sickle cell disease include iron overload Overview of Iron Overload Typical adults lose about 1 mg iron (Fe) per day in shed epidermal and gastrointestinal cells; menstruating females lose on average an additional 0.5 to 1 mg/day from menses. This iron loss... read more , liver dysfunction, thrombotic disorders Overview of Thrombotic Disorders In healthy people, homeostatic balance exists between procoagulant (clotting) forces and anticoagulant and fibrinolytic forces. Numerous genetic, acquired, and environmental factors can tip... read more , and chronic kidney disease Chronic Kidney Disease Chronic kidney disease (CKD) is long-standing, progressive deterioration of renal function. Symptoms develop slowly and in advanced stages include anorexia, nausea, vomiting, stomatitis, dysgeusia... read more .

Pathophysiologic mechanisms that cause pulmonary hypertension include

Increased pulmonary vascular resistance is caused by obliteration of the pulmonary vascular bed and/or by pathologic vasoconstriction. Pulmonary hypertension is characterized by variable and sometimes pathologic vasoconstriction and by endothelial and smooth muscle proliferation, hypertrophy, and chronic inflammation, resulting in vascular wall remodeling. Vasoconstriction is thought to be due in part to enhanced activity of thromboxane and endothelin-1 (both vasoconstrictors) and reduced activity of prostacyclin and nitric oxide (both vasodilators). The increased pulmonary vascular pressure that results from vascular obstruction further injures the endothelium. Injury activates coagulation at the intimal surface, which may worsen the hypertension. Thrombotic coagulopathy due to platelet dysfunction, increased activity of plasminogen activator inhibitor type 1 and fibrinopeptide A, and decreased tissue plasminogen activator activity may also contribute. Platelets, when stimulated, may also play a key role by secreting substances that increase proliferation of fibroblasts and smooth muscle cells such as platelet-derived growth factor (PDGF), vascular endothelial growth factor (VEGF), and transforming growth factor-beta (TGF-β). Focal coagulation at the endothelial surface should not be confused with chronic thromboembolic pulmonary hypertension, in which pulmonary hypertension is caused by organized pulmonary emboli. Mutations in the BMPR2 gene account for most cases of hereditary PAH and also occurs in idiopathic PAH. Aberrant BMPR2 signaling disturbs the TGF-β/BMP balance, favoring a pro-proliferative and anti-apoptotic response in pulmonary artery smooth muscle and endothelial cells. BMPR2 signaling, therefore, has become an increasingly studied drug target for pulmonary hypertension.

Increased pulmonary venous pressure is typically caused by disorders that affect the left side of the heart and raise left chamber pressures, which ultimately lead to elevated pressure in the pulmonary veins. Elevated pulmonary venous pressures can cause acute damage to the alveolar-capillary wall and subsequent edema. Persistently high pressures may eventually lead to irreversible thickening of the walls of the alveolar-capillary membrane, decreasing lung diffusion capacity. The most common setting for pulmonary venous hypertension is in left heart failure LV failure Heart failure (HF) is a syndrome of ventricular dysfunction. Left ventricular (LV) failure causes shortness of breath and fatigue, and right ventricular (RV) failure causes peripheral and abdominal... read more with preserved ejection fraction (HFpEF), typically in older women who have hypertension and metabolic syndrome Metabolic Syndrome Metabolic syndrome is characterized by a large waist circumference (due to excess abdominal adipose tissue), hypertension, abnormal fasting plasma glucose or insulin resistance, and dyslipidemia... read more .

In pulmonary hypertension secondary to HFpEF, certain hemodynamic parameters predict an increased risk of death. These parameters include

In most patients, pulmonary hypertension eventually leads to right ventricular hypertrophy followed by dilation and right ventricular failure RV failure Heart failure (HF) is a syndrome of ventricular dysfunction. Left ventricular (LV) failure causes shortness of breath and fatigue, and right ventricular (RV) failure causes peripheral and abdominal... read more . Right ventricular failure limits cardiac output during exertion.

Increased pulmonary venous blood flow due to congenital heart disease can cause pulmonary hypertension. This can occur in conditions such as atrial septal defects Atrial Septal Defect (ASD) An atrial septal defect (ASD) is an opening in the interatrial septum, causing a left-to-right shunt and volume overload of the right atrium and right ventricle. Children are rarely symptomatic... read more , ventricular septal defects Ventricular Septal Defect (VSD) A ventricular septal defect (VSD) is an opening in the interventricular septum, causing a shunt between ventricles. Large defects result in a significant left-to-right shunt and cause dyspnea... read more , and patent ductus arteriosus Patent Ductus Arteriosus (PDA) Patent ductus arteriosus (PDA) is a persistence of the fetal connection (ductus arteriosus) between the aorta and pulmonary artery after birth. In the absence of other structural heart abnormalities... read more , presumably through the development of characteristic pulmonary vascular lesions. However, the true effect of increased pulmonary blood flow is poorly defined and increased flow may lead to vascular obstruction only with concomitant pulmonary vascular resistance or a second stimulus.

Progressive exertional dyspnea and easy fatigability occur in almost all patients. Atypical chest discomfort and exertional light-headedness or presyncope may accompany dyspnea and indicate more severe disease. These symptoms are due primarily to insufficient cardiac output caused by right heart failure. Raynaud syndrome Raynaud Syndrome Raynaud syndrome is vasospasm of parts of the hand in response to cold or emotional stress, causing reversible discomfort and color changes (pallor, cyanosis, erythema, or a combination) in... read more occurs in about 10% of patients with idiopathic pulmonary arterial hypertension; the majority are women. Hemoptysis Hemoptysis Hemoptysis is coughing up of blood from the respiratory tract. Massive hemoptysis is production of ≥ 600 mL of blood (about a full kidney basin’s worth) within 24 hours. Most of the lung’s blood... read more is rare but may be fatal. Hoarseness due to recurrent laryngeal nerve compression by an enlarged pulmonary artery (ie, Ortner syndrome) also occurs rarely.

In advanced disease, signs of right heart failure may include right ventricular heave, widely split 2nd heart sound (S2), an accentuated pulmonic component (P2) of S2, a pulmonary ejection click, a right ventricular 3rd heart sound (S3), tricuspid regurgitation murmur, and jugular vein distention, possibly with v-waves. Liver congestion and peripheral edema are common late manifestations. Pulmonary auscultation is usually normal. Patients also may have manifestations of causative or associated disorders.

Pulmonary hypertension is suspected in patients with significant exertional dyspnea who are otherwise relatively healthy and have no history or signs of other disorders known to cause pulmonary symptoms.

Patients initially undergo chest x-ray Chest x-ray Chest imaging includes use of Conventional x-rays Computed tomography (CT) scanning Magnetic resonance imaging (MRI) Nuclear scanning, including positron emission tomography (PET) scanning read more , spirometry Airflow, Lung Volumes, and Flow-Volume Loop Airflow and lung volume measurements can be used to differentiate obstructive from restrictive pulmonary disorders, to characterize severity, and to measure responses to therapy. Measurements... read more , and ECG Electrocardiography (ECG) in Pulmonary Disorders Electrocardiography (ECG) is a useful adjunct to other pulmonary tests because it provides information about the right side of the heart and therefore pulmonary disorders such as chronic pulmonary... read more to identify more common causes of dyspnea, followed by transthoracic Doppler echocardiography Echocardiography This photo shows a patient having echocardiography. This image shows all 4 cardiac chambers and the tricuspid and mitral valves. Echocardiography uses ultrasound waves to produce an image of... read more to assess right ventricular function and pulmonary artery systolic pressures as well as to detect structural left heart disease that might be causing pulmonary hypertension. Complete blood count is obtained to document the presence or absence of erythrocytosis, anemia, and thrombocytopenia.

The most common x-ray finding in pulmonary hypertension is enlarged hilar vessels that rapidly prune into the periphery and a right ventricle that fills the anterior airspace on lateral view. Spirometry and lung volumes may be normal or show mild restriction, and diffusing capacity for carbon monoxide (DLCO) is usually reduced. Other ECG findings include right axis deviation, R > S in V1, S1Q3T3 (suggesting right ventricular hypertrophy), and peaked P waves (suggesting right atrial dilation) in lead II.

Additional tests are obtained as indicated to diagnose secondary causes that are not apparent clinically. These tests can include

Chronic thromboembolic pulmonary hypertension is suggested by CT angiography or ventilation/perfusion (VQ) scan findings and is confirmed by arteriography. CT angiography is useful to evaluate proximal clot and fibrotic encroachment of the vascular lumen. Other tests, such as HIV testing, liver tests, and polysomnography, are done in the appropriate clinical context.

When the initial evaluation suggests a diagnosis of pulmonary hypertension, pulmonary artery catheterization Pulmonary Artery Catheter (PAC) Monitoring Some monitoring of critical care patients depends on direct observation and physical examination and is intermittent, with the frequency depending on the patient’s illness. Other monitoring... read more is necessary to measure the following:

Right-sided oxygen saturation should be measured to exclude left-to-right shunt through atrial septal defect Atrial Septal Defect (ASD) An atrial septal defect (ASD) is an opening in the interatrial septum, causing a left-to-right shunt and volume overload of the right atrium and right ventricle. Children are rarely symptomatic... read more . Although finding a mean pulmonary arterial pressure of > 20 mm Hg and a pulmonary artery occlusion pressure ≤ 15 mm Hg in the absence of an underlying disorder identifies pulmonary arterial hypertension (PAH), most patients with PAH present with substantially higher pressure (eg, mean of 60 mm Hg).

Drugs that acutely dilate the pulmonary vessels, such as inhaled nitric oxide, IV epoprostenol, or adenosine, are often given during catheterization. Decreasing right-sided pressures in response to these drugs may help in the choice of drugs for treatment. Lung biopsy, once widely done, is neither needed nor recommended because of its associated high morbidity and mortality.

Echocardiography Echocardiography This photo shows a patient having echocardiography. This image shows all 4 cardiac chambers and the tricuspid and mitral valves. Echocardiography uses ultrasound waves to produce an image of... read more findings of right heart systolic dysfunction (eg, tricuspid annular plane systolic excursion) and certain right heart catheterization results (eg, low cardiac output, very high mean pulmonary artery pressures, and high right atrial pressures) indicate that pulmonary hypertension is severe.

Other indicators of severity in pulmonary hypertension are assessed to evaluate prognosis and to help monitor responses to therapy. They include a low 6-minute walk Six-minute walk test The two most common forms of exercise testing used to evaluate pulmonary disorders are the 6-minute walk test Cardiopulmonary exercise testing This simple test measures the maximal distance... read more distance and high plasma levels of N-terminal pro-brain natriuretic peptide (NT-pro-BNP) or brain natriuretic peptide (BNP).

Once pulmonary hypertension is diagnosed, the patient's family history should be reviewed to detect possible genetic transmission (eg, premature deaths in otherwise healthy members of the extended family). In familial PAH, genetic counseling is needed to advise mutation carriers of the risk of disease (about 20%) and to advocate serial screening with echocardiography. Testing for mutations in the BMPR2 gene in idiopathic PAH can help identify family members at risk. If patients are negative for BMPR2, gene testing for SMAD9, KCN3, and CAV1 can further help identify family members at risk.

Five-year survival for treated patients is about 50%. However, some patient registries suggest lower mortality (eg, 20 to 30% at 3 to 5 years in the French registry and 10 to 30% at 1 to 3 years in the REVEAL registry), presumably because currently available treatments are superior. Indicators of a poorer prognosis include

Patients with systemic sclerosis, sickle cell disease, or HIV infection with pulmonary arterial hypertension (PAH) have a worse prognosis than those without PAH. For example, patients with sickle cell disease and PAH have a 40% 4-year mortality rate.