Pulmonary Hypertension
Murali M. Chakinala
Adam Anderson
General Principles
Definition
Discrimination of the type of PH (i.e., precapillary vs. postcapillary) requires additional information about the left heart’s filling pressures and the pulmonary vascular resistance (PVR).
Classification
Individuals can have more than one underlying condition leading to a so-called mixed form of PH.
Pulmonary arterial hypertension (PAH, group 1) patients are stratified by World Health Organization (WHO) functional classes I–IV that guide therapies and provide a tool to monitor clinical response (Table 22-2).4
Epidemiology
The most common type of PH in the developed world is group 2, followed by group 3.
Group 3 PH tends to correlate with degree of severity of underlying lung disease and/or hypoxemia but exceptions include concomitant conditions having an additive effect, and a discordant degree of PH with the underlying lung disease as measured by spirometry (e.g., obstructive sleep apnea [OSA] and chronic obstructive pulmonary disease [COPD]).
Prevalence of PAH is estimated to be 15–25 cases per million with female/male ratio between 2:1 and 3:1. Prevalence of idiopathic pulmonary arterial hypertension (IPAH) is estimated at 6 per million.1
Survival rates for PAH at 1, 3, and 5 years are 84%, 67%, and 58%, respectively with a median survival of 3.6 years.5 However, survival can be substantially affected by etiology.
Estimated cumulative incidence of PH after acute pulmonary embolism (PE) is 1.0% at 6 months, 3.1% at 1 year, and 3.8% at 2 years with cumulative burden of emboli being a risk factor.6
Pathophysiology
The common finding in all forms of PH is elevated pressures within precapillary pulmonary vessels as blood flows across the pulmonary circuit.
Group 1 PH (PAH) involves complex mechanisms that progressively narrow and stiffen the pulmonary arterioles.
Pathogenesis in PAH may vary with the different etiologies but converges upon endothelial and smooth muscle cell proliferation and dysfunction that result in the complex interplay of the following factors:
Vasoconstriction caused by overproduction of vasoconstrictor compounds such as endothelin and insufficient production of vasodilators such as prostacyclin and nitric oxide.
TABLE 22-1 2008 DANA POINT CLINICAL CLASSIFICATION OF PULMONARY HYPERTENSION (PH)
Group 1: pulmonary arterial hypertension (PAH)
Idiopathic (IPAH)
Heritable
BMPR2
ALK-1, endoglin (with or without hereditary hemorrhagic telangiectasia)
Unknown
Drugs and toxins induced
Associated with (APAH)
Connective tissue diseases
HIV infection
Portal hypertension
Congenital heart disease
Schistosomiasis
Chronic hemolytic anemia
Persistent pulmonary hypertension of the newborn
Group 1′: pulmonary veno-occlusive disease and/or pulmonary capillary hemangiomatosis
Group 2: pulmonary hypertension due to left heart disease
Systolic dysfunction
Diastolic dysfunction
Valvular disease
Group 3: pulmonary hypertension due to lung disease and/or hypoxia
Chronic obstructive lung disease
Interstitial lung disease
Other pulmonary diseases with mixed restrictive and obstructive pattern
Sleep-disordered breathing
Alveolar hypoventilation disorders
Chronic exposure to high altitude
Developmental abnormalities
Group 4: chronic thromboembolic pulmonary hypertension (CTEPH)
Group 5: PH with unclear and/or multifactorial mechanisms
Hematologic disorders: myeloproliferative disorders, splenectomy
Systemic disorders: sarcoidosis, PLCH, LAM, neurofibromatosis, vasculitis
Metabolic disorders: glycogen storage disease, Gaucher disease, thyroid disorders
Others: tumoral obstruction, fibrosing mediastinitis, chronic renal failure on dialysis
BMPR2, bone morphogenic protein receptor, type 2; ALK-1, activin receptor-like kinase 1 gene; PLCH, pulmonary Langerhans cell histiocytosis; LAM, lymphangioleiomyomatosis.
Modified from Galiè N, Hoeper MM, Humbert M, et al. 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.
TABLE 22-2 WHO FUNCTIONAL CLASSIFICATION
Class I
No limitation of physical activity; ordinary physical activity does not cause undue dyspnea, fatigue, chest pain, or near syncope
Class II
Slight limitation of physical activity; comfortable at rest; ordinary activity causes undue dyspnea, fatigue, chest pain, or near syncope
Class III
Marked limitation of physical activity; comfortable at rest; less than ordinary activity causes undue dyspnea, fatigue, chest pain, or near syncope
Class IV
Unable to carry out any physical activity without symptoms; dyspnea and/or fatigue may be at rest; discomfort is increased by any physical activity
Data from Rich S. Executive summary from the World Symposium on primary pulmonary hypertension. Geneva: World Health Organization; 1998.
Endothelial and smooth muscle proliferation due to mitogenic properties of endothelin and thromboxane A2 in the setting of low levels of inhibitory molecules, such as prostacyclin and nitric oxide.
In situ thrombosis of small- and medium-sized pulmonary arteries resulting from platelet activation and aggregation.
The physiologic consequences of this proliferative vasculopathy are an increase in PVR and right ventricle (RV) afterload.
Complex origins of PAH include infectious/environmental insults in the setting of predisposing comorbidities and/or underlying genetic predisposition, for example, gene mutation of bone morphogenetic protein receptor II (BMPR II) or activin receptor-like kinase 1 (ALK1).1,7,8
Elevated pressures in groups 2–5 result from:
Elevated downstream pressures on the left side of the heart (group 2),
Hypoxemic vasoconstriction (group 3),
Occlusion of the vasculature by material foreign to the lung (group 4),
High flow that exceeds capacitance of the pulmonary circuit (group 5), or
Blood vessel narrowing and destruction from processes external to the vasculature (group 3, group 5).
Diagnosis
Clinical Presentation
An algorithm for evaluating PH is outlined in Figure 22-1.
History
Dyspnea with exertion is the most often reported symptom for patients with PH. Orthopnea and paroxysmal nocturnal dyspnea are important clues of left heart disease and group 2 PH. Symptoms that reflect more advanced disease and secondary RV dysfunction include fatigue, syncope, peripheral edema, and angina.
Hoarseness can also be encountered because of left recurrent laryngeal nerve compression by the enlarging pulmonary artery (i.e., Ortner syndrome).
FIGURE 22-1. Diagnostic approach to pulmonary arterial hypertension. PH, pulmonary hypertension; PFT, pulmonary function tests; ABG, arterial blood gases; HRCT, high-resolution CT; V/Q scan, ventilation/perfusion scan; CTEPH, chronic thromboembolic pulmonary hypertension; LFT, liver function test; HTN, hypertension; MCTD, mixed connective tissue disease; SLE, systemic lupus erythematosus; RA, rheumatoid arthritis; CTD, connective tissue disease; PAH, pulmonary arterial hypertension.
Past medical history relevant to several organ systems, including the respiratory, cardiovascular, hepatic, rheumatologic, and hematologic systems must be explored.
Particular emphasis should be placed on prior cardiac conditions, including myocardial infarction, heart failure (HF), arrhythmias, rheumatic heart disease, other valvular heart disease, and congenital heart disease.
Social history should focus on prior or current tobacco and alcohol use, as well as illicit or recreational drug use, particularly methamphetamines or cocaine.
Family history should also be explored to exclude a genetic predisposition.
Risk factors for exposure to HIV may disclose an unexpected etiology for PH.
Careful medication history to document use of current or past drugs linked to development of PH is also necessary. This includes anorexigens (e.g., fenfluramine, dexfenfluramine, diethylpropion) and chemotherapeutic agents (e.g., mitomycin).1
Physical Examination
A thorough physical examination to corroborate or refute suspicions of underlying medical problems should be performed; attention should be directed toward the cardiopulmonary examination.
Auscultatory examination of the heart may reveal an accentuated S2 sound with a prominent P2 component, systolic ejection murmur at left lower sternal border due to tricuspid regurgitation, and diastolic decrescendo murmur (Graham Steell murmur) along the left sternal border due to pulmonary insufficiency. Additional cardiac finding,
including continuous murmurs or rumbles and fixed-split S2, may suggest an underlying congenital cardiac defect.
As PH worsens and right HF ensues, resting tachycardia, S3 gallop, elevated jugular venous pulsation of the neck, hepatomegaly, ascites, peripheral edema, diminished peripheral pulses, and cyanosis occur. Presence of these findings, in the absence of clues of left heart disease, should raise suspicion for right HF due to PH.
Digital clubbing indicates underlying conditions such as interstitial lung disease (ILD), bronchiectasis, or congenital heart disease.
Diagnostic Criteria
PAH requires normal left ventricular (LV) filling pressures (i.e., pulmonary capillary wedge pressure (PCWP), left atrial pressure, or left ventricular end-diastolic pressure (LVEDP) ≤15 mm Hg).
Some centers also require an elevated PVR (≥3 Wood units) to establish PAH.
Diagnosis of PAH requires a right heart catheterization (RHC).
Pulmonary artery systolic pressure (PASP) can be estimated noninvasively by transthoracic echocardiography (TTE), whereby a PASP >40 mm Hg is considered abnormal and suggestive of PH but is not diagnostic.
Diagnostic Testing
Laboratories
Essential laboratory studies to evaluate unexplained PH mirror the studies of a general medical evaluation: complete blood count (CBC), comprehensive metabolic panel (CMP), and coagulation studies may offer diagnostic clues and direct further exploration. A prerenal pattern of blood urea nitrogen (BUN) and creatinine elevations in conjunction with passive congestion of the liver is a sign of advanced right HF and low cardiac output.
Screening for collagen vascular disease with antinuclear antibody (ANA), anticentromere antibody, rheumatoid factor (RF), anti-scl-70 antibody, and antiribonucleoprotein antibody should be completed, as the associated underlying conditions are linked to PAH.
Thyroid studies, hemoglobin electrophoresis for sickle cell disease, HIV serology, hepatitis serologies, antiphospholipid antibody, or anticardiolipin antibody should also be performed if clinical suspicions exist.
Arterial blood gas can provide invaluable information. Significant resting hypoxemia should raise suspicion for right-to-left shunt, severely reduced cardiac output, or underlying pulmonary disease. Significant hypercarbia supports a group 3 diagnosis.
Electrocardiography
RV enlargement is suspected by the presence of an R wave in V1 or an S wave in lead V6 while RV strain appears as a triad of S wave in lead I, Q wave in lead III, and inverted T wave in lead III. Other potential findings in cases of PH include right atrial enlargement and right bundle branch block.
LV hypertrophy, left atrial enlargement, left axis deviation, atrial fibrillation, or evidence of prior myocardial infarction provide clues of significant left heart disease that could lead to group 2 PH.
Imaging
CXR
Features indicative of PH are enlarged central pulmonary arteries on frontal views and RV enlargement on lateral examination. When PAPs reach systemic levels, pulmonary artery calcifications can be seen.
Obliteration of the distal pulmonary arteries leads to tapering of vessels in the peripheral third of the lung parenchyma, referred to as pruning, is classically seen in IPAH.
In contrast, prominent pulmonary arteries extending to the periphery of the lung suggest systemic-to-pulmonary shunts and a hypercirculatory state (e.g., atrial or ventricular septal defects).
CXR should also be reviewed for underlying cardiopulmonary diseases, including ILD, emphysema, or HF.
Ventilation/perfusion scan
Provides an easy and sensitive screen for the detection of chronic thromboembolic disease.
While PH due to nonembolic processes, such as IPAH, can display a heterogeneous or mottled perfusion pattern, anatomic perfusion defects of the segmental or lobar level are more concerning for thromboembolic disease.
Differential diagnosis for an abnormal perfusion scan also includes pulmonary veno-occlusive disease (widespread obstruction of the pulmonary veins due to fibrous tissue), mediastinal fibrosis, or pulmonary vasculitis.
Chest CT
While CT angiography can display features of chronic thromboembolic disease, it is less sensitive and less predictive of surgical response than the ventilation/perfusion scan.
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