Pulmonary Hypertension
Saurabh Rajpal
Jeremy Slivnick
William H. Marshall V
Zachary Garrett
INTRODUCTION
Rapid growth in understanding the pathophysiology of pulmonary hypertension (PH) and introduction of new medications in the past few decades have improved the life and longevity of patients with PH previously considered untreatable. In the next few sections, the pathophysiology, classification, diagnosis, risk stratification, and management of PH will be discussed in light of these recent developments.
The classification system and definition of PH have changed over time as there has been increased recognition of outcomes and options for treatment through efforts by the National Institutes of Health and the World Society of Pulmonary Hypertension (WSPH). The first WSPH conference was held in 1973, and PH was defined as a mean pulmonary artery (PA) pressure of 25 mm Hg or more. In the sixth WSPH held in 2018, this definition was updated as a mean PA pressure greater than 20 mm Hg.1
Normal Growth and Development of Pulmonary Vasculature
The PAs start to develop in the fifth week of human development along with development of lung buds. The proximal sixth aortic arches sprout the future PAs, which grow toward the capillary plexus surrounding the lung buds. Several growth factors and vasoactive molecules regulate development of the pulmonary vasculature, including endothelin, nitric oxide, and prostacyclin.2
During fetal life, pulmonary vascular resistance (PVR) is increased, PA pressures are high, and blood flow through the pulmonary vasculature is minimal. Accordingly, blood flow is directed right-to-left through the foramen ovale and ductus arteriosus. In the newborn period when respiration begins and placental blood flow ceases, the PVR decreases, the ductus arteriosus closes, and the right-sided chamber pressures decrease, whereas left-sided pressures increase. By 2 to 3 months of life, the PVR is near normal.2
PATHOGENESIS
PA pressures may be elevated for numerous reasons: an increase in PVR, pulmonary blood flow, and/or pulmonary capillary wedge pressure (PCWP). Elevated PA pressure may eventually lead to progressive right ventricular (RV) dysfunction and failure.
The progressive increase in PVR is due to obstructive remodeling and loss of the pulmonary vascular bed, which occurs because of accumulation of PA smooth muscle cells, endothelial cells, pericytes, and fibroblasts. This leads to endothelial dysfunction with altered secretion of pulmonary vasodilator and vasoconstrictor molecules and mesenchymal smooth muscle hypertrophy. Bronchopulmonary vascular anastomoses occur with the bronchial vessels to bypass PA occlusive lesions, causing increased flow and further muscular hyperplasia in the distal vessels. Dysregulation of the innate immune system with increased expression of inflammatory cytokines and cell adhesion molecules also occurs.
Approximately 10% to 20% of patients with pulmonary arterial hypertension (PAH) have mutations in the gene encoding bone morphogenetic protein receptor type 2, and other genes have been identified. Molecular mechanisms such as transcription factor modulation, altered DNA methylation, and mitochondrial dysfunction are implicated, causing altered gene expression in the pulmonary vascular cells.3
Hypoxia, pain, and sympathetic activation can also increase PVR. Table 16.1 outlines vasoactive mediators that act on the pulmonary vasculature and affect PVR. The endothelin pathway mediates vasoconstriction, whereas nitric oxide and prostacyclin pathways mediate vasodilation.
The outcome of patients with PH depends on the function of the right ventricle. The right ventricle is thin walled, crescent shaped, and has smaller myocytes in a more circumferential arrangement as compared to the left ventricle. Under normal physiologic conditions, the right ventricle facilitates venous return into the low-impedance pulmonary vasculature, with one-fourth of the stroke work of the left ventricle. PH leads to RV pressure overload, causing RV hypertrophy, flattening of the interventricular septum, and eventually progressive RV dilation and dysfunction.4
TABLE 16.1 Factors Affecting Pulmonary Vasculature | ||||||
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DIAGNOSIS
Hemodynamic Definitions and Clinical Definitions
In the sixth WSPH, PH was defined by a mean PA pressure greater than 20 mm Hg. This decrease from the previous cutoff of 25 mm Hg or more is based on evidence demonstrating increased mortality and disease progression in patients with mean PA pressure of 21 to 24 mm Hg.1 Precapillary PH is contrasted from postcapillary PH by the presence of elevated PVR and normal PCWP in the former (Table 16.2).1 A subset of patients with precapillary PH are further categorized by a positive response to invasive vasoreactivity testing (eg, nitric oxide), defined as a decrease in mean PA pressure 10 mm Hg or more to 40 mm Hg or less1,5 with vasodilator administration. As described further, these patients have more improved survival when treated with high-dose calcium channel blockers.5
The clinical PH groups and subgroups are displayed in Table 16.3.1 There are five clinical groups of PH: group I is PAH, group II is PH because of left heart disease, group III is PH because of lung disease, group IV is PH because of PA obstruction, and group V is PH because of unclear or multifactorial mechanisms. In addition to including chronic thromboembolic PH, group IV was recently reclassified to also include PH secondary to other causes of pulmonary obstruction such as tumors, PA stenosis, and arteritis. Additionally, hemolytic anemias were added to group V because of increasing recognition of their causal relationship.
Group I: Pulmonary Arterial Hypertension
Group I PH or PAH is composed of precapillary PAH subtypes including idiopathic PAH, heritable PAH, connective tissue disease-associated PAH, human immunodeficiency virus (HIV), portopulmonary hypertension, and drug/toxin-associated PAH. Idiopathic PAH refers to sporadic PAH occurring in the absence of family history or risk factors. Heritable PAH generally occurs as a result of growth factor mutations, mostly with an autosomal dominant inheritance pattern.3
Drugs/toxins with definitive association with PAH include methamphetamine, anorexigens, and dasatinib.6,7 Drugs with possible association with PAH include cocaine, St. John’s wort, amphetamine, and certain Chinese herbs.1 Of the connective tissue diseases, scleroderma has the strongest association with PAH and may be prevalent in as many as 10% of afflicted patients.8 Unfortunately, these patients have poorer survival when compared with idiopathic PAH.8 Portopulmonary hypertension is present in 2% to 6% of cirrhotic patients and is associated with high mortality when undergoing liver transplantation.9 Congenital heart diseases that result in precapillary PH are also classified as group I; this generally occurs from chronic left-to-right shunts such as atrial or ventricular septal defects and patent ductus arteriosus.
TABLE 16.2 Sixth WSPH Hemodynamic Definitions of Pulmonary Hypertension | ||||||||||||||||||||||||
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Pulmonary veno-occlusive disease is also categorized as group I PH, but it has a different pathophysiology compared with other group I subtypes: it is characterized by vascular remodeling of the pulmonary venules and septal veins.10 This leads to focal areas of pulmonary venous congestion in involved regions. It is most commonly associated with mutations in the EIF2AK4 gene,10 but it may also be seen in association with connective tissue diseases such as scleroderma or with certain drug/toxin exposures. Pulmonary veno-occlusive disease should be suspected in patients with markedly reduced diffusing capacity of the lung for carbon monoxide (DLCO) or in those who develop pulmonary edema in response to vasoreactivity testing. Additionally, the presence of centrilobular ground glass opacities, increased septal line thickness, and mediastinal lymphadenopathy on high-resolution computerized tomography is also suggestive of the diagnosis. These patients have a poor prognosis and frequently develop pulmonary edema in response to pulmonary vasodilators.10
Group II: Pulmonary Hypertension as a Result of Left Heart Disease
PH because of left heart disease is the most common of the five clinical groups of PH and is associated with a high morbidity and mortality. Left heart disorders—including heart failure with reduced ejection fraction (HFrEF), heart failure with preserved ejection fraction (HFpEF), valvular heart disease, or congenital heart disease—increase left atrial filling pressures that are subsequently transmitted to the pulmonary circuit resulting in PH.11 High-output heart failure, because of morbid obesity, arteriovenous shunts, or liver disease, is also associated with higher filling pressures and PA pressures.12
TABLE 16.3 Sixth WSPH Clinical Classifications of Pulmonary Hypertension | ||||||||||||||||||||||||||||
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The transpulmonary gradient (TPG) is the difference between mean PA and PCWP pressures. Traditionally, a TPG greater than 12 mm Hg is used to identify patients with PH out of proportion to left heart disease. The diastolic pulmonary gradient is the difference between PA diastolic pressure and mean PCWP.
In the sixth WSPH recommendations, PH because of left heart disease is defined hemodynamically by right heart catheterization as a mean PA pressure greater than 20 mm Hg and a PCWP greater than 15 mm Hg. It can be further classified as isolated postcapillary PH or combined postcapillary and precapillary PH.13 The term “isolated postcapillary PH” describes those patients whose PH is merely because of passive pulmonary venous congestion. A minority of patients subject to long-standing elevated left-sided heart filling pressures undergo structural and functional pathophysiologic changes in the precapillary vasculature, including remodeling and vasoconstriction, resulting in mean PA pressure disproportionately elevated relative to the PCWP. Such patients are described as having combined postcapillary and precapillary PH. Isolated postcapillary PAH is defined as a PVR less than 3 Wood units or diastolic pulmonary gradient less than 7 Wood units and combined post- and precapillary PH as PVR greater than 3 Wood units or diastolic pulmonary gradient greater than 7 Wood units. Combined precapillary PAH is associated with reduced exercise capacity compared to isolated postcapillary PH and a phenotype similar to PAH14 but may have a different genetic profile from isolated postcapillary PAH.15
Mortality and morbidity with PH because of left heart disease is associated with increasing PA pressures, mean PA pressures, PVR, and TPG. PH because of left heart failure is also associated with an increased 30-day mortality after orthotopic heart transplant in patients with a TPG greater than 15 mm Hg and PVR greater than 5 Wood units.14,15
The treatment of PH because of left heart disease is primarily focused on management of the underlying heart disease itself, as no PAH therapies have been shown to be beneficial in this condition.16,17 The placement of a left ventricular assist device decreases pulmonary pressures by ventricular unloading.18 PH because of left heart disease also improves with heart transplantation with the greater decrease in PVR 1 month after transplantation.19
Group III: Pulmonary Hypertension because of Lung Disease or Hypoxia
PH in chronic lung disease may be associated with chronic obstructive pulmonary disease (COPD), interstitial lung disease (ILD), cystic fibrosis, and bronchopulmonary dysplasia. In COPD, the destruction of lung parenchyma, decreased vascular dispensability, and decreased ability to recruit additional vasculature contribute to the development of PH.20
PH because of chronic lung disease should be considered and right heart catheterization pursued when symptoms or DLCO is out of proportion to the underlying lung disease; in those suspected to have concomitant PAH or chronic thromboembolic disease and when RV failure is present; and prior to undergoing lung transplantation or lung reduction surgery.20
PH because of chronic lung disease may be difficult to differentiate from PAH; however, significant lung disease (forced expiratory volume in one second [FEV1] <60% in COPD or forced vital capacity [FVC] <70 in ILD), characteristic lung parenchymal changes, absence of risk factors for PAH, and mild to moderate PH are more consistent with PH because of chronic lung disease. Severe PH is uncommon in isolated COPD or ILD alone but may be seen in mixed diseases.20,21
Treatment of PH-CLD is targeted toward the underlying lung disease. The use of PAH therapies is generally not recommended and may worsen outcomes.22,23 Some recent studies
have shown benefit of inhaled treprostinil in ILD-associated PH.24 Oxygen therapy may improve or potentially slow the progression of PH in COPD.25 Obstructive sleep apnea alone is rarely a cause of severe PH unless there is concomitant lung disease, such as COPD or obesity hypoventilation syndrome, and therapy is nocturnal noninvasive ventilation. When present, treatment of obstructive sleep apnea is of great importance whatever the subtype of PH: improved outcome has been shown in all types of PH with concomitant treatment of obstructive sleep apnea.20
have shown benefit of inhaled treprostinil in ILD-associated PH.24 Oxygen therapy may improve or potentially slow the progression of PH in COPD.25 Obstructive sleep apnea alone is rarely a cause of severe PH unless there is concomitant lung disease, such as COPD or obesity hypoventilation syndrome, and therapy is nocturnal noninvasive ventilation. When present, treatment of obstructive sleep apnea is of great importance whatever the subtype of PH: improved outcome has been shown in all types of PH with concomitant treatment of obstructive sleep apnea.20
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