William H. Marshall V
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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
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
Atrial natriuretic peptide
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