Clinical Pearls & Morning Reports
Published December 15, 2021
Pulmonary hypertension is a syndrome characterized by marked remodeling of the pulmonary vasculature and a progressive rise in the pulmonary vascular load, leading to hypertrophy and remodeling of the right ventricle. The several forms of pulmonary hypertension are categorized into five clinical groups. Pulmonary arterial hypertension (group 1) is a relatively rare form. Read the NEJM Review Article here.
Q: Is pulmonary hypertension a global health problem?
A: Pulmonary arterial hypertension affects 25 persons (most of whom are women) per 1 million population in Western countries, with an annual incidence of 2 to 5 cases per million. Pulmonary hypertension complicates highly prevalent viral infections (e.g., human immunodeficiency virus infection) and parasitic diseases (e.g., schistosomiasis), as well as hemoglobinopathies such as sickle cell disease and thalassemia; therefore, very large numbers of patients are affected in low- and middle-income areas of Africa, Asia, and South and Central America.
Q: How is the effect of pulmonary arterial hypertension on the right ventricle best assessed?
A: Cardiac MRI is the standard for right ventricular assessment because it provides accurate measurements of the cardiac chamber anatomy and volume, mass, function, and flow, as well as myocardial perfusion. Not widely available, it is increasingly used in centers with expertise in diagnosing and managing pulmonary hypertension. Other advanced imaging techniques that remain in the realm of research include three-dimensional echocardiography, four-dimensional flow MRI, and positron-emission tomography, which can provide unique insights into right ventricular metabolic activity.
A: The histologic features of pulmonary arterial hypertension are complex and variable because of the multiplicity of underlying diseases. However, there are common pathological features of the disorder, such as remodeling of the three layers of the distal pulmonary vasculature, which involves uncontrolled growth of endothelial and smooth-muscle cells and fibroblasts, and infiltration of inflammatory cells, which affects primarily precapillary vessels with a caliber of 50 to 500 μm. There is also extension of the smooth-muscle cell layer to typically nonmuscularized distal capillaries. These changes result in luminal narrowing or complete obliteration of small vessels. Events leading to severe remodeling have not been clearly identified, although endothelial dysfunction induced by shear stress, hypoxia, autoimmune phenomena, viral infections, drugs and toxins, or genetic alterations may initiate the process of excess vasoconstriction, inflammation, and uncontrolled cellular growth.
A: In 2000, two independent groups described heterozygous mutations in BMPR2 (bone morphogenetic protein [BMP] receptor type 2), a member of the transforming growth factor β superfamily. BMPR2 mutations are identified in approximately 80% of patients with familial pulmonary arterial hypertension, with variable penetrance between male and female carriers, and in up to 20% of patients with sporadic disease. The role of altered BMPR-II signaling in the pathogenesis of pulmonary arterial hypertension cannot be overestimated. Most discovered mutations involve BMPR2 or genes encoding proteins that form complexes or interact with BMP or BMPR-II signaling. BMPR-II functional loss leads to endothelial dysfunction and the altered balance between proliferation and apoptosis that is characteristic of pulmonary arterial hypertension, which explains the growing interest in therapy aimed at increasing BMPR-II expression or ligand levels.