Abbreviations
BCRP: breast cancer resistance protein
BNP: B-type natriuretic peptide
[Ca2+]cyt: cytosolic free Ca2+ concentration
CCB: calcium channel blocker
CTEPH: chronic thromboembolic pulmonary hypertension
CYP: cytochrome P450
DAG: diacylglycerol
EC: endothelial cell
ECE: endothelin-converting enzyme
EGF: epidermal growth factor
ER: endoplasmic reticulum
ERA: endothelin receptor antagonist
ET-1: endothelin 1
FDA: U.S. Food and Drug Administration
GPCR: G protein-coupled receptor
IP3: inositol triphosphate
IPR: prostacyclin receptor
mGC: membrane (or particulate) guanylate cyclase
NO: nitric oxide
NO2: nitric dioxide
PA: pulmonary artery
PAH: pulmonary arterial hypertension
PAP: pulmonary arterial pressure
PASMC: pulmonary artery smooth muscle cell
PDE: phosphodiesterase
PDGF: platelet-derived growth factor
PGI2: prostacyclin, prostaglandin I2
Pgp : P-glycoprotein
PH: pulmonary hypertension
PKA: protein kinase A
PKC: protein kinase C
PKG: protein kinase G
PLC: phospholipase C
PVR: pulmonary vascular resistance
REMS: Risk Evaluation and Mitigation Strategy
ROC: receptor-operated Ca2+ channel
RV: right ventricle
sGC: soluble guanylate cyclase
SR: sarcoplasmic reticulum
SVR: systemic vascular resistance
TGF-β: transforming growth factor-β
TKR: tyrosine kinase receptor
VDCC: voltage-dependent Ca2+ channel
VEGF: vascular endothelial growth factor
VIP: vasoactive intestinal peptide
V/Q: ventilation/perfusion
VSM: vascular smooth muscle
The pulmonary circulation plays a unique and essential role in gas exchange and oxygenation of venous blood in the lungs. It is a low-resistance and low-pressure circulatory system; the mean pulmonary arterial pressure (PAP) in healthy control subjects is 14.0 ± 3.3 mmHg. PAP is a function of cardiac output and pulmonary vascular resistance (PVR). Pulmonary hypertension (PH) is defined as a mean PAP greater than 20 mmHg at rest, measured by right heart catheterization (Simonneau et al., 2019). PH can be a primary disorder of the pulmonary vasculature, commonly referred to as pulmonary arterial hypertension (PAH), or can occur as a complication of other cardiopulmonary, vascular, and systemic diseases. Based on shared pathophysiological and pathological characteristics as well as response to therapy, PH is classified into five major groups (Simonneau et al., 2019), as shown in Box 35–1.
BOX 35–1: Classification of Pulmonary Hypertension
Pulmonary arterial hypertension (PAH)
Idiopathic PAH
Heritable PAH due to genetic variants
BMPR2 (most common)
TBX4, ACVRL1, ENG, SMAD9, KCNK3
Drug- and toxin-induced PAH
PAH associated with:
PAH long-term responders to calcium channel blockers
PAH with overt features of venous/capillary involvement
PAH of the newborn syndrome
PH due to left heart disease
PH due to lung diseases and/or hypoxia
PH due to pulmonary artery obstructions
PH with unclear and/or multifactorial mechanisms