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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)


  • Drug- and toxin-induced PAH

  • PAH associated with:

    • Connective tissue disease

    • HIV infection

    • Portal hypertension

    • Congenital heart disease

    • Schistosomiasis

  • 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

  • Heart failure

  • Valvular heart disease

  • Congenital/acquired cardiovascular conditions leading to postcapillary hypertension

PH due to lung diseases and/or hypoxia

  • Obstructive lung disease

  • Restrictive lung disease

  • Hypoxia without lung disease

  • Developmental lung disorders

PH due to pulmonary artery obstructions

  • Chronic thromboembolic pulmonary hypertension (CTEPH)

  • Other pulmonary artery obstructions

PH with unclear and/or multifactorial mechanisms

  • Hematological disorders

  • Systemic and metabolic disorders

  • Complex congenital heart disease

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