Pulmonary Hypertension: A Contemporary Review

Abstract

Major advances in pulmonary arterial hypertension, pulmonary hypertension (PH) associated with lung disease, and chronic thromboembolic PH cast new light on the pathogenetic mechanisms, epidemiology, diagnostic approach, and therapeutic armamentarium for pulmonary vascular disease. Here, we summarize key basic, translational, and clinical PH reports, emphasizing findings that build on current state-of-the-art research. This review includes cutting-edge progress in translational pulmonary vascular biology, with a guide to the diagnosis of patients in clinical practice, incorporating recent PH definition revisions that continue emphasis on early detection of disease. PH management is reviewed including an overview of the evolving considerations for the approach to treatment of PH in patients with cardiopulmonary comorbidities, as well as a discussion of the groundbreaking sotatercept data for the treatment of pulmonary arterial hypertension.

Keywords: pulmonary arterial hypertension; pulmonary hypertension; pulmonary vascular disease.

Figure 1.

Current treatment approaches and novel targets in pulmonary arterial hypertension. Current treatment approaches focus on endothelin, nitric oxide, and prostacyclin signaling. Novel treatment targets address 1) epigenetic mechanisms/transcriptional factors; 2) oxidative stress; 3) hypoxia and metabolic signaling; 4) BMPR2–mediated signaling; 5) tyrosine kinase and growth factor signaling; 6) fibrosis and extracellular matrix remodeling; and 7) inflammation and immune cell infiltration. 4PBA = 4-phenylbutyric acid; AA = arachidonic acid; ActRII = activin receptor type II; BMP = bone morphogenetic protein; BMPR2 = bone morphogenetic protein receptor type 2; cDC = conventional dendritic cell; DNMT3B = DNA methyltransferase 3 β; ET = endothelin; GDFs = growth and differentiation factors; HIF = hypoxia-inducible factor; JAGGED-1 = jagged canonical Notch ligand 1; JAK = Janus kinase; MAO-A = monoaminoxidase A; MMP = matrix metalloproteinase; NUDT1 = nudix hydrolase 1; NEDD9 = neural precursor cell–expressed developmentally downregulated protein 9; NFU1 = NFU1 iron-sulfur cluster scaffold; NO = nitric oxide; NOS = nitric oxide synthase; PAEC = pulmonary artery endothelial cell; PASMC = pulmonary arterial smooth muscle cell; PDE5 = phosphodiesterase 5; PGI2 = prostacyclin; PINK1 = phosphatase and tensin homolog–induced kinase 1; SDF1 = stromal cell–derived factor 1; sGC = soluble guanylate cyclase; SOX9 = SRY-box transcription factor 9; SOX17 = SRY-box transcription factor 17; SPARC = secreted protein acidic and rich in cysteine; TBX4 = T-box transcription factor 4; TET2 = Tet methylcytosine dioxygenase 2; TWIST1 = Twist family BHLH transcription factor 1; TYKRIL = tyrosine kinase receptor–inducing long noncoding RNA.

Figure 2.

Echocardiographic features supportive of pulmonary hypertension and characteristic confirmatory right heart catheterization tracings. (A) The velocity of the tricuspid regurgitant jet (3.75 m/s), measured with continuous‐wave Doppler imaging in the apical four‐chamber view, is used to calculate systolic pulmonary artery pressure (sPAP); sPAP = 4V² + CVP. (B) In the short‐axis two‐chamber view, the interventricular septum imaged at end systole is flat (“D sign”), indicative of RV volume and pressure overload. (C) TAPSE, a measure of right ventricular function, represents the apical displacement of the tricuspid annulus between diastole and systole measured by M‐mode echocardiography. (D) Typical pulmonary artery wedge pressure tracing at end-expiration with black line representing average pressure over the respiratory cycle which can be reported in cases with significant respiratory variation, as opposed to typical end-expiration; a-wave and v-wave are noted in red, with the v-wave falling outside the T-wave on an associated ECG. (E) Example of an optimal pulmonary artery pressure waveform with preserved dichroic notch. 4V² = V is the peak velocity (m/sec) of the tricuspid regurgitant jet; CVP = central venous pressure; RV = right ventricular; TAPSE = tricuspid annular plane of systolic excursion.

Figure 3.

Prognostic value of pulmonary vascular resistance (PVR) in pulmonary hypertension (PH) caused by interstitial lung disease (ILD). (A) Kaplan-Meier survival curve stratified by the current hemodynamic definition of severe PH in lung disease: mean pulmonary arterial pressure (mPAP) ⩾ 35 mm Hg or mPAP ⩾ 25 mm Hg with cardiac index <2.0 L/min/m². (B) Kaplan-Meier survival curve stratified by PVR ⩽ 5 WU and PVR > 5 WU. (C) Kaplan-Meier survival curve stratified by PVR ⩽ 8 WU and PVR > 8 WU. WU = Wood units. Reprinted by permission from Reference .

Figure 4.

Baseline pulmonary arterial hypertension (PAH) risk stratification. PAH treatment decisions should be made in the context of risk stratification. For example, the European Respiratory Society/European Society of Cardiology three-stratum risk stratification tool (presented here in an abbreviated form) is then paired with a treatment algorithm guided by risk (see Figure 5). BNP = brain natriuretic peptide; CI = cardiac index; NTproBNP = N-terminal–pro hormone brain natriuretic peptide; RA = right atrial; S$\dot{\mathrm{V}}$o₂ = mixed venous oxygen saturation; sPAP = systolic pulmonary arterial pressure; TAPSE = tricuspid annular plane systolic excursion; V_O2 = volume of oxygen consumption. Reprinted with permission from References and .

Figure 5.

Baseline pulmonary arterial hypertension (PAH) treatment algorithm. Dual-oral combination therapy is the standard of care for low- and intermediate-risk patients; parenteral prostacyclin analogue therapy should be added for high-risk patients. Treatment decisions for patients with PAH and cardiopulmonary comorbidities are different from those with isolated World Health Organization Group 1 PAH and should center around initial monotherapy. Cardiopulmonary comorbidities include left ventricular diastolic dysfunction, obesity, hypertension, diabetes mellitus, coronary artery disease, and parenchymal lung disease. Vasoreactivity testing° is recommended for patients with idiopathic, heritable, and drug-induced PAH. °Positive response, or “vasoreactive,” is defined as a mean pulmonary artery pressure reduction ⩾ 10 mm Hg to absolute value ⩽ 40 mm Hg with improved or unchanged cardiac output. ERA = endothelin receptor antagonist (either ambrisentan or macitentan); PDE5i = phosphodiesterase 5 inhibitor (either sildenafil or tadalafil); PH = pulmonary hypertension; I.V. = intravenous; S.Q. = subcutaneous, prostacyclin analog (either epoprostenol or treprostinil).

Figure 6.

The pathophysiology and risk associated with mild pulmonary hypertension (PH). (A) Compared with normal controls, pulmonary arterioles from patients with mild PH and hypertrophic cardiomyopathy demonstrate increased fibrosis and hypertrophy on Masson trichrome and elastin staining, respectively. Scale bar, 50 mm. Reproduced with permission from Reference . (B) When modeling mean pulmonary artery pressure (mPAP) as a continuous variable across a national cohort of 21,727 veterans, mortality risk that is associated with increases in mPAP emerges at 19 mm Hg. Subtle increases in mPAP between 19 and 24 mm Hg are associated with a much greater change in mortality, suggesting an opportunity to modulate clinical risk in the range of mild rather than severe PH. Reproduced with permission from Reference . (C) Increased mortality in an Australian national cohort of patients with mild PH suggested by echocardiography is associated with pathogenic changes to RA and right ventricular (RV) geometry. Reprinted with permission from Reference . (D) The pathogenicity of mild PH is suggested further by evidence of impaired tricuspid annular plane of systolic excursion (TAPSE) and surrogate for RV-pulmonary arterial coupling (TAPSE/RVSP). Reprinted with permission from Reference . ePH = echocardiographic PH; eRVSP = estimated right ventricular systolic pressure; H/E = hematoxylin and eosin; RA = right atrial; RVSP = right ventricular systolic pressure.

Figure 7.

Balloon pulmonary angioplasty of proximal and distal chronic pulmonary emboli. Representative pulmonary angiogram before and after balloon pulmonary angioplasty. (A) Global pulmonary angiogram in a patient with surgically accessible proximal lesions (Group 1). (A-a) Pulmonary angiogram before balloon pulmonary angioplasty (BPA). (A-b) Pulmonary angiogram after four BPA procedures. (B) Global pulmonary angiogram in a patient with surgically inaccessible distal lesions (Group 2). (B-a) Pulmonary angiogram before BPA. (B-b) Pulmonary angiogram after four BPA procedures. Reprinted by permission from Reference .

Figure 8.

Alternative clinical trial approaches. (A) Risk assessment–based eligibility criteria for enrichment. Green indicates low risk, yellow indicates intermediate risk, and red indicates high risk. (B) Adaptive enrichment recruitment based on interim analysis response. Dark blue indicates patients who might benefit from treatment A. Light blue indicates patients that might benefit from treatment B. All randomly assigned patients (light orange). (C) Randomized discontinuation study design. Dark blue indicates patients who improve with therapy, light blue indicates patients who are stable with treatment, and violet indicates patients who deteriorate with treatment. Reprinted by permission from Reference .