Revised Definition of Pulmonary Hypertension and Approach to Management: A Clinical Primer

Abstract

The definition of pulmonary hypertension (PH) has changed recently based, in part, on contemporary outcome data and to focus on early disease detection. Now, PH includes patients with mean pulmonary artery pressure >20 mm Hg measured by right heart catheterization. In contrast to the classical era, pulmonary vascular resistance >2.0 Wood units is also used for diagnosis and prognostication. These lowered thresholds aim to identify patients early in the disease course, which is important because delay to diagnosis of PH is common and linked to elevated morbidity and shortened lifespan. This clinical primer highlights key changes in diagnosis and approach to PH management, focusing on concepts that are likely to be encountered frequently in general practice. Specifically, this includes hemodynamic assessment of at-risk patients, pharmacotherapeutic management of pulmonary arterial hypertension, approach to PH in patients with heart failure with preserved ejection fraction, and newly established indications for early referral to PH centers to prompt comanagement of patients with pulmonary vascular disease experts.

Keywords: definition; pulmonary hypertension; treatment.

Figure 1. Clinical classification of pulmonary hypertension (PH).

There are 5 broad PH clinical groups that reflect the circumstances underlying elevated pulmonary artery pressure and other pathogenic cardiopulmonary hemodynamic findings on right heart catheterization (RHC). In pulmonary arterial hypertension (PAH), fibromuscular and plexigenic remodeling of distal pulmonary arterioles is caused by interplay between genetic and molecular events, induced by certain toxic drugs (eg, methamphetamines, desatinib, or anorexigens) or observed in association with systemic sclerosis, liver disease, HIV, or other predisposing conditions. Patients with PH attributable to left heart disease present with pulmonary venous hypertension, manifest by postcapillary PH on RHC, whereas PH severity in patients with underlying lung disease is variable. Thrombotic mechanical obstruction to normal pulmonary blood flow is the cornerstone feature of chronic thromboembolic PH (CTEPH). Reproduced from Humbert et al with permission. Copyright ©2023 European Society of Cardiology and European Respiratory Society. Cpc indicates combined precapillary+postcapillary PH; and Ipc, isolated postcapillary PH.

Figure 2. Selected transthoracic echocardiographic findings in pulmonary arterial hypertension (PAH).

A, Continuous‐wave Doppler imaging acquired from the apical 4‐chamber view in a patient with advanced‐stage PAH demonstrates severe tricuspid regurgitation. In the inset, the velocity of the tricuspid regurgitant jet is 4.8 m/s, well above the threshold of 2.8 m/s that suggests mild pulmonary hypertension (PH), and corresponds to an estimated right ventricular systolic pressure of 98 mm Hg and estimated pulmonary artery systolic pressure of 108 mm Hg. B, From the same view, severe right ventricular (RV) and right atrial (RA) dilation is noted. C, In the short‐axis 2‐chamber view, the interventricular septum imaged at end systole is flat (“D sign”), indicative of RV volume and pressure overload. D, Assessment of RV systolic function accomplished by measuring the tricuspid annular plane of systolic excursion (TAPSE), which quantitates the apical displacement of the tricuspid annulus between diastole and systole measured by M‐mode echocardiography. In patients with PH, TAPSE <1.7 cm is prognostic for adverse outcome. LV indicates left ventricle.

Figure 3. The relationship between pulmonary hypertension (PH) hemodynamic parameters and all‐cause mortality.

In a national cohort of patients referred for right heart catheterization, mean pulmonary artery pressure (mPAP) (N=21 727) (A) and pulmonary vascular resistance (PVR) restricted to patients with mPAP ≥19 mm Hg (N=32 725) (B) were modeled continuously, and the association with all‐cause mortality risk is shown. These results converge with normative data,, suggesting that the upper limits of normal for mPAP and PVR are ≈20 mm Hg and 2 WU, respectively. Taken together, these data establish an evidence‐based framework for the new hemodynamic definition of PH. The red disc represents the referent group. Adapted with permission from Maron BA, et al © 2016, American Heart Association, Inc (A); and Maron BA, et al © 2020, Elsevier Ltd (B). HR indicates hazard ratio; and WU, Wood units.

Figure 4. Approach to the management of patients with incident pulmonary arterial hypertension (PAH).

Newly diagnosed patients with idiopathic, hereditary, or drug‐induced PAH should be considered for vasoreactivity testing in the cardiac catheterization laboratory at an expert pulmonary hypertension center. In the absence of a high‐risk clinical profile, patients who demonstrate a positive vasoreactivity response, defined by decrease in mean pulmonary artery pressure ≥10 mm Hg from baseline to ≤40 mm Hg without a decrease in cardiac output, should be initiated on calcium channel antagonist therapy dose titrated to optimal clinical benefit/adverse effect balance. For patients with PAH without evidence of vasoreactivity but with high‐risk findings, consideration to up‐front therapy with the prostacyclin analogue treprostinil administered by intravenous (i.v.) or subcutaneous (s.c.) route plus the phosphodiesterase type‐5 inhibitor tadalafil and endothelin receptor antagonist ambrisentan is indicated. For patients with PAH without vasoreactivity or high‐risk findings, initial combination therapy with the tadalafil and ambrisentan or the alternate endothelin receptor antagonist macitentan should be considered. NT‐proBNP indicates N‐terminal pro‐B‐type natriuretic peptide; pVO₂, peak volume of oxygen consumption; PVR, pulmonary vascular resistance; and WHO‐FC, World Health Organization Functional Class; and WU, Wood units.