Pulmonary Arterial Hypertension: Diagnosis, Treatment, and Novel Advances

Abstract

The diagnosis and management of pulmonary arterial hypertension (PAH) includes several advances, such as a broader recognition of extrapulmonary vascular organ system involvement, validated point-of-care clinical assessment tools, and focus on the early initiation of multiple pharmacotherapeutics in appropriate patients. Indeed, a principal goal in PAH today is an early diagnosis for prompt initiation of treatment to achieve a minimal symptom burden; optimize the patient's biochemical, hemodynamic, and functional profile; and limit adverse events. To accomplish this end, clinicians must be familiar with novel risk factors and the revised hemodynamic definition for PAH. Fresh insights into the role of developmental biology (i.e., perinatal health) may also be useful for predicting incident PAH in early adulthood. Emergent or underused approaches to PAH management include a novel TGF-β ligand trap pharmacotherapy, remote pulmonary arterial pressure monitoring, next-generation imaging using inert gas-based magnetic resonance and other technologies, right atrial pacing, and pulmonary arterial denervation. These and other PAH state of the art advances are summarized here for the wider pulmonary medicine community.

Keywords: pulmonary arterial hypertension; pulmonary hypertension; risk stratification; treatment.

Figure 1.

The hemodynamic and clinical classification system for pulmonary hypertension (PH). (A) Patients undergoing right heart catheterization with an mPAP >20 mm Hg are considered further for classification as having precapillary PH, isolated postcapillary PH, or combined precapillary and postcapillary PH. (B) The PH clinical subgroups. Abstracted from Reference . CHD = congenital heart disease; CTD = connective tissue disease; CTEPH = chronic thromboembolic PH; Devlopm. = developmental; HPAH = hereditary PAH; HTN = hypertension; Hypovent. = hypoventilation; iPAH = idiopathic PAH; mPAP = mean pulmonary arterial pressure; PAH = pulmonary arterial hypertension; PAWP = pulmonary arterial wedge pressure; PVOD = pulmonary venoocclusive disease; PVR = pulmonary vascular resistance; WU = Wood units.

Figure 2.

Pulmonary arterial and right ventricular (RV) remodeling in pulmonary hypertension (PH) and pulmonary arterial hypertension (PAH). (A) A normal pulmonary artery (arrow) adjacent to a terminal Br (subpanel A); a marked medial and intimal thickening of a small pulmonary artery (arrow), partly surrounded by lymphoid cells form a cluster reminiscent of a primary follicle (arrowheads) (subpanel B); an idiopathic PH lung with a markedly muscularized, medium-sized pulmonary artery (arrow), which distally branches into a plexiform lesion (lower arrowhead) and an adjacent plexiform lesion (upper arrowhead) (subpanel C); a complex vascular lesion (circle) with a combination of telangiectasia-like dilations of the pulmonary artery (arrowheads) and a plexiform lesion (arrow) (subpanel D); a medium-sized pulmonary artery with complete lumen obliteration with loose collagen and a poorly defined cellular matrix (arrows) (subpanel E); and an intra- and/or interlobular septal, medium-sized vein (arrowhead) obliterated by loose connective tissue (arrows), likely the result of an organized thrombus, characteristic of venoocclusive disease (subpanel F). These representative images were provided courtesy of Dr. Rubin Tuder, obtained through the evaluation of the lungs collected by the PH Breakthrough Initiative, with a pulmonary vascular pathology spectrum similar to that reported in Reference . (B) Lipotoxicity in the RV in PAH, as indicated by ceramide deposition that corresponds to RV hypertrophy and remodeling (white arrows) on CMR. Reprinted by permission from Reference . (C) Compared with iPAH, RV fibrosis is observed to a greater extent in patients with Ssc–PAH. Passive tension as a function of escalating sarcomere length was measured in iPAH, SScPAH, and nonfailing control myocytes. *Post hoc P < 0.05 between control and IPAH; ^† post hoc P < 0.05 between control and SSc–PAH. Scale bar, 250 μm. Reprinted by permission from Reference . (D) Uniform, random, isotopically oriented RV sections stained with fluorescein isothiocyanate–lectin show the distribution of vessels. Scale bar, 100 μm. The relationship between RV volume and vessel length (left graph) and the diameter of RV tissue perfused by each vessel (right graph) are shown. Average radius of RV tissue served per vessel (n = 3–4/group; t test). Reprinted by permission from Reference . Br = bronchiole; CMR = cardiac magnetic resonance imaging; iPAH = idiopathic PAH; Ssc = systemic sclerosis.

Figure 3.

Right ventricle (RV)–pulmonary artery (PA) coupling predicts outcomes in pulmonary hypertension (PH). (A) Compared with the LV, the RV pressure–volume relationship is triangular and defined by less discrete transition points around valvular closing and opening. This is due, in part, to the noncompacted myocardium that serves as the framework for increased cardiac chamber compliance of the RV. The ratio of end-systolic elastance to RV afterload is a measure of RV contractility. When the end-systolic elastance is expressed relatively to the RV afterload, the efficiency of RV function is quantified as RV–PA coupling. Directly measuring RV–PA coupling requires transduction catheters, which are not in use in routine clinical practice. However, determining RV volume by using cardiac magnetic resonance imaging or other methods can be combined with pressure assessment from right heart catheterization to measure RV–PA coupling indirectly. Left ventricular loop is reproduced by permission from Reference 79. The right ventricular loop is reproduced by permission from Reference 80. (B) Typical flow patterns in the RV outflow tract at different cardiac phases for a patient with manifest PH (subpanels A, D, and G), a patient with latent PH (subpanels B, E, and H), and a control subject (subpanels C, F, and I). (Subpanels A–C) At maximum outflow, flow profiles were distributed homogenously across the cross-sections of the main PA in the group with manifest PH (subpanel A), the group with latent PH (subpanel B), and the control group (subpanel C). (Subpanels D–F) In later systole, a vortex was formed in the group with manifest PH (subpanel D). No such vortex could be found in the group with latent PH (subpanel E) or the control group (subpanel F). (Subpanels G–I) After pulmonary valve closure, the vortex in the group with PH persisted for some time. In all cases, continuous diastolic blood flows upward along the anterior wall of the main PA could be observed. Although this phenomenon disappeared quickly in control subjects (subpanel I), it was observed for a significantly longer period in those with latent PH (subpanel H) or manifest PH (subpanel G). Overall, these data show disorganized blood flow through the RV outflow tract in PH. Reprinted by permission from Reference . LV = left ventricle; PV = pulmonary valve.

Figure 4.

Integrated pathway for diagnosing pulmonary hypertension (PH). In patients suspected of having PH on the basis of history, physical examination results, and initial diagnostic testing results (e.g., ECG, chest X-ray), a transthoracic ECHO is often used as the first quantitative test. In patients with normal diagnostic test results at rest (e.g., ECG, echocardiography) but who report exercise limitation or have a risk factor for pulmonary vascular disease (e.g., systemic sclerosis), noninvasive cardiopulmonary exercise testing (CPET) may be helpful. Abnormal results from CPET can be used to advance the diagnostic evaluation for PH. Further evaluation of those with a moderate or high probability of PH determined on the basis of echocardiographic findings and results from assessment of left heart disease and pulmonary disease is warranted through the use of various diagnostic tests, including PFT + Dl _CO and HRCT. Serologic assessment may include ANA testing, HIV testing, and LFT. Patients should also be assessed for CTEPH, initially by using nuclear $\dot{\text{V}}$/$\dot{\text{Q}}$ scanning or contrast-enhanced chest CT. The diagnosis of PH is made by using right heart catheterization and requires a mean mPAP >20 mm Hg. Patients are then classified by hemodynamic category, which, together with the clinical profile and other supporting data (e.g., serologic and genetic testing results), is used to determine the PH clinical group (as outlined in detail in Figure 1). ANA = antinuclear antibody; AT = anaerobic threshold; CT = computed tomography; CTEPH = chronic thromboembolic PH; ECHO = echocardiogram; HRCT = high-resolution CT; LFT = liver function testing; mPAP = mean pulmonary arterial pressure; PFT = pulmonary function testing; p$\dot{\text{V}}$ o ₂ = peak $\dot{\text{V}}$ o ₂.

Figure 5.

Pulmonary hypertension (PH): disease inception. This schematic representation reflects potential mechanisms through which adverse maternal factors and critical gene–environment interactions may impair placental structure and function, leading to intrauterine stress and altered fetal programming. As proposed, premature birth and antenatal determinants may disrupt lung vascular development and increase the subsequent risk for pulmonary vascular disease, especially with secondary postnatal “hits,” which then contribute to PH during the postnatal period. The dashed line represents the timing of term birth. Adapted by permission from References and . PVD = peripheral vascular disease.

Figure 6.

Pulmonary arterial hypertension pharmacotherapies by molecular pathway target and delivery system. *Sotatercept is not U.S. Food and Drug Administration–approved; it is listed on the basis of data presented in Reference . **In addition to use in pulmonary arterial hypertension, iloprost is now supported for use in interstitial lung disease–pulmonary hypertension on the basis of clinical trial data from Reference .

Figure 7.

The CardioMEMS remote pulmonary arterial (PA) pressure (PAP)-monitoring device and the effect of right atrial pacing on hemodynamics in pulmonary arterial hypertension (PAH). (A) The CardioMEMS device was implanted in patients with PAH, and changes in PAP are shown before and after the initiation of prostacyclin therapy. (B) Tracking the effect of medication nonadherence on PAP in a patient requiring HFH. Images are courtesy of Dr. Ray Benza at Ohio State University. (C) The effect of right atrial pacing on hemodynamic parameters in a patient with systemic sclerosis–PAH. Images are courtesy of Dr. Ryan Tedford at the Medical University of South Carolina. BPM = beats per minute; dp/dt = change in pressure generated over time; HFH = heart failure hospitalization; IP = instantaneous pressure; IV = intravenous; RV = right ventricle.

Figure 8.

Advanced imaging in pulmonary vascular disease. (A) Ventilation, barrier uptake, and red blood cell (RBC) transfer maps show distinct patterns across a healthy control subject and patients with COPD, IPF, LHF, and pulmonary arterial hypertension (PAH). The color bins represent signal intensity (lowest, red; highest, blue; green, referent from the healthy control subject). Each map is quantified by the percentage of the D, L, and H (top). ¹²⁹Xe spectra are acquired every 20 ms and show cardiogenic Δ of RBC amplitude (%) and frequency shift (ppm) (bottom). Images are courtesy of Dr. Sudar Rajagopal at Duke University Medical Center. (B) Three-dimensional vascular reconstructions derived from clinically acquired computed tomographic angiography in a patient with dyspnea but no hemodynamic evidence of pulmonary vascular disease (top left) and a subject with connective tissue disease–associated PAH (top right). There is a net loss of volume in small vessels (red) as compared with a gain in volume encompassed by the larger vessels (blue and green). The bottom panels show an automated neural network–based arterial and venous labeling of each reconstruction. Images are courtesy of Dr. Farbod Rahgahi at Brigham and Women’s Hospital. COPD = chronic obstructive pulmonary disease; Δ = oscillations; D = defect; H = high; IPF = idiopathic pulmonary fibrosis; L = low; LHF = left heart failure; ppm = parts per million.