Illuminating the Importance of Pulmonary Arterial Compliance in Pulmonary Hypertension

Pulmonary hypertension (PH) is an abnormal increase in pulmonary arterial pressure that is a hemodynamic consequence of a broad range of cardiopulmonary and systemic diseases. PH is an umbrella term that has been iteratively classified into five clinical groups according to similar hemodynamic profiles, pathophysiology, associated conditions, and management (1). Over time, with new and accumulating data from large cohorts, the hemodynamic definitions and classification of PH have evolved. For example, the threshold for PH has been lowered from a mean pulmonary arterial pressure (mPAP) of ⩾25 mm Hg to >20 mm Hg based on systematic reviews of normal hemodynamics and large studies analyzing the relationships between hemodynamic variables and clinical outcomes (2, 3). Similarly, the threshold for an abnormal pulmonary vascular resistance (PVR) has been lowered from >3 Wood units to >2 Wood units based on evidence that an increased mortality risk is present starting at >2.2 Wood units (4). Pulmonary arterial compliance (PAC) has gained increasing attention as a useful hemodynamic marker in PH, with several studies showing an association between PAC and outcomes (5). PAC is calculated from the ratio of stroke volume (SV) to pulmonary arterial pulse pressure (systolic pulmonary arterial pressure minus diastolic pulmonary arterial pressure). As such, it contains information about the distensibility of the total pulmonary circulation, the pulsatile load on the right ventricle, and the function of the right ventricle (i.e., SV) (6).

In this issue of the Journal, Wang and colleagues (pp. 312–321) explore the clinical relevance of PAC in a large database of patients undergoing right heart catheterization in the Veterans Affairs system who had mild PH (mPAP 19–24 mm Hg) (7). They applied a novel network medicine framework to identify 21 unique subgroups (modules) of patients. In this approach, a patient (node) was defined by 79 clinical variables and then connected to similar patients by an edge, representing correlation coefficients between their clinical profiles of greater than 0.5. They then applied an optimized modularity function, which is an approach that finds structure in the network community whereby modules are groups of patients with many edges between them and few edges between different groups (8) (Figure 1A). Next, they determined which clinical variables drove the module assignment using a random forest variable selection and found that PAC was the strongest determinant of patient assignment to modules characterized by better survival, but not those characterized by higher mortality rates. In the large discovery and external validation cohort, they next observed that a PAC ⩾3 mL/mm Hg had a consistently strong relationship with survival in all patients with PH with an mPAP ⩾19 mm Hg, in those with mild PH (mPAP 19–24 mm Hg), in those with precapillary PH (pulmonary artery wedge pressure ⩽15 mm Hg), and in those with postcapillary PH (pulmonary artery wedge pressure >15 mm Hg). Similarly, a PAC ⩾3 mL/mm Hg was protective in those with increased PVR (⩾2.2 Wood units) and those with normal PVR (<2.2 Wood units). With its complex yet elegant analytic methods and robust sensitivity analyses, this study arrives at important insights into the clinical relevance of PAC in PH.

Figure 1.

(A) The concept of network modularity, which groups patients (nodes) into modules (shaded areas) based on the presence of many similarities (edges), with smaller numbers of edges between patients in different modules. (B) The inverse parabolic relationship between pulmonary arterial compliance (PAC) and pulmonary vascular resistance (PVR). Large decreases in PAC occur before PVR begins to increase. Similarly, large decreases in PVR occur before PAC increases. Pulmonary arterial wedge pressure (PAWP) shifts the relationship down and to the left, stiffening the pulmonary circulation, such that, at any given PVR, PCA is lower when PAWP is high. Created with Biorender.com.

There are a few limitations of the study to note, most importantly the need to restrict these analyses to cases with complete data; the exclusion of thousands of patients as a result of missing data could lead to bias even though it is probable that most data are randomly missing, and, with such large numbers, the results would likely be similar. Second, although widely used in clinical practice and research, PAC as calculated in this study (SV/pulse pressure) is a surrogate and may overestimate total arterial compliance (9). Nevertheless, the clinical relevance is considerable, and several important questions emerge (or reemerge) from this study.

First, although a high PAC is an important predictor of survival, is it better than the sum of its parts (i.e., SV and pulse pressure)? In our previous study of patients with pulmonary arterial hypertension, PAC did not predict survival better than indexed SV did (10). Yet, in the study by Wang and colleagues, PAC models performed better than those for SV and pulse pressure. The differences between these findings likely relate to vastly different patient populations, with the majority of patients in their study having postcapillary PH (mean pulmonary arterial wedge pressure, 18 mm Hg) and normal PVR (mean, 2.1 Wood units), with high prevalences of lung and cardiac disease. It seems likely that PCA is a more robust prognostic variable in the broader population and particularly in those with mild PH or early pulmonary vascular disease.

Should PAC be incorporated into the hemodynamic definitions of PH? The authors acknowledge that PAC is unlikely to replace PVR, but indeed could complement it. There is an inverse parabolic relationship between PAC and PVR (Figure 1B), such that large reductions in PAC occur before PVR substantially increases. Indeed, small reductions in PAC reflect stiffening of the pulmonary circulation. Early stiffening of the vascular extracellular matrix may be the initial trigger for pulmonary vascular cell proliferation via a mechanotransduction-mediated metabolic shift to glutaminolysis and glycolysis, which propagates vascular remodeling and the hemodynamic progression in PH (11). Thus, PAC may be a useful marker of early pulmonary vascular disease and can be estimated noninvasively (12). Based on the study of Wang and colleagues, we agree that PH definitions need to factor in PAC, but exactly how will likely be hotly debated.

Should a PAC >3 mL/mm Hg be a treatment goal across the spectrum of PH? PAC is sensitive to increases in left ventricular pressure: with higher pulmonary arterial wedge pressure, the PAC–PVR relationship is shifted left and down (13) (Figure 1B). Although a high PAC could be a novel treatment target in PH due to left heart failure, Wang and colleagues do not go so far as to prove this, showing only the robust relationship between a higher PAC at a single point in time and survival. Prospective longitudinal studies will be needed to determine whether therapy-induced changes in PAC or the attainment of PAC thresholds with treatment are meaningful. In specific populations with severe pulmonary vascular disease characterized by higher PVR and lower PAC, such as pulmonary arterial hypertension, PAC targets >3 mL/mm Hg may be difficult to achieve for most patients.

In the 1863 poem Auguries of Innocence, William Blake leads with “To see a world in a grain of sand/And heaven in a wildflower/Hold infinity in the palm of your hand/And eternity in an hour” (14), suggesting that insights into the complexities of the universe can be found in the smallest of things. This study evokes this sentiment, though inversely, in that deep insights into the properties and importance of microscopic vessels of the lungs can be revealed from sophisticated computational analyses of complex relationships among thousands of individuals. Using a novel network medicine analysis and unbiased approaches to variable selection to uncover novel patient phenotypes and identify significant determinants of better outcomes, Wang and colleagues illuminate the clinical importance of a higher PAC as a key determinant of survival across hemodynamic categories and across the most common forms of PH.