Evaluation of ePLAR, the echocardiographic pulmonary to left atrial ratio, in a large cohort with pulmonary hypertension

Abstract

Aims

Pre-capillary pulmonary hypertension (PHTN), typically due to intrinsic pulmonary pathology, requires right heart catheterization (RHC) for diagnosis. ePLAR, the echocardiographic pulmonary to left atrial ratio [calculated: tricuspid regurgitation maximum velocity (TRV_max) divided by mitral valve E to e′ wave ratio (E/e′)], has been demonstrated as a promising non-invasive surrogate for characterization of pre-capillary PHTN. As such, this study aimed to further evaluate the diagnostic utility of ePLAR in a large cohort of patients with PHTN.

Methods and results

All RHCs between 2018 and 2023 across three tertiary centres were retrospectively reviewed. Patients with PHTN were characterized as pre-capillary or post-capillary (isolated or combined). Concurrent ePLAR was calculated. ROC analysis evaluated the accuracy of ePLAR in detecting pre-capillary PHTN. Overall, 2235 patients had PHTN by RHC, mean age 63.5 ± 14.7 years, 53.5% male. Of these, 43.3% had pre-capillary PHTN. ROC analysis demonstrated ePLAR to have good accuracy in detection of pre-capillary PHTN (AUC 0.760), with a cutoff of 0.20 m/s demonstrating a sensitivity and specificity of 77% and 60% respectively. This persisted on sensitivity analysis for contemporaneous investigations and for right ventricular function.

Conclusion

In this large cohort, ePLAR was validated as an accurate tool for identifying patients with pre-capillary PHTN. This widely available, non-invasive, and reproducible parameter can have an important role in the work up of PHTN and may guide the need for invasive testing.

Introduction

Pulmonary hypertension (PHTN), a complex condition characterized by elevated pulmonary pressures, can arise from a wide range of underlying causes. Recognizing, characterizing, and addressing PHTN early is crucial for guiding adequate treatment options and improving patient outcomes.^1,2 Typically, diagnosis of PHTN requires invasive assessment with right heart catheterization (RHC).^1,3 Furthermore, this test facilitates characterization of either pre-capillary (predominantly driven by intrinsic pulmonary vascular pathologies) or post-capillary PHTN (driven by increased left-sided cardiac filling pressures).^3–5 Chronic elevation in left heart pressures can coexist with other pulmonary disorders, creating a complex, mixed form of PHTN known as combined pre/post-capillary PHTN.^2,6

Although RHC is the gold standard for this categorization, multiple non-invasive parameters, obtained on transthoracic echocardiography (TTE), have been evaluated to differentiate pre- and post-capillary forms.^3,7 Specifically, ePLAR, the echocardiographic pulmonary to left atrial ratio (ePLAR), has been suggested to accurately reflect the invasively obtained transpulmonary gradient (TPG), therefore characterizing pre-capillary PHTN, through the formula: tricuspid regurgitation maximum velocity (TRV_max) divided by mitral valve E-wave to e′-wave ratio.⁶ This parameter has been evaluated in smaller studies and some specific populations; however, its diagnostic utility is yet to be validated in a large cohort study.

Methods

All consecutive adult patients (age ≥ 18 years) who underwent RHC between 01 January 2018 and 31 December 2023 across three institutions in the United States (Mayo Clinic Minnesota, Arizona and Florida) were retrospectively reviewed. Patients were required to have at least one TTE within 6 months of RHC. Only patients with evidence of PHTN on RHC were included for further analysis. Baseline patient characteristics and medical comorbidities were abstracted from electronic medical records. This study was approved by the Mayo Clinic Institution Review Board.

RHC procedures were performed according to current guidelines and PHTN was defined as mean pulmonary artery pressure (mPAP) > 20 mmHg.³ Patients with PHTN were then categorized as either pre-capillary PHTN [pulmonary capillary wedge pressure (PCWP) ≤ 15 mmHg and pulmonary vascular resistance (PVR) > 2 WU] or post-capillary PHTN (PCWP >15 mmHg and PVR ≤2 WU for isolated post-capillary or PVR >2 WU for combined post-capillary).³

All TTEs within 6 months of RHC for each patient were reviewed. If a patient had multiple TTEs in the timeframe, the closest to the date of RHC was chosen. A sensitivity analysis was planned to include only patients who had both TTE and RHC performed on the same day, to minimize the impact of variability in haemodynamic status. Further sensitivity analysis was planned to evaluate ePLAR in patients with right ventricular (RV) dysfunction, as determined by Tricuspid Annular Plane Systolic Excursion (TAPSE) < 17 mm. Parameters were collected from TTE reports, measured as per current guidelines. Patients with incomplete TRV_max signals, other missing TTE data, or massive/torrential tricuspid regurgitation were excluded. For patients with atrial fibrillation, measurements were taken over an average of 5–7 beats, as per guidelines. For each patient, ePLAR was calculated as TRV_max divided by the ratio of medial mitral E/e′.⁶

The accuracy of ePLAR in discriminating pre-capillary PHTN was evaluated using Area under the Receiver Operating Characteristics curve (AUC ROC), in comparison to RHC characterization. Comparison between multiple ROC curves was performed using the DeLong method. Selection of the optimal cutoff value was determined using a clinically relevant approach, prioritizing a high sensitivity without significantly sacrificing specificity. Categorical variables were presented as frequency, percentages (n, %) and compared between groups using Chi-square test. Continuous variables were presented as either mean ± standard deviation or median [interquartile range (IQR)] and compared with independent samples student t-testing or non-parametric testing, depending on the normality of distribution. Statistical significance was considered as P < 0.05. All analyses were conducted using SPSS Statistical Software Suite (Version 28.0, IBM Statistics, New York, USA).

Results

Overall, 3790 patients were identified to have undergone RHC with available TTE data. Of these, 2376 patients had evidence of PHTN (Figure 1). Among them, a small number of patients, 141 (5.9%), had a normal PCWP (≤15 mmHg) with low PVR (<2 WU), and therefore were excluded from further analysis, not meeting criteria for either pre- or post-capillary PHTN. The mean age of the final cohort (n = 2235) was 63.5 ± 14.7 years, 53.3% male. Of these patients, 967 (40.7%) had pre-capillary PHTN and 1268 (53.4%) had post-capillary PHTN (418 patients with isolated post-capillary and 850 patients with combined post-capillary PHTN) on RHC. The median time between RHC and TTE was 13.3 [2.4–45.6] days. Baseline characteristics, medical comorbidities, RHC and TTE data are presented in Table 1.

Figure 1.

Calculation of ePLAR and study design. E/e′, mitral E to e′ wave ratio; ePLAR, echocardiographic pulmonary to left atrial ratio; PA, pulmonary artery; PCWP, pulmonary capillary wedge pressure; TPG, transpulmonary gradient; TRV_max, tricuspid regurgitation maximum velocity.

Table 1.

Baseline characteristics

Baseline patient characteristics	Pre-capillary pulmonary hypertension (RHC) (n = 967)	Post-capillary pulmonary hypertension (RHC) (n = 1268)	P-value (between pre- and post-capillary (RHC)	High-risk of pre-capillary pulmonary hypertension (ePLAR > 0.20 m/s) (n = 1259)	Low risk of pre-capillary pulmonary hypertension (ePLAR ≤ 0.20 m/s) (n = 976)	P-value (between ePLAR risk groups)
Sex, male, n (%)	422 (43.6%)	769 (60.6%)	<0.001	613 (48.7%)	578 (59.2%)	<0.001
Age at time of right heart catheter (years), mean ± SD	63.7 ± 14.8	63.3 ± 14.5	0.490	63.2 ± 15.2	63.9 ± 13.9	0.258
Body mass index (kg/m2), mean ± SD	29.6 ± 7.3	31.0 ± 7.7	<0.001	30.7 ± 8.0	30.0 ± 7.0	0.020
Diabetes mellitus, n (%)	240 (24.8%)	513 (40.5%)	<0.001	331 (26.3%)	422 (43.2%)	<0.001
Hypertension, n (%)	456 (47.2%)	679 (53.3%)	0.003	616 (48.9%)	519 (53.2%)	0.046
Atrial fibrillation, n (%)	255 (26.4%)	680 (53.6%)	<0.001	411 (32.6%)	524 (53.7%)	<0.001
Right heart catheterization measurements
Mean pulmonary artery pressure (mmHg), median [IQR]	33.0 [26.0–43.0]	35.0 [30.0–43.0]	<0.001	35.0 [28.0–45.0]	34.0 [28.0–41.0]	<0.001
Pulmonary capillary wedge pressure (mmHg), median [IQR]	11.0 [8.0–13.0]	22.0 [18.0–26.0]	<0.001	14.0 [10.0–19.0]	21.0 [16.0–25.0]	<0.001
Cardiac output (L/min), median [IQR]	4.5 [3.7–5.4]	4.3 [3.5–5.5]	0.103	4.5 [3.7–5.7]	4.2 [3.4–5.3]	0.168
Pulmonary vascular resistance (WU), median [IQR]	4.6 [3.0–7.6]	2.7 [1.8–4.2]	<0.001	4.0 [2.6–6.7]	2.9 [2.0–4.3]	<0.001
Transthoracic echocardiogram measurements
Left ventricular ejection fraction (%), median [IQR]	61.0 [54.0–65.0]	51.0 [25.0–61.0]	<0.001	60.0 [53.0–65.0]	46.0 [22.0–60.0]	<0.001
Right ventricular systolic pressure (mmHg), median [IQR]	54.0 [41.0–73.0]	51.0 [39.0–64.0]	<0.001	56.0 [43.0–72.0]	48.0 [37.0–61.0]	<0.001
Tricuspid regurgitation maximum velocity (m/s), median [IQR]	3.4 [2.9–4.0]	3.1 [2.7–3.5]	<0.001	3.4 [2.9–3.9]	3.0 [2.6–3.4]	<0.001
Mitral valve medial E/e′ ratio, median [IQR]	10.0 [8.3–15.0]	17.1 [12.5–23.3]	<0.001	10.0 [8.3–13.3]	22.0 [17.5–27.5]	<0.001
ePLAR, m/s, median [IQR]	0.30 [0.21–0.42]	0.18 [0.13–0.25]	<0.001	—	—	—
Tricuspid annular plane systolic excursion (mm), median [IQR]	19.0 [15.0–22.0]	17.0 [13.0–21.0]	<0.001	19.0 [15.0–22.0]	16.0 [12.0–20.0]	<0.001
Left atrial volume index (mL/m2), median [IQR]	31.0 [24.0–41.0]	48.0 [37.0–59.0]	<0.001	33.0 [25.0–46.0]	49.0 [39.0–59.0]	<0.001

Patients with pulmonary hypertension, stratified by right heart catheterization (RHC) measurements and by echocardiographic pulmonary to left atrial ratio (ePLAR).

ROC analysis of ePLAR for the characterization of pre-capillary PHTN demonstrated good accuracy (AUC = 0.760), superior to its components; TRV_max (AUC = 0.615) and septal mitral E/e′ (AUC 0.737), Figure 2A, P < 0.001 for both. The optimal ePLAR cutoff point for identifying pre-capillary PHTN was 0.20 m/s with a sensitivity of 77% and a specificity of 60%.

Figure 2.

Receiver operating characteristic curve analysis. (A) Evaluation of diagnostic accuracy of ePLAR, the echocardiographic pulmonary to left atrial ratio, and its components, tricuspid regurgitation maximum velocity (TRV_max) and mitral valve medial E-wave to e′-wave ratio (E/e′) for the discrimination of pre-capillary pulmonary hypertension as defined on right heart catheterization. (B) Sensitivity analysis of ePLAR including only patients with transthoracic echocardiography and right heart catheterization on the same day. (C) Sensitivity analysis of ePLAR including only patients with right ventricular dysfunction, defined as Tricuspid annular plane systolic excursion (TAPSE) < 17 mm.

Sensitivity analysis only including patients with TTE and RHC on the same day (n = 308) mirrored the results from the overall evaluation, with AUC of 0.774 (Figure 2B). Further sensitivity analysis of ePLAR, evaluating patients with RV dysfunction (TAPSE < 17 mm, n = 677), also demonstrated similar accuracy (AUC 0.754, Figure 2C).

Discussion

This study, directly assessing a large cohort of patients with PHTN confirmed on RHC, validates ePLAR, the previously proposed non-invasive surrogate for the characterization of pre-capillary PHTN. Clinically, this tool may offer utility in the early identification of patients with suspected pre-capillary PHTN and may serve as a gate-keeper to invasive investigation. Although the overall diagnostic performance of ePLAR showed only a good AUC of 0.760, the sensitivity of 77% indicates that this parameter performs well in correctly identifying patients with pre-capillary forms. In clinical practice, such sensitivity is valuable, as it minimizes the risk of missing true cases of pre-capillary PHTN and supports ePLAR as an effective non-invasive screening tool. Even with only moderate specificity, the ability of ePLAR to reliably ‘rule in’ candidates for further invasive assessment represents a meaningful strength in the diagnostic pathway.

The incidence of PHTN has increased over recent decades and is associated with significant mortality, regardless of the underlying pathology.^3,8 Elevation in pulmonary pressures may result from a complex interplay of aetiologies, with different management approaches. Pre-capillary PHTN is most commonly associated with primary pulmonary vascular disease or intrinsic lung disease, in comparison to post-capillary PHTN, which is typically driven by left heart disease and associated with elevation of left ventricular filling pressures.⁴ The early and accurate differentiation of PHTN mechanisms allows for more targeted therapy, with consequent improvement in morbidity and mortality. Currently, RHC remains the gold standard for evaluation of PHTN.³ This test is invasive and often complex, not without associated risks, and not widely available at all institutions. As such, the use of non-invasive measurements may be considered as part of the decision making process when referring for invasive RHC.⁷

ePLAR integrates the pressure gradient across the tricuspid valve (TRV_max) reflecting pulmonary artery systolic pressure, with the echocardiographic estimate of left atrial filling pressure (mitral E/e′), thereby approximating the physiological difference between pulmonary and left atrial pressures that defines the TPG.⁶ This TTE derived tool is easy to perform calculated with two basic parameters that are part of guideline directed standard measurements. In 2016, Scalia et al.⁶ proposed ePLAR as a non-invasive surrogate for RHC in 133 patients with PHTN, reporting an ePLAR of 0.28 m/s to have a sensitivity and specificity of 83% for the discrimination of pre-capillary PHTN.⁶ Since its initial development, ePLAR has been shown to be valuable in multiple specific cohorts.^9,10 Overall, although these studies show promise for its diverse clinical utility, they tended to involve small sample sizes and thus may not be generalizable to all patients with PHTN. In our large cohort, an ePLAR of 0.20 m/s was determined to accurately differentiate pre-capillary PHTN. This was further demonstrated on subgroup sensitivity analyses. This cutoff is lower than the initial validation cohort and may be explained by several potential mechanisms such as the severity of underlying pathology, in particular in patients with left heart disease (and therefore higher mitral E/e′ ratio).

Limitations

This study was a retrospective assessment across three centres, which may allow for the potential of confounding bias and limited generalizability. For optimal validation of ePLAR compared with invasive measurements, RHC and TTE should be performed on the same day. In our cohort, only 14% had same-day investigations, however the median time between investigations was only 13 days.

Conclusion

This large cohort study evaluated the diagnostic utility of the non-invasively derived ePLAR in characterizing pre-capillary PHTN. Clinically, this widely available, reproducible parameter can identify a cohort of patients at high-risk of pre-capillary PHTN who may benefit from further invasive investigation, subsequently allowing for earlier diagnosis and targeted interventions.

Data availability

Data will be made available on reasonable request to the authors.

Funding

No external funding.