Abstract
Normal limits for exercise Doppler echocardiography (ex-TTE) measurements of the right ventricle (RV), pulmonary artery (PA) and left atrial (LA) unit remain inadequately defined. This meta-analysis aims to establish normal limits for measurements of the RV-PA-LA unit. A comprehensive literature search of Medline, Web of Science and Scopus (1 January 1999–December 2024) was performed. We included ex-TTE studies performed using a supine/semi-recumbent cycle ergometer in healthy subjects that reported the following parameters: tricuspid regurgitation velocity (TRV), systolic pulmonary artery pressure (sPAP), mean pulmonary artery pressure (mPAP), mPAP/cardiac output (CO) slope, mitral Doppler E to tissue Doppler e′ ratio (E/e′), tricuspid annular plane excursion (TAPSE) and TAPSE/sPAP. Summary mean estimates were calculated using a restricted maximum-likelihood random-effects model. Lower and upper limits of normal (LLN and ULN) were defined as the 5th and 95th percentiles. Between-study heterogeneity was assessed using the Q-statistic and quantified with the inconsistency index. Data on 1122 healthy subjects (mean±sd age: 42.8±18.3 years) across 19 eligible studies were analysed. The pooled mean estimates and limits of normal for ex-TTE measurements were as follows: TRV 2.5 m·s−1 (ULN 3.4), sPAP 38.5 mmHg (ULN 57.8), mPAP 29.8 mmHg (ULN 43.0), mPAP/CO slope 1.4 mmHg·min·L−1 (ULN 3.0), E/e′ 7.1 (ULN 11.5), TAPSE 31.8 mm (LLN 24.6), TAPSE/sPAP 0.8 mm·mmHg−1 (LLN 0.4). Despite notable heterogeneity for several measurements, the present meta-analysis provides a robust framework for defining normal reference limits for ex-TTE measurements of the RV-PA-LA unit.
Shareable abstract
Normal limits for exercise echocardiography (ex-TTE) of the right ventricle (RV) and pulmonary circulation (PC) need to be better defined. The present meta-analysis provides a robust framework for defining RV-PC ex-TTE normal reference limits. https://bit.ly/4cWmHQh
Introduction
In recent years, accumulating evidence has demonstrated that exercise Doppler echocardiography (ex-TTE) of the right heart and pulmonary circulation is feasible, can unmask latent cardiorespiratory diseases and holds prognostic significance [1, 2]. Ex-TTE is now included in clinical guidelines, though its use remains limited. The recommended diagnostic approach for heart failure with preserved ejection fraction now relies primarily on clinical probability scoring. However, exercise-induced increases in tricuspid regurgitation velocity (TRV) >3.4 m·s−1 and a mitral Doppler E to tissue Doppler e′ wave ratio (E/e′) >15 are considered indicative of elevated left atrial (LA) pressure [3]. In the diagnostic algorithm of valvular heart disease, ex-TTE measurements are now recommended in selected patients, with particular emphasis on TRV or the derived systolic pulmonary artery pressure (sPAP) [4, 5]. In the diagnostic algorithm for pulmonary hypertension (PH), guidelines recommend assessing clinical probability, including a resting TRV >2.8 m·s−1. However, they still rely on invasive measurements such as mean pulmonary artery pressure (mPAP) or pulmonary artery wedge pressure (PAWP) and their relationships with cardiac output (CO), with slopes greater than 3 mmHg·min·L−1 for mPAP and 2 mmHg·min·L−1 for PAWP, to identify latent PH or heart failure [6]. The normal reference limits for ex-TTE of the right ventricle (RV), pulmonary artery (PA) and LA unit remain poorly defined, and most studies have primarily focused on exercise TRV or E/e′, often overlooking the functional aspects of the RV [7]. Therefore, the aim of the present meta-analysis was to comprehensively establish normal reference limits for ex-TTE indices of the RV-PA-LA unit.
Methods
Search strategy
A systematic literature search was conducted in accordance with the PRISMA (Preferred Reporting Items for Systematic Reviews and Meta-Analyses) guidelines, covering Medline, Web of Science and Scopus from 1 January 1999 to 3 December 2024. The meta-analysis was registered on PROSPERO (Registration number: CRD42022375137). Only peer-reviewed original articles published in English and involving adults or young adults aged >16 years were included. Abstracts without full text, review articles, editorial comments and letters to the editor were excluded. The search strategy targeted ex-TTE studies conducted in healthy subjects using a supine or semi-recumbent cycle ergometer. The following Medical Subject Headings terms and keywords of ex-TTE-derived parameters of the RV-PA-LA unit were included: “tricuspid regurgitation velocity”, “TRV”, “systolic pulmonary artery pressure”, “sPAP”, “mean pulmonary arterial pressure”, “mPAP”, “pulmonary vascular resistance”, “PVR”, “tricuspid annular plane excursion”, “TAPSE”, “tricuspid annular plane excursion/systolic pulmonary artery pressure”, “TAPSE/sPAP”, the average ratio of “early mitral flow velocity (E) to tissue Doppler imaging (TDI) early mitral annular velocity”, “E/e′”, “mean pulmonary artery pressure (mPAP)/cardiac output (CO) slope”, “mPAP/CO slope”, “right ventricle lateral wall tissue Doppler imaging peak systolic velocity”, “RV TDI S′”, “pulmonary artery wedge pressure” and “PAWP”.
Inclusion and exclusion criteria
We included ex-TTE studies performed using supine or semi-recumbent cycle ergometer in healthy subjects, provided they reported at least one exercise Doppler index of the RV-PA-LA unit. Due to lack of data in the available literature, exercise parameters of RV diastolic function were not included in present meta-analysis. Observational studies were excluded if control groups included individuals taking any medications or with cardiovascular risk factors (e.g. hypertension, smoking, diabetes mellitus, dyslipidaemia), a history of cardiovascular disease or systemic conditions known to affect the cardiovascular system. Additional exclusion criteria were 1) studies with small sample size (<10 subjects), 2) studies involving athletes, 3) absence of ex-TTE data, 4) ex-TTE studies utilising treadmill or upright exercise protocols, as these rely on post-exercise measurements that are less reliable due to the rapid normalisation of pulmonary vascular pressures and cardiac output [8], 5) studies using agitated contrast agents (succinylated gelatin and/or saline) to enhance Doppler signals, 6) duplicate analyses of the same parameter in the same population, whether by the same or different authors (only the study with the largest sample size was retained). An additional study from the same authors was included only if it reported previously unassessed ex-TTE parameters.
Additional details are reported in figure 1 and in the supplementary materials.
FIGURE 1.
Study design. This flowchart illustrates the selection process for published reports according to the PRISMA (Preferred Reporting Items for Systematic reviews and Meta-Analyses) 2020 statement. Reproduced from [55], with permission. CVD: cardiovascular disease; CVRF: cardiovascular risk factor.
Data extraction and quality assessment
Demographic, clinical and ex-TTE data were extracted by one researcher (V. Capone) and independently reviewed by a second researcher (A.M. Esposito). The same two researchers entered the verified data into an electronic database. Disagreements were resolved through consensus. The following formulas were used across all included studies to derive ex-TTE-derived haemodynamic parameters: 1) sPAP=4×(TRV)2+right atrial (RA) pressure [9]; RA pressure was taken as estimated from inferior vena cava diameter and collapsibility or assumed as a fixed value of 5 mmHg [9, 10]; 2) mPAP=sPAP×0.61+2 mmHg [11]; 3) PAWP=1.9+1.24×(E/e′) mmHg [12]; 4) CO=stroke volume (SV)×heart rate (HR); SV was calculated from left ventricular outflow tract Doppler flow-velocity and diameter [13]; and 5) PVR=mPAP−PAWP/CO [7].
Statistical analysis
Variables of each study were reported as means±sd for continuous variables and as absolute counts and percentages for categorical variables. When only median and interquartile range of variables were available in the included studies, they were transformed into mean±sd values using validated statistical formulas prior to applying the meta-analytic procedure [14]. In studies reporting multiple relevant groups, a single aggregate dataset was generated by calculating the weighted mean and weighted sd, in accordance with established methodological approaches for combining independent groups. Summary mean estimates of each resting and exercise measurement and the corresponding 95% confidence intervals were calculated using the restricted maximum-likelihood random-effects method [15]. Between-study heterogeneity was assessed using Cochran's Q-statistic and the inconsistency index (I2) was quantified. I2 values were interpreted as follows: <25%, 25–75% and >75%, representing low, medium and high heterogeneity, respectively [16]. Lower and upper limits of normal (LLN and ULN) were defined as the 5th and 95th percentiles [14]. In line with Cochrane methodological recommendations, meta-regression and publication bias analyses were performed only when at least 10 studies reported the variable of interest, as this threshold helps ensure the robustness of findings and reduces the risk of overestimating associations [14]. All analyses were performed with OPENMETA-ANALYST for 64-bit (Brown University) and R version 3.2.3 (Metafor and meta packages).
Results
Characteristics of included studies
A total of 962 potential articles were screened for relevance from database and registry searches, with an additional 21 identified through other sources (e.g. reference lists). Of these, 19 ex-TTE studies met the inclusion criteria, comprising a total of 1122 healthy subjects with a mean±sd age of 42.8±18.3 years (figure 1). Sex-specific data were not consistently reported across all studies. The baseline clinical characteristics of the 19 included studies are summarised in table 1 (tables E1–E10) [1, 17–34]. The estimated mean±sd values along with the calculated normal limits for ex-TTE parameters are listed in table 2. All included studies employed a graded semi-supine or semi-recumbent bicycle protocol (increasing by 20–25 W every 2 min) up to symptom-limited maximal exercise and all reported parameters were acquired at rest and at peak exercise (except for E/e′ ratio) with a uniform methodology (tables E1–E10).
TABLE 1.
Baseline clinical and exercise stress echocardiography characteristics of the included studies
| First author [ref.] (year) | Study design | Population N (female %) | Race/country | Age, years | Weight, kg | Height, cm | BMI, kg·m−2 | BSA, m2 | HR, bpm | SBP, mmHg | DBP, mmHg | Workload increase | Evaluated echocardiographic variable |
|---|---|---|---|---|---|---|---|---|---|---|---|---|---|
| Grünig [17] (2000) | Prospective single-centre study | 11 (0) | Caucasian/Germany | 37±11 | 76±7 | 179±6 | – | – | 61.0±8 | – | – | 25 W/2 min | sPAP |
| Kasimir [18] (2008) | Prospective single-centre study | 37 (49) | Caucasian/Austria, Germany | 30±6 | – | – | – | – | 71±8 | 122±14 | 83±8 | 25 W/2 min | TRV |
| Mahjoub [19] (2009) | Prospective single-centre study | 70 (51) | Caucasian/France | 48±16 | – | – | 24.6±4.2 | – | 71±12 | 135±16 | 80±10 | 25 W/2 min | sPAP |
| Argiento [20] (2010) | Prospective single-centre study | 25 (48) | Caucasian/Italy | 36±14 | 70±15 | 178±12 | 22.1 | – | 66±10 | 116±9 | – | 20 W/2 min | sPAP |
| Möller [23] (2010) | Prospective single-centre study | 88 (56) | Caucasian/Norway | 18.3±3.5 | 64.2±13 | 171.2±10.2 | 21.8±3.1 | – | – | – | – | 25 W/2 min | sPAP |
| Bombardini [21] (2011) | Prospective single-centre study | 16 (12) | Caucasian/Italy | 35±9 | – | – | – | – | 77±15 | 126±13 | 72±10 | – | sPAP |
| Argiento [24] (2012) | Prospective single-centre study | 113 (50) | Caucasian/Italy | 37.5±13.5 | – | – | – | 1.8±0.2 | – | – | – | 20–30 W/2 min | mPAP, mPAP/CO, PVR, PAWP |
| Vriz [25] (2015) | Prospective single-centre study | 25 (0) | Caucasian/Italy | 47±12 | – | – | – | 1.9±0.1 | 69±9 | 122±7 | 75±7 | 20 W/2 min | mPAP/CO, PAWP |
| D’Alto [26] (2017) | Prospective multi-centre study | 90 (50) | Caucasian/Italy, Belgium | 39±13 | 70±11 | 173±9 | – | – | 72±9 | 119±9 | 71±8 | 20–30 W·min−1 | sPAP, mPAP, TAPSE, RV TDI S′, TAPSE/sPAP, PAWP |
| Motoji [22] (2017) | Prospective multi-centre study | 26 (53) | Caucasian/Belgium | 22±3 | 66±12 | 170±10 | – | – | 178±12 | 180±34 | – | 20–30 W/2 min | PVR, RV TDI S′, mPAP, TAPSE, mPAP/CO, TAPSE/sPAP, PAWP |
| Forton [27] (2019) | Prospective single-centre study | 30 (47) | Caucasian/Belgium | 15±3 | 56±11 | 167±11 | 19.8±2.8 | 1.62±0.2 | 78±8 | 108±12 | 68±8 | 10–30 W·min−1 | PVR, PAWP |
| Wierzbowska-Drabik [28] (2019) | Prospective single-centre study | 39 | Caucasian/Poland | 38±9 | – | – | – | – | – | – | – | 25 W/2 min | TRV |
| Durand [29] (2020) | Prospective single-centre study | 10 (0) | Caucasian/France | 37.8±1.7 | – | – | 24.9±0.6 | – | 78±5 | – | – | 30–50 W/2 min | mPAP/CO, PVR, PAWP |
| D'Andrea [31] (2021) | Prospective multi-centre study | 150 (60) | Caucasian/Italy | 70.3±5.4 | – | – | 25.7±3.4 | 1.81±0.2 | 76.4±11.4 | 124.4±5.8 | 78.3±9.2 | 25 W/2 min | sPAP, TAPSE, RV TDI S′, E/e′ |
| Forton [30] (2021) | Prospective single-centre study | 80 (0) | Caucasian/Belgium | 28.5±12.1 | 65.5±9.6 | 172±9 | 22.1±2.31 | 2.1±0.2 | 83±13.5 | – | – | 20 W/2 min | mPAP, TAPSE, RV TDI S′, TAPSE/sPAP, mPAP/CO |
| Vriz [32] (2022) | Prospective multi-centre study | 145 (40) | Caucasian/EU, USA | 54±14.9 | – | – | 26±3.5 | 1.97±0.1 | 75±15 | 123±16 | 77±10 | 25 W/2 min | E/e′ |
| Zhou [33] (2022) | Prospective single-centre study | 17 (71) | Caucasian/Belgium | 46±12 | 64±11 | 169±9 | 22±2.1 | 1.7±0.2 | 65±8 | – | – | 10–15 W/2 min | mPAP, TAPSE, E/e′, TAPSE/sPAP, PAWP |
| Gargani [1] (2023) | Prospective multi-centre study | 375 (53) | Caucasian/EU, USA | 46±15 | – | – | 25.6±3.9 | – | 73±13 | 122±15 | 76±10 | 25 W/2 min | sPAP, mPAP, TAPSE, TAPSE/sPAP, mPAP/CO, PVR |
| Ferrara [34] (2025) | Prospective multi-centre study | 192 (49) | Caucasian/Italy | 46.3±14.7 | – | – | 26.0±3.9 | 1.8±0.1 | 73±12 | 122±14 | 75±9 | 25 W/2 min | E/e′, TRV |
Data are presented as mean±sd, unless stated otherwise. The final included studies all employed semi-supine or semi-recumbent body position; no upright position was detected in the final included studies. Exercise protocol was cycle in all the final included studies. –: not reported; BMI: body mass index; bpm: beats per min; BSA: body surface area; DBP: diastolic blood pressure; E/e′: early mitral flow velocity to early mitral annular velocity; HR: heart rate; mPAP: mean pulmonary arterial pressure; PAWP: pulmonary artery wedge pressure; PVR: pulmonary vascular resistance; RV TDI S': right ventricle lateral wall tissue Doppler imaging peak systolic velocity; SBP: systolic blood pressure; sPAP: systolic pulmonary arterial pressure; TAPSE: tricuspid annular plane excursion; TRV: tricuspid regurgitation velocity.
TABLE 2.
Normal values of resting and exercise Doppler echocardiography parameters
| Echocardiographic variable | Number of studies (N) | Rest | Peak | ||
|---|---|---|---|---|---|
| Estimated mean±sd values | Estimated normal ranges | Estimated mean±sd values | Estimated normal ranges | ||
| TRV (m·s−1) | 3 (268) | 2.0±0.4 | 1.3–2.5 | 2.5±0.3 | 1.6–3.4 |
| sPAP (mmHg) | 8 (825) | 23.5±2.5 | 15.0–31.4 | 38.5±7.5 | 18.8–57.8 |
| mPAP (mmHg) | 6 (701) | 15.7±0.2 | 11.2–20.3 | 29.8±4.6 | 16.2–43.0 |
| mPAP/CO slope (mmHg·min·L−1 | 6 (629) | – | – | 1.4±0.2 | 3.0# |
| E/e′ | 4 (504) | 6.4±0.5 | 10.2# | 7.1±2.7 | 11.5# |
| PAWP (mmHg) | 7 (311) | 8.7±0.7 | 10.3# | 10.7±0.9 | 12.4# |
| PVR (WU) | 5 (554) | 1.5±0.5 | 0.7–2.2 | 1.3±0.2 | 0.6–1.8 |
| TAPSE (mm) | 6 (738) | 24.8±1.2 | 18.6–30.1 | 31.8±2.7 | 24.6–36.3 |
| RV TDI S′ (cm·s−1) | 4 (346) | 14.3±0.5 | 9.2–19.6 | 22.7±3.9 | 14.9–27.4 |
| TAPSE/sPAP (mm·mmHg−1) | 5 (588) | 1.2±0.4 | 0.5–1.7 | 0.8±0.3 | 0.4–1.2 |
#: Refers to upper limit values. –: not reported; CO: cardiac output; E/e′: early mitral flow velocity (E) to tissue Doppler imaging early mitral annular velocity (e′); mPAP: mean pulmonary arterial pressure; PAWP: pulmonary artery wedge pressure; PVR: pulmonary vascular resistance; RV TDI S': right ventricle lateral wall tissue Doppler peak systolic velocity; sPAP: systolic pulmonary arterial pressure; TAPSE: tricuspid annular plane excursion; TRV: tricuspid regurgitation velocity.
Pulmonary pressures
The estimated normal range for TRV at rest was 1.3–2.5 m·s−1 and 1.6–3.4 m·s−1 during exercise. The pooled mean TRV was 2.0 at rest and 2.5 m·s−1 during exercise, based on three studies (n=268) (figure S5, table E1). Between-study heterogeneity was not significant for either condition, with an I2 of 0% for resting TRV and 59.9% for exercise TRV.
For sPAP, the estimated normal range at rest was 15.0–31.4 mmHg and 18.8–57.8 mmHg at peak exercise, derived from eight studies (n=825). The corresponding pooled mean values were 23.5 mmHg at rest and 38.5 mmHg during exercise (figure S1, table E2). Between-study heterogeneity was significant for both, with Cochran's Q-statistics of 70.8 (resting) and 355.4 (exercise) (both p<0.001), and high inconsistency indices (I2=92.8% and 98.4%, respectively).
The estimated normal range for mPAP was 11.2–20.3 mmHg at rest and 16.2–43.0 mmHg during exercise, based on six studies (n=701). The pooled mPAP was 15.7 at rest and 29.8 mmHg during exercise (figure S2, table E3). Between-study heterogeneity was low for resting mPAP (I2=12.7%) but significant heterogeneity was observed for exercise mPAP (Q=126.7, p<0.001; I2=96.8%).
mPAP/CO slope
The estimated ULN for the mPAP/CO slope was 3.0 mmHg·min·L–1 based on six studies (n=629). The pooled mean mPAP/CO slope was 1.4 mm·mmHg–1 (figure 2a, table E4). Between-study heterogeneity was not significant (Cochran Q-statistic of 8.6 and I2 value of 44.1%).
FIGURE 2.
a) Normal values of mean pulmonary artery pressure/cardiac output slope (mmHg·min·L–1). Normal values of tricuspid annular plane systolic excursion/systolic pulmonary artery pressure ratio (mm·mmHg–1) at b) rest and c) during exercise. I2 (%): Estimate of relative heterogeneity (percentage of total variation due to heterogeneity); Q: Cochran's Q statistics.
Average E/e′ ratio and PAWP
The estimated ULN for average E/e′ at rest and during exercise were 10.2 and 11.5, respectively, based on four studies (n=504). The pooled mean values for average E/e′ were 6.4 at rest and 7.1 during exercise (figure S3, table E5). Between-study heterogeneity was not significant (Cochran's Q-statistics of 7.1 (rest) and 3.0. (exercise), and I2 values of 57.9% and 0%, respectively).
For PAWP, the estimated ULN at rest and during exercise were 10.3 mmHg and 12.4 mmHg, respectively, based on seven studies (n=311). The pooled mean PAWP was 8.7 mmHg at rest and 10.7 mmHg during exercise (figure S6, table E6). Between-study heterogeneity was significant for both rest and exercise PAWP, with Q-statistics of 19.8 and 29.7 (both p<0.001), and I2 values of 71.2% and 83.2%, respectively.
Pulmonary vascular resistance
The estimated normal ranges for PVR were 0.7–2.2 at rest and 0.6–1.8 WU during exercise, based on five studies (n=554). The pooled mean PVR was 1.5 WU at rest and 1.3 WU during exercise (figure S7, table E7). Between-study heterogeneity was not significant for either condition (Cochran Q-statistics of 2.9 (rest) and 7.8 (exercise), I2 values of 0% and 49.4%, respectively).
Right ventricular function
The estimated normal ranges for TAPSE at rest and at peak exercise were 18.6–30.1 mm and 24.6–36.3 mm, respectively, based on six studies (n=738). The pooled mean TAPSE was 24.8 mm at rest and 31.8 mm during exercise (figure S4, table E8). Between-study heterogeneity was significant for both resting and exercise TAPSE, with Cochran's Q-statistics of 70.8 and 131.1 (both p<0.001), and corresponding I2 values of 92.8% and 95.6%, respectively.
The estimated normal ranges for RV TDI S′ at rest and during exercise were 9.2–19.6 cm·s−1 and 14.9–27.4 cm·s−1, respectively, based on four studies (n=346). The pooled mean RV TDI S′ was 14.3 cm·s−1 at rest and 22.7 cm·s−1 during exercise (figure S8, table E9). Between-study heterogeneity was not significant for resting RV TDI S′ (Cochran Q-statistic of 5.4 and I2 value of 45.4%). In contrast, significant heterogeneity was found for exercise RV TDI S′ with a Cochran Q-statistic of 7.8 (p<0.001) and an I2 value of 97.2%.
TAPSE/sPAP ratio
The estimated normal ranges for the TAPSE/sPAP ratio at rest and during exercise were 0.5–1.7 mm·mmHg–1 and 0.4–1.2 mm·mmHg–1, respectively, based on five studies (n=588). The pooled mean TAPSE/sPAP ratio was 1.2 mm·mmHg–1 at rest and 0.8 mm·mmHg–1 during exercise (figure 2b,c, table E10). Between-study heterogeneity was not significant for either condition, with Cochran Q-statistics of 0.8 (rest) and 1.8 (exercise), and I2 values of 0% for both.
Sensitivity analysis
Sensitivity analyses are presented in table E11. Leave-one-out analysis yielded similar summary mean estimates and heterogeneity measures for all ex-TTE parameters, indicating that individual studies did not significantly influence the overall results or introduce clinically significant variation.
Discussion
The present meta-analysis provides robust estimates of mean values and limits of normal for ex-TTE measurements of the RV-PA-LA unit (figure 3).
FIGURE 3.
Normal limits of exercise Doppler echocardiography (ex-TTE)-derived indices of the right heart, pulmonary circulation and left atrial unit: a systematic review and meta-analysis. a) Upper limit of normal (ULN) of mean pulmonary artery pressure (mPAP)/cardiac output (CO) slope and estimated weighted mean of mPAP/CO slope. b) ULN of average early mitral flow velocity (E) to tissue Doppler imaging early mitral annular velocity (e′) at rest and exercise. c) Lower limit of normal (LLN) of tricuspid annular plane systolic excursion (TAPSE)/systolic pulmonary artery pressure (sPAP) at rest and exercise. TRV: tricuspid regurgitation velocity.
Pulmonary pressures
The ULN for resting and exercise sPAP and mPAP are consistent with the findings from meta-analyses of these measurements obtained via right-heart catheterisation [35–37].
mPAP/CO slope
Since pulmonary pressures are flow-dependent, pulmonary vascular function is more appropriately expressed as multipoint mPAP/CO plots, with the most straightforward representation being the slope of the near-linear relationship between mPAP and CO [8, 38, 39]. Invasive assessments of mPAP/CO relationships have demonstrated an average slope of 1.5 mmHg·min·L–1 with a ULN of 3 mmHg·min·L–1 [8]. These values are corroborated by expert consensus documents [39] and PH guidelines [7]. The present meta-analysis shows that, on average, similar mean values and the same ULN for mPAP/CO relationships can be obtained noninvasively through ex-TTE.
Average E/e′ ratio and PAWP
The reference ranges for the exercise E/e′ ratio are derived from studies with small sample sizes, varying exercise protocols (cycle or treadmill ergometry) and considerable differences in measurement acquisition (e.g. different levels of exercise or post-exercise). Furthermore, there is variability in the sites used for E/e′ measurements (septal, lateral and/or average e′). This meta-analysis confirms that the average E/e′ ratio increases only slightly during exercise, with a ULN of 11.5. This value is lower than the commonly referenced cut-off of 15, which is used in the diagnosis of heart failure with preserved ejection fraction [4]. For comparison, corresponding PAWP values are 16 and 21 mmHg, respectively [8].
Invasive studies in healthy subjects show that PAWP normally does not exceed 25 mmHg during exercise [36] and increases proportionally with cardiac output, with a PAWP/CO slope typically below 2 mmHg·min·L–1 [40, 41]. In a recent ex-TTE study involving 192 healthy subjects, the ULN of the E/e′ as a function of CO slope was 0.6/L−1·min−1, corresponding to a PAWP/CO slope of 2.6 mmHg·min·L–1 [34]. However, E/e′ measurements at heart rates >110 beats per min are technically challenging due to frequent fusion of the E and A waves [34], which complicates comparisons between indirectly calculated and directly measured PAWP/CO slopes during moderate to maximal exercise. Moreover, the equation used to recalibrate PAWP (1.9+1.24×E/e′) may not be fully accurate for very low values below 2 mmHg, since the minimum possible estimate is 1.9 mmHg. This baseline exceeds the PAWP/CO slope observed during recovery.
Pulmonary vascular resistance
Supine exercise is associated with a slight reduction in PVR due to vascular distension in fully recruited lungs [8, 36, 38]. In the present study, the ULN for resting PVR was found to be <2 WU, in line with previous invasive studies summarised in PH guidelines [7]. However, in this meta-analysis, the exercise-induced decrease in PVR did not reach statistical significance (ULN 1.8 WU). This may be related to the inherent limitations in the precision of TTE measurements, particularly in estimating components of the PVR equation. Specifically, underestimation of PAWP from E/e′ during high levels of exercise and potential underestimation of CO may have contributed to this finding.
Accuracy versus precision of ex-TTE measurements
Bland–Altman analyses comparing invasive and TTE measurements of mPAP, PAWP and CO at rest show minimal or no bias, indicating good accuracy, but rather wide limits of agreement, suggesting moderate precision [42]. Similar findings of good accuracy but limited precision have been reported for TTE estimates of sPAP during exercise [43]. A concern with Doppler echocardiography is that it might underestimate cardiac output during exercise [44], which could lead to an artificially elevated slope in mPAP/CO relationships. However, the strong agreement between invasive and ex-TTE-derived average and ULN mPAP/CO slopes makes this hypothesis unlikely. Conversely, it is possible that the E/e′ ratio was underestimated, particularly at high levels of exercise, which could account for the lower slopes of E/e′ versus CO observed in our previous study [34] compared to invasive measurements [40, 41].
Right ventricular function
The lower limits of normal for resting TAPSE (18 mm) and RV TDI S′ velocity (10 cm·s−1) in this meta-analysis are consistent with previously reported values, which set normal thresholds for TAPSE >17 mm and RV TDI S′ velocity >9.5 cm·s−1, as outlined in recent studies and guidelines [45]. During exercise, RV contractility increases, and this can be assessed through TAPSE and S′ measurements [45]. However, the normal limits for exercise-induced changes in TAPSE or RV TDI S′ have not been previously defined. The present findings suggest that an increase in TAPSE <24 mm and in S′ <16 cm·s−1 during exercise may indicate an abnormal RV contractile reserve, reflecting insufficient adaptation of RV systolic function to the elevated pulmonary vascular load, as defined by increased CO and PAP.
TAPSE/sPAP ratio
The gold standard measures of RV contractility and afterload are end-systolic elastance (Ees) and pulmonary arterial elastance (Ea), respectively [46, 47]. The coupling of RV function to afterload, known as RV-PA coupling, is represented by the Ees/Ea ratio, which normally ranges from 1.5 to 5 at rest and remains stable during exercise [46, 47]. However, measurements of Ees and Ea require high-fidelity catheterisation technology, making them impractical for routine clinical use. A useful surrogate for these measurements is the ratio of TAPSE (as an indicator of Ees) to sPAP (as an indicator of Ea). The TAPSE/sPAP ratio has been validated against invasive measurements of Ees and Ea [48, 49] and has proven to be a strong predictor of outcomes in various cardiorespiratory conditions [1, 47].
The normal limits of the TAPSE/sPAP ratio vary widely, with an average value of around 1.0 mm·mmHg–1 and a range from 0.26 to 2.30 mm·mmHg–1 for the extreme limits of normal, as reported in a large population of normal subjects [50]. This wide variability likely reflects the diverse adaptations of RV systolic function to afterload [46, 47]. Prognostically, cut-off values in the range of 0.25 to 0.5 mm·mmHg–1 are typically associated with severe PH and/or heart failure [46, 47] but the ratio can increase to 0.7 mm·mmHg–1 in the absence of elevated pulmonary vascular pressures [1]. Our results show that a resting TAPSE/sPAP ratio of 0.5 mm·mmHg–1 represents a reasonable lower limit of normal. Furthermore, the TAPSE/sPAP ratio decreases during exercise [26] in healthy subjects as well as in patients with various cardiorespiratory conditions [1]. The present meta-analysis suggests that a peak exercise TAPSE/sPAP ratio <0.4 mm·mmHg–1 may be indicative of exercise RV-PA uncoupling.
Impact of demographic and anthropometric factors: evidence from previous studies
The following section summarises evidence from previously published studies to contextualise the interpretation of our findings and is not derived from the results of the present meta-analysis. Exercise haemodynamic measurements of the RV-PA-LA unit are influenced by several anthropometric and demographic factors, including age, body mass index (BMI), sex and race. While resting and exercise mPAP appear independent of sex and geographical origin [35], ageing is consistently associated with higher pulmonary pressures, PAWP and a steeper mPAP/CO slope during exercise [6, 35, 36]. Accordingly, an mPAP/CO slope >3 mmHg·min·L−1 is considered abnormal in individuals younger than 60 years but may fall within normal limits in those older than 60 years [6, 37, 39].
Noninvasive ex-TTE studies corroborate invasive data by demonstrating higher exercise-induced pulmonary pressures (TRV, mPAP, sPAP as well as a steeper mPAP/CO slope) in healthy older subjects (tables E1–E10) [19, 24, 26, 34]. Importantly, although indices of RV systolic performance during exercise (TAPSE, TAPSE/sPAP and RV TDI S′) decline with age [30, 34], exercise PVR and E/e′ do not appear to increase significantly in healthy subjects [24, 34]. Sex-related differences were less pronounced and appear largely attributable to differences in exercise capacity. Men tend to achieve higher workloads during exercise [24] and exhibit higher exercise pulmonary pressures (sPAP and mPAP) [19, 24, 26], accompanied by lower TAPSE/sPAP ratio [26]. However, no sex-specific differences were observed for exercise PVR, E/e′ or TAPSE [24, 26, 34].
Clinical implications
Although invasive measurement of the mPAP/CO slope remains the gold standard for diagnosing exercise PH [6], the reported normal limits of Doppler-derived RV-PA-LA measurements may provide additional value for comprehensive clinical assessment, particularly in community healthcare settings. These reference limits could help identify individuals at risk of exercise-induced PH, facilitating timely referral to specialised centres for confirmatory testing and further management [6].
Advanced echocardiographic methods
Despite growing interest, a significant gap persists in the targeted evaluation of RV adaptation during exercise and its clinical implications. Recent studies in patients with systemic sclerosis have demonstrated that exercise-induced impairments in regional and global RV free-wall strain may provide a more sensitive assessment of early, subclinical RV dysfunction and predict emerging pulmonary vascular disease better than conventional exercise echocardiographic parameters such as TAPSE or RV fractional area change [45]. However, technical and geometric challenges currently limit RV strain analysis during exercise to research settings, and it is not yet recommended for routine clinical use [45, 51]. In this regard, although RA structure and function assessed by strain analysis have shown significant prognostic value in PH, currently RA strain is not advised for clinical practice and studies investigating the impact of the RA response during exercise are still lacking [51]. Interestingly, in a recent study Thal et al. [52] evaluated 46 patients with PH and 19 controls using three-dimensional (3D) echocardiography, pressure–volume catheterisation and right heart catheterisation at rest and during stepwise semi-supine exercise ergometer. They identified two distinct patterns of RV adaptation during exercise, despite similar mPAP/CO slopes, as follows: 1) a homeometric group, characterised by stable RV volumes, increased RV end-systolic elastance and preserved RV–pulmonary arterial coupling (end-systolic/arterial elastance ratio), and 2) a heterometric group, showing marked diastolic and systolic RV dilatation with limited or absent increases in RV contractility, which was associated with clinical worsening and all-cause mortality (log-rank p=0.0006 and p=0.0246, respectively). These compelling findings open new perspectives for understanding RV adaptation during exercise. Nonetheless, further studies are warranted to validate these observations and determine their translational value in clinical practice.
Limitations
Several limitations of the present study should be acknowledged and discussed. 1) The substantial heterogeneity observed across included studies may reflect differences ex-TTE expertise among centres and operators, as well as variability in demographic characteristics of the studied populations. 2) Meta-regression and publication bias analyses could not be performed because fewer than 10 studies were available for most ex-TTE parameters [19]. Consequently, the age dependency of ex-TTE measurements could not be adequately explored and the proposed ex-TTE-derived thresholds should not be uniformly applied across all age groups, as higher exercise-induced pulmonary pressure values may be observed in healthy older individuals [24, 35–37]. 3) Body position represents an additional source of variability in exercise haemodynamic measurements. Compared with the supine position, upright exercise is associated with slightly lower mPAP, PAWP and CO, alongside an increased heart rate and PVR [35, 36, 53]. However, as only studies employing a semi-supine or semi-recumbent position were included, body position is unlikely to have influenced the reported thresholds. 4) Because pulmonary vascular pressures are exercise intensity-dependent, differences in achieved workload could theoretically affect the results. In this context, reporting pulmonary pressures in relation to cardiac output during ex-TTE may help overcome this limitation, allowing a more accurate differentiation between normal and abnormal haemodynamic responses, and should therefore be considered for implementation in clinical practice [6, 36, 37]. Nevertheless, all included studies applied comparable graded semi-supine or semi-recumbent bicycle exercise protocols, and Doppler echocardiographic parameters (except for E/e′) were uniformly acquired at peak exercise (defined as “up to symptom-limited maximal exercise”) supporting the robustness and comparability of the reported normal limits (tables E1–E10). Noninvasive assessment of the pulmonary circulation during exercise remains insufficiently validated against invasive standards. In particular, estimation of PAWP during exercise TTE is subject to notable methodological limitations. Feasibility at peak exercise is reduced, as transmitral flow signals frequently fuse at heart rates >110 beats per min, thereby restricting assessment to submaximal workloads. As a result, proposed upper limits of noninvasive exercise PAWP, typically derived at mid-exercise, are lower than invasive PAWP values measured at peak exercise [37, 54]. 5) Although the TAPSE/sPAP ratio is a useful surrogate of RV–PA coupling, its wide range of normal values may limit applicability for individual patient-level decision-making. Finally, incomplete reporting of ex-TTE variables across studies precluded formal assessment of the impact of missing data.
Conclusions and future directions
This meta-analysis establishes reference limits for ex-TTE indices of the RV-PA-LA unit in healthy individuals, providing a potential noninvasive standard for identifying abnormal responses to exercise. Notably, the ex-TTE-derived pulmonary pressure values closely align with previously reported invasive measurements, supporting their validity. However, further studies employing similarly rigorous methodologies are needed to reduce the variability inherent in noninvasive assessments and to more precisely define the influence of demographic and anthropometric factors on these measurements. In this context, age-adjusted interpretation of ex-TTE-derived normal limits appear particularly important. Standardisation and wider implementation of advanced imaging modalities, such as 3D echocardiography and myocardial strain analysis, may enhance the assessment of RV and RA function, enabling earlier detection of dysfunction and improved risk stratification.
Points for clinical practice
This meta-analysis allowed for a robust definition of normal limits of ex-TTE measurements of the RV-PA-LA unit.
Ex-TTE-derived pulmonary pressures are in keeping with previously reported invasive data.
Question for future research
Normal reference limits represent a potential noninvasive standard for identifying abnormal responses of the RV-PA-LA unit to exercise. Further studies are needed to define the impact of demographic and anthropometric factors on these measurements.
Footnotes
Provenance: Submitted article, peer reviewed.
The systematic review protocol was registered with PROSPERO (https://www.crd.york.ac.uk/prospero/) with identifier: CRD42022375137.
Conflict of interest: The authors declare that there is no conflict of interest.
Support statement: This work was supported by a Ricerca Corrente project of Italian Ministry of Health. Funding information for this article has been deposited with the Open Funder Registry.
Supplementary material
Please note: supplementary material is not edited by the Editorial Office, and is uploaded as it has been supplied by the author.
Supplementary table E1
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Supplementary table E2
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Supplementary table E3
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Supplementary figures S1-S8
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Data availability
This study is a meta-analysis of previously published data and does not involve any new data collection from human participants. Therefore, Institutional Review Board approval was not required. The data are available from the corresponding author on reasonable request.
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Associated Data
This section collects any data citations, data availability statements, or supplementary materials included in this article.
Supplementary Materials
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Supplementary table E1
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Supplementary figures S1-S8
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Data Availability Statement
This study is a meta-analysis of previously published data and does not involve any new data collection from human participants. Therefore, Institutional Review Board approval was not required. The data are available from the corresponding author on reasonable request.