ABSTRACT
Pulmonary artery pressures (PAPs) often become abnormal during exercise in patients with systemic sclerosis (SSc). This study sought to determine whether exercise‐induced pulmonary hypertension (EIPH) assessed by exercise stress echocardiography (ESE) would be associated with subsequent increases in resting PAPs in patients with SSc. Patients with SSc who underwent serial echocardiography > 6 months apart were retrospectively screened (n = 543). Of those, patients undergoing ESE were divided based on the presence of EIPH, defined as estimated mean PAP (mPAP) > 30 mmHg during exercise and a mPAP/cardiac output (CO) > 3 mmHg/L/min. Patients who did not undergo ESE and had a mPAP < 20 mmHg were selected as controls (n = 198). The primary endpoint was a longitudinal change in sPAP from baseline to last follow‐up echocardiography. Compared to controls and patients with non‐EIPH (n = 71), those with EIPH (n = 56) had a higher sPAP at baseline (22 ± 4 mmHg, 28 ± 6 mmHg, and 31 ± 6 mmHg, p < 0.0001). Over a median follow‐up duration of 2.4 years, a longitudinal change in resting sPAP from baseline to follow‐up echocardiography was higher in patients with EIPH than those without (+ 1.2 mmHg vs. −1.0 mmHg, p = 0.048). In a sensitivity analysis excluding 30 patients who received pulmonary vasodilators or heart failure medications after baseline echocardiography, the difference in sPAP change over time between the two groups increased further (+ 2.2 mmHg in the EIPH group vs. −1.6 mmHg in the non‐EIPH group, p = 0.0008). In conclusion, echocardiography‐derived EIPH was associated with a longitudinal increase in sPAP, supporting ESE as a non‐invasive tool for risk stratification in SSc‐PH.
Keywords: echocardiography, exercise‐induced pulmonary hypertension, exercise stress testing, longitudinal change, risk stratification, systemic sclerosis
Development of pulmonary hypertension (PH) is a strong predictor of mortality and morbidity in patients with connective tissue diseases, particularly those with systemic sclerosis (SSc) [1]. Despite the advances in pulmonary vasodilators, clinical outcomes of PH associated with SSc remain poor, with limited therapeutic efficacy compared to idiopathic pulmonary arterial hypertension [2]. The 2022 PH guidelines from the European Society of Cardiology and European Respiratory Society (ESC/ERS) have lowered the previous threshold for PH to mean pulmonary artery pressure (mPAP) > 20 mmHg [3]. This highlights the importance of early disease detection, particularly among patients at high risk for developing overt PH, such as individuals with SSc.
Due to a remarkable reserve capacity in the pulmonary circulation, PAPs and pulmonary vascular resistance (PVR) can remain normal in the early phase of pulmonary vascular disease [4]. However, PAPs often become abnormal during physiologic stress, such as exercise [5, 6, 7, 8]. The 2022 ESC/ERS guidelines have reintroduced exercise PH, as a steeper mPAP/cardiac output (CO) slope assessed by invasive exercise right heart catheterization (RHC) [3]. Exercise PH is associated with reduced exercise capacity, progression to overt PH, and worse clinical outcomes [6, 9, 10, 11]. However, the cost, risk, and requirement for specialized training and equipment involved in exercise RHC may limit the widespread application of exercise PH in practice.
Exercise stress echocardiography is a non‐invasive alternative to exercise RHC, enabling the assessment of both PA pressures and CO during exercise [5, 12, 13, 14]. Due to its broader use, exercise stress echocardiography may represent a potential screening tool to estimate exercise PH [3, 15, 16]. Although the ESC/ERS guidelines recommend exercise stress echocardiography to inform decisions about performing RHC in symptomatic patients with SSc [3], evidence supporting the clinical significance of this test remains limited. Demonstrating the value of exercise stress echocardiography in predicting deterioration of PH could provide strong clinical evidence for this practice.
Accordingly, we examined the association between exercise‐induced pulmonary hypertension (EIPH), as assessed by exercise stress echocardiography, and subsequent changes in resting PAPs in patients with SSc.
1. Methods
1.1. Study Population
Consecutive patients with SSc who underwent standard echocardiography between September 2019 and October 2024 at our hospital were retrospectively identified (Figure 1). The diagnosis of SSc was made by dermatologists or rheumatologists according to the 2013 classification criteria from the American College of Rheumatology/European League against Rheumatism [17]. From this group, patients with two or more echocardiographic examinations in a compensated state that were performed minimum of > 6 months from one another (baseline and follow‐up) were identified. When patients had multiple echocardiography after baseline, the most recent study was used as follow‐up evaluation.
FIGURE 1.
Patient enrollment flow chart. Among a total of 543 patients with SSc (1575 echocardiographic studies), 145 patients who underwent exercise stress echocardiography were screened. After excluding 18 patients, 56 met the definition of EIPH (EIPH group), and 71 did not (non‐EIPH group). Of 398 patients who did not undergo exercise stress echocardiography, 198 were identified as controls. EIPH, exercise‐induced pulmonary hypertension; mPAP, pulmonary artery mean pressure; sPAP, pulmonary artery systolic pressure; SSc, systemic sclerosis.
To assess the impact of EIPH on a subsequent change in PAPs, patients who underwent exercise stress echocardiography for the evaluation of dyspnea or upper normal or mildly elevated tricuspid regurgitant (TR) velocity were also identified from this cohort. Patients were divided into two groups according to the presence of EIPH. From patients who did not undergo exercise stress echocardiography, those with baseline mPAP < 20 mmHg were selected as controls. Patients with an ejection fraction of < 50%, mPAP ≥ 25 mmHg and PVR ≥ 3 WU by RHC, TR velocity ≥ 2.8/s, infiltrative, restrictive, or hypertrophic cardiomyopathies, and younger than 20 years old were excluded.
1.2. Echocardiographic Assessments at Baseline and Follow‐Up
Two‐dimensional and Doppler echocardiography were performed by experienced sonographers according to the recommendation from the American Society of Echocardiography and the European Association of Cardiovascular Imaging [18]. LV systolic function was assessed by left ventricular (LV) ejection fraction. LV diastolic function was assessed using transmitral velocities and septal E/e′ ratio. The left atrial (LA) volume was calculated using the disk method. LA volume and LV mass were then indexed to the body surface area. Right atrial pressure (RAP) was estimated from the diameter of the inferior vena cava and its respiratory change [8, 18]. Pulmonary artery systolic pressure (sPAP) was then calculated as 4 × (peak TR velocity)2 + estimated RAP. The PA mean pressure (mPAP) was calculated as 0.61 × sPAP + 2 [19]. Right ventricular (RV) systolic function was assessed by tricuspid annular plane systolic excursion and systolic tricuspid valve tissue velocity. Stroke volume (SV) was determined from the LV outflow dimension and pulse wave Doppler profile. In cases without pulse wave Doppler data, SV was estimated from the biplane disc methods if there was no significant mitral regurgitation. Cardiac output (CO) was calculated from the product of heart rate and SV [13]. The reproducibility of sPAP was assessed in 20 patients from a separate cohort. Intra‐ and inter‐observer agreement was evaluated after the same observer and another experienced reader repeated the analysis using intraclass correlation coefficients (ICCs).
1.3. Exercise Stress Echocardiography
Exercise stress echocardiography was performed in a semi‐supine position, as previously reported [20, 21, 22, 23]. Exercise started at 20 watts (W) for 5 min, with increments of 20 W in 3 min stages until participant‐reported exhaustion. Key echocardiographic parameters were obtained at baseline and at each stage of exercise, including TR velocity, LV outflow tract pulse wave Doppler, and inferior vena cava morphology. The EIPH was defined as an estimated mPAP > 30 mmHg during peak exercise, with a ratio of mPAP/CO at peak exercise > 3 mmHg/L/min [24].
1.4. Primary Endpoint
The primary endpoint was a longitudinal change in resting sPAP from baseline to follow‐up echocardiographic examinations between patients with and without EIPH.
1.5. Statistical Analysis
Data are reported as mean (standard deviation), median (interquartile range: IQR), or number (%) unless otherwise specified. Between‐group differences were compared using unpaired t‐test, Wilcoxon rank‐sum test, one‐way analysis of variance, the Kruskal–Wallis test, or Chi‐square test, as appropriate. Tukey's honestly significant difference test or the Steel–Dwass test was used to adjust for multiple testing in continuous variables. Categorical variables for multiple testing were compared with the Chi‐squared test with Bonferroni correction. Within‐group differences were compared by paired t‐test or Wilcoxon signed‐rank test. Multivariable linear regression analyses were used to determine whether the presence of EIPH independently associated with changes in sPAP after adjusting for confounders. Subgroup analyses of the primary endpoints were performed based on sex (men vs. women) and SSc subtype (diffuse vs. limited). All tests were two‐sided, with statistical significance set at p < 0.05. All statistical analyses were performed using JMP 17.0.0 (SAS Institute, Cary, NC, USA).
2. Results
2.1. Baseline Characteristics
Figure 1 summarizes the patient enrollment flow chart. Among a total of 543 patients with SSc (1575 echocardiographic studies), 145 patients who underwent exercise stress echocardiography were screened. After excluding 18 patients, 56 met the EIPH definition (EIPH group), and 71 did not (non‐EIPH group). Of 398 patients who did not undergo exercise stress echocardiography, 198 were identified as controls.
Participants were predominantly women, with no differences in the proportion of sex among the three groups (Table 1). Compared to controls, patients with EIPH were older and had a higher frequency of interstitial lung disease and use of diuretics. Approximately half of the patients were treated with prostacyclins, with no difference among groups. The prevalence of diabetes was the highest in the EIPH group. There were no differences in the prevalence of limited cutaneous SSc (lcSSc) type, disease duration, or positive rates of anticentromere antibody or anti‐U1 ribonucleoprotein antibody, or natriuretic peptide levels among the groups.
TABLE 1.
Baseline characteristics.
| Controls (n = 198) | Non‐EIPH (n = 71) | EIPH (n = 56) | p value | |
|---|---|---|---|---|
| Age (years) (n = 325) | 62 ± 12 | 63 ± 12 | 67 ± 9* | 0.01 |
| Female, n (%) (n = 325) | 179 (90) | 65 (92) | 48 (86) | 0.54 |
| Body mass index (kg/m2) (n = 325) | 21.5 ± 3.7 | 21.5 ± 3.7 | 21.6 ± 3.4 | 0.98 |
| Limited cutaneous type, n (%) (n = 264) | 132 (80%) | 37 (67%) | 31 (70%) | 0.11 |
| Disease duration (years) (n = 311) | 7.1 (3.1, 13.8) | 8.8 (3.5, 15.8) | 6.4 (3.2, 11.7) | 0.57 |
| Anti‐centromere positive, n (%) (n = 310) | 101 (53%) | 35 (53%) | 21 (40%) | 0.27 |
| Anti‐U1 RNP positive, n (%) (n = 288) | 24 (13%) | 10 (16%) | 10 (23%) | 0.30 |
| Follow‐up duration (years) (n = 325) | 2.3 (1.2, 3.3) | 2.6 (1.4, 3.4) | 2.7 (2.0, 3.4) | 0.32 |
| Indication of ESE (dyspnea, upper normal TR velocity), (%) | — | (89%, 11%) | (80%, 20%) | 0.19 |
| Comorbidities | ||||
| Hypertension, n (%) (n = 325) | 49 (25) | 26 (37) | 20 (36) | 0.09 |
| Diabetes mellitus, n (%) (n = 325) | 11 (6) | 3 (4) | 11 (20)*, # | 0.004 |
| Dyslipidemia, n (%) (n = 325) | 46 (23) | 14 (20) | 21 (38) | 0.06 |
| Atrial fibrillation, n (%) (n = 325) | 3 (2) | 0 (0) | 0 (0) | 0.22 |
| Coronary disease, n (%) (n = 325) | 10 (5) | 2 (3) | 1 (2) | 0.43 |
| Interstitial lung disease, n (%) (n = 325) | 69 (35) | 28 (39) | 31 (55)* | 0.02 |
| Medications | ||||
| ACEI or ARB, n (%) (n = 325) | 22 (11) | 13 (18) | 4 (7) | 0.14 |
| Beta‐blocker, n (%) (n = 325) | 11 (6) | 1 (1) | 3 (5) | 0.26 |
| Calcium channel blockers, n (%) (n = 325) | 38 (19) | 21 (30) | 12 (21) | 0.21 |
| Diuretics, n (%) | 1 (1) | 1 (1) | 4 (7)* | 0.02 |
| ERAs, n (%) (n = 325) | 16 (8) | 6 (8) | 4 (7) | 0.96 |
| PDE5 inhibitors, n (%) (n = 325) | 0 (0) | 0 (0) | 0 (0) | — |
| Prostacyclin, n (%) (n = 325) | 93 (47) | 34 (48) | 31 (55) | 0.53 |
| Laboratories | ||||
| BNP (pg/mL) (n = 158) | 26 (14, 49) | 35 (21, 64) | 40 (15, 72) | 0.07 |
| NT‐pro BNP (pg/mL) (n = 97) | 100 (44, 149) | 92 (64, 133) | 111 (50, 422) | 0.24 |
| Elevated NPs, n (%) (n = 224) | 42 (35) | 23 (42) | 25 (51) | 0.15 |
| Hemoglobin (g/dL) (n = 322) | 13.0 ± 1.2 | 12.7 ± 1.7 | 12.4 ± 1.6* | 0.02 |
| eGFR (mL/min/1.73m2) (n = 320) | 71 ± 19 | 73 ± 21* | 73 ± 20 | 0.81 |
| CRP (mg/dL) (n = 274) | 0.5 (0.2, 1.6) | 0.9 (0.5, 3.2)* | 0.9 (0.4, 1.7) | 0.004 |
Note: Data are mean ± SD, median (interquartile range), or n (%).
Abbreviations: ACEI, angiotensin‐converting enzyme inhibitors; ARB, angiotensin‐receptor blockers; BNP, B‐type natriuretic peptide; CRP, C‐reactive protein; eGFR, estimated glomerular filtration rate; EIPH, exercise‐induced pulmonary hypertension; ERA, Endothelin receptor antagonist; NP, natriuretic peptide; NT‐proBNP, N‐terminal pro B‐type natriuretic peptide; PDE5, phosphodiesterase type 5 inhibitor; SGLT2, sodium glucose cotransporter 2; TR, tricuspid regurgitant.
p < 0.05 vs. controls.
p < 0.05 vs. non‐EIPH.
LV mass index and LA volume index were larger, and RAP was higher in patients who underwent exercise stress echocardiography than in controls (Table 2). The control group exhibited normal TR velocity (2.2 ± 0.2 m/s), sPAP (22 ± 4 mmHg), and mPAP (16 ± 2 mmHg). Compared to the control group and the non‐EIPH patient group, the EIPH patient group demonstrated higher (upper normal) PAPs, with a mean TR velocity of 2.6 ± 0.3 m/s, sPAP of 31 ± 6 mmHg, and mPAP of 21 ± 4 mmHg. The intra‐ and inter‐observer ICCs for sPAP were 0.86 and 0.89.
TABLE 2.
Baseline echocardiographic measures.
| Controls (n = 198) | Non‐EIPH (n = 71) | EIPH (n = 56) | p value | |
|---|---|---|---|---|
| IVS thickness (mm) (n = 325) | 8.6 ± 1.6 | 8.8 ± 1.6 | 9.1 ± 1.5 | 0.11 |
| PW thickness (mm) (n = 325) | 8.3 ± 1.5 | 8.8 ± 1.1* | 8.7 ± 1.4 | 0.02 |
| LV diastolic diameter (mm) (n = 325) | 42 ± 4 | 42 ± 5 | 42 ± 5 | 0.88 |
| LV systolic diameter (mm) (n = 325) | 26 ± 3 | 26 ± 4 | 26 ± 4 | 0.89 |
| LV mass index (g/m2) (n = 325) | 71 ± 19 | 77 ± 18* | 77 ± 22* | 0.03 |
| LA volume index (mL/m2) (n = 325) | 23 (19, 27) | 25 (20, 33)* | 27 (21, 35)* | 0.004 |
| LV end‐diastolic volume (mL) (n = 130) | 62 ± 18 | 61 ± 13 | 61 ± 21 | 0.96 |
| LV end‐systolic volume (mL) (n = 130) | 21 ± 7 | 20 ± 5 | 21 ± 11 | 0.52 |
| LV ejection fraction (%) (n = 325) | 68 ± 6 | 69 ± 5 | 68 ± 7 | 0.67 |
| E‐wave (cm/s) (n = 325) | 69 ± 17 | 74 ± 18 | 70 ± 21 | 0.13 |
| Septal mitral e′ (cm/s) (n = 325) | 7.5 ± 2.7 | 7.2 ± 2.5 | 6.9 ± 2.4 | 0.27 |
| Septal mitral s′ (cm/s) (n = 325) | 7.5 ± 1.4 | 7.5 ± 1.3 | 7.6 ± 1.8 | 0.73 |
| E/e′ ratio (septal) (n = 325) | 10.0 ± 3.3 | 11.3 ± 3.9* | 11.1 ± 4.9 | 0.01 |
| Stroke volume (mL) (n = 209) | 58 ± 15 | 60 ± 16 | 58 ± 17 | 0.96 |
| Cardiac output (L/min) (n = 209) | 4.0 ± 1.3 | 4.3 ± 1.4 | 4.2 ± 1.2 | 0.43 |
| TAPSE (mm) (n = 325) | 21.7 ± 3.3 | 21.8 ± 3.9 | 22.2 ± 3.9 | 0.71 |
| TV s′ (cm/s) (n = 325) | 12.3 ± 2.5 | 12.8 ± 2.6 | 12.4 ± 2.5 | 0.35 |
| TR velocity (m/s) (n = 325) | 2.2 ± 0.2 | 2.5 ± 0.3* | 2.6 ± 0.3*, # | < 0.0001 |
| sPAP (mmHg) (n = 325) | 22 ± 4 | 28 ± 6* | 31 ± 6*, # | < 0.0001 |
| mPAP (mmHg) (n = 325) | 16 ± 2 | 19 ± 4* | 21 ± 4*, # | < 0.0001 |
| RAP (mmHg) (n = 325) | 3.1 ± 0.7 | 3.4 ± 1.4* | 3.5 ± 1.4* | 0.02 |
| Peak exercise | ||||
| TR velocity (m/s) (n = 127) | — | 2.8 ± 0.3 | 3.4 ± 0.2# | < 0.0001 |
| mPAP (mmHg) (n = 127) | — | 25 ± 4 | 34 ± 4# | < 0.0001 |
| mPAP/CO (mmHg/L/min) (n = 127) | — | 4.1 ± 1.5 | 5.1 ± 1.5# | 0.0002 |
Note: Data are mean ± SD or median (interquartile range).
Abbreviations: CO, cardiac output; E/e′ ratio, the ratio of early diastolic mitral inflow to mitral annular tissue velocities; IVS, interventricular septum; LA, left atrial; LV, left ventricular; mPAP, mean pulmonary artery pressure; PW, posterior wall; sPAP, systolic pulmonary artery pressure; TAPSE, tricuspid annular plane systolic excursion; TV, tricuspid valvular; and other abbreviations as in Table 1.
p < 0.05 vs. controls.
p < 0.05 vs. non‐EIPH.
There were no differences in LV structure, systolic and diastolic function, or RV function between patients with and without EIPH. By definition, the differences in TR velocity and mPAP between the groups increased further during ergometry exercise, with a higher mPAP/CO ratio in the EIPH patients than in non‐EIPH patients.
2.2. Longitudinal Changes in sPAP in Systemic Sclerosis
The median time between baseline and follow‐up echocardiographic examinations was 2.4 (IQR 1.3–3.3) years, with no difference among the three groups (p = 0.32). In the control group, there was no longitudinal change in sPAP over this period (22 ± 4 mmHg to 23 ± 5 mmHg, p = 0.06). Compared to the non‐EIPH group (mean change −1.0 mmHg), the change in sPAP was higher in the EIPH group (mean change +1.2 mmHg, p = 0.048) (Figure 2). The change in sPAP relative to the follow‐up period was −0.4 (−2.9, 1.2) mmHg/year in the non‐EIPH group and 0.4 (−0.7, 1.8) mmHg/year in the EIPH group, with a marginal difference between the two groups. The presence of EIPH remained a significant determinant of the change in sPAP over time after adjusting for age, sex, interstitial lung disease, baseline mPAP, use of pulmonary vasodilators or heart failure medications, and elevated natriuretic peptides. Pulmonary vasodilators or heart failure medications were initiated in 30 patients after exercise stress echocardiography (endothelin receptor antagonist [n = 6], soluble guanylate cyclase stimulator [n = 1], sodium‐glucose cotransporter‐2 inhibitor [n = 6], mineralocorticoid receptor antagonist [n = 12], angiotensin receptor blocker or angiotensin receptor neprilysin inhibitor [n = 2], and loop diuretic [n = 3]). In a sensitivity analysis excluding the 30 patients, the difference in the change in sPAP between patients with and without EIPH increased further (mean change +2.2 mmHg [+1.3 mmHg per year] in the EIPH group vs. −1.6 mmHg [−1.7 mmHg per year] in the non‐EIPH group, p = 0.0008).
FIGURE 2.
Longitudinal changes in pulmonary artery systolic pressure. Compared to the non‐EIPH group, the change in resting sPAP over time was higher in the EIPH group (mean change +1.2 mmHg vs. mean change −1.0 mmHg, #p = 0.048). Bars represent 95% confidence intervals. Abbreviations as in Figure 1.
Of all the participants (n = 325), 73 (22%) had an mPAP greater than 20 mmHg at baseline. After excluding the 73 patients, there was a gradual increase in the proportion of patients who developed mPAP > 20 mmHg at follow‐up, with 13 (7%) in the control group, 4 (11%) in the non‐EIPH group, and 7 (37%) in the EIPH group, respectively (Figure 3).
FIGURE 3.
The proportion of patients who developed mPAP > 20 mmHg at follow‐up. Of 252 patients who had mPAP ≤ 20 mmHg at baseline, the proportion of patients who developed mPAP > 20 mmHg at follow‐up assessment was higher in the EIPH group than in the control group (*p = 0.0004). Abbreviations as in Figure 1.
When analyzing patients who underwent exercise stress echocardiography, longitudinal changes in sPAP were greater in diffuse cutaneous SSc (dcSSc) than in lcSSc (Figure 4A) and in men than in women (Figure 4B).
FIGURE 4.
Differences in longitudinal changes in pulmonary artery systolic pressure according to patients' characteristics. In patients who underwent exercise stress echocardiography, longitudinal changes in sPAP were greater in men than in women (A) and in dcSSc than in lcSSc (B). Bars represent 95% confidence intervals. dc, diffuse cutaneous; lc, limited cutaneous. Abbreviations as in Figure 1.
2.3. Longitudinal Changes in Biventricular Function
In a subset of participants with available paired data, longitudinal changes in vital signs, left heart structure and function, and right ventricle (RV) function were examined. Over the median follow‐up duration of 2 years, systolic and diastolic blood pressure and heart rate remained unchanged in each group (Table 3). There was a significant reduction in CO in SSc patients in the EIPH group during this period (Figure 5A), with a mild decrease in mitral e′ velocity in both EIPH and non‐EIPH groups. The CO reduction along with the increase in sPAP over time was associated with an increase in mPAP/CO ratio in the EIPH group (Figure 5B), suggesting worsening pulmonary vascular disease. In contrast, E/e′ ratio, a surrogate of LA pressure, did not change over time.
TABLE 3.
Vital signs and echocardiographic parameters at baseline and follow‐up assessments.
| Controls | Non‐EIPH | EIPH | ||||
|---|---|---|---|---|---|---|
| Baseline | Follow‐up | Baseline | Follow‐up | Baseline | Follow‐up | |
| Heart rate (bpm) (n = 314) | 74 ± 16 | 74 ± 14 | 79 ± 14 | 79 ± 17 | 78 ± 15 | 75 ± 16 |
| Systolic BP (mmHg) (n = 314) | 132 ± 21 | 132 ± 20 | 132 ± 22 | 133 ± 22 | 140 ± 25 | 137 ± 26 |
| Diastolic BP (mmHg) (n = 314) | 74 ± 12 | 72 ± 12 | 73 ± 15 | 72 ± 15 | 75 ± 14 | 73 ± 12 |
| LV mass index (g/m2) (n = 321) | 71 ± 19 | 69 ± 18 | 76 ± 18* | 75 ± 18 | 77 ± 22 | 76 ± 19 |
| LA volume index (mL/m2) (n = 314) | 23 (19, 27) | 24 (10, 30)* | 25 (20, 34) | 27 (21, 32) | 27 (21, 35) | 26 (22, 34) |
| LV ejection fraction (%) (n = 324) | 68 ± 6 | 68 ± 6 | 69 ± 5 | 66 ± 7* | 68 ± 7 | 66 ± 7 |
| E‐wave (cm/s) (n = 320) | 69 ± 17 | 69 ± 18 | 74 ± 18 | 70 ± 21 | 70 ± 20 | 69 ± 24 |
| Septal mitral e′ (cm/s) (n = 321) | 7.5 ± 2.7 | 7.4 ± 2.5 | 7.1 ± 2.4 | 6.6 ± 2.4* | 6.8 ± 2.3 | 6.2 ± 2.0** |
| E/e′ ratio (septal) (n = 319) | 10.0 ± 3.3 | 10.1 ± 3.2 | 11.3 ± 3.9 | 12.0 ± 6.3 | 11.2 ± 5.0 | 11.9 ± 5.9 |
| Cardiac output (L/min) (n = 191) | 4.1 ± 1.3 | 3.9 ± 1.1 | 4.3 ± 1.4 | 4.2 ± 1.4 | 4.2 ± 1.2 | 3.7 ± 1.1* |
| TAPSE (mm) (n = 310) | 21.8 ± 3.3 | 21.2 ± 3.5* | 21.8 ± 3.8 | 20.8 ± 3.6 | 22.0 ± 3.9 | 20.8 ± 4.5 |
| TV s′ (cm/s) (n = 307) | 12.3 ± 2.5 | 12.2 ± 2.1 | 12.8 ± 2.5 | 12.5 ± 2.2 | 12.4 ± 2.5 | 11.9 ± 2.3 |
| mPAP/CO (mmHg/L/min) (n = 191) | 4.1 ± 1.4 | 4.4 ± 1.5* | 4.8 ± 1.7 | 4.9 ± 1.8 | 5.2 ± 1.5 | 6.3 ± 2.2* |
FIGURE 5.
Longitudinal changes in cardiac output and mPAP/CO. (A) In a subset of participants with paired data (n = 191), there was a reduction in cardiac output in the EIPH group during the observation period. (B) Similarly, mPAP/cardiac output ratio increased over time in the EIPH group. Bars represent 95% confidence intervals. Abbreviations as in Figure 1.
3. Discussion
EIPH, defined by a mPAP/CO slope > 3 mmHg/L/min by exercise RHC between rest and exercise, has been reintroduced in the 2022 ESC/ERS PH guidelines [3]. Invasively measured EIPH has been well studied and is associated with reduced exercise capacity, abnormal RV function, and poorer clinical outcomes [6, 9, 10]. One study reported that patients with EIPH, defined as mPAP/CO slope > 3 mmHg/L/min, exhibited exercise tolerance, ventilatory efficiency, and RV‐PA coupling intermediate between patients without PH and those with overt PH [25]. Other studies showed that patients with EIPH had lower survival or transplant‐free survival than those without [26, 27]. However, studies using exercise stress echocardiography have been limited, and there has been a lack of data regarding the clinical relevance of EIPH in patients with SSc as determined by noninvasive exercise echocardiography.
In the current study, we utilized exercise stress echocardiography to assess the impact of noninvasive EIPH on longitudinal changes in sPAP over time. Over a median duration of 2 years, SSc patients with EIPH demonstrated a higher increase in sPAP during this period than those without (mean change +1.2 mmHg vs. mean change −1.0 mmHg, p = 0.048). The result seems consistent with previous studies [16, 28]. Kusunose et al. demonstrated a higher rate of longitudinal change in mPAP (1.0 ± 0.4 mmHg per year) in patients with connective tissue disease (70% with SSc) who had a higher mPAP/CO slope by exercise stress echocardiography than those with a lower mPAP/CO slope [28]. These results support the role of exercise stress echocardiography as a non‐invasive tool for early risk stratification in SSc patients with upper normal TR velocity.
In the present study, the increase in sPAP was mild, even in the EIPH group. This may be due to the intervention by pulmonary vasodilators or HF therapies, which could have underestimated the increase in sPAP over time. A sensitivity analysis excluding patients who received these interventions revealed an even higher rate of sPAP increase in the EIPH group than in the non‐EIPH group ( + 1.3 mmHg per year vs. −1.7 mmHg per year, p = 0.0006), which supports this speculation. We believe that this magnitude of sPAP increase may be clinically meaningful. This is because a rate of mPAP increase (1.0 ± 0.4 mmHg per year) observed in the previous study was associated with the development of overt resting PH [28]. Indeed, we demonstrated that the proportion of patients who developed mPAP > 20 mmHg at follow‐up was higher in the EIPH group than in the non‐EIPH group. Furthermore, there could be treatment bias in this study, whereby the intervention group consisted of patients whom the clinician considered to be in worse condition. If they had not received treatment, their sPAP might have increased further over time.
From a pathophysiological viewpoint, PH associated with SSc can be complex and heterogeneous. This includes pulmonary vascular remodeling due to connective tissue diseases, lung disease, hypoxia, as well as PH due to LHD [5]. In the EIPH group, an increase in sPAP over time was associated with an increase in the mPAP/CO ratio and no change in the E/e′ ratio and LA volume index. Given the high prevalence of interstitial lung disease in the EIPH group, these results might suggest that the increase in sPAP is primarily driven by pre‐capillary component or pulmonary vascular remodeling rather than increased LA pressure or LHD [29]. Pulmonary vascular remodeling is likely a long‐term process, and therefore, a longer follow‐up period may be necessary to detect the effect of EIPH on the trajectory of PAPs. On the contrary, PAPs could increase to a greater extent if a patient developed LHD over time.
The current findings do not allow us to determine whether EIPH should be a therapeutic target in SSc patients with upper normal TR velocity. Rather, they emphasize the importance of regular echocardiographic surveillance for SSc patients with EIPH [30]. The ESC/ERS guidelines recommend annual evaluation of the risk of having PH for patients with SSc (Class I) [3]. The present results and others may support this practice [28]. We further found that longitudinal increases in sPAP were even greater in dcSSc than in lcSSc and in men than in women when limiting patients who underwent exercise stress echocardiography (baseline sPAP 29 ± 6 mmHg and mPAP 20 ± 4 mmHg). The classic form of PH in SSc is believed to develop after an extended period of lcSSc with positive anti‐centromere antibodies. In contrast, dcSSc has been reported to be associated with early PAP elevation [31]. Other studies reported that men with SSc were at a higher risk of PH progression than women and had a worse prognosis [32, 33, 34]. Our findings and others suggest that careful surveillance is necessary for patients with dcSSc or men.
3.1. Clinical Implications
Identification of PH is critical in the management of patients with SSc due to its high prevalence, as well as its high mortality and morbidity rates. Although echocardiography is the first‐line tool to screen PH, its sensitivity is not perfect [35]. The ESC/ERS PH guidelines recommend exercise stress echocardiography to help determine whether to perform RHC in symptomatic patients with SSc, yet it has not been established how this test should be utilized in practice [3]. Based on the current results and others demonstrating the association between EIPH and poor clinical outcomes and progression of PH [11, 26, 27, 28]. RHC may be considered for symptomatic patients with SSc who have EIPH on exercise stress echocardiography; if RHC is not performed, careful and regular echocardiographic surveillance may be necessary.
3.2. Limitations
This was a retrospective study conducted at a tertiary referral center. All participants were referred to echocardiography, introducing a selection bias. PAPs were not directly measured by RHC, but were estimated by echocardiography [36]. Echocardiography was not performed at prespecified intervals. Following exercise stress echocardiography, only a few patients underwent RHC for suspected incident PH. This limited a confirmation of PH and might decrease the chance of detecting incident PH. Data on RV structure or RV deformation analysis were not available. The ESC/ERS guidelines define EIPH as assessed by exercise RHC [3]. In this study, however, it was estimated by exercise stress echocardiography. The initiation of vasodilators or HF medications between echocardiographic examinations might underestimate longitudinal changes in PA pressures. Future prospective studies with prespecified intervals are needed to confirm the present results.
4. Conclusions
The presence of EIPH, as determined by exercise stress echocardiography, in SSc patients with upper normal TR velocity was associated with a higher longitudinal increase in sPAP over time, supporting the role of exercise stress echocardiography as a non‐invasive tool for early risk stratification in SSc‐related PH. Further studies are needed to determine the clinical relevance of EIPH in patients with SSc, as well as the optimal management strategy for this condition.
Author Contributions
Kazuki Kagami: conceptualization and methodology; investigation and writing original draft. Sei‐Ichiro Motegi: conceptualization and methodology. Masaru Obokata: conceptualization and methodology; funding acquisition; review and editing. Naoki Yuasa: data curation. Tomonari Harada: data curation. Yuta Tani: data curation. Yukie Endo: data curation. Noriaki Takama: review and editing. Naoki Wada: review and editing. Hideki Ishii: review and editing.
Ethics Statement
The study was approved by our Institutional Review Board with the waiver of consent (HS2024‐024), and was performed in accordance with the Declaration of Helsinki. All authors have read and agreed to the manuscript as written.
Conflicts of Interest
Dr. Obokata received speaker honoraria from Novartis, Otsuka Pharmaceutical, AstraZeneca Inc., Eli Lily, and Nippon Boehringer‐Ingelheim. Dr. Ishii received lecture fees from AstraZeneca Inc., Bayer Pharmaceutical Co. Ltd., Boehringer Ingelheim Japan, Bristol‐Myers Squibb Inc., Daiichi‐Sankyo Pharma Inc., MSD K. K., Mitsubishi Tanabe Pharma Co. Ltd., Mochida Pharmaceutical Co. Ltd., Novartis Japan, and Pfizer Japan Inc. Dr. Motegi received speaker honoraria from AbbVie, Sanofi, Eli Lilly & Co., Otsuka Pharmaceutical, Bristol Myers Squibb, Taiho Pharmaceutical, Janssen Pharma, Leo Pharma, Daiichi Sankyo, Kaken Pharma, Sun Pharma, Eisai, Pfizer Japan, and Maruho Co. All other authors declare no conflicts of interest. Dr. Wada received lecture fees from GlaxoSmithKline plc, Teijin Pharma, and Daiichi‐Sankyo Pharma Inc.
Guarantor
MO takes the responsibility for the content of the manuscript, including the data and analysis.
Acknowledgments
Dr. Obokata received research grants from the Japanese College of Cardiology, AMI Inc., Nippon Boehringer‐Ingelheim, Janssen Pharmaceutical K.K., JSPS KAKENHI (21K16078, 25K11404, 25K14374), and AMED (JP25jm0210104, JP256f0137008). Dr. Harada received research grants from the Bayer Academic Support. Dr. Ishii received scholarship funds or Donations from Abbott Medical Japan, Boehringer Ingelheim Japan, Bristol‐Myers Squibb Inc., and Pfizer Japan Inc. Dr. Motegi received research grants from Sun Pharma, Taiho Pharmaceutical, Novartis, Eli Lilly, and Maruho Co.
Data Availability Statement
The data underlying this article cannot be shared publicly due to the privacy of individuals that participated in the study.
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Associated Data
This section collects any data citations, data availability statements, or supplementary materials included in this article.
Data Availability Statement
The data underlying this article cannot be shared publicly due to the privacy of individuals that participated in the study.