Association of exercise-induced pulmonary hypertension with nailfold capillary density in systemic sclerosis: a single-center retrospective observational study

Abstract

Objectives

Exercise-induced pulmonary hypertension (exercise PH) is instrumental in the early detection of pulmonary arterial hypertension. However, the prevalence and specific characteristics of exercise PH in systemic sclerosis (SSc), as well as factors that might facilitate its identification, remain inadequately understood. We investigated the clinical profiles of SSc patients diagnosed as PH, exercise PH, or non-PH.

Methods

This study included 50 patients with SSc and exercise intolerance. We compared the physical examination findings, biochemistry tests, echocardiography, respiratory function tests, and resting and exercise right heart catheterization outcomes of the PH, exercise PH, or non-PH groups.

Results

In a cohort of 50 patients with SSc and exercise intolerance, 30.0% were diagnosed with PH, and 44.0% exhibited exercise PH. Symptoms such as exertional dyspnea and palpitations were more prevalent in the exercise PH group compared to the non-PH group. Furthermore, a lower nailfold capillary density was observed in the exericse PH group. However, there was no difference between the two groups in terms of NT-proBNP level, serum uric acid, inflammatory findings, %DLco%, FVC/%DLco ratio, six-minute walking distance, or peak tricuspid regurgitant velocity. exercise PH was detected in 87.5% of patients presented all with exertional dyspnoea, exertional palpitations, and capillary density ≤ 7/mm. In many patients within the exercise PH group, the pulmonary artery wedge pressure/cardiac output slope exceeded 2 mmHg/L/min, indicating latent heart failure with preserved ejection fraction (HFpEF).

Conclusion

In our study, 44.0% of patients with SSc and exercise intolerance exhibited exercise PH, with many potentially having HFpEF. Decreased nailfold capillary density, exertional dyspnea, and palpitations were indicative markers useful for exercise PH screening.

Supplementary Information

The online version contains supplementary material available at 10.1186/s13075-025-03633-5.

Key message

exercise PH was present in 44.0% of patients with SSc and exercise intolerance.

Most of SSc patients with exercise PH may have had HFpEF.

exercise PH was found in 87.5% of SSc patients with dyspnoea, palpitations, and capillary density ≤ 7.

Supplementary Information

The online version contains supplementary material available at 10.1186/s13075-025-03633-5.

Introduction

Early concomitant pulmonary vasodilator therapy greatly improves the survival prognosis of patients with pulmonary arterial hypertension (PAH) [1]. Therefore, early diagnosis of PAH is considered important [2]. Under these circumstances, the definitions of pulmonary hypertension (PH) were revised in the European Society of Cardiology/European Respiratory Society (ESC/ERS) 2022 guidelines [3], with a focus on early detection of pre-capillary PH. The definitions were lowered to a resting mean pulmonary arterial pressure (mPAP) of > 20 mmHg and pulmonary vascular resistance (PVR) of > 2 Wood units. A new concept of exercise-induced exertional pulmonary hypertension (exercise PH) based on exercise right heart catheterization (exercise RHC) was also defined. This enables patients to be diagnosed with exercise PH if the mean pulmonary arterial pressure/cardiac output (mPAP/CO) slope is > 3 mmHg/L/min, even if they do not meet the definitions at rest. Exercise intolerance (latent pulmonary vascular bed reduction) is the first stage of PH. Pulmonary circulation modeling allows for the estimation of pulmonary vascular obstruction based on mPAP and cardiac output. According to this model, when cardiac output is 5 L/min, an mPAP of 25 mmHg—the previous diagnostic threshold for PAH—corresponds to approximately 50% vascular obstruction (or the hemodynamic equivalent of a pneumonectomy), whereas the revised threshold of 20 mmHg corresponds to an estimated obstruction of 20–25% [4]. As elevated resting mPAP only appears after the disease has progressed, the diagnosis of exercise PH is important for assessing the patient’s condition and considering treatment [5, 6].

Systemic sclerosis (SSc) is a disease that causes impaired blood flow and fibrosis of organs throughout the body owing to autoimmune abnormalities and vascular lesions. The concomitant presence of PH and interstitial lung disease (ILD) is directly linked to the survival prognosis of patients with SSc. As described above, therapeutic outcomes for CTD-PAH are improving, but the survival prognosis for SSc-associated PH is poor compared with that for other forms of CTD-PAH [7, 8]. This may be attributed to the fact that, beyond mere PAH, there may be compromised dilation owing to myocardial fibrosis and PH due to lesions in the pulmonary veins. From this perspective, early diagnosis of PH is more important for patients with SSc than for those with PAH due to other diseases and may contribute to their long-term prognosis. The prevalence of pre-capillary PH in SSc is approximately 7–12% [9], which is higher than the incidence of PAH in the general population (around 4 cases per million [10]). Therefore, the pre-test probability is high, making screening particularly useful.

Exercise PH not only progresses to established PH, it also increases the risk of hospitalization for cardiovascular events [11]. However, exercise RHC can only be conducted in few institutions, and the SSc patient profile for which exercise RHC is indicated is unknown. In this study, we investigated the clinical characteristics of patients with SSc and non-PH, exercise PH, or PH to identify those for whom exercise RHC should be considered.

Methods

Subjects

This retrospective observational study included patients admitted to our hospital from April 2022 to April 2024 who fulfilled the classification criteria for SSc [12]. This study was designed based on the premise of performing exercise RHC in patients with SSc who exhibited exercise intolerance. As exercise RHC is a relatively novel clinical procedure, no established criteria have been reported to define its indication at the time of this study. Therefore, we included patients who had not been previously diagnosed with PH, reported symptoms of exercise intolerance, and provided informed consent for undergoing RHC. Exercise intolerance was defined as a self-reported history of exertional dyspnea or palpitations corresponding to New York Heart Association (NYHA) functional class II symptoms, as obtained through outpatient interviews. Exercise RHC was performed in conjunction with resting RHC. In cases where resting RHC led to a definitive diagnosis of PH, exercise RHC was not performed, as it was deemed unnecessary. Patients with a history of ischaemic heart disease or concomitant moderate or worse heart valve disease were excluded. Additionally, in order to ensure appropriate exercise testing, patients with contractures or significant limitations in joint range of motion were excluded. As there are no established criteria in the literature regarding the extent of skin sclerosis compatible with reliable evaluation, patients with diffuse cutaneous systemic sclerosis (dcSSc) were excluded from this study.

Study design

Fifty patients with SSc not diagnosed with PH, who experienced exercise intolerance but had not been started on a pulmonary vasodilator, were enrolled in the study. The PH group was defined as patients who met the diagnostic criteria for pre-capillary PH on resting RHC. Patients who did not meet the diagnostic criteria for PH during resting RHC underwent exercise RHC. Those for whom the mPAP/CO slope results met the criteria for exercise PH were allocated to the exercise PH group, and those who did not meet any of the criteria were allocated to the non-PH group (Supplementary Fig S1).

The primary endpoint of this study was the prevalence of exercise PH in patients with SSc and exercise intolerance. As an exploratory investigation, we also evaluated the clinical characteristics of patients with SSc and exercise PH and factors useful for diagnosis.

Clinical measurements

In the physical examination, we assessed the World Health Organization Functional Class (WHO FC) and six-minute walking distance (6MWD). As subjective symptoms, patients were considered positive for exercise intolerance if they reported exertional dyspnea or palpitations consistent with NYHA functional class II during the 6-minute walk test. Skin sclerosis was assessed using the modified Rodnan total skin thickness score (RSS). Nailfold capillary morphology and density (number of vessels/mm) were evaluated using nailfold video capillaroscopy (NVC). We also performed biochemical tests, respiratory function tests, and transthoracic echocardiography. Patients who did not meet the PAH criteria [3] on resting RHC underwent exercise RHC to evaluate the presence of exercise PH. All right heart catheterizations were performed in the supine position, and the pressure transducer was zeroed to atmospheric pressure at the mid-axillary line at the level of the fourth intercostal space. Regarding the exercise RHC, parameters such as mPAP, mean pulmonary artery wedge pressure (mPAWP), arterial oxygen saturation (SaO₂), mixed venous oxygen saturation (SvO₂), and CO were each recorded at rest and at peak exercise. In patients with obstructive lung disease, obesity, or ILD with coexisting obstructive impairment, elevated intrathoracic pressure may lead to overestimation of end-expiratory PAWP and LVEDP [13–15]. To minimize measurement error, hemodynamic parameters including RA pressure, mPAP, and PAWP were recorded at end-expiration and assessed as the average of three respiratory cycles. The exercise protocol began at 10 W of low-intensity load for the first 3 min, followed by a continuous increase of 1 W every 6 s (10 W Ramp method). The mPAP-CO slope was calculated as (mPAP at peak – mPAP at rest) ÷ (CO at peak – CO at rest). Cardiac output at each measurement point was calculated using the Fick method: CO = oxygen consumption (VO₂, ml/L) ÷ [(SaO₂, %) – (SvO₂, %) × 1.36 × hemoglobin (Hb, g/dL) × 10]. SaO₂ was obtained from arterial blood, and SvO₂ was obtained from pulmonary arterial blood samples. We also assessed exercise-induced left ventricular diastolic dysfunction and elevations in left atrial pressure. Based on previous studies [16], an mPAWP/CO slope greater than 2.0—calculated as (mPAWP at peak – mPAWP at rest) / (CO at peak – CO at rest)—was used to indicate heart failure with preserved ejection fraction (HFpEF).

Nailfold video capillaroscopy

NVC was performed using a video capillaroscope (Videocap 3.0; DS Medica, Roma, Italy or OptiPix Capillaroscope; Gadelius Medical K.K) at room temperature (22–25 °C), with the operator (S.K, Y.Todoroki, R.K, or Y.K) blinded to the patient’s clinical information. NVC was conducted using an oil-immersion lens to observe the nailfold in the central part of the finger, from the second to the fifth fingers of both hands. NVC findings were assessed by evaluators (S.K, Y.T, R.K, Y.K, and K.K) who were blinded to the clinical data. Capillary morphological abnormalities were evaluated based on the ‘fast track algorithm’, proposed by the EULAR Study Group on Microcirculation in Rheumatic Diseases [17–19]. Based on capillary morphology assessment (giant capillary, abnormal morphology, and microhaemorrhages), patients were classified into either a ‘non-scleroderma pattern’ or a ‘scleroderma pattern.’ Subsequently, the ‘scleroderma pattern’ was further subdivided into early, active, and late patterns. Capillary density was measured by counting the number of capillaries in a 1-mm-wide section at the centre of the nailfold and calculating the mean value of all the fingers for which this was measurable.

Statistical analysis

Differences between groups were compared using Fisher’s exact, Kruskal-Wallis, Wilcoxon rank-sum, and Steel-Dwass tests. All p-values in this study were two-tailed and were adjusted using the Bonferroni method when multiple tests were conducted. All analyses were conducted using JMP Pro ver. 15.2 (SAS Institute Inc., Cary, NC), with p < 0.05 regarded as significant.

Results

Comparisons of patient characteristics

Of the 50 patients with SSc and exercise intolerance, 15 (30%) were diagnosed with PH using resting RHC, and of the remaining 35 who did not meet the diagnostic criteria for pre-capillary PH, 22 (44.0%) were diagnosed with exercise PH (Supplementary Fig S2). This demonstrated that not only was the prevalence of exercise PH, the primary endpoint, high at 44.0%, but that when PH was also included, a total of 74.0% of patients with SSc and exercise intolerance exhibited either PH or pre-PH pathophysiology. The background characteristics of each group are presented in Table 1. The age of the patients in the PH group was higher, in line with the progression of the disease. However, there was no difference between any of the groups regarding the time from the appearance of Raynaud’s syndrome until RHC or regarding whether ILD was also present. There was also no obvious difference in the breakdown of autoantibodies between the groups.

Table 1.

Characteristics of each SSc patient group

	non-PH (n = 13)	exercise PH (N = 22)	PH (N = 15)	p-value
Patient characteristics
Age (years)	61.5 ± 9.9	69.4 ± 10.9	71.3 ± 7.0	0.01
Sex (female)	11 (84.6%)	21 (95.5%)	12 (80.0%)	0.30
Time since the appearance of Raynaud’s syndrome (months)	106.8 ± 121.2	159.4 ± 159.2	131.0 ± 106.9	0.43
WHO FC (I / II / III/ IV)	10 (76.9%) / 3 (23.1%) / 0 (0%) / 0 (0%)	12 (54.6%) / 10 (45.4%) / 0 (0%) / 0 (0%)	1 (6.7%) / 5 (33.3%) / 8 (53.3%) / 1 (6.7%)	< 0.0001
Interstitial lung disease present	8 (61.5%)	8 (36.4%)	10 (66.7%)	0.13
Autoantibodies
Anti-centromere antibodies	6 (46.2%)	11 (50.0%)	10 (66.7%)	0.48
Anti Scl-70 antibodies	3 (23.1%)	4 (18.2%)	3 (20.0%)	0.94
Anti-RNA polymerase III antibodies	0 (0%)	0 (0%)	0 (0%)	-
Anti-U1-RNP antibodies	1 (7.7%)	1 (4.6%)	1 (6.7%)	0.92
Anti-SS-A antibodies	1 (7.7%)	8 (36.4%)	4 (26.7%)	0.13

Values are reported as mean ± SD or as number (%). Statistical differences were determined using the Kruskal–Wallis, Wilcoxon signed-rank, and Fisher’s exact tests. P < 0.05 was considered significant

SSc, systemic sclerosis; PH, pulmonary hypertension; exercise PH, exercise-induced pulmonary hypertension; WHO FC, World Health Organization Functional Class; Scl-70, scleroderma-70; RNA polymerase III, ribonucleic acid polymerase III; U1-RNP, U1-ribonucleoprotein; SS-A, Sjögren’s-syndrome-related antigen A

Comparisons of subjective symptoms and serum markers

We compared physical findings and subjective symptoms between the groups (Supplementary Table S1, Fig. 1A). There was no difference in skin sclerosis (RSS) between the groups. Leg oedema was more frequent in the PH group, but there was no difference between the non-PH and exercise PH groups. However, there was a difference in exertional symptoms such as dyspnea and palpitations between the non-PH and exercise PH groups, with increased symptoms observed in the exercise PH group.

Fig. 1.

Comparison between the non-PH, exercise PH, and PH groups among patients with SSc. A. Comparison of skin scan scores between the non-PH, exercise PH, and PH groups of patients with SSc. The p-values were calculated using the Steel-Dwass test. Comparison of the rates of exertional shortness of breath, palpitation symptoms, and oedema of the legs. The p-values were calculated using Fisher’s exact test (adjusted using Bonferroni’s method). B. Comparison of serology tests between the non-PH, exercise PH, and PH groups of patients with SSc. The p-values were calculated using the Steel-Dwass test. C. Comparison of echocardiography findings between the non-PH, exercise PH, and PH groups of patients with SSc. The p-values were calculated using the Steel-Dwass test. D. Comparison of respiratory function tests between the non-PH, exercise PH, and PH groups of patients with SSc. The p-values were calculated using the Steel-Dwass test

SSc, systemic sclerosis; PH, pulmonary hypertension; exercise PH, exercise induced pulmonary hypertension; RSS, modified Rodnan total skin score; NT-proBNP; N-terminal fragment of brain natriuretic peptide precursor; KL-6, Krebs von den Lungen-6; UA, uric acid; eGFR, estimated glomerular filtration rate; CRP, C-reactive protein; ESR, erythrocyte sedimentation rate; LVEF, left ventricular ejection fraction; TR-PG, tricuspid regurgitant pressure gradient; TRV, tricuspid regurgitant velocity; FVC, forced vital capacity; FEV1.0%, forced expiratory volume in one second; DLco, diffusing capacity of carbon monoxide; 6MWD, 6-minute walking distance

Next, we compared the serology results of the different groups (Supplementary Table S1, Fig. 1B). Possibly reflecting the age cohorts in the different groups, estimated glomerular filtration rate (eGFR) was lower in the exercise PH group than in the non-PH group, but there was no significant difference between the non-PH and PH groups. N-terminal fragment of brain natriuretic peptide precursor (NT-proBNP) was elevated in the PH group, but there was no significant difference between the non-PH and exercise PH groups. Similarly, there were no significant differences in other serum marker levels between the exercise PH and non-PH groups.

Comparison of haemodynamics

Table 2 presents the results of RHC. As anticipated, RHC demonstrated progressive increases in mPAP and PVR across the disease spectrum, with the lowest values in the non-PH group, followed by the exercise PH group, and the highest in the PH group. Cardiac output tended to decrease as PH progressed; however, this difference was not significant. There was no difference in arterial blood oxygen saturation between the non-PH and exercise PH groups, but it was lower in the PH group. Interestingly, In all three groups, there was no elevation in E/e’, an indicator of left ventricular filling pressure [20–22], and left ventricular ejection fraction (LVEF) was preserved. Previous studies have reported that approximately half of patients with SSc-PH present with post-capillary PH, prompting us to investigate the potential coexistence of HFpEF [23] (Supplementary Table S2, Supplementary Fig. S3). An HFpEF prdiction scores of ≥ 2 has been proposed as indicative of HFpEF [21]. In right heart catheterization, a resting PAWP of 11–15 mmHg is considered a gray zone, suggestive of left heart involvement [15, 24]. The PAWP/CO slope (exceeding 2 mmHg/L/min), which is measured during exercise, is useful for detecting latent HFpEF [16]. As the disease progressed from the Non-PH group to the Exercise PH group and subsequently to the PH group, the proportion of patients meeting the criteria for HFpEF prediction scores ≥ 2, gray zone resting PAWP, and elevated PAWP/CO slope increased. Notably, 93.3% of patients in the PH group met the HFpEF prediction scores. In the Exercise PH group, 68.2% had an HFpEF prediction scores ≥ 2, and 22.7% fell into the gray zone PAWP range. However, the proportion of patients who exceeded a PAWP/CO slope > 2 mmHg/L/min in this group was even higher than with either marker, suggesting that latent HFpEF is highly prevalent in the underlying pathophysiology of Exercise PH.

Table 2.

Comparison of right heart catheterization results in each SSc patient group

	non-PH (n = 13)	exercise PH (N = 22)	PH (N = 15)	p-value
RHC
mPAWP (mmHg)	7.0 ± 3.3	8.7 ± 2.9	10.8 ± 3.6	0.01
mPAP (mmHg)	15.0 ± 3.2	16.3 ± 3.8	31.9 ± 11.2	< 0.0001
CO (L/min)	4.7 ± 1.7	4.5 ± 1.3	3.7 ± 1.1	0.08
PVR (Wood units)	1.8 ± 0.8	2.0 ± 1.7	6.4 ± 3.8	< 0.0001
SaO2 (%)	96.6 ± 1.0	96.5 ± 1.4	90.2 ± 7.5	0.005
SvO2 (%)	75.6 ± 5.4	74.3 ± 4.2	67.8 ± 11.7	0.02
exercise RHC
mPAWP/CO (mmHg/L·min)	1.0 ± 0.6	7.0 ± 7.2		< 0.0001
mPAP/CO (mmHg/L·min)	1.9 ± 0.7	14.9 ± 30.9		< 0.0001
peak SaO2 (%)	93.9 ± 2.7	94.1 ± 5.1		0.26
peak SvO2 (%)	56.8 ± 12.1	49.5 ± 7.5		0.08

Values are reported as mean ± SD. Statistical differences were determined using the Kruskal–Wallis, Wilcoxon signed-rank, and Fisher’s exact tests. P < 0.05 was considered significant

SSc, systemic sclerosis; PH, pulmonary hypertension; exercise PH, exercise-induced pulmonary hypertension; WHO FC, World Health Organization functional class; RHC, right heart catheterization; mPAWP, mean pulmonary artery wedge pressure; mPAP, mean pulmonary artery pressure; CO, cardiac output; PVR, pulmonary vascular resistance; SaO₂, arterial oxygen saturation; SvO₂, mixed venous oxygen saturation

Comparison of respiratory function tests

Respiratory function tests (Supplementary Table S1, Fig. 1D) showed that % forced vital capacity (FVC) was lower in the PH group and suggested progression not only of the pathophysiology of PAH but also of the pathophysiology of ILD in patients with concomitant ILD. % diffusing capacity of lung for carbon monoxide (DLco), which is useful in existing PH screening [25], was lower in the PH group. However, there was no difference between the non-PH and exercise PH groups in %DLco, and the same was true for the %FVC/%DLco ratio [26]. Similarly, the 6MWD and forced expiratory volume in one second (FEV1.0%) showed no substantial difference between the non-PH and exercise PH groups. This study underscores the importance of respiratory function tests previously validated for screening PH. Nonetheless, these assessments may not be effective for detecting exercise PH.

Comparison of nailfold video microscopy findings

NVC permits the nailfold capillaries to be viewed directly and noninvasively to evaluate capillary abnormalities [27]. The NVC findings for each group are shown in Table 3. Most patients exhibited a ‘scleroderma pattern,’ and the late NVC pattern tended to be more frequent in the PH group; however, no significant differences were observed between groups. Additionally, no differences were found in vascular morphological abnormalities. On the other hand, nailfold capillary density was significantly decreased in the exercise PH group compared to the non-PH group (Fig. 2A, B) and was similarly decreased in the PH group as in the exercise PH group. The cut-off value for exercise PH was established using Receiver operating characteristic curve (ROC) analysis for the non-PH and exercise PH groups at 7 capillaries/mm (Supplementary Fig S4). Applying this threshold, 77.8% of the patients were diagnosed as exercise PH, demonstrating a high detection rate (p = 0.0017, Fig. 2C).

Table 3.

Comparison of nailfold video capillaroscopy in each SSc patient group

	non-PH (n = 13)	exercise PH (N = 22)	PH (N = 15)	p-value	IPAH (N = 5)
Qualitative assessment
‘Non-scleroderma pattern’ (%)	4 (30.8)	2 (9.1)	1 (6.7)	0.19	5 (100)
‘Scleroderma pattern’ (%)	9 (69.2)	20 (90.9)	14 (93.3)		0 (0)
Early NVC pattern (%)	3 (33.3)	8 (40.0)	3 (20.0)		0 (0)
Active NVC pattern (%)	5 (55.6)	5 (25.0)	5 (33.3)	0.35	0 (0)
Late NVC pattern (%)	1 (11.1)	7 (35.0)	7 (46.7)		0 (0)
Quantitative assessment
Capillary density (/mm)	7.2 ± 1.6	5.0 ± 1.4	4.9 ± 1.9	0.001	8.6 ± 0.5
number of patients with giant capillaries (%)	6 (46.2)	14 (63.6)	12 (80.0)	0.19	0 (0)
number of patients with abnormal morphology (%)	6 (46.2)	13 (59.1)	10 (66.7)	0.54	0 (0)
numberof patients with microhaemorrhages (%)	6 (46.2)	12 (54.6)	10 (66.7)	0.54	0 (0)

Values are reported as mean ± SD. Statistical differences were determined using the Kruskal–Wallis and Fisher’s exact tests. P < 0.05 was considered significant

SSc, systemic sclerosis; PH, pulmonary hypertension; exercise PH, exercise-induced pulmonary hypertension; NVC, nailfold video capillaroscopy

Fig. 2.

Comparison of NVC findings in patients with SSc. A. Comparison of nailfold capillary density in the non-PH, exercise PH, and PH groups of patients with SSc. The photographs on the right show the typical nailfold capillary findings for each group. The p-values were calculated using the Steel-Dwass test. B. The photographs of the typical nailfold capillary findings for each group. C. Comparison of exercise PH positivity rates with the cut-off value of nailfold capillary density ≤ 7/mm calculated using ROC curve analysis. The p-value was calculated using Fisher’s exact test

SSc, systemic sclerosis; NVC, nailfold video capillaroscopy; PH, pulmonary hypertension; exercise PH, exercise-induced pulmonary hypertension; ROC curve, Receiver operating characteristic curve

Investigation of criteria predicting exercise PH

From our investigations, we extracted exertional dyspnoea, exertional palpitations, and decreased nailfold capillary density as predictive factors for the diagnosis of exercise PH. Multivariate analysis of these factors showed that the odds ratios for palpitations during exertion and nailfold capillary density ≤ 7 mm were between six and seven times higher, respectively, and these findings were therefore considered to predict exercise PH (Fig. 3A). An investigation of the prediction of exercise PH using each of these three risk factors found that 87.5% of patients who met all three criteria were positive for exercise PH, whereas no patient with none of these risk factors was positive for exercise PH (Fig. 3B).

Fig. 3.

Investigation of criteria predicting exercise PH in the non-PH and exercise PH groups of SSc patients. A. Forest plot showing the results of multivariate logistic regression analysis to evaluate the effects of exertional dyspnoea, exertional palpitations, and nailfold capillary density ≤ 7 mm on exercise PH positivity. The points show odds ratios, and the bars show 95% confidence intervals. B. Exercise PH positivity rates for the number of each of the three parameters of exertional dyspnoea, exertional palpitations, and nailfold capillary density ≤ 7/mm that are positive

SSc, systemic sclerosis; PH, pulmonary hypertension; exercise PH, exercise-induced pulmonary hypertension; OR, odds ratio; CI, confidence interval

Discussion

This study is the first to investigate the prevalence of exercise PH in patients with SSc based on the newly proposed diagnostic criteria, focusing on clinical features such as nailfold capillary density and exertional respiratory symptoms. The ESC/ERS 2022 guidelines recommend that patients with SSc undergo yearly PH risk evaluation [8]. Medical interview, physical findings, chest radiography, electrocardiography, respiratory function tests, and echocardiography are helpful for this evaluation, and TRV > 2.8 m/s on transthoracic echocardiography is considered a criterion for suspected PH. Other important findings suggestive of PH in patients with SSc include decreased %DLco [25] and %FVC/%DLco [26] in respiratory function tests. However, no specific clinical markers have been identified as effective for detecting exercise PH, which is considered a precursor to established PH.

This study confirmed previous findings that a TRV > 2.8 m/s, decreased %DLco, elevated serum uric acid, and NT-proBNP are reliable indicators for screening for resting PH. However, these markers proved ineffective for detecting exercise PH. Our results highlighted that subjective symptoms during exertion are crucial indicators of exercise PH. Although it may seem intuitive, given that exercise PH is diagnosed through exercise RHC, our findings emphasize that subjective symptoms are more significant than other test results. This underscores the critical role of detailed patient interviews in identifying exercise PH, a stage preceding PH. And exercise stress echocardiography, like exercise stress right heart catheterization, is a less invasive method for assessing hemodynamic changes during exercise. However, it is not currently included in the diagnostic criteria for exercise PH. Therefore, for a definitive diagnosis, exercise stress right heart catheterization remains essential.

Our study subjects included patients with SSc and PAWP ≤ 15 mmHg; however, most patients with SSc and exercise PH had HFpEF with a PAWP/CO slope exceeding 2 mmHg/L/min. Huez et al. reported that among four SSc patients who underwent right heart catheterization, two patients without resting PH met the criteria of mPAP ≥ 25 mmHg and PAWP > 15 mmHg during exercise, and both exhibited an increased E/e′ ratio on echocardiography compared with age-matched norms [28]. These findings suggest that patients at risk for exercise-induced PH may also have concurrent LV diastolic dysfunction. A similar trend was observed in our study, which assessed exercise PH using the current diagnostic criteria. During exercise, increased oxygen consumption leads to an increase in cardiac output and pulmonary blood flow, resulting in a physiological rise in mPAP and PAWP [29]. In particular, in patients with PAH, the presence of distal pulmonary arterial obstruction contributes to elevated pulmonary vascular resistance during exercise, which limits the rise in cardiac output and leads to vascular congestion, further increasing pulmonary arterial pressure [30]. Moreover, compared to PAH patients without left heart disease (LHD) or those with isolated post-capillary PH (IpcPH-LHD), patients with combined post-capillary and pre-capillary PH (CpcPH-LHD) exhibit more severe right ventricular–pulmonary artery (RV–PA) uncoupling during exercise. This results in a greater reduction in cardiac output and more pronounced pulmonary congestion. The presence of CpcPH-LHD has also been associated with reduced pulmonary diffusing capacity and increased ventilation-perfusion mismatch, suggesting that exercise-induced pulmonary vascular pressures may be more severe in PAH patients with underlying left heart conditions such as HFpEF [31]. In the absence of SSc, PH is typically classified as precapillary. On the other hand, SSc is thought to impair peripheral circulation through spasms in coronary microvessels and myocardial fibrosis [32]. With regard to the relationship between SSc and exercise-induced cardiac dysfunction, it has been reported that the TAPSE/sPAP ratio, a marker of right ventricular load, is useful not only for detecting established PAH but also for identifying exercise-induced PH. However, it should be noted that the hemodynamic parameters in such cases may also reflect underlying left heart involvement, as discussed above [31, 33]. It is known that both mPAP and mPAWP increase with age, and the majority of PH cases associated with SSc observed clinically occur in older patients who have had the disease for an extended period [34]. This indicates that in most instances, SSc-related postcapillary damage, compounded by age-related factors, may contribute to the development of exercise PH. Exercise PH represents the broad spectrum of PH that becomes apparent with exercise stress and is a complex condition that includes not only PAH but also elements of left heart disease and pulmonary diseases such as ILD. Among these, our findings suggest a high prevalence of HFpEF.

Currently, the efficacy of PAH-specific therapies has not been demonstrated for exercise PH or borderline PAH, where mPAP does not exceed 25 mmHg. However, given that HFpEF was present in nearly all cases of SSc in our study, further investigation is needed to evaluate whether HFpEF-supportive therapies, such as SGLT-2 inhibitors [15, 35] and aldosterone receptor antagonists [15, 36], may be beneficial for patients with SSc-PH or SSc-exercise PH.

Unlike most clinical findings, which are unsuitable for exercise PH screening, nailfold capillary abnormalities are suggestive of the presence of exercise PH. NVC is a non-invasive technique that uses an oil-immersion lens to observe the microvasculature of the nail fold [27]. We previously reported that the rate of SSc organ damage, including PAH, is higher in patients with SSc who have progressed to late-pattern NVC [37]. In the present study, we also found that as the condition progressed from non-PH to exercise PH and PH, the number of patients with the active pattern or late pattern increased. A decrease in the number of capillaries seen in the nailfold may reflect a decrease in the effective pulmonary vessel bed, which is important in the pathophysiology of PH [38]. Because nailfold capillary abnormalities reflect not only exercise PH but also damage to other organs [37], they provide an important screening test in the complex physiology of SSc-associated PH. Indeed, exercise RHC is indispensable for diagnosing exercise PH. However, since many facilities lack the capacity to perform this investigation, it is currently impractical as a routine diagnostic method. This study revealed that exertional dyspnoea, exertional palpitations, and decreased nailfold capillary density (≤ 7/mm) serve as useful indicator for considering exercise RHC. Palpitations are not a characteristic finding of PH and are not sufficient to suspect PH on their own; however, when combined with other clinical features, they may serve as a useful indicator. All of these can be assessed quickly, making them viable for use in a daily clinical practice.

This study had several limitations. Our sample size was limited by the fact that we conducted exercise RHC in patients with SSc, a rare disease. Studies with larger sample sizes are required for more rigorous verification. Due to the requirement for exercise stress right heart catheterization, patients with contractures due to skin sclerosis or impaired ADL that made exercise stress testing unfeasible were excluded. The presence of ILD was assessed in this study; however, the prevalence of other pulmonary comorbidities, such as chronic obstructive pulmonary disease (COPD), was not evaluated. In this study, decreased nailfold capillary density was correlated with age but not with disease duration; however, it is generally known that capillary loss is associated with disease duration in systemic sclerosis [39]. Additionally, the potential progression of non-PH and exercise PH has not been evaluated through subsequent follow-up assessments, and further investigation is necessary.

In conclusion, our findings suggest that while decreased %DLco and elevated TRV are effective in general PH screening, they fall short in detecting exercise PH. Notably, 44% of patients with SSc and exercise intolerance were found to have exercise PH, most of whom likely suffered from HFpEF. Indicators such as reduced nailfold capillary density, exertional dyspnoea, and exertional palpitations could enhance the detection of exercise PH.

Supplementary Information

Below is the link to the electronic supplementary material.

Abbreviations

PAH

Pulmonary arterial hypertension

CTD

Connective tissue disease

PH

Pulmonary hypertension

ESC/ERS

European Society of Cardiology/European Respiratory Society

mPAP

Mean pulmonary arterial pressure

PVR

Pulmonary vascular resistance

exercise PH

Exercise-induced pulmonary hypertension

RHC

Right heart catheterization

CO

Cardiac output

SSc

Systemic sclerosis

ILD

Interstitial lung disease

NYHA

New York Heart Association

ADL

Activities of daily living

IPAH

Idiopathic pulmonary arterial hypertension

WHO-FC

World Health Organization Functional Class

6MWD

Six-minute walking distance

RSS

Modified Rodnan total skin thickness score

NVC

Nailfold video capillaroscopy

mPAWP

Mean pulmonary artery wedge pressure

SaO₂

Arterial oxygen saturation

SvO₂

Mixed venous oxygen saturation

HFpEF

Heart failure with preserved ejection fraction

KL-6

Krebs von den lungen

CRP

C-reactive protein

eGFR

Estimated glomerular filtration rate

NT-proBNP

N-terminal fragment of brain natriuretic peptide precursor

LVEF

Left ventricular ejection fraction

TRV

Peak tricuspid regurgitation flow velocity

FVC

Forced vital capacity

DLco

Diffusing capacity of lung for carbon monoxide

FEV1.0%

Forced expiratory volume in one second

ROC

Receiver operating characteristic curve

AUC

Area under the curve

LHD

Left heart disease

CpcPH

Combined post-capillary and pre-capillary hypertension

COPD

Chronic obstructive pulmonary disease

Author contributions

All authors were involved in the drafting and critical revision of the manuscript. K.K and S.K had full access to all of the data in the study. Study conception and design: K.K, S.K, Y.Tanaka. Acquisition of data: K.K, Y.K, Y.Todoroki, R.K, K.S, M.K. Analysis and interpretation of data: K.K, S.K, S.N, I.M, Y.M, Y.K, Y.Todoroki, M.U, R.K, K.S, M.K, Y.Tanaka.

Funding

Not applicable.

Data availability

The datasets used and/or analysed in the current study are available from the corresponding author upon reasonable request.

Declarations

Ethics approval and consent to participate

We obtained consent from all patients to conduct various clinical tests. This study was conducted in compliance with the Declaration of Helsinki. Informed consent was obtained from all patients while utilising anonymised data.

Consent for publication

Not applicable.

Competing interests

S. Kubo has received speaking fees from Eli Lilly, GlaxoSmithKline, Bristol-Myers, Abbvie, Eisai, Pfizer, Astra-Zeneca and also research grants from Daiichi-Sankyo, Abbvie, Boehringer Ingelheim, and Astellas. S. Nakayamada has received consulting fees, speaking fees, lecture fees, and/or honoraria from AstraZeneca, GlaxoSmithKline, Pfizer, Bristol-Myers, Astellas, Asahi-Kasei, AbbVie, Chugai, Sanofi, Eisai, Gilead Sciences, Mitsubishi-Tanabe, Janssen, Eli Lilly, Boehringer Ingelheim and Ayumi. Y. Miyazaki has received consulting fees, speaking fees, lecture fees, and/or honoraria from AstraZeneca, GlaxoSmithKline, Bristol-Myers, Astellas, Asahi-Kasei, AbbVie, Chugai, Sanofi, Eisai, Eli Lilly, and Boehringer Ingelheim. M. Ueno has received speaking fees from GlaxoSmithKline. Y. Tanaka has received speaking fees and/or honoraria from Gilead, Abbvie, Behringer-Ingelheim, Eli Lilly, Mitsubishi-Tanabe, Chugai, Amgen, YL Biologics, Eisai, Astellas, Bristol-Myers, and Astra-Zeneca; received research grants from Asahi-Kasei, Abbvie, Chugai, Mitsubishi-Tanabe, Eisai, Takeda, Corrona, Daiichi-Sankyo, Kowa, and Behringer-Ingelheim; and received consultant fees from Eli Lilly, Daiichi-Sankyo, Taisho, Ayumi, Sanofi, GSK, and Abbvie. The other authors have no conflicts of interest to declare.