Study participants
Consecutive patients with SSc who exhibited dyspnea during exertion and suspected PH underwent cardiopulmonary exercise testing (CPX) with right heart catheterization (RHC) at our hospital between June 2013 and February 2020 were eligible for inclusion in the study. Patients with a high mean PAP (≥ 25 mmHg) and PAWP elevations (> 15 mmHg) at rest were excluded (Figure 1).
This study was approved by the Committee for Clinical Studies and Ethics of Kyorin University School of Medicine. The purposes and risks of the study were explained to the patients, who provided informed consent prior to participating. All methods were performed in accordance with the relevant guidelines and regulations.
Right heart catheterization and cardiopulmonary exercise testing
RHC was performed with a 6-F double-lumen, balloon-tipped, flow-directed Swan–Ganz catheter (Harmac Medical Products, Inc., Buffalo, NY, USA) via a transjugular approach. Baseline hemodynamic data were recorded, the zero-reference level (mid-chest) was adjusted at the start of pressure measurement, and the PAWP was obtained as the mean value of the arterial trace during occlusion. Measurements were obtained at the end of normal expirations with patients in the supine flat position to assess the right chamber, pulmonary artery pressure (mean PAP, systolic PAP, and diastolic PAP), and PAWP18.
An incremental symptom-limited exercise test was performed in the supine position, with an electromagnetically braked cycle ergometer (Nuclear Imaging Table with Angio Ergometer; Lode B.V.; Groningen, Netherlands) according to the ramp protocol. During cycling, the legs were elevated to approximately 30 degrees. After the parameters were stabilised, the test consisted of a 3-min rest, followed by 3 min of warmup at an ergometer setting of 10 W (60 rpm), and, finally, testing with a 1-W increase in exercise load every 6 s (totalling 10 W/min).
During the exercise, oxygen consumption (VO2), carbon dioxide output (VCO2), and minute ventilation (VE) were measured with a metabolic cart (Cpex-1; Inter Reha Corp., Tokyo, Japan). Prior to calculating the parameters with respiratory gas analysis, an eight-point moving average of the breath-by-breath data was obtained. Peak VO2 was defined as the average value obtained during the last 30 seconds of exercise. The anaerobic threshold (AT) point was determined using the V-slope method, along with the following conventional criteria: VE/VO2 increases after decreasing or registering as flat , whereas VE/VCO2 remains constant or decreases19. The VE vs VCO2 slope was calculated from the start of incremental exercise to the respiratory compensation point using a least-squares linear regression20.
Heart rate, arterial blood pressure directly recorded in the radial artery, and electrocardiogram were monitored continuously during the test. PAP and PAWP in the RHC were measured every minute. We used the averaged mean PAP and mean PAWP during several-second periods rather than end-expiratory measurements during exercise.
Oxygen (O2) saturation in arterial blood (SaO2) in the radial artery and O2 saturation in the pulmonary artery (SvO2) were measured at rest, AT, and peak exercise. Cardiac output (CO) was determined by the Fick method using the formula: CO (L/min) = VO2/{1.34 × hemoglobin × (SaO2 − SvO2)}. The cardiac index (L/min/m2) was determined as follows: CO/body surface area (BSA). Pulmonary vascular resistance (PVR), transpulmonary pressure gradient (TPG), and diastolic pulmonary pressure gradient (DPG) were calculated as: PVR (Wood units) = (mPAP – PAWP)/CO, TPG = mPAP – PAWP, and DPG = diastolic PAP – PAWP. All measurements during exercise testing were performed without supplemental oxygen.
We defined SSc with LVDD as PAWP increased during the RHC exercise test and divided the patients on this basis into two groups: occult LVDD group (PAWP ≥ 25 mmHg) and non-LVDD group (PAWP < 25 mmHg).
The 6-minute walk test (6MWT) was performed according to American Thoracic Society guidelines without supplemental O2 a day before RHC.
Echocardiography
A transthoracic Doppler echocardiogram at the resting state was obtained and stored digitally on an Artida (Toshiba, Tokyo, Japan) or EPIQ (Philips Healthcare, Cambridge, MA USA) ultrasound system within 3 months of the RHC. Each patient was given a unique identification number to ensure that the analysis of images could be performed blinded to all invasive data and patient characteristics. The frame rate was maintained at a minimum rate of 60 frames per second. For Doppler recordings, the average of 3 to 5 consecutive beats was measured using a horizontal sweep of 75 to 100 cm/s.
Left ventricular (LV) dimensions and left atrial diameter (LAD) were measured from the lv. The LV mass was calculated and indexed to BSA. Left ventricular ejection fraction (LVEF) was calculated using Simpson’s biplane method from the apical 4- and 2-chamber views.
The left atrium (LA) maximal and LA minimal volumes were estimated from the apical 4- and 2-chamber views using biplane planimetry. LA maximal volume was measured from the frame just before the mitral valve opening, and LA volume index (LAVi) was indexed for BSA.
Mitral inflow was assessed in the apical 4-chamber view with the pulsed-wave Doppler sample volume placed at the tips of the mitral valve leaflets during diastole; the early (E) and late (A) peak diastolic velocities of the mitral inflow and the E wave deceleration time were thus measured. Mitral annular motion was assessed using pulsed-wave tissue Doppler with the sample volume placed in the septal (e’ septal) and lateral mitral annulus (e’ lateral). The E/e ratio was calculated.
The right ventricular (RV) systolic function was assessed by measuring the tricuspid annular plane systolic excursion (TAPSE). The RV end-diastolic area (RVEDarea) and end-systolic area (RVESarea) were assessed by manual planimetry in the apical 4-chamber view, and the RV fractional area change (RVFAC) was derived using the formula: RVFAC = [(RVEDarea-RVESarea)/RVEDarea] ×10021.
Statistical analysis
Continuous variables are expressed as mean ± standard deviation (SD) or median with interquartile ranges (Q1–Q3) as appropriate. Categorical variables are expressed as numbers and percentages. Group comparisons were made using Student’s t-test or Mann-Whitney U test, as appropriate, for continuous variables and χ2 statistics or Fisher’s exact test, as appropriate, for categorical variables. Receiver operating characteristic (ROC) curves among resting hemodynamic parameters were drawn, and the area under the curve (AUC) was calculated. The cut-off value that resulted in the highest product sensitivity and specificity was considered the best for the detection of exercise PAWP elevation. Statistical comparisons were considered significant at p<0.05. All analyses were performed using SPSS statistical software (version 26.0; IBM Corp., Armonk, NY, USA).