Outpatient Point-of-Care Cardiopulmonary Exercise Testing in Chronic Thromboembolic Pulmonary Disease

Abstract

Background

Pulmonary vascular obstruction causes dyspnea in chronic thromboembolic pulmonary disease (CTEPD) and chronic thromboembolic pulmonary hypertension (CTEPH). Conventional assessments, like 6-minute walk test (6MWT) and World Health Organization (WHO) functional class (WHO-FC), poorly discriminate the mechanism of dyspnea. Cardiopulmonary exercise testing (CPET) offers direct evaluation of ventilatory efficiency and gas-exchange abnormalities.

Objectives

The purpose of this study was to evaluate the impact of balloon pulmonary angioplasty (BPA) and pulmonary thromboendarterectomy (PTE) on CPET-derived gas-exchange parameters.

Methods

In this prospective study, patients with CTEPD or CTEPH evaluated by a multidisciplinary team underwent outpatient point-of-care CPET (SHAPE-HF system) before and after BPA/PTE. The primary endpoint was change in ventilatory efficiency, assessed by the V_E/VCO₂ (minute ventilation/carbon dioxide production) slope. Secondary endpoints included changes in WHO-FC and 6MWT.

Results

Sixty patients were evaluated; 8 served as controls, and 52 underwent revascularization (20 PTE and 32 BPA). The V_E/VCO₂ slope improved from 43 to 31 (P < 0.001) after BPA and from 42 to 32 (P = 0.02) after PTE. WHO-FC improved from class III to I in both groups (P < 0.001). The mean 6MWT increased 38 m (381 ± 146 vs 419 ± 151 m; P = 0.03) in the BPA and PTE group (349 ± 162 vs 358 ± 140 m; P = 0.7). V_E/VCO₂ and Shape-HF Severity Score positively correlated (P < 0.001), but not with 6MWT (P = 0.83). Before and after revascularization, the Shape-HF score improved in the BPA (2.4 vs 1.5; P < 0.001) and the PTE (2.3 vs 1.6; P = 0.01) groups. Survival at 1-year follow-up was a 100%.

Conclusions

Point-of-care CPET provides objective assessment of gas-exchange improvements after pulmonary revascularization in mild-to-moderate CTEPH/CTEPD.

Central Illustration

Chronic thromboembolic pulmonary hypertension (CTEPH) is an uncommon complication of pulmonary embolism (PE).^1,2 Proximal thrombotic pulmonary vascular obstructions and microvasculopathy produce progressive pulmonary hypertension (PH), which leads to right heart failure and death, if left untreated. CTEPH is defined as the presence of precapillary PH with a mean pulmonary artery pressures (PAP) ≥20 mm Hg and radiographic evidence (computed tomography of the chest, magnetic resonance imaging of the pulmonary artery (PA), catheter-based pulmonary angiography) of organized thrombotic residua within the pulmonary vessels that persist despite a >3-month course of antithrombotic therapy.³ Chronic thromboembolic pulmonary disease (CTEPD) has recently been recognized as a separate entity and corresponds to the presence of similar persistent perfusion defects as CTEPH, but in the absence of PH at rest. PH therapeutic interventions in patients with CTEPH include pulmonary vasodilators, surgical pulmonary thromboendarterectomy (PTE), and balloon pulmonary angioplasty (BPA).³ The selection of therapeutic pathways for the patient with CTEPH requires the expert CTEPH multidisciplinary team, consisting of a PTE surgeon, PH specialist and BPA interventionalist, and CTEPH-trained radiologist.¹ Appropriate patient selection is associated with improved early outcomes.^4,5

Patients with CTEPH will have survival benefit with timely interventions. However, patients with CTEPD without PH may not evolve into CTEPH.⁶ Therefore, there is growing interest in understanding the impact of PH therapeutic interventions in patients with mild-to-moderate mean PAP or without PH. Symptoms in patients with CTEPH or CTEPD are evident during exercise but frequently the hemodynamic assessment is conducted at rest. PTE and BPA have been used for CTEPD in observational series and case reports.7, 8, 9 The preoperative clinical assessment of the true cause of functional limitations can be challenging when there are competing causes for dyspnea. As a consequence, the use of cardiopulmonary exercise test (CPET) can help provide rest and exercise gas-exchange assessment, and thus provides insight into the mechanisms of aerobic exercise impairment in patients with dyspnea. In chronic PE, pulmonary vascular obstruction may lead to gas-exchange evidence of ventilatory inefficiency (high V_E/VCO₂) and resting hypocapnia (low P_ETCO₂), which can be used to isolate chronic PE as the source of dyspnea amid competing sources of functional impairment. The goal of the proposed research is to discern the cause of dyspnea and the impact of therapeutic interventions in CTEPD and CTEPH with mild to moderate mean PAP by using CPET as a point of care test in the outpatient clinic.

Methods

Study design and participant enrollment

Observational, prospective, single-arm, single-center, nonrandomized study in the outpatient setting. Participants were identified in our multidisciplinary CTEPH meeting after reviewing medical history and ancillary studies (ie, chest x-ray, ventilation-perfusion scan, computed tomography of the chest, pulmonary angiography, hemodynamics, and echocardiogram). Patients were assessed as having operable chronic thromboembolic lesions based on imaging, and surgical candidacy was established by cardiothoracic surgeons, pulmonary vascular medicine physicians, BPA experts, and chest radiology. Treatment recommendations incorporate anatomic location, characteristics of fibrotic clot, and comorbidities of the patient. We consented participants at the time of the initial clinical visit. Institutional Review Board approval was obtained (Protocol 30121. Date approved April 13, 2023).

• 1)Inclusion criteria: adults ≥18 years old, individuals with CTEPD with and without PH and individuals able to exercise.
• 2)Exclusion criteria: unable to consent, pregnant, prisoners, individuals who do not understand English/Spanish, severe PH at rest (mean pulmonary artery pressure [mPAP] ≥50 mm Hg), inability to exercise due to musculoskeletal, acute myocardial infarction, unstable angina, uncontrolled arrhythmias, acute endocarditis, acute myocarditis or pericarditis, severe aortic stenosis, severe untreated systemic hypertension at rest systolic blood pressure >200 mm Hg, >120 mm Hg diastolic blood pressure, and acute PE.

Study measures and data collection

Patients were identified to have CTEPD or mild (mPAP 20-35-mm Hg) to moderate (mPAP 36-49-mm Hg) CTEPH during the multidisciplinary meeting and then scheduled for an outpatient office visit. Information regarding clinical history, demographics, World Health Organization Functional Class (WHO-FC), past medical history, medications, and physical examinations were completed. Baseline echocardiogram, right heart catheterization, and brain natriuretic peptide (BNP) were obtained. Then completed a 6-minute walk test (6MWT) and a Shape-HF CPET System assessment. The Shape-HF CPET was completed in a brief period of time (∼6 minutes). The patient begins with a spirometry maneuver, and then exercises utilizing a stepping stool at a pace directed by the patient and using a gas-exchange mask. The algorithms analyze gas exchange breath-by-breath, lung performance, tissue perfusion, and heart rate measures, and compares these against well-established ranges and cutoff values characteristic of functional derangements in common disease “silos.” The software-driven analytic processes 5 different disease silos: heart, pulmonary vascular, obstructive lung, restrictive and interstitial lung, and deconditioning (Supplemental Table 1). The Shape-HF system creates a multiparametric analysis of abnormal CPET variables (linear breathing efficiency slope, resting pulmonary perfusion, change in pulmonary perfusion during exercise, O₂ uptake efficiency slope, pulmonary vascular capacitance, and end exercise SpO₂), and it creates an index called Shape severity score. The Shape score is plotted as a graph with a “y” axis ranging from normal or <1.0 to mild, moderate and severe ranging from >1, 2, 3, 4, or 5, respectively. The Shape score is populated in the report of the test. The CPET parameters collected at baseline and follow-up were V_E/VCO₂ slope, O₂ uptake efficiency slope, pulmonary capacitance, rest and peak heart rate, rest and end exercise pulse oximetry, rest end tidal CO₂, respiratory exchange ratio (RER), and duration of the test. After the visit, patients were divided into 3 treatment groups: clinical observation, BPA, or PTE. Right heart catheterization, echocardiogram, and exercise data (WHO-FC, 6MWT, and Shape-HF CPET) were collected again after 3 months. Survival data were obtained at the 3-month follow-up. Once the BPA sessions were deemed completed by the interventional cardiologist, the follow-up assessments occurred. Twenty-five (78%) of the patients receiving BPA were on pulmonary vasodilators at baseline and at the 3 months follow-up without medication change. The follow-up PTE hemodynamics were obtained in the immediate postsurgical period after patients were weaned off pulmonary vasodilators (postop day 1 or 2).

Sample size

A sample size of 50 will have 80% power to detect a difference of 0.5 SD in gas-exchange parameters using a paired t-test with a 1% 2-sided significance level. The reduced significance level is chosen to account for multiple comparisons for up to 10 parameters.

Data analysis

For this exploratory study, outcomes were considered significant at P < 0.05. All tests were 2-sided. Differences from baseline to the end of the study were calculated. We used paired t-tests and linear regression if additional variables were needed in the models. Data were checked for normality and appropriate transformations applied when necessary. Nonparametric analysis methods were performed. Normality, the response variable was assessed using the Shapiro-Wilk statistic and normal probability plots. Tukey's reexpression ladder was used to identify transformations such that the relationships between the response and the covariates are linear. Nonparametric tests, such as the Wilcoxon signed rank test for paired data and the Mann-Whitney (Wilcoxon rank sum) test for unpaired data will be used rather than the paired and unpaired Student t-tests, respectively, if the normality assumption of the data is in question.

Results

We prospectively studied a cohort of 60 patients with CTEPD and CTEPH with mild-to-moderate mean PAP. The patients were divided in 3 groups: 8 (13.3%) were controls, 32 (53.3%) were in the BPA cohort, and 20 (33.3%) were in the PTE cohort. From the control group, 2 individuals refused pulmonary vasodilators/BPA/PTE, 3 started PH medical therapy, and 3 did not qualify for any pulmonary vasodilators. Four individuals were lost to follow-up in the post-PTE cohort as they were out of state referrals (Central Illustration).

Central Illustration.

Cardiopulmonary Exercise Testing In Chronic Thromboembolic Pulmonary Disease

Sixty patients were studied, including 52 who underwent revascularization (32 balloon pulmonary angioplasty, 20 pulmonary thromboendarterectomy). Ventilatory efficiency, measured by VE/VCO₂ slope, improved significantly after balloon pulmonary angioplasty (43-31; P < 0.001) and pulmonary thromboendarterectomy (42-32; P = 0.02). World Health Organization Functional Class improved from class III to class I in both groups, while 6-minute walk test changes were less consistent. SHAPE-HF severity scores improved significantly after intervention and correlated strongly with VE/VCO₂ slope, supporting CPET as a sensitive physiologic marker of therapeutic response. 6MWT = 6-minute walk test; BMI = body mass index; CTEPD = chronic thromboembolic pulmonary disease; CTEPH = chronic thromboembolic pulmonary hypertension; PAP = pulmonary artery pressure; RHC = Right heart catheterization; TTE = Transthoracic echocardiogram; WHO-FC = World Health Organization Functional Class; other abbreviations as in Figures 2 and 3.

Baseline characteristics

Baseline characteristics and comorbidities are presented in Table 1. The average age was 56.4 ± 15.2 years old, and the body mass index (BMI) was 31.8 ± 8.5-kg/m². Of the cohort, 33 (55%) were female, 37 (61.7%) were White, 16 (26.7%) were Black, and 6 (10%) were Latinx. The baseline WHO-FC was I in 3 (5%), II in 9 (15%), III in 41 (68.3%), and IV in 7 (11.7%). At baseline, PH medications were prescribed for 32 (53.3%) patients. The baseline mean 6MWT was 375 ± 134 m and median BNP was 85 pg/mL. Depending on the cohort observation, BPA or PTE, there were significant differences in age (53 ± 17 vs 51 ± 17 vs 60 ± 12 years old; P = 0.05) and BMI (29.4 ± 8.2 vs 30.8 ± 8.8 vs 34.4 ± 8 kg/m²; P = 0.04).

Table 1.

Baseline Characteristics, Demographics, and Medications

Age (y)	56.4 ± 15.2
BMI (kg/m2)	31.8 ± 8.5
Female	33 (55%)
Race/ethnicity
Asian	1 (1.7%)
Black	16 (26.7%)
Hispanic/Latinx	6 (10%)
White	37 (61.7%)
WHO FC
I	3 (5%)
II	9 (15%)
III	41 (68.3%)
IV	7 (11.7%)
Tobacco use	17 (28.3%)
Recreational drugs	2 (3.3%)
Vaping	2 (3.3%)
Comorbidities
Atrial fibrillation	4 (6.7%)
Coagulopathy	12 (20%)
Diabetes mellitus	9 (15%)
History of cancer	9 (15%)
History of PE	55 (91.7%)
History of DVT	32 (53.3%)
Hemoglobinopathy	2 (3.3%)
May Thurner syndrome	6 (10%)
Presence of indwelling line/defibrillator or pacemaker	6 (10%)
Splenectomy	3 (5%)
Family history of thromboembolic disease	4 (6.7%)
Sleep disorders of breathing	19 (31.7%)
Thyroid disease	9 (15%)
Medications
No PH medications	28 (46.7%)
Use of PH medications	32 (53.3%)
Sildenafil	3 (5%)
Taldalafil	1 (1.7%)
Riociguat	28 (46.7%)
Macitentan	7 (11.7%)
Epoprostenol	1 (1.7%)
1 PH medication	25 (41.7%)
2 PH medications	6 (10%)
3 PH medications	1 (1.7%)

Values are mean ± SD or n (%).

BMI = body mass index; DVT = deep vein thrombosis; PE = pulmonary embolism; PH = pulmonary hypertension; WHO FC = World Health Organization Functional Class.

Regarding comorbidities, tobacco abuse was reported in 17 (28.3%), atrial fibrillation in 4 (6.7%), coagulopathy in 12 (20%), diabetes mellitus in 9 (15%), history of cancer in 9 (15%), history of acute PE in 55 (91.7%), history of deep vein thrombosis in 32 (53.3%), hemoglobinopathy in 2 (3.3%), May Thurner syndrome in 6 (10%), presence of indwelling line/defibrillator or pacemaker in 6 (10%), splenectomy in 3 (5%), sleep disorders of breathing in 19 (31.7%), thyroid disease in 9 (15%), and a family history of thromboembolic disease in 4 (6.7%). There were no significant differences between the intervention groups regarding comorbidities.

The baseline characteristics by echocardiogram are described in Table 2 and Figure 1. This semiquantitative echo Doppler score has been described to evaluate the right ventricular (RV) in CTEPH.¹⁰ The cohort showed baseline mild (43%) to moderate (33.3%) interventricular septal flattening in systole, the RV size was mild (23.3%) to moderately (50%) enlarged. The RV shape from base-to-apex ratio was normal (25%), mildly abnormal (28.3%), and moderately abnormal (40%). Regarding the RV outflow tract pulse-wave Doppler flow, there was a normal parabolic shape in 13.3% of the patients, late systolic notching in 30%, and mid-systolic notching in 50%. There was moderate tricuspid regurgitation in 16.7% with mild or no tricuspid regurgitation in the remainder. The average PAP by echocardiogram was 54.9 ± 21.7 mm Hg, and tricuspid annular plane systolic excursion (TAPSE) was 1.9 ± 0.3 cm. The mean left ventricular ejection fraction was 62.2 ± 3.7%.

Table 2.

Echocardiogram Parameters of the Cohort (N = 60)

	Baseline	Follow-Up
Septum flattening during systole
None	11 (18.3%)	20 (33.3%)
Mild	26 (43.3%)	34 (56.7%)
Moderate	20 (33.3%)	6 (10%)
Severe	3 (5%)	0 (0%)
Right ventricular size
Normal	8 (13.3%)	16 (26.7%)
Mildly enlarged	14 (23.3%)	27 (45%)
Moderately enlarged	30 (50%)	17 (28.3%)
Severely enlarged	8 (13.3%)	0 (0%)
Base-to-apex RV ratio
Normal	15 (25%)	30 (50%)
Mild	17 (28.3%)	23 (38.3%)
Moderate	24 (40%)	7 (11.7%)
Severe	4 (6.7%)	0 (0%)
RVOT Doppler flow	a
Parabolic	8 (13.3%)	36 (60%)
Late systolic notching	18 (30%)	15 (25%)
Mid systolic notching	30 (50%)	9 (15%)
TV regurgitation	b
None	11 (18.3%)	25 (41.6%)
Mild	38 (63.3%)	31 (51.7%)
Moderate	10 (16.7%)	4 (6.7%)
Severe	0 (0%)	0 (0%)

Values are n (%).

RV = right ventricle; RVOT = right ventricular outflow tract; TV = tricuspid valve.

^a4 missing values.

^b1 missing values.

Figure 1.

Echocardiogram Parameters at Baseline and Follow-Up

RV = right ventricle; RVOT = right ventricular outflow tract; TR = tricuspid regurgitation.

The baseline hemodynamics (Table 3) had a mean right atrial (RA) pressure of 7.7 ± 4.5-mm Hg, mean PAP of 37.4 ± 12.4-mm Hg, pulmonary artery wedge pressure (PAWP) of 11.1 ± 4.4-mm Hg, cardiac index of 2.4 ± 0.5 lpm/m², stroke volume index (SVi) of 33.1 ± 9.6 cc/m², and pulmonary vascular resistance (PVR) of 5.9 ± 3.3 WU. The PA compliance, calculated as stroke volume/PA pulse pressure¹¹ was 1.9 ± 1.2 mL/mm Hg. The fractional flow pressure (FFP), calculated as PA pulse pressure/mean PAP¹² was 1.15 ± 0.31. Analysis of variance was performed, and no statistical differences were determined between the observation, BPA, and PTE groups in the following baseline 6MWT, hemodynamics, and BNP.

Table 3.

Hemodynamics of the Cohort Divided by Intervention Group

	All (N = 60)			Observation (n = 8)			BPA (n = 32)			PTE (n = 20)
	Baseline	Follow-Up	P Value	Baseline	Follow-Up	P Value	Baseline	Follow-Up	P Value	Baseline	Follow-Up	P Value
Heart rate (beats/min)	75 ± 12	74 ± 10	0.86	71 ± 11	73 ± 10.6	0.50	78 ± 14	74 ± 12	0.12	72 ± 9	76 ± 7	0.025
SBP (mm Hg)	130 ± 21	122 ± 17	0.05	117 ± 12	118 ± 18	0.20	132 ± 23	124 ± 17	0.13	133 ± 21	121 ± 20	0.10
DBP (mm Hg)	76 ± 14	70 ± 9.4	<0.001	67 ± 10	67 ± 13	0.60	77 ± 13	71 ± 8	0.05	77 ± 16	69 ± 15	0.09
MAP (mm Hg)	94 ± 15	88 ± 10.7	0.017	83 ± 8	84 ± 15	0.40	96 ± 15	89 ± 9	0.06	96 ± 16	86 ± 16	0.10
RAP (mm Hg)	7.7 ± 4.5	6.3 ± 2.9	0.029	6.9 ± 4.5	4.0 ± 0	0.30	8.1 ± 4.7	5.6 ± 2.8	0.007	7.5 ± 4.4	7.9 ± 2.8	0.50
Systolic PAP (mm Hg)	65 ± 22	46 ± 17	<0.001	59 ± 20	47 ± 7	0.60	65 ± 21	52 ± 17	<0.001	68 ± 25	36 ± 13	<0.001
Diastolic PAP (mm Hg)	23.2 ± 8.7	16.3 ± 4.7	<0.001	20.3 ± 6.7	11.0 ± 1.4	0.20	23.8 ± 8.7	16.9 ± 4.6	<0.001	23.1 ± 9.5	15.7 ± 4.9	0.001
Mean PAP (mm Hg)	37 ± 12	26 ± 8	0.001	33 ± 10.3	23 ± 1.4	0.30	37 ± 12	28 ± 8	<0.001	38 ± 13	22 ± 7	<0.001
PAWP (mm Hg)a	11.1 ± 4.4	11.1 ± 3.1	0.60	11.6 ± 6.6	14.0 ± 1.4	0.30	10.9 ± 3.6	10.8 ± 3.2	1.000	11.4 ± 4.8
CO (lpm)	4.9 ± 1.5	5.5 ± 1.2	0.05	4.65 ± 1.76	5 ± 0.7	0.70	4.7 ± 1.4	5.3 ± 1.2	0.02	5.4 ± 1.6	5.9 ± 1.2	0.40
Cardiac index (lpm/m2)	2.4 ± 0.5	2.6 ± 0.5	0.023	2.44 ± 0.53	2.4 ± 0.01	0.80	2.32 ± 0.5	2.62 ± 0.4	0.007	2.49 ± 0.6	2.65 ± 0.5	0.50
SVi (cc/m2)	33.1 ± 9.6	35.2 ± 9.2	0.30	35.5 ± 11.8	33.5 ± 4.9	0.60	31.4 ± 9.3	36.7 ± 8.9	0.006	34.8 ± 9.2	33 ± 9.84	0.50
PVR (WU) a	5.9 ± 3.9	3.4 ± 1.65		5.03 ± 3.35	1.7 ± 0.32	0.50	6.4 ± 4.5	3.49 ± 1.6	<0.001	5.5 ± 3.16
TPR (WU)	8.4 ± 4.3	4.9 ± 1.8	<0.001	7.61 ± 2.60	4.6 ± 0.36	0.30	8.9 ± 4.95	5.5 ± 1.68	<0.001	7.7 ± 3.47	3.9 ± 1.66	<0.001
SVR (dynes/cm−5)	1,522 ± 649	1,278 ± 287		1,477 ± 529	1,269 ± 63	0.70	1,591 ± 747	1,315 ± 294	0.06	1,430 ± 525	1,119 ± 259	0.10
PA compliance (mL/mm Hg)	1.9 ± 1.3	3.1 ± 1.9	<0.001	2.04 ± 1.35	1.95 ± 0.49	0.40	1.80 ± 1.11	2.4 ± 0.94	0.003	2.2 ± 1.5	4.4 ± 2.65	<0.001
FFP	1.15 ± 0.31	1.1 ± 0.33	0.616	1.2 ± 0.29	1.5 ± 0.28	0.10	1.12 ± 0.30	1.2 ± 0.32	0.23	1.1 ± 0.33	0.9 ± 0.23	0.001

BPA = balloon pulmonary angioplasty; CO = cardiac output; DBP = diastolic blood pressure; FFP = fractional flow pressure; MAP = mean arterial pressure; PA = pulmonary artery; PAP = pulmonary artery pressure; PAWP = pulmonary arterial wedge pressure; PTE = pulmonary thromboendarterectomy; PVR = pulmonary vascular resistance; SBP = systolic blood pressure; RAP = right atrial pressure; RV = right ventricle; SVi = stroke volume index; SVR = systemic vascular resistance; TPR = total pulmonary resistance.

^aNot included as post-PTE patients did not have immediate PAWP given postsurgical status within 72 hours.

Only 7 patients had a mean PAP <20 mm Hg, 4 had a mean PAP between 20-24 mm Hg, and 15 had a mean PAP between 25-35 mm Hg. We compared the group with mPA <20 (CTEPD) and CTEPH with mPA ≥20 mm Hg. There were no differences in comorbidities, but individuals with CTEPD were younger than CTEPH patients (mean age 39 vs 58; P value = 0.014), and their mean WHO-FC was lower (2.2 vs 2.9; P < 0.001) (Supplemental Table 2).

Follow-up

The mean WHO-FC improved from a mean of 2.3 to 1.6 in the observation/medical therapy group (P = 0.05), 2.9 to 1.2 in the BPA group (P < 0.001), and 3.1 to 1.5 in the PTE group (P < 0.001). There were changes in the WHO-FC to I in 68.3%, II in 28.3%, and III in 3.3%. The 6MWT was 372 ± 130 m with improvement to 398 ± 148 (Delta 26 m). There was 100% survival in the cohort during the study period.

We divided the groups by intervention (observation/medical therapy, BPA, and PTE) and conducted baseline vs (vs) follow-up comparisons using paired t-tests or Wilcoxon signed rank tests for 2 related samples (Supplemental Table 3). Regarding 6MWT, though it did not reach statistical significance, the observation/medical therapy group had numerical increase of 47 m (386 ± 79 vs 433 ± 97 m; P = 0.2), the BPA group had a statistically significant increase in 6MWT of 38 m (381 ± 146 vs 419 ± 151 m; P = 0.03), and the PTE group had an increase of 38 m although it did not have a statistical change (349 ± 162 vs 358 ± 140 m; P = 0.7). The median BNP worsened in the observation group (19 [IQR: 4-1,255] vs 51 [IQR: 2.5-167]-pg/mL; P = 0.7), improved in the BPA group (59 [IQR: 4-1,054] vs 24 [IQR: 4-335]-pg/mL; P = <0.001), and in the PTE group (158 [IQR: 5.6-1,626] vs 34 [IQR: 7-403] pg/mL; P < 0.001).

The echocardiograms showed evidence toward improvement in the follow-up. There was no evidence of septal flattening in systole in 33.3% and mild septal flattening in 56.7%, the RV size was mildly enlarged in 45%. The RV shape was normal in 50% of the individuals. Regarding the follow-up RV outflow tract Doppler flow, it was normal parabolic shape in 60% of the patients, late systolic notching in 25%, and mid-systolic notching in 15%. The average systolic PAP pressure by echocardiogram was 42.1 ± 18.7 mm Hg. TAPSE was 2.1 ± 0.6 cm in the observation/medical therapy and BPA group. TAPSE was not used for comparison in the post-PTE group. The follow-up mean left ventricular ejection fraction was 62.4 ± 4.5%.

Follow-up hemodynamics are shown in Table 3. The control group had no significant changes in hemodynamics. The BPA group had improvement in mean RA pressure (8 ± 4.6 vs 5.6 ± 2.8 mm Hg, P = 0.007), systolic PAP (65.2 ± 21.6 vs 52.3 ± 18 mm Hg; P < 0.001), diastolic PAP (23.8 ± 8.7 vs 16.9 ± 4.6 mm Hg; P < 0.001), mean PAP (37.8 ± 12.3 vs 28.7 ± 8 mm Hg; P < 0.001), cardiac index (2.3 ± 0.5 vs 2.62 ± 0.47 lpm/m²; P = 0.007), SVi (31.5 ± 8.4 vs 37 ± 9 cc/m²; P = 0.006), PVR (6.4 ± 4.5 vs 3.5 ± 1.6 WU; P < 0.001), and PA compliance (1.8 ± 1.1 vs 2.4 ± 0.9 mL/mm Hg; P = 0.003). The BPA group had no statistically significant changes in heart rate (78 ± 14 vs 74 ± 12 beats/min; P = 0.10), mean arterial pressure (96.5 ± 15.4 vs 89.5 ± 9 mm Hg; P = 0.06); PAWP (10.9 ± 3.6 vs 10.8 ± 3.2 mm Hg; P = 1.00), systemic vascular resistance (1,591.5 ± 747.2 vs 1,315.6 ± 294.6 dyn/cm⁻⁵; P = 0.06), and FFP (1.1 ± 0.3 vs 1.21 ± 0.32; P = 0.23). The PTE group had improvement in systolic PAP (68 ± 25 vs 36 ± 14 mm Hg; P < 0.001), diastolic PAP (23.1 ± 9.5 vs 15.7 ± 4.9 mm Hg; P < 0.001), mean PAP (39 ± 14 vs 22.5 ± 7.5 mm Hg; P < 0.001), total pulmonary resistance (TPR) (7.8 ± 3.5 vs 3.9 ± 1.7 WU; P < 0.001), PA compliance (2.2 ± 1.5 vs 4.4 ± 2.7 mL/mm Hg; <0.001), and FFP (1.18 ± 0.33 vs 0.9 ± 0.23; P = 0.001). The PTE group had no statistically significant changes in RA pressure (7.5 ± 4.4 vs 7.9 ± 2.8 mm Hg; P = 0.5) or cardiac index (2.5 ± 0.6 vs 2.65 ± 0.52 lpm/m²; P = 0.50). Analysis of variance was performed, and there were statistical differences determined between the observation, BPA, and PTE groups in the following variables at follow-up: RA pressure (4 vs 5.6 vs 7.9 mm Hg; P = 0.019), systolic PAP (47 vs 52 vs 36-mm Hg; P = 0.004), mean PAP (23 vs 28 vs 22 mm Hg; P = 0.021), PA compliance (2 vs 2.4 vs 4.4; P = 0.009), TPR (4.6 vs 5.5 vs 4-WU; P = 0.004), and FFP (1.6 vs 1.2 vs 0.9; P = 0.001).

Shape-HF CPET parameters

Shape-HF CPET parameters were measured at baseline and at follow-up (Table 4 and Figure 2). In the control group, there were no differences at baseline vs follow-up in V_E/VCO₂ slope (37.5 ± 12.1 vs 38 ± 11.3; P = 0.70), O₂ efficiency uptake slope (1.4 ± 0.6 vs 1.5 ± 0.6; P = 0.8), peak gas-exchange capacitance (334.7 ± 171 vs 319.5 ± 175; P = 0.90), peak heart rate (119 ± 30 vs 120 ± 38 beats/min; P = 0.90), rest SpO₂ (96 ± 3 vs 95% ± 5%; P = 0.20), end exercise SpO₂ (91 ± 6 vs 88% ± 8%; P = 0.09); resting PetCO₂ (30.1 ± 3.2 vs 30.8 ± 3.2-mm Hg; P = 0.50), dead space (121.2 ± 40.6 vs 117.2 ± 27.9-mL; P = 0.80), Shape HF score (ranging from 0 to 5) (2.3 ± 1.4 vs 2.2 ± 1.4; P = 0.90), and RER (1.1 ± 0.4 vs 1 ± 1.2; P = 0.40).

Table 4.

CPET Parameters in the Cohort Divided by Intervention Group

	All (N = 60)			Observation (n = 8)			BPA (n = 32)			PTE (n = 20)
	Baseline	Follow-Up	P Value	Baseline	Follow-Up	P Value	Baseline	Follow-Up	P Value	Baseline	Follow-Up	P Value
VE/VCO2 slope	42 ± 10.7	35 ± 9	<0.001	37 ± 12	38 ± 11.3	0.70	43.7 ± 11	34.9 ± 9	<0.001	41.3 ± 8.2	33.9 ± 8.3	0.02
O2 efficiency uptake slope	1.5 ± 0.6	1.6 ± 0.6	0.10	1.4 ± 0.6	1.5 ± 0.6	0.80	1.5 ± 0.7	1.7 ± 0.6	0.30	1.4 ± 0.4	1.5 ± 0.6	0.20
Peak gas exchange capacitance	334 ± 137	378 ± 163	0.008	334 ± 171	319 ± 175	0.90	319 ± 117	358 ± 139	0.10	355 ± 153	448 ± 187	0.02
Resting heart rate (beats/min)	78 ± 15	80 ± 15	0.20	71 ± 1	79.3 ± 16	0.02	80 ± 15.6	78 ± 15.6	0.70	78 ± 14.8	81 ± 12.1	0.20
Peak HR (beats/min)	112 ± 21	112 ± 24	0.90	119 ± 30	120 ± 38	0.90	119 ± 1	115 ± 19	0.20	107 ± 21	98 ± 17	0.10
Resting SpO2 (%)	94.3 ± 3.1	96 ± 2.6	0.06	96.2 ± 3.1	94.6 ± 4.6	0.20	93.9 ± 2.9	95.1 ± 2.1	0.01	94.2 ± 3.2	96.9 ± 2	0.004
End exercise SpO2 (%)	89 ± 4.4	91 ± 4.7	0.04	90.8 ± 5.6	87.8 ± 7.6	0.09	87.7 ± 3.8	90.5 ± 3	0.01	90 ± 4.4	93 ± 4.2	0.02
Resting PetCO2 (mm Hg)	29.1 ± 5.3	29 ± 5.7	0.30	30.1 ± 3.2	30.8 ± 3.2	0.50	28 ± 5.2	28.2 ± 6.9	0.90	29.8 ± 6.1	31.8 ± 3.2	0.20
End exercise PetCO2 (mm Hg)	27.1 ± 6.2	29 ± 5.2	<0.001	28.9 ± 7.9	28.8 ± 6.8	0.90	26 ± 6.03	30 ± 5.07	<0.001	27.9 ± 6.7	30.4 ± 5.0	0.10
Dead space in mL	135 ± 69.5	129 ± 53	0.50	121 ± 40.7	117 ± 27.9	0.80	140 ± 73	128 ± 41.9	0.10	132 ± 44.6	138 ± 65.6	0.40
Shape-HF score severity	2.4 ± 1.0	1.6 ± 1.1	<0.001	2.3 ± 1.4	2.2 ± 1.4	0.90	2.4 ± 1.1	1.5 ± 1	<0.001	2.3 ± 0.9	1.6 ± 1.1	0.01
Heart silo score	1.7 ± 0.7	1.4 ± 0.8	0.009	1.4 ± 0.8	1.3 ± 1.0	0.60	1.7 ± 0.7	1.3 ± 0.6	0.001	1.8 ± 0.6	1.7 ± 0.8	0.50
Pulmonary vascular silo score	1.6 ± 0.6	1.2 ± 0.5	<0.001	1.4 ± 0.6	1.6 ± 0.7	0.20	1.8 ± 0.5	1.2 ± 0.5	<0.001	1.5 ± 0.5	1.04 ± 0.5	0.006
Obstructive lung disease silo score	0.9 ± 0.8	0.7 ± 0.8	0.30	0.6 ± 0.7	1 ± 0.98	0.10	0.8 ± 0.89	0.62 ± 0.7	0.20	1.3 ± 0.8	0.84 ± 0.9	0.30
Restrictive lung disease silo score	1.2 ± 0.8	1 ± 0.8	0.01	0.8 ± 0.7	0.7 ± 0.5	0.80	1.4 ± 0.8	0.9 ± 0.9	0.002	1.2 ± 0.8	1.2 ± 0.8	0.80
Deconditioning silo score	2.2 ± 0.9	1.9 ± 0.9	0.07	1.9 ± 1.2	1.5 ± 1	0.01	1.9 ± 0.9	1.9 ± 0.9	0.90	2.6 ± 0.7	2.1 ± 0.5	0.02
RER	0.9 ± 0.3	0.9 ± 0.2	0.30	1.1 ± 0.4	1.0 ± 1.2	0.40	0.93 ± 0.3	0.9 ± 0.2	0.40	0.9 ± 0.2	1.0 ± 0.2	0.60
Duration of test (min)	4.6 ± 1.6	4.3 ± 2.3	0.30	4.4 ± 0.8	4.9 ± 1.2	0.40	4.9 ± 1.9	4.8 ± 2.3	0.70	4.15 ± 1.1	3.1 ± 2.5	0.10

Values are mean ± SD.

RER = respiratory exchange ratio; other abbreviations as in Table 3.

Figure 2.

Association Between VE/VCO₂ Slope, Shape‑HF Severity Score, and Functional Capacity

Relationship between baseline values of VE/VCO2 slope and Shape-HF Severity score (A) and 6 minute walk test (B). There was a positive correlation between V_E/VCO₂ and Shape-HF Severity Score (P < 0.001), but interestingly no correlation was seen with V_E/VCO₂ and 6-minute walk test (P = 0.83). There are differences seen in the Shape HF severity score depending on the intervention (C). BPA = balloon pulmonary angioplasty; PTE = pulmonary thromboendarterectomy.

In the BPA group, there were statistical differences in V_E/VCO₂ slope (43.7 ± 11.7 vs 34.9 ± 9; P < 0.001), rest SpO₂ (94% ± 3% vs 95% ± 2%; P = 0.01), end exercise SpO₂ (88% ± 4% vs 91% ± 3%; P = 0.01), end exercise PetCO₂ (26 ± 6 vs 30 ± 5; P < 0.001), Shape HF score (2.4 ± 1.1 vs 1.5 ± 1; P < 0.001), heart silo score (1.7 ± 0.7 vs 1.3 ± 0.6; P = 0.001), pulmonary vascular silo score (1.8 ± 0.5 vs 1.2 ± 0.5; P < 0.001), and restrictive lung disease silo score (1.4 ± 0.8 vs 0.9 ± 0.9; P = 0.002). There were no differences with O₂ efficiency uptake slope (1.5 ± 0.7 vs 1.7 ± 0.6; P = 0.30), peak gas-exchange capacitance (319 ± 117 vs 359 ± 139; P = 0.10), resting heart rate (81 ± 16 vs 79 ± 16 beats/min; P = 0.70), peak heart rate (120 ± 18 vs 116 ± 20 beats/min; P = 0.20), resting PetCO₂ (28.1 ± 5.2 vs 28.2 ± 6.9 mm Hg; P = 0.90), dead space (140.8 ± 73 vs 128 ± 42 mL; P = 0.10), obstructive lung disease silo score (0.8 ± 0.89 vs 0.62 ± 0.71; P = 0.20), deconditioning silo score (1.9 ± 0.9 vs 1.91 ± 0.9; P = 0.90), RER (0.93 ± 0.3 vs 0.9 ± 0.2; P = 0.40), and duration of test (4.9 ± 1.9 vs 4.8 ± 2.3 min; P = 0.70).

In the PTE group, there were statistical differences in V_E/VCO₂ slope (41.3 ± 8.2 vs 33.9 ± 8.3; P = 0.02), peak gas exchange capacitance (355.1 ± 153.9 vs 448.4 ± 187.8; P = 0.02), rest SpO2 (94 ± 3 vs 97% ± 2%; P = 0.004), end exercise SpO₂ (90 ± 4 vs 93% ± 4%; P = 0.02), Shape HF score (2.3 ± 0.9 vs 1.6 ± 1.1; P = 0.01), pulmonary vascular silo score (1.5 ± 0.5 vs 1.04 ± 0.5; P = 0.006), restrictive lung disease silo score (1.2 ± 0.8 vs 1.2 ± 0.81; P = 0.80), and deconditioning silo score (2.6 ± 0.6 vs 2.1 ± 0.5; P = 0.02). There were no differences with O₂ efficiency uptake slope (1.4 ± 0.4 vs 1.5 ± 0.6; P = 0.20), resting heart rate (78 ± 15 vs 82 ± 12 beats/min; P = 0.20), peak heart rate (107 ± 22 vs 99 ± 17 beats/min; P = 0.10), resting PetCO₂ (29.8 ± 6.1 vs 31.8 ± 3.2 mm Hg; P = 0.20), end exercise PetCO2 (27.9 ± 6.7 vs 30.4 ± 5.0 mm Hg; P = 0.1), dead space (132.7 ± 44.6 vs 138.23 ± 65.6-mL; P = 0.40), heart silo score (1.8 ± 0.6 vs 1.7 ± 0.8; P = 0.50), obstructive lung disease silo score (1.3 ± 0.8 vs 0.84 ± 0.9; P = 0.30), RER (0.9 ± 0.2 vs 1.0 ± 0.2; P = 0.60), and duration of test (4.15 ± 1.11 vs 3.1 ± 2.45 min; P = 0.10).

When comparing the baseline characteristics among treatment groups, the CPET parameters showed no statistical differences (Supplemental Table 4). The baseline deconditioning silo score was statistically different (1.9 ± 1.2 vs 1.9 ± 0.9 vs 2.6 ± 0.7; P = 0.007). In the follow-up, there were statistical differences in the observation vs BPA vs PTE groups in peak heart rate (120 ± 38.2 vs 115 ± 19.9 vs 98.5 ± 17.2; P = 0.019), resting SpO2 (94.6 ± 4.6 vs 95.1 ± 2.1 vs 96.9 ± 1.3; P = 0.025), resting PetCO₂ (30.8 ± 3.2 vs 28.2 ± 6.9 vs 21.8 ± 3.2; P = 0.027), and pulmonary vascular silo score (1.6 ± 0.7 vs 1.2 ± 0.5 vs 1 ± 0.5; P = 0.04).

We evaluated which parameters most directly correlated with the V_E/VCO₂ slope and PetCO₂ as they define evidence of ventilatory inefficiency. There was a positive correlation between V_E/VCO₂ and Shape-HF Severity Score (P < 0.001), but interestingly no correlation was seen with V_E/VCO₂ and 6MWT (P = 0.83) (Figure 2). The independent factors associated with V_E/VCO₂ slope that showed a positive correlation were mean PAP (P = 0.004), PVR (P = 0.02), and a negative correlation with PA compliance (P = 0.01) and BMI (P = 0.05) (Figure 3). Age, 6MWT, and baseline BNP did not correlate with V_E/VCO₂ slope. PetCO₂ did not correlate with age, BMI, mean PAP, CI, PA compliance, PVR, and baseline BNP.

Figure 3.

Association of VE/VCO₂ Slope with Hemodynamics

Relationship between baseline values of V_E/VCO₂ slope and mean pulmonary artery pressure (A), pulmonary vascular resistance (B), total pulmonary resistance (C), and pulmonary artery compliance (D). PA = pulmonary artery; PVR = pulmonary vascular resistance; TPR = total pulmonary resistance.

Discussion

The cause of the functional limitation is related to circulatory limitations or increased dead space ventilation in patients with CTEPH and CTEPD. In this prospective study, we were able to: 1) demonstrate the presence of ventilatory inefficiency in CTEPD and CTEPH with mild-to-moderate mean PAP elevation at rest; 2) demonstrate the improvement of CPET parameters (Shape-HF CPET score and V_E/VCO₂ slope) before and after BPA and PTE; and 3) identify independent factors associated with changes in V_E/VCO₂ slope (positive correlation with mean PAP [P = 0.004], PVR [P = 0.02], and negative correlation with PA compliance [P = 0.01] and BMI [P = 0.05]). This study adds to our understanding of gas exchange in patients with CTEPH and CTEPD who are undergoing PTE and BPA.

The CTEPH treatment algorithm includes a multimodal approach of medical therapy, BPA, and PTE.¹³ Surgical PTE is the only known cure for patients with accessible PA lesions,¹ as it normalizes PVR.¹⁴ The decision to undergo surgery is not only based on the anatomical disposition of the thromboembolic disease but also correlated with the severity of PH and comorbidities of the individuals. The candidate selection for definitive interventions will have an impact on the outcomes. We have incorporated the analysis of the Shape-HF CPET system to our algorithm to further phenotype the etiology of dyspnea in this population. Low-risk hemodynamics was classified based on markers of preserved RV adaptation to afterload. Invasive low-risk features included RA pressure <8 mm Hg and either cardiac index >2.5 L/min/m² or SVi >38 mL/m².¹⁵ Noninvasive low-risk features included preserved RV size and function on echocardiography and BNP <50 ng/L. These measures more directly reflect RV adaptation to pulmonary vascular disease. While on average, our sample cohort had some degree of PH preintervention, they also exhibited multiple low- or low-intermediate risk PH features as defined by current PH guidelines including, BNP, cardiac output (CO), right atrial pressure, and relatively preserved RV function. As a result, their resting studies did not adequately explain their degree of functional impairment. The incorporation of CPET data further allowed the phenotype evidence of increased dead space ventilation on exercise which could link chronic clot to their significant functional limitation (WHO-FC III). Eliciting increased dead space ventilation adds specificity when there are competing comorbidities which may lead to exercise impairment, as we saw with the positive correlation between V_E/VCO₂ and Shape-HF Severity Score. These same comorbidities limit the utility of WHO-FC or 6MWT due to their lack of specificity for CTEPD. We did not find correlation between V_E/VCO₂ and 6MWT (P = 0.83).

The Shape-HF CPET is a simplified CPET which allows a submaximal exercise step test and uses traditional symptom limited testing. It provides physiologic assessment of ventilatory efficiency in a format that is simpler and less resource-intensive than conventional CPET. The test can be performed as an extension of the office visit within the same clinical space and requires minimal equipment or physical space, allowing physiologic assessment to be incorporated into routine outpatient evaluation. Prior studies have validated the SHAPE system against conventional CPET platforms for submaximal exercise testing, demonstrating strong correlations for key gas exchange variables including VO₂ (r = 0.991), VCO₂ (r = 0.986), VE (r = 0.995), and PetCO₂ (r = 0.953).¹⁶ The automatic reports complete a comprehensive physiological assessment. The CPET parameters to evaluate pulmonary vascular disease are V_E/VCO₂, resting PetCO₂, oxygen uptake efficiency slope (OUES), O₂ saturation, and pulmonary vascular capacitance. The ventilatory efficiency slope (V_E/VCO₂) reflects efficient elimination of CO₂. A high slope depicts inefficient elimination of CO₂ and ventilation to perfusion mismatching in the lungs. The higher the slope, the more severe the ventilatory inefficiency suggestion of dead space physiology. Another important parameter is resting pulmonary perfusion (PetCO₂) which measured the pressure of CO₂ in the alveoli at the end of an expired breath. In normal subjects, the resting PetCO₂ values ≥ 34 mm Hg. A low PetCO₂ will imply lower CO/pulmonary blood flow. PetCO₂ can be significant lower in individuals with idiopathic pulmonary arterial hypertension and CTEPH.^17,18 Interestingly, PetCO₂ normalized after intervention, suggesting that after BPA and PTE there was resolution of the dead space ventilation. An additional parameter is OUES which assesses how well oxygen is extracted from the inhaled air, distributed to skeletal muscles by the heart/circulatory system, and utilized by the muscles in energy metabolism. OUES is derived as the plot of the log of minute ventilation (V_E) vs oxygen uptake (VO₂). A normal OUES is ≥2.12. A reduced slope depicts a patient with decreased oxygen uptake efficiency and is directly correlated with lower cardiopulmonary reserve in exercise. We did not see changes in this parameter before and after intervention in this cohort. Lastly, peak pulmonary vascular capacitance (GxCap) is a noninvasive exercise gas exchange correlate calculated at any point of the test using PetCO₂ × (change multiple symbol) O₂ pulse/heart beat. This value has an r = 0.86 to right heart catheterization determined PA capacitance using the formula PA capacitance = SV/PAP pulse pressure. The normal cutoff for GxCap is ≥400. We saw improvement in this parameter only after PTE.

There is prognostic relevance to exercise testing in CTEPD and CTEPH patients.^19,20 CPET provides risk-adapted initial evaluation and treatment of CTEPD and CTEPH, especially when there are competing causes of dyspnea (eg, obesity) or on follow-up to determine whether further optimization can be achieved with BPA sessions following PTE.²¹ Kim et al²² have utilized CPET in conjunction with exercise stress echocardiogram in CTEPD patients with mild or no PH at rest. They found that the presence of exercise impairment was related to reduced peak VO₂ correlated with worsening RV function apparent only on exercise. In a group of 32 patients with CTEPD without resting PH, Guth et al²³ demonstrated an improvement pre- vs post-PTE in the maximal exercise mean PAP (39 ± 8 vs 31 ± 6 mm Hg; P = 0.016), TPR (3.6 ± 0.8 WU to 2.7 ± 0.7 WU (P = 0.004), and mean PAP/CO slope (3.6 ± 1.0 to 2.3 ± 0.8 WU [P = 0.002]). They also demonstrated an increase in the peak O₂ uptake from 1.2 ± 0.4 to 1.5 ± 0.3 L·min-1 (P = 0.014) and a decrease V_E/VCO₂ slope from 39 ± 2 to 30 ± 2 (P = 0.002). We had similar findings post-BPA and PTE, as we demonstrated improvements in mean PAP, TPR, PA compliance, and V_E/VCO₂ slope. However, in contrast to these studies instead of formal CPET testing, we utilized the Shape-HF test. The advantages of the Shape-HF test include less equipment, physical space requirements, time requirements, and operator expertise compared to formal CPET testing. This allows for the Shape-HF test to be easily performed immediately after a clinic visit.

Taboada et al⁷ demonstrated that in patients with CTEPD undergoing PTE, there was no in-hospital mortality, but complications occurred in 40% of the patients, which suggests the importance of a cautious approach when selecting patients without severe hemodynamic phenotypes to undergo surgery to ensure that the risk-benefit ratio favors surgery. In our cohort, there was no in-hospital mortality, and there were no severe complications in the group that underwent PTE. In the case of BPA, there was an improvement in hemodynamics (PVR decrease 26% to 66%), right heart function, and exercise capacity.24, 25, 26, 27, 28, 29 We observed a 45% improvement in PVR in the patients with CTEPD and CTEPH with mild-to-moderate mean PAP, as well as an improvement in the PA compliance from 1.8 to 2.4 mL/mm Hg. No procedure-related complications were found in this group.

Interestingly, BPA and PTE had similar hemodynamics at baseline (mean PAP 38 and 39 mm Hg; CI 2.3 and 2.5 lpm/m²; TPR 8.8 and 7.9 WU, respectively) and gas exchange parameters (V_E/VCO₂ slope 44 and 41, rest PetCO₂ 28 and 30 mm Hg, respectively). Both groups (BPA and PTE) had improvement in the hemodynamics in follow-up (mean PAP 29 and 22 mm Hg; CI 2.6 and 2.6-lpm/m²; TPR 5.6 and 3.9 WU, respectively) and gas exchange parameters (V_E/VCO₂ slope 35 and 34, rest PetCO₂ 28 and 31 mm Hg, respectively). We noted improvements in the Shape-HF CPET score severity, WHO-FC, and BNP after interventions. Importantly, improvements in Shape-HF parameters showed a relationship with improvements in hemodynamic parameters, but no relationship to 6MWT. This highlights that CPET may provide better discrimination in serial assessment than 6MWT in a relatively low- or low-intermediate-risk PH group with other comorbidities which contribute to exercise impairment.

STUDY Limitations

There were limitations to our study. First, it was a single-center approach to the management of CTEPH. It is well-established that for severe CTEPH, the first-line therapy is surgical PTE, but PTE is a less-established first-line approach in patients with hemodynamically less severe disease with variability from center to center. The selection of therapy was related to center’s expertise. Our center is considered a CTEPH center given the volume of PTE 50/year and BPA 100/year.

We used submaximal CPET given the Shape-HF CPET System, suggested by a mean RER of 0.9 at end exercise, which did not allow us to establish a true peak VO₂ for our population. In submaximal testing, V_E/VCO₂ slope, O₂ uptake efficiency, and PetCO₂ can still be used for interpretation in patients with PH.^18,30 While the use of CPET testing in CTEPD is most tempting for those that have truly no resting PH, the sample size of this cohort of patients was quite small in this study. Only 7 patients had a mean PA < 20 mm Hg, and 4 had a mean PA between 20 and 24 mm Hg. However, the patients in our cohort had multiple low- or low-intermediate PH risk parameters and were able to exercise and ambulate. In average, they had at baseline 6MWT of 375 m, which is comparable to a WHO-FC between II and III. Hence, the inability to reproduce these findings in individuals who cannot complete exercise testing. To mitigate bias, we recoded WHO-FC before the 6MWD or CPET data were completed. From the control group, 2 individuals refused pulmonary vasodilators/BPA/PTE, 3 started PH medical therapy, and 3 did not qualify for any pulmonary vasodilators. The cohort did not demonstrate the effect of BPA or PTE, it showed that the gas exchange parameters did not change in the 3-month range, and this is reassuring when discussing lack variability of the results of the CPET over time. Some variability occurs in this cohort in their hemodynamics and 6MWT, but it was not statistically significant.

There is heterogeneity in the timing of postintervention hemodynamic assessment among the treatment groups. Patients undergoing BPA had hemodynamic measurements obtained 3 months after their final session, whereas PTE patients had measurements obtained in the immediate postoperative period. Previous studies have shown that residual PH can be present within the first 48 to 72 hours following surgery; this early postoperative value is what we reported. However, we acknowledge that further hemodynamic improvement may occur as the pulmonary vascular bed recovers after endarterectomy. This possibility is supported by the notable improvement in BNP matches the improved hemodynamics observed at the 3-month follow-up visit after PTE.

Conclusions

CPET can help with understanding the underlying mechanism of dyspnea in CTEPD and CTEPH. The Shape-HF CPET System is a convenient method which provides an objective assessment of gas-exchange improvement after pulmonary revascularization.

Perspectives.

COMPETENCY IN MEDICAL KNOWLEDGE 1: Patients with CTEPD and CTEPH frequently present with exertional dyspnea that is not fully explained by resting hemodynamics or increased dead space ventilation alone, particularly in those with multiple competing comorbidities. Conventional assessments, including WHO functional class and the 6MWT frequently lack the specificity to distinguish pulmonary vascular limitation from other contributors to exercise intolerance.

COMPETENCY IN MEDICAL KNOWLEDGE 2: Point-of-care CPET using the SHAPE-HF system is feasible in the outpatient setting and provides objective, physiologically relevant measures of pulmonary vascular limitation beyond resting hemodynamic assessment alone, helping clinicians better contextualize symptoms and evaluate candidacy for therapeutic intervention.

TRANSLATIONAL OUTLOOK: Both BPA and PTE result in substantial improvements in V_E/VCO₂ slope and SHAPE-HF severity scores, suggesting meaningful physiologic recovery not adequately captured by traditional clinical metrics. Incorporating point-of-care CPET into routine evaluation may enhance patient selection, refine treatment decision, and provide a more sensitive measure of therapeutic response.

Funding support and author disclosures

Johnson and Johnson Sponsored Award–American College of Cardiology Clinical Trial Award 2022. The authors have reported that they have no relationships relevant to the contents of this paper to disclose.