Exercise-induced desaturation during a six-minute walk test is associated with poor clinical outcomes in patients with pulmonary arterial hypertension

This was a single-center, retrospective, and observational cohort study of patients with pulmonary arterial hypertension (PAH) confirmed by right heart catheterization (RHC) between April 2016 and March 2021. The types of PAH were categorized according to etiologies, including idiopathic, congenital heart disease (CHD)-associated, connective tissue disease (CTD)-associated, and portopulmonary hypertension. Patients with any uncorrected CHD and suspected PAH unconfirmed by RHC were excluded. Additionally, patients in a decompensated state requiring advanced or intravenous medical therapy, patients who were not able to walk without oxygen support, and patients with other physical problems which interfered with exercise were also excluded.

The study protocol was approved by the institutional review board of the Pusan National University Hospital (approval number: H-1903–018-077). The clinical trial number is KCT0005132. This study was conducted according to the principles of the Declaration of Helsinki, and the requirement for informed consent was waived due to the retrospective nature of the research.

We assessed baseline demographic data and past medical history from the patients' medical records. Baseline anthropometric measurements were performed on the day of RHC. Body mass index (BMI) was calculated using height and weight with the standard formula. Hypertension was confirmed as the use of antihypertensive medication for a duration of more than 6 months, or a previous diagnosis of hypertension and being solely on lifestyle modification treatment.

Patients with diabetes mellitus (DM) were identified as those who were actively receiving treatment with oral hypoglycemic agents or insulin, or who had an abnormal fasting glucose level (≥ 126 mg/dL) or an abnormal 2-h postprandial glucose level (≥ 200 mg/dL) and were being treated with dietary modification only.

Risk assessment of PAH patients was done with the 3-strata model, low-, intermediate-, and high-risk, recommended in the current treatment guidelines depending on progression of symptoms and clinical manifestations, presence of syncope, World Health Organization (WHO) functional class, total distance at the 6MWT, cardiopulomonary exercise test, biomarkers, echocardiographic and cardiac magnetic resonance imaging data, and hemodynamic data.(Ref. 2) Because current treatment guidelines introduced in 2022, we used risk stratification model suggested by the previous guidelines [6].

We defined adverse clinical events as any of the following events that occurred during the follow-up period after the diagnosis including re-admission due to cardiopulmonary problem, lung transplantation surgery, and death.

All images were obtained using standard echocardiographic machines with standard techniques according to the American Society of Echocardiography guidelines [7]. Left ventricular (LV) end-diastolic and end-systolic volumes were calculated using the two-dimensional Simpson's method from the apical 2- and 4-chamber views, and left ventricular ejection fraction (LVEF) was calculated from these values [8]. Pulmonary arterial systolic pressure (PASP) was estimated from the peak tricuspid regurgitation jet velocity (TR Vmax) derived from the continuous wave Doppler tracing [9]. Right atrial (RA) pressure was estimated from the size and collapsibility of the inferior vena cava (IVC). RA area was calculated from the RV-focused apical 4-chamber view. Tricuspid annular plane systolic excursion (TAPSE) was measured as the distance between the end-diastolic and peak systolic points of the lateral tricuspid annulus. Tricuspid annular systolic velocity was measured at the lateral tricuspid annulus by pulsed-wave Doppler.

RHC was performed using a Swan-Ganz catheter via the right internal jugular vein. The mean pulmonary artery pressure (mPAP), pulmonary capillary wedge pressure (PCWP), and pulmonary vascular resistance (PVR) were measured and calculated according to the recent treatment guidelines of pulmonary hypertension.^{1, 2} Cardiac output (CO) was evaluated with a thermodilution method, and cardiac index (CI) was calculated as CO divided by body surface area.

A single, well-trained medical laboratory technologist administered the PFT using PONY Fx (Cosmed, Rome, Italy). All patients performed three repetitions, and the best result was accepted when the difference between each trial was within 0.150 L according to the 2017 American Thoracic Society (ATS) statement [10]. Standard spirometric measurements such as forced vital capacity, forced expiratory volume at one second (FEV1), and diffusing capacity of the lung for carbon monoxide (DLCO), were assessed.

Exercise performance was evaluated using the 6MWT with percutaneous oxygen saturation (SpO₂) monitoring and gas analysis. We used the result of the 6MWT close to the time of diagnosis of PAH. We used the result of 6MWT near the time of the diagnosis of PAH. The exercise tests were performed when the patient was in a medically stable state just before discharge or at the outpatient clinic. 6MWT was performed on a 30-m walking track according to the ATS guidelines and observed by one skilled physical therapist [11]. SpO₂ was observed using the wrist Ox 3150 pulse oximeter (Nonin Medical, Plymouth, MN) during the 6MWT. Using the K4b² system (Cosmed, Rome, Italy), peak oxygen uptake (VO₂peak) and the minute ventilation/carbon dioxide production (VE/VCO₂) slope were measured simultaneously [12].

We analyzed a total of 20 PAH patients (16 females, aged 48.4 ± 13.3 years) and summarized their baseline data in Table 1. Idiopathic PAH was the most common etiology (35%), and about 50% of patients had WHO functional class 3 and 4. At the diagnosis, 65% of patients were classified as low-risk profile.

Of total 20 patients, 10 had EID during the 6MWT. Comparison of variables according to the presence of EID is presented in Table 1. There was no statistical significance of clinical, echocardiographic and RHC variables between two groups. However, EID group had significantly lower predictive percentage of FEV1 (69.3 ± 14.7% vs. 81.4 ± 6.1%, P = 0.035). Also, EID group had significantly lower 6MWD (354.3 ± 124.4 m vs. 485.4 ± 41.4 m, P = 0.019) and lower peak VO₂ (12.9 ± 3.2 mL/kg⋅min vs. 16.4 ± 3.6 mL/kg⋅min, P = 0.019) during the 6MWT.

During the total follow-up duration of 51.9 ± 25.7 months, 17 patients had at least one adverse clinical event (2 deaths, 1 lung transplantation, and 13 hospital admissions). The results of univariate Cox-proportional hazard analysis are summarized in Table 2. Of several variables, high-risk profile at the diagnosis [hazard ratio (HR) = 4.745, 95% confidence interval (CI) = , P = 0.014], and 6MWD (HR = 0.992, 95% CI = 0.986–0.998, P = 0.009) were significantly associated with adverse clinical events. Also, EID was a significant determinant of adverse clinical event (HR = 6.099, 95% CI = 1.783–20.869, P = 0.004, Fig. 1).