Exercise intolerance in chronic thromboembolic pulmonary hypertension after pulmonary angioplasty

Hanako Kikuchi, Ayumi Goda, Kaori Takeuchi, Takumi Inami, Takashi Kohno, Konomi Sakata, Kyoko Soejima, Toru Satoh
European Respiratory Journal 2020 56: 1901982; DOI: 10.1183/13993003.01982-2019

Abstract

Introduction Exercise pulmonary hypertension is common in patients with chronic thromboembolic pulmonary hypertension (CTEPH) who experience shortness of breath during exercise and reduced exercise capacity despite normalised pulmonary arterial pressure (PAP) at rest; however, the relationship between exercise pulmonary hypertension and exercise capacity remains unclear. Here we aimed to determine whether exercise pulmonary hypertension is related to exercise capacity and ventilatory efficiency in CTEPH patients with normalised resting haemodynamics after pulmonary balloon angioplasty (BPA).

Patients and methods In total, 249 patients with CTEPH treated with BPA (mean±sd age 63±14 years; male:female 62:187) with normal mean PAP (mPAP) (<25 mmHg) and pulmonary arterial wedge pressure (≤15 mmHg) at rest underwent cardiopulmonary exercise testing with right heart catheterisation. mPAP–cardiac output (CO) during exercise was plotted using multipoint plots. Exercise pulmonary hypertension was defined by a mPAP–CO slope >3.0.

Results At rest, pulmonary vascular resistance was significantly higher in the exercise pulmonary hypertension group (n=116) than in the non-exercise pulmonary hypertension group (n=133). Lower peak oxygen consumption (13.5±3.8 versus 16.6±4.7 mL·min−1·kg−1; p<0.001) was observed in the former group. The mPAP–CO slope was negatively correlated with peak oxygen consumption (r= −0.45, p<0.001) and positively correlated with the minute ventilation versus carbon dioxide output slope (r=0.39, p<0.001).

Conclusions Impaired exercise capacity and ventilatory efficiency were observed in patients with CTEPH who had normalised PAP at rest but exercise pulmonary hypertension.

Abstract

Impaired exercise capacity and ventilatory efficiency were observed in patients with chronic thromboembolic pulmonary hypertension after BPA who had normalised pulmonary arterial pressure at rest but exercise pulmonary hypertension https://bit.ly/2JujDh1

Introduction

With advancements in the treatment of chronic thromboembolic pulmonary hypertension (CTEPH), including balloon pulmonary angioplasty (BPA), an increasing number of patients gradually achieve normal haemodynamics and mean pulmonary arterial pressure (mPAP) [1–4]. However, after BPA, some patients still have shortness of breath during exercise and a reduced exercise capacity despite an improved prognosis and normalisation of PAP at rest. Exercise capacity improvement immediately after BPA remains insufficient despite remarkably improved resting haemodynamics. Thus, exercise intolerance and symptoms on effort are also important issues for CTEPH after BPA [5]. In these patients, an abnormal response to PAP during exercise is observed after BPA, as well as after pulmonary endarterectomy (PEA) [6–8].

Recently, exercise pulmonary hypertension, defined as mPAP >30 mmHg at cardiac output (CO) 10 L·min−1 during exercise, has been considered a mild degree of pulmonary hypertension with mPAP <25 mmHg at rest. Exercise pulmonary hypertension may be indicative of pulmonary vasculopathy [9–11].

The prognosis, natural history and clinical characteristics of patients with CTEPH and exercise pulmonary hypertension after BPA have yet to be clarified. There are only a few reports on exercise capacity and ventilatory efficiency in patients with CTEPH and normalised haemodynamics after BPA [5].

This study aimed to determine whether exercise pulmonary hypertension among CTEPH patients with normalised resting haemodynamics after BPA is related to exercise capacity and ventilatory efficiency.

Patients and methods

This study was approved by the Committee for Clinical Studies and Ethics of Kyorin University School of Medicine, Tokyo, Japan (approval 490).

Study patients

Consecutive patients who underwent cardiopulmonary exercise testing with right heart catheterisation (RHC) at Kyorin University Hospital between May 2012 and August 2019 with CTEPH after treatment with BPA were considered eligible for this study.

Patients with high mPAP (≥25 mmHg) and/or pulmonary arterial wedge pressure (PAWP) elevation (>15 mmHg) at rest were excluded. Those whose data during exercise could not be used due to technical or mechanical difficulty were excluded. Patients who exhibited poor effort on the exercise test were also excluded.

Among patients with normal PAP and PAWP at rest, those with exercise PAWP elevation were excluded from the analysis. PAWP 25 mmHg at peak exercise was considered definite exercise-induced post-capillary pulmonary hypertension.

The purposes and risks of the study were explained to the patients, each of whom provided informed consent prior to participating.

RHC and cardiopulmonary exercise testing

RHC was performed using a 6-Fr double-lumen balloon-tipped flow-directed Swan–Ganz catheter (Harmac Medical Products, Buffalo, NY, USA) via the transjugular approach.

Baseline haemodynamic data were recorded; the zero reference level (mid-chest) was adjusted at the start of pressure measurement and PAWP was obtained as the mean value of the arterial trace during occlusion. Measurements were obtained at the end of a normal expiration with the patients in the supine position at the resting state to assess the right chamber, PAP (mPAP, systolic PAP and diastolic PAP) and PAWP [12].

An incremental symptom-limited exercise test was performed in the supine position using an electromagnetically braked cycle ergometer (Nuclear Imaging Table with Angio Ergometer; Lode, Groningen, Netherlands) according to the ramp protocol. For cycling, the legs were elevated. The test consisted of a 3-min rest period, followed by a 3-min warm-up at an ergometer setting of 10 W (60 revolutions·min−1) and testing with a 1 W increase in exercise load every 6 s (totalling 10 W·min−1).

During exercise, oxygen consumption (V′O2), carbon dioxide output (V′CO2) and minute ventilation (V′E) were measured using a metabolic cart (Cpex-1; Inter Reha, Tokyo, Japan). Prior to calculating the parameters from the respiratory gas analysis, an eight-point moving average of the breath-by-breath data was obtained. Peak V′O2 was defined as the average value obtained during the last 30 s of exercise. The anaerobic threshold point was determined using the V′ slope method in addition to the following conventional criteria: increased V′E/V′O2 after registering as flat or decreasing and constant or decreased V′E/V′CO2 [13, 14]. The V′E versus V′CO2 slope was calculated from the start of the incremental exercise to the respiratory compensation point using least-squares linear regression [15, 16].

Heart rate, arterial blood pressure directly recorded in the radial artery and electrocardiographic findings were monitored continuously during the test. PAP and PAWP during RHC were also measured every minute. We used average mPAP and mean PAWP during several-second periods rather than end-expiratory measurements during the exercise testing.

Arterial oxygen saturation (SaO2), partial pressure of arterial oxygen (PaO2), partial pressure of arterial carbon dioxide (PaCO2) in the radial artery and mixed venous oxygen saturation (SvO2) in the pulmonary artery were measured at rest, anaerobic threshold and peak exercise. CO was determined via the Fick method using the following formula: CO (L·min−1)=V′O2/(1.34×haemoglobin level×(SaO2−SvO2)). The arterial mixed venous oxygen content difference (Ca−vO2) was calculated as: 1.34×haemoglobin level×(SaO2−SvO2)/1000. Pulmonary vascular resistance (PVR) was calculated as: PVR (Wood Units (WU))=(mPAP−PAWP)/CO. All measurements during exercise testing were performed without supplemental oxygen.

The slope of the mPAP–flow relationship (mPAP–CO slope) was calculated from multipoint plots of mPAP and CO using least-squares linear regression. Exercise pulmonary hypertension was defined as a mPAP–CO slope >3 and/or mPAP >30 mmHg at CO 10 L·min−1.

Echocardiography

Transthoracic Doppler echocardiography at rest was performed within 3 months from the RHC and the results were stored digitally on the Artida (Toshiba, Tokyo, Japan) or EPIQ (Philips Healthcare, Cambridge, MA, USA) ultrasound system. On echocardiography, each patient was provided with a unique identification number to ensure the blind analysis of the images and patient characteristics. The frame rate was kept at a minimum of 60 frames·s−1. For Doppler recordings, the average of three to five consecutive beats was measured using a horizontal sweep of 75–100 cm·s−1.

Left ventricular dimensions and left atrial diameter were measured from the parasternal long-axis view. Left ventricular ejection fraction was calculated using Simpson's biplane method from the apical four- and two-chamber views.

Mitral inflow was assessed in the apical four-chamber view with the pulsed-wave Doppler sample volume placed at the tips of the mitral valve leaflets during diastole. From the pulsed-wave Doppler mode positioned at the tip of the mitral valve, the early (E) and late (A) peak diastolic velocities of the mitral inflow and the E-wave deceleration time were measured. Mitral annular motion was assessed using pulsed-wave tissue Doppler with the sample volume placed in the septal (e′ septal) and lateral (e′ lateral) mitral annuli. The E/e′ ratio was then calculated.

Right ventricular systolic function was assessed by measuring tricuspid annular plane systolic excursion (TAPSE). Right ventricular end-diastolic area (RVEDarea) and end-systolic area (RVESarea) were assessed via manual planimetry in the apical four-chamber view, and right ventricular fractional area change (RVFAC) was derived using: RVFAC=((RVEDarea−RVESarea)/RVEDarea)×100. Systolic tricuspid valve lateral annular velocity was measured using an analogous method over the anterior leaflet in the long-axis view of the right ventricle [17].

Statistical analysis

Data are presented as mean with standard deviation or median (interquartile range) as appropriate; categorical variables are expressed as numbers and percentages. The Shapiro–Wilk test was used to assess the normality of the data distribution. All continuous variables, except for brain natriuretic peptide level and interval from BPA, were distributed normally. The correlations between the mPAP–CO slope and cardiopulmonary exercise parameters were assessed using Pearson's correlation analysis. Statistical comparisons were considered significant at p<0.05. All analyses were performed using SPSS version 11.0 (SPSS, Chicago, IL, USA).

Results

Baseline data

The patient flowchart is shown in figure 1. Among the 375 patients who underwent exercise testing, 47 were excluded due to high PAP and/or PAWP at rest, 17 due to mechanical and technical difficulties, and 12 due to poor effort. Among the 299 patients with normal PAP and PAWP at rest, 50 showed PAWP elevation at peak exercise and were excluded. Finally, 249 patients (mean±sd age 63±14 years; male:female 62:187) were analysed. There were 116 patients in the exercise pulmonary hypertension group and 133 patients in the non-exercise pulmonary hypertension group. The baseline characteristics of the study groups classified by the presence or absence of exercise pulmonary hypertension are shown in table 1.

FIGURE 1
FIGURE 1

Flowchart of patients with chronic thromboembolic pulmonary hypertension (CTEPH) after balloon pulmonary angioplasty (BPA) who underwent cardiopulmonary exercise testing with right heart catheterisation. PAP: pulmonary arterial pressure; PAWP: pulmonary arterial wedge pressure.

View this table:
TABLE 1

Baseline characteristics of the study patients at rest

The patients with good haemodynamics at rest but dyspnoea on exertion and abnormal haemodynamics on exercise underwent an additional BPA session when the flow-limiting pulmonary artery had a treatable anatomy. 32 patients in our cohort received the additional BPA.

The distributions of mPAP by group are shown in figure 2.

FIGURE 2
FIGURE 2

Distribution of resting mean pulmonary arterial pressure (mPAP) and exercise pulmonary hypertension.

The exercise pulmonary hypertension group patients (n=116) were older and had higher brain natriuretic peptide levels, lower CO (4.6±1.3 versus 5.1±1.6 L·min−1; p=0.002) and higher PVR (2.5±1.0 versus 2.0±0.9 WU; p<0.001) at rest than the non-exercise pulmonary hypertension group patients (n=133).

More patients in the exercise pulmonary hypertension than non-exercise pulmonary hypertension group required ambulatory oxygen therapy (34% versus 20%; p=0.012) and prior PEA (15% versus 4%; p=0.003). The number of BPA sessions and interval from BPA did not differ significantly between the two groups. World Health Organization Functional Class was significantly higher and 6-min walk distance was significantly lower (432±102 versus 462±105 m; p=0.024) in the exercise pulmonary hypertension group. The prescription rate of soluble guanylate cyclase stimulators (SGCSs) was significantly lower in the exercise pulmonary hypertension group than in the non-exercise pulmonary hypertension group (34% versus 20%; p=0.012). All study patients were taking anticoagulants.

Exercise data

The exercise test responses at rest (after leg raise), anaerobic threshold and peak exercise are listed in table 2. Mean peak V′O2 was 14.4±3.9 mL·min−1·kg−1, with a respiratory quotient of 1.06±0.10, consistent with near-maximal effort.

View this table:
TABLE 2

Exercise parameters

The relationship of mPAP according to CO in each group is shown in figure 3. mPAP was higher in the exercise pulmonary hypertension group during exercise than in the non-exercise pulmonary hypertension group (anaerobic threshold: 40±8 versus 34±6 mmHg; p<0.001; peak: 44±8 versus 37±7 mmHg; p<0.001). CO was significantly lower during exercise in the exercise pulmonary hypertension group than in the non-exercise pulmonary hypertension group (anaerobic threshold: 8.2±2.1 versus 10.9±3.2 L·min−1; p<0.001; peak: 9.0±2.4 versus 12.6±3.8 L·min−1; p<0.001). Ca−vO2 in the exercise pulmonary hypertension group was also more impaired than in the non-exercise pulmonary hypertension group.

FIGURE 3
FIGURE 3

Relationship of cardiac output (CO) with mean pulmonary arterial pressure (mPAP) during exercise. *: p<0.05; **: p<0.001 (exercise pulmonary hypertension group versus non-exercise pulmonary hypertension group).

Absolute V′E during exercise in the exercise pulmonary hypertension group was lower; however, V′E at any given CO in the exercise pulmonary hypertension group was increased. The plot of V′E/V′CO2 as a function of PaCO2 measured at anaerobic threshold is shown in figure 4. V′E/V′CO2 at anaerobic threshold was significantly increased in the exercise pulmonary hypertension group (42.7±8.3 versus 39.3±7.1; p=0.001), whereas PaCO2 at anaerobic threshold was similar between both groups.

FIGURE 4
FIGURE 4

Plot of minute ventilation (V′E)/carbon dioxide output (V′CO2) as a function of arterial carbon dioxide tension (PaCO2) measured at anaerobic threshold. V′E/V′CO2 at anaerobic threshold was significantly increased in the exercise pulmonary hypertension group, whereas PaCO2 at anaerobic threshold was similar between both groups.

Lower peak V′O2 (13.5±3.8 versus 16.6±4.7 mL·min−1·kg−1; p<0.001) and higher V′E versus V′CO2 slope (39.7±9.0 versus 35.2±7.5; p<0.001) were observed in the exercise pulmonary hypertension group.

Relationship between the mPAP–CO slope and exercise capacity and ventilatory efficiency

The correlations between the mPAP–CO slope and peak V′O2 and between the mPAP–CO slope and the V′E versus V′CO2 slope are shown in figure 5. Peak V′O2 was negatively correlated with the mPAP–CO slope (r= −0.45, p<0.001), while the V′E versus V′CO2 slope was positively correlated with the mPAP–CO slope (r=0.39, p<0.001).

FIGURE 5
FIGURE 5

Correlation of the mean pulmonary arterial pressure (mPAP)–cardiac output (CO) slope with a) peak oxygen consumption (V′O2) and b) the minute ventilation (V′E) versus carbon dioxide output (V′CO2) slope. Peak V′O2 was negatively correlated with the mPAP–CO slope, while the V′E versus V′CO2 slope was positively correlated with the mPAP–CO slope.

Echocardiographic parameters

Echocardiographic data were obtained from 208 patients. The echocardiographic parameters of the two groups are shown in table 3. TAPSE in the exercise pulmonary hypertension group was significantly shorter than in the non-exercise pulmonary hypertension group (21.0±4.0 versus 22.4±4.0 mm; p=0.013).

View this table:
TABLE 3

Resting echocardiographic parameters

Discussion

The present study revealed that impaired exercise capacity and ventilatory efficiency are observed in patients with CTEPH after BPA who have a normalised PAP at rest but have exercise pulmonary hypertension.

Definition of exercise pulmonary hypertension

Recently, exercise pulmonary hypertension, defined as mPAP >30 mmHg at CO 10 L·min−1 on exercise, has been recognised as a mild degree of pulmonary hypertension with mPAP <25 mmHg at rest [9–11]. Additionally, mPAP–CO slopes >3.0, which are defined as being linearly correlated based on serial measurements of mPAP and CO during incremental exercise, reflect an abnormal pulmonary vascular response to exercise [18]. Exercise pulmonary hypertension screened by echocardiography can detect early pulmonary hypertension in patients with connective tissue disease [19]. In patients with pulmonary arterial hypertension (PAH) or CTEPH, the pressure–flow relationship during exercise predicted survival and was correlated with the established markers of disease severity and outcome [20]. Thus, exercise pulmonary hypertension may be indicative of pulmonary vasculopathy.

According to the 2015 European Society of Cardiology/European Respiratory Society guideline, pulmonary hypertension is defined as an elevation of mPAP to ≥25 mmHg [21]. However, the physiological upper limit of normal mPAP is considered 20 mmHg [22]. Douschan et al. [23] reported that a mildly increased mPAP to 17–20 mmHg is associated with decreased physical capacity and increased mortality, whereas an elevation of mPAP to 21–24 mmHg is an independent predictor of mortality versus normal mPAP. In our cohort, the average mPAP in the exercise pulmonary hypertension group was 19 mmHg. We speculate that the exercise pulmonary hypertension group showed a lower mPAP because, even at the same value of resting mPAP, CO varies and must be evaluated with the consideration of PVR. In our study patients, the resting PVR in the exercise pulmonary hypertension group was significantly higher than in the non-exercise pulmonary hypertension group.

Cause of residual shortness of breath after CTEPH treatment

BPA and PEA significantly improve the prognosis and quality of life of patients with CTEPH [1, 3]. However, some operated patients continue to experience limited exercise capacity despite normalisation of resting PAP and PVR [7]. Bonderman et al. [6] reported that, after successful PEA, patients with persistent exertional dyspnoea displayed an abnormal pulmonary haemodynamic response to exercise characterised by an increased PVR and decreased pulmonary compliance. Richter et al. [8] examined the haemodynamics before and after PEA, and reported that a flattened mPAP–CO slope indicated an increased capacity of the pulmonary vasculature for a higher CO after PEA. Thus, exercise-induced pulmonary hypertension is one factor related to exercise intolerance in patients with a normalised CTEPH after PEA.

The 6th World Symposium on Pulmonary Hypertension in 2018 included exercise pulmonary hypertension in its definition of chronic thromboembolic disease (CTED) [24]. van Kan et al. [25] reported that patients with CTED showed an abnormal pulmonary vascular response to exercise and decreased ventilator efficiency. Exercise capacity was reduced by 29% and 57% in patients with CTED and CTEPH, respectively, compared with control subjects [26]. The clinical phenotype of CTED in terms of exercise tolerance and cardiac reserve is considered to be between normal and CTEPH.

We previously reported that BPA for CTED positively impacts exercise tolerance and ventilation efficiency [27]. This may suggest the possible significance of BPA for CTED with exercise pulmonary hypertension. If patients with CTEPH after BPA or PEA have exercise pulmonary hypertension, additional treatment might be considered in terms of improving their exercise tolerance and ventilatory efficiency.

Mechanism of exercise capacity and ventilatory efficiency

Pulmonary vascular diseases cause haemodynamic resistance in the central circulation, making it difficult for the right ventricle to deliver blood to the left atrium at a sufficient rate to meet the increased CO needed for exercise. Because the CO increase in response to exercise is reduced, anaerobic threshold and peak V′O2 are impaired in patients with pulmonary vascular diseases [28, 29]. Even in patients with pulmonary hypertension only, the increase in CO during exercise is thought to be hindered.

Pulmonary vascular diseases are associated with hypoperfusion of the ventilated alveoli, particularly during exercise. Consequently, the alveoli with non-occluded capillaries must accept a greater than normal perfusion and be ventilated to a proportionately greater degree than normal to remove carbon dioxide and to maintain PaCO2, PaO2 and pulmonary hypertension at appropriate values. Because of the increase in physiological dead space ventilation, V′E is increased in patients with pulmonary vascular diseases at rest and to a greater degree during exercise [29–31]. The increased dead space ventilation results in a higher V′E versus V′CO2 slope.

An additional reason for the increased ventilator drive during exercise in patients with pulmonary vascular diseases is arterial hypoxaemia, which worsens during exercise. In the presence of pulmonary vascular diseases, the functional capillary bed is destroyed and the capillary bed reserved for recruitment during exercise is already recruited at rest. This is considered the cause of arterial hypoxaemia. The decrease in PaO2 stimulates chemoreceptors that stimulate ventilation. Even in our cases, exercise pulmonary hypertension showed greater hypoxaemia, which may be attributed to the mechanism of hyperventilation and ventilation–perfusion mismatch. Ulrich et al. [32] reported that the oxygen supply in PAH/CTEPH patients increased in exercise performance and reduced the excessive ventilatory response to exercise. This finding is consistent with that of our study. Plots of V′E/V′CO2 as a function of PaCO2 measured at anaerobic threshold are reportedly useful in determining whether the ventilatory inefficiency was due to increased dead space ventilation or increased chemosensitivity [33]. From our plots between V′E/V′CO2 and PaCO2 at anaerobic threshold, the breathlessness in patients with exercise pulmonary hypertension is thought to be contributed to by the increase in physiological dead space ventilation compared with non-exercise pulmonary hypertension.

Effects of right ventricle function

Regarding resting right ventricle function measured on echocardiography, except for TAPSE, there were no significant intergroup differences. This finding is consistent with those of previous reports. If the right ventricle function at peak exercise was measured, a difference might have been observed [7, 26].

There are no data showing that patients with a normalised PAP but with exercise pulmonary hypertension have worse outcomes. The benefit of PAH-specific drugs in patients with a normalised pressure and CTEPH would be for exercise capacity and ventilator efficiency, but supporting data are lacking. In this observational study, the prescription rate of SGCSs was significantly lower in the exercise pulmonary hypertension group. SGCSs may be effective in residual small vessel disease that are not dilated by BPA and might be beneficial for haemodynamic response to exercise in patients with stronger small vessel disease. Our data would actually support the premise that PAH-specific drugs may improve the response to exercise, which is linked to improved symptoms. In cases where exercise pulmonary hypertension and symptoms persist, but where it is difficult to perform BPA, SGCSs might be a therapeutic option. Thus, future randomised controlled trials are needed to elucidate this point.

Study limitations

Our study population did not include patients with high mPAP at rest or completely normal pulmonary vascular function.

Age is an important confounder of the pulmonary vascular response to exercise. It was reported that resting PAP also increases in the elderly [22]. PAP during exercise may also increase in the elderly. Age would have slightly affected exercise tolerance and echocardiographic parameters.

Respiratory function test data are also lacking; thus, the effect of respiratory function on exercise pulmonary hypertension is unknown.

Conclusions

Impaired exercise capacity and ventilatory efficiency are observed in patients with CTEPH after BPA, normalised PAP at rest and exercise pulmonary hypertension.

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Supplementary Material

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Footnotes

  • Author contributions: A. Goda and H. Kikuchi designed the study, analysed the data and wrote the manuscript. T. Kohno, K. Sakata, T. Satoh and K. Soejima reviewed the data and edited the manuscript. K. Takeuchi, H. Kikuchi, A. Goda and T. Inami performed the exercise tests and BPA.

  • Conflict of interest: H. Kikuchi has nothing to disclose.

  • Conflict of interest: A. Goda has nothing to disclose.

  • Conflict of interest: K. Takeuchi has nothing to disclose.

  • Conflict of interest: T. Inami has nothing to disclose.

  • Conflict of interest: T. Kohno has nothing to disclose.

  • Conflict of interest: K. Sakata has nothing to disclose.

  • Conflict of interest: K. Soejima has nothing to disclose.

  • Conflict of interest: T. Satoh has nothing to disclose.

  • Received October 10, 2019.
  • Accepted March 26, 2020.

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Exercise intolerance in chronic thromboembolic pulmonary hypertension after pulmonary angioplasty
Hanako Kikuchi, Ayumi Goda, Kaori Takeuchi, Takumi Inami, Takashi Kohno, Konomi Sakata, Kyoko Soejima, Toru Satoh
European Respiratory Journal Jul 2020, 56 (1) 1901982; DOI: 10.1183/13993003.01982-2019
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