In pulmonary hypertension, exercise is limited by an impaired right ventricular (RV) stroke volume response. We hypothesized that improvement in exercise capacity after pulmonary endarterectomy (PEA) for chronic thromboembolic pulmonary hypertension (CTEPH) is paralleled by an improved RV stroke volume response. We studied the extent of PEA-induced restoration of RV stroke volume index (SVI) response to exercise using cardiac magnetic resonance imaging (cMRI). Patients with CTEPH (n = 18) and 7 healthy volunteers were included. Cardiopulmonary exercise testing and cMRI were performed before and 1 year after PEA. For cMRI studies, pre- and post-operatively, all patients exercised at 40% of their preoperative cardiopulmonary exercise testing–assessed maximal workload. Post-PEA patients (n = 13) also exercised at 40% of their postoperative maximal workload. Control subjects exercised at 40% of their predicted maximal workload. Preoperatively, SVI (n = 18) decreased during exercise from 35.9 ± 7.4 to 33.0 ± 9.0 ml·m 2 (p = 0.023); in the control subjects, SVI increased (46.6 ± 7.6 vs 57.9 ± 11.8 ml·m −2 , p = 0.001). After PEA, the SVI response (ΔSVI) improved from −2.8 ± 4.6 to 4.0 ± 4.6 ml·m 2 (p <0.001; n = 17). On exercise at 40% of the postoperative maximal workload, SVI did not increase further and was still significantly lower compared with controls. Moreover, 4 patients retained a negative SVI response, despite (near) normalization of their pulmonary hemodynamics. The improvement in SVI response was accompanied by an increased exercise tolerance and restoration of RV remodeling. In conclusion, in CTEPH, exercise is limited by an impaired stroke volume response. PEA induces a restoration of SVI response to exercise that appears, however, incomplete and not evident in all patients.
In pulmonary hypertension (PH), a reduced exercise capacity is the main symptom. In PH, exercise is limited by the inability of the heart to sufficiently increase pulmonary blood flow because of a decreased right ventricular (RV) stroke volume (SV) response to exercise.
In chronic thromboembolic pulmonary hypertension (CTEPH), pulmonary endarterectomy (PEA) is the therapy of choice. PEA improves and often (near) normalizes pulmonary hemodynamics, resulting in improvement in exercise capacity and long-term survival. Moreover, PEA was found to induce restoration of cardiac remodeling, which was associated with improvement of RV function at rest. We hypothesized that postoperative improvement in exercise capacity is paralleled by an improved RV SV response. The aim of this study was to determine the extent of the PEA-induced restoration of RV SV response to exercise using cardiac magnetic resonance imaging (cMRI).
Methods
Patients with operable CTEPH were eligible for this study. CTEPH diagnosis was established based on reported procedures, by pulmonary angiography and right-sided cardiac catheterization. Preoperative routine workup included a 6-minute walk test and symptom-limited cardiopulmonary exercise testing (CPET). cMRI was performed within 1 week of the preassessed CPET. Postoperative hemodynamics were determined on the first or second day after PEA, before removal of the Swan-Ganz catheter. Both CPET and cMRI measurements were reassessed 1 year after PEA. A group of healthy control subjects was recruited, who underwent cMRI at rest and during exercise.
The study was conducted in accordance with the amended Declaration of Helsinki. All patients and control subjects gave written informed consent for the study protocol, which was approved by the local Medical Ethics Committee of the Academic Medical Center.
CPET was performed according to the American Thoracic Society guidelines, using a cycle ergometer in a semiupright position as described before.
The cMRI measurements were performed at rest and during submaximal exercise at 40% of the CPET-assessed individual maximum workload. One year after PEA, cMRI was repeated at the preoperative workload and, also, at 40% of the postoperative CPET-assessed maximal workload. cMRI was performed on a 1.5-T whole body system (“Sonata”; Siemens Medical Solutions, Erlangen, Germany), equipped with a 4-element body phased array coil, as described before.
The velocity-coded images were acquired with 5 phase-encoding lines per heartbeat, that is, 5 views per segment. Temporal resolution was 33 ms with echo sharing; 20 to 25 heartbeats were used. As breath-hold affects RV SV, no “breath-holding” commands were given.
For analysis we used MR Analytical Software System (Medis, Leiden, the Netherlands); all analyses were performed according to a previously described protocol.
Ventricular end-diastolic and end-systolic volumes were assessed from the stack of parallel short-axis images, and RV and left ventricular (LV) ejection fraction were calculated. RV and LV myocardial masses were determined as described before and corrected for body surface area.
The cMRI exercise protocol consisted of a 3-minute period of cycling in supine position on a recumbent bicycle (Lode, Groningen, the Netherlands). To enable patients to cycle, the table was moved outward 50 cm; the delay from completing exercise to imaging was <10 seconds. For the patients, work rate was increased within the first minute to 40% of their maximal CPET-assessed workload. The healthy control subjects performed their test at 40% of their predicted maximal workload. SV was determined using the flow in the aorta at rest and during exercise using MATLAB software (MathWorks, Natick, Massachusetts) and indexed for body surface area (stroke volume index [SVI]).
Results are expressed as mean ± SD. Analyses were performed using SPSS statistical package (SPSS 17.0; SPSS Inc., Chicago, Illinois). The effect of PEA was analyzed using the paired student t test. For the analysis of differences between patients and control subjects, an independent samples t test was used. The Pearson correlation test was used to assess correlations between magnetic resonance imaging parameters and CPET parameters and the results were tested for 2-sided significance. A p value of <0.05 was considered statistically significant.
Results
Demographic characteristics of patients (n = 18) and control subjects (n = 7) did not differ; patients with CTEPH experienced moderate to severe PH ( Table 1 ). Postoperatively, 1 patient with CTEPH died from massive alveolar hemorrhage. In the remaining 17 patients, PEA resulted in a significant hemodynamic and functional improvement ( Table 2 ). In all but one patient, near normalization of mean Pulmonary Artery Pressure (mPAP) was observed (mPAP ≤30 mm Hg, n = 16; mPAP ≤25 mm Hg, n = 13).
| Variable | Value |
|---|---|
| Age (years) | 58 ± 9 |
| Body surface area (m 2 ) | 1.9 ± 0.2 |
| Female/male | 7/11 |
| Mean pulmonary artery pressure (mm Hg) | 40 ± 11 |
| Mean right atrial pressure (mm Hg) | 7 ± 4 |
| Total pulmonary resistance (dynes.s.cm −5 ) | 671 ± 303 |
| Mixed venous hemoglobin oxygen saturation (%) | 63 ± 7 |
| Mixed arterial hemoglobin oxygen saturation (%) | 91 ± 3.4 |
| 6-Minute walk distance (meters) | 467 ± 106 |
| Variable | Controls | Pre-PEA (n = 18) | Post-PEA (n = 13) |
|---|---|---|---|
| Mean pulmonary artery pressure (mm Hg) | 40 ± 11 | 23 ± 5 ∗ | |
| Total pulmonary resistance (dynes.s.cm −5 ) | 639 ± 278 | 397 ± 146 ∗ | |
| 6-Minute walk test (meters) | 467 ± 106 | 554 ± 94 ∗ | |
| Peak oxygen uptake (%-predicted) | 72.5 ± 13.0 | 99 ± 13 ∗ | |
| Peak workload (%-predicted) | 71 ± 23 | 97 ± 30 ∗ | |
| Oxygen pulse (%-predicted) | 75 ± 13 | 95 ± 14 ∗ | |
| Ventilator equivalent for carbon dioxide | 49.8 ± 11.2 | 32.7 ± 4.0 ∗ | |
| Peak heat rate (%-predicted) | 91 ± 8 | 94 ± 10 | |
| Peak minute ventilation (%-predicted) | 98 ± 19 | 92 ± 14 | |
| Maximal work load (Watt) | 102 ± 40 | 40 ± 15 | 58 ± 14 |
| (n = 18) | (n = 17) | ||
| RV end diastolic volume index (ml.m −2 ) | 68.2 ± 12.9 | 70.8 ± 31.9 | 53.3 ± 15.7 ∗ † |
| RV end systolic volume index (ml.m −2 ) | 25.0 ± 9.4 | 45.9 ± 25.5 † | 23.3 ± 9.7 ∗ |
| RV mass index (g.m −2 ) | 24.9 ± 11.0 | 37.9 ± 13.2 † | 24.4 ± 6.1 ∗ |
| LV end diastolic volume index (ml.m −2 ) | 70.2 ± 13.8 | 57.0 ± 7.6 † | 60.9 ± 7.3 ∗ |
| LV end systolic volume index (ml.m −2 ) | 23.7 ± 6.9 | 21.7 ± 4.3 | 19.8 ± 6.8 |
| LV mass index (g.m −2 ) | 73.5 ± 22.3 | 60.0 ± 14.0 | 56.6 ± 20.7 |
| RV ejection fraction (%) | 82.1 ± 6.6 | 36.2 ± 11.7 † | 56.4 ± 12.9 ∗ † |
| LV ejection fraction (%) | 66.9 ± 4.9 | 61.9 ± 6.9 | 64.6 ± 9.5 |
∗ p <0.05 post-PEA compared with pre-PEA.
CPET data are reported in Table 2 . Preoperatively, 13 of 17 patients had by definition a reduced exercise capacity, that is, V’O 2 peak <84% of the predicted value. On average, V’O 2 peak, peak workload, and peak O 2 pulse were decreased. V’ E /V’CO 2 at the anaerobic threshold, reported to be deviant in P(A)H (pulmonary arterial hypertension), was increased (>34.0) in all but one patient. V’O 2 peak showed an inverse correlation with mPAP (r = −0.625, p = 0.007) and total pulmonary resistance (TPR) (r = −0.676, p = 0.003). Because of logistics, postoperative CPET was performed in 13 patients only. After PEA, exercise capacity increased and normalized in 11 of 13 patients. V’O 2 peak, peak workload, and peak O 2 pulse increased significantly; peak heart rate (HR) and peak V’ E remained unchanged. Also, V’ E /V’CO 2 showed a significant decrease and normalized in 8 of 13 patients. Changes in V’O 2 peak, from baseline to 1 year postoperatively, correlated with the changes in mPAP (r = −0.656, p = 0.015).
Before and after PEA, in all patients, cMRI was performed at 40% of their preoperative maximal workload. Postoperatively, in 13 patients, cMRI was also performed at 40% of their postoperative maximal workload ( Table 2 ). Preoperatively, SVI decreased significantly after 3 minutes of exercise; HR and cardiac index (CI) significantly increased ( Table 3 ). The SVI during exercise correlated with V’O 2 peak (expressed as percent predicted: r = 0.688; p = 0.002) and O 2 pulse (expressed as percent predicted: r = 0.759; p <0.001); exercise SVI correlated inversely with mPAP (r = −0.719, p = 0.001) and TPR (r = −0.656, p = 0.001). In contrast, in the control subjects, SVI significantly increased during exercise; also, HR and CI increased significantly ( Table 3 )
| Variable | Controls (n = 7) | Pre-PEA (n = 18) | Post-PEA (n = 17) | |||
|---|---|---|---|---|---|---|
| Rest | Exercise | Rest | Exercise | Rest | Exercise | |
| Stroke volume index (ml.m −2 ) | 46.6 ± 7.6 | 57.9 ± 11.8 | 35.9 ± 7.4 ∗ | 33.0 ± 9.0 ∗ † | 35.9 ± 5.2 ∗ | 39.9 ± 5.4 ∗ † ‡ |
| Heart rate (min −1 ) | 65 ± 10 | 94 ± 8 | 69 ± 12 | 93 ± 13 † | 73 ± 11 | 97 ± 9.0 † |
| Cardiac index (l. min −1 .m −2 ) | 3.0 ± 0.3 | 5.4 ± 1.1 | 2.4 ± 0.4 ∗ | 3.0 ± 0.8 ∗ † | 2.6 ± 0.5 | 3.8 ± 0.5 ∗ † ‡ |
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