Hemodynamic and ventilatory responses during exercise in chronic thromboembolic disease.

BACKGROUND: Patients with chronic thromboembolic disease (CTED) may suffer from exercise intolerance without pulmonary hypertension at rest. Pulmonary endarterectomy (PEA) for symptomatic CTED results in improvement of symptoms and quality of life. Neither the pathophysiology of the exercise limitation nor the underlying mechanisms of the PEA-induced improvement have been studied previously. OBJECTIVES: We studied hemodynamic and ventilatory responses upon exercise in 14 patients with CTED. After 1 year, we studied the underlying physiologic mechanisms of the PEA-induced symptomatic improvement. METHODS: Cardiopulmonary exercise testing (CPET) was performed during right heart catheterization, and noninvasive CPET was performed 1 year postoperatively. RESULTS: During exercise, we observed abnormal pulmonary vascular responses, that is, a steep mean pulmonary artery pressure/cardiac output (2.7 ± 1.2 mm Hg·min·L(-1)), and low pulmonary vascular compliance (2.8 ± 1.1 mL·mm Hg(-1)); mean pulmonary artery pressure/cardiac output slope correlated with dead-space ventilation (r = 0.586; P = .028) and ventilatory equivalents for carbon dioxide slope (r = .580; P = .030). Postoperatively, the improvement observed in exercise capacity was related to improvements in CPET-derived parameters pointing to restoration of right ventricle stroke volume response (oxygen pulse: 11.7 ± 3.1 to 13.3 ± 3.3; P = .027; heart rate response: 80.9 ± 12.4 to 72.0 ± 5.7; P = .003); and, indicating improved ventilatory efficiency, the ventilatory equivalents for carbon dioxide slope decreased from 38.2 ± 3.6 to 32.8 ± 7.0 (P = .014). CONCLUSIONS: Patients with CTED showed an abnormal pulmonary vascular response to exercise and a decreased ventilatory efficiency. Responses after PEA point to restoration of right ventricle stroke volume response and ventilatory efficiency.

Exercise tolerance, lung function abnormalities, anemia, and cardiothoracic ratio in sickle cell patients.

Many patients with sickle cell disease (SCD) have a reduced exercise capacity and abnormal lung function. Cardiopulmonary exercise testing (CPET) can identify causes of exercise limitation. Forty-four consecutive SCD patients (27 HbSS, 11 HbSC, and 6 HbS-beta thalassemia) with a median age (interquartile range) of 26 (21-41) years underwent pulmonary function tests, CPET, chest x-ray, and echocardiography to further characterize exercise limitation in SCD. Peak oxygen uptake (V'O2 -peak), expressing maximum exercise capacity, was decreased in 83% of the studied patients. V'O2 -peak correlated with hemoglobin levels (R = 0.440, P = 0.005), forced vital capacity (FVC) (R = 0.717, P < 0.0001). Cardiothoracic ratio on chest x-ray inversely correlated with FVC (R = -0.637, P < 0.001). According to criteria for exercise limitation, the patients were limited in exercise capacity due to anemia (n = 17), cardiovascular dysfunction (n = 2), musculoskeletal function (n = 10), pulmonary ventilatory abnormalities (n = 1), pulmonary vascular exercise limitation (n = 1), and poor effort (n = 3). In the present study we demonstrate that anemia is the most important determinant of reduced exercise tolerance observed in SCD patients without signs of pulmonary hypertension. We found a strong correlation between various parameters of lung volume and cardiothoracic ratio and we hypothesize that cardiomegaly and relative small chest size may be important causes of the impairment in pulmonary function, that is, reduced long volumes and diffusion capacity, in SCD. Taking into account anthropomorphic differences between SCD patients and controls could help to interpret lung function studies in SCD better.

Effect of pulmonary endarterectomy for chronic thromboembolic pulmonary hypertension on stroke volume response to exercise.

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.

Pulmonary vascular limitation to exercise and survival in idiopathic pulmonary fibrosis.

BACKGROUND AND OBJECTIVE: Pulmonary hypertension is frequently observed in advanced idiopathic pulmonary fibrosis (IPF) and is associated with poor prognosis. Cardiopulmonary exercise testing (CPET) can be used to detect less advanced pulmonary vascular impairment, and therefore may be of prognostic use. We studied the predictive value of non-invasive exercise parameters that were associated with elevated systolic pulmonary artery pressure (sPAP) for survival in IPF patients. METHODS: From our interstitial lung disease database, we reviewed records of consecutive patients with IPF in whom CPET and echocardiography were performed within 2 weeks (n = 38). RESULTS: Eleven patients (29%) had increased sPAP (≥40 mm Hg). From all non-invasive CPET parameters, only the ventilatory equivalent for CO2 (V'E /V'CO2 ) at anaerobic threshold differed significantly between patients with and without sPAP ≥ 40 mm Hg. The receiver-operator characteristic curve for V'E /V'CO2 resulted in areas under the curve of 0.77 (95% CI: 0.569-0.970; P = 0.026), with a cut-off value for predicting sPAP ≥ 40 mm Hg of >45.0. Patients with V'E /V'CO2 > 45.0 had significantly worse survival compared with patients with V'E /V'CO2 ≤ 45.0 (P = 0.001). In contrast, sPAP did not predict survival. CONCLUSIONS: V'E /V'CO2 , the only CPET parameter associated with elevated sPAP, appears a potentially useful non-invasive marker for early detection of pulmonary vascular impairment, and therefore may be of use for a more accurate prognostic assessment in IPF patients.

Bosentan treatment is associated with improvement of right ventricular function and remodeling in chronic thromboembolic pulmonary hypertension.

BACKGROUND: Medical pretreatment before pulmonary endarterectomy (PEA) can optimize right ventricular (RV) function and may improve postoperative outcome in high-risk patients. Using cardiac magnetic resonance imaging (cMRI), we determined whether the dual endothelin-1 antagonist bosentan improves RV function and remodeling in patients with chronic thromboembolic pulmonary hypertension (CTEPH) who waited for PEA. HYPOTHESIS: We hypothesized that medical therapy prior to PEA will be associated with improvements in RV remodeling and function. METHODS: In this pilot study, 15 operable CTEPH patients were randomly assigned to either bosentan (n = 8) or no bosentan (n = 7, control) for 16 weeks, next to "best standard of care." Both before and after treatment, RV stroke volume index (RVSVI), RV ejection fraction (RVEF), RV mass, RV isovolumic relaxation time (rIVRT), leftward ventricular septal bowing (LVSB), and left ventricular ejection fraction (LVEF) were determined using cMRI. RESULTS: After 16 weeks, the change (Δ) from baseline (median [range]) in the studied cMRI parameters differed significantly between the bosentan group and the controls: Δ RVSVI: 6 [-4-11] vs 1 [-6-3] mL/m(-2) ; Δ RVEF: 8 [-10-15] vs -4 [-7-5]%; Δ RV mass: -3 [-6--2] vs 2 [-1-3] g/m(-2) ; Δ rIVRT: -30 [-130-20] vs 10 [-30-30] msec; Δ LVSB: 0.03 [-0.03-0.13] vs -0.03[-0.08-0.04] cm(-1) ; and Δ LVEF: 8 [-5-17] vs -2 [-14-2]% (all P < 0.05). The change from baseline in mean pulmonary artery pressure (-11 [-17-11] vs 5 [-6-21] mm Hg, P < 0.05) and 6-minute walk distance (20 [3-88] vs -4 [-40-40] m, P < 0.05) also differed significantly. CONCLUSIONS: In CTEPH, compared with control, treatment with bosentan for 16 weeks was associated with a significant improvement in cMRI parameters of RV function and remodelling.

Impaired cardiac reserve in asymptomatic patients with moderate pulmonary restenosis late after relief of severe pulmonary stenosis: evidence for diastolic dysfunction.

BACKGROUND: Patients with moderate pulmonary valve restenosis late after relief of severe pulmonary stenosis (PS) may show decreased exercise tolerance. To elucidate the mechanism of decreased exercise tolerance, we evaluated cardiac response to physical and pharmacological stress in these patients and compared results with those of patients with native moderate PS. METHODS: Twenty asymptomatic patients with moderate PS were divided into 2 groups: Group I (late after relief of severe PS, n=9), and Group II (no previous intervention, n=11). All patients underwent an exercise test, dobutamine stress (DS) MRI, and delayed contrast enhanced MRI. The response to physical and pharmacological stress was compared between both groups. RESULTS: Group I showed impaired exercise capacity compared to Group II (VO2max=72.8% ± 3.5% vs. 102.5% ± 16.3%, p<0.001). During DS-MRI, RV-SV increased in Group II, but not in Group I (+13 ± 8 ml, -5 ± 8 ml, p<0.001). RV end-diastolic volume decreased significantly in Group I patients (p=0.006) while it did not significantly change in Group II patients. The amount of RV-SV increase (∆ RV-SV) correlated negatively with the period of moderate PS existence and the current PG in Group I (r=-0.82, p=0.007, and r=-0.68, p=0.04, respectively) but not in Group II (r=0.45, p=0.1, and r=0.40, p=0.2, respectively). Furthermore, ∆ RV-SV correlated negatively with the PG before valvuloplasty (r=-0.76, p=0.02). CONCLUSION: Impaired exercise capacity in patients with moderate pulmonary restenosis after relief of severe PS is probably caused by inability to increase RV-SV. Disturbed RV filling properties, worsening in time, might play a role.

Plasma brain natriuretic peptide as a biomarker for haemodynamic outcome and mortality following pulmonary endarterectomy for chronic thromboembolic pulmonary hypertension.

OBJECTIVES: In chronic thromboembolic pulmonary hypertension (CTEPH), right ventricular (RV) dysfunction is associated with increased morbidity and mortality following pulmonary endarterectomy. Plasma brain natriuretic peptide (BNP) levels were previously shown to correlate with RV (dys)function. We hypothesized that BNP can be used as a non-invasive biomarker to identify patients at 'high risk' for postoperative morbidity and mortality. METHODS: We studied the postoperative outcome in 73 consecutive patients. Patients were divided into three groups based on previously determined cut-off levels: BNP <11.5, indicating normal RV function (ejection fraction [EF] ≥45%), BNP >48.5 pmol/l, indicating RV dysfunction (right ventricular ejection fraction <30%) and BNP 11.5-48.5 pmol/l. Postoperative 'bad outcome' was defined as the presence of either residual pulmonary hypertension (PH) or (all-cause) mortality. RESULTS: Plasma BNP >48.5 pmol/l was shown to be an independent predictor of 'bad outcome'. Compared with BNP <11.5 pmol/l, BNP >48.5 pmol/l identified patients at higher risk for (all-cause) mortality (17 vs 0%; P = 0.009) and residual PH (56 vs 20%; P < 0.004). Also, the durations of mechanical ventilation and intensive care unit stay were significantly longer in patients with BNP >48.5 pmol/ml. CONCLUSIONS: Plasma BNP levels may be of use as a non-invasive biomarker reflecting RV dysfunction, next to other well-recognized (invasive) parameters, for better preoperative risk stratification of CTEPH patients.

Electrophysiologic remodeling of the left ventricle in pressure overload-induced right ventricular failure.

OBJECTIVES: The purpose of this study was to analyze the electrophysiologic remodeling of the atrophic left ventricle (LV) in right ventricular (RV) failure (RVF) after RV pressure overload. BACKGROUND: The LV in pressure-induced RVF develops dysfunction, reduction in mass, and altered gene expression, due to atrophic remodeling. LV atrophy is associated with electrophysiologic remodeling. METHODS: We conducted epicardial mapping in Langendorff-perfused hearts, patch-clamp studies, gene expression studies, and protein level studies of the LV in rats with pressure-induced RVF (monocrotaline [MCT] injection, n = 25; controls with saline injection, n = 18). We also performed epicardial mapping of the LV in patients with RVF after chronic thromboembolic pulmonary hypertension (CTEPH) (RVF, n = 10; no RVF, n = 16). RESULTS: The LV of rats with MCT-induced RVF exhibited electrophysiologic remodeling: longer action potentials (APs) at 90% repolarization and effective refractory periods (ERPs) (60 ± 1 ms vs. 44 ± 1 ms; p < 0.001), and slower longitudinal conduction velocity (62 ± 2 cm/s vs. 70 ± 1 cm/s; p = 0.003). AP/ERP prolongation agreed with reduced Kcnip2 expression, which encodes the repolarizing potassium channel subunit KChIP2 (0.07 ± 0.01 vs. 0.11 ± 0.02; p < 0.05). Conduction slowing was not explained by impaired impulse formation, as AP maximum upstroke velocity, whole-cell sodium current magnitude/properties, and mRNA levels of Scn5a were unaltered. Instead, impulse transmission in RVF was hampered by reduction in cell length (111.6 ± 0.7 µm vs. 122.0 ± 0.4 µm; p = 0.02) and width (21.9 ± 0.2 µm vs. 25.3 ± 0.3 µm; p = 0.002), and impaired cell-to-cell impulse transmission (24% reduction in Connexin-43 levels). The LV of patients with CTEPH with RVF also exhibited ERP prolongation (306 ± 8 ms vs. 268 ± 5 ms; p = 0.001) and conduction slowing (53 ± 3 cm/s vs. 64 ± 3 cm/s; p = 0.005). CONCLUSIONS: Pressure-induced RVF is associated with electrophysiologic remodeling of the atrophic LV.

Effect of age on exercise capacity and cardiac reserve in patients with pulmonary atresia with intact ventricular septum after biventricular repair.

OBJECTIVES: In patients with pulmonary atresia with intact ventricular septum (PAIVS), biventricular repair is considered to be the optimal treatment option in the absence of significant right ventricular (RV) hypoplasia. However, long-term clinical outcome studies are limited. We evaluated exercise capacity and cardiac function during pharmacological stress in children and young adults with PAIVS after biventricular repair. METHODS: Ten PAIVS patients after biventricular repair, with a median age of 12 years (range 9-42 years), underwent a cardiopulmonary exercise test, dobutamine stress magnetic resonance imaging (DS-MRI) and delayed contrast enhancement (DCE) MRI. RESULTS: The patients' ages negatively correlated with exercise capacity (r=-0.72, P=0.01) as well as left (LV) and RV stroke volume (SV) response to pharmacological stress (r=-0.72, P=0.02; and r=-0.64, P=0.04; respectively), Furthermore, older age was associated with decreased RV E/A volume ratio and increased pulmonary late diastolic forward flow percentage (r=0-0.65, P=0.04, r=0.66, P=0.03, respectively). RV E/A volume ratio positively correlated with RV-SV response to DS-MRI (r=0.77, P=0.009). and O2-pulse during physical stress correlated with biventricular SV response to DS-MRI. No RV or LV ventricular myocardial fibrosis was detected. CONCLUSIONS: In PAIVS patients after biventricular repair exercise capacity and cardiac reserve decrease with age. These findings appear to be related to impaired diastolic RV function and decreased RV filling, indicating that the function of the relatively small RV deteriorates with time.

Exercise capacity and cardiac reserve in children and adolescents with corrected pulmonary atresia with intact ventricular septum after univentricular palliation and biventricular repair.

OBJECTIVE: Management of pulmonary atresia with intact ventricular septum is challenging and depends on the severity of right ventricular hypoplasia. Clinical outcomes of biventricular repair seem favorable to univentricular palliation, but data on superiority of biventricular repair regarding exercise capacity are conflicting. We investigated the response to physical and pharmacologic stress in patients with surgically corrected pulmonary atresia with intact ventricular septum. METHODS: Sixteen patients (7 patients after univentricular palliation, age 11.8 ± 2.6 years; 7 patients after biventricular repair, age 12.9 ± 2.7 years; and 2 patients after 1.5 ventricular repair, age 12 and 19 years) underwent cardiopulmonary exercise test, dobutamine stress magnetic resonance imaging, and delayed contrast-enhanced magnetic resonance imaging. RESULTS: The univentricular group showed impaired exercise capacity in contrast with normal exercise capacity in the biventricular group. Left ventricular ejection fraction increased in both groups. With dobutamine, left ventricular stroke volume increased only in the biventricular group (+11.3 ± 5.0 mL, P < .001) and not in the univentricular group (-0.04 ± 3.6 mL, P = .9). Heart rate increase was inadequate in the univentricular group. Maximum oxygen consumption and oxygen pulse were strongly correlated with left ventricular stroke volume during stress but not at rest. The results of the 2 patients after 1.5 ventricular repair were comparable to those of the univentricular group. No myocardial fibrosis was detected. CONCLUSIONS: Impaired exercise capacity in children and adolescents with pulmonary atresia with intact ventricular septum after univentricular palliation is related to decreased cardiac reserve and inadequate chronotropic response. Young patients with pulmonary atresia with intact ventricular septum after biventricular repair show normal exercise capacity and cardiac reserve.

Exercise training improves exercise capacity in adult patients with a systemic right ventricle: a randomized clinical trial.

OBJECTIVE: To assess whether exercise training in adult patients with a systemic right ventricle (RV) improves exercise capacity and quality of life and lowers serum N-terminal prohormone brain natriuretic peptide (NT-proBNP) levels. DESIGN: Multi-centre parallel randomized controlled trial. PARTICIPANTS: Patients with a systemic RV due to congenitally or surgically corrected transposition of the great arteries. METHODS: Fifty-four adult patients with a systemic RV, were randomized using unmarked opaque envelopes to an intervention group (n = 28) with three training sessions per week for 10 consecutive weeks, and a control group (n = 26). Randomization was stratified by participating centre. At baseline, and follow-up, we determined maximal exercise capacity (V'O(2peak)), serum NT-proBNP levels, and quality of life by means of the SF-36, and the TAAQOL Congenital Heart Disease questionnaires. The final analysis was performed by linear regression, taking into account the stratified randomization. RESULTS: Forty-six patients were analysed (male 50%, age 32 ± 11 years, intervention group n = 24, control group n = 22). Analysis at 10 weeks showed a significant difference in V'O(2peak) (3.4 mL/kg/min, 95% CI: 0.2 to 6.7; P = 0.04) and resting systolic blood pressure (-7.6 mmHg, 95% CI: -14.0 to -1.3; P = 0.03) in favour of the exercise group. No significant changes were found in serum NT-proBNP levels or quality of life in the intervention group or in the control group nor between groups. None of the patients in the intervention group had to discontinue the training programme due to adverse events. CONCLUSION: In adult patients with a systemic RV exercise training improve exercise capacity. We recommend to revise restrictive guidelines, and to encourage patients to become physically active. ( TRIAL REGISTRATION: The study was registered at http://trialregister.nl. Identifier: NTR1909.).

Time course of restoration of systolic and diastolic right ventricular function after pulmonary endarterectomy for chronic thromboembolic pulmonary hypertension.

BACKGROUND: In chronic thromboembolic pulmonary hypertension, right ventricular (RV) pressure overload causes RV remodeling and dysfunction. Successful pulmonary endarterectomy (PEA) initiates restoration of RV remodeling and global function. Little is known on the restoration of systolic and diastolic RV function. Using transthoracic echocardiography, we studied the time course and extent of postoperative restoration of systolic and diastolic RV function. METHODS: In chronic thromboembolic pulmonary hypertension (n = 55, 36 women, age 52 ± 14 years), transthoracic echocardiography was performed before PEA (pre-PEA) and 2 weeks, 3 months, and 1 year postoperatively. RESULTS: Two weeks postoperatively, RV afterload and dimension had decreased significantly, without further improvement during follow-up. Global RV function, expressed by the myocardial performance index, showed a gradual improvement (from pre-PEA 0.58 ± 0.29 to 0.45 ± 0.38, 0.39 ± 0.19, and 0.37 ± 0.18). In contrast, 2 weeks after PEA systolic RV function, as assessed by tricuspid annular plane systolic velocity excursion and peak tricuspid annular systolic velocity of the RV, had worsened, with a subsequent incomplete restoration during follow-up: tricuspid annular plane systolic velocity excursion from 19.3 ± 5.0 to 12.4 ± 2.5, 15.3 ± 3.0, and 16.8 ± 2.9 mm and systolic velocity of the right ventricle from 11.4 ± 3.0 to 9.6 ± 2.0, 10.0 ± 1.8, and 10.3 ± 1.7 cm/s. Postoperative diastolic RV function also showed a biphasic response: tricuspid inflow-to-annulus ratio from 6.1 ± 3.0 to 9.5 ± 3.5, 6.8 ± 2.4, and 6.3 ± 2.2 cm/s. Dynamics and ultimate level of restoration of systolic and diastolic RV function were similar in patients with and without residual pulmonary hypertension. CONCLUSIONS: Postoperative reduction in RV afterload caused an immediate improvement in RV dimension and global function. In contrast, systolic and diastolic RV function deteriorated after PEA with subsequently a gradual yet incomplete restoration during 1-year follow-up.

Short-term increase of plasma free fatty acids does not interfere with intrinsic mitochondrial function in healthy young men.

Free fatty acid (FFA)- and obesity-induced insulin resistance has been associated with disturbed mitochondrial function. Elevated plasma FFA can impair insulin-induced increase of adenosine triphosphate synthesis and downregulate the expression of genes important in the biogenesis of mitochondria in human skeletal muscle. Whether FAs have a direct effect on intrinsic mitochondrial capacity remains to be established. Therefore, we measured ex vivo mitochondrial respiratory capacity in human skeletal muscle after exposure to hyperinsulinemia and high levels of plasma FFA. Nine healthy lean men were studied during a 6-hour hyperinsulinemic (600 pmol/L) euglycemic clamp with concomitant infusion of Intralipid (Fresensius Kabi Nederland, Den Bosch, the Netherlands) (FFA clamped at 0.5 mmol/L) or saline. Mitochondrial respiratory capacity was measured by high-resolution respirometry in permeabilized muscle fibers using an Oxygraph (OROBOROS Instruments, Innsbruck, Austria). Each participant served as his own control. Peripheral glucose uptake (rate of disappearance) was significantly lower during infusion of the lipid emulsion compared with the control saline infusion (68 µmol/kg·min [saline] vs 40 µmol/kg·min [lipid], P = .008). However, adenosine diphosphate-stimulated and maximal carbonylcyanide-4-(trifluoromethoxy)-phenylhydrazone-stimulated uncoupled respiration rates were not different in permeabilized skeletal muscle fibers after exposure to high levels of FFA compared with the control condition. We conclude that short-term elevation of FFA within the physiological range induces insulin resistance but does not affect intrinsic mitochondrial capacity in skeletal muscle in humans.

Longitudinal follow-up of six-minute walk distance after pulmonary endarterectomy.

BACKGROUND: The 6-minute walk test is a useful tool to assess functional outcome after pulmonary endarterectomy (PEA) in chronic thromboembolic pulmonary hypertension. However, little is known about the longitudinal dynamics in functional improvement. We performed a longitudinal follow-up of 6-minute walk distance, New York Heart Association functional class, and echocardiography after PEA. METHODS: We studied 71 patients with chronic thromboembolic pulmonary hypertension who underwent PEA. A 6-minute walk test and echocardiography were performed before PEA, at 3 months after, and at annual follow-up. At the time of this report, 52 patients had returned for 2-year follow-up, 32 for 3-year follow-up, 23 for 4-year follow-up, and 11 for 5-year follow-up. RESULTS: Preoperatively, the 6-minute walk distance (6-MWD) correlated with hemodynamic severity of disease (mean pulmonary artery pressure: r = -0.55, p < 0.001); total pulmonary resistance: r = -0.59, p < 0.001) After PEA, 6-MWD increased from 440 ± 109 to 524 ± 83 meters at 1 year (n = 71, p < 0.001). Further improvement was observed from 523 ± 87 meters at 1 year to 536 ± 91 meters at 2 years (n = 52, p < 0.012). After 2 years, no further improvement was observed. At 1 year, the change in 6-MWD from baseline correlated significantly with the change observed in pulmonary hemodynamics. Changes in 6-MWD and hemodynamics were more pronounced in patients with residual pulmonary hypertension after PEA, despite the worse absolute outcome. CONCLUSIONS: In patients with chronic thromboembolic pulmonary hypertension, 6-MWD showed a gradual improvement up to 2 years after PEA. Patients with residual pulmonary hypertension benefited most from treatment, despite the worse absolute outcome.

Pulmonary endarterectomy improves dyspnea by the relief of dead space ventilation.

BACKGROUND: In chronic thromboembolic pulmonary hypertension (CTEPH), dyspnea is considered to be related to increased dead space ventilation caused by vascular obstruction. Pulmonary endarterectomy releases the thromboembolic obstruction, thereby improving regional pulmonary blood flow. We hypothesized that pulmonary endarterectomy reduces dead space ventilation and that this reduction contributes to attenuation of dyspnea symptoms. METHODS: In this follow-up study we assessed dead space ventilation, hemodynamic severity of disease, and symptomatic dyspnea in 54 consecutive CTEPH patients, before and 1 year after pulmonary endarterectomy. Dead space ventilation was calculated using the Bohr-Enghoff equation. Dyspnea was assessed by Borg scores and the New York Heart Association functional classification. RESULTS: Preoperatively, dead space ventilation was increased (0.40 +/- 0.07) and correlated with severity of disease (mean pulmonary artery pressure: r = 0.49, p < 0.001; total pulmonary resistance: r = 0.53, p < 0.001), and resting (r = 0.35, p < 0.05) and post-exercise Borg dyspnea scores (r = 0.44, p < 0.01). Postoperatively, dead space ventilation (0.33 +/- 0.08, p < 0.001) and dyspnea symptoms decreased significantly. Changes in symptomatic dyspnea were independently associated with changes in pulmonary hemodynamics and absolute dead space. CONCLUSIONS: Dead space ventilation in CTEPH is increased and correlates significantly with hemodynamic severity of disease and dyspnea symptoms. Pulmonary endarterectomy decreases dead space ventilation. The induced change in dead space upon surgical removal of chronic thromboembolism contributes to the postoperative recovery of symptomatic dyspnea.

Mechanisms for cardiac output augmentation in patients with a systemic right ventricle.

BACKGROUND: Conflicting data have been published on the differences in cardiac response to exercise between patients with an atrially switched transposition of the great arteries (TGA), and patients with a congenitally corrected TGA (ccTGA). The purpose of our study was to evaluate the differences in cardiac response to exercise in these 2 patient groups with a systemic right ventricle (RV). METHODS: Thirty four patients (62% male; mean 35, range 21-69 years) with a systemic RV (20 with an atrially switched TGA and 14 with a ccTGA) were included. Exercise tests with Portapres measurements were performed to assess maximal exercise capacity (V'O(2peak)), cardiac index, stroke volume index, and heart rate augmentation. Cardiac function was assessed by Cardiovascular Magnetic Resonance or Computed Tomography, and serum NT-proBNP levels. RESULTS: We found that both groups were able to significantly augment cardiac index during exercise. Cardiac index augmentation during exercise was positively related to V'O(2peak) (r=0.37, p<0.05), and independent of resting cardiac function. Although the increase in cardiac index during exercise was similar in both patients with TGA and with ccTGA, mechanisms to achieve this increase differed between groups. ccTGA patients increased both stroke volume and heart rate during exercise. Atrially switched TGA patients augmented heart rate during exercise, but failed to increase stroke volume. CONCLUSION: Mechanisms to achieve cardiac output augmentation differ between ccTGA patients and TGA patients. We suggest that therapeutic approaches should be tailored to the specific patient group to avoid counterproductive effects.

Relation of physical activity, cardiac function, exercise capacity, and quality of life in patients with a systemic right ventricle.

Exercise is recommended in patients with left ventricular failure. Although right ventricular failure is common in patients with a systemic right ventricle (RV), no data are available on the effect of physical activity in these patients. The aim of this study was to evaluate the relation of physical activity and cardiac function, exercise capacity, and quality of life in patients with a systemic RV. Forty-seven patients (64% men, mean age 35 years, range 21 to 69) with a systemic RV (31 with an atrially switched transposition of the great arteries and 16 with a congenitally corrected transposition of the great arteries) were included. Cardiac function was assessed by cardiovascular magnetic resonance or computed tomography, exercise tests, and serum N-terminal prohormone brain natriuretic peptide (NT-pro-BNP) levels. Habitual physical activity was assessed using the Short Questionnaire to Assess Health-Enhancing Physical Activity (SQUASH) and quality of life using the Medical Outcomes Study Short Form 36-Item Health Survey. Mean systemic right ventricular ejection fraction was impaired (36.8 +/- 7.8%), as was maximal exercise capacity (78.5 +/- 23.9% of predicted). NT-pro-BNP level was increased (median 269 ng/L, range 34 to 4,476). Mean SQUASH score was 6,808 +/- 3,241, indicating a decreased level of habitual physical activity. Although patients' scores on mental quality-of-life domains were comparable to the general population, scores on most physical quality-of-life domains were significantly lower. SQUASH scores were found to be a significant predictor for exercise capacity (p <0.01) and physical quality of life (p <0.001). However, we found no relation between SQUASH scores and right ventricular ejection fraction or NT-pro-BNP. In conclusion, physical activity in patients with a systemic RV is positively associated with exercise capacity and quality of life, irrespective of cardiac performance.

Six-minute walk distance as parameter of functional outcome after pulmonary endarterectomy for chronic thromboembolic pulmonary hypertension.

OBJECTIVES: In chronic thromboembolic pulmonary hypertension, objective data to assess the functional outcome after pulmonary endarterectomy are lacking. We studied the 6-minute walk distance in relation to the clinical and hemodynamic severity of disease, and assessed the effect of pulmonary endarterectomy on the 6-minute walk distance. METHODS: A total of 50 consecutive patients with chronic thromboembolic pulmonary hypertension were studied. Subsequently, pulmonary endarterectomy was performed in 42 patients, 35 of whom underwent a 6-minute walk distance 1 year after surgery. RESULTS: The mean +/- standard error of the mean 6-minute walk distance was 391 +/- 19 m. The 6-minute walk distance decreased in proportion to New York Heart Association functional class and correlated (all P < .0001) with mean pulmonary artery pressure (r = -0.62), cardiac output (r = 0.76), total pulmonary resistance (r = -0.75), mixed venous oxygen saturation (r = 0.77), and brain natriuretic peptide (r = -0.65). One year after pulmonary endarterectomy, the 6-minute walk distance increased from 417 +/- 19 m to 517 +/- 16 m (P < .0001). The change from baseline in 6-minute walk distance correlated with the changes after 1 year in New York Heart Association functional class (P < .01) and brain natriuretic peptide (r = 0.57, P < .002), and with the observed hemodynamic changes directly after pulmonary endarterectomy (change in mean pulmonary artery pressure: r = 0.52; change in cardiac output: r = 0.70; change in total pulmonary resistance r = 0.70; all P < .001). In patients with residual pulmonary hypertension after pulmonary endarterectomy, the 6-minute walk distance was significantly lower than in hemodynamically normalized patients. However, the absolute increase in the 6-minute walk distance was higher in patients with residual pulmonary hypertension (137 +/- 26 m and 82 +/- 20 m, respectively; P = .03). CONCLUSIONS: The 6-minute walk distance was demonstrated to reflect the clinical and hemodynamic severity of disease in patients with chronic thromboembolic pulmonary hypertension. One year after pulmonary endarterectomy, the 6-minute walk distance had increased significantly, and the change in the 6-minute walk distance correlated with the observed clinical and hemodynamic improvement.