Exercise testing in chronic thromboembolic pulmonary hypertension and chronic thromboembolic pulmonary disease without pulmonary hypertension: a comprehensive systematic review and meta-analysis.

Exercise training for pulmonary hypertension: A systematic review and meta-analysis

Pulmonary Hypertension: From an Orphan Disease to a Public Health Problem

Objective To evaluate the sex differences of cardiopulmonary exercise testing (CPET) parameters in cardiac output (CO) prediction for patients with chronic thromboembolic pulmonary hypertension (CTEPH). Methods From May 2010 to February 2016, 73 cases (32 males and 41 females) with CTEPH were enrolled from Shanghai Pulmonary Hospital, all of whom underwent both right-heart catheterization and CPET.Multivariate regression analysis was applied to assess the prognostic value of CPET parameters. Results Sex differences were of no significance in both demographic and hemodynamic parameters in total patients, but younger in female patients.Male patients had higher O2 pulse at anaerobic threshold (AT), peak minute ventilation (VE), end-tidal partial pressure of oxygen output (PETO2) at AT, peak O2 pulse, VE at AT and nadir VE/carbon dioxide (VCO2), but lower oxygen uptake efficiency slope compared with female patients (all P<0.05). There was no significant difference in CPET parameters between male event group and male event-free group, but peak oxygen uptake(VO2)in female event group was lower than that in female event-free group (P<0.05). Female event group had lower peak VO2, VE at AT and peak VE compared to the male event group (all P<0.05). Nadir VE/VCO2 and peak PETO2 were independent predictors of CO for male and female CTEPH patients, respectively. Conclusions The independent predictors of CPET parameters are different in the assessment of CO in male and female CTEPH patients, which suggests that sex differences of CPET should be considered to be the better clinical assessment of CTEPH patients. Key words: Chronic thromboembolic pulmonary hypertension; Cardiopulmonary exercise testing; Sex characteristic; Cardiac output

In recent years the information about relevance of cardiopulmonary exercise testing (CPET) in complex assessment of pulmonary arterial hypertension (PAH) patients and chronic thromboembolic pulmonary hypertension (CTEPH) patients have been accumulating. Parameters of CPET, such as peak oxygen consumption (Vo2 peak) and ventilation equivalents (VE/Vco2) are very important in risk stratification in patients with PAH, also as distance in 6-minute walking test, the echocardiography and right heart catheterization results, N-terminal prohormone of natriuretic peptide according to the European Society of Cardiology and European Respiratory Society guidelines on diagnosis and treatment of pulmonary hypertension. However, there are no parameters, which can be used in clinical practice to reflect the risk of mortality during 1 year in patients with CTEPH. The aim of our study was to assess the role of CPET in risk stratification, achieving therapy goals and making decision about therapy escalation in patients with PAH and CTEPH. Results of our pilot study demonstrated, that CPET parameters are the reliable markers to reflect the PAH and CTEPH progression. The CPET is necessary for pathogenic therapy efficacy assessment and for making decision of therapy escalation in patients with PAH, also as in CTEPH patients. The critical role of CPET in risk stratification in PAH and CTEPH patients should be emphasized.

COUNTERPOINT: Pulmonary Vascular Resistance 2.0— Shedding Light or Casting Shadows?

N-Terminal Pro-B-Type Natriuretic Peptide as an Indicator of Disease Severity in a Heterogeneous Group of Patients With Chronic Precapillary Pulmonary Hypertension

Sleep-disordered breathing (SDB) and nocturnal hypoxemia were known to be present in patients with chronic thromboembolic pulmonary hypertension (CTEPH), but the difference betweenSDB and nocturnal hypoxemia in patients who have chronic thromboembolic pulmonary disease (CTEPD) with or without pulmonary hypertension (PH) at rest remains unknown. Patients who had CTEPH (n = 80) or CTEPD without PH (n= 40) and who had undergone sleep studies from July 2020 to October 2022 at Shanghai Pulmonary Hospital were enrolled. Nocturnal mean SpO2 (Mean SpO2) <90% was defined as nocturnal hypoxemia, and the percentage of time with a saturation below 90% (T90%) exceeding 10% was used to evaluate the severity of nocturnal hypoxemia. Logistic and linear regression analyses were performed to investigate the difference and potential predictor of SDB or nocturnal hypoxemia between CTEPH and CTEPD without PH. SDB was similarly prevalent in CTEPH and CTEPD without PH (P = 0.104), both characterised by obstructive sleep apnoea (OSA). Twenty-two patients with CTEPH were diagnosed with nocturnal hypoxemia, whereas only three were diagnosed with CTEPD without PH (P = 0.021). T90% was positively associated with mean pulmonary arterial pressure (mPAP) and pulmonary vascular resistance in patients with CTEPH and CTEPD without PH (P < 0.001); T90% was also negatively related to cardiac output in these patients. Single-breath carbon monoxide diffusing capacity, sex and mPAP were all correlated with nocturnal hypoxemia in CTEPH and CTEPD without PH (all P < 0.05). Nocturnal hypoxemia was worse in CTEPD with PH; T90%, but not SDB, was independently correlated with the hemodynamics in CTEPD with or without PH.

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Differences in Ventilatory Inefficiency Between Pulmonary Arterial Hypertension and Chronic Thromboembolic Pulmonary Hypertension

Cardiopulmonary exercise testing (CPET) assesses exercise capacity and causes of exercise limitation in patients with pulmonary hypertension (PH). At altitude, changes occur in the ventilatory pattern and a decrease in arterial oxygen pressure in healthy; these changes are increased in patients with cardiopulmonary disease. Our objective was to compare the response to exercise and gas exchange between patients with pulmonary arterial hypertension (PAH) and chronic thromboembolic pulmonary hypertension (CTEPH) residing at the altitude of Bogotá (2640 m). All patients performed an incremental CPET with measurement of oxygen consumption ( ), dead space (VD/VT), ventilatory equivalents (VE/ ), and alveolar-arterial oxygen gradient ( ). test and one-way analysis of variance were used for comparisons between PAH and CTEPH. We included 53 patients, 29 with PAH, 24 with CTEPH, and 102 controls as a reference of the normal response to exercise at altitude. CTEPH patients had a higher New York Health Association (NYHA) functional class than PAH (p = 0.037). There were no differences between patients with PAH and CTEPH in hemodynamics and % of predicted (67.8 18.7 vs. 66.0 19.8, p 0.05), but those with CTEPH had higher dyspnea, VD/VT (0.36 0.09 vs. 0.23 0.9, p 0.001), VE/ (45.8 7.1 vs. 39.3 5.6, p 0.001), and (19.9 7.6 vs. 13.5 7.6, p 0.001) than PAH patients. At altitude, patients with PH present severe alterations in gas exchange during exercise. There were no differences in exercise capacity between PAH and CTEPH, but patients with CTEPH had more dyspnea and greater alterations in gas exchange during exercise. CPET made it possible to identify alterations related to the pathophysiology of CTEPH that could explain the functional class and dyspnea in these patients.

Functional impairment is largely reported after symptomatic pulmonary embolism (PE). Chronic thromboembolic pulmonary disease (CTED) refers to the presence of chronic thrombotic pulmonary vascular occlusion in the absence of pulmonary hypertension (PH) at rest but with incipient vasculopathy responsible for exercise limitation. Exercise haemodynamic studies have emerged to detect an abnormal response suggesting an established vasculopathy or an abnormal left ventricular filling pressure. We hypothesized that exercise intolerance due to an abnormal haemodynamic response during exercise might be unmasked by the parameters exhibited at the cardiopulmonary exercise test (CPET) in diagnostic workup after PE in symptomatic patients. Our aim was to correlate the values reached in the CPET pattern with haemodynamic response during exercise right heart catheterization (RHC) in patients with CTED suspicion. Methods We selected symptomatic patients with confirmed perfusion defects in lung scintigraphy despite optimal anticoagulant therapy for a minimum of 3 months after a PE with normal lung function tests. Left heart disease and significant PH were ruled out with RHC (inclusion criteria implied mean pulmonary arterial pressure (mPAP) &amp;lt; 25 mmHg and pulmonary vascular resistance (PVR) &amp;lt; 3 WU and pulmonary arterial wedge pressure (PAWP) ≤15 mmHg). Exercise RHC was performed sequentially 24 hours after CPET. The exercise protocol was the same for both tests. Pulmonary pressure and cardiac output (CO) were collected at each exercise leel. Exercise PH (ex-PH) was considered when mPAP/CO slope &amp;gt;3 mmHg·L−1·min−1. We made a subanalysis according to the new PH criteria (mPAP &amp;gt;20mmHg &amp; PVR &amp;gt; 2 WU at rest). Results 39 patients (median age 52.7 ± 15.7 years, 36% females) were included. 21 (53.8%) showed abnormal haemodynamic behaviour, 6(15.4%) of them due to abnormal PWAP/CO slope. Baseline characteristics are summarized in Table 1. Patients with abnormal exercise response showed worse ventilatory efficiency at exercise: 1) reduced partial end-tidal of carbon dioxide (PetCO2) at the anaerobic threshold (AT) (32.0 Vs 36.4, p=0.001), 2) a steeper VE/CO2 slope (35.6 Vs 30.9, p=0.009) and 3) a higher ventilatory equivalent for CO2 at the AT (35.5 Vs 31.6, p=0.004) compared to the group with normal hemodynamic behaviour. Oxygen consumption at the AT and peak oxygen consumption were slightly decreased without statistically significant differences between groups.Of the global cohort, 11 patients reached new resting PH criteria, and 92% of them showed ex-PH. Ventilatory efficiency showed differences in the subgroup with normal resting hemodynamic values, especially lower PetCO2 at the AT (31.8 Vs 35.0, p=0.008) (Figure 2). Conclusion In the context of persistent dyspnoea after PE, ventilatory inefficiency is a sign of exercise pulmonary hypertension, and CPET could identify patients with abnormal exercise response despite normal hemodynamic values at rest.

Introduction Pathophysiology of chronic thromboembolic pulmonary hypertension (CTEPH) is characterized by thrombotic lesions at pulmonary arteries and arteriolar remodeling in distal regions. There is an increase in pulmonary vascular resistance that will lead to heart failure and early death without treatment. Currently, pulmonary endarterectomy (PE) is the potentially curative treatment for this condition. Cardiopulmonary exercise test (CPET) allows to quantify functional improvement after PE. Objective: To analyze changes in CPET and hemodynamic parameters after surgery in a cohort of patients with CTEPH. Methods 502 patients with CTEPH have been evaluated until December 2018, PE was performed in 255 (51%). In 49 patients, CPET was available before and 6 months after surgery. Residual pulmonary hypertension (RPH) was defined as mean pulmonary arterial pressure ≥30 mmHg evaluated by right cardiac catheterization at 3–6 months after PE. Results 54% were men, mean age 48±13 years. Two thirds of patients were in functional class II/III at time of diagnosis and with severe hemodynamic and functional profile. Hemodynamics and CPET parameters improved after surgery. However, in patients with RPH they did not improve significantly. Results are shown in table. Conclusions PE restores functional capacity in CTEPH, represented by significant improvement in CPET parameters. CPET is emerging as a non-invasive technique suitable of detecting RPH. More studies are needed to confirm this hypothesis. Funding Acknowledgement Type of funding source: None

BackgroundSex differences in chronic thromboembolic pulmonary hypertension (CTEPH) have been revealed in few studies. Although right heart catheterization (RHC) is the gold standard for clinical diagnosis and assessment of prognosis in pulmonary hypertension (PH), cardiopulmonary exercise testing (CPET) has been a more widely used assessment of functional capacity, disease severity, prognosis, and treatment response in PH. We hypothesized that the “sex-specific” CPET indices could estimate the severity of inoperable CTEPH.MethodsData were retrieved for 33 male (age, mean ± standard deviation [SD] =62.5±13.4 years) and 40 female (age, mean ± SD =56.3±11.8 years) patients with stable CTEPH who underwent both RHC and CPET at Shanghai Pulmonary Hospital from February 2010 to February 2016. Univariate and forward/backward multiple stepwise regression analysis was performed to assess the predictive value of CPET indices to hemodynamic parameters. Event-free survival was estimated using the Kaplan–Meier method and analyzed with the log-rank test. Cox proportional hazards models were performed to determine the independent event-free survival predictors.ResultsNumerous CPET parameters were different between male and female patients with CTEPH and the control group. There were no significant differences in both clinical variables and RHC parameters between male and female patients with CTEPH. O2 pulse, workload, minute ventilation (VE), and end-tidal partial pressure of O2 (PETO2) at anaerobic threshold, as well as peak O2 pulse, workload, VE, and nadir VE/CO2 were significantly higher in male patients than in female patients (P<0.05). Only oxygen uptake efficiency plateau (OUEP) showed a significantly higher difference in female than male patients (P<0.05). In addition, several CPET indices correlated with hemodynamic parameters, especially pulmonary vascular resistance (PVR), which was distinctly different between the sexes. Nadir VE/CO2 was an independent predictor of PVR in male patients with CTEPH, whereas OUEP was an independent predictor of PVR in female patients with CTEPH.ConclusionEven after confounding for age and body mass index, different CPET measurements of gas exchange efficiency correlated with PVR differently between male and female patients. This potentially could be used to estimate the severity of CTEPH.

Background:N-terminal pro-brain natriuretic peptide (NT-proBNP) and cardiopulmonary exercise testing (CPET) are useful for severity assessment in patients with pulmonary hypertension (PH). Correlations between these tests in pre-capillary PH patients is less well studied.Methods:We studied 23 patients with pre-capillary PH: 8 with idiopathic pulmonary arterial hypertension (IPAH), 6 with systemic sclerosis-associated PAH (SSc-PAH), and 9 with chronic thromboembolic pulmonary hypertension (CTEPH). Clinical evaluation, NT-proBNP levels, six-minute walking test (6MWT), spirometry, and CPET were evaluated on the same day. Correlation between NT-proBNP levels and CPET parameters were investigated.Results:In all patients, NT-proBNP levels were significantly correlated with peak oxygen uptake (VO2) (r = −0.47), peak oxygen pulse (r = −0.43), peak cardiac output (CO) (r = −0.57), peak end-tidal partial pressure of carbon dioxide (PETCO2) (r = −0.74), ventilatory equivalent to carbon dioxide (VE/VCO2) at anaerobic threshold (AT) (r = 0.73), and VE/VCO2 slope (r = 0.64). Significant correlations between NT-proBNP levels and peak PETCO2 and VE/VCO2 were found in IPAH and CTEPH subgroups, and a significant correlation between NT-proBNP levels and VO2 at AT was found in the CTEPH subgroup. No significant correlation was found in the SSc-PAH subgroup.Conclusion:NT-proBNP levels were significantly correlated with CPET parameters in patients with IPAH and CTEPH subgroups, but not in SSc-PAH subgroup. A further study with larger population is required to confirm these preliminary findings.

To evaluate the application value of cardiopulmonary exercise testing in patients with chronic thromboembolic pulmonary hypertension (CTEPH). A total of 116 consecutive patients admitted into the Cardiology Department of Fuwai Hospital.They were divided into 3 groups of CTEPH (n = 44), CPE (without pulmonary hypertension in chronic pulmonary embolism) (n = 24) and control (without pulmonary embolism or pulmonary hypertension) (n = 48) respectively. Their levels of N-terminal pro-brain natriuretic peptide (NT-proBNP) were measured. Incremental cardiopulmonary exercise testing was performed to compare its differential results among 3 groups and evaluate the correlation between NT-proBNP and its parameters. The body mass index (BMI) in the CTEPH group was lower than those in the CPE and control groups ((23.8 ± 3.9) vs (26.1 ± 3.6) and (26.7 ± 3.2) kg/m(2) ), both P < 0.05); the medical history in the CTEPH group was longer than those in the CPE and control groups ((58 ± 48) vs (12 ± 10) and (29 ± 25) months, both P < 0.05). The plasma concentrations of NT-proBNP in the CTEPH group were higher than those in the CPE and control groups ((1678 ± 1255) vs (577 ± 167) and (608 ± 247) pmol/L, both P < 0.05). All of them completed the test and there were no severe complications such as syncope or exacerbation of disease. Maximum oxygen consumption (VO2max), percentage of predicted maximum oxygen consumption (VO2 %), oxygen consumption in relation to body weight (VO2/kg), anaerobic threshold and O2 pulse in the CTEPH group were significantly lower than those in the CPE and control groups (P < 0.05). The ratios of dead space volume (VD) to tidal volume (VT) in the CTEPH and CPE groups were higher than those in the control group (P < 0.05). The plasma concentrations of NT-proBNP were inversely correlated with right ventricular internal diameter (r = -0.690, P = 0.000) and VO2/kg (r = -0.496, P = 0.000). The right ventricular internal diameter (β = 0.583, P = 0.000) and VO2/kg (β = 0.233, P = 0.032) were strong independent determinants of NT-proBNP. As a reliable pathophysiological indictor of CTEPH, cardiopulmonary exercise testing may be used objectively and safely to evaluate the cardiopulmonary function of CTEPH patients.